CN112638392A - 组合疗法 - Google Patents
组合疗法 Download PDFInfo
- Publication number
- CN112638392A CN112638392A CN201980056828.XA CN201980056828A CN112638392A CN 112638392 A CN112638392 A CN 112638392A CN 201980056828 A CN201980056828 A CN 201980056828A CN 112638392 A CN112638392 A CN 112638392A
- Authority
- CN
- China
- Prior art keywords
- adcx19
- bcl
- agent
- individual
- treatment
- 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
- 238000002648 combination therapy Methods 0.000 title abstract description 23
- 238000011282 treatment Methods 0.000 claims abstract description 198
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 171
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 103
- 201000011510 cancer Diseases 0.000 claims abstract description 66
- 238000000034 method Methods 0.000 claims description 122
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 118
- 102100024222 B-lymphocyte antigen CD19 Human genes 0.000 claims description 73
- 101000980825 Homo sapiens B-lymphocyte antigen CD19 Proteins 0.000 claims description 73
- 201000010099 disease Diseases 0.000 claims description 70
- 210000004027 cell Anatomy 0.000 claims description 58
- 208000024893 Acute lymphoblastic leukemia Diseases 0.000 claims description 50
- 201000009277 hairy cell leukemia Diseases 0.000 claims description 48
- 208000014697 Acute lymphocytic leukaemia Diseases 0.000 claims description 44
- 239000000203 mixture Substances 0.000 claims description 35
- 206010012818 diffuse large B-cell lymphoma Diseases 0.000 claims description 31
- 208000031671 Large B-Cell Diffuse Lymphoma Diseases 0.000 claims description 30
- 208000025205 Mantle-Cell Lymphoma Diseases 0.000 claims description 27
- 201000003444 follicular lymphoma Diseases 0.000 claims description 26
- 241000282414 Homo sapiens Species 0.000 claims description 25
- 208000036170 B-Cell Marginal Zone Lymphoma Diseases 0.000 claims description 24
- 201000000439 HCL-V Diseases 0.000 claims description 24
- 208000010956 Hairy cell leukemia variant Diseases 0.000 claims description 24
- 201000007924 marginal zone B-cell lymphoma Diseases 0.000 claims description 24
- 208000021937 marginal zone lymphoma Diseases 0.000 claims description 24
- 210000004214 philadelphia chromosome Anatomy 0.000 claims description 24
- 229940127089 cytotoxic agent Drugs 0.000 claims description 23
- 239000002246 antineoplastic agent Substances 0.000 claims description 21
- 230000002062 proliferating effect Effects 0.000 claims description 21
- 208000015914 Non-Hodgkin lymphomas Diseases 0.000 claims description 19
- 208000032839 leukemia Diseases 0.000 claims description 17
- 229950009758 loncastuximab tesirine Drugs 0.000 claims description 16
- 230000001684 chronic effect Effects 0.000 claims description 13
- 208000031422 Lymphocytic Chronic B-Cell Leukemia Diseases 0.000 claims description 12
- 206010052178 Lymphocytic lymphoma Diseases 0.000 claims description 12
- 239000000126 substance Substances 0.000 claims description 11
- 210000004882 non-tumor cell Anatomy 0.000 claims description 9
- 238000009097 single-agent therapy Methods 0.000 claims description 4
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- 208000006664 Precursor Cell Lymphoblastic Leukemia-Lymphoma Diseases 0.000 claims 1
- 229940049595 antibody-drug conjugate Drugs 0.000 abstract description 95
- 239000000611 antibody drug conjugate Substances 0.000 abstract description 69
- 230000001575 pathological effect Effects 0.000 abstract description 2
- 239000003814 drug Substances 0.000 description 60
- 239000000523 sample Substances 0.000 description 53
- 208000035475 disorder Diseases 0.000 description 42
- 230000014509 gene expression Effects 0.000 description 38
- 229940079593 drug Drugs 0.000 description 33
- 150000001875 compounds Chemical class 0.000 description 28
- 230000004044 response Effects 0.000 description 28
- 101000971171 Homo sapiens Apoptosis regulator Bcl-2 Proteins 0.000 description 23
- 102100021569 Apoptosis regulator Bcl-2 Human genes 0.000 description 21
- 231100000371 dose-limiting toxicity Toxicity 0.000 description 19
- 210000001519 tissue Anatomy 0.000 description 19
- 239000000427 antigen Substances 0.000 description 18
- 102000036639 antigens Human genes 0.000 description 18
- 108091007433 antigens Proteins 0.000 description 18
- -1 type 2) Proteins 0.000 description 18
- 238000001574 biopsy Methods 0.000 description 16
- IBXPAFBDJCXCDW-MHFPCNPESA-A [Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].Cc1cn([C@H]2C[C@H](O)[C@@H](COP([S-])(=O)O[C@H]3C[C@@H](O[C@@H]3COP([O-])(=S)O[C@H]3C[C@@H](O[C@@H]3COP([O-])(=S)O[C@H]3C[C@@H](O[C@@H]3COP([O-])(=S)O[C@H]3C[C@@H](O[C@@H]3COP([O-])(=S)O[C@H]3C[C@@H](O[C@@H]3COP([O-])(=S)O[C@H]3C[C@@H](O[C@@H]3COP([O-])(=S)O[C@H]3C[C@@H](O[C@@H]3COP([O-])(=S)O[C@H]3C[C@@H](O[C@@H]3COP([O-])(=S)O[C@H]3C[C@@H](O[C@@H]3COP([O-])(=S)O[C@H]3C[C@@H](O[C@@H]3COP([O-])(=S)O[C@H]3C[C@@H](O[C@@H]3COP([O-])(=S)O[C@H]3C[C@@H](O[C@@H]3COP([O-])(=S)O[C@H]3C[C@@H](O[C@@H]3COP([O-])(=S)O[C@H]3C[C@@H](O[C@@H]3COP([O-])(=S)O[C@H]3C[C@@H](O[C@@H]3COP([O-])(=S)O[C@H]3C[C@@H](O[C@@H]3COP([O-])(=S)O[C@H]3C[C@@H](O[C@@H]3CO)n3cc(C)c(=O)[nH]c3=O)n3ccc(N)nc3=O)n3cc(C)c(=O)[nH]c3=O)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3cnc4c3nc(N)[nH]c4=O)n3ccc(N)nc3=O)n3cnc4c3nc(N)[nH]c4=O)n3cc(C)c(=O)[nH]c3=O)n3cnc4c3nc(N)[nH]c4=O)n3ccc(N)nc3=O)n3cnc4c3nc(N)[nH]c4=O)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)O2)c(=O)[nH]c1=O Chemical compound [Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].Cc1cn([C@H]2C[C@H](O)[C@@H](COP([S-])(=O)O[C@H]3C[C@@H](O[C@@H]3COP([O-])(=S)O[C@H]3C[C@@H](O[C@@H]3COP([O-])(=S)O[C@H]3C[C@@H](O[C@@H]3COP([O-])(=S)O[C@H]3C[C@@H](O[C@@H]3COP([O-])(=S)O[C@H]3C[C@@H](O[C@@H]3COP([O-])(=S)O[C@H]3C[C@@H](O[C@@H]3COP([O-])(=S)O[C@H]3C[C@@H](O[C@@H]3COP([O-])(=S)O[C@H]3C[C@@H](O[C@@H]3COP([O-])(=S)O[C@H]3C[C@@H](O[C@@H]3COP([O-])(=S)O[C@H]3C[C@@H](O[C@@H]3COP([O-])(=S)O[C@H]3C[C@@H](O[C@@H]3COP([O-])(=S)O[C@H]3C[C@@H](O[C@@H]3COP([O-])(=S)O[C@H]3C[C@@H](O[C@@H]3COP([O-])(=S)O[C@H]3C[C@@H](O[C@@H]3COP([O-])(=S)O[C@H]3C[C@@H](O[C@@H]3COP([O-])(=S)O[C@H]3C[C@@H](O[C@@H]3COP([O-])(=S)O[C@H]3C[C@@H](O[C@@H]3CO)n3cc(C)c(=O)[nH]c3=O)n3ccc(N)nc3=O)n3cc(C)c(=O)[nH]c3=O)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3cnc4c3nc(N)[nH]c4=O)n3ccc(N)nc3=O)n3cnc4c3nc(N)[nH]c4=O)n3cc(C)c(=O)[nH]c3=O)n3cnc4c3nc(N)[nH]c4=O)n3ccc(N)nc3=O)n3cnc4c3nc(N)[nH]c4=O)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)O2)c(=O)[nH]c1=O IBXPAFBDJCXCDW-MHFPCNPESA-A 0.000 description 15
- 239000008280 blood Substances 0.000 description 14
- HPLNQCPCUACXLM-PGUFJCEWSA-N ABT-737 Chemical compound C([C@@H](CCN(C)C)NC=1C(=CC(=CC=1)S(=O)(=O)NC(=O)C=1C=CC(=CC=1)N1CCN(CC=2C(=CC=CC=2)C=2C=CC(Cl)=CC=2)CC1)[N+]([O-])=O)SC1=CC=CC=C1 HPLNQCPCUACXLM-PGUFJCEWSA-N 0.000 description 13
- 210000003719 b-lymphocyte Anatomy 0.000 description 13
- 210000004369 blood Anatomy 0.000 description 13
- 229960000435 oblimersen Drugs 0.000 description 13
- 230000008901 benefit Effects 0.000 description 12
- 231100000682 maximum tolerated dose Toxicity 0.000 description 12
- 241000880493 Leptailurus serval Species 0.000 description 11
- 230000000694 effects Effects 0.000 description 11
- 125000005647 linker group Chemical group 0.000 description 11
- 238000004519 manufacturing process Methods 0.000 description 11
- VYXJULKGMXJVGI-XIFFEERXSA-N n-(4-hydroxyphenyl)-3-[6-[(3s)-3-(morpholin-4-ylmethyl)-3,4-dihydro-1h-isoquinoline-2-carbonyl]-1,3-benzodioxol-5-yl]-n-phenyl-5,6,7,8-tetrahydroindolizine-1-carboxamide Chemical compound C1=CC(O)=CC=C1N(C=1C=CC=CC=1)C(=O)C1=C2CCCCN2C(C=2C(=CC=3OCOC=3C=2)C(=O)N2[C@@H](CC3=CC=CC=C3C2)CN2CCOCC2)=C1 VYXJULKGMXJVGI-XIFFEERXSA-N 0.000 description 11
- 210000002966 serum Anatomy 0.000 description 11
- 238000002560 therapeutic procedure Methods 0.000 description 11
- 206010025323 Lymphomas Diseases 0.000 description 10
- 238000012360 testing method Methods 0.000 description 10
- 229950009760 epratuzumab Drugs 0.000 description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- 208000023275 Autoimmune disease Diseases 0.000 description 8
- 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 8
- 108060003951 Immunoglobulin Proteins 0.000 description 8
- 125000000217 alkyl group Chemical group 0.000 description 8
- 239000000562 conjugate Substances 0.000 description 8
- 108010089804 glycyl-threonine Proteins 0.000 description 8
- 108010050848 glycylleucine Proteins 0.000 description 8
- 102000018358 immunoglobulin Human genes 0.000 description 8
- 230000003285 pharmacodynamic effect Effects 0.000 description 8
- 230000001225 therapeutic effect Effects 0.000 description 8
- 230000001988 toxicity Effects 0.000 description 8
- 231100000419 toxicity Toxicity 0.000 description 8
- FEHQLKKBVJHSEC-SZMVWBNQSA-N Leu-Glu-Trp Chemical compound C1=CC=C2C(C[C@H](NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](N)CC(C)C)C(O)=O)=CNC2=C1 FEHQLKKBVJHSEC-SZMVWBNQSA-N 0.000 description 7
- NKANXQFJJICGDU-QPLCGJKRSA-N Tamoxifen Chemical compound C=1C=CC=CC=1C(/CC)=C(C=1C=CC(OCCN(C)C)=CC=1)/C1=CC=CC=C1 NKANXQFJJICGDU-QPLCGJKRSA-N 0.000 description 7
- 108010086434 alanyl-seryl-glycine Proteins 0.000 description 7
- 230000001363 autoimmune Effects 0.000 description 7
- 150000003254 radicals Chemical class 0.000 description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 6
- BYYNJRSNDARRBX-YFKPBYRVSA-N Gly-Gln-Gly Chemical compound NCC(=O)N[C@@H](CCC(N)=O)C(=O)NCC(O)=O BYYNJRSNDARRBX-YFKPBYRVSA-N 0.000 description 6
- SOEGEPHNZOISMT-BYPYZUCNSA-N Gly-Ser-Gly Chemical compound NCC(=O)N[C@@H](CO)C(=O)NCC(O)=O SOEGEPHNZOISMT-BYPYZUCNSA-N 0.000 description 6
- BMKNXTJLHFIAAH-CIUDSAMLSA-N Ser-Ser-Leu Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(O)=O BMKNXTJLHFIAAH-CIUDSAMLSA-N 0.000 description 6
- XJDMUQCLVSCRSJ-VZFHVOOUSA-N Ser-Thr-Ala Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C)C(O)=O XJDMUQCLVSCRSJ-VZFHVOOUSA-N 0.000 description 6
- LGIMRDKGABDMBN-DCAQKATOSA-N Ser-Val-Lys Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CO)N LGIMRDKGABDMBN-DCAQKATOSA-N 0.000 description 6
- UOXPLPBMEPLZBW-WDSOQIARSA-N Trp-Val-Lys Chemical compound C1=CC=C2C(C[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(O)=O)=CNC2=C1 UOXPLPBMEPLZBW-WDSOQIARSA-N 0.000 description 6
- HTONZBWRYUKUKC-RCWTZXSCSA-N Val-Thr-Val Chemical compound CC(C)[C@H](N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(O)=O HTONZBWRYUKUKC-RCWTZXSCSA-N 0.000 description 6
- 108010069926 arginyl-glycyl-serine Proteins 0.000 description 6
- DDRJAANPRJIHGJ-UHFFFAOYSA-N creatinine Chemical compound CN1CC(=O)NC1=N DDRJAANPRJIHGJ-UHFFFAOYSA-N 0.000 description 6
- 238000003745 diagnosis Methods 0.000 description 6
- 108010037850 glycylvaline Proteins 0.000 description 6
- 125000005843 halogen group Chemical group 0.000 description 6
- 239000000463 material Substances 0.000 description 6
- 150000003839 salts Chemical class 0.000 description 6
- OMRPLUKQNWNZAV-CONSDPRKSA-N (6as)-3-[3-[[(6as)-2-methoxy-8-(4-methoxyphenyl)-11-oxo-6a,7-dihydropyrrolo[2,1-c][1,4]benzodiazepin-3-yl]oxy]propoxy]-8-(4-aminophenyl)-2-methoxy-6a,7-dihydropyrrolo[2,1-c][1,4]benzodiazepin-11-one Chemical compound C1=CC(OC)=CC=C1C1=CN2C(=O)C3=CC(OC)=C(OCCCOC=4C(=CC=5C(=O)N6C=C(C[C@H]6C=NC=5C=4)C=4C=CC(N)=CC=4)OC)C=C3N=C[C@@H]2C1 OMRPLUKQNWNZAV-CONSDPRKSA-N 0.000 description 5
- 102100036475 Alanine aminotransferase 1 Human genes 0.000 description 5
- 108010082126 Alanine transaminase Proteins 0.000 description 5
- 108010063104 Apoptosis Regulatory Proteins Proteins 0.000 description 5
- 102000010565 Apoptosis Regulatory Proteins Human genes 0.000 description 5
- 108010003415 Aspartate Aminotransferases Proteins 0.000 description 5
- 102000004625 Aspartate Aminotransferases Human genes 0.000 description 5
- ZFBBMCKQSNJZSN-AUTRQRHGSA-N Gln-Val-Gln Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(N)=O)C(O)=O ZFBBMCKQSNJZSN-AUTRQRHGSA-N 0.000 description 5
- LCNASHSOFMRYFO-WDCWCFNPSA-N Leu-Thr-Gln Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@H](C(O)=O)CCC(N)=O LCNASHSOFMRYFO-WDCWCFNPSA-N 0.000 description 5
- 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 5
- JVTHIXKSVYEWNI-JRQIVUDYSA-N Thr-Asn-Tyr Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O JVTHIXKSVYEWNI-JRQIVUDYSA-N 0.000 description 5
- RMRFSFXLFWWAJZ-HJOGWXRNSA-N Tyr-Tyr-Tyr Chemical compound C([C@H](N)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(O)=O)C1=CC=C(O)C=C1 RMRFSFXLFWWAJZ-HJOGWXRNSA-N 0.000 description 5
- OWFGFHQMSBTKLX-UFYCRDLUSA-N Val-Tyr-Tyr Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC1=CC=C(C=C1)O)C(=O)N[C@@H](CC2=CC=C(C=C2)O)C(=O)O)N OWFGFHQMSBTKLX-UFYCRDLUSA-N 0.000 description 5
- 238000012042 bayesian logistic regression model Methods 0.000 description 5
- 230000009286 beneficial effect Effects 0.000 description 5
- 230000004071 biological effect Effects 0.000 description 5
- 125000004432 carbon atom Chemical group C* 0.000 description 5
- 210000003169 central nervous system Anatomy 0.000 description 5
- 229960004679 doxorubicin Drugs 0.000 description 5
- 230000007717 exclusion Effects 0.000 description 5
- 229960002949 fluorouracil Drugs 0.000 description 5
- XKUKSGPZAADMRA-UHFFFAOYSA-N glycyl-glycyl-glycine Chemical compound NCC(=O)NCC(=O)NCC(O)=O XKUKSGPZAADMRA-UHFFFAOYSA-N 0.000 description 5
- 238000000338 in vitro Methods 0.000 description 5
- 208000014018 liver neoplasm Diseases 0.000 description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 5
- 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 5
- 229960002087 pertuzumab Drugs 0.000 description 5
- 229920001184 polypeptide Polymers 0.000 description 5
- 102000004196 processed proteins & peptides Human genes 0.000 description 5
- 108090000765 processed proteins & peptides Proteins 0.000 description 5
- 241000894007 species Species 0.000 description 5
- 230000009885 systemic effect Effects 0.000 description 5
- JBGSZRYCXBPWGX-BQBZGAKWSA-N Ala-Arg-Gly Chemical compound OC(=O)CNC(=O)[C@@H](NC(=O)[C@@H](N)C)CCCN=C(N)N JBGSZRYCXBPWGX-BQBZGAKWSA-N 0.000 description 4
- REAQAWSENITKJL-DDWPSWQVSA-N Ala-Met-Asp-Tyr Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O REAQAWSENITKJL-DDWPSWQVSA-N 0.000 description 4
- 108010047041 Complementarity Determining Regions Proteins 0.000 description 4
- UQJNXZSSGQIPIQ-FBCQKBJTSA-N Gly-Gly-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)CNC(=O)CN UQJNXZSSGQIPIQ-FBCQKBJTSA-N 0.000 description 4
- FFALDIDGPLUDKV-ZDLURKLDSA-N Gly-Thr-Ser Chemical compound [H]NCC(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(O)=O FFALDIDGPLUDKV-ZDLURKLDSA-N 0.000 description 4
- GBYYQVBXFVDJPJ-WLTAIBSBSA-N Gly-Tyr-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CC1=CC=C(C=C1)O)NC(=O)CN)O GBYYQVBXFVDJPJ-WLTAIBSBSA-N 0.000 description 4
- 208000009329 Graft vs Host Disease Diseases 0.000 description 4
- 108010021625 Immunoglobulin Fragments Proteins 0.000 description 4
- 102000008394 Immunoglobulin Fragments Human genes 0.000 description 4
- 108010065920 Insulin Lispro Proteins 0.000 description 4
- NKKFVJRLCCUJNA-QWRGUYRKSA-N Lys-Gly-Lys Chemical compound NCCCC[C@H](N)C(=O)NCC(=O)N[C@H](C(O)=O)CCCCN NKKFVJRLCCUJNA-QWRGUYRKSA-N 0.000 description 4
- SKRGVGLIRUGANF-AVGNSLFASA-N Lys-Leu-Glu Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(O)=O SKRGVGLIRUGANF-AVGNSLFASA-N 0.000 description 4
- PDIDTSZKKFEDMB-UWVGGRQHSA-N Lys-Pro-Gly Chemical compound [H]N[C@@H](CCCCN)C(=O)N1CCC[C@H]1C(=O)NCC(O)=O PDIDTSZKKFEDMB-UWVGGRQHSA-N 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 4
- 229930012538 Paclitaxel Natural products 0.000 description 4
- GNRMAQSIROFNMI-IXOXFDKPSA-N Phe-Thr-Ser Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(O)=O GNRMAQSIROFNMI-IXOXFDKPSA-N 0.000 description 4
- XXXAXOWMBOKTRN-XPUUQOCRSA-N Ser-Gly-Val Chemical compound [H]N[C@@H](CO)C(=O)NCC(=O)N[C@@H](C(C)C)C(O)=O XXXAXOWMBOKTRN-XPUUQOCRSA-N 0.000 description 4
- ADJDNJCSPNFFPI-FXQIFTODSA-N Ser-Pro-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@@H]1CCCN1C(=O)[C@@H](N)CO ADJDNJCSPNFFPI-FXQIFTODSA-N 0.000 description 4
- FOCVUCIESVLUNU-UHFFFAOYSA-N Thiotepa Chemical compound C1CN1P(N1CC1)(=S)N1CC1 FOCVUCIESVLUNU-UHFFFAOYSA-N 0.000 description 4
- FQPDRTDDEZXCEC-SVSWQMSJSA-N Thr-Ile-Ser Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(O)=O FQPDRTDDEZXCEC-SVSWQMSJSA-N 0.000 description 4
- YOPQYBJJNSIQGZ-JNPHEJMOSA-N Thr-Tyr-Tyr Chemical compound C([C@H](NC(=O)[C@@H](N)[C@H](O)C)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(O)=O)C1=CC=C(O)C=C1 YOPQYBJJNSIQGZ-JNPHEJMOSA-N 0.000 description 4
- SVGAWGVHFIYAEE-JSGCOSHPSA-N Trp-Gly-Gln Chemical compound C1=CC=C2C(C[C@H](N)C(=O)NCC(=O)N[C@@H](CCC(N)=O)C(O)=O)=CNC2=C1 SVGAWGVHFIYAEE-JSGCOSHPSA-N 0.000 description 4
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 description 4
- 125000003342 alkenyl group Chemical group 0.000 description 4
- 125000003118 aryl group Chemical group 0.000 description 4
- 108010092854 aspartyllysine Proteins 0.000 description 4
- 229960000397 bevacizumab Drugs 0.000 description 4
- 230000004663 cell proliferation Effects 0.000 description 4
- 239000003433 contraceptive agent Substances 0.000 description 4
- 230000000875 corresponding effect Effects 0.000 description 4
- 229960004397 cyclophosphamide Drugs 0.000 description 4
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 4
- 231100000433 cytotoxic Toxicity 0.000 description 4
- 230000001472 cytotoxic effect Effects 0.000 description 4
- 210000003743 erythrocyte Anatomy 0.000 description 4
- 239000012634 fragment Substances 0.000 description 4
- 108010063718 gamma-glutamylaspartic acid Proteins 0.000 description 4
- VPZXBVLAVMBEQI-UHFFFAOYSA-N glycyl-DL-alpha-alanine Natural products OC(=O)C(C)NC(=O)CN VPZXBVLAVMBEQI-UHFFFAOYSA-N 0.000 description 4
- 208000024908 graft versus host disease Diseases 0.000 description 4
- 230000012010 growth Effects 0.000 description 4
- 229940088597 hormone Drugs 0.000 description 4
- 239000005556 hormone Substances 0.000 description 4
- 229960001101 ifosfamide Drugs 0.000 description 4
- HOMGKSMUEGBAAB-UHFFFAOYSA-N ifosfamide Chemical compound ClCCNP1(=O)OCCCN1CCCl HOMGKSMUEGBAAB-UHFFFAOYSA-N 0.000 description 4
- 238000002347 injection Methods 0.000 description 4
- 239000007924 injection Substances 0.000 description 4
- 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 4
- 108010044374 isoleucyl-tyrosine Proteins 0.000 description 4
- 210000001165 lymph node Anatomy 0.000 description 4
- 230000003211 malignant effect Effects 0.000 description 4
- 210000004379 membrane Anatomy 0.000 description 4
- 239000012528 membrane Substances 0.000 description 4
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 4
- 229960001156 mitoxantrone Drugs 0.000 description 4
- JLYAXFNOILIKPP-KXQOOQHDSA-N navitoclax Chemical compound C([C@@H](NC1=CC=C(C=C1S(=O)(=O)C(F)(F)F)S(=O)(=O)NC(=O)C1=CC=C(C=C1)N1CCN(CC1)CC1=C(CCC(C1)(C)C)C=1C=CC(Cl)=CC=1)CSC=1C=CC=CC=1)CN1CCOCC1 JLYAXFNOILIKPP-KXQOOQHDSA-N 0.000 description 4
- QZGIWPZCWHMVQL-UIYAJPBUSA-N neocarzinostatin chromophore Chemical compound O1[C@H](C)[C@H](O)[C@H](O)[C@@H](NC)[C@H]1O[C@@H]1C/2=C/C#C[C@H]3O[C@@]3([C@@H]3OC(=O)OC3)C#CC\2=C[C@H]1OC(=O)C1=C(O)C=CC2=C(C)C=C(OC)C=C12 QZGIWPZCWHMVQL-UIYAJPBUSA-N 0.000 description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 238000009806 oophorectomy Methods 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
- 229960001592 paclitaxel Drugs 0.000 description 4
- 229960000402 palivizumab Drugs 0.000 description 4
- 239000008194 pharmaceutical composition Substances 0.000 description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 4
- 108010070643 prolylglutamic acid Proteins 0.000 description 4
- 102000004169 proteins and genes Human genes 0.000 description 4
- 108090000623 proteins and genes Proteins 0.000 description 4
- 125000004076 pyridyl group Chemical group 0.000 description 4
- ZAHRKKWIAAJSAO-UHFFFAOYSA-N rapamycin Natural products COCC(O)C(=C/C(C)C(=O)CC(OC(=O)C1CCCCN1C(=O)C(=O)C2(O)OC(CC(OC)C(=CC=CC=CC(C)CC(C)C(=O)C)C)CCC2C)C(C)CC3CCC(O)C(C3)OC)C ZAHRKKWIAAJSAO-UHFFFAOYSA-N 0.000 description 4
- 229960002930 sirolimus Drugs 0.000 description 4
- QFJCIRLUMZQUOT-HPLJOQBZSA-N sirolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 QFJCIRLUMZQUOT-HPLJOQBZSA-N 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 238000001356 surgical procedure Methods 0.000 description 4
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 4
- 125000001544 thienyl group Chemical group 0.000 description 4
- WYWHKKSPHMUBEB-UHFFFAOYSA-N tioguanine Chemical compound N1C(N)=NC(=S)C2=C1N=CN2 WYWHKKSPHMUBEB-UHFFFAOYSA-N 0.000 description 4
- 229960005486 vaccine Drugs 0.000 description 4
- 108010073969 valyllysine Proteins 0.000 description 4
- 229950009268 zinostatin Drugs 0.000 description 4
- VVIAGPKUTFNRDU-UHFFFAOYSA-N 6S-folinic acid Natural products C1NC=2NC(N)=NC(=O)C=2N(C=O)C1CNC1=CC=C(C(=O)NC(CCC(O)=O)C(O)=O)C=C1 VVIAGPKUTFNRDU-UHFFFAOYSA-N 0.000 description 3
- PMQXMXAASGFUDX-SRVKXCTJSA-N Ala-Lys-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)[C@H](C)N)CCCCN PMQXMXAASGFUDX-SRVKXCTJSA-N 0.000 description 3
- XWFWAXPOLRTDFZ-FXQIFTODSA-N Ala-Pro-Ser Chemical compound C[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CO)C(O)=O XWFWAXPOLRTDFZ-FXQIFTODSA-N 0.000 description 3
- NZGRHTKZFSVPAN-BIIVOSGPSA-N Ala-Ser-Pro Chemical compound C[C@@H](C(=O)N[C@@H](CO)C(=O)N1CCC[C@@H]1C(=O)O)N NZGRHTKZFSVPAN-BIIVOSGPSA-N 0.000 description 3
- IOFVWPYSRSCWHI-JXUBOQSCSA-N Ala-Thr-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](C)N IOFVWPYSRSCWHI-JXUBOQSCSA-N 0.000 description 3
- WVNFNPGXYADPPO-BQBZGAKWSA-N Arg-Gly-Ser Chemical compound NC(N)=NCCC[C@H](N)C(=O)NCC(=O)N[C@@H](CO)C(O)=O WVNFNPGXYADPPO-BQBZGAKWSA-N 0.000 description 3
- AOHKLEBWKMKITA-IHRRRGAJSA-N Arg-Phe-Ser Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)N[C@@H](CO)C(=O)O)NC(=O)[C@H](CCCN=C(N)N)N AOHKLEBWKMKITA-IHRRRGAJSA-N 0.000 description 3
- ADPACBMPYWJJCE-FXQIFTODSA-N Arg-Ser-Asp Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(O)=O)C(O)=O ADPACBMPYWJJCE-FXQIFTODSA-N 0.000 description 3
- POZKLUIXMHIULG-FDARSICLSA-N Arg-Trp-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)[C@H](CC1=CNC2=CC=CC=C21)NC(=O)[C@H](CCCN=C(N)N)N POZKLUIXMHIULG-FDARSICLSA-N 0.000 description 3
- AYKKKGFJXIDYLX-ACZMJKKPSA-N Asn-Gln-Asn Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O AYKKKGFJXIDYLX-ACZMJKKPSA-N 0.000 description 3
- KRXIWXCXOARFNT-ZLUOBGJFSA-N Asp-Ala-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC(O)=O KRXIWXCXOARFNT-ZLUOBGJFSA-N 0.000 description 3
- FAUPLTGRUBTXNU-FXQIFTODSA-N Asp-Pro-Ser Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CO)C(O)=O FAUPLTGRUBTXNU-FXQIFTODSA-N 0.000 description 3
- WMLFFCRUSPNENW-ZLUOBGJFSA-N Asp-Ser-Ala Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](C)C(O)=O WMLFFCRUSPNENW-ZLUOBGJFSA-N 0.000 description 3
- XYPJXLLXNSAWHZ-SRVKXCTJSA-N Asp-Ser-Tyr Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O XYPJXLLXNSAWHZ-SRVKXCTJSA-N 0.000 description 3
- MNQMTYSEKZHIDF-GCJQMDKQSA-N Asp-Thr-Ala Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C)C(O)=O MNQMTYSEKZHIDF-GCJQMDKQSA-N 0.000 description 3
- GCACQYDBDHRVGE-LKXGYXEUSA-N Asp-Thr-Ser Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H]([C@H](O)C)NC(=O)[C@@H](N)CC(O)=O GCACQYDBDHRVGE-LKXGYXEUSA-N 0.000 description 3
- 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 3
- 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 3
- 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 3
- 241000282693 Cercopithecidae Species 0.000 description 3
- 206010009944 Colon cancer Diseases 0.000 description 3
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 3
- VTJLJQGUMBWHBP-GUBZILKMSA-N Cys-His-Gln Chemical compound C1=C(NC=N1)C[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)O)NC(=O)[C@H](CS)N VTJLJQGUMBWHBP-GUBZILKMSA-N 0.000 description 3
- CMYVIUWVYHOLRD-ZLUOBGJFSA-N Cys-Ser-Ala Chemical compound [H]N[C@@H](CS)C(=O)N[C@@H](CO)C(=O)N[C@@H](C)C(O)=O CMYVIUWVYHOLRD-ZLUOBGJFSA-N 0.000 description 3
- UHDGCWIWMRVCDJ-CCXZUQQUSA-N Cytarabine Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O1 UHDGCWIWMRVCDJ-CCXZUQQUSA-N 0.000 description 3
- 206010012735 Diarrhoea Diseases 0.000 description 3
- 241000283073 Equus caballus Species 0.000 description 3
- JOYRKODLDBILNP-UHFFFAOYSA-N Ethyl urethane Chemical compound CCOC(N)=O JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- 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 3
- XOKGKOQWADCLFQ-GARJFASQSA-N Gln-Arg-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CCC(=O)N)N)C(=O)O XOKGKOQWADCLFQ-GARJFASQSA-N 0.000 description 3
- MADFVRSKEIEZHZ-DCAQKATOSA-N Gln-Gln-Lys Chemical compound C(CCN)C[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)N)NC(=O)[C@H](CCC(=O)N)N MADFVRSKEIEZHZ-DCAQKATOSA-N 0.000 description 3
- JXFLPKSDLDEOQK-JHEQGTHGSA-N Gln-Gly-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)CNC(=O)[C@@H](N)CCC(N)=O JXFLPKSDLDEOQK-JHEQGTHGSA-N 0.000 description 3
- DYFJZDDQPNIPAB-NHCYSSNCSA-N Glu-Arg-Val Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C(C)C)C(O)=O DYFJZDDQPNIPAB-NHCYSSNCSA-N 0.000 description 3
- INGJLBQKTRJLFO-UKJIMTQDSA-N Glu-Ile-Val Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)[C@H]([C@@H](C)CC)NC(=O)[C@@H](N)CCC(O)=O INGJLBQKTRJLFO-UKJIMTQDSA-N 0.000 description 3
- GJBUAAAIZSRCDC-GVXVVHGQSA-N Glu-Leu-Val Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(O)=O GJBUAAAIZSRCDC-GVXVVHGQSA-N 0.000 description 3
- SOYWRINXUSUWEQ-DLOVCJGASA-N Glu-Val-Val Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](N)CCC(O)=O SOYWRINXUSUWEQ-DLOVCJGASA-N 0.000 description 3
- PABFFPWEJMEVEC-JGVFFNPUSA-N Gly-Gln-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CCC(=O)N)NC(=O)CN)C(=O)O PABFFPWEJMEVEC-JGVFFNPUSA-N 0.000 description 3
- STVHDEHTKFXBJQ-LAEOZQHASA-N Gly-Glu-Ile Chemical compound [H]NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O STVHDEHTKFXBJQ-LAEOZQHASA-N 0.000 description 3
- FOCSWPCHUDVNLP-PMVMPFDFSA-N His-Trp-Tyr Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)N[C@@H](CC3=CC=C(C=C3)O)C(=O)O)NC(=O)[C@H](CC4=CN=CN4)N FOCSWPCHUDVNLP-PMVMPFDFSA-N 0.000 description 3
- 206010020751 Hypersensitivity Diseases 0.000 description 3
- NPAYJTAXWXJKLO-NAKRPEOUSA-N Ile-Met-Ser Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CO)C(=O)O)N NPAYJTAXWXJKLO-NAKRPEOUSA-N 0.000 description 3
- PXKACEXYLPBMAD-JBDRJPRFSA-N Ile-Ser-Ser Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)O)N PXKACEXYLPBMAD-JBDRJPRFSA-N 0.000 description 3
- 208000008839 Kidney Neoplasms Diseases 0.000 description 3
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 3
- KIZIOFNVSOSKJI-CIUDSAMLSA-N Leu-Ser-Cys Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CS)C(=O)O)N KIZIOFNVSOSKJI-CIUDSAMLSA-N 0.000 description 3
- MVJRBCJCRYGCKV-GVXVVHGQSA-N Leu-Val-Gln Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(N)=O)C(O)=O MVJRBCJCRYGCKV-GVXVVHGQSA-N 0.000 description 3
- UWKNTTJNVSYXPC-CIUDSAMLSA-N Lys-Ala-Ser Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CCCCN UWKNTTJNVSYXPC-CIUDSAMLSA-N 0.000 description 3
- MYZMQWHPDAYKIE-SRVKXCTJSA-N Lys-Leu-Ala Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C)C(O)=O MYZMQWHPDAYKIE-SRVKXCTJSA-N 0.000 description 3
- AIRZWUMAHCDDHR-KKUMJFAQSA-N Lys-Leu-Leu Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O AIRZWUMAHCDDHR-KKUMJFAQSA-N 0.000 description 3
- MIFFFXHMAHFACR-KATARQTJSA-N Lys-Ser-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CCCCN MIFFFXHMAHFACR-KATARQTJSA-N 0.000 description 3
- RMOKGALPSPOYKE-KATARQTJSA-N Lys-Thr-Ser Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(O)=O RMOKGALPSPOYKE-KATARQTJSA-N 0.000 description 3
- OGAZPKJHHZPYFK-GARJFASQSA-N Met-Glu-Pro Chemical compound CSCC[C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)N1CCC[C@@H]1C(=O)O)N OGAZPKJHHZPYFK-GARJFASQSA-N 0.000 description 3
- OOSPRDCGTLQLBP-NHCYSSNCSA-N Met-Glu-Val Chemical compound [H]N[C@@H](CCSC)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(O)=O OOSPRDCGTLQLBP-NHCYSSNCSA-N 0.000 description 3
- 206010027476 Metastases Diseases 0.000 description 3
- 241001529936 Murinae Species 0.000 description 3
- 241000283973 Oryctolagus cuniculus Species 0.000 description 3
- 206010033128 Ovarian cancer Diseases 0.000 description 3
- 206010061535 Ovarian neoplasm Diseases 0.000 description 3
- 239000012828 PI3K inhibitor Substances 0.000 description 3
- BPCLGWHVPVTTFM-QWRGUYRKSA-N Phe-Ser-Gly Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CO)C(=O)NCC(O)=O BPCLGWHVPVTTFM-QWRGUYRKSA-N 0.000 description 3
- VXCHGLYSIOOZIS-GUBZILKMSA-N Pro-Ala-Arg Chemical compound NC(N)=NCCC[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H]1CCCN1 VXCHGLYSIOOZIS-GUBZILKMSA-N 0.000 description 3
- CLNJSLSHKJECME-BQBZGAKWSA-N Pro-Gly-Ala Chemical compound OC(=O)[C@H](C)NC(=O)CNC(=O)[C@@H]1CCCN1 CLNJSLSHKJECME-BQBZGAKWSA-N 0.000 description 3
- AFXCXDQNRXTSBD-FJXKBIBVSA-N Pro-Gly-Thr Chemical compound [H]N1CCC[C@H]1C(=O)NCC(=O)N[C@@H]([C@@H](C)O)C(O)=O AFXCXDQNRXTSBD-FJXKBIBVSA-N 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 201000004681 Psoriasis Diseases 0.000 description 3
- 206010038389 Renal cancer Diseases 0.000 description 3
- DKKGAAJTDKHWOD-BIIVOSGPSA-N Ser-Asn-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CC(=O)N)NC(=O)[C@H](CO)N)C(=O)O DKKGAAJTDKHWOD-BIIVOSGPSA-N 0.000 description 3
- YUJLIIRMIAGMCQ-CIUDSAMLSA-N Ser-Leu-Ser Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(O)=O YUJLIIRMIAGMCQ-CIUDSAMLSA-N 0.000 description 3
- MUJQWSAWLLRJCE-KATARQTJSA-N Ser-Leu-Thr Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O MUJQWSAWLLRJCE-KATARQTJSA-N 0.000 description 3
- FPCGZYMRFFIYIH-CIUDSAMLSA-N Ser-Lys-Ser Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CO)C(O)=O FPCGZYMRFFIYIH-CIUDSAMLSA-N 0.000 description 3
- NUEHQDHDLDXCRU-GUBZILKMSA-N Ser-Pro-Arg Chemical compound OC[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCCN=C(N)N)C(O)=O NUEHQDHDLDXCRU-GUBZILKMSA-N 0.000 description 3
- SRSPTFBENMJHMR-WHFBIAKZSA-N Ser-Ser-Gly Chemical compound OC[C@H](N)C(=O)N[C@@H](CO)C(=O)NCC(O)=O SRSPTFBENMJHMR-WHFBIAKZSA-N 0.000 description 3
- BPEGJWRSRHCHSN-UHFFFAOYSA-N Temozolomide Chemical compound O=C1N(C)N=NC2=C(C(N)=O)N=CN21 BPEGJWRSRHCHSN-UHFFFAOYSA-N 0.000 description 3
- SPVHQURZJCUDQC-VOAKCMCISA-N Thr-Lys-Leu Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(O)=O SPVHQURZJCUDQC-VOAKCMCISA-N 0.000 description 3
- KPNSNVTUVKSBFL-ZJDVBMNYSA-N Thr-Met-Thr Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCSC)C(=O)N[C@@H]([C@@H](C)O)C(=O)O)N)O KPNSNVTUVKSBFL-ZJDVBMNYSA-N 0.000 description 3
- HUPLKEHTTQBXSC-YJRXYDGGSA-N Thr-Ser-Tyr Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 HUPLKEHTTQBXSC-YJRXYDGGSA-N 0.000 description 3
- FYBFTPLPAXZBOY-KKHAAJSZSA-N Thr-Val-Asp Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(O)=O)C(O)=O FYBFTPLPAXZBOY-KKHAAJSZSA-N 0.000 description 3
- 238000008050 Total Bilirubin Reagent Methods 0.000 description 3
- KCZGSXPFPNKGLE-WDSOQIARSA-N Trp-Met-His Chemical compound CSCC[C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)NC(=O)[C@H](CC2=CNC3=CC=CC=C32)N KCZGSXPFPNKGLE-WDSOQIARSA-N 0.000 description 3
- MQGGXGKQSVEQHR-KKUMJFAQSA-N Tyr-Ser-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 MQGGXGKQSVEQHR-KKUMJFAQSA-N 0.000 description 3
- LDKDSFQSEUOCOO-RPTUDFQQSA-N Tyr-Thr-Phe Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O LDKDSFQSEUOCOO-RPTUDFQQSA-N 0.000 description 3
- IQQYYFPCWKWUHW-YDHLFZDLSA-N Val-Asn-Tyr Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CC1=CC=C(C=C1)O)C(=O)O)N IQQYYFPCWKWUHW-YDHLFZDLSA-N 0.000 description 3
- 230000002159 abnormal effect Effects 0.000 description 3
- 230000005856 abnormality Effects 0.000 description 3
- 108010081404 acein-2 Proteins 0.000 description 3
- 239000004480 active ingredient Substances 0.000 description 3
- 108010005233 alanylglutamic acid Proteins 0.000 description 3
- 150000001413 amino acids Chemical group 0.000 description 3
- 229960003437 aminoglutethimide Drugs 0.000 description 3
- ROBVIMPUHSLWNV-UHFFFAOYSA-N aminoglutethimide Chemical compound C=1C=C(N)C=CC=1C1(CC)CCC(=O)NC1=O ROBVIMPUHSLWNV-UHFFFAOYSA-N 0.000 description 3
- 239000003242 anti bacterial agent Substances 0.000 description 3
- 229940088710 antibiotic agent Drugs 0.000 description 3
- 108010068380 arginylarginine Proteins 0.000 description 3
- 108010040443 aspartyl-aspartic acid Proteins 0.000 description 3
- VSRXQHXAPYXROS-UHFFFAOYSA-N azanide;cyclobutane-1,1-dicarboxylic acid;platinum(2+) Chemical compound [NH2-].[NH2-].[Pt+2].OC(=O)C1(C(O)=O)CCC1 VSRXQHXAPYXROS-UHFFFAOYSA-N 0.000 description 3
- 210000001124 body fluid Anatomy 0.000 description 3
- 229960004117 capecitabine Drugs 0.000 description 3
- 239000000969 carrier Substances 0.000 description 3
- 230000003833 cell viability Effects 0.000 description 3
- 229960003115 certolizumab pegol Drugs 0.000 description 3
- 229960004630 chlorambucil Drugs 0.000 description 3
- JCKYGMPEJWAADB-UHFFFAOYSA-N chlorambucil Chemical compound OC(=O)CCCC1=CC=C(N(CCCl)CCCl)C=C1 JCKYGMPEJWAADB-UHFFFAOYSA-N 0.000 description 3
- 230000002254 contraceptive effect Effects 0.000 description 3
- 229940109239 creatinine Drugs 0.000 description 3
- 238000004132 cross linking Methods 0.000 description 3
- 239000002254 cytotoxic agent Substances 0.000 description 3
- 230000003247 decreasing effect Effects 0.000 description 3
- 210000004443 dendritic cell Anatomy 0.000 description 3
- 239000002552 dosage form Substances 0.000 description 3
- FSIRXIHZBIXHKT-MHTVFEQDSA-N edatrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CC(CC)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FSIRXIHZBIXHKT-MHTVFEQDSA-N 0.000 description 3
- 229950006700 edatrexate Drugs 0.000 description 3
- 229930013356 epothilone Natural products 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- ODKNJVUHOIMIIZ-RRKCRQDMSA-N floxuridine Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(F)=C1 ODKNJVUHOIMIIZ-RRKCRQDMSA-N 0.000 description 3
- VVIAGPKUTFNRDU-ABLWVSNPSA-N folinic acid Chemical compound C1NC=2NC(N)=NC(=O)C=2N(C=O)C1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 VVIAGPKUTFNRDU-ABLWVSNPSA-N 0.000 description 3
- 235000008191 folinic acid Nutrition 0.000 description 3
- 239000011672 folinic acid Substances 0.000 description 3
- 229960002258 fulvestrant Drugs 0.000 description 3
- 230000006870 function Effects 0.000 description 3
- 230000002489 hematologic effect Effects 0.000 description 3
- 230000003054 hormonal effect Effects 0.000 description 3
- 230000009610 hypersensitivity Effects 0.000 description 3
- 208000026278 immune system disease Diseases 0.000 description 3
- 238000001727 in vivo Methods 0.000 description 3
- 238000011534 incubation Methods 0.000 description 3
- 230000008595 infiltration Effects 0.000 description 3
- 238000001764 infiltration Methods 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 210000003734 kidney Anatomy 0.000 description 3
- 201000010982 kidney cancer Diseases 0.000 description 3
- BCFGMOOMADDAQU-UHFFFAOYSA-N lapatinib Chemical compound O1C(CNCCS(=O)(=O)C)=CC=C1C1=CC=C(N=CN=C2NC=3C=C(Cl)C(OCC=4C=C(F)C=CC=4)=CC=3)C2=C1 BCFGMOOMADDAQU-UHFFFAOYSA-N 0.000 description 3
- GOTYRUGSSMKFNF-UHFFFAOYSA-N lenalidomide Chemical compound C1C=2C(N)=CC=CC=2C(=O)N1C1CCC(=O)NC1=O GOTYRUGSSMKFNF-UHFFFAOYSA-N 0.000 description 3
- 229960004942 lenalidomide Drugs 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
- 229960001691 leucovorin Drugs 0.000 description 3
- 210000000265 leukocyte Anatomy 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 230000036210 malignancy Effects 0.000 description 3
- GLVAUDGFNGKCSF-UHFFFAOYSA-N mercaptopurine Chemical compound S=C1NC=NC2=C1NC=N2 GLVAUDGFNGKCSF-UHFFFAOYSA-N 0.000 description 3
- 229960000485 methotrexate Drugs 0.000 description 3
- 239000002829 mitogen activated protein kinase inhibitor Substances 0.000 description 3
- 229960004857 mitomycin Drugs 0.000 description 3
- 239000013642 negative control Substances 0.000 description 3
- 108020004707 nucleic acids Proteins 0.000 description 3
- 102000039446 nucleic acids Human genes 0.000 description 3
- 150000007523 nucleic acids Chemical class 0.000 description 3
- 229910052760 oxygen Inorganic materials 0.000 description 3
- 229960005184 panobinostat Drugs 0.000 description 3
- FWZRWHZDXBDTFK-ZHACJKMWSA-N panobinostat Chemical compound CC1=NC2=CC=C[CH]C2=C1CCNCC1=CC=C(\C=C\C(=O)NO)C=C1 FWZRWHZDXBDTFK-ZHACJKMWSA-N 0.000 description 3
- 230000036961 partial effect Effects 0.000 description 3
- 210000003819 peripheral blood mononuclear cell Anatomy 0.000 description 3
- 108010070409 phenylalanyl-glycyl-glycine Proteins 0.000 description 3
- 229940043441 phosphoinositide 3-kinase inhibitor Drugs 0.000 description 3
- 230000035935 pregnancy Effects 0.000 description 3
- 108010029020 prolylglycine Proteins 0.000 description 3
- 235000018102 proteins Nutrition 0.000 description 3
- 238000011002 quantification Methods 0.000 description 3
- 238000001959 radiotherapy Methods 0.000 description 3
- 229960004622 raloxifene Drugs 0.000 description 3
- GZUITABIAKMVPG-UHFFFAOYSA-N raloxifene Chemical compound C1=CC(O)=CC=C1C1=C(C(=O)C=2C=CC(OCCN3CCCCC3)=CC=2)C2=CC=C(O)C=C2S1 GZUITABIAKMVPG-UHFFFAOYSA-N 0.000 description 3
- 108010071207 serylmethionine Proteins 0.000 description 3
- 229960003787 sorafenib Drugs 0.000 description 3
- 206010041823 squamous cell carcinoma Diseases 0.000 description 3
- 238000010186 staining Methods 0.000 description 3
- 238000011301 standard therapy Methods 0.000 description 3
- 150000003431 steroids Chemical class 0.000 description 3
- 229910052717 sulfur Inorganic materials 0.000 description 3
- 208000024891 symptom Diseases 0.000 description 3
- 229960001603 tamoxifen Drugs 0.000 description 3
- 229960001196 thiotepa Drugs 0.000 description 3
- 108010072986 threonyl-seryl-lysine Proteins 0.000 description 3
- 229960000575 trastuzumab Drugs 0.000 description 3
- 238000011269 treatment regimen Methods 0.000 description 3
- 210000004881 tumor cell Anatomy 0.000 description 3
- 208000035408 type 1 diabetes mellitus 1 Diseases 0.000 description 3
- LQBVNQSMGBZMKD-UHFFFAOYSA-N venetoclax Chemical compound C=1C=C(Cl)C=CC=1C=1CC(C)(C)CCC=1CN(CC1)CCN1C(C=C1OC=2C=C3C=CNC3=NC=2)=CC=C1C(=O)NS(=O)(=O)C(C=C1[N+]([O-])=O)=CC=C1NCC1CCOCC1 LQBVNQSMGBZMKD-UHFFFAOYSA-N 0.000 description 3
- 230000002861 ventricular Effects 0.000 description 3
- 229960004528 vincristine Drugs 0.000 description 3
- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 description 3
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 description 3
- LMGGOGHEVZMZCU-FGJMKEJPSA-N (2s,4s)-4-[(2r,4s,5s,6s)-4-amino-5-hydroxy-6-methyloxan-2-yl]oxy-2,5,7,12-tetrahydroxy-6,11-dioxo-3,4-dihydro-1h-tetracene-2-carboxylic acid Chemical compound C1[C@H](N)[C@H](O)[C@H](C)O[C@H]1O[C@@H]1C2=C(O)C(C(=O)C3=C(O)C=CC=C3C3=O)=C3C(O)=C2C[C@@](O)(C(O)=O)C1 LMGGOGHEVZMZCU-FGJMKEJPSA-N 0.000 description 2
- CGMTUJFWROPELF-YPAAEMCBSA-N (3E,5S)-5-[(2S)-butan-2-yl]-3-(1-hydroxyethylidene)pyrrolidine-2,4-dione Chemical compound CC[C@H](C)[C@@H]1NC(=O)\C(=C(/C)O)C1=O CGMTUJFWROPELF-YPAAEMCBSA-N 0.000 description 2
- FPVKHBSQESCIEP-UHFFFAOYSA-N (8S)-3-(2-deoxy-beta-D-erythro-pentofuranosyl)-3,6,7,8-tetrahydroimidazo[4,5-d][1,3]diazepin-8-ol Natural products C1C(O)C(CO)OC1N1C(NC=NCC2O)=C2N=C1 FPVKHBSQESCIEP-UHFFFAOYSA-N 0.000 description 2
- IEXUMDBQLIVNHZ-YOUGDJEHSA-N (8s,11r,13r,14s,17s)-11-[4-(dimethylamino)phenyl]-17-hydroxy-17-(3-hydroxypropyl)-13-methyl-1,2,6,7,8,11,12,14,15,16-decahydrocyclopenta[a]phenanthren-3-one Chemical compound C1=CC(N(C)C)=CC=C1[C@@H]1C2=C3CCC(=O)C=C3CC[C@H]2[C@H](CC[C@]2(O)CCCO)[C@@]2(C)C1 IEXUMDBQLIVNHZ-YOUGDJEHSA-N 0.000 description 2
- FDKXTQMXEQVLRF-ZHACJKMWSA-N (E)-dacarbazine Chemical compound CN(C)\N=N\c1[nH]cnc1C(N)=O FDKXTQMXEQVLRF-ZHACJKMWSA-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
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 2
- AZQWKYJCGOJGHM-UHFFFAOYSA-N 1,4-benzoquinone Chemical compound O=C1C=CC(=O)C=C1 AZQWKYJCGOJGHM-UHFFFAOYSA-N 0.000 description 2
- BTOTXLJHDSNXMW-POYBYMJQSA-N 2,3-dideoxyuridine Chemical compound O1[C@H](CO)CC[C@@H]1N1C(=O)NC(=O)C=C1 BTOTXLJHDSNXMW-POYBYMJQSA-N 0.000 description 2
- QCXJFISCRQIYID-IAEPZHFASA-N 2-amino-1-n-[(3s,6s,7r,10s,16s)-3-[(2s)-butan-2-yl]-7,11,14-trimethyl-2,5,9,12,15-pentaoxo-10-propan-2-yl-8-oxa-1,4,11,14-tetrazabicyclo[14.3.0]nonadecan-6-yl]-4,6-dimethyl-3-oxo-9-n-[(3s,6s,7r,10s,16s)-7,11,14-trimethyl-2,5,9,12,15-pentaoxo-3,10-di(propa Chemical compound C[C@H]1OC(=O)[C@H](C(C)C)N(C)C(=O)CN(C)C(=O)[C@@H]2CCCN2C(=O)[C@H](C(C)C)NC(=O)[C@H]1NC(=O)C1=C(N=C2C(C(=O)N[C@@H]3C(=O)N[C@H](C(N4CCC[C@H]4C(=O)N(C)CC(=O)N(C)[C@@H](C(C)C)C(=O)O[C@@H]3C)=O)[C@@H](C)CC)=C(N)C(=O)C(C)=C2O2)C2=C(C)C=C1 QCXJFISCRQIYID-IAEPZHFASA-N 0.000 description 2
- 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
- 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 2
- CLPFFLWZZBQMAO-UHFFFAOYSA-N 4-(5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-5-yl)benzonitrile Chemical compound C1=CC(C#N)=CC=C1C1N2C=NC=C2CCC1 CLPFFLWZZBQMAO-UHFFFAOYSA-N 0.000 description 2
- TVZGACDUOSZQKY-LBPRGKRZSA-N 4-aminofolic acid Chemical compound C1=NC2=NC(N)=NC(N)=C2N=C1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 TVZGACDUOSZQKY-LBPRGKRZSA-N 0.000 description 2
- NMUSYJAQQFHJEW-KVTDHHQDSA-N 5-azacytidine Chemical compound O=C1N=C(N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 NMUSYJAQQFHJEW-KVTDHHQDSA-N 0.000 description 2
- 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
- JBVSSSZFNTXJDX-YTLHQDLWSA-N Ala-Ala-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@H](C)N JBVSSSZFNTXJDX-YTLHQDLWSA-N 0.000 description 2
- VHEVVUZDDUCAKU-FXQIFTODSA-N Ala-Met-Asp Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(O)=O VHEVVUZDDUCAKU-FXQIFTODSA-N 0.000 description 2
- KLALXKYLOMZDQT-ZLUOBGJFSA-N Ala-Ser-Asn Chemical compound C[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@H](C(O)=O)CC(N)=O KLALXKYLOMZDQT-ZLUOBGJFSA-N 0.000 description 2
- 102000002260 Alkaline Phosphatase Human genes 0.000 description 2
- 108020004774 Alkaline Phosphatase Proteins 0.000 description 2
- CEIZFXOZIQNICU-UHFFFAOYSA-N Alternaria alternata Crofton-weed toxin Natural products CCC(C)C1NC(=O)C(C(C)=O)=C1O CEIZFXOZIQNICU-UHFFFAOYSA-N 0.000 description 2
- 208000002267 Anti-neutrophil cytoplasmic antibody-associated vasculitis Diseases 0.000 description 2
- UXJCMQFPDWCHKX-DCAQKATOSA-N Arg-Arg-Glu Chemical compound NC(N)=NCCC[C@H](N)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CCC(O)=O)C(O)=O UXJCMQFPDWCHKX-DCAQKATOSA-N 0.000 description 2
- HGKHPCFTRQDHCU-IUCAKERBSA-N Arg-Pro-Gly Chemical compound NC(N)=NCCC[C@H](N)C(=O)N1CCC[C@H]1C(=O)NCC(O)=O HGKHPCFTRQDHCU-IUCAKERBSA-N 0.000 description 2
- UVTGNSWSRSCPLP-UHFFFAOYSA-N Arg-Tyr Natural products NC(CCNC(=N)N)C(=O)NC(Cc1ccc(O)cc1)C(=O)O UVTGNSWSRSCPLP-UHFFFAOYSA-N 0.000 description 2
- OLVIPTLKNSAYRJ-YUMQZZPRSA-N Asn-Gly-Lys Chemical compound C(CCN)C[C@@H](C(=O)O)NC(=O)CNC(=O)[C@H](CC(=O)N)N OLVIPTLKNSAYRJ-YUMQZZPRSA-N 0.000 description 2
- WBDWQKRLTVCDSY-WHFBIAKZSA-N Asp-Gly-Asp Chemical compound OC(=O)C[C@H](N)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(O)=O WBDWQKRLTVCDSY-WHFBIAKZSA-N 0.000 description 2
- USNJAPJZSGTTPX-XVSYOHENSA-N Asp-Phe-Thr Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H]([C@@H](C)O)C(O)=O USNJAPJZSGTTPX-XVSYOHENSA-N 0.000 description 2
- 201000001320 Atherosclerosis Diseases 0.000 description 2
- 206010003658 Atrial Fibrillation Diseases 0.000 description 2
- 108091008875 B cell receptors Proteins 0.000 description 2
- 208000003950 B-cell lymphoma Diseases 0.000 description 2
- 208000023328 Basedow disease Diseases 0.000 description 2
- VGGGPCQERPFHOB-MCIONIFRSA-N Bestatin Chemical compound CC(C)C[C@H](C(O)=O)NC(=O)[C@@H](O)[C@H](N)CC1=CC=CC=C1 VGGGPCQERPFHOB-MCIONIFRSA-N 0.000 description 2
- BPYKTIZUTYGOLE-IFADSCNNSA-N Bilirubin Chemical compound N1C(=O)C(C)=C(C=C)\C1=C\C1=C(C)C(CCC(O)=O)=C(CC2=C(C(C)=C(\C=C/3C(=C(C=C)C(=O)N\3)C)N2)CCC(O)=O)N1 BPYKTIZUTYGOLE-IFADSCNNSA-N 0.000 description 2
- 206010005003 Bladder cancer Diseases 0.000 description 2
- 241000283690 Bos taurus Species 0.000 description 2
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 2
- 241000219198 Brassica Species 0.000 description 2
- 235000003351 Brassica cretica Nutrition 0.000 description 2
- 235000003343 Brassica rupestris Nutrition 0.000 description 2
- 206010006187 Breast cancer Diseases 0.000 description 2
- 208000026310 Breast neoplasm Diseases 0.000 description 2
- MBABCNBNDNGODA-LTGLSHGVSA-N Bullatacin Natural products O=C1C(C[C@H](O)CCCCCCCCCC[C@@H](O)[C@@H]2O[C@@H]([C@@H]3O[C@H]([C@@H](O)CCCCCCCCCC)CC3)CC2)=C[C@H](C)O1 MBABCNBNDNGODA-LTGLSHGVSA-N 0.000 description 2
- 206010006580 Bundle branch block left Diseases 0.000 description 2
- 102100027221 CD81 antigen Human genes 0.000 description 2
- SHHKQEUPHAENFK-UHFFFAOYSA-N Carboquone Chemical compound O=C1C(C)=C(N2CC2)C(=O)C(C(COC(N)=O)OC)=C1N1CC1 SHHKQEUPHAENFK-UHFFFAOYSA-N 0.000 description 2
- 201000009030 Carcinoma Diseases 0.000 description 2
- AOCCBINRVIKJHY-UHFFFAOYSA-N Carmofur Chemical compound CCCCCCNC(=O)N1C=C(F)C(=O)NC1=O AOCCBINRVIKJHY-UHFFFAOYSA-N 0.000 description 2
- DLGOEMSEDOSKAD-UHFFFAOYSA-N Carmustine Chemical compound ClCCNC(=O)N(N=O)CCCl DLGOEMSEDOSKAD-UHFFFAOYSA-N 0.000 description 2
- JWBOIMRXGHLCPP-UHFFFAOYSA-N Chloditan Chemical compound C=1C=CC=C(Cl)C=1C(C(Cl)Cl)C1=CC=C(Cl)C=C1 JWBOIMRXGHLCPP-UHFFFAOYSA-N 0.000 description 2
- 206010009900 Colitis ulcerative Diseases 0.000 description 2
- OZHXXYOHPLLLMI-CIUDSAMLSA-N Cys-Lys-Ala Chemical compound [H]N[C@@H](CS)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(O)=O OZHXXYOHPLLLMI-CIUDSAMLSA-N 0.000 description 2
- 108020004414 DNA Proteins 0.000 description 2
- 108010092160 Dactinomycin Proteins 0.000 description 2
- 108010013198 Daptomycin 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
- ZQZFYGIXNQKOAV-OCEACIFDSA-N Droloxifene Chemical compound C=1C=CC=CC=1C(/CC)=C(C=1C=C(O)C=CC=1)\C1=CC=C(OCCN(C)C)C=C1 ZQZFYGIXNQKOAV-OCEACIFDSA-N 0.000 description 2
- SAMRUMKYXPVKPA-VFKOLLTISA-N Enocitabine Chemical compound O=C1N=C(NC(=O)CCCCCCCCCCCCCCCCCCCCC)C=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O1 SAMRUMKYXPVKPA-VFKOLLTISA-N 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- 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 2
- HKVAMNSJSFKALM-GKUWKFKPSA-N Everolimus Chemical compound C1C[C@@H](OCCO)[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 HKVAMNSJSFKALM-GKUWKFKPSA-N 0.000 description 2
- 206010017993 Gastrointestinal neoplasms Diseases 0.000 description 2
- 208000009139 Gilbert Disease Diseases 0.000 description 2
- 208000022412 Gilbert syndrome Diseases 0.000 description 2
- OYTPNWYZORARHL-XHNCKOQMSA-N Gln-Ala-Pro Chemical compound C[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](CCC(=O)N)N OYTPNWYZORARHL-XHNCKOQMSA-N 0.000 description 2
- RGXXLQWXBFNXTG-CIUDSAMLSA-N Gln-Arg-Ala Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(O)=O RGXXLQWXBFNXTG-CIUDSAMLSA-N 0.000 description 2
- RBWKVOSARCFSQQ-FXQIFTODSA-N Gln-Gln-Ser Chemical compound NC(=O)CC[C@H](N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CO)C(O)=O RBWKVOSARCFSQQ-FXQIFTODSA-N 0.000 description 2
- XSBGUANSZDGULP-IUCAKERBSA-N Gln-Gly-Lys Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)NCC(=O)N[C@@H](CCCCN)C(O)=O XSBGUANSZDGULP-IUCAKERBSA-N 0.000 description 2
- KKCJHBXMYYVWMX-KQXIARHKSA-N Gln-Ile-Pro Chemical compound CC[C@H](C)[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](CCC(=O)N)N KKCJHBXMYYVWMX-KQXIARHKSA-N 0.000 description 2
- 206010018364 Glomerulonephritis Diseases 0.000 description 2
- CKOFNWCLWRYUHK-XHNCKOQMSA-N Glu-Asp-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CC(=O)O)NC(=O)[C@H](CCC(=O)O)N)C(=O)O CKOFNWCLWRYUHK-XHNCKOQMSA-N 0.000 description 2
- XTZDZAXYPDISRR-MNXVOIDGSA-N Glu-Ile-Lys Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CCC(=O)O)N XTZDZAXYPDISRR-MNXVOIDGSA-N 0.000 description 2
- VNCNWQPIQYAMAK-ACZMJKKPSA-N Glu-Ser-Ser Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(O)=O VNCNWQPIQYAMAK-ACZMJKKPSA-N 0.000 description 2
- LCNXZQROPKFGQK-WHFBIAKZSA-N Gly-Asp-Ser Chemical compound NCC(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(O)=O LCNXZQROPKFGQK-WHFBIAKZSA-N 0.000 description 2
- BPQYBFAXRGMGGY-LAEOZQHASA-N Gly-Gln-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)N)NC(=O)CN BPQYBFAXRGMGGY-LAEOZQHASA-N 0.000 description 2
- BHPQOIPBLYJNAW-NGZCFLSTSA-N Gly-Ile-Pro Chemical compound CC[C@H](C)[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)CN BHPQOIPBLYJNAW-NGZCFLSTSA-N 0.000 description 2
- FFJQHWKSGAWSTJ-BFHQHQDPSA-N Gly-Thr-Ala Chemical compound [H]NCC(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C)C(O)=O FFJQHWKSGAWSTJ-BFHQHQDPSA-N 0.000 description 2
- UIQGJYUEQDOODF-KWQFWETISA-N Gly-Tyr-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)CN)CC1=CC=C(O)C=C1 UIQGJYUEQDOODF-KWQFWETISA-N 0.000 description 2
- SBVMXEZQJVUARN-XPUUQOCRSA-N Gly-Val-Ser Chemical compound NCC(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CO)C(O)=O SBVMXEZQJVUARN-XPUUQOCRSA-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
- 208000015023 Graves' disease Diseases 0.000 description 2
- 206010019695 Hepatic neoplasm Diseases 0.000 description 2
- 208000005176 Hepatitis C Diseases 0.000 description 2
- 101000914479 Homo sapiens CD81 antigen Proteins 0.000 description 2
- 241000725303 Human immunodeficiency virus Species 0.000 description 2
- VSNHCAURESNICA-UHFFFAOYSA-N Hydroxyurea Chemical compound NC(=O)NO VSNHCAURESNICA-UHFFFAOYSA-N 0.000 description 2
- MPBVHIBUJCELCL-UHFFFAOYSA-N Ibandronate Chemical compound CCCCCN(C)CCC(O)(P(O)(O)=O)P(O)(O)=O MPBVHIBUJCELCL-UHFFFAOYSA-N 0.000 description 2
- 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 2
- 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 2
- FBGXMKUWQFPHFB-JBDRJPRFSA-N Ile-Ser-Cys Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CS)C(=O)O)N FBGXMKUWQFPHFB-JBDRJPRFSA-N 0.000 description 2
- OMDWJWGZGMCQND-CFMVVWHZSA-N Ile-Tyr-Asp Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC1=CC=C(C=C1)O)C(=O)N[C@@H](CC(=O)O)C(=O)O)N OMDWJWGZGMCQND-CFMVVWHZSA-N 0.000 description 2
- 208000022559 Inflammatory bowel disease Diseases 0.000 description 2
- 206010051792 Infusion related reaction Diseases 0.000 description 2
- 239000005411 L01XE02 - Gefitinib Substances 0.000 description 2
- 239000005551 L01XE03 - Erlotinib Substances 0.000 description 2
- 239000005511 L01XE05 - Sorafenib Substances 0.000 description 2
- 239000002136 L01XE07 - Lapatinib Substances 0.000 description 2
- 239000003798 L01XE11 - Pazopanib Substances 0.000 description 2
- 229920001491 Lentinan Polymers 0.000 description 2
- OXKYZSRZKBTVEY-ZPFDUUQYSA-N Leu-Asn-Ile Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O OXKYZSRZKBTVEY-ZPFDUUQYSA-N 0.000 description 2
- KAFOIVJDVSZUMD-DCAQKATOSA-N Leu-Gln-Gln Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(O)=O KAFOIVJDVSZUMD-DCAQKATOSA-N 0.000 description 2
- KAFOIVJDVSZUMD-UHFFFAOYSA-N Leu-Gln-Gln Natural products CC(C)CC(N)C(=O)NC(CCC(N)=O)C(=O)NC(CCC(N)=O)C(O)=O KAFOIVJDVSZUMD-UHFFFAOYSA-N 0.000 description 2
- GPICTNQYKHHHTH-GUBZILKMSA-N Leu-Gln-Ser Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CO)C(O)=O GPICTNQYKHHHTH-GUBZILKMSA-N 0.000 description 2
- IAJFFZORSWOZPQ-SRVKXCTJSA-N Leu-Leu-Asn Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(O)=O IAJFFZORSWOZPQ-SRVKXCTJSA-N 0.000 description 2
- VKVDRTGWLVZJOM-DCAQKATOSA-N Leu-Val-Ser Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CO)C(O)=O VKVDRTGWLVZJOM-DCAQKATOSA-N 0.000 description 2
- 108010000817 Leuprolide Proteins 0.000 description 2
- GQYIWUVLTXOXAJ-UHFFFAOYSA-N Lomustine Chemical compound ClCCN(N=O)C(=O)NC1CCCCC1 GQYIWUVLTXOXAJ-UHFFFAOYSA-N 0.000 description 2
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 2
- 208000005777 Lupus Nephritis Diseases 0.000 description 2
- QLFAPXUXEBAWEK-NHCYSSNCSA-N Lys-Val-Asp Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(O)=O)C(O)=O QLFAPXUXEBAWEK-NHCYSSNCSA-N 0.000 description 2
- 229940124647 MEK inhibitor Drugs 0.000 description 2
- VOOINLQYUZOREH-SRVKXCTJSA-N Met-Gln-Leu Chemical compound CC(C)C[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)N)NC(=O)[C@H](CCSC)N VOOINLQYUZOREH-SRVKXCTJSA-N 0.000 description 2
- SPSSJSICDYYTQN-HJGDQZAQSA-N Met-Thr-Gln Chemical compound CSCC[C@H](N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@H](C(O)=O)CCC(N)=O SPSSJSICDYYTQN-HJGDQZAQSA-N 0.000 description 2
- VFKZTMPDYBFSTM-KVTDHHQDSA-N Mitobronitol Chemical compound BrC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CBr VFKZTMPDYBFSTM-KVTDHHQDSA-N 0.000 description 2
- 241000699666 Mus <mouse, genus> Species 0.000 description 2
- HRNLUBSXIHFDHP-UHFFFAOYSA-N N-(2-aminophenyl)-4-[[[4-(3-pyridinyl)-2-pyrimidinyl]amino]methyl]benzamide Chemical compound NC1=CC=CC=C1NC(=O)C(C=C1)=CC=C1CNC1=NC=CC(C=2C=NC=CC=2)=N1 HRNLUBSXIHFDHP-UHFFFAOYSA-N 0.000 description 2
- ZDZOTLJHXYCWBA-VCVYQWHSSA-N N-debenzoyl-N-(tert-butoxycarbonyl)-10-deacetyltaxol Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=4C=CC=CC=4)C[C@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 ZDZOTLJHXYCWBA-VCVYQWHSSA-N 0.000 description 2
- 101710204212 Neocarzinostatin Proteins 0.000 description 2
- 108091034117 Oligonucleotide Proteins 0.000 description 2
- 229930187135 Olivomycin Natural products 0.000 description 2
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 2
- 241001494479 Pecora Species 0.000 description 2
- 208000031845 Pernicious anaemia Diseases 0.000 description 2
- MCIXMYKSPQUMJG-SRVKXCTJSA-N Phe-Ser-Ser Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(O)=O MCIXMYKSPQUMJG-SRVKXCTJSA-N 0.000 description 2
- KMSKQZKKOZQFFG-HSUXVGOQSA-N Pirarubicin Chemical compound O([C@H]1[C@@H](N)C[C@@H](O[C@H]1C)O[C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1CCCCO1 KMSKQZKKOZQFFG-HSUXVGOQSA-N 0.000 description 2
- HFVNWDWLWUCIHC-GUPDPFMOSA-N Prednimustine Chemical compound O=C([C@@]1(O)CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)[C@@H](O)C[C@@]21C)COC(=O)CCCC1=CC=C(N(CCCl)CCCl)C=C1 HFVNWDWLWUCIHC-GUPDPFMOSA-N 0.000 description 2
- IHCXPSYCHXFXKT-DCAQKATOSA-N Pro-Arg-Glu Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(O)=O IHCXPSYCHXFXKT-DCAQKATOSA-N 0.000 description 2
- IMNVAOPEMFDAQD-NHCYSSNCSA-N Pro-Val-Glu Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(O)=O)C(O)=O IMNVAOPEMFDAQD-NHCYSSNCSA-N 0.000 description 2
- RJKFOVLPORLFTN-LEKSSAKUSA-N Progesterone Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](C(=O)C)[C@@]1(C)CC2 RJKFOVLPORLFTN-LEKSSAKUSA-N 0.000 description 2
- 206010060862 Prostate cancer Diseases 0.000 description 2
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 206010039491 Sarcoma Diseases 0.000 description 2
- WDXYVIIVDIDOSX-DCAQKATOSA-N Ser-Arg-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)CO)CCCN=C(N)N WDXYVIIVDIDOSX-DCAQKATOSA-N 0.000 description 2
- FMDHKPRACUXATF-ACZMJKKPSA-N Ser-Gln-Ser Chemical compound OC[C@H](N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CO)C(O)=O FMDHKPRACUXATF-ACZMJKKPSA-N 0.000 description 2
- UQFYNFTYDHUIMI-WHFBIAKZSA-N Ser-Gly-Ala Chemical compound OC(=O)[C@H](C)NC(=O)CNC(=O)[C@@H](N)CO UQFYNFTYDHUIMI-WHFBIAKZSA-N 0.000 description 2
- KDGARKCAKHBEDB-NKWVEPMBSA-N Ser-Gly-Pro Chemical compound C1C[C@@H](N(C1)C(=O)CNC(=O)[C@H](CO)N)C(=O)O KDGARKCAKHBEDB-NKWVEPMBSA-N 0.000 description 2
- UIGMAMGZOJVTDN-WHFBIAKZSA-N Ser-Gly-Ser Chemical compound OC[C@H](N)C(=O)NCC(=O)N[C@@H](CO)C(O)=O UIGMAMGZOJVTDN-WHFBIAKZSA-N 0.000 description 2
- SFTZWNJFZYOLBD-ZDLURKLDSA-N Ser-Gly-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)CNC(=O)[C@@H](N)CO SFTZWNJFZYOLBD-ZDLURKLDSA-N 0.000 description 2
- FUMGHWDRRFCKEP-CIUDSAMLSA-N Ser-Leu-Ala Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C)C(O)=O FUMGHWDRRFCKEP-CIUDSAMLSA-N 0.000 description 2
- 208000021386 Sjogren Syndrome Diseases 0.000 description 2
- 206010041067 Small cell lung cancer Diseases 0.000 description 2
- ZSJLQEPLLKMAKR-UHFFFAOYSA-N Streptozotocin Natural products O=NN(C)C(=O)NC1C(O)OC(CO)C(O)C1O ZSJLQEPLLKMAKR-UHFFFAOYSA-N 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
- CGMTUJFWROPELF-UHFFFAOYSA-N Tenuazonic acid Natural products CCC(C)C1NC(=O)C(=C(C)/O)C1=O CGMTUJFWROPELF-UHFFFAOYSA-N 0.000 description 2
- NJEMRSFGDNECGF-GCJQMDKQSA-N Thr-Ala-Asp Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@H](C(O)=O)CC(O)=O NJEMRSFGDNECGF-GCJQMDKQSA-N 0.000 description 2
- NCXVJIQMWSGRHY-KXNHARMFSA-N Thr-Leu-Pro Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N1CCC[C@@H]1C(=O)O)N)O NCXVJIQMWSGRHY-KXNHARMFSA-N 0.000 description 2
- SGAOHNPSEPVAFP-ZDLURKLDSA-N Thr-Ser-Gly Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(=O)NCC(O)=O SGAOHNPSEPVAFP-ZDLURKLDSA-N 0.000 description 2
- COYHRQWNJDJCNA-NUJDXYNKSA-N Thr-Thr-Thr Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O COYHRQWNJDJCNA-NUJDXYNKSA-N 0.000 description 2
- 206010043561 Thrombocytopenic purpura Diseases 0.000 description 2
- RCMHSGRBJCMFLR-BPUTZDHNSA-N Trp-Met-Asn Chemical compound C1=CC=C2C(C[C@H](N)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(N)=O)C(O)=O)=CNC2=C1 RCMHSGRBJCMFLR-BPUTZDHNSA-N 0.000 description 2
- WMIUTJPFHMMUGY-ZFWWWQNUSA-N Trp-Pro-Gly Chemical compound C1C[C@H](N(C1)C(=O)[C@H](CC2=CNC3=CC=CC=C32)N)C(=O)NCC(=O)O WMIUTJPFHMMUGY-ZFWWWQNUSA-N 0.000 description 2
- YXSSXUIBUJGHJY-SFJXLCSZSA-N Trp-Thr-Phe Chemical compound C([C@H](NC(=O)[C@@H](NC(=O)[C@@H](N)CC=1C2=CC=CC=C2NC=1)[C@H](O)C)C(O)=O)C1=CC=CC=C1 YXSSXUIBUJGHJY-SFJXLCSZSA-N 0.000 description 2
- PKZIWSHDJYIPRH-JBACZVJFSA-N Trp-Tyr-Gln Chemical compound [H]N[C@@H](CC1=CNC2=C1C=CC=C2)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CCC(N)=O)C(O)=O PKZIWSHDJYIPRH-JBACZVJFSA-N 0.000 description 2
- SCCKSNREWHMKOJ-SRVKXCTJSA-N Tyr-Asn-Ser Chemical compound N[C@@H](Cc1ccc(O)cc1)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CO)C(O)=O SCCKSNREWHMKOJ-SRVKXCTJSA-N 0.000 description 2
- OHNXAUCZVWGTLL-KKUMJFAQSA-N Tyr-His-Cys Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)N[C@@H](CC2=CN=CN2)C(=O)N[C@@H](CS)C(=O)O)N)O OHNXAUCZVWGTLL-KKUMJFAQSA-N 0.000 description 2
- MVFQLSPDMMFCMW-KKUMJFAQSA-N Tyr-Leu-Asn Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(O)=O MVFQLSPDMMFCMW-KKUMJFAQSA-N 0.000 description 2
- NUQZCPSZHGIYTA-HKUYNNGSSA-N Tyr-Trp-Gly Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)NCC(=O)O)NC(=O)[C@H](CC3=CC=C(C=C3)O)N NUQZCPSZHGIYTA-HKUYNNGSSA-N 0.000 description 2
- 201000006704 Ulcerative Colitis Diseases 0.000 description 2
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 description 2
- CVUDMNSZAIZFAE-UHFFFAOYSA-N Val-Arg-Pro Natural products NC(N)=NCCCC(NC(=O)C(N)C(C)C)C(=O)N1CCCC1C(O)=O CVUDMNSZAIZFAE-UHFFFAOYSA-N 0.000 description 2
- COSLEEOIYRPTHD-YDHLFZDLSA-N Val-Asp-Tyr Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 COSLEEOIYRPTHD-YDHLFZDLSA-N 0.000 description 2
- JTWIMNMUYLQNPI-WPRPVWTQSA-N Val-Gly-Arg Chemical compound CC(C)[C@H](N)C(=O)NCC(=O)N[C@H](C(O)=O)CCCNC(N)=N JTWIMNMUYLQNPI-WPRPVWTQSA-N 0.000 description 2
- VHIZXDZMTDVFGX-DCAQKATOSA-N Val-Ser-Leu Chemical compound CC(C)C[C@@H](C(=O)O)NC(=O)[C@H](CO)NC(=O)[C@H](C(C)C)N VHIZXDZMTDVFGX-DCAQKATOSA-N 0.000 description 2
- 206010047115 Vasculitis Diseases 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 229930188522 aclacinomycin Natural products 0.000 description 2
- USZYSDMBJDPRIF-SVEJIMAYSA-N aclacinomycin A Chemical compound O([C@H]1[C@@H](O)C[C@@H](O[C@H]1C)O[C@H]1[C@H](C[C@@H](O[C@H]1C)O[C@H]1C[C@]([C@@H](C2=CC=3C(=O)C4=CC=CC(O)=C4C(=O)C=3C(O)=C21)C(=O)OC)(O)CC)N(C)C)[C@H]1CCC(=O)[C@H](C)O1 USZYSDMBJDPRIF-SVEJIMAYSA-N 0.000 description 2
- 229960004176 aclarubicin Drugs 0.000 description 2
- 229930183665 actinomycin Natural products 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 238000011366 aggressive therapy Methods 0.000 description 2
- 108010069020 alanyl-prolyl-glycine Proteins 0.000 description 2
- 229960000548 alemtuzumab Drugs 0.000 description 2
- 125000001931 aliphatic group Chemical group 0.000 description 2
- 125000005907 alkyl ester group Chemical group 0.000 description 2
- 125000002947 alkylene group Chemical group 0.000 description 2
- 125000000304 alkynyl group Chemical group 0.000 description 2
- 229960003896 aminopterin Drugs 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
- 238000004458 analytical method Methods 0.000 description 2
- BBDAGFIXKZCXAH-CCXZUQQUSA-N ancitabine Chemical compound N=C1C=CN2[C@@H]3O[C@H](CO)[C@@H](O)[C@@H]3OC2=N1 BBDAGFIXKZCXAH-CCXZUQQUSA-N 0.000 description 2
- 229950000242 ancitabine Drugs 0.000 description 2
- 208000007502 anemia Diseases 0.000 description 2
- 230000002491 angiogenic effect Effects 0.000 description 2
- 230000000340 anti-metabolite Effects 0.000 description 2
- 230000000259 anti-tumor effect Effects 0.000 description 2
- 238000009175 antibody therapy Methods 0.000 description 2
- 230000010056 antibody-dependent cellular cytotoxicity Effects 0.000 description 2
- 238000011394 anticancer treatment Methods 0.000 description 2
- 229940100197 antimetabolite Drugs 0.000 description 2
- 239000002256 antimetabolite Substances 0.000 description 2
- 229940045719 antineoplastic alkylating agent nitrosoureas Drugs 0.000 description 2
- 108010052670 arginyl-glutamyl-glutamic acid Proteins 0.000 description 2
- 206010003119 arrhythmia Diseases 0.000 description 2
- 230000006793 arrhythmia Effects 0.000 description 2
- 229950002882 aselizumab Drugs 0.000 description 2
- 108010038633 aspartylglutamate Proteins 0.000 description 2
- 108010068265 aspartyltyrosine Proteins 0.000 description 2
- 229960002756 azacitidine Drugs 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
- 229960000997 bicalutamide Drugs 0.000 description 2
- 230000002146 bilateral effect Effects 0.000 description 2
- 230000003115 biocidal effect Effects 0.000 description 2
- QKSKPIVNLNLAAV-UHFFFAOYSA-N bis(2-chloroethyl) sulfide Chemical compound ClCCSCCCl QKSKPIVNLNLAAV-UHFFFAOYSA-N 0.000 description 2
- GXJABQQUPOEUTA-RDJZCZTQSA-N bortezomib Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)B(O)O)NC(=O)C=1N=CC=NC=1)C1=CC=CC=C1 GXJABQQUPOEUTA-RDJZCZTQSA-N 0.000 description 2
- 229960001467 bortezomib Drugs 0.000 description 2
- 229940098773 bovine serum albumin Drugs 0.000 description 2
- 210000004556 brain Anatomy 0.000 description 2
- 210000000481 breast Anatomy 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- MBABCNBNDNGODA-LUVUIASKSA-N bullatacin Chemical compound O1[C@@H]([C@@H](O)CCCCCCCCCC)CC[C@@H]1[C@@H]1O[C@@H]([C@H](O)CCCCCCCCCC[C@@H](O)CC=2C(O[C@@H](C)C=2)=O)CC1 MBABCNBNDNGODA-LUVUIASKSA-N 0.000 description 2
- 108700002839 cactinomycin Proteins 0.000 description 2
- OJLHWPALWODJPQ-QNWVGRARSA-N canfosfamide Chemical compound ClCCN(CCCl)P(=O)(N(CCCl)CCCl)OCCS(=O)(=O)C[C@H](NC(=O)CC[C@H](N)C(O)=O)C(=O)N[C@@H](C(O)=O)C1=CC=CC=C1 OJLHWPALWODJPQ-QNWVGRARSA-N 0.000 description 2
- 229950000772 canfosfamide Drugs 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 229960004562 carboplatin Drugs 0.000 description 2
- 229960002115 carboquone Drugs 0.000 description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
- 229930188550 carminomycin Natural products 0.000 description 2
- XREUEWVEMYWFFA-CSKJXFQVSA-N carminomycin Chemical compound C1[C@H](N)[C@H](O)[C@H](C)O[C@H]1O[C@@H]1C2=C(O)C(C(=O)C3=C(O)C=CC=C3C3=O)=C3C(O)=C2C[C@@](O)(C(C)=O)C1 XREUEWVEMYWFFA-CSKJXFQVSA-N 0.000 description 2
- XREUEWVEMYWFFA-UHFFFAOYSA-N carminomycin I Natural products C1C(N)C(O)C(C)OC1OC1C2=C(O)C(C(=O)C3=C(O)C=CC=C3C3=O)=C3C(O)=C2CC(O)(C(C)=O)C1 XREUEWVEMYWFFA-UHFFFAOYSA-N 0.000 description 2
- 229960003261 carmofur Drugs 0.000 description 2
- 229960005243 carmustine Drugs 0.000 description 2
- 229950001725 carubicin Drugs 0.000 description 2
- 230000011712 cell development Effects 0.000 description 2
- 210000001175 cerebrospinal fluid Anatomy 0.000 description 2
- 229960005395 cetuximab Drugs 0.000 description 2
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 2
- 229960004316 cisplatin Drugs 0.000 description 2
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 2
- 208000029742 colonic neoplasm Diseases 0.000 description 2
- PSNOPSMXOBPNNV-VVCTWANISA-N cryptophycin 1 Chemical compound C1=C(Cl)C(OC)=CC=C1C[C@@H]1C(=O)NC[C@@H](C)C(=O)O[C@@H](CC(C)C)C(=O)O[C@H]([C@H](C)[C@@H]2[C@H](O2)C=2C=CC=CC=2)C/C=C/C(=O)N1 PSNOPSMXOBPNNV-VVCTWANISA-N 0.000 description 2
- PSNOPSMXOBPNNV-UHFFFAOYSA-N cryptophycin-327 Natural products C1=C(Cl)C(OC)=CC=C1CC1C(=O)NCC(C)C(=O)OC(CC(C)C)C(=O)OC(C(C)C2C(O2)C=2C=CC=CC=2)CC=CC(=O)N1 PSNOPSMXOBPNNV-UHFFFAOYSA-N 0.000 description 2
- IBAHLNWTOIHLKE-UHFFFAOYSA-N cyano cyanate Chemical compound N#COC#N IBAHLNWTOIHLKE-UHFFFAOYSA-N 0.000 description 2
- 125000000753 cycloalkyl group Chemical group 0.000 description 2
- 229960000684 cytarabine Drugs 0.000 description 2
- OPTASPLRGRRNAP-UHFFFAOYSA-N cytosine Chemical compound NC=1C=CNC(=O)N=1 OPTASPLRGRRNAP-UHFFFAOYSA-N 0.000 description 2
- 230000001086 cytosolic effect Effects 0.000 description 2
- 231100000599 cytotoxic agent Toxicity 0.000 description 2
- 230000003013 cytotoxicity Effects 0.000 description 2
- 231100000135 cytotoxicity Toxicity 0.000 description 2
- 229960003901 dacarbazine Drugs 0.000 description 2
- 229960002806 daclizumab Drugs 0.000 description 2
- DOAKLVKFURWEDJ-QCMAZARJSA-N daptomycin Chemical compound C([C@H]1C(=O)O[C@H](C)[C@@H](C(NCC(=O)N[C@@H](CCCN)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@H](C)C(=O)N[C@@H](CC(O)=O)C(=O)NCC(=O)N[C@H](CO)C(=O)N[C@H](C(=O)N1)[C@H](C)CC(O)=O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@@H](CC(N)=O)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)CCCCCCCCC)C(=O)C1=CC=CC=C1N DOAKLVKFURWEDJ-QCMAZARJSA-N 0.000 description 2
- 229960005484 daptomycin Drugs 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
- 230000002939 deleterious effect Effects 0.000 description 2
- 239000003534 dna topoisomerase inhibitor Substances 0.000 description 2
- 229960003668 docetaxel Drugs 0.000 description 2
- AMRJKAQTDDKMCE-UHFFFAOYSA-N dolastatin Chemical compound CC(C)C(N(C)C)C(=O)NC(C(C)C)C(=O)N(C)C(C(C)C)C(OC)CC(=O)N1CCCC1C(OC)C(C)C(=O)NC(C=1SC=CN=1)CC1=CC=CC=C1 AMRJKAQTDDKMCE-UHFFFAOYSA-N 0.000 description 2
- 229930188854 dolastatin Natural products 0.000 description 2
- 229950004203 droloxifene Drugs 0.000 description 2
- NOTIQUSPUUHHEH-UXOVVSIBSA-N dromostanolone propionate Chemical compound C([C@@H]1CC2)C(=O)[C@H](C)C[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H](OC(=O)CC)[C@@]2(C)CC1 NOTIQUSPUUHHEH-UXOVVSIBSA-N 0.000 description 2
- 229950004683 drostanolone propionate Drugs 0.000 description 2
- 238000002592 echocardiography Methods 0.000 description 2
- 229960002224 eculizumab Drugs 0.000 description 2
- 239000012636 effector Substances 0.000 description 2
- JOZGNYDSEBIJDH-UHFFFAOYSA-N eniluracil Chemical compound O=C1NC=C(C#C)C(=O)N1 JOZGNYDSEBIJDH-UHFFFAOYSA-N 0.000 description 2
- 229950010213 eniluracil Drugs 0.000 description 2
- 229950011487 enocitabine Drugs 0.000 description 2
- 229960001904 epirubicin Drugs 0.000 description 2
- 150000003883 epothilone derivatives Chemical class 0.000 description 2
- 229960001433 erlotinib Drugs 0.000 description 2
- 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 2
- ITSGNOIFAJAQHJ-BMFNZSJVSA-N esorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)C[C@H](C)O1 ITSGNOIFAJAQHJ-BMFNZSJVSA-N 0.000 description 2
- 229950002017 esorubicin Drugs 0.000 description 2
- 125000004185 ester group Chemical group 0.000 description 2
- 229960001842 estramustine Drugs 0.000 description 2
- FRPJXPJMRWBBIH-RBRWEJTLSA-N estramustine Chemical compound ClCCN(CCCl)C(=O)OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 FRPJXPJMRWBBIH-RBRWEJTLSA-N 0.000 description 2
- 229940011871 estrogen Drugs 0.000 description 2
- 239000000262 estrogen Substances 0.000 description 2
- VJJPUSNTGOMMGY-MRVIYFEKSA-N etoposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@H](C)OC[C@H]4O3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 VJJPUSNTGOMMGY-MRVIYFEKSA-N 0.000 description 2
- 229960005167 everolimus Drugs 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 229950011548 fadrozole Drugs 0.000 description 2
- 230000000893 fibroproliferative effect Effects 0.000 description 2
- 238000000684 flow cytometry Methods 0.000 description 2
- 229960000961 floxuridine Drugs 0.000 description 2
- 229960000390 fludarabine Drugs 0.000 description 2
- GIUYCYHIANZCFB-FJFJXFQQSA-N fludarabine phosphate Chemical compound C1=NC=2C(N)=NC(F)=NC=2N1[C@@H]1O[C@H](COP(O)(O)=O)[C@@H](O)[C@@H]1O GIUYCYHIANZCFB-FJFJXFQQSA-N 0.000 description 2
- 239000012530 fluid Substances 0.000 description 2
- 229960002074 flutamide Drugs 0.000 description 2
- 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 2
- OVBPIULPVIDEAO-LBPRGKRZSA-N folic acid Chemical compound C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-LBPRGKRZSA-N 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 229960004783 fotemustine Drugs 0.000 description 2
- YAKWPXVTIGTRJH-UHFFFAOYSA-N fotemustine Chemical compound CCOP(=O)(OCC)C(C)NC(=O)N(CCCl)N=O YAKWPXVTIGTRJH-UHFFFAOYSA-N 0.000 description 2
- CHPZKNULDCNCBW-UHFFFAOYSA-N gallium nitrate Chemical compound [Ga+3].[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O CHPZKNULDCNCBW-UHFFFAOYSA-N 0.000 description 2
- 210000001035 gastrointestinal tract Anatomy 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
- 229960005277 gemcitabine Drugs 0.000 description 2
- SDUQYLNIPVEERB-QPPQHZFASA-N gemcitabine Chemical compound O=C1N=C(N)C=CN1[C@H]1C(F)(F)[C@H](O)[C@@H](CO)O1 SDUQYLNIPVEERB-QPPQHZFASA-N 0.000 description 2
- 108010013768 glutamyl-aspartyl-proline Proteins 0.000 description 2
- 108010072405 glycyl-aspartyl-glycine Proteins 0.000 description 2
- 229960002913 goserelin Drugs 0.000 description 2
- 210000003714 granulocyte Anatomy 0.000 description 2
- 231100000226 haematotoxicity Toxicity 0.000 description 2
- 229910052736 halogen Inorganic materials 0.000 description 2
- 150000002367 halogens Chemical class 0.000 description 2
- 208000019622 heart disease Diseases 0.000 description 2
- 230000004217 heart function Effects 0.000 description 2
- 208000002672 hepatitis B Diseases 0.000 description 2
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 229960001330 hydroxycarbamide Drugs 0.000 description 2
- 230000003463 hyperproliferative effect Effects 0.000 description 2
- 238000009802 hysterectomy Methods 0.000 description 2
- 229940015872 ibandronate Drugs 0.000 description 2
- 229960000908 idarubicin Drugs 0.000 description 2
- 229960003685 imatinib mesylate Drugs 0.000 description 2
- YLMAHDNUQAMNNX-UHFFFAOYSA-N imatinib methanesulfonate Chemical compound CS(O)(=O)=O.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 YLMAHDNUQAMNNX-UHFFFAOYSA-N 0.000 description 2
- 230000001771 impaired effect Effects 0.000 description 2
- 208000015181 infectious disease Diseases 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 238000003780 insertion Methods 0.000 description 2
- 230000037431 insertion Effects 0.000 description 2
- 230000003993 interaction Effects 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 229960004768 irinotecan Drugs 0.000 description 2
- 108010031424 isoleucyl-prolyl-proline Proteins 0.000 description 2
- 229960004891 lapatinib Drugs 0.000 description 2
- 229940115286 lentinan Drugs 0.000 description 2
- 230000003902 lesion Effects 0.000 description 2
- GFIJNRVAKGFPGQ-LIJARHBVSA-N leuprolide Chemical compound CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CC(C)C)NC(=O)[C@@H](NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H]1NC(=O)CC1)CC1=CC=C(O)C=C1 GFIJNRVAKGFPGQ-LIJARHBVSA-N 0.000 description 2
- 229960004338 leuprorelin Drugs 0.000 description 2
- 210000004185 liver Anatomy 0.000 description 2
- 201000007270 liver cancer Diseases 0.000 description 2
- 208000019423 liver disease Diseases 0.000 description 2
- 230000004807 localization Effects 0.000 description 2
- 229960002247 lomustine Drugs 0.000 description 2
- DHMTURDWPRKSOA-RUZDIDTESA-N lonafarnib Chemical compound C1CN(C(=O)N)CCC1CC(=O)N1CCC([C@@H]2C3=C(Br)C=C(Cl)C=C3CCC3=CC(Br)=CN=C32)CC1 DHMTURDWPRKSOA-RUZDIDTESA-N 0.000 description 2
- YROQEQPFUCPDCP-UHFFFAOYSA-N losoxantrone Chemical compound OCCNCCN1N=C2C3=CC=CC(O)=C3C(=O)C3=C2C1=CC=C3NCCNCCO YROQEQPFUCPDCP-UHFFFAOYSA-N 0.000 description 2
- 229950008745 losoxantrone Drugs 0.000 description 2
- 210000004072 lung Anatomy 0.000 description 2
- 201000005202 lung cancer Diseases 0.000 description 2
- 208000020816 lung neoplasm Diseases 0.000 description 2
- 206010025135 lupus erythematosus Diseases 0.000 description 2
- 210000002751 lymph Anatomy 0.000 description 2
- 210000003563 lymphoid tissue Anatomy 0.000 description 2
- 210000002540 macrophage Anatomy 0.000 description 2
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 2
- 238000007726 management method Methods 0.000 description 2
- MQXVYODZCMMZEM-ZYUZMQFOSA-N mannomustine Chemical compound ClCCNC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CNCCCl MQXVYODZCMMZEM-ZYUZMQFOSA-N 0.000 description 2
- 229950008612 mannomustine Drugs 0.000 description 2
- 239000003550 marker Substances 0.000 description 2
- 230000010534 mechanism of action Effects 0.000 description 2
- 229960004961 mechlorethamine Drugs 0.000 description 2
- HAWPXGHAZFHHAD-UHFFFAOYSA-N mechlorethamine Chemical compound ClCCN(C)CCCl HAWPXGHAZFHHAD-UHFFFAOYSA-N 0.000 description 2
- 229960004296 megestrol acetate Drugs 0.000 description 2
- RQZAXGRLVPAYTJ-GQFGMJRRSA-N megestrol acetate Chemical compound C1=C(C)C2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(C)=O)(OC(=O)C)[C@@]1(C)CC2 RQZAXGRLVPAYTJ-GQFGMJRRSA-N 0.000 description 2
- 229960001924 melphalan Drugs 0.000 description 2
- SGDBTWWWUNNDEQ-LBPRGKRZSA-N melphalan Chemical compound OC(=O)[C@@H](N)CC1=CC=C(N(CCCl)CCCl)C=C1 SGDBTWWWUNNDEQ-LBPRGKRZSA-N 0.000 description 2
- 102000006240 membrane receptors Human genes 0.000 description 2
- 229960001428 mercaptopurine Drugs 0.000 description 2
- 230000009401 metastasis Effects 0.000 description 2
- 229960005485 mitobronitol Drugs 0.000 description 2
- VFKZTMPDYBFSTM-GUCUJZIJSA-N mitolactol Chemical compound BrC[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)CBr VFKZTMPDYBFSTM-GUCUJZIJSA-N 0.000 description 2
- 229950010913 mitolactol Drugs 0.000 description 2
- 229960000350 mitotane Drugs 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 201000006417 multiple sclerosis Diseases 0.000 description 2
- 235000010460 mustard Nutrition 0.000 description 2
- HPNSFSBZBAHARI-RUDMXATFSA-N mycophenolic acid Chemical compound OC1=C(C\C=C(/C)CCC(O)=O)C(OC)=C(C)C2=C1C(=O)OC2 HPNSFSBZBAHARI-RUDMXATFSA-N 0.000 description 2
- 229960005027 natalizumab Drugs 0.000 description 2
- 229950004847 navitoclax Drugs 0.000 description 2
- CTMCWCONSULRHO-UHQPFXKFSA-N nemorubicin Chemical compound C1CO[C@H](OC)CN1[C@@H]1[C@H](O)[C@H](C)O[C@@H](O[C@@H]2C3=C(O)C=4C(=O)C5=C(OC)C=CC=C5C(=O)C=4C(O)=C3C[C@](O)(C2)C(=O)CO)C1 CTMCWCONSULRHO-UHQPFXKFSA-N 0.000 description 2
- 229950010159 nemorubicin Drugs 0.000 description 2
- 229960002653 nilutamide Drugs 0.000 description 2
- XWXYUMMDTVBTOU-UHFFFAOYSA-N nilutamide Chemical compound O=C1C(C)(C)NC(=O)N1C1=CC=C([N+]([O-])=O)C(C(F)(F)F)=C1 XWXYUMMDTVBTOU-UHFFFAOYSA-N 0.000 description 2
- 229950010203 nimotuzumab Drugs 0.000 description 2
- 229960001420 nimustine Drugs 0.000 description 2
- VFEDRRNHLBGPNN-UHFFFAOYSA-N nimustine Chemical compound CC1=NC=C(CNC(=O)N(CCCl)N=O)C(N)=N1 VFEDRRNHLBGPNN-UHFFFAOYSA-N 0.000 description 2
- 150000002825 nitriles Chemical group 0.000 description 2
- CZDBNBLGZNWKMC-MWQNXGTOSA-N olivomycin Chemical compound O([C@@H]1C[C@@H](O[C@H](C)[C@@H]1O)OC=1C=C2C=C3C[C@H]([C@@H](C(=O)C3=C(O)C2=C(O)C=1)O[C@H]1O[C@@H](C)[C@H](O)[C@@H](OC2O[C@@H](C)[C@H](O)[C@@H](O)C2)C1)[C@H](OC)C(=O)[C@@H](O)[C@@H](C)O)[C@H]1C[C@H](O)[C@H](OC)[C@H](C)O1 CZDBNBLGZNWKMC-MWQNXGTOSA-N 0.000 description 2
- 229950005848 olivomycin Drugs 0.000 description 2
- 229950011093 onapristone Drugs 0.000 description 2
- 230000002018 overexpression Effects 0.000 description 2
- 201000002528 pancreatic cancer Diseases 0.000 description 2
- 208000008443 pancreatic 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
- 229960002340 pentostatin Drugs 0.000 description 2
- FPVKHBSQESCIEP-JQCXWYLXSA-N pentostatin Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(N=CNC[C@H]2O)=C2N=C1 FPVKHBSQESCIEP-JQCXWYLXSA-N 0.000 description 2
- 230000002688 persistence Effects 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 229960001221 pirarubicin Drugs 0.000 description 2
- 210000002381 plasma Anatomy 0.000 description 2
- 239000013641 positive control Substances 0.000 description 2
- 229960004694 prednimustine 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
- 108010077112 prolyl-proline Proteins 0.000 description 2
- 108010053725 prolylvaline Proteins 0.000 description 2
- 230000000069 prophylactic effect Effects 0.000 description 2
- RXWNCPJZOCPEPQ-NVWDDTSBSA-N puromycin Chemical compound C1=CC(OC)=CC=C1C[C@H](N)C(=O)N[C@H]1[C@@H](O)[C@H](N2C3=NC=NC(=C3N=C2)N(C)C)O[C@@H]1CO RXWNCPJZOCPEPQ-NVWDDTSBSA-N 0.000 description 2
- YUOCYTRGANSSRY-UHFFFAOYSA-N pyrrolo[2,3-i][1,2]benzodiazepine Chemical group C1=CN=NC2=C3C=CN=C3C=CC2=C1 YUOCYTRGANSSRY-UHFFFAOYSA-N 0.000 description 2
- 229960003876 ranibizumab Drugs 0.000 description 2
- 230000002829 reductive effect Effects 0.000 description 2
- 239000013074 reference sample Substances 0.000 description 2
- 230000001850 reproductive effect Effects 0.000 description 2
- 238000012552 review Methods 0.000 description 2
- 206010039073 rheumatoid arthritis Diseases 0.000 description 2
- MBABCNBNDNGODA-WPZDJQSSSA-N rolliniastatin 1 Natural products O1[C@@H]([C@@H](O)CCCCCCCCCC)CC[C@H]1[C@H]1O[C@@H]([C@H](O)CCCCCCCCCC[C@@H](O)CC=2C(O[C@@H](C)C=2)=O)CC1 MBABCNBNDNGODA-WPZDJQSSSA-N 0.000 description 2
- HXCHCVDVKSCDHU-PJKCJEBCSA-N s-[(2r,3s,4s,6s)-6-[[(2r,3s,4s,5r,6r)-5-[(2s,4s,5s)-5-(ethylamino)-4-methoxyoxan-2-yl]oxy-4-hydroxy-6-[[(2s,5z,9r,13e)-9-hydroxy-12-(methoxycarbonylamino)-13-[2-(methyltrisulfanyl)ethylidene]-11-oxo-2-bicyclo[7.3.1]trideca-1(12),5-dien-3,7-diynyl]oxy]-2-m Chemical compound C1[C@H](OC)[C@@H](NCC)CO[C@H]1O[C@H]1[C@H](O[C@@H]2C\3=C(NC(=O)OC)C(=O)C[C@@](C/3=C/CSSSC)(O)C#C\C=C/C#C2)O[C@H](C)[C@@H](NO[C@@H]2O[C@H](C)[C@@H](SC(=O)C=3C(=C(OC)C(O[C@H]4[C@@H]([C@H](OC)[C@@H](O)[C@H](C)O4)O)=C(I)C=3C)OC)[C@@H](O)C2)[C@@H]1O HXCHCVDVKSCDHU-PJKCJEBCSA-N 0.000 description 2
- 229940095743 selective estrogen receptor modulator Drugs 0.000 description 2
- 239000000333 selective estrogen receptor modulator Substances 0.000 description 2
- CYOHGALHFOKKQC-UHFFFAOYSA-N selumetinib Chemical compound OCCONC(=O)C=1C=C2N(C)C=NC2=C(F)C=1NC1=CC=C(Br)C=C1Cl CYOHGALHFOKKQC-UHFFFAOYSA-N 0.000 description 2
- 230000019491 signal transduction Effects 0.000 description 2
- 230000011664 signaling Effects 0.000 description 2
- 208000000587 small cell lung carcinoma Diseases 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- ICXJVZHDZFXYQC-UHFFFAOYSA-N spongistatin 1 Natural products OC1C(O2)(O)CC(O)C(C)C2CCCC=CC(O2)CC(O)CC2(O2)CC(OC)CC2CC(=O)C(C)C(OC(C)=O)C(C)C(=C)CC(O2)CC(C)(O)CC2(O2)CC(OC(C)=O)CC2CC(=O)OC2C(O)C(CC(=C)CC(O)C=CC(Cl)=C)OC1C2C ICXJVZHDZFXYQC-UHFFFAOYSA-N 0.000 description 2
- 208000017572 squamous cell neoplasm Diseases 0.000 description 2
- 239000003381 stabilizer Substances 0.000 description 2
- 230000001954 sterilising effect Effects 0.000 description 2
- 238000004659 sterilization and disinfection Methods 0.000 description 2
- PVYJZLYGTZKPJE-UHFFFAOYSA-N streptonigrin Chemical compound C=1C=C2C(=O)C(OC)=C(N)C(=O)C2=NC=1C(C=1N)=NC(C(O)=O)=C(C)C=1C1=CC=C(OC)C(OC)=C1O PVYJZLYGTZKPJE-UHFFFAOYSA-N 0.000 description 2
- 229960001052 streptozocin Drugs 0.000 description 2
- ZSJLQEPLLKMAKR-GKHCUFPYSA-N streptozocin Chemical compound O=NN(C)C(=O)N[C@H]1[C@@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O ZSJLQEPLLKMAKR-GKHCUFPYSA-N 0.000 description 2
- 238000010254 subcutaneous injection Methods 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 230000004083 survival effect Effects 0.000 description 2
- 208000011580 syndromic disease Diseases 0.000 description 2
- 230000002195 synergetic effect Effects 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- 238000002626 targeted therapy Methods 0.000 description 2
- 229960004964 temozolomide Drugs 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
- 229960005353 testolactone Drugs 0.000 description 2
- BPEWUONYVDABNZ-DZBHQSCQSA-N testolactone Chemical compound O=C1C=C[C@]2(C)[C@H]3CC[C@](C)(OC(=O)CC4)[C@@H]4[C@@H]3CCC2=C1 BPEWUONYVDABNZ-DZBHQSCQSA-N 0.000 description 2
- 206010043554 thrombocytopenia Diseases 0.000 description 2
- 206010043778 thyroiditis Diseases 0.000 description 2
- YFTWHEBLORWGNI-UHFFFAOYSA-N tiamiprine Chemical compound CN1C=NC([N+]([O-])=O)=C1SC1=NC(N)=NC2=C1NC=N2 YFTWHEBLORWGNI-UHFFFAOYSA-N 0.000 description 2
- 229950011457 tiamiprine Drugs 0.000 description 2
- 229960003087 tioguanine Drugs 0.000 description 2
- 229940044693 topoisomerase inhibitor Drugs 0.000 description 2
- 229930013292 trichothecene Natural products 0.000 description 2
- 150000003327 trichothecene derivatives Chemical class 0.000 description 2
- 229960000875 trofosfamide Drugs 0.000 description 2
- UMKFEPPTGMDVMI-UHFFFAOYSA-N trofosfamide Chemical compound ClCCN(CCCl)P1(=O)OCCCN1CCCl UMKFEPPTGMDVMI-UHFFFAOYSA-N 0.000 description 2
- 238000009810 tubal ligation Methods 0.000 description 2
- 108010003137 tyrosyltyrosine Proteins 0.000 description 2
- 229950009811 ubenimex Drugs 0.000 description 2
- 201000005112 urinary bladder cancer Diseases 0.000 description 2
- 229960000241 vandetanib Drugs 0.000 description 2
- UHTHHESEBZOYNR-UHFFFAOYSA-N vandetanib Chemical compound COC1=CC(C(/N=CN2)=N/C=3C(=CC(Br)=CC=3)F)=C2C=C1OCC1CCN(C)CC1 UHTHHESEBZOYNR-UHFFFAOYSA-N 0.000 description 2
- 238000007879 vasectomy Methods 0.000 description 2
- 239000003981 vehicle Substances 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
- WAEXFXRVDQXREF-UHFFFAOYSA-N vorinostat Chemical compound ONC(=O)CCCCCCC(=O)NC1=CC=CC=C1 WAEXFXRVDQXREF-UHFFFAOYSA-N 0.000 description 2
- 229960000237 vorinostat Drugs 0.000 description 2
- 229960000641 zorubicin Drugs 0.000 description 2
- FBTUMDXHSRTGRV-ALTNURHMSA-N zorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(\C)=N\NC(=O)C=1C=CC=CC=1)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 FBTUMDXHSRTGRV-ALTNURHMSA-N 0.000 description 2
- NNJPGOLRFBJNIW-HNNXBMFYSA-N (-)-demecolcine Chemical compound C1=C(OC)C(=O)C=C2[C@@H](NC)CCC3=CC(OC)=C(OC)C(OC)=C3C2=C1 NNJPGOLRFBJNIW-HNNXBMFYSA-N 0.000 description 1
- WDQLRUYAYXDIFW-RWKIJVEZSA-N (2r,3r,4s,5r,6r)-4-[(2s,3r,4s,5r,6r)-3,5-dihydroxy-4-[(2r,3r,4s,5s,6r)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-6-[[(2r,3r,4s,5s,6r)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxymethyl]oxan-2-yl]oxy-6-(hydroxymethyl)oxane-2,3,5-triol Chemical compound O[C@@H]1[C@@H](CO)O[C@@H](O)[C@H](O)[C@H]1O[C@H]1[C@H](O)[C@@H](O[C@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)O)[C@H](O)[C@@H](CO[C@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)O)O1 WDQLRUYAYXDIFW-RWKIJVEZSA-N 0.000 description 1
- IESDGNYHXIOKRW-YXMSTPNBSA-N (2s)-2-[[(2s)-1-[(2s)-6-amino-2-[[(2s,3r)-2-amino-3-hydroxybutanoyl]amino]hexanoyl]pyrrolidine-2-carbonyl]amino]-5-(diaminomethylideneamino)pentanoic acid Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@@H](CCCCN)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCCNC(N)=N)C(O)=O IESDGNYHXIOKRW-YXMSTPNBSA-N 0.000 description 1
- DIBLBAURNYJYBF-XLXZRNDBSA-N (2s)-2-[[(2s)-2-[[2-[[(2s)-6-amino-2-[[(2s)-2-amino-3-methylbutanoyl]amino]hexanoyl]amino]acetyl]amino]-3-phenylpropanoyl]amino]-3-(4-hydroxyphenyl)propanoic acid Chemical compound C([C@H](NC(=O)CNC(=O)[C@H](CCCCN)NC(=O)[C@@H](N)C(C)C)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(O)=O)C1=CC=CC=C1 DIBLBAURNYJYBF-XLXZRNDBSA-N 0.000 description 1
- SVNJBEMPMKWDCO-KCHLEUMXSA-N (2s)-2-[[(2s)-3-carboxy-2-[[2-[[(2s)-5-(diaminomethylideneamino)-2-[[4-oxo-4-[[4-(4-oxo-8-phenylchromen-2-yl)morpholin-4-ium-4-yl]methoxy]butanoyl]amino]pentanoyl]amino]acetyl]amino]propanoyl]amino]-3-hydroxypropanoate Chemical compound C=1C(=O)C2=CC=CC(C=3C=CC=CC=3)=C2OC=1[N+]1(COC(=O)CCC(=O)N[C@@H](CCCNC(=N)N)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C([O-])=O)CCOCC1 SVNJBEMPMKWDCO-KCHLEUMXSA-N 0.000 description 1
- FLWWDYNPWOSLEO-HQVZTVAUSA-N (2s)-2-[[4-[1-(2-amino-4-oxo-1h-pteridin-6-yl)ethyl-methylamino]benzoyl]amino]pentanedioic acid Chemical compound C=1N=C2NC(N)=NC(=O)C2=NC=1C(C)N(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FLWWDYNPWOSLEO-HQVZTVAUSA-N 0.000 description 1
- TVIRNGFXQVMMGB-OFWIHYRESA-N (3s,6r,10r,13e,16s)-16-[(2r,3r,4s)-4-chloro-3-hydroxy-4-phenylbutan-2-yl]-10-[(3-chloro-4-methoxyphenyl)methyl]-6-methyl-3-(2-methylpropyl)-1,4-dioxa-8,11-diazacyclohexadec-13-ene-2,5,9,12-tetrone Chemical compound C1=C(Cl)C(OC)=CC=C1C[C@@H]1C(=O)NC[C@@H](C)C(=O)O[C@@H](CC(C)C)C(=O)O[C@H]([C@H](C)[C@@H](O)[C@@H](Cl)C=2C=CC=CC=2)C/C=C/C(=O)N1 TVIRNGFXQVMMGB-OFWIHYRESA-N 0.000 description 1
- XRBSKUSTLXISAB-XVVDYKMHSA-N (5r,6r,7r,8r)-8-hydroxy-7-(hydroxymethyl)-5-(3,4,5-trimethoxyphenyl)-5,6,7,8-tetrahydrobenzo[f][1,3]benzodioxole-6-carboxylic acid Chemical compound COC1=C(OC)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@H](O)[C@@H](CO)[C@@H]2C(O)=O)=C1 XRBSKUSTLXISAB-XVVDYKMHSA-N 0.000 description 1
- XRBSKUSTLXISAB-UHFFFAOYSA-N (7R,7'R,8R,8'R)-form-Podophyllic acid Natural products COC1=C(OC)C(OC)=CC(C2C3=CC=4OCOC=4C=C3C(O)C(CO)C2C(O)=O)=C1 XRBSKUSTLXISAB-UHFFFAOYSA-N 0.000 description 1
- JXVAMODRWBNUSF-KZQKBALLSA-N (7s,9r,10r)-7-[(2r,4s,5s,6s)-5-[[(2s,4as,5as,7s,9s,9ar,10ar)-2,9-dimethyl-3-oxo-4,4a,5a,6,7,9,9a,10a-octahydrodipyrano[4,2-a:4',3'-e][1,4]dioxin-7-yl]oxy]-4-(dimethylamino)-6-methyloxan-2-yl]oxy-10-[(2s,4s,5s,6s)-4-(dimethylamino)-5-hydroxy-6-methyloxan-2 Chemical compound O([C@@H]1C2=C(O)C=3C(=O)C4=CC=CC(O)=C4C(=O)C=3C(O)=C2[C@@H](O[C@@H]2O[C@@H](C)[C@@H](O[C@@H]3O[C@@H](C)[C@H]4O[C@@H]5O[C@@H](C)C(=O)C[C@@H]5O[C@H]4C3)[C@H](C2)N(C)C)C[C@]1(O)CC)[C@H]1C[C@H](N(C)C)[C@H](O)[C@H](C)O1 JXVAMODRWBNUSF-KZQKBALLSA-N 0.000 description 1
- INAUWOVKEZHHDM-PEDBPRJASA-N (7s,9s)-6,9,11-trihydroxy-9-(2-hydroxyacetyl)-7-[(2r,4s,5s,6s)-5-hydroxy-6-methyl-4-morpholin-4-yloxan-2-yl]oxy-4-methoxy-8,10-dihydro-7h-tetracene-5,12-dione;hydrochloride Chemical compound Cl.N1([C@H]2C[C@@H](O[C@@H](C)[C@H]2O)O[C@H]2C[C@@](O)(CC=3C(O)=C4C(=O)C=5C=CC=C(C=5C(=O)C4=C(O)C=32)OC)C(=O)CO)CCOCC1 INAUWOVKEZHHDM-PEDBPRJASA-N 0.000 description 1
- RCFNNLSZHVHCEK-IMHLAKCZSA-N (7s,9s)-7-(4-amino-6-methyloxan-2-yl)oxy-6,9,11-trihydroxy-9-(2-hydroxyacetyl)-4-methoxy-8,10-dihydro-7h-tetracene-5,12-dione;hydrochloride Chemical compound [Cl-].O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)C1CC([NH3+])CC(C)O1 RCFNNLSZHVHCEK-IMHLAKCZSA-N 0.000 description 1
- XUBOMFCQGDBHNK-JTQLQIEISA-N (S)-gatifloxacin Chemical compound FC1=CC(C(C(C(O)=O)=CN2C3CC3)=O)=C2C(OC)=C1N1CCN[C@@H](C)C1 XUBOMFCQGDBHNK-JTQLQIEISA-N 0.000 description 1
- FONKWHRXTPJODV-DNQXCXABSA-N 1,3-bis[2-[(8s)-8-(chloromethyl)-4-hydroxy-1-methyl-7,8-dihydro-3h-pyrrolo[3,2-e]indole-6-carbonyl]-1h-indol-5-yl]urea Chemical compound C1([C@H](CCl)CN2C(=O)C=3NC4=CC=C(C=C4C=3)NC(=O)NC=3C=C4C=C(NC4=CC=3)C(=O)N3C4=CC(O)=C5NC=C(C5=C4[C@H](CCl)C3)C)=C2C=C(O)C2=C1C(C)=CN2 FONKWHRXTPJODV-DNQXCXABSA-N 0.000 description 1
- WNXJIVFYUVYPPR-UHFFFAOYSA-N 1,3-dioxolane Chemical compound C1COCO1 WNXJIVFYUVYPPR-UHFFFAOYSA-N 0.000 description 1
- MDKVDJZIHRFUBO-UHFFFAOYSA-N 2-amino-3-benzoyl-4-(2-benzoylphenyl)iminocyclohexa-2,5-dien-1-one Chemical compound C1=CC=C(C=C1)C(=O)C2=CC=CC=C2N=C3C=CC(=O)C(=C3C(=O)C4=CC=CC=C4)N MDKVDJZIHRFUBO-UHFFFAOYSA-N 0.000 description 1
- FLKFEULZGUGYQU-UHFFFAOYSA-N 2-amino-4-oxopentanoic acid Chemical compound NC(C(=O)O)CC(=O)C.NC(C(=O)O)CC(=O)C FLKFEULZGUGYQU-UHFFFAOYSA-N 0.000 description 1
- VNBAOSVONFJBKP-UHFFFAOYSA-N 2-chloro-n,n-bis(2-chloroethyl)propan-1-amine;hydrochloride Chemical compound Cl.CC(Cl)CN(CCCl)CCCl VNBAOSVONFJBKP-UHFFFAOYSA-N 0.000 description 1
- CTRPRMNBTVRDFH-UHFFFAOYSA-N 2-n-methyl-1,3,5-triazine-2,4,6-triamine Chemical compound CNC1=NC(N)=NC(N)=N1 CTRPRMNBTVRDFH-UHFFFAOYSA-N 0.000 description 1
- YIMDLWDNDGKDTJ-QLKYHASDSA-N 3'-deamino-3'-(3-cyanomorpholin-4-yl)doxorubicin Chemical compound N1([C@H]2C[C@@H](O[C@@H](C)[C@H]2O)O[C@H]2C[C@@](O)(CC=3C(O)=C4C(=O)C=5C=CC=C(C=5C(=O)C4=C(O)C=32)OC)C(=O)CO)CCOCC1C#N YIMDLWDNDGKDTJ-QLKYHASDSA-N 0.000 description 1
- PWMYMKOUNYTVQN-UHFFFAOYSA-N 3-(8,8-diethyl-2-aza-8-germaspiro[4.5]decan-2-yl)-n,n-dimethylpropan-1-amine Chemical compound C1C[Ge](CC)(CC)CCC11CN(CCCN(C)C)CC1 PWMYMKOUNYTVQN-UHFFFAOYSA-N 0.000 description 1
- IWCQHVUQEFDRIW-UHFFFAOYSA-N 3-[1-[[4-(6-phenyl-8H-imidazo[4,5-g]quinoxalin-7-yl)phenyl]methyl]piperidin-4-yl]-1H-benzimidazol-2-one Chemical compound O=c1[nH]c2ccccc2n1C1CCN(Cc2ccc(cc2)-c2[nH]c3cc4ncnc4cc3nc2-c2ccccc2)CC1 IWCQHVUQEFDRIW-UHFFFAOYSA-N 0.000 description 1
- IDPUKCWIGUEADI-UHFFFAOYSA-N 5-[bis(2-chloroethyl)amino]uracil Chemical compound ClCCN(CCCl)C1=CNC(=O)NC1=O IDPUKCWIGUEADI-UHFFFAOYSA-N 0.000 description 1
- HDZZVAMISRMYHH-UHFFFAOYSA-N 9beta-Ribofuranosyl-7-deazaadenin Natural products C1=CC=2C(N)=NC=NC=2N1C1OC(CO)C(O)C1O HDZZVAMISRMYHH-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 208000026872 Addison Disease Diseases 0.000 description 1
- 206010001367 Adrenal insufficiency Diseases 0.000 description 1
- 208000008190 Agammaglobulinemia Diseases 0.000 description 1
- CXRCVCURMBFFOL-FXQIFTODSA-N Ala-Ala-Pro Chemical compound C[C@H](N)C(=O)N[C@@H](C)C(=O)N1CCC[C@H]1C(O)=O CXRCVCURMBFFOL-FXQIFTODSA-N 0.000 description 1
- AWZKCUCQJNTBAD-SRVKXCTJSA-N Ala-Leu-Lys Chemical compound C[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](C(O)=O)CCCCN AWZKCUCQJNTBAD-SRVKXCTJSA-N 0.000 description 1
- OYJCVIGKMXUVKB-GARJFASQSA-N Ala-Leu-Pro Chemical compound C[C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N1CCC[C@@H]1C(=O)O)N OYJCVIGKMXUVKB-GARJFASQSA-N 0.000 description 1
- MDNAVFBZPROEHO-DCAQKATOSA-N Ala-Lys-Val Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C(C)C)C(O)=O MDNAVFBZPROEHO-DCAQKATOSA-N 0.000 description 1
- MDNAVFBZPROEHO-UHFFFAOYSA-N Ala-Lys-Val Natural products CC(C)C(C(O)=O)NC(=O)C(NC(=O)C(C)N)CCCCN MDNAVFBZPROEHO-UHFFFAOYSA-N 0.000 description 1
- IORKCNUBHNIMKY-CIUDSAMLSA-N Ala-Pro-Glu Chemical compound C[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCC(O)=O)C(O)=O IORKCNUBHNIMKY-CIUDSAMLSA-N 0.000 description 1
- WQLDNOCHHRISMS-NAKRPEOUSA-N Ala-Pro-Ile Chemical compound [H]N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)N[C@@H]([C@@H](C)CC)C(O)=O WQLDNOCHHRISMS-NAKRPEOUSA-N 0.000 description 1
- MSWSRLGNLKHDEI-ACZMJKKPSA-N Ala-Ser-Glu Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(O)=O)C(O)=O MSWSRLGNLKHDEI-ACZMJKKPSA-N 0.000 description 1
- HOVPGJUNRLMIOZ-CIUDSAMLSA-N Ala-Ser-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](CO)NC(=O)[C@H](C)N HOVPGJUNRLMIOZ-CIUDSAMLSA-N 0.000 description 1
- CREYEAPXISDKSB-FQPOAREZSA-N Ala-Thr-Tyr Chemical compound [H]N[C@@H](C)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O CREYEAPXISDKSB-FQPOAREZSA-N 0.000 description 1
- 201000004384 Alopecia Diseases 0.000 description 1
- 208000024827 Alzheimer disease Diseases 0.000 description 1
- 201000000736 Amenorrhea Diseases 0.000 description 1
- 206010001928 Amenorrhoea Diseases 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 239000004382 Amylase Substances 0.000 description 1
- 102000013142 Amylases Human genes 0.000 description 1
- 108010065511 Amylases Proteins 0.000 description 1
- 206010061424 Anal cancer Diseases 0.000 description 1
- 206010002388 Angina unstable Diseases 0.000 description 1
- 208000003343 Antiphospholipid Syndrome Diseases 0.000 description 1
- 108020000948 Antisense Oligonucleotides Proteins 0.000 description 1
- NGTYEHIRESTSRX-UWVGGRQHSA-N Arg-Lys-Gly Chemical compound NCCCC[C@@H](C(=O)NCC(O)=O)NC(=O)[C@@H](N)CCCN=C(N)N NGTYEHIRESTSRX-UWVGGRQHSA-N 0.000 description 1
- JCROZIFVIYMXHM-GUBZILKMSA-N Arg-Met-Ser Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](CCSC)NC(=O)[C@@H](N)CCCN=C(N)N JCROZIFVIYMXHM-GUBZILKMSA-N 0.000 description 1
- ISJWBVIYRBAXEB-CIUDSAMLSA-N Arg-Ser-Glu Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(O)=O)C(O)=O ISJWBVIYRBAXEB-CIUDSAMLSA-N 0.000 description 1
- FXGMURPOWCKNAZ-JYJNAYRXSA-N Arg-Val-Phe Chemical compound NC(N)=NCCC[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 FXGMURPOWCKNAZ-JYJNAYRXSA-N 0.000 description 1
- BFYIZQONLCFLEV-DAELLWKTSA-N Aromasine Chemical compound O=C1C=C[C@]2(C)[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CC(=C)C2=C1 BFYIZQONLCFLEV-DAELLWKTSA-N 0.000 description 1
- 102000014654 Aromatase Human genes 0.000 description 1
- 108010078554 Aromatase Proteins 0.000 description 1
- SLKLLQWZQHXYSV-CIUDSAMLSA-N Asn-Ala-Lys Chemical compound NC(=O)C[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCN)C(O)=O SLKLLQWZQHXYSV-CIUDSAMLSA-N 0.000 description 1
- XSGBIBGAMKTHMY-WHFBIAKZSA-N Asn-Asp-Gly Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(O)=O)C(=O)NCC(O)=O XSGBIBGAMKTHMY-WHFBIAKZSA-N 0.000 description 1
- OLGCWMNDJTWQAG-GUBZILKMSA-N Asn-Glu-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](N)CC(N)=O OLGCWMNDJTWQAG-GUBZILKMSA-N 0.000 description 1
- DXVMJJNAOVECBA-WHFBIAKZSA-N Asn-Gly-Asn Chemical compound NC(=O)C[C@H](N)C(=O)NCC(=O)N[C@@H](CC(N)=O)C(O)=O DXVMJJNAOVECBA-WHFBIAKZSA-N 0.000 description 1
- PNHQRQTVBRDIEF-CIUDSAMLSA-N Asn-Leu-Ala Chemical compound C[C@@H](C(=O)O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(=O)N)N PNHQRQTVBRDIEF-CIUDSAMLSA-N 0.000 description 1
- HDHZCEDPLTVHFZ-GUBZILKMSA-N Asn-Leu-Glu Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(O)=O HDHZCEDPLTVHFZ-GUBZILKMSA-N 0.000 description 1
- RBOBTTLFPRSXKZ-BZSNNMDCSA-N Asn-Phe-Tyr Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O RBOBTTLFPRSXKZ-BZSNNMDCSA-N 0.000 description 1
- SUIJFTJDTJKSRK-IHRRRGAJSA-N Asn-Pro-Tyr Chemical compound NC(=O)C[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 SUIJFTJDTJKSRK-IHRRRGAJSA-N 0.000 description 1
- LGCVSPFCFXWUEY-IHPCNDPISA-N Asn-Trp-Tyr Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)N[C@@H](CC3=CC=C(C=C3)O)C(=O)O)NC(=O)[C@H](CC(=O)N)N LGCVSPFCFXWUEY-IHPCNDPISA-N 0.000 description 1
- MRQQMVZUHXUPEV-IHRRRGAJSA-N Asp-Arg-Phe Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O MRQQMVZUHXUPEV-IHRRRGAJSA-N 0.000 description 1
- XYBJLTKSGFBLCS-QXEWZRGKSA-N Asp-Arg-Val Chemical compound NC(N)=NCCC[C@@H](C(=O)N[C@@H](C(C)C)C(O)=O)NC(=O)[C@@H](N)CC(O)=O XYBJLTKSGFBLCS-QXEWZRGKSA-N 0.000 description 1
- YNQIDCRRTWGHJD-ZLUOBGJFSA-N Asp-Asn-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](N)CC(O)=O YNQIDCRRTWGHJD-ZLUOBGJFSA-N 0.000 description 1
- HSWYMWGDMPLTTH-FXQIFTODSA-N Asp-Glu-Gln Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(N)=O)C(O)=O HSWYMWGDMPLTTH-FXQIFTODSA-N 0.000 description 1
- SNDBKTFJWVEVPO-WHFBIAKZSA-N Asp-Gly-Ser Chemical compound [H]N[C@@H](CC(O)=O)C(=O)NCC(=O)N[C@@H](CO)C(O)=O SNDBKTFJWVEVPO-WHFBIAKZSA-N 0.000 description 1
- QNFRBNZGVVKBNJ-PEFMBERDSA-N Asp-Ile-Gln Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)O)NC(=O)[C@H](CC(=O)O)N QNFRBNZGVVKBNJ-PEFMBERDSA-N 0.000 description 1
- HOBNTSHITVVNBN-ZPFDUUQYSA-N Asp-Ile-Leu Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC(C)C)C(=O)O)NC(=O)[C@H](CC(=O)O)N HOBNTSHITVVNBN-ZPFDUUQYSA-N 0.000 description 1
- KYQNAIMCTRZLNP-QSFUFRPTSA-N Asp-Ile-Val Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C(C)C)C(O)=O KYQNAIMCTRZLNP-QSFUFRPTSA-N 0.000 description 1
- NVFSJIXJZCDICF-SRVKXCTJSA-N Asp-Lys-Lys Chemical compound C(CCN)C[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CC(=O)O)N NVFSJIXJZCDICF-SRVKXCTJSA-N 0.000 description 1
- AHWRSSLYSGLBGD-CIUDSAMLSA-N Asp-Pro-Glu Chemical compound OC(=O)C[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCC(O)=O)C(O)=O AHWRSSLYSGLBGD-CIUDSAMLSA-N 0.000 description 1
- VNXQRBXEQXLERQ-CIUDSAMLSA-N Asp-Ser-Lys Chemical compound C(CCN)C[C@@H](C(=O)O)NC(=O)[C@H](CO)NC(=O)[C@H](CC(=O)O)N VNXQRBXEQXLERQ-CIUDSAMLSA-N 0.000 description 1
- YIDFBWRHIYOYAA-LKXGYXEUSA-N Asp-Ser-Thr Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(O)=O YIDFBWRHIYOYAA-LKXGYXEUSA-N 0.000 description 1
- SQIARYGNVQWOSB-BZSNNMDCSA-N Asp-Tyr-Phe Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O SQIARYGNVQWOSB-BZSNNMDCSA-N 0.000 description 1
- HTSSXFASOUSJQG-IHPCNDPISA-N Asp-Tyr-Trp Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC1=CNC2=C1C=CC=C2)C(O)=O HTSSXFASOUSJQG-IHPCNDPISA-N 0.000 description 1
- XWKPSMRPIKKDDU-RCOVLWMOSA-N Asp-Val-Gly Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)NCC(O)=O XWKPSMRPIKKDDU-RCOVLWMOSA-N 0.000 description 1
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 1
- 206010003571 Astrocytoma Diseases 0.000 description 1
- 206010003827 Autoimmune hepatitis Diseases 0.000 description 1
- 241000271566 Aves Species 0.000 description 1
- NOWKCMXCCJGMRR-UHFFFAOYSA-N Aziridine Chemical compound C1CN1 NOWKCMXCCJGMRR-UHFFFAOYSA-N 0.000 description 1
- 208000028564 B-cell non-Hodgkin lymphoma Diseases 0.000 description 1
- 230000003844 B-cell-activation Effects 0.000 description 1
- 239000012664 BCL-2-inhibitor Substances 0.000 description 1
- 108091012583 BCL2 Proteins 0.000 description 1
- 102000051485 Bcl-2 family Human genes 0.000 description 1
- 108700038897 Bcl-2 family Proteins 0.000 description 1
- 229940123711 Bcl2 inhibitor Drugs 0.000 description 1
- 208000009137 Behcet syndrome Diseases 0.000 description 1
- 208000008439 Biliary Liver Cirrhosis Diseases 0.000 description 1
- 208000033222 Biliary cirrhosis primary Diseases 0.000 description 1
- 229940122361 Bisphosphonate Drugs 0.000 description 1
- 108010006654 Bleomycin Proteins 0.000 description 1
- 208000019838 Blood disease Diseases 0.000 description 1
- 208000020084 Bone disease Diseases 0.000 description 1
- 206010006002 Bone pain Diseases 0.000 description 1
- 208000003174 Brain Neoplasms Diseases 0.000 description 1
- 206010006578 Bundle-Branch Block Diseases 0.000 description 1
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 1
- 229940045513 CTLA4 antagonist Drugs 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 241000282836 Camelus dromedarius 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
- 241000282465 Canis Species 0.000 description 1
- 241000283707 Capra Species 0.000 description 1
- 208000009458 Carcinoma in Situ Diseases 0.000 description 1
- 208000020446 Cardiac disease Diseases 0.000 description 1
- 206010007559 Cardiac failure congestive Diseases 0.000 description 1
- 208000031229 Cardiomyopathies Diseases 0.000 description 1
- 102000053642 Catalytic RNA Human genes 0.000 description 1
- 108090000994 Catalytic RNA Proteins 0.000 description 1
- 241000700198 Cavia Species 0.000 description 1
- 241000700199 Cavia porcellus Species 0.000 description 1
- 101150015280 Cel gene Proteins 0.000 description 1
- 108010001857 Cell Surface Receptors Proteins 0.000 description 1
- 102100025064 Cellular tumor antigen p53 Human genes 0.000 description 1
- 206010008342 Cervix carcinoma Diseases 0.000 description 1
- 201000006082 Chickenpox Diseases 0.000 description 1
- MKQWTWSXVILIKJ-LXGUWJNJSA-N Chlorozotocin Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](C=O)NC(=O)N(N=O)CCCl MKQWTWSXVILIKJ-LXGUWJNJSA-N 0.000 description 1
- 206010008609 Cholangitis sclerosing Diseases 0.000 description 1
- 206010008635 Cholestasis Diseases 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 208000015943 Coeliac disease Diseases 0.000 description 1
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 1
- 208000035473 Communicable disease Diseases 0.000 description 1
- 102100032768 Complement receptor type 2 Human genes 0.000 description 1
- 241000222511 Coprinus Species 0.000 description 1
- 241000699800 Cricetinae Species 0.000 description 1
- 208000011231 Crohn disease Diseases 0.000 description 1
- 229930188224 Cryptophycin Natural products 0.000 description 1
- SZQCDCKIGWQAQN-FXQIFTODSA-N Cys-Arg-Ala Chemical compound [H]N[C@@H](CS)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(O)=O SZQCDCKIGWQAQN-FXQIFTODSA-N 0.000 description 1
- GEEXORWTBTUOHC-FXQIFTODSA-N Cys-Arg-Ser Chemical compound C(C[C@@H](C(=O)N[C@@H](CO)C(=O)O)NC(=O)[C@H](CS)N)CN=C(N)N GEEXORWTBTUOHC-FXQIFTODSA-N 0.000 description 1
- ZXCAQANTQWBICD-DCAQKATOSA-N Cys-Lys-Val Chemical compound CC(C)[C@@H](C(=O)O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CS)N ZXCAQANTQWBICD-DCAQKATOSA-N 0.000 description 1
- PGBLJHDDKCVSTC-CIUDSAMLSA-N Cys-Met-Gln Chemical compound CSCC[C@H](NC(=O)[C@@H](N)CS)C(=O)N[C@@H](CCC(N)=O)C(O)=O PGBLJHDDKCVSTC-CIUDSAMLSA-N 0.000 description 1
- 102000018832 Cytochromes Human genes 0.000 description 1
- 108010052832 Cytochromes Proteins 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
- 206010011878 Deafness Diseases 0.000 description 1
- NNJPGOLRFBJNIW-UHFFFAOYSA-N Demecolcine Natural products C1=C(OC)C(=O)C=C2C(NC)CCC3=CC(OC)=C(OC)C(OC)=C3C2=C1 NNJPGOLRFBJNIW-UHFFFAOYSA-N 0.000 description 1
- AUGQEEXBDZWUJY-ZLJUKNTDSA-N Diacetoxyscirpenol Chemical compound C([C@]12[C@]3(C)[C@H](OC(C)=O)[C@@H](O)[C@H]1O[C@@H]1C=C(C)CC[C@@]13COC(=O)C)O2 AUGQEEXBDZWUJY-ZLJUKNTDSA-N 0.000 description 1
- AUGQEEXBDZWUJY-UHFFFAOYSA-N Diacetoxyscirpenol Natural products CC(=O)OCC12CCC(C)=CC1OC1C(O)C(OC(C)=O)C2(C)C11CO1 AUGQEEXBDZWUJY-UHFFFAOYSA-N 0.000 description 1
- BWGNESOTFCXPMA-UHFFFAOYSA-N Dihydrogen disulfide Chemical compound SS BWGNESOTFCXPMA-UHFFFAOYSA-N 0.000 description 1
- 238000008789 Direct Bilirubin Methods 0.000 description 1
- 229930193152 Dynemicin Natural products 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 208000017701 Endocrine disease Diseases 0.000 description 1
- 206010014733 Endometrial cancer Diseases 0.000 description 1
- 206010014759 Endometrial neoplasm Diseases 0.000 description 1
- AFMYMMXSQGUCBK-UHFFFAOYSA-N Endynamicin A Natural products C1#CC=CC#CC2NC(C=3C(=O)C4=C(O)C=CC(O)=C4C(=O)C=3C(O)=C3)=C3C34OC32C(C)C(C(O)=O)=C(OC)C41 AFMYMMXSQGUCBK-UHFFFAOYSA-N 0.000 description 1
- OBMLHUPNRURLOK-XGRAFVIBSA-N Epitiostanol Chemical compound C1[C@@H]2S[C@@H]2C[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CC[C@H]21 OBMLHUPNRURLOK-XGRAFVIBSA-N 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 241000289695 Eutheria Species 0.000 description 1
- 208000010201 Exanthema Diseases 0.000 description 1
- 108010087819 Fc receptors Proteins 0.000 description 1
- 102000009109 Fc receptors Human genes 0.000 description 1
- 208000002633 Febrile Neutropenia Diseases 0.000 description 1
- 241000282324 Felis Species 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 102000009123 Fibrin Human genes 0.000 description 1
- 108010073385 Fibrin Proteins 0.000 description 1
- BWGVNKXGVNDBDI-UHFFFAOYSA-N Fibrin monomer Chemical compound CNC(=O)CNC(=O)CN BWGVNKXGVNDBDI-UHFFFAOYSA-N 0.000 description 1
- 206010053717 Fibrous histiocytoma Diseases 0.000 description 1
- MPJKWIXIYCLVCU-UHFFFAOYSA-N Folinic acid Natural products NC1=NC2=C(N(C=O)C(CNc3ccc(cc3)C(=O)NC(CCC(=O)O)CC(=O)O)CN2)C(=O)N1 MPJKWIXIYCLVCU-UHFFFAOYSA-N 0.000 description 1
- 241001069765 Fridericia <angiosperm> Species 0.000 description 1
- 208000018522 Gastrointestinal disease Diseases 0.000 description 1
- 208000012671 Gastrointestinal haemorrhages Diseases 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 208000032612 Glial tumor Diseases 0.000 description 1
- 206010018338 Glioma Diseases 0.000 description 1
- DHNWZLGBTPUTQQ-QEJZJMRPSA-N Gln-Asp-Trp Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)O)NC(=O)[C@H](CCC(=O)N)N DHNWZLGBTPUTQQ-QEJZJMRPSA-N 0.000 description 1
- ZNZPKVQURDQFFS-FXQIFTODSA-N Gln-Glu-Ser Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(O)=O ZNZPKVQURDQFFS-FXQIFTODSA-N 0.000 description 1
- XKBASPWPBXNVLQ-WDSKDSINSA-N Gln-Gly-Asn Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)NCC(=O)N[C@@H](CC(N)=O)C(O)=O XKBASPWPBXNVLQ-WDSKDSINSA-N 0.000 description 1
- FGYPOQPQTUNESW-IUCAKERBSA-N Gln-Gly-Leu Chemical compound CC(C)C[C@@H](C(=O)O)NC(=O)CNC(=O)[C@H](CCC(=O)N)N FGYPOQPQTUNESW-IUCAKERBSA-N 0.000 description 1
- XZLLTYBONVKGLO-SDDRHHMPSA-N Gln-Lys-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CCCCN)NC(=O)[C@H](CCC(=O)N)N)C(=O)O XZLLTYBONVKGLO-SDDRHHMPSA-N 0.000 description 1
- WLRYGVYQFXRJDA-DCAQKATOSA-N Gln-Pro-Pro Chemical compound NC(=O)CC[C@H](N)C(=O)N1CCC[C@H]1C(=O)N1[C@H](C(O)=O)CCC1 WLRYGVYQFXRJDA-DCAQKATOSA-N 0.000 description 1
- XKPACHRGOWQHFH-IRIUXVKKSA-N Gln-Thr-Tyr Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O XKPACHRGOWQHFH-IRIUXVKKSA-N 0.000 description 1
- ZMXZGYLINVNTKH-DZKIICNBSA-N Gln-Val-Phe Chemical compound NC(=O)CC[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 ZMXZGYLINVNTKH-DZKIICNBSA-N 0.000 description 1
- FITIQFSXXBKFFM-NRPADANISA-N Gln-Val-Ser Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CO)C(O)=O FITIQFSXXBKFFM-NRPADANISA-N 0.000 description 1
- LKDIBBOKUAASNP-FXQIFTODSA-N Glu-Ala-Glu Chemical compound OC(=O)CC[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(O)=O LKDIBBOKUAASNP-FXQIFTODSA-N 0.000 description 1
- ITYRYNUZHPNCIK-GUBZILKMSA-N Glu-Ala-Leu Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(O)=O ITYRYNUZHPNCIK-GUBZILKMSA-N 0.000 description 1
- GLWXKFRTOHKGIT-ACZMJKKPSA-N Glu-Asn-Asn Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O GLWXKFRTOHKGIT-ACZMJKKPSA-N 0.000 description 1
- IESFZVCAVACGPH-PEFMBERDSA-N Glu-Asp-Ile Chemical compound CC[C@H](C)[C@@H](C(O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@@H](N)CCC(O)=O IESFZVCAVACGPH-PEFMBERDSA-N 0.000 description 1
- HNVFSTLPVJWIDV-CIUDSAMLSA-N Glu-Glu-Gln Chemical compound OC(=O)CC[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(N)=O)C(O)=O HNVFSTLPVJWIDV-CIUDSAMLSA-N 0.000 description 1
- KASDBWKLWJKTLJ-GUBZILKMSA-N Glu-Glu-Met Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCSC)C(O)=O KASDBWKLWJKTLJ-GUBZILKMSA-N 0.000 description 1
- VGBSZQSKQRMLHD-MNXVOIDGSA-N Glu-Leu-Ile Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O VGBSZQSKQRMLHD-MNXVOIDGSA-N 0.000 description 1
- IVGJYOOGJLFKQE-AVGNSLFASA-N Glu-Leu-Lys Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CCC(=O)O)N IVGJYOOGJLFKQE-AVGNSLFASA-N 0.000 description 1
- ALMBZBOCGSVSAI-ACZMJKKPSA-N Glu-Ser-Asn Chemical compound C(CC(=O)O)[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(=O)N)C(=O)O)N ALMBZBOCGSVSAI-ACZMJKKPSA-N 0.000 description 1
- DMYACXMQUABZIQ-NRPADANISA-N Glu-Ser-Val Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(O)=O DMYACXMQUABZIQ-NRPADANISA-N 0.000 description 1
- UQULNJAARAXSPO-ZCWPNWOLSA-N Glu-Thr-Thr-Tyr Chemical compound OC(=O)CC[C@H](N)C(=O)N[C@@H]([C@H](O)C)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 UQULNJAARAXSPO-ZCWPNWOLSA-N 0.000 description 1
- MFYLRRCYBBJYPI-JYJNAYRXSA-N Glu-Tyr-Lys Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CCC(=O)O)N)O MFYLRRCYBBJYPI-JYJNAYRXSA-N 0.000 description 1
- YQPFCZVKMUVZIN-AUTRQRHGSA-N Glu-Val-Gln Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(N)=O)C(O)=O YQPFCZVKMUVZIN-AUTRQRHGSA-N 0.000 description 1
- ZYRXTRTUCAVNBQ-GVXVVHGQSA-N Glu-Val-Lys Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CCC(=O)O)N ZYRXTRTUCAVNBQ-GVXVVHGQSA-N 0.000 description 1
- 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 1
- UGVQELHRNUDMAA-BYPYZUCNSA-N Gly-Ala-Gly Chemical compound [NH3+]CC(=O)N[C@@H](C)C(=O)NCC([O-])=O UGVQELHRNUDMAA-BYPYZUCNSA-N 0.000 description 1
- VSVZIEVNUYDAFR-YUMQZZPRSA-N Gly-Ala-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)CN VSVZIEVNUYDAFR-YUMQZZPRSA-N 0.000 description 1
- XCLCVBYNGXEVDU-WHFBIAKZSA-N Gly-Asn-Ser Chemical compound NCC(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CO)C(O)=O XCLCVBYNGXEVDU-WHFBIAKZSA-N 0.000 description 1
- GRIRDMVMJJDZKV-RCOVLWMOSA-N Gly-Asn-Val Chemical compound [H]NCC(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](C(C)C)C(O)=O GRIRDMVMJJDZKV-RCOVLWMOSA-N 0.000 description 1
- BIRKKBCSAIHDDF-WDSKDSINSA-N Gly-Glu-Cys Chemical compound NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CS)C(O)=O BIRKKBCSAIHDDF-WDSKDSINSA-N 0.000 description 1
- MIIVFRCYJABHTQ-ONGXEEELSA-N Gly-Leu-Val Chemical compound [H]NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(O)=O MIIVFRCYJABHTQ-ONGXEEELSA-N 0.000 description 1
- HAOUOFNNJJLVNS-BQBZGAKWSA-N Gly-Pro-Ser Chemical compound NCC(=O)N1CCC[C@H]1C(=O)N[C@@H](CO)C(O)=O HAOUOFNNJJLVNS-BQBZGAKWSA-N 0.000 description 1
- FKYQEVBRZSFAMJ-QWRGUYRKSA-N Gly-Ser-Tyr Chemical compound NCC(=O)N[C@@H](CO)C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 FKYQEVBRZSFAMJ-QWRGUYRKSA-N 0.000 description 1
- NVTPVQLIZCOJFK-FOHZUACHSA-N Gly-Thr-Asp Chemical compound [H]NCC(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(O)=O)C(O)=O NVTPVQLIZCOJFK-FOHZUACHSA-N 0.000 description 1
- CUVBTVWFVIIDOC-YEPSODPASA-N Gly-Thr-Val Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)[C@H]([C@@H](C)O)NC(=O)CN CUVBTVWFVIIDOC-YEPSODPASA-N 0.000 description 1
- KOYUSMBPJOVSOO-XEGUGMAKSA-N Gly-Tyr-Ile Chemical compound [H]NCC(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O KOYUSMBPJOVSOO-XEGUGMAKSA-N 0.000 description 1
- ZVXMEWXHFBYJPI-LSJOCFKGSA-N Gly-Val-Ile Chemical compound [H]NCC(=O)N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O ZVXMEWXHFBYJPI-LSJOCFKGSA-N 0.000 description 1
- 208000024869 Goodpasture syndrome Diseases 0.000 description 1
- 241000282575 Gorilla Species 0.000 description 1
- 102000004269 Granulocyte Colony-Stimulating Factor Human genes 0.000 description 1
- 108010017080 Granulocyte Colony-Stimulating Factor Proteins 0.000 description 1
- 102100039620 Granulocyte-macrophage colony-stimulating factor Human genes 0.000 description 1
- 206010072579 Granulomatosis with polyangiitis Diseases 0.000 description 1
- 206010062713 Haemorrhagic diathesis Diseases 0.000 description 1
- 206010019280 Heart failures Diseases 0.000 description 1
- 102000001554 Hemoglobins Human genes 0.000 description 1
- 108010054147 Hemoglobins Proteins 0.000 description 1
- 208000032843 Hemorrhage Diseases 0.000 description 1
- 206010019799 Hepatitis viral Diseases 0.000 description 1
- WMKXFMUJRCEGRP-SRVKXCTJSA-N His-Asn-His Chemical compound C1=C(NC=N1)C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CC2=CN=CN2)C(=O)O)N WMKXFMUJRCEGRP-SRVKXCTJSA-N 0.000 description 1
- TVMNTHXFRSXZGR-IHRRRGAJSA-N His-Lys-Val Chemical compound [H]N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C(C)C)C(O)=O TVMNTHXFRSXZGR-IHRRRGAJSA-N 0.000 description 1
- ZHHLTWUOWXHVQJ-YUMQZZPRSA-N His-Ser-Gly Chemical compound C1=C(NC=N1)C[C@@H](C(=O)N[C@@H](CO)C(=O)NCC(=O)O)N ZHHLTWUOWXHVQJ-YUMQZZPRSA-N 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 101000929495 Homo sapiens Adenosine deaminase Proteins 0.000 description 1
- 101100383038 Homo sapiens CD19 gene Proteins 0.000 description 1
- 101000941929 Homo sapiens Complement receptor type 2 Proteins 0.000 description 1
- 101000746373 Homo sapiens Granulocyte-macrophage colony-stimulating factor Proteins 0.000 description 1
- 101001012157 Homo sapiens Receptor tyrosine-protein kinase erbB-2 Proteins 0.000 description 1
- 241000282620 Hylobates sp. Species 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 206010020983 Hypogammaglobulinaemia Diseases 0.000 description 1
- 208000028482 Hypothalamic disease Diseases 0.000 description 1
- 208000010159 IgA glomerulonephritis Diseases 0.000 description 1
- 206010021263 IgA nephropathy Diseases 0.000 description 1
- MKWSZEHGHSLNPF-NAKRPEOUSA-N Ile-Ala-Val Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](C)C(=O)N[C@@H](C(C)C)C(=O)O)N MKWSZEHGHSLNPF-NAKRPEOUSA-N 0.000 description 1
- FADXGVVLSPPEQY-GHCJXIJMSA-N Ile-Cys-Asn Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(=O)N)C(=O)O)N FADXGVVLSPPEQY-GHCJXIJMSA-N 0.000 description 1
- NZGTYCMLUGYMCV-XUXIUFHCSA-N Ile-Lys-Arg Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCN=C(N)N)C(=O)O)N NZGTYCMLUGYMCV-XUXIUFHCSA-N 0.000 description 1
- GLYJPWIRLBAIJH-UHFFFAOYSA-N Ile-Lys-Pro Natural products CCC(C)C(N)C(=O)NC(CCCCN)C(=O)N1CCCC1C(O)=O GLYJPWIRLBAIJH-UHFFFAOYSA-N 0.000 description 1
- VGSPNSSCMOHRRR-BJDJZHNGSA-N Ile-Ser-Lys Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCCN)C(=O)O)N VGSPNSSCMOHRRR-BJDJZHNGSA-N 0.000 description 1
- 108090001007 Interleukin-8 Proteins 0.000 description 1
- 208000005016 Intestinal Neoplasms Diseases 0.000 description 1
- FHFHNVHRVKQQHN-UHFFFAOYSA-N Islandicin Chemical compound C1=CC=C2C(=O)C3=C(O)C(C)=CC(O)=C3C(=O)C2=C1O FHFHNVHRVKQQHN-UHFFFAOYSA-N 0.000 description 1
- 208000022120 Jeavons syndrome Diseases 0.000 description 1
- 208000007766 Kaposi sarcoma Diseases 0.000 description 1
- PMGDADKJMCOXHX-UHFFFAOYSA-N L-Arginyl-L-glutamin-acetat Natural products NC(=N)NCCCC(N)C(=O)NC(CCC(N)=O)C(O)=O PMGDADKJMCOXHX-UHFFFAOYSA-N 0.000 description 1
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 1
- TYYLDKGBCJGJGW-UHFFFAOYSA-N L-tryptophan-L-tyrosine Natural products C=1NC2=CC=CC=C2C=1CC(N)C(=O)NC(C(O)=O)CC1=CC=C(O)C=C1 TYYLDKGBCJGJGW-UHFFFAOYSA-N 0.000 description 1
- 239000002118 L01XE12 - Vandetanib Substances 0.000 description 1
- 241000283953 Lagomorpha Species 0.000 description 1
- OIARJGNVARWKFP-YUMQZZPRSA-N Leu-Asn-Gly Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)NCC(O)=O OIARJGNVARWKFP-YUMQZZPRSA-N 0.000 description 1
- USTCFDAQCLDPBD-XIRDDKMYSA-N Leu-Asn-Trp Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CC1=CNC2=CC=CC=C21)C(=O)O)N USTCFDAQCLDPBD-XIRDDKMYSA-N 0.000 description 1
- PVMPDMIKUVNOBD-CIUDSAMLSA-N Leu-Asp-Ser Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(O)=O PVMPDMIKUVNOBD-CIUDSAMLSA-N 0.000 description 1
- VPKIQULSKFVCSM-SRVKXCTJSA-N Leu-Gln-Arg Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O VPKIQULSKFVCSM-SRVKXCTJSA-N 0.000 description 1
- ZTLGVASZOIKNIX-DCAQKATOSA-N Leu-Gln-Glu Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H](CCC(=O)O)C(=O)O)N ZTLGVASZOIKNIX-DCAQKATOSA-N 0.000 description 1
- LLBQJYDYOLIQAI-JYJNAYRXSA-N Leu-Glu-Tyr Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O LLBQJYDYOLIQAI-JYJNAYRXSA-N 0.000 description 1
- QJUWBDPGGYVRHY-YUMQZZPRSA-N Leu-Gly-Cys Chemical compound CC(C)C[C@@H](C(=O)NCC(=O)N[C@@H](CS)C(=O)O)N QJUWBDPGGYVRHY-YUMQZZPRSA-N 0.000 description 1
- HYMLKESRWLZDBR-WEDXCCLWSA-N Leu-Gly-Thr Chemical compound CC(C)C[C@H](N)C(=O)NCC(=O)N[C@@H]([C@@H](C)O)C(O)=O HYMLKESRWLZDBR-WEDXCCLWSA-N 0.000 description 1
- NRFGTHFONZYFNY-MGHWNKPDSA-N Leu-Ile-Tyr Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 NRFGTHFONZYFNY-MGHWNKPDSA-N 0.000 description 1
- QNBVTHNJGCOVFA-AVGNSLFASA-N Leu-Leu-Glu Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](C(O)=O)CCC(O)=O QNBVTHNJGCOVFA-AVGNSLFASA-N 0.000 description 1
- YOKVEHGYYQEQOP-QWRGUYRKSA-N Leu-Leu-Gly Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)NCC(O)=O YOKVEHGYYQEQOP-QWRGUYRKSA-N 0.000 description 1
- VCHVSKNMTXWIIP-SRVKXCTJSA-N Leu-Lys-Ser Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CO)C(O)=O VCHVSKNMTXWIIP-SRVKXCTJSA-N 0.000 description 1
- BMVFXOQHDQZAQU-DCAQKATOSA-N Leu-Pro-Asp Chemical compound CC(C)C[C@@H](C(=O)N1CCC[C@H]1C(=O)N[C@@H](CC(=O)O)C(=O)O)N BMVFXOQHDQZAQU-DCAQKATOSA-N 0.000 description 1
- SBANPBVRHYIMRR-UHFFFAOYSA-N Leu-Ser-Pro Natural products CC(C)CC(N)C(=O)NC(CO)C(=O)N1CCCC1C(O)=O SBANPBVRHYIMRR-UHFFFAOYSA-N 0.000 description 1
- AIQWYVFNBNNOLU-RHYQMDGZSA-N Leu-Thr-Val Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(O)=O AIQWYVFNBNNOLU-RHYQMDGZSA-N 0.000 description 1
- YQFZRHYZLARWDY-IHRRRGAJSA-N Leu-Val-Lys Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@H](C(O)=O)CCCCN YQFZRHYZLARWDY-IHRRRGAJSA-N 0.000 description 1
- 102000004882 Lipase Human genes 0.000 description 1
- 108090001060 Lipase Proteins 0.000 description 1
- 239000004367 Lipase Substances 0.000 description 1
- 229940123917 Lipid kinase inhibitor Drugs 0.000 description 1
- MPGHETGWWWUHPY-CIUDSAMLSA-N Lys-Ala-Asp Chemical compound OC(=O)C[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CCCCN MPGHETGWWWUHPY-CIUDSAMLSA-N 0.000 description 1
- KPJJOZUXFOLGMQ-CIUDSAMLSA-N Lys-Asp-Asn Chemical compound C(CCN)C[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](CC(=O)N)C(=O)O)N KPJJOZUXFOLGMQ-CIUDSAMLSA-N 0.000 description 1
- XNKDCYABMBBEKN-IUCAKERBSA-N Lys-Gly-Gln Chemical compound NCCCC[C@H](N)C(=O)NCC(=O)N[C@H](C(O)=O)CCC(N)=O XNKDCYABMBBEKN-IUCAKERBSA-N 0.000 description 1
- OIYWBDBHEGAVST-BZSNNMDCSA-N Lys-His-Tyr Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O OIYWBDBHEGAVST-BZSNNMDCSA-N 0.000 description 1
- GOVDTWNJCBRRBJ-DCAQKATOSA-N Lys-Met-Asn Chemical compound CSCC[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)O)NC(=O)[C@H](CCCCN)N GOVDTWNJCBRRBJ-DCAQKATOSA-N 0.000 description 1
- WGILOYIKJVQUPT-DCAQKATOSA-N Lys-Pro-Asp Chemical compound [H]N[C@@H](CCCCN)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CC(O)=O)C(O)=O WGILOYIKJVQUPT-DCAQKATOSA-N 0.000 description 1
- WQDKIVRHTQYJSN-DCAQKATOSA-N Lys-Ser-Arg Chemical compound C(CCN)C[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCN=C(N)N)C(=O)O)N WQDKIVRHTQYJSN-DCAQKATOSA-N 0.000 description 1
- CTJUSALVKAWFFU-CIUDSAMLSA-N Lys-Ser-Cys Chemical compound C(CCN)C[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CS)C(=O)O)N CTJUSALVKAWFFU-CIUDSAMLSA-N 0.000 description 1
- IOQWIOPSKJOEKI-SRVKXCTJSA-N Lys-Ser-Leu Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(O)=O IOQWIOPSKJOEKI-SRVKXCTJSA-N 0.000 description 1
- DIBZLYZXTSVGLN-CIUDSAMLSA-N Lys-Ser-Ser Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(O)=O DIBZLYZXTSVGLN-CIUDSAMLSA-N 0.000 description 1
- IEVXCWPVBYCJRZ-IXOXFDKPSA-N Lys-Thr-His Chemical compound NCCCC[C@H](N)C(=O)N[C@@H]([C@H](O)C)C(=O)N[C@H](C(O)=O)CC1=CN=CN1 IEVXCWPVBYCJRZ-IXOXFDKPSA-N 0.000 description 1
- DLCAXBGXGOVUCD-PPCPHDFISA-N Lys-Thr-Ile Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O DLCAXBGXGOVUCD-PPCPHDFISA-N 0.000 description 1
- 238000000719 MTS assay Methods 0.000 description 1
- 231100000070 MTS assay Toxicity 0.000 description 1
- 102000007651 Macrophage Colony-Stimulating Factor Human genes 0.000 description 1
- 108010046938 Macrophage Colony-Stimulating Factor Proteins 0.000 description 1
- 241000289581 Macropus sp. Species 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- VJRAUFKOOPNFIQ-UHFFFAOYSA-N Marcellomycin Natural products C12=C(O)C=3C(=O)C4=C(O)C=CC(O)=C4C(=O)C=3C=C2C(C(=O)OC)C(CC)(O)CC1OC(OC1C)CC(N(C)C)C1OC(OC1C)CC(O)C1OC1CC(O)C(O)C(C)O1 VJRAUFKOOPNFIQ-UHFFFAOYSA-N 0.000 description 1
- 229930126263 Maytansine Natural products 0.000 description 1
- 201000005505 Measles Diseases 0.000 description 1
- 108010052285 Membrane Proteins Proteins 0.000 description 1
- 102000018697 Membrane Proteins Human genes 0.000 description 1
- SJDQOYTYNGZZJX-SRVKXCTJSA-N Met-Glu-Leu Chemical compound CSCC[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(O)=O SJDQOYTYNGZZJX-SRVKXCTJSA-N 0.000 description 1
- WRXOPYNEKGZWAZ-FXQIFTODSA-N Met-Ser-Cys Chemical compound CSCC[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CS)C(O)=O WRXOPYNEKGZWAZ-FXQIFTODSA-N 0.000 description 1
- 206010051696 Metastases to meninges Diseases 0.000 description 1
- 101710151803 Mitochondrial intermediate peptidase 2 Proteins 0.000 description 1
- 229930192392 Mitomycin Natural products 0.000 description 1
- HRHKSTOGXBBQCB-UHFFFAOYSA-N Mitomycin E Natural products O=C1C(N)=C(C)C(=O)C2=C1C(COC(N)=O)C1(OC)C3N(C)C3CN12 HRHKSTOGXBBQCB-UHFFFAOYSA-N 0.000 description 1
- 102000007474 Multiprotein Complexes Human genes 0.000 description 1
- 108010085220 Multiprotein Complexes Proteins 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 102100038895 Myc proto-oncogene protein Human genes 0.000 description 1
- 208000002033 Myoclonus Diseases 0.000 description 1
- YBAFDPFAUTYYRW-UHFFFAOYSA-N N-L-alpha-glutamyl-L-leucine Natural products CC(C)CC(C(O)=O)NC(=O)C(N)CCC(O)=O YBAFDPFAUTYYRW-UHFFFAOYSA-N 0.000 description 1
- SITLTJHOQZFJGG-UHFFFAOYSA-N N-L-alpha-glutamyl-L-valine Natural products CC(C)C(C(O)=O)NC(=O)C(N)CCC(O)=O SITLTJHOQZFJGG-UHFFFAOYSA-N 0.000 description 1
- OVBPIULPVIDEAO-UHFFFAOYSA-N N-Pteroyl-L-glutaminsaeure Natural products C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)NC(CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-UHFFFAOYSA-N 0.000 description 1
- 108010079364 N-glycylalanine Proteins 0.000 description 1
- 206010028813 Nausea Diseases 0.000 description 1
- 208000012902 Nervous system disease Diseases 0.000 description 1
- 208000025966 Neurological disease Diseases 0.000 description 1
- 206010059482 Neutropenic infection Diseases 0.000 description 1
- SBGPASZOVGSOFJ-FEBARNBZSA-N Nitrarine Natural products N1C2=CC=CC=C2C(CCN23)=C1[C@H]3[C@@H]1CC[C@@H]2[C@@H]2[C@H]1NCCC2 SBGPASZOVGSOFJ-FEBARNBZSA-N 0.000 description 1
- KGTDRFCXGRULNK-UHFFFAOYSA-N Nogalamycin Natural products COC1C(OC)(C)C(OC)C(C)OC1OC1C2=C(O)C(C(=O)C3=C(O)C=C4C5(C)OC(C(C(C5O)N(C)C)O)OC4=C3C3=O)=C3C=C2C(C(=O)OC)C(C)(O)C1 KGTDRFCXGRULNK-UHFFFAOYSA-N 0.000 description 1
- 206010033109 Ototoxicity Diseases 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 241000282577 Pan troglodytes Species 0.000 description 1
- VREZDOWOLGNDPW-ALTGWBOUSA-N Pancratistatin Chemical compound C1=C2[C@H]3[C@@H](O)[C@H](O)[C@@H](O)[C@@H](O)[C@@H]3NC(=O)C2=C(O)C2=C1OCO2 VREZDOWOLGNDPW-ALTGWBOUSA-N 0.000 description 1
- VREZDOWOLGNDPW-MYVCAWNPSA-N Pancratistatin Natural products O=C1N[C@H]2[C@H](O)[C@H](O)[C@H](O)[C@H](O)[C@@H]2c2c1c(O)c1OCOc1c2 VREZDOWOLGNDPW-MYVCAWNPSA-N 0.000 description 1
- 206010033645 Pancreatitis Diseases 0.000 description 1
- 241001504519 Papio ursinus Species 0.000 description 1
- 208000018737 Parkinson disease Diseases 0.000 description 1
- 206010034277 Pemphigoid Diseases 0.000 description 1
- 201000011152 Pemphigus Diseases 0.000 description 1
- 108010057150 Peplomycin Proteins 0.000 description 1
- 108091005804 Peptidases Proteins 0.000 description 1
- 241000405070 Percophidae Species 0.000 description 1
- 206010057249 Phagocytosis Diseases 0.000 description 1
- FSPGBMWPNMRWDB-AVGNSLFASA-N Phe-Cys-Gln Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CCC(=O)N)C(=O)O)N FSPGBMWPNMRWDB-AVGNSLFASA-N 0.000 description 1
- BWTKUQPNOMMKMA-FIRPJDEBSA-N Phe-Ile-Phe Chemical compound C([C@H](N)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)C1=CC=CC=C1 BWTKUQPNOMMKMA-FIRPJDEBSA-N 0.000 description 1
- MSHZERMPZKCODG-ACRUOGEOSA-N Phe-Leu-Phe Chemical compound C([C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)C1=CC=CC=C1 MSHZERMPZKCODG-ACRUOGEOSA-N 0.000 description 1
- JDMKQHSHKJHAHR-UHFFFAOYSA-N Phe-Phe-Leu-Tyr Natural products C=1C=C(O)C=CC=1CC(C(O)=O)NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)CC1=CC=CC=C1 JDMKQHSHKJHAHR-UHFFFAOYSA-N 0.000 description 1
- JLLJTMHNXQTMCK-UBHSHLNASA-N Phe-Pro-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@@H]1CCCN1C(=O)[C@@H](N)CC1=CC=CC=C1 JLLJTMHNXQTMCK-UBHSHLNASA-N 0.000 description 1
- WWPAHTZOWURIMR-ULQDDVLXSA-N Phe-Pro-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@@H](N)CC1=CC=CC=C1 WWPAHTZOWURIMR-ULQDDVLXSA-N 0.000 description 1
- IIEOLPMQYRBZCN-SRVKXCTJSA-N Phe-Ser-Cys Chemical compound N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CO)C(=O)N[C@@H](CS)C(=O)O IIEOLPMQYRBZCN-SRVKXCTJSA-N 0.000 description 1
- BPIMVBKDLSBKIJ-FCLVOEFKSA-N Phe-Thr-Phe Chemical compound C([C@H](N)C(=O)N[C@@H]([C@H](O)C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)C1=CC=CC=C1 BPIMVBKDLSBKIJ-FCLVOEFKSA-N 0.000 description 1
- 108091000080 Phosphotransferase Proteins 0.000 description 1
- 241000276498 Pollachius virens Species 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 206010036105 Polyneuropathy Diseases 0.000 description 1
- 241000282405 Pongo abelii Species 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 208000012654 Primary biliary cholangitis Diseases 0.000 description 1
- 241000288906 Primates Species 0.000 description 1
- TUYWCHPXKQTISF-LPEHRKFASA-N Pro-Cys-Pro Chemical compound C1C[C@H](NC1)C(=O)N[C@@H](CS)C(=O)N2CCC[C@@H]2C(=O)O TUYWCHPXKQTISF-LPEHRKFASA-N 0.000 description 1
- HJSCRFZVGXAGNG-SRVKXCTJSA-N Pro-Gln-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H]1CCCN1 HJSCRFZVGXAGNG-SRVKXCTJSA-N 0.000 description 1
- UAYHMOIGIQZLFR-NHCYSSNCSA-N Pro-Gln-Val Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](C(C)C)C(O)=O UAYHMOIGIQZLFR-NHCYSSNCSA-N 0.000 description 1
- LGSANCBHSMDFDY-GARJFASQSA-N Pro-Glu-Pro Chemical compound C1C[C@H](NC1)C(=O)N[C@@H](CCC(=O)O)C(=O)N2CCC[C@@H]2C(=O)O LGSANCBHSMDFDY-GARJFASQSA-N 0.000 description 1
- VPEVBAUSTBWQHN-NHCYSSNCSA-N Pro-Glu-Val Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(O)=O VPEVBAUSTBWQHN-NHCYSSNCSA-N 0.000 description 1
- JMVQDLDPDBXAAX-YUMQZZPRSA-N Pro-Gly-Gln Chemical compound NC(=O)CC[C@@H](C(O)=O)NC(=O)CNC(=O)[C@@H]1CCCN1 JMVQDLDPDBXAAX-YUMQZZPRSA-N 0.000 description 1
- ZLXKLMHAMDENIO-DCAQKATOSA-N Pro-Lys-Asp Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(O)=O)C(O)=O ZLXKLMHAMDENIO-DCAQKATOSA-N 0.000 description 1
- PCWLNNZTBJTZRN-AVGNSLFASA-N Pro-Pro-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@H]1NCCC1 PCWLNNZTBJTZRN-AVGNSLFASA-N 0.000 description 1
- FDMKYQQYJKYCLV-GUBZILKMSA-N Pro-Pro-Ser Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@H]1NCCC1 FDMKYQQYJKYCLV-GUBZILKMSA-N 0.000 description 1
- GOMUXSCOIWIJFP-GUBZILKMSA-N Pro-Ser-Arg Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O GOMUXSCOIWIJFP-GUBZILKMSA-N 0.000 description 1
- OWQXAJQZLWHPBH-FXQIFTODSA-N Pro-Ser-Asn Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(O)=O OWQXAJQZLWHPBH-FXQIFTODSA-N 0.000 description 1
- GMJDSFYVTAMIBF-FXQIFTODSA-N Pro-Ser-Asp Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(O)=O)C(O)=O GMJDSFYVTAMIBF-FXQIFTODSA-N 0.000 description 1
- PRKWBYCXBBSLSK-GUBZILKMSA-N Pro-Ser-Val Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(O)=O PRKWBYCXBBSLSK-GUBZILKMSA-N 0.000 description 1
- 239000004365 Protease Substances 0.000 description 1
- 102100035548 Protein Bop Human genes 0.000 description 1
- 108050008794 Protein Bop Proteins 0.000 description 1
- 201000001263 Psoriatic Arthritis Diseases 0.000 description 1
- 208000036824 Psoriatic arthropathy Diseases 0.000 description 1
- 108010025216 RVF peptide Proteins 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 208000003782 Raynaud disease Diseases 0.000 description 1
- 208000012322 Raynaud phenomenon Diseases 0.000 description 1
- 102100030086 Receptor tyrosine-protein kinase erbB-2 Human genes 0.000 description 1
- 108020004511 Recombinant DNA Proteins 0.000 description 1
- 208000015634 Rectal Neoplasms Diseases 0.000 description 1
- 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 description 1
- 208000025747 Rheumatic disease Diseases 0.000 description 1
- OWPCHSCAPHNHAV-UHFFFAOYSA-N Rhizoxin Natural products C1C(O)C2(C)OC2C=CC(C)C(OC(=O)C2)CC2CC2OC2C(=O)OC1C(C)C(OC)C(C)=CC=CC(C)=CC1=COC(C)=N1 OWPCHSCAPHNHAV-UHFFFAOYSA-N 0.000 description 1
- 229930194692 Rhodomycin Natural products 0.000 description 1
- 239000008156 Ringer's lactate solution Substances 0.000 description 1
- 241000283984 Rodentia Species 0.000 description 1
- 108010040181 SF 1126 Proteins 0.000 description 1
- 101100434411 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) ADH1 gene Proteins 0.000 description 1
- 206010061934 Salivary gland cancer Diseases 0.000 description 1
- 240000004274 Sarcandra glabra Species 0.000 description 1
- 235000010842 Sarcandra glabra Nutrition 0.000 description 1
- 206010039710 Scleroderma Diseases 0.000 description 1
- OYEDZGNMSBZCIM-XGEHTFHBSA-N Ser-Arg-Thr Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(O)=O OYEDZGNMSBZCIM-XGEHTFHBSA-N 0.000 description 1
- HBOABDXGTMMDSE-GUBZILKMSA-N Ser-Arg-Val Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C(C)C)C(O)=O HBOABDXGTMMDSE-GUBZILKMSA-N 0.000 description 1
- VGNYHOBZJKWRGI-CIUDSAMLSA-N Ser-Asn-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](N)CO VGNYHOBZJKWRGI-CIUDSAMLSA-N 0.000 description 1
- ULVMNZOKDBHKKI-ACZMJKKPSA-N Ser-Gln-Asp Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(O)=O)C(O)=O ULVMNZOKDBHKKI-ACZMJKKPSA-N 0.000 description 1
- GZFAWAQTEYDKII-YUMQZZPRSA-N Ser-Gly-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)CNC(=O)[C@@H](N)CO GZFAWAQTEYDKII-YUMQZZPRSA-N 0.000 description 1
- MOINZPRHJGTCHZ-MMWGEVLESA-N Ser-Ile-Pro Chemical compound CC[C@H](C)[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](CO)N MOINZPRHJGTCHZ-MMWGEVLESA-N 0.000 description 1
- UIPXCLNLUUAMJU-JBDRJPRFSA-N Ser-Ile-Ser Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(O)=O UIPXCLNLUUAMJU-JBDRJPRFSA-N 0.000 description 1
- GJFYFGOEWLDQGW-GUBZILKMSA-N Ser-Leu-Gln Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)O)NC(=O)[C@H](CO)N GJFYFGOEWLDQGW-GUBZILKMSA-N 0.000 description 1
- GZSZPKSBVAOGIE-CIUDSAMLSA-N Ser-Lys-Ala Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(O)=O GZSZPKSBVAOGIE-CIUDSAMLSA-N 0.000 description 1
- GDUZTEQRAOXYJS-SRVKXCTJSA-N Ser-Phe-Asn Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)O)NC(=O)[C@H](CO)N GDUZTEQRAOXYJS-SRVKXCTJSA-N 0.000 description 1
- HHJFMHQYEAAOBM-ZLUOBGJFSA-N Ser-Ser-Ala Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H](C)C(O)=O HHJFMHQYEAAOBM-ZLUOBGJFSA-N 0.000 description 1
- CUXJENOFJXOSOZ-BIIVOSGPSA-N Ser-Ser-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CO)NC(=O)[C@H](CO)N)C(=O)O CUXJENOFJXOSOZ-BIIVOSGPSA-N 0.000 description 1
- XQJCEKXQUJQNNK-ZLUOBGJFSA-N Ser-Ser-Ser Chemical compound OC[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(O)=O XQJCEKXQUJQNNK-ZLUOBGJFSA-N 0.000 description 1
- PYTKULIABVRXSC-BWBBJGPYSA-N Ser-Ser-Thr Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(O)=O PYTKULIABVRXSC-BWBBJGPYSA-N 0.000 description 1
- VGQVAVQWKJLIRM-FXQIFTODSA-N Ser-Ser-Val Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(O)=O VGQVAVQWKJLIRM-FXQIFTODSA-N 0.000 description 1
- PCJLFYBAQZQOFE-KATARQTJSA-N Ser-Thr-Lys Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CO)N)O PCJLFYBAQZQOFE-KATARQTJSA-N 0.000 description 1
- RCOUFINCYASMDN-GUBZILKMSA-N Ser-Val-Met Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCSC)C(O)=O RCOUFINCYASMDN-GUBZILKMSA-N 0.000 description 1
- SIEBDTCABMZCLF-XGEHTFHBSA-N Ser-Val-Thr Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O SIEBDTCABMZCLF-XGEHTFHBSA-N 0.000 description 1
- 229920000519 Sizofiran Polymers 0.000 description 1
- 208000000453 Skin Neoplasms Diseases 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 231100000632 Spindle poison Toxicity 0.000 description 1
- 208000005718 Stomach Neoplasms Diseases 0.000 description 1
- BXFOFFBJRFZBQZ-QYWOHJEZSA-N T-2 toxin Chemical compound C([C@@]12[C@]3(C)[C@H](OC(C)=O)[C@@H](O)[C@H]1O[C@H]1[C@]3(COC(C)=O)C[C@@H](C(=C1)C)OC(=O)CC(C)C)O2 BXFOFFBJRFZBQZ-QYWOHJEZSA-N 0.000 description 1
- 208000024313 Testicular Neoplasms Diseases 0.000 description 1
- 206010057644 Testis cancer Diseases 0.000 description 1
- PXQUBKWZENPDGE-CIQUZCHMSA-N Thr-Ala-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)[C@H](C)NC(=O)[C@H]([C@@H](C)O)N PXQUBKWZENPDGE-CIQUZCHMSA-N 0.000 description 1
- KEGBFULVYKYJRD-LFSVMHDDSA-N Thr-Ala-Phe Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 KEGBFULVYKYJRD-LFSVMHDDSA-N 0.000 description 1
- YOSLMIPKOUAHKI-OLHMAJIHSA-N Thr-Asp-Asp Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(O)=O)C(O)=O YOSLMIPKOUAHKI-OLHMAJIHSA-N 0.000 description 1
- ASJDFGOPDCVXTG-KATARQTJSA-N Thr-Cys-Leu Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(C)C)C(O)=O ASJDFGOPDCVXTG-KATARQTJSA-N 0.000 description 1
- KWQBJOUOSNJDRR-XAVMHZPKSA-N Thr-Cys-Pro Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CS)C(=O)N1CCC[C@@H]1C(=O)O)N)O KWQBJOUOSNJDRR-XAVMHZPKSA-N 0.000 description 1
- DSLHSTIUAPKERR-XGEHTFHBSA-N Thr-Cys-Val Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CS)C(=O)N[C@@H](C(C)C)C(O)=O DSLHSTIUAPKERR-XGEHTFHBSA-N 0.000 description 1
- GKWNLDNXMMLRMC-GLLZPBPUSA-N Thr-Glu-Gln Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CCC(=O)N)C(=O)O)N)O GKWNLDNXMMLRMC-GLLZPBPUSA-N 0.000 description 1
- GMXIJHCBTZDAPD-QPHKQPEJSA-N Thr-Ile-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)O)NC(=O)[C@H]([C@@H](C)O)N GMXIJHCBTZDAPD-QPHKQPEJSA-N 0.000 description 1
- AMXMBCAXAZUCFA-RHYQMDGZSA-N Thr-Leu-Arg Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O AMXMBCAXAZUCFA-RHYQMDGZSA-N 0.000 description 1
- FIFDDJFLNVAVMS-RHYQMDGZSA-N Thr-Leu-Met Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(O)=O FIFDDJFLNVAVMS-RHYQMDGZSA-N 0.000 description 1
- YOOAQCZYZHGUAZ-KATARQTJSA-N Thr-Leu-Ser Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(O)=O YOOAQCZYZHGUAZ-KATARQTJSA-N 0.000 description 1
- VRUFCJZQDACGLH-UVOCVTCTSA-N Thr-Leu-Thr Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O VRUFCJZQDACGLH-UVOCVTCTSA-N 0.000 description 1
- BDGBHYCAZJPLHX-HJGDQZAQSA-N Thr-Lys-Asn Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(O)=O BDGBHYCAZJPLHX-HJGDQZAQSA-N 0.000 description 1
- KKPOGALELPLJTL-MEYUZBJRSA-N Thr-Lys-Tyr Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@@H](CCCCN)C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 KKPOGALELPLJTL-MEYUZBJRSA-N 0.000 description 1
- DXPURPNJDFCKKO-RHYQMDGZSA-N Thr-Lys-Val Chemical compound CC(C)[C@H](NC(=O)[C@H](CCCCN)NC(=O)[C@@H](N)[C@@H](C)O)C(O)=O DXPURPNJDFCKKO-RHYQMDGZSA-N 0.000 description 1
- BIBYEFRASCNLAA-CDMKHQONSA-N Thr-Phe-Gly Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@H](C(=O)NCC(O)=O)CC1=CC=CC=C1 BIBYEFRASCNLAA-CDMKHQONSA-N 0.000 description 1
- WTMPKZWHRCMMMT-KZVJFYERSA-N Thr-Pro-Ala Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](C)C(O)=O WTMPKZWHRCMMMT-KZVJFYERSA-N 0.000 description 1
- MROIJTGJGIDEEJ-RCWTZXSCSA-N Thr-Pro-Pro Chemical compound C[C@@H](O)[C@H](N)C(=O)N1CCC[C@H]1C(=O)N1[C@H](C(O)=O)CCC1 MROIJTGJGIDEEJ-RCWTZXSCSA-N 0.000 description 1
- IVDFVBVIVLJJHR-LKXGYXEUSA-N Thr-Ser-Asp Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(O)=O)C(O)=O IVDFVBVIVLJJHR-LKXGYXEUSA-N 0.000 description 1
- XHWCDRUPDNSDAZ-XKBZYTNZSA-N Thr-Ser-Glu Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(=O)O)C(=O)O)N)O XHWCDRUPDNSDAZ-XKBZYTNZSA-N 0.000 description 1
- ZMYCLHFLHRVOEA-HEIBUPTGSA-N Thr-Thr-Ser Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(O)=O ZMYCLHFLHRVOEA-HEIBUPTGSA-N 0.000 description 1
- BEZTUFWTPVOROW-KJEVXHAQSA-N Thr-Tyr-Arg Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC1=CC=C(C=C1)O)C(=O)N[C@@H](CCCN=C(N)N)C(=O)O)N)O BEZTUFWTPVOROW-KJEVXHAQSA-N 0.000 description 1
- JAWUQFCGNVEDRN-MEYUZBJRSA-N Thr-Tyr-Leu Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC1=CC=C(C=C1)O)C(=O)N[C@@H](CC(C)C)C(=O)O)N)O JAWUQFCGNVEDRN-MEYUZBJRSA-N 0.000 description 1
- OGOYMQWIWHGTGH-KZVJFYERSA-N Thr-Val-Ala Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C)C(O)=O OGOYMQWIWHGTGH-KZVJFYERSA-N 0.000 description 1
- MNYNCKZAEIAONY-XGEHTFHBSA-N Thr-Val-Ser Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CO)C(O)=O MNYNCKZAEIAONY-XGEHTFHBSA-N 0.000 description 1
- KZTLZZQTJMCGIP-ZJDVBMNYSA-N Thr-Val-Thr Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O KZTLZZQTJMCGIP-ZJDVBMNYSA-N 0.000 description 1
- 208000024770 Thyroid neoplasm Diseases 0.000 description 1
- 239000000365 Topoisomerase I Inhibitor Substances 0.000 description 1
- IWEQQRMGNVVKQW-OQKDUQJOSA-N Toremifene citrate Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O.C1=CC(OCCN(C)C)=CC=C1C(\C=1C=CC=CC=1)=C(\CCCl)C1=CC=CC=C1 IWEQQRMGNVVKQW-OQKDUQJOSA-N 0.000 description 1
- 108090000340 Transaminases Proteins 0.000 description 1
- 102000003929 Transaminases Human genes 0.000 description 1
- 108091023040 Transcription factor Proteins 0.000 description 1
- 102000040945 Transcription factor Human genes 0.000 description 1
- 208000003441 Transfusion reaction Diseases 0.000 description 1
- UMILHIMHKXVDGH-UHFFFAOYSA-N Triethylene glycol diglycidyl ether Chemical compound C1OC1COCCOCCOCCOCC1CO1 UMILHIMHKXVDGH-UHFFFAOYSA-N 0.000 description 1
- FYAMXEPQQLNQDM-UHFFFAOYSA-N Tris(1-aziridinyl)phosphine oxide Chemical compound C1CN1P(N1CC1)(=O)N1CC1 FYAMXEPQQLNQDM-UHFFFAOYSA-N 0.000 description 1
- UKINEYBQXPMOJO-UBHSHLNASA-N Trp-Asn-Ser Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CO)C(=O)O)N UKINEYBQXPMOJO-UBHSHLNASA-N 0.000 description 1
- DQDXHYIEITXNJY-BPUTZDHNSA-N Trp-Gln-Gln Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H](CCC(=O)N)C(=O)O)N DQDXHYIEITXNJY-BPUTZDHNSA-N 0.000 description 1
- NXQAOORHSYJRGH-AAEUAGOBSA-N Trp-Gly-Ser Chemical compound C1=CC=C2C(C[C@H](N)C(=O)NCC(=O)N[C@@H](CO)C(O)=O)=CNC2=C1 NXQAOORHSYJRGH-AAEUAGOBSA-N 0.000 description 1
- GQHAIUPYZPTADF-FDARSICLSA-N Trp-Ile-Arg Chemical compound C1=CC=C2C(C[C@H](N)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCCN=C(N)N)C(O)=O)=CNC2=C1 GQHAIUPYZPTADF-FDARSICLSA-N 0.000 description 1
- NLWCSMOXNKBRLC-WDSOQIARSA-N Trp-Lys-Val Chemical compound [H]N[C@@H](CC1=CNC2=C1C=CC=C2)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C(C)C)C(O)=O NLWCSMOXNKBRLC-WDSOQIARSA-N 0.000 description 1
- 108010078814 Tumor Suppressor Protein p53 Proteins 0.000 description 1
- 102000014384 Type C Phospholipases Human genes 0.000 description 1
- 108010079194 Type C Phospholipases Proteins 0.000 description 1
- QJBWZNTWJSZUOY-UWJYBYFXSA-N Tyr-Ala-Cys Chemical compound C[C@@H](C(=O)N[C@@H](CS)C(=O)O)NC(=O)[C@H](CC1=CC=C(C=C1)O)N QJBWZNTWJSZUOY-UWJYBYFXSA-N 0.000 description 1
- QUILOGWWLXMSAT-IHRRRGAJSA-N Tyr-Gln-Gln Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(O)=O QUILOGWWLXMSAT-IHRRRGAJSA-N 0.000 description 1
- SLCSPPCQWUHPPO-JYJNAYRXSA-N Tyr-Glu-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 SLCSPPCQWUHPPO-JYJNAYRXSA-N 0.000 description 1
- AZGZDDNKFFUDEH-QWRGUYRKSA-N Tyr-Gly-Ser Chemical compound OC[C@@H](C(O)=O)NC(=O)CNC(=O)[C@@H](N)CC1=CC=C(O)C=C1 AZGZDDNKFFUDEH-QWRGUYRKSA-N 0.000 description 1
- CVXURBLRELTJKO-BWAGICSOSA-N Tyr-His-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CC1=CN=CN1)NC(=O)[C@H](CC2=CC=C(C=C2)O)N)O CVXURBLRELTJKO-BWAGICSOSA-N 0.000 description 1
- SINRIKQYQJRGDQ-MEYUZBJRSA-N Tyr-Lys-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 SINRIKQYQJRGDQ-MEYUZBJRSA-N 0.000 description 1
- NHOVZGFNTGMYMI-KKUMJFAQSA-N Tyr-Ser-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 NHOVZGFNTGMYMI-KKUMJFAQSA-N 0.000 description 1
- RIVVDNTUSRVTQT-IRIUXVKKSA-N Tyr-Thr-Gln Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)O)NC(=O)[C@H](CC1=CC=C(C=C1)O)N)O RIVVDNTUSRVTQT-IRIUXVKKSA-N 0.000 description 1
- ABZWHLRQBSBPTO-RNXOBYDBSA-N Tyr-Trp-Phe Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)O)NC(=O)[C@H](CC2=CNC3=CC=CC=C32)NC(=O)[C@H](CC4=CC=C(C=C4)O)N ABZWHLRQBSBPTO-RNXOBYDBSA-N 0.000 description 1
- ANHVRCNNGJMJNG-BZSNNMDCSA-N Tyr-Tyr-Cys Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)N[C@@H](CC2=CC=C(C=C2)O)C(=O)N[C@@H](CS)C(=O)O)N)O ANHVRCNNGJMJNG-BZSNNMDCSA-N 0.000 description 1
- WYOBRXPIZVKNMF-IRXDYDNUSA-N Tyr-Tyr-Gly Chemical compound C([C@H](N)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)NCC(O)=O)C1=CC=C(O)C=C1 WYOBRXPIZVKNMF-IRXDYDNUSA-N 0.000 description 1
- 208000025865 Ulcer Diseases 0.000 description 1
- 208000007814 Unstable Angina Diseases 0.000 description 1
- 208000024780 Urticaria Diseases 0.000 description 1
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 description 1
- 206010046851 Uveitis Diseases 0.000 description 1
- ZLFHAAGHGQBQQN-GUBZILKMSA-N Val-Ala-Pro Natural products CC(C)[C@H](N)C(=O)N[C@@H](C)C(=O)N1CCC[C@H]1C(O)=O ZLFHAAGHGQBQQN-GUBZILKMSA-N 0.000 description 1
- GNWUWQAVVJQREM-NHCYSSNCSA-N Val-Asn-His Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)N GNWUWQAVVJQREM-NHCYSSNCSA-N 0.000 description 1
- QHDXUYOYTPWCSK-RCOVLWMOSA-N Val-Asp-Gly Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)NCC(=O)O)N QHDXUYOYTPWCSK-RCOVLWMOSA-N 0.000 description 1
- WDIGUPHXPBMODF-UMNHJUIQSA-N Val-Glu-Pro Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)N1CCC[C@@H]1C(=O)O)N WDIGUPHXPBMODF-UMNHJUIQSA-N 0.000 description 1
- UEHRGZCNLSWGHK-DLOVCJGASA-N Val-Glu-Val Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(O)=O UEHRGZCNLSWGHK-DLOVCJGASA-N 0.000 description 1
- ZIGZPYJXIWLQFC-QTKMDUPCSA-N Val-His-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CC1=CN=CN1)NC(=O)[C@H](C(C)C)N)O ZIGZPYJXIWLQFC-QTKMDUPCSA-N 0.000 description 1
- XTDDIVQWDXMRJL-IHRRRGAJSA-N Val-Leu-His Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)NC(=O)[C@H](C(C)C)N XTDDIVQWDXMRJL-IHRRRGAJSA-N 0.000 description 1
- SYSWVVCYSXBVJG-RHYQMDGZSA-N Val-Leu-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](C(C)C)N)O SYSWVVCYSXBVJG-RHYQMDGZSA-N 0.000 description 1
- HPANGHISDXDUQY-ULQDDVLXSA-N Val-Lys-Phe Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)O)N HPANGHISDXDUQY-ULQDDVLXSA-N 0.000 description 1
- SBJCTAZFSZXWSR-AVGNSLFASA-N Val-Met-His Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)N SBJCTAZFSZXWSR-AVGNSLFASA-N 0.000 description 1
- SSYBNWFXCFNRFN-GUBZILKMSA-N Val-Pro-Ser Chemical compound CC(C)[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CO)C(O)=O SSYBNWFXCFNRFN-GUBZILKMSA-N 0.000 description 1
- KRAHMIJVUPUOTQ-DCAQKATOSA-N Val-Ser-His Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)N KRAHMIJVUPUOTQ-DCAQKATOSA-N 0.000 description 1
- BZDGLJPROOOUOZ-XGEHTFHBSA-N Val-Thr-Cys Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CS)C(=O)O)NC(=O)[C@H](C(C)C)N)O BZDGLJPROOOUOZ-XGEHTFHBSA-N 0.000 description 1
- TVGWMCTYUFBXAP-QTKMDUPCSA-N Val-Thr-His Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)NC(=O)[C@H](C(C)C)N)O TVGWMCTYUFBXAP-QTKMDUPCSA-N 0.000 description 1
- GVNLOVJNNDZUHS-RHYQMDGZSA-N Val-Thr-Lys Chemical compound [H]N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCCN)C(O)=O GVNLOVJNNDZUHS-RHYQMDGZSA-N 0.000 description 1
- DVLWZWNAQUBZBC-ZNSHCXBVSA-N Val-Thr-Pro Chemical compound C[C@H]([C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](C(C)C)N)O DVLWZWNAQUBZBC-ZNSHCXBVSA-N 0.000 description 1
- PGBMPFKFKXYROZ-UFYCRDLUSA-N Val-Tyr-Phe Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC1=CC=C(C=C1)O)C(=O)N[C@@H](CC2=CC=CC=C2)C(=O)O)N PGBMPFKFKXYROZ-UFYCRDLUSA-N 0.000 description 1
- IECQJCJNPJVUSB-IHRRRGAJSA-N Val-Tyr-Ser Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)N[C@@H](CO)C(O)=O IECQJCJNPJVUSB-IHRRRGAJSA-N 0.000 description 1
- ZLNYBMWGPOKSLW-LSJOCFKGSA-N Val-Val-Asp Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(O)=O)C(O)=O ZLNYBMWGPOKSLW-LSJOCFKGSA-N 0.000 description 1
- ZHWZDZFWBXWPDW-GUBZILKMSA-N Val-Val-Cys Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CS)C(O)=O ZHWZDZFWBXWPDW-GUBZILKMSA-N 0.000 description 1
- LLJLBRRXKZTTRD-GUBZILKMSA-N Val-Val-Ser Chemical compound CC(C)[C@@H](C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CO)C(=O)O)N LLJLBRRXKZTTRD-GUBZILKMSA-N 0.000 description 1
- 206010046980 Varicella Diseases 0.000 description 1
- 102000005789 Vascular Endothelial Growth Factors Human genes 0.000 description 1
- 108010019530 Vascular Endothelial Growth Factors Proteins 0.000 description 1
- JXLYSJRDGCGARV-WWYNWVTFSA-N Vinblastine Natural products O=C(O[C@H]1[C@](O)(C(=O)OC)[C@@H]2N(C)c3c(cc(c(OC)c3)[C@]3(C(=O)OC)c4[nH]c5c(c4CCN4C[C@](O)(CC)C[C@H](C3)C4)cccc5)[C@@]32[C@H]2[C@@]1(CC)C=CCN2CC3)C JXLYSJRDGCGARV-WWYNWVTFSA-N 0.000 description 1
- 206010047642 Vitiligo Diseases 0.000 description 1
- 206010047700 Vomiting Diseases 0.000 description 1
- 206010047741 Vulval cancer Diseases 0.000 description 1
- PVNFMCBFDPTNQI-UIBOPQHZSA-N [(1S,2R,5S,6S,16E,18E,20R,21S)-11-chloro-21-hydroxy-12,20-dimethoxy-2,5,9,16-tetramethyl-8,23-dioxo-4,24-dioxa-9,22-diazatetracyclo[19.3.1.110,14.03,5]hexacosa-10,12,14(26),16,18-pentaen-6-yl] acetate [(1S,2R,5S,6S,16E,18E,20R,21S)-11-chloro-21-hydroxy-12,20-dimethoxy-2,5,9,16-tetramethyl-8,23-dioxo-4,24-dioxa-9,22-diazatetracyclo[19.3.1.110,14.03,5]hexacosa-10,12,14(26),16,18-pentaen-6-yl] 3-methylbutanoate [(1S,2R,5S,6S,16E,18E,20R,21S)-11-chloro-21-hydroxy-12,20-dimethoxy-2,5,9,16-tetramethyl-8,23-dioxo-4,24-dioxa-9,22-diazatetracyclo[19.3.1.110,14.03,5]hexacosa-10,12,14(26),16,18-pentaen-6-yl] 2-methylpropanoate [(1S,2R,5S,6S,16E,18E,20R,21S)-11-chloro-21-hydroxy-12,20-dimethoxy-2,5,9,16-tetramethyl-8,23-dioxo-4,24-dioxa-9,22-diazatetracyclo[19.3.1.110,14.03,5]hexacosa-10,12,14(26),16,18-pentaen-6-yl] propanoate Chemical compound CO[C@@H]1\C=C\C=C(C)\Cc2cc(OC)c(Cl)c(c2)N(C)C(=O)C[C@H](OC(C)=O)[C@]2(C)OC2[C@H](C)[C@@H]2C[C@@]1(O)NC(=O)O2.CCC(=O)O[C@H]1CC(=O)N(C)c2cc(C\C(C)=C\C=C\[C@@H](OC)[C@@]3(O)C[C@H](OC(=O)N3)[C@@H](C)C3O[C@@]13C)cc(OC)c2Cl.CO[C@@H]1\C=C\C=C(C)\Cc2cc(OC)c(Cl)c(c2)N(C)C(=O)C[C@H](OC(=O)C(C)C)[C@]2(C)OC2[C@H](C)[C@@H]2C[C@@]1(O)NC(=O)O2.CO[C@@H]1\C=C\C=C(C)\Cc2cc(OC)c(Cl)c(c2)N(C)C(=O)C[C@H](OC(=O)CC(C)C)[C@]2(C)OC2[C@H](C)[C@@H]2C[C@@]1(O)NC(=O)O2 PVNFMCBFDPTNQI-UIBOPQHZSA-N 0.000 description 1
- IHGLINDYFMDHJG-UHFFFAOYSA-N [2-(4-methoxyphenyl)-3,4-dihydronaphthalen-1-yl]-[4-(2-pyrrolidin-1-ylethoxy)phenyl]methanone Chemical compound C1=CC(OC)=CC=C1C(CCC1=CC=CC=C11)=C1C(=O)C(C=C1)=CC=C1OCCN1CCCC1 IHGLINDYFMDHJG-UHFFFAOYSA-N 0.000 description 1
- CGZHFISPYUSNJI-QLERUFQFSA-N [C@@H]1([C@H](O)[C@H](O)[C@@H](CO)O1)N1C(=O)NC(=O)C=N1.[C@@H]1([C@H](O)[C@H](O)[C@@H](CO)O1)N1C(=O)NC(=O)C=N1 Chemical compound [C@@H]1([C@H](O)[C@H](O)[C@@H](CO)O1)N1C(=O)NC(=O)C=N1.[C@@H]1([C@H](O)[C@H](O)[C@@H](CO)O1)N1C(=O)NC(=O)C=N1 CGZHFISPYUSNJI-QLERUFQFSA-N 0.000 description 1
- USDJGQLNFPZEON-UHFFFAOYSA-N [[4,6-bis(hydroxymethylamino)-1,3,5-triazin-2-yl]amino]methanol Chemical compound OCNC1=NC(NCO)=NC(NCO)=N1 USDJGQLNFPZEON-UHFFFAOYSA-N 0.000 description 1
- 230000001594 aberrant effect Effects 0.000 description 1
- 229960001138 acetylsalicylic acid Drugs 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 206010000891 acute myocardial infarction Diseases 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 230000003044 adaptive effect Effects 0.000 description 1
- 101150102866 adc1 gene Proteins 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 229950004955 adozelesin Drugs 0.000 description 1
- BYRVKDUQDLJUBX-JJCDCTGGSA-N adozelesin Chemical compound C1=CC=C2OC(C(=O)NC=3C=C4C=C(NC4=CC=3)C(=O)N3C[C@H]4C[C@]44C5=C(C(C=C43)=O)NC=C5C)=CC2=C1 BYRVKDUQDLJUBX-JJCDCTGGSA-N 0.000 description 1
- 210000004100 adrenal gland Anatomy 0.000 description 1
- 208000017515 adrenocortical insufficiency Diseases 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 229930013930 alkaloid Natural products 0.000 description 1
- 229940045714 alkyl sulfonate alkylating agent Drugs 0.000 description 1
- 229940100198 alkylating agent Drugs 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- SHGAZHPCJJPHSC-YCNIQYBTSA-N all-trans-retinoic acid Chemical compound OC(=O)\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C SHGAZHPCJJPHSC-YCNIQYBTSA-N 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 231100000360 alopecia Toxicity 0.000 description 1
- 108010050025 alpha-glutamyltryptophan Proteins 0.000 description 1
- WYTGDNHDOZPMIW-RCBQFDQVSA-N alstonine Natural products C1=CC2=C3C=CC=CC3=NC2=C2N1C[C@H]1[C@H](C)OC=C(C(=O)OC)[C@H]1C2 WYTGDNHDOZPMIW-RCBQFDQVSA-N 0.000 description 1
- 229960000473 altretamine Drugs 0.000 description 1
- 231100000540 amenorrhea Toxicity 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 235000019418 amylase Nutrition 0.000 description 1
- 201000007538 anal carcinoma Diseases 0.000 description 1
- 239000002269 analeptic agent Substances 0.000 description 1
- 229960002932 anastrozole Drugs 0.000 description 1
- YBBLVLTVTVSKRW-UHFFFAOYSA-N anastrozole Chemical compound N#CC(C)(C)C1=CC(C(C)(C#N)C)=CC(CN2N=CN=C2)=C1 YBBLVLTVTVSKRW-UHFFFAOYSA-N 0.000 description 1
- 239000003098 androgen Substances 0.000 description 1
- 229940030486 androgens Drugs 0.000 description 1
- 239000004037 angiogenesis inhibitor Substances 0.000 description 1
- 239000010775 animal oil Substances 0.000 description 1
- 230000008485 antagonism Effects 0.000 description 1
- 230000002280 anti-androgenic effect Effects 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 238000011224 anti-cancer immunotherapy Methods 0.000 description 1
- 229940046836 anti-estrogen Drugs 0.000 description 1
- 230000001833 anti-estrogenic effect Effects 0.000 description 1
- 230000000690 anti-lymphoma Effects 0.000 description 1
- 239000000051 antiandrogen Substances 0.000 description 1
- 229940030495 antiandrogen sex hormone and modulator of the genital system Drugs 0.000 description 1
- 230000000890 antigenic effect Effects 0.000 description 1
- 239000013059 antihormonal agent Substances 0.000 description 1
- 229940030600 antihypertensive agent Drugs 0.000 description 1
- 239000002220 antihypertensive agent Substances 0.000 description 1
- 229940045687 antimetabolites folic acid analogs Drugs 0.000 description 1
- 229940045988 antineoplastic drug protein kinase inhibitors Drugs 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 239000000074 antisense oligonucleotide Substances 0.000 description 1
- 238000012230 antisense oligonucleotides Methods 0.000 description 1
- 239000003698 antivitamin K Substances 0.000 description 1
- 230000001640 apoptogenic effect Effects 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 150000008209 arabinosides Chemical class 0.000 description 1
- 108010008355 arginyl-glutamine Proteins 0.000 description 1
- 108010060035 arginylproline Proteins 0.000 description 1
- 239000003886 aromatase inhibitor Substances 0.000 description 1
- 229940046844 aromatase inhibitors Drugs 0.000 description 1
- 150000005840 aryl radicals Chemical class 0.000 description 1
- 230000001174 ascending effect Effects 0.000 description 1
- 108010047857 aspartylglycine Proteins 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 230000003140 astrocytic effect Effects 0.000 description 1
- 201000005000 autoimmune gastritis Diseases 0.000 description 1
- 208000010928 autoimmune thyroid disease Diseases 0.000 description 1
- 150000001541 aziridines Chemical class 0.000 description 1
- 229950001863 bapineuzumab Drugs 0.000 description 1
- 210000000270 basal cell Anatomy 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 229950008548 bisantrene Drugs 0.000 description 1
- 150000004663 bisphosphonates Chemical class 0.000 description 1
- 229960005522 bivatuzumab mertansine Drugs 0.000 description 1
- 229950006844 bizelesin Drugs 0.000 description 1
- 210000004952 blastocoel Anatomy 0.000 description 1
- 201000000053 blastoma Diseases 0.000 description 1
- 230000000740 bleeding effect Effects 0.000 description 1
- 229960001561 bleomycin Drugs 0.000 description 1
- 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 1
- 210000000601 blood cell Anatomy 0.000 description 1
- 239000010839 body fluid Substances 0.000 description 1
- 230000036760 body temperature Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 229960005520 bryostatin Drugs 0.000 description 1
- MJQUEDHRCUIRLF-YCVQJEHTSA-N bryostatins Chemical compound C([C@@H]1CC(/[C@@H]([C@@](C(C)(C)/C=C/2)(O)O1)OC(=O)/C=C/C=C/CCC)=C\C(=O)OC)C([C@@H](C)O)OC(=O)C[C@H](O)C[C@@H](O1)C[C@H](OC(C)=O)C(C)(C)[C@]1(O)C[C@@H]1C\C(=C\C(=O)OC)C[C@H]\2O1 MJQUEDHRCUIRLF-YCVQJEHTSA-N 0.000 description 1
- 208000000594 bullous pemphigoid Diseases 0.000 description 1
- 229960002092 busulfan Drugs 0.000 description 1
- 229950009908 cactinomycin Drugs 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- BMLSTPRTEKLIPM-UHFFFAOYSA-I calcium;potassium;disodium;hydrogen carbonate;dichloride;dihydroxide;hydrate Chemical compound O.[OH-].[OH-].[Na+].[Na+].[Cl-].[Cl-].[K+].[Ca+2].OC([O-])=O BMLSTPRTEKLIPM-UHFFFAOYSA-I 0.000 description 1
- ZEWYCNBZMPELPF-UHFFFAOYSA-J calcium;potassium;sodium;2-hydroxypropanoic acid;sodium;tetrachloride Chemical compound [Na].[Na+].[Cl-].[Cl-].[Cl-].[Cl-].[K+].[Ca+2].CC(O)C(O)=O ZEWYCNBZMPELPF-UHFFFAOYSA-J 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 229930195731 calicheamicin Natural products 0.000 description 1
- IVFYLRMMHVYGJH-PVPPCFLZSA-N calusterone Chemical compound C1C[C@]2(C)[C@](O)(C)CC[C@H]2[C@@H]2[C@@H](C)CC3=CC(=O)CC[C@]3(C)[C@H]21 IVFYLRMMHVYGJH-PVPPCFLZSA-N 0.000 description 1
- 229950009823 calusterone Drugs 0.000 description 1
- 229940112129 campath Drugs 0.000 description 1
- 229940127093 camptothecin Drugs 0.000 description 1
- VSJKWCGYPAHWDS-FQEVSTJZSA-N camptothecin Chemical compound C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-FQEVSTJZSA-N 0.000 description 1
- 229950007296 cantuzumab mertansine Drugs 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 230000000747 cardiac effect Effects 0.000 description 1
- BBZDXMBRAFTCAA-AREMUKBSSA-N carzelesin Chemical compound C1=2NC=C(C)C=2C([C@H](CCl)CN2C(=O)C=3NC4=CC=C(C=C4C=3)NC(=O)C3=CC4=CC=C(C=C4O3)N(CC)CC)=C2C=C1OC(=O)NC1=CC=CC=C1 BBZDXMBRAFTCAA-AREMUKBSSA-N 0.000 description 1
- 229950007509 carzelesin Drugs 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 230000024245 cell differentiation Effects 0.000 description 1
- 230000003915 cell function Effects 0.000 description 1
- 238000001516 cell proliferation assay Methods 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 230000036755 cellular response Effects 0.000 description 1
- 201000010881 cervical cancer Diseases 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 229960001480 chlorozotocin Drugs 0.000 description 1
- 231100000359 cholestasis Toxicity 0.000 description 1
- 230000007870 cholestasis Effects 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- 208000019902 chronic diarrheal disease Diseases 0.000 description 1
- 208000025302 chronic primary adrenal insufficiency Diseases 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- ACSIXWWBWUQEHA-UHFFFAOYSA-N clodronic acid Chemical compound OP(O)(=O)C(Cl)(Cl)P(O)(O)=O ACSIXWWBWUQEHA-UHFFFAOYSA-N 0.000 description 1
- 229960002286 clodronic acid Drugs 0.000 description 1
- 229960002271 cobimetinib Drugs 0.000 description 1
- 210000001072 colon Anatomy 0.000 description 1
- 230000002281 colonystimulating effect Effects 0.000 description 1
- 238000011284 combination treatment Methods 0.000 description 1
- 108010047295 complement receptors Proteins 0.000 description 1
- 102000006834 complement receptors Human genes 0.000 description 1
- 230000004540 complement-dependent cytotoxicity Effects 0.000 description 1
- 230000021615 conjugation Effects 0.000 description 1
- 210000002808 connective tissue Anatomy 0.000 description 1
- 238000011109 contamination Methods 0.000 description 1
- 239000013068 control sample Substances 0.000 description 1
- 238000011254 conventional chemotherapy Methods 0.000 description 1
- 238000012937 correction Methods 0.000 description 1
- 230000002596 correlated effect Effects 0.000 description 1
- 239000003246 corticosteroid Substances 0.000 description 1
- 201000003278 cryoglobulinemia Diseases 0.000 description 1
- 108010006226 cryptophycin Proteins 0.000 description 1
- 108010089438 cryptophycin 1 Proteins 0.000 description 1
- 108010090203 cryptophycin 8 Proteins 0.000 description 1
- 208000004921 cutaneous lupus erythematosus Diseases 0.000 description 1
- 108010081447 cytochrophin-4 Proteins 0.000 description 1
- 229940104302 cytosine Drugs 0.000 description 1
- 239000000824 cytostatic agent Substances 0.000 description 1
- 229950006418 dactolisib Drugs 0.000 description 1
- JOGKUKXHTYWRGZ-UHFFFAOYSA-N dactolisib Chemical compound O=C1N(C)C2=CN=C3C=CC(C=4C=C5C=CC=CC5=NC=4)=CC3=C2N1C1=CC=C(C(C)(C)C#N)C=C1 JOGKUKXHTYWRGZ-UHFFFAOYSA-N 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 229960005052 demecolcine Drugs 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 201000001981 dermatomyositis Diseases 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 238000002405 diagnostic procedure Methods 0.000 description 1
- 150000004985 diamines Chemical class 0.000 description 1
- 230000035487 diastolic blood pressure Effects 0.000 description 1
- WVYXNIXAMZOZFK-UHFFFAOYSA-N diaziquone Chemical compound O=C1C(NC(=O)OCC)=C(N2CC2)C(=O)C(NC(=O)OCC)=C1N1CC1 WVYXNIXAMZOZFK-UHFFFAOYSA-N 0.000 description 1
- 229950002389 diaziquone Drugs 0.000 description 1
- 239000000539 dimer 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
- 230000003828 downregulation Effects 0.000 description 1
- ZWAOHEXOSAUJHY-ZIYNGMLESA-N doxifluridine Chemical compound O[C@@H]1[C@H](O)[C@@H](C)O[C@H]1N1C(=O)NC(=O)C(F)=C1 ZWAOHEXOSAUJHY-ZIYNGMLESA-N 0.000 description 1
- 229950005454 doxifluridine Drugs 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 238000002651 drug therapy Methods 0.000 description 1
- 229960005501 duocarmycin Drugs 0.000 description 1
- VQNATVDKACXKTF-XELLLNAOSA-N duocarmycin Chemical compound COC1=C(OC)C(OC)=C2NC(C(=O)N3C4=CC(=O)C5=C([C@@]64C[C@@H]6C3)C=C(N5)C(=O)OC)=CC2=C1 VQNATVDKACXKTF-XELLLNAOSA-N 0.000 description 1
- 229930184221 duocarmycin Natural products 0.000 description 1
- AFMYMMXSQGUCBK-AKMKHHNQSA-N dynemicin a Chemical compound C1#C\C=C/C#C[C@@H]2NC(C=3C(=O)C4=C(O)C=CC(O)=C4C(=O)C=3C(O)=C3)=C3[C@@]34O[C@]32[C@@H](C)C(C(O)=O)=C(OC)[C@H]41 AFMYMMXSQGUCBK-AKMKHHNQSA-N 0.000 description 1
- 229960000284 efalizumab Drugs 0.000 description 1
- VLCYCQAOQCDTCN-UHFFFAOYSA-N eflornithine Chemical compound NCCCC(N)(C(F)F)C(O)=O VLCYCQAOQCDTCN-UHFFFAOYSA-N 0.000 description 1
- XOPYFXBZMVTEJF-PDACKIITSA-N eleutherobin Chemical compound C(/[C@H]1[C@H](C(=CC[C@@H]1C(C)C)C)C[C@@H]([C@@]1(C)O[C@@]2(C=C1)OC)OC(=O)\C=C\C=1N=CN(C)C=1)=C2\CO[C@@H]1OC[C@@H](O)[C@@H](O)[C@@H]1OC(C)=O XOPYFXBZMVTEJF-PDACKIITSA-N 0.000 description 1
- XOPYFXBZMVTEJF-UHFFFAOYSA-N eleutherobin Natural products C1=CC2(OC)OC1(C)C(OC(=O)C=CC=1N=CN(C)C=1)CC(C(=CCC1C(C)C)C)C1C=C2COC1OCC(O)C(O)C1OC(C)=O XOPYFXBZMVTEJF-UHFFFAOYSA-N 0.000 description 1
- 201000008184 embryoma Diseases 0.000 description 1
- 210000003372 endocrine gland Anatomy 0.000 description 1
- 208000030172 endocrine system disease Diseases 0.000 description 1
- 201000003914 endometrial carcinoma Diseases 0.000 description 1
- 230000002357 endometrial effect Effects 0.000 description 1
- 229950002973 epitiostanol Drugs 0.000 description 1
- HESCAJZNRMSMJG-KKQRBIROSA-N epothilone A Chemical class C/C([C@@H]1C[C@@H]2O[C@@H]2CCC[C@@H]([C@@H]([C@@H](C)C(=O)C(C)(C)[C@@H](O)CC(=O)O1)O)C)=C\C1=CSC(C)=N1 HESCAJZNRMSMJG-KKQRBIROSA-N 0.000 description 1
- 239000000328 estrogen antagonist Substances 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 229960005237 etoglucid Drugs 0.000 description 1
- 229960005420 etoposide Drugs 0.000 description 1
- 201000005884 exanthem Diseases 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 229960000255 exemestane Drugs 0.000 description 1
- 208000015700 familial long QT syndrome Diseases 0.000 description 1
- 230000035558 fertility Effects 0.000 description 1
- 210000003754 fetus Anatomy 0.000 description 1
- 229950003499 fibrin Drugs 0.000 description 1
- 235000019152 folic acid Nutrition 0.000 description 1
- 239000011724 folic acid Substances 0.000 description 1
- 229960000304 folic acid Drugs 0.000 description 1
- 150000002224 folic acids Chemical class 0.000 description 1
- 229960004421 formestane Drugs 0.000 description 1
- OSVMTWJCGUFAOD-KZQROQTASA-N formestane Chemical compound O=C1CC[C@]2(C)[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CCC2=C1O OSVMTWJCGUFAOD-KZQROQTASA-N 0.000 description 1
- 229940044658 gallium nitrate Drugs 0.000 description 1
- 206010017758 gastric cancer Diseases 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 229960003923 gatifloxacin Drugs 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 229960000578 gemtuzumab Drugs 0.000 description 1
- 229960003297 gemtuzumab ozogamicin Drugs 0.000 description 1
- 238000001415 gene therapy Methods 0.000 description 1
- 229910052732 germanium Inorganic materials 0.000 description 1
- GNPVGFCGXDBREM-UHFFFAOYSA-N germanium atom Chemical compound [Ge] GNPVGFCGXDBREM-UHFFFAOYSA-N 0.000 description 1
- 210000001280 germinal center Anatomy 0.000 description 1
- 230000000762 glandular Effects 0.000 description 1
- 208000005017 glioblastoma Diseases 0.000 description 1
- 108010078144 glutaminyl-glycine Proteins 0.000 description 1
- 108010049041 glutamylalanine Proteins 0.000 description 1
- 150000004676 glycans Chemical class 0.000 description 1
- 150000002334 glycols Chemical class 0.000 description 1
- 229930182470 glycoside Natural products 0.000 description 1
- 108010000434 glycyl-alanyl-leucine Proteins 0.000 description 1
- 108010050475 glycyl-leucyl-tyrosine Proteins 0.000 description 1
- 108010079413 glycyl-prolyl-glutamic acid Proteins 0.000 description 1
- 108010015792 glycyllysine Proteins 0.000 description 1
- 239000003102 growth factor Substances 0.000 description 1
- 201000010536 head and neck cancer Diseases 0.000 description 1
- 208000014829 head and neck neoplasm Diseases 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 231100000888 hearing loss Toxicity 0.000 description 1
- 230000010370 hearing loss Effects 0.000 description 1
- 208000016354 hearing loss disease Diseases 0.000 description 1
- 208000014951 hematologic disease Diseases 0.000 description 1
- 210000003958 hematopoietic stem cell Anatomy 0.000 description 1
- 208000018706 hematopoietic system disease Diseases 0.000 description 1
- 208000007475 hemolytic anemia Diseases 0.000 description 1
- 208000031169 hemorrhagic disease Diseases 0.000 description 1
- 230000002440 hepatic effect Effects 0.000 description 1
- 125000005842 heteroatom Chemical group 0.000 description 1
- UUVWYPNAQBNQJQ-UHFFFAOYSA-N hexamethylmelamine Chemical compound CN(C)C1=NC(N(C)C)=NC(N(C)C)=N1 UUVWYPNAQBNQJQ-UHFFFAOYSA-N 0.000 description 1
- 201000000284 histiocytoma Diseases 0.000 description 1
- 231100000508 hormonal effect Toxicity 0.000 description 1
- 102000043395 human ADA Human genes 0.000 description 1
- 210000004408 hybridoma Anatomy 0.000 description 1
- 208000003532 hypothyroidism Diseases 0.000 description 1
- 230000002989 hypothyroidism Effects 0.000 description 1
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Substances C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 1
- 210000002865 immune cell Anatomy 0.000 description 1
- 210000000987 immune system Anatomy 0.000 description 1
- 229940127121 immunoconjugate Drugs 0.000 description 1
- 229940072221 immunoglobulins Drugs 0.000 description 1
- 230000002055 immunohistochemical effect Effects 0.000 description 1
- 239000003018 immunosuppressive agent Substances 0.000 description 1
- 229940125721 immunosuppressive agent Drugs 0.000 description 1
- 238000002513 implantation Methods 0.000 description 1
- DBIGHPPNXATHOF-UHFFFAOYSA-N improsulfan Chemical compound CS(=O)(=O)OCCCNCCCOS(C)(=O)=O DBIGHPPNXATHOF-UHFFFAOYSA-N 0.000 description 1
- 229950008097 improsulfan Drugs 0.000 description 1
- 230000001976 improved effect Effects 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 201000004933 in situ carcinoma Diseases 0.000 description 1
- 230000002779 inactivation Effects 0.000 description 1
- 208000021267 infertility disease Diseases 0.000 description 1
- 208000027866 inflammatory disease Diseases 0.000 description 1
- 206010022000 influenza Diseases 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 201000004332 intermediate coronary syndrome Diseases 0.000 description 1
- 201000002313 intestinal cancer Diseases 0.000 description 1
- 210000000936 intestine Anatomy 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 230000002427 irreversible effect Effects 0.000 description 1
- 208000002551 irritable bowel syndrome Diseases 0.000 description 1
- 208000017169 kidney disease Diseases 0.000 description 1
- 229940043355 kinase inhibitor Drugs 0.000 description 1
- 230000002045 lasting effect Effects 0.000 description 1
- 201000001715 left bundle branch hemiblock Diseases 0.000 description 1
- 108010044311 leucyl-glycyl-glycine Proteins 0.000 description 1
- 108010073472 leucyl-prolyl-proline Proteins 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 235000019421 lipase Nutrition 0.000 description 1
- 229950001750 lonafarnib Drugs 0.000 description 1
- 229960003538 lonidamine Drugs 0.000 description 1
- WDRYRZXSPDWGEB-UHFFFAOYSA-N lonidamine Chemical compound C12=CC=CC=C2C(C(=O)O)=NN1CC1=CC=C(Cl)C=C1Cl WDRYRZXSPDWGEB-UHFFFAOYSA-N 0.000 description 1
- 201000005249 lung adenocarcinoma Diseases 0.000 description 1
- 230000001926 lymphatic effect Effects 0.000 description 1
- 210000004324 lymphatic system Anatomy 0.000 description 1
- 210000004698 lymphocyte Anatomy 0.000 description 1
- 210000003712 lysosome Anatomy 0.000 description 1
- 230000001868 lysosomic effect Effects 0.000 description 1
- 108010064235 lysylglycine Proteins 0.000 description 1
- 108010038320 lysylphenylalanine Proteins 0.000 description 1
- 108010017391 lysylvaline Proteins 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 241001515942 marmosets Species 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
- 230000007246 mechanism Effects 0.000 description 1
- 229960002868 mechlorethamine hydrochloride Drugs 0.000 description 1
- QZIQJVCYUQZDIR-UHFFFAOYSA-N mechlorethamine hydrochloride Chemical compound Cl.ClCCN(C)CCCl QZIQJVCYUQZDIR-UHFFFAOYSA-N 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 201000001441 melanoma Diseases 0.000 description 1
- 108020004084 membrane receptors Proteins 0.000 description 1
- 208000037819 metastatic cancer Diseases 0.000 description 1
- 208000011575 metastatic malignant neoplasm Diseases 0.000 description 1
- 229930182817 methionine Natural products 0.000 description 1
- VJRAUFKOOPNFIQ-TVEKBUMESA-N methyl (1r,2r,4s)-4-[(2r,4s,5s,6s)-5-[(2s,4s,5s,6s)-5-[(2s,4s,5s,6s)-4,5-dihydroxy-6-methyloxan-2-yl]oxy-4-hydroxy-6-methyloxan-2-yl]oxy-4-(dimethylamino)-6-methyloxan-2-yl]oxy-2-ethyl-2,5,7,10-tetrahydroxy-6,11-dioxo-3,4-dihydro-1h-tetracene-1-carboxylat Chemical compound O([C@H]1[C@@H](O)C[C@@H](O[C@H]1C)O[C@H]1[C@H](C[C@@H](O[C@H]1C)O[C@H]1C[C@]([C@@H](C2=CC=3C(=O)C4=C(O)C=CC(O)=C4C(=O)C=3C(O)=C21)C(=O)OC)(O)CC)N(C)C)[C@H]1C[C@H](O)[C@H](O)[C@H](C)O1 VJRAUFKOOPNFIQ-TVEKBUMESA-N 0.000 description 1
- HRHKSTOGXBBQCB-VFWICMBZSA-N methylmitomycin Chemical compound O=C1C(N)=C(C)C(=O)C2=C1[C@@H](COC(N)=O)[C@@]1(OC)[C@H]3N(C)[C@H]3CN12 HRHKSTOGXBBQCB-VFWICMBZSA-N 0.000 description 1
- HPNSFSBZBAHARI-UHFFFAOYSA-N micophenolic acid Natural products OC1=C(CC=C(C)CCC(O)=O)C(OC)=C(C)C2=C1C(=O)OC2 HPNSFSBZBAHARI-UHFFFAOYSA-N 0.000 description 1
- 230000000813 microbial effect Effects 0.000 description 1
- 239000004005 microsphere Substances 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 210000003470 mitochondria Anatomy 0.000 description 1
- 210000001700 mitochondrial membrane Anatomy 0.000 description 1
- 229960003539 mitoguazone Drugs 0.000 description 1
- MXWHMTNPTTVWDM-NXOFHUPFSA-N mitoguazone Chemical compound NC(N)=N\N=C(/C)\C=N\N=C(N)N MXWHMTNPTTVWDM-NXOFHUPFSA-N 0.000 description 1
- 229950007812 mocetinostat Drugs 0.000 description 1
- 239000003607 modifier Substances 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 230000000877 morphologic effect Effects 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- 206010028417 myasthenia gravis Diseases 0.000 description 1
- 229960000951 mycophenolic acid Drugs 0.000 description 1
- NJSMWLQOCQIOPE-OCHFTUDZSA-N n-[(e)-[10-[(e)-(4,5-dihydro-1h-imidazol-2-ylhydrazinylidene)methyl]anthracen-9-yl]methylideneamino]-4,5-dihydro-1h-imidazol-2-amine Chemical compound N1CCN=C1N\N=C\C(C1=CC=CC=C11)=C(C=CC=C2)C2=C1\C=N\NC1=NCCN1 NJSMWLQOCQIOPE-OCHFTUDZSA-N 0.000 description 1
- BRZOTEHEMOQUOY-UHFFFAOYSA-N n-[bis(aziridin-1-yl)phosphoryl]benzamide Chemical compound C=1C=CC=CC=1C(=O)NP(=O)(N1CC1)N1CC1 BRZOTEHEMOQUOY-UHFFFAOYSA-N 0.000 description 1
- 239000002105 nanoparticle Substances 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 230000008693 nausea Effects 0.000 description 1
- 230000001613 neoplastic effect Effects 0.000 description 1
- 230000001537 neural effect Effects 0.000 description 1
- 210000004498 neuroglial cell Anatomy 0.000 description 1
- 208000008795 neuromyelitis optica Diseases 0.000 description 1
- 201000001119 neuropathy Diseases 0.000 description 1
- 230000007823 neuropathy Effects 0.000 description 1
- 208000004235 neutropenia Diseases 0.000 description 1
- 210000000440 neutrophil Anatomy 0.000 description 1
- SBGPASZOVGSOFJ-CHBAHTGHSA-N nitrarine Chemical compound N1C2=CC=CC=C2C(CCN23)=C1[C@H]3[C@H]1CC[C@@H]2[C@H]2[C@@H]1NCCC2 SBGPASZOVGSOFJ-CHBAHTGHSA-N 0.000 description 1
- KGTDRFCXGRULNK-JYOBTZKQSA-N nogalamycin Chemical compound CO[C@@H]1[C@@](OC)(C)[C@@H](OC)[C@H](C)O[C@H]1O[C@@H]1C2=C(O)C(C(=O)C3=C(O)C=C4[C@@]5(C)O[C@H]([C@H]([C@@H]([C@H]5O)N(C)C)O)OC4=C3C3=O)=C3C=C2[C@@H](C(=O)OC)[C@@](C)(O)C1 KGTDRFCXGRULNK-JYOBTZKQSA-N 0.000 description 1
- 229950009266 nogalamycin Drugs 0.000 description 1
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 239000002777 nucleoside Substances 0.000 description 1
- 230000020520 nucleotide-excision repair Effects 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 229960000470 omalizumab Drugs 0.000 description 1
- 238000011275 oncology therapy Methods 0.000 description 1
- 230000000174 oncolytic effect Effects 0.000 description 1
- 229940127234 oral contraceptive Drugs 0.000 description 1
- 239000003539 oral contraceptive agent Substances 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 230000008816 organ damage Effects 0.000 description 1
- 201000008482 osteoarthritis Diseases 0.000 description 1
- 208000008798 osteoma Diseases 0.000 description 1
- 201000008968 osteosarcoma Diseases 0.000 description 1
- 231100000262 ototoxicity Toxicity 0.000 description 1
- 210000001672 ovary Anatomy 0.000 description 1
- 230000016087 ovulation Effects 0.000 description 1
- 238000011375 palliative radiation therapy Methods 0.000 description 1
- VREZDOWOLGNDPW-UHFFFAOYSA-N pancratistatine Natural products C1=C2C3C(O)C(O)C(O)C(O)C3NC(=O)C2=C(O)C2=C1OCO2 VREZDOWOLGNDPW-UHFFFAOYSA-N 0.000 description 1
- 210000000496 pancreas Anatomy 0.000 description 1
- 210000001819 pancreatic juice Anatomy 0.000 description 1
- 201000001976 pemphigus vulgaris Diseases 0.000 description 1
- 208000030940 penile carcinoma Diseases 0.000 description 1
- 201000008174 penis carcinoma Diseases 0.000 description 1
- QIMGFXOHTOXMQP-GFAGFCTOSA-N peplomycin Chemical compound N([C@H](C(=O)N[C@H](C)[C@@H](O)[C@H](C)C(=O)N[C@@H]([C@H](O)C)C(=O)NCCC=1SC=C(N=1)C=1SC=C(N=1)C(=O)NCCCN[C@@H](C)C=1C=CC=CC=1)[C@@H](O[C@H]1[C@H]([C@@H](O)[C@H](O)[C@H](CO)O1)O[C@@H]1[C@H]([C@@H](OC(N)=O)[C@H](O)[C@@H](CO)O1)O)C=1NC=NC=1)C(=O)C1=NC([C@H](CC(N)=O)NC[C@H](N)C(N)=O)=NC(N)=C1C QIMGFXOHTOXMQP-GFAGFCTOSA-N 0.000 description 1
- 229950003180 peplomycin Drugs 0.000 description 1
- 208000008494 pericarditis Diseases 0.000 description 1
- 208000033808 peripheral neuropathy Diseases 0.000 description 1
- 201000002628 peritoneum cancer Diseases 0.000 description 1
- 230000008823 permeabilization Effects 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 229950003203 pexelizumab Drugs 0.000 description 1
- 230000008782 phagocytosis Effects 0.000 description 1
- 108010024654 phenylalanyl-prolyl-alanine Proteins 0.000 description 1
- 108010051242 phenylalanylserine Proteins 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 102000020233 phosphotransferase Human genes 0.000 description 1
- 239000003757 phosphotransferase inhibitor Substances 0.000 description 1
- 239000003504 photosensitizing agent Substances 0.000 description 1
- 230000036314 physical performance Effects 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 229960000952 pipobroman Drugs 0.000 description 1
- NJBFOOCLYDNZJN-UHFFFAOYSA-N pipobroman Chemical compound BrCCC(=O)N1CCN(C(=O)CCBr)CC1 NJBFOOCLYDNZJN-UHFFFAOYSA-N 0.000 description 1
- NUKCGLDCWQXYOQ-UHFFFAOYSA-N piposulfan Chemical compound CS(=O)(=O)OCCC(=O)N1CCN(C(=O)CCOS(C)(=O)=O)CC1 NUKCGLDCWQXYOQ-UHFFFAOYSA-N 0.000 description 1
- 229950001100 piposulfan Drugs 0.000 description 1
- 150000003057 platinum Chemical class 0.000 description 1
- 239000008389 polyethoxylated castor oil Substances 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 208000005987 polymyositis Diseases 0.000 description 1
- 230000007824 polyneuropathy Effects 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 229950004406 porfiromycin Drugs 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 208000037920 primary disease Diseases 0.000 description 1
- 201000000742 primary sclerosing cholangitis Diseases 0.000 description 1
- 230000000861 pro-apoptotic effect Effects 0.000 description 1
- CPTBDICYNRMXFX-UHFFFAOYSA-N procarbazine Chemical compound CNNCC1=CC=C(C(=O)NC(C)C)C=C1 CPTBDICYNRMXFX-UHFFFAOYSA-N 0.000 description 1
- 229960000624 procarbazine Drugs 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 229960003387 progesterone Drugs 0.000 description 1
- 239000000186 progesterone Substances 0.000 description 1
- 230000002250 progressing effect Effects 0.000 description 1
- 208000037821 progressive disease Diseases 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 210000002307 prostate Anatomy 0.000 description 1
- 239000003909 protein kinase inhibitor Substances 0.000 description 1
- WOLQREOUPKZMEX-UHFFFAOYSA-N pteroyltriglutamic acid Chemical compound C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)NC(CCC(=O)NC(CCC(=O)NC(CCC(O)=O)C(O)=O)C(O)=O)C(O)=O)C=C1 WOLQREOUPKZMEX-UHFFFAOYSA-N 0.000 description 1
- 150000003212 purines Chemical class 0.000 description 1
- 229950010131 puromycin Drugs 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 150000003230 pyrimidines Chemical class 0.000 description 1
- 206010037844 rash Diseases 0.000 description 1
- BMKDZUISNHGIBY-UHFFFAOYSA-N razoxane Chemical compound C1C(=O)NC(=O)CN1C(C)CN1CC(=O)NC(=O)C1 BMKDZUISNHGIBY-UHFFFAOYSA-N 0.000 description 1
- 229960000460 razoxane Drugs 0.000 description 1
- 206010038038 rectal cancer Diseases 0.000 description 1
- 201000001275 rectum cancer Diseases 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000009256 replacement therapy Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000002271 resection Methods 0.000 description 1
- QEVHRUUCFGRFIF-MDEJGZGSSA-N reserpine Chemical compound O([C@H]1[C@@H]([C@H]([C@H]2C[C@@H]3C4=C(C5=CC=C(OC)C=C5N4)CCN3C[C@H]2C1)C(=O)OC)OC)C(=O)C1=CC(OC)=C(OC)C(OC)=C1 QEVHRUUCFGRFIF-MDEJGZGSSA-N 0.000 description 1
- 229930002330 retinoic acid Natural products 0.000 description 1
- OWPCHSCAPHNHAV-LMONGJCWSA-N rhizoxin Chemical compound C/C([C@H](OC)[C@@H](C)[C@@H]1C[C@H](O)[C@]2(C)O[C@@H]2/C=C/[C@@H](C)[C@]2([H])OC(=O)C[C@@](C2)(C[C@@H]2O[C@H]2C(=O)O1)[H])=C\C=C\C(\C)=C\C1=COC(C)=N1 OWPCHSCAPHNHAV-LMONGJCWSA-N 0.000 description 1
- 108091092562 ribozyme Proteins 0.000 description 1
- 229960004641 rituximab Drugs 0.000 description 1
- 229950004892 rodorubicin Drugs 0.000 description 1
- NSFWWJIQIKBZMJ-PAGWOCKZSA-N roridin a Chemical compound C([C@@]12[C@]3(C)[C@H]4C[C@H]1O[C@@H]1C=C(C)CC[C@@]13COC(=O)[C@@H](O)[C@H](C)CCO[C@H](\C=C\C=C/C(=O)O4)[C@H](O)C)O2 NSFWWJIQIKBZMJ-PAGWOCKZSA-N 0.000 description 1
- VHXNKPBCCMUMSW-FQEVSTJZSA-N rubitecan Chemical compound C1=CC([N+]([O-])=O)=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VHXNKPBCCMUMSW-FQEVSTJZSA-N 0.000 description 1
- 229950005374 ruplizumab Drugs 0.000 description 1
- 231100000279 safety data Toxicity 0.000 description 1
- 210000003296 saliva Anatomy 0.000 description 1
- 201000003804 salivary gland carcinoma Diseases 0.000 description 1
- 229930182947 sarcodictyin Natural products 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 208000010157 sclerosing cholangitis Diseases 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 230000003248 secreting effect Effects 0.000 description 1
- 210000000582 semen Anatomy 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 108010069117 seryl-lysyl-aspartic acid Proteins 0.000 description 1
- 108010048397 seryl-lysyl-leucine Proteins 0.000 description 1
- 229950001403 sizofiran Drugs 0.000 description 1
- 210000003491 skin Anatomy 0.000 description 1
- 238000007390 skin biopsy Methods 0.000 description 1
- 201000000849 skin cancer Diseases 0.000 description 1
- 208000017520 skin disease Diseases 0.000 description 1
- 239000008354 sodium chloride injection Substances 0.000 description 1
- 229950006315 spirogermanium Drugs 0.000 description 1
- 230000002269 spontaneous effect Effects 0.000 description 1
- 201000011549 stomach cancer Diseases 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 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 1
- 230000003319 supportive effect Effects 0.000 description 1
- 238000007910 systemic administration Methods 0.000 description 1
- 230000035488 systolic blood pressure Effects 0.000 description 1
- 201000003120 testicular cancer Diseases 0.000 description 1
- 230000001361 thrombopoietic effect Effects 0.000 description 1
- 201000002510 thyroid cancer Diseases 0.000 description 1
- PLHJCIYEEKOWNM-HHHXNRCGSA-N tipifarnib Chemical compound CN1C=NC=C1[C@](N)(C=1C=C2C(C=3C=C(Cl)C=CC=3)=CC(=O)N(C)C2=CC=1)C1=CC=C(Cl)C=C1 PLHJCIYEEKOWNM-HHHXNRCGSA-N 0.000 description 1
- 229960003989 tocilizumab Drugs 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 229960000303 topotecan Drugs 0.000 description 1
- 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 1
- 229960004167 toremifene citrate Drugs 0.000 description 1
- 238000009804 total hysterectomy Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 239000003053 toxin Substances 0.000 description 1
- 231100000765 toxin Toxicity 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- 230000005945 translocation Effects 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- IUCJMVBFZDHPDX-UHFFFAOYSA-N tretamine Chemical compound C1CN1C1=NC(N2CC2)=NC(N2CC2)=N1 IUCJMVBFZDHPDX-UHFFFAOYSA-N 0.000 description 1
- 229950001353 tretamine Drugs 0.000 description 1
- 229960001727 tretinoin Drugs 0.000 description 1
- KVJXBPDAXMEYOA-CXANFOAXSA-N trilostane Chemical compound OC1=C(C#N)C[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CC[C@@]32O[C@@H]31 KVJXBPDAXMEYOA-CXANFOAXSA-N 0.000 description 1
- 229960001670 trilostane Drugs 0.000 description 1
- NOYPYLRCIDNJJB-UHFFFAOYSA-N trimetrexate Chemical compound COC1=C(OC)C(OC)=CC(NCC=2C(=C3C(N)=NC(N)=NC3=CC=2)C)=C1 NOYPYLRCIDNJJB-UHFFFAOYSA-N 0.000 description 1
- 229960001099 trimetrexate Drugs 0.000 description 1
- 229950000212 trioxifene Drugs 0.000 description 1
- 229950010147 troxacitabine Drugs 0.000 description 1
- RXRGZNYSEHTMHC-BQBZGAKWSA-N troxacitabine Chemical compound O=C1N=C(N)C=CN1[C@H]1O[C@@H](CO)OC1 RXRGZNYSEHTMHC-BQBZGAKWSA-N 0.000 description 1
- 108010080629 tryptophan-leucine Proteins 0.000 description 1
- 108010038745 tryptophylglycine Proteins 0.000 description 1
- 108010044292 tryptophyltyrosine Proteins 0.000 description 1
- HDZZVAMISRMYHH-LITAXDCLSA-N tubercidin Chemical compound C1=CC=2C(N)=NC=NC=2N1[C@@H]1O[C@@H](CO)[C@H](O)[C@H]1O HDZZVAMISRMYHH-LITAXDCLSA-N 0.000 description 1
- 229960001005 tuberculin Drugs 0.000 description 1
- 239000000107 tumor biomarker Substances 0.000 description 1
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 1
- 108010079202 tyrosyl-alanyl-cysteine Proteins 0.000 description 1
- 108010017949 tyrosyl-glycyl-glycine Proteins 0.000 description 1
- 108010071635 tyrosyl-prolyl-arginine Proteins 0.000 description 1
- 231100000397 ulcer Toxicity 0.000 description 1
- 238000002604 ultrasonography Methods 0.000 description 1
- 229960001055 uracil mustard Drugs 0.000 description 1
- SPDZFJLQFWSJGA-UHFFFAOYSA-N uredepa Chemical compound C1CN1P(=O)(NC(=O)OCC)N1CC1 SPDZFJLQFWSJGA-UHFFFAOYSA-N 0.000 description 1
- 229950006929 uredepa Drugs 0.000 description 1
- 210000003932 urinary bladder Anatomy 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 206010046766 uterine cancer Diseases 0.000 description 1
- 208000012991 uterine carcinoma Diseases 0.000 description 1
- 239000006213 vaginal ring Substances 0.000 description 1
- 108010052774 valyl-lysyl-glycyl-phenylalanyl-tyrosine Proteins 0.000 description 1
- 230000001457 vasomotor Effects 0.000 description 1
- LLDWLPRYLVPDTG-UHFFFAOYSA-N vatalanib succinate Chemical compound OC(=O)CCC(O)=O.C1=CC(Cl)=CC=C1NC(C1=CC=CC=C11)=NN=C1CC1=CC=NC=C1 LLDWLPRYLVPDTG-UHFFFAOYSA-N 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 229960003048 vinblastine Drugs 0.000 description 1
- 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 1
- 201000001862 viral hepatitis Diseases 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- 229950004393 visilizumab Drugs 0.000 description 1
- 230000008673 vomiting Effects 0.000 description 1
- 108010047303 von Willebrand Factor Proteins 0.000 description 1
- 229960001771 vorozole Drugs 0.000 description 1
- XLMPPFTZALNBFS-INIZCTEOSA-N vorozole Chemical compound C1([C@@H](C2=CC=C3N=NN(C3=C2)C)N2N=CN=C2)=CC=C(Cl)C=C1 XLMPPFTZALNBFS-INIZCTEOSA-N 0.000 description 1
- 201000005102 vulva cancer Diseases 0.000 description 1
- 229960005080 warfarin Drugs 0.000 description 1
- PJVWKTKQMONHTI-UHFFFAOYSA-N warfarin Chemical compound OC=1C2=CC=CC=C2OC(=O)C=1C(CC(=O)C)C1=CC=CC=C1 PJVWKTKQMONHTI-UHFFFAOYSA-N 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 108010027345 wheylin-1 peptide Proteins 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
- A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
- A61K47/6849—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a receptor, a cell surface antigen or a cell surface determinant
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
- A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
- A61K31/5517—1,4-Benzodiazepines, e.g. diazepam or clozapine condensed with five-membered rings having nitrogen as a ring hetero atom, e.g. imidazobenzodiazepines, triazolam
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/63—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide
- A61K31/635—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide having a heterocyclic ring, e.g. sulfadiazine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
- A61K47/545—Heterocyclic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
- A61K47/55—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug, i.e. a dimer, oligomer or polymer of pharmacologically or therapeutically active compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
- A61K47/59—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
- A61K47/60—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
- A61K47/65—Peptidic linkers, binders or spacers, e.g. peptidic enzyme-labile linkers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
- A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
- A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
Abstract
本公开涉及用于治疗诸如癌症的病理疾患的组合疗法。具体而言,本公开涉及组合疗法,所述组合疗法包括使用抗CD19抗体药物缀合物(抗CD19ADC)和抗BCL‑2剂治疗。
Description
在先申请
本申请要求2018年8月31日提交的英国申请GB1814207.5和2019年6月10日提交的英国申请GB1908225.4的优先权。
技术领域
本公开涉及用于治疗诸如癌症的病理疾患的组合疗法。具体而言,本公开涉及组合疗法,所述组合疗法包括使用抗CD19抗体药物缀合物(抗CD19 ADC)和抗BCL-2剂治疗。
背景技术
抗体疗法
已经建立用于患有癌症、免疫和血管生成病症的受试者的靶向治疗的抗体疗法(Carter,P.(2006)Nature Reviews Immunology 6:343-357)。使用抗体-药物缀合物(ADC),即免疫缀合物,局部递送细胞毒性剂或细胞抑制剂(即,在癌症治疗中杀伤或抑制肿瘤细胞的药物)以将药物部分靶向递送至肿瘤,以及使之在肿瘤细胞内积聚,而这些未缀合药剂的全身施用可能对正常细胞造成不可接受的毒性水平(Xie等人(2006)Expert.Opin.Biol.Ther.6(3):281-291;Kovtun等人(2006)Cancer Res.66(6):3214-3121;Law等人(2006)Cancer Res.66(4):2328-2337;Wu等人(2005)Nature Biotech.23(9):1137-1145;Lambert J.(2005)Current Opin.in Pharmacol.5:543-549;Hamann P.(2005)Expert Opin.Ther.Patents 15(9):1087-1103;Payne,G.(2003)Cancer Cell 3:207-212;Trail等人(2003)Cancer Immunol.Immunother.52:328-337;Syrigos andEpenetos(1999)Anticancer Research 19:605-614)。
CD19
CD19是一种在B细胞分化的早期表达并且持续表达直到触发B细胞的终末分化的95kDa膜受体(Pezzutto等人(1987),J.Immunol 138:2793;Tedder等人(1994)lmmunolToday15:437)。CD19胞外结构域含有两个被较小的潜在二硫键连接的结构域分隔开的C2型免疫球蛋白(IG)样结构域。CD19胞质结构域在结构上是独特的,但是在人类、小鼠和豚鼠之间是高度保守的(Fujimoto等人,(1998)Semin Immunol.10:267)。CD19是存在于B淋巴细胞的细胞表面的蛋白质复合物的一部分。蛋白质复合物包括CD19、CD21(补体受体,2型)、CD81(TAPA-1)和CD225(Leu-13)(Fujimoto,出处同上)。
CD19是B细胞中的跨膜信号的重要调节因子。CD19的细胞表面密度的增加或减少会影响B细胞发育和功能,从而导致疾病(诸如自身免疫性疾病或低γ球蛋白血症)。CD19复合物通过存在于B细胞膜上的两种单独的信号转导复合物的交联来增强B细胞对体内抗原的反应。与膜IgM和CD19相关的两种信号转导复合物通过不同的机制来活化磷脂酶C(PLC)。CD19和B细胞受体交联减少了活化PLC所需的IgM分子的数量。CD19还充当Arc家族激酶的扩增的特化衔接蛋白(Hasegawa等人,(2001)J Immunol 167:3190)。
CD19结合已经显示出可以同时增强和抑制B细胞活化和增殖,这取决于发生的交联的量(Tedder,1994,Immunol.Today 15:437)。CD19在超过90%的B细胞淋巴瘤上表达,并且据预测会在体外和体内影响淋巴瘤的生长。
抗CD19 ADC的治疗用途
已经确立了包含抗CD19抗体(抗CD19-ADC)的抗体药物缀合物在例如癌症治疗中的功效-参见例如WO2014/057117和WO2016/166298。
继续进行研究以进一步改善抗CD19 ADC的功效、耐受性和临床实用性。为此,本发明人已经确定了临床上有利的组合疗法,其中抗CD19 ADC与至少一种抗BCL-2剂组合施用。
发明内容
本发明作者已经确定,将抗CD19 ADC和抗BCL-2剂的组合施用于个体会产生出乎意料的临床优点。本发明人还已经确定,将抗CD19 ADC施用于已经用或正在用抗BCL-2剂治疗的个体会产生治疗功效的协同增加。
因此,在第一方面,本公开提供了一种选择适合使用抗CD19 ADC治疗的个体的方法,其中如果个体已经或正在使用抗BCL-2剂治疗,则选择所述个体进行抗CD19 ADC治疗。如果个体使用抗BCL-2剂难以治疗或进一步治疗,则可以选择所述个体进行治疗。
在另一个方面,本公开提供了一种用于治疗个体的病症的方法,所述方法包括选择适合通过第一方面的方法治疗的个体,然后将有效量的抗CD19 ADC施用于所述个体。治疗方法可以另外包括将抗BCL-2剂与抗CD19 ADC组合施用。
在另一个方面,本公开提供了一种用于治疗个体的病症的方法,所述方法包括将有效量的抗CD19 ADC和抗BCL-2剂施用于个体。可以根据第一方面的方法选择个体进行治疗。
所述病症可以是增殖性疾病,例如癌症,诸如非霍奇金淋巴瘤(包括弥漫性大B细胞淋巴瘤(DLBCL)、滤泡性淋巴瘤(FL)、套细胞淋巴瘤(MCL)、慢性淋巴性淋巴瘤(CLL)和边缘区B细胞淋巴瘤(MZBL))和白血病(诸如毛细胞白血病(HCL)、毛细胞白血病变体(HCL-v)和急性淋巴母细胞性白血病(ALL)(诸如费城染色体阳性ALL(Ph+ALL)或费城染色体阴性ALL(Ph-ALL)))。
抗CD19-ADC可以是本文所述的ADCX19。
抗BCL-2剂可以是维奈妥拉(Venetoclax)(ABT-199)、纳维托克司(navitoclax)(ABT-263)、ABT-737、S55746/BCL201和奥利默森(oblimersen)(G3139)。优选地,抗BCL-2剂是维奈妥拉(ABT-199)。
个体可以是人类。个体可以患有癌症,或者可以已经确定为患有癌症。个体可以患有或已经确定为患有CD19+癌症或CD19+肿瘤相关的非肿瘤细胞,诸如CD19+浸润性B细胞。
在所公开的方法中,抗CD19 ADC可以在抗BCL-2剂之前、与抗BCL-2剂同时或在抗BCL-2剂之后施用。所公开的方法可以包括将另外的化学治疗剂施用于个体。
在另一个方面,本公开提供了用于如本文所述的治疗方法的抗CD19 ADC或包含抗CD19 ADC的组合物。
在一个方面,本公开提供了用于如本文所述的治疗方法的抗BCL-2剂或包含抗BCL-2剂的组合物。
在另一个方面,本公开提供了抗CD19 ADC或抗BCL-2ADC在制造用于治疗个体的病症的药物中的用途,其中所述治疗包括如本文所述的治疗方法。
---------------------------------
在另一个方面,本公开提供了用于治疗个体的病症的方法的包含抗CD19 ADC的第一组合物,其中所述治疗包括将第一组合物与包含抗BCL-2剂的第二组合物组合施用。
该方面还提供了用于治疗个体的病症的方法的包含抗BCL-2剂的第一组合物,其中所述治疗包括将第一组合物与包含抗CD19 ADC的第二组合物组合施用。
所述病症可以是增殖性疾病,例如癌症,诸如非霍奇金淋巴瘤(包括弥漫性大B细胞淋巴瘤(DLBCL)、滤泡性淋巴瘤(FL)、套细胞淋巴瘤(MCL)、慢性淋巴性淋巴瘤(CLL)和边缘区B细胞淋巴瘤(MZBL))和白血病(诸如毛细胞白血病(HCL)、毛细胞白血病变体(HCL-v)和急性淋巴母细胞性白血病(ALL)(诸如费城染色体阳性ALL(Ph+ALL)或费城染色体阴性ALL(Ph-ALL)))。
抗CD19-ADC可以是本文所述的ADCX19。
抗BCL-2剂可以是维奈妥拉(Venetoclax)(ABT-199)、纳维托克司(navitoclax)(ABT-263)、ABT-737、S55746/BCL201和奥利默森(oblimersen)(G3139)。优选地,抗BCL-2剂是维奈妥拉(ABT-199)。
个体可以是人类。个体可以患有癌症,或者可以已经确定为患有癌症。个体可以患有或已经确定为患有CD19+癌症或CD19+肿瘤相关的非肿瘤细胞,诸如CD19+浸润性B细胞。
第一组合物可以在第二组合物之前、与第二组合物同时或在第二组合物之后施用。治疗可以包括将另一种化学治疗剂施用于个体。
---------------------------------
在另一个方面,本公开提供了抗CD19 ADC在制造用于治疗个体的病症的药物中的用途,其中所述药物包括抗CD19 ADC,并且其中所述治疗包括将所述药物与包含抗BCL-2剂的组合物组合施用。
该方面还提供了抗BCL-2剂在制造用于治疗个体的病症的药物中的用途,其中所述药物包括抗BCL-2剂,并且其中所述治疗包括将所述药物与包含抗CD19 ADC的组合物组合施用。
所述病症可以是增殖性疾病,例如癌症,诸如非霍奇金淋巴瘤(包括弥漫性大B细胞淋巴瘤(DLBCL)、滤泡性淋巴瘤(FL)、套细胞淋巴瘤(MCL)、慢性淋巴性淋巴瘤(CLL)和边缘区B细胞淋巴瘤(MZBL))和白血病(诸如毛细胞白血病(HCL)、毛细胞白血病变体(HCL-v)和急性淋巴母细胞性白血病(ALL)(诸如费城染色体阳性ALL(Ph+ALL)或费城染色体阴性ALL(Ph-ALL)))。
抗CD19 ADC可以是如本文所述的ADCX19。
抗BCL-2剂可以是维奈妥拉(ABT-199)、纳维托克司(ABT-263)、ABT-737、S55746/BCL201和奥利默森(G3139)。优选地,抗BCL-2剂是维奈妥拉(ABT-199)。
个体可以是人类。个体可以患有癌症,或者可以已经确定为患有癌症。个体可以患有或已经确定为患有CD19+癌症或CD19+肿瘤相关的非肿瘤细胞,诸如CD19+浸润性B细胞。
药物可以在组合物之前、与组合物同时或在组合物之后施用。治疗可以包括将另一种化学治疗剂施用于个体。
---------------------------------
本公开的另一个方面提供了一种药盒,所述药盒包括:
第一药物,所述第一药物包括抗CD19 ADC;
包装插页,所述包装插页包括根据如本文公开的治疗方法的第一药物的施用说明。所述药盒可以另外包括第二药物,所述第二药物包括抗BCL-2剂。
本公开的另一个方面提供了一种药盒,所述药盒包括:
第一药物,所述第一药物包括抗CD19 ADC;
第二药物,所述第二药物包括抗BCL-2剂;以及任选地,
包装插页,所述包装插页包括将第一药物与第二药物组合施用于个体以治疗病症的说明。
该方面还提供了一种药盒,所述药盒包括包含抗CD19 ADC的药物和包装插页,所述包装插页包括将所述药物与包含抗BCL-2剂的组合物组合施用于个体以治疗病症的说明。
该方面还提供了一种药盒,所述药盒包括包含抗BCL-2剂的药物和包装插页,所述包装插页包括将所述药物与包含抗CD19 ADC的组合物组合施用于个体以治疗病症的说明。
所述病症可以是增殖性疾病,例如癌症,诸如非霍奇金淋巴瘤(包括弥漫性大B细胞淋巴瘤(DLBCL)、滤泡性淋巴瘤(FL)、套细胞淋巴瘤(MCL)、慢性淋巴性淋巴瘤(CLL)和边缘区B细胞淋巴瘤(MZBL))和白血病(诸如毛细胞白血病(HCL)、毛细胞白血病变体(HCL-v)和急性淋巴母细胞性白血病(ALL)(诸如费城染色体阳性ALL(Ph+ALL)或费城染色体阴性ALL(Ph-ALL)))。
抗CD19 ADC可以是如本文所述的ADCX19。
抗BCL-2剂可以是维奈妥拉(ABT-199)、纳维托克司(ABT-263)、ABT-737、S55746/BCL201和奥利默森(G3139)。优选地,抗BCL-2剂是维奈妥拉(ABT-199)。
个体可以是人类。个体可以患有癌症,或者可以已经确定为患有癌症。个体可以患有或已经确定为患有CD19+癌症或CD19+肿瘤相关的非肿瘤细胞,诸如CD19+浸润性B细胞。
包含抗CD19 ADC的药物或组合物可以在包含抗BCL-2剂的药物或组合物之前、与包含抗BCL-2剂的药物或组合物同时或者在包含抗BCL-2剂的药物或组合物之后施用。治疗可以包括将另一种化学治疗剂施用于个体。
---------------------------------
在又一个方面,本公开提供了包含抗CD19 ADC和抗BCL-2剂的组合物。
本公开的该方面还提供了一种治疗个体的病症的方法,所述方法包括将有效量的包含抗CD19 ADC和抗BCL-2剂的组合物施用于个体。
本公开的该方面还提供了用于治疗个体的病症的方法的包含抗CD19 ADC和抗BCL-2剂的组合物。
本公开的该方面还提供了包含抗CD19 ADC和抗BCL-2剂的组合物在制造用于治疗个体的病症的药物中的用途。
本公开的该方面还提供了一种药盒,所述药盒包括包含抗CD19 ADC和抗BCL-2剂的组合物以及将药物施用于个体以治疗病症的一组说明。
所述病症可以是增殖性疾病,例如癌症,诸如非霍奇金淋巴瘤(包括弥漫性大B细胞淋巴瘤(DLBCL)、滤泡性淋巴瘤(FL)、套细胞淋巴瘤(MCL)、慢性淋巴性淋巴瘤(CLL)和边缘区B细胞淋巴瘤(MZBL))和白血病(诸如毛细胞白血病(HCL)、毛细胞白血病变体(HCL-v)和急性淋巴母细胞性白血病(ALL)(诸如费城染色体阳性ALL(Ph+ALL)或费城染色体阴性ALL(Ph-ALL)))。
抗CD19-ADC可以是如本文所述的ADCX19。
抗BCL-2剂可以是维奈妥拉(ABT-199)、纳维托克司(ABT-263)、ABT-737、S55746/BCL201和奥利默森(G3139)。优选地,抗BCL-2剂是维奈妥拉(ABT-199)。
个体可以是人类。个体可以患有癌症,或者可以已经确定为患有癌症。个体可以患有或已经确定为患有CD19+癌症或CD19+肿瘤相关的非肿瘤细胞,诸如CD19+浸润性B细胞。
治疗可以包括将另一种化学治疗剂施用于个体。
具体实施方式
抗体药物缀合物(ADC)
本公开涉及ADC和抗BCL-2剂的组合的改善的功效。
ADC可以将药物递送至靶标位置。靶标位置优选地是增殖性细胞群。抗体是针对增殖性细胞群上存在的抗原的抗体。在一个方面,与增殖性细胞群(例如肿瘤细胞群)中存在的抗原的量相比,非增殖性细胞群中不存在抗原或存在低水平的抗原。
ADC可以包括可以被切割以将药物释放在靶标位置的接头。药物可以是选自RelA、RelB、RelC、RelD或RelE的化合物。因此,缀合物可以用于将化合物RelA、RelB、RelC、RelD或RelE选择性地提供至靶标位置。
接头可以被存在于靶标位置的酶切割。
本公开特别涉及使用WO2014/057117中公开并且如本文所述的抗CD19 ADC进行的治疗。
抗CD19 ADC
如本文所用,术语“抗CD19 ADC”或“CD19-ADC”是指其中抗体组分是抗CD19抗体的ADC。术语“PBD-ADC”是指其中药物组分是吡咯并苯并二氮杂(PBD)弹头的ADC。术语“抗CD19-ADC”是指其中抗体组分是抗CD19抗体,并且药物组分是PBD弹头的ADC。
ADC可以包含式L-(DL)p的缀合物,其中DL为式I或II:
其中:
L是抗体(Ab),即结合至CD19的抗体;
当C2’和C3’之间存在双键时,R12选自由以下各项组成的组:
(ia)C5-10芳基基团,它任选地被一个或多个选自包含以下各项的基团的取代基取代:卤基、硝基、氰基、醚、羧基、酯、C1-7烷基、C3-7杂环基和双-氧基-C1-3亚烷基;
(ib)C1-5饱和脂族烷基;
(ic)C3-6饱和环烷基;
当C2’和C3’之间存在单键时
R12是其中R26a和R26b独立地选自H、F、C1-4饱和烷基、C2-3烯基,所述烷基和烯基基团任选地被选自C1-4烷基胺基和C1-4烷基酯的基团取代;或者,当R26a和R26b中的一个是H时,另一个选自腈和C1-4烷基酯;
R6和R9独立地选自H、R、OH、OR、SH、SR、NH2、NHR、NRR’、硝基、Me3Sn和卤基;
其中R和R’独立地选自任选地取代的C1-12烷基、C3-20杂环基和C5-20芳基基团;
R7选自H、R、OH、OR、SH、SR、NH2、NHR、NHRR’、硝基、Me3Sn和卤基;
R”是C3-12亚烷基基团,其链可以间杂有一个或多个杂原子,例如O、S、NRN2(其中RN2是H或C1-4烷基),和/或芳环(例如苯或吡啶);
Y和Y'选自O、S或NH;
R6’、R7’、R9’选自分别与R6、R7和R9相同的基团。
[式I]
RL1’是用于连接至抗体(Ab)的接头;
R11a选自OH、ORA,其中RA是C1-4烷基,和SOzM,其中z为2或3,并且M是单价药学上可接受的阳离子;
R20和R21中的任一者在它们结合的氮和碳原子之间共同形成双键,或者;
R20选自H和RC,其中RC是加帽基团;
R21选自OH、ORA和SOzM;
当C2与C3之间存在双键时,R2选自由以下组成的组:
(ia)C5-10芳基基团,它任选地被一个或多个选自包含以下各项的基团的取代基取代:卤基、硝基、氰基、醚、羧基、酯、C1-7烷基、C3-7杂环基和双-氧基-C1-3亚烷基;
(ib)C1-5饱和脂族烷基;
(ic)C3-6饱和环烷基;
当C2和C3之间存在单键时,
R2是其中R16a和R16b独立地选自H、F、C1-4饱和烷基、C2-3烯基,其中烷基和烯基基团任选地被选自C1-4烷基胺基和C1-4烷基酯的基团取代;或者,当R16a和R16b中的一个是H时,另一个选自腈和C1-4烷基酯;
[式II]
R22具有式IIIa、式IIIb或式IIIc:
其中A是C5-7芳基基团,并且
(i)Q1是单键,并且Q2选自单键和-Z-(CH2)n-,其中Z选自单键、O、S和NH,并且n为1至3;或者
(ii)Q1是-CH=CH-,并且Q2是单键;
其中;
RC1、RC2和RC3独立地选自H和未取代的C1-2烷基;
其中Q选自O-RL2'、S-RL2'和NRN-RL2',并且RN选自H、甲基和乙基
X选自包含以下各项的基团:O-RL2’、SRL2’、CO2-RL2’、CO-RL2’、NH-C(=O)-RL2’、NHNH-RL2’、CONHNH-RL2’、NRNRL2’,其中RN选自包括以下的基团:H和C1-4烷基;
RL2'是用于连接至抗体(Ab)的接头;
R10和R11中的任一者在它们结合的氮和碳原子之间共同形成双键,或者;
R10是H,并且R11选自OH、ORA和SOzM;
R30和R31中的任一者在它们结合的氮和碳原子之间共同形成双键,或者;
R30是H,并且R31选自OH、ORA和SOzM。
在一些实施方案中,L-RL1’或L-RL2’是基团:
其中星号表示与PBD的连接点,Ab是抗体,L1是可切割的接头,A是将L1连接至抗体的连接基团,L2是共价键或与-OC(=O)-共同形成自分解的接头。
在这些实施方案中的一些中,L1是酶可切割的。
此前已经表明,此类ADC可用于治疗表达CD19的癌症(参见,例如,WO2014/057117,该专利通过引用以其整体并入本文)。
术语抗CD19-ADC可以包括WO2014/057117中描述的任何实施方案。具体而言,在优选的实施方案中,ADC可以具有以下化学结构:
抗体可以包含具有根据SEQ ID NO:1、2、3、4、5或6中的任一者的序列的VH结构域,任选地还包含具有根据SEQ ID NO:7、8、9、10、11或12中的任一者的序列的VL结构域。
在一些方面,抗CD19-ADC的抗体组分是包含以下结构域的抗体:VH和VL结构域,它们分别具有以下序列:SEQ ID NO:1和SEQ ID NO:7、SEQ ID NO:2和SEQ ID NO:8、SEQ IDNO:3和SEQ ID NO:9、SEQ ID NO:4和SEQ ID NO:10、SEQ ID NO:5和SEQ ID NO:11、或SEQID NO:6和SEQ ID NO:12。
在优选的实施方案中,抗体包含具有根据SEQ ID NO:2的序列的VH结构域。在优选的实施方案中,抗体包含具有根据SEQ ID NO:8的序列的VL结构域。
在优选的实施方案中,抗体包含VH结构域和VL结构域,所述VH结构域具有SEQ IDNO:2的序列,并且所述VL结构域具有SEQ ID NO:8的序列。
一个或多个VH和VL结构域可以配对,以形成结合CD19的抗体抗原结合位点。
在一些实施方案中,抗体是包含VH结构域和VL结构域的完整抗体,所述VH结构域和VL结构域具有SEQ ID NO:2和SEQ ID NO:8的序列。
在一些实施方案中,抗体是包含具有SEQ ID NO:13的序列的重链和具有SEQ IDNO:14的序列的轻链的抗体。
在一些实施方案中,抗体是完全人单克隆IgG1抗体,优选地IgG1,κ。
在一些实施方案中,抗体是WO2014/057117中所述的RB4v1.2抗体。
在一个方面,抗体是已经如下文所述被修饰(或进一步修饰)的如本文所述的抗体。在一些实施方案中,抗体是本文公开的抗体的人源化、去免疫化或表面重整型式。
如本文以下所述,本公开的方面所使用的最优选的抗CD19-ADC是ADCx19。
本公开的方面所使用的次优选的抗CD19-ADC是ADCT-402。
ADCx19
ADCx19是一种由抗人CD19的人源化抗体组成的抗体药物缀合物,所述人源化抗体经由可切割的接头附接至吡咯并苯并二氮杂(PBD)弹头。ADCX19的作用机制取决于CD19结合。CD19特异性抗体使抗体药物缀合物(ADC)靶向表达CD19的细胞。在结合后,ADC内化并且被转运至溶酶体,在溶酶体中切下蛋白酶敏感的接头,并且在靶细胞内释放出游离的PBD二聚体。由于RNA聚合酶的直接抑制或相关转录因子的相互作用的抑制,释放的PBD二聚体以序列选择性方式抑制转录。PBD二聚体产生共价交联,所述共价交联不会使DNA双螺旋变形,并且不被核苷酸切除修复因子识别,从而允许延长有效期(Hartley 2011)。
ADCX19具有以下化学结构:
Ab表示抗体RB4v1.2(具有分别SEQ ID NO:2和SEQ ID NO:8的VH和VL序列的抗体)。它可以如WO2014/057117(RB4v1.2-E)中所述合成,并且通常具有2+/-0.3的DAR(药物与抗体的比率)。
CD19结合
如本文所用,“结合CD19”用于指抗体以比非特异性配偶体(诸如牛血清白蛋白(BSA,Genbank登录号CAA76847,版本号CAA76847.1 GI:3336842,记录更新日期:2011年1月7日,下午2:30))更高的亲和力结合CD19。在一些实施方案中,抗体结合CD19,当在生理条件下测量时,缔合常数(Ka)为针对BSA的抗体缔合常数的至少2、3、4、5、10、20、50、100、200、500、1000、2000、5000、104、105或106倍。本发明的抗体可以以高亲和力结合CD19。例如,在一些实施方案中,抗体可以结合CD19,其中KD等于或小于约10-6M,诸如1×10-6、10-7、10-8、10-9、10-10、10-11、10-12、10-13或10-14。
在一些实施方案中,CD19多肽对应于Genbank登录号NP_001171569,版本号NP_001171569.1GI:296010921,记录更新日期:2012年9月10日,上午12:43。在一个实施方案中,编码CD19多肽的核酸对应于Genbank登录号NM_001178098,版本号NM_001178098.1GI:296010920,记录更新日期:2012年9月10日,上午12:43。在一些实施方案中,CD19多肽对应于Uniprot/Swiss-Prot登录号P15391。
抗BCL-2剂
合适的抗BCL-2剂包括维奈妥拉(ABT-199)、纳维托克司(ABT-263)、ABT-737、S55746/BCL201和奥利默森(G3139)。优选地,抗BCL-2剂是维奈妥拉(ABT-199)。
BCL-2定位于线粒体的外膜,在所述线粒体的外膜中它在促进细胞存活和抑制促凋亡蛋白的作用方面发挥重要作用。BCL-2家族中的促凋亡蛋白(包括Bax和Bak)通常作用于线粒体膜,以促进细胞色素C和ROS的透化和释放,细胞色素C和ROS是细胞凋亡级联中的重要信号。这些促凋亡蛋白继而被仅BH3的蛋白质活化,并且被BCL-2及其相对的BCL-Xl的功能抑制。除其他蛋白质之外,促凋亡和抗凋亡蛋白的动力学作用可以改变人类疾病中的BCL-2表达增加的重要性。然而,与BCL-2的异常表达相关的多种癌症类型(血液和非血液实体瘤二者)与它作为细胞凋亡调节因子的作用一致(参见Hanada M.等人,Blood.1993;82:1820-1828;Campos L.等人,Blood.1993;81:3091-3096;Lamers F.等人,Eur JCancer.2012;48:3093-3103)。
“抗BCL-2剂”在本文中用于指特异性结合至BCL-2和/或抑制BCL-2的生物学活性的任何剂。
如本文所用,“特异性结合BCL-2”用于指剂以比非特异性配偶体(诸如牛血清白蛋白(BSA,Genbank登录号CAA76847,版本号CAA76847.1 GI:3336842,记录更新日期:2011年1月7日,下午2:30))更高的亲和力结合BCL-2。在一些实施方案中,所述剂结合BCL-2,当在生理条件下测量时,缔合常数(Ka)为针对BSA的试剂缔合常数的至少2、3、4、5、10、20、50、100、200、500、1000、2000、5000、104、105或106倍。所述剂可以以高亲和力结合BCL-2。例如,在一些实施方案中,试剂可以结合BCL-2,其中KD等于或小于约10-6M,诸如1×10-6、10-7、10-8、10-9、10-10、10-11、10-12、10-13或10-14。
在一些实施方案中,BCL-2多肽对应于Genbank登录号AAB72092,版本号AAB72092.1,记录更新日期:2016年7月24日,下午2:22。在一个实施方案中,编码BCL-2多肽的核酸对应于Genbank登录号AF021792,版本号AF021792.1,记录更新日期:2016年7月24日,下午2:22。在一些实施方案中,BCL-2多肽对应于Uniprot/Swiss-Prot登录号Q92934。
为了显示CD19 ADC与抗BCL-2剂协同作用,用一系列浓度的抗CD19 ADC和抗BCL-2剂二者共处理一组CD19(+)细胞系。作为阴性对照,用一系列浓度的抗BCL-2剂或一系列浓度的抗CD19 ADC和媒介物处理同一组细胞系。在温育后,测量两个参数:表面CD19的量(通过流式细胞术来测定)和组合的体外细胞毒性(通过MTS测定法来测定)。为了测定细胞毒性,通过在每孔添加MTS并且在37℃下温育4小时来测量细胞活力。计算相对于未处理的对照的细胞活力百分比。通过以下方法来计算细胞毒性协同作用:将细胞活力数据转换为受影响的分数,并且使用CalcuSyn分析程序来计算组合指数。
适用于本公开的抗CBCL-2剂包括:
a)维奈妥拉(ABT-199)
i.CAS号→1257044-40-8
(参见http://www.cas.org/content/chemical-substances/faqs)
ii.Drugbank参考号→DB11581
(参见https://www.drugbank.ca/)
iii.唯一标识码(UNII)→N54AIC43PW
(参见http://www.fda.gov/ForIndustry/DataStandards/SubstanceRegistrationSystem-UniqueIngredientIdentifierUNII/default.htm)
式I:维奈妥拉
b)纳维托克司(ABT-263)
i.CAS号→923564-51-6
(参见http://www.cas.org/content/chemical-substances/faqs)
ii.唯一标识码(UNII)→XKJ5VVK2WD
(参见http://www.fda.gov/ForIndustry/DataStandards/SubstanceRegistrationSystem-UniqueIngredientIdentifierUNII/default.htm)
式II:纳维托克司
c)ABT-737
i.CAS号→852808-04-9
(参见http://www.cas.org/content/chemical-substances/faqs)
ii.唯一标识码(UNII)→Z5NFR173NV
(参见http://www.fda.gov/ForIndustry/DataStandards/SubstanceRegistrationSystem-UniqueIngredientIdentifierUNII/default.htm)
式III:ABT-737
d)S55746/BCL201
i.CAS号→1448584-12-0
(参见http://www.cas.org/content/chemical-substances/faqs)
式IV:SS55746
e)奥利默森(G3139)
i.CAS号→190977-41-4
(参见http://www.cas.org/content/chemical-substances/faqs)
ii.Drugbank参考号→DB06650
(参见https://www.drugbank.ca/)
iii.唯一标识码(UNII)→85J5ZP6YSL
(参见http://www.fda.gov/ForIndustry/DataStandards/ SubstanceRegistrationSystem-UniqueIngredientIdentifierUNII/default.htm)
iv.低聚核苷酸结构:D(P-硫代)(T-C-T-C-C-C-A-G-C-G-T-G-C-G-C-C-A-T)
------------------------------------------
所述组合的有利性质
当抗CD19 ADC和抗BCL-2剂二者用作单独的单一药剂时,它们已经展示出临床实用性,例如在癌症治疗方面的临床实用性。然而,如本文所述,预期与使用抗CD19 ADC或抗BCL-2剂中的任一者的治疗相比,抗CD19 ADC和抗BCL-2剂的组合可提供以下一个或多个优点:
1)有效治疗更广泛的癌症;
2)有效治疗病症(诸如癌症)的耐药性或难治性形式,以及患有在缓解期后复发的病症(诸如癌症)的个体;
3)提高对治疗的反应率;和/或
4)提高治疗的持久性。
有效治疗如本文所用的更广泛的癌症意指,在使用组合治疗后,在更大范围的公认癌症类型中观察到完全反应。也就是说,从此前未报道的对单独的抗CD19 ADC或抗BCL-2剂中的任一者产生完全反应的癌症类型中观察到完全反应。
如本文所用的耐药性、难治性或复发形式的有效治疗意指,在使用组合治疗后,在对使用单独的抗CD19 ADC或抗BCL-2剂中的任一者的治疗具有部分或完全耐药性或难治性的个体(例如,在使用任一种单独的试剂治疗后无反应或仅显示出部分反应的个体,或者患有复发性疾病的那些个体)中观察到完全反应。在一些实施方案中,在使用抗CD19 ADC/抗BCL-2剂组合治疗后,观察到至少10%的对使用单独的抗CD19 ADC或抗BCL-2剂中的任一者的治疗具有部分或完全耐药性或难治性的个体产生完全反应。在一些实施方案中,在使用抗CD19 ADC/抗BCL-2剂组合治疗后,观察到至少20%、至少30%、至少40%、至少50%、至少60%、至少70%、至少80%、至少90%、至少95%、至少98%或至少99%的对使用单独的抗CD19 ADC或抗BCL-2剂中的任一者的治疗具有部分或完全耐药性或难治性的个体产生完全反应。
提高的对如本文所用治疗的反应率意指,与在使用单独的抗CD19 ADC或抗BCL-2剂中的任一者的治疗后观察到的结果相比,在使用组合治疗后,在更大比例的个体中观察到完全反应。在一些实施方案中,在使用抗CD19 ADC/抗BCL-2剂组合治疗后,观察到至少10%的经治疗的个体产生完全反应。在一些实施方案中,在使用抗CD19 ADC/抗BCL-2剂组合治疗后,观察到至少20%、至少30%、至少40%、至少50%、至少60%、至少70%、至少80%、至少90%、至少95%、至少98%或至少99%的经治疗的个体产生完全反应。
如本文所用,提高的治疗的持久性意指在使用组合治疗的个体中完全反应的平均持续时间长于在使用单独的抗CD19 ADC或抗BCL-2剂中的任一者的治疗后实现完全反应的个体的持续时间。在一些实施方案中,在使用抗CD19 ADC/抗BCL-2剂组合治疗后,完全反应的平均持续时间为至少6个月。在一些实施方案中,在使用抗CD19 ADC/抗BCL-2剂组合治疗后,完全反应的平均持续时间为至少12个月、至少18个月、至少24个月、至少3年、至少4年、至少5年、至少6年、至少7年、至少8年、至少9年、至少10年、至少15年或至少20年。
“完全反应”在本文中用于指个体中不存在疾病的任何临床证据。可以使用本领域中的适当方法(例如CT或PET扫描,或者适当的活检)来评估证据。实现完全反应所需的剂量数可以是一剂、两剂、三剂、四剂、五剂、十剂或更多剂。在一些实施方案中,在第一剂施用后不超过一年,诸如在第一剂施用后不超过6个月、不超过3个月、不超过一个月、不超过两周或不超过一周,个体实现完全反应。
治疗的病症
本文所述的组合疗法包括可用于抗癌活性的那些疗法。具体而言,在某些方面,疗法包括缀合(即通过接头共价连接)至PBD药物部分(即毒素)的抗体。当药物未缀合至抗体时,PBD药物具有细胞毒性作用。因此,通过与抗体的缀合来调节PBD药物部分的生物学活性。本公开的抗体-药物缀合物(ADC)将有效剂量的细胞毒性剂选择性地递送至肿瘤组织,从而可以实现更高的选择性(即更低的有效剂量)。
因此,在一个方面,本公开提供了组合疗法,包括施用结合CD19以用于治疗的抗CD19 ADC,其中所述方法包括根据靶蛋白的表达来选择受试者。
在一个方面,本公开提供了使用标记的组合疗法,所述标记指明该疗法适合于与被确定为适用于这种使用的受试者一起使用。标记可以指明该疗法适用于具有CD19的表达(诸如CD19的过表达)的受试者。标记可以指明受试者患有特定类型的癌症。
癌症可以是淋巴瘤,诸如非霍奇金淋巴瘤。标记可以指明受试者患有CD19+淋巴瘤。
在另一个方面,还提供了如本文所述的用于治疗增殖性疾病的组合疗法。本公开的另一个方面提供了缀合化合物在制造用于治疗增殖性疾病的药物中的用途。
本领域的普通技术人员能够容易地确定候选组合疗法是否能够治疗任何特定细胞类型的增殖性疾病。例如,下文描述了可以方便地用于评估特定化合物提供的活性的测定法。
本文所述的组合疗法可以用于治疗增殖性疾病。术语“增殖性疾病”涉及过量或异常细胞的不想要的或不受控制的细胞增殖,所述过量或异常细胞的增殖是不期望的,诸如,体外或体内赘生性或增生性生长。
增殖性疾患的实例包括但不限于良性、癌变前和恶性细胞增殖,包括但不限于赘生物和肿瘤(例如组织细胞瘤、胶质瘤、星形细胞瘤、骨瘤)、癌症(例如肺癌、小细胞肺癌、胃肠道癌、肠癌、结肠癌、乳腺癌、卵巢癌、前列腺癌、睾丸癌、肝癌、肾癌、膀胱癌、胰腺癌、脑癌、肉瘤、骨肉瘤、卡波西氏肉瘤、黑素瘤)、淋巴瘤、白血病、银屑病、骨骼疾病、纤维增殖性病症(例如结缔组织的纤维增殖性病症)和动脉粥样硬化。所关注的癌症包括但不限于白血病和卵巢癌。
可以治疗任何类型的细胞,包括但不限于肺、胃肠道(包括例如肠、结肠)、乳腺(乳房)、卵巢、前列腺、肝脏(肝)、肾脏(肾)、膀胱、胰腺、脑和皮肤。
特别关注的增殖性疾病包括但不限于非霍奇金淋巴瘤(包括弥漫性大B细胞淋巴瘤(DLBCL)、滤泡性淋巴瘤(FL)、套细胞淋巴瘤(MCL)、慢性淋巴性淋巴瘤(CLL)和边缘区B细胞淋巴瘤(MZBL))和白血病(诸如毛细胞白血病(HCL)、毛细胞白血病变体(HCL-v)和急性淋巴母细胞性白血病(ALL)(诸如费城染色体阳性ALL(Ph+ALL)或费城染色体阴性ALL(Ph-ALL)))。[Fielding A.,Haematologica.2010年1月;95(1):8–12]。
预期本公开的组合疗法可以用于治疗各种疾病或病症,例如以肿瘤抗原的过表达为特征的疾病或病症。示例性疾患或过度增殖性病症包括良性或恶性肿瘤;白血病、血液学和淋巴类恶性肿瘤。其他疾病包括神经元疾病、神经胶质细胞疾病、星形胶质细胞疾病、下丘脑疾病、腺体疾病、巨噬细胞疾病、上皮疾病、基质疾病、囊胚腔疾病、炎性疾病、血管生成疾病和免疫疾病,包括自身免疫性病症和移植物抗宿主疾病(GVHD)。
通常,待治疗的疾病或病症是过度增殖性疾病(诸如癌症)。本文的待治疗的癌症的实例包括但不限于癌、淋巴瘤、母细胞瘤、肉瘤和白血病或淋巴类恶性肿瘤。此类癌症的更具体的实例包括鳞状细胞癌(例如上皮鳞状细胞癌)、肺癌(包括小细胞肺癌、非小细胞肺癌、肺的腺癌和肺的鳞状细胞癌)、腹膜癌、肝细胞癌、胃癌(包括胃肠道癌)、胰腺癌、胶质母细胞瘤、宫颈癌、卵巢癌、肝癌、膀胱癌、肝细胞瘤、乳腺癌、结肠癌、直肠癌、结肠直肠癌、子宫内膜或子宫癌、唾液腺癌、肾脏或肾脏癌、前列腺癌、外阴癌、甲状腺癌、肝癌、肛门癌、阴茎癌以及头颈癌。
可以使用组合疗法治疗的自身免疫性疾病包括风湿性疾病(例如,类风湿性关节炎、干燥综合征、硬皮病、狼疮(诸如SLE和狼疮性肾炎)、多发性肌炎/皮肌炎、冷球蛋白血症、抗磷脂抗体综合征和银屑病关节炎)、骨关节炎、自身免疫胃肠道病症和肝脏病症(例如,炎性肠病(例如溃疡性结肠炎和克罗恩病(Crohn's disease))、自身免疫性胃炎和恶性贫血、自身免疫性肝炎、原发性胆汁性肝硬化、原发性硬化性胆管炎和乳糜泻)、血管炎(例如,ANCA相关性血管炎,包括查格-施特劳斯血管炎(Churg-Strauss vasculitis)、韦格纳肉芽肿病(Wegener's granulomatosis)和多动脉炎)、自身免疫神经病症(例如,多发性硬化、眼阵挛-肌阵挛综合征、重症肌无力、视神经脊髓炎、帕金森病(Parkinson’s disease)、阿尔茨海默氏病(Alzheimer’s disease)和自身免疫性多发性神经病)、肾病(例如,肾小球肾炎、古德帕斯丘综合征(Goodpasture’s syndrome)和伯杰氏病(Berger’s disease))、自身免疫性皮肤病症(例如,银屑病、荨麻疹、麻疹、寻常性天疱疮、大疱性类天疱疮和皮肤红斑狼疮)、血液病症(例如,血小板减少性紫癜、血栓形成性血小板减少性紫癜、输血后紫癜和自身免疫性溶血性贫血)、动脉粥样硬化、葡萄膜炎、自身免疫性听力疾病(例如,内耳病和听力丧失)、贝赛特氏病(Behcet's disease)、雷诺综合征(Raynaud's syndrome)、器官移植、移植物抗宿主疾病(GVHD)以及自身免疫性内分泌病症(例如,糖尿病相关性免疫性疾病(诸如胰岛素依赖性糖尿病(IDDM))、阿狄森病(Addison’s disease)和自身免疫性甲状腺疾病(例如格雷夫斯病(Graves’disease)和甲状腺炎))。更优选的此类疾病包括例如类风湿性关节炎、溃疡性结肠炎、ANCA相关性血管炎、狼疮、多发性硬化、干燥综合征、格雷夫斯病、IDDM、恶性贫血、甲状腺炎和肾小球肾炎。
在一些方面,受试者患有增殖性疾病,所述增殖性疾病选自非霍奇金淋巴瘤(包括弥漫性大B细胞淋巴瘤(DLBCL)、滤泡性淋巴瘤(FL)、套细胞淋巴瘤(MCL)、慢性淋巴性淋巴瘤(CLL)和边缘区B细胞淋巴瘤(MZBL))和白血病(诸如毛细胞白血病(HCL)、毛细胞白血病变体(HCL-v)和急性淋巴母细胞性白血病(ALL)(诸如费城染色体阳性ALL(Ph+ALL)或费城染色体阴性ALL(Ph-ALL)))。[Fielding A.,Haematologica.2010年1月;95(1):8–12]。
在某些方面,受试者患有弥漫性大B细胞淋巴瘤。
患者选择
在某些方面,在施用治疗前,选择适用于使用组合疗法来治疗的个体。
如本文所用,被认为适用于治疗的个体是预期从治疗中受益或对治疗产生反应的个体。个体可以患有癌症,或被怀疑患有癌症,或具有患上癌症的风险。个体可以已经接受癌症诊断。具体而言,个体可以患有淋巴瘤,或被怀疑患有淋巴瘤,或具有患上淋巴瘤的风险。在一些情况下,个体可以患有实体癌,或被怀疑患有实体癌,或具有患上实体癌的风险,所述实体癌具有表达CD19的肿瘤相关性非肿瘤细胞,诸如表达CD19的浸润性细胞。
在一些方面,根据CD19的表达量或表达模式来选择个体。在一些方面,根据细胞表面的CD19表达进行选择。
在某些方面,靶标是BCL-2。在一些方面,根据BCL-2的表达进行选择。
在一些方面,根据细胞表面的CD19和BCL-2二者的水平进行选择。
在一些情况下,测定所关注的特定组织中的靶标的表达。例如,在淋巴组织或肿瘤组织的样品中。在一些情况下,测定靶标的全身表达。例如,在循环流体(诸如血液、血浆、血清或淋巴液)的样品中。
在一些方面,根据样品中靶标表达的存在来选择适合治疗的个体。在那些情况下,无靶标表达的个体可以被认为不适合治疗。
在其他方面,靶标表达水平用于选择适合治疗的个体。如果靶标表达水平高于阈值水平,则确定个体适合治疗。
在一些方面,样品细胞中的CD19和/或的存在表明个体适合使用包含抗CD19 ADC和抗BCL-2剂的组合治疗。在其他方面,CD19和/或表达的量必须高于阈值水平以表明个体适合治疗。在一些方面,与对照相比,样品中CD19和/或定位改变的观察结果表明个体适合治疗。
在一些方面,如果从淋巴结或结外部位获得的细胞与针对CD19的抗体反应以及/或者如通过IHC所确定,则表明个体适合治疗。
在一些方面,如果样品中所有细胞的至少5%、10%、15%、20%、25%、30%、35%、40%、45%、50%、55%、60%、65%、70%、75%、80%、85%、90%或更多表达CD19,则患者被确定为适合治疗。在本文公开的一些方面,如果样品中至少至少10%的细胞表达CD19,则患者被确定为适合治疗。
在一些方面,如果样品中所有细胞的至少5%、10%、15%、20%、25%、30%、35%、40%、45%、50%、55%、60%、65%、70%、75%、80%、85%、90%或更多表达,则患者被确定为适合治疗。在本文公开的一些方面,如果样品中至少至少10%的细胞表达,则患者被确定为适合治疗。
在一些方面,根据目前或此前的治疗方案来选择适合治疗的个体。在一些实施方案中,如果已经使用抗BCL-2剂治疗个体,则选择该个体进行抗CD19 ADC治疗。在一些实施方案中,如果正在使用抗BCL-2剂治疗个体,则选择该个体进行抗CD19 ADC治疗。在一些情况下,如果个体使用抗BCL-2剂难以治疗(或进一步治疗),则选择该个体进行治疗。在一些情况下,抗BCL-2剂可以是维奈妥拉。在个体正在接受或已经接受抗BCL-2剂治疗的实施方案中,抗CD19 ADC可以与抗BCL-2剂组合施用,或者在不连续施用抗BCL-2剂的情况下施用。
在一些实施方案中,将抗CD19 ADC与抗BCL-2剂组合施用于所选择的个体。在一些实施方案中,将抗CD19 ADC在不连续施用抗BCL-2剂的情况下施用于所选择的个体。抗BCL-2剂优选地是维奈妥拉。
术语“抗BCL-2剂治疗(或进一步治疗)难治性的”在本文中用于指,当以单药疗法施用时,病症(诸如癌症)对抗BCL-2剂的施用无反应或已经停止反应。在一些实施方案中,使用Cheson等人,2014(South Asian J Cancer.2014年1月-3月;3(1):66-70)公开的反应标准来鉴定患有难治性NHL的个体。在该文档中,无反应者的定义为满足以下任一项的个体:(i)任何此前鉴定的异常淋巴结的直径和积比最低点增加>50%,或(ii)在治疗期间或治疗结束时出现任何新病灶。在一些实施方案中,患有难治性白血病的个体被鉴定为已经完成一个完整的治疗周期的患有稳定或进行性疾病的个体,或者在两个或更多个完整的治疗周期后实现部分反应的个体。
术语“正在使用……治疗”在本文中用于指个体在此前3周内已经接受所讨论的药剂,或者被安排在接下来3周内接受所讨论的药剂。在一些实施方案中,术语“正在使用……治疗”在本文中用于指个体在相同的治疗周期中正在接受所讨论的药剂。
术语“已经使用……治疗”在本文中用于指个体在任何此前的时间点已经接受药剂。在一些实施方案中,术语“已经使用……治疗”在本文中用于指个体在此前12个月内,例如在此前3个月内已经接受所讨论的药剂。在一些实施方案中,术语“已经使用……治疗”在本文中用于指个体在此前刚刚进行的治疗周期中已经接受药剂。
样品
样品可以包括或可以来源于:一定数量的血液;一定数量的来源于个体血液的血清,它可以包括除去血纤蛋白凝块和血细胞后获得的血液的流体部分;一定数量的胰液;组织样品或活检物;或者从所述个体分离的细胞。
样品可以从任何组织或体液采集。在某些方面,样品可以包括或可以来源于所述个体的组织样品、活检物、切除物或分离的细胞。
在某些方面,样品是组织样品。样品可以是肿瘤组织(诸如癌性肿瘤组织)的样品。样品可以已经通过肿瘤活检获得。在一些方面,样品是淋巴组织样品,诸如淋巴病灶样品或淋巴结活检物。在一些情况下,样品是皮肤活检物。
在一些方面,样品从体液(更优选地在整个身体中循环的体液)采集。因此,样品可以是血液样品或淋巴样品。在一些情况下,样品是尿液样品或唾液样品。
在一些情况下,样品是血液样品或血源性样品。血源性样品可以是选定的个体血液级分,例如选定的含细胞级分或血浆或血清级分。
选定的含细胞级分可以含有所关注的细胞类型,所述细胞类型可以包括白细胞(WBC),尤其是外周血单核细胞(PBC)和/或粒细胞、和/或红细胞(RBC)。因此,根据本公开的方法可以涉及血液、白细胞、外周血单核细胞、粒细胞和/或红细胞中的第一靶标多肽或核酸的检测。
样品可以是新鲜的或存档的。例如,存档组织可以来自个体的首次诊断,或复发时的活检物。在某些方面,样品是新鲜的活检物。
第一靶标多肽可以是CD19。
个体状态
个体可以是动物、哺乳动物、胎盘哺乳动物、有袋动物(例如,袋鼠、袋熊)、单孔目动物(例如,鸭嘴兽)、啮齿动物(例如,豚鼠、仓鼠、大鼠、小鼠)、鼠科动物(例如,小鼠)、兔形目动物(例如,兔)、禽类(例如,鸟)、犬科动物(例如,狗)、猫科动物(例如,猫)、马科动物(例如,马)、猪类(例如,猪)、羊类(例如,绵羊)、牛(例如,奶牛)、灵长类动物、猿猴(例如,猴或猿)、猴(例如,狨猴、狒狒)、猿(例如,大猩猩、黑猩猩、猩猩、长臂猿)或人类。
此外,个体可以是任何发育形式,例如胎儿。在一个优选的实施方案中,个体是人类。术语“受试者”、“患者”和“个体”在本文中可互换使用。
在本文公开的一些方面,个体患有癌症,或被怀疑患有癌症,或已经被鉴定为具有患上癌症的风险。在本文公开的一些方面,个体已经接受癌症诊断。个体可以已经接受非霍奇金淋巴瘤(包括弥漫性大B细胞淋巴瘤(DLBCL)、滤泡性淋巴瘤(FL)、套细胞淋巴瘤(MCL)、慢性淋巴性淋巴瘤(CLL)和边缘区B细胞淋巴瘤(MZBL))和白血病(诸如毛细胞白血病(HCL)、毛细胞白血病变体(HCL-v)和急性淋巴母细胞性白血病(ALL)(诸如费城染色体阳性ALL(Ph+ALL)或费城染色体阴性ALL(Ph-ALL)))的诊断。[Fielding A.,Haematologica.2010年1月;95(1):8–12]。
在一些情况下,个体已经接受非霍奇金淋巴瘤(包括弥漫性大B细胞淋巴瘤(DLBCL)、滤泡性淋巴瘤(FL)、套细胞淋巴瘤(MCL)、慢性淋巴性淋巴瘤(CLL)和边缘区B细胞淋巴瘤(MZBL))和白血病(诸如毛细胞白血病(HCL)、毛细胞白血病变体(HCL-v)和急性淋巴母细胞性白血病(ALL)(诸如费城染色体阳性ALL(Ph+ALL)或费城染色体阴性ALL(Ph-ALL)))的诊断。[Fielding A.,Haematologica.2010年1月;95(1):8–12]。
在一些情况下,个体已经接受含有表达CD19+的浸润性细胞的实体癌的诊断。
个体可以正在接受或已经接受对该癌症的治疗性治疗。受试者可以此前已经接受或可以此前未接受ADCX19。在一些情况下,癌症是淋巴瘤,包括非霍奇金淋巴瘤。
个体可以正在接受或已经接受抗BCL-2剂治疗。在一些情况下,个体可以使用抗BCL-2剂难以治疗(或进一步治疗)。在一些情况下,抗BCL-2剂可以是维奈妥拉。在个体正在接受或已经接受抗BCL-2剂治疗的实施方案中,抗CD19 ADC可以与抗BCL-2剂组合施用,或者在不连续施用抗BCL-2剂的情况下施用。
对照
在一些方面,将个体中的靶标表达与对照中的靶标表达进行比较。对照可用于支持染色的有效性和鉴定实验伪像。
在一些情况下,对照可以是参考样品或参考数据集。参考可以是此前已经以已知的适当程度从个体获得的样品。参考可以是通过分析参考样品获得的数据集。
对照可以是靶分子已知存在或以高水平表达的阳性对照,或者靶分子已知不存在或以低水平表达的阴性对照。
对照可以是来自已知受益于治疗的个体的组织样品。组织可以是与所测试的样品相同类型的组织。例如,可以将来自个体的肿瘤组织的样品与来自已知适合治疗的个体(诸如此前已经对治疗产生反应的个体)的肿瘤组织的对照样品进行比较。
在一些情况下,对照可以是从与测试样品相同的个体,但是从已知健康的组织获得的样品。因此,可以将来自个体的癌性组织样品与非癌性组织样品进行比较。
在一些情况下,对照是细胞培养样品。
在一些情况下,在使用抗体温育之前对测试样品进行分析,以确定该样品固有的背景染色水平。
在一些情况下,使用同种型对照。同种型对照使用与靶标特异性抗体相同类别,但是与样品无免疫反应性的抗体。此类对照可用于区分靶特异性抗体的非特异性相互作用。
方法可以包括血液病理学家对形态学和免疫组织化学的解释,以确保对测试结果的准确解释。方法可以涉及确认表达模式与预期模式相关联。例如,在分析CD19和/或BCL-2表达的量的情况下,方法可以涉及确认通过细胞质组分以膜染色观察到测试样品中的表达。方法可以涉及确认靶标信噪比高于阈值水平,从而允许清晰地辨别特异性背景信号和非特异性背景信号。
治疗方法
如本文所用,在治疗疾患的上下文中,术语“治疗”整体涉及人类或动物的治疗和疗法(例如,在兽医应用中),其中实现了一些期望的治疗效果,例如疾患进展的抑制,并且包括进展的速率降低,进展的速率的停止、疾患的消退、疾患的改善和疾患的治愈。还包括作为预防性措施的治疗(即,预防、防止)。
如本文所用,术语“治疗有效量”或“有效量”涉及,当根据所期望的治疗方案施用时,有效产生一些与合理收益/风险比相称的期望治疗效果的活性化合物或者包含活性化合物的材料、组合物或剂型的量。
类似地,如本文所用,术语“预防有效量”涉及,当根据所期望的治疗方案施用时,有效产生一些期望的与合理收益/风险比相称的预防效果的活性化合物或者包含活性化合物的材料、组合物或剂型的量。
本文公开了治疗方法。还提供了包括将治疗有效量的抗CD19 ADC和抗BCL-2剂施用于需要治疗的受试者的治疗方法。术语“治疗有效量”是足以显示出对受试者的有益效果的量。这种有益效果可以至少是至少一种症状的改善。实际施用量以及施用的速率和时间过程将取决于所治疗的疾病的性质和严重度。治疗的处方(例如剂量的确定)属于全科医生和其他医生的责任。可以对受试者进行测试以确定根据本文公开的方法接受治疗的资格。治疗方法可以包括使用本文公开的方法来确定受试者是否符合治疗资格的步骤。
抗CD19 ADC包括抗CD19抗体。抗CD19抗体可以是RB4v1.2抗体。ADC可以包括作为PBD二聚体的药物。ADC可以是ADCx19。ADC可以是WO2014/057117中公开的ADC。
抗BCL-2剂可以是维奈妥拉(ABT-199)、纳维托克司(ABT-263)、ABT-737、S55746/BCL201和奥利默森(G3139)。优选地,抗BCL-2剂是维奈妥拉(ABT-199)。
治疗可以涉及抗CD19 ADC/抗BCL-2剂组合的单独施用,或者根据要治疗的疾患同时或按顺序与其他治疗进一步组合施用。
一种示例性治疗方法涉及:
(1)鉴定个体已经使用或正在使用抗BCL-2剂(诸如维奈妥拉)治疗;
(2)将抗CD19 ADC(诸如ADCx19)施用于个体;以及任选地
(3)将抗BCL-2剂(诸如维奈妥拉)与抗CD19 ADC组合施用于个体(例如,与ADC同时或在ADC后)。
治疗和疗法的实例包括但不限于化学疗法(活性剂,包括例如药物,诸如化学治疗剂的施用);手术;和放射疗法。
“化学治疗剂”是可用于治疗癌症的化合物,无论其作用机理如何。化学治疗剂的类别包括但不限于:烷基化剂、抗代谢物、纺锤体毒物植物生物碱、细胞毒性/抗肿瘤抗生素、拓扑异构酶抑制剂、抗体、光敏剂和激酶抑制剂。化学治疗剂包括用于“靶向治疗”和常规化学疗法的化合物。
化学治疗剂的实例包括:来那度胺(Lenalidomide)(Celgene)、伏立诺他(Vorinostat)(Merck)、帕比司他(panobinostat)(Novartis)、莫西妥他汀(Mocetinostat)(MGCD0103)、依维莫司(Everolimus)(Novartis)、苯达莫司汀(Bendamustine)( MundipharmaInternational)、厄洛替尼(erlotinib)(Genentech/OSI Pharm.)、多西他赛(docetaxel)(Sanofi-Aventis)、5-FU(氟尿嘧啶、5-氟尿嘧啶,CAS号51-21-8)、吉西他滨(gemcitabine)(Lilly)、PD-0325901(CAS号391210-10-9,Pfizer)、顺铂(cisplatin)(顺式二胺二氯合铂(II),CAS号15663-27-1)、卡铂(carboplatin)(CAS号41575-94-4)、紫杉醇(paclitaxel)(Bristol-MyersSquibb Oncology,Princeton,N.J.)、曲妥珠单抗(trastuzumab)(Genentech)、替莫唑胺(temozolomide)(4-甲基-5-氧代-2,3,4,6,8-五氮杂双环[4.3.0]壬-2,7,9-三烯-9-甲酰胺,CAS号85622-93-1,ScheringPlough)、他莫昔芬(tamoxifen)((Z)-2-[4-(1,2-二苯基丁-1-烯基)苯氧基]-N,N-二甲基乙胺, )和多柔比星(doxorubicin)Akti-1/2、HPPD和雷帕霉素(rapamycin)。
化学治疗剂的更多实例包括:奥沙利铂(oxaliplatin)(Sanofi)、硼替佐米(bortezomib)(Millennium Pharm.)、舒癌特(sutent)(SU11248,Pfizer)、来曲唑(letrozole)(Novartis)、甲磺酸伊马替尼(imatinib mesylate)(Novartis)、XL-518(Mek抑制剂,Exelixis,WO 2007/044515)、ARRY-886(Mek抑制剂,AZD6244,Array BioPharma,Astra Zeneca)、SF-1126(PI3K抑制剂,Semafore Pharmaceuticals)、BEZ-235(PI3K抑制剂,Novartis)、XL-147(PI3K抑制剂,Exelixis)、PTK787/ZK 222584(Novartis)、氟维司群(fulvestrant)(AstraZeneca)、甲酰四氢叶酸(leucovorin)(亚叶酸)、雷帕霉素(西罗莫司,Wyeth)、拉帕替尼(lapatinib)(GSK572016,Glaxo Smith Kline)、洛那法尼(lonafarnib)(SARASARTM,SCH 66336,Schering Plough)、索拉非尼(sorafenib)(BAY43-9006,Bayer Labs)、吉非替尼(gefitinib)(AstraZeneca)、伊立替康(irinotecan)(CPT-11,Pfizer)、替吡法尼(tipifarnib)(ZARNESTRATM,Johnson&Johnson)、ABRAXANETM(不含克列莫佛)、紫杉醇的白蛋白工程化的纳米颗粒制剂(American Pharmaceutical Partners,Schaumberg,Il)、凡德他尼(vandetanib)(rINN,ZD6474,AstraZeneca)、苯丁酸氮芥、AG1478、AG1571(SU5271;Sugen)、替西罗莫司(temsirolimus)(Wyeth)、帕唑帕尼(pazopanib)(GlaxoSmithKline)、堪佛司非米德(canfosfamide)(Telik)、噻替哌(thiotepa)和环磷酰胺 磺酸烷基酯,诸如白消安(busulfan)、英丙舒凡(improsulfan)和哌泊舒凡(piposulfan);氮丙啶,诸如苯佐替哌(benzodopa)、卡波醌(carboquone)、美妥替哌(meturedopa)和乌瑞替哌(uredopa);乙烯亚胺和甲基蜜胺,包括六甲蜜胺、三乙烯蜜胺、三乙烯磷酰胺、三乙烯硫代磷酰胺和三羟甲基蜜胺;多聚乙酰(acetogenin)(特别是布拉它辛(bullatacin)和布拉它辛酮(bullatacinone));喜树碱(包括合成类似物托泊替康(topotecan));苔藓抑素;凯利他汀(callystatin);CC-1065(包括它的阿多来新(adozelesin)、卡折来新(carzelesin)和比折来新(bizelesin)合成类似物);念珠藻素(cryptophycin)(特别是念珠藻素1和念珠藻素8);多拉司他汀(dolastatin);倍癌霉素(duocarmycin)(包括合成类似物KW-2189和CB1-TM1);艾榴塞洛素(eleutherobin);水鬼蕉碱(pancratistatin);匍枝珊瑚醇(sarcodictyin);海绵抑制素(spongistatin);氮芥,诸如苯丁酸氮芥、萘氮芥(chlornaphazine)、氯磷酰胺(chlorophosphamide)、雌氮芥(estramustine)、异环磷酰胺(ifosfamide)、甲氮芥(mechlorethamine)、盐酸甲氧氮芥、美法仑(melphalan)、新氮芥(novembichin)、苯芥胆甾醇(phenesterine)、泼尼莫司汀(prednimustine)、曲磷胺(trofosfamide)、尿嘧啶氮芥;亚硝基脲,诸如卡莫司汀(carmustine)、氯脲霉素(chlorozotocin)、福莫司汀(fotemustine)、洛莫司汀(lomustine)、尼莫司汀(nimustine)和雷莫司汀(ranimnustine);抗生素,诸如烯二炔抗生素(例如加利车霉素(calicheamicin)、加利车霉素γ1I、加利车霉素ωI1(Angew Chem.Intl.Ed.Engl.(1994)33:183-186);达内霉素(dynemicin)、达内霉素A(dynemicin A);双膦酸盐,诸如氯膦酸盐;埃斯波霉素(esperamicin);以及新制癌菌素(neocarzinostatin)发色团和相关的色蛋白烯二炔抗生素发色团)、阿克拉霉素(aclacinomysin)、放线菌素(actinomycin)、安曲霉素(authramycin)、重氮丝氨酸、博来霉素(bleomycin)、放线菌素C(cactinomycin)、卡柔比星(carabicin)、洋红霉素(carminomycin)、嗜癌菌素(carzinophilin)、色霉素、放线菌素D(dactinomycin)、柔红霉素(daunorubicin)、地托比星(detorubicin)、6-重氮基-5-氧代-L-正亮氨酸、吗啉代-多柔比星、氰基吗啉代-多柔比星、2-吡咯啉基-多柔比星和脱氧多柔比星)、表柔比星(epirubicin)、依索比星(esorubicin)、伊达比星(idarubicin)、奈莫柔比星(nemorubicin)、麻西罗霉素(marcellomycin)、丝裂霉素(诸如丝裂霉素C)、霉酚酸、诺加霉素(nogalamycin)、橄榄霉素(olivomycin)、培洛霉素(peplomycin)、泊非霉素(porfiromycin)、嘌呤霉素、三铁阿霉素(quelamycin)、罗多比星(rodorubicin)、链黑菌素(streptonigrin)、链脲霉素(streptozocin)、杀结核菌素(tubercidin)、乌苯美司(ubenimex)、净司他汀(zinostatin)、佐柔比星(zorubicin);抗代谢物,诸如氨甲蝶呤和5-氟尿嘧啶(5-FU);叶酸类似物,诸如二甲叶酸(denopterin)、氨甲蝶呤、蝶罗呤(pteropterin)、三甲曲沙(trimetrexate);嘌呤类似物,诸如氟达拉滨(fludarabine)、6-巯基嘌呤、硫咪嘌呤(thiamiprine)、硫鸟嘌呤;嘧啶类似物,诸如环胞苷(ancitabine)、阿扎胞苷(azacitidine)、6-氮尿苷(6-azauridine)、卡莫氟(carmofur)、阿糖胞苷(cytarabine)、二脱氧尿苷(dideoxyuridine)、脱氧氟尿苷(doxifluridine)、依诺他滨(enocitabine)、氟尿苷(floxuridine);雄激素,诸如卡普睾酮(calusterone)、丙酸屈他雄酮(dromostanolone propionate)、环硫雄醇(epitiostanol)、美雄烷(mepitiostane)、睾内酯(testolactone);抗肾上腺剂,诸如氨鲁米特(aminoglutethimide)、米托坦(mitotane)、曲洛司坦(trilostane);叶酸补充剂,诸如亚叶酸;醋葡醛酸内酯(aceglatone);醛磷酰胺糖苷(aldophosphamide glycoside);氨基乙酰丙酸(aminolevulinic acid);恩尿嘧啶(eniluracil);安吖啶(amsacrine);倍曲布西(bestrabucil);比生群(bisantrene);依达曲沙(edatraxate);地磷酰胺(defofamine);地美可辛(demecolcine);亚胺醌氨酯(diaziquone);依洛尼塞(elfornithine);依利醋铵(elliptinium acetate);埃博霉素(epothilone);依托格鲁(etoglucid);硝酸镓;羟基脲(hydroxyurea);香菇多糖(lentinan);氯尼达明(lonidainine);美登木素,诸如美登素(maytansine)和安丝菌素(ansamitocin);米托胍腙(mitoguazone);米托蒽醌(mitoxantrone);莫哌达醇(mopidanmol);二胺硝吖啶(nitraerine);喷司他汀(pentostatin);蛋氨氮芥(phenamet);吡柔比星(pirarubicin);洛索蒽醌(losoxantrone);鬼臼酸;2-乙基酰肼;甲基苄肼;多糖复合物(JHS NaturalProducts,Eugene,OR);雷佐生(razoxane);根霉素(rhizoxin);西佐喃(sizofiran);螺旋锗(spirogermanium);细交链孢菌酮酸(tenuazonic acid);三亚胺醌;2,2’,2”-三氯三乙胺;单端孢霉烯(trichothecene)(特别是T-2毒素、疣孢菌素A(verracurin A)、杆孢菌素A(roridin A)和蛇形菌素(anguidine));氨基甲酸乙酯(urethan);长春地辛(vindesine);达卡巴嗪(dacarbazine);甘露醇氮芥(mannomustine);二溴甘露醇(mitobronitol);二溴卫矛醇(mitolactol);哌泊溴烷(pipobroman);加西托星(gacytosine);阿拉伯糖苷(arabinoside)(“Ara-C”);环磷酰胺;噻替哌;6-硫鸟嘌呤;巯基嘌呤;甲氨蝶呤;铂类似物,诸如顺铂和卡铂;长春花碱;依托泊苷(VP-16);异环磷酰胺(ifosfamide);米托蒽醌(mitoxantrone);长春新碱(vincristine);长春瑞滨诺消灵(novantrone);替尼泊苷(teniposide);依达曲沙(edatrexate);道诺霉素(daunomycin);氨基蝶呤(aminopterin);卡培他滨(capecitabine)(Roche);伊班膦酸盐(ibandronate);CPT-11;拓扑异构酶抑制剂RFS 2000;二氟甲基鸟氨酸(DMFO);类视色素(retinoid),诸如视黄酸;以及任何上述化学治疗剂的药学上可接受的盐、酸和衍生物。可以使用试剂的组合,诸如CHP(多柔比星、泼尼松、环磷酰胺)或CHOP(多柔比星、泼尼松、环磷酰胺、长春新碱)。
“化学治疗剂”的定义中还包括:(i)发挥调节或抑制针对肿瘤的激素作用的抗激素剂,诸如抗雌激素和选择性雌激素受体调节剂(SERM),包括例如他莫昔芬(tamoxifen)(包括他莫昔芬柠檬酸盐)、雷洛昔芬(raloxifene)、屈洛昔芬(droloxifene)、4-羟基他莫昔芬、曲沃昔芬(trioxifene)、那洛昔芬(keoxifene)、LY117018、奥那司酮(onapristone)和(柠檬酸托瑞米芬(toremifinecitrate));(ii)抑制调节肾上腺中的雌激素产生的酶(芳香酶)的芳香酶抑制剂,例如4(5)-咪唑、氨鲁米特、(醋酸甲地孕酮(megestrol acetate))、(依西美坦(exemestane);Pfizer)、福美司坦(formestanie)、法倔唑(fadrozole)、(伏氯唑(vorozole))、(来曲唑(letrozole);Novartis)和(阿那曲唑(anastrozole);AstraZeneca);(iii)抗雄激素,诸如氟他胺(flutamide)、尼鲁米特(nilutamide)、比卡鲁胺(bicalutamide)、亮丙瑞林(leuprolide)和戈舍瑞林(goserelin);以及曲沙他滨(troxacitabine)(1,3-二氧戊环核苷胞嘧啶类似物);(iv)蛋白激酶抑制剂,诸如MEK抑制剂(WO 2007/044515);(v)脂质激酶抑制剂;(vi)反义低聚核苷酸,特别是抑制与异常细胞增殖相关的信号传导通路方面的基因表达的那些反义低聚核苷酸,例如PKC-α、Raf和H-Ras,诸如奥利默森(Genta Inc.);(vii)核酶,诸如VEGF表达抑制剂(例如,)和HER2表达抑制剂;(viii)疫苗,诸如基因治疗疫苗,例如和rIL-2;拓扑异构酶1抑制剂,诸如rmRH;(ix)抗血管生成剂,诸如贝伐单抗(bevacizumab)(Genentech);以及任何上述化学治疗剂的药学上可接受的盐、酸和衍生物。
“化学治疗剂”的定义中还包括治疗性抗体,诸如阿仑单抗(alemtuzumab)(Campath)、贝伐单抗(Genentech);西妥昔单抗(cetuximab)(Imclone);帕尼单抗(panitumumab)(Amgen)、帕妥珠单抗(pertuzumab)(PERJETATM,OMNITARGTM,2C4,Genentech)、曲妥珠单抗(Genentech)、MDX-060(Medarex)和抗体药物缀合物、吉妥珠单抗奥唑米星(gemtuzumab ozogamicin)(Wyeth)。
与本公开的缀合物组合的具有作为化学治疗剂的治疗潜力的人源化单克隆抗体包括:阿仑单抗、阿泊珠单抗(apolizumab)、阿塞珠单抗(aselizumab)、阿替珠單抗(atlizumab)、巴品珠单抗(bapineuzumab)、贝伐单抗、莫比伐珠单抗(bivatuzumabmertansine)、莫坎妥珠单抗(cantuzumab mertansine)、西利珠单抗(cedelizumab)、培塞妥珠单抗(certolizumab pegol)、西弗斯妥单抗(cidfusituzumab)、西地妥珠单抗(cidtuzumab)、达利珠单抗(daclizumab)、依库珠单抗(eculizumab)、依法利珠单抗(efalizumab)、依帕珠单抗(epratuzumab)、厄利珠单抗(erlizumab)、非维珠单抗(felvizumab)、芳妥珠单抗(fontolizumab)、吉妥珠单抗奥唑米星、英妥珠单抗奥唑米星(inotuzumab ozogamicin)、伊匹单抗(ipilimumab)、拉贝珠单抗(labetuzumab)、林妥珠单抗(lintuzumab)、马妥珠单抗(matuzumab)、美泊利单抗(mepolizumab)、莫维珠单抗(motavizumab)、莫妥维珠单抗(motovizumab)、那他珠单抗(natalizumab)、尼妥珠单抗(nimotuzumab)、诺洛维珠单抗(nolovizumab)、努马维珠单抗(numavizumab)、奥马珠单抗(omalizumab)、帕利珠单抗(palivizumab)、帕考珠单抗(pascolizumab)、帕氟珠单抗(pecfusituzumab)、pectuzumab、帕妥珠单抗、培克珠单抗(pexelizumab)、拉维珠单抗(ralivizumab)、兰尼单抗(ranibizumab)、瑞维珠单抗(reslivizumab)、瑞利珠单抗(reslizumab)、热西维珠单抗(resyvizumab)、罗维珠单抗(rovelizumab)、卢利珠单抗(ruplizumab)、西罗珠单抗(sibrotuzumab)、西利珠单抗(siplizumab)、索土珠单抗(sontuzumab)、替他珠单抗(tacatuzumab tetraxetan)、他度珠单抗(tadocizumab)、他利珠单抗(talizumab)、特非珠单抗(tefibazumab)、托珠单抗(tocilizumab)、托利珠单抗(toralizumab)、曲妥珠单抗、土库珠单抗西莫白介素(tucotuzumab celmoleukin)、土库妥珠单抗(tucusituzumab)、乌马维珠单抗(umavizumab)、乌珠单抗(urtoxazumab)和维西珠单抗(visilizumab)。
根据本公开的组合物优选地是药物组合物。根据本公开以及根据本公开使用的药物组合物,除活性成分(即缀合化合物)之外,还可以包含药学上可接受的赋形剂、载体、缓冲剂、稳定剂或本领域的技术人员熟知的其他材料。这些材料应是无毒的,并且不应干扰活性成分的功效。载体或其他材料的确切性质将取决于施用途径,所述施用途径可以是口服或注射,例如皮肤、皮下或静脉内注射。
用于口服施用的药物组合物可以是片剂、胶囊剂、粉末剂或液体形式。片剂可以包括固体载体或佐剂。液体药物组合物通常包含液体载体,诸如水、石油、动物油或植物油、矿物油或合成油。生理盐水溶液、葡萄糖或其他糖溶液或二醇(诸如乙二醇、丙二醇或聚乙二醇)也可以包括在内。胶囊剂可以包括固体载体,例如明胶。
对于静脉内、皮肤或皮下注射,或者在患处注射,活性成分将是肠胃外可接受的水溶液形式,该形式是无热原的并且具有合适的pH、等渗性和稳定性。本领域的相关技术人员能够使用例如等渗媒介物(诸如氯化钠注射液、林格氏注射液、乳酸林格氏注射液)来制备合适的溶液。根据需要,防腐剂、稳定剂、缓冲剂、抗氧化剂和/或其他添加剂也可以包括在内。
剂量
本领域的技术人员将会理解,抗CD19 ADC和/或抗BCL-2剂以及包含这些活性要素的组合物的合适剂量可以因受试者而异。测定最佳剂量通常将涉及治疗有益效果水平与任何风险或有害副作用的平衡。所选的剂量水平将取决于多种因素,包括但不限于特定化合物的活性、施用途径、施用时间、化合物的排泄率、治疗的持续时间、组合中所用的其他药物、化合物和/或材料,疾病的严重性以及受试者的物种、性别、年龄、体重、状态、总体健康状况和先前病史。化合物的量和施用途径最终将由内科医生、兽医或临床医生决定,但通常将选择剂量以实现作用部位的局部浓度,从而实现所期望的作用而不会引起实质上有害或有毒的副作用。
在某些方面,抗CD19 ADC的剂量由在从受试者获得的样品中观察到的CD19的表达确定。因此,样品中的CD19的表达水平或定位可以表示需要更高或更低剂量的抗CD19ADC。例如,CD19的高表达水平可以表示更高剂量的抗CD19 ADC将是合适的。在一些情况下,CD19的高表达水平可以表示除抗CD19 ADC之外还需要施用另一种试剂。例如,抗CD19 ADC与化学治疗剂联合施用。CD19的高表达水平可以表示更具侵袭性的疗法。
在某些方面,抗BCL-2剂的剂量由从受试者获得的样品中观察到的表达确定。因此,样品中的表达水平或定位可以表示需要更高或更低剂量的抗BCL-2剂。例如,BCL-2的高表达水平可以表示更高剂量的抗BCL-2剂将是合适的。在一些情况下,BCL-2的高表达水平可以表示除抗BCL-2剂之外还需要施用另一种试剂。例如,抗BCL-2剂与化学治疗剂联合施用。BCL-2的高表达水平可以表示更具侵袭性的疗法。
在整个治疗过程中,可以连续或间歇(例如,以适当的间隔分次)施用一个剂量。确定最有效的施用方式和剂量的方法是本领域的技术人员熟知的,并且将根据用于治疗的制剂、治疗的目的、所治疗的一种或多种靶细胞以及所治疗的受试者而变化。可以通过主治医生、兽医或临床医生选择的剂量水平和方式进行单次或多次施用。
通常,每种活性化合物的合适剂量在每天每千克受试者体重约100ng至约25mg(更通常地约1μg至约10mg)的范围内。在活性化合物是盐、酯、酰胺、前药等等的情况下,施用量根据母体化合物来计算,因此要使用的实际重量成比例地增加。
在一个实施方案中,根据以下剂量方案将每种活性化合物施用于人受试者:约100mg,每日3次。
在一个实施方案中,根据以下剂量方案将每种活性化合物施用于人受试者:约150mg,每日2次。
在一个实施方案中,根据以下剂量方案将每种活性化合物施用于人受试者:约200mg,每日2次。
然而,在一个实施方案中,根据以下剂量方案将每种缀合化合物施用于人受试者:约50或约75mg,每日3或4次。
在一个实施方案中,根据以下剂量方案将每种缀合化合物施用于人受试者:约100或约125mg,每日2次。
对于抗CD19 ADC,如果它是具有ADC的PBD,则上文所述的剂量可以施用于缀合物(包括PBD部分和抗体的接头)或所提供的有效量的PBD化合物,例如在接头切割后可释放的化合物的量。
抗CD19 ADC包括抗CD19抗体。抗CD19抗体可以是RB4v1.2抗体。ADC可以包括作为PBD二聚体的药物。抗CD19-ADC可以是ADCx19。ADC可以是WO2014/057117中公开的ADC。
抗BCL-2剂可以是维奈妥拉(ABT-199)、纳维托克司(ABT-263)、ABT-737、S55746/BCL201和奥利默森(G3139)。优选地,抗BCL-2剂是维奈妥拉(ABT-199)。
抗体
术语“抗体”在本文中以最广泛的意义使用,并且特别涵盖单克隆抗体、多克隆抗体、二聚体、多聚体、多特异性抗体(例如,双特异性抗体),完整抗体(也称为“全长”抗体)和抗体片段,只要它们表现出所期望的生物学活性,例如结合CD19的能力即可(Miller等人(2003)Jour.of Immunology 170:4854-4861)。抗体可以是鼠科动物、人、人源化、嵌合或来源于其他物种(诸如兔、山羊、绵羊、马或骆驼)的抗体。
抗体是由免疫系统产生的能够识别和结合至特定抗原的蛋白质。(Janeway,C.,Travers,P.,Walport,M.,Shlomchik(2001)Immuno Biology,第5版,Garland Publishing,New York)。靶抗原通常具有被多个抗体上的互补决定区(CDR)识别的多个结合位点,也称为表位。特异性结合至不同表位的每种抗体具有不同的结构。因此,一个抗原可以具有多于一个对应的抗体。抗体可以包含全长免疫球蛋白分子或全长免疫球蛋白分子的免疫活性部分,即,含有免疫特异性结合所关注的靶标或它们的一部分的抗原的抗原结合位点的分子,这些靶标包括但不限于癌细胞或产生与自身免疫性疾病相关的自身免疫抗体的细胞。免疫球蛋白可以属于任何类型(例如IgG、IgE、IgM、IgD和IgA)、类别(例如IgG1、IgG2、IgG3、IgG4、IgA1和IgA2)或子类、或同种异型(例如,人G1m1、G1m2、G1m3、非G1m1[即,除G1m1之外的任何同种异型]、G1m17、G2m23、G3m21、G3m28、G3m11、G3m5、G3m13、G3m14、G3m10、G3m15、G3m16、G3m6、G3m24、G3m26、G3m27、A2m1、A2m2、Km1、Km2和Km3)的免疫球蛋白分子。免疫球蛋白可以来源于任何物种,包括人类、鼠科动物或兔来源。
“抗体片段”包含全长抗体的一部分,通常是它们的抗原结合或可变区。抗体片段的实例包括Fab、Fab’、F(ab’)2和scFv片段;双体;线性抗体;由Fab表达文库产生的片段、抗独特型(抗Id)抗体、CDR(互补决定区)以及上述任一者的表位结合片段,这些片段免疫特异性结合至癌细胞抗原、病毒抗原或微生物抗原、单链抗体分子;以及由抗体片段形成的多特异性抗体。
如本文所用,术语“单克隆抗体”是指从基本上同质的抗体群体获得的抗体,即除可以少量存在的可能的天然存在的突变之外,构成所述群体的单个抗体是相同的。单克隆抗体具有高度特异性(针对单个抗原位点)。此外,与包含针对不同决定簇(表位)的不同抗体的多克隆抗体制备物相比,每种单克隆抗体针对抗原上的单个决定簇。除特异性之外,单克隆抗体的优点在于它们可以在不受其他抗体污染的情况下合成。修饰语“单克隆”表示从基本上同质的抗体群体获得的抗体特征,并且不应解释为需要通过任何特定方法来产生抗体。例如,根据本公开使用的单克隆抗体可以通过Kohler等人(1975)Nature 256:495首先描述的杂交瘤方法来制备,或者可以通过重组DNA方法来制备(参见US 4816567)。单克隆抗体也可以使用Clackson等人(1991)Nature,352:624-628;Marks等人(1991)J.Mol.Biol.,222:581-597描述的技术从噬菌体抗体文库分离,或者从携带完全人免疫球蛋白系统的转基因小鼠分离(Lonberg(2008)Curr.Opinion 20(4):450-459)。
本文的单克隆抗体明确包括这样的“嵌合”抗体:其中重链和/或轻链的一部分与来源于特定物类或属于特定抗体类别或子类的抗体中的相应序列相同或同源,而一条或多条链的其余部分与来源于另一个物类或属于另一个抗体类别或子类的抗体中的相应序列相同或同源;以及这些抗体的片段,只要它们表现出所需的生物学活性即可(US 4816567;和Morrison等人(1984)Proc.Natl.Acad.Sci.USA,81:6851-6855)。嵌合抗体包括“灵长类动物源化”抗体,该抗体包含来源于非人灵长类动物(例如,旧大陆猴或猿)的可变结构域抗原结合序列和人恒定区序列。
本文的“完整抗体”是包含VL结构域和VH结构域以及轻链恒定结构域(CL)和重链恒定结构域CH1、CH2和CH3的抗体。恒定结构域可以是天然序列恒定结构域(例如人天然序列恒定结构域)或它们的氨基酸序列变体。完整抗体可以具有一种或多种“效应子功能”,所述效应子功能是指可归因于抗体的Fc区(天然序列Fc区或氨基酸序列变体Fc区)的那些生物学活性。抗体效应子功能的实例包括C1q结合;补体依赖性细胞毒性;Fc受体结合;抗体依赖性细胞介导的细胞毒性(ADCC);吞噬作用;以及细胞表面受体(诸如B细胞受体和BCR)的下调。
根据重链恒定结构域的氨基酸序列,可以将完整抗体归类为不同的“类别”。完整抗体有五大类别:IgA、IgD、IgE、IgG和IgM,并且几个这些类别可以进一步分为“子类”(同种型),例如IgG1、IgG2、IgG3、IgG4、IgA和IgA2。对应于不同抗体类别的重链恒定结构域分别称为α、δ、ε、γ和μ。不同类别的免疫球蛋白的亚基结构和三维构型是熟知的。
附图说明
现在将参考附图讨论展示本公开原理的实施方案和实验,在附图中:
图1序列
本公开包括所描述的方面和优选特征的组合,除非明显不允许或明确避免这种组合。
本文使用的章节标题仅用于组织目的,而不应解释为限制所描述的主题。
现在将参考附图,通过示例方式展示本公开的方面和实施方案。对于本领域的技术人员而言,其他方面和实施方案将是显而易见的。本文中提及的所有文档均以引用的方式并入本文。
在整个说明书中,包括随后的权利要求,除非上下文另有要求,否则词语“包括/包含(comprise)”以及诸如“包括/包含(comprises和comprising)”的变化形式将被理解为意指包括所述整体或步骤或者整体或步骤的组,但不排除任何其他整体或步骤或者整体或步骤的组。
必须注意,如说明书和所附权利要求所用,除非上下文另外明确指明,否则单数形式“一个/种(a、an)”和“该/所述”包括复数指代物。在本文中,范围可以表述为从“约”一个特定值和/或至“约”另一个特定值。当表示这种范围时,另一个实施方案包括从一个特定值和/或至另一个特定值。类似地,通过使用先行词“约”将数值表述为近似值时,应当理解,该特定值构成另一个实施方案。
一些实施方案
以下段落描述了本公开的一些特定实施方案:
1.一种选择适合用ADCx19或ADCT-402或ADCT-402治疗的个体的方法,其中如果所述个体已经使用维奈妥拉治疗,则选择所述个体进行ADCx19或ADCT-402治疗。
2.一种选择适合用ADCx19或ADCT-402治疗的个体的方法,其中如果所述个体正在使用维奈妥拉治疗,则选择所述个体进行ADCx19或ADCT-402治疗。
3.根据前述段落中的任一者所述的方法,其中如果所述个体使用维奈妥拉难以治疗或进一步治疗,则选择所述个体进行治疗。
4.一种用于治疗个体的病症的方法,所述方法包括:
(i)选择适合通过根据第1至3段中的任一者所述的方法治疗的个体;以及
(ii)将有效量的ADCx19或ADCT-402施用于所述个体。
5.根据第4段所述的方法,还包括将维奈妥拉与ADCx19或ADCT-402组合施用。
6.一种用于治疗个体的病症的方法,所述方法包括将有效量的ADCx19或ADCT-402和维奈妥拉施用于所述个体。
7.根据第6段所述的方法,其中根据第1至3段中的任一者所述的方法选择所述个体进行治疗。
8.根据第5至7段中的任一者所述的方法,其中所述治疗包括在维奈妥拉之前、与维奈妥拉同时或在维奈妥拉之后施用ADCx19或ADCT-402。
9.根据前述段落中的任一者所述的方法,其中所述治疗还包括施用化学治疗剂。
10.根据前述段落中的任一者所述的方法,其中所述个体是人类。
11.根据前述段落中的任一者所述的方法,其中所述个体患有病症或已经确定为患有病症。
12.根据第11段所述的方法,其中所述个体患有或已经确定为患有表达CD19或CD19+肿瘤相关的非肿瘤细胞,诸如CD19+浸润性细胞的癌症。
13.根据前述段落中的任一者所述的方法,其中所述个体正在接受维奈妥拉治疗。
14.根据前述段落中的任一者所述的方法,其中所述个体已经接受维奈妥拉治疗。
15.根据前述段落中的任一者所述的方法,其中所述个体使用维奈妥拉难以治疗或进一步治疗。
16.根据前述段落中的任一者所述的方法,其中与单独使用ADCx19或ADCT-402或者维奈妥拉中的任一者的单药疗法相比,所述治疗具有增加的功效。
17.根据前述段落中的任一者所述的方法,其中所述病症是增殖性疾病。
18.根据第17段所述的方法,其中所述病症是癌症。
19.根据第18段所述的方法,其中所述病症选自包含以下各项的组:非霍奇金淋巴瘤(包括弥漫性大B细胞淋巴瘤(DLBCL)、滤泡性淋巴瘤(FL)、套细胞淋巴瘤(MCL)、慢性淋巴性淋巴瘤(CLL)和边缘区B细胞淋巴瘤(MZBL))和白血病(诸如毛细胞白血病(HCL)、毛细胞白血病变体(HCL-v)和急性淋巴母细胞性白血病(ALL)(诸如费城染色体阳性ALL(Ph+ALL)或费城染色体阴性ALL(Ph-ALL)))。
20.用于根据第4至19段中的任一者所述的治疗方法的ADCx19或ADCT-402。
21.一种包含ADCx19或ADCT-402的组合物,用于根据第4至19段中的任一者所述的治疗方法。
22.用于根据第5至19段中的任一者所述的治疗方法的维奈妥拉。
23.一种包含维奈妥拉的组合物,用于根据第5至19段中的任一者所述的治疗方法。
24.ADCx19或ADCT-402在制造用于治疗个体的病症的药物中的用途,其中所述治疗包括根据第4至19段中的任一者所述的方法。
25.维奈妥拉在制造用于治疗个体的病症的药物中的用途,其中所述治疗包括根据第5至19段中的任一者所述的方法。
26.一种药盒,所述药盒包括:
第一药物,所述第一药物包括ADCx19或ADCT-402;
包装插页,所述包装插页包括根据第4至19段中的任一者所述的方法的所述第一药物的施用说明。
27.根据第26段所述的药盒,还包括:
第二药物,所述第二药物包括维奈妥拉。
发明的声明
1.一种选择适合使用抗CD19 ADC治疗的个体的方法,其中如果所述个体已经使用抗BCL-2剂治疗,则选择所述个体进行所述抗CD19 ADC治疗。
2.一种选择适合使用抗CD19 ADC治疗的个体的方法,其中如果所述个体正在使用抗BCL-2剂治疗,则选择所述个体进行所述抗CD19 ADC治疗。
3.根据前述段落中的任一者所述的方法,其中如果所述个体使用所述抗BCL-2剂难以治疗或进一步治疗,则选择所述个体进行治疗。
4.一种用于治疗个体的病症的方法,所述方法包括:
(i)选择适合通过根据第1至3段中的任一者所述的方法治疗的个体;以及
(ii)将有效量的所述抗CD19 ADC施用于所述个体。
5.根据第4段所述的方法,还包括将抗BCL-2剂与所述抗CD19 ADC组合施用。
6.一种用于治疗个体的病症的方法,所述方法包括将有效量的抗CD19 ADC和抗BCL-2剂施用于所述个体。
7.根据第6段所述的方法,其中根据第1至3段中的任一者所述的方法选择所述个体进行治疗。
8.根据第5至7段中的任一者所述的方法,其中所述治疗包括在所述抗BCL-2剂之前、与所述抗BCL-2剂同时或在所述抗BCL-2剂之后施用所述抗CD19 ADC。
9.根据前述段落中的任一者所述的方法,其中所述治疗还包括施用化学治疗剂。
10.根据前述段落中的任一者所述的方法,其中所述个体是人类。
11.根据前述段落中的任一者所述的方法,其中所述个体患有病症或已经确定为患有病症。
12.根据第11段所述的方法,其中所述个体患有或已经确定为患有表达CD19或CD19+肿瘤相关的非肿瘤细胞,诸如CD19+浸润性细胞的癌症。
13.根据前述段落中的任一者所述的方法,其中所述个体正在接受抗BCL-2剂治疗。
14.根据前述段落中的任一者所述的方法,其中所述个体已经接受抗BCL-2剂治疗。
15.根据前述段落中的任一者所述的方法,其中所述个体使用所述抗BCL-2剂难以治疗或进一步治疗。
16.根据前述段落中的任一者所述的方法,其中与单独使用所述抗CD19 ADC或抗BCL-2剂中的任一者的单药疗法相比,所述治疗具有增加的功效。
17.根据前述段落中的任一者所述的方法,其中所述抗CD19 ADC是ADCx19。
17a.根据前述段落中的任一者所述的方法,其中所述抗CD19 ADC是ADCT-402。
18.根据前述段落中的任一者所述的方法,其中所述病症是增殖性疾病。
19.根据第18段所述的方法,其中所述病症是癌症。
20.根据第19段所述的方法,其中所述病症选自包含以下各项的组:非霍奇金淋巴瘤(包括弥漫性大B细胞淋巴瘤(DLBCL)、滤泡性淋巴瘤(FL)、套细胞淋巴瘤(MCL)、慢性淋巴性淋巴瘤(CLL)和边缘区B细胞淋巴瘤(MZBL))和白血病(诸如毛细胞白血病(HCL)、毛细胞白血病变体(HCL-v)和急性淋巴母细胞性白血病(ALL)(诸如费城染色体阳性ALL(Ph+ALL)或费城染色体阴性ALL(Ph-ALL)))。
21.根据前述段落中的任一者所述的方法,其中所述抗BCL-2剂选自由以下各项组成的组:维奈妥拉(ABT-199)、纳维托克司(ABT-263)、ABT-737、S55746/BCL201和奥利默森(G3139)。
22.根据前述段落中的任一者所述的方法,其中所述抗BCL-2剂是维奈妥拉。
23.用于根据第4至22段中的任一者所述的治疗方法的抗CD19 ADC。
24.一种包含抗CD19 ADC的组合物,用于根据第4至22段中的任一者所述的治疗方法。
25.用于根据第5至22段中的任一者所述的治疗方法的抗BCL-2剂。
26.一种包含抗BCL-2剂的组合物,用于根据第5至22段中的任一者所述的治疗方法。
27.抗CD19 ADC在制造用于治疗个体的病症的药物中的用途,其中所述治疗包括根据第4至22段中的任一者所述的方法。
28.抗BCL-2剂在制造用于治疗个体的病症的药物中的用途,其中所述治疗包括根据第5至22段中的任一者所述的方法。
29.一种药盒,所述药盒包括:
第一药物,所述第一药物包括抗CD19 ADC;
包装插页,所述包装插页包括根据第4至22段中的任一者所述的方法的所述第一药物的施用说明。
30.根据第29段所述的药盒,还包括:
第二药物,所述第二药物包括抗BCL-2剂。
实施例
在以下实施例中:
-适用于实施例的表达CD19的细胞系包括Ramos、Daudi、Raji、WSU-DLCL和NALM-6细胞。
-疾病A-弥漫性大B细胞淋巴瘤/DLBC是一种侵袭性类型的非霍奇金淋巴瘤,它从淋巴系统的B细胞发展而来。它构成了非霍奇金淋巴瘤的最大子组。
-疾病B-套细胞淋巴瘤/MCL是一种罕见的B细胞NHL,最常影响60岁以上的男性。该疾病可以是侵袭性的(快速增长),但是在一些患者中也可以表现得更加惰性(缓慢增长)。MCL约占所有NHL的百分之五。
-疾病C-滤泡性淋巴瘤/FL是一种相当惰性的NHL,具有较长的生存时间,但是很难治愈;它也可以转化为更具侵袭性的淋巴瘤形式。
实施例1
在一项单独的实验中,表达CD19的细胞系将与依托泊苷(阴性对照)和奥沙利铂(阳性对照)、1μg/mL抗CD19 ADC(靶向CD19的具有PBD二聚体弹头的ADC)、1μg/mL抗CD19(ADC中的抗体)和1μg/mL B12-SG3249(非结合对照ADC,其PBD有效负载与抗CD19 ADC相同)一起温育0、6、24和48小时。
在温育后,将细胞洗涤,再加入人树突细胞(DC)中,再放置24小时。随后通过DC群体上的CD86的表面表达增加(通过流式细胞术测定)以及通过测量DC介导的IL-8和MIP2的释放来测量DC的活化。
实施例2
本研究的目的是预先评估该组合的安全性、耐受性、药理学和临床活性
已经选择以下癌症类型进行研究:疾病A、疾病B和疾病C
两种药物均具有作为单一药剂的功效的证据:
·抗CD19 ADC(参见例如WO2014/057117、WO2016/166298、WO2014/057122和WO2016/166307)
·抗BCL-2剂(参见KS Peggs等人2009,Clinical and ExperimentalImmunology,157:9–19[doi:10.1111/j.1365-2249.2009.03912.x])
该研究的主要目的是研究这些药剂是否可以安全地组合,如果可以的话,则鉴定适用于进一步研究的一次或多次给药和方案。该研究还将评估每个组合是否诱导肿瘤的药理学变化,所述药理学变化将表明潜在临床有益效果。
此外,这将提供初步证据,表明与单一药剂抗CD19 ADC或抗BCL-2剂治疗的公布数据相比,组合可以增加反应率和反应持久性。
每个疾病组可以包括此前用抗BCL-2剂治疗的患者子集,以研究组合治疗是否可以克服对BCL-2药物治疗的耐药性。对于每种疾病,无意施加特定的分子选择,因为基于批准的分子诊断测试,目前可用的数据通常不支持排除患者。
抗CD19
ADC起始剂量的基本原理
已经建立的针对ADC的RDE(单位ug/kg,每三周施用一次)将用于该研究的所有患者。为了确保患者安全,将使用低于RDE的起始剂量;起始剂量水平将是仍然可以在研究ADC1中证明患者有益效果的剂量水平,这表明以这种剂量水平纳入的患者将通过参与获得至少一些有益效果。
抗BCL-2剂起始剂量的基本原理
已经建立的针对抗BCL-2剂的RDE(单位ug/kg,每三周施用一次)将用于该研究的所有患者。为了确保患者安全,将使用低于RDE的起始剂量;起始剂量水平将是仍然可以在研究SA1中证明患者有益效果的剂量水平,这表明以这种剂量水平纳入的患者将通过参与获得至少一些有益效果。
目标和相关终点
研究设计
这项Ib期、多中心、开放标签研究旨在表征患有疾病A、疾病B和疾病C的患者的ADC与抗BCL-2剂组合的安全性、耐受性、药代动力学(PK)、药效动力学(PD)和抗肿瘤活性。
该研究包括剂量递增部分和剂量扩大部分。
对于ADC和抗BCL-2剂,剂量递增将以降低的起始剂量(与它们各自推荐2期或许可的剂量水平相比)开始,以确保患者安全性。每种化合物的起始剂量将为RDE的33%(或50%)。随后,将首先使抗BCL-2剂的剂量递增,直到达到RDE或许可的剂量;如果出于耐受性原因,则必要时降低剂量。然后,使ADC的剂量递增,直到达到用于组合治疗的RDE。如下图所示:
如果确定剂量组合是安全的,则可以在其他患者中进行测试,以确认该剂量水平的安全性和耐受性。可以进一步调整每种化合物的剂量,并且/或者可以改变方案。
贝叶斯对数回归模型(BLRM)将根据在治疗的第一个(或前两个,TBC)周期中观察到的任何剂量限制性毒性(DLT)指导组合的剂量递增。BLRM的使用是一种行之有效的方法,以估计癌症患者的最大耐受剂量(MTD)/推荐增加剂量(RDE)。适应性BLRM将以过量控制递增(EWOC)原理为指导,以控制研究中未来患者的DLT风险。FDA和EMEA(“小规模人群临床试验指南”,2007年2月1日)已经接受针对小数据集的贝叶斯反应适应模型的使用,并且得到许多出版物的认可(Babb等人1998,Neuenschwander等人2008)。
新剂量组合的决定由研究者和资助研究人根据患者耐受性和安全性信息(包括DLT风险的BLRM汇总,如果适用)以及在决定时获得的PK、PD和初步活性信息在剂量递增安全性呼叫(DESC)中进行。
一旦确定针对组合的MTD/RDE,则可以启动研究的扩大部分,以进一步评估安全性、耐受性和初步功效。
■对于IO组合,肿瘤中的免疫浸润的变化还将在目标疾病适应症的组合治疗后表征。
鉴于该研究中药剂的现有临床经验,预期在大多数情况下,在不测试多数剂量水平或排程的情况下,可以确定组合剂量。为了评估组合的药效动力学活性,将要求患者在基线处接受肿瘤活检,并且在大约两个治疗周期后再次接受肿瘤活检。
■对于IO组合:免疫细胞(包括淋巴细胞和巨噬细胞)的肿瘤浸润的变化程度将有助于决定任何潜在的有益效果。
剂量递增部分
在研究的剂量递增部分期间,将通过i.v.施用的固定剂量的ADC以及增加抗BCL-2剂的剂量来治疗患者,直到达到抗BCL-2剂的RDE。随后,增加ADC的剂量(在不同的队列中),同时抗BCL-2剂的剂量保持恒定。
将在每个递增队列中治疗两到大约3或4名患有疾病A、疾病B或疾病C的患者,直到确定MTD/RDE为止。
在第二患者以剂量水平1纳入之前,将进行24小时观察。根据适当机构对IO治疗的要求,每种剂量水平的DLT观察期为1个周期(3周)或2个周期(6周),其后将确定是否递增至下一个剂量水平,并且保持在目前的剂量水平,或递减至下一个队列的此前剂量水平。不会从剂量水平1递减。不允许在患者体内进行剂量递增。
除非有2名或更多名患者在任何给定剂量水平的第一周期中都具有完整的DLT信息,否则不允许进行剂量递增。剂量递增将通过使用目标DLT率为30%、相等间隔为20%至35%的mCRM以及控制过量用药的剂量递增(EWOC)和无剂量跳跃的情况来确定。
患者将被分配到主动纳入的队列中。在完成一个周期的治疗后,将按每种组合进行剂量递增。将对所有纳入患者密切监测包括不良事件(AE)和实验室值在内的安全性评估,以鉴定任何DLT。将定义单个MTD/RDE;疾病特异性MTD/RDE将不会建立。
mCRM将在剂量递增指导委员会(DESC)的监督下针对DE实施。在审查所有可用的安全性数据后,DESC将确认每个递增剂量水平。来自该剂量水平和先前剂量水平的患者的PK数据也可为决策提供依据。根据新出现的PK、PD、毒性或反应数据,DESC可以在确定MTD之前停止剂量递增。
如果研究中至少有1名患者达到部分反应或更好的结果,或者如果DESC认为有必要对PK或PD数据进行进一步评估来确定RDE,则可以以任何剂量包括其他患者,以进一步评估安全性和耐受性。
在连续向3个队列(或至少6名患者)分配相同剂量水平后,将停止剂量递增。如果未达到MTD,则将确定推荐扩大剂量(RDE)。在确定MTD/RDE之前,必须使用组合治疗最少6名患者。
预期将在剂量递增期间从患者获得配对的肿瘤活检。这些活组织物的分析将有助于更好地理解剂量和组合药效动力学活性之间的关系。
剂量递增指导委员会的安全性监督
包括ADC Therapeutics和研究者的DESC将在DE期间持续审查患者的安全性,以确定mCRM规定的剂量递增排程是否需要修改。除安全性观察之外,PK和/或PD数据还可以为决策提供依据。在ADC Therapeutics和研究者达成协议后,可以分配中间剂量。在第2部分中,DESC可以继续提供监督。不会使用正式的数据安全性监测委员会(DSMB)。
剂量扩大部分
一旦公布MTD/RDE,就可以开始剂量扩大部分。扩大部分的主要目的是进一步评估MTD/RDE处研究治疗的安全性和耐受性,并且初步理解该组合与历史单一药剂功效数据相比的功效。
一个重要的探索目标是评估响应于治疗后肿瘤免疫浸润的变化。这将在从患者收集的配对肿瘤活检中进行评估,对于在MTD/RDE处接受治疗的患者,至少进行十对可评估的活检(活检样本必须包含足够的肿瘤以便进行分析)。如果这不可行,则可以停止收集这些活检物。计划在每个研究实验组中至少治疗10至20名患者,
将开放几个不同的研究实验组,每种疾病一个。剂量扩大中总共可以运行九个研究实验组。如果这些组中的任何一组的纳入都不可行,则可以在达到10至20个患者目标之前关闭该组的纳入。
在每个治疗组中,最多允许处理约六名接受先前单次施用(即不组合施用)抗BCL-2剂疗法并且进展的患者。如果组合显示有望克服对单次施用抗BCL-2剂的先前治疗的耐药性,则该数目可以增加。
患者群体
该研究将在患有上述晚期疾病A、疾病B或疾病C的成年患者中进行。研究者或指定人员必须确保仅满足以下所有纳入条件且不满足任何排除标准的患者在研究中得到治疗。
纳入标准
有资格纳入本研究的患者必须满足以下所有标准:
1.在进行任何程序之前,必须获得书面知情同意书
2.年龄为18岁。
3.具有RECIST 1.1版所确定的可测量疾病的晚期/转移性癌症的患者,尽管接受标准疗法仍已进展或对标准疗法不耐受,或者尚无针对所述患者的标准疗法。患者必须属于以下组之一:
·疾病A
·疾病B
·疾病C
4.ECOG体能状态0-1(或2TBC)
5.TBC:根据治疗机构的准则,患者必须具有适合活检的疾病部位并且是肿瘤活检的候选者。患者必须愿意在基线时接受新的肿瘤活检,并且在本研究的治疗期间再次进行。
6.允许先前使用抗BCL-2剂或相关化合物(即相同的MOA)进行治疗
排除标准
有资格进行这项研究的患者不得满足以下任何标准:
1.有对其他mAb(或与ADC中相同的主链mAb或对相同IO mAb,如果适用)发生严重超敏反应的历史
2.已知具有血清人ADA对ADC中mAb主链呈阳性的历史
3.仅中枢神经系统(CNS)疾病(如果适用)
4.症状性CNS转移或软脑膜疾病的证据(大脑MRI或此前记录的脑脊液(CSF)细胞学检查)
5.患者的实验室值超出范围,定义为:
·血清肌酐<=1.5×ULN。如果血清肌酐>1.5,则合格患者的肌酐清除率(使用Cockcroft-Gault公式计算或测量)必须>60mL/min/1.73m2
·总胆红素>1.5×ULN,但总胆红素>3.0×ULN或直接胆红素>1.5×ULN的吉尔伯特综合征(Gilbert's syndrome)患者除外
·丙氨酸氨基转移酶(ALT)>3×ULN,但有肝脏肿瘤累及的患者除外,如果ALT>5×ULN,则将其排除在外
·天门冬氨酸转氨酶(AST)>3×ULN,但有肝脏肿瘤累及的患者除外,如果AST>5×ULN,则将其排除在外
·中性粒细胞绝对计数<1.0×10e9/L
·血小板计数<75×10e9/L
·血红蛋白(Hgb)<8g/dL
·虽然进行了适当的替代治疗,但钾、镁、钙或磷酸盐异常>CTCAE 1级
6.具有损害的心脏功能或临床上显著的心脏疾病,包括以下任何一种:
·在使用或不使用抗高血压药的情况下,需要治疗的临床上显著和/或不受控制的心脏病诸如充血性心力衰竭(NYHA III或IV级)或由收缩压(SBP)160mmHg和/或舒张压(DBP)100mmHg定义的不受控制的高血压。
·使用弗雷德里恰(Fridericia)校正,先天性长QT综合征筛查ECG时,女性QTcF>470毫秒,或男性QTcF>450毫秒
·在<3个月(进入研究之前的月数)具有急性心肌梗塞或不稳定心绞痛
·临床上显著的瓣膜病,并且记录有心脏功能受损
·症状性心包炎
·具有心肌病史或正在记录的心肌病
·通过超声心动图(ECHO)或多门采集(MUGA)扫描确定的左室射血分数(LVEF)<40%
·任何临床上显著心律不齐的病史或存在,例如室性、室上性、淋巴结性心律不齐或传导异常(TBC限定词:……需要起搏器或不受药物控制)
·存在不稳定的心房颤动(心室反应率>100bpm)。
·完全性左束支传导阻滞(LBBB),双束传导阻滞
·任何临床上显著的ST段和/或T波异常
7.归因于此前的IO治疗的毒性导致治疗中断。不排除针对药物相关性皮疹或针对内分泌病用替代疗法经过充分治疗的患者,前提是这些毒性并未导致先前治疗停止。
8.患者患有活动性、已知或疑似自身免疫性疾病。允许患有以下疾病的受试者纳入:白癜风、I型糖尿病、由仅需激素替代的自身免疫性疾病导致的残留甲状腺功能减退,不需要全身治疗的银屑病或在没有外部触发因素的情况下不会复发的疾患,前提是所述触发因素可以避免。
9.人类免疫缺陷病毒(HIV)或活动性乙型肝炎(HBV)或丙型肝炎(HCV)病毒感染
10.除本研究中正在治疗的恶性疾病以外的恶性疾病。排除的例外情况包括以下:经过有疗效地治疗且在研究治疗前2年内未复发的恶性肿瘤;完全切除基底细胞和鳞状细胞皮肤癌;被认为是惰性的且从未需要治疗的任何恶性肿瘤;以及完全切除的任何类型的原位癌。
11.在研究治疗的第一剂后2周内进行全身抗癌治疗。对于具有重大延迟毒性的细胞毒性剂,例如丝裂霉素C和亚硝基脲,指示清除期为4周。对于接受抗癌免疫疗法诸如CTLA-4拮抗剂的患者,清除期为6周。
12.活动性腹泻CTCAE 2级或与慢性腹泻有关的医疗状况(诸如肠易激综合征、炎性肠病)
13.存在2:由于此前的癌症治疗引起的CTCAE 2级毒性(脱发,周围神经病变和耳毒性除外,如果>=CTCAE 3级则不包括在内)。
14.活动性感染需要全身抗生素治疗。
15.上消化道活动性溃疡或胃肠道出血
16.活动性出血素质或口服抗维生素K药物(低剂量华法令和阿司匹林或同等药物除外,只要INR<=2.0)
17.活动性自身免疫病,认为是自身免疫起源的运动神经病和其他CNS免疫性疾病
18.患者需要同时使用免疫抑制剂或长期使用皮质类固醇治疗,但以下情况除外:
19.在研究治疗开始后的4周内使用任何针对感染性疾病(例如流感、水痘、肺炎球菌)的活疫苗(NB在整个研究过程中均不允许使用活疫苗)
20.在开始研究药物之前<2周使用造血细胞集落刺激性生长因子(例如G-CSF、GMCSF、M-CSF)。红细胞刺激剂只要在研究治疗的第一次给药前至少2周开始就可使用。
21.在研究治疗的第一次给药后2周内进行大手术(NB纵隔镜检查、中央静脉通路装置的插入或饲管的插入不视为大手术)。
22.在首次施用研究药物后的2周内进行放射疗法,但对有限区域的姑息放射疗法除外,诸如用于治疗骨痛或局部疼痛的肿块。为了允许评估对治疗的反应,患者必须患有尚未辐照的其余可测量疾病
23.在第一剂研究治疗的2周内参加一项介入性研究。
24.研究者认为,由于安全问题,遵守临床研究程序或对研究结果的解释而导致患者无法参加临床研究的任何医疗状况。
25.性活跃的男性,除非他们在服药期间性交时和停止研究治疗后90天使用避孕套,并且在此期间不应孕育孩子。经历输精管切除术的男性也需要使用避孕套,以防止通过精液输送药物。
26.通过实验室测试hCG阳性证实怀孕或哺乳期的妇女,其中怀孕定义为女性受孕后直至妊娠终止的状态。在罕见的内分泌腺分泌型肿瘤的情况下,hCG水平可能高于正常限值,但患者未怀孕。在这些情况下,应重复进行血清hCG测试(无升高结果)和阴道/盆腔超声检查以排除妊娠。在确认结果并与医学代表讨论后,这些患者可以进入研究。
27.具有生育能力的妇女,定义为在生理上有能力怀孕的所有妇女,除非她们在研究治疗期间以及研究治疗的最后任一次给药后的90天内使用了高效的避孕方法。高效避孕方法包括:
·完全禁欲(当此符合患者的优选及惯常的生活方式时)。定期禁欲(例如,日历法、排卵法、症状体温法、排卵后方法)和戒断是不可接受的避孕方法
·接受研究治疗前至少6周,进行女性绝育手术(过去已经经历进行或不进行子宫切除术的双侧卵巢切除术)、全子宫切除术或输卵管结扎术。仅在进行卵巢切除术的情况下,只有通过随访激素水平评估来确定该妇女的生殖状况时
·男性绝育(筛查前至少6个月)。对于研究中的女性患者,经历输精管切除术的男性配偶体应为该患者的唯一配偶体。
·使用口服(雌激素和孕酮)、注射或植入激素的组合避孕方法或放置宫内节育器(IUD)或宫内节育系统(IUS)或其他具有相当疗效的激素避孕方法(失败率<1%),例如激素阴道环或经皮激素避孕。
如果妇女具有12个月的自然(自发)闭经且具有适当的临床特征(例如,适当的年龄、血管舒缩症状的病史)或进行了双侧卵巢切除术(进行或不进行子宫切除术)或输卵管结扎(至少6周前),则被认为是绝经后且没有生育能力的妇女)。仅在进行卵巢切除术的情况下,只有通过随访激素水平评估确认该妇女的生殖状况时才认为她没有生育能力。
剂量限制性毒性和剂量修改指南
剂量限制性毒性(DLT)定义为以下任何事件:在21天DLT评估期间发生的根据研究者的判断认为至少可能与ADC有关。与原发性疾病或另一种病因明确且直接相关的毒性不包括在该定义之内。
DLT定义
血液DLT定义为:
■3或4级发热性中性粒细胞减少或中性粒细胞减少感染
■4级中性粒细胞减少症持续>7天
■4级血小板减少
■具有临床上显著的出血的3级血小板减少或需要血小板输注的3级血小板减少
■需要输血的3级贫血
■4级贫血
非血液DLT定义为:
■4级非血液毒性
■虽然获得了最佳的支持治疗或医疗干预,但3级非血液毒性持续>3天
■一例海氏法则(AST和/或ALT>3×ULN,并且胆红素>2×ULN,并且没有胆汁郁积的初步发现血清碱性磷酸酶(ALP)活性<2×ULN),并且其他原因都无法解释转氨酶增加和血清总胆红素的组合,诸如甲型病毒性肝炎、乙型病毒性肝炎或丙型病毒性肝炎,此前或急性肝病或其他能够引起观察到的伤害的药物)
■3级或更高级的超敏性/输注相关反应(无论是否进行术前用药)。在发病后8小时内通过适当的临床管理解决的3级超敏/输注相关反应不符合DLT的资格。
■LVEF从基线降低至<40%或>20%
■4级肿瘤溶解综合征(除非导致不可逆的终末器官损害,否则3级TLS不构成DLT)
以下情况不被视为非血液DLT:
·3级疲劳持续≤7天
·在没有进行术前用药的情况下发生的3级腹泻、恶心或呕吐,其对治疗有反应,并且对于3级事件在3天内至少改善1级,或在7天内降至≤1级。
·AST或ALT升高≥5×ULN,但是≤8×ULN,而胆红素没有同时升高,在发生后5天内降级至≤2级。
·如果没有胰腺炎的临床体征或症状,3级血清脂肪酶或血清淀粉酶持续≤7天
经历在适当医疗管理下可解决或稳定的DLT的患者,研究者可在与资助者协商的情况下酌情决定继续治疗。
剂量修改
下表中详细列出了特定毒性的管理指南。为了管理表中未指定的事件,以下内容可以作为研究者指南:
实施例3
方法
在暴露于增加的ADCx19浓度(96小时)的细胞系上进行MTT增殖测定法和IC50计算。皮尔逊相关系数(r):计算IC50与细胞表面CD19表达水平(使用Quantum SimplyCellular微球进行绝对荧光定量;非绝对数据,来自PMID 29298756)和RNA水平(IlluminaHT-12阵列和HTG EdgeSeq肿瘤生物标志物小组,数据来自PMID 29066507)。在96小时通过Chou-Talalay组合指数(CI)(协同作用CI<0.9,加性CI=0.9-1.1,拮抗作用/无有益效果CI>1.1)对2个活化的B细胞样(ABC)DLBCL(OCI-LY-3,TMD8)和2个生发中心(GCB)DLBCL(VAL,WSU-DLCL2)进行协同作用评估。
结果
在48个B细胞淋巴瘤细胞系中,ADCx19 IC50的中位数为4pM(95%C.I,2-10pM),并且如根据CD19表达模式所预期,在9个T细胞淋巴瘤细胞系(3.5nM;95%CI,0.8-11nM)中,超过800倍。关注B细胞淋巴瘤,ADCx19体外活性与它在细胞表面蛋白水平上测定的靶标表达相关[(绝对定量,n=40,r-0.37P 0.02;非绝对定量,n=42,-0.48,P 0.001]和RNA水平[(阵列,n=39,-0.69P<0.001;HTG,n=31,-0.73P 0.001]。在DLBCL中,BCL2和MYC易位或TP53失活的存在不影响对ADCx19的敏感性。
然后将ADCx19与BCL2抑制剂维奈妥拉组合在GCB-和ABC-DLBCL细胞系中
将ADCx19与维奈妥拉组合使用可实现所有细胞系中的协同作用
细胞系:OCI-LY3
RRID细胞登录标识符:CVCL_8800
细胞系:TMD8
RRID细胞登录标识符:CVCL_A442
参考文献:Tohda等人,Leuk.Res.30:1385-1390(2006)
细胞系:VAL
RRID细胞登录标识符:CVCL_1819
细胞系:WSU-DLCL2
RRID细胞登录标识符:CVCL_1902
结论
ADCx19的强效单一药剂体外抗淋巴瘤活性与其靶标表达相关并且支持目前正在进行的复发/难治性DLBCL的临床研究。新型维奈妥拉组合数据表示临床协同作用。
SEQUENCE LISTING
<110> ADC治疗有限公司
免疫医疗有限公司
<120> 组合疗法
<130> P21111550WP
<150> GB 1814207.5
<151> 2018-08-31
<150> GB 1908225.4
<151> 2019-06-10
<160> 15
<170> PatentIn version 3.5
<210> 1
<211> 119
<212> PRT
<213> Artificial Sequence
<220>
<223> 抗CD19-ADC抗体RB4v1.0 VH
<400> 1
Gln Val Gln Leu Val Gln Pro Gly Ala Glu Val Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Leu Ser Cys Lys Thr Ser Gly Tyr Thr Phe Thr Ser Asn
20 25 30
Trp Met His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Glu Ile Asp Pro Ser Asp Ser Tyr Thr Asn Tyr Asn Gln Asn Phe
50 55 60
Lys Gly Lys Ala Lys Leu Thr Val Asp Lys Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Val Ser Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Ser Asn Pro Tyr Tyr Tyr Ala Met Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Ser Val Thr Val Ser
115
<210> 2
<211> 119
<212> PRT
<213> Artificial Sequence
<220>
<223> 抗CD19-ADC抗体RB4v1.2 VH
<400> 2
Gln Val Gln Leu Val Gln Pro Gly Ala Glu Val Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Leu Ser Cys Lys Thr Ser Gly Tyr Thr Phe Thr Ser Asn
20 25 30
Trp Met His Trp Val Lys Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Glu Ile Asp Pro Ser Asp Ser Tyr Thr Asn Tyr Asn Gln Asn Phe
50 55 60
Gln Gly Lys Ala Lys Leu Thr Val Asp Lys Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Val Ser Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Ser Asn Pro Tyr Tyr Tyr Ala Met Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Ser Val Thr Val Ser
115
<210> 3
<211> 121
<212> PRT
<213> Artificial Sequence
<220>
<223> 抗CD19-ADC抗体B43 VH
<400> 3
Gln Val Gln Leu Leu Glu Ser Gly Ala Glu Leu Val Arg Pro Gly Ser
1 5 10 15
Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ala Phe Ser Ser Tyr
20 25 30
Trp Met Asn Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Gln Ile Trp Pro Gly Asp Gly Asp Thr Asn Tyr Asn Gly Lys Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Ala Asp Glu Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Gln Leu Ser Ser Leu Arg Ser Glu Asp Ser Ala Val Tyr Ser Cys
85 90 95
Ala Arg Arg Glu Thr Thr Thr Val Gly Arg Tyr Tyr Tyr Ala Met Asp
100 105 110
Tyr Trp Gly Gln Gly Thr Thr Val Thr
115 120
<210> 4
<211> 123
<212> PRT
<213> Artificial Sequence
<220>
<223> 抗CD19-ADC抗体HD37 VH
<400> 4
Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Val Arg Pro Gly Ser
1 5 10 15
Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ala Phe Ser Ser Tyr
20 25 30
Trp Met Asn Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Gln Ile Trp Pro Gly Asp Gly Asp Thr Asn Tyr Asn Gly Lys Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Ala Asp Glu Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Gln Leu Ser Ser Leu Ala Ser Glu Asp Ser Ala Val Tyr Phe Cys
85 90 95
Ala Arg Arg Glu Thr Thr Thr Val Gly Arg Tyr Tyr Tyr Ala Met Asp
100 105 110
Tyr Trp Gly Gln Gly Thr Ser Val Thr Val Ser
115 120
<210> 5
<211> 120
<212> PRT
<213> Artificial Sequence
<220>
<223> 抗CD19-ADC抗体4G7 VH
<400> 5
Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Ile Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Val Met His Trp Val Lys Gln Lys Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Asn Pro Tyr Asn Asp Gly Thr Lys Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Ser Asp Lys Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Thr Tyr Tyr Tyr Gly Ser Arg Val Phe Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Thr Leu Thr Val Ser
115 120
<210> 6
<211> 119
<212> PRT
<213> Artificial Sequence
<220>
<223> 抗CD19-ADC抗体FMC63 VH
<400> 6
Glu Val Lys Leu Gln Glu Ser Gly Pro Gly Leu Val Ala Pro Ser Gln
1 5 10 15
Ser Leu Ser Val Thr Cys Thr Val Ser Gly Val Ser Leu Pro Asp Tyr
20 25 30
Gly Val Ser Trp Ile Arg Gln Pro Pro Arg Lys Gly Leu Glu Trp Leu
35 40 45
Gly Val Ile Trp Gly Ser Glu Thr Thr Tyr Tyr Asn Ser Ala Leu Lys
50 55 60
Ser Arg Leu Thr Ile Ile Lys Asp Asn Ser Lys Ser Gln Val Phe Leu
65 70 75 80
Lys Met Asn Ser Leu Gln Thr Asp Asp Thr Ala Ile Tyr Tyr Cys Ala
85 90 95
Lys His Tyr Tyr Tyr Gly Gly Ser Tyr Ala Met Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Ser Val Thr Val Ser
115
<210> 7
<211> 104
<212> PRT
<213> Artificial Sequence
<220>
<223> 抗CD19-ADC抗体RB4v1.0 VK
<400> 7
Glu Ile Val Leu Thr Gln Ser Pro Ala Ile Met Ser Ala Ser Pro Gly
1 5 10 15
Glu Arg Val Thr Met Thr Cys Ser Ala Ser Ser Gly Val Asn Tyr Met
20 25 30
His Trp Tyr Gln Gln Lys Pro Gly Thr Ser Pro Arg Arg Trp Ile Tyr
35 40 45
Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Ala Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Ser Met Glu Pro Glu
65 70 75 80
Asp Ala Ala Thr Tyr Tyr Cys His Gln Arg Gly Ser Tyr Thr Phe Gly
85 90 95
Gly Gly Thr Lys Leu Glu Ile Lys
100
<210> 8
<211> 104
<212> PRT
<213> Artificial Sequence
<220>
<223> 抗CD19-ADC抗体RB4v1.2 VK
<400> 8
Glu Ile Val Leu Thr Gln Ser Pro Ala Ile Met Ser Ala Ser Pro Gly
1 5 10 15
Glu Arg Val Thr Met Thr Cys Ser Ala Ser Ser Gly Val Asn Tyr Met
20 25 30
His Trp Tyr Gln Gln Lys Pro Gly Thr Ser Pro Arg Arg Trp Ile Tyr
35 40 45
Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Ala Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Ser Met Glu Pro Glu
65 70 75 80
Asp Ala Ala Thr Tyr Tyr Cys His Gln Arg Gly Ser Tyr Thr Phe Gly
85 90 95
Gly Gly Thr Lys Leu Glu Ile Lys
100
<210> 9
<211> 111
<212> PRT
<213> Artificial Sequence
<220>
<223> 抗CD19-ADC抗体B43 VK
<400> 9
Glu Leu Val Leu Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Gln Arg Ala Thr Ile Ser Cys Lys Ala Ser Gln Ser Val Asp Tyr Asp
20 25 30
Gly Asp Ser Tyr Leu Asn Trp Tyr Gln Gln Ile Pro Gly Gln Pro Pro
35 40 45
Lys Leu Leu Ile Tyr Asp Ala Ser Asn Leu Val Ser Gly Ile Pro Pro
50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Asn Ile His
65 70 75 80
Pro Val Glu Lys Val Asp Ala Ala Thr Tyr His Cys Gln Gln Ser Thr
85 90 95
Glu Asp Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 10
<211> 111
<212> PRT
<213> Artificial Sequence
<220>
<223> 抗CD19-ADC抗体HD37 VK
<400> 10
Asp Ile Leu Leu Thr Gln Thr Pro Ala Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Gln Arg Ala Thr Ile Ser Cys Lys Ala Ser Gln Ser Val Asp Tyr Asp
20 25 30
Gly Asp Ser Tyr Leu Asn Trp Tyr Gln Gln Ile Pro Gly Gln Pro Pro
35 40 45
Lys Leu Leu Ile Tyr Asp Ala Ser Asn Leu Val Ser Gly Ile Pro Pro
50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Asn Ile His
65 70 75 80
Pro Val Glu Lys Val Asp Ala Ala Thr Tyr His Cys Gln Gln Ser Thr
85 90 95
Glu Asp Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 11
<211> 112
<212> PRT
<213> Artificial Sequence
<220>
<223> 抗CD19-ADC抗体4G7 VK
<400> 11
Asp Ile Val Met Thr Gln Ala Ala Pro Ser Ile Pro Val Thr Pro Gly
1 5 10 15
Glu Ser Val Ser Ile Ser Cys Arg Ser Ser Lys Ser Leu Leu Asn Ser
20 25 30
Asn Gly Asn Thr Tyr Leu Tyr Trp Phe Leu Gln Arg Pro Gly Gln Ser
35 40 45
Pro Gln Leu Leu Ile Tyr Arg Met Ser Asn Leu Ala Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Ala Phe Thr Leu Arg Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln His
85 90 95
Leu Glu Tyr Pro Phe Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys
100 105 110
<210> 12
<211> 107
<212> PRT
<213> Artificial Sequence
<220>
<223> 抗CD19-ADC抗体FMC63 VK
<400> 12
Asp Ile Gln Met Thr Gln Thr Thr Ser Ser Leu Ser Ala Ser Leu Gly
1 5 10 15
Asp Arg Val Thr Ile Ser Cys Arg Ala Ser Gln Asp Ile Ser Lys Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Asp Gly Thr Val Lys Leu Leu Ile
35 40 45
Tyr His Thr Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile Ser Asn Leu Glu Gln
65 70 75 80
Glu Asp Ile Ala Thr Tyr Phe Cys Gln Gln Gly Asn Thr Leu Pro Tyr
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Thr
100 105
<210> 13
<211> 449
<212> PRT
<213> Artificial Sequence
<220>
<223> 抗CD19-ADC抗体RB4v1.2-HC
<400> 13
Gln Val Gln Leu Val Gln Pro Gly Ala Glu Val Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Leu Ser Cys Lys Thr Ser Gly Tyr Thr Phe Thr Ser Asn
20 25 30
Trp Met His Trp Val Lys Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Glu Ile Asp Pro Ser Asp Ser Tyr Thr Asn Tyr Asn Gln Asn Phe
50 55 60
Gln Gly Lys Ala Lys Leu Thr Val Asp Lys Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Val Ser Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Ser Asn Pro Tyr Tyr Tyr Ala Met Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Ser Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val
115 120 125
Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala
130 135 140
Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
145 150 155 160
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
165 170 175
Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
180 185 190
Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys
195 200 205
Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp
210 215 220
Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly
225 230 235 240
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
245 250 255
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
260 265 270
Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
275 280 285
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg
290 295 300
Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
305 310 315 320
Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu
325 330 335
Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
340 345 350
Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu
355 360 365
Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
370 375 380
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
385 390 395 400
Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp
405 410 415
Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His
420 425 430
Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
435 440 445
Gly
<210> 14
<211> 211
<212> PRT
<213> Artificial Sequence
<220>
<223> 抗CD19-ADC抗体RB4v1.2-LC
<400> 14
Glu Ile Val Leu Thr Gln Ser Pro Ala Ile Met Ser Ala Ser Pro Gly
1 5 10 15
Glu Arg Val Thr Met Thr Cys Ser Ala Ser Ser Gly Val Asn Tyr Met
20 25 30
His Trp Tyr Gln Gln Lys Pro Gly Thr Ser Pro Arg Arg Trp Ile Tyr
35 40 45
Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Ala Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Ser Met Glu Pro Glu
65 70 75 80
Asp Ala Ala Thr Tyr Tyr Cys His Gln Arg Gly Ser Tyr Thr Phe Gly
85 90 95
Gly Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala Pro Ser Val
100 105 110
Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser
115 120 125
Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln
130 135 140
Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val
145 150 155 160
Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu
165 170 175
Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu
180 185 190
Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg
195 200 205
Gly Glu Cys
210
<210> 15
<211> 18
<212> DNA
<213> Artificial Sequence
<220>
<223> 奥利默森 (G3139) 低聚核苷酸结构
<400> 15
tctcccagcg tgcgccat 18
Claims (22)
2.如权利要求6使用的ADCx19,其中所述方法包括在所述抗BCL-2剂之前、与所述抗BCL-2剂同时或在所述抗BCL-2剂之后施用ADCT-402。
3.如权利要求1和2任一项使用的ADCx19,其中所述方法还包括施用化学治疗剂。
4.如权利要求1至3任一项使用的ADCx19,其中所述个体是人类。
5.如权利要求1至4任一项使用的ADCx19,其中所述个体患有病症或已经确定为患有病症。
6.如权利要求5使用的ADCx19,其中所述个体患有或已经确定为患有表达CD19或CD19+肿瘤相关的非肿瘤细胞,诸如CD19+浸润性细胞的癌症。
7.如前述权利要求任一项使用的ADCx19,其中所述个体正在接受抗BCL-2剂治疗。
8.如前述权利要求任一项使用的ADCx19,其中所述个体已经接受抗BCL-2剂治疗。
9.如前述权利要求任一项使用的ADCx19,其中所述个体使用抗BCL-2剂难以治疗或进一步治疗。
10.如前述权利要求任一项使用的ADCx19,其中与单独使用ADCx19或抗BCL-2剂中的任一者的单药疗法相比,所述治疗具有增加的功效。
11.如前述权利要求任一项使用的ADCx19,其中所述病症是增殖性疾病。
12.如权利要求11使用的ADCx19,其中所述病症是癌症。
13.如权利要求18使用ADCx19的疾病,其中所述病症选自包含以下各项的组:非霍奇金淋巴瘤,包括弥漫性大B细胞淋巴瘤(DLBCL)、滤泡性淋巴瘤(FL)、套细胞淋巴瘤(MCL)、慢性淋巴性淋巴瘤(CLL)和边缘区B细胞淋巴瘤(MZBL);和白血病,诸如毛细胞白血病(HCL)、毛细胞白血病变体(HCL-v),和急性淋巴母细胞性白血病(ALL,诸如费城染色体阳性ALL(Ph+ALL)或费城染色体阴性ALL(Ph-ALL)。
16.如权利要求14或15任一项所述的方法,其中如果所述个体使用抗BCL-2剂难以治疗或进一步治疗,则选择所述个体进行治疗。
17.如权利要求1至13任一项使用的ADCx19,其中根据权利要求14至16中任一项所述的方法选择所述个体进行治疗。
19.如权利要求18使用的ADCx19,还包括将抗BCL-2剂与ADCx19组合施用。
20.如前述权利要求任一项使用的ADCx19或如前述权利要求任一项所述的方法,其中所述ADCx19包含在组合物中,任选地与药学上可接受的赋形剂组合。
21.一种抗BCL-2剂,其用于如权利要求1至13或17至20任一项所述的治疗方法中。
22.如前述权利要求任一项使用的ADCx19、如前述权利要求任一项使用的抗BCL-2剂或如前述权利要求任一项所述的方法,其中所述抗BCL-2剂是维奈妥拉。
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB1814207.5 | 2018-08-31 | ||
GBGB1814207.5A GB201814207D0 (en) | 2018-08-31 | 2018-08-31 | Combination Therapy |
GBGB1908225.4A GB201908225D0 (en) | 2019-06-10 | 2019-06-10 | Combination therapy |
GB1908225.4 | 2019-06-10 | ||
PCT/EP2019/073212 WO2020043878A1 (en) | 2018-08-31 | 2019-08-30 | Combination therapy |
Publications (1)
Publication Number | Publication Date |
---|---|
CN112638392A true CN112638392A (zh) | 2021-04-09 |
Family
ID=67841060
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201980056828.XA Pending CN112638392A (zh) | 2018-08-31 | 2019-08-30 | 组合疗法 |
Country Status (13)
Country | Link |
---|---|
US (1) | US20210322564A1 (zh) |
EP (1) | EP3843748A1 (zh) |
JP (1) | JP2021535110A (zh) |
KR (1) | KR20210054520A (zh) |
CN (1) | CN112638392A (zh) |
AU (1) | AU2019332979A1 (zh) |
BR (1) | BR112021003675A2 (zh) |
CA (1) | CA3107085A1 (zh) |
IL (1) | IL280968A (zh) |
MX (1) | MX2021001908A (zh) |
PH (1) | PH12021550376A1 (zh) |
SG (1) | SG11202101518QA (zh) |
WO (1) | WO2020043878A1 (zh) |
Families Citing this family (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CA3142645A1 (en) * | 2019-06-10 | 2020-12-17 | Adc Therapeutics Sa | Combination therapy comprising an anti-cd19 antibody drug conjugate and a pi3k inhibitor or a secondary agent |
GB202011993D0 (en) | 2020-07-31 | 2020-09-16 | Adc Therapeutics Sa | ANTI-IL 13Ra2 antibodies |
AU2022302769A1 (en) * | 2021-06-29 | 2024-02-08 | Adc Therapeutics Sa | Combination therapy using antibody-drug conjugates |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN105050661A (zh) * | 2012-10-12 | 2015-11-11 | Adc疗法责任有限公司 | 吡咯并苯并二氮杂卓-抗体结合物 |
WO2017160954A1 (en) * | 2016-03-15 | 2017-09-21 | Seattle Genetics, Inc. | Combinations of pbd-based antibody drug conjugates with bcl-2 inhibitors |
WO2018078123A1 (en) * | 2016-10-28 | 2018-05-03 | Morphosys Ag | Combination of anti cd19 antibody with a bcl-2 inhibitor and uses thereof |
Family Cites Families (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4816567A (en) | 1983-04-08 | 1989-03-28 | Genentech, Inc. | Recombinant immunoglobin preparations |
AU2006302415B2 (en) | 2005-10-07 | 2012-09-13 | Exelixis, Inc. | Azetidines as MEK inhibitors for the treatment of proliferative diseases |
US9919056B2 (en) | 2012-10-12 | 2018-03-20 | Adc Therapeutics S.A. | Pyrrolobenzodiazepine-anti-CD22 antibody conjugates |
GB201506399D0 (en) | 2015-04-15 | 2015-05-27 | Berkel Patricius H C Van And Howard Philip W | Site-specific antibody-drug conjugates |
GB201506402D0 (en) | 2015-04-15 | 2015-05-27 | Berkel Patricius H C Van And Howard Philip W | Site-specific antibody-drug conjugates |
CN110869765A (zh) * | 2017-04-20 | 2020-03-06 | Adc治疗有限公司 | 组合疗法 |
BR112019026564A2 (pt) * | 2017-06-14 | 2020-06-30 | Adc Therapeutics Sa | regimes de dosagem para a administração de um adc anti-cd19 |
-
2019
- 2019-08-30 CN CN201980056828.XA patent/CN112638392A/zh active Pending
- 2019-08-30 AU AU2019332979A patent/AU2019332979A1/en active Pending
- 2019-08-30 US US17/271,108 patent/US20210322564A1/en active Pending
- 2019-08-30 EP EP19762358.0A patent/EP3843748A1/en active Pending
- 2019-08-30 BR BR112021003675-0A patent/BR112021003675A2/pt not_active Application Discontinuation
- 2019-08-30 SG SG11202101518QA patent/SG11202101518QA/en unknown
- 2019-08-30 MX MX2021001908A patent/MX2021001908A/es unknown
- 2019-08-30 KR KR1020217006539A patent/KR20210054520A/ko unknown
- 2019-08-30 CA CA3107085A patent/CA3107085A1/en active Pending
- 2019-08-30 JP JP2021509758A patent/JP2021535110A/ja active Pending
- 2019-08-30 WO PCT/EP2019/073212 patent/WO2020043878A1/en unknown
-
2021
- 2021-02-18 IL IL280968A patent/IL280968A/en unknown
- 2021-02-23 PH PH12021550376A patent/PH12021550376A1/en unknown
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN105050661A (zh) * | 2012-10-12 | 2015-11-11 | Adc疗法责任有限公司 | 吡咯并苯并二氮杂卓-抗体结合物 |
WO2017160954A1 (en) * | 2016-03-15 | 2017-09-21 | Seattle Genetics, Inc. | Combinations of pbd-based antibody drug conjugates with bcl-2 inhibitors |
WO2018078123A1 (en) * | 2016-10-28 | 2018-05-03 | Morphosys Ag | Combination of anti cd19 antibody with a bcl-2 inhibitor and uses thereof |
Also Published As
Publication number | Publication date |
---|---|
KR20210054520A (ko) | 2021-05-13 |
SG11202101518QA (en) | 2021-03-30 |
IL280968A (en) | 2021-04-29 |
WO2020043878A1 (en) | 2020-03-05 |
BR112021003675A2 (pt) | 2021-05-18 |
CA3107085A1 (en) | 2020-03-05 |
AU2019332979A1 (en) | 2021-02-11 |
PH12021550376A1 (en) | 2021-11-29 |
JP2021535110A (ja) | 2021-12-16 |
MX2021001908A (es) | 2021-08-19 |
US20210322564A1 (en) | 2021-10-21 |
EP3843748A1 (en) | 2021-07-07 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US20230149556A1 (en) | Combination therapy | |
JP2020517640A5 (zh) | ||
US11596696B2 (en) | Combination therapy with an anti-CD25 antibody-drug conjugate | |
BR112019026564A2 (pt) | regimes de dosagem para a administração de um adc anti-cd19 | |
JP2020517629A5 (zh) | ||
CN112638392A (zh) | 组合疗法 | |
CN114302746A (zh) | 包含抗cd25抗体药物缀合物和另一剂的组合疗法 | |
CN112367999A (zh) | 组合疗法 | |
US20200129638A1 (en) | Combination therapy with an anti-psma antibody-drug conjugate | |
US20220305132A1 (en) | Combination therapy comprising an anti-cd19 antibody drug conjugate and a pi3k inhibitor or a secondary agent | |
WO2022074033A1 (en) | Combination therapy |
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 |