CN113795269A - 血管活性肠肽(vip)拮抗剂的组合物和用途 - Google Patents
血管活性肠肽(vip)拮抗剂的组合物和用途 Download PDFInfo
- Publication number
- CN113795269A CN113795269A CN201980089301.7A CN201980089301A CN113795269A CN 113795269 A CN113795269 A CN 113795269A CN 201980089301 A CN201980089301 A CN 201980089301A CN 113795269 A CN113795269 A CN 113795269A
- Authority
- CN
- China
- Prior art keywords
- certain embodiments
- peptide
- cells
- cancer
- cell
- 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
- 239000005557 antagonist Substances 0.000 title abstract description 12
- 108010003205 Vasoactive Intestinal Peptide Proteins 0.000 title description 56
- VBUWHHLIZKOSMS-RIWXPGAOSA-N invicorp Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](CCSC)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC=1NC=NC=1)C(C)C)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=C(O)C=C1 VBUWHHLIZKOSMS-RIWXPGAOSA-N 0.000 title description 53
- 239000000203 mixture Substances 0.000 title description 43
- 102000055135 Vasoactive Intestinal Peptide Human genes 0.000 title 2
- 108090000765 processed proteins & peptides Proteins 0.000 claims abstract description 162
- 238000000034 method Methods 0.000 claims abstract description 59
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 42
- -1 as disclosed herein Substances 0.000 claims abstract description 23
- 238000002156 mixing Methods 0.000 claims abstract description 11
- 210000004027 cell Anatomy 0.000 claims description 84
- 150000001413 amino acids Chemical class 0.000 claims description 82
- 210000001744 T-lymphocyte Anatomy 0.000 claims description 71
- 239000002105 nanoparticle Substances 0.000 claims description 33
- 150000007523 nucleic acids Chemical class 0.000 claims description 28
- 102000039446 nucleic acids Human genes 0.000 claims description 20
- 108020004707 nucleic acids Proteins 0.000 claims description 20
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 14
- 239000000843 powder Substances 0.000 claims description 9
- 230000002708 enhancing effect Effects 0.000 claims description 8
- 239000013598 vector Substances 0.000 claims description 8
- 239000002775 capsule Substances 0.000 claims description 7
- 239000003112 inhibitor Substances 0.000 claims description 7
- 239000006187 pill Substances 0.000 claims description 7
- 229910052757 nitrogen Inorganic materials 0.000 claims description 6
- 239000003826 tablet Substances 0.000 claims description 6
- 108091007960 PI3Ks Proteins 0.000 claims description 5
- 229910052799 carbon Inorganic materials 0.000 claims description 5
- 239000007788 liquid Substances 0.000 claims description 5
- 125000003396 thiol group Chemical group [H]S* 0.000 claims description 5
- 108090000430 Phosphatidylinositol 3-kinases Proteins 0.000 claims description 4
- 230000006044 T cell activation Effects 0.000 claims description 4
- 239000008187 granular material Substances 0.000 claims description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 4
- 229910052700 potassium Inorganic materials 0.000 claims description 4
- 239000003380 propellant Substances 0.000 claims description 4
- 239000007921 spray Substances 0.000 claims description 4
- 102000038030 PI3Ks Human genes 0.000 claims description 3
- 239000012266 salt solution Substances 0.000 claims description 3
- 229910052717 sulfur Inorganic materials 0.000 claims description 3
- 206010028980 Neoplasm Diseases 0.000 abstract description 99
- 201000011510 cancer Diseases 0.000 abstract description 60
- 102000004196 processed proteins & peptides Human genes 0.000 abstract description 48
- 238000011282 treatment Methods 0.000 abstract description 19
- 208000036142 Viral infection Diseases 0.000 abstract description 14
- 230000009385 viral infection Effects 0.000 abstract description 14
- 238000000338 in vitro Methods 0.000 abstract description 12
- 210000002865 immune cell Anatomy 0.000 abstract description 9
- 230000004936 stimulating effect Effects 0.000 abstract description 6
- 239000002548 vasoactive intestinal polypeptide antagonist Substances 0.000 abstract description 6
- FBYWUGLFWCEKAN-KQQCXCAZSA-N vip antagonist Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(N)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](CCSC)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H]1N(CCC1)C(=O)[C@@H](N)CCCCN)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=C(O)C=C1 FBYWUGLFWCEKAN-KQQCXCAZSA-N 0.000 abstract description 6
- 230000002265 prevention Effects 0.000 abstract description 5
- 229960005486 vaccine Drugs 0.000 description 67
- 235000001014 amino acid Nutrition 0.000 description 66
- 102400000015 Vasoactive intestinal peptide Human genes 0.000 description 53
- 229940024606 amino acid Drugs 0.000 description 38
- 108090000623 proteins and genes Proteins 0.000 description 29
- 102000004169 proteins and genes Human genes 0.000 description 28
- 235000018102 proteins Nutrition 0.000 description 24
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 20
- 241000700605 Viruses Species 0.000 description 20
- 108091007433 antigens Proteins 0.000 description 20
- 102000036639 antigens Human genes 0.000 description 20
- 230000014509 gene expression Effects 0.000 description 20
- 239000000427 antigen Substances 0.000 description 19
- 229960003722 doxycycline Drugs 0.000 description 18
- XQTWDDCIUJNLTR-CVHRZJFOSA-N doxycycline monohydrate Chemical compound O.O=C1C2=C(O)C=CC=C2[C@H](C)[C@@H]2C1=C(O)[C@]1(O)C(=O)C(C(N)=O)=C(O)[C@@H](N(C)C)[C@@H]1[C@H]2O XQTWDDCIUJNLTR-CVHRZJFOSA-N 0.000 description 18
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 17
- 125000000217 alkyl group Chemical group 0.000 description 17
- 239000003795 chemical substances by application Substances 0.000 description 17
- 239000003814 drug Substances 0.000 description 17
- 238000006467 substitution reaction Methods 0.000 description 16
- 239000003085 diluting agent Substances 0.000 description 15
- 108091026890 Coding region Proteins 0.000 description 14
- 230000000735 allogeneic effect Effects 0.000 description 14
- 229940002612 prodrug Drugs 0.000 description 14
- 239000000651 prodrug Substances 0.000 description 14
- 108010091350 (VIP-neurotensin) hybrid antagonist Proteins 0.000 description 13
- 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 13
- 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 13
- 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 13
- 150000001875 compounds Chemical class 0.000 description 13
- 229960001904 epirubicin Drugs 0.000 description 13
- 210000004698 lymphocyte Anatomy 0.000 description 13
- 229960000485 methotrexate Drugs 0.000 description 13
- 229960004556 tenofovir Drugs 0.000 description 13
- VCMJCVGFSROFHV-WZGZYPNHSA-N tenofovir disoproxil fumarate Chemical compound OC(=O)\C=C\C(O)=O.N1=CN=C2N(C[C@@H](C)OCP(=O)(OCOC(=O)OC(C)C)OCOC(=O)OC(C)C)C=NC2=C1N VCMJCVGFSROFHV-WZGZYPNHSA-N 0.000 description 13
- 208000032839 leukemia Diseases 0.000 description 12
- 125000005647 linker group Chemical group 0.000 description 12
- 125000001424 substituent group Chemical group 0.000 description 12
- 241000699670 Mus sp. Species 0.000 description 11
- KNHUKKLJHYUCFP-UHFFFAOYSA-N clofibrate Chemical compound CCOC(=O)C(C)(C)OC1=CC=C(Cl)C=C1 KNHUKKLJHYUCFP-UHFFFAOYSA-N 0.000 description 11
- 229960001214 clofibrate Drugs 0.000 description 11
- 229920001223 polyethylene glycol Polymers 0.000 description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- 102000004190 Enzymes Human genes 0.000 description 10
- 108090000790 Enzymes Proteins 0.000 description 10
- 208000015914 Non-Hodgkin lymphomas Diseases 0.000 description 10
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 10
- 239000011324 bead Substances 0.000 description 10
- 229940088598 enzyme Drugs 0.000 description 10
- 210000003958 hematopoietic stem cell Anatomy 0.000 description 10
- 210000004072 lung Anatomy 0.000 description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- 241000701806 Human papillomavirus Species 0.000 description 9
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 9
- 238000009739 binding Methods 0.000 description 9
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 9
- 230000028993 immune response Effects 0.000 description 9
- 210000000987 immune system Anatomy 0.000 description 9
- 150000002632 lipids Chemical class 0.000 description 9
- 230000035772 mutation Effects 0.000 description 9
- 229920001282 polysaccharide Polymers 0.000 description 9
- 239000005017 polysaccharide Substances 0.000 description 9
- 150000004804 polysaccharides Chemical class 0.000 description 9
- KILNVBDSWZSGLL-KXQOOQHDSA-N 1,2-dihexadecanoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCCCCCCCCC KILNVBDSWZSGLL-KXQOOQHDSA-N 0.000 description 8
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 8
- 108020004414 DNA Proteins 0.000 description 8
- 239000002202 Polyethylene glycol Substances 0.000 description 8
- 208000006664 Precursor Cell Lymphoblastic Leukemia-Lymphoma Diseases 0.000 description 8
- 229960004679 doxorubicin Drugs 0.000 description 8
- 201000001441 melanoma Diseases 0.000 description 8
- 101000914514 Homo sapiens T-cell-specific surface glycoprotein CD28 Proteins 0.000 description 7
- 108010002350 Interleukin-2 Proteins 0.000 description 7
- 102000000588 Interleukin-2 Human genes 0.000 description 7
- 108010000817 Leuprolide Proteins 0.000 description 7
- 229930012538 Paclitaxel Natural products 0.000 description 7
- 102100027213 T-cell-specific surface glycoprotein CD28 Human genes 0.000 description 7
- 239000002246 antineoplastic agent Substances 0.000 description 7
- 125000003118 aryl group Chemical group 0.000 description 7
- 210000004369 blood Anatomy 0.000 description 7
- 239000008280 blood Substances 0.000 description 7
- 210000004899 c-terminal region Anatomy 0.000 description 7
- 125000004432 carbon atom Chemical group C* 0.000 description 7
- 230000001684 chronic effect Effects 0.000 description 7
- 229960004316 cisplatin Drugs 0.000 description 7
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 7
- 229960004397 cyclophosphamide Drugs 0.000 description 7
- 230000000593 degrading effect Effects 0.000 description 7
- 201000010099 disease Diseases 0.000 description 7
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 7
- 230000001976 improved effect Effects 0.000 description 7
- 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 7
- 229960004338 leuprorelin Drugs 0.000 description 7
- 229960001592 paclitaxel Drugs 0.000 description 7
- 239000002935 phosphatidylinositol 3 kinase inhibitor Substances 0.000 description 7
- 150000003839 salts Chemical class 0.000 description 7
- 239000007787 solid Substances 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 7
- 229940124597 therapeutic agent Drugs 0.000 description 7
- 229960004528 vincristine Drugs 0.000 description 7
- 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 7
- 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 7
- 208000017604 Hodgkin disease Diseases 0.000 description 6
- 108060001084 Luciferase Proteins 0.000 description 6
- 239000005089 Luciferase Substances 0.000 description 6
- 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 6
- 206010035226 Plasma cell myeloma Diseases 0.000 description 6
- 230000006052 T cell proliferation Effects 0.000 description 6
- 125000003277 amino group Chemical group 0.000 description 6
- 210000004556 brain Anatomy 0.000 description 6
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 6
- 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 6
- 229960005420 etoposide Drugs 0.000 description 6
- 239000013604 expression vector Substances 0.000 description 6
- LPEPZBJOKDYZAD-UHFFFAOYSA-N flufenamic acid Chemical compound OC(=O)C1=CC=CC=C1NC1=CC=CC(C(F)(F)F)=C1 LPEPZBJOKDYZAD-UHFFFAOYSA-N 0.000 description 6
- 235000011187 glycerol Nutrition 0.000 description 6
- 208000006454 hepatitis Diseases 0.000 description 6
- 231100000283 hepatitis Toxicity 0.000 description 6
- IPCSVZSSVZVIGE-UHFFFAOYSA-N hexadecanoic acid Chemical compound CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 6
- 208000015181 infectious disease Diseases 0.000 description 6
- 238000001802 infusion Methods 0.000 description 6
- 238000004519 manufacturing process Methods 0.000 description 6
- 239000000463 material Substances 0.000 description 6
- 230000007246 mechanism Effects 0.000 description 6
- 239000007758 minimum essential medium Substances 0.000 description 6
- 210000000822 natural killer cell Anatomy 0.000 description 6
- 229920001184 polypeptide Polymers 0.000 description 6
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 6
- 239000011780 sodium chloride Substances 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 235000000346 sugar Nutrition 0.000 description 6
- 229960000575 trastuzumab Drugs 0.000 description 6
- 230000003612 virological effect Effects 0.000 description 6
- 101710148586 ADP,ATP carrier protein 1 Proteins 0.000 description 5
- 101710111394 ADP,ATP carrier protein 1, mitochondrial Proteins 0.000 description 5
- 101710102716 ADP/ATP translocase 1 Proteins 0.000 description 5
- 102100032533 ADP/ATP translocase 1 Human genes 0.000 description 5
- 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 5
- 108010006654 Bleomycin Proteins 0.000 description 5
- 208000003174 Brain Neoplasms Diseases 0.000 description 5
- 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 5
- 108010019670 Chimeric Antigen Receptors Proteins 0.000 description 5
- 241000701022 Cytomegalovirus Species 0.000 description 5
- 206010011831 Cytomegalovirus infection Diseases 0.000 description 5
- 208000010747 Hodgkins lymphoma Diseases 0.000 description 5
- 239000005511 L01XE05 - Sorafenib Substances 0.000 description 5
- 206010025323 Lymphomas Diseases 0.000 description 5
- 206010029260 Neuroblastoma Diseases 0.000 description 5
- 229940083963 Peptide antagonist Drugs 0.000 description 5
- 241000702670 Rotavirus Species 0.000 description 5
- 229920002472 Starch Polymers 0.000 description 5
- 230000001093 anti-cancer Effects 0.000 description 5
- 125000003710 aryl alkyl group Chemical group 0.000 description 5
- 239000011230 binding agent Substances 0.000 description 5
- 229960001561 bleomycin Drugs 0.000 description 5
- OYVAGSVQBOHSSS-UAPAGMARSA-O bleomycin A2 Chemical compound N([C@H](C(=O)N[C@H](C)[C@@H](O)[C@H](C)C(=O)N[C@@H]([C@H](O)C)C(=O)NCCC=1SC=C(N=1)C=1SC=C(N=1)C(=O)NCCC[S+](C)C)[C@@H](O[C@H]1[C@H]([C@@H](O)[C@H](O)[C@H](CO)O1)O[C@@H]1[C@H]([C@@H](OC(N)=O)[C@H](O)[C@@H](CO)O1)O)C=1N=CNC=1)C(=O)C1=NC([C@H](CC(N)=O)NC[C@H](N)C(N)=O)=NC(N)=C1C OYVAGSVQBOHSSS-UAPAGMARSA-O 0.000 description 5
- 238000002659 cell therapy Methods 0.000 description 5
- 235000014113 dietary fatty acids Nutrition 0.000 description 5
- HCFDWZZGGLSKEP-UHFFFAOYSA-N doxylamine Chemical compound C=1C=CC=NC=1C(C)(OCCN(C)C)C1=CC=CC=C1 HCFDWZZGGLSKEP-UHFFFAOYSA-N 0.000 description 5
- 229960005178 doxylamine Drugs 0.000 description 5
- 229940079593 drug Drugs 0.000 description 5
- 239000000194 fatty acid Substances 0.000 description 5
- 229930195729 fatty acid Natural products 0.000 description 5
- 108020001507 fusion proteins Proteins 0.000 description 5
- 102000037865 fusion proteins Human genes 0.000 description 5
- 238000009169 immunotherapy Methods 0.000 description 5
- 201000007270 liver cancer Diseases 0.000 description 5
- 201000011649 lymphoblastic lymphoma Diseases 0.000 description 5
- 244000005700 microbiome Species 0.000 description 5
- 239000002245 particle Substances 0.000 description 5
- 102000005962 receptors Human genes 0.000 description 5
- 108020003175 receptors Proteins 0.000 description 5
- 229960003787 sorafenib Drugs 0.000 description 5
- 239000008107 starch Substances 0.000 description 5
- 235000019698 starch Nutrition 0.000 description 5
- 210000001519 tissue Anatomy 0.000 description 5
- YBJHBAHKTGYVGT-ZKWXMUAHSA-N (+)-Biotin Chemical group N1C(=O)N[C@@H]2[C@H](CCCCC(=O)O)SC[C@@H]21 YBJHBAHKTGYVGT-ZKWXMUAHSA-N 0.000 description 4
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 4
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 4
- UEJJHQNACJXSKW-UHFFFAOYSA-N 2-(2,6-dioxopiperidin-3-yl)-1H-isoindole-1,3(2H)-dione Chemical compound O=C1C2=CC=CC=C2C(=O)N1C1CCC(=O)NC1=O UEJJHQNACJXSKW-UHFFFAOYSA-N 0.000 description 4
- 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 4
- 101710102715 ADP/ATP translocase 3 Proteins 0.000 description 4
- 102100026397 ADP/ATP translocase 3 Human genes 0.000 description 4
- 206010006187 Breast cancer Diseases 0.000 description 4
- 208000026310 Breast neoplasm Diseases 0.000 description 4
- 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 4
- 201000009030 Carcinoma Diseases 0.000 description 4
- DLGOEMSEDOSKAD-UHFFFAOYSA-N Carmustine Chemical compound ClCCNC(=O)N(N=O)CCCl DLGOEMSEDOSKAD-UHFFFAOYSA-N 0.000 description 4
- ZBNZXTGUTAYRHI-UHFFFAOYSA-N Dasatinib Chemical compound C=1C(N2CCN(CCO)CC2)=NC(C)=NC=1NC(S1)=NC=C1C(=O)NC1=C(C)C=CC=C1Cl ZBNZXTGUTAYRHI-UHFFFAOYSA-N 0.000 description 4
- 108010010803 Gelatin Proteins 0.000 description 4
- 206010018338 Glioma Diseases 0.000 description 4
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 4
- 241000709721 Hepatovirus A Species 0.000 description 4
- 241000700588 Human alphaherpesvirus 1 Species 0.000 description 4
- 241000701074 Human alphaherpesvirus 2 Species 0.000 description 4
- 241000701044 Human gammaherpesvirus 4 Species 0.000 description 4
- 241000725303 Human immunodeficiency virus Species 0.000 description 4
- 108091008036 Immune checkpoint proteins Proteins 0.000 description 4
- 102000037982 Immune checkpoint proteins Human genes 0.000 description 4
- 239000002067 L01XE06 - Dasatinib Substances 0.000 description 4
- GQYIWUVLTXOXAJ-UHFFFAOYSA-N Lomustine Chemical compound ClCCN(N=O)C(=O)NC1CCCCC1 GQYIWUVLTXOXAJ-UHFFFAOYSA-N 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 4
- 208000034578 Multiple myelomas Diseases 0.000 description 4
- ZDZOTLJHXYCWBA-VCVYQWHSSA-N N-debenzoyl-N-(tert-butoxycarbonyl)-10-deacetyltaxol Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=4C=CC=CC=4)C[C@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 ZDZOTLJHXYCWBA-VCVYQWHSSA-N 0.000 description 4
- 108091028043 Nucleic acid sequence Proteins 0.000 description 4
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 4
- 108091005804 Peptidases Proteins 0.000 description 4
- 102000035195 Peptidases Human genes 0.000 description 4
- 201000005702 Pertussis Diseases 0.000 description 4
- 206010060862 Prostate cancer Diseases 0.000 description 4
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 4
- 206010039491 Sarcoma Diseases 0.000 description 4
- 241000713880 Spleen focus-forming virus Species 0.000 description 4
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 4
- 229930006000 Sucrose Natural products 0.000 description 4
- BPEGJWRSRHCHSN-UHFFFAOYSA-N Temozolomide Chemical compound O=C1N(C)N=NC2=C(C(N)=O)N=CN21 BPEGJWRSRHCHSN-UHFFFAOYSA-N 0.000 description 4
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 description 4
- ATBOMIWRCZXYSZ-XZBBILGWSA-N [1-[2,3-dihydroxypropoxy(hydroxy)phosphoryl]oxy-3-hexadecanoyloxypropan-2-yl] (9e,12e)-octadeca-9,12-dienoate Chemical compound CCCCCCCCCCCCCCCC(=O)OCC(COP(O)(=O)OCC(O)CO)OC(=O)CCCCCCC\C=C\C\C=C\CCCCC ATBOMIWRCZXYSZ-XZBBILGWSA-N 0.000 description 4
- 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 4
- 239000000443 aerosol Substances 0.000 description 4
- 229960000548 alemtuzumab Drugs 0.000 description 4
- AWUCVROLDVIAJX-UHFFFAOYSA-N alpha-glycerophosphate Natural products OCC(O)COP(O)(O)=O AWUCVROLDVIAJX-UHFFFAOYSA-N 0.000 description 4
- 229960001830 amprenavir Drugs 0.000 description 4
- YMARZQAQMVYCKC-OEMFJLHTSA-N amprenavir Chemical compound C([C@@H]([C@H](O)CN(CC(C)C)S(=O)(=O)C=1C=CC(N)=CC=1)NC(=O)O[C@@H]1COCC1)C1=CC=CC=C1 YMARZQAQMVYCKC-OEMFJLHTSA-N 0.000 description 4
- 230000008485 antagonism Effects 0.000 description 4
- 239000003443 antiviral agent Substances 0.000 description 4
- 230000002238 attenuated effect Effects 0.000 description 4
- 229960002756 azacitidine Drugs 0.000 description 4
- 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 4
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 4
- 229960000397 bevacizumab Drugs 0.000 description 4
- 210000001185 bone marrow Anatomy 0.000 description 4
- 210000002798 bone marrow cell Anatomy 0.000 description 4
- 229960004117 capecitabine Drugs 0.000 description 4
- 229960004562 carboplatin Drugs 0.000 description 4
- 229960005243 carmustine Drugs 0.000 description 4
- 238000002512 chemotherapy Methods 0.000 description 4
- 125000000753 cycloalkyl group Chemical group 0.000 description 4
- 229940127089 cytotoxic agent Drugs 0.000 description 4
- 229960002448 dasatinib Drugs 0.000 description 4
- WHBIGIKBNXZKFE-UHFFFAOYSA-N delavirdine Chemical compound CC(C)NC1=CC=CN=C1N1CCN(C(=O)C=2NC3=CC=C(NS(C)(=O)=O)C=C3C=2)CC1 WHBIGIKBNXZKFE-UHFFFAOYSA-N 0.000 description 4
- 229960003668 docetaxel Drugs 0.000 description 4
- 241001493065 dsRNA viruses Species 0.000 description 4
- 239000003623 enhancer Substances 0.000 description 4
- 150000002148 esters Chemical class 0.000 description 4
- 210000003527 eukaryotic cell Anatomy 0.000 description 4
- 238000001943 fluorescence-activated cell sorting Methods 0.000 description 4
- 239000008273 gelatin Substances 0.000 description 4
- 229920000159 gelatin Polymers 0.000 description 4
- 235000019322 gelatine Nutrition 0.000 description 4
- 235000011852 gelatine desserts Nutrition 0.000 description 4
- 125000003827 glycol group Chemical group 0.000 description 4
- 239000001963 growth medium Substances 0.000 description 4
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 4
- 125000001183 hydrocarbyl group Chemical group 0.000 description 4
- 239000001257 hydrogen Substances 0.000 description 4
- 229910052739 hydrogen Inorganic materials 0.000 description 4
- 229940126546 immune checkpoint molecule Drugs 0.000 description 4
- 238000001727 in vivo Methods 0.000 description 4
- GUBGYTABKSRVRQ-QKKXKWKRSA-N lactose group Chemical group OC1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@@H](O)[C@H](O2)CO)[C@H](O1)CO GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 4
- 210000000265 leukocyte Anatomy 0.000 description 4
- 229960002247 lomustine Drugs 0.000 description 4
- 239000003580 lung surfactant Substances 0.000 description 4
- 208000003747 lymphoid leukemia Diseases 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 4
- GSNHKUDZZFZSJB-QYOOZWMWSA-N maraviroc Chemical compound CC(C)C1=NN=C(C)N1[C@@H]1C[C@H](N2CC[C@H](NC(=O)C3CCC(F)(F)CC3)C=3C=CC=CC=3)CC[C@H]2C1 GSNHKUDZZFZSJB-QYOOZWMWSA-N 0.000 description 4
- 229960004710 maraviroc Drugs 0.000 description 4
- 239000003550 marker Substances 0.000 description 4
- 229960001756 oxaliplatin Drugs 0.000 description 4
- 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 4
- 201000002528 pancreatic cancer Diseases 0.000 description 4
- 208000008443 pancreatic carcinoma Diseases 0.000 description 4
- 239000008177 pharmaceutical agent Substances 0.000 description 4
- 150000003904 phospholipids Chemical class 0.000 description 4
- 230000008488 polyadenylation Effects 0.000 description 4
- 229960000624 procarbazine Drugs 0.000 description 4
- CPTBDICYNRMXFX-UHFFFAOYSA-N procarbazine Chemical compound CNNCC1=CC=C(C(=O)NC(C)C)C=C1 CPTBDICYNRMXFX-UHFFFAOYSA-N 0.000 description 4
- AQHHHDLHHXJYJD-UHFFFAOYSA-N propranolol Chemical compound C1=CC=C2C(OCC(O)CNC(C)C)=CC=CC2=C1 AQHHHDLHHXJYJD-UHFFFAOYSA-N 0.000 description 4
- 230000002829 reductive effect Effects 0.000 description 4
- 229960004641 rituximab Drugs 0.000 description 4
- 230000011664 signaling Effects 0.000 description 4
- 210000000130 stem cell Anatomy 0.000 description 4
- 239000005720 sucrose Substances 0.000 description 4
- 150000008163 sugars Chemical class 0.000 description 4
- 229960004964 temozolomide Drugs 0.000 description 4
- 229960003433 thalidomide Drugs 0.000 description 4
- 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 4
- 229960000303 topotecan Drugs 0.000 description 4
- 229960005294 triamcinolone Drugs 0.000 description 4
- GFNANZIMVAIWHM-OBYCQNJPSA-N triamcinolone Chemical compound O=C1C=C[C@]2(C)[C@@]3(F)[C@@H](O)C[C@](C)([C@@]([C@H](O)C4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 GFNANZIMVAIWHM-OBYCQNJPSA-N 0.000 description 4
- 210000003171 tumor-infiltrating lymphocyte Anatomy 0.000 description 4
- WWYNJERNGUHSAO-XUDSTZEESA-N (+)-Norgestrel Chemical compound O=C1CC[C@@H]2[C@H]3CC[C@](CC)([C@](CC4)(O)C#C)[C@@H]4[C@@H]3CCC2=C1 WWYNJERNGUHSAO-XUDSTZEESA-N 0.000 description 3
- FDKXTQMXEQVLRF-ZHACJKMWSA-N (E)-dacarbazine Chemical compound CN(C)\N=N\c1[nH]cnc1C(N)=O FDKXTQMXEQVLRF-ZHACJKMWSA-N 0.000 description 3
- FWMNVWWHGCHHJJ-SKKKGAJSSA-N 4-amino-1-[(2r)-6-amino-2-[[(2r)-2-[[(2r)-2-[[(2r)-2-amino-3-phenylpropanoyl]amino]-3-phenylpropanoyl]amino]-4-methylpentanoyl]amino]hexanoyl]piperidine-4-carboxylic acid Chemical compound C([C@H](C(=O)N[C@H](CC(C)C)C(=O)N[C@H](CCCCN)C(=O)N1CCC(N)(CC1)C(O)=O)NC(=O)[C@H](N)CC=1C=CC=CC=1)C1=CC=CC=C1 FWMNVWWHGCHHJJ-SKKKGAJSSA-N 0.000 description 3
- 208000031261 Acute myeloid leukaemia Diseases 0.000 description 3
- 241000894006 Bacteria Species 0.000 description 3
- KUVIULQEHSCUHY-XYWKZLDCSA-N Beclometasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(Cl)[C@@H]1[C@@H]1C[C@H](C)[C@@](C(=O)COC(=O)CC)(OC(=O)CC)[C@@]1(C)C[C@@H]2O KUVIULQEHSCUHY-XYWKZLDCSA-N 0.000 description 3
- 206010005003 Bladder cancer Diseases 0.000 description 3
- 102100027207 CD27 antigen Human genes 0.000 description 3
- LUKZNWIVRBCLON-GXOBDPJESA-N Ciclesonide Chemical compound C1([C@H]2O[C@@]3([C@H](O2)C[C@@H]2[C@@]3(C[C@H](O)[C@@H]3[C@@]4(C)C=CC(=O)C=C4CC[C@H]32)C)C(=O)COC(=O)C(C)C)CCCCC1 LUKZNWIVRBCLON-GXOBDPJESA-N 0.000 description 3
- NENBAISIHCWPKP-UHFFFAOYSA-N Clofenamide Chemical compound NS(=O)(=O)C1=CC=C(Cl)C(S(N)(=O)=O)=C1 NENBAISIHCWPKP-UHFFFAOYSA-N 0.000 description 3
- 206010009944 Colon cancer Diseases 0.000 description 3
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 3
- 102000053602 DNA Human genes 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 3
- 208000021309 Germ cell tumor Diseases 0.000 description 3
- 208000032612 Glial tumor Diseases 0.000 description 3
- 208000009329 Graft vs Host Disease Diseases 0.000 description 3
- 108010017080 Granulocyte Colony-Stimulating Factor Proteins 0.000 description 3
- 102000004269 Granulocyte Colony-Stimulating Factor Human genes 0.000 description 3
- 241000711549 Hepacivirus C Species 0.000 description 3
- 241000700721 Hepatitis B virus Species 0.000 description 3
- 241000724675 Hepatitis E virus Species 0.000 description 3
- 208000037262 Hepatitis delta Diseases 0.000 description 3
- 241000724709 Hepatitis delta virus Species 0.000 description 3
- 101000914511 Homo sapiens CD27 antigen Proteins 0.000 description 3
- 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 3
- 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 3
- 102000006992 Interferon-alpha Human genes 0.000 description 3
- 108010047761 Interferon-alpha Proteins 0.000 description 3
- 108010050904 Interferons Proteins 0.000 description 3
- 102000014150 Interferons Human genes 0.000 description 3
- 102000013462 Interleukin-12 Human genes 0.000 description 3
- 108010065805 Interleukin-12 Proteins 0.000 description 3
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 3
- 239000002177 L01XE27 - Ibrutinib Substances 0.000 description 3
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 3
- 229930195725 Mannitol Natural products 0.000 description 3
- 208000033776 Myeloid Acute Leukemia Diseases 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 229910003827 NRaRb Inorganic materials 0.000 description 3
- 208000034176 Neoplasms, Germ Cell and Embryonal Diseases 0.000 description 3
- 102000003729 Neprilysin Human genes 0.000 description 3
- 108090000028 Neprilysin Proteins 0.000 description 3
- 101100037618 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) ant-1 gene Proteins 0.000 description 3
- 229960005552 PAC-1 Drugs 0.000 description 3
- 235000021314 Palmitic acid Nutrition 0.000 description 3
- 102000003993 Phosphatidylinositol 3-kinases Human genes 0.000 description 3
- 108090001050 Phosphoric Diester Hydrolases Proteins 0.000 description 3
- 102000004861 Phosphoric Diester Hydrolases Human genes 0.000 description 3
- 102000002808 Pituitary adenylate cyclase-activating polypeptide Human genes 0.000 description 3
- 108010004684 Pituitary adenylate cyclase-activating polypeptide Proteins 0.000 description 3
- 206010038389 Renal cancer Diseases 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- 208000021712 Soft tissue sarcoma Diseases 0.000 description 3
- 208000005718 Stomach Neoplasms Diseases 0.000 description 3
- 102000016266 T-Cell Antigen Receptors Human genes 0.000 description 3
- 206010043376 Tetanus Diseases 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- HDOVUKNUBWVHOX-QMMMGPOBSA-N Valacyclovir Chemical compound N1C(N)=NC(=O)C2=C1N(COCCOC(=O)[C@@H](N)C(C)C)C=N2 HDOVUKNUBWVHOX-QMMMGPOBSA-N 0.000 description 3
- 102100038388 Vasoactive intestinal polypeptide receptor 1 Human genes 0.000 description 3
- 101710137655 Vasoactive intestinal polypeptide receptor 1 Proteins 0.000 description 3
- JXLYSJRDGCGARV-WWYNWVTFSA-N Vinblastine Natural products O=C(O[C@H]1[C@](O)(C(=O)OC)[C@@H]2N(C)c3c(cc(c(OC)c3)[C@]3(C(=O)OC)c4[nH]c5c(c4CCN4C[C@](O)(CC)C[C@H](C3)C4)cccc5)[C@@]32[C@H]2[C@@]1(CC)C=CCN2CC3)C JXLYSJRDGCGARV-WWYNWVTFSA-N 0.000 description 3
- 125000003342 alkenyl group Chemical group 0.000 description 3
- 125000000304 alkynyl group Chemical group 0.000 description 3
- 125000000266 alpha-aminoacyl group Chemical group 0.000 description 3
- DKNWSYNQZKUICI-UHFFFAOYSA-N amantadine Chemical compound C1C(C2)CC3CC2CC1(N)C3 DKNWSYNQZKUICI-UHFFFAOYSA-N 0.000 description 3
- 229960003805 amantadine Drugs 0.000 description 3
- 230000003042 antagnostic effect Effects 0.000 description 3
- 239000000596 artificial lung surfactant Substances 0.000 description 3
- 229960002170 azathioprine Drugs 0.000 description 3
- LMEKQMALGUDUQG-UHFFFAOYSA-N azathioprine Chemical compound CN1C=NC([N+]([O-])=O)=C1SC1=NC=NC2=C1NC=N2 LMEKQMALGUDUQG-UHFFFAOYSA-N 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- 210000000601 blood cell Anatomy 0.000 description 3
- 238000010322 bone marrow transplantation Methods 0.000 description 3
- 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 3
- 229960001467 bortezomib Drugs 0.000 description 3
- 210000000133 brain stem Anatomy 0.000 description 3
- 210000000481 breast Anatomy 0.000 description 3
- 239000000872 buffer Substances 0.000 description 3
- 150000001732 carboxylic acid derivatives Chemical group 0.000 description 3
- 230000010261 cell growth Effects 0.000 description 3
- 230000001413 cellular effect Effects 0.000 description 3
- 235000012000 cholesterol Nutrition 0.000 description 3
- 229960003728 ciclesonide Drugs 0.000 description 3
- 229960002883 clofenamide Drugs 0.000 description 3
- 208000029742 colonic neoplasm Diseases 0.000 description 3
- 235000018417 cysteine Nutrition 0.000 description 3
- 229960003901 dacarbazine Drugs 0.000 description 3
- 210000004443 dendritic cell Anatomy 0.000 description 3
- 206010013023 diphtheria Diseases 0.000 description 3
- 239000002552 dosage form Substances 0.000 description 3
- 239000003937 drug carrier Substances 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 239000000839 emulsion Substances 0.000 description 3
- 230000002255 enzymatic effect Effects 0.000 description 3
- 210000003743 erythrocyte Anatomy 0.000 description 3
- 229960000390 fludarabine Drugs 0.000 description 3
- GIUYCYHIANZCFB-FJFJXFQQSA-N fludarabine phosphate Chemical compound C1=NC=2C(N)=NC(F)=NC=2N1[C@@H]1O[C@H](COP(O)(O)=O)[C@@H](O)[C@@H]1O GIUYCYHIANZCFB-FJFJXFQQSA-N 0.000 description 3
- 239000012530 fluid Substances 0.000 description 3
- 206010017758 gastric cancer Diseases 0.000 description 3
- 229960005277 gemcitabine Drugs 0.000 description 3
- 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 3
- 208000024908 graft versus host disease Diseases 0.000 description 3
- 231100000844 hepatocellular carcinoma Toxicity 0.000 description 3
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 3
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 3
- 229960001507 ibrutinib Drugs 0.000 description 3
- XYFPWWZEPKGCCK-GOSISDBHSA-N ibrutinib Chemical compound C1=2C(N)=NC=NC=2N([C@H]2CN(CCC2)C(=O)C=C)N=C1C(C=C1)=CC=C1OC1=CC=CC=C1 XYFPWWZEPKGCCK-GOSISDBHSA-N 0.000 description 3
- 229960000908 idarubicin Drugs 0.000 description 3
- 229960002751 imiquimod Drugs 0.000 description 3
- DOUYETYNHWVLEO-UHFFFAOYSA-N imiquimod Chemical compound C1=CC=CC2=C3N(CC(C)C)C=NC3=C(N)N=C21 DOUYETYNHWVLEO-UHFFFAOYSA-N 0.000 description 3
- 238000012606 in vitro cell culture Methods 0.000 description 3
- 229940079322 interferon Drugs 0.000 description 3
- 210000003734 kidney Anatomy 0.000 description 3
- 238000002372 labelling Methods 0.000 description 3
- 239000008101 lactose Substances 0.000 description 3
- 229960003881 letrozole Drugs 0.000 description 3
- 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 3
- 229960004400 levonorgestrel Drugs 0.000 description 3
- 230000036210 malignancy Effects 0.000 description 3
- 239000000594 mannitol Substances 0.000 description 3
- 235000010355 mannitol Nutrition 0.000 description 3
- 229960004961 mechlorethamine Drugs 0.000 description 3
- HAWPXGHAZFHHAD-UHFFFAOYSA-N mechlorethamine Chemical class ClCCN(C)CCCl HAWPXGHAZFHHAD-UHFFFAOYSA-N 0.000 description 3
- 229960001786 megestrol Drugs 0.000 description 3
- JBVNBBXAMBZTMQ-CEGNMAFCSA-N megestrol Chemical compound C1=CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(=O)C)(O)[C@@]1(C)CC2 JBVNBBXAMBZTMQ-CEGNMAFCSA-N 0.000 description 3
- 229960004857 mitomycin Drugs 0.000 description 3
- 210000001616 monocyte Anatomy 0.000 description 3
- WQEPLUUGTLDZJY-UHFFFAOYSA-N n-Pentadecanoic acid Natural products CCCCCCCCCCCCCCC(O)=O WQEPLUUGTLDZJY-UHFFFAOYSA-N 0.000 description 3
- 210000002569 neuron Anatomy 0.000 description 3
- 230000007935 neutral effect Effects 0.000 description 3
- NQDJXKOVJZTUJA-UHFFFAOYSA-N nevirapine Chemical compound C12=NC=CC=C2C(=O)NC=2C(C)=CC=NC=2N1C1CC1 NQDJXKOVJZTUJA-UHFFFAOYSA-N 0.000 description 3
- 244000052769 pathogen Species 0.000 description 3
- 230000001717 pathogenic effect Effects 0.000 description 3
- 210000005259 peripheral blood Anatomy 0.000 description 3
- 239000011886 peripheral blood Substances 0.000 description 3
- 229940043441 phosphoinositide 3-kinase inhibitor Drugs 0.000 description 3
- 210000004180 plasmocyte Anatomy 0.000 description 3
- 229960005205 prednisolone Drugs 0.000 description 3
- 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 3
- 239000000047 product Substances 0.000 description 3
- 230000000069 prophylactic effect Effects 0.000 description 3
- 229960004063 propylene glycol Drugs 0.000 description 3
- 235000013772 propylene glycol Nutrition 0.000 description 3
- 238000001959 radiotherapy Methods 0.000 description 3
- 235000011803 sesame oil Nutrition 0.000 description 3
- 239000008159 sesame oil Substances 0.000 description 3
- 150000003431 steroids Chemical class 0.000 description 3
- 201000011549 stomach cancer Diseases 0.000 description 3
- 239000000758 substrate Substances 0.000 description 3
- 239000004094 surface-active agent Substances 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 208000024891 symptom Diseases 0.000 description 3
- 239000000454 talc Substances 0.000 description 3
- 229910052623 talc Inorganic materials 0.000 description 3
- 235000012222 talc Nutrition 0.000 description 3
- 238000002560 therapeutic procedure Methods 0.000 description 3
- 238000013519 translation Methods 0.000 description 3
- 241001430294 unidentified retrovirus Species 0.000 description 3
- 201000005112 urinary bladder cancer Diseases 0.000 description 3
- 229940093257 valacyclovir Drugs 0.000 description 3
- 229960003048 vinblastine Drugs 0.000 description 3
- JXLYSJRDGCGARV-XQKSVPLYSA-N vincaleukoblastine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 JXLYSJRDGCGARV-XQKSVPLYSA-N 0.000 description 3
- GBABOYUKABKIAF-GHYRFKGUSA-N vinorelbine Chemical compound C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC GBABOYUKABKIAF-GHYRFKGUSA-N 0.000 description 3
- 229960002066 vinorelbine Drugs 0.000 description 3
- PUPZLCDOIYMWBV-UHFFFAOYSA-N (+/-)-1,3-Butanediol Chemical compound CC(O)CCO PUPZLCDOIYMWBV-UHFFFAOYSA-N 0.000 description 2
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 description 2
- FELGMEQIXOGIFQ-CYBMUJFWSA-N (3r)-9-methyl-3-[(2-methylimidazol-1-yl)methyl]-2,3-dihydro-1h-carbazol-4-one Chemical compound CC1=NC=CN1C[C@@H]1C(=O)C(C=2C(=CC=CC=2)N2C)=C2CC1 FELGMEQIXOGIFQ-CYBMUJFWSA-N 0.000 description 2
- IFGIYSGOEZJNBE-LHJYHSJWSA-N (3s,4r,4as,7ar,12bs)-3-(cyclopropylmethyl)-4a,9-dihydroxy-3-methyl-2,4,5,6,7a,13-hexahydro-1h-4,12-methanobenzofuro[3,2-e]isoquinoline-3-ium-7-one;bromide Chemical compound [Br-].C([N@@+]1(C)[C@@H]2CC=3C4=C(C(=CC=3)O)O[C@@H]3[C@]4([C@@]2(O)CCC3=O)CC1)C1CC1 IFGIYSGOEZJNBE-LHJYHSJWSA-N 0.000 description 2
- 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 2
- PAZGBAOHGQRCBP-ZCXUNETKSA-N 1-Palmitoyl-2-oleoylglycero-3-phosphoglycerol Chemical compound CCCCCCCCCCCCCCCC(=O)OCC(COP(O)(=O)OCC(O)CO)OC(=O)CCCCCCC\C=C/CCCCCCCC PAZGBAOHGQRCBP-ZCXUNETKSA-N 0.000 description 2
- YQNRVGJCPCNMKT-LFVJCYFKSA-N 2-[(e)-[[2-(4-benzylpiperazin-1-ium-1-yl)acetyl]hydrazinylidene]methyl]-6-prop-2-enylphenolate Chemical compound [O-]C1=C(CC=C)C=CC=C1\C=N\NC(=O)C[NH+]1CCN(CC=2C=CC=CC=2)CC1 YQNRVGJCPCNMKT-LFVJCYFKSA-N 0.000 description 2
- NDMPLJNOPCLANR-UHFFFAOYSA-N 3,4-dihydroxy-15-(4-hydroxy-18-methoxycarbonyl-5,18-seco-ibogamin-18-yl)-16-methoxy-1-methyl-6,7-didehydro-aspidospermidine-3-carboxylic acid methyl ester Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 NDMPLJNOPCLANR-UHFFFAOYSA-N 0.000 description 2
- LGZKGOGODCLQHG-CYBMUJFWSA-N 5-[(2r)-2-hydroxy-2-(3,4,5-trimethoxyphenyl)ethyl]-2-methoxyphenol Chemical compound C1=C(O)C(OC)=CC=C1C[C@@H](O)C1=CC(OC)=C(OC)C(OC)=C1 LGZKGOGODCLQHG-CYBMUJFWSA-N 0.000 description 2
- ZGMLACURZVGTPK-UHFFFAOYSA-N 5-fluoranyl-1h-pyrimidine-2,4-dione Chemical compound OC1=NC=C(F)C(O)=N1.FC1=CNC(=O)NC1=O ZGMLACURZVGTPK-UHFFFAOYSA-N 0.000 description 2
- WYWHKKSPHMUBEB-UHFFFAOYSA-N 6-Mercaptoguanine Natural products N1C(N)=NC(=S)C2=C1N=CN2 WYWHKKSPHMUBEB-UHFFFAOYSA-N 0.000 description 2
- XDBHURGONHZNJF-UHFFFAOYSA-N 6-[2-(3,4-diethoxyphenyl)-1,3-thiazol-4-yl]pyridine-2-carboxylic acid Chemical compound C1=C(OCC)C(OCC)=CC=C1C1=NC(C=2N=C(C=CC=2)C(O)=O)=CS1 XDBHURGONHZNJF-UHFFFAOYSA-N 0.000 description 2
- 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
- 101710148588 ADP,ATP carrier protein 2 Proteins 0.000 description 2
- 101710165307 ADP,ATP carrier protein 2, mitochondrial Proteins 0.000 description 2
- 101710102718 ADP/ATP translocase 2 Proteins 0.000 description 2
- 101710102720 ADP/ATP translocase 4 Proteins 0.000 description 2
- 102100026400 ADP/ATP translocase 4 Human genes 0.000 description 2
- 208000036764 Adenocarcinoma of the esophagus Diseases 0.000 description 2
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 2
- 102000001381 Arachidonate 5-Lipoxygenase Human genes 0.000 description 2
- 108010093579 Arachidonate 5-lipoxygenase Proteins 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
- AXRYRYVKAWYZBR-UHFFFAOYSA-N Atazanavir Natural products C=1C=C(C=2N=CC=CC=2)C=CC=1CN(NC(=O)C(NC(=O)OC)C(C)(C)C)CC(O)C(NC(=O)C(NC(=O)OC)C(C)(C)C)CC1=CC=CC=C1 AXRYRYVKAWYZBR-UHFFFAOYSA-N 0.000 description 2
- 108010019625 Atazanavir Sulfate Proteins 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 229930003347 Atropine Natural products 0.000 description 2
- 208000010839 B-cell chronic lymphocytic leukemia Diseases 0.000 description 2
- 208000032791 BCR-ABL1 positive chronic myelogenous leukemia Diseases 0.000 description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical class OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 2
- 241000283690 Bos taurus Species 0.000 description 2
- VOVIALXJUBGFJZ-KWVAZRHASA-N Budesonide Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@@H]2[C@@H]1[C@@H]1C[C@H]3OC(CCC)O[C@@]3(C(=O)CO)[C@@]1(C)C[C@@H]2O VOVIALXJUBGFJZ-KWVAZRHASA-N 0.000 description 2
- QAGYKUNXZHXKMR-UHFFFAOYSA-N CPD000469186 Natural products CC1=C(O)C=CC=C1C(=O)NC(C(O)CN1C(CC2CCCCC2C1)C(=O)NC(C)(C)C)CSC1=CC=CC=C1 QAGYKUNXZHXKMR-UHFFFAOYSA-N 0.000 description 2
- 101100462537 Caenorhabditis elegans pac-1 gene Proteins 0.000 description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical class [Ca] OYPRJOBELJOOCE-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
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 2
- 229920000623 Cellulose acetate phthalate Polymers 0.000 description 2
- 206010007953 Central nervous system lymphoma Diseases 0.000 description 2
- 206010008342 Cervix carcinoma Diseases 0.000 description 2
- VWFCHDSQECPREK-LURJTMIESA-N Cidofovir Chemical compound NC=1C=CN(C[C@@H](CO)OCP(O)(O)=O)C(=O)N=1 VWFCHDSQECPREK-LURJTMIESA-N 0.000 description 2
- 229920000858 Cyclodextrin Polymers 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
- 102000004127 Cytokines Human genes 0.000 description 2
- 108090000695 Cytokines Proteins 0.000 description 2
- 108010092160 Dactinomycin Proteins 0.000 description 2
- WEAHRLBPCANXCN-UHFFFAOYSA-N Daunomycin Natural products CCC1(O)CC(OC2CC(N)C(O)C(C)O2)c3cc4C(=O)c5c(OC)cccc5C(=O)c4c(O)c3C1 WEAHRLBPCANXCN-UHFFFAOYSA-N 0.000 description 2
- BXZVVICBKDXVGW-NKWVEPMBSA-N Didanosine Chemical compound O1[C@H](CO)CC[C@@H]1N1C(NC=NC2=O)=C2N=C1 BXZVVICBKDXVGW-NKWVEPMBSA-N 0.000 description 2
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 2
- 208000000461 Esophageal Neoplasms Diseases 0.000 description 2
- 239000001856 Ethyl cellulose Substances 0.000 description 2
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 2
- 108010029961 Filgrastim Proteins 0.000 description 2
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical class NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 2
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 2
- 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 2
- 108010069236 Goserelin Proteins 0.000 description 2
- 102100039619 Granulocyte colony-stimulating factor Human genes 0.000 description 2
- 102000004457 Granulocyte-Macrophage Colony-Stimulating Factor Human genes 0.000 description 2
- 108010017213 Granulocyte-Macrophage Colony-Stimulating Factor Proteins 0.000 description 2
- 208000002250 Hematologic Neoplasms Diseases 0.000 description 2
- 208000021519 Hodgkin lymphoma Diseases 0.000 description 2
- 241000282412 Homo Species 0.000 description 2
- 101000666868 Homo sapiens Vasoactive intestinal polypeptide receptor 2 Proteins 0.000 description 2
- 241000598171 Human adenovirus sp. Species 0.000 description 2
- 241000701085 Human alphaherpesvirus 3 Species 0.000 description 2
- 241001502974 Human gammaherpesvirus 8 Species 0.000 description 2
- 241000702617 Human parvovirus B19 Species 0.000 description 2
- VSNHCAURESNICA-UHFFFAOYSA-N Hydroxyurea Chemical compound NC(=O)NO VSNHCAURESNICA-UHFFFAOYSA-N 0.000 description 2
- RKUNBYITZUJHSG-UHFFFAOYSA-N Hyosciamin-hydrochlorid Natural products CN1C(C2)CCC1CC2OC(=O)C(CO)C1=CC=CC=C1 RKUNBYITZUJHSG-UHFFFAOYSA-N 0.000 description 2
- XQFRJNBWHJMXHO-RRKCRQDMSA-N IDUR Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(I)=C1 XQFRJNBWHJMXHO-RRKCRQDMSA-N 0.000 description 2
- ZJVFLBOZORBYFE-UHFFFAOYSA-N Ibudilast Chemical compound C1=CC=CC2=C(C(=O)C(C)C)C(C(C)C)=NN21 ZJVFLBOZORBYFE-UHFFFAOYSA-N 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical class C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- 206010061598 Immunodeficiency Diseases 0.000 description 2
- 102100040018 Interferon alpha-2 Human genes 0.000 description 2
- UQSXHKLRYXJYBZ-UHFFFAOYSA-N Iron oxide Chemical compound [Fe]=O UQSXHKLRYXJYBZ-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 241000701460 JC polyomavirus Species 0.000 description 2
- KJHKTHWMRKYKJE-SUGCFTRWSA-N Kaletra Chemical compound N1([C@@H](C(C)C)C(=O)N[C@H](C[C@H](O)[C@H](CC=2C=CC=CC=2)NC(=O)COC=2C(=CC=CC=2C)C)CC=2C=CC=CC=2)CCCNC1=O KJHKTHWMRKYKJE-SUGCFTRWSA-N 0.000 description 2
- 208000008839 Kidney Neoplasms Diseases 0.000 description 2
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 2
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 2
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 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
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 description 2
- KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical compound CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 description 2
- 239000005517 L01XE01 - Imatinib Substances 0.000 description 2
- 239000005411 L01XE02 - Gefitinib Substances 0.000 description 2
- 239000002147 L01XE04 - Sunitinib Substances 0.000 description 2
- 239000002136 L01XE07 - Lapatinib Substances 0.000 description 2
- 239000003798 L01XE11 - Pazopanib Substances 0.000 description 2
- 239000002146 L01XE16 - Crizotinib Substances 0.000 description 2
- XNRVGTHNYCNCFF-UHFFFAOYSA-N Lapatinib ditosylate monohydrate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1.CC1=CC=C(S(O)(=O)=O)C=C1.O1C(CNCCS(=O)(=O)C)=CC=C1C1=CC=C(N=CN=C2NC=3C=C(Cl)C(OCC=4C=C(F)C=CC=4)=CC=3)C2=C1 XNRVGTHNYCNCFF-UHFFFAOYSA-N 0.000 description 2
- 240000007472 Leucaena leucocephala Species 0.000 description 2
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 2
- 241000712899 Lymphocytic choriomeningitis mammarenavirus Species 0.000 description 2
- 239000004472 Lysine Substances 0.000 description 2
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 2
- 208000000172 Medulloblastoma Diseases 0.000 description 2
- BAPJBEWLBFYGME-UHFFFAOYSA-N Methyl acrylate Chemical compound COC(=O)C=C BAPJBEWLBFYGME-UHFFFAOYSA-N 0.000 description 2
- UCHDWCPVSPXUMX-TZIWLTJVSA-N Montelukast Chemical compound CC(C)(O)C1=CC=CC=C1CC[C@H](C=1C=C(\C=C\C=2N=C3C=C(Cl)C=CC3=CC=2)C=CC=1)SCC1(CC(O)=O)CC1 UCHDWCPVSPXUMX-TZIWLTJVSA-N 0.000 description 2
- 101100117764 Mus musculus Dusp2 gene Proteins 0.000 description 2
- 241001467552 Mycobacterium bovis BCG Species 0.000 description 2
- 201000003793 Myelodysplastic syndrome Diseases 0.000 description 2
- 208000033761 Myelogenous Chronic BCR-ABL Positive Leukemia Diseases 0.000 description 2
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 2
- 125000001429 N-terminal alpha-amino-acid group Chemical group 0.000 description 2
- GQPLMRYTRLFLPF-UHFFFAOYSA-N Nitrous Oxide Chemical compound [O-][N+]#N GQPLMRYTRLFLPF-UHFFFAOYSA-N 0.000 description 2
- 241001263478 Norovirus Species 0.000 description 2
- 108700001237 Nucleic Acid-Based Vaccines Proteins 0.000 description 2
- 206010030137 Oesophageal adenocarcinoma Diseases 0.000 description 2
- 206010030155 Oesophageal carcinoma Diseases 0.000 description 2
- 108091034117 Oligonucleotide Proteins 0.000 description 2
- 241000150452 Orthohantavirus Species 0.000 description 2
- JNTOCHDNEULJHD-UHFFFAOYSA-N Penciclovir Chemical compound N1C(N)=NC(=O)C2=C1N(CCC(CO)CO)C=N2 JNTOCHDNEULJHD-UHFFFAOYSA-N 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- IIXHQGSINFQLRR-UHFFFAOYSA-N Piceatannol Natural products Oc1ccc(C=Cc2c(O)c(O)c3CCCCc3c2O)cc1O IIXHQGSINFQLRR-UHFFFAOYSA-N 0.000 description 2
- 208000007452 Plasmacytoma Diseases 0.000 description 2
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical class [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- ATUOYWHBWRKTHZ-UHFFFAOYSA-N Propane Chemical compound CCC ATUOYWHBWRKTHZ-UHFFFAOYSA-N 0.000 description 2
- 239000004365 Protease Substances 0.000 description 2
- NCDNCNXCDXHOMX-UHFFFAOYSA-N Ritonavir Natural products C=1C=CC=CC=1CC(NC(=O)OCC=1SC=NC=1)C(O)CC(CC=1C=CC=CC=1)NC(=O)C(C(C)C)NC(=O)N(C)CC1=CSC(C(C)C)=N1 NCDNCNXCDXHOMX-UHFFFAOYSA-N 0.000 description 2
- 241001137861 Rotavirus B Species 0.000 description 2
- 241001506005 Rotavirus C Species 0.000 description 2
- 241000373026 Rotavirus D Species 0.000 description 2
- 241000315672 SARS coronavirus Species 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 108010090804 Streptavidin Proteins 0.000 description 2
- 108091008874 T cell receptors Proteins 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
- 229940032047 Tdap vaccine Drugs 0.000 description 2
- 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 2
- FOCVUCIESVLUNU-UHFFFAOYSA-N Thiotepa Chemical compound C1CN1P(N1CC1)(=S)N1CC1 FOCVUCIESVLUNU-UHFFFAOYSA-N 0.000 description 2
- 201000009365 Thymic carcinoma Diseases 0.000 description 2
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 2
- 208000023915 Ureteral Neoplasms Diseases 0.000 description 2
- 206010046392 Ureteric cancer Diseases 0.000 description 2
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 description 2
- 102100038286 Vasoactive intestinal polypeptide receptor 2 Human genes 0.000 description 2
- OIRDTQYFTABQOQ-UHTZMRCNSA-N Vidarabine Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@@H]1O OIRDTQYFTABQOQ-UHTZMRCNSA-N 0.000 description 2
- DDNCQMVWWZOMLN-IRLDBZIGSA-N Vinpocetine Chemical compound C1=CC=C2C(CCN3CCC4)=C5[C@@H]3[C@]4(CC)C=C(C(=O)OCC)N5C2=C1 DDNCQMVWWZOMLN-IRLDBZIGSA-N 0.000 description 2
- 208000033559 Waldenström macroglobulinemia Diseases 0.000 description 2
- 241000101098 Xenotropic MuLV-related virus Species 0.000 description 2
- YEEZWCHGZNKEEK-UHFFFAOYSA-N Zafirlukast Chemical compound COC1=CC(C(=O)NS(=O)(=O)C=2C(=CC=CC=2)C)=CC=C1CC(C1=C2)=CN(C)C1=CC=C2NC(=O)OC1CCCC1 YEEZWCHGZNKEEK-UHFFFAOYSA-N 0.000 description 2
- WREGKURFCTUGRC-POYBYMJQSA-N Zalcitabine Chemical compound O=C1N=C(N)C=CN1[C@@H]1O[C@H](CO)CC1 WREGKURFCTUGRC-POYBYMJQSA-N 0.000 description 2
- FPVRUILUEYSIMD-RPRRAYFGSA-N [(8s,9r,10s,11s,13s,14s,16r,17r)-9-fluoro-11-hydroxy-17-(2-hydroxyacetyl)-10,13,16-trimethyl-3-oxo-6,7,8,11,12,14,15,16-octahydrocyclopenta[a]phenanthren-17-yl] acetate Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(OC(C)=O)[C@@]1(C)C[C@@H]2O FPVRUILUEYSIMD-RPRRAYFGSA-N 0.000 description 2
- 229960004748 abacavir Drugs 0.000 description 2
- MCGSCOLBFJQGHM-SCZZXKLOSA-N abacavir Chemical compound C=12N=CN([C@H]3C=C[C@@H](CO)C3)C2=NC(N)=NC=1NC1CC1 MCGSCOLBFJQGHM-SCZZXKLOSA-N 0.000 description 2
- 229960004103 abiraterone acetate Drugs 0.000 description 2
- UVIQSJCZCSLXRZ-UBUQANBQSA-N abiraterone acetate Chemical compound C([C@@H]1[C@]2(C)CC[C@@H]3[C@@]4(C)CC[C@@H](CC4=CC[C@H]31)OC(=O)C)C=C2C1=CC=CN=C1 UVIQSJCZCSLXRZ-UBUQANBQSA-N 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 2
- 108010052004 acetyl-2-naphthylalanyl-3-chlorophenylalanyl-1-oxohexadecyl-seryl-4-aminophenylalanyl(hydroorotyl)-4-aminophenylalanyl(carbamoyl)-leucyl-ILys-prolyl-alaninamide Proteins 0.000 description 2
- 229960004150 aciclovir Drugs 0.000 description 2
- MKUXAQIIEYXACX-UHFFFAOYSA-N aciclovir Chemical compound N1C(N)=NC(=O)C2=C1N(COCCO)C=N2 MKUXAQIIEYXACX-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 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 2
- 125000004423 acyloxy group Chemical group 0.000 description 2
- 229960001997 adefovir Drugs 0.000 description 2
- WOZSCQDILHKSGG-UHFFFAOYSA-N adefovir depivoxil Chemical compound N1=CN=C2N(CCOCP(=O)(OCOC(=O)C(C)(C)C)OCOC(=O)C(C)(C)C)C=NC2=C1N WOZSCQDILHKSGG-UHFFFAOYSA-N 0.000 description 2
- 239000002671 adjuvant Substances 0.000 description 2
- 229940009456 adriamycin Drugs 0.000 description 2
- 125000003158 alcohol group Chemical group 0.000 description 2
- 108700025316 aldesleukin Proteins 0.000 description 2
- 229960005310 aldesleukin Drugs 0.000 description 2
- 235000010443 alginic acid Nutrition 0.000 description 2
- 229920000615 alginic acid Polymers 0.000 description 2
- 125000003545 alkoxy group Chemical group 0.000 description 2
- 125000005206 alkoxycarbonyloxymethyl group Chemical group 0.000 description 2
- 125000003282 alkyl amino group Chemical group 0.000 description 2
- 125000003368 amide group Chemical group 0.000 description 2
- 239000003708 ampul Substances 0.000 description 2
- 229960001220 amsacrine Drugs 0.000 description 2
- XCPGHVQEEXUHNC-UHFFFAOYSA-N amsacrine Chemical compound COC1=CC(NS(C)(=O)=O)=CC=C1NC1=C(C=CC=C2)C2=NC2=CC=CC=C12 XCPGHVQEEXUHNC-UHFFFAOYSA-N 0.000 description 2
- 229960002932 anastrozole Drugs 0.000 description 2
- YBBLVLTVTVSKRW-UHFFFAOYSA-N anastrozole Chemical compound N#CC(C)(C)C1=CC(C(C)(C#N)C)=CC(CN2N=CN=C2)=C1 YBBLVLTVTVSKRW-UHFFFAOYSA-N 0.000 description 2
- 230000006907 apoptotic process Effects 0.000 description 2
- YZXBAPSDXZZRGB-DOFZRALJSA-N arachidonic acid Chemical compound CCCCC\C=C/C\C=C/C\C=C/C\C=C/CCCC(O)=O YZXBAPSDXZZRGB-DOFZRALJSA-N 0.000 description 2
- 235000003704 aspartic acid Nutrition 0.000 description 2
- 229960003277 atazanavir Drugs 0.000 description 2
- AXRYRYVKAWYZBR-GASGPIRDSA-N atazanavir Chemical compound C([C@H](NC(=O)[C@@H](NC(=O)OC)C(C)(C)C)[C@@H](O)CN(CC=1C=CC(=CC=1)C=1N=CC=CC=1)NC(=O)[C@@H](NC(=O)OC)C(C)(C)C)C1=CC=CC=C1 AXRYRYVKAWYZBR-GASGPIRDSA-N 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- RKUNBYITZUJHSG-SPUOUPEWSA-N atropine Chemical compound O([C@H]1C[C@H]2CC[C@@H](C1)N2C)C(=O)C(CO)C1=CC=CC=C1 RKUNBYITZUJHSG-SPUOUPEWSA-N 0.000 description 2
- 229960000396 atropine Drugs 0.000 description 2
- 229950002916 avelumab Drugs 0.000 description 2
- 229960003005 axitinib Drugs 0.000 description 2
- 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 description 2
- 210000003719 b-lymphocyte Anatomy 0.000 description 2
- 229960000190 bacillus calmette–guérin vaccine Drugs 0.000 description 2
- 229950000210 beclometasone dipropionate Drugs 0.000 description 2
- 229960003094 belinostat Drugs 0.000 description 2
- NCNRHFGMJRPRSK-MDZDMXLPSA-N belinostat Chemical compound ONC(=O)\C=C\C1=CC=CC(S(=O)(=O)NC=2C=CC=CC=2)=C1 NCNRHFGMJRPRSK-MDZDMXLPSA-N 0.000 description 2
- 229960002707 bendamustine Drugs 0.000 description 2
- YTKUWDBFDASYHO-UHFFFAOYSA-N bendamustine Chemical compound ClCCN(CCCl)C1=CC=C2N(C)C(CCCC(O)=O)=NC2=C1 YTKUWDBFDASYHO-UHFFFAOYSA-N 0.000 description 2
- SESFRYSPDFLNCH-UHFFFAOYSA-N benzyl benzoate Chemical compound C=1C=CC=CC=1C(=O)OCC1=CC=CC=C1 SESFRYSPDFLNCH-UHFFFAOYSA-N 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 2
- 229960002938 bexarotene Drugs 0.000 description 2
- 229960000997 bicalutamide Drugs 0.000 description 2
- 201000009036 biliary tract cancer Diseases 0.000 description 2
- 208000020790 biliary tract neoplasm Diseases 0.000 description 2
- 229960002685 biotin Drugs 0.000 description 2
- 235000020958 biotin Nutrition 0.000 description 2
- 239000011616 biotin Substances 0.000 description 2
- 229960000517 boceprevir Drugs 0.000 description 2
- LHHCSNFAOIFYRV-DOVBMPENSA-N boceprevir Chemical compound O=C([C@@H]1[C@@H]2[C@@H](C2(C)C)CN1C(=O)[C@@H](NC(=O)NC(C)(C)C)C(C)(C)C)NC(C(=O)C(N)=O)CC1CCC1 LHHCSNFAOIFYRV-DOVBMPENSA-N 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 208000030224 brain astrocytoma Diseases 0.000 description 2
- 229960000455 brentuximab vedotin Drugs 0.000 description 2
- 229960004436 budesonide Drugs 0.000 description 2
- 239000011575 calcium Substances 0.000 description 2
- 229910052791 calcium Inorganic materials 0.000 description 2
- 239000001506 calcium phosphate Substances 0.000 description 2
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 2
- 239000008116 calcium stearate Substances 0.000 description 2
- 235000013539 calcium stearate Nutrition 0.000 description 2
- 125000001589 carboacyl group Chemical group 0.000 description 2
- 125000004452 carbocyclyl group Chemical group 0.000 description 2
- 150000001720 carbohydrates Chemical class 0.000 description 2
- 235000014633 carbohydrates Nutrition 0.000 description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 description 2
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 2
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 238000010523 cascade reaction Methods 0.000 description 2
- 239000004359 castor oil Substances 0.000 description 2
- 238000004113 cell culture Methods 0.000 description 2
- 230000004663 cell proliferation Effects 0.000 description 2
- 210000004671 cell-free system Anatomy 0.000 description 2
- 229940081734 cellulose acetate phthalate Drugs 0.000 description 2
- 210000003169 central nervous system Anatomy 0.000 description 2
- 201000010881 cervical cancer Diseases 0.000 description 2
- 229960005395 cetuximab Drugs 0.000 description 2
- 229960000541 cetyl alcohol Drugs 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 208000018805 childhood acute lymphoblastic leukemia Diseases 0.000 description 2
- 201000011633 childhood acute lymphocytic leukemia Diseases 0.000 description 2
- 108091006116 chimeric peptides Proteins 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
- OSASVXMJTNOKOY-UHFFFAOYSA-N chlorobutanol Chemical compound CC(C)(O)C(Cl)(Cl)Cl OSASVXMJTNOKOY-UHFFFAOYSA-N 0.000 description 2
- 229960000724 cidofovir Drugs 0.000 description 2
- 229960004703 clobetasol propionate Drugs 0.000 description 2
- CBGUOGMQLZIXBE-XGQKBEPLSA-N clobetasol propionate Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@H](C)[C@@](C(=O)CCl)(OC(=O)CC)[C@@]1(C)C[C@@H]2O CBGUOGMQLZIXBE-XGQKBEPLSA-N 0.000 description 2
- 210000001072 colon Anatomy 0.000 description 2
- LGZKGOGODCLQHG-UHFFFAOYSA-N combretastatin Natural products C1=C(O)C(OC)=CC=C1CC(O)C1=CC(OC)=C(OC)C(OC)=C1 LGZKGOGODCLQHG-UHFFFAOYSA-N 0.000 description 2
- PZBCKZWLPGJMAO-UHFFFAOYSA-N copanlisib Chemical compound C1=CC=2C3=NCCN3C(NC(=O)C=3C=NC(N)=NC=3)=NC=2C(OC)=C1OCCCN1CCOCC1 PZBCKZWLPGJMAO-UHFFFAOYSA-N 0.000 description 2
- 229950002550 copanlisib Drugs 0.000 description 2
- 229960005061 crizotinib Drugs 0.000 description 2
- KTEIFNKAUNYNJU-GFCCVEGCSA-N crizotinib Chemical compound O([C@H](C)C=1C(=C(F)C=CC=1Cl)Cl)C(C(=NC=1)N)=CC=1C(=C1)C=NN1C1CCNCC1 KTEIFNKAUNYNJU-GFCCVEGCSA-N 0.000 description 2
- 208000030381 cutaneous melanoma Diseases 0.000 description 2
- 125000004093 cyano group Chemical group *C#N 0.000 description 2
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 2
- 229960000684 cytarabine Drugs 0.000 description 2
- 230000001472 cytotoxic effect Effects 0.000 description 2
- 229960002465 dabrafenib Drugs 0.000 description 2
- BFSMGDJOXZAERB-UHFFFAOYSA-N dabrafenib Chemical compound S1C(C(C)(C)C)=NC(C=2C(=C(NS(=O)(=O)C=3C(=CC=CC=3F)F)C=CC=2)F)=C1C1=CC=NC(N)=N1 BFSMGDJOXZAERB-UHFFFAOYSA-N 0.000 description 2
- 229960000640 dactinomycin Drugs 0.000 description 2
- 229960005107 darunavir Drugs 0.000 description 2
- CJBJHOAVZSMMDJ-HEXNFIEUSA-N darunavir Chemical compound C([C@@H]([C@H](O)CN(CC(C)C)S(=O)(=O)C=1C=CC(N)=CC=1)NC(=O)O[C@@H]1[C@@H]2CCO[C@@H]2OC1)C1=CC=CC=C1 CJBJHOAVZSMMDJ-HEXNFIEUSA-N 0.000 description 2
- 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
- 229960002272 degarelix Drugs 0.000 description 2
- MEUCPCLKGZSHTA-XYAYPHGZSA-N degarelix Chemical compound C([C@H](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)NC(=O)[C@H](CC=1C=CC(NC(=O)[C@H]2NC(=O)NC(=O)C2)=CC=1)NC(=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(NC(N)=O)C=C1 MEUCPCLKGZSHTA-XYAYPHGZSA-N 0.000 description 2
- 229960005319 delavirdine Drugs 0.000 description 2
- 229960001251 denosumab Drugs 0.000 description 2
- CFCUWKMKBJTWLW-UHFFFAOYSA-N deoliosyl-3C-alpha-L-digitoxosyl-MTM Natural products CC=1C(O)=C2C(O)=C3C(=O)C(OC4OC(C)C(O)C(OC5OC(C)C(O)C(OC6OC(C)C(O)C(C)(O)C6)C5)C4)C(C(OC)C(=O)C(O)C(C)O)CC3=CC2=CC=1OC(OC(C)C1O)CC1OC1CC(O)C(O)C(C)O1 CFCUWKMKBJTWLW-UHFFFAOYSA-N 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 229960003657 dexamethasone acetate Drugs 0.000 description 2
- 239000008121 dextrose Substances 0.000 description 2
- 229960002656 didanosine Drugs 0.000 description 2
- 239000006185 dispersion Substances 0.000 description 2
- 239000003995 emulsifying agent Substances 0.000 description 2
- 210000003890 endocrine cell Anatomy 0.000 description 2
- 239000002702 enteric coating Substances 0.000 description 2
- 238000009505 enteric coating Methods 0.000 description 2
- 208000028653 esophageal adenocarcinoma Diseases 0.000 description 2
- 201000004101 esophageal cancer Diseases 0.000 description 2
- 239000003797 essential amino acid Chemical class 0.000 description 2
- 235000020776 essential amino acid Nutrition 0.000 description 2
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 description 2
- 235000019325 ethyl cellulose Nutrition 0.000 description 2
- 229920001249 ethyl cellulose Polymers 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 229960000255 exemestane Drugs 0.000 description 2
- 230000001747 exhibiting effect Effects 0.000 description 2
- 239000000284 extract Substances 0.000 description 2
- 150000004665 fatty acids Chemical class 0.000 description 2
- 229960004177 filgrastim Drugs 0.000 description 2
- 239000000945 filler Substances 0.000 description 2
- DBEPLOCGEIEOCV-WSBQPABSSA-N finasteride Chemical compound N([C@@H]1CC2)C(=O)C=C[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H](C(=O)NC(C)(C)C)[C@@]2(C)CC1 DBEPLOCGEIEOCV-WSBQPABSSA-N 0.000 description 2
- 229960004039 finasteride Drugs 0.000 description 2
- MHMNJMPURVTYEJ-UHFFFAOYSA-N fluorescein-5-isothiocyanate Chemical compound O1C(=O)C2=CC(N=C=S)=CC=C2C21C1=CC=C(O)C=C1OC1=CC(O)=CC=C21 MHMNJMPURVTYEJ-UHFFFAOYSA-N 0.000 description 2
- 229960002949 fluorouracil Drugs 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
- 235000008191 folinic acid Nutrition 0.000 description 2
- 239000011672 folinic acid Substances 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 230000002496 gastric effect Effects 0.000 description 2
- 229960002584 gefitinib Drugs 0.000 description 2
- XGALLCVXEZPNRQ-UHFFFAOYSA-N gefitinib Chemical compound C=12C=C(OCCCN3CCOCC3)C(OC)=CC2=NC=NC=1NC1=CC=C(F)C(Cl)=C1 XGALLCVXEZPNRQ-UHFFFAOYSA-N 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 235000013922 glutamic acid Nutrition 0.000 description 2
- 239000004220 glutamic acid Substances 0.000 description 2
- 229960002913 goserelin Drugs 0.000 description 2
- 230000003394 haemopoietic effect Effects 0.000 description 2
- 229910052736 halogen Inorganic materials 0.000 description 2
- 150000002367 halogens Chemical class 0.000 description 2
- 125000001072 heteroaryl group Chemical group 0.000 description 2
- 125000004446 heteroarylalkyl group Chemical group 0.000 description 2
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 2
- 229960001330 hydroxycarbamide Drugs 0.000 description 2
- 230000002267 hypothalamic effect Effects 0.000 description 2
- 229960002491 ibudilast Drugs 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
- 229960002411 imatinib Drugs 0.000 description 2
- KTUFNOKKBVMGRW-UHFFFAOYSA-N imatinib Chemical compound C1CN(C)CCN1CC1=CC=C(C(=O)NC=2C=C(NC=3N=C(C=CN=3)C=3C=NC=CC=3)C(C)=CC=2)C=C1 KTUFNOKKBVMGRW-UHFFFAOYSA-N 0.000 description 2
- 238000010348 incorporation Methods 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- 230000002458 infectious effect Effects 0.000 description 2
- 230000008595 infiltration Effects 0.000 description 2
- 238000001764 infiltration Methods 0.000 description 2
- 229960003971 influenza vaccine Drugs 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 201000010982 kidney cancer Diseases 0.000 description 2
- 210000000244 kidney pelvis Anatomy 0.000 description 2
- 229960001627 lamivudine Drugs 0.000 description 2
- JTEGQNOMFQHVDC-NKWVEPMBSA-N lamivudine Chemical compound O=C1N=C(N)C=CN1[C@H]1O[C@@H](CO)SC1 JTEGQNOMFQHVDC-NKWVEPMBSA-N 0.000 description 2
- 229960004891 lapatinib Drugs 0.000 description 2
- 229960003784 lenvatinib Drugs 0.000 description 2
- WOSKHXYHFSIKNG-UHFFFAOYSA-N lenvatinib Chemical compound C=12C=C(C(N)=O)C(OC)=CC2=NC=CC=1OC(C=C1Cl)=CC=C1NC(=O)NC1CC1 WOSKHXYHFSIKNG-UHFFFAOYSA-N 0.000 description 2
- 229960001691 leucovorin Drugs 0.000 description 2
- 230000000670 limiting effect Effects 0.000 description 2
- 239000008297 liquid dosage form Substances 0.000 description 2
- 208000014018 liver neoplasm Diseases 0.000 description 2
- 229960004525 lopinavir Drugs 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- 201000005202 lung cancer Diseases 0.000 description 2
- 208000020816 lung neoplasm Diseases 0.000 description 2
- 229940066294 lung surfactant Drugs 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- OCSMOTCMPXTDND-OUAUKWLOSA-N marimastat Chemical compound CNC(=O)[C@H](C(C)(C)C)NC(=O)[C@H](CC(C)C)[C@H](O)C(=O)NO OCSMOTCMPXTDND-OUAUKWLOSA-N 0.000 description 2
- 229950008959 marimastat Drugs 0.000 description 2
- 239000002609 medium Substances 0.000 description 2
- 229910044991 metal oxide Inorganic materials 0.000 description 2
- 150000004706 metal oxides Chemical class 0.000 description 2
- 208000037970 metastatic squamous neck cancer Diseases 0.000 description 2
- XVAIDCNLVLTVFM-UHFFFAOYSA-N methacetin Chemical compound COC1=CC=C(NC(C)=O)C=C1 XVAIDCNLVLTVFM-UHFFFAOYSA-N 0.000 description 2
- 229920003145 methacrylic acid copolymer Polymers 0.000 description 2
- 229940117841 methacrylic acid copolymer Drugs 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 229960002834 methylnaltrexone bromide Drugs 0.000 description 2
- BMGQWWVMWDBQGC-IIFHNQTCSA-N midostaurin Chemical compound CN([C@H]1[C@H]([C@]2(C)O[C@@H](N3C4=CC=CC=C4C4=C5C(=O)NCC5=C5C6=CC=CC=C6N2C5=C43)C1)OC)C(=O)C1=CC=CC=C1 BMGQWWVMWDBQGC-IIFHNQTCSA-N 0.000 description 2
- 229950010895 midostaurin Drugs 0.000 description 2
- 239000002480 mineral oil Substances 0.000 description 2
- 235000010446 mineral oil Nutrition 0.000 description 2
- CFCUWKMKBJTWLW-BKHRDMLASA-N mithramycin Chemical compound O([C@@H]1C[C@@H](O[C@H](C)[C@H]1O)OC=1C=C2C=C3C[C@H]([C@@H](C(=O)C3=C(O)C2=C(O)C=1C)O[C@@H]1O[C@H](C)[C@@H](O)[C@H](O[C@@H]2O[C@H](C)[C@H](O)[C@H](O[C@@H]3O[C@H](C)[C@@H](O)[C@@](C)(O)C3)C2)C1)[C@H](OC)C(=O)[C@@H](O)[C@@H](C)O)[C@H]1C[C@@H](O)[C@H](O)[C@@H](C)O1 CFCUWKMKBJTWLW-BKHRDMLASA-N 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- WOFMFGQZHJDGCX-ZULDAHANSA-N mometasone furoate Chemical compound O([C@]1([C@@]2(C)C[C@H](O)[C@]3(Cl)[C@@]4(C)C=CC(=O)C=C4CC[C@H]3[C@@H]2C[C@H]1C)C(=O)CCl)C(=O)C1=CC=CO1 WOFMFGQZHJDGCX-ZULDAHANSA-N 0.000 description 2
- 229960002744 mometasone furoate Drugs 0.000 description 2
- 210000005087 mononuclear cell Anatomy 0.000 description 2
- 229960005127 montelukast Drugs 0.000 description 2
- 210000000066 myeloid cell Anatomy 0.000 description 2
- 208000025113 myeloid leukemia Diseases 0.000 description 2
- 201000000050 myeloid neoplasm Diseases 0.000 description 2
- QAGYKUNXZHXKMR-HKWSIXNMSA-N nelfinavir Chemical compound CC1=C(O)C=CC=C1C(=O)N[C@H]([C@H](O)CN1[C@@H](C[C@@H]2CCCC[C@@H]2C1)C(=O)NC(C)(C)C)CSC1=CC=CC=C1 QAGYKUNXZHXKMR-HKWSIXNMSA-N 0.000 description 2
- 229960000884 nelfinavir Drugs 0.000 description 2
- WAXQNWCZJDTGBU-UHFFFAOYSA-N netupitant Chemical compound C=1N=C(N2CCN(C)CC2)C=C(C=2C(=CC=CC=2)C)C=1N(C)C(=O)C(C)(C)C1=CC(C(F)(F)F)=CC(C(F)(F)F)=C1 WAXQNWCZJDTGBU-UHFFFAOYSA-N 0.000 description 2
- 229960005163 netupitant Drugs 0.000 description 2
- 229960003301 nivolumab Drugs 0.000 description 2
- 229940023146 nucleic acid vaccine Drugs 0.000 description 2
- 239000002773 nucleotide Substances 0.000 description 2
- 125000003729 nucleotide group Chemical group 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 235000019198 oils Nutrition 0.000 description 2
- 229960000572 olaparib Drugs 0.000 description 2
- FAQDUNYVKQKNLD-UHFFFAOYSA-N olaparib Chemical compound FC1=CC=C(CC2=C3[CH]C=CC=C3C(=O)N=N2)C=C1C(=O)N(CC1)CCN1C(=O)C1CC1 FAQDUNYVKQKNLD-UHFFFAOYSA-N 0.000 description 2
- 229950008516 olaratumab Drugs 0.000 description 2
- 239000004006 olive oil Substances 0.000 description 2
- 229960005343 ondansetron Drugs 0.000 description 2
- 229960003752 oseltamivir Drugs 0.000 description 2
- NENPYTRHICXVCS-YNEHKIRRSA-N oseltamivir acid Chemical compound CCC(CC)O[C@@H]1C=C(C(O)=O)C[C@H](N)[C@H]1NC(C)=O NENPYTRHICXVCS-YNEHKIRRSA-N 0.000 description 2
- 229960004390 palbociclib Drugs 0.000 description 2
- AHJRHEGDXFFMBM-UHFFFAOYSA-N palbociclib Chemical compound N1=C2N(C3CCCC3)C(=O)C(C(=O)C)=C(C)C2=CN=C1NC(N=C1)=CC=C1N1CCNCC1 AHJRHEGDXFFMBM-UHFFFAOYSA-N 0.000 description 2
- CPZBLNMUGSZIPR-NVXWUHKLSA-N palonosetron Chemical compound C1N(CC2)CCC2[C@@H]1N1C(=O)C(C=CC=C2CCC3)=C2[C@H]3C1 CPZBLNMUGSZIPR-NVXWUHKLSA-N 0.000 description 2
- 229960002131 palonosetron Drugs 0.000 description 2
- 210000000496 pancreas Anatomy 0.000 description 2
- 201000002530 pancreatic endocrine carcinoma Diseases 0.000 description 2
- 229960001972 panitumumab Drugs 0.000 description 2
- 229960000639 pazopanib Drugs 0.000 description 2
- CUIHSIWYWATEQL-UHFFFAOYSA-N pazopanib Chemical compound C1=CC2=C(C)N(C)N=C2C=C1N(C)C(N=1)=CC=NC=1NC1=CC=C(C)C(S(N)(=O)=O)=C1 CUIHSIWYWATEQL-UHFFFAOYSA-N 0.000 description 2
- 210000004197 pelvis Anatomy 0.000 description 2
- 229960001179 penciclovir Drugs 0.000 description 2
- XRQDFNLINLXZLB-CKIKVBCHSA-N peramivir Chemical compound CCC(CC)[C@H](NC(C)=O)[C@@H]1[C@H](O)[C@@H](C(O)=O)C[C@H]1NC(N)=N XRQDFNLINLXZLB-CKIKVBCHSA-N 0.000 description 2
- 229960001084 peramivir Drugs 0.000 description 2
- SZFPYBIJACMNJV-UHFFFAOYSA-N perifosine Chemical compound CCCCCCCCCCCCCCCCCCOP([O-])(=O)OC1CC[N+](C)(C)CC1 SZFPYBIJACMNJV-UHFFFAOYSA-N 0.000 description 2
- 229950010632 perifosine Drugs 0.000 description 2
- 229960002087 pertuzumab Drugs 0.000 description 2
- 230000003285 pharmacodynamic effect Effects 0.000 description 2
- 229960005190 phenylalanine Drugs 0.000 description 2
- CDRPUGZCRXZLFL-OWOJBTEDSA-N piceatannol Chemical compound OC1=CC(O)=CC(\C=C\C=2C=C(O)C(O)=CC=2)=C1 CDRPUGZCRXZLFL-OWOJBTEDSA-N 0.000 description 2
- 229960002292 piperacillin Drugs 0.000 description 2
- WCMIIGXFCMNQDS-IDYPWDAWSA-M piperacillin sodium Chemical compound [Na+].O=C1C(=O)N(CC)CCN1C(=O)N[C@H](C=1C=CC=CC=1)C(=O)N[C@@H]1C(=O)N2[C@@H](C([O-])=O)C(C)(C)S[C@@H]21 WCMIIGXFCMNQDS-IDYPWDAWSA-M 0.000 description 2
- UFTCZKMBJOPXDM-XXFCQBPRSA-N pituitary adenylate cyclase-activating polypeptide Chemical compound C([C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(O)=O)C(=O)NCC(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C)C(=O)N[C@@H](C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCCN)C(N)=O)C1=CN=CN1 UFTCZKMBJOPXDM-XXFCQBPRSA-N 0.000 description 2
- 230000001817 pituitary effect Effects 0.000 description 2
- 229960003171 plicamycin Drugs 0.000 description 2
- YJGVMLPVUAXIQN-XVVDYKMHSA-N podophyllotoxin Chemical compound COC1=C(OC)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@H](O)[C@@H]3[C@@H]2C(OC3)=O)=C1 YJGVMLPVUAXIQN-XVVDYKMHSA-N 0.000 description 2
- 229960001539 poliomyelitis vaccine Drugs 0.000 description 2
- 229960000502 poloxamer Drugs 0.000 description 2
- 229920001983 poloxamer Polymers 0.000 description 2
- 108091033319 polynucleotide Proteins 0.000 description 2
- 102000040430 polynucleotide Human genes 0.000 description 2
- 239000002157 polynucleotide Substances 0.000 description 2
- 229940100467 polyvinyl acetate phthalate Drugs 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
- 229960000688 pomalidomide Drugs 0.000 description 2
- UVSMNLNDYGZFPF-UHFFFAOYSA-N pomalidomide Chemical compound O=C1C=2C(N)=CC=CC=2C(=O)N1C1CCC(=O)NC1=O UVSMNLNDYGZFPF-UHFFFAOYSA-N 0.000 description 2
- 239000011591 potassium Chemical class 0.000 description 2
- 230000003389 potentiating effect Effects 0.000 description 2
- OGSBUKJUDHAQEA-WMCAAGNKSA-N pralatrexate Chemical compound C1=NC2=NC(N)=NC(N)=C2N=C1CC(CC#C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 OGSBUKJUDHAQEA-WMCAAGNKSA-N 0.000 description 2
- 229960000214 pralatrexate Drugs 0.000 description 2
- 229960004618 prednisone Drugs 0.000 description 2
- XOFYZVNMUHMLCC-ZPOLXVRWSA-N prednisone Chemical compound O=C1C=C[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 XOFYZVNMUHMLCC-ZPOLXVRWSA-N 0.000 description 2
- 208000016800 primary central nervous system lymphoma Diseases 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 210000001236 prokaryotic cell Anatomy 0.000 description 2
- 230000002062 proliferating effect Effects 0.000 description 2
- 229960003712 propranolol Drugs 0.000 description 2
- 210000002307 prostate Anatomy 0.000 description 2
- 235000019833 protease Nutrition 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 229960003127 rabies vaccine Drugs 0.000 description 2
- 229960002633 ramucirumab Drugs 0.000 description 2
- 230000009257 reactivity Effects 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 201000007444 renal pelvis carcinoma Diseases 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 201000009410 rhabdomyosarcoma Diseases 0.000 description 2
- 229960000311 ritonavir Drugs 0.000 description 2
- NCDNCNXCDXHOMX-XGKFQTDJSA-N ritonavir Chemical compound N([C@@H](C(C)C)C(=O)N[C@H](C[C@H](O)[C@H](CC=1C=CC=CC=1)NC(=O)OCC=1SC=NC=1)CC=1C=CC=CC=1)C(=O)N(C)CC1=CSC(C(C)C)=N1 NCDNCNXCDXHOMX-XGKFQTDJSA-N 0.000 description 2
- MNDBXUUTURYVHR-UHFFFAOYSA-N roflumilast Chemical compound FC(F)OC1=CC=C(C(=O)NC=2C(=CN=CC=2Cl)Cl)C=C1OCC1CC1 MNDBXUUTURYVHR-UHFFFAOYSA-N 0.000 description 2
- 229960002586 roflumilast Drugs 0.000 description 2
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 2
- 230000009758 senescence Effects 0.000 description 2
- 210000002966 serum Anatomy 0.000 description 2
- 235000012239 silicon dioxide Nutrition 0.000 description 2
- 210000003491 skin Anatomy 0.000 description 2
- 201000003708 skin melanoma Diseases 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000011734 sodium Chemical class 0.000 description 2
- 239000007909 solid dosage form Substances 0.000 description 2
- 239000004334 sorbic acid Substances 0.000 description 2
- 235000010199 sorbic acid Nutrition 0.000 description 2
- 229940075582 sorbic acid Drugs 0.000 description 2
- 241000894007 species Species 0.000 description 2
- 238000010254 subcutaneous injection Methods 0.000 description 2
- 239000007929 subcutaneous injection Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 229960001796 sunitinib Drugs 0.000 description 2
- WINHZLLDWRZWRT-ATVHPVEESA-N sunitinib Chemical compound CCN(CC)CCNC(=O)C1=C(C)NC(\C=C/2C3=CC(F)=CC=C3NC\2=O)=C1C WINHZLLDWRZWRT-ATVHPVEESA-N 0.000 description 2
- 229960000235 temsirolimus Drugs 0.000 description 2
- QFJCIRLUMZQUOT-UHFFFAOYSA-N temsirolimus Natural products C1CC(O)C(OC)CC1CC(C)C1OC(=O)C2CCCCN2C(=O)C(=O)C(O)(O2)C(C)CCC2CC(OC)C(C)=CC=CC=CC(C)CC(C)C(=O)C(OC)C(O)C(C)=CC(C)C(=O)C1 QFJCIRLUMZQUOT-UHFFFAOYSA-N 0.000 description 2
- 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 2
- 229960001278 teniposide Drugs 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 229950002896 tetomilast Drugs 0.000 description 2
- ZFXYFBGIUFBOJW-UHFFFAOYSA-N theophylline Chemical compound O=C1N(C)C(=O)N(C)C2=C1NC=N2 ZFXYFBGIUFBOJW-UHFFFAOYSA-N 0.000 description 2
- 229960001196 thiotepa Drugs 0.000 description 2
- MNRILEROXIRVNJ-UHFFFAOYSA-N tioguanine Chemical compound N1C(N)=NC(=S)C2=NC=N[C]21 MNRILEROXIRVNJ-UHFFFAOYSA-N 0.000 description 2
- 229960003087 tioguanine Drugs 0.000 description 2
- 239000003053 toxin Substances 0.000 description 2
- 231100000765 toxin Toxicity 0.000 description 2
- 108700012359 toxins Proteins 0.000 description 2
- 238000013518 transcription Methods 0.000 description 2
- 230000035897 transcription Effects 0.000 description 2
- 238000012546 transfer Methods 0.000 description 2
- URAYPUMNDPQOKB-UHFFFAOYSA-N triacetin Chemical compound CC(=O)OCC(OC(C)=O)COC(C)=O URAYPUMNDPQOKB-UHFFFAOYSA-N 0.000 description 2
- 229960002117 triamcinolone acetonide Drugs 0.000 description 2
- YNDXUCZADRHECN-JNQJZLCISA-N triamcinolone acetonide Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@H]3OC(C)(C)O[C@@]3(C(=O)CO)[C@@]1(C)C[C@@H]2O YNDXUCZADRHECN-JNQJZLCISA-N 0.000 description 2
- 229960003962 trifluridine Drugs 0.000 description 2
- VSQQQLOSPVPRAZ-RRKCRQDMSA-N trifluridine Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(C(F)(F)F)=C1 VSQQQLOSPVPRAZ-RRKCRQDMSA-N 0.000 description 2
- PVNIQBQSYATKKL-UHFFFAOYSA-N tripalmitin Chemical compound CCCCCCCCCCCCCCCC(=O)OCC(OC(=O)CCCCCCCCCCCCCCC)COC(=O)CCCCCCCCCCCCCCC PVNIQBQSYATKKL-UHFFFAOYSA-N 0.000 description 2
- 241000712461 unidentified influenza virus Species 0.000 description 2
- 210000000626 ureter Anatomy 0.000 description 2
- 201000011294 ureter cancer Diseases 0.000 description 2
- 238000002255 vaccination Methods 0.000 description 2
- 239000003981 vehicle Substances 0.000 description 2
- 229960003636 vidarabine 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
- 229960004355 vindesine Drugs 0.000 description 2
- 229960000744 vinpocetine Drugs 0.000 description 2
- 229960004854 viral vaccine Drugs 0.000 description 2
- 210000000239 visual pathway Anatomy 0.000 description 2
- 230000004400 visual pathway Effects 0.000 description 2
- 229960001771 vorozole Drugs 0.000 description 2
- 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 2
- 239000000080 wetting agent Substances 0.000 description 2
- QDLHCMPXEPAAMD-QAIWCSMKSA-N wortmannin Chemical compound C1([C@]2(C)C3=C(C4=O)OC=C3C(=O)O[C@@H]2COC)=C4[C@@H]2CCC(=O)[C@@]2(C)C[C@H]1OC(C)=O QDLHCMPXEPAAMD-QAIWCSMKSA-N 0.000 description 2
- QDLHCMPXEPAAMD-UHFFFAOYSA-N wortmannin Natural products COCC1OC(=O)C2=COC(C3=O)=C2C1(C)C1=C3C2CCC(=O)C2(C)CC1OC(C)=O QDLHCMPXEPAAMD-UHFFFAOYSA-N 0.000 description 2
- 229960004764 zafirlukast Drugs 0.000 description 2
- 229960000523 zalcitabine Drugs 0.000 description 2
- ARAIBEBZBOPLMB-UFGQHTETSA-N zanamivir Chemical compound CC(=O)N[C@@H]1[C@@H](N=C(N)N)C=C(C(O)=O)O[C@H]1[C@H](O)[C@H](O)CO ARAIBEBZBOPLMB-UFGQHTETSA-N 0.000 description 2
- 229960001028 zanamivir Drugs 0.000 description 2
- HBOMLICNUCNMMY-XLPZGREQSA-N zidovudine Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](N=[N+]=[N-])C1 HBOMLICNUCNMMY-XLPZGREQSA-N 0.000 description 2
- 229960002555 zidovudine Drugs 0.000 description 2
- MWLSOWXNZPKENC-SSDOTTSWSA-N zileuton Chemical compound C1=CC=C2SC([C@H](N(O)C(N)=O)C)=CC2=C1 MWLSOWXNZPKENC-SSDOTTSWSA-N 0.000 description 2
- 229960005332 zileuton Drugs 0.000 description 2
- BMKDZUISNHGIBY-ZETCQYMHSA-N (+)-dexrazoxane Chemical compound C([C@H](C)N1CC(=O)NC(=O)C1)N1CC(=O)NC(=O)C1 BMKDZUISNHGIBY-ZETCQYMHSA-N 0.000 description 1
- JNYAEWCLZODPBN-JGWLITMVSA-N (2r,3r,4s)-2-[(1r)-1,2-dihydroxyethyl]oxolane-3,4-diol Chemical compound OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O JNYAEWCLZODPBN-JGWLITMVSA-N 0.000 description 1
- PUDHBTGHUJUUFI-SCTWWAJVSA-N (4r,7s,10s,13r,16s,19r)-10-(4-aminobutyl)-n-[(2s,3r)-1-amino-3-hydroxy-1-oxobutan-2-yl]-19-[[(2r)-2-amino-3-naphthalen-2-ylpropanoyl]amino]-16-[(4-hydroxyphenyl)methyl]-13-(1h-indol-3-ylmethyl)-6,9,12,15,18-pentaoxo-7-propan-2-yl-1,2-dithia-5,8,11,14,17-p Chemical compound C([C@H]1C(=O)N[C@H](CC=2C3=CC=CC=C3NC=2)C(=O)N[C@@H](CCCCN)C(=O)N[C@H](C(N[C@@H](CSSC[C@@H](C(=O)N1)NC(=O)[C@H](N)CC=1C=C2C=CC=CC2=CC=1)C(=O)N[C@@H]([C@@H](C)O)C(N)=O)=O)C(C)C)C1=CC=C(O)C=C1 PUDHBTGHUJUUFI-SCTWWAJVSA-N 0.000 description 1
- MWWSFMDVAYGXBV-MYPASOLCSA-N (7r,9s)-7-[(2r,4s,5s,6s)-4-amino-5-hydroxy-6-methyloxan-2-yl]oxy-6,9,11-trihydroxy-9-(2-hydroxyacetyl)-4-methoxy-8,10-dihydro-7h-tetracene-5,12-dione;hydrochloride Chemical compound Cl.O([C@@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 MWWSFMDVAYGXBV-MYPASOLCSA-N 0.000 description 1
- OYHQOLUKZRVURQ-NTGFUMLPSA-N (9Z,12Z)-9,10,12,13-tetratritiooctadeca-9,12-dienoic acid Chemical compound C(CCCCCCC\C(=C(/C\C(=C(/CCCCC)\[3H])\[3H])\[3H])\[3H])(=O)O OYHQOLUKZRVURQ-NTGFUMLPSA-N 0.000 description 1
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 description 1
- 125000005845 (C2-C12)alkanoyloxymethyl group Chemical group 0.000 description 1
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 1
- CDOOAUSHHFGWSA-OWOJBTEDSA-N (e)-1,3,3,3-tetrafluoroprop-1-ene Chemical compound F\C=C\C(F)(F)F CDOOAUSHHFGWSA-OWOJBTEDSA-N 0.000 description 1
- SZNJINHODJLULD-SDNWHVSQSA-N (e)-3-(4-hydroxy-3,5-dimethoxyphenyl)-n-(4-hydroxy-1-methyl-3-octoxy-2-oxoquinolin-7-yl)prop-2-enamide Chemical compound C1=C2N(C)C(=O)C(OCCCCCCCC)=C(O)C2=CC=C1NC(=O)\C=C\C1=CC(OC)=C(O)C(OC)=C1 SZNJINHODJLULD-SDNWHVSQSA-N 0.000 description 1
- 102000040650 (ribonucleotides)n+m Human genes 0.000 description 1
- YFMFNYKEUDLDTL-UHFFFAOYSA-N 1,1,1,2,3,3,3-heptafluoropropane Chemical compound FC(F)(F)C(F)C(F)(F)F YFMFNYKEUDLDTL-UHFFFAOYSA-N 0.000 description 1
- LVGUZGTVOIAKKC-UHFFFAOYSA-N 1,1,1,2-tetrafluoroethane Chemical compound FCC(F)(F)F LVGUZGTVOIAKKC-UHFFFAOYSA-N 0.000 description 1
- 229940058015 1,3-butylene glycol Drugs 0.000 description 1
- VIESAWGOYVNHLV-UHFFFAOYSA-N 1,3-dihydropyrrol-2-one Chemical compound O=C1CC=CN1 VIESAWGOYVNHLV-UHFFFAOYSA-N 0.000 description 1
- UBCHPRBFMUDMNC-UHFFFAOYSA-N 1-(1-adamantyl)ethanamine Chemical compound C1C(C2)CC3CC2CC1(C(N)C)C3 UBCHPRBFMUDMNC-UHFFFAOYSA-N 0.000 description 1
- HOCFDYZWQYGULA-UHFFFAOYSA-N 1-(5-bromopyridin-2-yl)-3-(2-pyridin-2-ylethyl)thiourea Chemical compound N1=CC(Br)=CC=C1NC(=S)NCCC1=CC=CC=N1 HOCFDYZWQYGULA-UHFFFAOYSA-N 0.000 description 1
- 125000005851 1-(N-(alkoxycarbonyl)amino)ethyl group Chemical group 0.000 description 1
- 125000005846 1-(alkanoyloxy)ethyl group Chemical group 0.000 description 1
- 125000005848 1-(alkoxycarbonyloxy)ethyl group Chemical group 0.000 description 1
- 125000005847 1-methyl-1-(alkanoyloxy)-ethyl group Chemical group 0.000 description 1
- 125000005849 1-methyl-1-(alkoxycarbonyloxy)ethyl group Chemical group 0.000 description 1
- RZRNAYUHWVFMIP-KTKRTIGZSA-N 1-oleoylglycerol Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC(O)CO RZRNAYUHWVFMIP-KTKRTIGZSA-N 0.000 description 1
- 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- YQNRVGJCPCNMKT-JLPGSUDCSA-N 2-(4-benzylpiperazin-1-yl)-n-[(2-hydroxy-3-prop-2-enyl-phenyl)methylideneamino]acetamide Chemical compound OC1=C(CC=C)C=CC=C1\C=N/NC(=O)CN1CCN(CC=2C=CC=CC=2)CC1 YQNRVGJCPCNMKT-JLPGSUDCSA-N 0.000 description 1
- MIJDSYMOBYNHOT-UHFFFAOYSA-N 2-(ethylamino)ethanol Chemical compound CCNCCO MIJDSYMOBYNHOT-UHFFFAOYSA-N 0.000 description 1
- RTQWWZBSTRGEAV-PKHIMPSTSA-N 2-[[(2s)-2-[bis(carboxymethyl)amino]-3-[4-(methylcarbamoylamino)phenyl]propyl]-[2-[bis(carboxymethyl)amino]propyl]amino]acetic acid Chemical compound CNC(=O)NC1=CC=C(C[C@@H](CN(CC(C)N(CC(O)=O)CC(O)=O)CC(O)=O)N(CC(O)=O)CC(O)=O)C=C1 RTQWWZBSTRGEAV-PKHIMPSTSA-N 0.000 description 1
- AFNOHTDETQTADW-IANFNVNHSA-N 2-azido-n-[(3r,4r,5r,6r)-2,4,5-trihydroxy-6-(hydroxymethyl)oxan-3-yl]acetamide Chemical compound OC[C@H]1OC(O)[C@H](NC(=O)CN=[N+]=[N-])[C@@H](O)[C@H]1O AFNOHTDETQTADW-IANFNVNHSA-N 0.000 description 1
- AFNOHTDETQTADW-YLRIPHBZSA-N 2-azido-n-[(3s,4r,5s,6r)-2,4,5-trihydroxy-6-(hydroxymethyl)oxan-3-yl]acetamide Chemical compound OC[C@H]1OC(O)[C@@H](NC(=O)CN=[N+]=[N-])[C@@H](O)[C@@H]1O AFNOHTDETQTADW-YLRIPHBZSA-N 0.000 description 1
- RXIUEIPPLAFSDF-CYBMUJFWSA-N 2-hydroxy-n,n-dimethyl-3-[[2-[[(1r)-1-(5-methylfuran-2-yl)propyl]amino]-3,4-dioxocyclobuten-1-yl]amino]benzamide Chemical compound N([C@H](CC)C=1OC(C)=CC=1)C(C(C1=O)=O)=C1NC1=CC=CC(C(=O)N(C)C)=C1O RXIUEIPPLAFSDF-CYBMUJFWSA-N 0.000 description 1
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 1
- 125000004080 3-carboxypropanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C(O[H])=O 0.000 description 1
- HZQKCJMOQHMNTI-UHFFFAOYSA-N 4-amino-2-methyl-3-oxobutanoic acid Chemical compound OC(=O)C(C)C(=O)CN HZQKCJMOQHMNTI-UHFFFAOYSA-N 0.000 description 1
- 102000004023 5-Lipoxygenase-Activating Proteins Human genes 0.000 description 1
- 108090000411 5-Lipoxygenase-Activating Proteins Proteins 0.000 description 1
- XAUDJQYHKZQPEU-KVQBGUIXSA-N 5-aza-2'-deoxycytidine Chemical compound O=C1N=C(N)N=CN1[C@@H]1O[C@H](CO)[C@@H](O)C1 XAUDJQYHKZQPEU-KVQBGUIXSA-N 0.000 description 1
- JLLYLQLDYORLBB-UHFFFAOYSA-N 5-bromo-n-methylthiophene-2-sulfonamide Chemical compound CNS(=O)(=O)C1=CC=C(Br)S1 JLLYLQLDYORLBB-UHFFFAOYSA-N 0.000 description 1
- IBSREHMXUMOFBB-JFUDTMANSA-N 5u8924t11h Chemical compound O1[C@@H](C)[C@H](O)[C@@H](OC)C[C@@H]1O[C@@H]1[C@@H](OC)C[C@H](O[C@@H]2C(=C/C[C@@H]3C[C@@H](C[C@@]4(O3)C=C[C@H](C)[C@@H](C(C)C)O4)OC(=O)[C@@H]3C=C(C)[C@@H](O)[C@H]4OC\C([C@@]34O)=C/C=C/[C@@H]2C)/C)O[C@H]1C.C1=C[C@H](C)[C@@H]([C@@H](C)CC)O[C@]11O[C@H](C\C=C(C)\[C@@H](O[C@@H]2O[C@@H](C)[C@H](O[C@@H]3O[C@@H](C)[C@H](O)[C@@H](OC)C3)[C@@H](OC)C2)[C@@H](C)\C=C\C=C/2[C@]3([C@H](C(=O)O4)C=C(C)[C@@H](O)[C@H]3OC\2)O)C[C@H]4C1 IBSREHMXUMOFBB-JFUDTMANSA-N 0.000 description 1
- SJVQHLPISAIATJ-ZDUSSCGKSA-N 8-chloro-2-phenyl-3-[(1S)-1-(7H-purin-6-ylamino)ethyl]-1-isoquinolinone Chemical compound C1([C@@H](NC=2C=3N=CNC=3N=CN=2)C)=CC2=CC=CC(Cl)=C2C(=O)N1C1=CC=CC=C1 SJVQHLPISAIATJ-ZDUSSCGKSA-N 0.000 description 1
- RTAPDZBZLSXHQQ-UHFFFAOYSA-N 8-methyl-3,7-dihydropurine-2,6-dione Chemical class N1C(=O)NC(=O)C2=C1N=C(C)N2 RTAPDZBZLSXHQQ-UHFFFAOYSA-N 0.000 description 1
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 1
- 208000030507 AIDS Diseases 0.000 description 1
- 208000002008 AIDS-Related Lymphoma Diseases 0.000 description 1
- 239000005660 Abamectin Substances 0.000 description 1
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 206010000830 Acute leukaemia Diseases 0.000 description 1
- 208000024893 Acute lymphoblastic leukemia Diseases 0.000 description 1
- 208000014697 Acute lymphocytic leukaemia Diseases 0.000 description 1
- 208000010507 Adenocarcinoma of Lung Diseases 0.000 description 1
- 206010001258 Adenoviral infections Diseases 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- 102000002260 Alkaline Phosphatase Human genes 0.000 description 1
- 108020004774 Alkaline Phosphatase Proteins 0.000 description 1
- 239000005995 Aluminium silicate Substances 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 206010061424 Anal cancer Diseases 0.000 description 1
- 208000007860 Anus Neoplasms Diseases 0.000 description 1
- 235000003276 Apios tuberosa Nutrition 0.000 description 1
- 102000007592 Apolipoproteins Human genes 0.000 description 1
- 108010071619 Apolipoproteins Proteins 0.000 description 1
- 244000105624 Arachis hypogaea Species 0.000 description 1
- 235000010777 Arachis hypogaea Nutrition 0.000 description 1
- 235000010744 Arachis villosulicarpa Nutrition 0.000 description 1
- 206010003571 Astrocytoma Diseases 0.000 description 1
- 206010060971 Astrocytoma malignant Diseases 0.000 description 1
- 108090001008 Avidin Proteins 0.000 description 1
- CWHUFRVAEUJCEF-UHFFFAOYSA-N BKM120 Chemical compound C1=NC(N)=CC(C(F)(F)F)=C1C1=CC(N2CCOCC2)=NC(N2CCOCC2)=N1 CWHUFRVAEUJCEF-UHFFFAOYSA-N 0.000 description 1
- 206010005949 Bone cancer Diseases 0.000 description 1
- 208000018084 Bone neoplasm Diseases 0.000 description 1
- 206010006143 Brain stem glioma Diseases 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
- 125000001433 C-terminal amino-acid group Chemical group 0.000 description 1
- 101100463133 Caenorhabditis elegans pdl-1 gene Proteins 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- 208000008889 California Encephalitis Diseases 0.000 description 1
- 241001493160 California encephalitis virus Species 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
- 108090000565 Capsid Proteins Proteins 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- 102000005367 Carboxypeptidases Human genes 0.000 description 1
- 108010006303 Carboxypeptidases Proteins 0.000 description 1
- 206010007279 Carcinoid tumour of the gastrointestinal tract Diseases 0.000 description 1
- 208000010667 Carcinoma of liver and intrahepatic biliary tract Diseases 0.000 description 1
- 102100023321 Ceruloplasmin Human genes 0.000 description 1
- 102000009410 Chemokine receptor Human genes 0.000 description 1
- 108050000299 Chemokine receptor Proteins 0.000 description 1
- 206010008761 Choriomeningitis lymphocytic Diseases 0.000 description 1
- 208000010833 Chronic myeloid leukaemia Diseases 0.000 description 1
- 108090000317 Chymotrypsin Proteins 0.000 description 1
- 101710185564 Chymotrypsin-1 Proteins 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
- 206010052360 Colorectal adenocarcinoma Diseases 0.000 description 1
- 208000035473 Communicable disease Diseases 0.000 description 1
- 108010060123 Conjugate Vaccines Proteins 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- 244000293323 Cosmos caudatus Species 0.000 description 1
- 235000005956 Cosmos caudatus Nutrition 0.000 description 1
- 229920002785 Croscarmellose sodium Polymers 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
- FFEARJCKVFRZRR-SCSAIBSYSA-N D-methionine Chemical compound CSCC[C@@H](N)C(O)=O FFEARJCKVFRZRR-SCSAIBSYSA-N 0.000 description 1
- 102000004163 DNA-directed RNA polymerases Human genes 0.000 description 1
- 108090000626 DNA-directed RNA polymerases Proteins 0.000 description 1
- 229940032046 DTaP vaccine Drugs 0.000 description 1
- ZINBFGBAIFRYSH-UHFFFAOYSA-N Demethoxyviridin Natural products CC12C(O)C(O)C(=O)c3coc(C(=O)c4c5CCC(=O)c5ccc14)c23 ZINBFGBAIFRYSH-UHFFFAOYSA-N 0.000 description 1
- 235000019739 Dicalciumphosphate Nutrition 0.000 description 1
- BWGNESOTFCXPMA-UHFFFAOYSA-N Dihydrogen disulfide Chemical compound SS BWGNESOTFCXPMA-UHFFFAOYSA-N 0.000 description 1
- 206010061818 Disease progression Diseases 0.000 description 1
- 229940124722 Ebola vaccine Drugs 0.000 description 1
- XPOQHMRABVBWPR-UHFFFAOYSA-N Efavirenz Natural products O1C(=O)NC2=CC=C(Cl)C=C2C1(C(F)(F)F)C#CC1CC1 XPOQHMRABVBWPR-UHFFFAOYSA-N 0.000 description 1
- LVGKNOAMLMIIKO-UHFFFAOYSA-N Elaidinsaeure-aethylester Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC LVGKNOAMLMIIKO-UHFFFAOYSA-N 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 206010014584 Encephalitis california Diseases 0.000 description 1
- 206010014733 Endometrial cancer Diseases 0.000 description 1
- 206010014759 Endometrial neoplasm Diseases 0.000 description 1
- 206010014967 Ependymoma Diseases 0.000 description 1
- 206010015108 Epstein-Barr virus infection Diseases 0.000 description 1
- 208000006168 Ewing Sarcoma Diseases 0.000 description 1
- 201000005866 Exanthema Subitum Diseases 0.000 description 1
- 208000017259 Extragonadal germ cell tumor Diseases 0.000 description 1
- 206010053717 Fibrous histiocytoma Diseases 0.000 description 1
- 239000004606 Fillers/Extenders Substances 0.000 description 1
- 241000710831 Flavivirus Species 0.000 description 1
- WJOHZNCJWYWUJD-IUGZLZTKSA-N Fluocinonide Chemical compound C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@]1(F)[C@@H]2[C@@H]2C[C@H]3OC(C)(C)O[C@@]3(C(=O)COC(=O)C)[C@@]2(C)C[C@@H]1O WJOHZNCJWYWUJD-IUGZLZTKSA-N 0.000 description 1
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 description 1
- VWUXBMIQPBEWFH-WCCTWKNTSA-N Fulvestrant Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3[C@H](CCCCCCCCCS(=O)CCCC(F)(F)C(F)(F)F)CC2=C1 VWUXBMIQPBEWFH-WCCTWKNTSA-N 0.000 description 1
- 229910052688 Gadolinium Inorganic materials 0.000 description 1
- 208000022072 Gallbladder Neoplasms Diseases 0.000 description 1
- 201000003741 Gastrointestinal carcinoma Diseases 0.000 description 1
- 208000015872 Gaucher disease Diseases 0.000 description 1
- 241000206672 Gelidium Species 0.000 description 1
- 108090000288 Glycoproteins Proteins 0.000 description 1
- 102000003886 Glycoproteins Human genes 0.000 description 1
- 208000031886 HIV Infections Diseases 0.000 description 1
- 208000037357 HIV infectious disease Diseases 0.000 description 1
- 101710154606 Hemagglutinin Proteins 0.000 description 1
- 206010019629 Hepatic adenoma Diseases 0.000 description 1
- 206010073069 Hepatic cancer Diseases 0.000 description 1
- 208000005176 Hepatitis C Diseases 0.000 description 1
- 208000005331 Hepatitis D Diseases 0.000 description 1
- 208000007514 Herpes zoster Diseases 0.000 description 1
- 229940124841 Herpesvirus vaccine Drugs 0.000 description 1
- 101000909983 Homo sapiens Chymase Proteins 0.000 description 1
- 101001139126 Homo sapiens Krueppel-like factor 6 Proteins 0.000 description 1
- 101001133600 Homo sapiens Pituitary adenylate cyclase-activating polypeptide type I receptor Proteins 0.000 description 1
- 101001080401 Homo sapiens Proteasome assembly chaperone 1 Proteins 0.000 description 1
- 101000612671 Homo sapiens Pulmonary surfactant-associated protein C Proteins 0.000 description 1
- 101001012157 Homo sapiens Receptor tyrosine-protein kinase erbB-2 Proteins 0.000 description 1
- 101000988419 Homo sapiens cAMP-specific 3',5'-cyclic phosphodiesterase 4D Proteins 0.000 description 1
- 108010001336 Horseradish Peroxidase Proteins 0.000 description 1
- 241000829111 Human polyomavirus 1 Species 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- 208000019758 Hypergammaglobulinemia Diseases 0.000 description 1
- 108060003951 Immunoglobulin Proteins 0.000 description 1
- 241000712431 Influenza A virus Species 0.000 description 1
- 241000713196 Influenza B virus Species 0.000 description 1
- 241000713297 Influenza C virus Species 0.000 description 1
- 108010014726 Interferon Type I Proteins 0.000 description 1
- 102000002227 Interferon Type I Human genes 0.000 description 1
- 108010078049 Interferon alpha-2 Proteins 0.000 description 1
- 108010079944 Interferon-alpha2b Proteins 0.000 description 1
- 206010061252 Intraocular melanoma Diseases 0.000 description 1
- VQTUBCCKSQIDNK-UHFFFAOYSA-N Isobutene Chemical group CC(C)=C VQTUBCCKSQIDNK-UHFFFAOYSA-N 0.000 description 1
- 108010044467 Isoenzymes Proteins 0.000 description 1
- 208000007766 Kaposi sarcoma Diseases 0.000 description 1
- 240000007839 Kleinhovia hospita Species 0.000 description 1
- 102100020679 Krueppel-like factor 6 Human genes 0.000 description 1
- 150000008575 L-amino acids Chemical class 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-N L-arginine Chemical compound OC(=O)[C@@H](N)CCCN=C(N)N ODKSFYDXXFIFQN-BYPYZUCNSA-N 0.000 description 1
- LEVWYRKDKASIDU-IMJSIDKUSA-N L-cystine Chemical compound [O-]C(=O)[C@@H]([NH3+])CSSC[C@H]([NH3+])C([O-])=O LEVWYRKDKASIDU-IMJSIDKUSA-N 0.000 description 1
- AGPKZVBTJJNPAG-WHFBIAKZSA-N L-isoleucine Chemical compound CC[C@H](C)[C@H](N)C(O)=O AGPKZVBTJJNPAG-WHFBIAKZSA-N 0.000 description 1
- AYFVYJQAPQTCCC-GBXIJSLDSA-N L-threonine Chemical compound C[C@@H](O)[C@H](N)C(O)=O AYFVYJQAPQTCCC-GBXIJSLDSA-N 0.000 description 1
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 description 1
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 1
- 239000005551 L01XE03 - Erlotinib Substances 0.000 description 1
- 239000002145 L01XE14 - Bosutinib Substances 0.000 description 1
- 239000002138 L01XE21 - Regorafenib Substances 0.000 description 1
- 239000002137 L01XE24 - Ponatinib Substances 0.000 description 1
- 201000009908 La Crosse encephalitis Diseases 0.000 description 1
- 241000713666 Lentivirus Species 0.000 description 1
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 description 1
- 206010024291 Leukaemias acute myeloid Diseases 0.000 description 1
- 206010061523 Lip and/or oral cavity cancer Diseases 0.000 description 1
- 208000002404 Liver Cell Adenoma Diseases 0.000 description 1
- 208000031422 Lymphocytic Chronic B-Cell Leukemia Diseases 0.000 description 1
- 208000028018 Lymphocytic leukaemia Diseases 0.000 description 1
- 206010025312 Lymphoma AIDS related Diseases 0.000 description 1
- 208000030289 Lymphoproliferative disease Diseases 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical class [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 208000004059 Male Breast Neoplasms Diseases 0.000 description 1
- 208000006644 Malignant Fibrous Histiocytoma Diseases 0.000 description 1
- 206010025997 Malignant neoplasm of islets of Langerhans Diseases 0.000 description 1
- 208000032271 Malignant tumor of penis Diseases 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 240000003183 Manihot esculenta Species 0.000 description 1
- 235000016735 Manihot esculenta subsp esculenta Nutrition 0.000 description 1
- 229930126263 Maytansine Natural products 0.000 description 1
- 241000712079 Measles morbillivirus Species 0.000 description 1
- 102000018697 Membrane Proteins Human genes 0.000 description 1
- 108010052285 Membrane Proteins Proteins 0.000 description 1
- 241000579048 Merkel cell polyomavirus Species 0.000 description 1
- 206010027406 Mesothelioma Diseases 0.000 description 1
- 241000237852 Mollusca Species 0.000 description 1
- 241000700560 Molluscum contagiosum virus Species 0.000 description 1
- 241000711386 Mumps virus Species 0.000 description 1
- 241001529936 Murinae Species 0.000 description 1
- 241000699660 Mus musculus Species 0.000 description 1
- 241000186366 Mycobacterium bovis Species 0.000 description 1
- 208000026305 Myelodysplastic-Myeloproliferative disease Diseases 0.000 description 1
- 102000003896 Myeloperoxidases Human genes 0.000 description 1
- 108090000235 Myeloperoxidases Proteins 0.000 description 1
- 208000014767 Myeloproliferative disease Diseases 0.000 description 1
- TXZBZODXIKVHOK-KEWYIRBNSA-N N(=[N+]=[N-])N[C@H]1C(O)(O[C@@H]([C@H]([C@@H]1O)O)CO)C(C)=O Chemical compound N(=[N+]=[N-])N[C@H]1C(O)(O[C@@H]([C@H]([C@@H]1O)O)CO)C(C)=O TXZBZODXIKVHOK-KEWYIRBNSA-N 0.000 description 1
- 125000005850 N-(alkoxycarbonyl)aminomethyl group Chemical group 0.000 description 1
- KJHOZAZQWVKILO-UHFFFAOYSA-N N-(diaminomethylidene)-4-morpholinecarboximidamide Chemical compound NC(N)=NC(=N)N1CCOCC1 KJHOZAZQWVKILO-UHFFFAOYSA-N 0.000 description 1
- GXCLVBGFBYZDAG-UHFFFAOYSA-N N-[2-(1H-indol-3-yl)ethyl]-N-methylprop-2-en-1-amine Chemical compound CN(CCC1=CNC2=C1C=CC=C2)CC=C GXCLVBGFBYZDAG-UHFFFAOYSA-N 0.000 description 1
- 208000002454 Nasopharyngeal Carcinoma Diseases 0.000 description 1
- 206010061306 Nasopharyngeal cancer Diseases 0.000 description 1
- MIBATSHDJRIUJK-ROJLCIKYSA-N Neferine Chemical compound C1=CC(OC)=CC=C1C[C@@H]1C2=CC(OC=3C(=CC=C(C[C@@H]4C5=CC(OC)=C(OC)C=C5CCN4C)C=3)O)=C(OC)C=C2CCN1C MIBATSHDJRIUJK-ROJLCIKYSA-N 0.000 description 1
- MIBATSHDJRIUJK-UHFFFAOYSA-N Neferine Natural products C1=CC(OC)=CC=C1CC1C2=CC(OC=3C(=CC=C(CC4C5=CC(OC)=C(OC)C=C5CCN4C)C=3)O)=C(OC)C=C2CCN1C MIBATSHDJRIUJK-UHFFFAOYSA-N 0.000 description 1
- 241000588650 Neisseria meningitidis Species 0.000 description 1
- 102000005348 Neuraminidase Human genes 0.000 description 1
- 108010006232 Neuraminidase Proteins 0.000 description 1
- 208000009277 Neuroectodermal Tumors Diseases 0.000 description 1
- 240000007817 Olea europaea Species 0.000 description 1
- 239000005642 Oleic acid Substances 0.000 description 1
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 1
- 206010031096 Oropharyngeal cancer Diseases 0.000 description 1
- 206010057444 Oropharyngeal neoplasm Diseases 0.000 description 1
- 240000007594 Oryza sativa Species 0.000 description 1
- 235000007164 Oryza sativa Nutrition 0.000 description 1
- 101710093908 Outer capsid protein VP4 Proteins 0.000 description 1
- 101710135467 Outer capsid protein sigma-1 Proteins 0.000 description 1
- 208000007571 Ovarian Epithelial Carcinoma Diseases 0.000 description 1
- 206010033128 Ovarian cancer Diseases 0.000 description 1
- 206010033268 Ovarian low malignant potential tumour Diseases 0.000 description 1
- 239000004100 Oxytetracycline Substances 0.000 description 1
- 229940116355 PI3 kinase inhibitor Drugs 0.000 description 1
- 229940124780 PI3K delta inhibitor Drugs 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 208000002774 Paraproteinemias Diseases 0.000 description 1
- 208000000821 Parathyroid Neoplasms Diseases 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- 208000002471 Penile Neoplasms Diseases 0.000 description 1
- 206010034299 Penile cancer Diseases 0.000 description 1
- 229940123932 Phosphodiesterase 4 inhibitor Drugs 0.000 description 1
- 208000007913 Pituitary Neoplasms Diseases 0.000 description 1
- 239000004743 Polypropylene Substances 0.000 description 1
- 101710176177 Protein A56 Proteins 0.000 description 1
- 108010029485 Protein Isoforms Proteins 0.000 description 1
- 102000001708 Protein Isoforms Human genes 0.000 description 1
- 108010001267 Protein Subunits Proteins 0.000 description 1
- 102000002067 Protein Subunits Human genes 0.000 description 1
- 108010007100 Pulmonary Surfactant-Associated Protein A Proteins 0.000 description 1
- 102000007620 Pulmonary Surfactant-Associated Protein C Human genes 0.000 description 1
- 108010007125 Pulmonary Surfactant-Associated Protein C Proteins 0.000 description 1
- 102100027773 Pulmonary surfactant-associated protein A2 Human genes 0.000 description 1
- 206010037549 Purpura Diseases 0.000 description 1
- 241001672981 Purpura Species 0.000 description 1
- 241000711798 Rabies lyssavirus Species 0.000 description 1
- 102100030086 Receptor tyrosine-protein kinase erbB-2 Human genes 0.000 description 1
- 208000015634 Rectal Neoplasms Diseases 0.000 description 1
- 208000006265 Renal cell carcinoma Diseases 0.000 description 1
- 241001068263 Replication competent viruses Species 0.000 description 1
- 108700008625 Reporter Genes Proteins 0.000 description 1
- 241000725643 Respiratory syncytial virus Species 0.000 description 1
- QNVSXXGDAPORNA-UHFFFAOYSA-N Resveratrol Natural products OC1=CC=CC(C=CC=2C=C(O)C(O)=CC=2)=C1 QNVSXXGDAPORNA-UHFFFAOYSA-N 0.000 description 1
- 201000000582 Retinoblastoma Diseases 0.000 description 1
- IWUCXVSUMQZMFG-AFCXAGJDSA-N Ribavirin Chemical compound N1=C(C(=O)N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 IWUCXVSUMQZMFG-AFCXAGJDSA-N 0.000 description 1
- 235000004443 Ricinus communis Nutrition 0.000 description 1
- 208000006257 Rinderpest Diseases 0.000 description 1
- 241000711897 Rinderpest morbillivirus Species 0.000 description 1
- 241000220317 Rosa Species 0.000 description 1
- 208000036485 Roseola Diseases 0.000 description 1
- 241000710799 Rubella virus Species 0.000 description 1
- 206010061934 Salivary gland cancer Diseases 0.000 description 1
- 108091081021 Sense strand Proteins 0.000 description 1
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 1
- 108020004682 Single-Stranded DNA Proteins 0.000 description 1
- 208000000453 Skin Neoplasms Diseases 0.000 description 1
- 201000011683 Small Cell Sarcoma Diseases 0.000 description 1
- 206010041067 Small cell lung cancer Diseases 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- 244000061456 Solanum tuberosum Species 0.000 description 1
- 235000002595 Solanum tuberosum Nutrition 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- SSZBUIDZHHWXNJ-UHFFFAOYSA-N Stearinsaeure-hexadecylester Natural products CCCCCCCCCCCCCCCCCC(=O)OCCCCCCCCCCCCCCCC SSZBUIDZHHWXNJ-UHFFFAOYSA-N 0.000 description 1
- UCKMPCXJQFINFW-UHFFFAOYSA-N Sulphide Chemical compound [S-2] UCKMPCXJQFINFW-UHFFFAOYSA-N 0.000 description 1
- 230000024932 T cell mediated immunity Effects 0.000 description 1
- 230000005867 T cell response Effects 0.000 description 1
- 108010092262 T-Cell Antigen Receptors Proteins 0.000 description 1
- 208000031673 T-Cell Cutaneous Lymphoma Diseases 0.000 description 1
- 206010042971 T-cell lymphoma Diseases 0.000 description 1
- 208000027585 T-cell non-Hodgkin lymphoma Diseases 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric Acid Chemical class [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 208000024313 Testicular Neoplasms Diseases 0.000 description 1
- 206010057644 Testis cancer Diseases 0.000 description 1
- 208000024770 Thyroid neoplasm Diseases 0.000 description 1
- LUKBXSAWLPMMSZ-OWOJBTEDSA-N Trans-resveratrol Chemical compound C1=CC(O)=CC=C1\C=C\C1=CC(O)=CC(O)=C1 LUKBXSAWLPMMSZ-OWOJBTEDSA-N 0.000 description 1
- 108091023040 Transcription factor Proteins 0.000 description 1
- 102000040945 Transcription factor Human genes 0.000 description 1
- DOOTYTYQINUNNV-UHFFFAOYSA-N Triethyl citrate Chemical compound CCOC(=O)CC(O)(C(=O)OCC)CC(=O)OCC DOOTYTYQINUNNV-UHFFFAOYSA-N 0.000 description 1
- DFBIRQPKNDILPW-CIVMWXNOSA-N Triptolide Chemical compound O=C1OCC([C@@H]2C3)=C1CC[C@]2(C)[C@]12O[C@H]1[C@@H]1O[C@]1(C(C)C)[C@@H](O)[C@]21[C@H]3O1 DFBIRQPKNDILPW-CIVMWXNOSA-N 0.000 description 1
- 108060005989 Tryptase Proteins 0.000 description 1
- 102000001400 Tryptase Human genes 0.000 description 1
- 208000015778 Undifferentiated pleomorphic sarcoma Diseases 0.000 description 1
- 206010046458 Urethral neoplasms Diseases 0.000 description 1
- 208000002495 Uterine Neoplasms Diseases 0.000 description 1
- 201000005969 Uveal melanoma Diseases 0.000 description 1
- 102000012088 Vasoactive Intestinal Peptide Receptors Human genes 0.000 description 1
- 108010075974 Vasoactive Intestinal Peptide Receptors Proteins 0.000 description 1
- 208000004354 Vulvar Neoplasms Diseases 0.000 description 1
- 208000008383 Wilms tumor Diseases 0.000 description 1
- 208000003152 Yellow Fever Diseases 0.000 description 1
- 240000008042 Zea mays Species 0.000 description 1
- 235000005824 Zea mays ssp. parviglumis Nutrition 0.000 description 1
- 235000002017 Zea mays subsp mays Nutrition 0.000 description 1
- 239000001089 [(2R)-oxolan-2-yl]methanol Substances 0.000 description 1
- DLGSOJOOYHWROO-WQLSENKSSA-N [(z)-(1-methyl-2-oxoindol-3-ylidene)amino]thiourea Chemical compound C1=CC=C2N(C)C(=O)\C(=N/NC(N)=S)C2=C1 DLGSOJOOYHWROO-WQLSENKSSA-N 0.000 description 1
- JLCPHMBAVCMARE-UHFFFAOYSA-N [3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-hydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methyl [5-(6-aminopurin-9-yl)-2-(hydroxymethyl)oxolan-3-yl] hydrogen phosphate Polymers Cc1cn(C2CC(OP(O)(=O)OCC3OC(CC3OP(O)(=O)OCC3OC(CC3O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c3nc(N)[nH]c4=O)C(COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3CO)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cc(C)c(=O)[nH]c3=O)n3cc(C)c(=O)[nH]c3=O)n3ccc(N)nc3=O)n3cc(C)c(=O)[nH]c3=O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)O2)c(=O)[nH]c1=O JLCPHMBAVCMARE-UHFFFAOYSA-N 0.000 description 1
- JNWFIPVDEINBAI-UHFFFAOYSA-N [5-hydroxy-4-[4-(1-methylindol-5-yl)-5-oxo-1H-1,2,4-triazol-3-yl]-2-propan-2-ylphenyl] dihydrogen phosphate Chemical compound C1=C(OP(O)(O)=O)C(C(C)C)=CC(C=2N(C(=O)NN=2)C=2C=C3C=CN(C)C3=CC=2)=C1O JNWFIPVDEINBAI-UHFFFAOYSA-N 0.000 description 1
- GLWHPRRGGYLLRV-XLPZGREQSA-N [[(2s,3s,5r)-3-azido-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl] phosphono hydrogen phosphate Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](COP(O)(=O)OP(O)(=O)OP(O)(O)=O)[C@@H](N=[N+]=[N-])C1 GLWHPRRGGYLLRV-XLPZGREQSA-N 0.000 description 1
- 229950008167 abamectin Drugs 0.000 description 1
- 210000001015 abdomen Anatomy 0.000 description 1
- 229950001573 abemaciclib Drugs 0.000 description 1
- 239000003655 absorption accelerator Substances 0.000 description 1
- 150000003869 acetamides Chemical class 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- IYKJEILNJZQJPU-UHFFFAOYSA-N acetic acid;butanedioic acid Chemical compound CC(O)=O.OC(=O)CCC(O)=O IYKJEILNJZQJPU-UHFFFAOYSA-N 0.000 description 1
- ZUAAPNNKRHMPKG-UHFFFAOYSA-N acetic acid;butanedioic acid;methanol;propane-1,2-diol Chemical compound OC.CC(O)=O.CC(O)CO.OC(=O)CCC(O)=O ZUAAPNNKRHMPKG-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 125000005042 acyloxymethyl group Chemical group 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 230000004721 adaptive immunity Effects 0.000 description 1
- 238000011467 adoptive cell therapy Methods 0.000 description 1
- 208000020990 adrenal cortex carcinoma Diseases 0.000 description 1
- 230000001919 adrenal effect Effects 0.000 description 1
- 210000004100 adrenal gland Anatomy 0.000 description 1
- 208000007128 adrenocortical carcinoma Diseases 0.000 description 1
- 239000003463 adsorbent Substances 0.000 description 1
- 208000014619 adult acute lymphoblastic leukemia Diseases 0.000 description 1
- 201000011184 adult acute lymphocytic leukemia Diseases 0.000 description 1
- 229960001686 afatinib Drugs 0.000 description 1
- ULXXDDBFHOBEHA-CWDCEQMOSA-N afatinib Chemical compound N1=CN=C2C=C(O[C@@H]3COCC3)C(NC(=O)/C=C/CN(C)C)=CC2=C1NC1=CC=C(F)C(Cl)=C1 ULXXDDBFHOBEHA-CWDCEQMOSA-N 0.000 description 1
- 229960002833 aflibercept Drugs 0.000 description 1
- 108010081667 aflibercept Proteins 0.000 description 1
- 235000010419 agar Nutrition 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
- 239000003570 air Substances 0.000 description 1
- 210000005039 airway nerve Anatomy 0.000 description 1
- 210000005091 airway smooth muscle Anatomy 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 125000004183 alkoxy alkyl group Chemical group 0.000 description 1
- 125000000278 alkyl amino alkyl group Chemical group 0.000 description 1
- 125000005907 alkyl ester group Chemical group 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 235000012211 aluminium silicate Nutrition 0.000 description 1
- 150000001408 amides Chemical group 0.000 description 1
- PECIYKGSSMCNHN-UHFFFAOYSA-N aminophylline Chemical compound NCCN.O=C1N(C)C(=O)N(C)C2=NC=N[C]21.O=C1N(C)C(=O)N(C)C2=NC=N[C]21 PECIYKGSSMCNHN-UHFFFAOYSA-N 0.000 description 1
- 229960003556 aminophylline Drugs 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 229960005447 anthrax vaccines Drugs 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000000719 anti-leukaemic effect Effects 0.000 description 1
- 230000000692 anti-sense effect Effects 0.000 description 1
- 239000003429 antifungal agent Substances 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 201000011165 anus cancer Diseases 0.000 description 1
- 239000012062 aqueous buffer Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 150000008209 arabinosides Chemical class 0.000 description 1
- 229940114079 arachidonic acid Drugs 0.000 description 1
- 235000021342 arachidonic acid Nutrition 0.000 description 1
- 125000005251 aryl acyl group Chemical group 0.000 description 1
- 229960003852 atezolizumab Drugs 0.000 description 1
- 229940068561 atripla Drugs 0.000 description 1
- 150000001540 azides Chemical class 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- 229940092705 beclomethasone Drugs 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
- 150000003936 benzamides Chemical class 0.000 description 1
- 150000001558 benzoic acid derivatives Chemical class 0.000 description 1
- 229960002903 benzyl benzoate Drugs 0.000 description 1
- 102000005936 beta-Galactosidase Human genes 0.000 description 1
- 108010005774 beta-Galactosidase Proteins 0.000 description 1
- 238000006065 biodegradation reaction Methods 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
- 239000000090 biomarker Substances 0.000 description 1
- 238000001574 biopsy Methods 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000006287 biotinylation Effects 0.000 description 1
- 238000007413 biotinylation Methods 0.000 description 1
- 229960003008 blinatumomab Drugs 0.000 description 1
- 210000001772 blood platelet Anatomy 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- 238000009583 bone marrow aspiration Methods 0.000 description 1
- 208000012172 borderline epithelial tumor of ovary Diseases 0.000 description 1
- 125000005620 boronic acid group Chemical class 0.000 description 1
- 229960003736 bosutinib Drugs 0.000 description 1
- UBPYILGKFZZVDX-UHFFFAOYSA-N bosutinib Chemical compound C1=C(Cl)C(OC)=CC(NC=2C3=CC(OC)=C(OCCCN4CCN(C)CC4)C=C3N=CC=2C#N)=C1Cl UBPYILGKFZZVDX-UHFFFAOYSA-N 0.000 description 1
- 229940124630 bronchodilator Drugs 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 239000006172 buffering agent Substances 0.000 description 1
- 229950003628 buparlisib Drugs 0.000 description 1
- CUWODFFVMXJOKD-UVLQAERKSA-N buserelin Chemical compound CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](COC(C)(C)C)NC(=O)[C@@H](NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H]1NC(=O)CC1)CC1=CC=C(O)C=C1 CUWODFFVMXJOKD-UVLQAERKSA-N 0.000 description 1
- 229960002719 buserelin Drugs 0.000 description 1
- 229960002092 busulfan Drugs 0.000 description 1
- 235000019437 butane-1,3-diol Nutrition 0.000 description 1
- 102100029170 cAMP-specific 3',5'-cyclic phosphodiesterase 4D Human genes 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 235000010216 calcium carbonate Nutrition 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 235000011148 calcium chloride Nutrition 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 244000309466 calf Species 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
- 229940127093 camptothecin Drugs 0.000 description 1
- 238000009566 cancer vaccine Methods 0.000 description 1
- 229940022399 cancer vaccine Drugs 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 208000025046 carcinoma of lip Diseases 0.000 description 1
- 208000011892 carcinosarcoma of the corpus uteri Diseases 0.000 description 1
- BLMPQMFVWMYDKT-NZTKNTHTSA-N carfilzomib Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC(C)C)C(=O)[C@]1(C)OC1)NC(=O)CN1CCOCC1)CC1=CC=CC=C1 BLMPQMFVWMYDKT-NZTKNTHTSA-N 0.000 description 1
- 108010021331 carfilzomib Proteins 0.000 description 1
- 229960002438 carfilzomib Drugs 0.000 description 1
- 235000019438 castor oil Nutrition 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 230000020411 cell activation Effects 0.000 description 1
- 230000024245 cell differentiation Effects 0.000 description 1
- 230000003915 cell function Effects 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 229920002301 cellulose acetate Polymers 0.000 description 1
- PNDKCRDVVKJPKG-WHERJAGFSA-N cenicriviroc Chemical compound C1=CC(OCCOCCCC)=CC=C1C1=CC=C(N(CC(C)C)CCC\C(=C/2)C(=O)NC=3C=CC(=CC=3)[S@@](=O)CC=3N(C=NC=3)CCC)C\2=C1 PNDKCRDVVKJPKG-WHERJAGFSA-N 0.000 description 1
- 229950011033 cenicriviroc Drugs 0.000 description 1
- 201000007335 cerebellar astrocytoma Diseases 0.000 description 1
- 239000013522 chelant Substances 0.000 description 1
- 125000003636 chemical group Chemical group 0.000 description 1
- 210000000038 chest Anatomy 0.000 description 1
- 201000002687 childhood acute myeloid leukemia Diseases 0.000 description 1
- 201000004018 childhood brain stem glioma Diseases 0.000 description 1
- 201000004677 childhood cerebellar astrocytic neoplasm Diseases 0.000 description 1
- 208000011654 childhood malignant neoplasm Diseases 0.000 description 1
- 201000005793 childhood medulloblastoma Diseases 0.000 description 1
- 229960004926 chlorobutanol Drugs 0.000 description 1
- 229960005004 cholera vaccine Drugs 0.000 description 1
- 210000000349 chromosome Anatomy 0.000 description 1
- 208000032852 chronic lymphocytic leukemia Diseases 0.000 description 1
- 229960002376 chymotrypsin Drugs 0.000 description 1
- 230000007699 co-inhibitory pathway Effects 0.000 description 1
- 238000004737 colorimetric analysis Methods 0.000 description 1
- 229940001442 combination vaccine Drugs 0.000 description 1
- 229940014461 combivir Drugs 0.000 description 1
- 239000013065 commercial product Substances 0.000 description 1
- 239000002299 complementary DNA Substances 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 235000008504 concentrate Nutrition 0.000 description 1
- 229940031670 conjugate vaccine Drugs 0.000 description 1
- 230000021615 conjugation Effects 0.000 description 1
- 229920001577 copolymer Polymers 0.000 description 1
- 235000005822 corn Nutrition 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 235000012343 cottonseed oil Nutrition 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 229960001681 croscarmellose sodium Drugs 0.000 description 1
- 229960000913 crospovidone Drugs 0.000 description 1
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 1
- 229940092456 curosurf Drugs 0.000 description 1
- 201000007241 cutaneous T cell lymphoma Diseases 0.000 description 1
- 208000035250 cutaneous malignant susceptibility to 1 melanoma Diseases 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 150000001945 cysteines Chemical class 0.000 description 1
- 210000001151 cytotoxic T lymphocyte Anatomy 0.000 description 1
- 229960003603 decitabine Drugs 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 229960004120 defibrotide Drugs 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- SWJBYJJNDIXFSA-KUHUBIRLSA-N demethoxyviridin Chemical compound O=C1C2=C3CCC(=O)C3=CC=C2[C@]2(C)C3=C1OC=C3C(=O)C[C@H]2O SWJBYJJNDIXFSA-KUHUBIRLSA-N 0.000 description 1
- 239000003398 denaturant Substances 0.000 description 1
- 108010017271 denileukin diftitox Proteins 0.000 description 1
- 229960002923 denileukin diftitox Drugs 0.000 description 1
- 239000005549 deoxyribonucleoside Substances 0.000 description 1
- 229960003957 dexamethasone Drugs 0.000 description 1
- UREBDLICKHMUKA-CXSFZGCWSA-N dexamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-CXSFZGCWSA-N 0.000 description 1
- 229960000605 dexrazoxane Drugs 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 125000004663 dialkyl amino group Chemical group 0.000 description 1
- NEFBYIFKOOEVPA-UHFFFAOYSA-K dicalcium phosphate Chemical compound [Ca+2].[Ca+2].[O-]P([O-])([O-])=O NEFBYIFKOOEVPA-UHFFFAOYSA-K 0.000 description 1
- 229910000390 dicalcium phosphate Inorganic materials 0.000 description 1
- 229940038472 dicalcium phosphate Drugs 0.000 description 1
- 210000002249 digestive system Anatomy 0.000 description 1
- UGMCXQCYOVCMTB-UHFFFAOYSA-K dihydroxy(stearato)aluminium Chemical compound CCCCCCCCCCCCCCCCCC(=O)O[Al](O)O UGMCXQCYOVCMTB-UHFFFAOYSA-K 0.000 description 1
- 229960003983 diphtheria toxoid Drugs 0.000 description 1
- 229960005097 diphtheria vaccines Drugs 0.000 description 1
- 230000005750 disease progression Effects 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- NYDXNILOWQXUOF-UHFFFAOYSA-L disodium;2-[[4-[2-(2-amino-4-oxo-1,7-dihydropyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]amino]pentanedioate Chemical compound [Na+].[Na+].C=1NC=2NC(N)=NC(=O)C=2C=1CCC1=CC=C(C(=O)NC(CCC([O-])=O)C([O-])=O)C=C1 NYDXNILOWQXUOF-UHFFFAOYSA-L 0.000 description 1
- 239000002270 dispersing agent Substances 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
- MOTZDAYCYVMXPC-UHFFFAOYSA-N dodecyl hydrogen sulfate Chemical compound CCCCCCCCCCCCOS(O)(=O)=O MOTZDAYCYVMXPC-UHFFFAOYSA-N 0.000 description 1
- 229940043264 dodecyl sulfate Drugs 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 229950009791 durvalumab Drugs 0.000 description 1
- 229950004949 duvelisib Drugs 0.000 description 1
- 229960003804 efavirenz Drugs 0.000 description 1
- XPOQHMRABVBWPR-ZDUSSCGKSA-N efavirenz Chemical compound C([C@]1(C2=CC(Cl)=CC=C2NC(=O)O1)C(F)(F)F)#CC1CC1 XPOQHMRABVBWPR-ZDUSSCGKSA-N 0.000 description 1
- 230000005686 electrostatic field Effects 0.000 description 1
- 229960004137 elotuzumab Drugs 0.000 description 1
- 229960003239 encephalitis vaccine Drugs 0.000 description 1
- 230000002124 endocrine Effects 0.000 description 1
- 210000003372 endocrine gland Anatomy 0.000 description 1
- 230000002357 endometrial effect Effects 0.000 description 1
- 150000002084 enol ethers Chemical class 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
- 229930013356 epothilone Natural products 0.000 description 1
- 150000003883 epothilone derivatives Chemical class 0.000 description 1
- 229960001433 erlotinib Drugs 0.000 description 1
- AAKJLRGGTJKAMG-UHFFFAOYSA-N erlotinib Chemical compound C=12C=C(OCCOC)C(OCCOC)=CC2=NC=NC=1NC1=CC=CC(C#C)=C1 AAKJLRGGTJKAMG-UHFFFAOYSA-N 0.000 description 1
- 229940093499 ethyl acetate Drugs 0.000 description 1
- 229960004667 ethyl cellulose Drugs 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
- 230000017188 evasion or tolerance of host immune response Effects 0.000 description 1
- 208000021045 exocrine pancreatic carcinoma Diseases 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 208000024519 eye neoplasm Diseases 0.000 description 1
- 201000007741 female breast cancer Diseases 0.000 description 1
- 201000002276 female breast carcinoma Diseases 0.000 description 1
- 229960004887 ferric hydroxide Drugs 0.000 description 1
- 210000004700 fetal blood Anatomy 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 235000013312 flour Nutrition 0.000 description 1
- 229960001347 fluocinolone acetonide Drugs 0.000 description 1
- FEBLZLNTKCEFIT-VSXGLTOVSA-N fluocinolone acetonide Chemical compound C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@]1(F)[C@@H]2[C@@H]2C[C@H]3OC(C)(C)O[C@@]3(C(=O)CO)[C@@]2(C)C[C@@H]1O FEBLZLNTKCEFIT-VSXGLTOVSA-N 0.000 description 1
- 229960000785 fluocinonide 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
- 229960002074 flutamide Drugs 0.000 description 1
- XTULMSXFIHGYFS-VLSRWLAYSA-N fluticasone furoate Chemical compound O([C@]1([C@@]2(C)C[C@H](O)[C@]3(F)[C@@]4(C)C=CC(=O)C=C4[C@@H](F)C[C@H]3[C@@H]2C[C@H]1C)C(=O)SCF)C(=O)C1=CC=CO1 XTULMSXFIHGYFS-VLSRWLAYSA-N 0.000 description 1
- 229960001469 fluticasone furoate Drugs 0.000 description 1
- 229960000289 fluticasone propionate Drugs 0.000 description 1
- WMWTYOKRWGGJOA-CENSZEJFSA-N fluticasone propionate Chemical compound C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@]1(F)[C@@H]2[C@@H]2C[C@@H](C)[C@@](C(=O)SCF)(OC(=O)CC)[C@@]2(C)C[C@@H]1O WMWTYOKRWGGJOA-CENSZEJFSA-N 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 229960002258 fulvestrant Drugs 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 230000004927 fusion Effects 0.000 description 1
- UIWYJDYFSGRHKR-UHFFFAOYSA-N gadolinium atom Chemical compound [Gd] UIWYJDYFSGRHKR-UHFFFAOYSA-N 0.000 description 1
- 201000010175 gallbladder cancer Diseases 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 201000006585 gastric adenocarcinoma Diseases 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 229960000578 gemtuzumab Drugs 0.000 description 1
- 229960003297 gemtuzumab ozogamicin Drugs 0.000 description 1
- 201000007116 gestational trophoblastic neoplasm Diseases 0.000 description 1
- 208000005017 glioblastoma Diseases 0.000 description 1
- 229940124750 glucocorticoid receptor agonist Drugs 0.000 description 1
- 235000001727 glucose Nutrition 0.000 description 1
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 1
- YQEMORVAKMFKLG-UHFFFAOYSA-N glycerine monostearate Natural products CCCCCCCCCCCCCCCCCC(=O)OC(CO)CO YQEMORVAKMFKLG-UHFFFAOYSA-N 0.000 description 1
- RZRNAYUHWVFMIP-HXUWFJFHSA-N glycerol monolinoleate Natural products CCCCCCCCC=CCCCCCCCC(=O)OC[C@H](O)CO RZRNAYUHWVFMIP-HXUWFJFHSA-N 0.000 description 1
- SVUQHVRAGMNPLW-UHFFFAOYSA-N glycerol monostearate Natural products CCCCCCCCCCCCCCCCC(=O)OCC(O)CO SVUQHVRAGMNPLW-UHFFFAOYSA-N 0.000 description 1
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 1
- 150000002313 glycerolipids Chemical class 0.000 description 1
- 229940075507 glyceryl monostearate Drugs 0.000 description 1
- 239000001087 glyceryl triacetate Substances 0.000 description 1
- 235000013773 glyceryl triacetate Nutrition 0.000 description 1
- 125000003147 glycosyl group Chemical group 0.000 description 1
- 210000003714 granulocyte Anatomy 0.000 description 1
- 238000001631 haemodialysis Methods 0.000 description 1
- 210000003128 head Anatomy 0.000 description 1
- 201000010536 head and neck cancer Diseases 0.000 description 1
- 208000014829 head and neck neoplasm Diseases 0.000 description 1
- 210000002443 helper t lymphocyte Anatomy 0.000 description 1
- 239000000185 hemagglutinin Substances 0.000 description 1
- 230000002489 hematologic effect Effects 0.000 description 1
- 238000011134 hematopoietic stem cell transplantation Methods 0.000 description 1
- 150000002373 hemiacetals Chemical group 0.000 description 1
- 230000000322 hemodialysis Effects 0.000 description 1
- 229960004443 hemophilus influenzae b vaccines Drugs 0.000 description 1
- 230000002439 hemostatic effect Effects 0.000 description 1
- 208000005252 hepatitis A Diseases 0.000 description 1
- 208000002672 hepatitis B Diseases 0.000 description 1
- 201000010284 hepatitis E Diseases 0.000 description 1
- 201000002735 hepatocellular adenoma Diseases 0.000 description 1
- IPCSVZSSVZVIGE-UHFFFAOYSA-M hexadecanoate Chemical compound CCCCCCCCCCCCCCCC([O-])=O IPCSVZSSVZVIGE-UHFFFAOYSA-M 0.000 description 1
- 210000003630 histaminocyte Anatomy 0.000 description 1
- 201000000284 histiocytoma Diseases 0.000 description 1
- 102000044292 human CMA1 Human genes 0.000 description 1
- 102000047087 human SFTPC Human genes 0.000 description 1
- 208000033519 human immunodeficiency virus infectious disease Diseases 0.000 description 1
- 239000003906 humectant Substances 0.000 description 1
- 230000036571 hydration Effects 0.000 description 1
- 238000006703 hydration reaction Methods 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical group 0.000 description 1
- 150000005828 hydrofluoroalkanes Chemical class 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 125000001165 hydrophobic group Chemical group 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 1
- 229940031704 hydroxypropyl methylcellulose phthalate Drugs 0.000 description 1
- 229920003132 hydroxypropyl methylcellulose phthalate Polymers 0.000 description 1
- 229920000639 hydroxypropylmethylcellulose acetate succinate Polymers 0.000 description 1
- 230000003463 hyperproliferative effect Effects 0.000 description 1
- 208000013010 hypopharyngeal carcinoma Diseases 0.000 description 1
- 210000003016 hypothalamus Anatomy 0.000 description 1
- 229960001001 ibritumomab tiuxetan Drugs 0.000 description 1
- IFSDAJWBUCMOAH-HNNXBMFYSA-N idelalisib Chemical compound C1([C@@H](NC=2C=3N=CNC=3N=CN=2)CC)=NC2=CC=CC(F)=C2C(=O)N1C1=CC=CC=C1 IFSDAJWBUCMOAH-HNNXBMFYSA-N 0.000 description 1
- 238000003384 imaging method Methods 0.000 description 1
- 230000002163 immunogen Effects 0.000 description 1
- 102000018358 immunoglobulin Human genes 0.000 description 1
- 230000001506 immunosuppresive effect Effects 0.000 description 1
- 239000003018 immunosuppressive agent Substances 0.000 description 1
- 229940124589 immunosuppressive drug Drugs 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 238000010874 in vitro model Methods 0.000 description 1
- 229940031551 inactivated vaccine Drugs 0.000 description 1
- 229960001936 indinavir Drugs 0.000 description 1
- CBVCZFGXHXORBI-PXQQMZJSSA-N indinavir Chemical compound C([C@H](N(CC1)C[C@@H](O)C[C@@H](CC=2C=CC=CC=2)C(=O)N[C@H]2C3=CC=CC=C3C[C@H]2O)C(=O)NC(C)(C)C)N1CC1=CC=CN=C1 CBVCZFGXHXORBI-PXQQMZJSSA-N 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 239000003701 inert diluent Substances 0.000 description 1
- 229940026289 infasurf Drugs 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 229940033324 influenza A vaccine Drugs 0.000 description 1
- 208000037798 influenza B Diseases 0.000 description 1
- 208000037799 influenza C Diseases 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 230000015788 innate immune response Effects 0.000 description 1
- 238000011081 inoculation Methods 0.000 description 1
- 238000003780 insertion Methods 0.000 description 1
- 230000037431 insertion Effects 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 229940117681 interleukin-12 Drugs 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 229960005386 ipilimumab Drugs 0.000 description 1
- 229960004768 irinotecan Drugs 0.000 description 1
- UWKQSNNFCGGAFS-XIFFEERXSA-N irinotecan Chemical compound C1=C2C(CC)=C3CN(C(C4=C([C@@](C(=O)OC4)(O)CC)C=4)=O)C=4C3=NC2=CC=C1OC(=O)N(CC1)CCC1N1CCCCC1 UWKQSNNFCGGAFS-XIFFEERXSA-N 0.000 description 1
- 235000013980 iron oxide Nutrition 0.000 description 1
- IEECXTSVVFWGSE-UHFFFAOYSA-M iron(3+);oxygen(2-);hydroxide Chemical compound [OH-].[O-2].[Fe+3] IEECXTSVVFWGSE-UHFFFAOYSA-M 0.000 description 1
- KQNPFQTWMSNSAP-UHFFFAOYSA-N isobutyric acid Chemical compound CC(C)C(O)=O KQNPFQTWMSNSAP-UHFFFAOYSA-N 0.000 description 1
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 1
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 1
- 239000007951 isotonicity adjuster Substances 0.000 description 1
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
- DKYWVDODHFEZIM-UHFFFAOYSA-N ketoprofen Chemical compound OC(=O)C(C)C1=CC=CC(C(=O)C=2C=CC=CC=2)=C1 DKYWVDODHFEZIM-UHFFFAOYSA-N 0.000 description 1
- 229960000991 ketoprofen Drugs 0.000 description 1
- 108010021336 lanreotide Proteins 0.000 description 1
- 229960002437 lanreotide Drugs 0.000 description 1
- 229910001476 lanthanide phosphate Inorganic materials 0.000 description 1
- 201000005264 laryngeal carcinoma Diseases 0.000 description 1
- 229960004942 lenalidomide Drugs 0.000 description 1
- GOTYRUGSSMKFNF-UHFFFAOYSA-N lenalidomide Chemical compound C1C=2C(N)=CC=CC=2C(=O)N1C1CCC(=O)NC1=O GOTYRUGSSMKFNF-UHFFFAOYSA-N 0.000 description 1
- 150000002617 leukotrienes Chemical class 0.000 description 1
- UAWXGRJVZSAUSZ-UHFFFAOYSA-N licofelone Chemical compound OC(=O)CC=1N2CC(C)(C)CC2=C(C=2C=CC=CC=2)C=1C1=CC=C(Cl)C=C1 UAWXGRJVZSAUSZ-UHFFFAOYSA-N 0.000 description 1
- 229950003488 licofelone Drugs 0.000 description 1
- 208000012987 lip and oral cavity carcinoma Diseases 0.000 description 1
- 125000003473 lipid group Chemical group 0.000 description 1
- 230000029226 lipidation Effects 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 201000002250 liver carcinoma Diseases 0.000 description 1
- 244000144972 livestock Species 0.000 description 1
- 230000033001 locomotion Effects 0.000 description 1
- 229960003744 loteprednol etabonate Drugs 0.000 description 1
- DMKSVUSAATWOCU-HROMYWEYSA-N loteprednol etabonate Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(=O)OCCl)(OC(=O)OCC)[C@@]1(C)C[C@@H]2O DMKSVUSAATWOCU-HROMYWEYSA-N 0.000 description 1
- 201000005249 lung adenocarcinoma Diseases 0.000 description 1
- 201000005296 lung carcinoma Diseases 0.000 description 1
- 210000004324 lymphatic system Anatomy 0.000 description 1
- 208000001419 lymphocytic choriomeningitis Diseases 0.000 description 1
- 210000003563 lymphoid tissue Anatomy 0.000 description 1
- 201000001268 lymphoproliferative syndrome Diseases 0.000 description 1
- 239000008176 lyophilized powder Substances 0.000 description 1
- 201000000564 macroglobulinemia Diseases 0.000 description 1
- 210000002540 macrophage Anatomy 0.000 description 1
- 239000011777 magnesium Chemical class 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 230000005415 magnetization Effects 0.000 description 1
- 208000010907 male breast carcinoma Diseases 0.000 description 1
- 230000003211 malignant effect Effects 0.000 description 1
- 208000006178 malignant mesothelioma Diseases 0.000 description 1
- 208000020984 malignant renal pelvis neoplasm Diseases 0.000 description 1
- 208000026045 malignant tumor of parathyroid gland Diseases 0.000 description 1
- 238000007726 management method Methods 0.000 description 1
- 208000008585 mastocytosis Diseases 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
- 229940041323 measles vaccine Drugs 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 210000004379 membrane Anatomy 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 229940124731 meningococcal vaccine Drugs 0.000 description 1
- 229960005037 meningococcal vaccines Drugs 0.000 description 1
- GLVAUDGFNGKCSF-UHFFFAOYSA-N mercaptopurine Chemical compound S=C1NC=NC2=C1NC=N2 GLVAUDGFNGKCSF-UHFFFAOYSA-N 0.000 description 1
- 229960001428 mercaptopurine Drugs 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- IWVKTOUOPHGZRX-UHFFFAOYSA-N methyl 2-methylprop-2-enoate;2-methylprop-2-enoic acid Chemical compound CC(=C)C(O)=O.COC(=O)C(C)=C IWVKTOUOPHGZRX-UHFFFAOYSA-N 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- CXHHBNMLPJOKQD-UHFFFAOYSA-N methyl hydrogen carbonate Chemical class COC(O)=O CXHHBNMLPJOKQD-UHFFFAOYSA-N 0.000 description 1
- IQSHMXAZFHORGY-UHFFFAOYSA-N methyl prop-2-enoate;2-methylprop-2-enoic acid Chemical compound COC(=O)C=C.CC(=C)C(O)=O IQSHMXAZFHORGY-UHFFFAOYSA-N 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 229960003152 metisazone Drugs 0.000 description 1
- 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 1
- 229960001156 mitoxantrone Drugs 0.000 description 1
- 238000007799 mixed lymphocyte reaction assay Methods 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 239000001788 mono and diglycerides of fatty acids Substances 0.000 description 1
- CQDGTJPVBWZJAZ-UHFFFAOYSA-N monoethyl carbonate Chemical compound CCOC(O)=O CQDGTJPVBWZJAZ-UHFFFAOYSA-N 0.000 description 1
- 150000002772 monosaccharides Chemical class 0.000 description 1
- 229960005389 moroxydine Drugs 0.000 description 1
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- 238000010172 mouse model Methods 0.000 description 1
- 229940095293 mumps vaccine Drugs 0.000 description 1
- 201000005962 mycosis fungoides Diseases 0.000 description 1
- 125000001419 myristoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- OKFDRAHPFKMAJH-UHFFFAOYSA-N n-(3,5-dichloropyridin-4-yl)-4-(difluoromethoxy)-8-(methanesulfonamido)dibenzofuran-1-carboxamide Chemical compound C=12C3=CC(NS(=O)(=O)C)=CC=C3OC2=C(OC(F)F)C=CC=1C(=O)NC1=C(Cl)C=NC=C1Cl OKFDRAHPFKMAJH-UHFFFAOYSA-N 0.000 description 1
- UZWDCWONPYILKI-UHFFFAOYSA-N n-[5-[(4-ethylpiperazin-1-yl)methyl]pyridin-2-yl]-5-fluoro-4-(7-fluoro-2-methyl-3-propan-2-ylbenzimidazol-5-yl)pyrimidin-2-amine Chemical compound C1CN(CC)CCN1CC(C=N1)=CC=C1NC1=NC=C(F)C(C=2C=C3N(C(C)C)C(C)=NC3=C(F)C=2)=N1 UZWDCWONPYILKI-UHFFFAOYSA-N 0.000 description 1
- IJDNQMDRQITEOD-UHFFFAOYSA-N n-butane Chemical compound CCCC IJDNQMDRQITEOD-UHFFFAOYSA-N 0.000 description 1
- 201000007425 nasal cavity carcinoma Diseases 0.000 description 1
- 201000011216 nasopharynx carcinoma Diseases 0.000 description 1
- 229950003726 navarixin Drugs 0.000 description 1
- 239000006199 nebulizer Substances 0.000 description 1
- 230000009826 neoplastic cell growth Effects 0.000 description 1
- 229950008835 neratinib Drugs 0.000 description 1
- JWNPDZNEKVCWMY-VQHVLOKHSA-N neratinib Chemical compound C=12C=C(NC(=O)\C=C\CN(C)C)C(OCC)=CC2=NC=C(C#N)C=1NC(C=C1Cl)=CC=C1OCC1=CC=CC=N1 JWNPDZNEKVCWMY-VQHVLOKHSA-N 0.000 description 1
- 230000007433 nerve pathway Effects 0.000 description 1
- 210000000653 nervous system Anatomy 0.000 description 1
- 230000001537 neural effect Effects 0.000 description 1
- 229960000689 nevirapine Drugs 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 239000001272 nitrous oxide Substances 0.000 description 1
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 1
- 239000012457 nonaqueous media Substances 0.000 description 1
- NVGOPFQZYCNLDU-UHFFFAOYSA-N norflurazon Chemical compound O=C1C(Cl)=C(NC)C=NN1C1=CC=CC(C(F)(F)F)=C1 NVGOPFQZYCNLDU-UHFFFAOYSA-N 0.000 description 1
- 239000002777 nucleoside Substances 0.000 description 1
- 125000003835 nucleoside group Chemical group 0.000 description 1
- 229960003347 obinutuzumab Drugs 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 description 1
- 201000008106 ocular cancer Diseases 0.000 description 1
- 201000002575 ocular melanoma Diseases 0.000 description 1
- 229950000175 oglemilast Drugs 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 235000021313 oleic acid Nutrition 0.000 description 1
- 238000006384 oligomerization reaction Methods 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 210000001328 optic nerve Anatomy 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 210000004789 organ system Anatomy 0.000 description 1
- 150000002895 organic esters Chemical class 0.000 description 1
- 201000006958 oropharynx cancer Diseases 0.000 description 1
- PGZUMBJQJWIWGJ-ONAKXNSWSA-N oseltamivir phosphate Chemical compound OP(O)(O)=O.CCOC(=O)C1=C[C@@H](OC(CC)CC)[C@H](NC(C)=O)[C@@H](N)C1 PGZUMBJQJWIWGJ-ONAKXNSWSA-N 0.000 description 1
- 229960003278 osimertinib Drugs 0.000 description 1
- DUYJMQONPNNFPI-UHFFFAOYSA-N osimertinib Chemical compound COC1=CC(N(C)CCN(C)C)=C(NC(=O)C=C)C=C1NC1=NC=CC(C=2C3=CC=CC=C3N(C)C=2)=N1 DUYJMQONPNNFPI-UHFFFAOYSA-N 0.000 description 1
- 201000008968 osteosarcoma Diseases 0.000 description 1
- 229940047091 other immunostimulants in atc Drugs 0.000 description 1
- 208000021284 ovarian germ cell tumor Diseases 0.000 description 1
- 210000001672 ovary Anatomy 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 125000004043 oxo group Chemical group O=* 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- IWVCMVBTMGNXQD-PXOLEDIWSA-N oxytetracycline Chemical compound C1=CC=C2[C@](O)(C)[C@H]3[C@H](O)[C@H]4[C@H](N(C)C)C(O)=C(C(N)=O)C(=O)[C@@]4(O)C(O)=C3C(=O)C2=C1O IWVCMVBTMGNXQD-PXOLEDIWSA-N 0.000 description 1
- 229960000625 oxytetracycline Drugs 0.000 description 1
- 235000019366 oxytetracycline Nutrition 0.000 description 1
- 239000006179 pH buffering agent Substances 0.000 description 1
- 229940023569 palmate Drugs 0.000 description 1
- 125000001312 palmitoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229960002566 papillomavirus vaccine Drugs 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 210000003695 paranasal sinus Anatomy 0.000 description 1
- 208000022775 paranasal sinus carcinoma Diseases 0.000 description 1
- 230000000849 parathyroid Effects 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- HQQSBEDKMRHYME-UHFFFAOYSA-N pefloxacin mesylate Chemical compound [H+].CS([O-])(=O)=O.C1=C2N(CC)C=C(C(O)=O)C(=O)C2=CC(F)=C1N1CCN(C)CC1 HQQSBEDKMRHYME-UHFFFAOYSA-N 0.000 description 1
- 108010044644 pegfilgrastim Proteins 0.000 description 1
- 229960001373 pegfilgrastim Drugs 0.000 description 1
- 229960002621 pembrolizumab Drugs 0.000 description 1
- QOFFJEBXNKRSPX-ZDUSSCGKSA-N pemetrexed Chemical compound C1=N[C]2NC(N)=NC(=O)C2=C1CCC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 QOFFJEBXNKRSPX-ZDUSSCGKSA-N 0.000 description 1
- 229960005079 pemetrexed Drugs 0.000 description 1
- 229960003349 pemetrexed disodium Drugs 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- PNJWIWWMYCMZRO-UHFFFAOYSA-N pent‐4‐en‐2‐one Natural products CC(=O)CC=C PNJWIWWMYCMZRO-UHFFFAOYSA-N 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 210000001428 peripheral nervous system Anatomy 0.000 description 1
- 210000004303 peritoneum Anatomy 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 230000002085 persistent effect Effects 0.000 description 1
- 229940066827 pertussis vaccine Drugs 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- 229960003742 phenol Drugs 0.000 description 1
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 1
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 1
- 208000028591 pheochromocytoma Diseases 0.000 description 1
- 239000010452 phosphate Chemical class 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical class [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- WTJKGGKOPKCXLL-RRHRGVEJSA-N phosphatidylcholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCC=CCCCCCCCC WTJKGGKOPKCXLL-RRHRGVEJSA-N 0.000 description 1
- 239000002587 phosphodiesterase IV inhibitor Substances 0.000 description 1
- 235000011007 phosphoric acid Nutrition 0.000 description 1
- 150000003016 phosphoric acids Chemical class 0.000 description 1
- 230000035479 physiological effects, processes and functions Effects 0.000 description 1
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 210000003635 pituitary gland Anatomy 0.000 description 1
- 208000010916 pituitary tumor Diseases 0.000 description 1
- 210000002826 placenta Anatomy 0.000 description 1
- 229960004545 plague vaccines Drugs 0.000 description 1
- 239000013612 plasmid Substances 0.000 description 1
- 229960000471 pleconaril Drugs 0.000 description 1
- KQOXLKOJHVFTRN-UHFFFAOYSA-N pleconaril Chemical compound O1N=C(C)C=C1CCCOC1=C(C)C=C(C=2N=C(ON=2)C(F)(F)F)C=C1C KQOXLKOJHVFTRN-UHFFFAOYSA-N 0.000 description 1
- YIQPUIGJQJDJOS-UHFFFAOYSA-N plerixafor Chemical compound C=1C=C(CN2CCNCCCNCCNCCC2)C=CC=1CN1CCCNCCNCCCNCC1 YIQPUIGJQJDJOS-UHFFFAOYSA-N 0.000 description 1
- 229960002169 plerixafor Drugs 0.000 description 1
- 229960001237 podophyllotoxin Drugs 0.000 description 1
- YVCVYCSAAZQOJI-UHFFFAOYSA-N podophyllotoxin Natural products COC1=C(O)C(OC)=CC(C2C3=CC=4OCOC=4C=C3C(O)C3C2C(OC3)=O)=C1 YVCVYCSAAZQOJI-UHFFFAOYSA-N 0.000 description 1
- 229920000058 polyacrylate Polymers 0.000 description 1
- 229920002704 polyhistidine Polymers 0.000 description 1
- 229930001119 polyketide Natural products 0.000 description 1
- 125000000830 polyketide group Chemical group 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 229920005862 polyol Polymers 0.000 description 1
- 150000003077 polyols Chemical class 0.000 description 1
- 229920001155 polypropylene Polymers 0.000 description 1
- 229920002744 polyvinyl acetate phthalate Polymers 0.000 description 1
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 description 1
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229960001131 ponatinib Drugs 0.000 description 1
- PHXJVRSECIGDHY-UHFFFAOYSA-N ponatinib Chemical compound C1CN(C)CCN1CC(C(=C1)C(F)(F)F)=CC=C1NC(=O)C1=CC=C(C)C(C#CC=2N3N=CC=CC3=NC=2)=C1 PHXJVRSECIGDHY-UHFFFAOYSA-N 0.000 description 1
- 230000004481 post-translational protein modification Effects 0.000 description 1
- 229940069328 povidone Drugs 0.000 description 1
- 230000035935 pregnancy Effects 0.000 description 1
- 208000025638 primary cutaneous T-cell non-Hodgkin lymphoma Diseases 0.000 description 1
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- 229960004919 procaine Drugs 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 230000001902 propagating effect Effects 0.000 description 1
- 239000001294 propane Substances 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000030788 protein refolding Effects 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- 150000003856 quaternary ammonium compounds Chemical class 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 230000002285 radioactive effect Effects 0.000 description 1
- CZFFBEXEKNGXKS-UHFFFAOYSA-N raltegravir Chemical compound O1C(C)=NN=C1C(=O)NC(C)(C)C1=NC(C(=O)NCC=2C=CC(F)=CC=2)=C(O)C(=O)N1C CZFFBEXEKNGXKS-UHFFFAOYSA-N 0.000 description 1
- 229960004742 raltegravir Drugs 0.000 description 1
- 206010038038 rectal cancer Diseases 0.000 description 1
- 201000001275 rectum cancer Diseases 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 229960004836 regorafenib Drugs 0.000 description 1
- FNHKPVJBJVTLMP-UHFFFAOYSA-N regorafenib Chemical compound C1=NC(C(=O)NC)=CC(OC=2C=C(F)C(NC(=O)NC=3C=C(C(Cl)=CC=3)C(F)(F)F)=CC=2)=C1 FNHKPVJBJVTLMP-UHFFFAOYSA-N 0.000 description 1
- 210000003289 regulatory T cell Anatomy 0.000 description 1
- 201000010174 renal carcinoma Diseases 0.000 description 1
- 208000010639 renal pelvis urothelial carcinoma Diseases 0.000 description 1
- 230000010076 replication Effects 0.000 description 1
- 230000003362 replicative effect Effects 0.000 description 1
- 230000000241 respiratory effect Effects 0.000 description 1
- 230000029058 respiratory gaseous exchange Effects 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- LUKBXSAWLPMMSZ-UHFFFAOYSA-N resveratrol Chemical compound C1=CC(O)=CC=C1C=CC1=CC(O)=CC(O)=C1 LUKBXSAWLPMMSZ-UHFFFAOYSA-N 0.000 description 1
- 229940016667 resveratrol Drugs 0.000 description 1
- 235000021283 resveratrol Nutrition 0.000 description 1
- PYWVYCXTNDRMGF-UHFFFAOYSA-N rhodamine B Chemical compound [Cl-].C=12C=CC(=[N+](CC)CC)C=C2OC2=CC(N(CC)CC)=CC=C2C=1C1=CC=CC=C1C(O)=O PYWVYCXTNDRMGF-UHFFFAOYSA-N 0.000 description 1
- 229960000329 ribavirin Drugs 0.000 description 1
- HZCAHMRRMINHDJ-DBRKOABJSA-N ribavirin Natural products O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1N=CN=C1 HZCAHMRRMINHDJ-DBRKOABJSA-N 0.000 description 1
- 239000002342 ribonucleoside Substances 0.000 description 1
- 210000003705 ribosome Anatomy 0.000 description 1
- 235000009566 rice Nutrition 0.000 description 1
- 229960000888 rimantadine Drugs 0.000 description 1
- 229960003131 rubella vaccine Drugs 0.000 description 1
- HMABYWSNWIZPAG-UHFFFAOYSA-N rucaparib Chemical compound C1=CC(CNC)=CC=C1C(N1)=C2CCNC(=O)C3=C2C1=CC(F)=C3 HMABYWSNWIZPAG-UHFFFAOYSA-N 0.000 description 1
- 229950004707 rucaparib Drugs 0.000 description 1
- 201000003804 salivary gland carcinoma Diseases 0.000 description 1
- 229960001852 saquinavir Drugs 0.000 description 1
- QWAXKHKRTORLEM-UGJKXSETSA-N saquinavir Chemical compound C([C@@H]([C@H](O)CN1C[C@H]2CCCC[C@H]2C[C@H]1C(=O)NC(C)(C)C)NC(=O)[C@H](CC(N)=O)NC(=O)C=1N=C2C=CC=CC2=CC=1)C1=CC=CC=C1 QWAXKHKRTORLEM-UGJKXSETSA-N 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
- 230000003248 secreting effect Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 150000004760 silicates Chemical class 0.000 description 1
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 235000020183 skimmed milk Nutrition 0.000 description 1
- 201000000849 skin cancer Diseases 0.000 description 1
- 201000008261 skin carcinoma Diseases 0.000 description 1
- 208000000587 small cell lung carcinoma Diseases 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 229940083538 smallpox vaccine Drugs 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- RYYKJJJTJZKILX-UHFFFAOYSA-M sodium octadecanoate Chemical compound [Na+].CCCCCCCCCCCCCCCCCC([O-])=O RYYKJJJTJZKILX-UHFFFAOYSA-M 0.000 description 1
- 210000004872 soft tissue Anatomy 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 239000003549 soybean oil Substances 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- 125000006850 spacer group Chemical group 0.000 description 1
- 210000000952 spleen Anatomy 0.000 description 1
- 208000037969 squamous neck cancer Diseases 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 238000011476 stem cell transplantation Methods 0.000 description 1
- 239000008227 sterile water for injection Substances 0.000 description 1
- 229940031626 subunit vaccine Drugs 0.000 description 1
- 150000003455 sulfinic acids Chemical class 0.000 description 1
- 150000003460 sulfonic acids Chemical class 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 229940063649 survanta Drugs 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 229940061367 tamiflu Drugs 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- NHKZSTHOYNWEEZ-AFCXAGJDSA-N taribavirin Chemical compound N1=C(C(=N)N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 NHKZSTHOYNWEEZ-AFCXAGJDSA-N 0.000 description 1
- 229950006081 taribavirin Drugs 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- SGOIRFVFHAKUTI-ZCFIWIBFSA-N tenofovir (anhydrous) Chemical compound N1=CN=C2N(C[C@@H](C)OCP(O)(O)=O)C=NC2=C1N SGOIRFVFHAKUTI-ZCFIWIBFSA-N 0.000 description 1
- IWVCMVBTMGNXQD-UHFFFAOYSA-N terramycin dehydrate Natural products C1=CC=C2C(O)(C)C3C(O)C4C(N(C)C)C(O)=C(C(N)=O)C(=O)C4(O)C(O)=C3C(=O)C2=C1O IWVCMVBTMGNXQD-UHFFFAOYSA-N 0.000 description 1
- 201000003120 testicular cancer Diseases 0.000 description 1
- 210000001550 testis Anatomy 0.000 description 1
- 229960002766 tetanus vaccines Drugs 0.000 description 1
- BSYVTEYKTMYBMK-UHFFFAOYSA-N tetrahydrofurfuryl alcohol Chemical compound OCC1CCCO1 BSYVTEYKTMYBMK-UHFFFAOYSA-N 0.000 description 1
- 229960000278 theophylline Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 150000003573 thiols Chemical group 0.000 description 1
- 208000008732 thymoma Diseases 0.000 description 1
- 210000001541 thymus gland Anatomy 0.000 description 1
- 201000002510 thyroid cancer Diseases 0.000 description 1
- 210000001685 thyroid gland Anatomy 0.000 description 1
- 239000004408 titanium dioxide Substances 0.000 description 1
- 235000010215 titanium dioxide Nutrition 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 231100000167 toxic agent Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 231100000563 toxic property Toxicity 0.000 description 1
- 229940031572 toxoid vaccine Drugs 0.000 description 1
- 229960004066 trametinib Drugs 0.000 description 1
- LIRYPHYGHXZJBZ-UHFFFAOYSA-N trametinib Chemical compound CC(=O)NC1=CC=CC(N2C(N(C3CC3)C(=O)C3=C(NC=4C(=CC(I)=CC=4)F)N(C)C(=O)C(C)=C32)=O)=C1 LIRYPHYGHXZJBZ-UHFFFAOYSA-N 0.000 description 1
- 238000011830 transgenic mouse model Methods 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- 229960001612 trastuzumab emtansine Drugs 0.000 description 1
- 229960002622 triacetin 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
- 239000001069 triethyl citrate Substances 0.000 description 1
- VMYFZRTXGLUXMZ-UHFFFAOYSA-N triethyl citrate Natural products CCOC(=O)C(O)(C(=O)OCC)C(=O)OCC VMYFZRTXGLUXMZ-UHFFFAOYSA-N 0.000 description 1
- 235000013769 triethyl citrate Nutrition 0.000 description 1
- 230000001960 triggered effect Effects 0.000 description 1
- 229960001947 tripalmitin Drugs 0.000 description 1
- YKUJZZHGTWVWHA-UHFFFAOYSA-N triptolide Natural products COC12CC3OC3(C(C)C)C(O)C14OC4CC5C6=C(CCC25C)C(=O)OC6 YKUJZZHGTWVWHA-UHFFFAOYSA-N 0.000 description 1
- 230000001573 trophoblastic effect Effects 0.000 description 1
- 229950000977 trovirdine Drugs 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 229960004224 tyloxapol Drugs 0.000 description 1
- 229920001664 tyloxapol Polymers 0.000 description 1
- MDYZKJNTKZIUSK-UHFFFAOYSA-N tyloxapol Chemical compound O=C.C1CO1.CC(C)(C)CC(C)(C)C1=CC=C(O)C=C1 MDYZKJNTKZIUSK-UHFFFAOYSA-N 0.000 description 1
- 229960004626 umifenovir Drugs 0.000 description 1
- KCFYEAOKVJSACF-UHFFFAOYSA-N umifenovir Chemical compound CN1C2=CC(Br)=C(O)C(CN(C)C)=C2C(C(=O)OCC)=C1CSC1=CC=CC=C1 KCFYEAOKVJSACF-UHFFFAOYSA-N 0.000 description 1
- 241001529453 unidentified herpesvirus Species 0.000 description 1
- 229930195735 unsaturated hydrocarbon Natural products 0.000 description 1
- 201000007433 ureter carcinoma Diseases 0.000 description 1
- 201000000334 ureter transitional cell carcinoma Diseases 0.000 description 1
- 210000002936 ureteral cell Anatomy 0.000 description 1
- 206010046766 uterine cancer Diseases 0.000 description 1
- 201000005290 uterine carcinosarcoma Diseases 0.000 description 1
- 208000037965 uterine sarcoma Diseases 0.000 description 1
- 206010046885 vaginal cancer Diseases 0.000 description 1
- 208000013139 vaginal neoplasm Diseases 0.000 description 1
- 229960004295 valine Drugs 0.000 description 1
- 229940124742 varicella zoster vaccine Drugs 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 101150084623 vip gene Proteins 0.000 description 1
- 239000011782 vitamin Chemical class 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 229930003231 vitamin Chemical class 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
- 229940055760 yervoy Drugs 0.000 description 1
Images
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
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/575—Hormones
- C07K14/57563—Vasoactive intestinal peptide [VIP]; Related peptides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
- C12N5/06—Animal cells or tissues; Human cells or tissues
- C12N5/0602—Vertebrate cells
- C12N5/0634—Cells from the blood or the immune system
- C12N5/0636—T lymphocytes
- C12N5/0638—Cytotoxic T lymphocytes [CTL] or lymphokine activated killer cells [LAK]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2319/00—Fusion polypeptide
- C07K2319/01—Fusion polypeptide containing a localisation/targetting motif
- C07K2319/10—Fusion polypeptide containing a localisation/targetting motif containing a tag for extracellular membrane crossing, e.g. TAT or VP22
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2501/00—Active agents used in cell culture processes, e.g. differentation
- C12N2501/30—Hormones
- C12N2501/35—Vasoactive intestinal peptide [VIP]; Pituitary adenylate cyclase activating polypeptide [PACAP]
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2501/00—Active agents used in cell culture processes, e.g. differentation
- C12N2501/50—Cell markers; Cell surface determinants
- C12N2501/515—CD3, T-cell receptor complex
Abstract
本公开涉及一种用于管理癌症和病毒感染的治疗或预防的VIP拮抗剂。在某些实施例中,本公开涉及如本文所公开的肽等VIP拮抗剂的嵌合变体以及包括所述嵌合变体的药物组合物。在某些实施例中,本公开设想了通过将免疫细胞与本文所公开的肽在体外混合来刺激免疫细胞靶向癌症并且进一步向需要癌症治疗的受试者施用有效量的经刺激的免疫细胞的方法。
Description
相关申请的交叉引用
本申请要求于2018年11月15日提交的美国临时申请第62/768,060号的权益。此申请的全部内容出于所有目的通过引用并入。
通过引用并入通过办公室电子归档***(EFS-WEB)以文本文件形式提交的材料
与本申请相关联的序列表以文本格式提供以代替纸质副本,并且在此通过引用并入本说明书中。含有序列表的文本文件的名称为18223PCT_ST25.txt。文本文件为12KB、创建于2019年11月15日并且通过EFSWeb以电子方式提交。
背景技术
血管活性肠肽(VIP)是在包含中枢神经***中的免疫细胞、神经元和内分泌细胞的多种细胞中产生的。由于内源性VIP存在于气道平滑肌和肺内肺血管的神经中,因此VIP用作支气管扩张剂。VIP还具有通过VIP受体VPAC1和VPAC2改变细胞增殖和产生炎性信号的能力。已开发出一种被称为VIPhyb的嵌合肽,其具有提供膜通透性的N端序列,然后是VIP的C端22个氨基酸序列。随着天然VIP的六个N末端氨基酸被代替,VIPhyb已经改变了充当VIP拮抗剂的生物活性。VIP拮抗剂也在美国专利第6,630,124号和第5,217,953号中进行报告。
传统上,癌症治疗通常利用外科手术、化学疗法和放射疗法。然而,报告了强化免疫***攻击癌细胞的替代性方法。这些方法包含收集、扩增和改变T细胞,以便靶向和刺激免疫***以侵略性地消除癌细胞。在嵌合抗原受体(CAR)T细胞疗法中,将分离的T细胞工程化以表达嵌合蛋白,并且再返回施用于患者。然而,需要鉴定改进的疗法。
Petersen等人报告了在急性白血病的鼠类模型中施用VIPhyb会增强自体抗白血病T细胞应答。《肿瘤免疫学(Oncoimmunology)》,2017,6(5):e1304336。Petersen等人报告了使用利用PI3Kδ抑制剂和VIP拮抗剂的离体治疗改进过继T细胞疗法的T细胞扩增和功能。《血液进展(BloodAdv.)》2018,2(3):210-223。
本文所引用的参考文献并非对现有技术的承认。
发明内容
本公开涉及一种用于管理癌症和病毒感染的治疗或预防的VIP拮抗剂。在某些实施例中,本公开涉及如本文所公开的肽等VIP拮抗剂的嵌合变体以及包括所述嵌合变体的药物组合物。在某些实施例中,本公开设想了通过将免疫细胞与本文所公开的肽在体外混合来刺激免疫细胞靶向癌症并且进一步向需要癌症治疗的受试者施用有效量的经刺激的免疫细胞的方法。
在某些实施例中,所述VIP拮抗剂是肽,所述肽包括K P R R P Y X1X2N X3T X4L RK Q X5A V X6K Y X7N X8I L N(SEQ ID NO:11),其中X1是A或任何氨基酸;X2是V或任何氨基酸;X3是C或任何氨基酸;X4是S或任何氨基酸;X5是I或任何氨基酸;X6是N或任何氨基酸;X7是M或任何氨基酸;X8是I或任何氨基酸;并且条件是所述肽不是KPRRPYTDNYTRLRKQMAVKKYLNSILN(SEQ ID NO:1)或其中X1是T、X2是D、X3是Y、X4是R、X5是M、X6是K、X7是L并且X8是S的组合。
在某些实施例中,所述肽包括以下或由以下组成:K P R R P Y X1X2N X3T X4L RK Q X5A V X6K Y X7N X8I L N(SEQ ID NO:11),其中X1是A或T,其中仅当X2是V,X3是C,X4是S,X5是I,X6是N,X7是M或X8是I时,X1才是T;其中X2是V或D,其中仅当X1是A,X3是C,X4是S,X5是I,X6是N,X7是M或X8是I时,X2才是D;其中X3是C或Y,其中仅当X1是A,X2是V,X4是S,X5是I,X6是N,X7是M或X8是I时,X3才是Y;其中X4是S或R,其中仅当X1是A,X2是V,X3是C,X5是I,X6是N,X7是M或X8是I时,X4才是R;其中X5是I或M,其中仅当X1是A,X2是V,X3是C,X4是S,X6是N,X7是M或X8是I时,X5才是M;其中X6是N或K,其中仅当X1是A,X2是V,X3是C,X4是S,X5是I,X7是M或X8是I时,X6才是K;其中X7是M或L,其中仅当X1是A,X2是V,X3是C,X4是S,X5是I,X6是N或X8是I时,X7才是L;并且其中X8是I或S,其中仅当X1是A,X2是V,X3是C,X4是S,X5是I,X6是N或X7是M时,X8才是S。
在某些实施例中,所述肽包括以下或由以下组成:
KPRRPYADNYTRLRKQMAVKKYLNSILN(SEQ ID NO:3);
KPRRPYTVNYTRLRKQMAVKKYLNSILN(SEQ ID NO:4);
KPRRPYTDNCTRLRKQMAVKKYLNSILN(SEQ ID NO:5);
KPRRPYTDNYTSLRKQMAVKKYLNSILN(SEQ ID NO:6);
KPRRPYTDNYTRLRKQIAVKKYLNSILN(SEQ ID NO:7);
KPRRPYTDNYTRLRKQMAVNKYLNSILN(SEQ ID NO:8);
KPRRPYTDNYTRLRKQMAVKKYMNSILN(SEQ ID NO:9);或者
KPRRPYTDNYTRLRKQMAVKKYLNLILN(SEQ ID NO:10)。
在某些实施例中,本文所公开的肽中的氨基、羧基、羟基或硫醇基被取代。在某些实施例中,所述肽与纳米颗粒缀合。在某些实施例中,本公开设想了本文所公开的具有例如荧光或放射性标记的肽。
在某些实施例中,本公开涉及包括本文所公开的肽的组合物,如药物组合物和细胞生长培养基。在某些实施例中,本公开涉及包括本文所公开的肽和药学上可接受的赋形剂的药物组合物。在某些实施例中,所述药物组合物呈胶囊、片剂、丸剂、粉末或颗粒剂的形式。在某些实施例中,所述药物组合物呈灭菌的pH缓冲水性盐溶液的形式。在某些实施例中,所述药物组合物呈容器的形式,所述容器被配置成用推进剂喷洒液体或密封的容器。
在某些实施例中,本公开涉及一种核酸,所述核酸与启动子可操作地组合对如本文所公开的肽进行编码。在某些实施例中,本公开涉及一种重组载体,所述重组载体包括与启动子可操作地组合对如本文所公开的肽进行编码的核酸。在某些实施例中,本公开涉及一种包括本文所公开的重组载体的表达***或细胞。
在某些实施例中,本公开涉及治疗或增强针对癌症的免疫应答或治疗癌症的方法,所述方法包括向有需要的受试者施用有效量的本文所公开的肽。在某些实施例中,所述肽与另一种化疗剂组合施用。
在某些实施例中,本公开涉及加强T细胞活化和离体扩增的方法,所述方法包括将T细胞与本文所公开的肽混合。在某些实施例中,混合T细胞与抗CD3抗体和/或抗CD28抗体组合。在某些实施例中,混合T细胞与磷脂酰肌醇3-激酶δ(PI3Kδ)抑制剂组合。
在某些实施例中,本公开涉及治疗或预防受试者的宿主抗移植物疾病的方法,所述方法包括向要接受或接受移植的同种异体组织或细胞的受试者施用有效量的本文所公开的肽。
在某些实施例中,本公开涉及治疗癌症的方法,所述方法包括:使受试者暴露于辐射和/或向所述受试者施用化疗剂;将同种异体造血干细胞移植到所述受试者中;以及向所述受试者施用本文所公开的肽。
在某些实施例中,本公开涉及管理病毒感染的方法,所述方法包括向有需要的受试者施用有效量的如本文所公开的肽。
在某些实施例中,所述受试者是哺乳动物,通常是人。
附图说明
图1示出了与SEQ ID NO:1的VIPhyb内部氨基酸不同的拮抗肽。天然VIP为SEQ IDNO:2。根据内部氨基酸(标记为“ANT”)的存在或不存在,将序列指定为ANT-1到8。具体地,ANT-1在SEQ ID NO:3的氨基酸位置七处具有氨基酸T变为A取代。ANT-2序列在SEQ ID NO:4的氨基酸位置编号8处具有氨基取代D变为V。ANT-3肽在SEQ ID NO:5的氨基酸位置编号10处具有氨基酸取代Y变为C。ANT-4在SEQ ID NO:6的氨基酸位置12处具有氨基酸取代R变为S。ANT-5在SEQ ID NO:7的氨基酸位置编号17处具有氨基酸取代M变为I。ANT-6在SEQ IDNO:8的氨基酸位置20处具有氨基酸取代K变为N。ANT-7在SEQ ID NO:9的氨基酸位置编号23处具有氨基酸取代L变为M。ANT-8在SEQ ID NO:10的氨基酸位置编号25处具有氨基酸取代S变为L。
图2示出了在存在原始VIPhyb和Ant 1到Ant8的情况下在24小时时T细胞增殖的数据。采集来自荧光素酶+C57/BL6小鼠的T细胞,并且在存在1μM下的原始VIPhyb、Ant-1、Ant-2、Ant-3、Ant-4、Ant-5、Ant-6、Ant-7或Ant-8的情况下在96孔板中与1μg/ml抗CD3抗体和30U/ml IL-2一起培养。
图3示出了在存在原始VIPhyb和Ant-8的情况下在24小时时T细胞增殖的数据。采集来自荧光素酶+C57/BL6小鼠的T细胞,并且在存在0.5μM、1μM或3μM下的原始VIPhyb或Ant-8的情况下在96孔板中与0.5μg/ml或1μg/ml抗CD3抗体和30U/ml IL-2一起培养。
图4示出了从静脉内接种白血病细胞后第二天起每天向小鼠皮下注射VIPhyb、Ant8或PBS持续7天的数据。
图5示出了用ANT-8处理的荷白血病小鼠(C1498)的存活数据。
图6A示出了使用注射到用Ant-08和/或抗PD1处理的免疫活性小鼠的胰腺尾中的KPC luc(即经鼠类荧光素酶转染的胰腺癌细胞系)的数据。在经Ant-08+抗PD1处理的小鼠中观察到较慢的肿瘤生长速率。
图6B示出了常位KPC模型中的肿瘤负荷的数据。对处死时(第24天)从上述小鼠中分离出的胰腺进行称重以得到肿瘤负荷。在经Ant-08+抗-PD1处理的小鼠中观察到显著小的肿瘤负荷。
图6C示出了常位KPC模型中的CD+4T细胞浸润的数据。在用Ant-08+抗PD1处理的小鼠的肿瘤中观察到CD4T细胞的浸润增加。
图6D示出了第26天时小鼠的IVIS和MRI成像。通过H&E和CD4对来自这些小鼠的肿瘤进行染色。
图7示出了使用ANT8的数据,表明在用抗CD3/28珠和30U/mL IL-2进行离体扩增期间,来自慢性淋巴细胞性白血病(CLL)供体的T细胞产率增强。
具体实施方式
在更详细地描述本公开之前,应理解的是,本公开不限于所描述的具体实施例,并且因此当然可以变化。还应当理解,本文所使用的术语仅仅是出于描述具体实施例的目的,并且不旨在是限制性的,因为本公开的范围将仅由所附权利要求限定。
除非另外定义,否则本文所使用的所有技术术语和科学术语具有与本公开所属领域的普通技术人员通常所理解的含义相同的含义。虽然与本文所描述的那些方法和材料类似或等同的任何方法和材料也可以用于本公开的实践和测试中,但是现在描述优选的方法和材料。
本说明书中引用的所有出版物和专利均通过引用并入本文中,就好像每个单独的出版物或专利被具体地并单独地指示为通过引用并入和通过引用并入本文中一样,以结合所引用的出版物来公开和描述所述方法和/或材料。对任何出版物的引用是针对其在提交日之前的公开内容,并且不应被解释为承认本公开因先前的公开而无权先于此类出版物。此外,所提供的公开日期可能与实际的公开日期不同,实际的公开日期可能需要单独确认。
如对于本领域技术人员将显而易见的是,在阅读本公开时,本文描述和展示的单独实施例中的每一个均具有离散的组成部分和特征,所述组成部分和特征可以在不偏离本公开的范围或精神的情况下易于与其它若干实施例中的任何实施例的特征分离或组合。任何所叙述的方法都可以按所叙述的事件顺序或逻辑上可能的任何其它顺序进行。
除非另有说明,否则本公开的实施例将采用在本领域技术范围内的免疫学、医学、有机化学、生物化学、分子生物学、药理学、生理学等技术。此类技术在文献中进行了充分解释。
必须注意,如在说明书和所附权利要求中所使用,单数形式“一个/一种(a/an)”和“所述(the)”包含复数指示物,除非上下文另外清楚地指示。在本说明书和以下权利要求中,将参考大量术语,这些术语将被定义为具有以下含义,除非具有明显的相反意图。
术语“蛋白质”和“肽”是指包括通过肽键接合的氨基酸的化合物,并且可互换使用。氨基酸可以是天然的或非天然的。“嵌合蛋白”或“融合蛋白”是其中蛋白质的不同部分源自不同来源使得整个分子不是天然存在的分子。嵌合蛋白可以含有来自不同物种的相同物种的氨基酸序列,只要所述氨基酸序列没有以其以天然状态存在的相同方式布置在一起。嵌合蛋白的实例包含本文所公开的序列,所述序列含有一个、两个或更多个与C末端或N末端附接的氨基酸,所述氨基酸与任何天然存在的蛋白质都不相同,如在添加含有胺侧链基团的氨基酸(例如,赖氨酸)、含有羧酸侧链基团的氨基酸(如天冬氨酸或谷氨酸)、聚组氨酸标签(例如通常是四个或更多个组氨酸氨基酸)的情况下。
关于具有氨基酸序列的肽,术语“包括”是指可以含有另外的N端(胺端)或C端(羧酸端)氨基酸的肽,即所述术语旨在包含较大肽内的氨基酸序列。关于具有氨基酸序列的肽,术语“由......组成”是指在序列中具有确切数量的氨基酸,并且不超过或具有不超过权利要求中明确指定的一系列氨基酸的肽。在某些实施例中,本公开设想到“肽的N端可以由氨基酸序列组成”,其是指在序列中具有确切数量的氨基酸并且不超过或具有不超过权利要求中指定的一系列氨基酸然而C端可以连接到另外的氨基酸例如作为较大的肽的一部分的肽的N端。类似地,本公开设想到“肽的C端可以由氨基酸序列组成”,其是指在序列中具有确切数量的氨基酸并且不超过或具有不超过权利要求中指定的一系列氨基酸然而N端可以连接到另外的氨基酸例如作为较大的肽的一部分的肽的C端。
在某些实施例中,本公开涉及包括本文所公开的序列或其融合体的重组肽,其中氨基酸序列的氨基末端或碳末端任选地附接到异源氨基酸序列、标记或报告分子。“标记”是指与另一个分子(如抗体或蛋白质)直接或间接缀合以促进所述分子的检测的可检测化合物或组合物。标记的具体的非限制性实例包含荧光标签、酶键和放射性同位素。在一个实例中,“标记受体”是指在受体中掺入异源多肽。标记包含放射性标记的氨基酸的掺入或生物素基部分与多肽的共价附接,所述多肽可以通过标记的亲和素(例如,含有可以通过光学或比色法检测到的荧光标志物或酶活性的链霉亲和素)来检测。标记多肽和糖蛋白的各种方法是本领域已知的并且可以使用。多肽的标记的实例包含但不限于以下:放射性同位素或放射性核素(如35S或131I)、荧光标记(如异硫氰酸荧光素(FITC)、罗丹明、镧系元素磷)、酶标记(如辣根过氧化物酶、β-半乳糖苷酶、荧光素酶、碱性磷酸酶)、化学发光标志物、生物素基、由二级报告基因识别的预定肽表位(如亮氨酸拉链对序列、二级抗体的结合位点、金属结合结构域、表位标签)或磁性药剂(如钆螯合物)。在一些实施例中,标记通过各种长度的间隔臂附接,以减少潜在的空间位阻。
如本文所使用的,术语“衍生物”是指保留所鉴定类似物的足够功能属性的结构上类似的肽。衍生物可能在结构上类似,因为其缺少一个或多个原子,例如以不同的水合/氧化态用氢、取代的盐代替氨基、羟基或硫醇基,或者因为分子内的一个或多个原子是交换的,如但不限于用硫原子代替氧原子或用羟基代替氨基。衍生物可以是前药,包括脂质、聚乙二醇、糖、多糖。衍生物可以是通过连接基团连接在一起的两个或更多个肽。可设想到连接基团可以是可生物降解的。衍生物可以通过合成或有机化学教材中呈现的各种合成方法或适当的适应来制备,如三月份的《高级有机化学:反应、机制和结构(Advanced OrganicChemistry:Reactions,Mechanisms,and Structure)》,威利出版社(Wiley),第6版(2007),Michael B.Smith或《有机合成中的多米诺反应(Domino Reactions in Organic Sy)》,威利出版社(2006),Lutz F.Tietze,所述文献通过引用并入。
在某些实施例中,本文所公开的肽具有至少一种非天然存在的分子修饰,如附接聚乙二醇、附接产生嵌合肽的另一种肽、附接包括芳香族基团、荧光肽、能够结合放射性核素(如18F、N端乙酰基、丙酰基、肉豆蔻酰基和棕榈酰基、或N端甲基化或C端烷基酯)的螯合剂的荧光染料。在某些实施例中,本公开设想了使用可商购获得的生物素化试剂标记本文所公开的肽。生物素化的肽可以用于链霉亲和素亲和力结合、纯化和检测。在某些实施例中,本公开设想了本文所公开的肽含有天然存在的单糖的叠氮化物衍生物,如N-叠氮基乙酰基葡糖胺、N-叠氮基乙酰基甘露糖胺和N-叠氮基乙酰基半乳糖胺。
在某些实施例中,本公开设想了本文所公开的肽的衍生物,其中一个或多个氨基酸被任选地通过接头连接的化学基团取代以改进药代动力学性质,如溶解度和血清半衰期。在某些实施例中,此类衍生物可以是前药,其中取代基或接头是可生物降解的,或取代基或接头是不可生物降解的。在某些实施例中,设想的取代基包含糖、多糖、乙酰基、脂肪酸、脂质和/或聚乙二醇。取代基可以通过在肽的C端或N端上形成酰胺键共价键合,所述酰胺键任选地通过接头连接。在某些实施例中,可设想到取代基可以通过肽内的氨基酸,例如通过包括本文所公开的序列的肽内的胺侧链基团(如赖氨酸)或含有羧酸侧链基团(如天冬氨酸或谷氨酸)的氨基酸共价键合。在某些实施例中,可设想到取代基可以通过半胱氨酸以本文所公开的序列共价键合,任选地通过接头连接。在某些实施例中,取代基通过与半胱氨酸氨基酸侧基形成二硫化物的接头连接。
术语“经取代的”是指其中至少一个氢原子被取代基代替的分子。当被取代时,这些基团中的一个或多个基团是“取代基”。分子可以被多重取代。在氧代取代基(“=O”)的情况下,两个氢原子被代替。在此上下文内的示例取代基可以包含卤素、羟基、烷基、烷氧基、硝基、氰基、氧代、碳环基、碳环烷基、杂碳环基、杂碳环烷基、芳基、芳基烷基、杂芳基、杂芳基烷基、-NRaRb、-NRaC(=O)Rb、-NRaC(=O)NRaNRb、-NRaC(=O)ORb、-NRaSO2Rb、-C(=O)Ra、-C(=O)ORa、-C(=O)NRaRb、-OC(=O)NRaRb、-ORa、-SRa、-SORa、-S(=O)2Ra、-OS(=O)2Ra和-S(=O)2ORa。此上下文中的Ra和Rb可以相同或不同并且独立地是氢、卤素、羟基、烷基、烷氧基、烷基、氨基、烷基氨基、二烷基氨基、碳环基、碳环烷基、杂碳环基、杂碳环烷基、芳基、芳基烷基、杂芳基和杂芳基烷基。取代基可以进一步任选地被取代。
如本文所使用的,“脂质”基团是指天然或非天然存在的高度不溶于水的疏水基团。如本文所使用的,当脂质上的连接点用氢代替并且所得化合物的溶解度小于0.63×10-4%w/w(在25℃下)(其是辛烷在水中的溶解度重量百分比)时,脂质基团被视为高度不溶于水的。参见《溶剂回收手册(Solvent Recovery Handbook)》,第2版,Smallwood,2002布莱克威尔科学出版公司(Blackwell Science),第195页。天然存在的脂质的实例包含在脂肪酸、甘油脂、胆固醇、类固醇、聚酮化合物和衍生物中发现的饱和或不饱和烃链。非天然存在的脂质包含天然存在的脂质、丙烯酸聚合物、芳香族和烷基化化合物的衍生物和其衍生物。
术语“前药”是指在体内转化为生物活性形式的药剂。因为在一些情况下前药可能比母体化合物更易于施用,所以前药通常是有用的。前药还可以在药物组合物中具有改进的超过母体药物的溶解性。前药可以通过各种机制(包含酶促过程和代谢水解)转化成母体药物。典型的前药是药学上可接受的酯。前药包含其中羟基、氨基或巯基(硫醇)分别与当将活性化合物的前药施用于受试者时裂解形成游离羟基、游离氨基或游离巯基的任何基团键合的化合物。前药的实例包含但不限于活性化合物中的醇或乙酰胺的乙酸酯、甲酸酯和苯甲酸酯衍生物、胺官能团的甲酰胺和苯甲酰胺衍生物等。
例如,如果所公开的肽或肽的药学上可接受的形式含有羧酸官能基,则前药可以包括通过用如以下等基团代替酸基的氢原子形成的药学上可接受的酯:(C1-C8)烷基、(C2-C12)烷酰基氧基甲基、具有4到9个碳原子的1-(烷酰基氧基)乙基、具有5到10个碳原子的1-甲基-1-(烷酰基氧基)-乙基、具有3到6个碳原子的烷氧基羰氧基甲基、具有4到7个碳原子的1-(烷氧基羰基氧基)乙基、具有5到8个碳原子的1-甲基-1-(烷氧基羰基氧基)乙基、具有3到9个碳原子的N-(烷氧基羰基)氨基甲基、具有4到10个碳原子的1-(N(烷氧基羰基)氨基)乙基、3-酞基、4-巴豆酸内酯基、γ-丁内酯-4-基、二-N,N-(C1-C2)烷基氨基(C2-C3)烷基(如β-二甲基氨基乙基)、氨基甲酰基-(C1-C2)烷基、N,N-二(C1-C2)烷基氨基甲酰基-(C1-C2)烷基以及哌啶代-、吡咯烷代-或吗啉代(C2-C3)烷基。
如果所公开的肽或所述肽的药学上可接受的形式含有醇官能团,则前药可以通过用如以下等基团代替醇基的氢原子而形成:(C1-C6)烷酰基氧基甲基、1-((C1-C6)烷酰基氧基)乙基、1-甲基-1((C1-C6)烷酰基氧基)乙基、(C1-C6)烷氧基羰基氧基甲基、-N-(C1-C6)烷氧基羰基氨基甲基、琥珀酰基、(C1-C6)烷酰基、α-氨基(C1-C4)烷酰基、芳基酰基和α-氨基酰基或α-氨基酰基-α-氨基酰基,其中每个α-氨基酰基均独立地选自天然存在的L-氨基酸P(O)(OH)2、-P(O)(O(C1-C6)烷基)2和糖基(通过去除半缩醛形式的碳水化合物的羟基而产生的基团)。
如果所公开的肽或所述肽的药学上可接受的形式并入胺官能团,则前药可以通过用如以下等基团代替胺基团中的氢原子而形成:R-羰基、RO-羰基、NRR′-羰基,其中R和R′各自独立地为(C1-C10)烷基、(C3-C7)环烷基、苄基、天然α-氨基酰基、-C(OH)C(O)OYl,其中Y1是H、(C1-C6)烷基或苄基,-C(OY2)Y3,其中Y2是(C1-C4)烷基并且Y3是(C1-C6)烷基、羧基(C1-C6)烷基、氨基(C1-C4)烷基或单-N或二-N,N-(C1-C6)烷基氨基烷基,-C(Y4)Y5,其中Y4是H或甲基并且Y5是单-N-或二-N,N-(C1-C6)烷基氨基、吗啉基、哌啶-1-基或吡咯烷-1-基。
如本文所使用的,“药学上可接受的酯”包含但不限于酸性基团(包含但不限于羧酸、磷酸、次膦酸、磺酸、亚磺酸和硼酸)的烷基酯、烯基酯、炔基酯、芳基酯、芳基烷基酯和环烷基酯。
如本文所使用的,“药学上可接受的烯醇醚”包含但不限于式-C=C(OR)的衍生物,其中R可以选自烷基、烯基、炔基、芳基、芳烷基和环烷基。“药学上可接受的烯醇酯”包含但不限于式-C=C(OC(O)R)的衍生物,其中R可以选自氢、烷基、烯基、炔基、芳基、芳烷基和环烷基。
“连接基团”是指可以用于使分子部分桥接在一起的任何种类的分子布置。示例式可以是-Rm-,其中R在每次出现时单独且独立地选择为:-CRmRm-、-CHRm-、-CH-、-C-、-CH2-、-C(OH)Rm、-C(OH)(OH)-、-C(OH)H、-C(Hal)Rm-、-C(Hal)(Hal)-、-C(Hal)H-、-C(N3)Rm-、-C(CN)Rm-、-C(CN)(CN)-、-C(CN)H-、-C(N3)(N3)-、-C(N3)H-、-O-、-S-、-N-、-NH-、-NRm-、-(C=O)-、-(C=NH)-、-(C=S)-、-(C=CH2)-,其在R基团之间可以单独且独立地含有单键、双键或三键。如果R带有Rm支链,则可以用如-CH3、-H、-CH=CH2、-CCH、-OH、-SH、-NH2、-N3、-CN或-Hal等基团封端,或者两个支链的R可以形成环状结构。可设想的是,在某些情况下,总R或“m”可以小于100、或50、或25或10。连接基团的实例包含桥接烷基和烷氧基烷基。连接基团可以被一个或多个取代基取代。
术语“核酸”是指核苷酸或多核苷酸的聚合物。所述术语用于指定单个分子或分子的集合。核酸可以是单链或双链的,并且可以包含编码区和各种控制元件的区,如下文所描述的。
术语“编码指定肽的核酸序列”是指包括肽的编码区的核酸序列,或者换句话说,是指编码肽产物的核酸序列。编码区可以以cDNA、基因组DNA或RNA形式存在。当以DNA形式存在时,寡核苷酸、多核苷酸或核酸可以是单链的(即,有义链)或双链的。如果需要允许适当地启动初级RNA转录物的转录和/或正确加工,则可以将合适的控制元件(如增强子/启动子、剪接点、聚腺苷酸化信号等)放置在编码区附近。可替代地,表达载体中利用的编码区可以含有内源性增强子/启动子、剪接点、***序列、聚腺苷酸化信号等、或内源性控制元件和外源性控制元件两者的组合。
术语“载体”或“表达载体”是指含有期望的编码序列和在例如细胞或无细胞的特定宿主生物体或表达***中表达可操作连接的编码序列所必需的适当核酸序列的重组核酸。在原核生物中表达所必需的核酸序列通常包含启动子、操纵子(任选的)和核糖体结合位点,所述核酸序列常常与其它序列一起。已知真核细胞利用启动子、增强子以及终止信号和聚腺苷酸化信号。
蛋白质“表达***”是指体内和体外(无细胞)***。用于重构蛋白表达的***通常利用用含有模板的DNA表达载体转染的细胞。在使得细胞翻译期望的蛋白质的条件下培养细胞。提取经表达的蛋白质以供随后纯化。使用原核和真核细胞的体内蛋白质表达***是众所周知的。同样,使用变性剂和蛋白质重折叠程序回收一些蛋白质。体外(无细胞)蛋白质表达***通常使用全细胞或组合物的翻译相容性提取物,所述翻译相容性提取物含有足以进行转录、翻译和任选地翻译后修饰的组分,如RNA聚合酶、调节蛋白因子、转录因子、核糖体、tRNA辅因子、氨基酸和核苷酸。在存在表达载体的情况下,这些提取物和组分可以合成所关注的蛋白质。无细胞***通常不含有蛋白酶,并且能够用经修饰的氨基酸标记蛋白质。一些无细胞***并入经编码的组分以翻译成表达载体。参见例如Shimizu等人,用经纯化的组分重构无细胞翻译(Cell-free translation reconstituted with purifiedcomponents),2001,《自然生物技术(Nat.Biotectmol.)》,19,751-755以及Asahara和Chong,《核酸研究(Nucleic Acids Research)》,2010,38(13):e141,两者均以全文引用的方式并入。
“癌症”是指具有由细胞增殖表征的恶性赘生物的各种细胞疾病中的任何一种。患病的细胞并不旨在实际上必须侵入周围组织并转移到新的身***点。癌症可以涉及身体的任何组织,并且在每个身体部位都具有许多不同的形式。在某些实施例的上下文中,“癌症是否减少”可以通过本领域技术人员已知的多种诊断方式来鉴定,包含但不限于观察肿瘤块的大小或数量的减少或者如果观察到癌细胞凋亡增加,例如,与没有化合物的对照相比,如果观察到样品化合物的癌细胞凋亡增加超过5%。也可以通过相关生物标志物或基因表达谱的变化来鉴定,如***癌的PSA、乳腺癌的HER2等。
在本公开的上下文中要治疗的癌症可以是任何类型的癌症或肿瘤。这些肿瘤或癌症包含但不限于造血组织和淋巴组织的肿瘤或造血和淋巴恶性肿瘤、影响血液、骨髓、淋巴和淋巴***的肿瘤。血液恶性肿瘤可能源自两种主要血细胞谱系中的任一种:骨髓细胞系和淋巴细胞系。骨髓细胞系通常产生粒细胞、红细胞、血小板、巨噬细胞和肥大细胞;淋巴细胞系产生B细胞、T细胞、NK细胞和浆细胞。淋巴瘤、淋巴细胞性白血病和骨髓瘤来自淋巴系,而急性和慢性骨髓性白血病、骨髓增生异常综合征和骨髓增生性疾病均为骨髓来源的。
还设想到位于结肠、腹部、骨骼、***、消化***、肝脏、胰腺、腹膜、内分泌腺(肾上腺、甲状旁腺、垂体、睾丸、卵巢、胸腺、甲状腺)、眼睛、头部和颈部、(中枢和外周)神经***、淋巴***、骨盆、皮肤、软组织、脾脏、胸部和泌尿生殖器设备中的恶性肿瘤,并且更具体地是儿童急性淋巴母细胞性白血病、急性淋巴母细胞性白血病、急性淋巴细胞白血病、急性髓样白血病、肾上腺皮质癌、成人(原发性)肝细胞癌、成人(原发性)肝癌、成人急性淋巴细胞白血病、成人急性髓样白血病、成人霍奇金氏病(Hodgkin′s disease)、成人霍奇金氏淋巴瘤、成人淋巴细胞白血病、成人非霍奇金氏淋巴瘤、成人原发性肝癌、成人软组织肉瘤、AIDS相关淋巴瘤、AIDS相关恶性肿瘤、***癌、星形细胞瘤、胆道癌、膀胱癌、骨癌、脑干神经胶质瘤、脑瘤、乳腺癌、肾盂和输尿管癌、原发性中枢神经***淋巴瘤、中枢神经***淋巴瘤、小脑星形细胞瘤、脑星形细胞瘤、***、儿童(原发性)肝细胞癌、儿童(原发性)肝癌、儿童急性淋巴母细胞性白血病、儿童急性髓样白血病、儿童脑干神经胶质瘤、儿童小脑星形细胞瘤、儿童脑星形细胞瘤、儿童颅外生殖细胞肿瘤、儿童霍奇金氏病、儿童霍奇金氏淋巴瘤、儿童视觉通路和下丘脑神经胶质瘤、儿童淋巴母细胞白血病、儿童成神经管细胞瘤、儿童非霍奇金氏淋巴瘤、儿童幕上原始神经外胚层和松果体肿瘤、儿童原发性肝癌、儿童横纹肌肉瘤、儿童软组织肉瘤、儿童视觉通路和下丘脑神经胶质瘤、慢性淋巴细胞白血病、慢性髓样白血病、结肠癌、皮肤T细胞淋巴瘤、内分泌胰岛细胞癌、子宫内膜癌、室管膜瘤、上皮癌、食管癌、尤因氏肉瘤(Ewing′s sarcoma)和相关肿瘤、外分泌胰腺癌、颅外生殖细胞肿瘤、性腺外生殖细胞瘤、肝外胆道癌、眼癌、女性乳腺癌、高雪氏病(Gaucher′s disease)、胆囊癌、胃癌、胃肠道类癌肿瘤、胃肠道肿瘤、生殖细胞瘤、妊娠滋养细胞肿瘤、头颈癌、肝细胞癌、霍奇金氏病、霍奇金氏淋巴瘤、高丙种球蛋白血症、下咽癌、肠癌、眼内黑色素瘤、胰岛细胞癌、胰岛细胞胰腺癌、卡波氏肉瘤(Kaposi′s sarcoma)、肾脏癌、喉癌、嘴唇和口腔癌、肝癌、肺癌、淋巴增殖性障碍、巨球蛋白血症、男性乳腺癌、恶性间皮瘤、恶性胸腺瘤、成神经管细胞瘤、黑色素瘤、间皮瘤、隐匿性原发性转移性鳞状颈癌、原发性转移性鳞状颈癌、转移性鳞状颈癌、多发性骨髓瘤、多发性骨髓瘤/浆细胞瘤、骨髓增生异常综合征、骨髓性白血病、髓样白血病、骨髓增殖性病症、鼻旁窦和鼻腔癌、鼻咽癌、成神经细胞瘤、怀孕期间非霍奇金氏淋巴瘤、非黑色素瘤皮肤癌、非小细胞肺癌、原发性隐匿性转移性鳞状颈癌、口咽癌、恶性纤维组织细胞瘤、恶性纤维性骨肉瘤/骨组织细胞瘤、上皮性卵巢癌、卵巢生殖细胞肿瘤、卵巢低恶性潜在肿瘤、胰腺癌、副蛋白血症、紫癜、甲状旁腺癌、***癌、嗜铬细胞瘤、脑垂体瘤、浆细胞瘤/多发性骨髓瘤、原发性中枢神经***淋巴瘤、原发性肝癌、***癌、直肠癌、肾细胞癌、肾盂和输尿管癌、视网膜母细胞瘤、横纹肌肉瘤、唾液腺癌、结节病、肉瘤、皮肤癌、小细胞肺癌、小肠癌、软组织肉瘤、鳞状颈癌、胃癌、松果体和幕上原始神经外胚层肿瘤、T细胞淋巴瘤、睾丸癌、胸腺瘤、甲状腺癌、肾盂和输尿管移行细胞癌、移行肾盂及输尿管癌、滋养叶瘤、肾盂和输尿管细胞癌、尿道癌、子宫癌、子宫肉瘤、***癌、视神经通路和下丘脑神经胶质瘤、外阴癌、瓦尔登斯特伦巨球蛋白血症(Waldenstrom′s macroglobulinemia)、维尔姆斯瘤(Wilms′tumor)和位于先前提到的器官***中的任何其它过度增殖性疾病以及瘤形成。
“化疗剂”、“化学疗法”、“抗癌剂”等是指被认为有助于癌症治疗的分子。所设想的实例包含以下分子或衍生物,如阿仑单抗(alemtuzumab)、曲妥珠单抗(trastuzumab)、替伊莫单抗(ibritumomab tiuxetan)、本妥昔单抗(brentuximab vedotin)、替莫唑胺(temozolomide)、阿多曲妥珠单抗美坦新(ado-trastuzumab emtansine)、地尼白介素(denileukin diftitox)、博纳吐单抗(blinatumomab)、干扰素α(interferon alpha)、阿地白介素(aldesleukin)、卡莫司汀(carmustine)、贝伐单抗(bevacizumab)、丙卡巴肼(procarbazine)、洛莫司丁(lomustine)、长春新碱(vincristine)、吉非替尼(gefitinib)、埃罗替尼(erlotinib)、顺铂(cisplatin)、卡铂(carboplatin)、奥沙利铂(oxaliplatin)、5-氟尿嘧啶(5-fluorouracil)、吉西他滨(gemcitabine)、替加氟(tegafur)、雷替曲塞(raltitrexed)、甲氨蝶呤(methotrexate)、阿糖胞苷(cytosine arabinoside)、羟基脲(hydroxyurea)、阿霉素(adriamycin)、博莱霉素(bleomycin)、多柔比星(doxorubicin)、道诺霉素(daunomycin)、表柔比星(epirubicin)、伊达比星(idarubicin)、丝裂霉素C(mitomycin-C)、更生霉素(dactinomycin)、光神霉素(mithramycin)、长春花碱(vinblastine)、长春地辛(vindesine)、长春瑞滨(vinorelbine)、紫杉醇(paclitaxel)、他克唑(taxol)、多西他赛(docetaxel)、依托泊苷(etoposide)、替尼泊苷(teniposide)、安吖啶(amsacrine)、拓扑替康(topotecan)、喜树碱(camptothecin)、硼替佐米(bortezomib)、阿那格雷(anagrelide)、它莫西芬(tamoxifen)、托瑞米芬(toremifene)、雷洛昔芬(raloxifene)、屈洛昔芬(droloxifene)、氟维司群(fulvestrant)、比卡鲁胺(bicalutamide)、氟他胺(flutamide)、尼鲁米特(nilutamide)、环丙孕酮(cyproterone)、戈舍瑞林(goserelin)、亮丙瑞林(leuprorelin)、乙基酰胺(buserelin)、甲地孕酮(megestrol)、阿那曲唑(anastrozole)、来曲唑(letrozole)、伏氯唑(vorozole)、依西美坦(exemestane)、非那雄胺(finasteride)、马马司他(marimastat)、曲妥珠单抗、西妥昔单抗(cetuximab)、达沙替尼(dasatinib)、伊马替尼(imatinib)、康普瑞汀(combretastatin)、沙利度胺(thalidomide)、阿扎胞苷(azacitidine)、硫唑嘌呤(azathioprine)、卡培他滨(capecitabine)、苯丁酸氮芥(chlorambucil)、环磷酰胺(cyclophosphamide)、阿糖孢苷(cytarabine)、道诺霉素、去氧氟尿苷(doxifluridine)、埃博霉素(epothilone)、伊立替康(irinotecan)、氮芥(mechlorethamine)、巯嘌呤(mercaptopurine)、米托蒽醌(mitoxantrone)、培美曲塞(pemetrexed)、硫鸟嘌呤(tioguanine)、戊柔比星(valrubicin)、利妥昔单抗(rituximab)和/或来那度胺(lenalidomide)或其组合,如环磷酰胺(cyclophosphamide)、甲氨蝶呤(methotrexate)、5-氟尿嘧啶(5-fluorouracil)(CMF);多柔比星、环磷酰胺(AC);氮芥(mustine)、长春新碱、丙卡巴肼、***龙(MOPP);阿霉素(adriamycin)、博来霉素、长春花碱、达卡巴嗪(dacarbazine)(ABVD);环磷酰胺、多柔比星、长春新碱、***龙(CHOP);利妥昔单抗、环磷酰胺、多柔比星、长春新碱、***龙(RCHOP);博莱霉素、依托泊苷、顺铂(BEP);表柔比星、顺铂、5-氟尿嘧啶(ECF);表柔比星、顺铂、卡培他滨(ECX);甲氨蝶呤、长春新碱、阿霉素、顺铂(MVAC)。
在某些实施例中,癌症的治疗可以与另一种抗癌剂组合。在某些实施例中,抗癌剂选自阿贝西尼(abemaciclib)、醋酸阿比特龙(abiraterone acetate)、甲氨蝶呤、紫杉醇、阿霉素、阿卡替尼(acalabrutinib)、本妥昔单抗、阿多曲妥珠单抗美坦新、阿柏西普(aflibercept)、阿法替尼(afatinib)、奈妥吡坦(netupitant)、帕洛诺司琼(palonosetron)、咪喹莫特(imiquimod)、阿地白介素、艾乐替尼(alectinib)、阿仑单抗、培美曲塞二钠(pemetrexed disodium)、库潘尼西(copanlisib)、美法仑(melphalan)、布加替尼(brigatinib)、苯丁酸氮芥、氨磷汀(amifostine)、氨基乙酰丙酸(aminolevulinicacid)、阿那曲唑(anastrozole)、阿帕鲁胺(apalutamide)、阿瑞匹坦(aprepitant)、帕米膦酸二钠(pamidronate disodium)、依西美坦(exemestane)、奈拉滨(nelarabine)、三氧化二砷(arsenic trioxide)、奥法木单抗(ofatumumab)、阿特朱单抗(atezolizumab)、贝伐单抗、阿维单抗(avelumab)、轴突阿霉素(axicabtagene ciloleucel)、阿昔替尼(axitinib)、阿扎胞苷、卡莫司汀(carmustine)、贝利司他(belinostat)、苯达莫司汀(bendamustine)、奥英妥珠单抗(inotuzumab ozogamicin)、贝伐单抗、贝沙罗汀(bexarotene)、比卡鲁胺(bicalutamide)、博来霉素、博纳吐单抗、硼替佐米、博舒替尼(bosutinib)、本妥昔单抗、(布加替尼、白消安(busulfan)、伊立替康、卡培他滨、氟尿嘧啶(fluorouracil)、卡铂(carboplatin)、卡非佐米(carfilzomib)、色瑞替尼(ceritinib)、道诺霉素、西妥昔单抗(cetuximab)、顺铂、克拉屈滨(cladribine)、环磷酰胺、氯法拉滨(clofarabine)、考比替尼(cobimetinib)、苹果酸卡博替尼(cabozantinib-S-malate)、更生霉素、克唑替尼(crizotinib)、异环磷酰胺(ifosfamide)、雷莫芦单抗(ramucirumab)、阿糖孢苷、达拉菲尼(dabrafenib)、达卡巴嗪、地西他滨(decitabine)、达雷木单抗(daratumumab)、达沙替尼(dasatinib)、去纤苷(defibrotide)、地加瑞克(degarelix)、地尼白介素、地诺单抗(denosumab)、***(dexamethasone)、右雷佐生(dexrazoxane)、地那昔单抗(dinutuximab)、多西他赛(docetaxel)、多柔比星、度伐鲁单抗(durvalumab)、拉布立酶(rasburicase)、表柔比星、埃罗妥珠单抗(elotuzumab)、奥沙利铂、艾曲波帕乙醇胺(eltrombopag olamine)、恩西地平(enasidenib)、恩杂鲁胺(enzalutamide)、艾日布林(eribulin)、维莫德吉(vismodegib)、埃罗替尼(erlotinib)、依托泊苷、依维莫司(everolimus)、雷洛昔芬(raloxifene)、托瑞米芬(toremifene)、帕比司他(panobinostat)、氟维司群、来曲唑、非格司亭(filgrastim)、氟达拉滨(fludarabine)、氟他胺、普拉曲沙(pralatrexate)、奥比努单抗(obinutuzumab)、吉非替尼(gefitinib)、吉西他滨(gemcitabine)、吉妥单抗(gemtuzumab ozogamicin)、羧肽酶(glucarpidase)、戈舍瑞林(goserelin)、***(propranolol)、曲妥单抗(trastuzumab)、拓扑替康(topotecan)、帕博西尼(palbociclib)、替伊莫单抗(ibritumomab tiuxetan)、依鲁替尼(ibrutinib)、帕纳替尼(ponatinib)、伊达比星(idarubicin)、艾代拉里斯(idelalisib)、伊马替尼(imatinib)、泰利莫齐拉赫帕雷(talimogene laherparepvec)、伊匹单抗(ipilimumab)、罗米地辛(romidepsin)、伊沙匹隆(ixabepilone)、伊沙佐米(ixazomib)、鲁索替尼(ruxolitinib)、卡巴他赛(cabazitaxel)、帕利夫明(palifermin)、派姆单抗(pembrolizumab)、瑞博西尼(ribociclib)、替萨根微核素(tisagenlecleucel)、兰瑞肽(lanreotide)、拉帕替尼(lapatinib)、奥拉单抗(olaratumab)、来那度胺、乐伐替尼(lenvatinib)、亚叶酸(leucovorin)、亮丙瑞林(leuprolide)、洛莫司丁(lomustine)、三氟尿苷(trifluridine)、奥拉帕尼(olaparib)、长春新碱、丙卡巴肼、氮芥、甲地孕酮(megestrol)、曲美替尼(trametinib)、替莫唑胺(temozolomide)、溴化甲基纳曲酮(methylnaltrexone bromide)、米哚妥林(midostaurin)、丝裂霉素C、米托蒽醌、普乐沙福(plerixafor)、长春瑞滨、耐昔妥珠单抗(necitumumab)、来那替尼(neratinib)、索拉非尼(sorafenib)、尼鲁米特(nilutamide)、尼罗替尼(nilotinib)、尼拉帕尼(niraparib)、纳武单抗(nivolumab)、它莫西芬(tamoxifen)、罗米司亭(romiplostim)、索尼德吉(sonidegib)、高三尖杉酯碱(omacetaxine)、培门冬酶(pegaspargase)、昂丹司琼(ondansetron)、奥希替尼(osimertinib)、帕尼单抗(panitumumab)、帕唑帕尼(pazopanib)、干扰素α-2b、帕妥珠单抗(pertuzumab)、泊马度胺(pomalidomide)、巯嘌呤(mercaptopurine)、瑞戈非尼(regorafenib)、利妥昔单抗(rituximab)、罗拉吡坦(rolapitant)、卢卡帕尼(rucaparib)、司妥昔单抗(siltuximab)、舒尼替尼(sunitinib)、硫鸟嘌呤(thioguanine)、替西罗莫司(temsirolimus)、沙利度胺(thalidomide)、噻替派(thiotepa)、曲贝替定(trabectedin)、戊柔比星、凡德他尼(vandetanib)、长春花碱、维莫非尼(vemurafenib)、伏立诺他(vorinostat)、唑来膦酸(zoledronic acid)或其组合。
在某些实施例中,施用方法是在患有淋巴衰竭环境的受试者中。在某些实施例中,淋巴清除剂是环磷酰胺和氟达拉滨。
如本文所使用的,术语“艾代拉里斯”是指化合物(S)-2-(1-(9H-嘌呤-6-基氨基)丙基)-5-氟-3-苯基喹唑啉-4(3H)-酮或其替代性盐。
如本文所使用的,“对CD28和/或CD27呈阴性的T细胞”是指当与健康受试者中表达CD3表面抗原标志物的正常T细胞相比,这些标志物的相对浓度低表达或缺乏表达。
术语“荧光活化细胞分选”或“FACS”是指一种基于每个细胞的荧光特性、分别施加的电荷以及通过静电场移动进行的分离将细胞混合物分选到两个或更多个区域中(通常一次一个细胞)的方法。通常,振动机制使细胞流***成单独的液滴。在液滴形成之前,流体中的细胞会穿过用于测量细胞的荧光的区域。在流***成液滴的点处配置充电机构。基于荧光强度测量,当液滴从流中破裂时,在液滴上施加相应的电荷。带电的液滴然后移动通过静电偏转***,所述***会基于其相对电荷将液滴转移到各个区域中。在一些***中,电荷直接施加到流中,并且中断的液滴保留与流相同符号的电荷。在液滴中断后,流然后返回中性。在其它***中,在导管上提供电荷,从而在液滴上诱导相反的电荷。通常通过将细胞与特异性结合标志物的抗体混合来使细胞发荧光,所述标志物通过与荧光分子缀合而发荧光。然而,可以设想使细胞发荧光的其它方法,如通过使用分子信标。
“最小必需培养基”是指含有钙、镁、钾、钠、磷酸盐和碳酸氢盐的盐、维生素和必需氨基酸的培养基。12种必需氨基酸是:L-精氨酸;L-胱氨酸;L-谷氨酰胺;L-组氨酸;L-异亮氨酸;L-亮氨酸;L-甲硫氨酸;L-苯丙氨酸;L-苏氨酸;L-色氨酸;L-酪氨酸;以及L-缬氨酸。MEM常常补充有如碳酸氢盐或谷氨酰胺等组分。在某些实施例中,本公开设想了补充有以下非必需氨基酸的最小必需培养基:L-ala;L-asn;L-asp;L-glu;L-gly;L-pro和L-ser。在某些实施例中,本公开设想了补充有核苷(核糖核苷和/或脱氧核糖核苷)的最小必需培养基。
当涉及核酸分子时,术语“重组”是指包含通过分子生物技术的方式接合在一起的核酸的区段的核酸分子。当涉及蛋白质或多肽时,术语“重组”是指使用重组核酸分子表达的蛋白质分子。术语重组核酸不同于由同源染色体之间的互换产生的天然重组体。如本文所使用的,重组核酸是来自非同源来源(通常来自不同生物体)的核酸的非天然结合。
术语“载体”或“表达载体”是指含有期望的编码序列和在例如细胞或无细胞的特定宿主生物体或表达***中表达可操作连接的编码序列所必需的适当核酸序列的重组核酸。在原核生物中表达所必需的核酸序列通常包含启动子、操纵子(任选的)和核糖体-结合位点,所述核酸序列常常与其它序列一起。已知真核细胞利用启动子、增强子以及终止信号和聚腺苷酸化信号。
除非上下文另有说明,否则术语“血管活性肠肽”和“VIP”是指(SEQ ID NO:2)HSDAVFTDNYTRLRKQMAVKKYLNSILN。VIP是在多个水平的免疫细胞分化和活化下调节先天免疫和适应性免疫两者的多功能内源性多肽。VIP通常由如神经元(在中枢神经***和外周神经***两者中)、B细胞、T细胞和辅助细胞等多种细胞分泌。VIP和密切相关的神经肽垂体腺苷酸环化酶活化多肽(PACAP)与三个已知受体——VPAC1、VPAC2和PAC1结合。据信T细胞和树突状细胞(DC)表达VPAC1和VPAC2,但不表达PAC1。PAC1主要表达在脑和垂体以及肾上腺的神经元和内分泌细胞上,并且以大多数形式选择性结合PACAP。
“受试者”是指任何动物,优选地人类患者、家畜或家养宠物。
如本文所使用的,术语“预防(prevent和preventing)”包含对复发、传播或发作的预防。本公开并不旨在限于完全预防。在一些实施例中,发作被延缓,或者疾病的严重程度被降低。
如本文所使用的,术语“治疗(treat和treating)”并不限于受试者(例如,患者)被治愈并且疾病被根除的情况。相反,本公开的实施例还设想了仅减轻症状和/或延缓疾病进展的治疗。
如本文所使用的,当用于描述与另外的治疗一起施用时,术语“与......组合”意指药剂可以在另外的治疗之前、与其一起、或之后、或其组合被施用。
组合物
在某些实施例中,本公开设想了一种药物组合物,其包括本文所公开的肽或其纳米颗粒,或任选地其它药剂、或其药学上可接受的盐以及药学上可接受的赋形剂。
在某些实施例中,本公开涉及包括本文所公开的肽的组合物,如药物组合物和细胞生长培养基。在某些实施例中,本公开涉及包括本文所公开的肽和药学上可接受的赋形剂的药物组合物。在某些实施例中,所述药物组合物呈胶囊、片剂、丸剂、粉末或颗粒剂的形式。在某些实施例中,所述药物组合物呈灭菌的pH缓冲水性盐溶液的形式。在某些实施例中,所述药物组合物呈容器的形式,所述容器被配置成用推进剂喷洒液体或密封的容器。
可以根据源自体外或动物模型测试***的剂量-应答曲线来外推有效剂量。对于本文所公开的肽或其纳米颗粒或其它药剂,向患者施用的剂量通常为0.0001mg/kg到100mg/kg患者体重。优选地,向患者施用的剂量介于0.0001mg/kg与20mg/kg之间、0.0001mg/kg与10mg/kg之间、0.0001mg/kg与5mg/kg之间、0.0001mg/kg与2mg/kg之间、0.0001mg/kg与1mg/kg之间、0.0001mg/kg与0.75mg/kg之间、0.0001mg/kg与0.5mg/kg之间、0.0001mg/kg到0.25mg/kg、0.0001mg/kg到0.15mg/kg、0.0001mg/kg到0.10mg/kg、0.001mg/kg到0.5mg/kg、0.01mg/kg到0.25mg/kg或0.01mg/kg到0.10mg/kg患者体重。进一步地,本文所公开的肽或其纳米颗粒或药剂的施用剂量和频率可以通过修饰(例如,脂质化和包含天然或人工肺表面活性剂)增强摄取和组织渗透来降低。
组合物包含可用于制造药物组合物(例如,不纯或非无菌组合物)的原料药物组合物和可以用于制备单位剂型的药物组合物(即,适用于向受试者或患者施用的组合物)。此类组合物包括预防或治疗有效量的本文所公开的预防剂和/或治疗剂或那些药剂与药学上可接受的载体的组合。在某些实施例中,药物组合物含有药学上可接受的赋形剂,其为增溶剂,如脂质、胆固醇、脂肪酸、脂肪酸烷基酯、亚油酸、油酸、花生四烯酸、糖、多糖、环糊精、2-羟丙基(环糊精)或其组合。
在某些实施例中,药学上可接受的赋形剂选自乳糖、蔗糖、甘露醇、柠檬酸三乙酯、右旋糖、纤维素、甲基纤维素、乙基纤维素、羟丙基纤维素、羟丙基甲基纤维素、羧甲基纤维素、交联羧甲基纤维素钠、聚乙烯基N-吡咯烷酮、交联聚维酮、乙基纤维素、聚维酮、丙烯酸甲酯和丙烯酸乙酯共聚物、聚乙二醇、山梨糖醇的脂肪酸酯、十二烷基硫酸盐、明胶、甘油、单油酸甘油酯、二氧化硅、二氧化钛、滑石粉、玉米淀粉、硬脂酸、山梨酸、硬脂酸镁、硬脂酸钙、蓖麻油、矿物油、磷酸钙、淀粉、淀粉的羧甲基醚、氧化铁、三醋酸甘油酯、***胶、酯或其盐。
在某些实施例中,药物组合物呈固体形式,被肠溶衣(即应用于口服用药的预防其在胃环境中溶解或崩解的聚合物屏障)包围。通常在肠溶衣中发现的化合物包含丙烯酸甲酯-甲基丙烯酸共聚物、邻苯二甲酸乙酸纤维素(CAP)、乙酸琥珀酸纤维素、羟丙基甲基纤维素邻苯二甲酸酯、羟丙基甲基纤维素乙酸琥珀酸酯(羟丙甲纤维素乙酸琥珀酸酯)、聚乙酸乙烯邻苯二甲酸酯(PVAP)、甲基丙烯酸甲酯-甲基丙烯酸共聚物和其组合。
在具体实施例中,术语“药学上可接受的”意指由联邦或州政府的管理机构批准的或在美国药典或其它普遍认可的药典中列出的可用于动物、并且更具体地用于人的。术语“载体”是指与治疗剂一起施用的稀释剂、佐剂(例如,弗氏佐剂(Freund′s adjuvant))(完全和不完全)、赋形剂或媒剂。此类药物载体可以是天然肺表面活性剂和人工肺表面活性剂两者、无菌液体,如水和油,包含石油、动物、植物或合成来源的那些油,如花生油、大豆油、矿物油、芝麻油等。当静脉内施用药物组合物时,水是优选的载体。盐溶液以及右旋糖和甘油水溶液也可以用作液体载体,特别是用于可注射溶液。合适的药物赋形剂包含淀粉、葡萄糖、乳糖、蔗糖、明胶、麦芽、稻米、面粉、白垩、硅胶、硬脂酸钠、单硬脂酸甘油酯、滑石、氯化钠、脱脂奶粉、甘油、丙二醇、水、乙醇等。如果需要,组合物还可以含有少量的润湿剂或乳化剂或pH缓冲剂。这些组合物可以采取溶液、悬浮液、乳剂、片剂、丸剂、胶囊、粉末、缓释调配物等形式。
一般地,将组合物的成分分开或混合在一起以单位剂型提供,例如,作为在气密封容器中的干燥冻干粉或无水浓缩剂,所述气密封容器如指示活性剂的量的安瓿。在通过输注施用组合物时,可以用含有无菌药用级水或盐水的输注瓶分配。当组合物通过注射施用时,可以提供无菌注射用水或盐水的安瓿,使得成分可以在施用之前混合。
组合物可以调配成中性或盐形式。药学上可接受的盐包含但不限于与阴离子(如源自盐酸、磷酸、乙酸、草酸、酒石酸等的那些阴离子)形成的那些盐以及与阳离子(如源自钠、钾、铵、钙、氢氧化铁、异丙胺、三乙胺、2-乙基氨基乙醇、组氨酸、普鲁卡因等的那些阳离子)形成的那些盐。
一个实施例提供了一种药物包或试剂盒,其包括用本文所公开的肽或其纳米颗粒或本文所公开的药剂填充的一个或多个容器。另外地,可用于治疗疾病的一种或多种其它预防剂或治疗剂也可以包含在药物包或试剂盒中。一个实施例提供了一种药物包或试剂盒,其包含用药物组合物的成分中的一种或多种成分填充的一个或多个容器。任选地,与此类一个或多个容器相关联的可以是由管理药物或生物制品的制造、使用或销售的政府机构规定的形式的公告,所述公告反映了该机构对针对人类施用的制造、使用或销售的许可。
在某些实施例中,本公开设想了包括本文所公开的肽或其纳米颗粒以及本文所公开的药剂和药学上可接受的赋形剂的药物组合物。在某些实施例中,本公开设想了包括本文所公开的肽或其纳米颗粒或本文所公开的药剂的药物的生产以及用于本文所公开的方法的用途。
在某些实施例中,本公开涉及包括本文所公开的肽或其纳米颗粒以及本文所公开的药剂和药学上可接受的赋形剂的药物组合物。在某些实施例中,组合物是丸剂或呈胶囊形式,或者组合物是水性缓冲液,例如pH介于6与8之间。在某些实施例中,药学上可接收的赋形剂选自填充剂、助流剂、粘合剂、崩解剂、润滑剂和糖。
适于胃肠外注射的组合物可以包括生理上可接受的无菌水性溶液或无菌非水性溶液、分散体、悬浮液或乳液以及用于重构为无菌可注射溶液或分散体的无菌粉末。合适的水性和非水性载体、稀释剂、溶剂或媒剂的实例包含水、乙醇、多元醇(丙二醇、聚乙二醇、甘油等)、其合适的混合物、植物(如橄榄油、芝麻油和viscoleo)、并入到肺表面活性剂(天然和人工两者)中的制剂和可注射有机酯(如油酸乙酯)。
可以通过添加各种抗细菌剂和抗真菌剂中的任一种,例如对羟基苯甲酸酯、氯丁醇、苯酚、山梨酸等来控制预防微生物的作用。还可以令人希望的是包含等渗剂,例如糖、氯化钠等。可以通过使用延迟吸收的药剂(例如,单硬脂酸铝和明胶)来实现可注射药物形式的延长的吸收。
用于口服施用的固体剂型包含胶囊、片剂、丸剂、粉末和颗粒剂。在此类固体剂型中,可以将本文所公开的肽或其纳米颗粒或药剂与至少一种惰性惯用赋形剂(或载体)混合,如柠檬酸钠或磷酸二钙或:(a)填充剂或增量剂,例如淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸;(b)粘合剂,例如羧甲基纤维素、海藻酸盐、明胶、聚乙烯吡咯烷酮、蔗糖和***胶;(c)保湿剂,例如甘油;(d)崩解剂,例如琼脂-琼脂、碳酸钙、马铃薯或木薯淀粉、海藻酸、某些复合硅酸盐和碳酸钠;(e)溶液缓凝剂,例如石蜡;(f)吸收促进剂,例如季铵化合物;(g)湿润剂,例如鲸蜡醇和单硬脂酸甘油酯;(h)吸附剂,例如高岭土和膨润土;以及(i)润滑剂,例如滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、月桂基硫酸钠或其混合物。在胶囊、片剂和丸剂的情况下,剂型还可以包括缓冲剂。
用于口服施用的液体剂型包含药学上可接受的乳剂、溶液、悬浮液、糖浆和酏剂。除了本文所公开的肽或其纳米颗粒和药剂之外,液体剂型可以含有本领域常用的惰性稀释剂,如水或其它溶剂、增溶剂和乳化剂,例如乙醇、异丙醇、碳酸乙酯、乙酸乙酯、苯甲醇、苯甲酸苄酯、丙二醇、1,3-丁二醇、二甲基甲酰胺、油,具体地为棉籽油、花生油、玉米胚芽油、橄榄油、蓖麻油和芝麻油、甘油、四氢糠醇、聚乙二醇和脱水山梨醇的脂肪酸酯或这些物质的混合物等等。
在某些实施例中,设想了生产过程,已经以准备要重构在一起的组合干燥形式提供了本文所公开的肽或其纳米颗粒和本文所公开的试剂的两种组分。在其它实施例中,可设想到将本文所述公开的肽或其纳米颗粒和任选地本文所公开的药剂与药物载体混合以提供药物组合物。
仅通过向容器中的组合物中添加合适的药学上可接受的稀释剂,就可以在一步过程中提供药物组合物。在某些实施例中,容器优选地是注射器以在与稀释剂接触后施用重构的药物组合物。在某些实施例中,可以将本文所公开的肽或其纳米颗粒或药剂填充到注射器中,并且然后可以用塞子封闭注射器。稀释剂的用量应达到期望的最终浓度。药物组合物可以含有其它有用的组分,如离子、缓冲剂、赋形剂、稳定剂等。
“干燥”药物组合物通常仅具有残留的水分含量,其可以大致对应于可比较的商业产品的水分含量,例如,具有约12%的水分作为干燥产品。通常,根据本发明的干燥药物组合物的残留水分含量优选地低于10%水分,更优选地低于5%水分,特别是低于1%水分。药物组合物还可以具有更低的水分含量,例如0.1%或甚至更低。在某些实施例中,药物组合物应以干燥形式提供,以防止降解并实现储存稳定性。
容器可以是适合于容纳(和储存)药物组合物的任何容器,如吸入器、注射器、小瓶、管等。然后可以通过致动或注射器的特定针或通过合适的导管来应用药物组合物。典型的稀释剂包括注射用水和NaCl(优选地50到150mM,特别是110mM)、CaCl2(优选地10到80mM,特别是40mM)、乙酸钠(优选地0到50mM,特别是20mM)和甘露醇(优选地高达10%w/w,特别是2%w/w)。优选地,稀释剂还可以包含缓冲剂或缓冲剂***,以便缓冲重构的干燥组合物的pH,优选地在6.2到7.5的pH下,特别是在6.9到7.1的pH下。
在某些实施例中,本公开设想了一种试剂盒,其包括本文所公开的药物组合物(如本文所公开的肽)或其纳米颗粒或药剂以及任选地具有合适的稀释剂的容器。试剂盒的另外的组成部分可以是使用说明、施用装置(如吸入器、注射器、导管、刷子等(如果施用装置中尚未提供组合物))或供医疗(外科手术)实践中使用所必需的其它组件,如取代针或导管、额外小瓶或另外的伤口覆盖装置。在某些实施例中,试剂盒包括容纳干燥且稳定的止血组合物的注射器和含有稀释剂(或被提供以从另一个稀释剂容器中抽吸稀释剂)的注射器。
在某些实施例中,稀释剂在单独的容器中提供。这可以优选地是注射器。然后可以容易地将注射器中的稀释剂应用于容器以重构干组合物。如果容器也是注射器,则两个注射器可以一起打包在包中。因此,优选在注射器中提供干燥组合物,所述干燥组合物用稀释剂注射器打包,所述稀释剂注射器具有用于重构所述干燥且稳定的组合物的药学上可接受的稀释剂。
可设想到本文所公开的肽中的任何肽都可以用烃基或聚乙二醇基团修饰,以便提供改进的性质,如溶解度、生物利用度和/或生物降解。
在某些实施例中,本公开涉及将本文所公开的肽与纳米颗粒偶联的方法。在某些实施例中,纳米颗粒包含泊洛沙姆(poloxamer)稳定的硫化聚丙烯。在某些实施例中,纳米颗粒的直径介于10与100nm之间。在某些实施例中,纳米颗粒的直径介于20与50nm之间,优选地30nm。
在某些实施例中,本公开设想当与纳米颗粒偶联的肽序列含有本文所公开的肽加C端接头肽GGGGSC(SEQ ID NO:15)时使用本文所公开的颗粒。在某些实施例中,颗粒含有肽序列,例如KPRRPYTDNYTRLRKQMAVKKYLNLILNGGGGSC(SEQ ID NO:12)。在某些实施例中,本文所公开的肽与纳米颗粒之间的化学键是二硫键。
在某些实施例中,药学上可接受的赋形剂是气雾剂或磷脂。在某些实施例中,气雾剂是氢氟烷烃、1,1,1,2-四氟乙烷、1,1,1,2,3,3,3-七氟丙烷、丙烷、正丁烷、异丁烯、二氧化碳、空气、氮气、一氧化二氮、二甲醚、反式1,3,3,3-四氟丙-1-烯或其组合。在某些实施例中,磷脂是二棕榈酰磷脂酰胆碱、棕榈酰-油酰磷脂酰甘油、磷脂酰甘油或其组合。
在某些实施例中,药物组合物可以储存在喷雾器、吸入器或任选地密封或在用于推动一种或多种药物药剂的压力下的其它容器中。容器可以含有手动致动或加压的喷涂设备。定量吸入器(MDI)通常具有手持式气雾罐,一旦被推动,所述气雾罐就会释放出一定量的药物以供吸入。干粉吸入器(DPI)不使用推进剂来释放药物。而是,在呼吸后将干粉形式的肽或其纳米颗粒或药剂吸入到肺中。在某些配置中,将包括本文所公开的肽或其纳米颗粒的容器***装置。按下装置上的按钮或部分会刺穿容器。可以通过装置上的吹口吸入容器中含有的粉末。
在某些实施例中,药物组合物可以含有天然或非天然存在的肺表面活性剂组合物。所设想的天然肺表面活性剂组合物通常包括70-90%磷脂(PC),如二棕榈酰磷脂酰胆碱(DPPC)、磷脂酰胆碱和磷脂酰甘油(PG);以及1-10%表面活性剂相关蛋白、载脂蛋白SP-A(SFTPA1)、B(SFTPB)、C(SFTPC)和D(SFTPD)(SP代表“表面活性剂相关蛋白”);以及1-10%胆固醇(中性脂质)。人工肺表面活性剂包含棕榈酸考福西利(colfosceril palmitate)、添加作为分散剂的DPPC与十六烷醇和泰洛沙泊的混合物;嘌吗坦(pumactant)(人工肺扩张化合物或ALEC)、DPPC和PG的混合物;KL-4,其由DPPC、棕榈酰基-油酰基磷脂酰甘油和棕榈酸构成,与模拟SP-B的结构特性的21个氨基酸合成肽组合;以及由DPPC、PG、棕榈酸和重组SP-C构成的组合物,所述组合物与人SP-C共享几乎相同的序列,除了不存在棕榈酰化的半胱氨酸并且已被苯丙氨酸代替以消除蛋白质寡聚之外。所设想的动物源性表面活性剂包含:从牛肺灌洗液中提取的贝拉克坦(beractant)(AlveofactTM)和与另外的DPPC、棕榈酸和三棕榈酸甘油酯一起从切碎的牛肺中提取的(SurvantaTM);从牛犊肺灌洗液中提取的外源性肺泡表面活性剂(calfactant)(InfasurfTM);以及猪肺磷脂α(CurosurfTM)-从源自切碎的猪肺的材料中提取。
在某些实施例中,本文所公开的药物组合物进一步包括选自以下的呼吸剂:糖皮质激素受体激动剂(类固醇和非类固醇),如曲安西龙(triamcinolone)、曲安奈德(triamcinolone acetonide)、***(prednisone)、糠酸莫米他松(mometasonefuroate)、氯替泼诺(loteprednol etabonate)、丙酸氟替卡松(fluticasonepropionate)、糠酸氟替卡松(fluticasone furoate)、氟轻松醋酸酯(fluocinoloneacetonide)、***培酯(dexamethasone cipecilate)、去异丁酸酯环索奈德(desisobutyryl ciclesonide)、丙酸氯倍他索(clobetasol propionate)、环索奈德(ciclesonide)、布***(budesonide)、二丙酸倍氯米松(beclomethasonedipropionate)、二丙酸阿氯米松(alclometasone dipropionate);p38拮抗剂,如洛批莫德(losmapimod);磷酸二酯酶(PDE)抑制剂,如甲基黄嘌呤、茶碱和氨茶碱;选择性PDE同工酶抑制剂、PDE4抑制剂和同种型PDE4D,如替托司特(tetomilast)、罗氟司特(roflumilast)、奥格司特(oglemilast)、异丁司特(ibudilast);趋化因子受体功能的调节剂,如马拉韦罗(maraviroc)、赛尼维罗克(cenicriviroc)、纳瓦拉欣(navarixin);白三烯生物合成抑制剂、5-脂氧合酶(5-LO)抑制剂和5-脂氧合酶活化蛋白(FLAP)拮抗剂,如TA270(4-羟基-1-甲基-3-辛氧基-7-芥子酰基氨基-2(1H)-喹啉酮),如利克飞龙(licofelone)、齐留通(zileuton)、扎鲁司特(zafirlukast)或孟鲁司特(montelukast);以及髓过氧化物酶拮抗剂,如白藜芦醇(resveratrol)和白皮杉醇(piceatannol)。
在某些实施例中,本公开涉及体外细胞培养组合物,其包括最小必需培养基和本文所公开的肽或其纳米颗粒。
使用方法
在某些实施例中,本公开涉及在治疗癌症的方法中使用的本文所公开的肽,例如Ant-8,KPRRPYTDNYTRLRKQMAVKKYLNLILN(SEQ ID NO:10)。在某些实施例中,本公开设想了治疗癌症的方法,所述方法包括任选地与化疗剂组合施用有效量的本文所公开的肽。在某些实施例中,本公开涉及使用本文所公开的肽(任选地与纳米颗粒缀合)与针对免疫检查点分子的抗体的组合治疗或增强对有需要的受试者的癌症的免疫应答的方法。
在某些实施例中,受试者被诊断患有选自以下组的癌症:黑色素瘤、肺癌、肾癌、白血病、非霍奇金淋巴瘤、霍奇金淋巴瘤、骨髓瘤、膀胱癌、胰腺癌、胃癌、食管癌、成胶质细胞瘤、结肠癌、乳腺癌和***癌。
在某些实施例中,针对免疫检查点分子的抗体选自包含派姆单抗(KeytrudaTM)和纳武单抗(OpdivoTM)的抗PD1抗体的组。在某些实施例中,针对免疫检查点分子的抗体选自包含阿特朱单抗(TecentfiqTM)、阿维单抗(Bavencio)和度伐鲁单抗(ImfinziTM)的抗PDL1抗体的组。在某些实施例中,针对免疫检查点分子的抗体是伊匹单抗(YervoyTM)。
在某些实施例中,肽治疗剂通过静脉内或皮下注射给予。在某些实施例中,通过吸入给予肽治疗剂以将药物递送到肺泡。在某些实施例中,将肽治疗剂施用于由压缩气体驱动的手持式递送装置。在某些实施例中,将肽治疗剂溶解在无菌盐水溶液中并且以气雾剂形式施用。
在某些实施例中,可设想到本文所公开的肽用于有效治疗癌症的某些细胞免疫疗法,如淋巴细胞输注或同种异体骨髓移植。供体免疫细胞,具体地是NK细胞和T细胞,具有抗癌细胞毒性活性。肽的VIP拮抗作用增强了体内的细胞免疫应答。VIP拮抗作用增加了抗原特异性T细胞和NK细胞的细胞毒性活性。预期VIP拮抗作用会增加NK细胞或抗原特异性T细胞的抗癌活性。预期与细胞免疫疗法结合的VIP拮抗作用增加了所述疗法的功效。据信,在同种异体骨髓移植的接受者中,不存在VIP不会增加供体淋巴细胞的“脱靶”移植物抗宿主病的活性。因此,向患有癌症的接受细胞疗法(例如,供体淋巴细胞输注或同种异体骨髓移植)的受试者施用VIP拮抗剂将增加所述疗法的抗癌活性。
在某些实施例中,本公开涉及增强对细胞疗法的免疫应答的方法,所述方法包括向受试者施用本文所公开的肽与细胞的组合。在某些实施例中,受试者被诊断患有白血病或淋巴瘤。在某些实施例中,所述细胞是血细胞、骨髓细胞、白细胞、T细胞、自然杀伤细胞、造血干细胞、G-CSF动员或非动员的血液单核细胞。
在某些实施例中,所述细胞选自由以下组成的组:自体T细胞、来自HLA匹配供体的同种异体细胞或来自HLA错配供体的同种异体细胞。在某些实施例中,所述细胞是骨髓细胞。在某些实施例中,所述细胞是包括/表达粒细胞集落刺激因子的血液单核细胞。细胞疗法可以用非动员的血液单核细胞进行。
在某些实施例中,可设想到可以在包含接受者或供体的基于细胞的免疫疗法之前、期间或之后向受试者施用本文所公开的肽。免疫疗法可以与化学疗法和/或放射疗法组合进行。可设想到肽可以与其它免疫刺激剂组合使用,所述其它免疫刺激剂包含但不限于CpG寡核苷酸、粒细胞集落刺激因子、粒细胞-巨噬细胞集落刺激因子、干扰素α、聚乙二醇化干扰素、白介素-12、白介素-2和培非格司亭(pegfilgrastim)。
在某些实施例中,本公开涉及治疗或预防受试者的移植物抗宿主病的方法,所述方法包括向造血干细胞移植后的受试者或将要接受或接受移植的同种异体组织或细胞的受试者施用有效量的本文所公开的肽。在某些实施例中,受试者接受了移植的同种异体造血干细胞。在某些实施例中,受试者接受了与外周血分离的移植的同种异体造血干细胞。在某些实施例中,在接受移植的同种异体造血干细胞之前,受试者接受了化学疗法以进行放射治疗。
在某些实施例中,本公开涉及通过进行干细胞移植来治疗癌症的方法,所述方法包括与移植源自受试者(自身)或供体的多能造血干细胞组合向受试者施用本文所公开的肽。可以从如脐带血或胎盘源性干细胞等外周血或从骨髓中收集干细胞。为了限制移植的干细胞排斥或严重的移植物抗宿主病的风险,供体通常会具有与接受者基本上相同的人白细胞抗原(HLA);然而,供体可能与某些抗原错配。
在某些实施例中,本公开涉及在造血祖细胞移植后提供淋巴细胞输注以治疗血液恶性肿瘤(例如,血癌或骨髓癌,如白血病或淋巴瘤)的方法。通常向移植接受者输注在白细胞去除术中从原始同种异体干细胞(造血祖细胞)供体中获得的淋巴细胞。
在某些实施例中,本公开涉及从血液中提取淋巴细胞并且针对一种或多种肿瘤抗原体外扩增,以及任选地用适当的刺激性细胞因子和/或本文所公开的肽来暴露细胞。
在某些实施例中,本公开涉及增强局部免疫疗法的方法,所述方法包括与提供包括引起T细胞活化的产生干扰素的药物的免疫增强霜(如咪喹莫特)组合施用本文所公开的肽。
在某些实施例中,可设想到本文所公开的肽可以与过继细胞疗法组合使用。例如,可能发现对癌症具有天然存在的反应性的T细胞在受试者的肿瘤中浸润。可以采集肿瘤,并且可以使用白介素-2(IL-2)、抗CD3和同种异体反应性饲养层在体外扩增这些肿瘤浸润淋巴细胞(TIL)或使其更有效。然后可以将这些T细胞与VIP拮抗剂的施用一起转移回受试者中。在重新输注之前,通常会进行接受者的淋巴细胞清除,以消除调节T细胞以及与所转移的细胞竞争的正常内源性淋巴细胞。还可设想到可以用对识别癌症抗原的T细胞受体(TCR)进行编码的载体转导淋巴细胞的过继细胞转移。
在某些实施例中,本公开涉及通过将人T细胞与含有VIP信号传导的小分子拮抗剂的纳米颗粒共温育来加强T细胞活化和离体扩增的方法。在某些实施例中,人T细胞用与板结合的抗CD3抗体活化。在某些实施例中,人T细胞在混合淋巴细胞反应中被活化。在某些实施例中,人T细胞通过与肿瘤相关抗原共温育而在体外活化。在某些实施例中,肿瘤相关抗原呈递在肿瘤微囊泡上。在某些实施例中,经活化的人T细胞被输注到患有癌症的人患者中。
在某些实施例中,经活化的人T细胞被输注到患有癌症的人患者中。在某些实施例中,患有癌症的人患者患有白血病。在某些实施例中,患有癌症的人患者患有淋巴瘤。在某些实施例中,患有癌症的人患者患有多发性骨髓瘤。在某些实施例中,患有癌症的人患者患有上皮癌。在某些实施例中,所述人患者患有肺癌。在某些实施例中,所述人患者患有乳腺癌。在某些实施例中,所述人患者患有结肠癌。在某些实施例中,所述人患者患有***癌。在某些实施例中,所述人患者患有恶性黑色素瘤。在某些实施例中,所述人患者患有脑癌。
在某些实施例中,本公开涉及治疗诊断患有癌症的受试者的方法,所述方法包括向有需要的受试者施用细胞与本文所公开的肽的组合。在某些实施例中,所述受试者被诊断患有白血病。在某些实施例中,所述受试者被诊断患有淋巴瘤。在某些实施例中,所述细胞是血液单核细胞。在某些实施例中,所述细胞是骨髓细胞。在某些实施例中,所述细胞是白细胞。在某些实施例中,所述细胞是T细胞。在某些实施例中,所述细胞是自然杀伤细胞。在某些实施例中,所述细胞是造血干细胞。在某些实施例中,所述细胞是G-CSF动员的血液单核细胞。在某些实施例中,所述细胞是HLA匹配或错配的同种异体细胞。在某些实施例中,所述细胞是同基因细胞。在某些实施例中,所述细胞是自体细胞。在某些实施例中,所述肽具有C端酰胺和/或任选地用烃或聚乙二醇基团修饰。
在某些实施例中,本公开涉及治疗白血病的方法,所述方法包括与移植造血干细胞组合地向受试者施用本文所公开的肽。在某些实施例中,本公开涉及包括体外扩增淋巴细胞以提供经扩增的细胞并且用本文所公开的肽暴露所扩增的细胞的方法。
在某些实施例中,淋巴细胞从血液中提取或通过白细胞去除术获得。在某些实施例中,将经扩增的细胞进一步暴露于刺激性细胞因子或干扰素。
在某些实施例中,本公开涉及通过输注本文所公开的肽或表达本文所公开的肽的纳米颗粒来加强抗癌免疫应答的方法。在某些实施例中,经活化的T细胞被输注到患有慢性CMV感染的患者中。在某些实施例中,经活化的T细胞被输注到患有慢性EBV感染的患者中。在某些实施例中,经活化的T细胞被输注到患有慢性BK病毒感染的患者中。在某些实施例中,经活化的T细胞被输注到患有慢性腺病毒感染的患者中。
在某些实施例中,本公开涉及通过中断血管活性肠肽(VIP)信号传导和/或抑制磷脂酰肌醇-3-激酶(PI3激酶)抑制剂信号传导来逆转T细胞衰老的组合物和方法以及管理癌症和慢性病毒感染的用途。在某些实施例中,本公开设想了通过将T细胞与本文所公开的肽或包括本文所公开的肽的纳米颗粒在体外混合来逆转T细胞衰老的方法,所述肽或纳米颗粒预防VIP与VIP受体相互作用和/或添加PI3激酶抑制剂。在某些实施例中,本公开设想了通过与PI3激酶抑制剂、本文所公开的纳米颗粒或肽、VIP降解酶和其组合混合来扩增衰老T细胞。
在某些实施例中,本公开设想了通过将T细胞体外暴露于结合CD3和/或CD28的抗体与PI3激酶抑制剂、艾代拉里斯、本文所公开的肽或本文所公开的纳米颗粒、VIP降解酶和其组合的组合来刺激分离的T细胞或扩增衰老T细胞的方法。在某些实施例中,本公开设想了使用抗CD3抗体和抗CD28抗体或任选地连接到固体底物(如磁珠)的结合剂。
在某些实施例中,本公开设想了使用如本文所公开的体外细胞培养物来增殖对CD28和/或CD27呈阴性的T细胞的方法,所述方法提供了与复制前的水平相比具有增加的CD28和/或CD27表达的复制的T细胞。
在某些实施例中,本公开设想了增殖T细胞的方法,其中在增殖T细胞之前、期间或之后,将所述T细胞与具有对嵌合抗原受体进行编码的核酸序列的载体混合,其中所述嵌合抗原受体包括癌症靶向性序列、跨膜结构域、T细胞共刺激分子结构域和T细胞抗原受体结构域的信号转导组分,使得细胞表达细胞表面上的嵌合抗原受体。
在某些实施例中,本公开涉及体外细胞培养组合物,其包括最小必需培养基以及本文所公开的T细胞和肽或包括本文所公开的肽和磷脂酰肌醇-3-激酶抑制剂、VIP降解酶和其组合的纳米颗粒,并且任选地进一步包括任选地固定在如珠等固体底物上的抗CD3抗体和抗CD28抗体。在某些实施例中,从骨髓细胞或血细胞、外周血中纯化T细胞。
在某些实施例中,磷脂酰肌醇-3-激酶抑制剂选自艾代拉里斯、渥曼青霉素(wortmannin)、脱甲氧基维立汀(demethoxyviridin)、哌立福辛(perifosine)、布帕尼(buparlisib)、达维利西(duvelisib)、库潘尼西(copanlisib)和阿培利西(alpelisib)。在某些实施例中,磷脂酰肌醇-3-激酶抑制剂选自培养物中的艾代拉里斯,其浓度大于0.001、0.1、1、10、100nM、或介于10nM与10微摩尔之间、或介于10nM与500nM之间或介于10nM与1微摩尔之间。
在某些实施例中,培养物包括水解VIP的酶。在某些实施例中,培养物包括VIP降解酶,如肽酶、丝氨酸肽酶、类胰蛋白酶、糜酶或人糜酶1(CMA1)。在某些实施例中,培养物具有至少0.001、0.01、0.1或1微克每mL VIP降解酶,如肥大细胞糜酶。在某些实施例中,本公开设想了一种T细胞培养物,其包括最小必需培养基和表达CD3和/或CD4和/或CD8并且对CD27和/或CD28呈阴性的分离的细胞以及PI3激酶抑制剂、本文所公开的肽或包括本文所公开的肽的纳米颗粒以及其组合。可以通过使用附接到固体支持物(如荧光结合剂的珠、磁珠或颗粒)的结合剂进行阴性或阳性选择来分离细胞。
在某些实施例中,将抗CD3抗体和抗CD28抗体固定在珠、磁珠或固体表面上。在某些实施例中,培养物中的超过5.0%、或10%或15%的总细胞表达CD3和/或CD4和/或CD8。在某些实施例中,超过20%、25%或50%的总细胞表达CD3和/或CD4和/或CD8。在某些实施例中,培养物中的超过15%、或20%或30%的T细胞对CD28和/或CD27呈阴性。在某些实施例中,超过20%、25%或50%的T细胞对CD28和/或CD27呈阴性。
在某些实施例中,经纯化的T细胞是在使得血浆和红细胞分开从而在血浆与红细胞之间的白细胞混合物中提供经纯化的T细胞的条件下通过离心血液获得的。在某些实施例中,经纯化的T细胞是通过骨髓穿刺或骨髓活检获得的。
在某些实施例中,经纯化的T细胞是通过将细胞与结合CD3的荧光标志物混合并且通过荧光活化的细胞分选纯化细胞而获得的。在某些实施例中,经纯化的T细胞是通过将细胞与结合CD3的磁化标志物混合并且通过磁性分选纯化细胞而获得的。在某些实施例中,经纯化的T细胞是通过将细胞与结合CD3和/或CD4和/或CD8的荧光标志物混合并且通过荧光活化的细胞分选纯化细胞而获得的。在某些实施例中,经纯化的T细胞是通过将细胞与结合CD3和/或CD4和/或CD8的磁化标志物混合并且通过磁性分选纯化细胞而获得的。
在某些实施例中,本公开设想了固体底物,如珠,所述固体底物具有抗CD3抗体和抗CD28抗体并且具有与表面偶联的VIP降解酶。在某些实施例中,可设想到将珠布置在培养基中,并且使T细胞在培养基的顶部上扩增,使得珠是亚细胞的。
在某些实施例中,VIP降解酶包括人CMA1登录号GenBank:AAI03975.1:
在某些实施例中,VIP降解酶是人重组脑啡肽酶(中性内肽酶,EC 3.4.24.11),其具有(SEQ ID NO:14):
在某些实施例中,本文所描述的细胞培养物和方法进一步包含IL-12。在某些实施例中,设想IL-12增强本文所公开的肽或其纳米颗粒对用针对CD3和CD28的抗体在体外刺激的T细胞增殖的作用。
在某些实施例中,本发明涉及扩增T细胞或在T细胞中扩增或逆转衰老,其中可以发现癌症的天然存在的反应性在受试者的肿瘤中浸润。可以采集肿瘤,并且可以使用本文所公开的方法扩增这些肿瘤浸润淋巴细胞(TIL)。
一些癌症是由病毒引起的,并且针对这些病毒的传统疫苗(如HPV疫苗和乙型肝炎疫苗)将预防这些癌症。可设想到本文所公开的肽可以与这些疫苗组合施用以改进治疗功效。
据信,癌细胞会产生免疫***并被免疫***破坏,并且癌症在免疫***无法破坏所述癌细胞时形成。一种癌症疫苗接种的方法是从癌细胞中分离蛋白质,并且使癌症患者针对这些蛋白质进行免疫,从而刺激杀死癌细胞的免疫应答。设想癌症疫苗用于治疗乳腺癌、肺癌、结肠癌、皮肤癌、肾癌、***癌和其它癌症。在某些实施例中,本发明涉及通过施用本文所公开的肽与癌症抗原的组合来治疗癌症。
在某些实施例中,本公开涉及治疗或预防病毒感染的方法,所述方法包括向有病毒感染的风险、表现出病毒感染症状或被诊断患有病毒感染的受试者施用本文所公开的肽。在某些实施例中,所述受试者是免疫低下的,或者所述受试者是同种异体骨髓移植供体或接受者。在典型的实施例中,所述受试者是正在经受血液透析、被诊断患有癌症、正在接受免疫抑制药物和/或被诊断患有HIV感染的器官移植接受者。在某些实施例中,本公开涉及通过施用本文所公开的肽和任选地一种或多种抗病毒剂来预防有感染风险的免疫低下的受试者感染病毒。
在一些实施例中,本公开涉及本文所公开的肽的用途,其用于产生用于治疗病毒感染的抗病毒药物。在一些实施例中,受试者被诊断患有慢性病毒感染。在某些实施例中,所述受试者经受血清监测。在一些实施例中,施用是在不再检测到病毒感染的条件下进行的。在一些实施例中,受试者被诊断患有RNA病毒、DNA病毒或逆转录病毒。在一些实施例中,受试者被诊断患有病毒,所述病毒是双链DNA病毒、有义单链DNA病毒、双链RNA病毒、有义单链RNA病毒、反义单链RNA病毒、有义单链RNA逆转录病毒或双链DNA逆转录病毒。在一些实施例中,受试者被诊断患有轮状病毒、流感病毒、疱疹病毒、肝炎病毒或慢病毒。在一些实施例中,与治疗前相比,治疗后受试者的病毒滴度降低。
在一些实施例中,受试者被诊断患有以下病毒:甲型流感病毒(包含亚型H1N1)、乙型流感病毒、丙型流感病毒、轮状病毒A、轮状病毒B、轮状病毒C、轮状病毒D、轮状病毒E、SARS冠状病毒、(HAdV-1到55)型人腺病毒、16、18、31、33、35、39、45、51、52、56、58、59型人***瘤病毒(HPV)、细小病毒B19、***病毒、JC病毒(JCV)、BK病毒、默克尔细胞多瘤病毒(Merkel cell polyomavirus)、甲型柯萨奇病毒、诺如病毒、风疹病毒、淋巴细胞性脉络丛脑膜炎病毒(LCMV)、黄热病毒、麻疹病毒、腮腺炎病毒、呼吸道合胞病毒、牛瘟病毒、加利福尼亚脑炎病毒(California encephalitis virus)、汉坦病毒、狂犬病病毒、埃博拉病毒、马尔堡病毒(marburg virus)、单纯性疱疹病毒-1(HSV-1)、单纯性疱疹病毒-2(HSV-2)、水痘带状疱疹病毒(VZV)、埃-巴二氏病毒(Epstein-Barr virus,EBV)、巨细胞病毒(CMV)、疱疹淋巴细胞病毒、玫瑰疹病毒、卡波西氏肉瘤相关疱疹病毒、甲型肝炎病毒(HAV)、乙型肝炎病毒(HBV)、丙型肝炎病毒(HCV)、丁型肝炎病毒(HDV)、戊型肝炎病毒(HEV)、人免疫缺陷病毒(HIV)、I型人T淋巴细胞白血病病毒(HTLV-1)、弗罗德脾脏病灶形成病毒(Friend spleenfocus-forming virus)(SFFV)或嗜异性MuLV相关病毒(XMRV)。
在一些实施例中,本公开涉及通过施用本文所公开的肽与第二抗病毒剂的组合来治疗或预防病毒感染。在另外的实施例中,向受试者共施用阿巴卡韦(abacavir)、阿昔洛韦(acyclovir)、阿昔洛韦(acyclovir)、阿德福韦(adefovir)、金刚烷胺(amantadine)、安普那韦(amprenavir)、安普利近(ampligen)、阿比多尔(arbidol)、阿扎那韦(atazanavir)、立普妥(atripla)、博赛泼维(boceprevir)、西多福韦(cidofovir)、可比韦(combivir)、地瑞那韦(darunavir)、地拉夫定(delavirdine)、地达诺新(didanosine)、二十二醇(docosanol)、依度尿苷(edoxudine)、依法韦仑(efavirenz)、恩曲他滨(emtricitabine)、恩夫韦地(enfuvirtide)、恩替卡韦(entecavir)、泛昔洛韦(famciclovir)、膦沙那韦(fosamprenavir)、膦甲酸(foscarnet)、更昔洛韦(ganciclovir)、碘苷(idoxuridine)、咪喹莫特(imiquimod)、茚地那韦(indinavir)、肌苷(inosine)、III型干扰素、II型干扰素、I型干扰素、拉米夫定(lamivudine)、洛匹那韦(lopinavir)、马拉韦罗(maraviroc)、吗啉胍(moroxydine)、甲吲噻腙(methisazone)、奈非那韦(nelfinavir)、奈韦拉平(nevirapine)、奥司他韦(oseltamivir)(特敏福(Tamiflu))、聚乙二醇化干扰素α-2a(peginterferonalfa-2a)、喷昔洛韦(penciclovir)、帕拉米韦(peramivir)、普可那利(pleconaril)、鬼臼毒素(podophyllotoxin)、雷特格韦(raltegravir)、利巴韦林(ribavirin)、金刚乙胺(rimantadine)、利托那韦(ritonavir)、沙奎那韦(saquinavir)、司他夫定(stavudine)、替诺福韦(tenofovir)、替诺福韦酯(tenofovir disoproxil)、替普那韦(tipranavir)、三氟尿苷(trifluridine)、拉米夫定(trizivir)、曲金刚胺(tromantadine)、TruvadaTM(恩曲他滨(emtricitabine)/富马酸替诺福韦酯(tenofovir disoproxil fumarate))、伐昔洛韦(valaciclovir)、伐昔洛韦、维立韦罗(vicriviroc)、维达拉滨(vidarabine)、塔利韦林(viramidine)、扎西他滨(zalcitabine)、扎那米韦(zanamivir)和/或齐多夫定(zidovudine)。在某些实施例中,向受试者施用包括本文所公开的肽和第二抗病毒剂的药物组合物。
在某些实施例中,本公开涉及通过施用本文所公开的肽和免疫球蛋白来治疗感染后患有病毒感染的受试者。
在某些实施例中,本公开涉及通过施用本文所公开的肽和病毒疫苗或在不存在病毒疫苗的情况下治疗或预防病毒感染。
在某些实施例中,本公开涉及增强对疫苗的免疫应答,其包括向有需要的受试者施用本文所公开的肽。通常,疫苗选自由以下组成的疫苗的组:带状疱疹疫苗、天花疫苗、脊髓灰质炎疫苗、百日咳疫苗、流感疫苗、白喉疫苗、破伤风疫苗、脑膜炎球菌疫苗、包含H1N1亚型疫苗的甲型流感疫苗、乙型流感疫苗、丙型流感疫苗、轮状病毒A疫苗、轮状病毒B疫苗、轮状病毒C疫苗、轮状病毒D疫苗、轮状病毒E疫苗、SARS冠状病毒疫苗、人腺病毒(HAdV-1到55)型疫苗、人类***瘤病毒(HPV)疫苗、细小病毒B19疫苗、传染性软体动物疫苗、JC疫苗、BK疫苗、默克尔细胞多瘤病毒疫苗、柯萨奇A疫苗、诺如病毒疫苗、风疹疫苗、淋巴细胞性脉络膜脑膜炎疫苗、黄热病疫苗、麻疹疫苗、腮腺炎疫苗、呼吸道合胞疫苗、牛瘟疫苗、加利福尼亚脑炎疫苗、汉坦病毒疫苗、狂犬病疫苗、埃博拉疫苗、马尔堡疫苗、单纯疱疹病毒1(HSV-1)疫苗、单纯疱疹病毒2(HSV-2)疫苗、水痘带状疱疹疫苗、爱泼斯坦-巴尔病毒(EBV)疫苗、巨细胞病毒(CMV)疫苗、疱疹淋巴疫苗、玫瑰花叶病毒疫苗、卡波西氏肉瘤相关疱疹病毒疫苗、甲型肝炎(HAV)疫苗、乙型肝炎(HBV)疫苗、丙型肝炎(HCV)疫苗、丁型肝炎(HDV)疫苗、戊型肝炎(HEV)疫苗、人免疫缺陷病毒(HIV)疫苗、人T淋巴细胞病毒I型(HTLV-1)疫苗、弗氏脾脏聚焦形成病毒(SFFV)疫苗和异源性MuLV相关病毒(XMRV)疫苗。在某些实施例中,疫苗用于被诊断患有慢性病毒感染的受试者。
在某些实施例中,疫苗包括蛋白质或肽、碳水化合物、糖、多糖或核酸。通常,疫苗是减毒的有复制能力的病毒或灭活病毒。在某些实施例中,疫苗包括活的或杀死的或灭活的原核或真核细胞。
在某些实施例中,人T细胞通过与病毒抗原共温育而在体外活化。在某些实施例中,病毒抗原呈递在微囊泡上。在某些实施例中,病毒抗原呈递在树突状细胞上。
对核酸疫苗(通常是DNA质粒)进行基因工程化以对一种或多种抗原进行编码和/或由病原体产生一种或多种抗原。核酸转染或感染宿主细胞,其中细胞的内部机制表达蛋白质。因为这些蛋白质被识别为外来蛋白质,所以当所述蛋白质被宿主细胞加工并在其表面上展示时,就会触发免疫应答。通过与共刺激分子(如GM-CSF、B7-1或B7-2)共接种,也可以增强细胞毒性T淋巴细胞应答。在某些实施例中,本文所公开的肽可以与核酸疫苗或其它共刺激分子组合施用。
在某些实施例中,本公开涉及包括本文所公开的肽的疫苗组合物以及与疫苗组合施用本文所公开的肽的方法。在某些实施例中,疫苗含有来自病原体的抗原,并且从弱化或杀死的微生物或其毒素形式呈递给免疫***。抗原刺激免疫***。疫苗可以是预防性的(例如,以预防或改善任何病原体将来感染的效应),也可以在感染或诊断出疾病后施用治疗。
一些疫苗含有被杀死的但先前剧毒的微生物,所述微生物已被化学药品或高温破坏。流感疫苗、霍乱疫苗、鼠疫疫苗、脊髓灰质炎疫苗、甲型肝炎疫苗和狂犬病疫苗是本公开设想的灭活疫苗的实例。
一些疫苗含有活的减毒的微生物。通常,这些是已经在禁用某些剧毒性质或使用紧密相关但危险性较小的生物体以产生广泛免疫应答的条件下培养的活病毒;然而,有些本质上是细菌。
在某些实施例中,疫苗是蛋白质亚基。其片段可以用于产生免疫应答,而不是将灭活或减毒的微生物引入到免疫***。实例包含仅由病毒表面蛋白构成的抗乙型肝炎病毒的亚单位疫苗、由病毒主要衣壳蛋白构成的针对人***瘤病毒(HPV)的病毒样颗粒(VLP)疫苗以及流感病毒的血凝素和神经氨酸酶亚基。
在某些实施例中,疫苗包括多糖。某些细菌具有通常具有免疫原性的多糖外衣。通过将这些多糖与蛋白质(例如,毒素)连接,可以使免疫***识别多糖,就好像其是蛋白质抗原一样。
类毒素疫苗是由灭活的有毒化合物制成的。基于类毒素的疫苗的实例包含白喉和破伤风类毒素。在某些实施例中,与DPT组合施用本文所公开的肽。DPT(也被称为DTP和DTwP)是指一类针对以下人类三种传染病的组合疫苗:白喉、百日咳(顿咳)和破伤风。疫苗组分包含白喉和破伤风类毒素,并且杀死了引起百日咳(wP)的有机体全细胞。DTaP(也被称为Tdap、DTPa和TDaP)是指百日咳组分无细胞的类似组合疫苗。还设想了缺少百日咳组分的DT或TD疫苗。
本公开设想的其它特异性疫苗包含炭疽疫苗,例如未包囊的被称为V770-NP1-R的无毒菌株的培养滤液;卡介苗(BCG),例如减毒的活牛结核杆菌菌株;乙型流感嗜血杆菌疫苗,例如Hib多糖-蛋白缀合物疫苗;甲型肝炎疫苗,例如灭活的甲型肝炎病毒;乙型肝炎疫苗,例如乙型肝炎表面抗原;人***瘤病毒(HPV)疫苗,例如由HPV 6型、11型、16型和18型L1蛋白组装而成的非感染性病毒样颗粒;脑膜炎球菌疫苗,例如与白喉类毒素蛋白单独缀合的脑膜炎奈瑟氏球菌血清组A、C、Y和W-135菌株的荚膜多糖抗原。
在某些实施例中,本公开涉及治疗活性巨细胞病毒感染的方法,所述方法包括向诊断患有活性巨细胞病毒感染并且表现出其迹象或症状的受试者施用有效量的本文所公开的血管活性肠肽拮抗剂,其中所述血管活性肠肽拮抗剂包括具有C端酰胺基的肽,并且任选地用烃基或聚乙二醇基团修饰。
在某些实施例中,受试者的免疫***受损。在某些实施例中,受试者是移植接受者。
在某些实施例中,本公开涉及减少活性巨细胞病毒感染的方法,所述方法包括向患有活性巨细胞病毒感染的受试者施用有效量的本文所公开的血管活性肠肽拮抗剂,其中所述血管活性肠肽拮抗剂包括具有C端酰胺基的肽,并且任选地用烃基或聚乙二醇基团修饰。在某些实施例中,与预治疗相比,在施用血管活性肠肽拮抗剂之后,受试者中巨细胞病毒的滴度降低。
实例
经改进的VIP拮抗剂
评估血管活性肠多肽的肿瘤特异性表达是否代表肿瘤介导的免疫逃逸机制。存在跨肿瘤的VIP表达谱,其中在胰腺外分泌癌中可见最高表达,并且在黑色素瘤中可见最低表达。通常,肿瘤的VIP表达水平与其它共抑制途径分子(如PDL1)的表达成反比。表达和分泌VIP的肿瘤可能在VIP编码序列中具有突变,使得所得肽分子在肿瘤微环境中具有经改进的药代动力学或药效学。药代动力学优势可能是突变的结果,所述突变减少了对蛋白酶较不敏感的VIP,从而改进其半衰期。药效学优势可能是增强与受体的结合亲和力从而增强信号传导的突变的结果。
进行实验以确定由肿瘤产生的突变的VIP是否会导致在肿瘤微环境中更持久地抑制抗癌T细胞。分析从所沉积的肿瘤序列中挑选出的特异性基因的突变,多种癌症中存在VIP编码序列中的突变。具体地,在癌基因组图谱中列出的VIP基因簇内有140个错义突变和17个截短突变。在28个氨基酸VIP肽的编码序列内,在存在于乳腺癌、***腺癌、食管腺癌、皮肤黑色素瘤、小细胞肺癌、胃腺癌、子宫内膜癌、皮肤黑色素瘤、食管腺癌、大肠腺癌、子宫癌肉瘤、肝细胞腺瘤、肺腺癌、胃腺癌中的VIP编码序列中鉴定出突变。八种特异性突变存在于C端氨基酸中,包含结合受体的VIP的α螺旋。
α螺旋序列在免疫抑制的VIP(即肽激动剂)之间是常见的。VIPhyb(SEQ ID NO:1),与来自天然VIP(SEQ ID NO:2)的六个内部氨基酸不同的拮抗肽(参见图1)。在存在VIPhyb的六个N端氨基酸的情况下制备了八个序列,即ANT-1到8(参见图1中的SEQ ID NO:3-10)。具体地,ANT-1序列在氨基酸位置七处具有氨基酸T变为A取代。ANT-2序列在氨基酸位置编号8处具有氨基取代D变为V。ANT-3在氨基酸位置编号10处具有氨基酸取代Y变为C。ANT-4在氨基酸位置12处具有氨基酸取代R变为S。ANT-5在氨基酸位置编号17处具有氨基酸取代M变为I。ANT-6在氨基酸位置20处具有氨基酸取代K变为N。ANT-7在氨基酸位置编号23处具有氨基酸取代L变为M。ANT-8在氨基酸位置编号25处具有氨基酸取代S变为L。合成了替代性拮抗肽序列ANT-1到ANT-8中的每一个。
将肽(图1中的SEQ ID NO:3-10)添加到荧光素酶阳性T细胞的短期培养物中,所述短期培养物是在存在结合板的抗CD3抗体的情况下在96孔板中培养的。抗CD3抗体的浓度为0.5mcg/ml或1mcg/ml。在存在低剂量IL-2的情况下添加来自荧光素酶转基因小鼠的T细胞,并且添加0.5微摩尔、1微摩尔或3微摩尔浓度的原始VIPhyb肽或替代性ANT-1到ANT-8肽序列。图2示出了在存在1微摩尔浓度的Ant-1到Ant-8的情况下在24小时时的T细胞增殖。图3示出了与在相同对应浓度下的原始VIPhyb肽相比,在存在0.5微摩尔、1微摩尔和3微摩尔浓度下的ANT-8肽的情况下,在24小时时增强的T细胞增殖。
与含有结合板的抗CD3抗体但没有添加肽的对照培养物相比,使用较低浓度的具有ANT-8肽的抗CD3的增强的T细胞增殖更为适度,并且与含有且仅少量增加的对照培养物没有显著差异。鉴定了与天然VIPhyb相比具有改进的拮抗活性的独特肽序列ANT-8(SEQ IDNO:10)。
Claims (15)
1.一种肽,其包括KPRRPYX1X2NX3TX4LRKQX5AVX6KYX7NX8ILN(SEQ ID NO:11),其中X1是A或任何氨基酸;
X2是V或任何氨基酸;
X3是C或任何氨基酸;
X4是S或任何氨基酸;
X5是I或任何氨基酸;
X6是N或任何氨基酸;
X7是M或任何氨基酸;
X8是I或任何氨基酸;并且
条件是所述肽不是KPRRPYTDNYTRLRKQMAVKKYLNSILN(SEQ ID NO:1)或其中X1是T、X2是D、X3是Y、X4是R、X5是M、X6是K、X7是L并且X8是S的组合。
2.根据权利要求1所述的肽,其包括以下或由以下组成:KPRRPYX1X2NX3TX4LRKQX5AVX6KYX7NX8ILN(SEQ ID NO:11),
其中X1是A或T,其中仅当X2是V,X3是C,X4是S,X5是I,X6是N,X7是M或X8是I时,X1才是T;
其中X2是V或D,其中仅当X1是A,X3是C,X4是S,X5是I,X6是N,X7是M或X8是I时,X2才是D;
其中X3是C或Y,其中仅当X1是A,X2是V,X4是S,X5是I,X6是N,X7是M或X8是I时,X3才是Y;
其中X4是S或R,其中仅当X1是A,X2是V,X3是C,X5是I,X6是N,X7是M或X8是I时,X4才是R;
其中X5是I或M,其中仅当X1是A,X2是V,X3是C,X4是S,X6是N,X7是M或X8是I时,X5才是M;
其中X6是N或K,其中仅当X1是A,X2是V,X3是C,X4是S,X5是I,X7是M或X8是I时,X6才是K;
其中X7是M或L,其中仅当X1是A,X2是V,X3是C,X4是S,X5是I,X6是N或X8是I时,X7才是L;并且
其中X8是I或S,其中仅当X1是A,X2是V,X3是C,X4是S,X5是I,X6是N或X7是M时,X8才是S。
3.根据权利要求1所述的肽,其包括KPRRPYTDNYTRLRKQMAVKKYLNLILN(SEQ ID NO:10)。
4.根据权利要求1所述的肽,其中所述肽中的氨基、羧基、羟基或硫醇基被取代。
5.根据权利要求1所述的肽,其中所述肽与纳米颗粒缀合。
6.一种药物组合物,其包括根据权利要求1所述的肽以及药学上可接受的赋形剂。
7.根据权利要求6所述的药物组合物,其呈胶囊、片剂、丸剂、粉末或颗粒剂的形式。
8.根据权利要求6所述的药物组合物,其呈灭菌的pH缓冲水性盐溶液的形式。
9.根据权利要求6所述的药物组合物,其呈容器的形式,所述容器被配置成用推进剂喷洒液体或密封的容器。
10.一种核酸,其与启动子可操作地组合对根据权利要求1到4中任一项所述的肽进行编码。
11.一种重组载体,其包括根据权利要求1所述的核酸。
12.一种细胞,其包括根据权利要求7所述的重组载体。
13.一种加强T细胞活化和离体扩增的方法,所述方法包括将T细胞与根据权利要求1到4中任一项所述的肽混合。
14.根据权利要求13所述的方法,其中混合T细胞与抗CD3抗体和/或抗CD28抗体组合。
15.根据权利要求13所述的方法,其中混合T细胞与磷脂酰肌醇3-激酶δ(PI3Kδ)抑制剂组合。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201862768060P | 2018-11-15 | 2018-11-15 | |
US62/768,060 | 2018-11-15 | ||
PCT/US2019/061760 WO2020102694A1 (en) | 2018-11-15 | 2019-11-15 | Compositions and uses of vasoactive intestinal peptide (vip) antagonists |
Publications (1)
Publication Number | Publication Date |
---|---|
CN113795269A true CN113795269A (zh) | 2021-12-14 |
Family
ID=70730919
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201980089301.7A Pending CN113795269A (zh) | 2018-11-15 | 2019-11-15 | 血管活性肠肽(vip)拮抗剂的组合物和用途 |
Country Status (7)
Country | Link |
---|---|
US (1) | US20220002372A1 (zh) |
EP (1) | EP3880228A4 (zh) |
JP (1) | JP2022507688A (zh) |
CN (1) | CN113795269A (zh) |
AU (1) | AU2019381809A1 (zh) |
CA (1) | CA3120248A1 (zh) |
WO (1) | WO2020102694A1 (zh) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AU2022279136A1 (en) * | 2021-05-17 | 2023-11-09 | Cambium Oncology Llc | Vasoactive intestinal peptide (vip) receptor antagonists |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5565424A (en) * | 1994-02-07 | 1996-10-15 | Ramot - University Authority For Applied Research And Industrial Development Ltd. | Superactive VIP antagonists |
JPH1067676A (ja) * | 1996-08-16 | 1998-03-10 | Natl Inst Of Immunology | 癌治療用薬剤 |
US6630124B1 (en) * | 1998-10-16 | 2003-10-07 | Ramot-University Authority For Applied Research And Industrial Development Ltd. | Combination therapy with VIP antagonist |
WO2017176932A1 (en) * | 2016-04-08 | 2017-10-12 | Emory University | Methods of treating cancer and infectious diseases using cell based therapies |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20090175821A1 (en) * | 1999-05-17 | 2009-07-09 | Bridon Dominique P | Modified therapeutic peptides with extended half-lives in vivo |
WO2012161755A2 (en) * | 2011-02-02 | 2012-11-29 | Emory University | Antagonism of the vip signaling pathway |
-
2019
- 2019-11-15 JP JP2021527094A patent/JP2022507688A/ja active Pending
- 2019-11-15 US US17/294,248 patent/US20220002372A1/en active Pending
- 2019-11-15 CA CA3120248A patent/CA3120248A1/en active Pending
- 2019-11-15 CN CN201980089301.7A patent/CN113795269A/zh active Pending
- 2019-11-15 EP EP19885139.6A patent/EP3880228A4/en active Pending
- 2019-11-15 WO PCT/US2019/061760 patent/WO2020102694A1/en unknown
- 2019-11-15 AU AU2019381809A patent/AU2019381809A1/en active Pending
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5565424A (en) * | 1994-02-07 | 1996-10-15 | Ramot - University Authority For Applied Research And Industrial Development Ltd. | Superactive VIP antagonists |
JPH1067676A (ja) * | 1996-08-16 | 1998-03-10 | Natl Inst Of Immunology | 癌治療用薬剤 |
US6630124B1 (en) * | 1998-10-16 | 2003-10-07 | Ramot-University Authority For Applied Research And Industrial Development Ltd. | Combination therapy with VIP antagonist |
WO2017176932A1 (en) * | 2016-04-08 | 2017-10-12 | Emory University | Methods of treating cancer and infectious diseases using cell based therapies |
CN108778312A (zh) * | 2016-04-08 | 2018-11-09 | 爱默蕾大学 | 使用基于细胞的疗法治疗癌症和传染病的方法 |
Also Published As
Publication number | Publication date |
---|---|
CA3120248A1 (en) | 2020-05-22 |
EP3880228A1 (en) | 2021-09-22 |
EP3880228A4 (en) | 2022-09-28 |
WO2020102694A1 (en) | 2020-05-22 |
AU2019381809A1 (en) | 2021-06-17 |
US20220002372A1 (en) | 2022-01-06 |
JP2022507688A (ja) | 2022-01-18 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US11760782B2 (en) | Peptides and methods for the treatment of diabetes | |
Panagioti et al. | Immunostimulatory bacterial antigen–armed oncolytic measles virotherapy significantly increases the potency of anti-PD1 checkpoint therapy | |
EP3393511A1 (en) | Leveraging immune memory from common childhood vaccines to fight disease | |
CA3127459A1 (en) | Compositions and methods for stimulating natural killer cells | |
CA3196553A1 (en) | Oncolytic virus boosts t cell response for effective til therapy | |
US11149052B2 (en) | 2′3′-cyclic dinucleotides | |
CN113795269A (zh) | 血管活性肠肽(vip)拮抗剂的组合物和用途 | |
US20230190865A1 (en) | VIP Antagonists and Uses in Treating Cancer | |
KR20240056684A (ko) | 혈관활성 장 펩티드(vip) 수용체 길항제 | |
AU2021386252A1 (en) | Combinations of small molecule drug conjugate and car-expressing cytotoxic lymphocytes and methods of treating cancer using the same | |
US20210186977A1 (en) | Medical uses | |
CN117402831B (zh) | 规模化、定制化的树突状细胞外泌体在抗肿瘤中的应用 | |
US20230414565A1 (en) | Compositions and methods for treating hematological malignancies | |
CA3194929A1 (en) | Modified cxcl10 for immunotherapy of cancer diseases | |
JP2004059574A (ja) | インターロイキン21を用いた免疫治療用医薬組成物 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination |