EP4359445A1 - Isolated bispecific antibody that specifically binds to cd47 and pd-l1 - Google Patents
Isolated bispecific antibody that specifically binds to cd47 and pd-l1Info
- Publication number
- EP4359445A1 EP4359445A1 EP22828864.3A EP22828864A EP4359445A1 EP 4359445 A1 EP4359445 A1 EP 4359445A1 EP 22828864 A EP22828864 A EP 22828864A EP 4359445 A1 EP4359445 A1 EP 4359445A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- amino acid
- seq
- acid sequence
- bispecific antibody
- antigen
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 101000868279 Homo sapiens Leukocyte surface antigen CD47 Proteins 0.000 claims abstract description 140
- 102100032913 Leukocyte surface antigen CD47 Human genes 0.000 claims abstract description 133
- 102000008096 B7-H1 Antigen Human genes 0.000 claims abstract description 125
- 108010074708 B7-H1 Antigen Proteins 0.000 claims abstract description 123
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 87
- 150000007523 nucleic acids Chemical class 0.000 claims abstract description 51
- 102000039446 nucleic acids Human genes 0.000 claims abstract description 50
- 108020004707 nucleic acids Proteins 0.000 claims abstract description 50
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 46
- 238000000034 method Methods 0.000 claims abstract description 45
- 150000001875 compounds Chemical class 0.000 claims abstract description 44
- 208000035475 disorder Diseases 0.000 claims abstract description 44
- 201000010099 disease Diseases 0.000 claims abstract description 43
- 230000001404 mediated effect Effects 0.000 claims abstract description 33
- 239000013604 expression vector Substances 0.000 claims abstract description 21
- 238000004519 manufacturing process Methods 0.000 claims abstract description 15
- 125000003275 alpha amino acid group Chemical group 0.000 claims description 144
- 239000000427 antigen Substances 0.000 claims description 125
- 102000036639 antigens Human genes 0.000 claims description 124
- 108091007433 antigens Proteins 0.000 claims description 124
- 230000027455 binding Effects 0.000 claims description 116
- 239000012634 fragment Substances 0.000 claims description 84
- 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 claims description 62
- 238000011282 treatment Methods 0.000 claims description 44
- 206010028980 Neoplasm Diseases 0.000 claims description 39
- 229960004679 doxorubicin Drugs 0.000 claims description 38
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 claims description 38
- 239000003795 chemical substances by application Substances 0.000 claims description 37
- 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 claims description 37
- 229930012538 Paclitaxel Natural products 0.000 claims description 36
- 229960001592 paclitaxel Drugs 0.000 claims description 36
- 201000011510 cancer Diseases 0.000 claims description 27
- 239000002246 antineoplastic agent Substances 0.000 claims description 26
- 229940127089 cytotoxic agent Drugs 0.000 claims description 26
- 208000005718 Stomach Neoplasms Diseases 0.000 claims description 23
- 206010017758 gastric cancer Diseases 0.000 claims description 23
- 201000011549 stomach cancer Diseases 0.000 claims description 23
- 208000003721 Triple Negative Breast Neoplasms Diseases 0.000 claims description 22
- 201000010536 head and neck cancer Diseases 0.000 claims description 22
- 208000014829 head and neck neoplasm Diseases 0.000 claims description 22
- 208000022679 triple-negative breast carcinoma Diseases 0.000 claims description 22
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 claims description 21
- 229960002949 fluorouracil Drugs 0.000 claims description 21
- 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 claims description 19
- 229910052697 platinum Inorganic materials 0.000 claims description 19
- 108020004414 DNA Proteins 0.000 claims description 18
- 229960004562 carboplatin Drugs 0.000 claims description 18
- 229960003668 docetaxel Drugs 0.000 claims description 18
- 229940121358 tyrosine kinase inhibitor Drugs 0.000 claims description 18
- 239000005483 tyrosine kinase inhibitor Substances 0.000 claims description 18
- 229960003005 axitinib Drugs 0.000 claims description 17
- RITAVMQDGBJQJZ-FMIVXFBMSA-N axitinib Chemical compound CNC(=O)C1=CC=CC=C1SC1=CC=C(C(\C=C\C=2N=CC=CC=2)=NN2)C2=C1 RITAVMQDGBJQJZ-FMIVXFBMSA-N 0.000 claims description 17
- 229960000575 trastuzumab Drugs 0.000 claims description 17
- 102000018071 Immunoglobulin Fc Fragments Human genes 0.000 claims description 12
- 108010091135 Immunoglobulin Fc Fragments Proteins 0.000 claims description 12
- 206010008342 Cervix carcinoma Diseases 0.000 claims description 11
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 claims description 11
- 201000010881 cervical cancer Diseases 0.000 claims description 11
- 210000003236 esophagogastric junction Anatomy 0.000 claims description 11
- 239000000178 monomer Substances 0.000 claims description 11
- 208000031261 Acute myeloid leukaemia Diseases 0.000 claims description 10
- 208000010507 Adenocarcinoma of Lung Diseases 0.000 claims description 10
- 206010005003 Bladder cancer Diseases 0.000 claims description 10
- 208000032818 Microsatellite Instability Diseases 0.000 claims description 10
- 208000034578 Multiple myelomas Diseases 0.000 claims description 10
- 201000003793 Myelodysplastic syndrome Diseases 0.000 claims description 10
- 208000033776 Myeloid Acute Leukemia Diseases 0.000 claims description 10
- 206010033128 Ovarian cancer Diseases 0.000 claims description 10
- 206010061535 Ovarian neoplasm Diseases 0.000 claims description 10
- 206010035226 Plasma cell myeloma Diseases 0.000 claims description 10
- 208000006265 Renal cell carcinoma Diseases 0.000 claims description 10
- 206010041067 Small cell lung cancer Diseases 0.000 claims description 10
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 claims description 10
- 201000005249 lung adenocarcinoma Diseases 0.000 claims description 10
- 208000002154 non-small cell lung carcinoma Diseases 0.000 claims description 10
- 208000000587 small cell lung carcinoma Diseases 0.000 claims description 10
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 claims description 10
- 201000005112 urinary bladder cancer Diseases 0.000 claims description 10
- 238000001794 hormone therapy Methods 0.000 claims description 8
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 8
- 238000012258 culturing Methods 0.000 claims description 6
- 230000004071 biological effect Effects 0.000 claims description 5
- 239000001963 growth medium Substances 0.000 claims description 5
- FWMNVWWHGCHHJJ-SKKKGAJSSA-N 4-amino-1-[(2r)-6-amino-2-[[(2r)-2-[[(2r)-2-[[(2r)-2-amino-3-phenylpropanoyl]amino]-3-phenylpropanoyl]amino]-4-methylpentanoyl]amino]hexanoyl]piperidine-4-carboxylic acid Chemical compound C([C@H](C(=O)N[C@H](CC(C)C)C(=O)N[C@H](CCCCN)C(=O)N1CCC(N)(CC1)C(O)=O)NC(=O)[C@H](N)CC=1C=CC=CC=1)C1=CC=CC=C1 FWMNVWWHGCHHJJ-SKKKGAJSSA-N 0.000 claims description 4
- 230000002401 inhibitory effect Effects 0.000 claims description 4
- 230000005764 inhibitory process Effects 0.000 claims description 4
- 230000009466 transformation Effects 0.000 claims description 4
- 190000008236 carboplatin Chemical compound 0.000 claims 4
- 239000003814 drug Substances 0.000 abstract description 15
- 210000004027 cell Anatomy 0.000 description 95
- 108090000623 proteins and genes Proteins 0.000 description 56
- 230000003993 interaction Effects 0.000 description 39
- 102000004169 proteins and genes Human genes 0.000 description 38
- 239000000203 mixture Substances 0.000 description 31
- 239000013598 vector Substances 0.000 description 28
- 239000012491 analyte Substances 0.000 description 25
- 230000014509 gene expression Effects 0.000 description 25
- 238000002474 experimental method Methods 0.000 description 20
- NFGXHKASABOEEW-UHFFFAOYSA-N 1-methylethyl 11-methoxy-3,7,11-trimethyl-2,4-dodecadienoate Chemical compound COC(C)(C)CCCC(C)CC=CC(C)=CC(=O)OC(C)C NFGXHKASABOEEW-UHFFFAOYSA-N 0.000 description 18
- 239000000872 buffer Substances 0.000 description 18
- 239000000243 solution Substances 0.000 description 18
- 239000002773 nucleotide Substances 0.000 description 17
- 125000003729 nucleotide group Chemical group 0.000 description 17
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 15
- 101000863873 Homo sapiens Tyrosine-protein phosphatase non-receptor type substrate 1 Proteins 0.000 description 14
- 102100029948 Tyrosine-protein phosphatase non-receptor type substrate 1 Human genes 0.000 description 14
- 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 14
- 238000012360 testing method Methods 0.000 description 14
- 101001012157 Homo sapiens Receptor tyrosine-protein kinase erbB-2 Proteins 0.000 description 13
- 102100040678 Programmed cell death protein 1 Human genes 0.000 description 13
- 102100030086 Receptor tyrosine-protein kinase erbB-2 Human genes 0.000 description 13
- 238000011068 loading method Methods 0.000 description 13
- 101710089372 Programmed cell death protein 1 Proteins 0.000 description 12
- 239000013612 plasmid Substances 0.000 description 12
- 102000004196 processed proteins & peptides Human genes 0.000 description 12
- 108090000765 processed proteins & peptides Proteins 0.000 description 12
- 108091028043 Nucleic acid sequence Proteins 0.000 description 11
- 230000000903 blocking effect Effects 0.000 description 11
- 229920001184 polypeptide Polymers 0.000 description 11
- 230000001225 therapeutic effect Effects 0.000 description 11
- 238000000746 purification Methods 0.000 description 10
- 108060003951 Immunoglobulin Proteins 0.000 description 9
- -1 benzodopa Chemical class 0.000 description 9
- 102000018358 immunoglobulin Human genes 0.000 description 9
- 239000002594 sorbent Substances 0.000 description 9
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 8
- 230000002776 aggregation Effects 0.000 description 8
- 238000004220 aggregation Methods 0.000 description 8
- 150000001413 amino acids Chemical class 0.000 description 8
- 239000007864 aqueous solution Substances 0.000 description 8
- 239000002552 dosage form Substances 0.000 description 8
- 238000009472 formulation Methods 0.000 description 8
- 230000035772 mutation Effects 0.000 description 8
- 239000013641 positive control Substances 0.000 description 8
- 239000007974 sodium acetate buffer Substances 0.000 description 8
- 230000009870 specific binding Effects 0.000 description 8
- 229940124597 therapeutic agent Drugs 0.000 description 8
- 108010058590 CD47 Antigen Proteins 0.000 description 7
- 102000006355 CD47 Antigen Human genes 0.000 description 7
- 102000044459 human CD47 Human genes 0.000 description 7
- 238000005259 measurement Methods 0.000 description 7
- 230000008929 regeneration Effects 0.000 description 7
- 238000011069 regeneration method Methods 0.000 description 7
- 230000004044 response Effects 0.000 description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 6
- 241000124008 Mammalia Species 0.000 description 6
- 108010076504 Protein Sorting Signals Proteins 0.000 description 6
- 238000012575 bio-layer interferometry Methods 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 6
- 238000010494 dissociation reaction Methods 0.000 description 6
- 230000005593 dissociations Effects 0.000 description 6
- 230000036541 health Effects 0.000 description 6
- 238000002347 injection Methods 0.000 description 6
- 239000007924 injection Substances 0.000 description 6
- 238000012545 processing Methods 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 230000010076 replication Effects 0.000 description 6
- 238000003786 synthesis reaction Methods 0.000 description 6
- 238000001890 transfection Methods 0.000 description 6
- 229960005486 vaccine Drugs 0.000 description 6
- 108010047041 Complementarity Determining Regions Proteins 0.000 description 5
- 230000009471 action Effects 0.000 description 5
- 239000004480 active ingredient Substances 0.000 description 5
- 238000004458 analytical method Methods 0.000 description 5
- 239000003242 anti bacterial agent Substances 0.000 description 5
- 102000015694 estrogen receptors Human genes 0.000 description 5
- 108010038795 estrogen receptors Proteins 0.000 description 5
- 239000000499 gel Substances 0.000 description 5
- 230000001900 immune effect Effects 0.000 description 5
- 239000003550 marker Substances 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- 238000007911 parenteral administration Methods 0.000 description 5
- 229920002401 polyacrylamide Polymers 0.000 description 5
- 238000003259 recombinant expression Methods 0.000 description 5
- 150000003839 salts Chemical class 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- 238000006467 substitution reaction Methods 0.000 description 5
- 241000588724 Escherichia coli Species 0.000 description 4
- 101001117317 Homo sapiens Programmed cell death 1 ligand 1 Proteins 0.000 description 4
- 229920002873 Polyethylenimine Polymers 0.000 description 4
- 150000001412 amines Chemical class 0.000 description 4
- 125000000539 amino acid group Chemical group 0.000 description 4
- 239000003886 aromatase inhibitor Substances 0.000 description 4
- 229940046844 aromatase inhibitors Drugs 0.000 description 4
- 230000001580 bacterial effect Effects 0.000 description 4
- 230000000295 complement effect Effects 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 238000001962 electrophoresis Methods 0.000 description 4
- 239000003623 enhancer Substances 0.000 description 4
- 238000009093 first-line therapy Methods 0.000 description 4
- 230000006870 function Effects 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 238000001990 intravenous administration Methods 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 230000005180 public health Effects 0.000 description 4
- 238000010791 quenching Methods 0.000 description 4
- 230000000171 quenching effect Effects 0.000 description 4
- 230000001105 regulatory effect Effects 0.000 description 4
- 239000011780 sodium chloride Substances 0.000 description 4
- 239000003381 stabilizer Substances 0.000 description 4
- 238000007920 subcutaneous administration Methods 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 208000024891 symptom Diseases 0.000 description 4
- WYWHKKSPHMUBEB-UHFFFAOYSA-N tioguanine Chemical compound N1C(N)=NC(=S)C2=C1N=CN2 WYWHKKSPHMUBEB-UHFFFAOYSA-N 0.000 description 4
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 3
- 241000701022 Cytomegalovirus Species 0.000 description 3
- 239000004471 Glycine Substances 0.000 description 3
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 3
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 3
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 3
- 241000829100 Macaca mulatta polyomavirus 1 Species 0.000 description 3
- 108091034117 Oligonucleotide Proteins 0.000 description 3
- 239000012980 RPMI-1640 medium Substances 0.000 description 3
- 229920002684 Sepharose Polymers 0.000 description 3
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 3
- 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 3
- 239000008351 acetate buffer Substances 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 239000013543 active substance Substances 0.000 description 3
- 239000000556 agonist Substances 0.000 description 3
- 229940088710 antibiotic agent Drugs 0.000 description 3
- 238000013459 approach Methods 0.000 description 3
- HXCHCVDVKSCDHU-LULTVBGHSA-N calicheamicin Chemical compound C1[C@H](OC)[C@@H](NCC)CO[C@H]1O[C@H]1[C@H](O[C@@H]2C\3=C(NC(=O)OC)C(=O)C[C@](C/3=C/CSSSC)(O)C#C\C=C/C#C2)O[C@H](C)[C@@H](NO[C@@H]2O[C@H](C)[C@@H](SC(=O)C=3C(=C(OC)C(O[C@H]4[C@@H]([C@H](OC)[C@@H](O)[C@H](C)O4)O)=C(I)C=3C)OC)[C@@H](O)C2)[C@@H]1O HXCHCVDVKSCDHU-LULTVBGHSA-N 0.000 description 3
- 229930195731 calicheamicin Natural products 0.000 description 3
- 239000000969 carrier Substances 0.000 description 3
- 229940124447 delivery agent Drugs 0.000 description 3
- CYQFCXCEBYINGO-IAGOWNOFSA-N delta1-THC Chemical compound C1=C(C)CC[C@H]2C(C)(C)OC3=CC(CCCCC)=CC(O)=C3[C@@H]21 CYQFCXCEBYINGO-IAGOWNOFSA-N 0.000 description 3
- 239000003085 diluting agent Substances 0.000 description 3
- 238000002296 dynamic light scattering Methods 0.000 description 3
- 239000012636 effector Substances 0.000 description 3
- 239000000945 filler Substances 0.000 description 3
- 230000002068 genetic effect Effects 0.000 description 3
- 229940088597 hormone Drugs 0.000 description 3
- 239000005556 hormone Substances 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 238000001802 infusion Methods 0.000 description 3
- 239000003112 inhibitor Substances 0.000 description 3
- 238000007918 intramuscular administration Methods 0.000 description 3
- UWKQSNNFCGGAFS-XIFFEERXSA-N irinotecan Chemical compound C1=C2C(CC)=C3CN(C(C4=C([C@@](C(=O)OC4)(O)CC)C=4)=O)C=4C3=NC2=CC=C1OC(=O)N(CC1)CCC1N1CCCCC1 UWKQSNNFCGGAFS-XIFFEERXSA-N 0.000 description 3
- 238000012933 kinetic analysis Methods 0.000 description 3
- GLVAUDGFNGKCSF-UHFFFAOYSA-N mercaptopurine Chemical compound S=C1NC=NC2=C1NC=N2 GLVAUDGFNGKCSF-UHFFFAOYSA-N 0.000 description 3
- 230000001394 metastastic effect Effects 0.000 description 3
- 206010061289 metastatic neoplasm Diseases 0.000 description 3
- 229960000485 methotrexate 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
- 230000003204 osmotic effect Effects 0.000 description 3
- 239000002953 phosphate buffered saline Substances 0.000 description 3
- 239000013600 plasmid vector Substances 0.000 description 3
- 102000040430 polynucleotide Human genes 0.000 description 3
- 108091033319 polynucleotide Proteins 0.000 description 3
- 239000002157 polynucleotide Substances 0.000 description 3
- 230000002035 prolonged effect Effects 0.000 description 3
- 238000003998 size exclusion chromatography high performance liquid chromatography Methods 0.000 description 3
- 238000010561 standard procedure Methods 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 230000005030 transcription termination Effects 0.000 description 3
- 230000014616 translation Effects 0.000 description 3
- 241000701161 unidentified adenovirus Species 0.000 description 3
- 229960004528 vincristine Drugs 0.000 description 3
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 description 3
- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 description 3
- 230000003612 virological effect Effects 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- XRASPMIURGNCCH-UHFFFAOYSA-N zoledronic acid Chemical compound OP(=O)(O)C(P(O)(O)=O)(O)CN1C=CN=C1 XRASPMIURGNCCH-UHFFFAOYSA-N 0.000 description 3
- VVIAGPKUTFNRDU-UHFFFAOYSA-N 6S-folinic acid Natural products C1NC=2NC(N)=NC(=O)C=2N(C=O)C1CNC1=CC=C(C(=O)NC(CCC(O)=O)C(O)=O)C=C1 VVIAGPKUTFNRDU-UHFFFAOYSA-N 0.000 description 2
- 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 2
- BFYIZQONLCFLEV-DAELLWKTSA-N Aromasine Chemical compound O=C1C=C[C@]2(C)[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CC(=C)C2=C1 BFYIZQONLCFLEV-DAELLWKTSA-N 0.000 description 2
- 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
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 238000012935 Averaging Methods 0.000 description 2
- MLDQJTXFUGDVEO-UHFFFAOYSA-N BAY-43-9006 Chemical compound C1=NC(C(=O)NC)=CC(OC=2C=CC(NC(=O)NC=3C=C(C(Cl)=CC=3)C(F)(F)F)=CC=2)=C1 MLDQJTXFUGDVEO-UHFFFAOYSA-N 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 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
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 2
- 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 2
- 238000001712 DNA sequencing Methods 0.000 description 2
- 108010092160 Dactinomycin Proteins 0.000 description 2
- 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 2
- 102000001301 EGF receptor Human genes 0.000 description 2
- 108060006698 EGF receptor Proteins 0.000 description 2
- 241000196324 Embryophyta Species 0.000 description 2
- VWUXBMIQPBEWFH-WCCTWKNTSA-N Fulvestrant Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3[C@H](CCCCCCCCCS(=O)CCCC(F)(F)C(F)(F)F)CC2=C1 VWUXBMIQPBEWFH-WCCTWKNTSA-N 0.000 description 2
- 239000001828 Gelatine Substances 0.000 description 2
- 101000611936 Homo sapiens Programmed cell death protein 1 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
- 241000282567 Macaca fascicularis Species 0.000 description 2
- 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 2
- 108091007491 NSP3 Papain-like protease domains Proteins 0.000 description 2
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 description 2
- 229920001213 Polysorbate 20 Polymers 0.000 description 2
- IIDJRNMFWXDHID-UHFFFAOYSA-N Risedronic acid Chemical compound OP(=O)(O)C(P(O)(O)=O)(O)CC1=CC=CN=C1 IIDJRNMFWXDHID-UHFFFAOYSA-N 0.000 description 2
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 2
- 235000014680 Saccharomyces cerevisiae Nutrition 0.000 description 2
- CYQFCXCEBYINGO-UHFFFAOYSA-N THC Natural products C1=C(C)CCC2C(C)(C)OC3=CC(CCCCC)=CC(O)=C3C21 CYQFCXCEBYINGO-UHFFFAOYSA-N 0.000 description 2
- NAVMQTYZDKMPEU-UHFFFAOYSA-N Targretin Chemical compound CC1=CC(C(CCC2(C)C)(C)C)=C2C=C1C(=C)C1=CC=C(C(O)=O)C=C1 NAVMQTYZDKMPEU-UHFFFAOYSA-N 0.000 description 2
- FOCVUCIESVLUNU-UHFFFAOYSA-N Thiotepa Chemical compound C1CN1P(N1CC1)(=S)N1CC1 FOCVUCIESVLUNU-UHFFFAOYSA-N 0.000 description 2
- DKJJVAGXPKPDRL-UHFFFAOYSA-N Tiludronic acid Chemical compound OP(O)(=O)C(P(O)(O)=O)SC1=CC=C(Cl)C=C1 DKJJVAGXPKPDRL-UHFFFAOYSA-N 0.000 description 2
- 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 2
- IBXPAFBDJCXCDW-MHFPCNPESA-A [Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].Cc1cn([C@H]2C[C@H](O)[C@@H](COP([S-])(=O)O[C@H]3C[C@@H](O[C@@H]3COP([O-])(=S)O[C@H]3C[C@@H](O[C@@H]3COP([O-])(=S)O[C@H]3C[C@@H](O[C@@H]3COP([O-])(=S)O[C@H]3C[C@@H](O[C@@H]3COP([O-])(=S)O[C@H]3C[C@@H](O[C@@H]3COP([O-])(=S)O[C@H]3C[C@@H](O[C@@H]3COP([O-])(=S)O[C@H]3C[C@@H](O[C@@H]3COP([O-])(=S)O[C@H]3C[C@@H](O[C@@H]3COP([O-])(=S)O[C@H]3C[C@@H](O[C@@H]3COP([O-])(=S)O[C@H]3C[C@@H](O[C@@H]3COP([O-])(=S)O[C@H]3C[C@@H](O[C@@H]3COP([O-])(=S)O[C@H]3C[C@@H](O[C@@H]3COP([O-])(=S)O[C@H]3C[C@@H](O[C@@H]3COP([O-])(=S)O[C@H]3C[C@@H](O[C@@H]3COP([O-])(=S)O[C@H]3C[C@@H](O[C@@H]3COP([O-])(=S)O[C@H]3C[C@@H](O[C@@H]3COP([O-])(=S)O[C@H]3C[C@@H](O[C@@H]3CO)n3cc(C)c(=O)[nH]c3=O)n3ccc(N)nc3=O)n3cc(C)c(=O)[nH]c3=O)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3cnc4c3nc(N)[nH]c4=O)n3ccc(N)nc3=O)n3cnc4c3nc(N)[nH]c4=O)n3cc(C)c(=O)[nH]c3=O)n3cnc4c3nc(N)[nH]c4=O)n3ccc(N)nc3=O)n3cnc4c3nc(N)[nH]c4=O)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)O2)c(=O)[nH]c1=O Chemical compound [Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].Cc1cn([C@H]2C[C@H](O)[C@@H](COP([S-])(=O)O[C@H]3C[C@@H](O[C@@H]3COP([O-])(=S)O[C@H]3C[C@@H](O[C@@H]3COP([O-])(=S)O[C@H]3C[C@@H](O[C@@H]3COP([O-])(=S)O[C@H]3C[C@@H](O[C@@H]3COP([O-])(=S)O[C@H]3C[C@@H](O[C@@H]3COP([O-])(=S)O[C@H]3C[C@@H](O[C@@H]3COP([O-])(=S)O[C@H]3C[C@@H](O[C@@H]3COP([O-])(=S)O[C@H]3C[C@@H](O[C@@H]3COP([O-])(=S)O[C@H]3C[C@@H](O[C@@H]3COP([O-])(=S)O[C@H]3C[C@@H](O[C@@H]3COP([O-])(=S)O[C@H]3C[C@@H](O[C@@H]3COP([O-])(=S)O[C@H]3C[C@@H](O[C@@H]3COP([O-])(=S)O[C@H]3C[C@@H](O[C@@H]3COP([O-])(=S)O[C@H]3C[C@@H](O[C@@H]3COP([O-])(=S)O[C@H]3C[C@@H](O[C@@H]3COP([O-])(=S)O[C@H]3C[C@@H](O[C@@H]3COP([O-])(=S)O[C@H]3C[C@@H](O[C@@H]3CO)n3cc(C)c(=O)[nH]c3=O)n3ccc(N)nc3=O)n3cc(C)c(=O)[nH]c3=O)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3cnc4c3nc(N)[nH]c4=O)n3ccc(N)nc3=O)n3cnc4c3nc(N)[nH]c4=O)n3cc(C)c(=O)[nH]c3=O)n3cnc4c3nc(N)[nH]c4=O)n3ccc(N)nc3=O)n3cnc4c3nc(N)[nH]c4=O)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)O2)c(=O)[nH]c1=O IBXPAFBDJCXCDW-MHFPCNPESA-A 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 150000007513 acids Chemical class 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
- 230000001154 acute effect Effects 0.000 description 2
- 239000000443 aerosol Substances 0.000 description 2
- 229960003437 aminoglutethimide Drugs 0.000 description 2
- ROBVIMPUHSLWNV-UHFFFAOYSA-N aminoglutethimide Chemical compound C=1C=C(N)C=CC=1C1(CC)CCC(=O)NC1=O ROBVIMPUHSLWNV-UHFFFAOYSA-N 0.000 description 2
- 229940046836 anti-estrogen Drugs 0.000 description 2
- 230000001833 anti-estrogenic effect Effects 0.000 description 2
- 230000010056 antibody-dependent cellular cytotoxicity Effects 0.000 description 2
- QZPQTZZNNJUOLS-UHFFFAOYSA-N beta-lapachone Chemical compound C12=CC=CC=C2C(=O)C(=O)C2=C1OC(C)(C)CC2 QZPQTZZNNJUOLS-UHFFFAOYSA-N 0.000 description 2
- GXJABQQUPOEUTA-RDJZCZTQSA-N bortezomib Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)B(O)O)NC(=O)C=1N=CC=NC=1)C1=CC=CC=C1 GXJABQQUPOEUTA-RDJZCZTQSA-N 0.000 description 2
- 238000004113 cell culture Methods 0.000 description 2
- 238000002512 chemotherapy Methods 0.000 description 2
- 210000004978 chinese hamster ovary cell Anatomy 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
- 230000002759 chromosomal effect Effects 0.000 description 2
- ACSIXWWBWUQEHA-UHFFFAOYSA-N clodronic acid Chemical compound OP(O)(=O)C(Cl)(Cl)P(O)(O)=O ACSIXWWBWUQEHA-UHFFFAOYSA-N 0.000 description 2
- 230000004154 complement system Effects 0.000 description 2
- 239000012531 culture fluid Substances 0.000 description 2
- OPTASPLRGRRNAP-UHFFFAOYSA-N cytosine Chemical compound NC=1C=CNC(=O)N=1 OPTASPLRGRRNAP-UHFFFAOYSA-N 0.000 description 2
- 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 2
- 238000000502 dialysis Methods 0.000 description 2
- UGMCXQCYOVCMTB-UHFFFAOYSA-K dihydroxy(stearato)aluminium Chemical compound CCCCCCCCCCCCCCCCCC(=O)O[Al](O)O UGMCXQCYOVCMTB-UHFFFAOYSA-K 0.000 description 2
- 239000003937 drug carrier Substances 0.000 description 2
- 230000009977 dual effect Effects 0.000 description 2
- 239000000328 estrogen antagonist Substances 0.000 description 2
- 238000001943 fluorescence-activated cell sorting Methods 0.000 description 2
- OVBPIULPVIDEAO-LBPRGKRZSA-N folic acid Chemical compound C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-LBPRGKRZSA-N 0.000 description 2
- 235000008191 folinic acid Nutrition 0.000 description 2
- 239000011672 folinic acid Substances 0.000 description 2
- VVIAGPKUTFNRDU-ABLWVSNPSA-N folinic acid Chemical compound C1NC=2NC(N)=NC(=O)C=2N(C=O)C1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 VVIAGPKUTFNRDU-ABLWVSNPSA-N 0.000 description 2
- 238000004108 freeze drying Methods 0.000 description 2
- 230000004927 fusion Effects 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
- 229920000159 gelatin Polymers 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 238000007429 general method Methods 0.000 description 2
- 230000013595 glycosylation Effects 0.000 description 2
- 238000006206 glycosylation reaction Methods 0.000 description 2
- 238000011194 good manufacturing practice Methods 0.000 description 2
- 230000012010 growth Effects 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 239000000833 heterodimer Substances 0.000 description 2
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 2
- 102000048776 human CD274 Human genes 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
- 210000000987 immune system Anatomy 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 238000002955 isolation Methods 0.000 description 2
- 239000007951 isotonicity adjuster Substances 0.000 description 2
- 210000003734 kidney Anatomy 0.000 description 2
- HPJKCIUCZWXJDR-UHFFFAOYSA-N letrozole Chemical compound C1=CC(C#N)=CC=C1C(N1N=CN=C1)C1=CC=C(C#N)C=C1 HPJKCIUCZWXJDR-UHFFFAOYSA-N 0.000 description 2
- 229960001691 leucovorin Drugs 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
- 239000000314 lubricant Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 210000004962 mammalian cell Anatomy 0.000 description 2
- 229960004296 megestrol acetate Drugs 0.000 description 2
- RQZAXGRLVPAYTJ-GQFGMJRRSA-N megestrol acetate Chemical compound C1=C(C)C2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(C)=O)(OC(=O)C)[C@@]1(C)CC2 RQZAXGRLVPAYTJ-GQFGMJRRSA-N 0.000 description 2
- 229960001428 mercaptopurine Drugs 0.000 description 2
- 229960001156 mitoxantrone Drugs 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- QZGIWPZCWHMVQL-UIYAJPBUSA-N neocarzinostatin chromophore Chemical compound O1[C@H](C)[C@H](O)[C@H](O)[C@@H](NC)[C@H]1O[C@@H]1C/2=C/C#C[C@H]3O[C@@]3([C@@H]3OC(=O)OC3)C#CC\2=C[C@H]1OC(=O)C1=C(O)C=CC2=C(C)C=C(OC)C=C12 QZGIWPZCWHMVQL-UIYAJPBUSA-N 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 235000019198 oils Nutrition 0.000 description 2
- 150000002895 organic esters Chemical class 0.000 description 2
- 229960001756 oxaliplatin Drugs 0.000 description 2
- DWAFYCQODLXJNR-BNTLRKBRSA-L oxaliplatin Chemical compound O1C(=O)C(=O)O[Pt]11N[C@@H]2CCCC[C@H]2N1 DWAFYCQODLXJNR-BNTLRKBRSA-L 0.000 description 2
- WRUUGTRCQOWXEG-UHFFFAOYSA-N pamidronate Chemical compound NCCC(O)(P(O)(O)=O)P(O)(O)=O WRUUGTRCQOWXEG-UHFFFAOYSA-N 0.000 description 2
- 230000007170 pathology Effects 0.000 description 2
- 229920001983 poloxamer Polymers 0.000 description 2
- 230000008488 polyadenylation Effects 0.000 description 2
- 229920005862 polyol Polymers 0.000 description 2
- 150000003077 polyols Chemical class 0.000 description 2
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 2
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 2
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 2
- 229920000053 polysorbate 80 Polymers 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- RXWNCPJZOCPEPQ-NVWDDTSBSA-N puromycin Chemical compound C1=CC(OC)=CC=C1C[C@H](N)C(=O)N[C@H]1[C@@H](O)[C@H](N2C3=NC=NC(=C3N=C2)N(C)C)O[C@@H]1CO RXWNCPJZOCPEPQ-NVWDDTSBSA-N 0.000 description 2
- 238000003127 radioimmunoassay Methods 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
- 238000010188 recombinant method Methods 0.000 description 2
- 230000028327 secretion Effects 0.000 description 2
- 229940095743 selective estrogen receptor modulator Drugs 0.000 description 2
- 239000000333 selective estrogen receptor modulator Substances 0.000 description 2
- 239000001509 sodium citrate Substances 0.000 description 2
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 2
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 2
- 238000003860 storage 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
- 150000005846 sugar alcohols Polymers 0.000 description 2
- 239000000375 suspending agent Substances 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- 229960001196 thiotepa Drugs 0.000 description 2
- 229960003087 tioguanine Drugs 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- UCFGDBYHRUNTLO-QHCPKHFHSA-N topotecan Chemical compound C1=C(O)C(CN(C)C)=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 UCFGDBYHRUNTLO-QHCPKHFHSA-N 0.000 description 2
- 238000013518 transcription Methods 0.000 description 2
- 230000035897 transcription Effects 0.000 description 2
- 238000003146 transient transfection Methods 0.000 description 2
- 238000013519 translation Methods 0.000 description 2
- 238000012384 transportation and delivery Methods 0.000 description 2
- JXLYSJRDGCGARV-CFWMRBGOSA-N vinblastine Chemical compound C([C@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 JXLYSJRDGCGARV-CFWMRBGOSA-N 0.000 description 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
- 229960004276 zoledronic acid Drugs 0.000 description 2
- HDTRYLNUVZCQOY-UHFFFAOYSA-N α-D-glucopyranosyl-α-D-glucopyranoside Natural products OC1C(O)C(O)C(CO)OC1OC1C(O)C(O)C(O)C(CO)O1 HDTRYLNUVZCQOY-UHFFFAOYSA-N 0.000 description 1
- DNXHEGUUPJUMQT-UHFFFAOYSA-N (+)-estrone Natural products OC1=CC=C2C3CCC(C)(C(CC4)=O)C4C3CCC2=C1 DNXHEGUUPJUMQT-UHFFFAOYSA-N 0.000 description 1
- NNJPGOLRFBJNIW-HNNXBMFYSA-N (-)-demecolcine Chemical compound C1=C(OC)C(=O)C=C2[C@@H](NC)CCC3=CC(OC)=C(OC)C(OC)=C3C2=C1 NNJPGOLRFBJNIW-HNNXBMFYSA-N 0.000 description 1
- RGHNJXZEOKUKBD-NRXMZTRTSA-N (2r,3r,4r,5s)-2,3,4,5,6-pentahydroxyhexanoic acid Chemical compound OC[C@H](O)[C@@H](O)[C@@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-NRXMZTRTSA-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
- RIWLPSIAFBLILR-WVNGMBSFSA-N (2s)-1-[(2s)-2-[[(2s,3s)-2-[[(2s)-2-[[(2s,3r)-2-[[(2r,3s)-2-[[(2s)-2-[[2-[[2-[acetyl(methyl)amino]acetyl]amino]acetyl]amino]-3-methylbutanoyl]amino]-3-methylpentanoyl]amino]-3-hydroxybutanoyl]amino]pentanoyl]amino]-3-methylpentanoyl]amino]-5-(diaminomethy Chemical compound CC(=O)N(C)CC(=O)NCC(=O)N[C@@H](C(C)C)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N1CCC[C@H]1C(=O)NCC RIWLPSIAFBLILR-WVNGMBSFSA-N 0.000 description 1
- YXTKHLHCVFUPPT-YYFJYKOTSA-N (2s)-2-[[4-[(2-amino-5-formyl-4-oxo-1,6,7,8-tetrahydropteridin-6-yl)methylamino]benzoyl]amino]pentanedioic acid;(1r,2r)-1,2-dimethanidylcyclohexane;5-fluoro-1h-pyrimidine-2,4-dione;oxalic acid;platinum(2+) Chemical compound [Pt+2].OC(=O)C(O)=O.[CH2-][C@@H]1CCCC[C@H]1[CH2-].FC1=CNC(=O)NC1=O.C1NC=2NC(N)=NC(=O)C=2N(C=O)C1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 YXTKHLHCVFUPPT-YYFJYKOTSA-N 0.000 description 1
- FLWWDYNPWOSLEO-HQVZTVAUSA-N (2s)-2-[[4-[1-(2-amino-4-oxo-1h-pteridin-6-yl)ethyl-methylamino]benzoyl]amino]pentanedioic acid Chemical compound C=1N=C2NC(N)=NC(=O)C2=NC=1C(C)N(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FLWWDYNPWOSLEO-HQVZTVAUSA-N 0.000 description 1
- 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
- TVIRNGFXQVMMGB-OFWIHYRESA-N (3s,6r,10r,13e,16s)-16-[(2r,3r,4s)-4-chloro-3-hydroxy-4-phenylbutan-2-yl]-10-[(3-chloro-4-methoxyphenyl)methyl]-6-methyl-3-(2-methylpropyl)-1,4-dioxa-8,11-diazacyclohexadec-13-ene-2,5,9,12-tetrone Chemical compound C1=C(Cl)C(OC)=CC=C1C[C@@H]1C(=O)NC[C@@H](C)C(=O)O[C@@H](CC(C)C)C(=O)O[C@H]([C@H](C)[C@@H](O)[C@@H](Cl)C=2C=CC=CC=2)C/C=C/C(=O)N1 TVIRNGFXQVMMGB-OFWIHYRESA-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
- 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
- INAUWOVKEZHHDM-PEDBPRJASA-N (7s,9s)-6,9,11-trihydroxy-9-(2-hydroxyacetyl)-7-[(2r,4s,5s,6s)-5-hydroxy-6-methyl-4-morpholin-4-yloxan-2-yl]oxy-4-methoxy-8,10-dihydro-7h-tetracene-5,12-dione;hydrochloride Chemical compound Cl.N1([C@H]2C[C@@H](O[C@@H](C)[C@H]2O)O[C@H]2C[C@@](O)(CC=3C(O)=C4C(=O)C=5C=CC=C(C=5C(=O)C4=C(O)C=32)OC)C(=O)CO)CCOCC1 INAUWOVKEZHHDM-PEDBPRJASA-N 0.000 description 1
- RCFNNLSZHVHCEK-IMHLAKCZSA-N (7s,9s)-7-(4-amino-6-methyloxan-2-yl)oxy-6,9,11-trihydroxy-9-(2-hydroxyacetyl)-4-methoxy-8,10-dihydro-7h-tetracene-5,12-dione;hydrochloride Chemical compound [Cl-].O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)C1CC([NH3+])CC(C)O1 RCFNNLSZHVHCEK-IMHLAKCZSA-N 0.000 description 1
- NOPNWHSMQOXAEI-PUCKCBAPSA-N (7s,9s)-7-[(2r,4s,5s,6s)-4-(2,3-dihydropyrrol-1-yl)-5-hydroxy-6-methyloxan-2-yl]oxy-6,9,11-trihydroxy-9-(2-hydroxyacetyl)-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)CCC=C1 NOPNWHSMQOXAEI-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
- IEXUMDBQLIVNHZ-YOUGDJEHSA-N (8s,11r,13r,14s,17s)-11-[4-(dimethylamino)phenyl]-17-hydroxy-17-(3-hydroxypropyl)-13-methyl-1,2,6,7,8,11,12,14,15,16-decahydrocyclopenta[a]phenanthren-3-one Chemical compound C1=CC(N(C)C)=CC=C1[C@@H]1C2=C3CCC(=O)C=C3CC[C@H]2[C@H](CC[C@]2(O)CCCO)[C@@]2(C)C1 IEXUMDBQLIVNHZ-YOUGDJEHSA-N 0.000 description 1
- FDKXTQMXEQVLRF-ZHACJKMWSA-N (E)-dacarbazine Chemical compound CN(C)\N=N\c1[nH]cnc1C(N)=O FDKXTQMXEQVLRF-ZHACJKMWSA-N 0.000 description 1
- LKJPYSCBVHEWIU-KRWDZBQOSA-N (R)-bicalutamide Chemical compound C([C@@](O)(C)C(=O)NC=1C=C(C(C#N)=CC=1)C(F)(F)F)S(=O)(=O)C1=CC=C(F)C=C1 LKJPYSCBVHEWIU-KRWDZBQOSA-N 0.000 description 1
- 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
- FONKWHRXTPJODV-DNQXCXABSA-N 1,3-bis[2-[(8s)-8-(chloromethyl)-4-hydroxy-1-methyl-7,8-dihydro-3h-pyrrolo[3,2-e]indole-6-carbonyl]-1h-indol-5-yl]urea Chemical compound C1([C@H](CCl)CN2C(=O)C=3NC4=CC=C(C=C4C=3)NC(=O)NC=3C=C4C=C(NC4=CC=3)C(=O)N3C4=CC(O)=C5NC=C(C5=C4[C@H](CCl)C3)C)=C2C=C(O)C2=C1C(C)=CN2 FONKWHRXTPJODV-DNQXCXABSA-N 0.000 description 1
- WNXJIVFYUVYPPR-UHFFFAOYSA-N 1,3-dioxolane Chemical compound C1COCO1 WNXJIVFYUVYPPR-UHFFFAOYSA-N 0.000 description 1
- MQLACMBJVPINKE-UHFFFAOYSA-N 10-[(3-hydroxy-4-methoxyphenyl)methylidene]anthracen-9-one Chemical compound C1=C(O)C(OC)=CC=C1C=C1C2=CC=CC=C2C(=O)C2=CC=CC=C21 MQLACMBJVPINKE-UHFFFAOYSA-N 0.000 description 1
- WNWHHMBRJJOGFJ-UHFFFAOYSA-N 16-methylheptadecan-1-ol Chemical class CC(C)CCCCCCCCCCCCCCCO WNWHHMBRJJOGFJ-UHFFFAOYSA-N 0.000 description 1
- BTOTXLJHDSNXMW-POYBYMJQSA-N 2,3-dideoxyuridine Chemical compound O1[C@H](CO)CC[C@@H]1N1C(=O)NC(=O)C=C1 BTOTXLJHDSNXMW-POYBYMJQSA-N 0.000 description 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
- 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
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 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
- LGEXGKUJMFHVSY-UHFFFAOYSA-N 2-n,4-n,6-n-trimethyl-1,3,5-triazine-2,4,6-triamine Chemical compound CNC1=NC(NC)=NC(NC)=N1 LGEXGKUJMFHVSY-UHFFFAOYSA-N 0.000 description 1
- YIMDLWDNDGKDTJ-QLKYHASDSA-N 3'-deamino-3'-(3-cyanomorpholin-4-yl)doxorubicin 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)CCOCC1C#N YIMDLWDNDGKDTJ-QLKYHASDSA-N 0.000 description 1
- NDMPLJNOPCLANR-UHFFFAOYSA-N 3,4-dihydroxy-15-(4-hydroxy-18-methoxycarbonyl-5,18-seco-ibogamin-18-yl)-16-methoxy-1-methyl-6,7-didehydro-aspidospermidine-3-carboxylic acid methyl ester Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 NDMPLJNOPCLANR-UHFFFAOYSA-N 0.000 description 1
- PWMYMKOUNYTVQN-UHFFFAOYSA-N 3-(8,8-diethyl-2-aza-8-germaspiro[4.5]decan-2-yl)-n,n-dimethylpropan-1-amine Chemical compound C1C[Ge](CC)(CC)CCC11CN(CCCN(C)C)CC1 PWMYMKOUNYTVQN-UHFFFAOYSA-N 0.000 description 1
- QGJZLNKBHJESQX-UHFFFAOYSA-N 3-Epi-Betulin-Saeure Natural products C1CC(O)C(C)(C)C2CCC3(C)C4(C)CCC5(C(O)=O)CCC(C(=C)C)C5C4CCC3C21C QGJZLNKBHJESQX-UHFFFAOYSA-N 0.000 description 1
- CLOUCVRNYSHRCF-UHFFFAOYSA-N 3beta-Hydroxy-20(29)-Lupen-3,27-oic acid Natural products C1CC(O)C(C)(C)C2CCC3(C)C4(C(O)=O)CCC5(C)CCC(C(=C)C)C5C4CCC3C21C CLOUCVRNYSHRCF-UHFFFAOYSA-N 0.000 description 1
- 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
- CLPFFLWZZBQMAO-UHFFFAOYSA-N 4-(5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-5-yl)benzonitrile Chemical compound C1=CC(C#N)=CC=C1C1N2C=NC=C2CCC1 CLPFFLWZZBQMAO-UHFFFAOYSA-N 0.000 description 1
- AKJHMTWEGVYYSE-AIRMAKDCSA-N 4-HPR Chemical compound C=1C=C(O)C=CC=1NC(=O)/C=C(\C)/C=C/C=C(C)C=CC1=C(C)CCCC1(C)C AKJHMTWEGVYYSE-AIRMAKDCSA-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
- TVZGACDUOSZQKY-LBPRGKRZSA-N 4-aminofolic acid Chemical compound C1=NC2=NC(N)=NC(N)=C2N=C1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 TVZGACDUOSZQKY-LBPRGKRZSA-N 0.000 description 1
- IDPUKCWIGUEADI-UHFFFAOYSA-N 5-[bis(2-chloroethyl)amino]uracil Chemical compound ClCCN(CCCl)C1=CNC(=O)NC1=O IDPUKCWIGUEADI-UHFFFAOYSA-N 0.000 description 1
- 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
- WYXSYVWAUAUWLD-SHUUEZRQSA-N 6-azauridine Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C=N1 WYXSYVWAUAUWLD-SHUUEZRQSA-N 0.000 description 1
- YCWQAMGASJSUIP-YFKPBYRVSA-N 6-diazo-5-oxo-L-norleucine Chemical compound OC(=O)[C@@H](N)CCC(=O)C=[N+]=[N-] YCWQAMGASJSUIP-YFKPBYRVSA-N 0.000 description 1
- 229960005538 6-diazo-5-oxo-L-norleucine Drugs 0.000 description 1
- ZGXJTSGNIOSYLO-UHFFFAOYSA-N 88755TAZ87 Chemical compound NCC(=O)CCC(O)=O ZGXJTSGNIOSYLO-UHFFFAOYSA-N 0.000 description 1
- FUXVKZWTXQUGMW-FQEVSTJZSA-N 9-Aminocamptothecin Chemical compound C1=CC(N)=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 FUXVKZWTXQUGMW-FQEVSTJZSA-N 0.000 description 1
- HDZZVAMISRMYHH-UHFFFAOYSA-N 9beta-Ribofuranosyl-7-deazaadenin Natural products C1=CC=2C(N)=NC=NC=2N1C1OC(CO)C(O)C1O HDZZVAMISRMYHH-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 102000007469 Actins Human genes 0.000 description 1
- 108010085238 Actins Proteins 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- 108010012934 Albumin-Bound Paclitaxel Proteins 0.000 description 1
- OGSPWJRAVKPPFI-UHFFFAOYSA-N Alendronic Acid Chemical compound NCCCC(O)(P(O)(O)=O)P(O)(O)=O OGSPWJRAVKPPFI-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 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
- 108020000948 Antisense Oligonucleotides Proteins 0.000 description 1
- 241000219194 Arabidopsis Species 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- NOWKCMXCCJGMRR-UHFFFAOYSA-N Aziridine Chemical class C1CN1 NOWKCMXCCJGMRR-UHFFFAOYSA-N 0.000 description 1
- 239000012664 BCL-2-inhibitor Substances 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 229940123711 Bcl2 inhibitor Drugs 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
- DIZWSDNSTNAYHK-XGWVBXMLSA-N Betulinic acid Natural products CC(=C)[C@@H]1C[C@H]([C@H]2CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@@]34C)[C@@H]12)C(=O)O DIZWSDNSTNAYHK-XGWVBXMLSA-N 0.000 description 1
- 108010006654 Bleomycin Proteins 0.000 description 1
- MBABCNBNDNGODA-LTGLSHGVSA-N Bullatacin Natural products O=C1C(C[C@H](O)CCCCCCCCCC[C@@H](O)[C@@H]2O[C@@H]([C@@H]3O[C@H]([C@@H](O)CCCCCCCCCC)CC3)CC2)=C[C@H](C)O1 MBABCNBNDNGODA-LTGLSHGVSA-N 0.000 description 1
- KGGVWMAPBXIMEM-ZRTAFWODSA-N Bullatacinone Chemical compound O1[C@@H]([C@@H](O)CCCCCCCCCC)CC[C@@H]1[C@@H]1O[C@@H]([C@H](O)CCCCCCCCCC[C@H]2OC(=O)[C@H](CC(C)=O)C2)CC1 KGGVWMAPBXIMEM-ZRTAFWODSA-N 0.000 description 1
- KGGVWMAPBXIMEM-JQFCFGFHSA-N Bullatacinone Natural products O=C(C[C@H]1C(=O)O[C@H](CCCCCCCCCC[C@H](O)[C@@H]2O[C@@H]([C@@H]3O[C@@H]([C@@H](O)CCCCCCCCCC)CC3)CC2)C1)C KGGVWMAPBXIMEM-JQFCFGFHSA-N 0.000 description 1
- 108010037003 Buserelin Proteins 0.000 description 1
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 1
- 101150084532 CD47 gene 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
- 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
- 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
- 241000701489 Cauliflower mosaic virus Species 0.000 description 1
- JWBOIMRXGHLCPP-UHFFFAOYSA-N Chloditan Chemical compound C=1C=CC=C(Cl)C=1C(C(Cl)Cl)C1=CC=C(Cl)C=C1 JWBOIMRXGHLCPP-UHFFFAOYSA-N 0.000 description 1
- XCDXSSFOJZZGQC-UHFFFAOYSA-N Chlornaphazine Chemical compound C1=CC=CC2=CC(N(CCCl)CCCl)=CC=C21 XCDXSSFOJZZGQC-UHFFFAOYSA-N 0.000 description 1
- 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
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 108091026890 Coding region Proteins 0.000 description 1
- 108091035707 Consensus sequence Proteins 0.000 description 1
- 241000699800 Cricetinae Species 0.000 description 1
- 241000699802 Cricetulus griseus Species 0.000 description 1
- 229930188224 Cryptophycin Natural products 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-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
- 230000004568 DNA-binding Effects 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
- XXGMIHXASFDFSM-UHFFFAOYSA-N Delta9-tetrahydrocannabinol Natural products CCCCCc1cc2OC(C)(C)C3CCC(=CC3c2c(O)c1O)C XXGMIHXASFDFSM-UHFFFAOYSA-N 0.000 description 1
- NNJPGOLRFBJNIW-UHFFFAOYSA-N Demecolcine Natural products C1=C(OC)C(=O)C=C2C(NC)CCC3=CC(OC)=C(OC)C(OC)=C3C2=C1 NNJPGOLRFBJNIW-UHFFFAOYSA-N 0.000 description 1
- 241000702421 Dependoparvovirus Species 0.000 description 1
- 108010002156 Depsipeptides Proteins 0.000 description 1
- AUGQEEXBDZWUJY-ZLJUKNTDSA-N Diacetoxyscirpenol Chemical compound C([C@]12[C@]3(C)[C@H](OC(C)=O)[C@@H](O)[C@H]1O[C@@H]1C=C(C)CC[C@@]13COC(=O)C)O2 AUGQEEXBDZWUJY-ZLJUKNTDSA-N 0.000 description 1
- AUGQEEXBDZWUJY-UHFFFAOYSA-N Diacetoxyscirpenol Natural products CC(=O)OCC12CCC(C)=CC1OC1C(O)C(OC(C)=O)C2(C)C11CO1 AUGQEEXBDZWUJY-UHFFFAOYSA-N 0.000 description 1
- ZQZFYGIXNQKOAV-OCEACIFDSA-N Droloxifene Chemical compound C=1C=CC=CC=1C(/CC)=C(C=1C=C(O)C=CC=1)\C1=CC=C(OCCN(C)C)C=C1 ZQZFYGIXNQKOAV-OCEACIFDSA-N 0.000 description 1
- CYQFCXCEBYINGO-DLBZAZTESA-N Dronabinol Natural products C1=C(C)CC[C@H]2C(C)(C)OC3=CC(CCCCC)=CC(O)=C3[C@H]21 CYQFCXCEBYINGO-DLBZAZTESA-N 0.000 description 1
- 229930193152 Dynemicin Natural products 0.000 description 1
- 238000002965 ELISA Methods 0.000 description 1
- LVGKNOAMLMIIKO-UHFFFAOYSA-N Elaidinsaeure-aethylester Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC LVGKNOAMLMIIKO-UHFFFAOYSA-N 0.000 description 1
- AFMYMMXSQGUCBK-UHFFFAOYSA-N Endynamicin A Natural products C1#CC=CC#CC2NC(C=3C(=O)C4=C(O)C=CC(O)=C4C(=O)C=3C(O)=C3)=C3C34OC32C(C)C(C(O)=O)=C(OC)C41 AFMYMMXSQGUCBK-UHFFFAOYSA-N 0.000 description 1
- 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
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 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
- 241000588722 Escherichia Species 0.000 description 1
- 229930189413 Esperamicin Natural products 0.000 description 1
- JOYRKODLDBILNP-UHFFFAOYSA-N Ethyl urethane Chemical compound CCOC(N)=O JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 description 1
- DBVJJBKOTRCVKF-UHFFFAOYSA-N Etidronic acid Chemical compound OP(=O)(O)C(O)(C)P(O)(O)=O DBVJJBKOTRCVKF-UHFFFAOYSA-N 0.000 description 1
- 241000206602 Eukaryota Species 0.000 description 1
- 108010087819 Fc receptors Proteins 0.000 description 1
- 102000009109 Fc receptors Human genes 0.000 description 1
- MPJKWIXIYCLVCU-UHFFFAOYSA-N Folinic acid Natural products NC1=NC2=C(N(C=O)C(CNc3ccc(cc3)C(=O)NC(CCC(=O)O)CC(=O)O)CN2)C(=O)N1 MPJKWIXIYCLVCU-UHFFFAOYSA-N 0.000 description 1
- 241000206672 Gelidium Species 0.000 description 1
- 108700028146 Genetic Enhancer Elements Proteins 0.000 description 1
- 102000003886 Glycoproteins Human genes 0.000 description 1
- 108090000288 Glycoproteins Proteins 0.000 description 1
- 108010069236 Goserelin Proteins 0.000 description 1
- BLCLNMBMMGCOAS-URPVMXJPSA-N Goserelin Chemical compound C([C@@H](C(=O)N[C@H](COC(C)(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N1[C@@H](CCC1)C(=O)NNC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H]1NC(=O)CC1)C1=CC=C(O)C=C1 BLCLNMBMMGCOAS-URPVMXJPSA-N 0.000 description 1
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 description 1
- 241000238631 Hexapoda Species 0.000 description 1
- 101000834898 Homo sapiens Alpha-synuclein Proteins 0.000 description 1
- 101000848922 Homo sapiens Protein FAM72A Proteins 0.000 description 1
- 101000652359 Homo sapiens Spermatogenesis-associated protein 2 Proteins 0.000 description 1
- VSNHCAURESNICA-UHFFFAOYSA-N Hydroxyurea Chemical compound NC(=O)NO VSNHCAURESNICA-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
- JJKOTMDDZAJTGQ-DQSJHHFOSA-N Idoxifene Chemical compound C=1C=CC=CC=1C(/CC)=C(C=1C=CC(OCCN2CCCC2)=CC=1)/C1=CC=C(I)C=C1 JJKOTMDDZAJTGQ-DQSJHHFOSA-N 0.000 description 1
- 108010054477 Immunoglobulin Fab Fragments Proteins 0.000 description 1
- 102000001706 Immunoglobulin Fab Fragments Human genes 0.000 description 1
- 102000008394 Immunoglobulin Fragments Human genes 0.000 description 1
- 108010021625 Immunoglobulin Fragments Proteins 0.000 description 1
- 241000235058 Komagataella pastoris Species 0.000 description 1
- PWKSKIMOESPYIA-BYPYZUCNSA-N L-N-acetyl-Cysteine Chemical compound CC(=O)N[C@@H](CS)C(O)=O PWKSKIMOESPYIA-BYPYZUCNSA-N 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
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 1
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 1
- 239000005511 L01XE05 - Sorafenib Substances 0.000 description 1
- 244000207740 Lemna minor Species 0.000 description 1
- 235000006439 Lemna minor Nutrition 0.000 description 1
- 229920001491 Lentinan Polymers 0.000 description 1
- 108010000817 Leuprolide Proteins 0.000 description 1
- MEPSBMMZQBMKHM-UHFFFAOYSA-N Lomatiol Natural products CC(=C/CC1=C(O)C(=O)c2ccccc2C1=O)CO MEPSBMMZQBMKHM-UHFFFAOYSA-N 0.000 description 1
- GQYIWUVLTXOXAJ-UHFFFAOYSA-N Lomustine Chemical compound ClCCN(N=O)C(=O)NC1CCCCC1 GQYIWUVLTXOXAJ-UHFFFAOYSA-N 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- 241000282560 Macaca mulatta Species 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
- 206010027476 Metastases Diseases 0.000 description 1
- 206010063916 Metastatic gastric cancer Diseases 0.000 description 1
- 206010050513 Metastatic renal cell carcinoma Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 102000029749 Microtubule Human genes 0.000 description 1
- 108091022875 Microtubule Proteins 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
- 229930192392 Mitomycin Natural products 0.000 description 1
- 101100407308 Mus musculus Pdcd1lg2 gene Proteins 0.000 description 1
- QPCDCPDFJACHGM-UHFFFAOYSA-N N,N-bis{2-[bis(carboxymethyl)amino]ethyl}glycine Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(=O)O)CCN(CC(O)=O)CC(O)=O QPCDCPDFJACHGM-UHFFFAOYSA-N 0.000 description 1
- OVBPIULPVIDEAO-UHFFFAOYSA-N N-Pteroyl-L-glutaminsaeure Natural products C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)NC(CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-UHFFFAOYSA-N 0.000 description 1
- 108010072915 NAc-Sar-Gly-Val-(d-allo-Ile)-Thr-Nva-Ile-Arg-ProNEt Proteins 0.000 description 1
- 206010061309 Neoplasm progression Diseases 0.000 description 1
- 241000208125 Nicotiana Species 0.000 description 1
- SYNHCENRCUAUNM-UHFFFAOYSA-N Nitrogen mustard N-oxide hydrochloride Chemical compound Cl.ClCC[N+]([O-])(C)CCCl SYNHCENRCUAUNM-UHFFFAOYSA-N 0.000 description 1
- KGTDRFCXGRULNK-UHFFFAOYSA-N Nogalamycin Natural products COC1C(OC)(C)C(OC)C(C)OC1OC1C2=C(O)C(C(=O)C3=C(O)C=C4C5(C)OC(C(C(C5O)N(C)C)O)OC4=C3C3=O)=C3C=C2C(C(=O)OC)C(C)(O)C1 KGTDRFCXGRULNK-UHFFFAOYSA-N 0.000 description 1
- 229930187135 Olivomycin Natural products 0.000 description 1
- 238000012408 PCR amplification Methods 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- VREZDOWOLGNDPW-ALTGWBOUSA-N Pancratistatin Chemical compound C1=C2[C@H]3[C@@H](O)[C@H](O)[C@@H](O)[C@@H](O)[C@@H]3NC(=O)C2=C(O)C2=C1OCO2 VREZDOWOLGNDPW-ALTGWBOUSA-N 0.000 description 1
- VREZDOWOLGNDPW-MYVCAWNPSA-N Pancratistatin Natural products O=C1N[C@H]2[C@H](O)[C@H](O)[C@H](O)[C@H](O)[C@@H]2c2c1c(O)c1OCOc1c2 VREZDOWOLGNDPW-MYVCAWNPSA-N 0.000 description 1
- 108010057150 Peplomycin Proteins 0.000 description 1
- 208000037581 Persistent Infection Diseases 0.000 description 1
- KMSKQZKKOZQFFG-HSUXVGOQSA-N Pirarubicin Chemical compound O([C@H]1[C@@H](N)C[C@@H](O[C@H]1C)O[C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1CCCCO1 KMSKQZKKOZQFFG-HSUXVGOQSA-N 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 241001505332 Polyomavirus sp. Species 0.000 description 1
- 235000001855 Portulaca oleracea Nutrition 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
- 108700030875 Programmed Cell Death 1 Ligand 2 Proteins 0.000 description 1
- 102100024213 Programmed cell death 1 ligand 2 Human genes 0.000 description 1
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 1
- 102100034514 Protein FAM72A Human genes 0.000 description 1
- 102100024924 Protein kinase C alpha type Human genes 0.000 description 1
- 101710109947 Protein kinase C alpha type Proteins 0.000 description 1
- 241000508269 Psidium Species 0.000 description 1
- 108020004511 Recombinant DNA Proteins 0.000 description 1
- OWPCHSCAPHNHAV-UHFFFAOYSA-N Rhizoxin Natural products C1C(O)C2(C)OC2C=CC(C)C(OC(=O)C2)CC2CC2OC2C(=O)OC1C(C)C(OC)C(C)=CC=CC(C)=CC1=COC(C)=N1 OWPCHSCAPHNHAV-UHFFFAOYSA-N 0.000 description 1
- NSFWWJIQIKBZMJ-YKNYLIOZSA-N Roridin A Chemical compound C([C@]12[C@]3(C)[C@H]4C[C@H]1O[C@@H]1C=C(C)CC[C@@]13COC(=O)[C@@H](O)[C@H](C)CCO[C@H](\C=C\C=C/C(=O)O4)[C@H](O)C)O2 NSFWWJIQIKBZMJ-YKNYLIOZSA-N 0.000 description 1
- CIEYTVIYYGTCCI-UHFFFAOYSA-N SJ000286565 Natural products C1=CC=C2C(=O)C(CC=C(C)C)=C(O)C(=O)C2=C1 CIEYTVIYYGTCCI-UHFFFAOYSA-N 0.000 description 1
- 241000235346 Schizosaccharomyces Species 0.000 description 1
- 238000012300 Sequence Analysis Methods 0.000 description 1
- 229920000519 Sizofiran Polymers 0.000 description 1
- 244000061456 Solanum tuberosum Species 0.000 description 1
- 235000002595 Solanum tuberosum Nutrition 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 241000187747 Streptomyces Species 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical class O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 229930006000 Sucrose Chemical class 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-N Sulfurous acid Chemical class OS(O)=O LSNNMFCWUKXFEE-UHFFFAOYSA-N 0.000 description 1
- BXFOFFBJRFZBQZ-QYWOHJEZSA-N T-2 toxin Chemical compound C([C@@]12[C@]3(C)[C@H](OC(C)=O)[C@@H](O)[C@H]1O[C@H]1[C@]3(COC(C)=O)C[C@@H](C(=C1)C)OC(=O)CC(C)C)O2 BXFOFFBJRFZBQZ-QYWOHJEZSA-N 0.000 description 1
- 210000001744 T-lymphocyte Anatomy 0.000 description 1
- WFWLQNSHRPWKFK-UHFFFAOYSA-N Tegafur Chemical compound O=C1NC(=O)C(F)=CN1C1OCCC1 WFWLQNSHRPWKFK-UHFFFAOYSA-N 0.000 description 1
- CBPNZQVSJQDFBE-FUXHJELOSA-N Temsirolimus Chemical compound C1C[C@@H](OC(=O)C(C)(CO)CO)[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 CBPNZQVSJQDFBE-FUXHJELOSA-N 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
- 238000012338 Therapeutic targeting Methods 0.000 description 1
- 241000723873 Tobacco mosaic virus Species 0.000 description 1
- 101710183280 Topoisomerase Proteins 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
- HDTRYLNUVZCQOY-WSWWMNSNSA-N Trehalose Natural products O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-WSWWMNSNSA-N 0.000 description 1
- UMILHIMHKXVDGH-UHFFFAOYSA-N Triethylene glycol diglycidyl ether Chemical compound C1OC1COCCOCCOCCOCC1CO1 UMILHIMHKXVDGH-UHFFFAOYSA-N 0.000 description 1
- 235000021307 Triticum Nutrition 0.000 description 1
- 244000098338 Triticum aestivum Species 0.000 description 1
- 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 1
- 229940122803 Vinca alkaloid Drugs 0.000 description 1
- 241000700605 Viruses Species 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
- 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
- SPJCRMJCFSJKDE-ZWBUGVOYSA-N [(3s,8s,9s,10r,13r,14s,17r)-10,13-dimethyl-17-[(2r)-6-methylheptan-2-yl]-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1h-cyclopenta[a]phenanthren-3-yl] 2-[4-[bis(2-chloroethyl)amino]phenyl]acetate Chemical compound O([C@@H]1CC2=CC[C@H]3[C@@H]4CC[C@@H]([C@]4(CC[C@@H]3[C@@]2(C)CC1)C)[C@H](C)CCCC(C)C)C(=O)CC1=CC=C(N(CCCl)CCCl)C=C1 SPJCRMJCFSJKDE-ZWBUGVOYSA-N 0.000 description 1
- IFJUINDAXYAPTO-UUBSBJJBSA-N [(8r,9s,13s,14s,17s)-17-[2-[4-[4-[bis(2-chloroethyl)amino]phenyl]butanoyloxy]acetyl]oxy-13-methyl-6,7,8,9,11,12,14,15,16,17-decahydrocyclopenta[a]phenanthren-3-yl] benzoate Chemical compound C([C@@H]1[C@@H](C2=CC=3)CC[C@]4([C@H]1CC[C@@H]4OC(=O)COC(=O)CCCC=1C=CC(=CC=1)N(CCCl)CCCl)C)CC2=CC=3OC(=O)C1=CC=CC=C1 IFJUINDAXYAPTO-UUBSBJJBSA-N 0.000 description 1
- IHGLINDYFMDHJG-UHFFFAOYSA-N [2-(4-methoxyphenyl)-3,4-dihydronaphthalen-1-yl]-[4-(2-pyrrolidin-1-ylethoxy)phenyl]methanone Chemical compound C1=CC(OC)=CC=C1C(CCC1=CC=CC=C11)=C1C(=O)C(C=C1)=CC=C1OCCN1CCCC1 IHGLINDYFMDHJG-UHFFFAOYSA-N 0.000 description 1
- 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
- 108010023617 abarelix Proteins 0.000 description 1
- AIWRTTMUVOZGPW-HSPKUQOVSA-N abarelix Chemical compound C([C@@H](C(=O)N[C@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCNC(C)C)C(=O)N1[C@@H](CCC1)C(=O)N[C@H](C)C(N)=O)N(C)C(=O)[C@H](CO)NC(=O)[C@@H](CC=1C=NC=CC=1)NC(=O)[C@@H](CC=1C=CC(Cl)=CC=1)NC(=O)[C@@H](CC=1C=C2C=CC=CC2=CC=1)NC(C)=O)C1=CC=C(O)C=C1 AIWRTTMUVOZGPW-HSPKUQOVSA-N 0.000 description 1
- 229960002184 abarelix Drugs 0.000 description 1
- 230000001594 aberrant effect Effects 0.000 description 1
- 229940028652 abraxane Drugs 0.000 description 1
- ZOZKYEHVNDEUCO-XUTVFYLZSA-N aceglatone Chemical compound O1C(=O)[C@H](OC(C)=O)[C@@H]2OC(=O)[C@@H](OC(=O)C)[C@@H]21 ZOZKYEHVNDEUCO-XUTVFYLZSA-N 0.000 description 1
- 229950002684 aceglatone Drugs 0.000 description 1
- 229960004308 acetylcysteine Drugs 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 229930183665 actinomycin Natural products 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
- 230000003213 activating effect Effects 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 229940037127 actonel Drugs 0.000 description 1
- 229950004955 adozelesin Drugs 0.000 description 1
- BYRVKDUQDLJUBX-JJCDCTGGSA-N adozelesin Chemical compound C1=CC=C2OC(C(=O)NC=3C=C4C=C(NC4=CC=3)C(=O)N3C[C@H]4C[C@]44C5=C(C(C=C43)=O)NC=C5C)=CC2=C1 BYRVKDUQDLJUBX-JJCDCTGGSA-N 0.000 description 1
- 229940009456 adriamycin Drugs 0.000 description 1
- 238000001042 affinity chromatography Methods 0.000 description 1
- 235000010419 agar Nutrition 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 229940062527 alendronate Drugs 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 229940045714 alkyl sulfonate alkylating agent Drugs 0.000 description 1
- 150000008052 alkyl sulfonates Chemical class 0.000 description 1
- 229940100198 alkylating agent Drugs 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- SHGAZHPCJJPHSC-YCNIQYBTSA-N all-trans-retinoic acid Chemical compound OC(=O)\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C SHGAZHPCJJPHSC-YCNIQYBTSA-N 0.000 description 1
- HDTRYLNUVZCQOY-LIZSDCNHSA-N alpha,alpha-trehalose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-LIZSDCNHSA-N 0.000 description 1
- 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
- 229960002749 aminolevulinic acid Drugs 0.000 description 1
- 229960003896 aminopterin Drugs 0.000 description 1
- 229960000723 ampicillin Drugs 0.000 description 1
- 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 1
- 230000003321 amplification Effects 0.000 description 1
- 229960001220 amsacrine Drugs 0.000 description 1
- XCPGHVQEEXUHNC-UHFFFAOYSA-N amsacrine Chemical compound COC1=CC(NS(C)(=O)=O)=CC=C1NC1=C(C=CC=C2)C2=NC2=CC=CC=C12 XCPGHVQEEXUHNC-UHFFFAOYSA-N 0.000 description 1
- 229960002932 anastrozole Drugs 0.000 description 1
- YBBLVLTVTVSKRW-UHFFFAOYSA-N anastrozole Chemical compound N#CC(C)(C)C1=CC(C(C)(C#N)C)=CC(CN2N=CN=C2)=C1 YBBLVLTVTVSKRW-UHFFFAOYSA-N 0.000 description 1
- 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
- 238000000137 annealing Methods 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 230000002280 anti-androgenic effect Effects 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000000340 anti-metabolite Effects 0.000 description 1
- 230000005809 anti-tumor immunity Effects 0.000 description 1
- 239000000051 antiandrogen Substances 0.000 description 1
- 229940030495 antiandrogen sex hormone and modulator of the genital system Drugs 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 239000003429 antifungal agent Substances 0.000 description 1
- 229940100197 antimetabolite Drugs 0.000 description 1
- 239000002256 antimetabolite Substances 0.000 description 1
- 229940045687 antimetabolites folic acid analogs Drugs 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 239000000074 antisense oligonucleotide Substances 0.000 description 1
- 238000012230 antisense oligonucleotides Methods 0.000 description 1
- 150000008209 arabinosides Chemical class 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 229940087620 aromasin Drugs 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 229960002756 azacitidine Drugs 0.000 description 1
- 229950011321 azaserine Drugs 0.000 description 1
- 150000001541 aziridines Chemical class 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 239000000440 bentonite Substances 0.000 description 1
- 229910000278 bentonite Inorganic materials 0.000 description 1
- SVPXDRXYRYOSEX-UHFFFAOYSA-N bentoquatam Chemical compound O.O=[Si]=O.O=[Al]O[Al]=O SVPXDRXYRYOSEX-UHFFFAOYSA-N 0.000 description 1
- QGJZLNKBHJESQX-FZFNOLFKSA-N betulinic acid Chemical compound C1C[C@H](O)C(C)(C)[C@@H]2CC[C@@]3(C)[C@]4(C)CC[C@@]5(C(O)=O)CC[C@@H](C(=C)C)[C@@H]5[C@H]4CC[C@@H]3[C@]21C QGJZLNKBHJESQX-FZFNOLFKSA-N 0.000 description 1
- 229960002938 bexarotene Drugs 0.000 description 1
- 229960000997 bicalutamide Drugs 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 229950008548 bisantrene Drugs 0.000 description 1
- 229950006844 bizelesin Drugs 0.000 description 1
- 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 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 229960001467 bortezomib Drugs 0.000 description 1
- 229960005520 bryostatin Drugs 0.000 description 1
- MJQUEDHRCUIRLF-TVIXENOKSA-N bryostatin 1 Chemical compound C([C@@H]1CC(/[C@@H]([C@@](C(C)(C)/C=C/2)(O)O1)OC(=O)/C=C/C=C/CCC)=C\C(=O)OC)[C@H]([C@@H](C)O)OC(=O)C[C@H](O)C[C@@H](O1)C[C@H](OC(C)=O)C(C)(C)[C@]1(O)C[C@@H]1C\C(=C\C(=O)OC)C[C@H]\2O1 MJQUEDHRCUIRLF-TVIXENOKSA-N 0.000 description 1
- MUIWQCKLQMOUAT-AKUNNTHJSA-N bryostatin 20 Natural products COC(=O)C=C1C[C@@]2(C)C[C@]3(O)O[C@](C)(C[C@@H](O)CC(=O)O[C@](C)(C[C@@]4(C)O[C@](O)(CC5=CC(=O)O[C@]45C)C(C)(C)C=C[C@@](C)(C1)O2)[C@@H](C)O)C[C@H](OC(=O)C(C)(C)C)C3(C)C MUIWQCKLQMOUAT-AKUNNTHJSA-N 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 239000006172 buffering agent Substances 0.000 description 1
- MBABCNBNDNGODA-LUVUIASKSA-N bullatacin Chemical compound O1[C@@H]([C@@H](O)CCCCCCCCCC)CC[C@@H]1[C@@H]1O[C@@H]([C@H](O)CCCCCCCCCC[C@@H](O)CC=2C(O[C@@H](C)C=2)=O)CC1 MBABCNBNDNGODA-LUVUIASKSA-N 0.000 description 1
- CUWODFFVMXJOKD-UVLQAERKSA-N buserelin Chemical compound CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](COC(C)(C)C)NC(=O)[C@@H](NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H]1NC(=O)CC1)CC1=CC=C(O)C=C1 CUWODFFVMXJOKD-UVLQAERKSA-N 0.000 description 1
- 229960002719 buserelin Drugs 0.000 description 1
- 229960002092 busulfan Drugs 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 210000004899 c-terminal region Anatomy 0.000 description 1
- 108700002839 cactinomycin Proteins 0.000 description 1
- 229950009908 cactinomycin Drugs 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 235000010216 calcium carbonate Nutrition 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
- 229940088954 camptosar Drugs 0.000 description 1
- 229940127093 camptothecin Drugs 0.000 description 1
- VSJKWCGYPAHWDS-FQEVSTJZSA-N camptothecin Chemical compound C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-FQEVSTJZSA-N 0.000 description 1
- 229960004117 capecitabine Drugs 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 229960002115 carboquone Drugs 0.000 description 1
- 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 1
- 229930188550 carminomycin Natural products 0.000 description 1
- 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 1
- 229960003261 carmofur Drugs 0.000 description 1
- 229960005243 carmustine Drugs 0.000 description 1
- 229950001725 carubicin Drugs 0.000 description 1
- 229950007509 carzelesin Drugs 0.000 description 1
- BBZDXMBRAFTCAA-AREMUKBSSA-N carzelesin Chemical compound C1=2NC=C(C)C=2C([C@H](CCl)CN2C(=O)C=3NC4=CC=C(C=C4C=3)NC(=O)C3=CC4=CC=C(C=C4O3)N(CC)CC)=C2C=C1OC(=O)NC1=CC=CC=C1 BBZDXMBRAFTCAA-AREMUKBSSA-N 0.000 description 1
- 108010047060 carzinophilin Proteins 0.000 description 1
- 238000005341 cation exchange Methods 0.000 description 1
- 229960000590 celecoxib Drugs 0.000 description 1
- RZEKVGVHFLEQIL-UHFFFAOYSA-N celecoxib Chemical compound C1=CC(C)=CC=C1C1=CC(C(F)(F)F)=NN1C1=CC=C(S(N)(=O)=O)C=C1 RZEKVGVHFLEQIL-UHFFFAOYSA-N 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 230000007969 cellular immunity Effects 0.000 description 1
- 239000002738 chelating agent Substances 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 235000015218 chewing gum Nutrition 0.000 description 1
- 229950008249 chlornaphazine Drugs 0.000 description 1
- 229960001480 chlorozotocin Drugs 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 229960004316 cisplatin Drugs 0.000 description 1
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 1
- 230000007012 clinical effect Effects 0.000 description 1
- 229960002286 clodronic acid Drugs 0.000 description 1
- HJKBJIYDJLVSAO-UHFFFAOYSA-L clodronic acid disodium salt Chemical compound [Na+].[Na+].OP([O-])(=O)C(Cl)(Cl)P(O)([O-])=O HJKBJIYDJLVSAO-UHFFFAOYSA-L 0.000 description 1
- 230000004186 co-expression Effects 0.000 description 1
- 238000002648 combination therapy Methods 0.000 description 1
- 238000013329 compounding Methods 0.000 description 1
- 239000000356 contaminant Substances 0.000 description 1
- 235000005822 corn Nutrition 0.000 description 1
- 229940111134 coxibs Drugs 0.000 description 1
- COFJBSXICYYSKG-OAUVCNBTSA-N cph2u7dndy Chemical compound OS(O)(=O)=O.C([C@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(N)=O)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 COFJBSXICYYSKG-OAUVCNBTSA-N 0.000 description 1
- 108010089438 cryptophycin 1 Proteins 0.000 description 1
- PSNOPSMXOBPNNV-VVCTWANISA-N cryptophycin 1 Chemical compound C1=C(Cl)C(OC)=CC=C1C[C@@H]1C(=O)NC[C@@H](C)C(=O)O[C@@H](CC(C)C)C(=O)O[C@H]([C@H](C)[C@@H]2[C@H](O2)C=2C=CC=CC=2)C/C=C/C(=O)N1 PSNOPSMXOBPNNV-VVCTWANISA-N 0.000 description 1
- 108010090203 cryptophycin 8 Proteins 0.000 description 1
- PSNOPSMXOBPNNV-UHFFFAOYSA-N cryptophycin-327 Natural products C1=C(Cl)C(OC)=CC=C1CC1C(=O)NCC(C)C(=O)OC(CC(C)C)C(=O)OC(C(C)C2C(O2)C=2C=CC=CC=2)CC=CC(=O)N1 PSNOPSMXOBPNNV-UHFFFAOYSA-N 0.000 description 1
- 238000009109 curative therapy Methods 0.000 description 1
- 239000003255 cyclooxygenase 2 inhibitor Substances 0.000 description 1
- 229960004397 cyclophosphamide Drugs 0.000 description 1
- 229960000684 cytarabine Drugs 0.000 description 1
- 229940104302 cytosine Drugs 0.000 description 1
- 230000001086 cytosolic effect Effects 0.000 description 1
- 239000000824 cytostatic agent Substances 0.000 description 1
- 230000001085 cytostatic effect Effects 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 229960003901 dacarbazine Drugs 0.000 description 1
- 229960000640 dactinomycin Drugs 0.000 description 1
- 238000007405 data analysis Methods 0.000 description 1
- 238000013523 data management Methods 0.000 description 1
- 229960000975 daunorubicin Drugs 0.000 description 1
- 229960005052 demecolcine Drugs 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 229950003913 detorubicin Drugs 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 239000000032 diagnostic agent Substances 0.000 description 1
- 229940039227 diagnostic agent Drugs 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
- RGLYKWWBQGJZGM-ISLYRVAYSA-N diethylstilbestrol Chemical compound C=1C=C(O)C=CC=1C(/CC)=C(\CC)C1=CC=C(O)C=C1 RGLYKWWBQGJZGM-ISLYRVAYSA-N 0.000 description 1
- 229960000452 diethylstilbestrol Drugs 0.000 description 1
- PZXJOHSZQAEJFE-UHFFFAOYSA-N dihydrobetulinic acid Natural products C1CC(O)C(C)(C)C2CCC3(C)C4(C)CCC5(C(O)=O)CCC(C(C)C)C5C4CCC3C21C PZXJOHSZQAEJFE-UHFFFAOYSA-N 0.000 description 1
- 238000006471 dimerization reaction Methods 0.000 description 1
- 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 1
- 208000037765 diseases and disorders Diseases 0.000 description 1
- VSJKWCGYPAHWDS-UHFFFAOYSA-N dl-camptothecin Natural products C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)C5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-UHFFFAOYSA-N 0.000 description 1
- 239000003534 dna topoisomerase inhibitor Substances 0.000 description 1
- AMRJKAQTDDKMCE-UHFFFAOYSA-N dolastatin Chemical compound CC(C)C(N(C)C)C(=O)NC(C(C)C)C(=O)N(C)C(C(C)C)C(OC)CC(=O)N1CCCC1C(OC)C(C)C(=O)NC(C=1SC=CN=1)CC1=CC=CC=C1 AMRJKAQTDDKMCE-UHFFFAOYSA-N 0.000 description 1
- 229930188854 dolastatin Natural products 0.000 description 1
- ZWAOHEXOSAUJHY-ZIYNGMLESA-N doxifluridine Chemical compound O[C@@H]1[C@H](O)[C@@H](C)O[C@H]1N1C(=O)NC(=O)C(F)=C1 ZWAOHEXOSAUJHY-ZIYNGMLESA-N 0.000 description 1
- 229950005454 doxifluridine Drugs 0.000 description 1
- NKZRZOVSJNSBFR-FEMMEMONSA-N doxorubicinol 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@@H](O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 NKZRZOVSJNSBFR-FEMMEMONSA-N 0.000 description 1
- 229950004203 droloxifene Drugs 0.000 description 1
- 229960004242 dronabinol Drugs 0.000 description 1
- 229940126534 drug product Drugs 0.000 description 1
- 229960005501 duocarmycin Drugs 0.000 description 1
- VQNATVDKACXKTF-XELLLNAOSA-N duocarmycin Chemical compound COC1=C(OC)C(OC)=C2NC(C(=O)N3C4=CC(=O)C5=C([C@@]64C[C@@H]6C3)C=C(N5)C(=O)OC)=CC2=C1 VQNATVDKACXKTF-XELLLNAOSA-N 0.000 description 1
- 229930184221 duocarmycin Natural products 0.000 description 1
- AFMYMMXSQGUCBK-AKMKHHNQSA-N dynemicin a Chemical compound C1#C\C=C/C#C[C@@H]2NC(C=3C(=O)C4=C(O)C=CC(O)=C4C(=O)C=3C(O)=C3)=C3[C@@]34O[C@]32[C@@H](C)C(C(O)=O)=C(OC)[C@H]41 AFMYMMXSQGUCBK-AKMKHHNQSA-N 0.000 description 1
- FSIRXIHZBIXHKT-MHTVFEQDSA-N edatrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CC(CC)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FSIRXIHZBIXHKT-MHTVFEQDSA-N 0.000 description 1
- 229950006700 edatrexate Drugs 0.000 description 1
- 229940121647 egfr inhibitor Drugs 0.000 description 1
- XOPYFXBZMVTEJF-UHFFFAOYSA-N eleutherobin Natural products C1=CC2(OC)OC1(C)C(OC(=O)C=CC=1N=CN(C)C=1)CC(C(=CCC1C(C)C)C)C1C=C2COC1OCC(O)C(O)C1OC(C)=O XOPYFXBZMVTEJF-UHFFFAOYSA-N 0.000 description 1
- XOPYFXBZMVTEJF-PDACKIITSA-N eleutherobin Chemical compound C(/[C@H]1[C@H](C(=CC[C@@H]1C(C)C)C)C[C@@H]([C@@]1(C)O[C@@]2(C=C1)OC)OC(=O)\C=C\C=1N=CN(C)C=1)=C2\CO[C@@H]1OC[C@@H](O)[C@@H](O)[C@@H]1OC(C)=O XOPYFXBZMVTEJF-PDACKIITSA-N 0.000 description 1
- 229950000549 elliptinium acetate Drugs 0.000 description 1
- 210000002257 embryonic structure Anatomy 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- JOZGNYDSEBIJDH-UHFFFAOYSA-N eniluracil Chemical compound O=C1NC=C(C#C)C(=O)N1 JOZGNYDSEBIJDH-UHFFFAOYSA-N 0.000 description 1
- 229950010213 eniluracil Drugs 0.000 description 1
- 229950011487 enocitabine Drugs 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 238000006911 enzymatic reaction Methods 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
- 229930013356 epothilone Natural products 0.000 description 1
- 150000003883 epothilone derivatives Chemical class 0.000 description 1
- ITSGNOIFAJAQHJ-BMFNZSJVSA-N esorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)C[C@H](C)O1 ITSGNOIFAJAQHJ-BMFNZSJVSA-N 0.000 description 1
- 229950002017 esorubicin Drugs 0.000 description 1
- LJQQFQHBKUKHIS-WJHRIEJJSA-N esperamicin Chemical compound O1CC(NC(C)C)C(OC)CC1OC1C(O)C(NOC2OC(C)C(SC)C(O)C2)C(C)OC1OC1C(\C2=C/CSSSC)=C(NC(=O)OC)C(=O)C(OC3OC(C)C(O)C(OC(=O)C=4C(=CC(OC)=C(OC)C=4)NC(=O)C(=C)OC)C3)C2(O)C#C\C=C/C#C1 LJQQFQHBKUKHIS-WJHRIEJJSA-N 0.000 description 1
- 229960001842 estramustine Drugs 0.000 description 1
- FRPJXPJMRWBBIH-RBRWEJTLSA-N estramustine Chemical compound ClCCN(CCCl)C(=O)OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 FRPJXPJMRWBBIH-RBRWEJTLSA-N 0.000 description 1
- 229940011871 estrogen Drugs 0.000 description 1
- 239000000262 estrogen Substances 0.000 description 1
- JKKFKPJIXZFSSB-CBZIJGRNSA-N estrone 3-sulfate Chemical compound OS(=O)(=O)OC1=CC=C2[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CCC2=C1 JKKFKPJIXZFSSB-CBZIJGRNSA-N 0.000 description 1
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 description 1
- QSRLNKCNOLVZIR-KRWDZBQOSA-N ethyl (2s)-2-[[2-[4-[bis(2-chloroethyl)amino]phenyl]acetyl]amino]-4-methylsulfanylbutanoate Chemical compound CCOC(=O)[C@H](CCSC)NC(=O)CC1=CC=C(N(CCCl)CCCl)C=C1 QSRLNKCNOLVZIR-KRWDZBQOSA-N 0.000 description 1
- LVGKNOAMLMIIKO-QXMHVHEDSA-N ethyl oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC LVGKNOAMLMIIKO-QXMHVHEDSA-N 0.000 description 1
- 229940093471 ethyl oleate Drugs 0.000 description 1
- 229940009626 etidronate Drugs 0.000 description 1
- 229960005237 etoglucid Drugs 0.000 description 1
- 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 1
- 229960004945 etoricoxib Drugs 0.000 description 1
- MNJVRJDLRVPLFE-UHFFFAOYSA-N etoricoxib Chemical compound C1=NC(C)=CC=C1C1=NC=C(Cl)C=C1C1=CC=C(S(C)(=O)=O)C=C1 MNJVRJDLRVPLFE-UHFFFAOYSA-N 0.000 description 1
- 210000003527 eukaryotic cell Anatomy 0.000 description 1
- 230000007717 exclusion Effects 0.000 description 1
- 229960000255 exemestane Drugs 0.000 description 1
- 239000013613 expression plasmid Substances 0.000 description 1
- 229950011548 fadrozole Drugs 0.000 description 1
- 229940043168 fareston Drugs 0.000 description 1
- 229940087861 faslodex Drugs 0.000 description 1
- 229940087476 femara Drugs 0.000 description 1
- 229950003662 fenretinide Drugs 0.000 description 1
- 239000000796 flavoring agent Substances 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
- 229960000390 fludarabine Drugs 0.000 description 1
- GIUYCYHIANZCFB-FJFJXFQQSA-N fludarabine phosphate Chemical compound C1=NC=2C(N)=NC(F)=NC=2N1[C@@H]1O[C@H](COP(O)(O)=O)[C@@H](O)[C@@H]1O GIUYCYHIANZCFB-FJFJXFQQSA-N 0.000 description 1
- 102000034287 fluorescent proteins Human genes 0.000 description 1
- 108091006047 fluorescent proteins Proteins 0.000 description 1
- 229960001751 fluoxymesterone Drugs 0.000 description 1
- YLRFCQOZQXIBAB-RBZZARIASA-N fluoxymesterone Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1CC[C@](C)(O)[C@@]1(C)C[C@@H]2O YLRFCQOZQXIBAB-RBZZARIASA-N 0.000 description 1
- 229960002074 flutamide Drugs 0.000 description 1
- MKXKFYHWDHIYRV-UHFFFAOYSA-N flutamide Chemical compound CC(C)C(=O)NC1=CC=C([N+]([O-])=O)C(C(F)(F)F)=C1 MKXKFYHWDHIYRV-UHFFFAOYSA-N 0.000 description 1
- 235000019152 folic acid Nutrition 0.000 description 1
- 239000011724 folic acid Substances 0.000 description 1
- 229960000304 folic acid Drugs 0.000 description 1
- 150000002224 folic acids Chemical class 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 229960004421 formestane Drugs 0.000 description 1
- OSVMTWJCGUFAOD-KZQROQTASA-N formestane Chemical compound O=C1CC[C@]2(C)[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CCC2=C1O OSVMTWJCGUFAOD-KZQROQTASA-N 0.000 description 1
- 229960004783 fotemustine Drugs 0.000 description 1
- YAKWPXVTIGTRJH-UHFFFAOYSA-N fotemustine Chemical compound CCOP(=O)(OCC)C(C)NC(=O)N(CCCl)N=O YAKWPXVTIGTRJH-UHFFFAOYSA-N 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- 229960002258 fulvestrant Drugs 0.000 description 1
- 230000002538 fungal effect Effects 0.000 description 1
- 239000000417 fungicide Substances 0.000 description 1
- 229940044658 gallium nitrate Drugs 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 239000007903 gelatin capsule Substances 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
- 229940020967 gemzar Drugs 0.000 description 1
- 238000001415 gene therapy Methods 0.000 description 1
- 210000004602 germ cell Anatomy 0.000 description 1
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 1
- 102000005396 glutamine synthetase Human genes 0.000 description 1
- 108020002326 glutamine synthetase Proteins 0.000 description 1
- 229930182470 glycoside Natural products 0.000 description 1
- 229960002913 goserelin Drugs 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 1
- 231100000844 hepatocellular carcinoma Toxicity 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
- 239000000710 homodimer Substances 0.000 description 1
- 229940125697 hormonal agent Drugs 0.000 description 1
- 102000048362 human PDCD1 Human genes 0.000 description 1
- 238000009396 hybridization Methods 0.000 description 1
- 229940088013 hycamtin Drugs 0.000 description 1
- 229960001330 hydroxycarbamide Drugs 0.000 description 1
- KNOSIOWNDGUGFJ-UHFFFAOYSA-N hydroxysesamone Natural products C1=CC(O)=C2C(=O)C(CC=C(C)C)=C(O)C(=O)C2=C1O KNOSIOWNDGUGFJ-UHFFFAOYSA-N 0.000 description 1
- 229940015872 ibandronate Drugs 0.000 description 1
- 229960000908 idarubicin Drugs 0.000 description 1
- 229950002248 idoxifene Drugs 0.000 description 1
- 239000007943 implant Substances 0.000 description 1
- 238000002513 implantation Methods 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
- 230000006872 improvement Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000002779 inactivation Effects 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000008595 infiltration Effects 0.000 description 1
- 238000001764 infiltration Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 239000007972 injectable composition Substances 0.000 description 1
- 239000002054 inoculum Substances 0.000 description 1
- 238000001361 intraarterial administration Methods 0.000 description 1
- 238000007917 intracranial administration Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000007919 intrasynovial administration Methods 0.000 description 1
- 238000007913 intrathecal administration Methods 0.000 description 1
- 238000007915 intraurethral administration Methods 0.000 description 1
- 238000007914 intraventricular administration Methods 0.000 description 1
- 229960004768 irinotecan 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
- 229960000318 kanamycin Drugs 0.000 description 1
- 229930182823 kanamycin A Natural products 0.000 description 1
- 210000003292 kidney cell Anatomy 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- SIUGQQMOYSVTAT-UHFFFAOYSA-N lapachol Natural products CC(=CCC1C(O)C(=O)c2ccccc2C1=O)C SIUGQQMOYSVTAT-UHFFFAOYSA-N 0.000 description 1
- CWPGNVFCJOPXFB-UHFFFAOYSA-N lapachol Chemical compound C1=CC=C2C(=O)C(=O)C(CC=C(C)C)=C(O)C2=C1 CWPGNVFCJOPXFB-UHFFFAOYSA-N 0.000 description 1
- 229940115286 lentinan Drugs 0.000 description 1
- 229960003881 letrozole Drugs 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 239000002502 liposome Substances 0.000 description 1
- 229960002247 lomustine Drugs 0.000 description 1
- YROQEQPFUCPDCP-UHFFFAOYSA-N losoxantrone Chemical compound OCCNCCN1N=C2C3=CC=CC(O)=C3C(=O)C3=C2C1=CC=C3NCCNCCO YROQEQPFUCPDCP-UHFFFAOYSA-N 0.000 description 1
- 229950008745 losoxantrone Drugs 0.000 description 1
- 108010078259 luprolide acetate gel depot Proteins 0.000 description 1
- RVFGKBWWUQOIOU-NDEPHWFRSA-N lurtotecan Chemical compound O=C([C@]1(O)CC)OCC(C(N2CC3=4)=O)=C1C=C2C3=NC1=CC=2OCCOC=2C=C1C=4CN1CCN(C)CC1 RVFGKBWWUQOIOU-NDEPHWFRSA-N 0.000 description 1
- 229950002654 lurtotecan Drugs 0.000 description 1
- 235000019359 magnesium stearate Nutrition 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
- 238000013507 mapping Methods 0.000 description 1
- 229940099262 marinol Drugs 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
- 229960004961 mechlorethamine Drugs 0.000 description 1
- HAWPXGHAZFHHAD-UHFFFAOYSA-N mechlorethamine Chemical compound ClCCN(C)CCCl HAWPXGHAZFHHAD-UHFFFAOYSA-N 0.000 description 1
- 229940126601 medicinal product Drugs 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- PSGAAPLEWMOORI-PEINSRQWSA-N medroxyprogesterone acetate Chemical compound C([C@@]12C)CC(=O)C=C1[C@@H](C)C[C@@H]1[C@@H]2CC[C@]2(C)[C@@](OC(C)=O)(C(C)=O)CC[C@H]21 PSGAAPLEWMOORI-PEINSRQWSA-N 0.000 description 1
- 229960002985 medroxyprogesterone acetate Drugs 0.000 description 1
- 229960001924 melphalan Drugs 0.000 description 1
- SGDBTWWWUNNDEQ-LBPRGKRZSA-N melphalan Chemical compound OC(=O)[C@@H](N)CC1=CC=C(N(CCCl)CCCl)C=C1 SGDBTWWWUNNDEQ-LBPRGKRZSA-N 0.000 description 1
- 108020004999 messenger RNA Proteins 0.000 description 1
- 239000002184 metal Chemical class 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 230000009401 metastasis Effects 0.000 description 1
- 229930182817 methionine Natural products 0.000 description 1
- 229960004452 methionine Drugs 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
- 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 1
- 244000005700 microbiome Species 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 210000004688 microtubule Anatomy 0.000 description 1
- 229960005485 mitobronitol Drugs 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
- 229960004857 mitomycin Drugs 0.000 description 1
- 229960000350 mitotane Drugs 0.000 description 1
- 238000010369 molecular cloning Methods 0.000 description 1
- PJUIMOJAAPLTRJ-UHFFFAOYSA-N monothioglycerol Chemical compound OCC(O)CS PJUIMOJAAPLTRJ-UHFFFAOYSA-N 0.000 description 1
- 230000004682 mucosal barrier function Effects 0.000 description 1
- 229960000951 mycophenolic acid Drugs 0.000 description 1
- 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 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
- 239000002105 nanoparticle Substances 0.000 description 1
- 239000007923 nasal drop Substances 0.000 description 1
- 229940100662 nasal drops Drugs 0.000 description 1
- 229940097496 nasal spray Drugs 0.000 description 1
- 239000007922 nasal spray Substances 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 229940086322 navelbine Drugs 0.000 description 1
- 239000013642 negative control Substances 0.000 description 1
- MQYXUWHLBZFQQO-UHFFFAOYSA-N nepehinol Natural products C1CC(O)C(C)(C)C2CCC3(C)C4(C)CCC5(C)CCC(C(=C)C)C5C4CCC3C21C MQYXUWHLBZFQQO-UHFFFAOYSA-N 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 230000003472 neutralizing effect Effects 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
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- KGTDRFCXGRULNK-JYOBTZKQSA-N nogalamycin Chemical compound CO[C@@H]1[C@@](OC)(C)[C@@H](OC)[C@H](C)O[C@H]1O[C@@H]1C2=C(O)C(C(=O)C3=C(O)C=C4[C@@]5(C)O[C@H]([C@H]([C@@H]([C@H]5O)N(C)C)O)OC4=C3C3=O)=C3C=C2[C@@H](C(=O)OC)[C@@](C)(O)C1 KGTDRFCXGRULNK-JYOBTZKQSA-N 0.000 description 1
- 229950009266 nogalamycin Drugs 0.000 description 1
- 229940085033 nolvadex Drugs 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 239000002777 nucleoside Substances 0.000 description 1
- 229960000435 oblimersen Drugs 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 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
- 229950011093 onapristone Drugs 0.000 description 1
- 238000011275 oncology therapy Methods 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 230000000065 osmolyte Effects 0.000 description 1
- 239000002357 osmotic agent Substances 0.000 description 1
- 210000001672 ovary Anatomy 0.000 description 1
- 230000002018 overexpression Effects 0.000 description 1
- 238000002638 palliative care Methods 0.000 description 1
- 229940046231 pamidronate Drugs 0.000 description 1
- VREZDOWOLGNDPW-UHFFFAOYSA-N pancratistatine Natural products C1=C2C3C(O)C(O)C(O)C(O)C3NC(=O)C2=C(O)C2=C1OCO2 VREZDOWOLGNDPW-UHFFFAOYSA-N 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 229960003330 pentetic acid 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
- 230000010412 perfusion Effects 0.000 description 1
- 229950010632 perifosine Drugs 0.000 description 1
- SZFPYBIJACMNJV-UHFFFAOYSA-N perifosine Chemical compound CCCCCCCCCCCCCCCCCCOP([O-])(=O)OC1CC[N+](C)(C)CC1 SZFPYBIJACMNJV-UHFFFAOYSA-N 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 230000002688 persistence Effects 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 239000006187 pill Substances 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
- 229960004403 pixantrone Drugs 0.000 description 1
- PEZPMAYDXJQYRV-UHFFFAOYSA-N pixantrone Chemical compound O=C1C2=CN=CC=C2C(=O)C2=C1C(NCCN)=CC=C2NCCN PEZPMAYDXJQYRV-UHFFFAOYSA-N 0.000 description 1
- 238000013492 plasmid preparation Methods 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 229960001237 podophyllotoxin Drugs 0.000 description 1
- 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 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
- 229960000502 poloxamer Drugs 0.000 description 1
- 238000002264 polyacrylamide gel electrophoresis Methods 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 1
- 229920005606 polypropylene copolymer Polymers 0.000 description 1
- 229920001451 polypropylene glycol Polymers 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 150000004804 polysaccharides Chemical class 0.000 description 1
- 229940068977 polysorbate 20 Drugs 0.000 description 1
- 229940068968 polysorbate 80 Drugs 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 230000004481 post-translational protein modification Effects 0.000 description 1
- 229960004694 prednimustine Drugs 0.000 description 1
- OIGNJSKKLXVSLS-VWUMJDOOSA-N prednisolone Chemical compound O=C1C=C[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 OIGNJSKKLXVSLS-VWUMJDOOSA-N 0.000 description 1
- 229960005205 prednisolone Drugs 0.000 description 1
- 229940063238 premarin Drugs 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 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
- 230000008569 process Effects 0.000 description 1
- 230000003623 progesteronic effect Effects 0.000 description 1
- 210000001236 prokaryotic cell Anatomy 0.000 description 1
- 239000003380 propellant Substances 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 230000004845 protein aggregation Effects 0.000 description 1
- 238000001742 protein purification Methods 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
- 150000003212 purines Chemical class 0.000 description 1
- 229950010131 puromycin Drugs 0.000 description 1
- 150000003230 pyrimidines Chemical class 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
- 239000003488 releasing hormone Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 229930002330 retinoic acid Natural products 0.000 description 1
- 230000001177 retroviral effect Effects 0.000 description 1
- OWPCHSCAPHNHAV-LMONGJCWSA-N rhizoxin Chemical compound C/C([C@H](OC)[C@@H](C)[C@@H]1C[C@H](O)[C@]2(C)O[C@@H]2/C=C/[C@@H](C)[C@]2([H])OC(=O)C[C@@](C2)(C[C@@H]2O[C@H]2C(=O)O1)[H])=C\C=C\C(\C)=C\C1=COC(C)=N1 OWPCHSCAPHNHAV-LMONGJCWSA-N 0.000 description 1
- 229940089617 risedronate Drugs 0.000 description 1
- 229950004892 rodorubicin Drugs 0.000 description 1
- MBABCNBNDNGODA-WPZDJQSSSA-N rolliniastatin 1 Natural products O1[C@@H]([C@@H](O)CCCCCCCCCC)CC[C@H]1[C@H]1O[C@@H]([C@H](O)CCCCCCCCCC[C@@H](O)CC=2C(O[C@@H](C)C=2)=O)CC1 MBABCNBNDNGODA-WPZDJQSSSA-N 0.000 description 1
- IMUQLZLGWJSVMV-UOBFQKKOSA-N roridin A Natural products CC(O)C1OCCC(C)C(O)C(=O)OCC2CC(=CC3OC4CC(OC(=O)C=C/C=C/1)C(C)(C23)C45CO5)C IMUQLZLGWJSVMV-UOBFQKKOSA-N 0.000 description 1
- 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
- 239000000523 sample Substances 0.000 description 1
- 238000007480 sanger sequencing Methods 0.000 description 1
- 229930182947 sarcodictyin Natural products 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 239000012679 serum free medium Substances 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 150000004760 silicates Chemical class 0.000 description 1
- 238000009097 single-agent therapy Methods 0.000 description 1
- 229950001403 sizofiran Drugs 0.000 description 1
- 229940112726 skelid Drugs 0.000 description 1
- 230000008591 skin barrier function Effects 0.000 description 1
- 235000011083 sodium citrates Nutrition 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 229960003787 sorafenib Drugs 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 229950006315 spirogermanium Drugs 0.000 description 1
- ICXJVZHDZFXYQC-UHFFFAOYSA-N spongistatin 1 Natural products OC1C(O2)(O)CC(O)C(C)C2CCCC=CC(O2)CC(O)CC2(O2)CC(OC)CC2CC(=O)C(C)C(OC(C)=O)C(C)C(=C)CC(O2)CC(C)(O)CC2(O2)CC(OC(C)=O)CC2CC(=O)OC2C(O)C(CC(=C)CC(O)C=CC(Cl)=C)OC1C2C ICXJVZHDZFXYQC-UHFFFAOYSA-N 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 238000010186 staining Methods 0.000 description 1
- 238000011255 standard chemotherapy Methods 0.000 description 1
- 238000011301 standard therapy Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 230000003637 steroidlike Effects 0.000 description 1
- 150000003431 steroids Chemical class 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
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 239000005720 sucrose Chemical class 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229960001603 tamoxifen Drugs 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 229940099419 targretin 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
- 229940063683 taxotere Drugs 0.000 description 1
- 229960001674 tegafur Drugs 0.000 description 1
- WFWLQNSHRPWKFK-ZCFIWIBFSA-N tegafur Chemical compound O=C1NC(=O)C(F)=CN1[C@@H]1OCCC1 WFWLQNSHRPWKFK-ZCFIWIBFSA-N 0.000 description 1
- 230000002123 temporal effect Effects 0.000 description 1
- 229960000235 temsirolimus Drugs 0.000 description 1
- NRUKOCRGYNPUPR-QBPJDGROSA-N teniposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@@H](OC[C@H]4O3)C=3SC=CC=3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 NRUKOCRGYNPUPR-QBPJDGROSA-N 0.000 description 1
- 229960001278 teniposide Drugs 0.000 description 1
- 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
- 230000008646 thermal stress Effects 0.000 description 1
- 239000002562 thickening agent Substances 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
- 229940019375 tiludronate Drugs 0.000 description 1
- PLHJCIYEEKOWNM-HHHXNRCGSA-N tipifarnib Chemical compound CN1C=NC=C1[C@](N)(C=1C=C2C(C=3C=C(Cl)C=CC=3)=CC(=O)N(C)C2=CC=1)C1=CC=C(Cl)C=C1 PLHJCIYEEKOWNM-HHHXNRCGSA-N 0.000 description 1
- 229950009158 tipifarnib Drugs 0.000 description 1
- 230000001256 tonic effect Effects 0.000 description 1
- 229940044693 topoisomerase inhibitor Drugs 0.000 description 1
- 229960000303 topotecan Drugs 0.000 description 1
- 229960005026 toremifene Drugs 0.000 description 1
- XFCLJVABOIYOMF-QPLCGJKRSA-N toremifene Chemical compound C1=CC(OCCN(C)C)=CC=C1C(\C=1C=CC=CC=1)=C(\CCCl)C1=CC=CC=C1 XFCLJVABOIYOMF-QPLCGJKRSA-N 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 230000005026 transcription initiation Effects 0.000 description 1
- 230000002103 transcriptional effect Effects 0.000 description 1
- 239000012096 transfection reagent Substances 0.000 description 1
- 230000010474 transient expression Effects 0.000 description 1
- 238000011269 treatment regimen Methods 0.000 description 1
- 229950001353 tretamine Drugs 0.000 description 1
- IUCJMVBFZDHPDX-UHFFFAOYSA-N tretamine Chemical compound C1CN1C1=NC(N2CC2)=NC(N2CC2)=N1 IUCJMVBFZDHPDX-UHFFFAOYSA-N 0.000 description 1
- 229960001727 tretinoin Drugs 0.000 description 1
- PXSOHRWMIRDKMP-UHFFFAOYSA-N triaziquone Chemical compound O=C1C(N2CC2)=C(N2CC2)C(=O)C=C1N1CC1 PXSOHRWMIRDKMP-UHFFFAOYSA-N 0.000 description 1
- 229960004560 triaziquone Drugs 0.000 description 1
- 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
- 229930013292 trichothecene Natural products 0.000 description 1
- 150000003327 trichothecene derivatives Chemical class 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
- 229950000212 trioxifene 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
- 229950010147 troxacitabine Drugs 0.000 description 1
- RXRGZNYSEHTMHC-BQBZGAKWSA-N troxacitabine Chemical compound O=C1N=C(N)C=CN1[C@H]1O[C@@H](CO)OC1 RXRGZNYSEHTMHC-BQBZGAKWSA-N 0.000 description 1
- HDZZVAMISRMYHH-LITAXDCLSA-N tubercidin Chemical compound C1=CC=2C(N)=NC=NC=2N1[C@@H]1O[C@@H](CO)[C@H](O)[C@H]1O HDZZVAMISRMYHH-LITAXDCLSA-N 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 230000005751 tumor progression Effects 0.000 description 1
- 230000007306 turnover Effects 0.000 description 1
- 229950009811 ubenimex Drugs 0.000 description 1
- 241001430294 unidentified retrovirus Species 0.000 description 1
- 229960001055 uracil mustard Drugs 0.000 description 1
- 229940099039 velcade Drugs 0.000 description 1
- 229960003048 vinblastine Drugs 0.000 description 1
- GBABOYUKABKIAF-IELIFDKJSA-N vinorelbine Chemical compound C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC GBABOYUKABKIAF-IELIFDKJSA-N 0.000 description 1
- 229960002066 vinorelbine Drugs 0.000 description 1
- CILBMBUYJCWATM-PYGJLNRPSA-N vinorelbine ditartrate Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O.OC(=O)[C@H](O)[C@@H](O)C(O)=O.C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC CILBMBUYJCWATM-PYGJLNRPSA-N 0.000 description 1
- 239000013603 viral vector Substances 0.000 description 1
- 229960001771 vorozole Drugs 0.000 description 1
- XLMPPFTZALNBFS-INIZCTEOSA-N vorozole Chemical compound C1([C@@H](C2=CC=C3N=NN(C3=C2)C)N2N=CN=C2)=CC=C(Cl)C=C1 XLMPPFTZALNBFS-INIZCTEOSA-N 0.000 description 1
- 229940053867 xeloda Drugs 0.000 description 1
- 210000005253 yeast cell Anatomy 0.000 description 1
- 229950009268 zinostatin Drugs 0.000 description 1
- 229940002005 zometa 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
- C07K16/2827—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against B7 molecules, e.g. CD80, CD86
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
- C07K2317/31—Immunoglobulins specific features characterized by aspects of specificity or valency multispecific
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
- C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
- C07K2317/92—Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
-
- 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
- C07K2317/94—Stability, e.g. half-life, pH, temperature or enzyme-resistance
Definitions
- the present invention relates to the field of biotechnology and medicine, in particular to a bispecific antibody that specifically binds to CD47 and PD-L1.
- the invention further relates to a nucleic acid encoding said bispecific antibody, an expression vector, a host cell for producing said bispecific antibody and a method for producing said cell, pharmaceutical compositions comprising the bispecific antibody according to the invention, pharmaceutical compositions comprising the bispecific antibody according to the invention and other therapeutically active compounds, methods for treating diseases or disorders mediated by CD47 and PD-L1, use of the bispecific antibody or pharmaceutical compositions thereof for treating diseases or disorders mediated by CD47 and PD-L1, and the use of the bispecific antibody according to the invention and other therapeutically active compounds for treating diseases or disorders mediated by CD47 and PD-L1.
- Monoclonal antibodies in the form of chimeric, humanized or fully human molecules have proven to be useful as effective medicine for treating a number of disorders and diseases.
- Naturally occurring human antibody molecules consist of two heavy chain homodimers, each of which forms a heterodimer in partnership with two identical light chain molecules.
- Conventional monoclonal antibodies in the form of whole molecules consist of bivalent (“two-armed”) heterodimers of heavy and light chains.
- Bispecific antibodies are capable of binding and thereby neutralizing two different antigens per antibody molecule.
- the potential for a significant improvement in the therapeutic properties (and value) of medicinal products as compared to monoclonal antibodies has made bispecific antibodies an active area of research.
- the literature has described many solutions regarding engineered versions of bispecific antibodies, as described in Brinkmann, U and RE Kontermann, 2017, The Making of Bispecific Antibodies, MAbs; 209 Feb/Mar; 9(2):182-212, doi: 10.1080/19420862.2016.1268307.
- Inhibition of PD-L 1 signals has been suggested as a means to increase T cell immunity (for example, antitumor immunity) for treating cancer and infection, including both acute and chronic infection.
- Inhibitors blocking the PD-Ll/PD-1 interaction are known, for example, from patent applications W02004004771, W02006121168, W02007005874, WO2008156712, W02010036959, W02010077634 and WO2011066389.
- CD47 expression and/or activity have been observed in a number of diseases and disorders. Accordingly, there exists a need for therapies that target CD47.
- Bi specific antibodies that specifically bind to CD47 and PD-L1 with different formats of the first and second antigen-binding sites are known from patent application EA201791961 (W02019068302).
- the bispecific antibody that specifically binds to CD47 and PD-L1 and has a common (identical) light chain within the first and second antigen -binding fragments has higher colloidal, thermal and aggregation stability as compared to a bispecific antibody that specifically binds to CD47 and PD-L1 and has a different format of the first and second antigen binding fragments, for example, Fab and scFv format.
- the bispecific antibody that specifically binds to CD47 and PD-L1 and has a common light chain within the first and second antigen-binding fragments has a high affinity for targets.
- bispecific antibody The use of a common (identical) light chain in the first and second antigen-binding portions of a bispecific antibody has been described in Van Blarcom T ET AL., Productive common light chain libraries yield diverse panels of high affinity bispecific antibodies, MAbs. 2018 Feb/Mar; 10(2):256-268. doi: 10.1080/19420862.2017.1406570.
- This format of a bispecific antibody makes it possible to solve the urgent problem of incorrect pairing of two different light chains to their cognate heavy chains for producing bispecific antibodies.
- the present invention relates to an isolated bispecific antibody that specifically binds to CD47 and PD-L1 and includes:
- a second antigen-binding fragment that specifically binds to PD-L1 includes:
- the isolated bispecific antibody characterized in that the first antigen-binding fragment that specifically binds to CD47 is a Fab bound to an Fc fragment monomer.
- the isolated bispecific antibody characterized in that the second antigen-binding fragment that specifically binds to PD-L1 is a Fab bound to the Fc fragment monomer.
- the isolated bispecific antibody is characterized in that the antibody is a full-length IgG antibody.
- the isolated bispecific antibody is a full-length IgG antibody that is of human IgGl, IgG2, IgG3 or IgG4 isotype.
- the isolated bispecific antibody is a full-length IgG antibody that is of human IgGl isotype.
- the isolated bispecific antibody includes a heavy chain variable domain of the first antigen-binding fragment that specifically binds to CD47 and comprises the amino acid sequence of SEQ ID NO: 22.
- the isolated bispecific antibody includes a heavy chain variable domain of the second antigen-binding fragment that specifically binds to PD-L1 and comprises the amino acid sequence of SEQ ID NO: 24.
- the isolated bispecific antibody includes a variable domain of the common light chain for the first and second antigen-binding fragments, which comprises the amino acid sequence of SEQ ID NO: 23.
- the isolated bispecific antibody includes a first antigen binding fragment that specifically binds to CD47 and comprises:
- the isolated bispecific antibody includes the heavy chain of the first antigen-binding fragment that specifically binds to CD47 and comprises the amino acid sequence of SEQ ID NO: 25.
- the isolated bispecific antibody includes the heavy chain of the antigen-binding fragment that specifically binds to PD-L1 and comprises the amino acid sequence of SEQ ID NO: 27.
- the isolated bispecific antibody includes a common light chain for the first and second antigen-binding fragments, which comprises the amino acid sequence of SEQ ID NO: 26.
- the isolated bispecific antibody includes a first antigen binding fragment that specifically binds to CD47 and comprises:
- the isolated bispecific antibody is a bivalent antibody.
- the present invention relates to an isolated nucleic acid that encodes any of the above bispecific antibodies.
- the nucleic acid is DNA.
- the present invention relates to an expression vector comprising any of the above nucleic acids.
- the present invention relates to a method for producing a host cell for producing any of the above bispecific antibodies and includes transformation of a cell with the above expression vector.
- the present invention relates to a host cell for producing any of the above bispecific antibodies, the host cell comprises any of the above nucleic acids.
- the present invention relates to a method for producing any of the above bispecific antibodies, which comprises culturing the above host cell in a growth medium under conditions sufficient to produce said antibody, if necessary, followed by isolation and purification of the resulting antibody.
- the present invention relates to a pharmaceutical composition used for treating a disease or disorder mediated by PD-L1 and CD47, which comprises any of the above bispecific antibodies in a therapeutically effective amount in combination with one or more pharmaceutically acceptable excipients.
- the present invention relates to a pharmaceutical composition for treating a disease or disorder mediated by PD-L1 and CD47, the pharmaceutical combination comprising any of the above bispecific antibodies and at least one other therapeutically active compound.
- the disease or disorder mediated by PD-L1 and CD47 is selected from the group: triple-negative breast cancer (TNBC), head and neck cancer (HNC), gastric cancer (GC), esophagogastric junction cancer, lung adenocarcinoma, non-small cell lung cancer, small cell lung cancer, acute myeloid leukemia, myelodysplastic syndrome, high microsatellite instability malignant neoplasm, multiple myeloma, ovarian cancer, renal cell carcinoma, bladder cancer, cervical cancer.
- TNBC triple-negative breast cancer
- HNC head and neck cancer
- GC gastric cancer
- esophagogastric junction cancer lung adenocarcinoma
- non-small cell lung cancer small cell lung cancer
- acute myeloid leukemia myelodysplastic syndrome
- high microsatellite instability malignant neoplasm multiple myeloma
- ovarian cancer renal cell carcinoma
- renal cell carcinoma bladder cancer
- cervical cancer cervical cancer
- the other therapeutically active compound is an antibody, chemotherapeutic agent, hormone therapy agent, or any combination thereof.
- the chemotherapeutic agent is selected from the group that comprises: docetaxel, paclitaxel, doxorubicin, platinum agents, carboplatin, 5- fluorouracil, tyrosine kinase inhibitors, axitinib, liposomal doxorubicin, liposomal paclitaxel, or any combination thereof.
- the other therapeutically active compound is an antibody that specifically binds to HER2 (human epidermal growth factor receptor 2).
- the therapeutically active compound is trastuzumab.
- the other therapeutically active compound is trastuzumab and a chemotherapeutic agent that is selected from the group comprising docetaxel, paclitaxel, doxorubicin, platinum agents, carboplatin, 5-fluorouracil, tyrosine kinase inhibitors, axitinib, liposomal doxorubicin, liposomal paclitaxel or any combination thereof.
- a chemotherapeutic agent that is selected from the group comprising docetaxel, paclitaxel, doxorubicin, platinum agents, carboplatin, 5-fluorouracil, tyrosine kinase inhibitors, axitinib, liposomal doxorubicin, liposomal paclitaxel or any combination thereof.
- the present invention relates to a method for inhibiting the biological activity of PD-L1 and CD47 in a subject in need of such inhibition, which comprises administering to the subject an effective amount of any of the above bispecific antibodies.
- the present invention relates to a method for treating a disease or disorder mediated by PD-L1 and CD47, which comprises administering to a subject in need of such treatment any of the above bispecific antibodies or any of the above pharmaceutical compositions in a therapeutically effective amount.
- the present invention relates to a method for treating a disease or disorder mediated by PD-L1 and CD47, which comprises administering to a subject in need of such treatment any of the above bispecific antibodies and at least one other therapeutically active compound.
- the disease or disorder mediated by PD-L1 and CD47 is selected from the group: triple-negative breast cancer (TNBC), head and neck cancer (HNC), gastric cancer (GC), esophagogastric junction cancer, lung adenocarcinoma, non-small cell lung cancer, small cell lung cancer, acute myeloid leukemia, myelodysplastic syndrome, high microsatellite instability malignant neoplasm, multiple myeloma, ovarian cancer, renal cell carcinoma, bladder cancer, cervical cancer.
- TNBC triple-negative breast cancer
- HNC head and neck cancer
- GC gastric cancer
- esophagogastric junction cancer lung adenocarcinoma
- non-small cell lung cancer small cell lung cancer
- acute myeloid leukemia myelodysplastic syndrome
- high microsatellite instability malignant neoplasm multiple myeloma
- ovarian cancer renal cell carcinoma
- renal cell carcinoma bladder cancer
- cervical cancer cervical cancer
- the other therapeutically active compound is an antibody, chemotherapeutic agent, hormone therapy agent, or any combination thereof.
- the chemotherapeutic agent is selected from the group that comprises: docetaxel, paclitaxel, doxorubicin, platinum agents, carboplatin, 5- fluorouracil, tyrosine kinase inhibitors, axitinib, liposomal doxorubicin, liposomal paclitaxel, or any combination thereof.
- the other therapeutically active compound is an antibody that specifically binds to HER2 (human epidermal growth factor receptor 2).
- the other therapeutically active compound is trastuzumab.
- the other therapeutically active compound is trastuzumab and a chemotherapeutic agent selected from the group comprising docetaxel, paclitaxel, doxorubicin, platinum agents, carboplatin, 5-fluorouracil, tyrosine kinase inhibitors, axitinib, liposomal doxorubicin, liposomal paclitaxel, or any combination thereof.
- a chemotherapeutic agent selected from the group comprising docetaxel, paclitaxel, doxorubicin, platinum agents, carboplatin, 5-fluorouracil, tyrosine kinase inhibitors, axitinib, liposomal doxorubicin, liposomal paclitaxel, or any combination thereof.
- the present invention relates to the use of any of the above bi specific antibodies or any of the above pharmaceutical compositions for treating a disease or disorder mediated by PD-L1 and CD47 in a subject in need of such treatment.
- the present invention relates to the use of any of the above bispecific antibodies and at least one other therapeutically active compound for treating a disease or disorder mediated by PD- L1 and CD47 in a subject in need of such treatment.
- the disease or disorder mediated by PD-L1 and CD47 is selected from the group: triple-negative breast cancer (TNBC), head and neck cancer (HNC), gastric cancer (GC), esophagogastric junction cancer, lung adenocarcinoma, non-small cell lung cancer, small cell lung cancer, acute myeloid leukemia, myelodysplastic syndrome, high microsatellite instability malignant neoplasm, multiple myeloma, ovarian cancer, renal cell carcinoma, bladder cancer, cervical cancer.
- TNBC triple-negative breast cancer
- HNC head and neck cancer
- GC gastric cancer
- esophagogastric junction cancer lung adenocarcinoma
- non-small cell lung cancer small cell lung cancer
- acute myeloid leukemia myelodysplastic syndrome
- high microsatellite instability malignant neoplasm multiple myeloma
- ovarian cancer renal cell carcinoma
- renal cell carcinoma bladder cancer
- cervical cancer cervical cancer
- the other therapeutically active compound is an antibody, chemotherapeutic agent, hormone therapy agent, or any combination thereof.
- the chemotherapeutic agent is selected from the group that comprises: docetaxel, paclitaxel, doxorubicin, platinum agents, carboplatin, 5-fluorouracil, tyrosine kinase inhibitors, axitinib, liposomal doxorubicin, liposomal paclitaxel, or any combination thereof.
- the other therapeutically active compound is an antibody that specifically binds to HER2 (human epidermal growth factor receptor 2).
- the other therapeutically active compound is trastuzumab.
- the other therapeutically active compound is trastuzumab and a chemotherapeutic agent that is selected from the group comprising docetaxel, paclitaxel, doxorubicin, platinum agents, carboplatin, 5-fluorouracil, tyrosine kinase inhibitors, axitinib, liposomal doxorubicin, liposomal paclitaxel or any combination thereof.
- a chemotherapeutic agent that is selected from the group comprising docetaxel, paclitaxel, doxorubicin, platinum agents, carboplatin, 5-fluorouracil, tyrosine kinase inhibitors, axitinib, liposomal doxorubicin, liposomal paclitaxel or any combination thereof.
- Figure l is a map of the plasmid vector pEE_HCknobLALA_VH_CD47.
- Figure 2 is a map of the plasmid vector pEE CLC.
- Figure 3 is a map of the plasmid vector pEE HCholeLALA VH PD-Ll.
- Figure 4 is an electrophoregram of 09-001 in 7.5 % polyacrylamide gel under denaturing non reducing conditions following the first stage of purification on Protein A sorbent.
- Figure 5 is an electrophoregram of 09-001 in 7.5 % polyacrylamide gel under denaturing non reducing conditions following purification on SP Sepharose HP sorbent.
- Figure 6 is an electrophoregram of 09-001 in 12 % polyacrylamide gel under denaturing reducing conditions following purification on SP Sepharose HP sorbent.
- Figure 7 is a schematic representation of the format of the bispecific antibody with a common light chain, which specifically binds to CD47 and PD-L1.
- KD in this description refers to the affinity constant (or equilibrium constant, or equilibrium dissociation constant), which is calculated from the ratio of Kd to Ka (i.e. Kd/Ka), and it is expressed as a molar concentration (M).
- Binding affinity generally refers to the strength of the sum total of noncovalent interactions between a single binding site of a molecule (e.g. an antibody) and its binding partner (e.g. an antigen). Unless indicated otherwise, "binding affinity” refers to intrinsic (characteristic, true) binding affinity which reflects a 1:1 interaction between members of a binding pair (e.g. antibody and antigen).
- the affinity of a molecule X for its binding partner Y can generally be represented by the affinity constant (KD).
- the preferred Kd value is about 200 nM, 150 nM, 100 nM, 60 nM, 50 nM, 40 nM, 30 nM, 20 nM, 10 nM, 8 nM, 6 nM, 4 nM, 2 nM, 1 nM, or less.
- Affinity can be measured by common methods known in the art, including those described in the present description. Low-affinity antibodies generally bind an antigen slowly and tend to dissociate readily, whereas high-affinity antibodies generally bind an antigen faster and tend to remain bound longer. A variety of methods of measuring binding affinity are known in the art, any of which can be used for the purposes of the present invention.
- Kd refers to the off rate constant of a particular interaction between a binding molecule and antigen.
- the off rate constant koff can be measured using bio-layer interferometry, for example, using OctetTM system.
- Ka "kon” or "on-rate” refers to the association rate constant.
- Response refers to the antibody-antigen binding signal.
- the present invention relates to a bispecific antibody that specifically binds to CD47 and PD-L1.
- the bispecific antibody according to the invention is a monoclonal antibody.
- mAb refers to an antibody that is synthesized and isolated by a separate clonal population of cells.
- the bispecific antibody according to the invention is a recombinant antibody.
- recombinant antibody refers to an antibody that is expressed in a cell or cell line comprising nucleotide sequence(s) encoding antibodies, wherein said nucleotide sequence(s) is (are) not associated with the cell in nature.
- the bispecific antibody according to the invention is an isolated antibody.
- isolated used to describe various antibodies according to this description refers to an antibody which has been identified and separated and/or regenerated from a cell or cell culture, in which the antibody is expressed.
- Impurities contaminant components
- the isolated polypeptide is typically prepared by at least one purification step.
- the bispecific antibody according to the invention has a common light chain (CLC) for the first and second antigen-binding fragments.
- CLC common light chain
- Figure 7 shows a schematic representation of the format of the bispecific antibody with a common light chain, which specifically binds to CD47 and PD-L1.
- the present invention relates to an isolated bispecific antibody that specifically binds to CD47 and PD-L1 and includes:
- a second antigen-binding fragment that specifically binds to PD-L1 includes:
- Amplification of the CD47 gene and/or overexpression of protein thereof have been observed in many cancers, for example, in any of the diseases from the group: triple-negative breast cancer (TNBC), head and neck cancer (HNC), gastric cancer (GC), esophagogastric junction cancer, lung adenocarcinoma, non-small cell lung cancer, small cell lung cancer, acute myeloid leukemia, myelodysplastic syndrome, high microsatellite instability malignant neoplasm, multiple myeloma, ovarian cancer, renal cell carcinoma, bladder cancer, cervical cancer.
- TNBC triple-negative breast cancer
- HNC head and neck cancer
- GC gastric cancer
- esophagogastric junction cancer lung adenocarcinoma
- non-small cell lung cancer small cell lung cancer
- acute myeloid leukemia myelodysplastic syndrome
- high microsatellite instability malignant neoplasm multiple myeloma
- ovarian cancer renal cell carcinoma
- antibody or “immunoglobulin” (Ig), as used in the present description, includes whole antibodies.
- the term “antibody” refers to a glycoprotein comprising at least two heavy (H) chains and two light (L) chains interconnected by disulfide bonds. Each heavy chain comprises a heavy chain variable region (abbreviated referred to in the present description as VET) and a heavy chain constant region.
- VET heavy chain variable region
- the constant region is identical in all antibodies of the same isotype, but differs in antibodies of different isotypes.
- Heavy chains g, a and d have a constant region composed of three constant domains CHI, CH2 and CH3 (in a line), and a hinge region for added flexibility (Woof J., Burton D., Nat Rev Immunol 4, 2004, pp.89-99).
- lambda (l) and kappa (K) Each light chain consists of a light chain variable region (abbreviated referred to in the present description as VL) and light chain constant region.
- VL light chain variable region
- the approximate length of a light chain is 211 to 217 amino acids.
- the light chain is a lambda (l) light chain
- the constant domain CL is preferably C lambda (l).
- VL and VH regions may be further subdivided into hyper-variability regions called complementarity determining regions (CDRs), located between regions that are more conserved, termed framework regions (FRs).
- CDRs complementarity determining regions
- FRs framework regions
- Each VH and VL is composed of three CDRs and four FRs, arranged from amino-terminus to carboxy-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4.
- the variable regions of heavy and light chains contain a binding domain that interacts with an antigen.
- the constant regions of antibodies may mediate the binding of immunoglobulin to host tissues or factors, including various cells of the immune system (e.g. effector cells) and the first component (Clq) of the classical complement system.
- antigen-binding portion of antibody or "antigen -binding fragment”, as used in the present description, refers to one or more antibody fragments that retain the ability to specifically bind to an antigen. It has been shown that the antigen-binding function of antibody can be performed by fragments of a full-length antibody.
- antigen -binding fragment means a Fab-fragment, i.e. a monovalent fragment, consisting of VL, VH, CL and CHI domains, which is linked with the Fc-fragment monomer.
- the isolated bispecific antibody characterized in that the first antigen-binding fragment that specifically binds to CD47 is a Fab bound to an Fc fragment monomer.
- the isolated bispecific antibody characterized in that the second antigen-binding fragment that specifically binds to PD-L1 is a Fab bound to the Fc fragment monomer.
- variable refers to the fact that certain portions of the variable domains greatly differ in sequence among antibodies.
- the V domain mediates antigen binding and determines specificity of each particular antibody for its particular antigen.
- variability is not evenly distributed across the 110-amino acid span of the variable domains.
- the V regions consist of invariant fragments termed framework regions (FRs) of 15-30 amino acids separated by shorter regions of extreme variability termed “hypervariable regions” or CDRs.
- FRs framework regions
- hypervariable regions or CDRs.
- the variable domains of native heavy and light chains each comprise four FRs, largely adopting a beta-sheet configuration, connected by three hypervariable regions, which form loops connecting, and in some cases forming part of, the beta-sheet structure.
- the hypervariable regions in each chain are held together in close proximity by FRs and, with the hypervariable regions from the other chain, contribute to the formation of the antigen-binding site of antibodies (see Kabat et al., Sequences of Proteins of Immunological Interest. 5 th Ed. Public Health Service, National Institutes of Health, Bethesda, MD. (1991)).
- the constant domains are not involved directly in binding of antibody to antigen, but exhibit various effector functions, such as participation of antibody in antibody-dependent cellular cytotoxicity (ADCC).
- hypervariable region refers to the amino acid residues of antibody which are responsible for antigen binding.
- the hypervariable region typically comprises amino acid residues from a “complementarity determining region” or "CDR" and/or those residues from a “hypervariable loop”.
- Kabat numbering scheme or “numbering according to Kabat” as used in this application refers to the system for numbering of amino acid residues that are more variable (i.e. hypervariable) than other amino acid residues in variable regions of heavy and light chains of the antibody (Kabat et al. Ann. N.Y. Acad. Sci., 190:382-93 (1971); Kabat et al. Sequences of Proteins of Immunological Interest, Fifth Edition, U.S. Department of Health and Human Services, NIH Publication No. 91-3242 (1991)).
- the antibody of the present invention "which binds" a target antigen refers to an antibody that binds the antigen with sufficient affinity such that the antibody can be used as a diagnostic and/or therapeutic agent targeting a protein or cell or tissue expressing the antigen, and slightly cross-reacts with other proteins.
- analytical methods fluorescence-activated cell sorting (FACS), radioimmunoassay (RIA) or ELISA, in such embodiments, the degree of antibody binding to a non target protein is less than 10 % of antibody binding to a specific target protein.
- the term “specific binding” or “specifically binds to” or “is specific for” a particular polypeptide or an epitope on a particular target polypeptide means binding that is significantly (measurably) different from a non-specific interaction.
- Specific binding may be measured, for example, by determining binding of a molecule as compared to binding of a control molecule. For example, specific binding may be determined by competition with another molecule that is similar to the target, for example, an excess of non-labeled target. In this case, specific binding is indicated if the binding of the labeled target to a probe is competitively inhibited by the excess of unlabeled target.
- the term “specific binding” or phrases “specifically binds to” or " is specific for” a particular polypeptide or an epitope on a particular target polypeptide may be described by example of a molecule having a Kd for the target of at least about 200 nM, or at least about 150 nM, or at least about 100 nM, or at least about 60 nM, or at least about 50 nM, or at least about 40 nM, or at least about 30 nM, or at least about 20 nM, or at least about 10 nM, or at least about 8 nM, or at least about 6 nM, or at least about 4 nM, or at least about 2 nM, or at least about 1 nM, or greater.
- the term “specific binding” refers to binding where a molecule binds to a particular polypeptide or epitope on a particular polypeptide without substantially binding to any other polypeptide or epitope on a polypeptide.
- bispecific antibody refers to an antibody having antigen-binding fragments that are capable of specific binding to two distinct epitopes on a single biological molecule or capable of specific binding to epitopes on two distinct biological molecules.
- the bispecific antibody is also referred to herein as having "dual specificity” or as being a “dual specificity” antibody.
- the fragment crystallizable region (“Fc region, Fc”) of an immunoglobulin is the "tail” region of an immunoglobulin molecule that interacts with cell surface Fc-receptor, as well as some proteins of the complement system. This property allows antibodies to activate the immune system.
- the Fc region is composed of two identical protein fragments, derived from the second and third constant domains, respectively, of the two heavy chains.
- the "Fc fragment monomer” refers to the Fc region from the second and third constant domains of any one of the two heavy chains (for IgG, IgA and IgD isotypes).
- the isolated bispecific antibody is characterized in that the antibody is a full-length IgG antibody.
- the isolated bispecific antibody is a full-length IgG antibody that is of human IgGl, IgG2, IgG3 or IgG4 isotype.
- the isolated bispecific antibody is a full-length IgG antibody that is of human IgGl isotype.
- the isolated bispecific antibody includes a heavy chain variable domain of the first antigen-binding fragment that specifically binds to CD47 and comprises the amino acid sequence of SEQ ID NO: 22.
- the isolated bispecific antibody includes a heavy chain variable domain of the second antigen-binding fragment that specifically binds to PD-L1 and comprises the amino acid sequence of SEQ ID NO: 24.
- the isolated bispecific antibody includes a variable domain of the common light chain for the first and second antigen-binding fragments, which comprises the amino acid sequence of SEQ ID NO: 23.
- the isolated bispecific antibody includes a first antigen binding fragment that specifically binds to CD47 and comprises:
- the bispecific antibody according to the invention includes a CH3 domain of one heavy chain, which is modified to form Knob, and a CH3 domain of another heavy chain, which is modified to form Hole, or vice versa.
- “Knobs-into-holes” (interactions of the "knobs -into-holes” type) is an approach that enables to circumvent the problem associated with mispaired byproducts. This approach aims at forcing the pairing of two different antibody heavy chains by introducing mutations into the CH3 domains to modify the contact interfaces. On one chain, bulky amino acids were replaced by amino acids with short side chains to create a "hole”. Conversely, amino acids with large side chains were introduced into the other CH3 domain to create a "knob”.
- the bispecific antibody includes a CH3 domain of one heavy chain, which domain has amino acid substitutions S354C/T366W, to form Knob, and a CH3 domain of another heavy chain, which domain has amino acid substitutions Y349C/T366S/L368A/Y407V, to form Hole.
- the bispecific antibody includes a CH3 domain of one heavy chain, which domain has amino acid substitutions Y349C/T366S/L368A/Y407, to form Hole, and a CH3 domain of another heavy chain, which domain has amino acid substitutions S354C/T366W, to form Knob.
- the bispecific antibody includes an Fc fragment monomer, wherein LALA substitutions (L234A and L235A) are further introduced. These mutations are introduced to reduce the antibody effector function.
- the above mutations in the Fc fragment are numbered according to EU numbering for amino acid chains of antibodies (Edelman, G.M., et ak, Proc. Natl. Acad. Sci. USA 63 (1969), pp. 78-85; Kabat, E.A., et ak, Sequences of Proteins of Immunological Interest, 5th ed., Public Health Service, National Institutes of Health, Bethesda, MD, (1991).
- the isolated bispecific antibody includes the heavy chain of the first antigen-binding fragment that specifically binds to CD47 and comprises the amino acid sequence of SEQ ID NO: 25.
- the isolated bispecific antibody includes the heavy chain of the antigen-binding fragment that specifically binds to PD-L1 and comprises the amino acid sequence of SEQ ID NO: 27. In some embodiments of the invention, the isolated bispecific antibody includes a common light chain for the first and second antigen-binding fragments, which comprises the amino acid sequence of SEQ ID NO: 26.
- the isolated bispecific antibody includes a first antigen binding fragment that specifically binds to CD47 and comprises:
- the isolated bispecific antibody is a bivalent antibody.
- the isolated bispecific antibody that specifically binds to CD47 and PD-L1 is antibody 09-001.
- the bispecific antibody 09-001 includes:
- a second antigen-binding fragment that specifically binds to PD-L1 includes:
- the bispecific antibody 09-001 includes:
- a first antigen-binding fragment that specifically binds to CD47 and includes: (a) a heavy chain variable domain comprising:
- a second antigen-binding fragment that specifically binds to PD-L1 includes:
- the bispecific antibody 09-001 includes:
- a first antigen-binding fragment that specifically binds to CD47 and includes a common light chain variable domain comprising:
- a second antigen-binding fragment that specifically binds to PD-L1 and includes a common light chain variable domain comprising:
- the bispecific antibody 09-001 includes a first antigen-binding fragment that specifically binds to CD47 and comprises:
- the bispecific antibody 09-001 includes: the first Fc fragment monomer that comprises the second and third constant domains of the heavy chain (CH2 and CH3) with LALA mutations (L251A, L252A according to sequential numbering from the beginning of the chain (L234A, L235A according to EU or L247A, L248A according to kabat)) and mutations S371C, T383W according to sequential numbering from the beginning of the chain (S354C, T366W according to EU or S375C, T389W according to kabat) as compared to CH2 and CH3 of wild type human IgGl; and the second Fc fragment monomer that comprises the second and third constant domains of the heavy chain (CH2 and CH3) with LALA mutations (L240A, L241 A according to sequential numbering from the beginning of the chain (L234A, L235A according to EU or L247A, L248A according to kabat)) and mutations Y355C, T372S,
- the bispecific antibody 09-001 includes a first antigen-binding fragment that specifically binds to CD47 and comprises:
- the bispecific antibody 09-001 was developed on the basis of antibody BCD 106-02-001 from the patent document EA201791961A1 and therefore 09-001 is compared with BCD106-02-001 in the examples. Sequences of the antigen-binding fragment in the scFv format, which specifically binds to CD47, of antibody BCD106-02-001 were recloned into Fab format to produce 09-001. Further, for the bispecific antibody 09-001, we selected a new format with a common light chain (CLC) for the first and second antigen-binding fragments.
- CLC common light chain
- Antibody BCD106-02-001 from patent document EA201791961A1 includes a first antigen binding fragment that specifically binds to CD47 and is provided in the scFv format, and a second antigen-binding fragment that specifically binds to PD-L1 and is provided in the Fab format.
- Antibody BCD106-02-001 from patent document EA201791961A1 includes a first antigen binding fragment that specifically binds to CD47 and comprises:
- the present invention relates to a nucleic acid that encodes any of the above bispecific antibodies.
- the nucleic acid molecules may be isolated.
- nucleic acid means a precise sequence of nucleotides, modified or not, determining a fragment or a region of a nucleic acid, containing unnatural nucleotides or not, and being either a double-strand DNA or RNA, a single-strand DNA or RNA, or transcription products of said DNAs.
- the present invention does not relate to nucleotide sequences in their natural chromosomal environment, i.e. in a natural state.
- the sequences of the present invention have been isolated and/or purified, i.e., they were sampled directly or indirectly, for example by copying, their environment having been at least partially modified.
- isolated nucleic acids obtained by recombinant genetics, by means, for example, of host cells, or obtained by chemical synthesis should also be mentioned here.
- a reference to a nucleotide sequence encompasses the complement thereof unless otherwise specified.
- a reference to a nucleic acid having a particular sequence should be understood as one which encompasses the complementary strand thereof with the complementary sequence thereof.
- An "isolated" nucleic acid molecule is one which is identified and separated from at least one nucleic acid molecule-impurity, which the former is bound to in the natural source of antibody nucleic acid.
- An isolated nucleic acid molecule is different from the form or set in which it is found under natural conditions.
- an isolated nucleic acid molecule is different from a nucleic acid molecule that exists in cells under natural conditions.
- the present invention relates to a nucleic acid molecule comprising a nucleotide sequence encoding an amino acid sequence selected from SEQ ID NOs: 1-27.
- a nucleic acid molecule can also comprise any combination of said nucleotide sequences.
- DNA sequences can encode the amino acid sequence of the light chain or heavy chain of the above bispecific antibody according to the invention or fragments thereof (VH, VL, CDR, etc.). It is well within the skill of a person trained in the art to create these alternative DNA sequences encoding the same amino acid sequences. Such variant DNA sequences are within the scope of the present invention.
- the isolated nucleic acid is DNA.
- a nucleic acid molecule of the invention may be isolated from any source that produces the bispecific antibody that specifically binds to CD47 and PD-L1 according to the invention.
- the nucleic acid molecule of the invention may be synthesized, rather than isolated.
- the nucleic acid is a nucleic acid that encodes the amino acid sequence of the variable domain of the heavy chain of the first antigen-binding fragment, which specifically binds to CD47, of the bispecific antibody 09-001 and includes a nucleotide sequence with SEQ ID NO: 28.
- the nucleic acid is a nucleic acid that encodes the amino acid sequence of the variable domain of the common light chain for the first and second antigen-binding fragments of the bispecific antibody 09-001 and includes a nucleotide sequence with SEQ ID NO: 29.
- the nucleic acid is a nucleic acid that encodes the amino acid sequence of the variable domain of the heavy chain of the second antigen-binding fragment, which specifically binds to PD-LI, of the bispecific antibody 09-001 and includes a nucleotide sequence with SEQ ID NO: 30.
- the nucleic acid is a nucleic acid that encodes the amino acid sequence of the heavy chain of the first antigen-binding fragment, which specifically binds to CD47, of the bispecific antibody 09-001 and includes a nucleotide sequence with SEQ ID NO: 31.
- the nucleic acid is a nucleic acid that encodes the amino acid sequence of the light chain for the first and second antigen-binding fragments of the bispecific antibody 09-001 and includes a nucleotide sequence with SEQ ID NO: 32.
- the nucleic acid is a nucleic acid that encodes the amino acid sequence of the heavy chain of the second anti gen -binding fragment, which specifically binds to PD-LI, of the bispecific antibody 09-001 and includes a nucleotide sequence with SEQ ID NO: 33.
- the nucleic acid molecules may be used to express the bispecific antibodies according to the invention.
- the present invention relates to an expression vector comprising any of the above nucleic acids.
- the present invention relates to a vector suitable for the expression of any of nucleotide sequences described herein.
- the term "vector” as used herein means a nucleic acid molecule capable of transporting another nucleic acid to which it has been linked.
- the vector is a plasmid, i.e. a circular double stranded piece of DNA into which additional DNA segments may be ligated.
- the vector is a viral vector, wherein additional DNA segments may be ligated into the viral genome.
- vectors are capable of autonomous replication in a host cell into which they are introduced (e.g.
- vectors having a bacterial origin site of replication and episomal mammalian vectors.
- vectors e.g. non-episomal mammalian vectors
- certain vectors are capable of directing the expression of genes to which they are operably linked. Such vectors are referred to herein as "recombinant expression vectors" (or simply, "expression vectors").
- the present invention relates to vectors comprising the above nucleic acid molecules that encode the above bispecific antibody, or structural portions thereof selected from: a heavy chain variable domain with the amino acid sequence of SEQ ID NO: 22, a common light chain variable domain with the amino acid sequence of SEQ ID NO: 23; a heavy chain variable domain with the amino acid sequence of SEQ ID NO: 24, a heavy chain with the amino acid sequence of SEQ ID NO: 25, a common light chain with the amino acid sequence of SEQ ID NO: 26; a heavy chain with the amino acid sequence of SEQ ID NO: 27, as described herein.
- Expression vectors include plasmids, retroviruses, adenoviruses, adeno-associated viruses (AAVs), plant viruses, such as cauliflower mosaic virus, tobacco mosaic virus, cosmids, YACs, EBV derived episomes, and the like.
- DNA molecules may be ligated into a vector such that transcriptional and translational control sequences within the vector serve their intended function of regulating the transcription and translation of the DNA.
- An expression vector and expression control sequences may be chosen to be compatible with the expression host cell used.
- DNA molecules partially or fully encoding the sequences of first and second binding domains (for example, heavy and light chain sequences where a binding domain comprises a heavy and light chain sequence) can be introduced into individual vectors.
- any combination of said DNA molecules is introduced into the same expression vector.
- DNA molecules may be introduced into an expression vector by standard methods (e.g. ligation of complementary restriction sites on an antibody gene fragment and vector, or blunt end ligation if no restriction sites are present).
- a suitable vector is one that includes restriction sites such that any VH or VL sequence can easily be inserted and expressed, as described above. Polyadenylation and transcription termination may occur at a native chromosomal site downstream of coding regions.
- a recombinant expression vector can also encode a signal peptide that facilitates secretion of an antibody chain from a host cell.
- An antibody chain gene may be cloned into a vector such that the signal peptide is linked in-frame to the amino terminus of an immunoglobulin chain.
- the signal peptide may be an immunoglobulin signal peptide or a heterologous signal peptide (i.e. a signal peptide from a non immunoglobulin protein).
- the recombinant vector expression of the invention can carry regulatory sequences that control the expression of antibody chain genes in a host cell. It will be understood by those skilled in the art that the design of an expression vector, including the selection of regulatory sequences, may depend on such factors as the choice of a host cell to be transformed, the level of expression of a desired protein, and so forth.
- Preferred control sequences for an expression host cell in mammals include viral elements that ensure high levels of protein expression in mammalian cells, such as promoters and/or enhancers derived from a retroviral LTR, cytomegalovirus (CMV) (such as a CMV promoter/enhancer), simian virus 40 (SV40) (such as a SV40 promoter/enhancer), adenovirus, (e.g. the major late promoter adenovirus (AdMLP)), polyomavirus and strong mammalian promoters such as native immunoglobulin promoter or actin promoter.
- CMV cytomegalovirus
- SV40 simian virus 40
- AdMLP major late promoter adenovirus
- polyomavirus e.g. the major late promoter adenovirus (AdMLP)
- AdMLP major late promoter adenovirus
- the recombinant expression vectors of the invention may carry additional sequences, such as sequences that regulate replication of a vector in host cells (e.g. origins of replication) and selectable marker genes.
- the selectable marker gene facilitates the selection of host cells into which a vector has been introduced.
- the vector may include an expression control sequence.
- expression control sequence refers to polynucleotide sequences that are necessary to effect the expression and processing of coding sequences to which they are ligated. Expression control sequences include appropriate transcription initiation, termination, promoter and enhancer sequences; efficient RNA processing signals such as splicing and polyadenylation signals; sequences that stabilize cytoplasmic mRNA; sequences that enhance translation efficiency (i.e., Kozak consensus sequence); sequences that enhance protein stability; and when desired, sequences that enhance protein secretion.
- control sequences differs depending upon the host organism; in prokaryotes, such control sequences generally include the promoter of ribosome binding site, and transcription termination sequences; in eukaryotes, typically, such control sequences include promoters and transcription termination sequences.
- control sequences includes at least all components, the presence of which is essential for expression and processing, and can also include additional components, the presence of which is advantageous, for example, leader sequences and fusion partner sequences.
- the present invention relates to a method for producing a host cell for producing any of the above bispecific antibodies and includes transformation of a cell with the above expression vector.
- the present invention relates to a host cell for producing any of the above bi specific antibodies, the host cell comprises any of the above nucleic acids.
- recombinant host cell refers to a cell into which a recombinant expression vector has been introduced.
- the present invention relates to host cells, which may include, for example, a vector according to the invention described above.
- the present invention further relates to host cells that include, for example, a nucleotide sequence encoding the first heavy chain of the bispecific antibody according to the invention, a nucleotide sequence encoding the common light chain of the bispecific antibody according to the invention, or a nucleotide sequence encoding the second heavy chain of the bispecific antibody according to the invention, or all of the above three sequences.
- host cells that include, for example, a nucleotide sequence encoding the first heavy chain of the bispecific antibody according to the invention, a nucleotide sequence encoding the common light chain of the bispecific antibody according to the invention, or a nucleotide sequence encoding the second heavy chain of the bispecific antibody according to the invention, or all of the above three sequences.
- “recombinant host cell” and "host cell” refer not only to a particular subject cell but to the progeny of such a cell as well. Since modifications may occur in succeeding generations due to either mutation or environmental influences, such progeny may
- Nucleic acid molecules comprising a nucleotide sequence that encodes the amino acid sequence of the light chain or heavy chain of the above bispecific antibody, selected from: a heavy chain with the amino acid sequence of SEQ ID NO: 25, a common light chain with the amino acid sequence of SEQ ID NO: 26; a heavy chain with the amino acid sequence of SEQ ID NO: 27.
- Mammalian cell lines used as hosts for transformation are well known in the art and include a plurality of immortalized cell lines available. These include, e.g., Chinese hamster ovary (CHO) cells, NSO cells, SP2 cells, HEK-293T cells, FreeStyle 293 cells (Invitrogen), NIH-3T3 cells, HeLa cells, baby hamster kidney (BHK) cells, African green monkey kidney cells (COS), human hepatocellular carcinoma cells (e.g., Hep G2), A549 cells, and a number of other cell lines. Cell lines are selected by determining which cell lines have high expression levels and provide for necessary characteristics of the protein produced. Other cell lines that may be used are insect cell lines, such as Sf9 or Sf21 cells.
- the above bispecific antibody is produced by culturing the host cells for a period of time sufficient to express the above bispecific antibody or a portion thereof according to the invention in the host cells, or, more preferably, secrete the above bispecific antibody into the culture medium in which the host cells are cultured.
- the above bispecific antibody may be isolated from culture medium using standard protein purification techniques.
- Plant host cells include e.g. Nicotiana , Arabidopsis , duckweed, corn, wheat, potato, etc.
- Bacterial host cells include Escherichia and Streptomyces species.
- Yeast host cells include Schizosaccharomyce pombe , Saccharomyces cerevisiae and Pichia pastoris.
- level of production of the bispecific antibody of the invention from a producing cell line may be enhanced using a number of known techniques.
- the glutamine synthetase gene expression system (the GS system) is a common approach for enhancing expression under certain conditions.
- the GS system is discussed in whole or part in connection with EP Nos. 0216846, 0256055, 0323997 and 0338841.
- bispecific antibody of the invention in different cell lines or host cells will have different glycosylation patterns from each other.
- the bispecific antibody disclosed herein is part of this invention, regardless of the state of glycosylation of the binding molecules and, in general, regardless of the presence or absence of post-translational modifications.
- the above host cell does not refer to a host cell produced using human embryos.
- the above host cell does not refer to a host cell produced by modifying the genetic integrity of human germline cells.
- the present invention relates to a method for producing any of the above bispecific antibodies, which comprises culturing the above host cell in a growth medium under conditions sufficient to produce said antibody, if necessary, followed by isolation and purification of the resulting antibody.
- the present invention relates to methods for producing the bispecific antibodies of the present invention.
- One embodiment of the invention relates to a method for producing bispecific antibodies as defined herein, comprising producing a recombinant host cell capable of expressing the bispecific antibody, culturing said host cells under conditions suitable for expression of the bispecific antibodies, and isolating the resulting bispecific antibodies.
- the bispecific antibody produced by such expression in such recombinant host cells is referred to herein as "bispecific antibody”.
- compositions in one aspect, relates to a pharmaceutical composition for treating a disease or disorder mediated by PD-L1 and CD47, the pharmaceutical combination comprising any of the above bispecific antibodies.
- the present invention relates to a pharmaceutical composition used for treating a disease or disorder mediated by PD-L1 and CD47, which comprises any of the above bispecific antibodies in a therapeutically effective amount in combination with one or more pharmaceutically acceptable excipients.
- “Pharmaceutical composition” refers to a composition comprising an antibody of the present invention and at least one of components selected from the group comprising pharmaceutically acceptable and pharmacologically compatible fillers, solvents, diluents, carriers, auxiliary, distributing and sensing agents, delivery agents, such as preservatives, stabilizers, filler, disintegrators, moisteners, emulsifiers, suspending agents, thickeners, sweeteners, flavouring agents, aromatizing agents, antibacterial agents, fungicides, lubricants, and prolonged delivery controllers, the choice and suitable proportions of which depend on the type and way of administration and dosage.
- pharmaceutically acceptable and pharmacologically compatible fillers such as preservatives, stabilizers, filler, disintegrators, moisteners, emulsifiers, suspending agents, thickeners, sweeteners, flavouring agents, aromatizing agents, antibacterial agents, fungicides, lubricants, and prolonged delivery controllers, the choice and suitable proportions of which depend
- suspending agents examples include ethoxylated isostearyl alcohol, polyoxyethene, sorbitol and sorbitol ether, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacant and their mixtures as well. Protection against action of microorganisms can be provided by various antibacterial and antifungal agents, such as, for example, parabens, chlorobutanole, sorbic acid, and similar compounds.
- the composition may also contain isotonic agents, such as, for example, sugars, polyols, sodium chloride, and the like. Prolonged action of the composition may be achieved by agents slowing down absorption of active ingredient, for example, aluminum monostearate and gelatine.
- suitable carriers, solvents, diluents and delivery agents are water, ethanol, polyalcohols and their mixtures, natural oils (such as olive oil) and organic esters (such as ethyl oleate) for injections.
- suitable carriers are lactose, milk sugar, sodium citrate, calcium carbonate, calcium phosphate, and the like.
- disintegrators and distributors are starch, alginic acid and its salts, silicates and the like.
- lubricants are magnesium stearate, sodium lauryl sulfate, talc, and polyethylene glycol of high molecular weight as well.
- the pharmaceutical composition for peroral, sublingual, transdermal, intraocular, intramuscular, intravenous, subcutaneous, local or rectal administration of active ingredient, alone or in combination with another active compound may be administered to human and animals in a standard administration form, in a mixture with traditional pharmaceutical carriers.
- suitable standard administration forms include peroral forms such as tablets, gelatin capsules, pills, powders, granules, chewing-gums and peroral solutions or suspensions; sublingual and transbuccal administration forms; aerosols; implants; local, transdermal, subcutaneous, intramuscular, intravenous, intranasal or intraocular administration forms and rectal administration forms.
- excipient is used herein to describe any ingredient other than the antibody of the present invention. These are substances of inorganic or organic nature which are used in the pharmaceutical production/manufacturing in order to give drug products the necessary physicochemical properties.
- compositions are intended to improve, prevent, or treat disorders that may be associated with CD47 and/or PD-L1.
- disease or disorder mediated by CD47 and PD-L1 refers to any disease or disorder that is either directly, or indirectly associated with CD47 and/or PD-L1, including etiology, development, progression, persistence or pathology of a disease or disorder.
- Treat”, “treating” and “treatment” refer to a method of alleviating or abrogating a biological disorder and/or at least one of its attendant symptoms.
- to “alleviate” a disease, disorder or condition means reducing the severity and/or occurrence frequency of the symptoms of the disease, disorder, or condition.
- references herein to “treatment” include references to curative, palliative and prophylactic treatment.
- the subject of treatment, or patient is a mammal, preferably a human subject.
- Said subject may be either male or female, of any age.
- disorder means any condition that would benefit from treatment with the compound of the present invention.
- the definition includes chronic and acute disorders or diseases including those pathological conditions that predispose the mammal to the disorder in question.
- “Therapeutically effective amount” refers to that amount of the therapeutic agent being administered during treatment which will relieve to some extent one or more of the symptoms of the disease being treated.
- the pharmaceutical compositions of the present invention and methods of preparation thereof will be undoubtedly apparent to those skilled in the art.
- the pharmaceutical compositions should preferably be manufactured in compliance with the GMP (Good Manufacturing Practice) requirements.
- the composition may comprise a buffer composition, tonicity agents, stabilizers and solubilizers. Prolonged action of composition may be achieved by agents slowing down absorption of active pharmaceutical ingredient, for example, aluminum monostearate and gelatine.
- suitable carriers, solvents, diluents and delivery agents include water, ethanol, polyalcohols and their mixtures, oils, and organic esters for injections.
- pharmaceutically acceptable refers to one or more compatible liquid or solid components that are suitable for administration in a mammal, preferably a human.
- buffer refers to a solution, which is capable of resisting changes in pH by the action of its acid-base conjugate components, and which allows the product of bispecific antibody that specifically binds to CD47 and PD-L1 according to the present invention to resist changes in pH.
- the pharmaceutical composition preferably has a pH in the range from 4.0 to 8.0.
- buffers used include, but are not limited to, acetate, phosphate, citrate, histidine, succinate, etc. buffer solutions.
- tonic agent refers to an excipient that can increase the osmotic pressure of a liquid antibody formulation.
- "Isotonic” drug is a drug that has an osmotic pressure equivalent to that of human blood. Isotonic drugs typically have an osmotic pressure from about 250 to 350 mOsm/kg. Isotonic agents used include, but are not limited to, polyols, saccharides and sucrose, amino acids, metal salts, for example, sodium chloride, etc.
- Stabilizer refers to an excipient or a mixture of two or more excipients that provide the physical and/or chemical stability of the active agent.
- Stabilizers may be amino acids, for example, but not limited to, arginine, histidine, glycine, lysine, glutamine, proline; surfactants, for example, but not limited to, polysorbate 20 (trade name: Tween 20), polysorbate 80 (trade name: Tween 80), polyethylene- polypropylene glycol and copolymers thereof (trade names: Poloxamer, Pluronic, sodium dodecyl sulfate (SDS); antioxidants, for example, but not limited to, methionine, acetylcysteine, ascorbic acid, monothioglycerol, sulfurous acid salts, etc.; chelating agents, for example, but not limited to, ethylenediaminetetraacetic acid (EDTA), diethylenetriaminepentaacetic acid (DTP A), sodium cit
- the pharmaceutical composition according to the invention is a stable composition.
- the pharmaceutical composition is "stable" if the active agent retains physical stability and/or chemical stability and/or biological activity thereof during the specified shelf life at storage temperature, for example, of 2-8 °C.
- the active agent retains both physical and chemical stability, as well as biological activity. Storage period is adjusted based on the results of stability test in accelerated or natural aging conditions.
- a pharmaceutical composition according to the invention may be manufactured, packaged, or widely sold in the form of a single unit dose or a plurality of single unit doses in the form of a ready formulation.
- single unit dose refers to discrete quantity of a pharmaceutical composition containing a predetermined quantity of an active ingredient.
- the quantity of the active ingredient typically equals the dose of the active ingredient to be administered in a subject, or a convenient portion of such dose, for example, half or a third of such dose.
- compositions according to the present invention are typically suitable for parenteral administration as sterile formulations intended for administration in a human body through the breach in skin or mucosal barriers, bypassing the gastrointestinal tract by virtue of injection, infusion and implantation.
- parenteral administration includes, inter alia, subcutaneous, intraperitoneal, intramuscular, intravenous, intraarterial, intrathecal, intraventricular, intraurethral, intracranial, intrasynovial, transdermal injection or infusion, and kidney dialytic infusion techniques.
- Intra-tumor delivery for example, intra-tumor injection, may also be employed. Regional perfusion is also contemplated.
- Preferred embodiments include intravenous and subcutaneous routes.
- Any method for administering peptides, proteins or antibodies which is accepted in the art may be suitably employed for the bispecific antibody that specifically binds to CD47 and PD-L1 according to the invention.
- Injectable formulations may be prepared, packaged, or sold, without limitation, in unit dosage form, such as in ampoules, vials, in plastic containers, pre-filled syringes, autoinjection devices.
- Formulations for parenteral administration include, inter alia, suspensions, solutions, emulsions in oily or aqueous bases, pastes, and the like.
- the invention provides a composition for parenteral administration comprising a pharmaceutical composition which is provided in dry (i.e. powder or granular) form for reconstitution with a suitable base (e.g. sterile pyrogen-free water) prior to administration.
- a suitable base e.g. sterile pyrogen-free water
- Such medicinal formulation may be prepared by, for example, lyophilization, i.e. a process, which is known in the art as freeze drying, and which involves freezing a product followed by removal of solvent from frozen material.
- the bispecific antibody that specifically binds to CD47 and PD-L1 according to the invention can also be administered intranasally or by inhalation, either alone, as a mixture with a suitable pharmaceutically acceptable excipient from an inhaler, such as a pressurised aerosol container, pump, spray, atomiser, or nebuliser, wherein a suitable propellant is used or not used, or as nasal drops, or spray.
- an inhaler such as a pressurised aerosol container, pump, spray, atomiser, or nebuliser, wherein a suitable propellant is used or not used, or as nasal drops, or spray.
- Medicinal formulations for parenteral administration may be formulated to be immediate or modified release.
- Modified release medicinal formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.
- the present invention relates to a pharmaceutical composition for treating a disease or disorder mediated by PD-L1 and CD47, the pharmaceutical combination comprising any of the above bispecific antibodies and at least one other therapeutically active compound.
- the disease or disorder mediated by PD-L1 and CD47 is selected from the group: triple-negative breast cancer (TNBC), head and neck cancer (HNC), gastric cancer (GC), esophagogastric junction cancer, lung adenocarcinoma, non-small cell lung cancer, small cell lung cancer, acute myeloid leukemia, myelodysplastic syndrome, high microsatellite instability malignant neoplasm, multiple myeloma, ovarian cancer, renal cell carcinoma, bladder cancer, cervical cancer.
- TNBC triple-negative breast cancer
- HNC head and neck cancer
- GC gastric cancer
- esophagogastric junction cancer lung adenocarcinoma
- non-small cell lung cancer small cell lung cancer
- acute myeloid leukemia myelodysplastic syndrome
- high microsatellite instability malignant neoplasm multiple myeloma
- ovarian cancer renal cell carcinoma
- renal cell carcinoma bladder cancer
- cervical cancer cervical cancer
- the other therapeutically active compound is an antibody, chemotherapeutic agent, hormone therapy agent, or any combination thereof.
- the chemotherapeutic agent is selected from the group comprising docetaxel, paclitaxel, doxorubicin, platinum agents, carboplatin, 5- fluorouracil, tyrosine kinase inhibitors, axitinib, liposomal doxorubicin, liposomal paclitaxel or any combination thereof.
- the other therapeutically active compound is an antibody that specifically binds to HER2 (human epidermal growth factor receptor 2).
- the therapeutically active compound is trastuzumab.
- the other therapeutically active compound is trastuzumab and a chemotherapeutic agent that is selected from the group comprising docetaxel, paclitaxel, doxorubicin, platinum agents, carboplatin, 5-fluorouracil, tyrosine kinase inhibitors, axitinib, liposomal doxorubicin, liposomal paclitaxel or any combination thereof.
- a chemotherapeutic agent that is selected from the group comprising docetaxel, paclitaxel, doxorubicin, platinum agents, carboplatin, 5-fluorouracil, tyrosine kinase inhibitors, axitinib, liposomal doxorubicin, liposomal paclitaxel or any combination thereof.
- the bispecific antibody that specifically binds to CD47 and PD-L1 is used in the treatment of disorders mediated by CD47 and PD-L1 activity.
- the subject of treatment, or patient is a mammal, preferably a human subject.
- Said subject may be either male or female, of any age.
- the therapeutically effective amount of the bispecific antibody that specifically binds to CD47 and PD-L1 may reduce the number of cancer cells; reduce the initial tumor size; inhibit (i.e., slow to some extent and preferably stop) cancer cell infiltration into peripheral organs; inhibit (i.e., slow to some extent and preferably stop) tumor metastasis; inhibit, to some extent, tumor growth; and/or relieve to some extent one or more of the symptoms associated with the disorder.
- the bispecific antibody of the invention may to some extent prevent growth and/or kill existing cancer cells, it may be cytostatic and/or cytotoxic.
- in vivo efficacy can, for example, be measured by assessing survival, time to tumor progression (TTP), tumor response rate to treatment (RR), duration of response and/or quality of life.
- the bispecific antibody that specifically binds to CD47 and PD-L1 may be administered without further therapeutic treatment, i.e., as an independent therapy.
- the present invention relates to a method for inhibiting the biological activity of PD-L1 and CD47 in a subject in need of such inhibition, which comprises administering to the subject an effective amount of any of the above bispecific antibodies.
- the present invention relates to a method for treating a disease or disorder mediated by PD-L1 and CD47, which comprises administering to a subject in need of such treatment any of the above bispecific antibodies or any of the above pharmaceutical compositions in a therapeutically effective amount.
- the present invention relates to a method for treating a disease or disorder mediated by PD-L1 and CD47, which comprises administering to a subject in need of such treatment any of the above bispecific antibodies and at least one other therapeutically active compound.
- the disease or disorder mediated by PD-L1 and CD47 is selected from the group: triple-negative breast cancer (TNBC), head and neck cancer (HNC), gastric cancer (GC), esophagogastric junction cancer, lung adenocarcinoma, non-small cell lung cancer, small cell lung cancer, acute myeloid leukemia, myelodysplastic syndrome, high microsatellite instability malignant neoplasm, multiple myeloma, ovarian cancer, renal cell carcinoma, bladder cancer, cervical cancer.
- TNBC triple-negative breast cancer
- HNC head and neck cancer
- GC gastric cancer
- esophagogastric junction cancer lung adenocarcinoma
- non-small cell lung cancer small cell lung cancer
- acute myeloid leukemia myelodysplastic syndrome
- high microsatellite instability malignant neoplasm multiple myeloma
- ovarian cancer renal cell carcinoma
- renal cell carcinoma bladder cancer
- cervical cancer cervical cancer
- the other therapeutically active compound is an antibody, chemotherapeutic agent, hormone therapy agent, or any combination thereof.
- a "chemotherapeutic agent” is a chemical compound useful in the treatment of a malignant neoplasm.
- chemotherapeutic agents include alkylating agents such as thiotepa and cyclosphosphamide (CYTOXAN®); alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines including altretamine, triethylenemelamine, trietylenephosphoramide, triethiylenethiophosphoramide and trimethylmelamine; acetogenins (e.g.
- bullatacin and bullatacinone delta-9-tetrahydrocannabinol (dronabinol MARINOL®); beta-lapachone; lapachol; colchicines; betulinic acid; camptothecin (including the synthetic analogue topotecan (HYCAMTIN®), CPT-11 (irinotecan, CAMPTOSAR®), acetylcamptothecin, scopolectin, and 9-aminocamptothecin); bryostatin; cally statin; CC-1065 (including its adozelesin, carzelesin and bizelesin synthetic analogues); podophyllotoxin; podophyllinic acid; teniposide; cryptophycins (e.g.
- cryptophycin 1 and cryptophycin 8 dolastatin; duocarmycin (including the synthetic analogues, KW-2189 and CB1-TM1); eleutherobin; pancrati statin; sarcodictyin; spongistatin; nitrogen mustards such as chlorambucil, chlornaphazine, cholophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimnustine; antibiotics such as the enediyne antibiotics (e.g.
- calicheamicin e.g. calicheamicin gamma II and calicheamicin omega II (see, e.g. Agnew, Chem. Inti. Ed. Engl., 33: 183-186 (1994)); dynemicin, including dynemicin A; esperamicin; as well as neocarzinostatin chromophore and related chromoprotein enediyne antibiotic chromophores), aclacinomysins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, carabicin, carminomycin, carzinophilin, chromomycins, dactinomycin, daunorubicin, detorubicin, 6- diazo-5-oxo-L-norleucine, doxorubicin (including ADRIAMYCIN®, morpholino-doxorubicin, cyanomorpholino
- ELOXATINTM oxaliplatin
- Hormonal agents are agents that act to regulate or inhibit hormone action on tumors.
- anti -estrogens with mixed agonist/antagonist profile including, tamoxifen (NOLVADEX®), 4-hydroxytamoxifen, toremifene (FARESTON®), idoxifene, droloxifene, raloxifene (EVTSTA®), trioxifene, keoxifene, and selective estrogen receptor modulators (SERMs), such as SERM3; pure anti-estrogens without agonist properties, such as fulvestrant (FASLODEX®), and EM800 (such agents may block estrogen receptor (ER) dimerization, inhibit DNA binding, increase ER turnover, and/or suppress ER levels); aromatase inhibitors, including steroidal aromatase inhibitors, such as formestane and exemestane (AROMASIN®), and nonsteroidal aromatase inhibitors, such as anastrazole (AREVIIDEX®
- the chemotherapeutic agent is selected from the group comprising docetaxel, paclitaxel, doxorubicin, platinum agents, carboplatin, 5-fluorouracil, tyrosine kinase inhibitors, axitinib, liposomal doxorubicin, liposomal paclitaxel or any combination thereof.
- the other therapeutically active compound is an antibody that specifically binds to HER2 (human epidermal growth factor receptor 2).
- the other therapeutically active compound is trastuzumab.
- the other therapeutically active compound is trastuzumab and a chemotherapeutic agent that is selected from the group comprising docetaxel, paclitaxel, doxorubicin, platinum agents, carboplatin, 5-fluorouracil, tyrosine kinase inhibitors, axitinib, liposomal doxorubicin, liposomal paclitaxel or any combination thereof.
- a chemotherapeutic agent that is selected from the group comprising docetaxel, paclitaxel, doxorubicin, platinum agents, carboplatin, 5-fluorouracil, tyrosine kinase inhibitors, axitinib, liposomal doxorubicin, liposomal paclitaxel or any combination thereof.
- the present invention relates to the use of any of the above bi specific antibodies or any of the above pharmaceutical compositions for treating a disease or disorder mediated by PD-L1 and CD47 in a subject in need of such treatment.
- the present invention relates to the use of any of the above bispecific antibodies and at least one other therapeutically active compound for treating a disease or disorder mediated by PD- L1 and CD47 in a subject in need of such treatment.
- the disease or disorder mediated by PD-L1 and CD47 is selected from the group: triple-negative breast cancer (TNBC), head and neck cancer (HNC), gastric cancer (GC), esophagogastric junction cancer, lung adenocarcinoma, non-small cell lung cancer, small cell lung cancer, acute myeloid leukemia, myelodysplastic syndrome, high microsatellite instability malignant neoplasm, multiple myeloma, ovarian cancer, renal cell carcinoma, bladder cancer, cervical cancer.
- the other therapeutically active compound is an antibody, chemotherapeutic agent, hormone therapy agent, or any combination thereof.
- the chemotherapeutic agent is selected from the group comprising docetaxel, paclitaxel, doxorubicin, platinum agents, carboplatin, 5-fluorouracil, tyrosine kinase inhibitors, axitinib, liposomal doxorubicin, liposomal paclitaxel or any combination thereof.
- the other therapeutically active compound is an antibody that specifically binds to HER2 (human epidermal growth factor receptor 2).
- the other therapeutically active compound is trastuzumab.
- the other therapeutically active compound is trastuzumab and a chemotherapeutic agent that is selected from the group comprising docetaxel, paclitaxel, doxorubicin, platinum agents, carboplatin, 5-fluorouracil, tyrosine kinase inhibitors, axitinib, liposomal doxorubicin, liposomal paclitaxel or any combination thereof.
- a chemotherapeutic agent that is selected from the group comprising docetaxel, paclitaxel, doxorubicin, platinum agents, carboplatin, 5-fluorouracil, tyrosine kinase inhibitors, axitinib, liposomal doxorubicin, liposomal paclitaxel or any combination thereof.
- the bispecific antibody that specifically binds to CD47 and PD-L1 according to the invention is used in combination with paclitaxel or docetaxel or doxorubicin or variants thereof or with carboplatin for treating locally advanced or metastatic triple negative breast cancer (TNBC) with tumors that express PD-L1 or CD47, as first-line therapy.
- TNBC triple negative breast cancer
- the bispecific antibody that specifically binds to CD47 and PD-L1 according to the invention is used as monotherapy or in combination with chemotherapy including a platinum agent and 5-fluorouracil (5-FU) for treating locally advanced or metastatic head and neck cancer (HNC), as first-line therapy.
- chemotherapy including a platinum agent and 5-fluorouracil (5-FU) for treating locally advanced or metastatic head and neck cancer (HNC), as first-line therapy.
- the bispecific antibody that specifically binds to CD47 and PD-L1 according to the invention is used in combination with standard chemotherapy and/or trastuzumab for treating locally advanced or metastatic gastric cancer (GS) or esophagogastric junction cancer with tumors that express HER2 or PD-L1, following 2 or more lines of standard therapy.
- GS metastatic gastric cancer
- esophagogastric junction cancer with tumors that express HER2 or PD-L1, following 2 or more lines of standard therapy.
- the bispecific antibody that specifically binds to CD47 and PD-L1 according to the invention is used in combination with tyrosine kinase inhibitors (for example, axitinib or another product) for treating locally advanced or metastatic renal cell carcinoma with tumors that express CD47, as first-line therapy.
- tyrosine kinase inhibitors for example, axitinib or another product
- the bispecific antibody that specifically binds to CD47 and PD-L1 according to the invention is used in combination with chemotherapy including a platinum agent and paclitaxel or variants thereof for treating locally advanced or metastatic cervical cancer with tumors that express CD47, as first-line therapy.
- the bispecific antibody that specifically binds to CD47 and PD-L1 according to the invention will be administered in an amount that is effective in treatment of the condition in question, i.e. in doses and during the periods of time required to achieve the desired result.
- a therapeutically effective amount may vary according to factors such as the particular condition being treated, the age, sex and weight of the patient, and whether the bispecific antibody that specifically binds to CD47 and PD-L1 according to the invention is being administered as a stand-alone treatment or in combination with one or more additional drugs or treatments.
- Dosage regimens may be adjusted to provide the optimum desired response. For example, a single bolus may be administered, several divided doses may be administered over time or the dose may be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation. It is especially advantageous to formulate parenteral compositions in a unit dosage form for ease of administration and uniformity of dosage.
- a unit dosage form as used herein refers to physically discrete units suited as unitary dosages for patients/subjects to be treated; each unit contains a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the desired pharmaceutical carrier.
- unit dosage forms of the invention are typically dictated by and directly dependent on (a) the unique characteristics of a therapeutic agent and particular therapeutic or prophylactic effect to be achieved, and (b) the limitations inherent in the art of compounding such an active compound for the treatment of sensitivity in subjects.
- the doses and dosage regimen are adjusted in accordance with methods well-known in the therapeutic arts. That is, the maximum tolerable dose can be readily established, and the effective amount providing a detectable therapeutic effect to a patient may also be determined, as can the temporal requirements for administering each agent to provide a detectable therapeutic effect to a patient.
- certain doses and administration regimens are exemplified herein, these examples in no way limit the doses and administration regimens that may be provided to a patient in practicing the embodiments of the invention.
- dosage values may vary with the type and severity of the condition to be alleviated, and may include single or multiple doses.
- specific dosage regimens should be adjusted over time according to the individual need and the judgment of a medical professional administering or supervising the administration of the bispecific antibody, and that dosage ranges set forth in the present description are exemplary only and are not intended to limit the scope or practice of the claimed bispecific antibodies.
- the dosage regimen with the compositions of the present invention can be based on various factors, including the type of a disease, age, weight, gender, patient's health condition, severity of a condition, route of administration of the bispecific antibody that specifically binds to CD47 and PD-L1 according to this invention.
- the dosage regimen may vary widely, but can be determined routinely using standard methods. For example, doses may be adjusted based on pharmacokinetic and pharmacodynamic parameters, which may include clinical effects such as toxic effects or laboratory values.
- the present invention encompasses intra-patient dose-escalation as determined by one skilled in the art. Methods for determining appropriate dosage and regimen are well-known in the art and would be understood by a skilled artisan once provided the ideas disclosed herein.
- a suitable dose of the bispecific antibody that specifically binds to CD47 and PD-L1 according to the invention will be in the range of 0.1-200 mg/kg, preferably 0.1-100 mg/kg, including about 0.5-50 mg/kg, for example about 1-20 mg/kg.
- the bispecific antibody that specifically binds to CD47 and PD-L1 according to the invention may be administered, e.g. in a dose of at least 0.25 mg/kg, such as at least 0.5 mg/kg, including at least 1 mg/kg, e.g. at least 1.5 mg/kg, such as at least 2 mg/kg, e.g. at least 3 mg/kg, including at least 4 mg/kg, e.g.
- the administration will typically be repeated in appropriate time intervals, such as once a week, once every two weeks, once every three weeks or once every four weeks, and for as long as deemed appropriate by a responsible physician, who may, in some cases, increase or reduce the dose if necessary.
- Desired gene segments were prepared from oligonucleotides made by chemical synthesis.
- the gene segments of 300-1400 bp long, which were flanked by singular restriction sites, were assembled by annealing and ligation of oligonucleotides including PCR amplification and subsequently cloned via the restriction sites.
- the DNA sequences of the subcloned gene fragments were confirmed by DNA sequencing.
- DNA sequences were determined by Sanger sequencing.
- the Unipro's UGENE suite version 1.29 and SnapGene Viewer were used for sequence creation, mapping, analysis, annotation and illustration.
- variants of expression plasmids intended for expression of antibodies in prokaryotic cells E.coli
- transient expression in eukaryotic cells e.g., in CHO cells
- the vectors contained: an origin of replication which allows replication of said plasmid in E. coli , genes which confer resistance in E. coli to various antibiotics (e.g. to ampicillin, kanamycin).
- the fusion genes comprising the described antibody chains as described below were generated by PCR and/or gene synthesis and assembled with known recombinant methods and techniques by connection of the according nucleic acid segments, e.g. using unique restriction sites in the corresponding vectors. The subcloned nucleic acid sequences were verified by DNA sequencing. For transient transfections, larger quantities of the plasmids were prepared by plasmid preparation from transformed E. coli cultures.
- the plasmid pEE HCholeLALA VH PD-Ll was produced by recloning the variable fragment in pEE HCholeLALA at Sal I / Nhe I restriction sites ( Figure 3).
- the common light chain for the first and second antigen-binding fragments was produced using the plasmid pEE CLC ( Figure 2).
- Antibody 09-001 was produced using plasmids shown in Table 1.
- Full-length antibodies 09-001 were produced in established cell line cells obtained from Chinese hamster ovary cells (CHO-T line). The cells were cultured in a serum-free medium HyCell TransFx-C by HyClone supplemented with 8 mM L-Glutamine and 1 g/1 Pluronic 68 in baffled flasks on orbital incubator shakers at a temperature of +37°C, humidity of 70% and in the presence of 5% CO2 at 150 rpm. The cells were passaged every 3-4 days at a density of 0.3*10 6 cells/ml.
- Target plasmids were used in an equal ratio. Plasmids and PEI diluted in RPMI-1640 were combined and incubated for 10 minutes, thereafter the transfection mixture was introduced to the cells. Suspension cultivation was carried out in 1000 ml baffled flasks on orbital incubator shakers at +37 0 C, in the presence of 5% CO2 and humidity of 70%, at 150 rpm. The next day following transfection, 30% Trypton up to 1% concentration and 200 mM L-Glutamine up to 4 mM were added to the cells and fluorescence parameters were measured on a Guava flow cytometer to assess the transfection efficiency by the expression of fluorescent protein.
- the culture fluid was transferred to 2000 ml baffled flasks, and then 12% Boost 4 to 0.4% concentration and BalanCD Growth A in a volume equal to inoculant were added.
- the resulting product for antibody 09-001 was removed on day 10 day of culturing.
- the culture liquid was filtered through a filter module with 0.22 pm pore size, and then the protein concentration was measured on ForteBio.
- Antibody 09-001 was isolated from the culture fluid and purified using a column with Protein A affinity chromatography sorbent. Cleared culture liquid was passed through a column at a load of 10-20 mg of protein per 1 ml of sorbent, which was pre-equilibrated with phosphate buffered saline (PBS, pH 7.4). The column was then washed with PBS to remove non-specifically binding components. Bound antibodies were eluted using 0.1 M glycine buffer (pH 3.5). Collected eluate was exposed to acidic pH for 30 min for the purpose of viral inactivation, and then neutralized with 1M Tris-HCl solution to pH 7.0.
- PBS phosphate buffered saline
- the protein was then transferred to 20 mM acetate buffer pH 5.0 using dialysis cassettes to conduct additional purification on SP Sepharose HP cation-exchange sorbent in order to remove aggregates and fragments of antibodies.
- the column with sorbent was equilibrated with 20 mM acetate buffer pH 5.0.
- the antibodies were then applied onto the column at a load of 10-20 mg of protein per 1 ml of sorbent.
- the antibodies bound to sorbent were eluted in a salt gradient using a solution of 20 mM NaAcO + 1 M NaCl pH 5.0.
- the protein was transferred to a 20 mM acetate buffer (pH 5.0) supplemented with 100 mM trehalose using dialysis cassettes, filtered through 0.22 pm Millex GP, transferred to test tubes and stored at -70 °C.
- the affinity of the interaction between antibody 09-001 and the human CD47 antigen was studied by bio-layer interferometry on the Octet Red384 instrument (ForteBio).
- the CD47-FcLama antigen was used for the study.
- the sensors were activated in an aqueous solution comprising 20 mM EDC and 10 mM sNHS for 300 s.
- the antigen was loaded onto the surface of biosensors in a sodium -acetate buffer with a pH 5.0 for 300 s.
- 3 concentrations of antibodies were selected for analysis as follows: 68.9 nM, 34.4 nM, 17.2 nM.
- step duration was 600 s
- the sensors were immersed into wells with a kinetic buffer, in which the baseline was recorded.
- the measurements were carried out at a temperature of 30 °C; we employed tangential stirring at 1000 rpm in all steps.
- the reference sensors went through all the steps as the sensors used to record analyte sensograms did, with the exception of the association step - at the association step, the sensors were immersed in a kinetic buffer without analyte (the reference sensor signals were measured in parallel with the recording of the main sensograms).
- the reference signal was subtracted from the signal received on sensors interacting with the analyte during the processing of sensograms.
- the sensors were regenerated in 10 mM glycine solution with HC1 (pH 1.8) to remove bound antibodies (3 regeneration cycles - 5 s regeneration, followed by 5 s neutralization in kinetic buffer). Then the baseline, association, dissociation and regeneration steps were repeated. A total of 4 sets of sensograms were produced as follows: 1 set before regeneration and 3 sets following regeneration. No significant effect of regeneration on the constant values was revealed, therefore, we obtained average values for three measurements following regeneration.
- Antibody 09-001 interacts with the human CD47 antigen, the KD value is 83 nM.
- Antibody 09-001 interacts with the human PD-L1 antigen with an affinity of approximately 3 nM.
- the affinity of the interaction between antibody 09-001 and the cynomolgus CD47 antigen was studied by bio-layer interferometry on the Octet Red384 instrument (ForteBio).
- the cynomolgus CD47 antigen cynoCD47(ARCO), ARCO BioSystems, Cat. No.: CD7-C5252; Cynomolgus / Rhesus macaque CD47 Protein, Fc Tag
- Antibody 09-001 interacts with the cynomolgus CD47 antigen (cynoCD47(ARCO)), the KD value is 57 nM.
- the interaction signal at the last step of the experiment is detected in the presence of a bispecific antibody capable of simultaneously binding to PD- L1 present on sensors and CD47 present in solution.
- Table 6 shows the complete list of steps (stages).
- the sensors were activated in an aqueous solution comprising 20 mM EDC and 10 mM sNHS for 300 s.
- the PD-L1 antigen was loaded onto the surface of biosensors in a sodium-acetate buffer with a pH 5.0 for 300 s.
- the concentration of PD-L1 protein for loading was 20 pg/ml.
- Unreacted active centers on the sensor surfaces were quenched in 1M aqueous solution of ethanolamine with pH 8.5 for 300 s. All steps of the experiment following the quenching step were carried out in the kinetic buffer.
- Antibody 09-001 was loaded onto sensors with immobilized PD-L1 for 300 s, antibody concentration was 20 pg/ml (137.7 nM).
- the sensors were immersed in a solution with CD47 concentration of 100 pg/ml (1280 nM).
- a sensor with immobilized PD-L1 not loaded with antibody 09-001 was used (at the antibody loading step, the sensor was immersed in a kinetic buffer, all other steps are similar to those performed with the sensor being analyzed).
- Sensograms were processed using ForteBio Octet Data Analysisn 9.0 software. Simultaneous interaction with two different antigens was determined by analyzing the signal level (response parameter) at the end of the CD47 interaction step. The results are shown in Table 7.
- Antibody 09-001 demonstrates simultaneous binding to two different antigens, PD-L1 and
- the sensors were activated in an aqueous solution comprising 20 mM EDC and 10 mM sNHS for 300 s.
- the SIRPa antigen was loaded onto the surface of biosensors in a sodium -acetate buffer with a pH 5.0 for 600 s.
- the concentration of SIRPa protein for loading was 20 pg/ml.
- an antigen-free sensor at the loading step, the sensor was immersed in sodium acetate buffer with pH 5.0; all other steps are similar to those used for the sensor loaded with antigen). Unreacted active centers on the sensor surfaces were quenched in 1M aqueous solution of ethanolamine with pH 8.5 for 300 s.
- step duration was 1200 s
- sensors with loaded protein were immersed into wells with an analyte solution.
- a solution containing 250 nM antibody 09-001 and 50 nM CD47 in a kinetic buffer was used as an analyte at the association step.
- a solution (analyte) with CD47 concentration of 50 nM served as a positive control.
- the measurements were carried out at a temperature of 30 °C; we employed tangential stirring at 1000 rpm in all steps.
- the reference sensors went through all the steps as the sensors used to record analyte sensograms did, with the exception of the association step - at the association step, the sensors were immersed in a kinetic buffer without analyte (the reference sensor signals were measured in parallel with the recording of the main sensograms). The reference signal was subtracted from the signal received on sensors interacting with the analyte during the processing of sensograms. Sensograms were processed using ForteBio Octet Data Analysisn 9.0 software. The results of the experiment are shown in Table 9.
- Antibody 09-001 blocks the interaction between CD47 and SIRPa.
- Example 8 Testing of blocking of interaction between PD-1 and PD-L1 by antibody 09-001 on Forte Bio Octert RED 384
- Table 10 shows the list of experiment steps. Table 10. Steps of experiment to test the blocking of interaction between PD-1 and PD-L1 by antibody
- the sensors were activated in an aqueous solution comprising 20 mM EDC and 10 mM sNHS for 300 s.
- the PD-1 antigen was loaded onto the surface of biosensors in a sodium-acetate buffer with a pH 5.0 for 300 s.
- the concentration of PD-1 protein for loading was 20 pg/ml.
- an antigen-free sensor at the loading step, the sensor was immersed in sodium acetate buffer with pH 5.0; all other steps are similar to those used for the sensor loaded with antigen). Unreacted active centers on the sensor surfaces were quenched in 1M aqueous solution of ethanolamine with pH 8.5 for 300 s.
- step duration was 300 s
- sensors with loaded protein were immersed into wells with an analyte solution.
- a solution containing 250 nM antibody 09-001 and 50 nM PD-L1 in a kinetic buffer was used as an analyte at the association step.
- a solution (analyte) with PD-L1 at a concentration of 50 nM served as a positive control.
- the measurements were carried out at a temperature of 30 °C; we employed tangential stirring at 1000 rpm in all steps.
- the reference sensors went through all the steps as the sensors used to record analyte sensograms did, with the exception of the association step - at the association step, the sensors were immersed in a kinetic buffer without analyte (the reference sensor signals were measured in parallel with the recording of the main sensograms). The reference signal was subtracted from the signal received on sensors interacting with the analyte during the processing of sensograms. Sensograms were processed using ForteBio Octet Data Analysisn 9.0 software. The results of the experiment are shown in Table .
- positive control shows a signal of analyte binding to PD-1 (1,429 nm), whereas no signal ofbindingtoPD-1 (0.007 nm, background signal value) was detected for the analyte containing PD-L1 and antibodies 09-001.
- Antibody 09-001 blocks interaction between PD-1 and PD-L1.
- test samples were placed in a thermostated air bath and thermostated at 50°C for 48 hours. After heating, intact and stressed samples were transferred for analysis by size-exclusion HPLC with a UV detector. Chromatography was performed on the Agilent 1100 HPLC system, detection was performed at a wavelength of 220 nm and 280 nm.
- Example 10 Determination of colloidal and thermal stability by protein aggregation point using dynamic light scattering
- Antibody BCD106-02-001 shows a lower level of thermocolloidal stability as compared to 09-001.
- Example 11 Comparison of initial bispecific antibody in scFv-Fab format and bispecific antibody in CLC format (bispecific antibody with common light chain). Table 14 shows data for antibodies BCD106-02-001 and 09-001 by way of comparison.
- antibody 09-001 has a higher aggregation stability as compared to antibody BCD 106-02-001 according to the purity study by SE HPLC. Further, antibody 09-001 has a higher aggregation temperature as compared to BCD 106-02-001, which fact indicates a greater thermocolloidal stability relative to antibody BCD 106-02-001.
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Immunology (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Biophysics (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Genetics & Genomics (AREA)
- Biochemistry (AREA)
- Veterinary Medicine (AREA)
- General Chemical & Material Sciences (AREA)
- Public Health (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Peptides Or Proteins (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
Abstract
The present invention relates to the field of biotechnology and medicine, in particular to a bispecific antibody that specifically binds to CD47 and PD-L1. The invention further relates to a nucleic acid encoding said bispecific antibody, an expression vector, a host cell for producing said bispecific antibody and a method for producing said cell, pharmaceutical compositions comprising the bispecific antibody according to the invention, pharmaceutical compositions comprising the bispecific antibody according to the invention and other therapeutically active compounds, methods for treating diseases or disorders mediated by CD47 and PD-L1, use of the bispecific antibody or pharmaceutical compositions thereof for treating diseases or disorders mediated by CD47 and PD-L1, and the use of the bispecific antibody according to the invention and other therapeutically active compounds for treating diseases or disorders mediated by CD47 and PD-L1.
Description
Isolated hispecific antibody that specifically binds to CD47 and PD-L1
Field of the invention
The present invention relates to the field of biotechnology and medicine, in particular to a bispecific antibody that specifically binds to CD47 and PD-L1. The invention further relates to a nucleic acid encoding said bispecific antibody, an expression vector, a host cell for producing said bispecific antibody and a method for producing said cell, pharmaceutical compositions comprising the bispecific antibody according to the invention, pharmaceutical compositions comprising the bispecific antibody according to the invention and other therapeutically active compounds, methods for treating diseases or disorders mediated by CD47 and PD-L1, use of the bispecific antibody or pharmaceutical compositions thereof for treating diseases or disorders mediated by CD47 and PD-L1, and the use of the bispecific antibody according to the invention and other therapeutically active compounds for treating diseases or disorders mediated by CD47 and PD-L1.
Background of the invention
Monoclonal antibodies in the form of chimeric, humanized or fully human molecules have proven to be useful as effective medicine for treating a number of disorders and diseases.
Naturally occurring human antibody molecules consist of two heavy chain homodimers, each of which forms a heterodimer in partnership with two identical light chain molecules. Conventional monoclonal antibodies in the form of whole molecules consist of bivalent ("two-armed") heterodimers of heavy and light chains.
Diseases are often caused as a result of several pathologies and are accompanied by many concomitant diseases. Bispecific antibodies are capable of binding and thereby neutralizing two different antigens per antibody molecule. The potential for a significant improvement in the therapeutic properties (and value) of medicinal products as compared to monoclonal antibodies has made bispecific antibodies an active area of research. Over the past twenty years, the literature has described many solutions regarding engineered versions of bispecific antibodies, as described in Brinkmann, U and RE Kontermann, 2017, The Making of Bispecific Antibodies, MAbs; 209 Feb/Mar; 9(2):182-212, doi: 10.1080/19420862.2016.1268307.
Therapeutic targeting of PD-1 and other molecules that transduce a signal through interaction with PD-1, such as PD-L1 and PD-L2, has received strong attention. Inhibition of PD-L 1 signals has been suggested as a means to increase T cell immunity (for example, antitumor immunity) for treating cancer and infection, including both acute and chronic infection. Inhibitors blocking the PD-Ll/PD-1 interaction are known, for example, from patent applications W02004004771, W02006121168, W02007005874, WO2008156712, W02010036959, W02010077634 and WO2011066389.
CD47 expression and/or activity have been observed in a number of diseases and disorders. Accordingly, there exists a need for therapies that target CD47.
Antibodies inhibiting the interaction between CD47 and SIRPa ligand have been described in the following patent applications: WO2014123580, WO2013119714, WO2015191861,
WO201 1143624, WO2014093678, WO2017053423.
Bi specific antibodies that specifically bind to CD47 and PD-L1 with different formats of the first and second antigen-binding sites are known from patent application EA201791961 (W02019068302).
To date, no bispecific antibody that specifically binds to CD47 and PD-L1 and that is approved for therapeutic use exists in the world. In connection with the above, it is relevant to create novel bispecific antibodies that specifically bind to CD47 and PD-L1 and have high affinity for targets, good colloidal, thermal and aggregation stability values.
Description of the invention
The authors of the invention surprisingly found that the bispecific antibody that specifically binds to CD47 and PD-L1 and has a common (identical) light chain within the first and second antigen -binding fragments has higher colloidal, thermal and aggregation stability as compared to a bispecific antibody that specifically binds to CD47 and PD-L1 and has a different format of the first and second antigen binding fragments, for example, Fab and scFv format. The bispecific antibody that specifically binds to CD47 and PD-L1 and has a common light chain within the first and second antigen-binding fragments has a high affinity for targets.
The use of a common (identical) light chain in the first and second antigen-binding portions of a bispecific antibody has been described in Van Blarcom T ET AL., Productive common light chain libraries yield diverse panels of high affinity bispecific antibodies, MAbs. 2018 Feb/Mar; 10(2):256-268. doi: 10.1080/19420862.2017.1406570. This format of a bispecific antibody makes it possible to solve the urgent problem of incorrect pairing of two different light chains to their cognate heavy chains for producing bispecific antibodies.
Brief description of the invention
In one aspect, the present invention relates to an isolated bispecific antibody that specifically binds to CD47 and PD-L1 and includes:
1) a first antigen-binding fragment that specifically binds to CD47 and includes:
(a) a heavy chain variable domain comprising:
(i) CDR1 with the amino acid sequence of SEQ ID NO: 1,
(ii) CDR2 with the amino acid sequence of SEQ ID NO: 2,
(iii) CDR3 with the amino acid sequence of SEQ ID NO: 3; and
(b) a common light chain variable domain comprising:
(i) CDR1 with the amino acid sequence of SEQ ID NO: 4,
(ii) CDR2 with the amino acid sequence of SEQ ID NO: 5,
(iii) CDR3 with the amino acid sequence of SEQ ID NO: 6;
2) a second antigen-binding fragment that specifically binds to PD-L1 and includes:
(a) a heavy chain variable domain comprising:
(i) CDR1 with the amino acid sequence of SEQ ID NO: 7,
(ii) CDR2 with the amino acid sequence of SEQ ID NO: 8,
(iii) CDR3 with the amino acid sequence of SEQ ID NO: 9; and
(b) a common light chain variable domain comprising:
(i) CDR1 with the amino acid sequence of SEQ ID NO: 4,
(ii) CDR2 with the amino acid sequence of SEQ ID NO: 5,
(iii) CDR3 with the amino acid sequence of SEQ ID NO: 6.
In some embodiments of the invention, the isolated bispecific antibody characterized in that the first antigen-binding fragment that specifically binds to CD47 is a Fab bound to an Fc fragment monomer.
In some embodiments of the invention, the isolated bispecific antibody characterized in that the second antigen-binding fragment that specifically binds to PD-L1 is a Fab bound to the Fc fragment monomer.
In some embodiments of the invention, the isolated bispecific antibody is characterized in that the antibody is a full-length IgG antibody.
In some embodiments of the invention, the isolated bispecific antibody is a full-length IgG antibody that is of human IgGl, IgG2, IgG3 or IgG4 isotype.
In some embodiments of the invention, the isolated bispecific antibody is a full-length IgG antibody that is of human IgGl isotype.
In some embodiments of the invention, the isolated bispecific antibody includes a heavy chain variable domain of the first antigen-binding fragment that specifically binds to CD47 and comprises the amino acid sequence of SEQ ID NO: 22.
In some embodiments of the invention, the isolated bispecific antibody includes a heavy chain variable domain of the second antigen-binding fragment that specifically binds to PD-L1 and comprises the amino acid sequence of SEQ ID NO: 24.
In some embodiments of the invention, the isolated bispecific antibody includes a variable domain of the common light chain for the first and second antigen-binding fragments, which comprises the amino acid sequence of SEQ ID NO: 23.
In some embodiments of the invention, the isolated bispecific antibody includes a first antigen binding fragment that specifically binds to CD47 and comprises:
(a) a heavy chain variable domain with the amino acid sequence of SEQ ID NO: 22;
(b) a common light chain variable domain with the amino acid sequence of SEQ ID NO: 23; and a second antigen-binding fragment that specifically binds to PD-L1 and comprises:
(a) a heavy chain variable domain with the amino acid sequence of SEQ ID NO: 24,
(b) a common light chain variable domain with the amino acid sequence of SEQ ID NO: 23.
In some embodiments of the invention, the isolated bispecific antibody includes the heavy chain of the first antigen-binding fragment that specifically binds to CD47 and comprises the amino acid sequence of SEQ ID NO: 25.
In some embodiments of the invention, the isolated bispecific antibody includes the heavy chain of the antigen-binding fragment that specifically binds to PD-L1 and comprises the amino acid sequence of SEQ ID NO: 27.
In some embodiments of the invention, the isolated bispecific antibody includes a common light chain for the first and second antigen-binding fragments, which comprises the amino acid sequence of SEQ ID NO: 26.
In some embodiments of the invention, the isolated bispecific antibody includes a first antigen binding fragment that specifically binds to CD47 and comprises:
(a) a heavy chain with the amino acid sequence of SEQ ID NO: 25,
(b) a common light chain with the amino acid sequence of SEQ ID NO: 26; and a second antigen-binding fragment that specifically binds to PD-L1 and comprises:
(a) a heavy chain with the amino acid sequence of SEQ ID NO: 27,
(b) a common light chain with the amino acid sequence of SEQ ID NO: 26.
In some embodiments of the invention, the isolated bispecific antibody is a bivalent antibody.
In one aspect, the present invention relates to an isolated nucleic acid that encodes any of the above bispecific antibodies.
In some embodiments of the invention, the nucleic acid is DNA.
In one aspect, the present invention relates to an expression vector comprising any of the above nucleic acids.
In one aspect, the present invention relates to a method for producing a host cell for producing any of the above bispecific antibodies and includes transformation of a cell with the above expression vector.
In one aspect, the present invention relates to a host cell for producing any of the above bispecific antibodies, the host cell comprises any of the above nucleic acids.
In one aspect, the present invention relates to a method for producing any of the above bispecific antibodies, which comprises culturing the above host cell in a growth medium under conditions sufficient to produce said antibody, if necessary, followed by isolation and purification of the resulting antibody.
In one aspect, the present invention relates to a pharmaceutical composition used for treating a disease or disorder mediated by PD-L1 and CD47, which comprises any of the above bispecific antibodies in a therapeutically effective amount in combination with one or more pharmaceutically acceptable excipients.
In one aspect, the present invention relates to a pharmaceutical composition for treating a disease or disorder mediated by PD-L1 and CD47, the pharmaceutical combination comprising any of the above bispecific antibodies and at least one other therapeutically active compound.
In some embodiments of the pharmaceutical composition, the disease or disorder mediated by PD-L1 and CD47 is selected from the group: triple-negative breast cancer (TNBC), head and neck cancer (HNC), gastric cancer (GC), esophagogastric junction cancer, lung adenocarcinoma, non-small cell lung cancer, small cell lung cancer, acute myeloid leukemia, myelodysplastic syndrome, high microsatellite instability malignant neoplasm, multiple myeloma, ovarian cancer, renal cell carcinoma, bladder cancer, cervical cancer.
In some embodiments of the pharmaceutical composition, the other therapeutically active compound is an antibody, chemotherapeutic agent, hormone therapy agent, or any combination thereof.
In some embodiments of the pharmaceutical composition, the chemotherapeutic agent is selected from the group that comprises: docetaxel, paclitaxel, doxorubicin, platinum agents, carboplatin, 5- fluorouracil, tyrosine kinase inhibitors, axitinib, liposomal doxorubicin, liposomal paclitaxel, or any combination thereof.
In some embodiments of the pharmaceutical composition, the other therapeutically active compound is an antibody that specifically binds to HER2 (human epidermal growth factor receptor 2).
In some embodiments of the pharmaceutical composition, the therapeutically active compound is trastuzumab.
In some embodiments of the pharmaceutical composition, the other therapeutically active compound is trastuzumab and a chemotherapeutic agent that is selected from the group comprising docetaxel, paclitaxel, doxorubicin, platinum agents, carboplatin, 5-fluorouracil, tyrosine kinase inhibitors, axitinib, liposomal doxorubicin, liposomal paclitaxel or any combination thereof.
In one aspect, the present invention relates to a method for inhibiting the biological activity of PD-L1 and CD47 in a subject in need of such inhibition, which comprises administering to the subject an effective amount of any of the above bispecific antibodies.
In one aspect, the present invention relates to a method for treating a disease or disorder mediated by PD-L1 and CD47, which comprises administering to a subject in need of such treatment any of the above bispecific antibodies or any of the above pharmaceutical compositions in a therapeutically effective amount.
In one aspect, the present invention relates to a method for treating a disease or disorder mediated by PD-L1 and CD47, which comprises administering to a subject in need of such treatment any of the above bispecific antibodies and at least one other therapeutically active compound.
In some embodiments of the method of treatment, the disease or disorder mediated by PD-L1 and CD47 is selected from the group: triple-negative breast cancer (TNBC), head and neck cancer (HNC), gastric cancer (GC), esophagogastric junction cancer, lung adenocarcinoma, non-small cell lung cancer, small cell lung cancer, acute myeloid leukemia, myelodysplastic syndrome, high microsatellite instability malignant neoplasm, multiple myeloma, ovarian cancer, renal cell carcinoma, bladder cancer, cervical cancer.
In some embodiments of the method of treatment, the other therapeutically active compound is an antibody, chemotherapeutic agent, hormone therapy agent, or any combination thereof.
In some embodiments of the method of treatment, the chemotherapeutic agent is selected from the group that comprises: docetaxel, paclitaxel, doxorubicin, platinum agents, carboplatin, 5- fluorouracil, tyrosine kinase inhibitors, axitinib, liposomal doxorubicin, liposomal paclitaxel, or any combination thereof.
In some embodiments of the method of treatment, the other therapeutically active compound is an antibody that specifically binds to HER2 (human epidermal growth factor receptor 2).
In some embodiments of the method of treatment, the other therapeutically active compound is trastuzumab.
In some embodiments of the method of treatment, the other therapeutically active compound is trastuzumab and a chemotherapeutic agent selected from the group comprising docetaxel, paclitaxel, doxorubicin, platinum agents, carboplatin, 5-fluorouracil, tyrosine kinase inhibitors, axitinib, liposomal doxorubicin, liposomal paclitaxel, or any combination thereof.
In one aspect, the present invention relates to the use of any of the above bi specific antibodies or any of the above pharmaceutical compositions for treating a disease or disorder mediated by PD-L1 and CD47 in a subject in need of such treatment.
In one aspect, the present invention relates to the use of any of the above bispecific antibodies and at least one other therapeutically active compound for treating a disease or disorder mediated by PD- L1 and CD47 in a subject in need of such treatment.
In some embodiments of the use, the disease or disorder mediated by PD-L1 and CD47 is selected from the group: triple-negative breast cancer (TNBC), head and neck cancer (HNC), gastric cancer (GC),
esophagogastric junction cancer, lung adenocarcinoma, non-small cell lung cancer, small cell lung cancer, acute myeloid leukemia, myelodysplastic syndrome, high microsatellite instability malignant neoplasm, multiple myeloma, ovarian cancer, renal cell carcinoma, bladder cancer, cervical cancer.
In some embodiments of the use, the other therapeutically active compound is an antibody, chemotherapeutic agent, hormone therapy agent, or any combination thereof.
In some embodiments of the use, the chemotherapeutic agent is selected from the group that comprises: docetaxel, paclitaxel, doxorubicin, platinum agents, carboplatin, 5-fluorouracil, tyrosine kinase inhibitors, axitinib, liposomal doxorubicin, liposomal paclitaxel, or any combination thereof.
In some embodiments of the use, the other therapeutically active compound is an antibody that specifically binds to HER2 (human epidermal growth factor receptor 2).
In some embodiments of the use, the other therapeutically active compound is trastuzumab.
In some embodiments of the use, the other therapeutically active compound is trastuzumab and a chemotherapeutic agent that is selected from the group comprising docetaxel, paclitaxel, doxorubicin, platinum agents, carboplatin, 5-fluorouracil, tyrosine kinase inhibitors, axitinib, liposomal doxorubicin, liposomal paclitaxel or any combination thereof.
Brief description of drawings
Figure l is a map of the plasmid vector pEE_HCknobLALA_VH_CD47.
Figure 2 is a map of the plasmid vector pEE CLC.
Figure 3 is a map of the plasmid vector pEE HCholeLALA VH PD-Ll.
For Figures 1 to 3
Figure 4 is an electrophoregram of 09-001 in 7.5 % polyacrylamide gel under denaturing non reducing conditions following the first stage of purification on Protein A sorbent.
1 -molecular weight marker.
2- antibody 09-001 (10 pg).
3- antibody 09-001 (40 pg).
Figure 5 is an electrophoregram of 09-001 in 7.5 % polyacrylamide gel under denaturing non reducing conditions following purification on SP Sepharose HP sorbent.
1 -molecular weight marker.
2- antibody 09-001 (10 pg).
3- antibody 09-001 (40 pg).
Figure 6 is an electrophoregram of 09-001 in 12 % polyacrylamide gel under denaturing reducing conditions following purification on SP Sepharose HP sorbent.
1 -molecular weight marker.
2- antibody 09-001 (10 pg).
Figure 7 is a schematic representation of the format of the bispecific antibody with a common light chain, which specifically binds to CD47 and PD-L1.
Definitions and general methods
Unless defined otherwise herein, all technical and scientific terms used in connection with the present invention will have the same meaning as is commonly understood by those skilled in the art.
Furthermore, unless otherwise required by context, singular terms shall include plural terms, and the plural terms shall include the singular terms. Typically, the present classification and methods of cell culture, molecular biology, immunology, microbiology, genetics, analytical chemistry, organic synthesis chemistry, medical and pharmaceutical chemistry, as well as hybridization and chemistry of protein and nucleic acids described herein are well known by those skilled and widely used in the art. Enzyme reactions and purification methods are performed according to the manufacturer's guidelines, as is common in the art, or as described herein.
The term "KD" in this description refers to the affinity constant (or equilibrium constant, or equilibrium dissociation constant), which is calculated from the ratio of Kd to Ka (i.e. Kd/Ka), and it is expressed as a molar concentration (M).
"Binding affinity" generally refers to the strength of the sum total of noncovalent interactions between a single binding site of a molecule (e.g. an antibody) and its binding partner (e.g. an antigen). Unless indicated otherwise, "binding affinity" refers to intrinsic (characteristic, true) binding affinity which reflects a 1:1 interaction between members of a binding pair (e.g. antibody and antigen). The
affinity of a molecule X for its binding partner Y can generally be represented by the affinity constant (KD). The preferred Kd value is about 200 nM, 150 nM, 100 nM, 60 nM, 50 nM, 40 nM, 30 nM, 20 nM, 10 nM, 8 nM, 6 nM, 4 nM, 2 nM, 1 nM, or less. Affinity can be measured by common methods known in the art, including those described in the present description. Low-affinity antibodies generally bind an antigen slowly and tend to dissociate readily, whereas high-affinity antibodies generally bind an antigen faster and tend to remain bound longer. A variety of methods of measuring binding affinity are known in the art, any of which can be used for the purposes of the present invention.
The term "Kd", "koff ' or "kdis" refers to the off rate constant of a particular interaction between a binding molecule and antigen. The off rate constant koff can be measured using bio-layer interferometry, for example, using Octet™ system.
The term "Ka", "kon" or "on-rate" refers to the association rate constant.
The term "Response" refers to the antibody-antigen binding signal.
As used in the present description and claims that follow, unless otherwise dictated by the context, the words "include" and "comprise," or variations thereof such as "includes", "including", "comprises," or "comprising," will be understood to imply the inclusion of a stated integer or group of integers but not the exclusion of any other integer or group of integers.
Detailed description of the invention
Bispecific antibody
The present invention relates to a bispecific antibody that specifically binds to CD47 and PD-L1.
The bispecific antibody according to the invention is a monoclonal antibody.
The term "monoclonal antibody" or "mAb" refers to an antibody that is synthesized and isolated by a separate clonal population of cells.
The bispecific antibody according to the invention is a recombinant antibody.
The term "recombinant antibody" refers to an antibody that is expressed in a cell or cell line comprising nucleotide sequence(s) encoding antibodies, wherein said nucleotide sequence(s) is (are) not associated with the cell in nature.
The bispecific antibody according to the invention is an isolated antibody.
The term "isolated" used to describe various antibodies according to this description refers to an antibody which has been identified and separated and/or regenerated from a cell or cell culture, in which the antibody is expressed. Impurities (contaminant components) from natural environment are materials which typically interfere with diagnostic or therapeutic uses of the polypeptide, and may include enzymes, hormones, and other proteinaceous or nonproteinaceous solutes. The isolated polypeptide is typically prepared by at least one purification step.
The bispecific antibody according to the invention has a common light chain (CLC) for the first
and second antigen-binding fragments.
Figure 7 shows a schematic representation of the format of the bispecific antibody with a common light chain, which specifically binds to CD47 and PD-L1.
In one aspect, the present invention relates to an isolated bispecific antibody that specifically binds to CD47 and PD-L1 and includes:
1) a first antigen-binding fragment that specifically binds to CD47 and includes:
(a) a heavy chain variable domain comprising:
(i) CDR1 with the amino acid sequence of SEQ ID NO: 1,
(ii) CDR2 with the amino acid sequence of SEQ ID NO: 2,
(iii) CDR3 with the amino acid sequence of SEQ ID NO: 3; and
(b) a common light chain variable domain comprising:
(i) CDR1 with the amino acid sequence of SEQ ID NO: 4,
(ii) CDR2 with the amino acid sequence of SEQ ID NO: 5,
(iii) CDR3 with the amino acid sequence of SEQ ID NO: 6;
2) a second antigen-binding fragment that specifically binds to PD-L1 and includes:
(a) a heavy chain variable domain comprising:
(i) CDR1 with the amino acid sequence of SEQ ID NO: 7,
(ii) CDR2 with the amino acid sequence of SEQ ID NO: 8,
(iii) CDR3 with the amino acid sequence of SEQ ID NO: 9; and
(b) a common light chain variable domain comprising:
(i) CDR1 with the amino acid sequence of SEQ ID NO: 4,
(ii) CDR2 with the amino acid sequence of SEQ ID NO: 5,
(iii) CDR3 with the amino acid sequence of SEQ ID NO: 6.
Amplification of the CD47 gene and/or overexpression of protein thereof have been observed in many cancers, for example, in any of the diseases from the group: triple-negative breast cancer (TNBC), head and neck cancer (HNC), gastric cancer (GC), esophagogastric junction cancer, lung adenocarcinoma, non-small cell lung cancer, small cell lung cancer, acute myeloid leukemia, myelodysplastic syndrome, high microsatellite instability malignant neoplasm, multiple myeloma, ovarian cancer, renal cell carcinoma, bladder cancer, cervical cancer.
The term "antibody" or "immunoglobulin" (Ig), as used in the present description, includes whole antibodies. The term "antibody" refers to a glycoprotein comprising at least two heavy (H) chains and two light (L) chains interconnected by disulfide bonds. Each heavy chain comprises a heavy chain variable region (abbreviated referred to in the present description as VET) and a heavy chain constant region. The constant region is identical in all antibodies of the same isotype, but differs in antibodies of different isotypes. Heavy chains g, a and d have a constant region composed of three constant domains
CHI, CH2 and CH3 (in a line), and a hinge region for added flexibility (Woof J., Burton D., Nat Rev Immunol 4, 2004, pp.89-99). In mammals, known are only two types of light chains denoted by lambda (l) and kappa (K). Each light chain consists of a light chain variable region (abbreviated referred to in the present description as VL) and light chain constant region. The approximate length of a light chain is 211 to 217 amino acids. Preferably, the light chain is a lambda (l) light chain, and the constant domain CL is preferably C lambda (l).
VL and VH regions may be further subdivided into hyper-variability regions called complementarity determining regions (CDRs), located between regions that are more conserved, termed framework regions (FRs). Each VH and VL is composed of three CDRs and four FRs, arranged from amino-terminus to carboxy-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. The variable regions of heavy and light chains contain a binding domain that interacts with an antigen. The constant regions of antibodies may mediate the binding of immunoglobulin to host tissues or factors, including various cells of the immune system (e.g. effector cells) and the first component (Clq) of the classical complement system.
The term "antigen-binding portion" of antibody or "antigen -binding fragment", as used in the present description, refers to one or more antibody fragments that retain the ability to specifically bind to an antigen. It has been shown that the antigen-binding function of antibody can be performed by fragments of a full-length antibody. As used in the present invention, the term "antigen -binding fragment" means a Fab-fragment, i.e. a monovalent fragment, consisting of VL, VH, CL and CHI domains, which is linked with the Fc-fragment monomer.
In some embodiments of the invention, the isolated bispecific antibody characterized in that the first antigen-binding fragment that specifically binds to CD47 is a Fab bound to an Fc fragment monomer.
In some embodiments of the invention, the isolated bispecific antibody characterized in that the second antigen-binding fragment that specifically binds to PD-L1 is a Fab bound to the Fc fragment monomer.
The term "variable" refers to the fact that certain portions of the variable domains greatly differ in sequence among antibodies. The V domain mediates antigen binding and determines specificity of each particular antibody for its particular antigen. However, the variability is not evenly distributed across the 110-amino acid span of the variable domains. Instead, the V regions consist of invariant fragments termed framework regions (FRs) of 15-30 amino acids separated by shorter regions of extreme variability termed "hypervariable regions" or CDRs. The variable domains of native heavy and light chains each comprise four FRs, largely adopting a beta-sheet configuration, connected by three hypervariable regions, which form loops connecting, and in some cases forming part of, the beta-sheet structure. The hypervariable regions in each chain are held together in close proximity by FRs and, with
the hypervariable regions from the other chain, contribute to the formation of the antigen-binding site of antibodies (see Kabat et al., Sequences of Proteins of Immunological Interest. 5 th Ed. Public Health Service, National Institutes of Health, Bethesda, MD. (1991)). The constant domains are not involved directly in binding of antibody to antigen, but exhibit various effector functions, such as participation of antibody in antibody-dependent cellular cytotoxicity (ADCC).
The term "hypervariable region" according to the present description refers to the amino acid residues of antibody which are responsible for antigen binding. The hypervariable region typically comprises amino acid residues from a "complementarity determining region" or "CDR" and/or those residues from a "hypervariable loop".
“Kabat numbering scheme” or “numbering according to Kabat” as used in this application refers to the system for numbering of amino acid residues that are more variable (i.e. hypervariable) than other amino acid residues in variable regions of heavy and light chains of the antibody (Kabat et al. Ann. N.Y. Acad. Sci., 190:382-93 (1971); Kabat et al. Sequences of Proteins of Immunological Interest, Fifth Edition, U.S. Department of Health and Human Services, NIH Publication No. 91-3242 (1991)).
The antibody of the present invention "which binds" a target antigen refers to an antibody that binds the antigen with sufficient affinity such that the antibody can be used as a diagnostic and/or therapeutic agent targeting a protein or cell or tissue expressing the antigen, and slightly cross-reacts with other proteins. According to analytical methods: fluorescence-activated cell sorting (FACS), radioimmunoassay (RIA) or ELISA, in such embodiments, the degree of antibody binding to a non target protein is less than 10 % of antibody binding to a specific target protein. With regard to the binding of antibody to a target molecule, the term “specific binding” or “specifically binds to” or “is specific for” a particular polypeptide or an epitope on a particular target polypeptide means binding that is significantly (measurably) different from a non-specific interaction.
Specific binding may be measured, for example, by determining binding of a molecule as compared to binding of a control molecule. For example, specific binding may be determined by competition with another molecule that is similar to the target, for example, an excess of non-labeled target. In this case, specific binding is indicated if the binding of the labeled target to a probe is competitively inhibited by the excess of unlabeled target. As used in the present description, the term "specific binding" or phrases "specifically binds to" or " is specific for" a particular polypeptide or an epitope on a particular target polypeptide may be described by example of a molecule having a Kd for the target of at least about 200 nM, or at least about 150 nM, or at least about 100 nM, or at least about 60 nM, or at least about 50 nM, or at least about 40 nM, or at least about 30 nM, or at least about 20 nM, or at least about 10 nM, or at least about 8 nM, or at least about 6 nM, or at least about 4 nM, or at least about 2 nM, or at least about 1 nM, or greater. In one embodiment, the term "specific binding" refers to
binding where a molecule binds to a particular polypeptide or epitope on a particular polypeptide without substantially binding to any other polypeptide or epitope on a polypeptide.
The term "bispecific antibody" refers to an antibody having antigen-binding fragments that are capable of specific binding to two distinct epitopes on a single biological molecule or capable of specific binding to epitopes on two distinct biological molecules. The bispecific antibody is also referred to herein as having "dual specificity" or as being a "dual specificity" antibody.
The fragment crystallizable region ("Fc region, Fc") of an immunoglobulin is the "tail" region of an immunoglobulin molecule that interacts with cell surface Fc-receptor, as well as some proteins of the complement system. This property allows antibodies to activate the immune system. In IgG, IgA and IgD isotypes, the Fc region is composed of two identical protein fragments, derived from the second and third constant domains, respectively, of the two heavy chains.
The "Fc fragment monomer" refers to the Fc region from the second and third constant domains of any one of the two heavy chains (for IgG, IgA and IgD isotypes).
In some embodiments of the invention, the isolated bispecific antibody is characterized in that the antibody is a full-length IgG antibody.
In some embodiments of the invention, the isolated bispecific antibody is a full-length IgG antibody that is of human IgGl, IgG2, IgG3 or IgG4 isotype.
In some embodiments of the invention, the isolated bispecific antibody is a full-length IgG antibody that is of human IgGl isotype.
In some embodiments of the invention, the isolated bispecific antibody includes a heavy chain variable domain of the first antigen-binding fragment that specifically binds to CD47 and comprises the amino acid sequence of SEQ ID NO: 22.
In some embodiments of the invention, the isolated bispecific antibody includes a heavy chain variable domain of the second antigen-binding fragment that specifically binds to PD-L1 and comprises the amino acid sequence of SEQ ID NO: 24.
In some embodiments of the invention, the isolated bispecific antibody includes a variable domain of the common light chain for the first and second antigen-binding fragments, which comprises the amino acid sequence of SEQ ID NO: 23.
In some embodiments of the invention, the isolated bispecific antibody includes a first antigen binding fragment that specifically binds to CD47 and comprises:
(a) a heavy chain variable domain with the amino acid sequence of SEQ ID NO: 22;
(b) a common light chain variable domain with the amino acid sequence of SEQ ID NO: 23; and a second antigen-binding fragment that specifically binds to PD-L1 and comprises:
(a) a heavy chain variable domain with the amino acid sequence of SEQ ID NO: 24,
(b) a common light chain variable domain with the amino acid sequence of SEQ ID NO: 23.
In some embodiments of the invention, the bispecific antibody according to the invention includes a CH3 domain of one heavy chain, which is modified to form Knob, and a CH3 domain of another heavy chain, which is modified to form Hole, or vice versa.
"Knobs-into-holes" (interactions of the "knobs -into-holes" type) is an approach that enables to circumvent the problem associated with mispaired byproducts. This approach aims at forcing the pairing of two different antibody heavy chains by introducing mutations into the CH3 domains to modify the contact interfaces. On one chain, bulky amino acids were replaced by amino acids with short side chains to create a "hole". Conversely, amino acids with large side chains were introduced into the other CH3 domain to create a "knob". Co-expression of these two heavy chains produced a high yield of the heterodimer formation ("knob-hole") relative to the homodimer formation ("hole-hole" or "knob-knob") (WO9627011 and WO9850431, as well as Merchant AM ET ALL., An efficient route to human bispecific IgG, Nat Biotechnol. 1998 Jul;16(7):677-81).
In some embodiments of the invention, the bispecific antibody includes a CH3 domain of one heavy chain, which domain has amino acid substitutions S354C/T366W, to form Knob, and a CH3 domain of another heavy chain, which domain has amino acid substitutions Y349C/T366S/L368A/Y407V, to form Hole.
In some embodiments of the invention, the bispecific antibody includes a CH3 domain of one heavy chain, which domain has amino acid substitutions Y349C/T366S/L368A/Y407, to form Hole, and a CH3 domain of another heavy chain, which domain has amino acid substitutions S354C/T366W, to form Knob.
In some embodiments of the invention, the bispecific antibody includes an Fc fragment monomer, wherein LALA substitutions (L234A and L235A) are further introduced. These mutations are introduced to reduce the antibody effector function.
The above mutations in the Fc fragment are numbered according to EU numbering for amino acid chains of antibodies (Edelman, G.M., et ak, Proc. Natl. Acad. Sci. USA 63 (1969), pp. 78-85; Kabat, E.A., et ak, Sequences of Proteins of Immunological Interest, 5th ed., Public Health Service, National Institutes of Health, Bethesda, MD, (1991).
In some embodiments of the invention, the isolated bispecific antibody includes the heavy chain of the first antigen-binding fragment that specifically binds to CD47 and comprises the amino acid sequence of SEQ ID NO: 25.
In some embodiments of the invention, the isolated bispecific antibody includes the heavy chain of the antigen-binding fragment that specifically binds to PD-L1 and comprises the amino acid sequence of SEQ ID NO: 27.
In some embodiments of the invention, the isolated bispecific antibody includes a common light chain for the first and second antigen-binding fragments, which comprises the amino acid sequence of SEQ ID NO: 26.
In some embodiments of the invention, the isolated bispecific antibody includes a first antigen binding fragment that specifically binds to CD47 and comprises:
(a) a heavy chain with the amino acid sequence of SEQ ID NO: 25,
(b) a common light chain with the amino acid sequence of SEQ ID NO: 26; and a second antigen-binding fragment that specifically binds to PD-L1 and comprises:
(a) a heavy chain with the amino acid sequence of SEQ ID NO: 27,
(b) a common light chain with the amino acid sequence of SEQ ID NO: 26.
In some embodiments of the invention, the isolated bispecific antibody is a bivalent antibody.
In some embodiments of the invention, the isolated bispecific antibody that specifically binds to CD47 and PD-L1 is antibody 09-001.
The bispecific antibody 09-001 includes:
1) a first antigen-binding fragment that specifically binds to CD47 and includes:
(a) a heavy chain variable domain comprising:
(i) CDR1 (Kabat) with the amino acid sequence of SEQ ID NO: 1,
(ii) CDR2 (Kabat) with the amino acid sequence of SEQ ID NO: 2,
(iii) CDR3 (Kabat) with the amino acid sequence of SEQ ID NO: 3; and
(b) a common light chain variable domain comprising:
(i) CDR1 (Kabat) with the amino acid sequence of SEQ ID NO: 4,
(ii) CDR2 (Kabat) with the amino acid sequence of SEQ ID NO: 5,
(iii) CDR3 (Kabat) with the amino acid sequence of SEQ ID NO: 6; and
2) a second antigen-binding fragment that specifically binds to PD-L1 and includes:
(a) a heavy chain variable domain comprising:
(i) CDR1 (Kabat) with the amino acid sequence of SEQ ID NO: 7,
(ii) CDR2 (Kabat) with the amino acid sequence of SEQ ID NO: 8,
(iii) CDR3 (Kabat) with the amino acid sequence of SEQ ID NO: 9; and
(b) a common light chain variable domain comprising:
(i) CDR1 (Kabat) with the amino acid sequence of SEQ ID NO: 4,
(ii) CDR2 (Kabat) with the amino acid sequence of SEQ ID NO: 5,
(iii) CDR3 (Kabat) with the amino acid sequence of SEQ ID NO: 6.
The bispecific antibody 09-001 includes:
1) a first antigen-binding fragment that specifically binds to CD47 and includes:
(a) a heavy chain variable domain comprising:
(i) CDR1 (Chothia) with the amino acid sequence of SEQ ID NO: 10,
(ii) CDR2 (Chothia) with the amino acid sequence of SEQ ID NO: 11,
(iii) CDR3 (Chothia) with the amino acid sequence of SEQ ID NO: 12; and
(b) a common light chain variable domain comprising:
(i) CDR1 (Chothia) with the amino acid sequence of SEQ ID NO: 13,
(ii) CDR2 (Chothia) with the amino acid sequence of SEQ ID NO: 14,
(iii) CDR3 (Chothia) with the amino acid sequence SEQ ID NO: 15; and
2) a second antigen-binding fragment that specifically binds to PD-L1 and includes:
(a) a heavy chain variable domain comprising:
(i) CDR1 (Chothia) with the amino acid sequence of SEQ ID NO: 16,
(ii) CDR2 (Chothia) with the amino acid sequence of SEQ ID NO: 17,
(iii) CDR3 (Chothia) with the amino acid sequence of SEQ ID NO: 18; and
(b) a common light chain variable domain comprising:
(i) CDR1 (Chothia) with the amino acid sequence of SEQ ID NO: 13,
(ii) CDR2 (Chothia) with the amino acid sequence of SEQ ID NO: 14,
(iii) CDR3 (Chothia) with the amino acid sequence SEQ ID NO: 15.
The bispecific antibody 09-001 includes:
1) a first antigen-binding fragment that specifically binds to CD47 and includes a common light chain variable domain comprising:
(i) CDR1 (IMGT) with the amino acid sequence of SEQ ID NO: 19,
(ii) CDR2 (IMGT) with the amino acid sequence of SEQ ID NO: 20,
(iii) CDR3 (IMGT) with the amino acid sequence of SEQ ID NO: 21; and
2) a second antigen-binding fragment that specifically binds to PD-L1 and includes a common light chain variable domain comprising:
(i) CDR1 (IMGT) with the amino acid sequence of SEQ ID NO: 19,
(ii) CDR2 (IMGT) with the amino acid sequence of SEQ ID NO: 20,
(iii) CDR3 (IMGT) with the amino acid sequence of SEQ ID NO: 21.
The bispecific antibody 09-001 includes a first antigen-binding fragment that specifically binds to CD47 and comprises:
(a) a heavy chain variable domain with the amino acid sequence of SEQ ID NO: 22;
(b) a common light chain variable domain with the amino acid sequence of SEQ ID NO: 23; and a second antigen-binding fragment that specifically binds to PD-L1 and comprises:
(a) a heavy chain variable domain with the amino acid sequence of SEQ ID NO: 24,
(b) a common light chain variable domain with the amino acid sequence of SEQ ID NO: 23.
The bispecific antibody 09-001 includes: the first Fc fragment monomer that comprises the second and third constant domains of the heavy chain (CH2 and CH3) with LALA mutations (L251A, L252A according to sequential numbering from the beginning of the chain (L234A, L235A according to EU or L247A, L248A according to kabat)) and mutations S371C, T383W according to sequential numbering from the beginning of the chain (S354C, T366W according to EU or S375C, T389W according to kabat) as compared to CH2 and CH3 of wild type human IgGl; and the second Fc fragment monomer that comprises the second and third constant domains of the heavy chain (CH2 and CH3) with LALA mutations (L240A, L241 A according to sequential numbering from the beginning of the chain (L234A, L235A according to EU or L247A, L248A according to kabat)) and mutations Y355C, T372S, L374A, Y413V according to sequential numbering from the beginning of the chain (Y349C, T366S, L368A, Y407V according to EU or Y370C, T389S, L391A, Y438V according to kabat) as compared to CH2 and CH3 of wild type human IgGl .
The bispecific antibody 09-001 includes a first antigen-binding fragment that specifically binds to CD47 and comprises:
(a) a heavy chain with the amino acid sequence of SEQ ID NO: 25,
(b) a common light chain with the amino acid sequence of SEQ ID NO: 26; and a second antigen-binding fragment that specifically binds to PD-L1 and comprises:
(a) a heavy chain with the amino acid sequence of SEQ ID NO: 27,
(b) a common light chain with the amino acid sequence of SEQ ID NO: 26.
The bispecific antibody 09-001 was developed on the basis of antibody BCD 106-02-001 from the patent document EA201791961A1 and therefore 09-001 is compared with BCD106-02-001 in the examples. Sequences of the antigen-binding fragment in the scFv format, which specifically binds to CD47, of antibody BCD106-02-001 were recloned into Fab format to produce 09-001. Further, for the bispecific antibody 09-001, we selected a new format with a common light chain (CLC) for the first and second antigen-binding fragments.
Antibody BCD106-02-001 from patent document EA201791961A1 includes a first antigen binding fragment that specifically binds to CD47 and is provided in the scFv format, and a second antigen-binding fragment that specifically binds to PD-L1 and is provided in the Fab format.
Antibody BCD106-02-001 from patent document EA201791961A1 includes a first antigen binding fragment that specifically binds to CD47 and comprises:
(a) a heavy chain variable domain with the amino acid sequence of SEQ ID NO: 22;
(b) a common light chain variable domain with the amino acid sequence of SEQ ID NO: 34; and a second antigen-binding fragment that specifically binds to PD-L1 and comprises:
(a) a heavy chain variable domain with the amino acid sequence of SEQ ID NO: 24,
(b) a common light chain variable domain with the amino acid sequence of SEQ ID NO: 23.
Nucleic acid molecule
In one aspect, the present invention relates to a nucleic acid that encodes any of the above bispecific antibodies.
In any of the above embodiments, the nucleic acid molecules may be isolated.
The terms "nucleic acid", "nucleic sequence", "nucleic acid sequence", "polynucleotide", "oligonucleotide", "polynucleotide sequence" and "nucleotide sequence", used interchangeably in the present description, mean a precise sequence of nucleotides, modified or not, determining a fragment or a region of a nucleic acid, containing unnatural nucleotides or not, and being either a double-strand DNA or RNA, a single-strand DNA or RNA, or transcription products of said DNAs.
It should also be included here that the present invention does not relate to nucleotide sequences in their natural chromosomal environment, i.e. in a natural state. The sequences of the present invention have been isolated and/or purified, i.e., they were sampled directly or indirectly, for example by copying, their environment having been at least partially modified. Thus, isolated nucleic acids obtained by recombinant genetics, by means, for example, of host cells, or obtained by chemical synthesis should also be mentioned here.
A reference to a nucleotide sequence encompasses the complement thereof unless otherwise specified. Thus, a reference to a nucleic acid having a particular sequence should be understood as one which encompasses the complementary strand thereof with the complementary sequence thereof.
An "isolated" nucleic acid molecule is one which is identified and separated from at least one nucleic acid molecule-impurity, which the former is bound to in the natural source of antibody nucleic acid. An isolated nucleic acid molecule is different from the form or set in which it is found under natural conditions. Thus, an isolated nucleic acid molecule is different from a nucleic acid molecule that exists in cells under natural conditions.
In one aspect, the present invention relates to a nucleic acid molecule comprising a nucleotide sequence encoding an amino acid sequence selected from SEQ ID NOs: 1-27. A nucleic acid molecule can also comprise any combination of said nucleotide sequences.
As would be appreciated by those skilled in the art, because of the redundancy of the genetic code, a variety of different DNA sequences can encode the amino acid sequence of the light chain or heavy chain of the above bispecific antibody according to the invention or fragments thereof (VH, VL, CDR, etc.). It is well within the skill of a person trained in the art to create these alternative DNA
sequences encoding the same amino acid sequences. Such variant DNA sequences are within the scope of the present invention.
In some embodiments of the invention, the isolated nucleic acid is DNA.
A nucleic acid molecule of the invention may be isolated from any source that produces the bispecific antibody that specifically binds to CD47 and PD-L1 according to the invention. In certain embodiments of the invention, the nucleic acid molecule of the invention may be synthesized, rather than isolated.
In some embodiments of the invention, the nucleic acid is a nucleic acid that encodes the amino acid sequence of the variable domain of the heavy chain of the first antigen-binding fragment, which specifically binds to CD47, of the bispecific antibody 09-001 and includes a nucleotide sequence with SEQ ID NO: 28.
In some embodiments of the invention, the nucleic acid is a nucleic acid that encodes the amino acid sequence of the variable domain of the common light chain for the first and second antigen-binding fragments of the bispecific antibody 09-001 and includes a nucleotide sequence with SEQ ID NO: 29.
In some embodiments of the invention, the nucleic acid is a nucleic acid that encodes the amino acid sequence of the variable domain of the heavy chain of the second antigen-binding fragment, which specifically binds to PD-LI, of the bispecific antibody 09-001 and includes a nucleotide sequence with SEQ ID NO: 30.
In some embodiments of the invention, the nucleic acid is a nucleic acid that encodes the amino acid sequence of the heavy chain of the first antigen-binding fragment, which specifically binds to CD47, of the bispecific antibody 09-001 and includes a nucleotide sequence with SEQ ID NO: 31.
In some embodiments of the invention, the nucleic acid is a nucleic acid that encodes the amino acid sequence of the light chain for the first and second antigen-binding fragments of the bispecific antibody 09-001 and includes a nucleotide sequence with SEQ ID NO: 32.
In some embodiments of the invention, the nucleic acid is a nucleic acid that encodes the amino acid sequence of the heavy chain of the second anti gen -binding fragment, which specifically binds to PD-LI, of the bispecific antibody 09-001 and includes a nucleotide sequence with SEQ ID NO: 33.
The nucleic acid molecules may be used to express the bispecific antibodies according to the invention.
Expression vector
In one aspect, the present invention relates to an expression vector comprising any of the above nucleic acids. The present invention relates to a vector suitable for the expression of any of nucleotide sequences described herein.
The term "vector" as used herein means a nucleic acid molecule capable of transporting another nucleic acid to which it has been linked. In some embodiments of the invention, the vector is a plasmid, i.e. a circular double stranded piece of DNA into which additional DNA segments may be ligated. In some embodiments of the invention, the vector is a viral vector, wherein additional DNA segments may be ligated into the viral genome. In some embodiments of the invention, vectors are capable of autonomous replication in a host cell into which they are introduced (e.g. bacterial vectors having a bacterial origin site of replication and episomal mammalian vectors). In further embodiments of the invention, vectors (e.g. non-episomal mammalian vectors) may be integrated into the genome of a host cell upon introduction into a host cell, and thereby are replicated along with the host gene. Moreover, certain vectors are capable of directing the expression of genes to which they are operably linked. Such vectors are referred to herein as "recombinant expression vectors" (or simply, "expression vectors").
The present invention relates to vectors comprising the above nucleic acid molecules that encode the above bispecific antibody, or structural portions thereof selected from: a heavy chain variable domain with the amino acid sequence of SEQ ID NO: 22, a common light chain variable domain with the amino acid sequence of SEQ ID NO: 23; a heavy chain variable domain with the amino acid sequence of SEQ ID NO: 24, a heavy chain with the amino acid sequence of SEQ ID NO: 25, a common light chain with the amino acid sequence of SEQ ID NO: 26; a heavy chain with the amino acid sequence of SEQ ID NO: 27, as described herein.
Expression vectors include plasmids, retroviruses, adenoviruses, adeno-associated viruses (AAVs), plant viruses, such as cauliflower mosaic virus, tobacco mosaic virus, cosmids, YACs, EBV derived episomes, and the like. DNA molecules may be ligated into a vector such that transcriptional and translational control sequences within the vector serve their intended function of regulating the transcription and translation of the DNA. An expression vector and expression control sequences may be chosen to be compatible with the expression host cell used. DNA molecules partially or fully encoding the sequences of first and second binding domains (for example, heavy and light chain sequences where a binding domain comprises a heavy and light chain sequence) can be introduced into individual vectors. In one embodiment, any combination of said DNA molecules is introduced into the same expression vector. DNA molecules may be introduced into an expression vector by standard methods (e.g. ligation of complementary restriction sites on an antibody gene fragment and vector, or blunt end ligation if no restriction sites are present).
In some embodiments of the invention, a suitable vector is one that includes restriction sites such that any VH or VL sequence can easily be inserted and expressed, as described above. Polyadenylation and transcription termination may occur at a native chromosomal site downstream of coding regions. A
recombinant expression vector can also encode a signal peptide that facilitates secretion of an antibody chain from a host cell. An antibody chain gene may be cloned into a vector such that the signal peptide is linked in-frame to the amino terminus of an immunoglobulin chain. The signal peptide may be an immunoglobulin signal peptide or a heterologous signal peptide (i.e. a signal peptide from a non immunoglobulin protein).
In some embodiments of the invention, in addition to antibody chain genes, the recombinant vector expression of the invention can carry regulatory sequences that control the expression of antibody chain genes in a host cell. It will be understood by those skilled in the art that the design of an expression vector, including the selection of regulatory sequences, may depend on such factors as the choice of a host cell to be transformed, the level of expression of a desired protein, and so forth. Preferred control sequences for an expression host cell in mammals include viral elements that ensure high levels of protein expression in mammalian cells, such as promoters and/or enhancers derived from a retroviral LTR, cytomegalovirus (CMV) (such as a CMV promoter/enhancer), simian virus 40 (SV40) (such as a SV40 promoter/enhancer), adenovirus, (e.g. the major late promoter adenovirus (AdMLP)), polyomavirus and strong mammalian promoters such as native immunoglobulin promoter or actin promoter. Methods for expressing polypeptides in bacterial cells or fungal cells, e.g. yeast cells, are also well known in the art.
In some embodiments of the invention, in addition to antibody chain genes and regulatory sequences, the recombinant expression vectors of the invention may carry additional sequences, such as sequences that regulate replication of a vector in host cells (e.g. origins of replication) and selectable marker genes. The selectable marker gene facilitates the selection of host cells into which a vector has been introduced.
In some embodiments of the invention, the vector may include an expression control sequence. The term "expression control sequence" as used in the present description refers to polynucleotide sequences that are necessary to effect the expression and processing of coding sequences to which they are ligated. Expression control sequences include appropriate transcription initiation, termination, promoter and enhancer sequences; efficient RNA processing signals such as splicing and polyadenylation signals; sequences that stabilize cytoplasmic mRNA; sequences that enhance translation efficiency (i.e., Kozak consensus sequence); sequences that enhance protein stability; and when desired, sequences that enhance protein secretion. The nature of such control sequences differs depending upon the host organism; in prokaryotes, such control sequences generally include the promoter of ribosome binding site, and transcription termination sequences; in eukaryotes, typically, such control sequences include promoters and transcription termination sequences. The term "control sequences" includes at least all components, the presence of which is essential for expression and processing, and can also
include additional components, the presence of which is advantageous, for example, leader sequences and fusion partner sequences.
Host cell
In one aspect, the present invention relates to a method for producing a host cell for producing any of the above bispecific antibodies and includes transformation of a cell with the above expression vector.
In one aspect, the present invention relates to a host cell for producing any of the above bi specific antibodies, the host cell comprises any of the above nucleic acids.
The term "recombinant host cell" (or simply "host cell") as used herein refers to a cell into which a recombinant expression vector has been introduced. The present invention relates to host cells, which may include, for example, a vector according to the invention described above.
The present invention further relates to host cells that include, for example, a nucleotide sequence encoding the first heavy chain of the bispecific antibody according to the invention, a nucleotide sequence encoding the common light chain of the bispecific antibody according to the invention, or a nucleotide sequence encoding the second heavy chain of the bispecific antibody according to the invention, or all of the above three sequences. It should be understood that "recombinant host cell" and "host cell" refer not only to a particular subject cell but to the progeny of such a cell as well. Since modifications may occur in succeeding generations due to either mutation or environmental influences, such progeny may not, in fact, be identical to a parental cell; however, such cells are still included within the scope of the term "host cell" as used herein.
Nucleic acid molecules comprising a nucleotide sequence that encodes the amino acid sequence of the light chain or heavy chain of the above bispecific antibody, selected from: a heavy chain with the amino acid sequence of SEQ ID NO: 25, a common light chain with the amino acid sequence of SEQ ID NO: 26; a heavy chain with the amino acid sequence of SEQ ID NO: 27.
Mammalian cell lines used as hosts for transformation are well known in the art and include a plurality of immortalized cell lines available. These include, e.g., Chinese hamster ovary (CHO) cells, NSO cells, SP2 cells, HEK-293T cells, FreeStyle 293 cells (Invitrogen), NIH-3T3 cells, HeLa cells, baby hamster kidney (BHK) cells, African green monkey kidney cells (COS), human hepatocellular carcinoma cells (e.g., Hep G2), A549 cells, and a number of other cell lines. Cell lines are selected by determining which cell lines have high expression levels and provide for necessary characteristics of the protein produced. Other cell lines that may be used are insect cell lines, such as Sf9 or Sf21 cells. When the recombinant expression vectors encoding the above bispecific antibody or a portion thereof are introduced into mammalian host cells, the above bispecific antibody is produced by culturing the host
cells for a period of time sufficient to express the above bispecific antibody or a portion thereof according to the invention in the host cells, or, more preferably, secrete the above bispecific antibody into the culture medium in which the host cells are cultured. The above bispecific antibody may be isolated from culture medium using standard protein purification techniques. Plant host cells include e.g. Nicotiana , Arabidopsis , duckweed, corn, wheat, potato, etc. Bacterial host cells include Escherichia and Streptomyces species. Yeast host cells include Schizosaccharomyce pombe , Saccharomyces cerevisiae and Pichia pastoris.
Furthermore, level of production of the bispecific antibody of the invention from a producing cell line may be enhanced using a number of known techniques. For example, the glutamine synthetase gene expression system (the GS system) is a common approach for enhancing expression under certain conditions. The GS system is discussed in whole or part in connection with EP Nos. 0216846, 0256055, 0323997 and 0338841.
It is likely that the bispecific antibody of the invention in different cell lines or host cells will have different glycosylation patterns from each other. However, the bispecific antibody disclosed herein is part of this invention, regardless of the state of glycosylation of the binding molecules and, in general, regardless of the presence or absence of post-translational modifications.
The above host cell does not refer to a host cell produced using human embryos.
The above host cell does not refer to a host cell produced by modifying the genetic integrity of human germline cells.
Method of producing the antibody
In one aspect, the present invention relates to a method for producing any of the above bispecific antibodies, which comprises culturing the above host cell in a growth medium under conditions sufficient to produce said antibody, if necessary, followed by isolation and purification of the resulting antibody.
The present invention relates to methods for producing the bispecific antibodies of the present invention. One embodiment of the invention relates to a method for producing bispecific antibodies as defined herein, comprising producing a recombinant host cell capable of expressing the bispecific antibody, culturing said host cells under conditions suitable for expression of the bispecific antibodies, and isolating the resulting bispecific antibodies. The bispecific antibody produced by such expression in such recombinant host cells is referred to herein as "bispecific antibody".
Pharmaceutical compositions
In one aspect, the present invention relates to a pharmaceutical composition for treating a disease or disorder mediated by PD-L1 and CD47, the pharmaceutical combination comprising any of the above bispecific antibodies.
In one aspect, the present invention relates to a pharmaceutical composition used for treating a disease or disorder mediated by PD-L1 and CD47, which comprises any of the above bispecific antibodies in a therapeutically effective amount in combination with one or more pharmaceutically acceptable excipients.
"Pharmaceutical composition" refers to a composition comprising an antibody of the present invention and at least one of components selected from the group comprising pharmaceutically acceptable and pharmacologically compatible fillers, solvents, diluents, carriers, auxiliary, distributing and sensing agents, delivery agents, such as preservatives, stabilizers, filler, disintegrators, moisteners, emulsifiers, suspending agents, thickeners, sweeteners, flavouring agents, aromatizing agents, antibacterial agents, fungicides, lubricants, and prolonged delivery controllers, the choice and suitable proportions of which depend on the type and way of administration and dosage. Examples of suspending agents are ethoxylated isostearyl alcohol, polyoxyethene, sorbitol and sorbitol ether, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacant and their mixtures as well. Protection against action of microorganisms can be provided by various antibacterial and antifungal agents, such as, for example, parabens, chlorobutanole, sorbic acid, and similar compounds. The composition may also contain isotonic agents, such as, for example, sugars, polyols, sodium chloride, and the like. Prolonged action of the composition may be achieved by agents slowing down absorption of active ingredient, for example, aluminum monostearate and gelatine. Examples of suitable carriers, solvents, diluents and delivery agents are water, ethanol, polyalcohols and their mixtures, natural oils (such as olive oil) and organic esters (such as ethyl oleate) for injections. Examples of fillers are lactose, milk sugar, sodium citrate, calcium carbonate, calcium phosphate, and the like. Examples of disintegrators and distributors are starch, alginic acid and its salts, silicates and the like. Examples of lubricants are magnesium stearate, sodium lauryl sulfate, talc, and polyethylene glycol of high molecular weight as well. The pharmaceutical composition for peroral, sublingual, transdermal, intraocular, intramuscular, intravenous, subcutaneous, local or rectal administration of active ingredient, alone or in combination with another active compound may be administered to human and animals in a standard administration form, in a mixture with traditional pharmaceutical carriers. Suitable standard administration forms include peroral forms such as tablets, gelatin capsules, pills, powders, granules, chewing-gums and peroral solutions or suspensions; sublingual and transbuccal administration forms; aerosols; implants; local, transdermal, subcutaneous, intramuscular, intravenous, intranasal or intraocular administration forms and rectal administration forms.
The term "excipient" is used herein to describe any ingredient other than the antibody of the present invention. These are substances of inorganic or organic nature which are used in the pharmaceutical production/manufacturing in order to give drug products the necessary physicochemical properties.
In some embodiments, the compositions are intended to improve, prevent, or treat disorders that may be associated with CD47 and/or PD-L1.
The term "disease or disorder mediated by CD47 and PD-L1" refers to any disease or disorder that is either directly, or indirectly associated with CD47 and/or PD-L1, including etiology, development, progression, persistence or pathology of a disease or disorder.
“Treat”, “treating” and “treatment” refer to a method of alleviating or abrogating a biological disorder and/or at least one of its attendant symptoms. As used herein, to “alleviate” a disease, disorder or condition means reducing the severity and/or occurrence frequency of the symptoms of the disease, disorder, or condition. Further, references herein to “treatment” include references to curative, palliative and prophylactic treatment.
In one aspect, the subject of treatment, or patient, is a mammal, preferably a human subject. Said subject may be either male or female, of any age.
The term "disorder" means any condition that would benefit from treatment with the compound of the present invention. The definition includes chronic and acute disorders or diseases including those pathological conditions that predispose the mammal to the disorder in question.
“Therapeutically effective amount” refers to that amount of the therapeutic agent being administered during treatment which will relieve to some extent one or more of the symptoms of the disease being treated.
The pharmaceutical compositions of the present invention and methods of preparation thereof will be undoubtedly apparent to those skilled in the art. The pharmaceutical compositions should preferably be manufactured in compliance with the GMP (Good Manufacturing Practice) requirements. The composition may comprise a buffer composition, tonicity agents, stabilizers and solubilizers. Prolonged action of composition may be achieved by agents slowing down absorption of active pharmaceutical ingredient, for example, aluminum monostearate and gelatine. Examples of suitable carriers, solvents, diluents and delivery agents include water, ethanol, polyalcohols and their mixtures, oils, and organic esters for injections.
The term "pharmaceutically acceptable" refers to one or more compatible liquid or solid components that are suitable for administration in a mammal, preferably a human.
The terms "buffer", "buffer composition", "buffering agent" refers to a solution, which is capable of resisting changes in pH by the action of its acid-base conjugate components, and which allows the product of bispecific antibody that specifically binds to CD47 and PD-L1 according to the present
invention to resist changes in pH. Generally, the pharmaceutical composition preferably has a pH in the range from 4.0 to 8.0. Examples of buffers used include, but are not limited to, acetate, phosphate, citrate, histidine, succinate, etc. buffer solutions.
The terms "tonic agent", "osmolyte" or "osmotic agent", as used herein, refer to an excipient that can increase the osmotic pressure of a liquid antibody formulation. "Isotonic" drug is a drug that has an osmotic pressure equivalent to that of human blood. Isotonic drugs typically have an osmotic pressure from about 250 to 350 mOsm/kg. Isotonic agents used include, but are not limited to, polyols, saccharides and sucrose, amino acids, metal salts, for example, sodium chloride, etc.
"Stabilizer" refers to an excipient or a mixture of two or more excipients that provide the physical and/or chemical stability of the active agent. Stabilizers may be amino acids, for example, but not limited to, arginine, histidine, glycine, lysine, glutamine, proline; surfactants, for example, but not limited to, polysorbate 20 (trade name: Tween 20), polysorbate 80 (trade name: Tween 80), polyethylene- polypropylene glycol and copolymers thereof (trade names: Poloxamer, Pluronic, sodium dodecyl sulfate (SDS); antioxidants, for example, but not limited to, methionine, acetylcysteine, ascorbic acid, monothioglycerol, sulfurous acid salts, etc.; chelating agents, for example, but not limited to, ethylenediaminetetraacetic acid (EDTA), diethylenetriaminepentaacetic acid (DTP A), sodium citrate, etc.
The pharmaceutical composition according to the invention is a stable composition.
The pharmaceutical composition is "stable" if the active agent retains physical stability and/or chemical stability and/or biological activity thereof during the specified shelf life at storage temperature, for example, of 2-8 °C. Preferably, the active agent retains both physical and chemical stability, as well as biological activity. Storage period is adjusted based on the results of stability test in accelerated or natural aging conditions.
A pharmaceutical composition according to the invention may be manufactured, packaged, or widely sold in the form of a single unit dose or a plurality of single unit doses in the form of a ready formulation. The term "single unit dose" as used herein refers to discrete quantity of a pharmaceutical composition containing a predetermined quantity of an active ingredient. The quantity of the active ingredient typically equals the dose of the active ingredient to be administered in a subject, or a convenient portion of such dose, for example, half or a third of such dose.
The pharmaceutical compositions according to the present invention are typically suitable for parenteral administration as sterile formulations intended for administration in a human body through the breach in skin or mucosal barriers, bypassing the gastrointestinal tract by virtue of injection, infusion and implantation. In particular, it is contemplated that parenteral administration includes, inter alia, subcutaneous, intraperitoneal, intramuscular, intravenous, intraarterial, intrathecal, intraventricular, intraurethral, intracranial, intrasynovial, transdermal injection or infusion, and kidney dialytic infusion
techniques. Intra-tumor delivery, for example, intra-tumor injection, may also be employed. Regional perfusion is also contemplated. Preferred embodiments include intravenous and subcutaneous routes.
Any method for administering peptides, proteins or antibodies which is accepted in the art may be suitably employed for the bispecific antibody that specifically binds to CD47 and PD-L1 according to the invention.
Injectable formulations may be prepared, packaged, or sold, without limitation, in unit dosage form, such as in ampoules, vials, in plastic containers, pre-filled syringes, autoinjection devices. Formulations for parenteral administration include, inter alia, suspensions, solutions, emulsions in oily or aqueous bases, pastes, and the like.
In another embodiment, the invention provides a composition for parenteral administration comprising a pharmaceutical composition which is provided in dry (i.e. powder or granular) form for reconstitution with a suitable base (e.g. sterile pyrogen-free water) prior to administration. Such medicinal formulation may be prepared by, for example, lyophilization, i.e. a process, which is known in the art as freeze drying, and which involves freezing a product followed by removal of solvent from frozen material.
The bispecific antibody that specifically binds to CD47 and PD-L1 according to the invention can also be administered intranasally or by inhalation, either alone, as a mixture with a suitable pharmaceutically acceptable excipient from an inhaler, such as a pressurised aerosol container, pump, spray, atomiser, or nebuliser, wherein a suitable propellant is used or not used, or as nasal drops, or spray.
Medicinal formulations for parenteral administration may be formulated to be immediate or modified release. Modified release medicinal formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.
In one aspect, the present invention relates to a pharmaceutical composition for treating a disease or disorder mediated by PD-L1 and CD47, the pharmaceutical combination comprising any of the above bispecific antibodies and at least one other therapeutically active compound.
In some embodiments of the pharmaceutical composition, the disease or disorder mediated by PD-L1 and CD47 is selected from the group: triple-negative breast cancer (TNBC), head and neck cancer (HNC), gastric cancer (GC), esophagogastric junction cancer, lung adenocarcinoma, non-small cell lung cancer, small cell lung cancer, acute myeloid leukemia, myelodysplastic syndrome, high microsatellite instability malignant neoplasm, multiple myeloma, ovarian cancer, renal cell carcinoma, bladder cancer, cervical cancer.
In some embodiments of the pharmaceutical composition, the other therapeutically active compound is an antibody, chemotherapeutic agent, hormone therapy agent, or any combination thereof.
In some embodiments of the pharmaceutical composition, the chemotherapeutic agent is selected from the group comprising docetaxel, paclitaxel, doxorubicin, platinum agents, carboplatin, 5- fluorouracil, tyrosine kinase inhibitors, axitinib, liposomal doxorubicin, liposomal paclitaxel or any combination thereof.
In some embodiments of the pharmaceutical composition, the other therapeutically active compound is an antibody that specifically binds to HER2 (human epidermal growth factor receptor 2).
In some embodiments of the pharmaceutical composition, the therapeutically active compound is trastuzumab.
In some embodiments of the pharmaceutical composition, the other therapeutically active compound is trastuzumab and a chemotherapeutic agent that is selected from the group comprising docetaxel, paclitaxel, doxorubicin, platinum agents, carboplatin, 5-fluorouracil, tyrosine kinase inhibitors, axitinib, liposomal doxorubicin, liposomal paclitaxel or any combination thereof.
Therapeutic use of the bispecific antibody that specifically binds to CD 47 and PD-L1
In one aspect, the bispecific antibody that specifically binds to CD47 and PD-L1 is used in the treatment of disorders mediated by CD47 and PD-L1 activity.
In one aspect, the subject of treatment, or patient, is a mammal, preferably a human subject. Said subject may be either male or female, of any age.
In the case of a tumor (for example, cancer), the therapeutically effective amount of the bispecific antibody that specifically binds to CD47 and PD-L1 may reduce the number of cancer cells; reduce the initial tumor size; inhibit (i.e., slow to some extent and preferably stop) cancer cell infiltration into peripheral organs; inhibit (i.e., slow to some extent and preferably stop) tumor metastasis; inhibit, to some extent, tumor growth; and/or relieve to some extent one or more of the symptoms associated with the disorder. The bispecific antibody of the invention may to some extent prevent growth and/or kill existing cancer cells, it may be cytostatic and/or cytotoxic. For cancer therapy, in vivo efficacy can, for example, be measured by assessing survival, time to tumor progression (TTP), tumor response rate to treatment (RR), duration of response and/or quality of life.
The uses or methods used herein relating to the bispecific antibody that specifically binds to CD47 and PD-L1 with one or more other therapeutic agents are contemplated to mean, refer to and include the following:
1) simultaneous administration of such combination of the bispecific antibody that specifically binds to CD47 and PD-L1 and a therapeutic agent to a patient in need of treatment, when such components are formulated together into a single dosage form which releases said components at substantially the same time to said patient,
2) simultaneous administration of such combination of the bispecific antibody that specifically binds to CD47 and PD-L1 and a therapeutic agent to a patient in need of treatment, when such components are formulated apart from each other into separate dosage forms which are taken at substantially the same time by said patient, whereupon said components are released at substantially the same time to said patient,
3) sequential administration of such combination of the bispecific antibody that specifically binds to CD47 and PD-L1 and a therapeutic agent to a patient in need of treatment, when such components are formulated apart from each other into separate dosage forms which are taken at consecutive times by said patient with a significant time interval between each administration, whereupon said components are released at substantially different times to said patient; and
4) sequential administration of such combination of the bispecific antibody that specifically binds to CD47 and PD-L1 and a therapeutic agent to a patient in need of treatment, when such components are formulated together into a single dosage form which releases said components in a controlled manner, whereupon they are concurrently, consecutively, or jointly released at the same and/or different times to said patient, where each portion may be administered by either the same or different routes.
The bispecific antibody that specifically binds to CD47 and PD-L1 may be administered without further therapeutic treatment, i.e., as an independent therapy.
In one aspect, the present invention relates to a method for inhibiting the biological activity of PD-L1 and CD47 in a subject in need of such inhibition, which comprises administering to the subject an effective amount of any of the above bispecific antibodies.
In one aspect, the present invention relates to a method for treating a disease or disorder mediated by PD-L1 and CD47, which comprises administering to a subject in need of such treatment any of the above bispecific antibodies or any of the above pharmaceutical compositions in a therapeutically effective amount.
In one aspect, the present invention relates to a method for treating a disease or disorder mediated by PD-L1 and CD47, which comprises administering to a subject in need of such treatment any of the above bispecific antibodies and at least one other therapeutically active compound.
In some embodiments of the method of treatment, the disease or disorder mediated by PD-L1 and CD47 is selected from the group: triple-negative breast cancer (TNBC), head and neck cancer (HNC), gastric cancer (GC), esophagogastric junction cancer, lung adenocarcinoma, non-small cell lung cancer, small cell lung cancer, acute myeloid leukemia, myelodysplastic syndrome, high microsatellite instability malignant neoplasm, multiple myeloma, ovarian cancer, renal cell carcinoma, bladder cancer, cervical cancer.
In some embodiments of the method of treatment, the other therapeutically active compound is an antibody, chemotherapeutic agent, hormone therapy agent, or any combination thereof.
A "chemotherapeutic agent" is a chemical compound useful in the treatment of a malignant neoplasm. Examples of chemotherapeutic agents include alkylating agents such as thiotepa and cyclosphosphamide (CYTOXAN®); alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines including altretamine, triethylenemelamine, trietylenephosphoramide, triethiylenethiophosphoramide and trimethylmelamine; acetogenins (e.g. bullatacin and bullatacinone); delta-9-tetrahydrocannabinol (dronabinol MARINOL®); beta-lapachone; lapachol; colchicines; betulinic acid; camptothecin (including the synthetic analogue topotecan (HYCAMTIN®), CPT-11 (irinotecan, CAMPTOSAR®), acetylcamptothecin, scopolectin, and 9-aminocamptothecin); bryostatin; cally statin; CC-1065 (including its adozelesin, carzelesin and bizelesin synthetic analogues); podophyllotoxin; podophyllinic acid; teniposide; cryptophycins (e.g. cryptophycin 1 and cryptophycin 8); dolastatin; duocarmycin (including the synthetic analogues, KW-2189 and CB1-TM1); eleutherobin; pancrati statin; sarcodictyin; spongistatin; nitrogen mustards such as chlorambucil, chlornaphazine, cholophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimnustine; antibiotics such as the enediyne antibiotics (e.g. calicheamicin, e.g. calicheamicin gamma II and calicheamicin omega II (see, e.g. Agnew, Chem. Inti. Ed. Engl., 33: 183-186 (1994)); dynemicin, including dynemicin A; esperamicin; as well as neocarzinostatin chromophore and related chromoprotein enediyne antibiotic chromophores), aclacinomysins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, carabicin, carminomycin, carzinophilin, chromomycins, dactinomycin, daunorubicin, detorubicin, 6- diazo-5-oxo-L-norleucine, doxorubicin (including ADRIAMYCIN®, morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin, doxorubicin HC1 liposome injection (DOXOL®), liposomal doxorubicin TLC D-99 (MYOCET®), peglylated liposomal doxorubicin (CAELYX®), and deoxydoxorubicin), epirubicin, esorubicin, idarubicin, marcellomycin, mitomycins such as mitomycin C, mycophenolic acid, nogalamycin, olivomycins, peplomycin, potfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; anti-metabolites such as methotrexate, gemcitabine (GEMZAR®), tegafur (UFTORAL®), capecitabine (XELODA®), epothilone, and 5-fluorouracil (5-FU); folic acid analogues such as denopterin, methotrexate, pteropterin,trimetrexate; purine analogs such as fludarabine, 6- mercaptopurine, thiamiprine, thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6- azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine; anti-adrenals such as aminoglutethimide, mitotane, trilostane; folic acid replenisher such as folinic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; eniluracil; amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elfomithine; elliptinium acetate; etoglucid; gallium
nitrate; hydroxyurea; lentinan; lonidainine; maytansinoids such as maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidanmol; nitraerine; pentostatin; phenamet; pirarubicin; losoxantrone; 2-ethylhydrazide; procarbazine; PSK® polysaccharide complex (JHS Natural Products, Eugene, OR); razoxane; rhizoxin; sizofiran; spirogermanium; tenuazonic acid; triaziquone; 2, 2', 2"- trichlorotriethylamine; trichothecenes (e.g., T-2 toxin, verracurin A, roridin A and anguidine); urethan; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside ("Ara-C"); thiotepa; taxoid, e.g., paclitaxel (TAXOL®), albumin-engineered nanoparticle formulation of paclitaxel (ABRAXANE), and docetaxel (TAXOTERE®); chlorambucil; 6-thioguanine; mercaptopurine; methotrexate; platinum agents such as cisplatin, oxaliplatin, and carboplatin; vinca alkaloids, which prevent tubulin polymerization from forming microtubules, including vinblastine (VELBAN®), vincristine (ONCOVIN®), vindesine (ELDISINE®), FILDESIN®), and vinorelbine (NAVELBINE®); etoposide (VP- 16); ifosfamide; mitoxantrone; leucovorin; novantrone; edatrexate; daunomycin; aminopterin; ibandronate; topoisomerase inhibitor RFS 2000; difluorometlhylornithine (DMFO); retinoids such as retinoic acid, including bexarotene (TARGRETIN®); biphosphonates such as clodronate (for example, BONEFOS® or OSTAC®), etidronate (DIDROCAL®), NE- 58095, zoledronic acid/zoledronate (ZOMETA®), alendronate (FOSAMAJX®), pamidronate (AREDIA®), tiludronate (SKELID®), or risedronate (ACTONEL®); troxacitabine (1,3-dioxolane nucleoside cytosine analog); antisense oligonucleotides, e.g. those that inhibit expression of genes in signaling pathways implicated in aberrant cell proliferation, such as for example, PKC-alpha, Raf, H-Ras, and epidermal growth factor receptor (EGF-R); vaccines such as THERATOPE® vaccine and gene therapy vaccines, for example, ALLOVECTIN® vaccine, LEUVECTIN® vaccine, and VAXID® vaccine; topoisomerase 1 inhibitor (e.g. LURTOTECAN®); rrnRH (e.g., ABARELIX®); BAY439006 (sorafenib; Bayer); SU-11248 (Pfizer); perifosine, COX-2 inhibitor (e.g. celecoxib or etoricoxib), proteosome inhibitor (e.g. PS341); bortezomib (VELCADE®); CCI-779; tipifarnib (811577); orafenib, ABT510; Bcl-2 inhibitor such as oblimersen sodium (GENASENSE®); pixantrone; EGFR inhibitors (see definition below); tyrosine kinase inhibitors (see definition below); and pharmaceutically acceptable salts, acids or derivatives of any of the above; as well as combinations of two or more of the above such as CHOP, an abbreviation for a combined therapy of cyclophosphamide, doxorubicin, vincristine, and prednisolone, and FOLFOX, an abbreviation for a treatment regimen with oxaliplatin (ELOXATINTM) combined with 5-FU and leucovovin.
Hormonal agents are agents that act to regulate or inhibit hormone action on tumors. Examples of such agents are anti -estrogens with mixed agonist/antagonist profile, including, tamoxifen (NOLVADEX®), 4-hydroxytamoxifen, toremifene (FARESTON®), idoxifene, droloxifene, raloxifene (EVTSTA®), trioxifene, keoxifene, and selective estrogen receptor modulators (SERMs), such as SERM3; pure anti-estrogens without agonist properties, such as fulvestrant (FASLODEX®), and
EM800 (such agents may block estrogen receptor (ER) dimerization, inhibit DNA binding, increase ER turnover, and/or suppress ER levels); aromatase inhibitors, including steroidal aromatase inhibitors, such as formestane and exemestane (AROMASIN®), and nonsteroidal aromatase inhibitors, such as anastrazole (AREVIIDEX®), letrozole (FEMARA®) and aminoglutethimide, and other aromatase inhibitors including vorozole (RIVISOR®), megestrol acetate (MEGASE®), fadrozole, imidazole; lutenizing hormone-releasing hormone agonists, including leuprolide (LEIPRON® and ELIGARD®), goserelin, buserelin, and tripterelin; sex steroids, including progestines, such as megestrol acetate and medroxyprogesterone acetate, estrogens, such as diethylstilbestrol and premarin, and androgens/retinoids such as fluoxymesterone, all transretionic acid and fenretinide; onapristone; anti- progesterones; estrogen receptor down-regulators (ERDs); anti-androgens, such as flutamide, nilutamide and bicalutamide; testolactone; and pharmaceutically acceptable salts, acids or derivatives of any of the above; as well as combinations of two or more of the above.
In some embodiments of the method of treatment, the chemotherapeutic agent is selected from the group comprising docetaxel, paclitaxel, doxorubicin, platinum agents, carboplatin, 5-fluorouracil, tyrosine kinase inhibitors, axitinib, liposomal doxorubicin, liposomal paclitaxel or any combination thereof.
In some embodiments of the method of treatment, the other therapeutically active compound is an antibody that specifically binds to HER2 (human epidermal growth factor receptor 2).
In some embodiments of the method of treatment, the other therapeutically active compound is trastuzumab.
In some embodiments of the method of treatment, the other therapeutically active compound is trastuzumab and a chemotherapeutic agent that is selected from the group comprising docetaxel, paclitaxel, doxorubicin, platinum agents, carboplatin, 5-fluorouracil, tyrosine kinase inhibitors, axitinib, liposomal doxorubicin, liposomal paclitaxel or any combination thereof.
In one aspect, the present invention relates to the use of any of the above bi specific antibodies or any of the above pharmaceutical compositions for treating a disease or disorder mediated by PD-L1 and CD47 in a subject in need of such treatment.
In one aspect, the present invention relates to the use of any of the above bispecific antibodies and at least one other therapeutically active compound for treating a disease or disorder mediated by PD- L1 and CD47 in a subject in need of such treatment.
In some embodiments of the use, the disease or disorder mediated by PD-L1 and CD47 is selected from the group: triple-negative breast cancer (TNBC), head and neck cancer (HNC), gastric cancer (GC), esophagogastric junction cancer, lung adenocarcinoma, non-small cell lung cancer, small cell lung cancer, acute myeloid leukemia, myelodysplastic syndrome, high microsatellite instability malignant neoplasm, multiple myeloma, ovarian cancer, renal cell carcinoma, bladder cancer, cervical cancer.
In some embodiments of the use, the other therapeutically active compound is an antibody, chemotherapeutic agent, hormone therapy agent, or any combination thereof.
In some embodiments of the use, the chemotherapeutic agent is selected from the group comprising docetaxel, paclitaxel, doxorubicin, platinum agents, carboplatin, 5-fluorouracil, tyrosine kinase inhibitors, axitinib, liposomal doxorubicin, liposomal paclitaxel or any combination thereof.
In some embodiments of the use, the other therapeutically active compound is an antibody that specifically binds to HER2 (human epidermal growth factor receptor 2).
In some embodiments of the use, the other therapeutically active compound is trastuzumab.
In some embodiments of the use, the other therapeutically active compound is trastuzumab and a chemotherapeutic agent that is selected from the group comprising docetaxel, paclitaxel, doxorubicin, platinum agents, carboplatin, 5-fluorouracil, tyrosine kinase inhibitors, axitinib, liposomal doxorubicin, liposomal paclitaxel or any combination thereof.
In some embodiments of the method of treatment, the bispecific antibody that specifically binds to CD47 and PD-L1 according to the invention is used in combination with paclitaxel or docetaxel or doxorubicin or variants thereof or with carboplatin for treating locally advanced or metastatic triple negative breast cancer (TNBC) with tumors that express PD-L1 or CD47, as first-line therapy.
In some embodiments of the method of treatment, the bispecific antibody that specifically binds to CD47 and PD-L1 according to the invention is used as monotherapy or in combination with chemotherapy including a platinum agent and 5-fluorouracil (5-FU) for treating locally advanced or metastatic head and neck cancer (HNC), as first-line therapy.
In some embodiments of the method of treatment, the bispecific antibody that specifically binds to CD47 and PD-L1 according to the invention is used in combination with standard chemotherapy and/or trastuzumab for treating locally advanced or metastatic gastric cancer (GS) or esophagogastric junction cancer with tumors that express HER2 or PD-L1, following 2 or more lines of standard therapy.
In some embodiments of the method of treatment, the bispecific antibody that specifically binds to CD47 and PD-L1 according to the invention is used in combination with tyrosine kinase inhibitors (for example, axitinib or another product) for treating locally advanced or metastatic renal cell carcinoma with tumors that express CD47, as first-line therapy.
In some embodiments of the method of treatment, the bispecific antibody that specifically binds to CD47 and PD-L1 according to the invention is used in combination with chemotherapy including a platinum agent and paclitaxel or variants thereof for treating locally advanced or metastatic cervical cancer with tumors that express CD47, as first-line therapy.
Doses and routes of administration
The bispecific antibody that specifically binds to CD47 and PD-L1 according to the invention will be administered in an amount that is effective in treatment of the condition in question, i.e. in doses and during the periods of time required to achieve the desired result. A therapeutically effective amount may vary according to factors such as the particular condition being treated, the age, sex and weight of the patient, and whether the bispecific antibody that specifically binds to CD47 and PD-L1 according to the invention is being administered as a stand-alone treatment or in combination with one or more additional drugs or treatments.
Dosage regimens may be adjusted to provide the optimum desired response. For example, a single bolus may be administered, several divided doses may be administered over time or the dose may be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation. It is especially advantageous to formulate parenteral compositions in a unit dosage form for ease of administration and uniformity of dosage. A unit dosage form as used herein refers to physically discrete units suited as unitary dosages for patients/subjects to be treated; each unit contains a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the desired pharmaceutical carrier. Specification for the unit dosage forms of the invention is typically dictated by and directly dependent on (a) the unique characteristics of a therapeutic agent and particular therapeutic or prophylactic effect to be achieved, and (b) the limitations inherent in the art of compounding such an active compound for the treatment of sensitivity in subjects.
Thus, a skilled artisan would appreciate, based upon the disclosure provided herein, that the doses and dosage regimen are adjusted in accordance with methods well-known in the therapeutic arts. That is, the maximum tolerable dose can be readily established, and the effective amount providing a detectable therapeutic effect to a patient may also be determined, as can the temporal requirements for administering each agent to provide a detectable therapeutic effect to a patient. Thus, while certain doses and administration regimens are exemplified herein, these examples in no way limit the doses and administration regimens that may be provided to a patient in practicing the embodiments of the invention.
It is to be noted that dosage values may vary with the type and severity of the condition to be alleviated, and may include single or multiple doses. Furthermore, it is to be understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the judgment of a medical professional administering or supervising the administration of the bispecific antibody, and that dosage ranges set forth in the present description are exemplary only and are not intended to limit the scope or practice of the claimed bispecific antibodies. Furthermore, the dosage regimen with the compositions of the present invention can be based on various factors, including the type of a disease, age, weight, gender, patient's health condition, severity of a condition, route of administration of the bispecific antibody that specifically binds to CD47 and PD-L1 according to this
invention. Thus, the dosage regimen may vary widely, but can be determined routinely using standard methods. For example, doses may be adjusted based on pharmacokinetic and pharmacodynamic parameters, which may include clinical effects such as toxic effects or laboratory values. Thus, the present invention encompasses intra-patient dose-escalation as determined by one skilled in the art. Methods for determining appropriate dosage and regimen are well-known in the art and would be understood by a skilled artisan once provided the ideas disclosed herein.
Examples of suitable administration methods are provided above.
It is believed that a suitable dose of the bispecific antibody that specifically binds to CD47 and PD-L1 according to the invention will be in the range of 0.1-200 mg/kg, preferably 0.1-100 mg/kg, including about 0.5-50 mg/kg, for example about 1-20 mg/kg. The bispecific antibody that specifically binds to CD47 and PD-L1 according to the invention may be administered, e.g. in a dose of at least 0.25 mg/kg, such as at least 0.5 mg/kg, including at least 1 mg/kg, e.g. at least 1.5 mg/kg, such as at least 2 mg/kg, e.g. at least 3 mg/kg, including at least 4 mg/kg, e.g. at least 5 mg/kg; and for example up to a maximum of 50 mg/kg, including up to a maximum of 30 mg/kg, e.g. up to a maximum of 20 mg/kg, including up to a maximum of 15 mg/kg. The administration will typically be repeated in appropriate time intervals, such as once a week, once every two weeks, once every three weeks or once every four weeks, and for as long as deemed appropriate by a responsible physician, who may, in some cases, increase or reduce the dose if necessary.
Examples
The following examples are provided for better understanding of the invention. These examples are for purposes of illustration only and are not to be construed as limiting the scope of the invention in any manner.
All publications, patents, and patent applications cited in this specification are incorporated herein by reference. Although the foregoing invention has been described in detail by way of illustration and example for purposes of clarity of understanding, it will be readily apparent to those of ordinary skill in the art in light of the teachings of this invention that certain changes and modifications may be made thereto without departing from the spirit or scope of the appended embodiments.
Materials and general methods
General information regarding the nucleotide sequences of human immunoglobulin light and heavy chains is given in: Kabat, E.A., et ah, Sequences of Proteins of Immunological Interest, 5th ed., Public Health Service, National Institutes of Health, Bethesda, MD (1991). Amino acids of antibody chains are numbered according to EU numbering (Edelman, G.M., et ah, Proc. Natl. Acad. Sci. USA 63
(1969) 78-85; Kabat, E.A., et al., Sequences of Proteins of Immunological Interest, 5th ed., Public Health Service, National Institutes of Health, Bethesda, MD, (1991).
Recombinant DNA techniques
Standard methods were used to manipulate DNA as described in Sambrook, J. et al, Molecular cloning: A laboratory manual; Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York, 1989. The molecular biological reagents were used according to the manufacturer protocols.
Gene synthesis
Desired gene segments were prepared from oligonucleotides made by chemical synthesis. The gene segments of 300-1400 bp long, which were flanked by singular restriction sites, were assembled by annealing and ligation of oligonucleotides including PCR amplification and subsequently cloned via the restriction sites. The DNA sequences of the subcloned gene fragments were confirmed by DNA sequencing.
DNA sequence determination
DNA sequences were determined by Sanger sequencing.
DNA and protein sequence analysis and sequence data management
The Unipro's UGENE suite version 1.29 and SnapGene Viewer were used for sequence creation, mapping, analysis, annotation and illustration.
Expression vectors
For the expression of the antibodies described in the application materials, variants of expression plasmids intended for expression of antibodies in prokaryotic cells (E.coli), transient expression in eukaryotic cells (e.g., in CHO cells) were applied. Beside the antibody expression cassette, the vectors contained: an origin of replication which allows replication of said plasmid in E. coli , genes which confer resistance in E. coli to various antibiotics (e.g. to ampicillin, kanamycin).
The fusion genes comprising the described antibody chains as described below were generated by PCR and/or gene synthesis and assembled with known recombinant methods and techniques by connection of the according nucleic acid segments, e.g. using unique restriction sites in the corresponding vectors. The subcloned nucleic acid sequences were verified by DNA sequencing. For transient transfections, larger quantities of the plasmids were prepared by plasmid preparation from transformed E. coli cultures.
Example 1. Synthesis of genetic constructs
Sequences of an anti gen -binding fragment in scFv format from candidate BCD 106-02-001 (EA201791961A1) were recloned into Fab.
To this end, we generated PCR products comprising the genes of heavy chain variable domains of the antibody, with primers comprising restriction sites.
The resulting heavy chain variable domains were cloned into the vector pEE HCknobLALA at Sal I / Nhe I restriction sites.
As a result, the plasmid pEE_HCknobLALA_VH_CD47 (Figure 1) was produced.
The plasmid pEE HCholeLALA VH PD-Ll was produced by recloning the variable fragment in pEE HCholeLALA at Sal I / Nhe I restriction sites (Figure 3).
The common light chain for the first and second antigen-binding fragments was produced using the plasmid pEE CLC (Figure 2).
Antibody 09-001 was produced using plasmids shown in Table 1.
Table 1. Plasmids for producing antibody 09-001.
Example 2. Production and purification of antibody 09-001
Full-length antibodies 09-001 were produced in established cell line cells obtained from Chinese hamster ovary cells (CHO-T line). The cells were cultured in a serum-free medium HyCell TransFx-C by HyClone supplemented with 8 mM L-Glutamine and 1 g/1 Pluronic 68 in baffled flasks on orbital incubator shakers at a temperature of +37°C, humidity of 70% and in the presence of 5% CO2 at 150 rpm. The cells were passaged every 3-4 days at a density of 0.3*106 cells/ml.
The day before transfection, cells from day 3 were inoculated at a density of 0.9* 106 cells/ml. Transient transfection was performed at a concentration of 1.9-2.1*106 cells/ml. RPMI-1640 medium was employed to prepare the transfection mixture. In 5% of the total volume of the RPMI-1640 seed material, we diluted separately plasmids at a load of 0.75 pg/ml and transfection reagent polyethylenimine (PEI), at DNA:PEI ratio of 1:7 by weight. The mixture was prepared using the cotransfection vector E2.60 encoding the protein production enhancer XBP-1S and the cotransfection vector E2.13 encoding RFP, 5% of the total DNA load per reaction. Target plasmids were used in an equal ratio. Plasmids and PEI diluted in RPMI-1640 were combined and incubated for 10 minutes, thereafter the transfection mixture was introduced to the cells. Suspension cultivation was carried out in 1000 ml baffled flasks on orbital incubator shakers at +370 C, in the presence of 5% CO2 and humidity of 70%, at 150 rpm. The next day following transfection, 30% Trypton up to 1% concentration and 200
mM L-Glutamine up to 4 mM were added to the cells and fluorescence parameters were measured on a Guava flow cytometer to assess the transfection efficiency by the expression of fluorescent protein. On day 2 following transfection, the culture fluid was transferred to 2000 ml baffled flasks, and then 12% Boost 4 to 0.4% concentration and BalanCD Growth A in a volume equal to inoculant were added. The resulting product for antibody 09-001 was removed on day 10 day of culturing. The culture liquid was filtered through a filter module with 0.22 pm pore size, and then the protein concentration was measured on ForteBio.
Antibody 09-001 was isolated from the culture fluid and purified using a column with Protein A affinity chromatography sorbent. Cleared culture liquid was passed through a column at a load of 10-20 mg of protein per 1 ml of sorbent, which was pre-equilibrated with phosphate buffered saline (PBS, pH 7.4). The column was then washed with PBS to remove non-specifically binding components. Bound antibodies were eluted using 0.1 M glycine buffer (pH 3.5). Collected eluate was exposed to acidic pH for 30 min for the purpose of viral inactivation, and then neutralized with 1M Tris-HCl solution to pH 7.0. The protein was then transferred to 20 mM acetate buffer pH 5.0 using dialysis cassettes to conduct additional purification on SP Sepharose HP cation-exchange sorbent in order to remove aggregates and fragments of antibodies. The column with sorbent was equilibrated with 20 mM acetate buffer pH 5.0. The antibodies were then applied onto the column at a load of 10-20 mg of protein per 1 ml of sorbent. The antibodies bound to sorbent were eluted in a salt gradient using a solution of 20 mM NaAcO + 1 M NaCl pH 5.0. Following purification, the protein was transferred to a 20 mM acetate buffer (pH 5.0) supplemented with 100 mM trehalose using dialysis cassettes, filtered through 0.22 pm Millex GP, transferred to test tubes and stored at -70 °C.
Polyacrylamide gel electrophoresis and size-exclusion HPLC were used to monitor the purity of the candidates. Electrophoresis was performed in 7.5% polyacrylamide gel under denaturing non-reducing conditions (Figure 4, Figure 5) and in 12% polyacrylamide gel under denaturing reducing conditions (Figure 6). The protein purity was determined by the intensity of band staining at a protein load of 40 pg per lane. Size-exclusion HPLC was performed in a mobile phase of 0.05M NaHiPCri, 0.3 M NaCl pH=7.0. Results for antibody 09-001 production are shown in Table 2.
Table 2. Summary table for antibody 09-001 production.
Example 3. Determination of affinity of antibody 09-001 on Forte Bio Octet RED 384 to human CD47 antigen
The affinity of the interaction between antibody 09-001 and the human CD47 antigen was studied by bio-layer interferometry on the Octet Red384 instrument (ForteBio). The CD47-FcLama antigen was used for the study.
The study was conducted using covalent immobilization of protein (antigens) on AR2G biosensors (Amine Reactive Second-Generation (AR2G) Biosensors, ForteBio). The kinetic constants experiment consisted of the following main steps: activating sensors, loading protein onto sensors, quenching unreacted activated groups, recording baselines, recording analyte association, recording dissociation. The sensors were activated in an aqueous solution comprising 20 mM EDC and 10 mM sNHS for 300 s. The antigen was loaded onto the surface of biosensors in a sodium -acetate buffer with a pH 5.0 for 300 s. The loading protein concentration was 20 pg/ml for the human CD47 antigen (CD47- FcLama). Unreacted active centers on the sensor surfaces were quenched in 1M aqueous solution of ethanolamine with pH 8.5 for 300 s. To check the nonspecific interaction between the analyte and the sensors, we used an antigen-free sensor (at the loading step, the sensor was immersed in sodium acetate buffer with pH 5.0; all other steps are similar to those used for the sensor loaded with antigen). The baseline and all subsequent steps of the experiment were carried out in a kinetic buffer. At the association step (step duration was 300 s), sensors with loaded protein were immersed into wells with a solution of analyte (antibody 09-001) prepared in a kinetic buffer. 3 concentrations of antibodies were selected for analysis as follows: 68.9 nM, 34.4 nM, 17.2 nM. At the dissociation step (step duration was 600 s), the sensors were immersed into wells with a kinetic buffer, in which the baseline was recorded. The measurements were carried out at a temperature of 30 °C; we employed tangential stirring at 1000 rpm in all steps. The reference sensors went through all the steps as the sensors used to record analyte sensograms did, with the exception of the association step - at the association step, the sensors were immersed in a kinetic buffer without analyte (the reference sensor signals were measured in parallel with the recording of the main sensograms). The reference signal was subtracted from the signal received on sensors interacting with the analyte during the processing of sensograms.
Following measurement, the sensors were regenerated in 10 mM glycine solution with HC1 (pH 1.8) to remove bound antibodies (3 regeneration cycles - 5 s regeneration, followed by 5 s neutralization in kinetic buffer). Then the baseline, association, dissociation and regeneration steps were repeated. A total of 4 sets of sensograms were produced as follows: 1 set before regeneration and 3 sets following regeneration. No significant effect of regeneration on the constant values was revealed, therefore, we obtained average values for three measurements following regeneration.
To obtain numerical values of kinetic constants (kon is the on/association rate constant, kdis is the dissociation rate constant, KD is the equilibrium dissociation constant), the resulting sensograms
were processed according to the 1 : 1 interaction model using Global Fit (selection of one set of kon, kdis, KD constants to analyze several sensograms of different concentrations) of the ForteBio Octet Data Analysis 9.0 software. The results are shown in Table 3.
Table 3. Results of kinetic analysis of final candidates in interaction with human CD47 antigen.
Conclusion
Antibody 09-001 interacts with the human CD47 antigen, the KD value is 83 nM.
Example 4. Determination of affinity of antibody 09-001 on Forte Bio Octet RED 384 to human CD47 antigen
The study was conducted similarly to that described in Example 3. 3 sets of sensograms were obtained. The final kon, kdis, KD values were obtained by averaging these values from three measurements. The results are shown in Table 4.
Table 4. Results of kinetic analysis of antibody 09-001 in interaction with human PD-L1 antigen.
Conclusion
Antibody 09-001 interacts with the human PD-L1 antigen with an affinity of approximately 3 nM.
Example 5. Determination of affinity of antibody 09-001 on Forte Bio Octert RED 384 to cynomolgus monkey CD47 antigen
The affinity of the interaction between antibody 09-001 and the cynomolgus CD47 antigen was studied by bio-layer interferometry on the Octet Red384 instrument (ForteBio). The cynomolgus CD47 antigen (cynoCD47(ARCO), ARCO BioSystems, Cat. No.: CD7-C5252; Cynomolgus / Rhesus macaque CD47 Protein, Fc Tag) was employed for the study.
The study was conducted similarly to that described in Example 3. 3 sets of sensograms were obtained. The final kon, kdis, KD values were obtained by averaging these values from three measurements. The results are shown in Table 5.
Table 5. Results of kinetic analysis of final candidates in interaction with cynomolgus CD47 antigen.
Conclusion
Antibody 09-001 interacts with the cynomolgus CD47 antigen (cynoCD47(ARCO)), the KD value is 57 nM.
Example 6. Test of simultaneous interaction between two PD-L1 and CD47 antigens and antibody 09-001 on Forte Bio Octert RED 384
Simultaneous interaction between two different antigens (PD-L1 and CD47) and the 09-001 antibody was studied by bio-layer interferometry on the Octet Red384 instrument (ForteBio). Proprietary PD-L1 and CD47 antigens were used for the study.
The study was conducted using covalent immobilization of protein (antigens) on AR2G biosensors (Amine Reactive Second-Generation (AR2G) Biosensors, ForteBio). The experiment consisted of the following main steps: loading PD-L1 onto sensors, loading antibody 09-001 onto sensors with PD-L1, interacting with CD47 (analyte). Thus, the interaction signal at the last step of the experiment is detected in the presence of a bispecific antibody capable of simultaneously binding to PD- L1 present on sensors and CD47 present in solution. Table 6 shows the complete list of steps (stages).
Table 6. Steps of the experiment to test the simultaneous interaction between antibody 09-001 and two different antigens (PD-L1 and CD47).
The sensors were activated in an aqueous solution comprising 20 mM EDC and 10 mM sNHS for 300 s. The PD-L1 antigen was loaded onto the surface of biosensors in a sodium-acetate buffer with a pH 5.0 for 300 s. The concentration of PD-L1 protein for loading was 20 pg/ml. Unreacted active centers on the sensor surfaces were quenched in 1M aqueous solution of ethanolamine with pH 8.5 for 300 s. All steps of the experiment following the quenching step were carried out in the kinetic buffer. Antibody 09-001 was loaded onto sensors with immobilized PD-L1 for 300 s, antibody concentration was 20 pg/ml (137.7 nM). At the association stage (interaction with CD47), the sensors were immersed in a solution with CD47 concentration of 100 pg/ml (1280 nM). To test nonspecific interaction of CD47 analyte (negative control), a sensor with immobilized PD-L1 not loaded with antibody 09-001 was used (at the antibody loading step, the sensor was immersed in a kinetic buffer, all other steps are similar to those performed with the sensor being analyzed). Sensograms were processed using ForteBio Octet Data Analysisn 9.0 software. Simultaneous interaction with two different antigens was determined by analyzing the signal level (response parameter) at the end of the CD47 interaction step. The results are shown in Table 7.
Table 7. Results of the experiment to test the simultaneous interaction between antibody 09-001 and two antigens, PD-L1 and CD47.
At the last step of the experiment (CD47 association), we observed an interaction signal of 0.6088 nm for antibody 09-001, whereas no nonspecific signal of CD47 binding to sensors not loaded with the antibody was detected.
Conclusion
Antibody 09-001 demonstrates simultaneous binding to two different antigens, PD-L1 and
CD47.
Example 7. Test of blocking of interaction between CD47 and SIRPa by antibody 09-001 on Forte Bio Octert RED 384
Blocking of interaction between CD47 and SIRPa (Signal-regulatory protein alpha) by antibodies 09-001 was studied by bio-layer interferometry on the Octet Red384 instrument (ForteBio). Proprietary human CD47 and SIRPa antigens were used for the study.
The study was conducted using covalent immobilization of protein (antigens) on AR2G biosensors (Amine Reactive Second-Generation (AR2G) Biosensors, ForteBio). The experiment consisted of the following main steps: loading the SIRPa antigen onto sensors, testing the binding of SIRPa antigen to CD47/antibodies 09-001 mixtures (premix). CD47 solution without antibodies served as a positive control,. Blocking of interaction was determing by comparing the premix signal (response) and positive control signal. Table 8 shows the list of experiment steps.
Table 8. Steps of experiment to test the blocking of interaction between CD47 and SIRPa by antibodies
09-001.
The sensors were activated in an aqueous solution comprising 20 mM EDC and 10 mM sNHS for 300 s. The SIRPa antigen was loaded onto the surface of biosensors in a sodium -acetate buffer with a pH 5.0 for 600 s. The concentration of SIRPa protein for loading was 20 pg/ml. To check the nonspecific interaction between the analyte and the sensors, we used an antigen-free sensor (at the loading step, the sensor was immersed in sodium acetate buffer with pH 5.0; all other steps are similar to those used for the sensor loaded with antigen). Unreacted active centers on the sensor surfaces were quenched in 1M aqueous solution of ethanolamine with pH 8.5 for 300 s. All steps of the experiment following the quenching step were carried out in the kinetic buffer. At the association step (step duration was 1200 s), sensors with loaded protein were immersed into wells with an analyte solution. A solution containing 250 nM antibody 09-001 and 50 nM CD47 in a kinetic buffer was used as an analyte at the association step. A solution (analyte) with CD47 concentration of 50 nM served as a positive control. The measurements were carried out at a temperature of 30 °C; we employed tangential stirring at 1000 rpm in all steps. The reference sensors went through all the steps as the sensors used to record analyte sensograms did, with the exception of the association step - at the association step, the sensors were immersed in a kinetic buffer without analyte (the reference sensor signals were measured in parallel with the recording of the main sensograms). The reference signal was subtracted from the signal received on sensors interacting with the analyte during the processing of sensograms. Sensograms were processed using ForteBio Octet Data Analysisn 9.0 software. The results of the experiment are shown in Table 9.
At the association step, positive control showed a signal of binding to SIRPa of 0.297 nm, whereas the analyte containing CD47 and antibodies 09-001 showed no signal of binding to SIRPa.
Table 9. Results of experiment to test the blocking of interaction between CD47 and SIRPa by antibody
09-001.
Conclusion
Antibody 09-001 blocks the interaction between CD47 and SIRPa.
Example 8. Testing of blocking of interaction between PD-1 and PD-L1 by antibody 09-001 on Forte Bio Octert RED 384
Blocking of interaction between PD-1 and PD-L1 by antibody 09-001 was studied by bio-layer interferometry on the Octet Red384 instrument (ForteBio). Human PD-1 and PD-L1 antigens were used for the study.
The study was conducted using covalent immobilization of protein (antigens) on AR2G biosensors (Amine Reactive Second-Generation (AR2G) Biosensors, ForteBio). The experiment consisted of the following main steps: loading the PD-1 antigen onto sensors, testing the binding of the PD-1 antigen to PD-Ll/antibody 09-001 mixture (premix). PD-L1 solution without antibodies served as a positive control. Blocking of interaction was determined by comparing the premix signal (response) and positive control signal. Table 10 shows the list of experiment steps.
Table 10. Steps of experiment to test the blocking of interaction between PD-1 and PD-L1 by antibody
09-001.
The sensors were activated in an aqueous solution comprising 20 mM EDC and 10 mM sNHS for 300 s. The PD-1 antigen was loaded onto the surface of biosensors in a sodium-acetate buffer with a pH 5.0 for 300 s. The concentration of PD-1 protein for loading was 20 pg/ml. To check the nonspecific interaction between the analyte and the sensors, we used an antigen-free sensor (at the loading step, the sensor was immersed in sodium acetate buffer with pH 5.0; all other steps are similar to those used for the sensor loaded with antigen). Unreacted active centers on the sensor surfaces were quenched in 1M aqueous solution of ethanolamine with pH 8.5 for 300 s. All steps of the experiment following the quenching step were carried out in the kinetic buffer. At the association step (step duration was 300 s), sensors with loaded protein were immersed into wells with an analyte solution. A solution containing 250 nM antibody 09-001 and 50 nM PD-L1 in a kinetic buffer was used as an analyte at the association step. A solution (analyte) with PD-L1 at a concentration of 50 nM served as a positive control.
The measurements were carried out at a temperature of 30 °C; we employed tangential stirring at 1000 rpm in all steps. The reference sensors went through all the steps as the sensors used to record analyte sensograms did, with the exception of the association step - at the association step, the sensors were immersed in a kinetic buffer without analyte (the reference sensor signals were measured in parallel with the recording of the main sensograms). The reference signal was subtracted from the signal received on sensors interacting with the analyte during the processing of sensograms. Sensograms were processed using ForteBio Octet Data Analysisn 9.0 software. The results of the experiment are shown in Table .
At the association step, positive control shows a signal of analyte binding to PD-1 (1,429 nm), whereas
no signal ofbindingtoPD-1 (0.007 nm, background signal value) was detected for the analyte containing PD-L1 and antibodies 09-001.
Table 11. Results of experiment to test the blocking of interaction between PD1 and PD-L1 by antibodies 09-001.
Conclusion
Antibody 09-001 blocks interaction between PD-1 and PD-L1.
Example 9. Determination of thermal stability under thermal stress at 50°C
The test samples were placed in a thermostated air bath and thermostated at 50°C for 48 hours. After heating, intact and stressed samples were transferred for analysis by size-exclusion HPLC with a UV detector. Chromatography was performed on the Agilent 1100 HPLC system, detection was performed at a wavelength of 220 nm and 280 nm.
The resulting stability data for 09-001 under incubation at 50 °C are shown in Table 12.
Overall conclusion: the samples show high level of thermal stability.
Table 12. Results of determination of thermal stability for antibody 09-001 by SE HPLC.
Example 10. Determination of colloidal and thermal stability by protein aggregation point using dynamic light scattering
In order to determine the aggregation temperature of the samples under study by dynamic light scattering (DLS), dependence of particle size in the medium on temperature was obtained using DynaPro® Plate Reader II with gradual heating from 25 to 80 °C. The results are shown in Table 13. This analysis studied antibody 09-001 and antibody BCD106-02-001 from EA201791961A1.
Table 13. Aggregation point of BCD 106-02-001 and 09-001.
It can be concluded that 09-001 shows a high level of therm ocolloidal stability (aggregation point in20mM sodium-acetate buffer pH =5.0 is above 60.0 °C). Antibody BCD106-02-001 shows a lower level of thermocolloidal stability as compared to 09-001.
Example 11. Comparison of initial bispecific antibody in scFv-Fab format and bispecific antibody in CLC format (bispecific antibody with common light chain).
Table 14 shows data for antibodies BCD106-02-001 and 09-001 by way of comparison.
Table 14. Results of determination of aggregation stability for antibodies BCD 106-02-001 and 09-001 by SE HPLC.
These results show that antibody 09-001 has a higher aggregation stability as compared to antibody BCD 106-02-001 according to the purity study by SE HPLC. Further, antibody 09-001 has a higher aggregation temperature as compared to BCD 106-02-001, which fact indicates a greater thermocolloidal stability relative to antibody BCD 106-02-001.
Claims
1. An isolated bispecifie antibody that specifically binds to CD47 and PD-L1 and includes:
1) a first antigen-binding fragment that specifically binds to CD47 and includes:
(a) a heavy chain variable domain comprising:
(i) CDR1 with the amino acid sequence of SEQ ID NO: 1,
(ii) CDR2 with the amino acid sequence of SEQ ID NO: 2,
(iii) CDR3 with the amino acid sequence of SEQ ID NO: 3; and
(b) a common light chain variable domain comprising:
(i) CDR1 with the amino acid sequence of SEQ ID NO: 4,
(ii) CDR2 with the amino acid sequence of SEQ ID NO: 5,
(iii) CDR3 with the amino acid sequence of SEQ ID NO: 6;
2) a second antigen-binding fragment that specifically binds to PD-L1 and includes:
(a) a heavy chain variable domain comprising:
(i) CDR1 with the amino acid sequence of SEQ ID NO: 7,
(ii) CDR2 with the amino acid sequence of SEQ ID NO: 8,
(iii) CDR3 with the amino acid sequence of SEQ ID NO: 9; and
(b) a common light chain variable domain comprising:
(i) CDR1 with the amino acid sequence of SEQ ID NO: 4,
(ii) CDR2 with the amino acid sequence of SEQ ID NO: 5,
(iii) CDR3 with the amino acid sequence of SEQ ID NO: 6.
2. The isolated bispecific antibody according to claim 1, characterized in that the first antigen-binding fragment that specifically binds to CD47 is a Fab bound to an Fc fragment monomer.
3. The isolated bispecific antibody according to claim 3L characterized in that the second antigen-binding fragment that specifically binds to PD-L1 is a Fab bound to an Fc fragment monomer.
4. The isolated bi specific antibody according to claim 1, characterized in that the antibody is a full-length IgG antibody.
5. The isolated bi specific antibody according to claim 4, wherein the full-length IgG antibody is of human IgGl, IgG2, IgG3 or IgG4 isotype.
6. The isolated bi specific antibody according to claim 1, wherein the heavy chain variable domain of the first antigen-binding fragment that specifically binds to CD47 comprises the amino acid sequence of SEQ ID NO: 22.
7. The isolated b specific antibody according to claim 1, wherein the heavy chain variable domain of the second antigen-binding fragment that specifically binds to PD-L1 comprises the amino acid sequence of SEQ ID NO: 24.
8. The isolated bispecific antibody according to claim 1, wherein the variable domain of the common light chain for the first and second antigen-binding fragments comprises the amino acid sequence of SEQ ID NO: 23.
9. The isolated bispecific antibody according to claim 1, wherein the first antigen-binding fragment that specifically binds to CD47 includes:
(a) a heavy chain variable domain with the amino acid sequence of SEQ ID NO: 22;
(b) a common light chain variable domain with the amino acid sequence of SEQ ID NO: 23; wherein the second antigen-binding fragment that specifically binds to PD-L1 includes:
(a) a heavy chain variable domain with the amino acid sequence of SEQ ID NO: 24,
(b) a common light chain variable domain with the amino acid sequence of SEQ ID NO: 23.
10. The isolated bispecific antibody according to claim 1, wherein the heavy chain of the first antigen-binding fragment that specifically binds to CD47 comprises the amino acid sequence of SEQ ID NO: 25.
11. The isolated bispecific antibody according to claim 1, wherein the heavy chain of the second antigen-binding fragment that specifically binds to PD-L1 comprises the amino acid sequence of SEQ ID NO: 27.
12. The isolated bispecific antibody according to claim 1, wherein the common light chain for the first and second antigen-binding fragments comprises the amino acid sequence of SEQ ID NO: 26.
13. The isolated bispecific antibody according to claim 1, wherein the first antigen-binding fragment that specifically binds to CD47 includes:
(a) a heavy chain with the amino acid sequence of SEQ ID NO: 25,
(b) a common light chain with the amino acid sequence of SEQ ID NO: 26; wherein the second antigen-binding fragment that specifically binds to PD-L1 includes:
(a) a heavy chain with the amino acid sequence of SEQ ID NO: 27,
(b) a common light chain with the amino acid sequence of SEQ ID NO: 26.
14. The isolated bispecific antibody according to claim 1, which is a bivalent antibody.
15. An isolated nucleic acid that encodes the bispecific antibody according to any of claims 1 to 14.
16. The isolated nucleic acid according to claim 15, wherein the nucleic acid is DNA.
17. An expression vector comprising the nucleic acid according to any of claims 15 to 16.
18. A method for producing a host cell to produce the bispecific antibody according to any of claims 1 to 14, comprising transformation of the cell by the expression vector according to claim 17.
19. A host cell for producing the bispecific antibody according to any of claims 1 to 14, comprising the nucleic acid according to any of claims 15 to 16.
20. A method for producing the bispecific antibody according to any of claims 1 to 14, comprising culturing the host cell according to claim 19 in a culture medium under conditions sufficient to produce said antibody, if necessary, followed by isolating and purifying the resulting antibody.
21. A pharmaceutical composition comprising the bispecific antibody according to any of claims 1 to 14 in a therapeutically effective amount in combination with one or more pharmaceutically acceptable excipients.
22. A pharmaceutical composition comprising the bispecific antibody according to any of claims 1 to 14 and at least one other therapeutically active compound.
23. The pharmaceutical composition according to claim 22, wherein the other therapeutically active compound is an antibody, a chemotherapeutic agent, a hormone therapy agent or any combination thereof.
24. The pharmaceutical composition according to claim 23, wherein the chemotherapeutic agent is selected from a group that includes: docetaxel, paclitaxel, doxorubicin, platinum agents, carboplatin, 5-fluorouracil, tyrosine kinase inhibitors, axitinib, liposomal doxorubicin, liposomal paclitaxel, or any combination thereof; wherein the antibody is trastuzumab; wherein the combination is trastuzumab and a chemotherapeutic agent selected from the group including docetaxel, paclitaxel, doxorubicin, platinum agents, carboplatin, 5-fluorouracil, tyrosine kinase inhibitors, axitinib, liposomal doxorubicin, liposomal paclitaxel, or any combination thereof.
25. A method for inhibiting biological activity of PD-L1 and CD47 in a subject in need of such inhibition, including administering to the subject an effective amount of the bispecific antibody according to any of claims 1 to 14.
26. The bispecific antibody according to any of claims 1 to 14 or the pharmaceutical composition according to any of claims 22, 23, 24 for use in the treatment of a disease or disorder mediated by PD-L1 and CD47.
27. The bispecific antibody according to any of claims 1 to 14 or the pharmaceutical composition according to any of claims 22, 23, 24 for use according to claim 30, wherein the disease or disorder mediated by PD-L1 and CD47 is selected from the group: triple-negative
breast cancer (TNBC), head and neck cancer (HNC), gastric cancer (GC), esophagogastric junction cancer, lung adenocarcinoma, non-small cell lung cancer, small cell lung cancer, acute myeloid leukemia, myelodysplastic syndrome, high microsatellite instability malignant neoplasm, multiple myeloma, ovarian cancer, renal cell carcinoma, bladder cancer, cervical cancer.
28. Use of the bispecific antibody according to any of claims 1 to 14 or the pharmaceutical composition according to any of claims 22, 23, 24 for treating a disease or disorder mediated by PD-L1 and CD47.
29. The use according to claim 28, wherein the disease or disorder mediated by PD-L1 and CD47 is selected from the group: triple-negative breast cancer (TNBC), head and neck cancer (HNC), gastric cancer (GC), esophagogastric junction cancer, lung adenocarcinoma, non small cell lung cancer, small cell lung cancer, acute myeloid leukemia, myelodysplastic syndrome, high microsatellite instability malignant neoplasm, multiple myeloma, ovarian cancer, renal cell carcinoma, bladder cancer, cervical cancer.
30. Use of the bispecific antibody according to any of claims 1 to 14 and at least one other therapeutically active compound for treating a disease or disorder mediated by PD-L1 and CD47.
31. The use according to claim 30, wherein the disease or disorder mediated by PD-L1 and CD47 is selected from the group: triple-negative breast cancer (TNBC), head and neck cancer (HNC), gastric cancer (GC), esophagogastric junction cancer, lung adenocarcinoma, non small cell lung cancer, small cell lung cancer, acute myeloid leukemia, myelodysplastic syndrome, high microsatellite instability malignant neoplasm, multiple myeloma, ovarian cancer, renal cell carcinoma, bladder cancer, cervical cancer.
32. The use according to any of claims 30 to 31, wherein the other therapeutically active compound is an antibody, a chemotherapeutic agent, a hormone therapy agent or any combination thereof.
33. The use according to claim 32, wherein the chemotherapeutic agent is selected from a group that includes: docetaxel, paclitaxel, doxorubicin, platinum agents, carboplatin, 5- fluorouracil, tyrosine kinase inhibitors, axitinib, liposomal doxorubicin, liposomal paclitaxel, or any combination thereof; wherein the antibody is trastuzumab; wherein the combination is trastuzumab and a chemotherapeutic agent, which is selected from a group including docetaxel, paclitaxel, doxorubicin, platinum agents, carboplatin, 5- fluorouracil, tyrosine kinase inhibitors, axitinib, liposomal doxorubicin, liposomal paclitaxel, or any combination thereof.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
RU2021118025A RU2815823C2 (en) | 2021-06-21 | Isolated bispecific antibody that specifically binds to cd47 and pd-l1 | |
PCT/RU2022/050195 WO2022271053A1 (en) | 2021-06-21 | 2022-06-21 | Isolated bispecific antibody that specifically binds to cd47 and pd-l1 |
Publications (1)
Publication Number | Publication Date |
---|---|
EP4359445A1 true EP4359445A1 (en) | 2024-05-01 |
Family
ID=84544589
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP22828864.3A Pending EP4359445A1 (en) | 2021-06-21 | 2022-06-21 | Isolated bispecific antibody that specifically binds to cd47 and pd-l1 |
Country Status (9)
Country | Link |
---|---|
EP (1) | EP4359445A1 (en) |
CN (1) | CN117858904A (en) |
AR (1) | AR126185A1 (en) |
BR (1) | BR112023026982A2 (en) |
CO (1) | CO2023018165A2 (en) |
EC (1) | ECSP23097121A (en) |
MX (1) | MX2024000266A (en) |
TW (1) | TW202306998A (en) |
WO (1) | WO2022271053A1 (en) |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
SI2387391T1 (en) * | 2009-07-24 | 2017-04-26 | Mika Pharma Gesellschaft Fuer Die Entwicklung Und Vermarktung Pharmazeutischer Produkte Mbh | Method for developing a liquid composition to be applied to the skin as a foam and a composition that can be applied topically |
RU2665790C1 (en) * | 2017-04-17 | 2018-09-04 | Закрытое Акционерное Общество "Биокад" | Monoclonal pd-l1 antibody |
EA039662B1 (en) * | 2017-10-03 | 2022-02-24 | Закрытое Акционерное Общество "Биокад" | Antibodies specific to cd47 and pd-l1 |
-
2022
- 2022-06-21 TW TW111123100A patent/TW202306998A/en unknown
- 2022-06-21 WO PCT/RU2022/050195 patent/WO2022271053A1/en active Application Filing
- 2022-06-21 CN CN202280044514.XA patent/CN117858904A/en active Pending
- 2022-06-21 BR BR112023026982A patent/BR112023026982A2/en unknown
- 2022-06-21 AR ARP220101614A patent/AR126185A1/en unknown
- 2022-06-21 EP EP22828864.3A patent/EP4359445A1/en active Pending
- 2022-06-21 MX MX2024000266A patent/MX2024000266A/en unknown
-
2023
- 2023-12-21 CO CONC2023/0018165A patent/CO2023018165A2/en unknown
- 2023-12-27 EC ECSENADI202397121A patent/ECSP23097121A/en unknown
Also Published As
Publication number | Publication date |
---|---|
MX2024000266A (en) | 2024-01-31 |
BR112023026982A2 (en) | 2024-03-12 |
WO2022271053A1 (en) | 2022-12-29 |
CO2023018165A2 (en) | 2024-05-30 |
CN117858904A (en) | 2024-04-09 |
AR126185A1 (en) | 2023-09-27 |
TW202306998A (en) | 2023-02-16 |
ECSP23097121A (en) | 2024-02-29 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US11840567B2 (en) | Bispecific antibodies with specific binding to CD47 and PD-L1 | |
US11174320B2 (en) | HER3 specific monoclonal antibodies for diagnostic and therapeutic use | |
US11236167B2 (en) | Monoclonal antibody to PD-L1 | |
US20230011234A1 (en) | Immunocytokine comprising heterodymeric protein complex based on il-15/il-15ra | |
EP3964525A2 (en) | Monoclonal antibody that binds specifically to gitr | |
WO2021139682A1 (en) | Anti-galectin-9 antibody and uses thereof | |
WO2021129744A1 (en) | Compositions and methods for treating autoimmune diseases and cancers by targeting igsf8 | |
EP4359445A1 (en) | Isolated bispecific antibody that specifically binds to cd47 and pd-l1 | |
EP4259123A1 (en) | Cancer treatment using bosentan in combination with a checkpoint inhibitor | |
RU2796937C2 (en) | Monoclonal antibody or its antigen-binding fragment which specifically binds to gd2 (gd2 ganglioside) and its use | |
US20240034764A1 (en) | Immunocytokine for activating human il-10ra receptor and use thereof | |
RU2751249C1 (en) | Monoclonal antibody that specifically binds to csf-1r | |
RU2815823C2 (en) | Isolated bispecific antibody that specifically binds to cd47 and pd-l1 | |
EA047594B1 (en) | A MONOCLONAL ANTIBODY THAT BINDS SPECIFICALLY TO GD2 | |
OA21499A (en) | Immunocytokine for activating human IL10RA receptor and use thereof. | |
WO2022203552A1 (en) | Monoclonal antibody that specifically binds to gd2 | |
EA043937B1 (en) | IMMUNOCYTOKINE, INCLUDING A HETERODIMERIC PROTEIN COMPLEX BASED ON IL-15 AND IL-15Rα, AND ITS APPLICATION |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: THE INTERNATIONAL PUBLICATION HAS BEEN MADE |
|
PUAI | Public reference made under article 153(3) epc to a published international application that has entered the european phase |
Free format text: ORIGINAL CODE: 0009012 |
|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: REQUEST FOR EXAMINATION WAS MADE |
|
17P | Request for examination filed |
Effective date: 20231219 |
|
AK | Designated contracting states |
Kind code of ref document: A1 Designated state(s): AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR |