CN113272322A - 神经内分泌癌靶向治疗 - Google Patents
神经内分泌癌靶向治疗 Download PDFInfo
- Publication number
- CN113272322A CN113272322A CN201980079726.XA CN201980079726A CN113272322A CN 113272322 A CN113272322 A CN 113272322A CN 201980079726 A CN201980079726 A CN 201980079726A CN 113272322 A CN113272322 A CN 113272322A
- Authority
- CN
- China
- Prior art keywords
- ser
- leu
- gly
- antibody
- val
- 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
- 238000011282 treatment Methods 0.000 title description 41
- 201000002120 neuroendocrine carcinoma Diseases 0.000 title description 4
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 112
- 201000011510 cancer Diseases 0.000 claims abstract description 49
- 238000000034 method Methods 0.000 claims abstract description 44
- 230000000955 neuroendocrine Effects 0.000 claims abstract description 43
- 150000007523 nucleic acids Chemical class 0.000 claims abstract description 36
- 239000013598 vector Substances 0.000 claims abstract description 28
- 239000002246 antineoplastic agent Substances 0.000 claims abstract description 22
- 210000004027 cell Anatomy 0.000 claims description 164
- 101000829127 Homo sapiens Somatostatin receptor type 2 Proteins 0.000 claims description 96
- 102100023802 Somatostatin receptor type 2 Human genes 0.000 claims description 89
- 239000000203 mixture Substances 0.000 claims description 43
- 125000003275 alpha amino acid group Chemical group 0.000 claims description 37
- IEDXPSOJFSVCKU-HOKPPMCLSA-N [4-[[(2S)-5-(carbamoylamino)-2-[[(2S)-2-[6-(2,5-dioxopyrrolidin-1-yl)hexanoylamino]-3-methylbutanoyl]amino]pentanoyl]amino]phenyl]methyl N-[(2S)-1-[[(2S)-1-[[(3R,4S,5S)-1-[(2S)-2-[(1R,2R)-3-[[(1S,2R)-1-hydroxy-1-phenylpropan-2-yl]amino]-1-methoxy-2-methyl-3-oxopropyl]pyrrolidin-1-yl]-3-methoxy-5-methyl-1-oxoheptan-4-yl]-methylamino]-3-methyl-1-oxobutan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]-N-methylcarbamate Chemical group CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@H](C)[C@@H](O)c1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)C(=O)OCc1ccc(NC(=O)[C@H](CCCNC(N)=O)NC(=O)[C@@H](NC(=O)CCCCCN2C(=O)CCC2=O)C(C)C)cc1)C(C)C IEDXPSOJFSVCKU-HOKPPMCLSA-N 0.000 claims description 21
- 102100035360 Cerebellar degeneration-related antigen 1 Human genes 0.000 claims description 8
- 102100035361 Cerebellar degeneration-related protein 2 Human genes 0.000 claims description 8
- 101000737793 Homo sapiens Cerebellar degeneration-related antigen 1 Proteins 0.000 claims description 8
- 101000737796 Homo sapiens Cerebellar degeneration-related protein 2 Proteins 0.000 claims description 8
- 101100112922 Candida albicans CDR3 gene Proteins 0.000 claims description 6
- 108091028043 Nucleic acid sequence Proteins 0.000 claims description 6
- 229960005277 gemcitabine Drugs 0.000 claims description 5
- 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 claims description 5
- 108010093470 monomethyl auristatin E Proteins 0.000 claims description 4
- 210000004881 tumor cell Anatomy 0.000 claims description 3
- QNVSXXGDAPORNA-UHFFFAOYSA-N Resveratrol Natural products OC1=CC=CC(C=CC=2C=C(O)C(O)=CC=2)=C1 QNVSXXGDAPORNA-UHFFFAOYSA-N 0.000 claims description 2
- LUKBXSAWLPMMSZ-OWOJBTEDSA-N Trans-resveratrol Chemical compound C1=CC(O)=CC=C1\C=C\C1=CC(O)=CC(O)=C1 LUKBXSAWLPMMSZ-OWOJBTEDSA-N 0.000 claims description 2
- LUKBXSAWLPMMSZ-UHFFFAOYSA-N resveratrol Chemical compound C1=CC(O)=CC=C1C=CC1=CC(O)=CC(O)=C1 LUKBXSAWLPMMSZ-UHFFFAOYSA-N 0.000 claims description 2
- 235000021283 resveratrol Nutrition 0.000 claims description 2
- 229940016667 resveratrol Drugs 0.000 claims description 2
- WOWDZACBATWTAU-FEFUEGSOSA-N (2s)-2-[[(2s)-2-(dimethylamino)-3-methylbutanoyl]amino]-n-[(3r,4s,5s)-1-[(2s)-2-[(1r,2r)-3-[[(1s,2r)-1-hydroxy-1-phenylpropan-2-yl]amino]-1-methoxy-2-methyl-3-oxopropyl]pyrrolidin-1-yl]-3-methoxy-5-methyl-1-oxoheptan-4-yl]-n,3-dimethylbutanamide Chemical compound CC(C)[C@H](N(C)C)C(=O)N[C@@H](C(C)C)C(=O)N(C)[C@@H]([C@@H](C)CC)[C@H](OC)CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@H](C)[C@@H](O)C1=CC=CC=C1 WOWDZACBATWTAU-FEFUEGSOSA-N 0.000 claims 1
- 239000003814 drug Substances 0.000 abstract description 47
- 239000000611 antibody drug conjugate Substances 0.000 abstract description 41
- 229940049595 antibody-drug conjugate Drugs 0.000 abstract description 41
- 102000039446 nucleic acids Human genes 0.000 abstract description 27
- 108020004707 nucleic acids Proteins 0.000 abstract description 27
- 108050001286 Somatostatin Receptor Proteins 0.000 abstract description 10
- 102000011096 Somatostatin receptor Human genes 0.000 abstract description 10
- 210000001519 tissue Anatomy 0.000 description 56
- 241000282414 Homo sapiens Species 0.000 description 54
- 238000009739 binding Methods 0.000 description 49
- 230000027455 binding Effects 0.000 description 48
- 108090000765 processed proteins & peptides Proteins 0.000 description 47
- 108090000623 proteins and genes Proteins 0.000 description 44
- XKUKSGPZAADMRA-UHFFFAOYSA-N glycyl-glycyl-glycine Natural products NCC(=O)NCC(=O)NCC(O)=O XKUKSGPZAADMRA-UHFFFAOYSA-N 0.000 description 34
- 229960000390 fludarabine Drugs 0.000 description 33
- 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 33
- 102000004196 processed proteins & peptides Human genes 0.000 description 32
- 229940079593 drug Drugs 0.000 description 29
- 239000012634 fragment Substances 0.000 description 28
- 229920001184 polypeptide Polymers 0.000 description 28
- 239000002502 liposome Substances 0.000 description 26
- 102000004169 proteins and genes Human genes 0.000 description 26
- 241000699670 Mus sp. Species 0.000 description 25
- 235000018102 proteins Nutrition 0.000 description 24
- 230000037396 body weight Effects 0.000 description 23
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 23
- 239000000427 antigen Substances 0.000 description 22
- 108091007433 antigens Proteins 0.000 description 22
- 102000036639 antigens Human genes 0.000 description 22
- 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 21
- 235000001014 amino acid Nutrition 0.000 description 21
- 230000008685 targeting Effects 0.000 description 21
- 238000001727 in vivo Methods 0.000 description 20
- 229940024606 amino acid Drugs 0.000 description 19
- 150000001413 amino acids Chemical group 0.000 description 19
- 230000000694 effects Effects 0.000 description 19
- 210000000056 organ Anatomy 0.000 description 19
- 239000000243 solution Substances 0.000 description 19
- 230000001093 anti-cancer Effects 0.000 description 18
- 238000000684 flow cytometry Methods 0.000 description 18
- 108010067216 glycyl-glycyl-glycine Proteins 0.000 description 18
- 210000004408 hybridoma Anatomy 0.000 description 18
- 150000002632 lipids Chemical class 0.000 description 18
- 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 17
- 238000003384 imaging method Methods 0.000 description 17
- 108010051242 phenylalanylserine Proteins 0.000 description 17
- 241000699666 Mus <mouse, genus> Species 0.000 description 16
- 238000002347 injection Methods 0.000 description 16
- 239000007924 injection Substances 0.000 description 16
- 238000001262 western blot Methods 0.000 description 16
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 15
- 238000004519 manufacturing process Methods 0.000 description 15
- 208000021010 pancreatic neuroendocrine tumor Diseases 0.000 description 15
- 238000010186 staining Methods 0.000 description 15
- 108060003951 Immunoglobulin Proteins 0.000 description 14
- 210000004556 brain Anatomy 0.000 description 14
- 239000003795 chemical substances by application Substances 0.000 description 14
- 108010089804 glycyl-threonine Proteins 0.000 description 14
- 102000018358 immunoglobulin Human genes 0.000 description 14
- 238000000338 in vitro Methods 0.000 description 14
- 210000004185 liver Anatomy 0.000 description 14
- 108090000586 somatostatin receptor 2 Proteins 0.000 description 14
- 102000004052 somatostatin receptor 2 Human genes 0.000 description 14
- 108010047041 Complementarity Determining Regions Proteins 0.000 description 13
- 108020004414 DNA Proteins 0.000 description 13
- 102000053602 DNA Human genes 0.000 description 13
- 238000002965 ELISA Methods 0.000 description 13
- 108010021625 Immunoglobulin Fragments Proteins 0.000 description 13
- 102000008394 Immunoglobulin Fragments Human genes 0.000 description 13
- 208000035475 disorder Diseases 0.000 description 13
- 208000023356 medullary thyroid gland carcinoma Diseases 0.000 description 13
- 102000004127 Cytokines Human genes 0.000 description 12
- 108090000695 Cytokines Proteins 0.000 description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- 208000037196 Medullary thyroid carcinoma Diseases 0.000 description 12
- 210000001744 T-lymphocyte Anatomy 0.000 description 12
- 238000001218 confocal laser scanning microscopy Methods 0.000 description 12
- 238000011534 incubation Methods 0.000 description 12
- 208000013818 thyroid gland medullary carcinoma Diseases 0.000 description 12
- HKZAAJSTFUZYTO-LURJTMIESA-N (2s)-2-[[2-[[2-[[2-[(2-aminoacetyl)amino]acetyl]amino]acetyl]amino]acetyl]amino]-3-hydroxypropanoic acid Chemical compound NCC(=O)NCC(=O)NCC(=O)NCC(=O)N[C@@H](CO)C(O)=O HKZAAJSTFUZYTO-LURJTMIESA-N 0.000 description 11
- 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 11
- 239000000872 buffer Substances 0.000 description 11
- 230000004663 cell proliferation Effects 0.000 description 11
- 238000011156 evaluation Methods 0.000 description 11
- 210000000496 pancreas Anatomy 0.000 description 11
- 102000005962 receptors Human genes 0.000 description 11
- 108020003175 receptors Proteins 0.000 description 11
- 239000011780 sodium chloride Substances 0.000 description 11
- 229940124597 therapeutic agent Drugs 0.000 description 11
- 239000003981 vehicle Substances 0.000 description 11
- KXEVYGKATAMXJJ-ACZMJKKPSA-N Ala-Glu-Asp Chemical compound C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(O)=O KXEVYGKATAMXJJ-ACZMJKKPSA-N 0.000 description 10
- 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 10
- NYQHSUGFEWDWPD-ACZMJKKPSA-N Asp-Gln-Ala Chemical compound C[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)N)NC(=O)[C@H](CC(=O)O)N NYQHSUGFEWDWPD-ACZMJKKPSA-N 0.000 description 10
- HSJIGJRZYUADSS-IHRRRGAJSA-N Met-Lys-Leu Chemical compound [H]N[C@@H](CCSC)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(O)=O HSJIGJRZYUADSS-IHRRRGAJSA-N 0.000 description 10
- 241001465754 Metazoa Species 0.000 description 10
- 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 10
- YMTLKLXDFCSCNX-BYPYZUCNSA-N Ser-Gly-Gly Chemical compound OC[C@H](N)C(=O)NCC(=O)NCC(O)=O YMTLKLXDFCSCNX-BYPYZUCNSA-N 0.000 description 10
- 108010008685 alanyl-glutamyl-aspartic acid Proteins 0.000 description 10
- 201000010099 disease Diseases 0.000 description 10
- 238000012377 drug delivery Methods 0.000 description 10
- 108020001507 fusion proteins Proteins 0.000 description 10
- 102000037865 fusion proteins Human genes 0.000 description 10
- 230000007246 mechanism Effects 0.000 description 10
- 239000012528 membrane Substances 0.000 description 10
- 239000008194 pharmaceutical composition Substances 0.000 description 10
- 108010020755 prolyl-glycyl-glycine Proteins 0.000 description 10
- 108010087846 prolyl-prolyl-glycine Proteins 0.000 description 10
- 210000002307 prostate Anatomy 0.000 description 10
- 238000002626 targeted therapy Methods 0.000 description 10
- 238000002560 therapeutic procedure Methods 0.000 description 10
- 108010033670 threonyl-aspartyl-tyrosine Proteins 0.000 description 10
- 230000001988 toxicity Effects 0.000 description 10
- 231100000419 toxicity Toxicity 0.000 description 10
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 9
- HGCNKOLVKRAVHD-UHFFFAOYSA-N L-Met-L-Phe Natural products CSCCC(N)C(=O)NC(C(O)=O)CC1=CC=CC=C1 HGCNKOLVKRAVHD-UHFFFAOYSA-N 0.000 description 9
- YCEWAVIRWNGGSS-NQCBNZPSSA-N Phe-Trp-Ile Chemical compound C([C@H](N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O)C1=CC=CC=C1 YCEWAVIRWNGGSS-NQCBNZPSSA-N 0.000 description 9
- HQYVQDRYODWONX-DCAQKATOSA-N Val-His-Ser Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)N[C@@H](CO)C(=O)O)N HQYVQDRYODWONX-DCAQKATOSA-N 0.000 description 9
- BZOSBRIDWSSTFN-AVGNSLFASA-N Val-Leu-Met Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CCSC)C(=O)O)NC(=O)[C@H](C(C)C)N BZOSBRIDWSSTFN-AVGNSLFASA-N 0.000 description 9
- 239000000969 carrier Substances 0.000 description 9
- 238000011161 development Methods 0.000 description 9
- 230000018109 developmental process Effects 0.000 description 9
- 239000013604 expression vector Substances 0.000 description 9
- 229940088597 hormone Drugs 0.000 description 9
- 210000004072 lung Anatomy 0.000 description 9
- 238000010172 mouse model Methods 0.000 description 9
- 102000040430 polynucleotide Human genes 0.000 description 9
- 108091033319 polynucleotide Proteins 0.000 description 9
- 239000002157 polynucleotide Substances 0.000 description 9
- 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 8
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 8
- GNPVTZJUUBPZKW-WDSKDSINSA-N Gly-Gln-Ser Chemical compound [H]NCC(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CO)C(O)=O GNPVTZJUUBPZKW-WDSKDSINSA-N 0.000 description 8
- YABRDIBSPZONIY-BQBZGAKWSA-N Gly-Ser-Met Chemical compound [H]NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CCSC)C(O)=O YABRDIBSPZONIY-BQBZGAKWSA-N 0.000 description 8
- YGHSQRJSHKYUJY-SCZZXKLOSA-N Gly-Val-Pro Chemical compound CC(C)[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)CN YGHSQRJSHKYUJY-SCZZXKLOSA-N 0.000 description 8
- FKQPWMZLIIATBA-AJNGGQMLSA-N Leu-Lys-Ile Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O FKQPWMZLIIATBA-AJNGGQMLSA-N 0.000 description 8
- SPLBRAKYXGOFSO-UNQGMJICSA-N Pro-Phe-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CC1=CC=CC=C1)NC(=O)[C@@H]2CCCN2)O SPLBRAKYXGOFSO-UNQGMJICSA-N 0.000 description 8
- 108700008625 Reporter Genes Proteins 0.000 description 8
- XNCUYZKGQOCOQH-YUMQZZPRSA-N Ser-Leu-Gly Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)NCC(O)=O XNCUYZKGQOCOQH-YUMQZZPRSA-N 0.000 description 8
- 238000004458 analytical method Methods 0.000 description 8
- 230000008901 benefit Effects 0.000 description 8
- 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 8
- 238000002512 chemotherapy Methods 0.000 description 8
- 230000016396 cytokine production Effects 0.000 description 8
- 238000005516 engineering process Methods 0.000 description 8
- 210000002950 fibroblast Anatomy 0.000 description 8
- 239000005556 hormone Substances 0.000 description 8
- 239000003550 marker Substances 0.000 description 8
- 239000000463 material Substances 0.000 description 8
- 210000002741 palatine tonsil Anatomy 0.000 description 8
- 108010026333 seryl-proline Proteins 0.000 description 8
- 238000002415 sodium dodecyl sulfate polyacrylamide gel electrophoresis Methods 0.000 description 8
- 238000007920 subcutaneous administration Methods 0.000 description 8
- HUZGPXBILPMCHM-IHRRRGAJSA-N Asn-Arg-Phe Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O HUZGPXBILPMCHM-IHRRRGAJSA-N 0.000 description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
- 102000000588 Interleukin-2 Human genes 0.000 description 7
- 108010002350 Interleukin-2 Proteins 0.000 description 7
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 7
- AVEGDIAXTDVBJS-XUXIUFHCSA-N Leu-Ile-Arg Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O AVEGDIAXTDVBJS-XUXIUFHCSA-N 0.000 description 7
- QESXLSQLQHHTIX-RHYQMDGZSA-N Leu-Val-Thr Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O QESXLSQLQHHTIX-RHYQMDGZSA-N 0.000 description 7
- GILLQRYAWOMHED-DCAQKATOSA-N Lys-Val-Ser Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](N)CCCCN GILLQRYAWOMHED-DCAQKATOSA-N 0.000 description 7
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 7
- 208000033383 Neuroendocrine tumor of pancreas Diseases 0.000 description 7
- LEIKGVHQTKHOLM-IUCAKERBSA-N Pro-Pro-Gly Chemical compound OC(=O)CNC(=O)[C@@H]1CCCN1C(=O)[C@H]1NCCC1 LEIKGVHQTKHOLM-IUCAKERBSA-N 0.000 description 7
- 102100024216 Programmed cell death 1 ligand 1 Human genes 0.000 description 7
- 102100040678 Programmed cell death protein 1 Human genes 0.000 description 7
- 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 7
- 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 7
- VYQQQIRHIFALGE-UWJYBYFXSA-N Tyr-Ser-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 VYQQQIRHIFALGE-UWJYBYFXSA-N 0.000 description 7
- JIODCDXKCJRMEH-NHCYSSNCSA-N Val-Arg-Gln Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CCC(=O)N)C(=O)O)N JIODCDXKCJRMEH-NHCYSSNCSA-N 0.000 description 7
- 150000001875 compounds Chemical class 0.000 description 7
- 238000009169 immunotherapy Methods 0.000 description 7
- 231100000682 maximum tolerated dose Toxicity 0.000 description 7
- 239000002953 phosphate buffered saline Substances 0.000 description 7
- 230000003389 potentiating effect Effects 0.000 description 7
- 238000001959 radiotherapy Methods 0.000 description 7
- 229920002477 rna polymer Polymers 0.000 description 7
- 239000000126 substance Substances 0.000 description 7
- DEQANNDTNATYII-OULOTJBUSA-N (4r,7s,10s,13r,16s,19r)-10-(4-aminobutyl)-19-[[(2r)-2-amino-3-phenylpropanoyl]amino]-16-benzyl-n-[(2r,3r)-1,3-dihydroxybutan-2-yl]-7-[(1r)-1-hydroxyethyl]-13-(1h-indol-3-ylmethyl)-6,9,12,15,18-pentaoxo-1,2-dithia-5,8,11,14,17-pentazacycloicosane-4-carboxa Chemical compound C([C@@H](N)C(=O)N[C@H]1CSSC[C@H](NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](CC=2C3=CC=CC=C3NC=2)NC(=O)[C@H](CC=2C=CC=CC=2)NC1=O)C(=O)N[C@H](CO)[C@H](O)C)C1=CC=CC=C1 DEQANNDTNATYII-OULOTJBUSA-N 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- KTXKIYXZQFWJKB-VZFHVOOUSA-N Ala-Thr-Ser Chemical compound [H]N[C@@H](C)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(O)=O KTXKIYXZQFWJKB-VZFHVOOUSA-N 0.000 description 6
- PQWTZSNVWSOFFK-FXQIFTODSA-N Arg-Asp-Asn Chemical compound C(C[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](CC(=O)N)C(=O)O)N)CN=C(N)N PQWTZSNVWSOFFK-FXQIFTODSA-N 0.000 description 6
- TTXYKSADPSNOIF-IHRRRGAJSA-N Arg-Asp-Phe Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O TTXYKSADPSNOIF-IHRRRGAJSA-N 0.000 description 6
- UDSVWSUXKYXSTR-QWRGUYRKSA-N Asn-Gly-Tyr Chemical compound [H]N[C@@H](CC(N)=O)C(=O)NCC(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O UDSVWSUXKYXSTR-QWRGUYRKSA-N 0.000 description 6
- RCFGLXMZDYNRSC-CIUDSAMLSA-N Asn-Lys-Ala Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(O)=O RCFGLXMZDYNRSC-CIUDSAMLSA-N 0.000 description 6
- AYFVRYXNDHBECD-YUMQZZPRSA-N Asp-Leu-Gly Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)NCC(O)=O AYFVRYXNDHBECD-YUMQZZPRSA-N 0.000 description 6
- ZQFZEBRNAMXXJV-KKUMJFAQSA-N Asp-Tyr-His Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)N[C@@H](CC2=CN=CN2)C(=O)O)NC(=O)[C@H](CC(=O)O)N)O ZQFZEBRNAMXXJV-KKUMJFAQSA-N 0.000 description 6
- ZUNMTUPRQMWMHX-LSJOCFKGSA-N Asp-Val-Val Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(O)=O ZUNMTUPRQMWMHX-LSJOCFKGSA-N 0.000 description 6
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 6
- 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 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- MSHXWFKYXJTLEZ-CIUDSAMLSA-N Gln-Met-Asn Chemical compound CSCC[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)O)NC(=O)[C@H](CCC(=O)N)N MSHXWFKYXJTLEZ-CIUDSAMLSA-N 0.000 description 6
- 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 6
- 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 6
- KRRMJKMGWWXWDW-STQMWFEESA-N Gly-Arg-Phe Chemical compound NC(=N)NCCC[C@H](NC(=O)CN)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 KRRMJKMGWWXWDW-STQMWFEESA-N 0.000 description 6
- 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 6
- WNZOCXUOGVYYBJ-CDMKHQONSA-N Gly-Phe-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CC1=CC=CC=C1)NC(=O)CN)O WNZOCXUOGVYYBJ-CDMKHQONSA-N 0.000 description 6
- XHVONGZZVUUORG-WEDXCCLWSA-N Gly-Thr-Lys Chemical compound NCC(=O)N[C@@H]([C@H](O)C)C(=O)N[C@H](C(O)=O)CCCCN XHVONGZZVUUORG-WEDXCCLWSA-N 0.000 description 6
- WZUVPPKBWHMQCE-UHFFFAOYSA-N Haematoxylin Chemical compound C12=CC(O)=C(O)C=C2CC2(O)C1C1=CC=C(O)C(O)=C1OC2 WZUVPPKBWHMQCE-UHFFFAOYSA-N 0.000 description 6
- 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 6
- LHSGPCFBGJHPCY-UHFFFAOYSA-N L-leucine-L-tyrosine Natural products CC(C)CC(N)C(=O)NC(C(O)=O)CC1=CC=C(O)C=C1 LHSGPCFBGJHPCY-UHFFFAOYSA-N 0.000 description 6
- 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 6
- 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 6
- 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 6
- 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 6
- JGKHAFUAPZCCDU-BZSNNMDCSA-N Leu-Tyr-Leu Chemical compound CC(C)C[C@H]([NH3+])C(=O)N[C@H](C(=O)N[C@@H](CC(C)C)C([O-])=O)CC1=CC=C(O)C=C1 JGKHAFUAPZCCDU-BZSNNMDCSA-N 0.000 description 6
- AIMGJYMCTAABEN-GVXVVHGQSA-N Leu-Val-Glu Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(O)=O)C(O)=O AIMGJYMCTAABEN-GVXVVHGQSA-N 0.000 description 6
- 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 6
- 108010016076 Octreotide Proteins 0.000 description 6
- NOFBJKKOPKJDCO-KKXDTOCCSA-N Phe-Ala-Tyr Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](C)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O NOFBJKKOPKJDCO-KKXDTOCCSA-N 0.000 description 6
- BIYWZVCPZIFGPY-QWRGUYRKSA-N Phe-Gly-Ser Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)NCC(=O)N[C@@H](CO)C(O)=O BIYWZVCPZIFGPY-QWRGUYRKSA-N 0.000 description 6
- 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 6
- QYSFWUIXDFJUDW-DCAQKATOSA-N Ser-Leu-Arg Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O QYSFWUIXDFJUDW-DCAQKATOSA-N 0.000 description 6
- KCGIREHVWRXNDH-GARJFASQSA-N Ser-Leu-Pro Chemical compound CC(C)C[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](CO)N KCGIREHVWRXNDH-GARJFASQSA-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
- JNQZPAWOPBZGIX-RCWTZXSCSA-N Thr-Arg-Val Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)[C@@H](C)O)CCCN=C(N)N JNQZPAWOPBZGIX-RCWTZXSCSA-N 0.000 description 6
- KRPKYGOFYUNIGM-XVSYOHENSA-N Thr-Asp-Phe Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)O)N)O KRPKYGOFYUNIGM-XVSYOHENSA-N 0.000 description 6
- YUPVPKZBKCLFLT-QTKMDUPCSA-N Thr-His-Val Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)N[C@@H](C(C)C)C(=O)O)N)O YUPVPKZBKCLFLT-QTKMDUPCSA-N 0.000 description 6
- 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 6
- 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 6
- KZSYAEWQMJEGRZ-RHYQMDGZSA-N Thr-Leu-Val Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(O)=O KZSYAEWQMJEGRZ-RHYQMDGZSA-N 0.000 description 6
- DEGCBBCMYWNJNA-RHYQMDGZSA-N Thr-Pro-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@@H](N)[C@@H](C)O DEGCBBCMYWNJNA-RHYQMDGZSA-N 0.000 description 6
- 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 6
- NRFTYDWKWGJLAR-MELADBBJSA-N Tyr-Asp-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CC(=O)O)NC(=O)[C@H](CC2=CC=C(C=C2)O)N)C(=O)O NRFTYDWKWGJLAR-MELADBBJSA-N 0.000 description 6
- SMLCYZYQFRTLCO-UWJYBYFXSA-N Tyr-Cys-Ala Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CS)C(=O)N[C@@H](C)C(O)=O SMLCYZYQFRTLCO-UWJYBYFXSA-N 0.000 description 6
- 108010081404 acein-2 Proteins 0.000 description 6
- 108010060035 arginylproline Proteins 0.000 description 6
- 230000000903 blocking effect Effects 0.000 description 6
- 238000010276 construction Methods 0.000 description 6
- 229940127089 cytotoxic agent Drugs 0.000 description 6
- 230000003013 cytotoxicity Effects 0.000 description 6
- 231100000135 cytotoxicity Toxicity 0.000 description 6
- 230000006378 damage Effects 0.000 description 6
- FSXRLASFHBWESK-UHFFFAOYSA-N dipeptide phenylalanyl-tyrosine Natural products C=1C=C(O)C=CC=1CC(C(O)=O)NC(=O)C(N)CC1=CC=CC=C1 FSXRLASFHBWESK-UHFFFAOYSA-N 0.000 description 6
- 108010057083 glutamyl-aspartyl-leucine Proteins 0.000 description 6
- 108010001064 glycyl-glycyl-glycyl-glycine Proteins 0.000 description 6
- 230000012010 growth Effects 0.000 description 6
- 230000001965 increasing effect Effects 0.000 description 6
- 108010012058 leucyltyrosine Proteins 0.000 description 6
- 239000003446 ligand Substances 0.000 description 6
- 108010064235 lysylglycine Proteins 0.000 description 6
- 239000002609 medium Substances 0.000 description 6
- 238000002493 microarray Methods 0.000 description 6
- 229960002700 octreotide Drugs 0.000 description 6
- 230000001575 pathological effect Effects 0.000 description 6
- 230000001105 regulatory effect Effects 0.000 description 6
- 230000019491 signal transduction Effects 0.000 description 6
- 230000004083 survival effect Effects 0.000 description 6
- 230000001225 therapeutic effect Effects 0.000 description 6
- 210000001685 thyroid gland Anatomy 0.000 description 6
- WYWHKKSPHMUBEB-UHFFFAOYSA-N tioguanine Chemical compound N1C(N)=NC(=S)C2=C1N=CN2 WYWHKKSPHMUBEB-UHFFFAOYSA-N 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- FRBAHXABMQXSJQ-FXQIFTODSA-N Arg-Ser-Ser Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(O)=O FRBAHXABMQXSJQ-FXQIFTODSA-N 0.000 description 5
- AUZAXCPWMDBWEE-HJGDQZAQSA-N Arg-Thr-Glu Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCC(O)=O)C(O)=O AUZAXCPWMDBWEE-HJGDQZAQSA-N 0.000 description 5
- NONWUQAWAANERO-BZSNNMDCSA-N Asp-Phe-Tyr Chemical compound C([C@H](NC(=O)[C@H](CC(O)=O)N)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(O)=O)C1=CC=CC=C1 NONWUQAWAANERO-BZSNNMDCSA-N 0.000 description 5
- XUVTWGPERWIERB-IHRRRGAJSA-N Asp-Pro-Phe Chemical compound N[C@@H](CC(O)=O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](Cc1ccccc1)C(O)=O XUVTWGPERWIERB-IHRRRGAJSA-N 0.000 description 5
- LPIKVBWNNVFHCQ-GUBZILKMSA-N Gln-Ser-Leu Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(O)=O LPIKVBWNNVFHCQ-GUBZILKMSA-N 0.000 description 5
- OONBGFHNQVSUBF-KBIXCLLPSA-N Ile-Gln-Cys Chemical compound CC[C@H](C)[C@H](N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CS)C(O)=O OONBGFHNQVSUBF-KBIXCLLPSA-N 0.000 description 5
- XLXPYSDGMXTTNQ-UHFFFAOYSA-N Ile-Phe-Leu Natural products CCC(C)C(N)C(=O)NC(C(=O)NC(CC(C)C)C(O)=O)CC1=CC=CC=C1 XLXPYSDGMXTTNQ-UHFFFAOYSA-N 0.000 description 5
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 5
- 229930182816 L-glutamine Natural products 0.000 description 5
- 241000880493 Leptailurus serval Species 0.000 description 5
- 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 5
- QWTGQXGNNMIUCW-BPUTZDHNSA-N Met-Asn-Trp Chemical compound [H]N[C@@H](CCSC)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC1=CNC2=C1C=CC=C2)C(O)=O QWTGQXGNNMIUCW-BPUTZDHNSA-N 0.000 description 5
- 101100534340 Mus musculus Sstr2 gene Proteins 0.000 description 5
- BQVUABVGYYSDCJ-UHFFFAOYSA-N Nalpha-L-Leucyl-L-tryptophan Natural products C1=CC=C2C(CC(NC(=O)C(N)CC(C)C)C(O)=O)=CNC2=C1 BQVUABVGYYSDCJ-UHFFFAOYSA-N 0.000 description 5
- AMBLXEMWFARNNQ-DCAQKATOSA-N Pro-Asn-Leu Chemical compound CC(C)C[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)N)NC(=O)[C@@H]1CCCN1 AMBLXEMWFARNNQ-DCAQKATOSA-N 0.000 description 5
- RMODQFBNDDENCP-IHRRRGAJSA-N Pro-Lys-Leu Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(O)=O RMODQFBNDDENCP-IHRRRGAJSA-N 0.000 description 5
- 102100024213 Programmed cell death 1 ligand 2 Human genes 0.000 description 5
- 101710089372 Programmed cell death protein 1 Proteins 0.000 description 5
- YQHZVYJAGWMHES-ZLUOBGJFSA-N Ser-Ala-Ser Chemical compound OC[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](CO)C(O)=O YQHZVYJAGWMHES-ZLUOBGJFSA-N 0.000 description 5
- 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 5
- LKEKWDJCJSPXNI-IRIUXVKKSA-N Thr-Glu-Tyr Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 LKEKWDJCJSPXNI-IRIUXVKKSA-N 0.000 description 5
- BYSKNUASOAGJSS-NQCBNZPSSA-N Trp-Ile-Phe Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)O)NC(=O)[C@H](CC2=CNC3=CC=CC=C32)N BYSKNUASOAGJSS-NQCBNZPSSA-N 0.000 description 5
- XGFGVFMXDXALEV-XIRDDKMYSA-N Trp-Leu-Asn Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)O)NC(=O)[C@H](CC1=CNC2=CC=CC=C21)N XGFGVFMXDXALEV-XIRDDKMYSA-N 0.000 description 5
- DIOSYUIWOQCXNR-ONGXEEELSA-N Val-Lys-Gly Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](CCCCN)C(=O)NCC(O)=O DIOSYUIWOQCXNR-ONGXEEELSA-N 0.000 description 5
- 125000000539 amino acid group Chemical group 0.000 description 5
- 230000010261 cell growth Effects 0.000 description 5
- 230000021615 conjugation Effects 0.000 description 5
- 210000000805 cytoplasm Anatomy 0.000 description 5
- 239000012091 fetal bovine serum Substances 0.000 description 5
- 238000009472 formulation Methods 0.000 description 5
- 230000006870 function Effects 0.000 description 5
- 210000001035 gastrointestinal tract Anatomy 0.000 description 5
- 230000002068 genetic effect Effects 0.000 description 5
- 239000008103 glucose Substances 0.000 description 5
- 108010050848 glycylleucine Proteins 0.000 description 5
- 230000002055 immunohistochemical effect Effects 0.000 description 5
- 238000011532 immunohistochemical staining Methods 0.000 description 5
- 238000011503 in vivo imaging Methods 0.000 description 5
- 239000003112 inhibitor Substances 0.000 description 5
- 108010057821 leucylproline Proteins 0.000 description 5
- 239000000693 micelle Substances 0.000 description 5
- 239000013642 negative control Substances 0.000 description 5
- 239000002773 nucleotide Substances 0.000 description 5
- 125000003729 nucleotide group Chemical group 0.000 description 5
- 108010064486 phenylalanyl-leucyl-valine Proteins 0.000 description 5
- 230000005855 radiation Effects 0.000 description 5
- 238000011160 research Methods 0.000 description 5
- 229960004641 rituximab Drugs 0.000 description 5
- 239000000523 sample Substances 0.000 description 5
- 230000009870 specific binding Effects 0.000 description 5
- 210000000952 spleen Anatomy 0.000 description 5
- 238000001356 surgical procedure Methods 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- 238000002054 transplantation Methods 0.000 description 5
- 210000003462 vein Anatomy 0.000 description 5
- 238000012447 xenograft mouse model Methods 0.000 description 5
- FDKXTQMXEQVLRF-ZHACJKMWSA-N (E)-dacarbazine Chemical compound CN(C)\N=N\c1[nH]cnc1C(N)=O FDKXTQMXEQVLRF-ZHACJKMWSA-N 0.000 description 4
- NDMPLJNOPCLANR-UHFFFAOYSA-N 3,4-dihydroxy-15-(4-hydroxy-18-methoxycarbonyl-5,18-seco-ibogamin-18-yl)-16-methoxy-1-methyl-6,7-didehydro-aspidospermidine-3-carboxylic acid methyl ester Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 NDMPLJNOPCLANR-UHFFFAOYSA-N 0.000 description 4
- VGPWRRFOPXVGOH-BYPYZUCNSA-N Ala-Gly-Gly Chemical compound C[C@H](N)C(=O)NCC(=O)NCC(O)=O VGPWRRFOPXVGOH-BYPYZUCNSA-N 0.000 description 4
- 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 4
- VKKYFICVTYKFIO-CIUDSAMLSA-N Arg-Ala-Glu Chemical compound OC(=O)CC[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CCCN=C(N)N VKKYFICVTYKFIO-CIUDSAMLSA-N 0.000 description 4
- COXMUHNBYCVVRG-DCAQKATOSA-N Arg-Leu-Ser Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(O)=O COXMUHNBYCVVRG-DCAQKATOSA-N 0.000 description 4
- 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 4
- PRLPSDIHSRITSF-UNQGMJICSA-N Arg-Phe-Thr Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H]([C@@H](C)O)C(O)=O PRLPSDIHSRITSF-UNQGMJICSA-N 0.000 description 4
- PBSQFBAJKPLRJY-BYULHYEWSA-N Asn-Gly-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)CNC(=O)[C@H](CC(=O)N)N PBSQFBAJKPLRJY-BYULHYEWSA-N 0.000 description 4
- JWQWPRCDYWNVNM-ACZMJKKPSA-N Asn-Ser-Gln Chemical compound C(CC(=O)N)[C@@H](C(=O)O)NC(=O)[C@H](CO)NC(=O)[C@H](CC(=O)N)N JWQWPRCDYWNVNM-ACZMJKKPSA-N 0.000 description 4
- 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 4
- 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 4
- 210000001266 CD8-positive T-lymphocyte Anatomy 0.000 description 4
- 241000283707 Capra Species 0.000 description 4
- 108010058546 Cyclin D1 Proteins 0.000 description 4
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 4
- AMRLSQGGERHDHJ-FXQIFTODSA-N Cys-Ala-Arg Chemical compound [H]N[C@@H](CS)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O AMRLSQGGERHDHJ-FXQIFTODSA-N 0.000 description 4
- YFXFOZPXVFPBDH-VZFHVOOUSA-N Cys-Ala-Thr Chemical compound C[C@@H](O)[C@H](NC(=O)[C@H](C)NC(=O)[C@@H](N)CS)C(O)=O YFXFOZPXVFPBDH-VZFHVOOUSA-N 0.000 description 4
- 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 4
- 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 4
- IPHGBVYWRKCGKG-FXQIFTODSA-N Gln-Cys-Glu Chemical compound NC(=O)CC[C@H](N)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCC(O)=O)C(O)=O IPHGBVYWRKCGKG-FXQIFTODSA-N 0.000 description 4
- 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 4
- 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 4
- YWAQATDNEKZFFK-BYPYZUCNSA-N Gly-Gly-Ser Chemical compound NCC(=O)NCC(=O)N[C@@H](CO)C(O)=O YWAQATDNEKZFFK-BYPYZUCNSA-N 0.000 description 4
- 101001012157 Homo sapiens Receptor tyrosine-protein kinase erbB-2 Proteins 0.000 description 4
- JHNJNTMTZHEDLJ-NAKRPEOUSA-N Ile-Ser-Arg Chemical compound CC[C@H](C)[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCN=C(N)N)C(O)=O JHNJNTMTZHEDLJ-NAKRPEOUSA-N 0.000 description 4
- 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 4
- ZUWSVOYKBCHLRR-MGHWNKPDSA-N Ile-Tyr-Lys Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC1=CC=C(C=C1)O)C(=O)N[C@@H](CCCCN)C(=O)O)N ZUWSVOYKBCHLRR-MGHWNKPDSA-N 0.000 description 4
- JDBQSGMJBMPNFT-AVGNSLFASA-N Leu-Pro-Val Chemical compound CC(C)C[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](C(C)C)C(O)=O JDBQSGMJBMPNFT-AVGNSLFASA-N 0.000 description 4
- YPLVCBKEPJPBDQ-MELADBBJSA-N Lys-Leu-Pro Chemical compound CC(C)C[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](CCCCN)N YPLVCBKEPJPBDQ-MELADBBJSA-N 0.000 description 4
- PFZWARWVRNTPBR-IHPCNDPISA-N Lys-Leu-Trp Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CC1=CNC2=CC=CC=C21)C(=O)O)NC(=O)[C@H](CCCCN)N PFZWARWVRNTPBR-IHPCNDPISA-N 0.000 description 4
- HDNOQCZWJGGHSS-VEVYYDQMSA-N Met-Asn-Thr Chemical compound CSCC[C@H](N)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O HDNOQCZWJGGHSS-VEVYYDQMSA-N 0.000 description 4
- 206010027476 Metastases Diseases 0.000 description 4
- 101100407308 Mus musculus Pdcd1lg2 gene Proteins 0.000 description 4
- 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 4
- 229930012538 Paclitaxel Natural products 0.000 description 4
- 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 4
- XQLBWXHVZVBNJM-FXQIFTODSA-N Pro-Ala-Ser Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H]1CCCN1 XQLBWXHVZVBNJM-FXQIFTODSA-N 0.000 description 4
- HAAQQNHQZBOWFO-LURJTMIESA-N Pro-Gly-Gly Chemical compound OC(=O)CNC(=O)CNC(=O)[C@@H]1CCCN1 HAAQQNHQZBOWFO-LURJTMIESA-N 0.000 description 4
- FKYKZHOKDOPHSA-DCAQKATOSA-N Pro-Leu-Ser Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(O)=O FKYKZHOKDOPHSA-DCAQKATOSA-N 0.000 description 4
- 108700030875 Programmed Cell Death 1 Ligand 2 Proteins 0.000 description 4
- 102100030086 Receptor tyrosine-protein kinase erbB-2 Human genes 0.000 description 4
- JFWDJFULOLKQFY-QWRGUYRKSA-N Ser-Gly-Phe Chemical compound [H]N[C@@H](CO)C(=O)NCC(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O JFWDJFULOLKQFY-QWRGUYRKSA-N 0.000 description 4
- 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 4
- PPCZVWHJWJFTFN-ZLUOBGJFSA-N Ser-Ser-Asp Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(O)=O)C(O)=O PPCZVWHJWJFTFN-ZLUOBGJFSA-N 0.000 description 4
- 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 4
- DCLBXIWHLVEPMQ-JRQIVUDYSA-N Thr-Asp-Tyr Chemical compound C[C@@H](O)[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 DCLBXIWHLVEPMQ-JRQIVUDYSA-N 0.000 description 4
- KGKWKSSSQGGYAU-SUSMZKCASA-N Thr-Gln-Thr Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H]([C@@H](C)O)C(=O)O)N)O KGKWKSSSQGGYAU-SUSMZKCASA-N 0.000 description 4
- 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 4
- MXNAOGFNFNKUPD-JHYOHUSXSA-N Thr-Phe-Thr Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H]([C@@H](C)O)C(O)=O MXNAOGFNFNKUPD-JHYOHUSXSA-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
- DVLHKUWLNKDINO-PMVMPFDFSA-N Trp-Tyr-Leu 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](CC(C)C)C(O)=O DVLHKUWLNKDINO-PMVMPFDFSA-N 0.000 description 4
- NKUGCYDFQKFVOJ-JYJNAYRXSA-N Tyr-Leu-Gln Chemical compound NC(=O)CC[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 NKUGCYDFQKFVOJ-JYJNAYRXSA-N 0.000 description 4
- YKCXQOBTISTQJD-BZSNNMDCSA-N Tyr-Leu-His Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)NC(=O)[C@H](CC2=CC=C(C=C2)O)N YKCXQOBTISTQJD-BZSNNMDCSA-N 0.000 description 4
- UPODKYBYUBTWSV-BZSNNMDCSA-N Tyr-Phe-Cys Chemical compound C([C@H](N)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CS)C(O)=O)C1=CC=C(O)C=C1 UPODKYBYUBTWSV-BZSNNMDCSA-N 0.000 description 4
- 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 4
- AGKDVLSDNSTLFA-UMNHJUIQSA-N Val-Gln-Pro Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)N1CCC[C@@H]1C(=O)O)N AGKDVLSDNSTLFA-UMNHJUIQSA-N 0.000 description 4
- OQWNEUXPKHIEJO-NRPADANISA-N Val-Glu-Ser Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CO)C(=O)O)N OQWNEUXPKHIEJO-NRPADANISA-N 0.000 description 4
- ZRSZTKTVPNSUNA-IHRRRGAJSA-N Val-Lys-Leu Chemical compound CC(C)C[C@H](NC(=O)[C@H](CCCCN)NC(=O)[C@@H](N)C(C)C)C(O)=O ZRSZTKTVPNSUNA-IHRRRGAJSA-N 0.000 description 4
- DEGUERSKQBRZMZ-FXQIFTODSA-N Val-Ser-Ala Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@@H](C)C(O)=O DEGUERSKQBRZMZ-FXQIFTODSA-N 0.000 description 4
- KSFXWENSJABBFI-ZKWXMUAHSA-N Val-Ser-Asn Chemical compound [H]N[C@@H](C(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(O)=O KSFXWENSJABBFI-ZKWXMUAHSA-N 0.000 description 4
- LCHZBEUVGAVMKS-RHYQMDGZSA-N Val-Thr-Leu Chemical compound CC(C)C[C@H](NC(=O)[C@@H](NC(=O)[C@@H](N)C(C)C)[C@@H](C)O)C(O)=O LCHZBEUVGAVMKS-RHYQMDGZSA-N 0.000 description 4
- 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 4
- 241000700605 Viruses Species 0.000 description 4
- 108010076324 alanyl-glycyl-glycine Proteins 0.000 description 4
- 238000010364 biochemical engineering Methods 0.000 description 4
- 210000005013 brain tissue Anatomy 0.000 description 4
- 230000025084 cell cycle arrest Effects 0.000 description 4
- 210000001638 cerebellum Anatomy 0.000 description 4
- 229960004397 cyclophosphamide Drugs 0.000 description 4
- 230000001472 cytotoxic effect Effects 0.000 description 4
- 239000003937 drug carrier Substances 0.000 description 4
- 239000000839 emulsion Substances 0.000 description 4
- 230000002124 endocrine Effects 0.000 description 4
- 235000013922 glutamic acid Nutrition 0.000 description 4
- 239000004220 glutamic acid Substances 0.000 description 4
- 239000005090 green fluorescent protein Substances 0.000 description 4
- 102000045539 human SSTR2 Human genes 0.000 description 4
- KTUFNOKKBVMGRW-UHFFFAOYSA-N imatinib Chemical compound C1CN(C)CCN1CC1=CC=C(C(=O)NC=2C=C(NC=3N=C(C=CN=3)C=3C=NC=CC=3)C(C)=CC=2)C=C1 KTUFNOKKBVMGRW-UHFFFAOYSA-N 0.000 description 4
- 230000028993 immune response Effects 0.000 description 4
- 230000002163 immunogen Effects 0.000 description 4
- 229940072221 immunoglobulins Drugs 0.000 description 4
- 230000002401 inhibitory effect Effects 0.000 description 4
- 230000005764 inhibitory process Effects 0.000 description 4
- 210000001165 lymph node Anatomy 0.000 description 4
- 108010017391 lysylvaline Proteins 0.000 description 4
- 230000001404 mediated effect Effects 0.000 description 4
- 108020004999 messenger RNA Proteins 0.000 description 4
- 230000009401 metastasis Effects 0.000 description 4
- 230000001394 metastastic effect Effects 0.000 description 4
- 206010061289 metastatic neoplasm Diseases 0.000 description 4
- 238000002156 mixing Methods 0.000 description 4
- 229960003301 nivolumab Drugs 0.000 description 4
- 210000001672 ovary Anatomy 0.000 description 4
- 229960001592 paclitaxel Drugs 0.000 description 4
- 238000007911 parenteral administration Methods 0.000 description 4
- 239000012071 phase Substances 0.000 description 4
- 239000002504 physiological saline solution Substances 0.000 description 4
- 230000002829 reductive effect Effects 0.000 description 4
- 150000003384 small molecules Chemical class 0.000 description 4
- 125000006850 spacer group Chemical group 0.000 description 4
- 238000006467 substitution reaction Methods 0.000 description 4
- 239000013589 supplement Substances 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- 238000004114 suspension culture Methods 0.000 description 4
- 231100000057 systemic toxicity Toxicity 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
- 210000001541 thymus gland Anatomy 0.000 description 4
- 238000013518 transcription Methods 0.000 description 4
- 230000035897 transcription Effects 0.000 description 4
- 108010080629 tryptophan-leucine Proteins 0.000 description 4
- 230000004614 tumor growth Effects 0.000 description 4
- 108010003137 tyrosyltyrosine Proteins 0.000 description 4
- 230000035899 viability Effects 0.000 description 4
- 229960003048 vinblastine Drugs 0.000 description 4
- 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 4
- HHJUWIANJFBDHT-KOTLKJBCSA-N vindesine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(N)=O)N4C)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 HHJUWIANJFBDHT-KOTLKJBCSA-N 0.000 description 4
- 229960004355 vindesine Drugs 0.000 description 4
- GBABOYUKABKIAF-GHYRFKGUSA-N vinorelbine Chemical compound C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC GBABOYUKABKIAF-GHYRFKGUSA-N 0.000 description 4
- 229960002066 vinorelbine Drugs 0.000 description 4
- 239000013603 viral vector Substances 0.000 description 4
- DCXYFEDJOCDNAF-UHFFFAOYSA-N Asparagine Chemical compound OC(=O)C(N)CC(N)=O DCXYFEDJOCDNAF-UHFFFAOYSA-N 0.000 description 3
- 108010074708 B7-H1 Antigen Proteins 0.000 description 3
- 108010062802 CD66 antigens Proteins 0.000 description 3
- 108010021064 CTLA-4 Antigen Proteins 0.000 description 3
- 102000008203 CTLA-4 Antigen Human genes 0.000 description 3
- 102100024533 Carcinoembryonic antigen-related cell adhesion molecule 1 Human genes 0.000 description 3
- DLGOEMSEDOSKAD-UHFFFAOYSA-N Carmustine Chemical compound ClCCNC(=O)N(N=O)CCCl DLGOEMSEDOSKAD-UHFFFAOYSA-N 0.000 description 3
- 102000019034 Chemokines Human genes 0.000 description 3
- 108010012236 Chemokines Proteins 0.000 description 3
- PTOAARAWEBMLNO-KVQBGUIXSA-N Cladribine Chemical compound C1=NC=2C(N)=NC(Cl)=NC=2N1[C@H]1C[C@H](O)[C@@H](CO)O1 PTOAARAWEBMLNO-KVQBGUIXSA-N 0.000 description 3
- 108091026890 Coding region Proteins 0.000 description 3
- PMATZTZNYRCHOR-CGLBZJNRSA-N Cyclosporin A Chemical compound CC[C@@H]1NC(=O)[C@H]([C@H](O)[C@H](C)C\C=C\C)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C1=O PMATZTZNYRCHOR-CGLBZJNRSA-N 0.000 description 3
- 108010036949 Cyclosporine Proteins 0.000 description 3
- 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 3
- HGJREIGJLUQBTJ-SZMVWBNQSA-N Glu-Trp-Leu Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC1=CNC2=C1C=CC=C2)C(=O)N[C@@H](CC(C)C)C(O)=O HGJREIGJLUQBTJ-SZMVWBNQSA-N 0.000 description 3
- VBOBNHSVQKKTOT-YUMQZZPRSA-N Gly-Lys-Ala Chemical compound [H]NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(O)=O VBOBNHSVQKKTOT-YUMQZZPRSA-N 0.000 description 3
- JENKOCSDMSVWPY-SRVKXCTJSA-N His-Leu-Asn Chemical compound [H]N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(O)=O JENKOCSDMSVWPY-SRVKXCTJSA-N 0.000 description 3
- 241000282412 Homo Species 0.000 description 3
- 101001117317 Homo sapiens Programmed cell death 1 ligand 1 Proteins 0.000 description 3
- 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 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
- 239000005517 L01XE01 - Imatinib Substances 0.000 description 3
- RDFIVFHPOSOXMW-ACRUOGEOSA-N Leu-Tyr-Phe Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O RDFIVFHPOSOXMW-ACRUOGEOSA-N 0.000 description 3
- KCXUCYYZNZFGLL-SRVKXCTJSA-N Lys-Ala-Leu Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(O)=O KCXUCYYZNZFGLL-SRVKXCTJSA-N 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- 206010027457 Metastases to liver Diseases 0.000 description 3
- 241001529936 Murinae Species 0.000 description 3
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 3
- 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 3
- 208000015914 Non-Hodgkin lymphomas Diseases 0.000 description 3
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 3
- 108700020796 Oncogene Proteins 0.000 description 3
- 241000283973 Oryctolagus cuniculus Species 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- 108091005804 Peptidases Proteins 0.000 description 3
- 102000035195 Peptidases Human genes 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- FUOGXAQMNJMBFG-WPRPVWTQSA-N Pro-Val-Gly Chemical compound OC(=O)CNC(=O)[C@H](C(C)C)NC(=O)[C@@H]1CCCN1 FUOGXAQMNJMBFG-WPRPVWTQSA-N 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 239000004365 Protease Substances 0.000 description 3
- 108010029485 Protein Isoforms Proteins 0.000 description 3
- 102000001708 Protein Isoforms Human genes 0.000 description 3
- 102100033810 RAC-alpha serine/threonine-protein kinase Human genes 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- PZBFGYYEXUXCOF-UHFFFAOYSA-N TCEP Chemical compound OC(=O)CCP(CCC(O)=O)CCC(O)=O PZBFGYYEXUXCOF-UHFFFAOYSA-N 0.000 description 3
- MBLJBGZWLHTJBH-SZMVWBNQSA-N Trp-Val-Arg Chemical compound C1=CC=C2C(C[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCN=C(N)N)C(O)=O)=CNC2=C1 MBLJBGZWLHTJBH-SZMVWBNQSA-N 0.000 description 3
- 108090000704 Tubulin Proteins 0.000 description 3
- 102000004243 Tubulin Human genes 0.000 description 3
- 102100022153 Tumor necrosis factor receptor superfamily member 4 Human genes 0.000 description 3
- 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 3
- 238000009825 accumulation Methods 0.000 description 3
- 239000004480 active ingredient Substances 0.000 description 3
- 238000004115 adherent culture Methods 0.000 description 3
- 210000004100 adrenal gland Anatomy 0.000 description 3
- 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 3
- 230000000890 antigenic effect Effects 0.000 description 3
- 229940041181 antineoplastic drug Drugs 0.000 description 3
- 229940076005 apoptosis modulator Drugs 0.000 description 3
- 230000006907 apoptotic process Effects 0.000 description 3
- 108010008355 arginyl-glutamine 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
- 229960002170 azathioprine Drugs 0.000 description 3
- LMEKQMALGUDUQG-UHFFFAOYSA-N azathioprine Chemical compound CN1C=NC([N+]([O-])=O)=C1SC1=NC=NC2=C1NC=N2 LMEKQMALGUDUQG-UHFFFAOYSA-N 0.000 description 3
- 210000003719 b-lymphocyte Anatomy 0.000 description 3
- 230000004071 biological effect Effects 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- 210000001185 bone marrow Anatomy 0.000 description 3
- 210000000481 breast Anatomy 0.000 description 3
- 229960004562 carboplatin Drugs 0.000 description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 3
- 208000002458 carcinoid tumor Diseases 0.000 description 3
- 229960005243 carmustine Drugs 0.000 description 3
- 210000000170 cell membrane Anatomy 0.000 description 3
- 210000003679 cervix uteri Anatomy 0.000 description 3
- 230000008859 change Effects 0.000 description 3
- 238000012512 characterization method Methods 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 229960001265 ciclosporin Drugs 0.000 description 3
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 3
- 229960004316 cisplatin Drugs 0.000 description 3
- 229960002436 cladribine Drugs 0.000 description 3
- 210000001072 colon Anatomy 0.000 description 3
- 238000004624 confocal microscopy Methods 0.000 description 3
- 239000000470 constituent Substances 0.000 description 3
- 229930182912 cyclosporin Natural products 0.000 description 3
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 3
- 235000018417 cysteine Nutrition 0.000 description 3
- 231100000433 cytotoxic Toxicity 0.000 description 3
- 239000002254 cytotoxic agent Substances 0.000 description 3
- 231100000599 cytotoxic agent Toxicity 0.000 description 3
- 229960003901 dacarbazine Drugs 0.000 description 3
- 238000012217 deletion Methods 0.000 description 3
- 230000037430 deletion Effects 0.000 description 3
- 239000008121 dextrose Substances 0.000 description 3
- 239000003085 diluting agent Substances 0.000 description 3
- 229960003668 docetaxel Drugs 0.000 description 3
- 210000004696 endometrium Anatomy 0.000 description 3
- 102000052116 epidermal growth factor receptor activity proteins Human genes 0.000 description 3
- 108700015053 epidermal growth factor receptor activity proteins Proteins 0.000 description 3
- 210000003238 esophagus Anatomy 0.000 description 3
- 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 3
- 229960005420 etoposide Drugs 0.000 description 3
- 239000000499 gel Substances 0.000 description 3
- 210000004602 germ cell Anatomy 0.000 description 3
- 108010050475 glycyl-leucyl-tyrosine Proteins 0.000 description 3
- 108010037850 glycylvaline Proteins 0.000 description 3
- 239000003102 growth factor Substances 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 108010025306 histidylleucine Proteins 0.000 description 3
- 229960002411 imatinib Drugs 0.000 description 3
- 238000002649 immunization Methods 0.000 description 3
- 230000003053 immunization Effects 0.000 description 3
- 230000016784 immunoglobulin production Effects 0.000 description 3
- 230000008676 import Effects 0.000 description 3
- 239000002054 inoculum Substances 0.000 description 3
- 238000001990 intravenous administration Methods 0.000 description 3
- 210000003734 kidney Anatomy 0.000 description 3
- 229960004942 lenalidomide Drugs 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
- 230000000670 limiting effect Effects 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 230000036210 malignancy Effects 0.000 description 3
- 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 3
- GLVAUDGFNGKCSF-UHFFFAOYSA-N mercaptopurine Chemical compound S=C1NC=NC2=C1NC=N2 GLVAUDGFNGKCSF-UHFFFAOYSA-N 0.000 description 3
- 230000004060 metabolic process Effects 0.000 description 3
- 229960000485 methotrexate Drugs 0.000 description 3
- 230000025090 microtubule depolymerization Effects 0.000 description 3
- 210000003205 muscle Anatomy 0.000 description 3
- 210000004165 myocardium Anatomy 0.000 description 3
- YOHYSYJDKVYCJI-UHFFFAOYSA-N n-[3-[[6-[3-(trifluoromethyl)anilino]pyrimidin-4-yl]amino]phenyl]cyclopropanecarboxamide Chemical compound FC(F)(F)C1=CC=CC(NC=2N=CN=C(NC=3C=C(NC(=O)C4CC4)C=CC=3)C=2)=C1 YOHYSYJDKVYCJI-UHFFFAOYSA-N 0.000 description 3
- -1 olive oil) Chemical compound 0.000 description 3
- 238000011275 oncology therapy Methods 0.000 description 3
- 210000003101 oviduct Anatomy 0.000 description 3
- 230000007170 pathology Effects 0.000 description 3
- 210000003899 penis Anatomy 0.000 description 3
- 210000000578 peripheral nerve Anatomy 0.000 description 3
- 210000003800 pharynx Anatomy 0.000 description 3
- 210000002826 placenta Anatomy 0.000 description 3
- 239000013612 plasmid Substances 0.000 description 3
- 239000003755 preservative agent Substances 0.000 description 3
- 229960000624 procarbazine Drugs 0.000 description 3
- CPTBDICYNRMXFX-UHFFFAOYSA-N procarbazine Chemical compound CNNCC1=CC=C(C(=O)NC(C)C)C=C1 CPTBDICYNRMXFX-UHFFFAOYSA-N 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 230000002685 pulmonary effect Effects 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 229960003876 ranibizumab Drugs 0.000 description 3
- 230000009467 reduction Effects 0.000 description 3
- 230000022983 regulation of cell cycle Effects 0.000 description 3
- 230000010076 replication Effects 0.000 description 3
- 238000002271 resection Methods 0.000 description 3
- 230000001177 retroviral effect Effects 0.000 description 3
- 238000012552 review Methods 0.000 description 3
- 210000003296 saliva Anatomy 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 238000012216 screening Methods 0.000 description 3
- BTIHMVBBUGXLCJ-OAHLLOKOSA-N seliciclib Chemical compound C=12N=CN(C(C)C)C2=NC(N[C@@H](CO)CC)=NC=1NCC1=CC=CC=C1 BTIHMVBBUGXLCJ-OAHLLOKOSA-N 0.000 description 3
- 230000011664 signaling Effects 0.000 description 3
- 210000002027 skeletal muscle Anatomy 0.000 description 3
- 210000003491 skin Anatomy 0.000 description 3
- 210000000813 small intestine Anatomy 0.000 description 3
- 239000001509 sodium citrate Substances 0.000 description 3
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 3
- 241000894007 species Species 0.000 description 3
- 210000002784 stomach Anatomy 0.000 description 3
- 239000000758 substrate Substances 0.000 description 3
- 208000024891 symptom Diseases 0.000 description 3
- NRUKOCRGYNPUPR-QBPJDGROSA-N teniposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@@H](OC[C@H]4O3)C=3SC=CC=3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 NRUKOCRGYNPUPR-QBPJDGROSA-N 0.000 description 3
- 229960001278 teniposide Drugs 0.000 description 3
- 210000001550 testis Anatomy 0.000 description 3
- 229960003087 tioguanine Drugs 0.000 description 3
- 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 3
- 229960000303 topotecan Drugs 0.000 description 3
- 238000013519 translation Methods 0.000 description 3
- 210000003932 urinary bladder Anatomy 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
- 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
- NMDYYWFGPIMTKO-HBVLKOHWSA-N vinflunine Chemical compound C([C@@](C1=C(C2=CC=CC=C2N1)C1)(C2=C(OC)C=C3N(C)[C@@H]4[C@@]5(C3=C2)CCN2CC=C[C@]([C@@H]52)([C@H]([C@]4(O)C(=O)OC)OC(C)=O)CC)C(=O)OC)[C@H]2C[C@@H](C(C)(F)F)CN1C2 NMDYYWFGPIMTKO-HBVLKOHWSA-N 0.000 description 3
- 229960000922 vinflunine Drugs 0.000 description 3
- 239000008096 xylene Substances 0.000 description 3
- YBJHBAHKTGYVGT-ZKWXMUAHSA-N (+)-Biotin Chemical compound N1C(=O)N[C@@H]2[C@H](CCCCC(=O)O)SC[C@@H]21 YBJHBAHKTGYVGT-ZKWXMUAHSA-N 0.000 description 2
- ALBODLTZUXKBGZ-JUUVMNCLSA-N (2s)-2-amino-3-phenylpropanoic acid;(2s)-2,6-diaminohexanoic acid Chemical compound NCCCC[C@H](N)C(O)=O.OC(=O)[C@@H](N)CC1=CC=CC=C1 ALBODLTZUXKBGZ-JUUVMNCLSA-N 0.000 description 2
- PUDHBTGHUJUUFI-SCTWWAJVSA-N (4r,7s,10s,13r,16s,19r)-10-(4-aminobutyl)-n-[(2s,3r)-1-amino-3-hydroxy-1-oxobutan-2-yl]-19-[[(2r)-2-amino-3-naphthalen-2-ylpropanoyl]amino]-16-[(4-hydroxyphenyl)methyl]-13-(1h-indol-3-ylmethyl)-6,9,12,15,18-pentaoxo-7-propan-2-yl-1,2-dithia-5,8,11,14,17-p Chemical compound C([C@H]1C(=O)N[C@H](CC=2C3=CC=CC=C3NC=2)C(=O)N[C@@H](CCCCN)C(=O)N[C@H](C(N[C@@H](CSSC[C@@H](C(=O)N1)NC(=O)[C@H](N)CC=1C=C2C=CC=CC2=CC=1)C(=O)N[C@@H]([C@@H](C)O)C(N)=O)=O)C(C)C)C1=CC=C(O)C=C1 PUDHBTGHUJUUFI-SCTWWAJVSA-N 0.000 description 2
- SGKRLCUYIXIAHR-AKNGSSGZSA-N (4s,4ar,5s,5ar,6r,12ar)-4-(dimethylamino)-1,5,10,11,12a-pentahydroxy-6-methyl-3,12-dioxo-4a,5,5a,6-tetrahydro-4h-tetracene-2-carboxamide Chemical compound C1=CC=C2[C@H](C)[C@@H]([C@H](O)[C@@H]3[C@](C(O)=C(C(N)=O)C(=O)[C@H]3N(C)C)(O)C3=O)C3=C(O)C2=C1O SGKRLCUYIXIAHR-AKNGSSGZSA-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
- VSNHCAURESNICA-NJFSPNSNSA-N 1-oxidanylurea Chemical compound N[14C](=O)NO VSNHCAURESNICA-NJFSPNSNSA-N 0.000 description 2
- UEJJHQNACJXSKW-UHFFFAOYSA-N 2-(2,6-dioxopiperidin-3-yl)-1H-isoindole-1,3(2H)-dione Chemical compound O=C1C2=CC=CC=C2C(=O)N1C1CCC(=O)NC1=O UEJJHQNACJXSKW-UHFFFAOYSA-N 0.000 description 2
- UAIUNKRWKOVEES-UHFFFAOYSA-N 3,3',5,5'-tetramethylbenzidine Chemical compound CC1=C(N)C(C)=CC(C=2C=C(C)C(N)=C(C)C=2)=C1 UAIUNKRWKOVEES-UHFFFAOYSA-N 0.000 description 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
- 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
- IDPUKCWIGUEADI-UHFFFAOYSA-N 5-[bis(2-chloroethyl)amino]uracil Chemical compound ClCCN(CCCl)C1=CNC(=O)NC1=O IDPUKCWIGUEADI-UHFFFAOYSA-N 0.000 description 2
- XAUDJQYHKZQPEU-KVQBGUIXSA-N 5-aza-2'-deoxycytidine Chemical compound O=C1N=C(N)N=CN1[C@@H]1O[C@H](CO)[C@@H](O)C1 XAUDJQYHKZQPEU-KVQBGUIXSA-N 0.000 description 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
- SLXKOJJOQWFEFD-UHFFFAOYSA-N 6-aminohexanoic acid Chemical compound NCCCCCC(O)=O SLXKOJJOQWFEFD-UHFFFAOYSA-N 0.000 description 2
- STQGQHZAVUOBTE-UHFFFAOYSA-N 7-Cyan-hept-2t-en-4,6-diinsaeure Natural products C1=2C(O)=C3C(=O)C=4C(OC)=CC=CC=4C(=O)C3=C(O)C=2CC(O)(C(C)=O)CC1OC1CC(N)C(O)C(C)O1 STQGQHZAVUOBTE-UHFFFAOYSA-N 0.000 description 2
- PBCZSGKMGDDXIJ-HQCWYSJUSA-N 7-hydroxystaurosporine Chemical compound N([C@H](O)C1=C2C3=CC=CC=C3N3C2=C24)C(=O)C1=C2C1=CC=CC=C1N4[C@H]1C[C@@H](NC)[C@@H](OC)[C@]3(C)O1 PBCZSGKMGDDXIJ-HQCWYSJUSA-N 0.000 description 2
- 230000007730 Akt signaling Effects 0.000 description 2
- CCDFBRZVTDDJNM-GUBZILKMSA-N Ala-Leu-Glu Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(O)=O CCDFBRZVTDDJNM-GUBZILKMSA-N 0.000 description 2
- 239000012114 Alexa Fluor 647 Substances 0.000 description 2
- BFYIZQONLCFLEV-DAELLWKTSA-N Aromasine Chemical compound O=C1C=C[C@]2(C)[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CC(=C)C2=C1 BFYIZQONLCFLEV-DAELLWKTSA-N 0.000 description 2
- GQRDIVQPSMPQME-ZPFDUUQYSA-N Asn-Ile-Leu Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(C)C)C(O)=O GQRDIVQPSMPQME-ZPFDUUQYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 102100022005 B-lymphocyte antigen CD20 Human genes 0.000 description 2
- 108010037003 Buserelin Proteins 0.000 description 2
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 2
- KLWPJMFMVPTNCC-UHFFFAOYSA-N Camptothecin Natural products CCC1(O)C(=O)OCC2=C1C=C3C4Nc5ccccc5C=C4CN3C2=O KLWPJMFMVPTNCC-UHFFFAOYSA-N 0.000 description 2
- GAGWJHPBXLXJQN-UORFTKCHSA-N Capecitabine Chemical compound C1=C(F)C(NC(=O)OCCCCC)=NC(=O)N1[C@H]1[C@H](O)[C@H](O)[C@@H](C)O1 GAGWJHPBXLXJQN-UORFTKCHSA-N 0.000 description 2
- 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 2
- AOCCBINRVIKJHY-UHFFFAOYSA-N Carmofur Chemical compound CCCCCCNC(=O)N1C=C(F)C(=O)NC1=O AOCCBINRVIKJHY-UHFFFAOYSA-N 0.000 description 2
- 102000006311 Cyclin D1 Human genes 0.000 description 2
- ZGERHCJBLPQPGV-ACZMJKKPSA-N Cys-Ser-Gln Chemical compound C(CC(=O)N)[C@@H](C(=O)O)NC(=O)[C@H](CO)NC(=O)[C@H](CS)N ZGERHCJBLPQPGV-ACZMJKKPSA-N 0.000 description 2
- UHDGCWIWMRVCDJ-CCXZUQQUSA-N Cytarabine Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O1 UHDGCWIWMRVCDJ-CCXZUQQUSA-N 0.000 description 2
- 241000701022 Cytomegalovirus Species 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 108010016626 Dipeptides Proteins 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
- 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
- BFPYWIDHMRZLRN-SLHNCBLASA-N Ethinyl estradiol Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@](CC4)(O)C#C)[C@@H]4[C@@H]3CCC2=C1 BFPYWIDHMRZLRN-SLHNCBLASA-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
- 108090000331 Firefly luciferases Proteins 0.000 description 2
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 2
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 2
- VWUXBMIQPBEWFH-WCCTWKNTSA-N Fulvestrant Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3[C@H](CCCCCCCCCS(=O)CCCC(F)(F)C(F)(F)F)CC2=C1 VWUXBMIQPBEWFH-WCCTWKNTSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- WMOMPXKOKASNBK-PEFMBERDSA-N Gln-Asn-Ile Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O WMOMPXKOKASNBK-PEFMBERDSA-N 0.000 description 2
- FQCILXROGNOZON-YUMQZZPRSA-N Gln-Pro-Gly Chemical compound NC(=O)CC[C@H](N)C(=O)N1CCC[C@H]1C(=O)NCC(O)=O FQCILXROGNOZON-YUMQZZPRSA-N 0.000 description 2
- SXFPZRRVWSUYII-KBIXCLLPSA-N Gln-Ser-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(=O)N)N SXFPZRRVWSUYII-KBIXCLLPSA-N 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 2
- 108010069236 Goserelin Proteins 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
- 206010019280 Heart failures Diseases 0.000 description 2
- 101000897405 Homo sapiens B-lymphocyte antigen CD20 Proteins 0.000 description 2
- 101000611936 Homo sapiens Programmed cell death protein 1 Proteins 0.000 description 2
- 241000701044 Human gammaherpesvirus 4 Species 0.000 description 2
- 241000725303 Human immunodeficiency virus Species 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- JJKOTMDDZAJTGQ-DQSJHHFOSA-N Idoxifene Chemical compound C=1C=CC=CC=1C(/CC)=C(C=1C=CC(OCCN2CCCC2)=CC=1)/C1=CC=C(I)C=C1 JJKOTMDDZAJTGQ-DQSJHHFOSA-N 0.000 description 2
- XLXPYSDGMXTTNQ-DKIMLUQUSA-N Ile-Phe-Leu Chemical compound CC[C@H](C)[C@H](N)C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](CC(C)C)C(O)=O XLXPYSDGMXTTNQ-DKIMLUQUSA-N 0.000 description 2
- FHPZJWJWTWZKNA-LLLHUVSDSA-N Ile-Phe-Pro Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N2CCC[C@@H]2C(=O)O)N FHPZJWJWTWZKNA-LLLHUVSDSA-N 0.000 description 2
- 229940076838 Immune checkpoint inhibitor Drugs 0.000 description 2
- 108010054477 Immunoglobulin Fab Fragments Proteins 0.000 description 2
- 102000001706 Immunoglobulin Fab Fragments Human genes 0.000 description 2
- 108010091135 Immunoglobulin Fc Fragments Proteins 0.000 description 2
- 108010067060 Immunoglobulin Variable Region Proteins 0.000 description 2
- 102000017727 Immunoglobulin Variable Region Human genes 0.000 description 2
- 208000009164 Islet Cell Adenoma Diseases 0.000 description 2
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 2
- 239000002147 L01XE04 - Sunitinib Substances 0.000 description 2
- 239000002136 L01XE07 - Lapatinib Substances 0.000 description 2
- HPBCTWSUJOGJSH-MNXVOIDGSA-N Leu-Glu-Ile Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O HPBCTWSUJOGJSH-MNXVOIDGSA-N 0.000 description 2
- HYIFFZAQXPUEAU-QWRGUYRKSA-N Leu-Gly-Leu Chemical compound CC(C)C[C@H](N)C(=O)NCC(=O)N[C@H](C(O)=O)CC(C)C HYIFFZAQXPUEAU-QWRGUYRKSA-N 0.000 description 2
- POZULHZYLPGXMR-ONGXEEELSA-N Leu-Gly-Val Chemical compound CC(C)C[C@H](N)C(=O)NCC(=O)N[C@@H](C(C)C)C(O)=O POZULHZYLPGXMR-ONGXEEELSA-N 0.000 description 2
- LMDVGHQPPPLYAR-IHRRRGAJSA-N Leu-Val-His Chemical compound N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC1=CNC=N1)C(=O)O LMDVGHQPPPLYAR-IHRRRGAJSA-N 0.000 description 2
- 239000000232 Lipid Bilayer Substances 0.000 description 2
- GQYIWUVLTXOXAJ-UHFFFAOYSA-N Lomustine Chemical compound ClCCN(N=O)C(=O)NC1CCCCC1 GQYIWUVLTXOXAJ-UHFFFAOYSA-N 0.000 description 2
- HGNRJCINZYHNOU-LURJTMIESA-N Lys-Gly Chemical compound NCCCC[C@H](N)C(=O)NCC(O)=O HGNRJCINZYHNOU-LURJTMIESA-N 0.000 description 2
- 241000829100 Macaca mulatta polyomavirus 1 Species 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- 108010052285 Membrane Proteins Proteins 0.000 description 2
- 101100519207 Mus musculus Pdcd1 gene Proteins 0.000 description 2
- NWIBSHFKIJFRCO-WUDYKRTCSA-N Mytomycin Chemical compound C1N2C(C(C(C)=C(N)C3=O)=O)=C3[C@@H](COC(N)=O)[C@@]2(OC)[C@@H]2[C@H]1N2 NWIBSHFKIJFRCO-WUDYKRTCSA-N 0.000 description 2
- 206010061309 Neoplasm progression Diseases 0.000 description 2
- 102000038030 PI3Ks Human genes 0.000 description 2
- 108091007960 PI3Ks Proteins 0.000 description 2
- RAGOJJCBGXARPO-XVSYOHENSA-N Phe-Thr-Asp Chemical compound OC(=O)C[C@@H](C(O)=O)NC(=O)[C@H]([C@H](O)C)NC(=O)[C@@H](N)CC1=CC=CC=C1 RAGOJJCBGXARPO-XVSYOHENSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-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
- 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 2
- WWXNZNWZNZPDIF-SRVKXCTJSA-N Pro-Val-Arg Chemical compound NC(N)=NCCC[C@@H](C(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H]1CCCN1 WWXNZNWZNZPDIF-SRVKXCTJSA-N 0.000 description 2
- YDTUEBLEAVANFH-RCWTZXSCSA-N Pro-Val-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H]1CCCN1 YDTUEBLEAVANFH-RCWTZXSCSA-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
- 108010076504 Protein Sorting Signals Proteins 0.000 description 2
- LCTONWCANYUPML-UHFFFAOYSA-N Pyruvic acid Chemical compound CC(=O)C(O)=O LCTONWCANYUPML-UHFFFAOYSA-N 0.000 description 2
- 241000283984 Rodentia Species 0.000 description 2
- 241000714474 Rous sarcoma virus Species 0.000 description 2
- JPIDMRXXNMIVKY-VZFHVOOUSA-N Ser-Ala-Thr Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O JPIDMRXXNMIVKY-VZFHVOOUSA-N 0.000 description 2
- 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 2
- RIAKPZVSNBBNRE-BJDJZHNGSA-N Ser-Ile-Leu Chemical compound OC[C@H](N)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(C)C)C(O)=O RIAKPZVSNBBNRE-BJDJZHNGSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 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
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- QJJXYPPXXYFBGM-LFZNUXCKSA-N Tacrolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1\C=C(/C)[C@@H]1[C@H](C)[C@@H](O)CC(=O)[C@H](CC=C)/C=C(C)/C[C@H](C)C[C@H](OC)[C@H]([C@H](C[C@H]2C)OC)O[C@@]2(O)C(=O)C(=O)N2CCCC[C@H]2C(=O)O1 QJJXYPPXXYFBGM-LFZNUXCKSA-N 0.000 description 2
- MECLEFZMPPOEAC-VOAKCMCISA-N Thr-Leu-Lys Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)O)N)O MECLEFZMPPOEAC-VOAKCMCISA-N 0.000 description 2
- 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 2
- CXPJPTFWKXNDKV-NUTKFTJISA-N Trp-Leu-Ala Chemical compound C1=CC=C2C(C[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C)C(O)=O)=CNC2=C1 CXPJPTFWKXNDKV-NUTKFTJISA-N 0.000 description 2
- 102100024598 Tumor necrosis factor ligand superfamily member 10 Human genes 0.000 description 2
- 101710097160 Tumor necrosis factor ligand superfamily member 10 Proteins 0.000 description 2
- 101710165473 Tumor necrosis factor receptor superfamily member 4 Proteins 0.000 description 2
- URIRWLJVWHYLET-ONGXEEELSA-N Val-Gly-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)CNC(=O)[C@@H](N)C(C)C URIRWLJVWHYLET-ONGXEEELSA-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
- 238000010317 ablation therapy Methods 0.000 description 2
- 235000011054 acetic acid Nutrition 0.000 description 2
- 239000002253 acid Substances 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
- 229960002964 adalimumab Drugs 0.000 description 2
- 230000002411 adverse Effects 0.000 description 2
- 239000000556 agonist Substances 0.000 description 2
- 108010050025 alpha-glutamyltryptophan Proteins 0.000 description 2
- 229960000473 altretamine Drugs 0.000 description 2
- BIIVYFLTOXDAOV-YVEFUNNKSA-N alvocidib Chemical compound O[C@@H]1CN(C)CC[C@@H]1C1=C(O)C=C(O)C2=C1OC(C=1C(=CC=CC=1)Cl)=CC2=O BIIVYFLTOXDAOV-YVEFUNNKSA-N 0.000 description 2
- 229950010817 alvocidib Drugs 0.000 description 2
- 229960002684 aminocaproic acid Drugs 0.000 description 2
- 229960003896 aminopterin Drugs 0.000 description 2
- 229960002550 amrubicin Drugs 0.000 description 2
- VJZITPJGSQKZMX-XDPRQOKASA-N amrubicin Chemical compound O([C@H]1C[C@](CC2=C(O)C=3C(=O)C4=CC=CC=C4C(=O)C=3C(O)=C21)(N)C(=O)C)[C@H]1C[C@H](O)[C@H](O)CO1 VJZITPJGSQKZMX-XDPRQOKASA-N 0.000 description 2
- 229960002932 anastrozole Drugs 0.000 description 2
- 230000002280 anti-androgenic effect Effects 0.000 description 2
- 230000002927 anti-mitotic effect Effects 0.000 description 2
- 230000000692 anti-sense effect Effects 0.000 description 2
- 230000000259 anti-tumor effect Effects 0.000 description 2
- 239000000051 antiandrogen Substances 0.000 description 2
- 239000004599 antimicrobial Substances 0.000 description 2
- 239000003963 antioxidant agent Substances 0.000 description 2
- 235000006708 antioxidants Nutrition 0.000 description 2
- 230000001640 apoptogenic effect Effects 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 238000003491 array Methods 0.000 description 2
- 235000009582 asparagine Nutrition 0.000 description 2
- 229960001230 asparagine Drugs 0.000 description 2
- 235000003704 aspartic acid Nutrition 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 229960002756 azacitidine Drugs 0.000 description 2
- KLNFSAOEKUDMFA-UHFFFAOYSA-N azanide;2-hydroxyacetic acid;platinum(2+) Chemical compound [NH2-].[NH2-].[Pt+2].OCC(O)=O KLNFSAOEKUDMFA-UHFFFAOYSA-N 0.000 description 2
- 229960004669 basiliximab Drugs 0.000 description 2
- LNHWXBUNXOXMRL-VWLOTQADSA-N belotecan Chemical compound C1=CC=C2C(CCNC(C)C)=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 LNHWXBUNXOXMRL-VWLOTQADSA-N 0.000 description 2
- 229950011276 belotecan Drugs 0.000 description 2
- 238000003339 best practice Methods 0.000 description 2
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 2
- 239000003124 biologic agent Substances 0.000 description 2
- 230000005540 biological transmission Effects 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
- 238000002725 brachytherapy Methods 0.000 description 2
- CUWODFFVMXJOKD-UVLQAERKSA-N buserelin Chemical compound CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](COC(C)(C)C)NC(=O)[C@@H](NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H]1NC(=O)CC1)CC1=CC=C(O)C=C1 CUWODFFVMXJOKD-UVLQAERKSA-N 0.000 description 2
- 229960002719 buserelin Drugs 0.000 description 2
- 229960002092 busulfan Drugs 0.000 description 2
- 210000004899 c-terminal region Anatomy 0.000 description 2
- VSJKWCGYPAHWDS-FQEVSTJZSA-N camptothecin Chemical compound C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-FQEVSTJZSA-N 0.000 description 2
- 229940127093 camptothecin Drugs 0.000 description 2
- 229960004117 capecitabine Drugs 0.000 description 2
- 229960003261 carmofur Drugs 0.000 description 2
- 230000015556 catabolic process Effects 0.000 description 2
- 238000004113 cell culture Methods 0.000 description 2
- 230000022131 cell cycle Effects 0.000 description 2
- 230000030833 cell death Effects 0.000 description 2
- 230000003915 cell function Effects 0.000 description 2
- 210000003169 central nervous system Anatomy 0.000 description 2
- 239000002738 chelating agent Substances 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 229960004630 chlorambucil Drugs 0.000 description 2
- JCKYGMPEJWAADB-UHFFFAOYSA-N chlorambucil Chemical compound OC(=O)CCCC1=CC=C(N(CCCl)CCCl)C=C1 JCKYGMPEJWAADB-UHFFFAOYSA-N 0.000 description 2
- 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
- 238000003776 cleavage reaction Methods 0.000 description 2
- 238000010367 cloning Methods 0.000 description 2
- 238000010226 confocal imaging Methods 0.000 description 2
- 239000000562 conjugate Substances 0.000 description 2
- 229960000684 cytarabine Drugs 0.000 description 2
- 230000001086 cytosolic effect Effects 0.000 description 2
- 229960002806 daclizumab 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
- 229960003603 decitabine Drugs 0.000 description 2
- 238000013461 design Methods 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 229960003957 dexamethasone Drugs 0.000 description 2
- UREBDLICKHMUKA-CXSFZGCWSA-N dexamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-CXSFZGCWSA-N 0.000 description 2
- RNPXCFINMKSQPQ-UHFFFAOYSA-N dicetyl hydrogen phosphate Chemical compound CCCCCCCCCCCCCCCCOP(O)(=O)OCCCCCCCCCCCCCCCC RNPXCFINMKSQPQ-UHFFFAOYSA-N 0.000 description 2
- RGLYKWWBQGJZGM-ISLYRVAYSA-N diethylstilbestrol Chemical compound C=1C=C(O)C=CC=1C(/CC)=C(\CC)C1=CC=C(O)C=C1 RGLYKWWBQGJZGM-ISLYRVAYSA-N 0.000 description 2
- 229960000452 diethylstilbestrol Drugs 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- MWRBNPKJOOWZPW-CLFAGFIQSA-N dioleoyl phosphatidylethanolamine Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC(COP(O)(=O)OCCN)OC(=O)CCCCCCC\C=C/CCCCCCCC MWRBNPKJOOWZPW-CLFAGFIQSA-N 0.000 description 2
- 238000009826 distribution Methods 0.000 description 2
- VSJKWCGYPAHWDS-UHFFFAOYSA-N dl-camptothecin Natural products C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)C5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-UHFFFAOYSA-N 0.000 description 2
- 231100000673 dose–response relationship Toxicity 0.000 description 2
- 229960004679 doxorubicin Drugs 0.000 description 2
- 229960003722 doxycycline Drugs 0.000 description 2
- 229950004203 droloxifene Drugs 0.000 description 2
- 230000009977 dual effect Effects 0.000 description 2
- 239000000975 dye Substances 0.000 description 2
- 210000001163 endosome Anatomy 0.000 description 2
- 239000003623 enhancer Substances 0.000 description 2
- 230000002255 enzymatic effect Effects 0.000 description 2
- 229960001904 epirubicin Drugs 0.000 description 2
- 229960005167 everolimus Drugs 0.000 description 2
- 229960000255 exemestane Drugs 0.000 description 2
- 210000001808 exosome Anatomy 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000007850 fluorescent dye Substances 0.000 description 2
- 229960002949 fluorouracil 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
- 230000004907 flux Effects 0.000 description 2
- 229960002258 fulvestrant Drugs 0.000 description 2
- 239000011521 glass Substances 0.000 description 2
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 2
- 108010078144 glutaminyl-glycine Proteins 0.000 description 2
- 229960002913 goserelin Drugs 0.000 description 2
- UUVWYPNAQBNQJQ-UHFFFAOYSA-N hexamethylmelamine Chemical compound CN(C)C1=NC(N(C)C)=NC(N(C)C)=N1 UUVWYPNAQBNQJQ-UHFFFAOYSA-N 0.000 description 2
- 108010018006 histidylserine Proteins 0.000 description 2
- JYGXADMDTFJGBT-VWUMJDOOSA-N hydrocortisone Chemical compound O=C1CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 JYGXADMDTFJGBT-VWUMJDOOSA-N 0.000 description 2
- 229950002248 idoxifene Drugs 0.000 description 2
- 210000000987 immune system Anatomy 0.000 description 2
- 239000012274 immune-checkpoint protein inhibitor Substances 0.000 description 2
- 238000013388 immunohistochemistry analysis Methods 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 238000011065 in-situ storage Methods 0.000 description 2
- APFVFJFRJDLVQX-AHCXROLUSA-N indium-111 Chemical compound [111In] APFVFJFRJDLVQX-AHCXROLUSA-N 0.000 description 2
- 230000001939 inductive effect Effects 0.000 description 2
- 229960000598 infliximab Drugs 0.000 description 2
- 238000001802 infusion Methods 0.000 description 2
- 230000003993 interaction Effects 0.000 description 2
- 230000003834 intracellular effect Effects 0.000 description 2
- 238000010253 intravenous injection Methods 0.000 description 2
- 230000009545 invasion Effects 0.000 description 2
- 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 2
- 229960004768 irinotecan Drugs 0.000 description 2
- FABUFPQFXZVHFB-CFWQTKTJSA-N ixabepilone Chemical compound C/C([C@@H]1C[C@@H]2O[C@]2(C)CCC[C@@H]([C@@H]([C@H](C)C(=O)C(C)(C)[C@H](O)CC(=O)N1)O)C)=C\C1=CSC(C)=N1 FABUFPQFXZVHFB-CFWQTKTJSA-N 0.000 description 2
- 229960002014 ixabepilone Drugs 0.000 description 2
- 238000005304 joining Methods 0.000 description 2
- 238000002372 labelling Methods 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 108010021336 lanreotide Proteins 0.000 description 2
- 229960002437 lanreotide Drugs 0.000 description 2
- 229960004891 lapatinib Drugs 0.000 description 2
- 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 2
- 229950005692 larotaxel Drugs 0.000 description 2
- SEFGUGYLLVNFIJ-QDRLFVHASA-N larotaxel dihydrate Chemical compound O.O.O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@@]23[C@H]1[C@@]1(CO[C@@H]1C[C@@H]2C3)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 SEFGUGYLLVNFIJ-QDRLFVHASA-N 0.000 description 2
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 2
- 201000007270 liver cancer Diseases 0.000 description 2
- 208000014018 liver neoplasm Diseases 0.000 description 2
- 230000004807 localization Effects 0.000 description 2
- 229940124302 mTOR inhibitor Drugs 0.000 description 2
- 210000004962 mammalian cell Anatomy 0.000 description 2
- 239000003628 mammalian target of rapamycin inhibitor Substances 0.000 description 2
- 229960004296 megestrol acetate Drugs 0.000 description 2
- 229960001428 mercaptopurine Drugs 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 239000004005 microsphere Substances 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 238000010369 molecular cloning Methods 0.000 description 2
- 229940124303 multikinase inhibitor Drugs 0.000 description 2
- 229960005027 natalizumab Drugs 0.000 description 2
- 230000001338 necrotic effect Effects 0.000 description 2
- 229950007221 nedaplatin Drugs 0.000 description 2
- 210000000653 nervous system Anatomy 0.000 description 2
- 201000011519 neuroendocrine tumor Diseases 0.000 description 2
- 229950010203 nimotuzumab Drugs 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 230000009871 nonspecific binding Effects 0.000 description 2
- 238000009206 nuclear medicine Methods 0.000 description 2
- 229960002450 ofatumumab Drugs 0.000 description 2
- 229960000470 omalizumab Drugs 0.000 description 2
- BWKDAMBGCPRVPI-ZQRPHVBESA-N ortataxel Chemical compound O([C@@H]1[C@]23OC(=O)O[C@H]2[C@@H](C(=C([C@@H](OC(C)=O)C(=O)[C@]2(C)[C@@H](O)C[C@H]4OC[C@]4([C@H]21)OC(C)=O)C3(C)C)C)OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)CC(C)C)C(=O)C1=CC=CC=C1 BWKDAMBGCPRVPI-ZQRPHVBESA-N 0.000 description 2
- 229950001094 ortataxel Drugs 0.000 description 2
- 229960001756 oxaliplatin Drugs 0.000 description 2
- DWAFYCQODLXJNR-BNTLRKBRSA-L oxaliplatin Chemical compound O1C(=O)C(=O)O[Pt]11N[C@@H]2CCCC[C@H]2N1 DWAFYCQODLXJNR-BNTLRKBRSA-L 0.000 description 2
- 208000022102 pancreatic neuroendocrine neoplasm Diseases 0.000 description 2
- 229960001972 panitumumab Drugs 0.000 description 2
- 239000012188 paraffin wax Substances 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- 230000006320 pegylation Effects 0.000 description 2
- 229960005079 pemetrexed Drugs 0.000 description 2
- WBXPDJSOTKVWSJ-ZDUSSCGKSA-L pemetrexed(2-) Chemical compound C=1NC=2NC(N)=NC(=O)C=2C=1CCC1=CC=C(C(=O)N[C@@H](CCC([O-])=O)C([O-])=O)C=C1 WBXPDJSOTKVWSJ-ZDUSSCGKSA-L 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
- 229960002340 pentostatin Drugs 0.000 description 2
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 2
- 229960002087 pertuzumab Drugs 0.000 description 2
- 229960001221 pirarubicin Drugs 0.000 description 2
- 229920000642 polymer Polymers 0.000 description 2
- 239000013641 positive control Substances 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 238000004886 process control Methods 0.000 description 2
- 230000035755 proliferation Effects 0.000 description 2
- 108010053725 prolylvaline Proteins 0.000 description 2
- 239000012217 radiopharmaceutical Substances 0.000 description 2
- 229940121896 radiopharmaceutical Drugs 0.000 description 2
- 230000002799 radiopharmaceutical effect Effects 0.000 description 2
- 229960004622 raloxifene Drugs 0.000 description 2
- GZUITABIAKMVPG-UHFFFAOYSA-N raloxifene Chemical compound C1=CC(O)=CC=C1C1=C(C(=O)C=2C=CC(OCCN3CCCCC3)=CC=2)C2=CC=C(O)C=C2S1 GZUITABIAKMVPG-UHFFFAOYSA-N 0.000 description 2
- 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 2
- 230000004044 response Effects 0.000 description 2
- 230000002441 reversible effect Effects 0.000 description 2
- 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 2
- 229950009213 rubitecan Drugs 0.000 description 2
- 229960005399 satraplatin Drugs 0.000 description 2
- 190014017285 satraplatin Chemical compound 0.000 description 2
- 238000013341 scale-up Methods 0.000 description 2
- 230000007017 scission Effects 0.000 description 2
- 210000002966 serum Anatomy 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 229960002930 sirolimus Drugs 0.000 description 2
- 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 2
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 2
- DAEPDZWVDSPTHF-UHFFFAOYSA-M sodium pyruvate Chemical compound [Na+].CC(=O)C([O-])=O DAEPDZWVDSPTHF-UHFFFAOYSA-M 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 238000003756 stirring Methods 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
- 229960001796 sunitinib Drugs 0.000 description 2
- WINHZLLDWRZWRT-ATVHPVEESA-N sunitinib Chemical compound CCN(CC)CCNC(=O)C1=C(C)NC(\C=C/2C3=CC(F)=CC=C3NC\2=O)=C1C WINHZLLDWRZWRT-ATVHPVEESA-N 0.000 description 2
- 238000013268 sustained release Methods 0.000 description 2
- 239000012730 sustained-release form Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 229960001603 tamoxifen Drugs 0.000 description 2
- 229960001674 tegafur Drugs 0.000 description 2
- WFWLQNSHRPWKFK-ZCFIWIBFSA-N tegafur Chemical compound O=C1NC(=O)C(F)=CN1[C@@H]1OCCC1 WFWLQNSHRPWKFK-ZCFIWIBFSA-N 0.000 description 2
- MODVSQKJJIBWPZ-VLLPJHQWSA-N tesetaxel Chemical compound O([C@H]1[C@@H]2[C@]3(OC(C)=O)CO[C@@H]3CC[C@@]2(C)[C@H]2[C@@H](C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=4C(=CC=CN=4)F)C[C@]1(O)C3(C)C)O[C@H](O2)CN(C)C)C(=O)C1=CC=CC=C1 MODVSQKJJIBWPZ-VLLPJHQWSA-N 0.000 description 2
- 229950009016 tesetaxel Drugs 0.000 description 2
- 229960003433 thalidomide Drugs 0.000 description 2
- ZMZDMBWJUHKJPS-UHFFFAOYSA-N thiocyanic acid Chemical compound SC#N ZMZDMBWJUHKJPS-UHFFFAOYSA-N 0.000 description 2
- 229960005026 toremifene Drugs 0.000 description 2
- XFCLJVABOIYOMF-QPLCGJKRSA-N toremifene Chemical compound C1=CC(OCCN(C)C)=CC=C1C(\C=1C=CC=CC=1)=C(\CCCl)C1=CC=CC=C1 XFCLJVABOIYOMF-QPLCGJKRSA-N 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 238000012546 transfer Methods 0.000 description 2
- 230000009466 transformation Effects 0.000 description 2
- 210000003956 transport vesicle Anatomy 0.000 description 2
- 229960000575 trastuzumab Drugs 0.000 description 2
- 229950007217 tremelimumab Drugs 0.000 description 2
- IEDVJHCEMCRBQM-UHFFFAOYSA-N trimethoprim Chemical compound COC1=C(OC)C(OC)=CC(CC=2C(=NC(N)=NC=2)N)=C1 IEDVJHCEMCRBQM-UHFFFAOYSA-N 0.000 description 2
- 229960001082 trimethoprim Drugs 0.000 description 2
- 190014017283 triplatin tetranitrate Chemical compound 0.000 description 2
- 229950002860 triplatin tetranitrate Drugs 0.000 description 2
- 230000005751 tumor progression Effects 0.000 description 2
- 241001430294 unidentified retrovirus Species 0.000 description 2
- 229960001055 uracil mustard Drugs 0.000 description 2
- 229960000653 valrubicin Drugs 0.000 description 2
- ZOCKGBMQLCSHFP-KQRAQHLDSA-N valrubicin Chemical compound O([C@H]1C[C@](CC2=C(O)C=3C(=O)C4=CC=CC(OC)=C4C(=O)C=3C(O)=C21)(O)C(=O)COC(=O)CCCC)[C@H]1C[C@H](NC(=O)C(F)(F)F)[C@H](O)[C@H](C)O1 ZOCKGBMQLCSHFP-KQRAQHLDSA-N 0.000 description 2
- 108010009962 valyltyrosine Proteins 0.000 description 2
- 230000003612 virological effect Effects 0.000 description 2
- 239000003643 water by type Substances 0.000 description 2
- 229950009002 zanolimumab 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
- DIGQNXIGRZPYDK-WKSCXVIASA-N (2R)-6-amino-2-[[2-[[(2S)-2-[[2-[[(2R)-2-[[(2S)-2-[[(2R,3S)-2-[[2-[[(2S)-2-[[2-[[(2S)-2-[[(2S)-2-[[(2R)-2-[[(2S,3S)-2-[[(2R)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[2-[[(2S)-2-[[(2R)-2-[[2-[[2-[[2-[(2-amino-1-hydroxyethylidene)amino]-3-carboxy-1-hydroxypropylidene]amino]-1-hydroxy-3-sulfanylpropylidene]amino]-1-hydroxyethylidene]amino]-1-hydroxy-3-sulfanylpropylidene]amino]-1,3-dihydroxypropylidene]amino]-1-hydroxyethylidene]amino]-1-hydroxypropylidene]amino]-1,3-dihydroxypropylidene]amino]-1,3-dihydroxypropylidene]amino]-1-hydroxy-3-sulfanylpropylidene]amino]-1,3-dihydroxybutylidene]amino]-1-hydroxy-3-sulfanylpropylidene]amino]-1-hydroxypropylidene]amino]-1,3-dihydroxypropylidene]amino]-1-hydroxyethylidene]amino]-1,5-dihydroxy-5-iminopentylidene]amino]-1-hydroxy-3-sulfanylpropylidene]amino]-1,3-dihydroxybutylidene]amino]-1-hydroxy-3-sulfanylpropylidene]amino]-1,3-dihydroxypropylidene]amino]-1-hydroxyethylidene]amino]-1-hydroxy-3-sulfanylpropylidene]amino]-1-hydroxyethylidene]amino]hexanoic acid Chemical compound C[C@@H]([C@@H](C(=N[C@@H](CS)C(=N[C@@H](C)C(=N[C@@H](CO)C(=NCC(=N[C@@H](CCC(=N)O)C(=NC(CS)C(=N[C@H]([C@H](C)O)C(=N[C@H](CS)C(=N[C@H](CO)C(=NCC(=N[C@H](CS)C(=NCC(=N[C@H](CCCCN)C(=O)O)O)O)O)O)O)O)O)O)O)O)O)O)O)N=C([C@H](CS)N=C([C@H](CO)N=C([C@H](CO)N=C([C@H](C)N=C(CN=C([C@H](CO)N=C([C@H](CS)N=C(CN=C(C(CS)N=C(C(CC(=O)O)N=C(CN)O)O)O)O)O)O)O)O)O)O)O)O DIGQNXIGRZPYDK-WKSCXVIASA-N 0.000 description 1
- AGGWFDNPHKLBBV-YUMQZZPRSA-N (2s)-2-[[(2s)-2-amino-3-methylbutanoyl]amino]-5-(carbamoylamino)pentanoic acid Chemical compound CC(C)[C@H](N)C(=O)N[C@H](C(O)=O)CCCNC(N)=O AGGWFDNPHKLBBV-YUMQZZPRSA-N 0.000 description 1
- CITHEXJVPOWHKC-UUWRZZSWSA-N 1,2-di-O-myristoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCCCCCCC CITHEXJVPOWHKC-UUWRZZSWSA-N 0.000 description 1
- BDNKZNFMNDZQMI-UHFFFAOYSA-N 1,3-diisopropylcarbodiimide Chemical compound CC(C)N=C=NC(C)C BDNKZNFMNDZQMI-UHFFFAOYSA-N 0.000 description 1
- MQLACMBJVPINKE-UHFFFAOYSA-N 10-[(3-hydroxy-4-methoxyphenyl)methylidene]anthracen-9-one Chemical compound C1=C(O)C(OC)=CC=C1C=C1C2=CC=CC=C2C(=O)C2=CC=CC=C21 MQLACMBJVPINKE-UHFFFAOYSA-N 0.000 description 1
- VTHUYJIXSMGYOQ-KOORYGTMSA-N 17-hydroxyprogesterone acetate Chemical compound C1CC2=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 VTHUYJIXSMGYOQ-KOORYGTMSA-N 0.000 description 1
- BFPYWIDHMRZLRN-UHFFFAOYSA-N 17alpha-ethynyl estradiol Natural products OC1=CC=C2C3CCC(C)(C(CC4)(O)C#C)C4C3CCC2=C1 BFPYWIDHMRZLRN-UHFFFAOYSA-N 0.000 description 1
- KGRVJHAUYBGFFP-UHFFFAOYSA-N 2,2'-Methylenebis(4-methyl-6-tert-butylphenol) Chemical compound CC(C)(C)C1=CC(C)=CC(CC=2C(=C(C=C(C)C=2)C(C)(C)C)O)=C1O KGRVJHAUYBGFFP-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- 108020005029 5' Flanking Region Proteins 0.000 description 1
- BMKPVDQDJQWBPD-UHFFFAOYSA-N 6-chloro-7-[2-(4-morpholinyl)ethylamino]quinoline-5,8-dione Chemical compound O=C1C2=NC=CC=C2C(=O)C(Cl)=C1NCCN1CCOCC1 BMKPVDQDJQWBPD-UHFFFAOYSA-N 0.000 description 1
- PBCZSGKMGDDXIJ-UHFFFAOYSA-N 7beta-hydroxystaurosporine Natural products C12=C3N4C5=CC=CC=C5C3=C3C(O)NC(=O)C3=C2C2=CC=CC=C2N1C1CC(NC)C(OC)C4(C)O1 PBCZSGKMGDDXIJ-UHFFFAOYSA-N 0.000 description 1
- 102100022142 Achaete-scute homolog 1 Human genes 0.000 description 1
- 102000007469 Actins Human genes 0.000 description 1
- 108010085238 Actins Proteins 0.000 description 1
- 102100034540 Adenomatous polyposis coli protein Human genes 0.000 description 1
- 239000012099 Alexa Fluor family Substances 0.000 description 1
- 102000002260 Alkaline Phosphatase Human genes 0.000 description 1
- 108020004774 Alkaline Phosphatase Proteins 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 102400000068 Angiostatin Human genes 0.000 description 1
- 108010079709 Angiostatins Proteins 0.000 description 1
- 102100021569 Apoptosis regulator Bcl-2 Human genes 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- ALHMNHZJBYBYHS-DCAQKATOSA-N Asn-Lys-Arg Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O ALHMNHZJBYBYHS-DCAQKATOSA-N 0.000 description 1
- ZRUBWRCKIVDCFS-XPCJQDJLSA-N Asp-Leu-Thr-Ser Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(O)=O ZRUBWRCKIVDCFS-XPCJQDJLSA-N 0.000 description 1
- 102000015790 Asparaginase Human genes 0.000 description 1
- 108010024976 Asparaginase Proteins 0.000 description 1
- 241000714230 Avian leukemia virus Species 0.000 description 1
- 208000010839 B-cell chronic lymphocytic leukemia Diseases 0.000 description 1
- PGFQXGLPJUCTOI-WYMLVPIESA-N BIBR-1532 Chemical compound C=1C=C2C=CC=CC2=CC=1C(/C)=C/C(=O)NC1=CC=CC=C1C(O)=O PGFQXGLPJUCTOI-WYMLVPIESA-N 0.000 description 1
- 229940125565 BMS-986016 Drugs 0.000 description 1
- 102100026189 Beta-galactosidase Human genes 0.000 description 1
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- 102100032366 C-C motif chemokine 7 Human genes 0.000 description 1
- 101710155834 C-C motif chemokine 7 Proteins 0.000 description 1
- 102000001902 CC Chemokines Human genes 0.000 description 1
- 108010040471 CC Chemokines Proteins 0.000 description 1
- 108010029697 CD40 Ligand Proteins 0.000 description 1
- 102100032937 CD40 ligand Human genes 0.000 description 1
- 108091007914 CDKs Proteins 0.000 description 1
- 101100314454 Caenorhabditis elegans tra-1 gene Proteins 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- 206010007275 Carcinoid tumour Diseases 0.000 description 1
- 102000053642 Catalytic RNA Human genes 0.000 description 1
- 108090000994 Catalytic RNA Proteins 0.000 description 1
- 108010072135 Cell Adhesion Molecule-1 Proteins 0.000 description 1
- 102100024649 Cell adhesion molecule 1 Human genes 0.000 description 1
- 108010035563 Chloramphenicol O-acetyltransferase Proteins 0.000 description 1
- 108020004705 Codon Proteins 0.000 description 1
- 108091035707 Consensus sequence Proteins 0.000 description 1
- 102000004420 Creatine Kinase Human genes 0.000 description 1
- 108010042126 Creatine kinase Proteins 0.000 description 1
- 241000699802 Cricetulus griseus Species 0.000 description 1
- 102000016736 Cyclin Human genes 0.000 description 1
- 108050006400 Cyclin Proteins 0.000 description 1
- 102100033270 Cyclin-dependent kinase inhibitor 1 Human genes 0.000 description 1
- 102000003903 Cyclin-dependent kinases Human genes 0.000 description 1
- 108090000266 Cyclin-dependent kinases Proteins 0.000 description 1
- 229930105110 Cyclosporin A Natural products 0.000 description 1
- UCMIKRLLIOVDRJ-XKBZYTNZSA-N Cys-Gln-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)N)NC(=O)[C@H](CS)N)O UCMIKRLLIOVDRJ-XKBZYTNZSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- WQZGKKKJIJFFOK-QTVWNMPRSA-N D-mannopyranose Chemical compound OC[C@H]1OC(O)[C@@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-QTVWNMPRSA-N 0.000 description 1
- 102000004163 DNA-directed RNA polymerases Human genes 0.000 description 1
- 108090000626 DNA-directed RNA polymerases Proteins 0.000 description 1
- WEAHRLBPCANXCN-UHFFFAOYSA-N Daunomycin Natural products CCC1(O)CC(OC2CC(N)C(O)C(C)O2)c3cc4C(=O)c5c(OC)cccc5C(=O)c4c(O)c3C1 WEAHRLBPCANXCN-UHFFFAOYSA-N 0.000 description 1
- 241000702421 Dependoparvovirus Species 0.000 description 1
- 206010012735 Diarrhoea Diseases 0.000 description 1
- BWGNESOTFCXPMA-UHFFFAOYSA-N Dihydrogen disulfide Chemical compound SS BWGNESOTFCXPMA-UHFFFAOYSA-N 0.000 description 1
- GZDFHIJNHHMENY-UHFFFAOYSA-N Dimethyl dicarbonate Chemical compound COC(=O)OC(=O)OC GZDFHIJNHHMENY-UHFFFAOYSA-N 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- 208000012661 Dyskinesia Diseases 0.000 description 1
- 208000000059 Dyspnea Diseases 0.000 description 1
- 206010013975 Dyspnoeas Diseases 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 101150029707 ERBB2 gene Proteins 0.000 description 1
- LVGKNOAMLMIIKO-UHFFFAOYSA-N Elaidinsaeure-aethylester Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC LVGKNOAMLMIIKO-UHFFFAOYSA-N 0.000 description 1
- 102400001047 Endostatin Human genes 0.000 description 1
- 108010079505 Endostatins Proteins 0.000 description 1
- 208000010201 Exanthema Diseases 0.000 description 1
- 108010008177 Fd immunoglobulins Proteins 0.000 description 1
- 102100020715 Fms-related tyrosine kinase 3 ligand protein Human genes 0.000 description 1
- 101710162577 Fms-related tyrosine kinase 3 ligand protein Proteins 0.000 description 1
- 108700012941 GNRH1 Proteins 0.000 description 1
- 108700039691 Genetic Promoter Regions Proteins 0.000 description 1
- DUGYCMAIAKAQPB-GLLZPBPUSA-N Gln-Thr-Glu Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCC(O)=O)C(O)=O DUGYCMAIAKAQPB-GLLZPBPUSA-N 0.000 description 1
- RAUDKMVXNOWDLS-WDSKDSINSA-N Glu-Gly-Ser Chemical compound OC(=O)CC[C@H](N)C(=O)NCC(=O)N[C@@H](CO)C(O)=O RAUDKMVXNOWDLS-WDSKDSINSA-N 0.000 description 1
- VSRCAOIHMGCIJK-SRVKXCTJSA-N Glu-Leu-Arg Chemical compound OC(=O)CC[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCN=C(N)N)C(O)=O VSRCAOIHMGCIJK-SRVKXCTJSA-N 0.000 description 1
- ARIORLIIMJACKZ-KKUMJFAQSA-N Glu-Pro-Tyr Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O ARIORLIIMJACKZ-KKUMJFAQSA-N 0.000 description 1
- WDEHMRNSGHVNOH-VHSXEESVSA-N Gly-Lys-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CCCCN)NC(=O)CN)C(=O)O WDEHMRNSGHVNOH-VHSXEESVSA-N 0.000 description 1
- LCRDMSSAKLTKBU-ZDLURKLDSA-N Gly-Ser-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)[C@H](CO)NC(=O)CN LCRDMSSAKLTKBU-ZDLURKLDSA-N 0.000 description 1
- GWNIGUKSRJBIHX-STQMWFEESA-N Gly-Tyr-Arg Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)N[C@@H](CCCN=C(N)N)C(=O)O)NC(=O)CN)O GWNIGUKSRJBIHX-STQMWFEESA-N 0.000 description 1
- 108090000288 Glycoproteins Proteins 0.000 description 1
- 102000003886 Glycoproteins Human genes 0.000 description 1
- 239000000579 Gonadotropin-Releasing Hormone Substances 0.000 description 1
- 108010017213 Granulocyte-Macrophage Colony-Stimulating Factor Proteins 0.000 description 1
- 102100039620 Granulocyte-macrophage colony-stimulating factor Human genes 0.000 description 1
- 108010043121 Green Fluorescent Proteins Proteins 0.000 description 1
- 102000004144 Green Fluorescent Proteins Human genes 0.000 description 1
- 102000001554 Hemoglobins Human genes 0.000 description 1
- 108010054147 Hemoglobins Proteins 0.000 description 1
- 241000238631 Hexapoda Species 0.000 description 1
- 101000901099 Homo sapiens Achaete-scute homolog 1 Proteins 0.000 description 1
- 101000971171 Homo sapiens Apoptosis regulator Bcl-2 Proteins 0.000 description 1
- 101000959820 Homo sapiens Interferon alpha-1/13 Proteins 0.000 description 1
- 101000639975 Homo sapiens Sodium-dependent noradrenaline transporter Proteins 0.000 description 1
- 101000914514 Homo sapiens T-cell-specific surface glycoprotein CD28 Proteins 0.000 description 1
- 108010001336 Horseradish Peroxidase Proteins 0.000 description 1
- DOMWKUIIPQCAJU-LJHIYBGHSA-N Hydroxyprogesterone caproate Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(C)=O)(OC(=O)CCCCC)[C@@]1(C)CC2 DOMWKUIIPQCAJU-LJHIYBGHSA-N 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- BOTVMTSMOUSDRW-GMOBBJLQSA-N Ile-Arg-Asn Chemical compound CC[C@H](C)[C@H](N)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CC(N)=O)C(O)=O BOTVMTSMOUSDRW-GMOBBJLQSA-N 0.000 description 1
- 108010009817 Immunoglobulin Constant Regions Proteins 0.000 description 1
- 102000009786 Immunoglobulin Constant Regions Human genes 0.000 description 1
- 102000018071 Immunoglobulin Fc Fragments Human genes 0.000 description 1
- 108700005091 Immunoglobulin Genes Proteins 0.000 description 1
- 102000012745 Immunoglobulin Subunits Human genes 0.000 description 1
- 108010079585 Immunoglobulin Subunits Proteins 0.000 description 1
- 102100040019 Interferon alpha-1/13 Human genes 0.000 description 1
- 108010050904 Interferons Proteins 0.000 description 1
- 102000014150 Interferons Human genes 0.000 description 1
- 108090000978 Interleukin-4 Proteins 0.000 description 1
- 108090001005 Interleukin-6 Proteins 0.000 description 1
- 108010002586 Interleukin-7 Proteins 0.000 description 1
- FADYJNXDPBKVCA-UHFFFAOYSA-N L-Phenylalanyl-L-lysin Natural products NCCCCC(C(O)=O)NC(=O)C(N)CC1=CC=CC=C1 FADYJNXDPBKVCA-UHFFFAOYSA-N 0.000 description 1
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 1
- DCXYFEDJOCDNAF-REOHCLBHSA-N L-asparagine Chemical compound OC(=O)[C@@H](N)CC(N)=O DCXYFEDJOCDNAF-REOHCLBHSA-N 0.000 description 1
- AGPKZVBTJJNPAG-WHFBIAKZSA-N L-isoleucine Chemical compound CC[C@H](C)[C@H](N)C(O)=O AGPKZVBTJJNPAG-WHFBIAKZSA-N 0.000 description 1
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 description 1
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 1
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 1
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 description 1
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 1
- KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical compound CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 description 1
- 239000005411 L01XE02 - Gefitinib Substances 0.000 description 1
- 239000005551 L01XE03 - Erlotinib Substances 0.000 description 1
- 102000017578 LAG3 Human genes 0.000 description 1
- 101150030213 Lag3 gene Proteins 0.000 description 1
- 241000713666 Lentivirus Species 0.000 description 1
- 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 1
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 description 1
- 206010024612 Lipoma Diseases 0.000 description 1
- 108060001084 Luciferase Proteins 0.000 description 1
- 239000005089 Luciferase Substances 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- GGAPIOORBXHMNY-ULQDDVLXSA-N Lys-Arg-Tyr Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)O)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CCCCN)N)O GGAPIOORBXHMNY-ULQDDVLXSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 208000007054 Medullary Carcinoma Diseases 0.000 description 1
- 108010090054 Membrane Glycoproteins Proteins 0.000 description 1
- 102000012750 Membrane Glycoproteins Human genes 0.000 description 1
- 102000018697 Membrane Proteins Human genes 0.000 description 1
- JMEWFDUAFKVAAT-WDSKDSINSA-N Met-Asn Chemical compound CSCC[C@H]([NH3+])C(=O)N[C@H](C([O-])=O)CC(N)=O JMEWFDUAFKVAAT-WDSKDSINSA-N 0.000 description 1
- 102000003792 Metallothionein Human genes 0.000 description 1
- 108090000157 Metallothionein Proteins 0.000 description 1
- VFKZTMPDYBFSTM-KVTDHHQDSA-N Mitobronitol Chemical compound BrC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CBr VFKZTMPDYBFSTM-KVTDHHQDSA-N 0.000 description 1
- 241000713333 Mouse mammary tumor virus Species 0.000 description 1
- 241000699660 Mus musculus Species 0.000 description 1
- 241000204031 Mycoplasma Species 0.000 description 1
- 102000003505 Myosin Human genes 0.000 description 1
- 108060008487 Myosin Proteins 0.000 description 1
- QPCDCPDFJACHGM-UHFFFAOYSA-N N,N-bis{2-[bis(carboxymethyl)amino]ethyl}glycine Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(=O)O)CCN(CC(O)=O)CC(O)=O QPCDCPDFJACHGM-UHFFFAOYSA-N 0.000 description 1
- 108010002311 N-glycylglutamic acid Proteins 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 108091034117 Oligonucleotide Proteins 0.000 description 1
- 239000012270 PD-1 inhibitor Substances 0.000 description 1
- 239000012668 PD-1-inhibitor Substances 0.000 description 1
- 239000002033 PVDF binder Substances 0.000 description 1
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 1
- 108090000526 Papain Proteins 0.000 description 1
- 102000057297 Pepsin A Human genes 0.000 description 1
- 108090000284 Pepsin A Proteins 0.000 description 1
- 102000012288 Phosphopyruvate Hydratase Human genes 0.000 description 1
- 108010022181 Phosphopyruvate Hydratase Proteins 0.000 description 1
- 206010035226 Plasma cell myeloma Diseases 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 229920001213 Polysorbate 20 Polymers 0.000 description 1
- QDDJNKWPTJHROJ-UFYCRDLUSA-N Pro-Tyr-Tyr Chemical compound C([C@@H](C(=O)O)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H]1NCCC1)C1=CC=C(O)C=C1 QDDJNKWPTJHROJ-UFYCRDLUSA-N 0.000 description 1
- 101710094000 Programmed cell death 1 ligand 1 Proteins 0.000 description 1
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 1
- 239000012980 RPMI-1640 medium Substances 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 108020004511 Recombinant DNA Proteins 0.000 description 1
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 1
- 238000012300 Sequence Analysis Methods 0.000 description 1
- CDVFZMOFNJPUDD-ACZMJKKPSA-N Ser-Gln-Asn Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O CDVFZMOFNJPUDD-ACZMJKKPSA-N 0.000 description 1
- 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 1
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 1
- 108010090804 Streptavidin Proteins 0.000 description 1
- 238000000692 Student's t-test Methods 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 230000006052 T cell proliferation Effects 0.000 description 1
- 108091008874 T cell receptors Proteins 0.000 description 1
- 102000016266 T-Cell Antigen Receptors Human genes 0.000 description 1
- 102100027213 T-cell-specific surface glycoprotein CD28 Human genes 0.000 description 1
- 108700012920 TNF Proteins 0.000 description 1
- 102000002259 TNF-Related Apoptosis-Inducing Ligand Receptors Human genes 0.000 description 1
- 108010000449 TNF-Related Apoptosis-Inducing Ligand Receptors Proteins 0.000 description 1
- 229940123237 Taxane Drugs 0.000 description 1
- GKLVYJBZJHMRIY-OUBTZVSYSA-N Technetium-99 Chemical compound [99Tc] GKLVYJBZJHMRIY-OUBTZVSYSA-N 0.000 description 1
- 108010017842 Telomerase Proteins 0.000 description 1
- 239000004098 Tetracycline Substances 0.000 description 1
- FOCVUCIESVLUNU-UHFFFAOYSA-N Thiotepa Chemical compound C1CN1P(N1CC1)(=S)N1CC1 FOCVUCIESVLUNU-UHFFFAOYSA-N 0.000 description 1
- STUAPCLEDMKXKL-LKXGYXEUSA-N Thr-Ser-Asn Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(O)=O STUAPCLEDMKXKL-LKXGYXEUSA-N 0.000 description 1
- AYFVYJQAPQTCCC-UHFFFAOYSA-N Threonine Natural products CC(O)C(N)C(O)=O AYFVYJQAPQTCCC-UHFFFAOYSA-N 0.000 description 1
- 239000004473 Threonine Substances 0.000 description 1
- IVTVGDXNLFLDRM-HNNXBMFYSA-N Tomudex Chemical compound C=1C=C2NC(C)=NC(=O)C2=CC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)S1 IVTVGDXNLFLDRM-HNNXBMFYSA-N 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- 229920004890 Triton X-100 Polymers 0.000 description 1
- GLNADSQYFUSGOU-GPTZEZBUSA-J Trypan blue Chemical compound [Na+].[Na+].[Na+].[Na+].C1=C(S([O-])(=O)=O)C=C2C=C(S([O-])(=O)=O)C(/N=N/C3=CC=C(C=C3C)C=3C=C(C(=CC=3)\N=N\C=3C(=CC4=CC(=CC(N)=C4C=3O)S([O-])(=O)=O)S([O-])(=O)=O)C)=C(O)C2=C1N GLNADSQYFUSGOU-GPTZEZBUSA-J 0.000 description 1
- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 description 1
- 108060008683 Tumor Necrosis Factor Receptor Proteins 0.000 description 1
- 102400000731 Tumstatin Human genes 0.000 description 1
- RCLOWEZASFJFEX-KKUMJFAQSA-N Tyr-Asp-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 RCLOWEZASFJFEX-KKUMJFAQSA-N 0.000 description 1
- NMKJPMCEKQHRPD-IRXDYDNUSA-N Tyr-Gly-Tyr Chemical compound C([C@H](N)C(=O)NCC(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(O)=O)C1=CC=C(O)C=C1 NMKJPMCEKQHRPD-IRXDYDNUSA-N 0.000 description 1
- KZSNJWFQEVHDMF-UHFFFAOYSA-N Valine Natural products CC(C)C(N)C(O)=O KZSNJWFQEVHDMF-UHFFFAOYSA-N 0.000 description 1
- 241000251539 Vertebrata <Metazoa> Species 0.000 description 1
- 229940122803 Vinca alkaloid Drugs 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 208000038016 acute inflammation Diseases 0.000 description 1
- 230000006022 acute inflammation Effects 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 238000001261 affinity purification Methods 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 235000004279 alanine Nutrition 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 150000001338 aliphatic hydrocarbons Chemical class 0.000 description 1
- 229940100198 alkylating agent Drugs 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 230000000172 allergic effect Effects 0.000 description 1
- WNROFYMDJYEPJX-UHFFFAOYSA-K aluminium hydroxide Chemical compound [OH-].[OH-].[OH-].[Al+3] WNROFYMDJYEPJX-UHFFFAOYSA-K 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- LXQXZNRPTYVCNG-YPZZEJLDSA-N americium-241 Chemical compound [241Am] LXQXZNRPTYVCNG-YPZZEJLDSA-N 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 150000001414 amino alcohols Chemical class 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 229960003437 aminoglutethimide Drugs 0.000 description 1
- ROBVIMPUHSLWNV-UHFFFAOYSA-N aminoglutethimide Chemical compound C=1C=C(N)C=CC=1C1(CC)CCC(=O)NC1=O ROBVIMPUHSLWNV-UHFFFAOYSA-N 0.000 description 1
- 239000000908 ammonium hydroxide Substances 0.000 description 1
- AVKUERGKIZMTKX-NJBDSQKTSA-N ampicillin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=CC=C1 AVKUERGKIZMTKX-NJBDSQKTSA-N 0.000 description 1
- 230000033115 angiogenesis Effects 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 230000001772 anti-angiogenic effect Effects 0.000 description 1
- 229940046836 anti-estrogen Drugs 0.000 description 1
- 230000001833 anti-estrogenic effect Effects 0.000 description 1
- 229940121363 anti-inflammatory agent Drugs 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 230000000340 anti-metabolite Effects 0.000 description 1
- 230000005809 anti-tumor immunity Effects 0.000 description 1
- 229940030495 antiandrogen sex hormone and modulator of the genital system Drugs 0.000 description 1
- 238000011091 antibody purification Methods 0.000 description 1
- 238000009175 antibody therapy Methods 0.000 description 1
- 238000011394 anticancer treatment Methods 0.000 description 1
- 229940100197 antimetabolite Drugs 0.000 description 1
- 239000002256 antimetabolite Substances 0.000 description 1
- 239000003080 antimitotic agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 230000005775 apoptotic pathway Effects 0.000 description 1
- 239000008365 aqueous carrier Substances 0.000 description 1
- 239000003125 aqueous solvent Substances 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 229940078010 arimidex Drugs 0.000 description 1
- 239000003886 aromatase inhibitor Substances 0.000 description 1
- 229940046844 aromatase inhibitors Drugs 0.000 description 1
- 150000004982 aromatic amines Chemical class 0.000 description 1
- 239000000823 artificial membrane Substances 0.000 description 1
- 229960003272 asparaginase Drugs 0.000 description 1
- DCXYFEDJOCDNAF-UHFFFAOYSA-M asparaginate Chemical compound [O-]C(=O)C(N)CC(N)=O DCXYFEDJOCDNAF-UHFFFAOYSA-M 0.000 description 1
- FZCSTZYAHCUGEM-UHFFFAOYSA-N aspergillomarasmine B Natural products OC(=O)CNC(C(O)=O)CNC(C(O)=O)CC(O)=O FZCSTZYAHCUGEM-UHFFFAOYSA-N 0.000 description 1
- 208000010668 atopic eczema Diseases 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 239000007640 basal medium Substances 0.000 description 1
- 238000010923 batch production Methods 0.000 description 1
- 239000011324 bead Substances 0.000 description 1
- 230000003542 behavioural effect Effects 0.000 description 1
- 108010005774 beta-Galactosidase Proteins 0.000 description 1
- 229960000397 bevacizumab Drugs 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 229920002988 biodegradable polymer Polymers 0.000 description 1
- 239000004621 biodegradable polymer Substances 0.000 description 1
- 230000008827 biological function Effects 0.000 description 1
- 238000010170 biological method Methods 0.000 description 1
- 239000000090 biomarker Substances 0.000 description 1
- 229960000074 biopharmaceutical Drugs 0.000 description 1
- 238000001815 biotherapy Methods 0.000 description 1
- 229960002685 biotin Drugs 0.000 description 1
- 235000020958 biotin Nutrition 0.000 description 1
- 239000011616 biotin Substances 0.000 description 1
- OWMVSZAMULFTJU-UHFFFAOYSA-N bis-tris Chemical compound OCCN(CCO)C(CO)(CO)CO OWMVSZAMULFTJU-UHFFFAOYSA-N 0.000 description 1
- 238000010322 bone marrow transplantation Methods 0.000 description 1
- 229940098773 bovine serum albumin Drugs 0.000 description 1
- 239000007975 buffered saline Substances 0.000 description 1
- 239000008366 buffered solution Substances 0.000 description 1
- 239000006172 buffering agent Substances 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- BPKIGYQJPYCAOW-FFJTTWKXSA-I calcium;potassium;disodium;(2s)-2-hydroxypropanoate;dichloride;dihydroxide;hydrate Chemical compound O.[OH-].[OH-].[Na+].[Na+].[Cl-].[Cl-].[K+].[Ca+2].C[C@H](O)C([O-])=O BPKIGYQJPYCAOW-FFJTTWKXSA-I 0.000 description 1
- 229940112129 campath Drugs 0.000 description 1
- 230000004611 cancer cell death Effects 0.000 description 1
- 230000009702 cancer cell proliferation Effects 0.000 description 1
- 238000002619 cancer immunotherapy Methods 0.000 description 1
- 239000012830 cancer therapeutic Substances 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 235000014633 carbohydrates Nutrition 0.000 description 1
- 238000005341 cation exchange Methods 0.000 description 1
- 125000002091 cationic group Chemical group 0.000 description 1
- 230000001364 causal effect Effects 0.000 description 1
- 230000024245 cell differentiation Effects 0.000 description 1
- 230000015861 cell surface binding Effects 0.000 description 1
- 238000003570 cell viability assay Methods 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 230000036755 cellular response Effects 0.000 description 1
- 230000004700 cellular uptake Effects 0.000 description 1
- TVFDJXOCXUVLDH-RNFDNDRNSA-N cesium-137 Chemical compound [137Cs] TVFDJXOCXUVLDH-RNFDNDRNSA-N 0.000 description 1
- 229960005395 cetuximab Drugs 0.000 description 1
- 238000012412 chemical coupling Methods 0.000 description 1
- 230000010109 chemoembolization Effects 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- 239000013611 chromosomal DNA Substances 0.000 description 1
- 210000000349 chromosome Anatomy 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 208000037976 chronic inflammation Diseases 0.000 description 1
- 230000006020 chronic inflammation Effects 0.000 description 1
- 239000007979 citrate buffer Substances 0.000 description 1
- 229960002173 citrulline Drugs 0.000 description 1
- 229960000928 clofarabine Drugs 0.000 description 1
- WDDPHFBMKLOVOX-AYQXTPAHSA-N clofarabine Chemical compound C1=NC=2C(N)=NC(Cl)=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@@H]1F WDDPHFBMKLOVOX-AYQXTPAHSA-N 0.000 description 1
- 238000013373 clone screening Methods 0.000 description 1
- 230000008045 co-localization Effects 0.000 description 1
- 238000012761 co-transfection Methods 0.000 description 1
- GUTLYIVDDKVIGB-YPZZEJLDSA-N cobalt-57 Chemical compound [57Co] GUTLYIVDDKVIGB-YPZZEJLDSA-N 0.000 description 1
- 239000000084 colloidal system Substances 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 230000001143 conditioned effect Effects 0.000 description 1
- 230000001268 conjugating effect Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- RYGMFSIKBFXOCR-AKLPVKDBSA-N copper-67 Chemical compound [67Cu] RYGMFSIKBFXOCR-AKLPVKDBSA-N 0.000 description 1
- 239000003246 corticosteroid Substances 0.000 description 1
- 229960001334 corticosteroids Drugs 0.000 description 1
- 230000037029 cross reaction Effects 0.000 description 1
- 238000009109 curative therapy Methods 0.000 description 1
- 239000002875 cyclin dependent kinase inhibitor Substances 0.000 description 1
- 229940043378 cyclin-dependent kinase inhibitor Drugs 0.000 description 1
- 230000009089 cytolysis Effects 0.000 description 1
- 230000001461 cytolytic effect Effects 0.000 description 1
- 210000000172 cytosol Anatomy 0.000 description 1
- 239000002619 cytotoxin Substances 0.000 description 1
- 229960002204 daratumumab Drugs 0.000 description 1
- 229960000975 daunorubicin Drugs 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 210000004443 dendritic cell Anatomy 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 239000003599 detergent Substances 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 229940039227 diagnostic agent Drugs 0.000 description 1
- 239000000032 diagnostic agent Substances 0.000 description 1
- 238000000502 dialysis Methods 0.000 description 1
- 229940093541 dicetylphosphate Drugs 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 235000015872 dietary supplement Nutrition 0.000 description 1
- BPHQZTVXXXJVHI-UHFFFAOYSA-N dimyristoyl phosphatidylglycerol Chemical compound CCCCCCCCCCCCCC(=O)OCC(COP(O)(=O)OCC(O)CO)OC(=O)CCCCCCCCCCCCC BPHQZTVXXXJVHI-UHFFFAOYSA-N 0.000 description 1
- 229960003724 dimyristoylphosphatidylcholine Drugs 0.000 description 1
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 1
- 239000003534 dna topoisomerase inhibitor Substances 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 230000035622 drinking Effects 0.000 description 1
- 229950009791 durvalumab Drugs 0.000 description 1
- 238000004043 dyeing Methods 0.000 description 1
- 229960000284 efalizumab Drugs 0.000 description 1
- 229940121647 egfr inhibitor Drugs 0.000 description 1
- 239000003792 electrolyte Substances 0.000 description 1
- 238000001962 electrophoresis Methods 0.000 description 1
- 238000004520 electroporation Methods 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 210000000750 endocrine system Anatomy 0.000 description 1
- 230000012202 endocytosis Effects 0.000 description 1
- 230000003511 endothelial effect Effects 0.000 description 1
- YQGOJNYOYNNSMM-UHFFFAOYSA-N eosin Chemical compound [Na+].OC(=O)C1=CC=CC=C1C1=C2C=C(Br)C(=O)C(Br)=C2OC2=C(Br)C(O)=C(Br)C=C21 YQGOJNYOYNNSMM-UHFFFAOYSA-N 0.000 description 1
- SEACYXSIPDVVMV-UHFFFAOYSA-L eosin Y Chemical compound [Na+].[Na+].[O-]C(=O)C1=CC=CC=C1C1=C2C=C(Br)C(=O)C(Br)=C2OC2=C(Br)C([O-])=C(Br)C=C21 SEACYXSIPDVVMV-UHFFFAOYSA-L 0.000 description 1
- 229930013356 epothilone Natural products 0.000 description 1
- 150000003883 epothilone derivatives Chemical class 0.000 description 1
- 229960001433 erlotinib Drugs 0.000 description 1
- AAKJLRGGTJKAMG-UHFFFAOYSA-N erlotinib Chemical compound C=12C=C(OCCOC)C(OCCOC)=CC2=NC=NC=1NC1=CC=CC(C#C)=C1 AAKJLRGGTJKAMG-UHFFFAOYSA-N 0.000 description 1
- 239000003797 essential amino acid Substances 0.000 description 1
- 235000020776 essential amino acid Nutrition 0.000 description 1
- 239000000328 estrogen antagonist Substances 0.000 description 1
- 150000002169 ethanolamines Chemical class 0.000 description 1
- 229960002568 ethinylestradiol Drugs 0.000 description 1
- LVGKNOAMLMIIKO-QXMHVHEDSA-N ethyl oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC LVGKNOAMLMIIKO-QXMHVHEDSA-N 0.000 description 1
- 229940093471 ethyl oleate Drugs 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 201000005884 exanthem Diseases 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 238000001125 extrusion Methods 0.000 description 1
- 235000013861 fat-free Nutrition 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 239000010408 film Substances 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 238000011010 flushing procedure Methods 0.000 description 1
- 229960002074 flutamide Drugs 0.000 description 1
- 210000003953 foreskin Anatomy 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 238000013467 fragmentation Methods 0.000 description 1
- 238000006062 fragmentation reaction Methods 0.000 description 1
- 239000012520 frozen sample Substances 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 230000004927 fusion Effects 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 229960002584 gefitinib Drugs 0.000 description 1
- 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 1
- 238000002523 gelfiltration Methods 0.000 description 1
- 238000003500 gene array Methods 0.000 description 1
- 238000001476 gene delivery Methods 0.000 description 1
- 239000003193 general anesthetic agent Substances 0.000 description 1
- 229940080856 gleevec Drugs 0.000 description 1
- 239000003862 glucocorticoid Substances 0.000 description 1
- 229930195712 glutamate Natural products 0.000 description 1
- RWSXRVCMGQZWBV-WDSKDSINSA-N glutathione Chemical compound OC(=O)[C@@H](N)CCC(=O)N[C@@H](CS)C(=O)NCC(O)=O RWSXRVCMGQZWBV-WDSKDSINSA-N 0.000 description 1
- PCHJSUWPFVWCPO-OUBTZVSYSA-N gold-198 Chemical compound [198Au] PCHJSUWPFVWCPO-OUBTZVSYSA-N 0.000 description 1
- 239000000122 growth hormone Substances 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 210000002216 heart Anatomy 0.000 description 1
- XLYOFNOQVPJJNP-ZSJDYOACSA-N heavy water Substances [2H]O[2H] XLYOFNOQVPJJNP-ZSJDYOACSA-N 0.000 description 1
- 238000007490 hematoxylin and eosin (H&E) staining Methods 0.000 description 1
- 229940022353 herceptin Drugs 0.000 description 1
- 231100000171 higher toxicity Toxicity 0.000 description 1
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 1
- 238000000265 homogenisation Methods 0.000 description 1
- 230000003054 hormonal effect Effects 0.000 description 1
- 102000055827 human SLC6A2 Human genes 0.000 description 1
- 210000005260 human cell Anatomy 0.000 description 1
- 238000011577 humanized mouse model Methods 0.000 description 1
- 229940048921 humira Drugs 0.000 description 1
- OAKJQQAXSVQMHS-UHFFFAOYSA-N hydrazine Substances NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 1
- 229960000890 hydrocortisone Drugs 0.000 description 1
- 229920001600 hydrophobic polymer Polymers 0.000 description 1
- 229940065346 hydroxyprogesterone acetate Drugs 0.000 description 1
- 229950000801 hydroxyprogesterone caproate Drugs 0.000 description 1
- 210000002865 immune cell Anatomy 0.000 description 1
- 238000003018 immunoassay Methods 0.000 description 1
- 238000003364 immunohistochemistry Methods 0.000 description 1
- 239000003018 immunosuppressive agent Substances 0.000 description 1
- 229940125721 immunosuppressive agent Drugs 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 238000002513 implantation Methods 0.000 description 1
- 229940055742 indium-111 Drugs 0.000 description 1
- 239000011261 inert gas Substances 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 238000003780 insertion Methods 0.000 description 1
- 230000037431 insertion Effects 0.000 description 1
- 229940079322 interferon Drugs 0.000 description 1
- 230000031146 intracellular signal transduction Effects 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- XMBWDFGMSWQBCA-AHCXROLUSA-M iodine-123(1-) Chemical compound [123I-] XMBWDFGMSWQBCA-AHCXROLUSA-M 0.000 description 1
- XMBWDFGMSWQBCA-RNFDNDRNSA-M iodine-131(1-) Chemical compound [131I-] XMBWDFGMSWQBCA-RNFDNDRNSA-M 0.000 description 1
- 229960005386 ipilimumab Drugs 0.000 description 1
- GKOZUEZYRPOHIO-IGMARMGPSA-N iridium-192 Chemical compound [192Ir] GKOZUEZYRPOHIO-IGMARMGPSA-N 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 201000002529 islet cell tumor Diseases 0.000 description 1
- 210000004153 islets of langerhan Anatomy 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- AGPKZVBTJJNPAG-UHFFFAOYSA-N isoleucine Natural products CCC(C)C(N)C(O)=O AGPKZVBTJJNPAG-UHFFFAOYSA-N 0.000 description 1
- 229960000310 isoleucine Drugs 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 210000002414 leg Anatomy 0.000 description 1
- 238000001638 lipofection Methods 0.000 description 1
- 150000002634 lipophilic molecules Chemical class 0.000 description 1
- 239000006193 liquid solution Substances 0.000 description 1
- 239000006194 liquid suspension Substances 0.000 description 1
- 238000010859 live-cell imaging Methods 0.000 description 1
- 244000144972 livestock Species 0.000 description 1
- 229960002247 lomustine Drugs 0.000 description 1
- 201000005296 lung carcinoma Diseases 0.000 description 1
- RVFGKBWWUQOIOU-NDEPHWFRSA-N lurtotecan Chemical compound O=C([C@]1(O)CC)OCC(C(N2CC3=4)=O)=C1C=C2C3=NC1=CC=2OCCOC=2C=C1C=4CN1CCN(C)CC1 RVFGKBWWUQOIOU-NDEPHWFRSA-N 0.000 description 1
- 229950002654 lurtotecan Drugs 0.000 description 1
- 230000006674 lysosomal degradation Effects 0.000 description 1
- 230000002132 lysosomal effect Effects 0.000 description 1
- 210000002540 macrophage Anatomy 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 230000003211 malignant effect Effects 0.000 description 1
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 1
- 238000007726 management method Methods 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 229960004616 medroxyprogesterone Drugs 0.000 description 1
- FRQMUZJSZHZSGN-HBNHAYAOSA-N medroxyprogesterone Chemical compound C([C@@]12C)CC(=O)C=C1[C@@H](C)C[C@@H]1[C@@H]2CC[C@]2(C)[C@@](O)(C(C)=O)CC[C@H]21 FRQMUZJSZHZSGN-HBNHAYAOSA-N 0.000 description 1
- PSGAAPLEWMOORI-PEINSRQWSA-N medroxyprogesterone acetate Chemical compound C([C@@]12C)CC(=O)C=C1[C@@H](C)C[C@@H]1[C@@H]2CC[C@]2(C)[C@@](OC(C)=O)(C(C)=O)CC[C@H]21 PSGAAPLEWMOORI-PEINSRQWSA-N 0.000 description 1
- 229940090004 megace Drugs 0.000 description 1
- 229960001924 melphalan Drugs 0.000 description 1
- SGDBTWWWUNNDEQ-LBPRGKRZSA-N melphalan Chemical compound OC(=O)[C@@H](N)CC1=CC=C(N(CCCl)CCCl)C=C1 SGDBTWWWUNNDEQ-LBPRGKRZSA-N 0.000 description 1
- 230000003340 mental effect Effects 0.000 description 1
- 230000037323 metabolic rate Effects 0.000 description 1
- 229930182817 methionine Natural products 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 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
- 238000010208 microarray analysis Methods 0.000 description 1
- 238000000520 microinjection Methods 0.000 description 1
- 239000011859 microparticle Substances 0.000 description 1
- 235000013336 milk Nutrition 0.000 description 1
- 239000008267 milk Substances 0.000 description 1
- 210000004080 milk Anatomy 0.000 description 1
- 230000003278 mimic effect Effects 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 229960005485 mitobronitol Drugs 0.000 description 1
- 229960004857 mitomycin Drugs 0.000 description 1
- 230000000394 mitotic effect Effects 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 229940125645 monoclonal antibody drug Drugs 0.000 description 1
- 230000004660 morphological change Effects 0.000 description 1
- 229960004866 mycophenolate mofetil Drugs 0.000 description 1
- RTGDFNSFWBGLEC-SYZQJQIISA-N mycophenolate mofetil Chemical compound COC1=C(C)C=2COC(=O)C=2C(O)=C1C\C=C(/C)CCC(=O)OCCN1CCOCC1 RTGDFNSFWBGLEC-SYZQJQIISA-N 0.000 description 1
- HPNSFSBZBAHARI-RUDMXATFSA-N mycophenolic acid Chemical compound OC1=C(C\C=C(/C)CCC(O)=O)C(OC)=C(C)C2=C1C(=O)OC2 HPNSFSBZBAHARI-RUDMXATFSA-N 0.000 description 1
- 229960000951 mycophenolic acid Drugs 0.000 description 1
- 201000000050 myeloid neoplasm Diseases 0.000 description 1
- 239000002088 nanocapsule Substances 0.000 description 1
- 239000002105 nanoparticle Substances 0.000 description 1
- 230000035407 negative regulation of cell proliferation Effects 0.000 description 1
- 230000017066 negative regulation of growth Effects 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 231100000957 no side effect Toxicity 0.000 description 1
- 239000012457 nonaqueous media Substances 0.000 description 1
- 239000000346 nonvolatile oil Substances 0.000 description 1
- 238000012633 nuclear imaging Methods 0.000 description 1
- 238000011580 nude mouse model Methods 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- 230000009437 off-target effect Effects 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 230000006712 oncogenic signaling pathway Effects 0.000 description 1
- 238000001543 one-way ANOVA Methods 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 150000002895 organic esters Chemical class 0.000 description 1
- 238000007500 overflow downdraw method Methods 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 238000002638 palliative care Methods 0.000 description 1
- 201000002528 pancreatic cancer Diseases 0.000 description 1
- 208000008443 pancreatic carcinoma Diseases 0.000 description 1
- 238000012335 pathological evaluation Methods 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 229940121655 pd-1 inhibitor Drugs 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 229960002621 pembrolizumab Drugs 0.000 description 1
- 125000001151 peptidyl group Chemical group 0.000 description 1
- 210000005259 peripheral blood Anatomy 0.000 description 1
- 239000011886 peripheral blood Substances 0.000 description 1
- 102000013415 peroxidase activity proteins Human genes 0.000 description 1
- 108040007629 peroxidase activity proteins Proteins 0.000 description 1
- 238000002823 phage display Methods 0.000 description 1
- 210000000680 phagosome Anatomy 0.000 description 1
- 238000011170 pharmaceutical development Methods 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229940127557 pharmaceutical product Drugs 0.000 description 1
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 1
- 108010024607 phenylalanylalanine Proteins 0.000 description 1
- 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 description 1
- 238000000053 physical method Methods 0.000 description 1
- 229960004403 pixantrone Drugs 0.000 description 1
- PEZPMAYDXJQYRV-UHFFFAOYSA-N pixantrone Chemical compound O=C1C2=CN=CC=C2C(=O)C2=C1C(NCCN)=CC=C2NCCN PEZPMAYDXJQYRV-UHFFFAOYSA-N 0.000 description 1
- 150000003057 platinum Chemical class 0.000 description 1
- 238000005498 polishing Methods 0.000 description 1
- 230000008488 polyadenylation Effects 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 238000006116 polymerization reaction Methods 0.000 description 1
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 1
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 1
- 229920002981 polyvinylidene fluoride Polymers 0.000 description 1
- 238000002600 positron emission tomography Methods 0.000 description 1
- 231100000683 possible toxicity Toxicity 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 229960004618 prednisone Drugs 0.000 description 1
- 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 1
- 238000002360 preparation method Methods 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 239000000186 progesterone Substances 0.000 description 1
- 229960003387 progesterone Drugs 0.000 description 1
- 239000000583 progesterone congener Substances 0.000 description 1
- 230000002062 proliferating effect Effects 0.000 description 1
- 108010029020 prolylglycine Proteins 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 108020001580 protein domains Proteins 0.000 description 1
- 238000000751 protein extraction Methods 0.000 description 1
- 229940063222 provera Drugs 0.000 description 1
- LLBIOIRWAYBCKK-UHFFFAOYSA-N pyranthrene-8,16-dione Chemical compound C12=CC=CC=C2C(=O)C2=CC=C3C=C4C5=CC=CC=C5C(=O)C5=C4C4=C3C2=C1C=C4C=C5 LLBIOIRWAYBCKK-UHFFFAOYSA-N 0.000 description 1
- WKSAUQYGYAYLPV-UHFFFAOYSA-N pyrimethamine Chemical compound CCC1=NC(N)=NC(N)=C1C1=CC=C(Cl)C=C1 WKSAUQYGYAYLPV-UHFFFAOYSA-N 0.000 description 1
- 229960000611 pyrimethamine Drugs 0.000 description 1
- 229940107700 pyruvic acid Drugs 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 230000002285 radioactive effect Effects 0.000 description 1
- 238000007674 radiofrequency ablation Methods 0.000 description 1
- 230000003439 radiotherapeutic effect Effects 0.000 description 1
- 229910052705 radium Inorganic materials 0.000 description 1
- HCWPIIXVSYCSAN-UHFFFAOYSA-N radium atom Chemical compound [Ra] HCWPIIXVSYCSAN-UHFFFAOYSA-N 0.000 description 1
- 229960004432 raltitrexed Drugs 0.000 description 1
- 206010037844 rash Diseases 0.000 description 1
- 230000010837 receptor-mediated endocytosis Effects 0.000 description 1
- 238000010188 recombinant method Methods 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 230000022532 regulation of transcription, DNA-dependent Effects 0.000 description 1
- 229940116176 remicade Drugs 0.000 description 1
- 108091008146 restriction endonucleases Proteins 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 238000003757 reverse transcription PCR Methods 0.000 description 1
- 108091092562 ribozyme Proteins 0.000 description 1
- OHRURASPPZQGQM-GCCNXGTGSA-N romidepsin Chemical compound O1C(=O)[C@H](C(C)C)NC(=O)C(=C/C)/NC(=O)[C@H]2CSSCC\C=C\[C@@H]1CC(=O)N[C@H](C(C)C)C(=O)N2 OHRURASPPZQGQM-GCCNXGTGSA-N 0.000 description 1
- 229960003452 romidepsin Drugs 0.000 description 1
- 238000003118 sandwich ELISA Methods 0.000 description 1
- 230000003248 secreting effect Effects 0.000 description 1
- 238000012163 sequencing technique Methods 0.000 description 1
- 229940126586 small molecule drug Drugs 0.000 description 1
- 235000009518 sodium iodide Nutrition 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 229940054269 sodium pyruvate Drugs 0.000 description 1
- 238000000527 sonication Methods 0.000 description 1
- 210000004989 spleen cell Anatomy 0.000 description 1
- 230000002269 spontaneous effect Effects 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 238000011272 standard treatment Methods 0.000 description 1
- 210000000130 stem cell Anatomy 0.000 description 1
- 238000011476 stem cell transplantation Methods 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 239000012089 stop solution Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 230000003319 supportive effect Effects 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 238000011477 surgical intervention Methods 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 238000004885 tandem mass spectrometry Methods 0.000 description 1
- 239000008399 tap water Substances 0.000 description 1
- 235000020679 tap water Nutrition 0.000 description 1
- 229960002180 tetracycline Drugs 0.000 description 1
- 229930101283 tetracycline Natural products 0.000 description 1
- 235000019364 tetracycline Nutrition 0.000 description 1
- 150000003522 tetracyclines Chemical class 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 229960001196 thiotepa Drugs 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 229940044693 topoisomerase inhibitor Drugs 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 230000005026 transcription initiation Effects 0.000 description 1
- 230000002103 transcriptional effect Effects 0.000 description 1
- 238000010361 transduction Methods 0.000 description 1
- 230000026683 transduction Effects 0.000 description 1
- 238000001890 transfection Methods 0.000 description 1
- 230000009261 transgenic effect Effects 0.000 description 1
- 238000011830 transgenic mouse model Methods 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- 238000011277 treatment modality Methods 0.000 description 1
- 125000005270 trialkylamine group Chemical group 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 230000004565 tumor cell growth Effects 0.000 description 1
- 102000003298 tumor necrosis factor receptor Human genes 0.000 description 1
- 108010012374 type IV collagen alpha3 chain Proteins 0.000 description 1
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 1
- 229940121358 tyrosine kinase inhibitor Drugs 0.000 description 1
- 239000005483 tyrosine kinase inhibitor Substances 0.000 description 1
- 229940079023 tysabri Drugs 0.000 description 1
- 238000000108 ultra-filtration Methods 0.000 description 1
- 241000701161 unidentified adenovirus Species 0.000 description 1
- 241001529453 unidentified herpesvirus Species 0.000 description 1
- 238000011144 upstream manufacturing Methods 0.000 description 1
- 238000010200 validation analysis Methods 0.000 description 1
- 239000004474 valine Substances 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 239000011534 wash buffer Substances 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 230000004580 weight loss Effects 0.000 description 1
- 229940099073 xolair Drugs 0.000 description 1
- 229950008250 zalutumumab Drugs 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
- 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
- A61K47/68—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
- A61K47/68031—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates the drug being an auristatin
-
- 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
- A61K47/6889—Conjugates wherein the antibody being the modifying agent and wherein the linker, binder or spacer confers particular properties to the conjugates, e.g. peptidic enzyme-labile linkers or acid-labile linkers, providing for an acid-labile immuno conjugate wherein the drug may be released from its antibody conjugated part in an acidic, e.g. tumoural or environment
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/2869—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against hormone receptors
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
- C07K2317/33—Crossreactivity, e.g. for species or epitope, or lack of said crossreactivity
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
- C07K2317/34—Identification of a linear epitope shorter than 20 amino acid residues or of a conformational epitope defined by amino acid residues
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
- C07K2317/73—Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
- C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
- C07K2317/77—Internalization into the cell
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Life Sciences & Earth Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Immunology (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Organic Chemistry (AREA)
- Epidemiology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Neurology (AREA)
- Biochemistry (AREA)
- Biophysics (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Biomedical Technology (AREA)
- Endocrinology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Cell Biology (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Peptides Or Proteins (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
Abstract
大部分神经内分泌(NE)癌过度表达生长抑素受体(SSTRs)。本文公开了用作NE癌靶向治疗剂的抗SSTR2单克隆抗体和抗体药物缀合物(ADC)。还公开了编码所公开抗体的分离核酸,以及含有可操作地连接至表达控制序列的此分离核酸的核酸载体。还公开了用这些载体转染的细胞和这些细胞用以产生所公开的重组抗体的用途。还公开了一种治疗受试者的神经内分泌(NE)癌的方法,其包含向所述受试者施用有效量的与抗癌剂结合的所公开抗体。
Description
相关申请的交叉引用
本申请要求于2018年10月8日提交的美国临时申请第62/742,567号的权益,所述临时申请以全文引用的方式并入本文中。
序列表
本申请包含作为ASCII.txt文件名称为“222104_2890_Sequence_Listing_ST25”创建于2019年10月8日、以电子形式提交的序列表。所述序列表的内容以全文引用的方式并入本文中。
背景技术
神经内分泌(NE)癌,如类癌、胰岛细胞瘤和甲状腺髓样癌(MTC)经常转移至肝脏(Adler JT等人,肿瘤学家(Oncologist.)200813(7):779-93;Pinchot SN等人,研究性药物的现代观点(Curr Opin Investig Drugs.)20089(6):576-82;Chen H等人,美国外科医学杂志(J Am Coll Surg.)1998187(1):88-92;Chen H等人,胃肠外科杂志(J GastrointestSurg.)19982(2):151-5;Chen H等人,外科肿瘤学杂志(J Surg Oncol.)200897(3):203-4)。它们是流行性第二高的GI恶性肿瘤(Yao JC等人,临床肿瘤学杂志(J Clin Oncol.)200826(18):3063-72)。90%的胰腺类癌患者和50%的胰岛细胞瘤患者发展出孤立性肝转移(Hiller N等人,腹部影像(Abdom Imaging.)199823(2):188-90;Brown KT等人,血管与介入放射学杂志(J Vasc Interv Radiol.)199910(4):397-403;Pinchot SN等人.肿瘤学家200813(12):1255-69;Isozaki T等人,内科医学(Intern Med.)199938(1):17-21)。具有未经治疗的孤立性神经内分泌肝转移的患者具有<30%的5年存活概率。据报道,在美国有超过100,000名与NE癌共存的患者,每年有16,000例新诊断,且估计有超过200,000例未诊断病例(Chen H等人,美国外科医学杂志1998187(1):88-92;Norton JA.临床胃肠病学最佳实践与研究(Best Pract Res Clin Gastroenterol.)200519(4):577-8)。因此,有必要开发治疗NE癌的新型治疗。
对于具有局部肿瘤的早期疾病,单独手术切除通常是可以治愈的,但是40-95%的NE癌患者在最初诊断时是转移性的(Shiba S等人,胰腺病学(Pancreatology).201616(1):99-105),且广泛的转移使得完全切除无法实现。考虑到NE癌对肝的高度侵犯,许多患者不适合手术介入,且NE癌切除后往往在外科床内就会复发。其它形式的治疗,包括化疗栓塞术、放射栓塞术、射频消融、冷冻消融和化疗(即mTOR抑制剂“依维莫司(everolimus)”和多激酶抑制剂“舒尼替尼(sunitinib)”),显示出有限的疗效且引起重度全身性毒性(BrownKT等人,血管与介入放射学杂志199910(4):397-403;Isozaki T等人,内科医学1999 38(1):17-21;Eriksson B等人,神经内分泌学(Neuroendocrinology)200887(1):8-19;Lal A等人,肿瘤学现代观点(Curr Opin Oncol.)2006 18(1):9-15;Lehnert T.器官移植(Transplantation)199866(10):1307-12;Zhang R等人,内分泌学(Endocrinology)1999140(5):2152-8;Boudreaux JP等人,外科学年鉴(Ann Surg.)2005241(6):839-45;Nguyen C等人,核医学杂志(J Nucl Med.)200445(10):1660-8;Fiorentini G等人,化疗杂志(J Chemother.)200416(3):293-7;Zuetenhorst JM等人,内分泌相关癌症(EndocrRelat Cancer.)200411(3):553-61)。因此,除手术以外,不存在针对转移性NE癌的治愈性治疗。此外,由于这些肿瘤的特征为激素分泌过多,因此NE癌肝转移患者常伴有虚弱症状,如无法控制的腹泻、潮红、皮疹和心力衰竭(Brown KT等人,血管与介入放射学杂志199910(4):397-403;Miller CA等人,北美肿瘤外科临床(Surg Oncol Clin N Am.)19987(4):863-79)。因此,NE癌患者往往具有较差的生活质量,此凸显出迫切需要开发新的治疗策略以减少NE恶性肿瘤的进展。
发明内容
大部分神经内分泌(NE)癌过度表达生长抑素受体(SSTR),其中SSTR2亚型主要发现于70-100%的NE肿瘤(NET)中的细胞表面上。更确切地说,NET中的SSTR2的表面表达水平比正常细胞中的SSTR2的表面表达水平高大约20倍。因此,本文公开了用作NE癌靶向治疗剂的抗SSTR2单克隆抗体(mAb,IgG)和抗体药物缀合物(ADC)。在一些实施例中,所公开的mAb下调致癌信号传导路径,减少激素积聚和相关类癌心脏衰竭,且增加T细胞的细胞因子产生。更重要的是,mAb证实对过度表达SSTR2的NET有高特异性、强结合和有效的药物递送能力。这样,所公开的ADC具有SSTR2靶向mAb和由mAb递送的强力药物的整合临床益处,从而可克服传统化疗中所观察到的非特异性结合和重度全身性毒性。
所公开的抗SSTR2单克隆抗体是使用从人类SSTR2的第2和第4细胞外结构域克隆的两种肽产生的。还公开了一种特异性结合SSTR2的抗体片段。例如,抗体可以是特异性结合SSTR2的抗体的Fab或单链可变片段(scFv)。本文还公开了至少包含所公开的抗体的抗原结合区的重组、人源化和/或嵌合抗体。在一些实施例中,抗SSTR2区(例如scFv)可包含具有CDR1、CDR2和CDR3序列的可变重(VH)结构域和具有CDR1、CDR2和CDR3序列的可变轻(VL)结构域。
在一些实施例中,VH结构域的CDR1序列包含氨基酸序列DYHLN(SEQ ID NO:1)DYHMN(SEQ ID NO:26);VH结构域的CDR2序列包含氨基酸序列IRNKRYGYRTEYSASVKG(SEQ IDNO:2)或LIRNKANGYRTEYSASVKG(SEQ ID NO:27);VH结构域的CDR3序列包含氨基酸序列DFYDPFAY(SEQ ID NO:3);VL的CDR1序列包含氨基酸序列RSSQSLVHSNGNTYLH(SEQ ID NO:4);VL结构域的CDR2序列包含氨基酸序列KVSNRFS(SEQ ID NO:5);且VL结构域的CDR3序列包含氨基酸序列SQSTHVPFT(SEQ ID NO:6)或SQSTRVPFT(SEQ ID NO:28)。
在一些实施例中,抗SSTR2 VH结构域包含氨基酸序列:EVKLVESGGGLVQPGGSLRLSCATSGFTFTDYHLNWVRQPPGKALEWLALIRNKRYGYRTEYSASVKGRFTISRDNSQSILYLQMNTLRAEDSATYYCARDFYDPFAYWGQGTLVTVSA(SEQ ID NO:7)。
在一些实施例中,抗SSTR2 VH结构域包含氨基酸序列:EVKLVESGGGLVQPGGSLRLSCATSGFTFTDYHMNWVRQPPGKALEWLALIRNKANGYRTEYSASVKGRFTISRDNSQNILYLQMNTLRAEDSATYYCARDFYDPFAYWGQGTLVTVSA(SEQ ID NO:18)。
在一些实施例中,抗SSTR2 VL结构域包含氨基酸序列:
DVVMTQTPLSLPVSLGDQASISCRSSQSLVHSNGNTYLHWYLQRPGQSPKLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDLGVYFCSQSTHVPFTFGSGTKLEIK(SEQ ID NO:8)。
在一些实施例中,抗SSTR2 VL结构域包含氨基酸序列:DVVMTQTPLSLPVSLGDQASISCRSSQSLVHSNGNTYLHWYLQRPGQSPNLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDLGLYFCSQSTRVPFTFGSGTKLEIK(SEQ ID NO:19)。
在一些实施例中,VH或VL结构域进一步包含信号肽,如MKLWLNWIFLVTLLNGIQC(SEQID NO:29)或MKLPVGLLVLMFWIPASSS(SEQ ID NO:30)。
重链和轻链优选地通过接头分离。适用于scFv抗体的接头为本领域中已知的。在一些实施例中,接头包含氨基酸序列GGGGSGGGGSGGGGS(SEQ ID NO:9)、SSGGGGSGGGGSGGS(SEQ ID NO:10)或GSTSGSGKPGSGEGSTKG(SEQ ID NO:11)。scFv可具有式NH3-VH-接头-VL-COOH或NH3-VL-接头-VH-COOH。
因此,在一些实施例中,抗SSTR2 scFv包含氨基酸序列:MKLWLNWIFLVTLLNGIQCEVKLVESGGGLVQPGGSLRLSCATSGFTFTDYHLNWVRQPPGKALEWLALIRNKRYGYRTEYSASVKGRFTISRDNSQSILYLQMNTLRAEDSATYYCARDFYDPFAYWGQGTLVTVSAGGGGSGGGGSGGGGSMKLPVRLLVLMFWIPASSSDVVMTQTPLSLPVSLGDQASISCRSSQSLVHSNGNTYLHWYLQRPGQSPKLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDLGVYFCSQSTHVPFTFGSGTKLEIK(SEQ ID NO:12)。
因此,在一些实施例中,抗SSTR2 scFv包含氨基酸序列:MKLPVRLLVLMFWIPASSSDVVMTQTPLSLPVSLGDQASISCRSSQSLVHSNGNTYLHWYLQRPGQSPKLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDLGVYFCSQSTHVPFTFGSGTKLEIKGGGGSGGGGSGGGGSMKLWLNWIFLVTLLNGIQCEVKLVESGGGLVQPGGSLRLSCATSGFTFTDYHLNWVRQPPGKALEWLALIRNKRYGYRTEYSASVKGRFTISRDNSQSILYLQMNTLRAEDSATYYCARDFYDPFAYWGQGTLVTVSA(SEQ ID NO:13)。
因此,在一些实施例中,抗SSTR2 scFv包含氨基酸序列:MKLWLNWIFPVTLLNGIQCEVKLVESGGGLVQPGGSLRLSCATSGFTFTDYHMNWVRQPPGKALEWLALIRNKANGYRTEYSASVKGRFTISRDNSQNILYLQMNTLRAEDSATYYCARDFYDPFAYWGQGTLVTVSAGGGGSGGGGSGGGGSMKLPVGLLVLMFWIPASSSDVVMTQTPLSLPVSLGDQASISCRSSQSLVHSNGNTYLHWYLQRPGQSPNLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDLGLYFCSQSTRVPFTFGSGTKLEIK(SEQ ID NO:20)。
因此,在一些实施例中,抗SSTR2 scFv包含氨基酸序列:MKLPVGLLVLMFWIPASSSDVVMTQTPLSLPVSLGDQASISCRSSQSLVHSNGNTYLHWYLQRPGQSPNLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDLGLYFCSQSTRVPFTFGSGTKLEIKGGGGSGGGGSGGGGSMKLWLNWIFPVTLLNGIQCEVKLVESGGGLVQPGGSLRLSCATSGFTFTDYHMNWVRQPPGKALEWLALIRNKANGYRTEYSASVKGRFTISRDNSQNILYLQMNTLRAEDSATYYCARDFYDPFAYWGQGTLVTVSA(SEQ ID NO:21)。
因此,在一些实施例中,抗SSTR2 scFv包含氨基酸序列:MKLWLNWIFLVTLLNGIQCEVKLVESGGGLVQPGGSLRLSCATSGFTFTDYHLNWVRQPPGKALEWLALIRNKRYGYRTEYSASVKGRFTISRDNSQSILYLQMNTLRAEDSATYYCARDFYDPFAYWGQGTLVTVSAGGGGSGGGGSGGGGSMKLPVGLLVLMFWIPASSSDVVMTQTPLSLPVSLGDQASISCRSSQSLVHSNGNTYLHWYLQRPGQSPNLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDLGLYFCSQSTRVPFTFGSGTKLEIK(SEQ ID NO:22)。
因此,在一些实施例中,抗SSTR2 scFv包含氨基酸序列:MKLPVGLLVLMFWIPASSSDVVMTQTPLSLPVSLGDQASISCRSSQSLVHSNGNTYLHWYLQRPGQSPNLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDLGLYFCSQSTRVPFTFGSGTKLEIKGGGGSGGGGSGGGGSMKLWLNWIFLVTLLNGIQCEVKLVESGGGLVQPGGSLRLSCATSGFTFTDYHLNWVRQPPGKALEWLALIRNKRYGYRTEYSASVKGRFTISRDNSQSILYLQMNTLRAEDSATYYCARDFYDPFAYWGQGTLVTVSA(SEQ ID NO:23)。
因此,在一些实施例中,抗SSTR2 scFv包含氨基酸序列:MKLWLNWIFPVTLLNGIQCEVKLVESGGGLVQPGGSLRLSCATSGFTFTDYHMNWVRQPPGKALEWLALIRNKANGYRTEYSASVKGRFTISRDNSQNILYLQMNTLRAEDSATYYCARDFYDPFAYWGQGTLVTVSAGGGGSGGGGSGGGGSMKLPVRLLVLMFWIPASSSDVVMTQTPLSLPVSLGDQASISCRSSQSLVHSNGNTYLHWYLQRPGQSPKLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDLGVYFCSQSTHVPFTFGSGTKLEIK(SEQ ID NO:24)。
因此,在一些实施例中,抗SSTR2 scFv包含氨基酸序列:MKLPVRLLVLMFWIPASSSDVVMTQTPLSLPVSLGDQASISCRSSQSLVHSNGNTYLHWYLQRPGQSPKLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDLGVYFCSQSTHVPFTFGSGTKLEIKGGGGSGGGGSGGGGSMKLWLNWIFPVTLLNGIQCEVKLVESGGGLVQPGGSLRLSCATSGFTFTDYHMNWVRQPPGKALEWLALIRNKANGYRTEYSASVKGRFTISRDNSQNILYLQMNTLRAEDSATYYCARDFYDPFAYWGQGTLVTVSA(SEQ ID NO:25)。
还公开编码所公开抗体的分离核酸,以及含有可操作地连接至表达控制序列的此分离核酸的核酸载体。还公开用这些载体转染的细胞以及使用这些细胞来产生所公开重组抗体。
还公开一种组合物,其包含与抗癌剂缀合的所公开的抗体。所公开的抗体可用于将任何有效负载递送至受试者的NE癌。有效负载可以是治疗剂或诊断剂。在一些实施例中,有效负载为可以引起靶向肿瘤细胞的细胞凋亡或细胞焦亡的抗癌剂。在一些实施例中,抗癌剂为小分子药物。在一些实施例中,抗癌剂为单甲基奥利他汀E(monomethyl auristatinE)、吉西他滨(gemcitabine)或白藜芦醇(resveratrol)。抗癌剂可以是化疗剂,如终止DNA构建块合成的药物(例如氨甲蝶呤(methotrexate)、氟尿嘧啶(fluorouracil)、羟基脲(hydroxyurea)、勒托替康(lurtotecan)、巯基嘌呤(mercaptopurine)、喷司他丁(pentostatin)和吡柔比星(pirarubicin));直接损伤DNA的药物(例如顺铂(cisplatin)、道诺霉素(daunorubicin)、阿霉素(doxorubicin)、依托泊苷(etoposide)、替尼泊苷(teniposide)、喜树碱(camptothecin)、拓扑替康(topotecan)、伊立替康(irinotecan)、鲁比替康(rubitecan)、贝洛替康(belotecan));影响有丝分裂纺锤体合成或分解的药物(如长春碱(vinblastine)、长春新碱(vincristine)、长春瑞滨(vinorelbine)、长春氟宁(vinflunine)、长春地辛(vindesine)、多西他赛(docetaxel)、拉洛他赛(larotaxel)、奥他赛(ortataxel)、紫杉醇(paclitaxel)、特西他赛(tesetaxel)、伊沙匹隆(ixabepilone)和环氧噻酮(epithilones));或干扰血管生成的药物(如抗VEGF抗体、血管生长抑素、内皮抑制素和肿瘤抑制素)。可替代地,抗癌剂可以是放疗剂(例如90Y、125I、188Re、111In DTPA或131I碘化钠)。
附加至本文所述的肿瘤靶向肽的抗癌药物或抗肿瘤药物的实例包括但不限于:阿克拉霉素(aclarubicin)、六甲蜜胺(altretamine)、氨基喋呤(aminopterin)、氨柔比星(amrubicin)、阿扎胞苷(azacitidine)、硫唑嘌呤(azathioprine)、贝洛替康、白消安(busulfan)、喜树碱、卡培他滨(capecitabine)、卡铂(carboplatin)、卡莫氟(carmofur)、卡莫司汀(carmustine)、苯丁酸氮芥(chlorambucil)、顺铂、克拉屈滨(cladribine)、氯法拉滨(clofarabine)、环磷酰胺(cyclophosphamide)、阿糖胞苷(cytarabine)、道诺霉素、地西他滨(decitabine)、阿霉素、表柔比星(epirubicin)、依托泊苷、氟尿苷(floxuridine)、氟达拉滨(fludarabine)、5-氟尿嘧啶、氟尿嘧啶、吉西他滨(gemcitabine)、伊达比星(idarubicin)、异环磷酰胺(ifosfamide)、伊立替康、氮芥(mechlorethamine)、美法仑(melphalan)、巯基嘌呤、氨甲蝶呤、米托蒽醌(mitoxantrone)、奈达铂(nedaplatin)、奥沙利铂(oxaliplatin)、紫杉醇、培美曲塞(pemetrexed)、喷司他丁、吡柔比星、吡蒽醌(pixantrone)、丙卡巴肼(procarbazine)、乙胺嘧啶(pyrimethamine)、雷替曲塞(raltitrexed)、鲁比替康、赛特铂(satraplatin)、链脲霉素(streptozocin)、硫鸟嘌呤(thioguanine)、四硝酸三铂(triplatin tetranitrate)、替尼泊苷、拓扑替康、替加氟(tegafur)、甲氧苄啶(trimethoprim)、乌拉莫司汀(uramustine)、戊柔比星(valrubicin)、长春碱、长春新碱、长春地辛、长春氟宁、长春瑞滨和佐柔比星(zorubicin)。
在一些实施例中,所公开的抗体与抗癌剂相关的运载体连接。在一个实例中,运载体囊封抗癌剂。运载体包括但不限于:外泌体、胶束、脂质体(例如阳离子脂质体)、纳米颗粒、微球或生物可降解聚合物。肿瘤靶向肽可以通过多种键(例如二硫键、酸不稳定键、肽基键、氧氨基键或肼键)系栓至运载体。为改善抗体与运载体之间的结合,肽可通过适合的聚合物(如PEG(聚乙二醇化))改性。可检测标记或抗癌剂可经由例如与亲脂性分子结合而在运载体内囊封,所述亲脂性分子可帮助将可检测标记或抗癌剂递送至运载体内部。
在一些实施例中,本文所述的肿瘤靶向抗体连结至囊封一或多种所关注的药剂(例如抗癌剂)的脂质体(作为运载体)。脂质体为包含一或多个同心有序脂质双层的囊泡,其囊封水相。水相通常含有待递送至标靶部位(如肿瘤部位)的药剂。在到达标靶部位后,脂质体与局部细胞的质膜融合以将药剂释放至胞质溶胶中。可替代地,脂质体被细胞内吞或以其它方式作为运输囊泡(例如内体或吞噬体)的内容物被细胞吸收。一旦在运输囊泡中,脂质体降解囊泡的膜或与囊泡的膜融合且释放其内容物。可构建脂质体膜使得其在附近环境变成酸性时变得不稳定(参见例如美国国家科学院院刊(PNAS)84:7851,1987;生物化学(Biochemistry)28:908,1989)。因此,当脂质体进入靶细胞时,脂质体变得不稳定以释放其囊封的内容物。此不稳定过程被称为融合发生(fusogenesis)。二油酰基磷脂酰乙醇胺(DOPE)通常用于促进此过程。
多种方法可用于制备脂质体。参见例如Szoka等人,生物物理学和生物工程年鉴(Ann.Rev.Biophys.Bioeng.)9:467(1980)、美国专利第4,186,183号、第4,217,344号、第4,235,871号、第4,261,975号、第4,485,054号、第4,501,728号、第4,774,085号、第4,837,028号、第4,235,871号、第4,261,975号、第4,485,054号、第4,501,728号、第4,774,085号、第4,837,028号、第4,946,787号、PCT公开第WO 91/17424号、Deamer&Bangham,生物化学与生物物理学报(Biochim.Biophys.Acta)443:629-634(1976);Fraley等人,PNAS 76:3348-3352(1979);Hope等人,生物化学与生物物理学报812:55-65(1985);Mayer等人,生物化学与生物物理学报858:161-168(1986);Williams等人,美国国家科学院院刊85:242-246(1988);脂质体(Liposomes)(Ostro(编辑),1983,章节1);Hope等人,脂质的化学与物理(Chem.Phys.Lip.)40:89(1986);Gregoriadis,脂质体技术(Liposome Technology)(1984)和Lasic,脂质体:从物理到应用(Liposomes:from Physics to Applications)(1993))。适合的方法包括例如超声处理、挤压、高压/均质化、微流体化、清洁剂透析、小脂质体运载体的钙诱导融合和醚融合方法,所有这些方法为本领域中众所周知的。
在抗体药物缀合物中,抗体可直接缀合至细胞毒性剂或经由接头结合。合适的接头包括例如可裂解和非可裂解接头。可裂解接头通常容易在细胞内条件下裂解。适合的可裂解接头包括例如可由细胞内蛋白酶(如溶酶体蛋白酶或内体蛋白酶)裂解的肽接头。在一些实施例中,接头可以是二肽接头,如缬氨酸-瓜氨酸(val-cit)或苯丙氨酸-赖氨酸(phe-lys)接头。其它合适的接头包括可在小于5.5的pH值下水解的接头,如腙接头。其它适合的可裂解接头包括二硫键接头。
还公开一种药物组合物,其包含在药学上可接受的载剂中的本文所公开的肿瘤靶向抗体和有效负载。还公开一种用于治疗受试者的NE癌的方法,其涉及向所述受试者施用治疗有效量的所公开的药物组合物。
在以下附图和描述中阐述本发明的一或多个实施例的细节。本发明的其它特征、目的和优点将从描述和附图和权利要求书而变得显而易见。
附图说明
图1显示SSTR2靶向治疗经由以下各者来治疗NET:1)通过mAb递送的药物使微管蛋白解聚合,2)通过内化mAb抑制激素产生,3)通过mAb阻断SSTR2来下调细胞增殖信号传导路径,或4)活化T细胞的细胞因子产生。
图2A至2C显示SSTR2表达的评估。(A)RT-PCR指示BON细胞中的高SSTR2水平。(B)全细胞细胞蛋白质印迹显示非癌性细胞(917和WI38)中的低SSTR2,但NET细胞系(BON、QGP和H727)中的高SSTR2;膜蛋白质印迹证实非癌性细胞(917)中的低SSTR2,但NET细胞(H727)中的高SSTR2。(C)CLSM显示在活的PanNET细胞(BON)、PanNET异种移植物组织和患者组织中的高SSTR2。
图3A和3B显示抗SSTR2 mAb的特异性靶向。(A)活体动物IVIS成像显示在皮下NET异种移植物中的mAb-AF488积聚。(左):来自稳定转染的NET-Luc细胞的生物发光信号。(右):来自NET异种移植物的高度增生区域的荧光信号指示特定SSTR2-mAb。(B)流式细胞测量术展示mAb的高表面结合。
图4A和4B显示抗SSTR2 mAb介导的抗NET。(A)蛋白质印迹展示mAb下调PI3K/AKT(细胞增殖)的表达、改变细胞周期蛋白D1和p21(细胞周期)的水平和降低ASCL/CgA(激素);(B)流式细胞测量术分析显示通过mAb增加人类T细胞的IL2和IFNγ(细胞因子)两者。
图5A至5B显示ADC毒性。ADC对BON细胞具有较高的毒性IC50<10nM。
图6显示在皮下异种移植物小鼠模型中的体内抗癌功效。用8mg/kgBW ADC或运载体治疗的小鼠通过卡尺测量平均肿瘤体积。误差条代表在n=6处的标准差;**p≤0.01;***p≤0.001。
图7A和7B为显示患者中的强SSTR2表达的组织微阵列(TMA)。图7A显示TMA的H&E染色,所述TMA包括人类胰腺NET组织(第2-9列,n=38)和正常组织(对照,第1列,n=5)。图7B显示TMA的IHC分析显示SSTR2的阳性染色。比例尺等于20μm。71%的这些核心对SSTR2呈阳性且显示强膜定位。
图8A和8B显示如通过免疫组织化学所验证,抗SSTR2抗体独特地与NET细胞结合,但与正常器官或组织不存在或存在极低的结合。图8A1显示33个正常人类器官(US Biomax,FDA662a,n=2)中的阴性或极低表面SSTR2染色,所述器官代表大脑、小脑、外周神经、肾上腺、甲状腺、脾脏、胸腺、骨髓、淋巴结、扁桃体、胰腺、肝、食道、胃、小肠、结肠、肺、唾液、咽、肾、膀胱、睾丸、前列腺、阴茎、卵巢、输卵管、乳腺、子宫内膜、子宫颈、心肌、骨骼肌、间皮和皮肤。图8A2显示胰腺NET患者组织(n=12)中的细胞表面上的阳性SSTR2染色。图8B显示小脑、大脑、肝、肺、肌肉、皮肤、扁桃体、前列腺、胰腺和胰腺NET的代表性高分辨率IHC成像。比例尺等于50μm。
图9A到9E显示抗SSTR2 mAb的发展和产生。图9A显示基于ELISA筛选中的滴度的顶级抗SSTR2 mAb克隆的等级(数据代表平均值±SEM,n=3)。图9B显示使用流式细胞测量术的前4个克隆的评估。图9C显示SDS-PAGE证实mAb的完整性和纯度(M:标记;1-4:克隆1-4)。图9D显示对照细胞系(WI38和917)和NET细胞系(BON和QGP)中克隆#4的SSTR2结合的评估。图9E显示分批进料悬浮培养物中的mAb产生和杂交瘤细胞生长(数据代表平均值±SEM,n=3)。活细胞密度(VCD):▲、细胞存活率:Δ、比生长速率(μ):□。
图10A至10C显示通过我们的抗SSTR2 mAb的表面结合的体外评估。图10A显示活细胞CLSM动态成像,其显示抗SSTR2 mAb在60分钟内快速且有效地结合至BON细胞表面,随后在70分钟内内化。双色CLSM:标记有GFP的全细胞和标记有AF647的SSTR2mAb-MMAE。图10B显示流式细胞测量术,其显示我们的抗SSTR2mAb在高水平下与BON细胞结合且不与SSTR2阴性对照结合,且我们的mAb具有比商业mAb高得多的结合百分比。在冰上用1μg mAb-AF647/百万细胞染色30分钟。图10C显示AF647 mAb内化于三种NE癌细胞(绿色)中,包括BON、TT和MZ。比例尺等于5μm。
图11A和11B显示通过我们的抗SSTR2 mAb的NET靶向的体内评估。图11A显示IVIS的体内成像,其显示mAb可在小鼠模型中特异性靶向皮下NET异种移植物。抗SSTR2 mAb用荧光染料Cy7标记且使用蛋白A柱纯化。通过尾静脉进行静脉内(i.v.)注射总计50μg Cy5.5-mAb。在Cy5.5-mAb注射后24小时获取IVIS成像。图11B显示mAb靶向人类NET(BON)异种移植组织和小鼠MTC组织两者(n=3-4)。
图12A至12F显示ADC构建和体外特征。图12A显示使用维持mAb完整性的再桥接接头的抗SSTR2 mAb-MMAE的分子结构。图12B显示MS展示就三种产品形式而言接头-MMAE药物的正确结构和恰当缀合。图12显示游离药物(●)、使用商业抗SSTR2 mAb构建的ADC(安迪生物公司(R&D Systems),▲)和使用我们的抗SSTR2mAb构建的ADC的IC50抗癌毒性(■)(数据代表平均值±SEM,n=3)。图12D显示SDS-PAGE凝胶,其显示mAb-MMAE的良好完整性。图12E显示蛋白质印迹,其揭示抗SSTR2 mAb和ADC两者皆抑制细胞增殖信号传导路径(AKT、细胞周期蛋白D1和P21),而不改变SSTR2表面表达。图12F显示MMAE药物引起BON细胞系中的微管解聚合。比例尺等于20μm。
图13A和13B显示皮下PanNET异种移植小鼠模型中MTD和PK研究和ADC对脑部的影响。图13A显示,测试包括4、8、12、16和20mg/kg-BW的五个ADC剂量的作用的MTD研究,其显示出对小鼠体重和行为无负面影响,且未达到最大剂量(n=2)。图13B显示H&E染色,其显示ADC治疗没有改变脑部形态且对脑部没有损伤。比例尺等于200μm。图13C显示PK研究,其显示ADC的稳定性和动力学参数(数据代表平均值±SEM,n=4)。
图14A至14H显示在PanNET(BON-Luc)异种移植模型中ADC的抗NET功效研究。图14A显示在Bon-Luc细胞注射和治疗之后肿瘤体积变化(数据代表平均值±SEM,n=6)。肿瘤使用卡尺测量,且计算为椭圆体。黑色箭头指示ADC(8mg/kg BW)治疗日期。图14B显示使用IVIS成像系统的肿瘤荧光通量测量(数据代表平均值±SEM,n=6)。图14C显示收集携带肿瘤的小鼠。图14D显示在第29天从收集的小鼠身上切除的肿瘤的重量。图14E显示在治疗期间小鼠的体重。▲:用ADC注射的治疗组、●:用mAb注射的对照组和■:用生理盐水注射的对照组。图14F显示来自代表小鼠的肿瘤的蛋白质印迹(n=3)。图14G显示生理盐水和ADC治疗的肿瘤的抗SSTR2 IHC染色。图14H显示生理盐水或ADC治疗的肿瘤的H&E染色。比例尺等于50μm。***p≤0.001。
图15A和15B显示使用蛋白质印迹评估NET细胞系(BON、H727和QGP)和正常细胞系(917和WI38)中SSTR2表达(图15A),和使用共焦显微镜成像评估PanNET异种移植物肿瘤组织和患者肿瘤组织中SSTR2表达(图15B)。比例尺等于20或40μm。
图16显示流式细胞测量术分析,其显示通过我们的抗SSTR2mAb和SST类似物(奥曲肽(Octreotide)),人类T细胞的IL2和IFN-γ(细胞因子)两者均增加。
图17显示用于NET治疗的基于抗SSTR2 mAb的ADC的假设机制。(1)通过mAb递送的药物使微管蛋白解聚合;(2)通过mAb阻断SSTR2下调细胞增殖信号传导路径;和(3)活化T细胞的细胞因子产生。
具体实施方式
在更详细地描述本公开之前,应理解,本公开不限于所述特定实施例,且因此,当然可变化。还应理解,本文所用的术语仅用于描述特定实施例的目的,并且不希望具有限制性,因为本公开的范围仅由所附权利要求书限定。
当提供值的范围时,应理解,在所述范围的上限与下限之间的各中间值(除非上下文另外明确指示,否则为下限单位的十分之一)与所述陈述范围中的任何其它值或中间值皆涵盖在本公开内。这些较小范围的上限和下限可以独立地包括在所述较小范围内并且也涵盖于本公开内,受到在所陈述的范围内的任何特定地排除的限定。当所陈述的范围包括限值中的一个或两个时,排除所包括的那些限值中的任一个或两个的范围也包括在本公开中。
除非另外定义,本文中所使用的所有技术和科学术语都具有与本公开所属领域的一般技术人员通常所理解相同的含义。尽管在本公开的操作或测试中也可以使用与本文所描述的方法和材料类似或等效的任何方法和材料,但是现在描述优选方法和材料。
本说明书中引用的所有公开和专利均以引用的方式并入本文中,如同每一个别公开或专利经特定且个别地指示以引用的方式并入一般,且以引用的方式并入本文中以公开和描述结合引用的公开的方法和/或材料。对任何公开的引用是针对其在申请日之前的公开内容,并且不应解释为承认本公开无权先于依据先前公开的此类公开内容。此外,所提供的公开的日期可能不同于可能需要独立确认的实际公开日期。
如所属领域的技术人员在阅读本公开之后将显而易见,本文中所描述和说明的个别实施例中的每一者具有离散的组件和特征,所述特征可容易与其它若干实施例中的任一个的特征分离或与其组合而不脱离本公开的范围或精神。任何所叙述的方法均可以所叙述事件的顺序或以逻辑上可能的任何其它顺序来实施。
除非另外指示,本公开的实施例将采用在所属领域的技术内的化学、生物学等的技术。
提出以下实例以便向所属领域的一般技术人员提供如何执行所述方法和使用本文所公开和所要求的探针的完整公开内容和描述。已经做出努力来确保关于数字(例如量、温度等)的准确性,但应考虑一些误差和偏差。除非另外指示,否则份数为重量份,温度以℃计,且压力在大气压下或接近大气压。标准温度和压力被定义为20℃和1大气压。
在详细描述本公开的实施例之前,应理解,除非另外指示,本公开不限于特定材料、试剂、反应材料、制造工艺等,因而可变化。还应理解,本文中所使用的术语仅出于描述特定实施例的目的,且并不意图为限制性的。在本公开中还可能以不同顺序执行步骤,这在逻辑上是可能的。
必须注意,除非上下文另外明确规定,否则如本说明书和所附权利要求书中所使用的单数形式“一/一个(种)(a)”、“一/一个(种)(an)”以及“所述(the)”包括复数个指示物。
术语“氨基酸序列”是指代表氨基酸残基的缩写、字母、字符或词语的列表。本文所使用的氨基酸缩写为氨基酸的常规一个字母代码,且如下表述:A,丙氨酸;B,天冬酰胺或天冬氨酸;C,半胱氨酸;D,天冬氨酸;E,谷氨酸(glutamate)、谷氨酸(glutamic acid);F,苯丙氨酸;G,甘氨酸;H,组氨酸;I,异亮氨酸;K,赖氨酸;L,亮氨酸;M,甲硫氨酸;N,天冬酰胺;P,脯氨酸;Q,谷氨酰胺;R,精氨酸;S,丝氨酸;T,苏氨酸;V,缬氨酸;W,色氨酸;Y,酪氨酸;Z,谷氨酰胺或谷氨酸。
术语“抗体”是指维持特异性结合能力的免疫球蛋白、其衍生物和具有与免疫球蛋白结合域同源或很大程度上同源的结合域的蛋白质。这些蛋白质可源自天然来源,或部分或完全以合成方式产生。抗体可以是单克隆或多克隆的。抗体可以是来自任何物种的任何免疫球蛋白类别的成员,包括人类类别中的任一种:IgG、IgM、IgA、IgD和IgE。在例示性实施例中,与本文所述的方法和组合物一起使用的抗体为IgG类别的衍生物。除了完整免疫球蛋白分子之外,还包括在术语“抗体”内的为选择性地结合靶抗原的那些免疫球蛋白分子和人类或人类化形式的免疫球蛋白分子的片段或聚合物。
术语“抗体片段”是指小于全长的抗体的任何衍生物。在例示性实施例中,抗体片段保留全长抗体的至少相当大部分的特异性结合能力。抗体片段的实例包括但不限于Fab、Fab'、F(ab′)2、scFv、Fv、dsFv双功能抗体、Fc和Fd片段。抗体片段可以通过任何方式产生。举例来说,抗体片段可通过完整抗体的片段化以酶促方式或以化学方式产生,其可以重组方式由编码部分抗体序列的基因产生,或其可以完全或部分地以合成方式产生。抗体片段可以任选地为单链抗体片段。可替代地,片段可包含例如通过二硫键连接在一起的多个链。片段还可以任选地为多分子复合物。功能性抗体片段将通常包含至少约50个氨基酸,且更通常将包含至少约200个氨基酸。
术语“载剂”是指当与化合物或组合物组合时,有助于或促进化合物或组合物的制备、储存、施用、递送、有效性、选择性或任何其它特征以达到其预期用途或目的的化合物、组合物、物质或结构。例如,载剂可选择以使活性成分的任何降解降到最低且使受试者的任何不良副作用降到最低。
术语“嵌合分子”是指通过接合两个或更多个以其天然状态中分别存在的分子而产生的单一分子。单一嵌合分子具有其所有构成分子的所要功能性。一种类型的嵌合分子为融合蛋白。
术语“工程化抗体”是指包含至少一种抗体片段的重组分子,所述抗体片段包含来源于抗体的重链和/或轻链的可变结构域的抗原结合位点,且可任选地包含来自Ig类别中的任一者(例如IgA、IgD、IgE、IgG、IgM和IgY)的抗体的可变和/或恒定结构域的全部或部分。
术语“表位”是指抗体优先且特异结合于其的抗原区域。单克隆抗体优先结合于可在分子上定义的分子的单一特定表位。在本发明中,多个表位可以由多特异性抗体识别。
术语“融合蛋白”是指通过使两种或更多种多肽经由一种多肽的氨基末端与另一种多肽的羧基末端之间形成的肽键接合而形成的多肽。融合蛋白可以通过组成性多肽的化学偶合形成,或可以从编码单一连续融合蛋白的核酸序列表达为单一多肽。单链融合蛋白为具有单一连续多肽主链的融合蛋白。融合蛋白可以使用分子生物学中的常规技术来制备,以将两个基因在框内接合成单一核酸,且随后在产生融合蛋白的条件下在合适的宿主细胞中表达核酸。
术语“Fab片段”是指抗体的片段,其包含通过抗体以酶木瓜蛋白酶裂解产生的抗原结合位点,所述酶木瓜蛋白酶在铰链区N-末端处切割至H-链间二硫键且从一个抗体分子产生两个Fab片段。
术语“F(ab′)2片段”是指含有两种抗原结合位点的抗体的片段,所述抗原结合位点通过抗体分子以酶胃蛋白酶裂解产生,所述酶胃蛋白酶在铰链区C-末端处剪切至H-链间二硫键。
术语“Fc片段”是指包含其重链恒定结构域的抗体的片段。
术语“Fv片段”是指包含其重链和轻链的可变结构域的抗体的片段。
“基因构建体”是指核酸,如载体、质粒、病毒基因组等,其包括用于多肽或以其它方式可转录成生物活性RNA(例如反义、诱饵、核酶等)的“编码序列”,可以转染至细胞(例如在某些实施例中为哺乳动物细胞)内,且可能引起编码序列在用构建体转染的细胞中的表达。基因构建体可包括一个或多个可操作地连接至编码序列的调节元件,以及内含子序列、聚腺苷酸化位点、复制起点、标记基因等。
术语“一致性"是指两种核酸分子或多肽之间的序列一致性。一致性可以各自通过比较每个序列中可以出于比较目的比对的位置来进行测定。当比较序列中的位置由相同碱基占据时,那么分子在所述位置处为相同的。核酸或氨基酸序列之间的相似性或一致性程度是由核酸序列共享的位置处的相同或匹配核苷酸的数目的函数。各种比对算法和/或程序可用于计算两个序列之间的一致性,所述算法包括FASTA或BLAST,其可用作GCG序列分析包(威斯康星州麦迪逊威斯康星大学(University of Wisconsin,Madison,Wis.))的一部分,且可与例如默认设置(default setting)一起使用。例如,涵盖与本文所述的特定多肽具有至少70%、85%、90%、95%、98%或99%一致性且优选地展现大体上相同功能的多肽,以及编码此类多肽的多核苷酸。除非另外指示,相似性分数将基于BLOSUM62的使用。当使用BLASTP时,相似性百分比是基于BLASTP阳性分数,且序列一致性百分比是基于BLASTP一致性分数。BLASTP“一致性”显示高分序列对中的总残基的数目和分数相同;且BLASTP“阳性”显示比对分数具有正值且彼此类似的残基的数目和分数。本公开涵盖且包含与本文所公开的氨基酸序列具有这些一致性或相似性程度或任何中间相似性程度的氨基酸序列。类似多肽的多核苷酸序列使用遗传密码推断出,且可以通过常规方式获得,确切地说,通过使用遗传密码反向翻译其氨基酸序列获得。
术语“接头”为此领域理解的且是指连接两种化合物(如两种多肽)的分子或分子群组。接头可以包含单一连接分子或可包含旨在使连接分子与化合物以特定距离分离的连接分子和间隔分子。
术语“核酸”是指天然或合成分子,其包含单核苷酸或由一个核苷酸的3'位置处的磷酸基连接至另一核苷酸的5'末端的两个或更多个核苷酸。核酸不受长度限制,且因此核酸可包括脱氧核糖核酸(DNA)或核糖核酸(RNA)。
术语“可操作地连接至”是指核酸与另一核酸序列的功能关系。启动子、增强子、转录和转译终止位点以及其它信号序列为可操作地连接至其它序列的核酸序列的实例。例如,将DNA可操作连接至启动子的是指DNA与启动子之间的物理和功能关系,使得此类DNA的转录通过RNA聚合酶从启动子起始,所述RNA聚合酶特异性地识别、结合到DNA且转录DNA。
术语“肽”、“蛋白质”和“多肽”互换使用是指包含通过一个氨基酸的羧基键联到另一个氨基酸的α氨基的两个或更多个氨基酸的天然或合成分子。
术语“药学上可接受的”是指在合理医学判断范围内适用于与人类和动物的组织接触而无过度毒性、刺激、过敏反应或其它问题或与合理效益/风险比相称的并发症的化合物、材料组合物和/或剂型。
当参考特定多肽使用时,术语“多肽片段”或“片段”是指其中相比于参考多肽自身,氨基酸残基缺失但其中剩余的氨基酸序列通常与参考多肽的氨基酸序列相同的多肽。此类缺失可能发生在参考多肽的氨基末端或羧基末端,或二者皆有。片段通常为至少约5、6、8或10个氨基酸长,至少约14个氨基酸长,至少约20、30、40或50个氨基酸长,至少约75个氨基酸长,或至少约100、150、200、300、500个或更多个氨基酸长。片段可保留参考多肽的生物活性中的一个或多个。在各种实施例中,片段可包含参考多肽的酶活性和/或相互作用位点。在另一实施例中,片段可具有免疫原性特性。
术语“蛋白结构域”是指蛋白质的一部分、蛋白质的部分或显示结构完整性的整个蛋白质;此测定可基于蛋白质的一部分、蛋白质的部分或整个蛋白质的氨基酸组成。
术语“单链可变片段”或“scFv”是指其中重链结构域和轻链结构域连接的Fv片段。一或多个scFv片段可以连接至其它抗体片段(例如重链或轻链的恒定结构域)以形成具有一或多个抗原识别位点的抗体构建体。
如本文所用,“间隔子”是指接合包含融合蛋白的蛋白质的肽。一般来说,除了接合蛋白质或保留它们之间的一定最小距离或其它空间关系以外,间隔子将不具有特定生物活性。然而,可以选择间隔子的构成氨基酸以对分子的一些特性产生影响,如分子的折叠、净电荷或疏水性。
当指多肽(包括抗体)或受体时,如本文所用的术语“特异性结合”是指决定蛋白质或多肽或受体在蛋白质和其它生物制剂的非均质分子群体中存在的结合反应。因此,在指定条件(例如抗体的情况下的免疫分析条件)下,当特定配位体或抗体并未与样品中存在的其它蛋白质或与所述配位体或抗体在生物体中可能接触的其它蛋白质大量结合时,所述特定配位体或抗体“特异性结合”至其特定“靶”(例如抗体特异性结合至内皮抗原)。一般来说,“特异性结合”第二分子的第一分子具有与第二分子大于约105M-1的亲和力常数(Ka)(例如106M-1、107M-1、108M-1、109M-1、1010M-1、1011M-1和1012M-1或更大)。
如本文所用,术语“特异性递送”是指分子与携有特定靶分子或标记的细胞或组织的优先结合,而不与不具有所述靶分子的细胞或组织的优先结合。当然,认识到分子与非靶细胞或组织之间可存在某种程度的非特异性相互相用。然而,特异性递送可通过靶分子的特异性识别来介导而区分。通常特异性递送促使所递送的分子与携有靶分子的细胞之间的结合比所传递的分子与不具有靶分子的细胞之间的结合强得多。
术语“受试者”是指为施用或治疗的目标的任何个体。受试者可以是脊椎动物,例如哺乳动物。因此,受试者可以是人类或家畜患者。术语“患者”是指在临床医生(例如医师)的治疗下的受试者。
术语“治疗有效”是指所使用的组合物的量是足以改善疾病或病症的一或多种起因或症状的量。这种改善仅需要降低或改变,不必消除。
术语“转化”和“转染”意指将核酸(例如表达载体)引入至接受者细胞中,包括将核酸引入至所述细胞的染色体DNA中。
术语“治疗”是指以治愈、改善、稳定或预防疾病、病理性病状或病症为意图而对患者进行医学管理。这一术语包括积极治疗,即专门为了改善疾病、病理性病状或病症而进行的治疗,并且还包括病因治疗,即专门为了去除相关疾病、病理性病状或病症的原因而进行的治疗。另外,此术语包括姑息性治疗,即设计用于缓解症状而非治愈疾病、病理性病状或病症的治疗;预防性治疗,即针对最小化或部分或完全抑制相关疾病、病理性病状或病症的发展的治疗;以及支持性治疗,即用于补充针对相关疾病、病理性病状或病症的改善的另一种特异性疗法的治疗。
术语“变异体”是指具有保守性氨基酸取代、非保守性氨基酸取代(即简并变异体)、编码氨基酸的每个密码子(即DNA和RNA)的摆动位置内的取代、添加到肽的C末端的氨基酸的氨基酸序列或肽序列;或与参考序列具有60%、70%、80%、90%、95%、96%、97%、98%、99%序列一致性的肽。
术语“载体”是指能够将载体序列所连接的另一核酸运输至细胞中的核酸序列。术语“表达载体”包括任何载体(例如质粒、粘粒或噬菌体染色体),其含有适合于由细胞表达的形式的基因构建体(例如连接至转录控制元件)。
本文公开选择性地结合癌细胞上的人类SSTR2的单克隆抗体。本文还公开可以特异性地识别表达SSTR2的癌症(如NE癌)的重组抗体。
可以用于所公开的组合物和方法中的抗体包括任何类别的全免疫球蛋白(即,完整抗体)、其片段和至少含有抗体的抗原结合可变结构域的合成蛋白质。抗体之间的可变结构域序列不同且可变结构域被用于每种特定抗体对其特定抗原的结合和特异性。然而,变异性通常不是均匀分布在抗体的可变结构域中的。它通常集中在轻链和重链可变结构域中三个称为互补决定区(complementarity determining region,CDR)或高变区的区段中。可变结构域的更高度保守的部分称为构架(FR)。天然重链和轻链的可变结构域各自包含四个大部分采用β片层构型的FR区,所述FR区通过三个CDR连接,从而形成环,所述环连接β片层结构并且在一些情况下形成β片层结构的一部分。每条链中的CDR通过FR区紧密靠近地保持在一起,并且与来自另一条链的CDR一起有助于形成抗体的抗原结合位点。
可以采用在免疫后能够在无内源免疫球蛋白产生存在下产生完全人类抗体库的转基因动物(例如小鼠)。例如,已描述嵌合和种系突变小鼠中抗体重链接合区(J(H))基因的纯合缺失导致内源性抗体产生的完全抑制。在此类种系突变小鼠中人类种系免疫球蛋白基因阵列的转移将在抗原攻击时导致人类抗体产生(参见例如Jakobovits等人,美国国家科学院院刊,90:2551-255(1993);Jakobovits等人,自然(nature),362:255-258(1993);Bruggemann等人,免疫学年鉴(Year in Immunol.),7:33(1993))。人类抗体还可以在噬菌体呈现库中产生(Hoogenboom等人,分子生物学杂志(J.Mol.Biol.),227:381(1991);Marks等人,分子生物学杂志,222:581(1991))。Cote等人和Boerner等人的技术也可用于制备人类单克隆抗体(Cole等人,单克隆抗体和癌症治疗(Monoclonal Antibodies and CancerTherapy),Alan R.Liss,第77页(1985);Boerner等人,免疫学杂志(J.Immunol.),147(1):86-95(1991))。
任选地,抗体在其它物种中产生并且“人源化”用于在人类中施用。非人类(例如鼠)抗体的人源化形式为含有来源于非人类免疫球蛋白的最小序列的嵌合免疫球蛋白、免疫球蛋白链或其片段(如Fv、Fab、Fab'、F(ab')2或抗体的其它抗原结合子序列)。人源化抗体包括人类免疫球蛋白(接受体抗体),其中来自接受体抗体的互补决定区(CDR)的残基被具有所需特异性、亲和力和能力的来自非人类物种(供体抗体)(如小鼠、大鼠或兔)的CDR的残基置换。在一些情况下,人类免疫球蛋白的Fv构架残基被相应非人类残基置换。人源化抗体还可包含在接受体抗体中和在所输入的CDR或构架序列中都不存在的残基。一般来说,人源化抗体将包含实质上所有的至少一个并且通常两个可变结构域,其中所有或实质上所有的CDR区对应于非人类免疫球蛋白的CDR区并且所有或实质上所有的FR区是人类免疫球蛋白共有序列的FR区。人源化抗体最佳还将包含免疫球蛋白恒定区(Fc),通常是人类免疫球蛋白的恒定区的至少一部分(Jones等人,自然,321:522-525(1986);Riechmann等人,自然,332:323-327(1988);和Presta,现代结构生物学评(Curr.Op.Struct.Biol.),2:593-596(1992))。
人源化非人类抗体的方法为所属领域中众所周知的。一般来说,人源化抗体具有一或多个从非人类来源引入到其中的氨基酸残基。这些非人类氨基酸残基常常被称为“输入(import)”残基,其通常取自“输入”可变结构域。抗体人源化技术通常涉及使用重组DNA技术来操纵编码抗体分子的一或多条多肽链的DNA序列。人源化可以按照Winter和合作者的方法通过用啮齿动物CDR或CDR序列取代相应人类抗体序列来进行(Jones等人,自然,321:522-525(1986);Riechmann等人,自然,332:323-327(1988);Verhoeyen等人,科学(Science),239:1534-1536(1988))。因此,非人类抗体(或其片段)的人源化形式为嵌合抗体或片段(美国专利低4,816,567),其中实质上小于完整人类可变结构域被来自非人类物种的相应序列取代。实际上,人源化抗体通常是一些CDR残基和可能一些FR残基被来自啮齿动物抗体中的类似位点的残基取代的人类抗体。
还公开具有生物活性的抗体的片段。片段无论是否与其它序列连接,都可以包括特定区域或特定氨基酸残基的插入、缺失、取代或所选择的其它修饰,其条件是与未修饰的抗体或抗体片段相比,所述片段的活性不会显著改变或受损。
技术还可以适合于产生对本公开的抗原蛋白具有特异性的单链抗体。单链抗体的产生方法为所属领域的技术人员众所周知的。可以通过使用短肽接头使重链和轻链的可变结构域融合在一起来产生单链抗体,从而在单个分子上重构抗原结合位点。已开发如下单链抗体可变片段(scFv):其中一个可变结构域的C末端通过15至25个氨基酸肽或接头系栓至其它可变结构域的N末端而不显著破坏抗原结合或结合的特异性。接头经过选择以使重链和轻链能以其适当的构象取向结合在一起。
还公开一种药物组合物,其包含药学上可接受的载剂中所公开的抗体。药物载剂为所属领域技术人员已知。这些载剂最通常将为用于将药物施用于人类的标准载剂,包括溶液,如无菌水、生理盐水和在生理pH下的缓冲溶液。例如,合适载剂和其配制物描述于雷明顿:医药科学和实践(Remington:The Science and Practice of Pharmacy)(21版),PP.Gerbino编,宾夕法尼亚州费城的利平科特威廉姆斯和维尔金斯出版社(LippincottWilliams&Wilkins,Philadelphia,PA.)2005。通常,适当量的药学上可接受的盐用于配制物中以使配制物等张。药学上可接受的载剂的实例包括但不限于:生理盐水、林格氏溶液(Ringer's solution)和右旋糖溶液。溶液的pH值优选为约5至约8,并且更优选为约7至约7.5。溶液应不含RNA酶。其它载剂包括持续释放制剂,如含有抗体的固体疏水性聚合物的半渗透基质,所述基质呈成形物品形式,例如薄膜、脂质体或微米粒子。所属领域的技术人员将显而易见,取决于例如施用途径和施用的组合物的浓度,某些载剂可更优选。
药物组合物除所选分子外还可包括载剂、增稠剂、稀释剂、缓冲剂、防腐剂、表面活性剂等。药物组合物还可包括一或多种活性成分,例如抗微生物剂、消炎剂、麻醉剂等。
肠胃外施用的制剂包括无菌水性或非水性溶液、悬浮液和乳液。非水性溶剂的实例为丙二醇、聚乙二醇、植物油(如橄榄油),和可注射有机酯(如油酸乙酯)。水性载剂包括水、醇性/水性溶液、乳液或悬浮液、包括生理盐水和缓冲介质。肠胃外运载体包括氯化钠溶液、林格氏右旋糖、右旋糖和氯化钠、乳酸林格氏溶液或不挥发性油。静脉内运载体包括流体和营养补充剂、电解质补充剂(例如基于林格氏右旋糖的补充剂)等。还可以存在防腐剂和其它添加剂,例如抗微生物剂、抗氧化剂、螯合剂和惰性气体等。
一些组合物可能呈药学上可接受的酸加成盐或碱加成盐形式施用,所述酸加成盐或碱加成盐是通过与以下酸反应形成:无机酸,如盐酸、氢溴酸、过氯酸、硝酸、硫氰酸、硫酸和磷酸;和有机酸,如甲酸、乙酸、丙酸、乙醇酸、乳酸、丙酮酸、草酸、丙二酸、琥珀酸、顺丁烯二酸和反丁烯二酸;或通过与以下碱反应形成:无机碱,如氢氧化钠、氢氧化铵、氢氧化钾;和有机碱,如单烷基胺、二烷基、三烷基胺和芳基胺以及被取代的乙醇胺。
还公开编码所公开的SSTR2特异性抗体的多核苷酸和多核苷酸载体。编码所公开的抗体和其区域的核酸序列可使用所属领域中已知的重组方法来获得,例如使用标准技术通过从表达基因的细胞中筛选文库;通过由已知的包括所述基因的载体衍生基因;或通过与含有所述基因的细胞和组织直接分离。可替代地,所关注基因可以合成而非克隆的方式产生。
编码抗体的核酸的表达通常通过将编码所述抗体的核酸可操作地连接至启动子并且将所述构建体并入表达载体中来实现。典型的克隆载体含有转录与翻译终止子、起始序列和适用于调节所需核酸序列表达的启动子。
所公开的核酸可以克隆到许多类型的载体中。例如,可将核酸克隆到载体中,所述载体包括但不限于质粒、噬菌粒、噬菌体衍生物、动物病毒和粘粒。备受关注的载体包括表达载体、复制载体、探针产生载体和测序载体。
此外,可按病毒载体的形式,将表达载体提供给细胞。病毒载体技术在所属领域中为众所周知的,并且描述于例如Sambrook等人(2001,分子克隆:实验指南(MolecularCloning:A Laboratory Manual),纽约冷泉港实验室(Cold Spring Harbor Laboratory,New York))中,和其它病毒学和分子生物学手册中。作为载体是有用的病毒包括但不限于逆转录病毒、腺病毒、腺相关病毒、疱疹病毒和慢病毒。一般来说,适合的载体含有至少一种生物体中作用的复制起点、启动子序列、适宜的限制性核酸内切酶位点和一或多种可选标记。在一些实施例中,多核苷酸载体为慢病毒或逆转录病毒载体。
已经开发了许多基于病毒的系统,用于将基因转移至哺乳动物细胞中。例如,逆转录病毒为基因递送系统提供方便的平台。所选择的基因可以插入到载体中且使用所属领域中已知的技术将其包装于逆转录病毒粒子中。然后重组病毒可以分离并且体内或离体递送至受试者的细胞。
合适的启动子的一个实例为立即早期巨细胞病毒(CMV)启动子序列。此启动子序列为强组成型启动子序列,能够驱动与其可操作连接的任何多核苷酸序列的高水平表达。合适的启动子的另一实例为延伸生长因子-1α(EF-1α)。然而,还可使用其它组成型启动子序列,包括但不限于猿猴病毒40(SV40)早期启动子、小鼠乳腺肿瘤病毒(MMTV)、人类免疫缺陷病毒(HIV)长末端重复序列(LTR)启动子、MoMuLV启动子、禽类白血病病毒启动子、埃-巴二氏病毒(Epstein-Barr virus)立即早期启动子、劳氏肉瘤病毒(Rous sarcoma virus)启动子、以及人类基因启动子,如但不限于肌动蛋白启动子、肌球蛋白启动子、血红蛋白启动子和肌酸激酶启动子。可替代地,启动子可为诱导型启动子。诱导型启动子的实例包括但不限于金属硫蛋白启动子、糖皮质激素启动子、孕酮启动子和四环素启动子。
额外启动子元件(例如增强子)调节转录起始的频率。通常,这些元件位于起始位点上游30-110bp的区域,尽管最近已显示许多启动子也含有起始位点下游的功能元件。启动子元件之间的间距通常是灵活的,使得当元件相对于彼此倒置或移动时,启动子功能得以保留。
为了评估抗体或其部分的表达,待引入细胞中的表达载体还可含有可选标志基因或报告基因,或两者,以促进从寻求通过病毒载体转染或感染的细胞群中识别和选择表达细胞。在其它方面,可选标记可携带在单独的DNA片段上且用于共转染程序。可选标记和报告基因两者均可侧接有适当的调节序列,以使得能够在宿主细胞中表达。适用的可选标记包括例如抗生素抗性基因。
报告基因用于识别潜在转染的细胞和评估调节序列的功能。一般来说,报告基因为不存在于接受体生物体或组织中或不由其表达的基因,且编码通过一些易于检测的特性(例如酶活性)来体现表达的多肽。在DNA已引入至接受体细胞之后的合适时间分析报告基因的表达。合适的报告基因可包括编码荧光素酶、β-半乳糖苷酶、氯霉素乙酰转移酶、分泌型碱性磷酸酶的基因或绿色荧光蛋白质基因。合适的表达系统为众所周知的且可使用已知技术制备或商业上获得。一般来说,将具有最小5'侧接区,显示最高水平的报告基因表达的构建体识别为启动子。这类启动子区可与报告基因连接且用于评估药剂用于调节启动子驱动的转录的能力。
将基因引入和表达至细胞中的方法为所属领域中已知的。在表达载体的情形下,载体可以通过所属领域中的任何方法容易地引入至宿主细胞,例如哺乳动物、细菌、酵母或昆虫细胞中。例如,表达载体可以通过物理、化学或生物方式转移至宿主细胞中。
将多核苷酸引入至宿主细胞中的物理方法包括磷酸钙沉淀、脂质体转染、粒子轰击、显微注射、电穿孔等。用于产生包含载体和/或外源性核酸的细胞的方法在所属领域中众所周知。参见例如,Sambrook等人(2001,分子克隆:实验指南,纽约冷泉港实验室)。
用于将所关注的多核苷酸引入至宿主细胞中的生物方法包括使用DNA和RNA载体。病毒载体,且尤其逆转录病毒载体已成为将基因插入哺乳动物(例如人类细胞)中最广泛使用的方法。
用于将多核苷酸引入至宿主细胞中的化学方式包括胶体分散系统,如大分子复合物、纳米胶囊、微球、珠粒和基于脂质的系统,包括水包油乳液、胶束、混合胶束和脂质体。适用作体外和体内递送运载体的例示性胶状系统为脂质体(例如人工膜囊泡)。
在利用非病毒递送系统的情况下,例示性递送运载体为脂质体。在另一方面,核酸可与脂质结合。与脂质结合的核酸可以囊封在脂质体的水性内部中、散布在脂质体的脂质双层内、经由与脂质体和寡核苷酸两者结合的连接分子连接至脂质体、包覆在脂质体中、与脂质体复合、分散在含有脂质的溶液中、与脂质混合、与脂质组合、以脂质的悬浮液形式包含在内、含有胶束或与胶束复合、或以其它方式与脂质结合。脂质、脂质/DNA或脂质/表达载体相关组合物不限于溶液中的任何特定结构。例如,其可存在于双层结构如胶束中,或以“折叠”结构存在。其还可简单地散布在溶液中,可能形成大小或形状不均匀的聚集物。脂质为脂肪物质,其可以是天然存在的或合成脂质。例如,脂质包括天然存在于细胞质中的脂肪滴以及含有长链脂肪族烃和其衍生物的化合物类别,如脂肪酸、醇、胺、氨基醇和醛。适合使用的脂质可从商业来源获得。例如,二肉豆蔻基磷脂酰胆碱(“DMPC”)可从密苏里州圣路易斯的西格玛获得(Sigma,St.Louis,Mo.);磷酸二鲸蜡酯(“DCP”)可从纽约州的普莱恩维尤的K&K实验室(K&K Laboratories,Plainview,N.Y.)获得;胆固醇(“Choi”)可从卡尔贝林生物化学公司(Calbiochem Behring)获得;二肉豆蔻基磷脂酰甘油(“DMPG”)和其它脂质可从阿拉巴马州伯明翰的阿万蒂极性脂质公司(Avanti Polar Lipids,Inc,Birmingham,Ala.)获得。
还公开一种通过向受试者施用治疗有效量的所公开的药物组合物来治疗个体中的表达SSTR2的癌症的方法。所公开的组合物,包括药物组合物,可以用多种方式施用,取决于是否需要局部或全身性治疗和取决于待治疗的区域。例如,所公开的组合物可静脉内、腹膜内、肌肉内、皮下、腔内或经皮施用。组合物可以经口、经肠胃外(例如静脉内)、通过肌肉内注射、通过腹膜内注射、经皮、体外、经眼、经阴道、经直肠、鼻内、局部等施用,包括局部鼻内施用或通过吸入器施用。
如果使用,肠胃外施用组合物的特征通常为注射。可注射剂可以以常规形式作为液体溶液或悬浮液、作为适合于在注射之前形成溶液或液体中悬浮液的固体、或作为乳液制备。修改的肠胃外施用方法涉及使用缓慢释放或持续释放系统使得恒定剂量被维持。
本文中所公开的组合物可以预防性地施用于处于罹患表达SSTR2癌症风险下的患者或受试者。因此,所述方法可进一步包含在施用本文所公开的组合物之前识别处于表达SSTR2癌症风险下的受试者。
所需的组合物的准确量将随各受试者而变化,取决于受试者的物种、年龄、体重和一般病状、所治疗的过敏性病症的严重程度、所使用的具体核酸或载体、其施用模式等等。因此,不可能限定每种组合物的准确量。然而,所属领域的一般技术人员可以仅使用本文中的教示提供的常规实验来确定适当量。例如,用于施用组合物的有效剂量和时程可以凭经验确定,且进行这类测定在所属领域的技术范围内。用于施用组合物的剂量范围为足以产生影响症状病症的所要作用的那些剂量范围。剂量应不大到引起不良副作用,如非所需交叉反应、过敏性反应等。一般来说,剂量将随着年龄、病状、性别和患者疾病的程度、施用的途径,或其它药物是否包括在疗程中变化,并且可由所属领域的技术人员确定。在任何反向指示的情况下,个别医生可调节剂量。剂量可以变化,并且可以每天一或多次施用剂量进行施用,持续一天或若干天。可以在文献中找到针对给定类别的药物产品的适当剂量的指导。单独使用的所公开的组合物的典型每日剂量可以在每天约1μg/kg至多达100mg/kg体重范围内,取决于上文提及的因素。
在一些实施例中,以相当于肠胃外施用约0.1ng至约100g每公斤体重、约10ng至约50g每公斤体重、约100ng至约1g每公斤体重、约1μg至约100mg每公斤体重、约1μg至约50mg每公斤体重、约1mg至约500mg每公斤体重;且约1mg至约50mg每公斤体重的剂量来施用分子。可替代地,所施用以实现治疗有效剂量的含有来那度胺(lenalidomide)的分子的量为约0.1ng、1ng、10ng、100ng、1μg、10μg、100μg、1mg、2mg、3mg、4mg、5mg、6mg、7mg、8mg、9mg、10mg、11mg、12mg、13mg、14mg、15mg、16mg、17mg、18mg、19mg、20mg、30mg、40mg、50mg、60mg、70mg、80mg、90mg、100mg、500mg每公斤体重或更高。
所公开的抗体可以单独施用或以与稀释剂和/或其它组分(例如IL-2、IL-15或其它细胞因子或细胞群体)组合的药物组合物形式施用。简单地说,药物组合物可包含如本文所述的靶细胞群体,以及一或多种药学上或生理学上可接受的载体、稀释剂或赋形剂。这种组合物可以包含缓冲剂,如中性缓冲生理盐水、磷酸盐缓冲盐水等;碳水化合物,如葡萄糖、甘露糖、蔗糖或聚葡聚糖,甘露醇;蛋白质;多肽或氨基酸,如甘氨酸;抗氧化剂;螯合剂,如EDTA或谷胱甘肽;佐剂(例如,氢氧化铝);和防腐剂。在一些实施例中,用于所公开的方法的组合物被调配用于静脉内施用。药物组合物可以任何适当治疗MM的方式施用。施用的量和频率由例如患者的病状和患者疾病的严重程度等因素决定,但适当剂量可以通过临床试验确定。
所公开的组合物的施用可以任何适宜方式进行,包括通过注射、输注或植入进行。本文所述的组合物可以皮下、皮内、瘤内、结节内、髓内、肌肉内、通过静脉内(i.v.)注射或腹膜内向患者施用。在一些实施例中,通过皮内或皮下注射向患者施用所公开的组合物。在一些实施例中,所公开的组合物通过静脉内注射施用。组合物还可直接注射至肿瘤、淋巴结或感染部位处。
在某些实施例中,所公开的抗体与任何数目的相关治疗模式结合(例如在其之前、同时或之后)向患者施用,所述治疗模式包括但不限于沙立度胺(thalidomide)、地塞米松(dexamethasone)、硼替佐米(bortezomib)和来那度胺。在另外的实施例中,所公开的抗体可与化疗、放射、免疫抑制剂(如环孢素、硫唑嘌呤、氨甲蝶呤、霉酚酸酯和FK506)、抗体或其它免疫消融剂(如CAM PATH)、抗CD3抗体或其它抗体治疗、细胞毒素(cytoxin)、氟达拉滨(fludaribine)、环孢素(cyclosporin)、FK506、雷帕霉素(rapamycin)、霉酚酸、类固醇、FR901228、细胞因子和辐射组合使用。在一些实施例中,所公开的抗体与下述结合(例如在其之前、同时或之后)向患者施用:骨髓移植、使用化疗剂(如氟达拉滨)、外部光束放疗(XRT)、环磷酰胺或抗体(如OKT3或CAMPATH)的T细胞消融疗法。在另一实施例中,本发明的细胞组合物在B细胞消融疗法,如与CD20反应的药剂,例如美罗华(Rituxan)之后施用。例如,在一些实施例中,受试者可经历伴随大剂量化疗的标准治疗,继之以周边血液干细胞移植。在某些实施例中,在移植之后,受试者接受本发明的扩增免疫细胞的输注。在额外实施例中,扩增细胞在手术之前或之后施用。
所公开的方法的癌症可以是受试者中经历不受调控生长、侵袭或癌转移的表达SSTR2的细胞。在一些实施例中,表达SSTR2的癌症为神经内分泌(NE)癌。神经内分泌肿瘤(NETs)为由内分泌(激素)和神经系统的细胞产生的赘瘤。许多为良性的,而一些则为恶性的。传统上,神经内分泌肿瘤已经通过其来源的解剖部位分类。在身体的许多不同区域中可产生NET。其最通常在肠道中出现,其中其通常被称为类癌肿瘤,但其也发现于胰腺、肺和身体的其余部分中。NETs包括胃肠道和胰岛细胞的某些肿瘤、某些胸腺和肺肿瘤以及甲状腺滤泡旁细胞的髓质癌。
在一些实施例中,所公开的抗体可以与检查点抑制剂组合使用。两种已知抑制检查点路径涉及通过细胞毒性T淋巴细胞抗原-4(CTLA-4)和程序性死亡1(PD-1)受体的信号传导。这些蛋白质为在T细胞功能的所有阶段中发挥重要作用的协同信号传导分子的CD28-B7家族的成员。PD-1受体(也称为CD279)在活化T细胞的表面上表达。其配位体PD-L1(B7-H1;CD274)和PD-L2(B7-DC;CD273)在APC(如树突状细胞或巨噬细胞)的表面上表达。PD-L1是主要配位体,而PD-L2具有更多限制的表达模式。当配位体结合至PD-1时,抑制性信号传输至T细胞中,这降低细胞因子产生且抑制T细胞增殖。检查点抑制剂包括但不限于阻断阻断PD-1的抗体(纳武单抗(Nivolumab)(BMS-936558或MDX1106)、CT-011、MK-3475)、PD-L1(MDX-1105(BMS-936559)、MPDL3280A、MSB0010718C)、PD-L2(rHIgM12B7)、CTLA-4(伊匹单抗(Ipilimumab)(MDX-010)、曲美单抗(Tremelimumab)(CP-675,206))、IDO、B7-H3(MGA271)、B7-H4、TIM3、LAG-3(BMS-986016)。
针对程序性死亡1(PD-1)的人类单克隆抗体和单独使用抗PD-1抗体或与其它免疫治疗组合治疗癌症的方法描述于美国专利第8,008,449号中,其并入作为这些抗体的参考。抗PD-L1抗体和其用途描述于美国专利第8,552,154号中,其并入作为这些抗体的参考。包含抗PD-1抗体或抗PD-L1抗体的抗癌剂描述于美国专利第8,617,546号中,其并入作为这些抗体的参考。
在一些实施例中,PDL1抑制剂包含特异性结合PDL1的抗体,如BMS-936559(百时美施贵宝(Bristol-Myers Squibb))或MPDL3280A(罗氏(Roche))。在一些实施例中,PD1抑制剂包含特异性结合PD1的抗体,如拉立珠单抗(默克(Merck))、纳武单抗(百时美施贵宝)或MEDI4736(阿斯利康公司(AstraZeneca))。针对PD-1的人类单克隆抗体和单独使用抗PD-1抗体或与其它免疫治治疗组合治疗癌症的方法描述于美国专利第8,008,449号中,其并入作为这些抗体的参考。抗PD-L1抗体和其用途描述于美国专利第8,552,154号中,其并入作为这些抗体的参考。包含抗PD-1抗体或抗PD-L1抗体的抗癌剂描述于美国专利第8,617,546号中,其并入作为这些抗体的参考。
所公开的抗体可以与其它癌症免疫治疗组合使用。存在两种不同类型的免疫治疗:被动免疫治疗使用免疫系统的组分来引导针对癌细胞的靶向细胞毒性活性,而不一定引发患者的免疫反应,而主动免疫治疗则主动地触发内源性免疫反应。被动策略包括使用由B细胞响应于特定抗原而产生的单克隆抗体(mAb)。1970年代杂交瘤技术的发展和肿瘤特异性抗原的鉴别允许mAbs的药物开发,所述mAbs可特异性地靶向肿瘤细胞以被免疫系统破坏。到目前为止,mAbs已经成为免疫治疗中最成功的案例;2012年中最畅销的前三种抗癌药物为mAbs。其中一种为利妥昔单抗(rituximab)(美罗华,基因泰克公司(Genentech)),其结合至在B细胞恶性肿瘤的表面上高度表达的CD20蛋白质,所述B细胞恶性肿瘤如非霍奇金淋巴瘤(non-Hodgkin's lymphoma,NHL)。利妥昔单抗经FDA批准与化疗组合用于治疗NHL和慢性淋巴细胞性白血病(CLL)。另一重要mAb为曲妥珠单抗(trastuzumab)(赫赛汀(Herceptin);基因泰克公司),其通过靶向HER2的表达来彻底改变HER2(人类表皮生长因子受体2)阳性乳癌的治疗。
产生最优“杀伤”CD8 T细胞反应还需要T细胞受体活化加共刺激,其可以通过肿瘤坏死因子受体家族成员的连接来提供,所述肿瘤坏死因子受体家族成员包括OX40(CD134)和4-1BB(CD137)。OX40备受关注,因与活化(促效剂)抗OX40 mAb治疗增强了T细胞分化和细胞溶解功能,这引起增强的针对多种肿瘤的抗肿瘤免疫性。
在一些实施例中,此类额外治疗剂可以选自抗代谢物,如氨甲蝶呤、6-巯基嘌呤、6-硫鸟嘌呤、阿糖胞苷、氟达拉宾、5-氟尿嘧啶、达卡巴嗪(dacarbazine)、羟基脲、天冬酰胺酶、吉西他滨或克拉瑞滨。
在一些实施例中,此类额外治疗剂可以选自烷基化剂,如氮芥、塞替派(thioepa)、苯丁酸氮芥、美法仑、卡莫司汀(BSNU)、洛莫司汀(lomustine)(CCNU)、环磷酰胺、白消安、二溴甘露醇、链脲佐菌素、达卡巴嗪(DTIC)、丙卡巴肼、丝裂霉素C、顺铂和其它铂衍生物,如卡铂。
在一些实施例中,此类额外治疗剂可以选自抗有丝分裂剂,如紫杉烷(例如多西他赛)和紫杉醇;和长春花生物碱,例如长春地辛、长春新碱、长春碱和长春瑞滨。
在一些实施例中,此类额外治疗剂可以选自拓扑异构酶抑制剂,如拓扑替康或伊立替康;或细胞生长抑制药物,如依托泊苷和替尼泊苷。
在一些实施例中,此类额外治疗剂可以选自生长因子抑制剂,如ErbBl(EGFR)的抑制剂(如EGFR抗体,例如扎芦木单抗(zalutumumab)、西妥昔单抗(cetuximab)、帕尼单抗(panitumumab)或尼妥珠单抗(nimotuzumab)或其它EGFR抑制剂,如吉非替尼(gefitinib)或厄洛替尼(erlotinib))、ErbB2的另一种抑制剂(HER2/neu)(如HER2抗体,例如曲妥珠单抗、曲妥珠单抗-DM l或帕妥珠单抗(pertuzumab))或EGFR和HER2两者的抑制剂,如拉帕替尼(lapatinib))。
在一些实施例中,此类额外治疗剂可以选自酪氨酸激酶抑制剂,如伊马替尼(imatinib)(Glivec,Gleevec STI571)或拉帕替尼。
因此,在一些实施例中,所公开的抗体与以下各者组合使用:奥法木单抗(ofatumumab)、扎木单抗(zanolimumab)、达雷木单抗(daratumumab)、雷珠单抗(ranibizumab)、尼妥珠单抗、帕尼单抗、Hu806、达克珠单抗(daclizumab)(Zenapax)、巴利昔单抗(basiliximab)(Simulect)、英利昔单抗(infliximab)(Remicade)、阿达木单抗(adalimumab)(Humira)、那他珠单抗(natalizumab)(Tysabri)、奥马珠单抗(omalizumab)(Xolair)、依法利珠单抗(efalizumab)(Raptiva)和/或利妥昔单抗。
在一些实施例中,与用于治疗如上文所描述的病症的所公开的抗体组合使用的治疗剂可以是抗癌细胞因子、趋化因子或其组合。合适的细胞因子和生长因子的实例包括IFNy、IL-2、IL-4、IL-6、IL-7、IL-10、IL-12、IL-13、IL-15、IL-18、IL-23、IL-24、IL-27、IL-28a、IL-28b、IL-29、KGF、IFNa(例如INFa2b)、IFN、GM-CSF、CD40L、Flt3配位体、干细胞因子、安塞司亭(ancestim)和TNFa。合适的趋化因子可包括Glu-Leu-Arg(ELR)-负趋化因子,如来自人类CXC和C-C趋化因子家族的IP-10、MCP-3、MIG和SDF-la。合适的细胞因子包括细胞因子衍生物、细胞因子变异体、细胞因子片段和细胞因子融合蛋白。
在一些实施例中,与用于治疗如上文所描述的病症的所公开的抗体组合使用的治疗剂可以是细胞周期控制/细胞凋亡调节剂(或“调节剂(regulating agent)”)。细胞周期控制/细胞凋亡调节剂可以包括靶向和调节细胞周期控制/细胞凋亡调节剂的分子,如(i)cdc-25(如NSC663284)、(ii)过度刺激细胞周期的细胞周期蛋白依赖性激酶(如夫拉平度(flavopiridol)(L868275、HMR1275)、7-羟基星形孢菌素(UCN-01,KW-2401)和罗斯维汀(roscovitine)(R-roscovitine,CYC202)))和(iii)端粒酶调节剂(如BIBR1532、SOT-095、GRN163和例如描述于US6,440,735和US 6,713,055中的组合物)。干扰细胞凋亡路径的分子的非限制性实例包括TNF相关细胞凋亡诱导配位体(TRAIL)/细胞凋亡-2配位体(Apo-2L)、活化TRAIL受体的抗体、IFN和反义Bcl-2。
在一些实施例中,与用于治疗如上文所描述的病症的所公开的抗体组合使用的治疗剂可以是激素调节剂,如适用于抗雄激素和抗雌激素治疗的药剂。此类激素调节剂的实例为他莫昔芬(tamoxifen)、艾多昔芬(idoxifene)、氟维司群(fulvestrant)、屈洛昔芬(droloxifene)、托瑞米芬(toremifene)、雷洛昔芬(raloxifene)、己烯雌酚(diethylstilbestrol)、炔雌醇(ethinyl estradiol/estinyl)、抗雄激素(antiandrogen)(如氟他胺(flutaminde/eulexin))、孕酮(progestin)(如己酸羟孕酮(hydroxyprogesterone caproate)、甲羟孕酮(medroxy-progesterone/provera)、醋酸甲地孕酮(megestrol acetate/megace)、肾上腺皮质类固醇(如氢化可的松(hydrocortisone)、泼尼松(prednisone))、促黄体激素释放激素(和其类似物和其它LHRH激动剂,如布舍瑞林(buserelin)和戈舍瑞林(goserelin))、芳香酶抑制剂(如阿那曲唑(anastrazole/arimidex)、氨鲁米特(aminoglutethimide/cytraden)、依西美坦(exemestane))或激素抑制剂(如奥曲肽(octreotide/sandostatin))。
在一些实施例中,与用于治疗如上文所描述的病症的所公开的抗体组合使用的治疗剂可以是抗癌核酸或抗癌抑制性RNA分子。
如上文所述,组合施用可以同时、单独或依序施用。对于同时施用,药剂可以按需要以一种组合物或以分开的组合物施用。
在一些实施例中,所公开的抗体与放疗组合施用。放疗可包括放射或向患者提供放射性药物的相关施用。放射源可以在所治疗的患者的外部或内部(放射治疗可以例如呈外射束放疗(EBRT)或近接疗法(BT)的形式)。可用于实践此类方法的放射性元素包括例如镭、铯-137、铱-192、镅-241、金-198、钴-57、铜-67、锝-99、碘化物-123、碘化物-131和铟-111。
在一些实施例中,所公开的抗体与手术组合施用。
已描述本发明的多个实施例。然而,应理解,在不脱离本发明的精神和范围的情况下可以进行各种修改。因此,其它实施例在所附权利要求书的范围内。
实例
实例1:总体设计
大部分NE癌过度表达生长抑素受体(SSTR),其中SSTR2亚型主要发现于70-100%的NE肿瘤中的细胞表面上(Pinchot SN等人,肿瘤学家200813(12):1255-6;Zatelli MC等人,临床内分泌学与新陈代谢杂志(J Clin Endocrinol Metab.)200186(5):2161-9;SunLC等人,当代药物递送(Curr Drug Deliv.)20118(1):2-10)。更确切地说,NETs中的SSTR2的表面表达水平比正常细胞中的SSTR2的表面表达水平高约20倍(Pinchot SN等人,肿瘤学家200813(12):1255-6;Zatelli MC等人,临床内分泌学与新陈代谢杂志200186(5):2161-9;Sun LC等人,当代药物递送20118(1):2-10)。因此,抗SSTR2单克隆抗体和抗体药物缀合物(ADC)已被开发作为NE癌靶向治疗剂,所述治疗剂调节肿瘤进展并将细胞毒性剂直接递送至表达SSTR2的NET细胞同时限制全身性毒性(图1)。
已经开发如单克隆抗体(mAb)和ADC的靶向治疗以有效治疗实体肿瘤,同时使对正常细胞的副作用降到最低(24-30),但这些治疗都未应用于治疗NE癌。作为抗癌生物药剂的ADC集成了mAb的优点,其可以特异性结合肿瘤相关的表面受体且调节受体相关的细胞内信号传导路径和小分子化学治疗剂的有效细胞毒性(图1)。mAb能够使得所递送的药物循环通过血流直到其与肿瘤特定表面抗原结合。在结合之后,ADC经由受体介导的内吞作用而被内化,形成晚期内体,发生溶酶体降解,随后细胞毒性药物释放到细胞质中,且此引起癌细胞死亡。
利用所公开的mAb的ADC可以实现NETs中的特异性靶向和高效细胞毒性,同时使全身性毒性降到最低。抗体药物缀合物(ADC)开发为NE癌靶向治疗剂。mAb的高度特异性靶向能力对于改进ADC的临床功效是必不可少的。通过使用纯化的全SSTR2蛋白作为免疫原开发了仅有的市售人类抗SSTR2 mAb,但所述mAb在NET表面上并未显示出与SSTR2的高结合亲和力。使用两种细胞外肽作为抗原开发的所公开的抗SSTR2 mAb在靶向NETs方面更有效。此抗SSTR2mAb的高特异性确保药物的成功递送且能够选择具有高细胞毒性效力的小分子(如MMAE)。尽管MMAE在体外有效,但其需要肿瘤靶向递送以在体内实现具有临床意义的治疗指数。
被开发以模拟人类NE癌中所观测到的肿瘤进展和微环境的创新肝癌转移鼠类模型或NET皮下异种移植物模型,能够实现mAb和ADC的完全表征,且能够通过体内系统验证NE癌对ADC和mAb的反应。偶发性MTC小鼠模型可以用于研究mAb介导的免疫反应(Pozo K等人,癌细胞(Cancer Cell)201324(4):499-511;Pozo K等人,肿瘤标靶(Oncotarget)2015;6(14):12080-93)。
先进的体外和体内成像技术能够直接观测mAb和ADC的特异性靶向和生物分布。使用共聚焦激光扫描显微镜(CLSM)的多色活细胞成像技术能够使得我们在细胞水平上监测用Alexa Fluor 647标记的mAb ADC的特异性结合以及内化和裂解。使用正电子发射断层扫描(PET)设备的动态核成像技术对活体动物体内生物分布和肿瘤特异性靶向进行评估。
实例2:生成特异性靶向NETs的抗体药物缀合物(ADC)。
表面受体识别和评估:转录水平上SSTR2的定量检测到胰腺NET(PanNET)细胞(BON)中的SSTR2表达高于非癌细胞(WI38成纤维细胞)中的SSTR2表达(图2A)。另外,PanNET(BON和QGP)、肺NET(H727)和非癌细胞(917和WI38成纤维细胞)的蛋白质印迹分析证实NE癌中的高SSTR2表达,但在非癌细胞中近乎没有表达(图2B)。使用共聚焦激光扫描显微镜(CLSM)和高亲和力多克隆抗体,我们测定SSTR2在BON细胞、BON异种移植物和PanNET人体组织中的强膜阳性(图2C)。
抗SSTR2 mAb开发:尚无市售抗SSTR2 mAb出于治疗目的来靶向表面SSTR2。为实现与NET细胞的高亲和力和特异性结合,我们使用杂交瘤技术开发且完全评估五种小鼠抗人类SSTR2 mAb,这些mAb分别靶向第2细胞外结构域(cQTEPYYDLTSNA,SEQ ID NO:14)、第4细胞外结构域(c cALVHWPFGKAICRVV,SEQ ID NO:15)或第2细胞外结构域和第4细胞外结构域两者。我们使用基于肽的酶联免疫吸附测定(ELISA)、流式细胞测量术和活细胞CLSM筛选40多个克隆。
重组mAb产生:由于杂交瘤细胞系可能随时间推移而变得不稳定且mAb产率极低,因此对来自杂交瘤的RNA分离物进行测序以测定重链和轻链可变区。使用中国仓鼠卵巢(CHO)细胞来克隆和表达嵌合顶级mAb。在具有精确过程控制的7-L搅拌槽生物反应器中进行具有营养供给的分批进料细胞培养。如我们的先前公开(Xu N等人,生物化学工程杂志(Biochem Eng J.)2017;124:122-9)中所述的恒定过程控制应用至mAb生产,即,温度为37℃且在第3天转变为36℃,pH为6.8,DO为50%,以75rpm搅拌和气体喷射为0.01VVM。
ADC构建:ADC通过将抗体经由再桥接双肽Mc-Val-Cit-PABC-PNP接头与高效抗有丝分裂单甲基奥利他E(MMAE;ADC的模型药物)缀合来产生(Xu N等人,化学科学与工程前沿(Frontiers of Chemical Science&Engineering.)20179(3):376-80;Willuda J等人,分子癌症治疗学(Mol Cancer Ther.)201716(5):893-904;McCombs JR等人,美国制药科学家协会(AAPS J.)201517(2):339-51)。首先,再桥接接头通过在100℃下在20mL乙酸中混合3.91mmol 6-氨基己酸与3.91mmol 3,4-二溴苯呋喃-2,5-二酮18小时来合成,且通过硅胶用二氯甲烷/乙酸乙酯的0-40%洗脱溶液来纯化。其次,通过在0.25mL二氯甲烷中混合13.55μmol N,N'-二异丙基碳化二亚胺、13.55μmol N,N-二异丙基乙胺和33.85μmol,随后添加13.55μmol MMAE来合成再桥连接头-MMAE。在混合16小时之后,接头-MMAE用配备有反相C18柱的沃特世(Waters)HPLC进行纯化,且用安捷伦(Agilent)6500Q-TOF LC/MS来表征。第三,使用原位缀合产生ADC:通过7当量的三(2-羧乙基)膦(TCEP)将5mg/mL mAb还原;同时接头-MMAE与7当量的TCEP反应;且通过G-25凝胶过滤来纯化合成的ADC。
实例3:体外评估ADC的抗NET毒性和机制。
评估mAb的NET特异性靶向和抗NET特性:体内成像系统(IVIS)确认AF488标记的抗SSTR2 mAb特异性靶向源自BON-Luc细胞的NET皮下异种移植物(图3A)。流式细胞测量术分析显示mAb具有与BON细胞极强的表面结合(99.7%)(图3B)。因此,我们的新颖抗SSTR2mAb具有极大的潜力作为以ADC形式的药物递送载剂。蛋白质印迹显示mAb下调PI3K/AKT(细胞增殖)、细胞周期蛋白D1(致癌基因)和p21(细胞周期停滞),且显著降低CgA和ASCL1(NET标记)的表达(图4A)。使用流式细胞测量术,我们分析了我们的SSTR2 mAb对在与mAb培育2天后CD3/CD28刺激的人类CD8+T细胞中细胞因子的表达的影响。如图4B所示,SSTR2 mAb使IL2表达增加1.6倍且使IFNγ增加2.2倍。
评估ADC的抗NET毒性:3天MTT细胞增殖分析显示用原位再桥接构建的ADC不仅保留mAb的结构完整性和生物功能,且对NET细胞具有高细胞毒性,其中对BON的IC50<10nM(图5A)。我们证实MMAE通过微管解聚合抑制NET细胞增殖(图5B),其结果产生尤其在G2/M过渡期的细胞周期停滞和生长中断。
实例4:表征ADC在体内的抗癌功效。
为了建立类似动物模型,将NET细胞皮下注射至裸鼠(即,皮下异种移植物)中,且此模型用于研究ADC的抗癌功效。MTD研究显示,剂量≤20mg/kgBW的mAb-MMAE治疗并未引起体重或存活率的任何显著变化。剂量为8mg/kgBW的抗癌研究显示,与用生理盐水治疗的对照组相比,肿瘤体积减少约60%(图6)。此外,对治疗的小鼠的不同器官(肝、脑、心和腿)的H&E染色切片的病理学评估并未显示任何急性或慢性炎症或细胞凋亡和坏死区域的迹象,表明此治疗对除NET结节外的其它器官是安全的,且正常组织对ADC的潜在脱靶摄取不会造成可检测的损伤。
实例5:用于神经内分泌癌治疗的抗体药物缀合物
神经内分泌(NE)癌包括由内分泌和神经系统产生的多种激素分泌性赘瘤。目前的化疗和放疗的疗效微乎其微。本研究旨在开发一种新颖药物缀合物(ADC)以有效地治疗NE肿瘤(NETs)。
方法
NET患者组织微阵列(TMA)以分析受体表达。组织微阵列是由大学病理学研究中心准备的。患者组织通过机构审查委员会(Institutional Review Board,IRB)批准的方案从大学手术肿瘤库获得。TMA由三十八个胰腺神经内分泌患者组织核心和五个阴性对照核心组成,所述阴性对照核心包括来自肝脏、脾脏、胎盘、前列腺和扁桃体的组织。所有组织均为石蜡包埋的。
用以分析SSTR2分布的多个人体器官正常组织阵列。33个器官组织微阵列载玻片(目录号:FDA662a)购自马里兰州罗克维尔的美国生物底物公司(US Biomax,Rockville,MD)。进行IHC染色(程序在以下章节中详细描述)以分析这些器官中的细胞表面SSTR2表达。33个器官为大脑、小脑、外周神经、肾上腺、甲状腺、脾脏、胸腺、骨髓、淋巴结、扁桃体、胰腺、肝、食道、胃、小肠、结肠、肺、唾液、咽、肾、膀胱、睾丸、前列腺、阴茎、卵巢、输卵管、乳腺、子宫内膜、子宫颈、心肌、骨骼肌、间皮和皮肤。作为阳性对照,还在相同条件下使用我们开发的抗SSTR2 mAb对NET患者组织进行染色。
NET细胞系和接种培养物。多种人类NET细胞系用于体外或体内研究,包括BON-1(胰腺NET)、QGP-1(胰腺NET)、携带萤火虫荧光素酶报告基因的BON-1细胞系(BON-Luc)、MZ-CRC-1(甲状腺NET)和TT(甲状腺NET)。BON-1和MZ-CRC-1细胞系维持在补充有10%胎牛血清(FBS)和4mM L-谷氨酰胺的DMEM/F12基础培养基中;TT细胞系维持在补充有20%FBS和4mML-谷氨酰胺的RPMI-1640中。包括WI-38(肺成纤维细胞)和917(包皮成纤维细胞)的非癌性阴性对照细胞系维持于补充有10%FBS、1%非必需氨基酸和1%丙酮酸钠的MEM-E培养基中。所有细胞系在T25或T75烧瓶中在37℃和5%CO2下在湿气培育箱(Caron,Marietta,OH)中培育。使用Countess II自动化细胞计数器或锥虫兰(Trypan Blue)(马萨诸塞州沃尔瑟姆的赛默飞世尔科技(Thermo Fisher Scientific,Waltham,MA))测量细胞生长,即活细胞密度(VCD)和存活率。除非另外指明,本研究中所用的所有基础培养基、补充剂和试剂均购自赛默飞世尔科技或生命技术公司(飞世尔公司的部分)。
杂交瘤细胞系和接种培养物。产生抗SSTR2 mAb的杂交瘤克隆的贴壁培养物维持在补充有10%FBS的DMEM的T形烧瓶中,其用于流式细胞测量术和共聚焦显微镜成像中的克隆评估。为了在搅拌槽生物反应器中产生大规模mAb,将前四种杂交瘤克隆从贴壁培养物调整为无血清悬浮液培养物,且将细胞在补充有4mM L-谷氨酰胺和1%抗结块剂(v/v)的杂交瘤-SFM培养基中在37℃、5%CO2和130rpm下在摇瓶中培育。
抗SSTR2 mAb的开发。人类SSTR2(同种型A,UniProtKB P30874)和小鼠SSTR2(同种型A,UniProtKB P30875)两者均为具有相同拓扑的整体膜糖蛋白,所述拓扑包括四个细胞外拓扑结构域、七个螺旋跨膜和四个细胞质拓扑结构域。蛋白质blast分析显示四个细胞外结构域分别具有81%、100%、100%和90%的相似性。为开发一种可以靶向人类和小鼠SSTR2两者的单克隆抗体,我们使用杂交瘤技术开发了一种靶向第1细胞外结构域(cQTEPYYDLTSNA,aa 33-44,SEQ ID NO:14)和第2细胞外结构域(cALVHWPFGKAICRVV,aa104-118,SEQ ID NO:15)的抗人类SSTR2 mAb。将合成抗原肽静脉内(i.v.)注射至五只balb/c小鼠中进行免疫接种,且每两周接种一次,连续接种十周(五次注射),此通过ProMab按照标准方案进行。使用基于抗原肽的夹心酶联免疫吸附测定(ELISA)和蛋白质印迹对从免疫小鼠采集的血清(免疫前血清和抗SSTR2血清两者)中的抗SSTR2 mAb进行滴定。来自具有最佳抗SSTR2抗体滴度的小鼠的免疫脾细胞与骨髓瘤细胞(Sp2/0)融合以获得杂交瘤克隆。
mAb产生杂交瘤克隆体的筛选。总共100个亚克隆产生,在筛选的前两个阶段期间在96孔板中培育。使用混合抗原双结构域基于SSTR2 mAb体积生产力(即最终滴度)进行初级克隆筛选,产生前40个克隆。在二次筛选中,使用基于肽(第1或第2细胞外结构域)的ELISA筛选前4个克隆。在三次筛选中,我们将前四个克隆在无血清悬浮培养物中进行调整且在摇瓶中进行分批培养。使用蛋白质A试剂盒纯化mAb,且按照制造方案用AF647标记以评估流式细胞测量术和共聚焦显微镜成像中的癌症表面结合。具有与NET(BON-1)强细胞表面结合、与非癌性H727对照细胞弱结合的前导克隆被定义用於进一步评价和构建ADC。
ELISA。在早期免疫接种和杂交瘤克隆筛选中使用ELISA。简言之,96孔板用在pH为9.6的50mM碳酸盐中稀释的抗原涂布且在4℃下培育过夜。以每孔100μL添加含有mAb的废培养基或稀释于阻断缓冲剂中的纯化mAb,且在室温(RT)下培育1小时。抗SSTR2 mAb是通过每孔添加50μL以1:10,000稀释于阻断缓冲剂中的HRP标记的的抗小鼠IgG(Sigma,St.Louis,MO,目录号:RABHRP2-10UL)来捕获并检测。含有0.1M Na3C6H5O7·2H2O和1.5%CH4N2O·H2O2的缓冲剂A和含有3,3',5,5'-四甲基联苯胺和0.1M C6H8O7·H2O的缓冲剂B用于显色。在添加停止溶液之后,在微板读数仪上以450nm读取板。
同型评估。市售小鼠抗体同型试剂盒用于测定所开发的mAb的同型。具体来说,山羊抗小鼠IgG、IgA和IgM用于涂布板。在添加mAb样品之后,添加子类别特异性兔抗小鼠IgG1、IgG2a、IgG2b、IgG3、IgA、IgM、κ和λ。HRP标记的抗兔IgG和底物溶液用来显色。
抗SSTR2 mAb生产。产生前导SSTR2 mAb的杂交瘤克隆维持于125-mL摇瓶中。以工作体积为1L且以80rpm搅拌,将接种列按比例扩大到3-L旋转烧瓶。在以温度为37℃,pH为7.0,DO为50%,以70rpm搅拌控制的5-L搅拌槽生物反应器细胞培养物中进行mAb生产。具体而言,在生物反应器中将分批生产培养物以0.3-0.5×106个细胞/毫升的VCD接种于杂交瘤-SFM中,所述杂交瘤-SFM补充有6g/L葡萄糖、6mM L-谷氨酰胺、3.5g/L Cell Boost#6和1%抗结块剂。每天对生产培养物进行取样以使用细胞计数器监测细胞生长(即,VCD、存活率、增倍时间和生长速率)、使用葡萄糖分析仪监测葡萄糖和使用NGC系统(加利福尼亚州埃库莱斯的拜耳雷德公司(Bio-Rad,Hercules,CA))监测mAb生产。当存活率下降至约80%时,收集废培养基且使用离心机并以0.22μm超滤进行澄清以进一步纯化mAb。
mAb纯化。先前开发的使用NGC系统的两步抗体纯化方案(Ou J等人,公共科学图书馆·综合(PLoS One.)2018 10月23日13(10):e0206246;Xu N等人,生物化学工程改造杂志(Biochemical Engineering Journal.)2018145:177-85)用于纯化抗SSTR2 mAb。具体来说,进行主要蛋白质A亲和力纯化以捕获UNOsphere SUPrA柱中的mAb,所述柱用包含0.02M磷酸钠和0.02M柠檬酸钠的pH为7.5的缓冲剂平衡。在洗涤柱之后,mAb用含有0.02M柠檬酸钠和0.1M氯化钠的pH为3.0的缓冲剂洗脱,且用1M Tris溶液中和至7.0。使用阳离子交换柱Foresight Nuvia S进行抛光纯化,且使用20mM至200mM氯化钠溶液洗脱mAb。纯化的mAb使用NGC滴定,并且使用如以下章节中所述的SDS-PAGE、蛋白质印迹、流式细胞测量术和共焦显微镜进行表征。
ADC构建。已公开的基于半胱氨酸的缀合程序平台(Ou J等人,公共科学图书馆·综合201810月23日13(10):e0206246)用于构建ADC。首先,再桥接接头通过在60℃下将6-氨基己酸与3,4-二溴苯呋喃-2,5-二酮以1:1的摩尔比混合30分钟来合成,在100℃下加热18小时,且通过硅胶用0-40%二氯甲烷/乙酸乙酯作为洗脱溶液纯化。第二,在25℃下,将N,N-二异丙基碳化二亚胺、N,N-二异丙基乙胺和再桥连接头以1:1:2.5的摩尔比在二氯甲烷中混合1小时。然后,添加相同摩尔浓度的MMAE,且频繁混合16小时以合成接头-有效负载,其通过配备有5μm C18(2)和250×10mm的反相C18柱(加利福尼亚州托兰斯的菲罗门公司(Phenomenex,Torrance,CA))的HPLC系统(马萨诸塞州米尔福德的沃特世公司)进行纯化。第三,将交换至50mM硼酸盐缓冲剂(pH 8.0)的抗SSTR2 mAb与MMAE以1:7的摩尔比缀合,并且通过PD SpinTrapTM G25柱(通用电气医疗集团(GE Healthcare))进行纯化。最后,平均药物抗体比率(DAR)被计算为比率=(εAb 248-RεAb 280)/(RεD 280-εD 248),其中R=A248/A280=吸光度比(Ou J等人,公共科学图书馆·综合201810月23日13(10):e0206246),并且使用液体色谱-电喷雾电离-串联质谱(LC-ESI-MS)进行确认。
体外抗癌毒性(IC50)。利用BON细胞系比较ADC的毒性。在96孔板的每孔中添加75μL含有密度为5×104个细胞/毫升的细胞(存活率>95%)的培养基。ADC或MMAE溶液通过0.2μm过滤器灭菌并且用完整培养基稀释至不同浓度。在常规细胞培育箱中培育4小时之后,将75μL具有梯度浓度的ADC或MMAE与96孔板中的细胞混合。在治疗期间,用另一个装满PBS的96孔板覆盖孔板,以防止介质蒸发。在培育3天之后,通过发光细胞存活率分析(麦迪逊的普洛麦格公司(Promega,Madison,MI))产生毒性结果。
SDS-PAGE和蛋白质印迹。使用Mem-PER加膜蛋白质提取试剂盒提取用于表面受体评估的膜蛋白质。蛋白质浓度按照制造方案通过皮尔斯BCA分析测定。非还原SDS-PAGE使用具有4-12%Bis-Tris蛋白质凝胶的NuPAGETM的电泳系统运行。将凝胶蛋白电转移至PVDF膜,并且在室温下用含有5%无脂乳粉和0.1%吐温20的TBS洗涤缓冲剂阻断1小时。将从1mg/mL储备液中以1:5,000稀释的一级兔抗小鼠抗体(Abcam,Cambridge,MA,Catalog#:ab190475)与阻断膜在4℃下培育过夜、用TBS缓冲剂冲洗三次,且随后用以1:3,000稀释的HRP缀合的二级抗兔抗体(Abcam,目录号:ab205718))在室温下培育1小时。最后,印迹膜用LuminataForte Western HRP底物(马萨诸塞州波士顿的密理博公司(Millipore,Boston,MA))处理,用MyECL成像器成像,并且用ImageJ软件定量。
流式细胞测量术以定量表面受体密度和mAb结合。纯化的抗SSTR2 mAb用AlexaFluorTM647抗体标记试剂盒标记,且用于使用BD LSRII流式细胞仪(加利福尼亚州圣路易斯的BD生物科学公司(BD Biosciences,San Jose,CA))定量评估与NET细胞系(BON、TT和MZ)和阴性对照成纤维细胞细胞系(917)的表面受体结合能力。当汇合达到70%时从烧瓶收集1×106个细胞,用流式细胞测量术缓冲剂洗涤,并且与1μg AF647标记的mAb在冰上或在黑暗中在室温下培育30分钟。洗涤三次后,将细胞再悬浮于1mL流式细胞仪缓冲剂中,并且用BD生物科学公司的BD LSRII流式细胞仪进行分析。设定选通,其中阴性样品具有<0.5%荧光群体。作为对照,在流式细胞测量术中使用市售抗SSTR2 mAb(明尼苏达州明尼阿波利斯的RD系统公司,目录号:MAB4224)。
共焦成像以评估ADC结合和内化。将层粘连蛋白以10μg/mL的浓度涂布于玻璃盖玻片(康涅狄格州汉登的华纳仪器公司(Warner Instruments,Hamden,CT))上以增强粘合效率且在4℃下培育24小时。在24孔板中,以5×104个细胞/毫升的密度将NET细胞或阴性细胞接种至玻璃盖片上,并且在37℃下培育4小时。当细胞达到50%汇合时,将BacMam GFPTransduction Control添加至转导细胞中并且培育过夜,对细胞质和细胞核进行染色。接着用PBS将AF647标记的mAb稀释至2μg/mL的浓度。含有转导细胞的盖玻片接着用PBS冲洗两次,转移至适当的微培育阶段适配器(micro-incubation stage adapter)中,且在37℃下在黑暗中在含有10%失活山羊血清和1%牛血清白蛋白的PBS缓冲剂中用500μl的2μg/mLAF647-mAb染色30分钟。使用奥林巴斯(Olympus)1×-81共焦显微镜,用奥林巴斯FV-1000激光扫描头使用共焦显微镜(宾夕法尼亚州中央谷的奥林巴斯IX81)观察细胞。使用奥林巴斯FV1000共焦显微镜记录MitoSox成像以监测AF647-mAb的表面结合和内化。具有0.2%透射率和519V的PMT电压的488nm激光用于观察BacMam感染细胞,而具有31%透射率和686V的PMT电压的635nm激光用于观察荧光标记的mAb。用ImageJ软件离线分析图像。
异种移植物小鼠模型生成和抗NET功效研究。BON-Luc接种培养物在按比例扩大之前以无支原体形式进行测试。将细胞浓缩并且以1×106个细胞/小鼠的密度、>95%的存活率注射至各裸(nu/nu)小鼠(4-6周龄,雄性和雌性)(Jackson实验室)的背部上。肿瘤允许在异种移植5天后生长。选择具有50~60mm3肿瘤体积的小鼠用于ADC功效研究。将小鼠随机分为3组(n=6):生理盐水组、抗SSTR2 mAb组、mAb-MMAE缀合物组。在注射后第6天开始治疗:通过尾静脉按照12mg/kg-BW剂量,2次注射/周来施用mAb/ADC;在生理盐水组中注射相同体积的生理盐水。每两天测量实体肿瘤的体积和小鼠体重。在整个治疗期间以平均注射间隔为4.5天进行四次注射。在异种移植后第28天处死小鼠。收集实体肿瘤和其它器官(脑部和肝脏)用于成像和进一步分析。
通过体内成像系统(IVIS)进行生物分布。使用以上方法产生异种移植物小鼠模型。在异种移植后第7天,选择具有100-150mm3实体肿瘤的小鼠用于mAb生物分布研究。使用Sulfo-Cyanine5.5抗体标记试剂盒(Lumiprobe)用荧光染料标记抗SSTR2 mAb。在灭菌之后,将25μg Cy5.5-mAb通过尾静脉注射至每只小鼠中。小鼠注射后24小时在体内成像系统下成像。参数设置为660nm/710nm(激发/发射)波长。
药代动力学研究。为研究ADC的代谢速率,将5种不同浓度(4、8、12、16、20mg/kgBW)的ADC注射至5组随机小鼠(n=4)中。注射后2、5、24、48、72、120小时(总共6个时间点)从尾部收集血液样品。将血液在2,000g下离心5分钟以使细胞沉淀,并且收集上清液以用于ELISA分析。标准夹心ELISA用于定量小鼠血浆中保持的ADC。利用SSTR2肽涂布96孔板。辣根过氧化酶缀合的山羊抗小鼠IgG抗体和3,3',5,5'-四甲基联苯胺(TMB)用于显色。将血浆中的ADC稀释且使用检测范围为0-300ng/mL的ELISA进行滴定。使用先前开发的PK模型(参考)计算建议剂量(D)和给药间隔(τ):D=Cmax(所要)·ke·Vd·T·(1-e-keτ)/(1-e-keT)和τ=ln(Cmax(所要)/Cmin(所要))/ke+T,其用于抗癌功效动物研究。
苏木精和伊红(H&E)染色。在染色之前将切片去石蜡。添加200μL的苏木精溶液以将切片染色,随后在25℃下培育5分钟。通过反向流动的自来水将染料洗掉。将切片在PBS中冲洗5分钟。随后,将切片在400μL的伊红Y溶液中染色30秒并且使用流动的自来水洗涤。将切片在无水乙醇中通过两次2分钟的反应进行脱水并且在二甲苯中进行澄清。
免疫组织化学(IHC)染色。福尔马林固定且石蜡包埋的NET组织由UAB病理学系的基于组织的转化研究实验室进行制备且切片。正常器官TMA购自美国生物底物公司。将切片澄清并且使用二甲苯和乙醇再水合。玻片接着浸没于柠檬酸盐缓冲剂(BioGenex,Fermont,CA)中持续十分钟压力锅循环以实现抗原回收。通过在3%过氧化氢中培育玻片持续十分钟来淬灭内源性过氧化酶活性。用3%的山羊血清和0.3%的Triton-X100在PBS中在室温下阻断1小时。SSTR2使用1.8mg/mL的抗SSTR2 mAb,在4℃下的培育过夜进行检测。使用经抗小鼠生物素标记的二级抗体,接着与HRP抗生蛋白链菌素一起培育30分钟。玻片用DAB色原体(丹科液体DAB+底物K3468)染色并且用苏木精反向染色。在盖片滑动和成像之前,将玻片脱水并且使用乙醇和二甲苯澄清。
统计。所有数据均呈现为平均值±平均值的标准误差(SEM)。双尾学生t检验用于测定两组之间的显著性。使用单因素方差分析接着事后(邓尼特(Dunnett))分析进行多组当中的比较。通过先前研究和公开的ADC治疗研究(68)测定动物研究的样品大小。所有试验均考虑了***P值<0.001的统计显著性。
研究批准。NET患者的肿瘤组织样品通过机构审查委员会(IRB)批准的方案从UAB手术肿瘤库获得。用依序分配的数字替换识别患者的信息。正常人类器官组织购自美国生物底物公司。动物研究按照UAB IACUC(IACUC-20422)制定的研究动物的护理和使用指南进行。
结果
SSTR2在NET患者肿瘤组织中过度表达,但不在正常器官中过度表达。为评估患者的NET组织的细胞表面上SSTR2的表达水平,对组织微阵列(TMA)进行免疫组织化学(IHC)染色分析。TMA由来自不同患者的38个福尔马林固定且石蜡包埋的胰腺NET的核心(图7中第2-9列)和作为阴性对照的5个正常非癌性组织(包括脾脏、肝、前列腺、胎盘和扁桃体)的核心(图7中第1列)组成。首先使用苏木精和伊红(H&E)对TMA进行染色,以指示每个核心中NET细胞的存在和位置(图7A)。IHC染色表明约71%的患者核心对SSTR2呈阳性,且具有强细胞膜定位(图7B)。此外,SSTR2的表达仅仅见于NET组织中,但在5个正常组织中并未检测到。
人类Atlas项目数据库报道了脑部、肺、肝、肌肉、皮肤、胎盘、前列腺、扁桃体和胰腺中的高水平SSTR2 mRNA。高水平mRNA不总是与蛋白质的高表达相关,而SSTR2的表面表达对于开发靶向治疗更为重要。因此,使用抗SSTR2 mAb进行IHC染色,研究SSTR2在这些正常组织和其它正常组织中的蛋白表达。市售的多器官TMA(US Biomax,FDA662a,冷冻样品)用于IHC染色,其含有33类正常人类器官组织,包括大脑、小脑、外周神经、肾上腺、甲状腺、脾脏、胸腺、骨髓、淋巴结、扁桃体、胰腺、肝、食道、胃、小肠、结肠、肺、唾液、咽、肾、膀胱、睾丸、前列腺、阴茎、卵巢、输卵管、乳腺、子宫内膜、子宫颈、心肌、骨骼肌、间皮和皮肤。如图8A中所示,在除显示弱阳性信号的胰腺和皮肤以外的大多数正常人类组织中未检测到SSTR2表达(图8A和表1)。图8B中的脑部、肝、肺、肌肉、皮肤、扁桃体、前列腺和胰腺的高分辨率图像清楚地显示最小或检测不到的表面SSTR2受体。作为阳性对照,与正常组织相比,使用我们的mAb的NET患者组织显示出阳性和强信号。
此外,在NET细胞系中也证实SSTR2的高水平表达。定量蛋白质印迹分析显示在两种胰腺NET细胞系(BON-1和QGP-1)和肺NET细胞系(H727)中SSTR2的高水平表达,但在非癌、成纤维细胞细胞系(917和WI-38)中存在最小表达(图15A)。此外,共聚焦激光扫描显微镜(CLSM)还揭露BON-1异种移植物和NET患者组织两者中的SSTR2的强膜阳性(图15B)。从患者肿瘤组织、正常器官和细胞系收集的所有数据表明SSTR2为用于NET治疗的理想标靶。
标靶NETs的抗SSTR2 mAb。为有效靶向NETs中的表面受体SSTR2,使用杂交瘤技术开发了靶向第1细胞外结构域(cQTEPYYDLTSNA,aa 33-44,SEQ ID NO:14)和第2细胞外结构域(cALVHWPFGKAICRVV,aa 104-118,SEQ ID NO:15)的小鼠抗人类SSTR2 mAb。首先使用酶联免疫吸附分析(ELISA),基于抗体滴度筛选出抗SSTR2 mAb的杂交瘤亚克隆。基于mAb对SSTR2的第1结构域和第2结构域的结合效率,对前40个克隆进行分级(图9A)。选择四个克隆用于进一步评估,包括与第2结构域具有最强结合但与第1结构域具有低结合的克隆1;与第1结构域具有最高结合但与第2结构域具有低结合的克隆2;以及与第1和第2细胞外结构域具有高结合的克隆3和克隆4。
通过测试由这4个克隆产生的抗SSTR2 mAb与NET细胞系的表面结合来进一步评估所述抗SSTR2 mAb。同型分析显示,克隆1-4分别为IgG1κ、IgG2aκ、IgG1κ和IgG1κ。为了定义前导克隆,使用流式细胞测量术比较每个mAb对于BON-1细胞中的SSTR2的结合能力并且进行分级。如图9B中所示,克隆1-4的表面结合百分比分别为50%、80%、90%和98%。十二烷基硫酸钠聚丙烯酰胺凝胶电泳(SDS-PAGE)分析证实,由这四个克隆产生的相应抗SSTR2mAb的分子量为约150kDa(图9C)。基于mAb表达和SSTR2特异性结合能力的结果,克隆4被选择为最佳克隆并且因此被定义为“前导克隆”。如图9D中所呈现,进一步评估显示,前导抗SSTR2 mAb具有与NET细胞系BON-1和QGP-1的高表面结合(>90%)和与成纤维细胞细胞系917和WI-38的低结合(<7.5%)。因此,此前导杂交瘤克隆在本研究的其余部分中贯穿使用,用于大规模mAb生产和ADC构建。
为了最优地按比例扩大并且生产高质量的抗SSTR2 mAb,我们将杂交瘤细胞从T形烧瓶中的贴壁培养物调整为旋转烧瓶和搅拌槽生物反应器中的悬浮培养物。在补充有6g/L葡萄糖、6mM L-谷氨酰胺、3.5g/L Cell Boost#6和1%抗结块剂(v/v)的Gibco杂交瘤SFM培养基中进行mAb生产(图9E)。在T形烧瓶、旋转烧瓶和搅拌槽生物反应器中的培养物分别以0.016、0.024和0.035h-1的比生长速率产生8.6、39.8和53.3mg/L的抗SSTR2 mAb(图9F)。按照我们先前报道的程序(Ou J等人,公共科学图书馆·综合2018年10月23日13(10):e0206246;Xu N等人,生物化学工程改造杂志2018145:177-85)纯化抗SSTR2 mAb。
抗SSTR2 mAb显示在体外和体内对NET的高表面结合。为评估抗SSTR2 mAb对SSTR2的体外NET特异性靶向,使用NET细胞系进行动态活细胞CLSM成像和流式细胞测量术。为观察和追踪表面结合过程,用BacMam GFP对照转染BON-1细胞,并将Alexa Fluor 647染料(AF647,标记为红色,ex./em.650/665nm)与抗SSTR2 mAb缀合。如图10A中所示,在与细胞一起培育之后20分钟,抗SSTR2 mAb由于免疫亲和力而积聚在BON-1细胞表面上,显示为“圆形”。然后mAb通过内吞作用内化并且在40分钟内定位于细胞质中。用流式细胞测量术比较开发的mAb与市售mAb(安迪生物公司)的表面结合能力。如图10B中所述,在相同染色条件下,在本研究中开发的mAb与市售mAb相比对BON-1细胞的表面结合要强得多,为95%比38%。此外,共焦成像显示抗SSTR2 mAb在培育后70分钟内与PanNET细胞系(BON-1)和MTC细胞系(TT和MZ-CRC-1)结合并被它们完全内化(图10C)。
此外,使用NET异种移植小鼠模型评估抗SSTR2 mAb的体内靶向能力。小鼠模型携带用萤火虫荧光素酶(一种生物发光报告基因)转染的BON-1-Luc细胞。在注射mAb后4-8小时的IVIS成像指示Cy7-mAb在BON-Luc异种移植物中的强积聚,但在鼠循环系统中也有少量的mAb剩余。24小时成像证实来自BON-Luc异种移植物的生物发光信号和来自Cy7-mAb的荧光信号的完全共定位(图11A)。收集BON-Luc异种移植物、肝和脑,并且将它们切片以使用CLSM测试mAb结合。发现未检测到Cy7-mAb与肝或脑的非特异性结合,但在BON-Luc异种移植物的切片上检测到强荧光信号。总之,本文中进行的体外和体内研究都证实,开发的抗SSTR2 mAb可以靶向过度表达SSTR2的NET细胞系、异种移植物和患者组织。因此,显而易见的是,新型mAb有潜力以ADC的形式靶向并且递送高效的小分子。
抗SSTR2 mAb检测人和小鼠SSTR2两者。在人类中,SSTR2在细胞膜上内源性表达为具有四个细胞外结构域、七个螺旋跨膜结构域和四个细胞质结构域的糖蛋白(Yamada Y等人,美国国家科学院院刊199289(1):251-5;Petersenn S等人,分子细胞内分泌学(MolCell Endocrinol.)1999157(1-2):75-85;Ota T等人,自然遗传学(Nat Genet.)200436(1):40-5)。如表2中所概述,UniProtKB数据库显示人类SSTR2(UniProt P30874)和小鼠SSTR2(UniProt P30875)的同种型A具有相同拓扑。所公开的小鼠抗人类SSTR2 mAb使用来自人类SSTR2的与小鼠SSTR2具有100%相似性的第1和第2细胞外结构域来产生。利用此设计,预期所公开的抗SSTR2 mAb可检测人和小鼠SSTR2两者。为测试这一假设而进行了蛋白质印迹,其显示所公开的抗SSTR2 mAb可检测到BON-1异种移植物中和来自自发性MTC小鼠模型的分离的甲状腺髓样癌(MTC)细胞中存在的SSTR2(图11C)。此MTC模型先前被开发为第一个可靠且临床上准确的条件MTC小鼠模型(Pozo K等人,癌细胞2013 24(4):499-511;Pozo K等人,肿瘤标靶2015;6(14):12080-93)。双转基因小鼠系经工程化以允许在神经特异性烯醇化酶(NSE)启动子的控制下的p25(p25OE)的多西环素(doxycycline)依赖性抑制。本研究显示抗SSTR2 mAb可检测到人类和小鼠SSTR2受体两者。
ADC构建和表征。已确立的基于半胱氨酸的缀合程序平台(Ou J等人,公共科学图书馆·综合201810月23日13(10):e0206246)用于构建ADC。在此,基于再桥接肽的接头合成出以维持mAb的高完整性(图12A),与抗有丝分裂单甲基奥瑞他汀E(MMAE)缀合,并且使用沃特斯高效液相色谱(HPLC)纯化。使用安捷伦6500Q-TOF LC/MS对接头的结构进行表征(图12B),并且使用SDS-PAGE确认ADC结构的完整性(图12C)。所构建的ADC的平均药物抗体比率(DAR)为约4.0。
抗SSTR2 ADC的体外抗癌毒性显示低IC50。通过比较游离药物(MMAE)和包括在本研究中开发的mAb或来自安迪生物公司的mAb的两种不同ADC来评估抗SSTR2 ADC在BON-1细胞中的体外抗癌毒性。MMAE被选择为ADC的药物,因为它是一种有效的细胞毒素,其已得到临床验证的事实(Francisco JA等人,血液(Blood)2003102(4):1458-65;Yao H等人,国际分子科学杂志(Int J Mol Sci.)201617(2))为一种微管蛋白聚合阻断剂(Cunningham D等人,前列腺(Prostate)201676(15):1420-30;Li H等人,癌症生物学与治疗(Cancer BiolTher.)201617(4):346-54)。然而,MMAE从未在NET中测试过。在本研究中,MMAE、来自所公开的抗SSTR2 mAb的ADC和来自市售mAb的ADC的IC50值分别为2.00nM、4.27nM和5.62nM(图12D)。显然,mAb-MMAE-ADC对NET细胞具有与高度有效的游离药物MMAE类似的纳摩尔细胞毒性。由于具有强的NET靶向能力,所公开的基于mAb的ADC有望在体内获得比游离药物更好的治疗效果。
抗SSTR2 ADC具有多种潜在的抗癌机制。为理解除递送MMAE引起的细胞毒性以外的抗SSTR2 ADC的其它潜在抗癌机制,在用ADC治疗三天的BON-1细胞中分析与细胞增殖信号传导路径相关的若干个标记物。蛋白质印迹显示单独抗SSTR2 mAb和ADC都可以阻断经由PI3K-AKT路径的细胞增殖信号传导、下调致癌基因细胞周期蛋白D1,并且诱导细胞周期停滞,如通过检测标记p21所示(图12E)。这些研究发现ADC释放的MMAE通过微管解聚合抑制NET细胞增殖(图12F)。
此外,还测试所公开的抗SSTR2 mAb对CD8+T细胞中的细胞因子产生的可能影响。CD3/CD28刺激后,人类CD8+T细胞与100nM SST类似物(奥曲肽)或100nM抗SSTR2 mAb培育2天。在培育之后,进行流式细胞测量术以分析IL-2和IFN-γ的表达。如图16中所示,抗SSTR2mAb和奥曲肽两者使IL-2表达增加了1.6倍,并且使IFN-γ表达增加了2.2倍。
综上所述,提出用于NET的抗SSTR2 ADC治疗的若干可能的作用机制(图17)。第一种机制为抗SSTR2 mAb充当针对NET细胞的药物的靶向递送运载体,且药物有效负载经由解聚合微管蛋白抑制癌细胞增殖。第二种潜在机制为PI3K-AKT增殖信号传导路径由mAb结合下调且随后阻断SSTR2。第三种潜在机制为抗SSTR2 mAb增强T细胞的细胞因子产生。
抗SSTR2 ADC的MTD未显示出副作用。为研究抗SSTR2 ADC的最大耐受剂量(MTD),将其以5种不同浓度注射至5只野生型(非肿瘤携带)小鼠的尾静脉中:4、8、12、16和20mg/kg体重(BW)。在注射后六小时和每天两次共21天的时间里,对小鼠进行监测,未发现行为改变的迹象,如饮水、呼吸困难、体重迅速减轻、行走障碍和/或精神状态。如图13A中所示,在4-20mg/kg BW的浓度范围下的ADC对小鼠体重或总存活率没有明显的副作用。监测总共三周后,处死小鼠并且收集脑部组织用于进一步研究。如H&E染色所示(图13B),施用抗SSTR2ADC后,脑组织未出现形态上的改变。未观测到明显的药物递送,且未观测到任何急性或慢性炎症迹象或任何细胞凋亡或坏死区域。这些结果表明抗SSTR2 ADC治疗不具有明显的脱靶效应,并且不造成体内脑部的可检测的损伤。
PK指示抗SSTR2ADC的高稳定性。将ADC以五种不同浓度通过静脉内注射至携带皮下NET异种移植物的小鼠中来进行初步药物动力学(PK)研究,所述浓度为:4、8、12、16和20mg/kg BW(n=4)。在ADC注射后0小时、2小时、8小时、16小时、1天、2天、3天、5天和7天的时间点,从尾静脉收集血浆样品用于PK分析(各10-50μL),且随后使用ELISA分析进行滴定(图13C)。如表3中所呈现,PK建模证实所计算的半衰期(t1/2)=1.38-2.33天,分布体积Vd=63.05-94.42mL/kg,清除率(CL)=28.01-37.45mL/天/kg,生物可用性(F)=568.58-1293.26%,建议剂量(D)=3.78-14.30mg/kg BW,建议给药间隔(τ)=4.40-9.10天。基于这些结果,选择8mg/kg BW的浓度和4-5天的给药间隔用于剩余抗癌体内研究。
抗SSTR2 ADC的体内抗癌功效。携带BON-Luc异种移植物的小鼠使用浓度为8mg/kg的抗SSTR2 ADC、作为运载体对照的生理盐水和抗SSTR2 mAb(对照,8mg/kg)分为三组(n=6),以4.5天的给药间隔进行治疗。图14A显示,与对照组相比,在用抗SSTR2 ADC治疗的小鼠中,肿瘤生长被显著抑制,肿瘤大小减少62-67%。肿瘤荧光通量还用IVIS成像系统测量,且显示与对照组相比,用ADC治疗的组中的肿瘤生长减少71-73%(图14B)。在研究结束时收集NET肿瘤(图14C),且湿重也证实肿瘤生长的显著抑制(图14D)。三个组之间在总体体重上不存在明显差异(图14E)。蛋白质印迹分析显示在治疗期间NET肿瘤中存在SSTR2表达(图14F)。来自ADC治疗组肿瘤中SSTR2的表面染色似乎低于对照组中所见的染色(图14G),很可能归因于ADC所引起的NET细胞死亡,其通过H&E染色证实(图14H)。此体内抗癌功效研究证实,抗SSTR2 mAb为一种良好的药物递送运载体,并且抗体药物缀合物可有效抑制NET生长。
论述
SSTR2受体为理想的NET标靶。为开发有效且安全的靶向癌症治疗,必须识别和彻底表征独特生物标记,其特异性地從非癌性细胞界定癌细胞。正如本研究所报导,在38名NET患者中,约70%的患者SSTR2过度表达。其它研究也已报导,70-100%的NETs在细胞表面大量表达SSTR2(Pinchot SN等人,肿瘤学家200813(12):1255-69;Zatelli MC等人,临床内分泌学与新陈代谢杂志200186(5):2161-9;Sun LC等人,当代药物递送20118(1):2-10)。尽管有报导称SSTR2可在中枢神经系统(CNS)、胃肠道(GI)和胰腺中正常表达(Cakir M等人,细胞与分子医学杂志(J Cell Mol Med.)201014(11):2570-84),使用本研究和文献中描述的IHC分析,在组织微阵列中观测到NET组织中SSTR2的表达比正常组织高>20倍(PinchotSN等人,肿瘤学家200813(12):1255-69;Zatelli MC等人,临床内分泌学与新陈代谢杂志200186(5):2161-9;Sun LC等人,当代药物递送20118(1):2-10)。考虑到基于mAb的ADC为剂量依赖性靶向治疗,NETs与其它组织之间的SSTR2表达的巨大差异确保可安全地利用SSTR2。
然而,并非所有患有NETs的患者都过度表达SSTR2(Righi L等人,肿瘤学年鉴(AnnOncol.)201021(3):548-55;Sherman SK等人,外科研究杂志(J Surg Res.)2014190(2):587-93)。据报导45-66%患有肺NET的患者(Righi L等人,肿瘤学年鉴201021(3):548-55)和80-95%患有胃肠胰腺NETs的患者表达SSTR2。在这一研究中进行的组织微阵列分析显示,在染色的38名患者组织中,仅约71%显示可检测的SSTR2表达。为了使缺乏SSTR2的高表达的患者受益,需努力去使用比较膜蛋白质组学和蛋白质印迹来识别NETs中的其它潜在表面标记,如癌胚相关细胞粘附分子1(CEACAM1)。我们已发现CEACAM1在两种胰腺NET细胞系(BON-1和QGP-1)中高表达,并且胰腺癌细胞系(PANC-1和MiAPaCa-1)和成纤维细胞系(WI-38)中均不表达。其它研究还报导CEACAM1在各种其它癌症中的表达,包括代表NET类型的甲状腺髓样癌细胞系(Thies A等人,临床肿瘤学杂志200220(10):2530-6;Tilki D等人,癌基因(Oncogene)200625(36):4965-74)。此发现表明,对于具有最小SSTR2密度的NET患者,CEACAM1可用作SSTR2的替代方案。
所公开的抗SSTR2 mAb为一种有效的药物递送运载体。此研究表明SSTR2为NET治疗的合适标靶。与使用全SSTR2膜蛋白作为免疫原开发的市售抗SSTR2 mAb不同,在本研究中开发的新型抗SSTR2mAb是使用SSTR2的两个细胞外结构域作为免疫原来产生。因此,它显示与NET细胞的结合能力是市售抗SSTR2 mAb的5倍以上。
人类Atlas项目报道了多个正常人类组织中的SSTR2的高mRNA水平,但SSTR2的表面蛋白表达水平为靶向癌症治疗的主要考虑因素,而非转录水平。此研究分析了多个正常人体器官组织阵列(总共33个器官),包括大部分所报道的具有高mRNA的组织,证实这些组织的细胞表面上的SSTR2蛋白表达低或检测不到。活体动物IVIS成像证实,我们的抗SSTR2mAb只在NET异种移植物中积聚。因为所公开的mAb可以靶向人类和小鼠SSTR2两者,所以小鼠模型中对NET的体内特异性靶向可以指示患者中的特异性靶向。另外,评估抗SSTR2 ADC对小鼠、特别是对脑组织的可能毒性。MTD数据显示,剂量高达20mg ADC/kg BW并未引起小鼠的任何体重或行为变化。重要的是,鼠脑组织的H&E染色没有显示出任何损伤或细胞形态改变的证据。因此,所公开的抗SSTR2 mAb为一种潜在安全的药物递送运载体。
有效治疗NET的创新靶向治疗。mTOR抑制剂(依维莫司)、多激酶抑制剂(舒尼替尼)和SST类似物(例如奥曲肽和兰瑞肽(Lanreotide)已被开发用于治疗NET(Brown KT等人,血管与介入放射学杂志199910(4):397-403;Isozaki T等人,内科医学199938(1):17-21;Eriksson B等人,神经内分泌学200887(1):8-19;Lal A等人,肿瘤学现代观点2006 18(1):9-15;Lehnert T.器官移植199866(10):1307-12;Zhang R等人,内分泌学1999 140(5):2152-8;Boudreaux JP等人,外科学年鉴2005241(6):839-45;Nguyen C等人,核医学杂志200445(10):1660-8;Fiorentini G等人,化疗杂志200416(3):293-7;Zuetenhorst JM等人,内分泌相关癌症200411(3):553-61;Oberg K等人,肿瘤学年鉴200415(6):966-73),但这些药物的治疗效果有限。在本研究中,首次以单克隆抗体药物缀合物的形式开发了SSTR2靶向治疗以靶向NET。ADC具有包括以下的优点:经由强表面结合增强的细胞吸收、递送至癌细胞的小分子有效负载的高细胞毒性,和最小副作用。此体内抗癌功效研究证实,肿瘤生长在用抗SSTR2 ADC治疗后显著降低,这表明所公开的mAb可以有效地靶向NET细胞并且递送缀合的毒性药物。此外,所公开的抗SSTR2mAb可用于标记脂质体和外泌体的表面,以促进其它药物的靶向递送。还可以克隆单链可变片段(scFv)以构建CAR-T细胞用于进行NET免疫治疗。
抗SSTR2 mAb和抗SSTR2 ADC的协同治疗。其它研究已报导可驱动由SSTR2介导的抗肿瘤作用的多个直接和间接机制。例如,直接的抗细胞增殖机制包括细胞凋亡(uillermet J等人,美国国家科学院院刊2003100(1):155-60),细胞周期蛋白依赖性激酶抑制剂的调节,和细胞增殖信号的抑制(Lahlou H等人,纽约科学院年报(Ann N Y AcadSci.)20041014:121-31)。潜在间接抗肿瘤作用包括抑制生长因子和激素释放、抗血管生成作用(Woltering EA.癌症生物治疗和放射性药物(Cancer Biother Radiopharm.)200318(4):601-9)和免疫反应调节(Elliott DE等人,欧洲免疫学杂志(Eur J Immunol.)199929(8):2454-63)。在本研究中进行的体外评估显示所公开的抗SSTR2mAb下调与细胞增殖相关的PI3K/AKT信号传导,下调致癌基因细胞周期蛋白D1的表达,上调与细胞周期停滞相关的p21表达,且通过增加细胞因子产生来活化CD8+T细胞。这些发现指示此基于抗SSTR2mAb的ADC可充当具有临床潜力的多用途生物制剂,如:通过将细胞毒性有效负载释放至细胞质中直接引起细胞死亡;经由SSTR2介导的信号传导级联调节抑制肿瘤细胞生长;和通过增加细胞因子产生来再活化T细胞功能。需要进一步使用偶发性MTC小鼠模型、人源化小鼠模型和肝癌转移小鼠模型研究以更好地理解抗SSTR2 mAb和ADC对于体内NET治疗的可能协同作用。
所公开的靶向治疗的影响。所公开的抗SSTR2 ADC与治疗转移性NE癌的传统化疗、放疗和手术相比具有优势。与外科手术相比,抗SSTR2 ADC可以靶向并且治疗转移性结节。与化疗相比,此治疗可降低非所要的副作用且提高抗癌治疗功效。与FDA批准用于靶向治疗的其它受体类似,SSTR2不是绝对NET特异性受体,因此有必要进一步评估其潜在的副作用。结合在NET中SSTR2的表达高于正常组织,SSTR2在大多数正常器官中几乎没有或检测不到表面表达的事实,并且ADC是一种剂量依赖性治疗策略,可以最大限度地减少可能的脱靶副作用。本研究开发的靶向治疗与其它治疗方法相结合,对提高NE癌患者的生活质量和生存率具有极大的潜力。
除非另外定义,本文所使用的所有技术和科学术语都具有与所公开的本发明所属领域的技术人员通常所理解的相同的含义。本文所引用的出版物以及其所引用的材料通过引用具体并入。
所属领域的技术人员将认识到或能够使用不超过常规实验来确定本文所描述的本发明的具体实施例的许多等效物。这类等效物意图由以下权利要求书涵盖。
序列表
<110> UAB研究基金会(The UAB Research Foundation)
<120> 神经内分泌癌靶向治疗
<130> 222104-2890
<150> US 62/742,56
<151> 2018-10-08
<160> 30
<170> PatentIn版本3.5
<210> 1
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 合成构建体
<400> 1
Asp Tyr His Leu Asn
1 5
<210> 2
<211> 18
<212> PRT
<213> 人工序列
<220>
<223> 合成构建体
<400> 2
Ile Arg Asn Lys Arg Tyr Gly Tyr Arg Thr Glu Tyr Ser Ala Ser Val
1 5 10 15
Lys Gly
<210> 3
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 合成构建体
<400> 3
Asp Phe Tyr Asp Pro Phe Ala Tyr
1 5
<210> 4
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 合成构建体
<400> 4
Arg Ser Ser Gln Ser Leu Val His Ser Asn Gly Asn Thr Tyr Leu His
1 5 10 15
<210> 5
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 合成构建体
<400> 5
Lys Val Ser Asn Arg Phe Ser
1 5
<210> 6
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 合成构建体
<400> 6
Ser Gln Ser Thr His Val Pro Phe Thr
1 5
<210> 7
<211> 119
<212> PRT
<213> 人工序列
<220>
<223> 合成构建体
<400> 7
Glu Val Lys Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Thr Ser Gly Phe Thr Phe Thr Asp Tyr
20 25 30
His Leu Asn Trp Val Arg Gln Pro Pro Gly Lys Ala Leu Glu Trp Leu
35 40 45
Ala Leu Ile Arg Asn Lys Arg Tyr Gly Tyr Arg Thr Glu Tyr Ser Ala
50 55 60
Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Gln Ser Ile
65 70 75 80
Leu Tyr Leu Gln Met Asn Thr Leu Arg Ala Glu Asp Ser Ala Thr Tyr
85 90 95
Tyr Cys Ala Arg Asp Phe Tyr Asp Pro Phe Ala Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ala
115
<210> 8
<211> 112
<212> PRT
<213> 人工序列
<220>
<223> 合成构建体
<400> 8
Asp Val Val Met Thr Gln Thr Pro Leu Ser Leu Pro Val Ser Leu Gly
1 5 10 15
Asp Gln Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Val His Ser
20 25 30
Asn Gly Asn Thr Tyr Leu His Trp Tyr Leu Gln Arg Pro Gly Gln Ser
35 40 45
Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Phe Cys Ser Gln Ser
85 90 95
Thr His Val Pro Phe Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 9
<211> 15
<212> PRT
<213> 人工序列
<220>
<223> 合成构建体
<400> 9
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
1 5 10 15
<210> 10
<211> 15
<212> PRT
<213> 人工序列
<220>
<223> 合成构建体
<400> 10
Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Ser
1 5 10 15
<210> 11
<211> 18
<212> PRT
<213> 人工序列
<220>
<223> 合成构建体
<400> 11
Gly Ser Thr Ser Gly Ser Gly Lys Pro Gly Ser Gly Glu Gly Ser Thr
1 5 10 15
Lys Gly
<210> 12
<211> 284
<212> PRT
<213> 人工序列
<220>
<223> 合成构建体
<400> 12
Met Lys Leu Trp Leu Asn Trp Ile Phe Leu Val Thr Leu Leu Asn Gly
1 5 10 15
Ile Gln Cys Glu Val Lys Leu Val Glu Ser Gly Gly Gly Leu Val Gln
20 25 30
Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Thr Ser Gly Phe Thr Phe
35 40 45
Thr Asp Tyr His Leu Asn Trp Val Arg Gln Pro Pro Gly Lys Ala Leu
50 55 60
Glu Trp Leu Ala Leu Ile Arg Asn Lys Arg Tyr Gly Tyr Arg Thr Glu
65 70 75 80
Tyr Ser Ala Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser
85 90 95
Gln Ser Ile Leu Tyr Leu Gln Met Asn Thr Leu Arg Ala Glu Asp Ser
100 105 110
Ala Thr Tyr Tyr Cys Ala Arg Asp Phe Tyr Asp Pro Phe Ala Tyr Trp
115 120 125
Gly Gln Gly Thr Leu Val Thr Val Ser Ala Gly Gly Gly Gly Ser Gly
130 135 140
Gly Gly Gly Ser Gly Gly Gly Gly Ser Met Lys Leu Pro Val Arg Leu
145 150 155 160
Leu Val Leu Met Phe Trp Ile Pro Ala Ser Ser Ser Asp Val Val Met
165 170 175
Thr Gln Thr Pro Leu Ser Leu Pro Val Ser Leu Gly Asp Gln Ala Ser
180 185 190
Ile Ser Cys Arg Ser Ser Gln Ser Leu Val His Ser Asn Gly Asn Thr
195 200 205
Tyr Leu His Trp Tyr Leu Gln Arg Pro Gly Gln Ser Pro Lys Leu Leu
210 215 220
Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro Asp Arg Phe Ser
225 230 235 240
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile Ser Arg Val Glu
245 250 255
Ala Glu Asp Leu Gly Val Tyr Phe Cys Ser Gln Ser Thr His Val Pro
260 265 270
Phe Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys
275 280
<210> 13
<211> 284
<212> PRT
<213> 人工序列
<220>
<223> 合成构建体
<400> 13
Met Lys Leu Pro Val Arg Leu Leu Val Leu Met Phe Trp Ile Pro Ala
1 5 10 15
Ser Ser Ser Asp Val Val Met Thr Gln Thr Pro Leu Ser Leu Pro Val
20 25 30
Ser Leu Gly Asp Gln Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu
35 40 45
Val His Ser Asn Gly Asn Thr Tyr Leu His Trp Tyr Leu Gln Arg Pro
50 55 60
Gly Gln Ser Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser
65 70 75 80
Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
85 90 95
Leu Lys Ile Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Phe Cys
100 105 110
Ser Gln Ser Thr His Val Pro Phe Thr Phe Gly Ser Gly Thr Lys Leu
115 120 125
Glu Ile Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
130 135 140
Gly Ser Met Lys Leu Trp Leu Asn Trp Ile Phe Leu Val Thr Leu Leu
145 150 155 160
Asn Gly Ile Gln Cys Glu Val Lys Leu Val Glu Ser Gly Gly Gly Leu
165 170 175
Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Thr Ser Gly Phe
180 185 190
Thr Phe Thr Asp Tyr His Leu Asn Trp Val Arg Gln Pro Pro Gly Lys
195 200 205
Ala Leu Glu Trp Leu Ala Leu Ile Arg Asn Lys Arg Tyr Gly Tyr Arg
210 215 220
Thr Glu Tyr Ser Ala Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp
225 230 235 240
Asn Ser Gln Ser Ile Leu Tyr Leu Gln Met Asn Thr Leu Arg Ala Glu
245 250 255
Asp Ser Ala Thr Tyr Tyr Cys Ala Arg Asp Phe Tyr Asp Pro Phe Ala
260 265 270
Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ala
275 280
<210> 14
<211> 13
<212> PRT
<213> 人工序列
<220>
<223> 合成构建体
<400> 14
Cys Gln Thr Glu Pro Tyr Tyr Asp Leu Thr Ser Asn Ala
1 5 10
<210> 15
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 合成构建体
<400> 15
Cys Ala Leu Val His Trp Pro Phe Gly Lys Ala Ile Cys Arg Val Val
1 5 10 15
<210> 16
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> 合成构建体
<400> 16
Gln Thr Glu Pro Tyr Tyr Asp Leu Thr Ser Asn Ala
1 5 10
<210> 17
<211> 15
<212> PRT
<213> 人工序列
<220>
<223> 合成构建体
<400> 17
Ala Leu Val His Trp Pro Phe Gly Lys Ala Ile Cys Arg Val Val
1 5 10 15
<210> 18
<211> 119
<212> PRT
<213> 人工序列
<220>
<223> 合成构建体
<400> 18
Glu Val Lys Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Thr Ser Gly Phe Thr Phe Thr Asp Tyr
20 25 30
His Met Asn Trp Val Arg Gln Pro Pro Gly Lys Ala Leu Glu Trp Leu
35 40 45
Ala Leu Ile Arg Asn Lys Ala Asn Gly Tyr Arg Thr Glu Tyr Ser Ala
50 55 60
Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Gln Asn Ile
65 70 75 80
Leu Tyr Leu Gln Met Asn Thr Leu Arg Ala Glu Asp Ser Ala Thr Tyr
85 90 95
Tyr Cys Ala Arg Asp Phe Tyr Asp Pro Phe Ala Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ala
115
<210> 19
<211> 112
<212> PRT
<213> 人工序列
<220>
<223> 合成构建体
<400> 19
Asp Val Val Met Thr Gln Thr Pro Leu Ser Leu Pro Val Ser Leu Gly
1 5 10 15
Asp Gln Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Val His Ser
20 25 30
Asn Gly Asn Thr Tyr Leu His Trp Tyr Leu Gln Arg Pro Gly Gln Ser
35 40 45
Pro Asn Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Leu Gly Leu Tyr Phe Cys Ser Gln Ser
85 90 95
Thr Arg Val Pro Phe Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 20
<211> 284
<212> PRT
<213> 人工序列
<220>
<223> 合成构建体
<400> 20
Met Lys Leu Trp Leu Asn Trp Ile Phe Pro Val Thr Leu Leu Asn Gly
1 5 10 15
Ile Gln Cys Glu Val Lys Leu Val Glu Ser Gly Gly Gly Leu Val Gln
20 25 30
Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Thr Ser Gly Phe Thr Phe
35 40 45
Thr Asp Tyr His Met Asn Trp Val Arg Gln Pro Pro Gly Lys Ala Leu
50 55 60
Glu Trp Leu Ala Leu Ile Arg Asn Lys Ala Asn Gly Tyr Arg Thr Glu
65 70 75 80
Tyr Ser Ala Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser
85 90 95
Gln Asn Ile Leu Tyr Leu Gln Met Asn Thr Leu Arg Ala Glu Asp Ser
100 105 110
Ala Thr Tyr Tyr Cys Ala Arg Asp Phe Tyr Asp Pro Phe Ala Tyr Trp
115 120 125
Gly Gln Gly Thr Leu Val Thr Val Ser Ala Gly Gly Gly Gly Ser Gly
130 135 140
Gly Gly Gly Ser Gly Gly Gly Gly Ser Met Lys Leu Pro Val Gly Leu
145 150 155 160
Leu Val Leu Met Phe Trp Ile Pro Ala Ser Ser Ser Asp Val Val Met
165 170 175
Thr Gln Thr Pro Leu Ser Leu Pro Val Ser Leu Gly Asp Gln Ala Ser
180 185 190
Ile Ser Cys Arg Ser Ser Gln Ser Leu Val His Ser Asn Gly Asn Thr
195 200 205
Tyr Leu His Trp Tyr Leu Gln Arg Pro Gly Gln Ser Pro Asn Leu Leu
210 215 220
Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro Asp Arg Phe Ser
225 230 235 240
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile Ser Arg Val Glu
245 250 255
Ala Glu Asp Leu Gly Leu Tyr Phe Cys Ser Gln Ser Thr Arg Val Pro
260 265 270
Phe Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys
275 280
<210> 21
<211> 284
<212> PRT
<213> 人工序列
<220>
<223> 合成构建体
<400> 21
Met Lys Leu Pro Val Gly Leu Leu Val Leu Met Phe Trp Ile Pro Ala
1 5 10 15
Ser Ser Ser Asp Val Val Met Thr Gln Thr Pro Leu Ser Leu Pro Val
20 25 30
Ser Leu Gly Asp Gln Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu
35 40 45
Val His Ser Asn Gly Asn Thr Tyr Leu His Trp Tyr Leu Gln Arg Pro
50 55 60
Gly Gln Ser Pro Asn Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser
65 70 75 80
Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
85 90 95
Leu Lys Ile Ser Arg Val Glu Ala Glu Asp Leu Gly Leu Tyr Phe Cys
100 105 110
Ser Gln Ser Thr Arg Val Pro Phe Thr Phe Gly Ser Gly Thr Lys Leu
115 120 125
Glu Ile Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
130 135 140
Gly Ser Met Lys Leu Trp Leu Asn Trp Ile Phe Pro Val Thr Leu Leu
145 150 155 160
Asn Gly Ile Gln Cys Glu Val Lys Leu Val Glu Ser Gly Gly Gly Leu
165 170 175
Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Thr Ser Gly Phe
180 185 190
Thr Phe Thr Asp Tyr His Met Asn Trp Val Arg Gln Pro Pro Gly Lys
195 200 205
Ala Leu Glu Trp Leu Ala Leu Ile Arg Asn Lys Ala Asn Gly Tyr Arg
210 215 220
Thr Glu Tyr Ser Ala Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp
225 230 235 240
Asn Ser Gln Asn Ile Leu Tyr Leu Gln Met Asn Thr Leu Arg Ala Glu
245 250 255
Asp Ser Ala Thr Tyr Tyr Cys Ala Arg Asp Phe Tyr Asp Pro Phe Ala
260 265 270
Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ala
275 280
<210> 22
<211> 284
<212> PRT
<213> 人工序列
<220>
<223> 合成构建体
<400> 22
Met Lys Leu Trp Leu Asn Trp Ile Phe Leu Val Thr Leu Leu Asn Gly
1 5 10 15
Ile Gln Cys Glu Val Lys Leu Val Glu Ser Gly Gly Gly Leu Val Gln
20 25 30
Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Thr Ser Gly Phe Thr Phe
35 40 45
Thr Asp Tyr His Leu Asn Trp Val Arg Gln Pro Pro Gly Lys Ala Leu
50 55 60
Glu Trp Leu Ala Leu Ile Arg Asn Lys Arg Tyr Gly Tyr Arg Thr Glu
65 70 75 80
Tyr Ser Ala Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser
85 90 95
Gln Ser Ile Leu Tyr Leu Gln Met Asn Thr Leu Arg Ala Glu Asp Ser
100 105 110
Ala Thr Tyr Tyr Cys Ala Arg Asp Phe Tyr Asp Pro Phe Ala Tyr Trp
115 120 125
Gly Gln Gly Thr Leu Val Thr Val Ser Ala Gly Gly Gly Gly Ser Gly
130 135 140
Gly Gly Gly Ser Gly Gly Gly Gly Ser Met Lys Leu Pro Val Gly Leu
145 150 155 160
Leu Val Leu Met Phe Trp Ile Pro Ala Ser Ser Ser Asp Val Val Met
165 170 175
Thr Gln Thr Pro Leu Ser Leu Pro Val Ser Leu Gly Asp Gln Ala Ser
180 185 190
Ile Ser Cys Arg Ser Ser Gln Ser Leu Val His Ser Asn Gly Asn Thr
195 200 205
Tyr Leu His Trp Tyr Leu Gln Arg Pro Gly Gln Ser Pro Asn Leu Leu
210 215 220
Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro Asp Arg Phe Ser
225 230 235 240
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile Ser Arg Val Glu
245 250 255
Ala Glu Asp Leu Gly Leu Tyr Phe Cys Ser Gln Ser Thr Arg Val Pro
260 265 270
Phe Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys
275 280
<210> 23
<211> 284
<212> PRT
<213> 人工序列
<220>
<223> 合成构建体
<400> 23
Met Lys Leu Pro Val Gly Leu Leu Val Leu Met Phe Trp Ile Pro Ala
1 5 10 15
Ser Ser Ser Asp Val Val Met Thr Gln Thr Pro Leu Ser Leu Pro Val
20 25 30
Ser Leu Gly Asp Gln Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu
35 40 45
Val His Ser Asn Gly Asn Thr Tyr Leu His Trp Tyr Leu Gln Arg Pro
50 55 60
Gly Gln Ser Pro Asn Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser
65 70 75 80
Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
85 90 95
Leu Lys Ile Ser Arg Val Glu Ala Glu Asp Leu Gly Leu Tyr Phe Cys
100 105 110
Ser Gln Ser Thr Arg Val Pro Phe Thr Phe Gly Ser Gly Thr Lys Leu
115 120 125
Glu Ile Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
130 135 140
Gly Ser Met Lys Leu Trp Leu Asn Trp Ile Phe Leu Val Thr Leu Leu
145 150 155 160
Asn Gly Ile Gln Cys Glu Val Lys Leu Val Glu Ser Gly Gly Gly Leu
165 170 175
Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Thr Ser Gly Phe
180 185 190
Thr Phe Thr Asp Tyr His Leu Asn Trp Val Arg Gln Pro Pro Gly Lys
195 200 205
Ala Leu Glu Trp Leu Ala Leu Ile Arg Asn Lys Arg Tyr Gly Tyr Arg
210 215 220
Thr Glu Tyr Ser Ala Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp
225 230 235 240
Asn Ser Gln Ser Ile Leu Tyr Leu Gln Met Asn Thr Leu Arg Ala Glu
245 250 255
Asp Ser Ala Thr Tyr Tyr Cys Ala Arg Asp Phe Tyr Asp Pro Phe Ala
260 265 270
Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ala
275 280
<210> 24
<211> 284
<212> PRT
<213> 人工序列
<220>
<223> 合成构建体
<400> 24
Met Lys Leu Trp Leu Asn Trp Ile Phe Pro Val Thr Leu Leu Asn Gly
1 5 10 15
Ile Gln Cys Glu Val Lys Leu Val Glu Ser Gly Gly Gly Leu Val Gln
20 25 30
Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Thr Ser Gly Phe Thr Phe
35 40 45
Thr Asp Tyr His Met Asn Trp Val Arg Gln Pro Pro Gly Lys Ala Leu
50 55 60
Glu Trp Leu Ala Leu Ile Arg Asn Lys Ala Asn Gly Tyr Arg Thr Glu
65 70 75 80
Tyr Ser Ala Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser
85 90 95
Gln Asn Ile Leu Tyr Leu Gln Met Asn Thr Leu Arg Ala Glu Asp Ser
100 105 110
Ala Thr Tyr Tyr Cys Ala Arg Asp Phe Tyr Asp Pro Phe Ala Tyr Trp
115 120 125
Gly Gln Gly Thr Leu Val Thr Val Ser Ala Gly Gly Gly Gly Ser Gly
130 135 140
Gly Gly Gly Ser Gly Gly Gly Gly Ser Met Lys Leu Pro Val Arg Leu
145 150 155 160
Leu Val Leu Met Phe Trp Ile Pro Ala Ser Ser Ser Asp Val Val Met
165 170 175
Thr Gln Thr Pro Leu Ser Leu Pro Val Ser Leu Gly Asp Gln Ala Ser
180 185 190
Ile Ser Cys Arg Ser Ser Gln Ser Leu Val His Ser Asn Gly Asn Thr
195 200 205
Tyr Leu His Trp Tyr Leu Gln Arg Pro Gly Gln Ser Pro Lys Leu Leu
210 215 220
Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro Asp Arg Phe Ser
225 230 235 240
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile Ser Arg Val Glu
245 250 255
Ala Glu Asp Leu Gly Val Tyr Phe Cys Ser Gln Ser Thr His Val Pro
260 265 270
Phe Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys
275 280
<210> 25
<211> 284
<212> PRT
<213> 人工序列
<220>
<223> 合成构建体
<400> 25
Met Lys Leu Pro Val Arg Leu Leu Val Leu Met Phe Trp Ile Pro Ala
1 5 10 15
Ser Ser Ser Asp Val Val Met Thr Gln Thr Pro Leu Ser Leu Pro Val
20 25 30
Ser Leu Gly Asp Gln Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu
35 40 45
Val His Ser Asn Gly Asn Thr Tyr Leu His Trp Tyr Leu Gln Arg Pro
50 55 60
Gly Gln Ser Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser
65 70 75 80
Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
85 90 95
Leu Lys Ile Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Phe Cys
100 105 110
Ser Gln Ser Thr His Val Pro Phe Thr Phe Gly Ser Gly Thr Lys Leu
115 120 125
Glu Ile Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
130 135 140
Gly Ser Met Lys Leu Trp Leu Asn Trp Ile Phe Pro Val Thr Leu Leu
145 150 155 160
Asn Gly Ile Gln Cys Glu Val Lys Leu Val Glu Ser Gly Gly Gly Leu
165 170 175
Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Thr Ser Gly Phe
180 185 190
Thr Phe Thr Asp Tyr His Met Asn Trp Val Arg Gln Pro Pro Gly Lys
195 200 205
Ala Leu Glu Trp Leu Ala Leu Ile Arg Asn Lys Ala Asn Gly Tyr Arg
210 215 220
Thr Glu Tyr Ser Ala Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp
225 230 235 240
Asn Ser Gln Asn Ile Leu Tyr Leu Gln Met Asn Thr Leu Arg Ala Glu
245 250 255
Asp Ser Ala Thr Tyr Tyr Cys Ala Arg Asp Phe Tyr Asp Pro Phe Ala
260 265 270
Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ala
275 280
<210> 26
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 合成构建体
<400> 26
Asp Tyr His Met Asn
1 5
<210> 27
<211> 19
<212> PRT
<213> 人工序列
<220>
<223> 合成构建体
<400> 27
Leu Ile Arg Asn Lys Ala Asn Gly Tyr Arg Thr Glu Tyr Ser Ala Ser
1 5 10 15
Val Lys Gly
<210> 28
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 合成构建体
<400> 28
Ser Gln Ser Thr Arg Val Pro Phe Thr
1 5
<210> 29
<211> 19
<212> PRT
<213> 人工序列
<220>
<223> 合成构建体
<400> 29
Met Lys Leu Trp Leu Asn Trp Ile Phe Leu Val Thr Leu Leu Asn Gly
1 5 10 15
Ile Gln Cys
<210> 30
<211> 19
<212> PRT
<213> 人工序列
<220>
<223> 合成构建体
<400> 30
Met Lys Leu Pro Val Gly Leu Leu Val Leu Met Phe Trp Ile Pro Ala
1 5 10 15
Ser Ser Ser
Claims (12)
1.一种选择性结合肿瘤细胞上的SSTR2细胞外表位的分离抗体,其特征在于:包含具有CDR1、CDR2和CDR3序列的可变重(VH)结构域和具有CDR1、CDR2和CDR3序列的可变轻(VL)结构域,其中所述VH结构域的所述CDR1序列包含氨基酸序列SEQ ID NO:1或SEQ ID NO:26;所述VH结构域的所述CDR2序列包含氨基酸序列SEQ ID NO:2或SEQ ID NO:27;所述VH结构域的所述CDR3序列包含氨基酸序列SEQ ID NO:3;所述VL的所述CDR1序列包含氨基酸序列SEQ IDNO:4;所述VL结构域的所述CDR2序列包含氨基酸序列SEQ ID NO:5;且所述VL结构域的所述CDR3序列包含氨基酸序列SEQ ID NO:6或SEQ ID NO:28。
2.根据权利要求1所述的抗体,其特征在于:抗SSTR2 VH结构域包含氨基酸序列SEQ IDNO:7或SEQ ID NO:18。
3.根据权利要求1或2所述的抗体,其特征在于:抗SSTR2 VH结构域包含氨基酸序列SEQID NO:8或SEQ ID NO:19。
4.根据权利要求1所述的抗体,其特征在于:包含氨基酸序列SEQ ID NO:12、SEQ IDNO:13、SEQ ID NO:20、SEQ ID NO:21、SEQ ID NO:22、SEQ ID NO:23、SEQ ID NO:24或SEQID NO:25。
5.根据权利要求1至4中任一项所述的抗体,其特征在于:所述抗体为重组抗体。
6.根据权利要求5所述的抗体,其特征在于:所述抗体为单链(scFv)抗体。
7.一种分离核酸序列,其特征在于:编码根据权利要求1至6中任一项所述的重组抗体。
8.一种载体,其特征在于:包含根据权利要求7所述的分离核酸序列。
9.一种细胞,其特征在于:包含根据权利要求8所述的载体。
10.一种组合物,其特征在于:包含与抗癌剂缀合的根据权利要求1至6中任一项所述的抗体。
11.根据权利要求10所述的组合物,其特征在于:所述抗癌剂为单甲基奥利他汀E(monomethyl auristatin E)、吉西他滨(gemcitabine)或白藜芦醇(resveratrol)。
12.一种治疗受试者中的神经内分泌(NE)癌的方法,其特征在于:包含向所述受试者施用有效量的根据权利要求10或11所述的组合物。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201862742567P | 2018-10-08 | 2018-10-08 | |
US62/742,567 | 2018-10-08 | ||
PCT/US2019/055145 WO2020076791A2 (en) | 2018-10-08 | 2019-10-08 | Neuroendocrine cancer targeted therapy |
Publications (1)
Publication Number | Publication Date |
---|---|
CN113272322A true CN113272322A (zh) | 2021-08-17 |
Family
ID=70165156
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201980079726.XA Pending CN113272322A (zh) | 2018-10-08 | 2019-10-08 | 神经内分泌癌靶向治疗 |
Country Status (4)
Country | Link |
---|---|
US (1) | US20210340264A1 (zh) |
EP (1) | EP3864039B1 (zh) |
CN (1) | CN113272322A (zh) |
WO (1) | WO2020076791A2 (zh) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2024112866A1 (en) * | 2022-11-22 | 2024-05-30 | Expression Therapeutics, Llc | Engineered t cells |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6815540B1 (en) * | 1996-07-16 | 2004-11-09 | University Of Zurich | Immunoglobulin superfamily domains and fragments with increased solubility |
US20130189285A1 (en) * | 2007-04-25 | 2013-07-25 | Medella Therapeutics Limited | Antibodies against ramp3 |
CN107530435A (zh) * | 2015-03-02 | 2018-01-02 | 科赛普特治疗学股份有限公司 | 使用糖皮质激素受体拮抗剂和生长抑素治疗acth分泌型肿瘤 |
US20180118827A1 (en) * | 2016-06-28 | 2018-05-03 | Xencor, Inc. | Heterodimeric antibodies that bind somatostatin receptor 2 |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2013508287A (ja) * | 2009-10-14 | 2013-03-07 | ヤンセン バイオテツク,インコーポレーテツド | 抗体を親和性成熟する方法 |
CN109422809A (zh) * | 2017-08-24 | 2019-03-05 | 孙立春 | 全人源或人源化生长抑素受体ii单克隆抗体及其药物或诊断试剂的开发与应用 |
-
2019
- 2019-10-08 WO PCT/US2019/055145 patent/WO2020076791A2/en unknown
- 2019-10-08 US US17/283,326 patent/US20210340264A1/en active Pending
- 2019-10-08 EP EP19870180.7A patent/EP3864039B1/en active Active
- 2019-10-08 CN CN201980079726.XA patent/CN113272322A/zh active Pending
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6815540B1 (en) * | 1996-07-16 | 2004-11-09 | University Of Zurich | Immunoglobulin superfamily domains and fragments with increased solubility |
US20130189285A1 (en) * | 2007-04-25 | 2013-07-25 | Medella Therapeutics Limited | Antibodies against ramp3 |
CN107530435A (zh) * | 2015-03-02 | 2018-01-02 | 科赛普特治疗学股份有限公司 | 使用糖皮质激素受体拮抗剂和生长抑素治疗acth分泌型肿瘤 |
US20180118827A1 (en) * | 2016-06-28 | 2018-05-03 | Xencor, Inc. | Heterodimeric antibodies that bind somatostatin receptor 2 |
Non-Patent Citations (2)
Title |
---|
CHIEN-TSUN KUAN 等: ""Detection of Amino-terminal Extracellular Domain of Somatostatin Receptor 2 by Specific Monoclonal Antibodies and Quantification of Receptor Density in Medulloblastoma"", 《HYBRIDOMA》, vol. 28, no. 6, pages 389 - 403, XP055729271, DOI: 10.1089/hyb.2009.0049 * |
陈书凯 等: ""生长抑素受体在人神经内分泌癌组织中的表达及受体激活对细胞生长的抑制"", 《中国生物化学与分子生物学报》, vol. 34, no. 3, pages 310 - 317 * |
Also Published As
Publication number | Publication date |
---|---|
EP3864039B1 (en) | 2023-12-06 |
WO2020076791A2 (en) | 2020-04-16 |
EP3864039A4 (en) | 2022-06-29 |
US20210340264A1 (en) | 2021-11-04 |
WO2020076791A3 (en) | 2020-07-30 |
EP3864039A2 (en) | 2021-08-18 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP7464764B2 (ja) | 抗ror1抗体とその作製及び使用方法 | |
JP2021531826A (ja) | 栄養膜細胞表面抗原2(trop2)に対する特異的な抗体 | |
US7067131B2 (en) | Methods for using anti-MUC18 antibodies | |
US20100278818A1 (en) | Antibody specific for the Tn antigen for the treatment of cancer | |
KR101971770B1 (ko) | 이중특이성 항체 및 이의 용도 | |
DK3049118T3 (en) | MONOCLONAL ANTIBODY AND DERIVATIVES | |
EP3683236A2 (en) | Antibody against human dlk1 and use thereof | |
CA2442531A1 (en) | Peptides and antibodies to muc 1 proteins | |
KR102608028B1 (ko) | 인간 원형질막 소포 관련 단백질 pv-1에 특이적으로 결합하는 단일클론항체 및 이의 제조방법과 용도 | |
WO2017118613A1 (en) | Bispecific antibodies targeting human cd73 | |
JP7048567B2 (ja) | 二重特異性抗原結合ポリペプチド | |
US20220411502A1 (en) | Antibody against c-kit and use thereof | |
CA3044534A1 (en) | Methods of treating prlr positive breast cancer | |
JP2021531825A (ja) | 葉酸受容体アルファに特異的な抗体 | |
CN116333140A (zh) | 网蛋白-1结合抗体及其用途 | |
CN112794911A (zh) | 人源化抗叶酸受体1抗体及其应用 | |
WO2023169583A1 (zh) | 基于Pep42构建的双特异性细胞接合器分子的制备及其应用 | |
AU2014342610A1 (en) | Anti-EFNA4 antibody-drug conjugates | |
CN113272322A (zh) | 神经内分泌癌靶向治疗 | |
WO2023143535A1 (zh) | 一种靶向il-18bp的抗体及其应用 | |
EP4342914A1 (en) | Anti-bcam antibody or antigen-binding fragment thereof | |
CA3171531A1 (en) | Anti- muc1-sea antibodies | |
CN115521375A (zh) | 抗新冠病毒广谱中和性单抗的制备和应用 | |
CN116333143A (zh) | Scube2中和抗体及其医药用途 | |
CN113307871A (zh) | 新型抗cd19抗体和cd19-car-t细胞的制备及其应用 |
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 | ||
WD01 | Invention patent application deemed withdrawn after publication | ||
WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20210817 |