CN114106195A - 一种多功能融合蛋白及其用途 - Google Patents
一种多功能融合蛋白及其用途 Download PDFInfo
- Publication number
- CN114106195A CN114106195A CN202110971791.2A CN202110971791A CN114106195A CN 114106195 A CN114106195 A CN 114106195A CN 202110971791 A CN202110971791 A CN 202110971791A CN 114106195 A CN114106195 A CN 114106195A
- Authority
- CN
- China
- Prior art keywords
- ser
- val
- gly
- thr
- leu
- 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
- 108020001507 fusion proteins Proteins 0.000 title claims abstract description 140
- 102000037865 fusion proteins Human genes 0.000 title claims abstract description 140
- 102000003812 Interleukin-15 Human genes 0.000 claims abstract description 80
- 108090000172 Interleukin-15 Proteins 0.000 claims abstract description 80
- 239000000427 antigen Substances 0.000 claims abstract description 29
- 102000036639 antigens Human genes 0.000 claims abstract description 29
- 108091007433 antigens Proteins 0.000 claims abstract description 29
- 210000001744 T-lymphocyte Anatomy 0.000 claims abstract description 22
- 108010053727 Interleukin-15 Receptor alpha Subunit Proteins 0.000 claims abstract description 16
- 210000000822 natural killer cell Anatomy 0.000 claims abstract description 12
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 30
- 102000004127 Cytokines Human genes 0.000 claims description 22
- 108090000695 Cytokines Proteins 0.000 claims description 22
- 150000001413 amino acids Chemical group 0.000 claims description 22
- 108060003951 Immunoglobulin Proteins 0.000 claims description 21
- 102000018358 immunoglobulin Human genes 0.000 claims description 21
- 102100038078 CD276 antigen Human genes 0.000 claims description 20
- 101000884279 Homo sapiens CD276 antigen Proteins 0.000 claims description 20
- 230000035772 mutation Effects 0.000 claims description 19
- 102000005962 receptors Human genes 0.000 claims description 18
- 108020003175 receptors Proteins 0.000 claims description 18
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 claims description 11
- 108010017535 Interleukin-15 Receptors Proteins 0.000 claims description 7
- 102000004556 Interleukin-15 Receptors Human genes 0.000 claims description 7
- 238000006467 substitution reaction Methods 0.000 claims description 7
- 102220578647 Chorion-specific transcription factor GCMb_N65D_mutation Human genes 0.000 claims description 6
- 101000623901 Homo sapiens Mucin-16 Proteins 0.000 claims description 6
- 102220485610 Liver carboxylesterase 1_N79A_mutation Human genes 0.000 claims description 6
- 102100023123 Mucin-16 Human genes 0.000 claims description 6
- 102220481907 Probable rRNA-processing protein EBP2_N112A_mutation Human genes 0.000 claims description 6
- 102220311640 rs1382779104 Human genes 0.000 claims description 6
- 239000004471 Glycine Substances 0.000 claims description 5
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 claims description 4
- 102100023635 Alpha-fetoprotein Human genes 0.000 claims description 3
- 102100032530 Glypican-3 Human genes 0.000 claims description 3
- 101000914324 Homo sapiens Carcinoembryonic antigen-related cell adhesion molecule 5 Proteins 0.000 claims description 3
- 101000914321 Homo sapiens Carcinoembryonic antigen-related cell adhesion molecule 7 Proteins 0.000 claims description 3
- 101001014668 Homo sapiens Glypican-3 Proteins 0.000 claims description 3
- 101001133056 Homo sapiens Mucin-1 Proteins 0.000 claims description 3
- 101100460850 Homo sapiens NCR3LG1 gene Proteins 0.000 claims description 3
- 101001024605 Homo sapiens Next to BRCA1 gene 1 protein Proteins 0.000 claims description 3
- 101000617725 Homo sapiens Pregnancy-specific beta-1-glycoprotein 2 Proteins 0.000 claims description 3
- 101001012157 Homo sapiens Receptor tyrosine-protein kinase erbB-2 Proteins 0.000 claims description 3
- 101000884271 Homo sapiens Signal transducer CD24 Proteins 0.000 claims description 3
- 101710123134 Ice-binding protein Proteins 0.000 claims description 3
- 101710082837 Ice-structuring protein Proteins 0.000 claims description 3
- 102100034256 Mucin-1 Human genes 0.000 claims description 3
- 102100029527 Natural cytotoxicity triggering receptor 3 ligand 1 Human genes 0.000 claims description 3
- 102100022019 Pregnancy-specific beta-1-glycoprotein 2 Human genes 0.000 claims description 3
- 102100030086 Receptor tyrosine-protein kinase erbB-2 Human genes 0.000 claims description 3
- 102100038081 Signal transducer CD24 Human genes 0.000 claims description 3
- 101710107540 Type-2 ice-structuring protein Proteins 0.000 claims description 3
- 102000052116 epidermal growth factor receptor activity proteins Human genes 0.000 claims description 3
- 108700015053 epidermal growth factor receptor activity proteins Proteins 0.000 claims description 3
- 210000002540 macrophage Anatomy 0.000 claims 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 claims description 3
- 102200042996 rs1057521927 Human genes 0.000 claims description 3
- 102220289243 rs573603690 Human genes 0.000 claims description 3
- 102220114664 rs886038997 Human genes 0.000 claims description 3
- 206010028980 Neoplasm Diseases 0.000 abstract description 61
- 102000017420 CD3 protein, epsilon/gamma/delta subunit Human genes 0.000 abstract description 35
- 230000000694 effects Effects 0.000 abstract description 22
- 238000013461 design Methods 0.000 abstract description 20
- 230000004913 activation Effects 0.000 abstract description 13
- 230000008685 targeting Effects 0.000 abstract description 13
- 230000015572 biosynthetic process Effects 0.000 abstract description 8
- 210000004881 tumor cell Anatomy 0.000 abstract description 8
- 150000001875 compounds Chemical class 0.000 abstract description 7
- 230000004071 biological effect Effects 0.000 abstract description 6
- 238000013459 approach Methods 0.000 abstract description 4
- 230000002085 persistent effect Effects 0.000 abstract description 4
- 210000002966 serum Anatomy 0.000 abstract description 4
- 206010059866 Drug resistance Diseases 0.000 abstract description 2
- 229940125644 antibody drug Drugs 0.000 abstract description 2
- 231100000331 toxic Toxicity 0.000 abstract description 2
- 230000002588 toxic effect Effects 0.000 abstract description 2
- 230000007115 recruitment Effects 0.000 abstract 1
- 210000000225 synapse Anatomy 0.000 abstract 1
- 210000004027 cell Anatomy 0.000 description 68
- 230000027455 binding Effects 0.000 description 41
- 239000002773 nucleotide Substances 0.000 description 36
- 125000003729 nucleotide group Chemical group 0.000 description 36
- 125000003275 alpha amino acid group Chemical group 0.000 description 35
- 108090000623 proteins and genes Proteins 0.000 description 29
- 239000013598 vector Substances 0.000 description 24
- 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 18
- 235000001014 amino acid Nutrition 0.000 description 18
- XKUKSGPZAADMRA-UHFFFAOYSA-N glycyl-glycyl-glycine Natural products NCC(=O)NCC(=O)NCC(O)=O XKUKSGPZAADMRA-UHFFFAOYSA-N 0.000 description 18
- 229920001184 polypeptide Polymers 0.000 description 17
- 102000004196 processed proteins & peptides Human genes 0.000 description 17
- 241000880493 Leptailurus serval Species 0.000 description 16
- UQLDLKMNUJERMK-UHFFFAOYSA-L di(octadecanoyloxy)lead Chemical compound [Pb+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O UQLDLKMNUJERMK-UHFFFAOYSA-L 0.000 description 16
- 239000012634 fragment Substances 0.000 description 16
- 108010001064 glycyl-glycyl-glycyl-glycine Proteins 0.000 description 16
- 102000004169 proteins and genes Human genes 0.000 description 16
- 238000005406 washing Methods 0.000 description 16
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 15
- 230000000638 stimulation Effects 0.000 description 15
- 108020004414 DNA Proteins 0.000 description 14
- 229940024606 amino acid Drugs 0.000 description 14
- 230000014509 gene expression Effects 0.000 description 14
- 150000007523 nucleic acids Chemical class 0.000 description 14
- 210000003819 peripheral blood mononuclear cell Anatomy 0.000 description 14
- 108010031719 prolyl-serine Proteins 0.000 description 14
- 235000018102 proteins Nutrition 0.000 description 14
- 239000000243 solution Substances 0.000 description 14
- 108010076504 Protein Sorting Signals Proteins 0.000 description 13
- 201000011510 cancer Diseases 0.000 description 13
- 238000011534 incubation Methods 0.000 description 13
- 239000013612 plasmid Substances 0.000 description 13
- 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 12
- HNDMFDBQXYZSRM-IHRRRGAJSA-N Ser-Val-Phe Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O HNDMFDBQXYZSRM-IHRRRGAJSA-N 0.000 description 12
- 108010063718 gamma-glutamylaspartic acid Proteins 0.000 description 12
- 108020004707 nucleic acids Proteins 0.000 description 12
- 102000039446 nucleic acids Human genes 0.000 description 12
- 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 11
- 108091028043 Nucleic acid sequence Proteins 0.000 description 11
- 238000002835 absorbance Methods 0.000 description 11
- 230000000903 blocking effect Effects 0.000 description 11
- 108040006849 interleukin-2 receptor activity proteins Proteins 0.000 description 11
- OHLLDUNVMPPUMD-DCAQKATOSA-N Cys-Leu-Val Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](C(C)C)C(=O)O)NC(=O)[C@H](CS)N OHLLDUNVMPPUMD-DCAQKATOSA-N 0.000 description 10
- VUBIPAHVHMZHCM-KKUMJFAQSA-N Leu-Tyr-Ser Chemical compound CC(C)C[C@H](N)C(=O)N[C@H](C(=O)N[C@@H](CO)C(O)=O)CC1=CC=C(O)C=C1 VUBIPAHVHMZHCM-KKUMJFAQSA-N 0.000 description 10
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 10
- 230000006870 function Effects 0.000 description 10
- 108010017391 lysylvaline Proteins 0.000 description 10
- 230000035755 proliferation Effects 0.000 description 10
- 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 9
- IHCXPSYCHXFXKT-DCAQKATOSA-N Pro-Arg-Glu Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(O)=O IHCXPSYCHXFXKT-DCAQKATOSA-N 0.000 description 9
- UQFYNFTYDHUIMI-WHFBIAKZSA-N Ser-Gly-Ala Chemical compound OC(=O)[C@H](C)NC(=O)CNC(=O)[C@@H](N)CO UQFYNFTYDHUIMI-WHFBIAKZSA-N 0.000 description 9
- YUJLIIRMIAGMCQ-CIUDSAMLSA-N Ser-Leu-Ser Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(O)=O YUJLIIRMIAGMCQ-CIUDSAMLSA-N 0.000 description 9
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 9
- 238000000034 method Methods 0.000 description 9
- 108010073969 valyllysine Proteins 0.000 description 9
- 102000004190 Enzymes Human genes 0.000 description 8
- 108090000790 Enzymes Proteins 0.000 description 8
- 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 8
- SJRQWEDYTKYHHL-SLFFLAALSA-N Phe-Tyr-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CC2=CC=C(C=C2)O)NC(=O)[C@H](CC3=CC=CC=C3)N)C(=O)O SJRQWEDYTKYHHL-SLFFLAALSA-N 0.000 description 8
- ZOHGLPQGEHSLPD-FXQIFTODSA-N Ser-Gln-Glu Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(O)=O ZOHGLPQGEHSLPD-FXQIFTODSA-N 0.000 description 8
- 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 8
- JJNXZIPLIXIGBX-HJPIBITLSA-N Tyr-Ile-Cys Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CS)C(=O)O)NC(=O)[C@H](CC1=CC=C(C=C1)O)N JJNXZIPLIXIGBX-HJPIBITLSA-N 0.000 description 8
- BMGOFDMKDVVGJG-NHCYSSNCSA-N Val-Asp-Lys Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](CCCCN)C(=O)O)N BMGOFDMKDVVGJG-NHCYSSNCSA-N 0.000 description 8
- 108010086434 alanyl-seryl-glycine Proteins 0.000 description 8
- 108010050025 alpha-glutamyltryptophan Proteins 0.000 description 8
- 239000003085 diluting agent Substances 0.000 description 8
- 201000010099 disease Diseases 0.000 description 8
- 239000003814 drug Substances 0.000 description 8
- 229940088598 enzyme Drugs 0.000 description 8
- 108010067216 glycyl-glycyl-glycine Proteins 0.000 description 8
- IOFVWPYSRSCWHI-JXUBOQSCSA-N Ala-Thr-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](C)N IOFVWPYSRSCWHI-JXUBOQSCSA-N 0.000 description 7
- 108020004705 Codon Proteins 0.000 description 7
- 208000000461 Esophageal Neoplasms Diseases 0.000 description 7
- 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 7
- BRTVHXHCUSXYRI-CIUDSAMLSA-N Leu-Ser-Ser Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(O)=O BRTVHXHCUSXYRI-CIUDSAMLSA-N 0.000 description 7
- 206010030155 Oesophageal carcinoma Diseases 0.000 description 7
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 7
- WDXYVIIVDIDOSX-DCAQKATOSA-N Ser-Arg-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)CO)CCCN=C(N)N WDXYVIIVDIDOSX-DCAQKATOSA-N 0.000 description 7
- 208000005718 Stomach Neoplasms Diseases 0.000 description 7
- FYBFTPLPAXZBOY-KKHAAJSZSA-N Thr-Val-Asp Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(O)=O)C(O)=O FYBFTPLPAXZBOY-KKHAAJSZSA-N 0.000 description 7
- 238000007792 addition Methods 0.000 description 7
- 108010052670 arginyl-glutamyl-glutamic acid Proteins 0.000 description 7
- 108010092854 aspartyllysine Proteins 0.000 description 7
- 238000012217 deletion Methods 0.000 description 7
- 230000037430 deletion Effects 0.000 description 7
- 239000012636 effector Substances 0.000 description 7
- 201000004101 esophageal cancer Diseases 0.000 description 7
- 239000013604 expression vector Substances 0.000 description 7
- 206010017758 gastric cancer Diseases 0.000 description 7
- VPZXBVLAVMBEQI-UHFFFAOYSA-N glycyl-DL-alpha-alanine Natural products OC(=O)C(C)NC(=O)CN VPZXBVLAVMBEQI-UHFFFAOYSA-N 0.000 description 7
- 108010050848 glycylleucine Proteins 0.000 description 7
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 7
- 239000013642 negative control Substances 0.000 description 7
- 201000002528 pancreatic cancer Diseases 0.000 description 7
- 208000008443 pancreatic carcinoma Diseases 0.000 description 7
- 201000011549 stomach cancer Diseases 0.000 description 7
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 6
- MNZHHDPWDWQJCQ-YUMQZZPRSA-N Ala-Leu-Gly Chemical compound C[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)NCC(O)=O MNZHHDPWDWQJCQ-YUMQZZPRSA-N 0.000 description 6
- WQKAQKZRDIZYNV-VZFHVOOUSA-N Ala-Ser-Thr Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(O)=O WQKAQKZRDIZYNV-VZFHVOOUSA-N 0.000 description 6
- YJHKTAMKPGFJCT-NRPADANISA-N Ala-Val-Glu Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(O)=O)C(O)=O YJHKTAMKPGFJCT-NRPADANISA-N 0.000 description 6
- HNXWVVHIGTZTBO-LKXGYXEUSA-N Asn-Ser-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC(N)=O HNXWVVHIGTZTBO-LKXGYXEUSA-N 0.000 description 6
- PUUPMDXIHCOPJU-HJGDQZAQSA-N Asn-Thr-Lys Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CC(=O)N)N)O PUUPMDXIHCOPJU-HJGDQZAQSA-N 0.000 description 6
- MJIJBEYEHBKTIM-BYULHYEWSA-N Asn-Val-Asn Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)O)NC(=O)[C@H](CC(=O)N)N MJIJBEYEHBKTIM-BYULHYEWSA-N 0.000 description 6
- 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 6
- 238000002965 ELISA Methods 0.000 description 6
- ZFBBMCKQSNJZSN-AUTRQRHGSA-N Gln-Val-Gln Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(N)=O)C(O)=O ZFBBMCKQSNJZSN-AUTRQRHGSA-N 0.000 description 6
- GJBUAAAIZSRCDC-GVXVVHGQSA-N Glu-Leu-Val Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(O)=O GJBUAAAIZSRCDC-GVXVVHGQSA-N 0.000 description 6
- UQJNXZSSGQIPIQ-FBCQKBJTSA-N Gly-Gly-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)CNC(=O)CN UQJNXZSSGQIPIQ-FBCQKBJTSA-N 0.000 description 6
- FGPLUIQCSKGLTI-WDSKDSINSA-N Gly-Ser-Glu Chemical compound NCC(=O)N[C@@H](CO)C(=O)N[C@H](C(O)=O)CCC(O)=O FGPLUIQCSKGLTI-WDSKDSINSA-N 0.000 description 6
- GBYYQVBXFVDJPJ-WLTAIBSBSA-N Gly-Tyr-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CC1=CC=C(C=C1)O)NC(=O)CN)O GBYYQVBXFVDJPJ-WLTAIBSBSA-N 0.000 description 6
- FULZDMOZUZKGQU-ONGXEEELSA-N Gly-Val-His Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)NC(=O)CN FULZDMOZUZKGQU-ONGXEEELSA-N 0.000 description 6
- TTYKEFZRLKQTHH-MELADBBJSA-N His-Lys-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CCCCN)NC(=O)[C@H](CC2=CN=CN2)N)C(=O)O TTYKEFZRLKQTHH-MELADBBJSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- RCFDOSNHHZGBOY-UHFFFAOYSA-N L-isoleucyl-L-alanine Natural products CCC(C)C(N)C(=O)NC(C)C(O)=O RCFDOSNHHZGBOY-UHFFFAOYSA-N 0.000 description 6
- WSGXUIQTEZDVHJ-GARJFASQSA-N Leu-Ala-Pro Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](C)C(=O)N1CCC[C@@H]1C(O)=O WSGXUIQTEZDVHJ-GARJFASQSA-N 0.000 description 6
- KAFOIVJDVSZUMD-DCAQKATOSA-N Leu-Gln-Gln Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(O)=O KAFOIVJDVSZUMD-DCAQKATOSA-N 0.000 description 6
- KAFOIVJDVSZUMD-UHFFFAOYSA-N Leu-Gln-Gln Natural products CC(C)CC(N)C(=O)NC(CCC(N)=O)C(=O)NC(CCC(N)=O)C(O)=O KAFOIVJDVSZUMD-UHFFFAOYSA-N 0.000 description 6
- 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 6
- XOWMDXHFSBCAKQ-SRVKXCTJSA-N Leu-Ser-Leu Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@H](C(O)=O)CC(C)C XOWMDXHFSBCAKQ-SRVKXCTJSA-N 0.000 description 6
- ILDSIMPXNFWKLH-KATARQTJSA-N Leu-Thr-Ser Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(O)=O ILDSIMPXNFWKLH-KATARQTJSA-N 0.000 description 6
- UWKNTTJNVSYXPC-CIUDSAMLSA-N Lys-Ala-Ser Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CCCCN UWKNTTJNVSYXPC-CIUDSAMLSA-N 0.000 description 6
- NTBFKPBULZGXQL-KKUMJFAQSA-N Lys-Asp-Tyr Chemical compound NCCCC[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 NTBFKPBULZGXQL-KKUMJFAQSA-N 0.000 description 6
- RFQATBGBLDAKGI-VHSXEESVSA-N Lys-Gly-Pro Chemical compound C1C[C@@H](N(C1)C(=O)CNC(=O)[C@H](CCCCN)N)C(=O)O RFQATBGBLDAKGI-VHSXEESVSA-N 0.000 description 6
- VOOINLQYUZOREH-SRVKXCTJSA-N Met-Gln-Leu Chemical compound CC(C)C[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)N)NC(=O)[C@H](CCSC)N VOOINLQYUZOREH-SRVKXCTJSA-N 0.000 description 6
- QARPMYDMYVLFMW-KKUMJFAQSA-N Phe-Pro-Glu Chemical compound C([C@H](N)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCC(O)=O)C(O)=O)C1=CC=CC=C1 QARPMYDMYVLFMW-KKUMJFAQSA-N 0.000 description 6
- 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 6
- VAUMZJHYZQXZBQ-WHFBIAKZSA-N Ser-Asn-Gly Chemical compound OC[C@H](N)C(=O)N[C@@H](CC(N)=O)C(=O)NCC(O)=O VAUMZJHYZQXZBQ-WHFBIAKZSA-N 0.000 description 6
- QPFJSHSJFIYDJZ-GHCJXIJMSA-N Ser-Asp-Ile Chemical compound CC[C@H](C)[C@@H](C(O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@@H](N)CO QPFJSHSJFIYDJZ-GHCJXIJMSA-N 0.000 description 6
- 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 6
- 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 6
- OZPDGESCTGGNAD-CIUDSAMLSA-N Ser-Ser-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CO OZPDGESCTGGNAD-CIUDSAMLSA-N 0.000 description 6
- XJDMUQCLVSCRSJ-VZFHVOOUSA-N Ser-Thr-Ala Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C)C(O)=O XJDMUQCLVSCRSJ-VZFHVOOUSA-N 0.000 description 6
- SNXUIBACCONSOH-BWBBJGPYSA-N Ser-Thr-Ser Chemical compound OC[C@H](N)C(=O)N[C@@H]([C@H](O)C)C(=O)N[C@@H](CO)C(O)=O SNXUIBACCONSOH-BWBBJGPYSA-N 0.000 description 6
- 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 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
- JMBRNXUOLJFURW-BEAPCOKYSA-N Thr-Phe-Pro Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N2CCC[C@@H]2C(=O)O)N)O JMBRNXUOLJFURW-BEAPCOKYSA-N 0.000 description 6
- XHWCDRUPDNSDAZ-XKBZYTNZSA-N Thr-Ser-Glu Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(=O)O)C(=O)O)N)O XHWCDRUPDNSDAZ-XKBZYTNZSA-N 0.000 description 6
- QYSBJAUCUKHSLU-JYJNAYRXSA-N Tyr-Arg-Val Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C(C)C)C(O)=O QYSBJAUCUKHSLU-JYJNAYRXSA-N 0.000 description 6
- HGJRMXOWUWVUOA-GVXVVHGQSA-N Val-Leu-Gln Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)O)NC(=O)[C@H](C(C)C)N HGJRMXOWUWVUOA-GVXVVHGQSA-N 0.000 description 6
- SSYBNWFXCFNRFN-GUBZILKMSA-N Val-Pro-Ser Chemical compound CC(C)[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CO)C(O)=O SSYBNWFXCFNRFN-GUBZILKMSA-N 0.000 description 6
- SDHZOOIGIUEPDY-JYJNAYRXSA-N Val-Ser-Trp Chemical compound C1=CC=C2C(C[C@H](NC(=O)[C@H](CO)NC(=O)[C@@H](N)C(C)C)C(O)=O)=CNC2=C1 SDHZOOIGIUEPDY-JYJNAYRXSA-N 0.000 description 6
- JVGDAEKKZKKZFO-RCWTZXSCSA-N Val-Val-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](C(C)C)NC(=O)[C@H](C(C)C)N)O JVGDAEKKZKKZFO-RCWTZXSCSA-N 0.000 description 6
- KOSRFJWDECSPRO-UHFFFAOYSA-N alpha-L-glutamyl-L-glutamic acid Natural products OC(=O)CCC(N)C(=O)NC(CCC(O)=O)C(O)=O KOSRFJWDECSPRO-UHFFFAOYSA-N 0.000 description 6
- 108010047857 aspartylglycine Proteins 0.000 description 6
- 238000003556 assay Methods 0.000 description 6
- 238000013368 capillary electrophoresis sodium dodecyl sulfate analysis Methods 0.000 description 6
- 108010060199 cysteinylproline Proteins 0.000 description 6
- 238000002474 experimental method Methods 0.000 description 6
- 108010055341 glutamyl-glutamic acid Proteins 0.000 description 6
- 108010000434 glycyl-alanyl-leucine Proteins 0.000 description 6
- 108010050475 glycyl-leucyl-tyrosine Proteins 0.000 description 6
- 108010089804 glycyl-threonine Proteins 0.000 description 6
- 108010010147 glycylglutamine Proteins 0.000 description 6
- 230000003993 interaction Effects 0.000 description 6
- 230000002147 killing effect Effects 0.000 description 6
- 108010044311 leucyl-glycyl-glycine Proteins 0.000 description 6
- 108010064235 lysylglycine Proteins 0.000 description 6
- 108010038320 lysylphenylalanine Proteins 0.000 description 6
- 230000007246 mechanism Effects 0.000 description 6
- 230000001404 mediated effect Effects 0.000 description 6
- 108010024654 phenylalanyl-prolyl-alanine Proteins 0.000 description 6
- 108010073101 phenylalanylleucine Proteins 0.000 description 6
- 238000002360 preparation method Methods 0.000 description 6
- 108010077112 prolyl-proline Proteins 0.000 description 6
- 238000009097 single-agent therapy Methods 0.000 description 6
- 239000006228 supernatant Substances 0.000 description 6
- 108010071097 threonyl-lysyl-proline Proteins 0.000 description 6
- 108010038745 tryptophylglycine Proteins 0.000 description 6
- 108010052774 valyl-lysyl-glycyl-phenylalanyl-tyrosine Proteins 0.000 description 6
- 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 5
- YNQIDCRRTWGHJD-ZLUOBGJFSA-N Asp-Asn-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](N)CC(O)=O YNQIDCRRTWGHJD-ZLUOBGJFSA-N 0.000 description 5
- 241000283707 Capra Species 0.000 description 5
- 101001003140 Homo sapiens Interleukin-15 receptor subunit alpha Proteins 0.000 description 5
- TYYLDKGBCJGJGW-UHFFFAOYSA-N L-tryptophan-L-tyrosine Natural products C=1NC2=CC=CC=C2C=1CC(N)C(=O)NC(C(O)=O)CC1=CC=C(O)C=C1 TYYLDKGBCJGJGW-UHFFFAOYSA-N 0.000 description 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
- PDIDTSZKKFEDMB-UWVGGRQHSA-N Lys-Pro-Gly Chemical compound [H]N[C@@H](CCCCN)C(=O)N1CCC[C@H]1C(=O)NCC(O)=O PDIDTSZKKFEDMB-UWVGGRQHSA-N 0.000 description 5
- 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 5
- VRUFCJZQDACGLH-UVOCVTCTSA-N Thr-Leu-Thr Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O VRUFCJZQDACGLH-UVOCVTCTSA-N 0.000 description 5
- WPSKTVVMQCXPRO-BWBBJGPYSA-N Thr-Ser-Ser Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(O)=O WPSKTVVMQCXPRO-BWBBJGPYSA-N 0.000 description 5
- UOXPLPBMEPLZBW-WDSOQIARSA-N Trp-Val-Lys Chemical compound C1=CC=C2C(C[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(O)=O)=CNC2=C1 UOXPLPBMEPLZBW-WDSOQIARSA-N 0.000 description 5
- OWFGFHQMSBTKLX-UFYCRDLUSA-N Val-Tyr-Tyr Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC1=CC=C(C=C1)O)C(=O)N[C@@H](CC2=CC=C(C=C2)O)C(=O)O)N OWFGFHQMSBTKLX-UFYCRDLUSA-N 0.000 description 5
- 239000000872 buffer Substances 0.000 description 5
- 238000006243 chemical reaction Methods 0.000 description 5
- 238000010790 dilution Methods 0.000 description 5
- 239000012895 dilution Substances 0.000 description 5
- 239000000833 heterodimer Substances 0.000 description 5
- 238000000338 in vitro Methods 0.000 description 5
- 238000001727 in vivo Methods 0.000 description 5
- 108010034529 leucyl-lysine Proteins 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 230000002829 reductive effect Effects 0.000 description 5
- 230000001105 regulatory effect Effects 0.000 description 5
- 230000004044 response Effects 0.000 description 5
- 108010044292 tryptophyltyrosine Proteins 0.000 description 5
- DPNZTBKGAUAZQU-DLOVCJGASA-N Ala-Leu-His Chemical compound C[C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)N DPNZTBKGAUAZQU-DLOVCJGASA-N 0.000 description 4
- OINVDEKBKBCPLX-JXUBOQSCSA-N Ala-Lys-Thr Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(O)=O OINVDEKBKBCPLX-JXUBOQSCSA-N 0.000 description 4
- ZJBUILVYSXQNSW-YTWAJWBKSA-N Arg-Thr-Pro Chemical compound C[C@H]([C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](CCCN=C(N)N)N)O ZJBUILVYSXQNSW-YTWAJWBKSA-N 0.000 description 4
- BVLIJXXSXBUGEC-SRVKXCTJSA-N Asn-Asn-Tyr Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O BVLIJXXSXBUGEC-SRVKXCTJSA-N 0.000 description 4
- OLVIPTLKNSAYRJ-YUMQZZPRSA-N Asn-Gly-Lys Chemical compound C(CCN)C[C@@H](C(=O)O)NC(=O)CNC(=O)[C@H](CC(=O)N)N OLVIPTLKNSAYRJ-YUMQZZPRSA-N 0.000 description 4
- WQLJRNRLHWJIRW-KKUMJFAQSA-N Asn-His-Tyr Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)O)NC(=O)[C@H](CC2=CN=CN2)NC(=O)[C@H](CC(=O)N)N)O WQLJRNRLHWJIRW-KKUMJFAQSA-N 0.000 description 4
- NYGILGUOUOXGMJ-YUMQZZPRSA-N Asn-Lys-Gly Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)NCC(O)=O NYGILGUOUOXGMJ-YUMQZZPRSA-N 0.000 description 4
- KBQOUDLMWYWXNP-YDHLFZDLSA-N Asn-Val-Phe Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)O)NC(=O)[C@H](CC(=O)N)N KBQOUDLMWYWXNP-YDHLFZDLSA-N 0.000 description 4
- WSGVTKZFVJSJOG-RCOVLWMOSA-N Asp-Gly-Val Chemical compound [H]N[C@@H](CC(O)=O)C(=O)NCC(=O)N[C@@H](C(C)C)C(O)=O WSGVTKZFVJSJOG-RCOVLWMOSA-N 0.000 description 4
- CUQDCPXNZPDYFQ-ZLUOBGJFSA-N Asp-Ser-Asp Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(O)=O)C(O)=O CUQDCPXNZPDYFQ-ZLUOBGJFSA-N 0.000 description 4
- YUELDQUPTAYEGM-XIRDDKMYSA-N Asp-Trp-Leu Chemical compound CC(C)C[C@@H](C(=O)O)NC(=O)[C@H](CC1=CNC2=CC=CC=C21)NC(=O)[C@H](CC(=O)O)N YUELDQUPTAYEGM-XIRDDKMYSA-N 0.000 description 4
- SMEYEQDCCBHTEF-FXQIFTODSA-N Cys-Pro-Ala Chemical compound [H]N[C@@H](CS)C(=O)N1CCC[C@H]1C(=O)N[C@@H](C)C(O)=O SMEYEQDCCBHTEF-FXQIFTODSA-N 0.000 description 4
- KSMSFCBQBQPFAD-GUBZILKMSA-N Cys-Pro-Pro Chemical compound SC[C@H](N)C(=O)N1CCC[C@H]1C(=O)N1[C@H](C(O)=O)CCC1 KSMSFCBQBQPFAD-GUBZILKMSA-N 0.000 description 4
- ALTQTAKGRFLRLR-GUBZILKMSA-N Cys-Val-Val Chemical compound CC(C)[C@@H](C(=O)N[C@@H](C(C)C)C(=O)O)NC(=O)[C@H](CS)N ALTQTAKGRFLRLR-GUBZILKMSA-N 0.000 description 4
- KCJJFESQRXGTGC-BQBZGAKWSA-N Gln-Glu-Gly Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)NCC(O)=O KCJJFESQRXGTGC-BQBZGAKWSA-N 0.000 description 4
- AQPZYBSRDRZBAG-AVGNSLFASA-N Gln-Phe-Asn Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)O)NC(=O)[C@H](CCC(=O)N)N AQPZYBSRDRZBAG-AVGNSLFASA-N 0.000 description 4
- HMIXCETWRYDVMO-GUBZILKMSA-N Gln-Pro-Glu Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCC(O)=O)C(O)=O HMIXCETWRYDVMO-GUBZILKMSA-N 0.000 description 4
- RFDHKPSHTXZKLL-IHRRRGAJSA-N Glu-Gln-Phe Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)N)NC(=O)[C@H](CCC(=O)O)N RFDHKPSHTXZKLL-IHRRRGAJSA-N 0.000 description 4
- YHOJJFFTSMWVGR-HJGDQZAQSA-N Glu-Met-Thr Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCSC)C(=O)N[C@@H]([C@@H](C)O)C(O)=O YHOJJFFTSMWVGR-HJGDQZAQSA-N 0.000 description 4
- AAJHGGDRKHYSDH-GUBZILKMSA-N Glu-Pro-Gln Chemical compound C1C[C@H](N(C1)C(=O)[C@H](CCC(=O)O)N)C(=O)N[C@@H](CCC(=O)N)C(=O)O AAJHGGDRKHYSDH-GUBZILKMSA-N 0.000 description 4
- ZALGPUWUVHOGAE-GVXVVHGQSA-N Glu-Val-His Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)NC(=O)[C@H](CCC(=O)O)N ZALGPUWUVHOGAE-GVXVVHGQSA-N 0.000 description 4
- WGYHAAXZWPEBDQ-IFFSRLJSSA-N Glu-Val-Thr Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O WGYHAAXZWPEBDQ-IFFSRLJSSA-N 0.000 description 4
- OOCFXNOVSLSHAB-IUCAKERBSA-N Gly-Pro-Pro Chemical compound NCC(=O)N1CCC[C@H]1C(=O)N1[C@H](C(O)=O)CCC1 OOCFXNOVSLSHAB-IUCAKERBSA-N 0.000 description 4
- JSLVAHYTAJJEQH-QWRGUYRKSA-N Gly-Ser-Phe Chemical compound NCC(=O)N[C@@H](CO)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 JSLVAHYTAJJEQH-QWRGUYRKSA-N 0.000 description 4
- 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 4
- PXKACEXYLPBMAD-JBDRJPRFSA-N Ile-Ser-Ser Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)O)N PXKACEXYLPBMAD-JBDRJPRFSA-N 0.000 description 4
- VWHGTYCRDRBSFI-ZETCQYMHSA-N Leu-Gly-Gly Chemical compound CC(C)C[C@H](N)C(=O)NCC(=O)NCC(O)=O VWHGTYCRDRBSFI-ZETCQYMHSA-N 0.000 description 4
- BKTXKJMNTSMJDQ-AVGNSLFASA-N Leu-His-Gln Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)N[C@@H](CCC(=O)N)C(=O)O)N BKTXKJMNTSMJDQ-AVGNSLFASA-N 0.000 description 4
- AUNMOHYWTAPQLA-XUXIUFHCSA-N Leu-Met-Ile Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O AUNMOHYWTAPQLA-XUXIUFHCSA-N 0.000 description 4
- UHNQRAFSEBGZFZ-YESZJQIVSA-N Leu-Phe-Pro Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N2CCC[C@@H]2C(=O)O)N UHNQRAFSEBGZFZ-YESZJQIVSA-N 0.000 description 4
- DPURXCQCHSQPAN-AVGNSLFASA-N Leu-Pro-Pro Chemical compound CC(C)C[C@H](N)C(=O)N1CCC[C@H]1C(=O)N1[C@H](C(O)=O)CCC1 DPURXCQCHSQPAN-AVGNSLFASA-N 0.000 description 4
- CHJKEDSZNSONPS-DCAQKATOSA-N Leu-Pro-Ser Chemical compound [H]N[C@@H](CC(C)C)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CO)C(O)=O CHJKEDSZNSONPS-DCAQKATOSA-N 0.000 description 4
- AIQWYVFNBNNOLU-RHYQMDGZSA-N Leu-Thr-Val Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(O)=O AIQWYVFNBNNOLU-RHYQMDGZSA-N 0.000 description 4
- WSXTWLJHTLRFLW-SRVKXCTJSA-N Lys-Ala-Lys Chemical compound NCCCC[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCN)C(O)=O WSXTWLJHTLRFLW-SRVKXCTJSA-N 0.000 description 4
- YKIRNDPUWONXQN-GUBZILKMSA-N Lys-Asn-Gln Chemical compound C(CCN)C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CCC(=O)N)C(=O)O)N YKIRNDPUWONXQN-GUBZILKMSA-N 0.000 description 4
- KWUKZRFFKPLUPE-HJGDQZAQSA-N Lys-Asp-Thr Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O KWUKZRFFKPLUPE-HJGDQZAQSA-N 0.000 description 4
- CAVRAQIDHUPECU-UVOCVTCTSA-N Lys-Thr-Thr Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O CAVRAQIDHUPECU-UVOCVTCTSA-N 0.000 description 4
- 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 4
- YBAFDPFAUTYYRW-UHFFFAOYSA-N N-L-alpha-glutamyl-L-leucine Natural products CC(C)CC(C(O)=O)NC(=O)C(N)CCC(O)=O YBAFDPFAUTYYRW-UHFFFAOYSA-N 0.000 description 4
- KZNQNBZMBZJQJO-UHFFFAOYSA-N N-glycyl-L-proline Natural products NCC(=O)N1CCCC1C(O)=O KZNQNBZMBZJQJO-UHFFFAOYSA-N 0.000 description 4
- 108010079364 N-glycylalanine Proteins 0.000 description 4
- JDMKQHSHKJHAHR-UHFFFAOYSA-N Phe-Phe-Leu-Tyr Natural products C=1C=C(O)C=CC=1CC(C(O)=O)NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)CC1=CC=CC=C1 JDMKQHSHKJHAHR-UHFFFAOYSA-N 0.000 description 4
- CGBYDGAJHSOGFQ-LPEHRKFASA-N Pro-Ala-Pro Chemical compound C[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@@H]2CCCN2 CGBYDGAJHSOGFQ-LPEHRKFASA-N 0.000 description 4
- WFHYFCWBLSKEMS-KKUMJFAQSA-N Pro-Glu-Phe Chemical compound N([C@@H](CCC(=O)O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)C(=O)[C@@H]1CCCN1 WFHYFCWBLSKEMS-KKUMJFAQSA-N 0.000 description 4
- VPEVBAUSTBWQHN-NHCYSSNCSA-N Pro-Glu-Val Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(O)=O VPEVBAUSTBWQHN-NHCYSSNCSA-N 0.000 description 4
- ULWBBFKQBDNGOY-RWMBFGLXSA-N Pro-Lys-Pro Chemical compound C1C[C@H](NC1)C(=O)N[C@@H](CCCCN)C(=O)N2CCC[C@@H]2C(=O)O ULWBBFKQBDNGOY-RWMBFGLXSA-N 0.000 description 4
- KBUAPZAZPWNYSW-SRVKXCTJSA-N Pro-Pro-Val Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@H]1NCCC1 KBUAPZAZPWNYSW-SRVKXCTJSA-N 0.000 description 4
- UEJYSALTSUZXFV-SRVKXCTJSA-N Rigin Chemical compound NCC(=O)N[C@@H](CCC(N)=O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCCN=C(N)N)C(O)=O UEJYSALTSUZXFV-SRVKXCTJSA-N 0.000 description 4
- HZWAHWQZPSXNCB-BPUTZDHNSA-N Ser-Arg-Trp Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC1=CNC2=C1C=CC=C2)C(O)=O HZWAHWQZPSXNCB-BPUTZDHNSA-N 0.000 description 4
- MOVJSUIKUNCVMG-ZLUOBGJFSA-N Ser-Cys-Ser Chemical compound C([C@@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CO)C(=O)O)N)O MOVJSUIKUNCVMG-ZLUOBGJFSA-N 0.000 description 4
- 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 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
- DJACUBDEDBZKLQ-KBIXCLLPSA-N Ser-Ile-Glu Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCC(O)=O)C(O)=O DJACUBDEDBZKLQ-KBIXCLLPSA-N 0.000 description 4
- MUJQWSAWLLRJCE-KATARQTJSA-N Ser-Leu-Thr Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O MUJQWSAWLLRJCE-KATARQTJSA-N 0.000 description 4
- QJKPECIAWNNKIT-KKUMJFAQSA-N Ser-Lys-Tyr Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O QJKPECIAWNNKIT-KKUMJFAQSA-N 0.000 description 4
- CUXJENOFJXOSOZ-BIIVOSGPSA-N Ser-Ser-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CO)NC(=O)[C@H](CO)N)C(=O)O CUXJENOFJXOSOZ-BIIVOSGPSA-N 0.000 description 4
- LAFLAXHTDVNVEL-WDCWCFNPSA-N Thr-Gln-Lys Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H](CCCCN)C(=O)O)N)O LAFLAXHTDVNVEL-WDCWCFNPSA-N 0.000 description 4
- YOOAQCZYZHGUAZ-KATARQTJSA-N Thr-Leu-Ser Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(O)=O YOOAQCZYZHGUAZ-KATARQTJSA-N 0.000 description 4
- SSSDKJMQMZTMJP-BVSLBCMMSA-N Trp-Tyr-Val Chemical compound C([C@@H](C(=O)N[C@@H](C(C)C)C(O)=O)NC(=O)[C@@H](N)CC=1C2=CC=CC=C2NC=1)C1=CC=C(O)C=C1 SSSDKJMQMZTMJP-BVSLBCMMSA-N 0.000 description 4
- GZUIDWDVMWZSMI-KKUMJFAQSA-N Tyr-Lys-Cys Chemical compound NCCCC[C@@H](C(=O)N[C@@H](CS)C(O)=O)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 GZUIDWDVMWZSMI-KKUMJFAQSA-N 0.000 description 4
- SCBITHMBEJNRHC-LSJOCFKGSA-N Val-Asp-Val Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](C(C)C)C(=O)O)N SCBITHMBEJNRHC-LSJOCFKGSA-N 0.000 description 4
- SBJCTAZFSZXWSR-AVGNSLFASA-N Val-Met-His Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)N SBJCTAZFSZXWSR-AVGNSLFASA-N 0.000 description 4
- 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 4
- NZYNRRGJJVSSTJ-GUBZILKMSA-N Val-Ser-Val Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(O)=O NZYNRRGJJVSSTJ-GUBZILKMSA-N 0.000 description 4
- BGTDGENDNWGMDQ-KJEVXHAQSA-N Val-Tyr-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CC1=CC=C(C=C1)O)NC(=O)[C@H](C(C)C)N)O BGTDGENDNWGMDQ-KJEVXHAQSA-N 0.000 description 4
- 108010081404 acein-2 Proteins 0.000 description 4
- 239000004480 active ingredient Substances 0.000 description 4
- 108010087924 alanylproline Proteins 0.000 description 4
- 125000000539 amino acid group Chemical group 0.000 description 4
- 230000000259 anti-tumor effect Effects 0.000 description 4
- 108010001271 arginyl-glutamyl-arginine Proteins 0.000 description 4
- 230000008901 benefit Effects 0.000 description 4
- 229910002092 carbon dioxide Inorganic materials 0.000 description 4
- 230000022534 cell killing Effects 0.000 description 4
- 230000004186 co-expression Effects 0.000 description 4
- 238000012258 culturing Methods 0.000 description 4
- 239000001963 growth medium Substances 0.000 description 4
- 108010073472 leucyl-prolyl-proline Proteins 0.000 description 4
- 239000003550 marker Substances 0.000 description 4
- 230000004048 modification Effects 0.000 description 4
- 238000012986 modification Methods 0.000 description 4
- 239000008194 pharmaceutical composition Substances 0.000 description 4
- 108010051242 phenylalanylserine Proteins 0.000 description 4
- 108010070643 prolylglutamic acid Proteins 0.000 description 4
- 238000010257 thawing Methods 0.000 description 4
- 238000001890 transfection Methods 0.000 description 4
- 108010051110 tyrosyl-lysine Proteins 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- QDRGPQWIVZNJQD-CIUDSAMLSA-N Ala-Arg-Gln Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(N)=O)C(O)=O QDRGPQWIVZNJQD-CIUDSAMLSA-N 0.000 description 3
- WCBVQNZTOKJWJS-ACZMJKKPSA-N Ala-Cys-Glu Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCC(O)=O)C(O)=O WCBVQNZTOKJWJS-ACZMJKKPSA-N 0.000 description 3
- OBVSBEYOMDWLRJ-BFHQHQDPSA-N Ala-Gly-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)CNC(=O)[C@H](C)N OBVSBEYOMDWLRJ-BFHQHQDPSA-N 0.000 description 3
- DEAGTWNKODHUIY-MRFFXTKBSA-N Ala-Tyr-Trp Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC1=CNC2=C1C=CC=C2)C(O)=O DEAGTWNKODHUIY-MRFFXTKBSA-N 0.000 description 3
- HGKHPCFTRQDHCU-IUCAKERBSA-N Arg-Pro-Gly Chemical compound NC(N)=NCCC[C@H](N)C(=O)N1CCC[C@H]1C(=O)NCC(O)=O HGKHPCFTRQDHCU-IUCAKERBSA-N 0.000 description 3
- ULBHWNVWSCJLCO-NHCYSSNCSA-N Arg-Val-Glu Chemical compound OC(=O)CC[C@@H](C(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](N)CCCN=C(N)N ULBHWNVWSCJLCO-NHCYSSNCSA-N 0.000 description 3
- QNJIRRVTOXNGMH-GUBZILKMSA-N Asn-Gln-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](N)CC(N)=O QNJIRRVTOXNGMH-GUBZILKMSA-N 0.000 description 3
- OLGCWMNDJTWQAG-GUBZILKMSA-N Asn-Glu-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](N)CC(N)=O OLGCWMNDJTWQAG-GUBZILKMSA-N 0.000 description 3
- VLDRQOHCMKCXLY-SRVKXCTJSA-N Asn-Ser-Phe Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O VLDRQOHCMKCXLY-SRVKXCTJSA-N 0.000 description 3
- SNDBKTFJWVEVPO-WHFBIAKZSA-N Asp-Gly-Ser Chemical compound [H]N[C@@H](CC(O)=O)C(=O)NCC(=O)N[C@@H](CO)C(O)=O SNDBKTFJWVEVPO-WHFBIAKZSA-N 0.000 description 3
- CYCKJEFVFNRWEZ-UGYAYLCHSA-N Asp-Ile-Asn Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(N)=O)C(O)=O CYCKJEFVFNRWEZ-UGYAYLCHSA-N 0.000 description 3
- KYQNAIMCTRZLNP-QSFUFRPTSA-N Asp-Ile-Val Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C(C)C)C(O)=O KYQNAIMCTRZLNP-QSFUFRPTSA-N 0.000 description 3
- VNXQRBXEQXLERQ-CIUDSAMLSA-N Asp-Ser-Lys Chemical compound C(CCN)C[C@@H](C(=O)O)NC(=O)[C@H](CO)NC(=O)[C@H](CC(=O)O)N VNXQRBXEQXLERQ-CIUDSAMLSA-N 0.000 description 3
- XYPJXLLXNSAWHZ-SRVKXCTJSA-N Asp-Ser-Tyr Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O XYPJXLLXNSAWHZ-SRVKXCTJSA-N 0.000 description 3
- HTSSXFASOUSJQG-IHPCNDPISA-N Asp-Tyr-Trp Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC1=CNC2=C1C=CC=C2)C(O)=O HTSSXFASOUSJQG-IHPCNDPISA-N 0.000 description 3
- 206010006187 Breast cancer Diseases 0.000 description 3
- 208000026310 Breast neoplasm Diseases 0.000 description 3
- 102000002029 Claudin Human genes 0.000 description 3
- 108050009302 Claudin Proteins 0.000 description 3
- 241000588724 Escherichia coli Species 0.000 description 3
- FGYPOQPQTUNESW-IUCAKERBSA-N Gln-Gly-Leu Chemical compound CC(C)C[C@@H](C(=O)O)NC(=O)CNC(=O)[C@H](CCC(=O)N)N FGYPOQPQTUNESW-IUCAKERBSA-N 0.000 description 3
- JVSBYEDSSRZQGV-GUBZILKMSA-N Glu-Asp-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@@H](N)CCC(O)=O JVSBYEDSSRZQGV-GUBZILKMSA-N 0.000 description 3
- PXHABOCPJVTGEK-BQBZGAKWSA-N Glu-Gln-Gly Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)NCC(O)=O PXHABOCPJVTGEK-BQBZGAKWSA-N 0.000 description 3
- DMYACXMQUABZIQ-NRPADANISA-N Glu-Ser-Val Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(O)=O DMYACXMQUABZIQ-NRPADANISA-N 0.000 description 3
- BGVYNAQWHSTTSP-BYULHYEWSA-N Gly-Asn-Ile Chemical compound [H]NCC(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O BGVYNAQWHSTTSP-BYULHYEWSA-N 0.000 description 3
- BIRKKBCSAIHDDF-WDSKDSINSA-N Gly-Glu-Cys Chemical compound NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CS)C(O)=O BIRKKBCSAIHDDF-WDSKDSINSA-N 0.000 description 3
- WTUSRDZLLWGYAT-KCTSRDHCSA-N Gly-Trp-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)[C@H](CC1=CNC2=CC=CC=C21)NC(=O)CN WTUSRDZLLWGYAT-KCTSRDHCSA-N 0.000 description 3
- 101001055157 Homo sapiens Interleukin-15 Proteins 0.000 description 3
- 101000581981 Homo sapiens Neural cell adhesion molecule 1 Proteins 0.000 description 3
- JZNVOBUNTWNZPW-GHCJXIJMSA-N Ile-Ser-Asp Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(=O)O)C(=O)O)N JZNVOBUNTWNZPW-GHCJXIJMSA-N 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
- 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 3
- MPGHETGWWWUHPY-CIUDSAMLSA-N Lys-Ala-Asp Chemical compound OC(=O)C[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CCCCN MPGHETGWWWUHPY-CIUDSAMLSA-N 0.000 description 3
- LMVOVCYVZBBWQB-SRVKXCTJSA-N Lys-Asp-Lys Chemical compound NCCCC[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@H](C(O)=O)CCCCN LMVOVCYVZBBWQB-SRVKXCTJSA-N 0.000 description 3
- NKKFVJRLCCUJNA-QWRGUYRKSA-N Lys-Gly-Lys Chemical compound NCCCC[C@H](N)C(=O)NCC(=O)N[C@H](C(O)=O)CCCCN NKKFVJRLCCUJNA-QWRGUYRKSA-N 0.000 description 3
- DIBZLYZXTSVGLN-CIUDSAMLSA-N Lys-Ser-Ser Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(O)=O DIBZLYZXTSVGLN-CIUDSAMLSA-N 0.000 description 3
- XABXVVSWUVCZST-GVXVVHGQSA-N Lys-Val-Gln Chemical compound NC(=O)CC[C@@H](C(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](N)CCCCN XABXVVSWUVCZST-GVXVVHGQSA-N 0.000 description 3
- 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 3
- 102100027347 Neural cell adhesion molecule 1 Human genes 0.000 description 3
- 241000283973 Oryctolagus cuniculus Species 0.000 description 3
- HXSUFWQYLPKEHF-IHRRRGAJSA-N Phe-Asn-Arg Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CCCN=C(N)N)C(=O)O)N HXSUFWQYLPKEHF-IHRRRGAJSA-N 0.000 description 3
- MMJJFXWMCMJMQA-STQMWFEESA-N Phe-Pro-Gly Chemical compound C([C@H](N)C(=O)N1[C@@H](CCC1)C(=O)NCC(O)=O)C1=CC=CC=C1 MMJJFXWMCMJMQA-STQMWFEESA-N 0.000 description 3
- JHSRGEODDALISP-XVSYOHENSA-N Phe-Thr-Asn Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(O)=O JHSRGEODDALISP-XVSYOHENSA-N 0.000 description 3
- KLYYKKGCPOGDPE-OEAJRASXSA-N Phe-Thr-Leu Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(O)=O KLYYKKGCPOGDPE-OEAJRASXSA-N 0.000 description 3
- GNRMAQSIROFNMI-IXOXFDKPSA-N Phe-Thr-Ser Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(O)=O GNRMAQSIROFNMI-IXOXFDKPSA-N 0.000 description 3
- CLNJSLSHKJECME-BQBZGAKWSA-N Pro-Gly-Ala Chemical compound OC(=O)[C@H](C)NC(=O)CNC(=O)[C@@H]1CCCN1 CLNJSLSHKJECME-BQBZGAKWSA-N 0.000 description 3
- FDMKYQQYJKYCLV-GUBZILKMSA-N Pro-Pro-Ser Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@H]1NCCC1 FDMKYQQYJKYCLV-GUBZILKMSA-N 0.000 description 3
- NADLKBTYNKUJEP-KATARQTJSA-N Ser-Thr-Leu Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(O)=O NADLKBTYNKUJEP-KATARQTJSA-N 0.000 description 3
- BEBVVQPDSHHWQL-NRPADANISA-N Ser-Val-Glu Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(O)=O)C(O)=O BEBVVQPDSHHWQL-NRPADANISA-N 0.000 description 3
- DWYAUVCQDTZIJI-VZFHVOOUSA-N Thr-Ala-Ser Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](CO)C(O)=O DWYAUVCQDTZIJI-VZFHVOOUSA-N 0.000 description 3
- CEXFELBFVHLYDZ-XGEHTFHBSA-N Thr-Arg-Ser Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(O)=O CEXFELBFVHLYDZ-XGEHTFHBSA-N 0.000 description 3
- JVTHIXKSVYEWNI-JRQIVUDYSA-N Thr-Asn-Tyr Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O JVTHIXKSVYEWNI-JRQIVUDYSA-N 0.000 description 3
- RCEHMXVEMNXRIW-IRIUXVKKSA-N Thr-Gln-Tyr Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H](CC1=CC=C(C=C1)O)C(=O)O)N)O RCEHMXVEMNXRIW-IRIUXVKKSA-N 0.000 description 3
- GKWNLDNXMMLRMC-GLLZPBPUSA-N Thr-Glu-Gln Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CCC(=O)N)C(=O)O)N)O GKWNLDNXMMLRMC-GLLZPBPUSA-N 0.000 description 3
- NDZYTIMDOZMECO-SHGPDSBTSA-N Thr-Thr-Ala Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C)C(O)=O NDZYTIMDOZMECO-SHGPDSBTSA-N 0.000 description 3
- YRJOLUDFVAUXLI-GSSVUCPTSA-N Thr-Thr-Asp Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@H](C(O)=O)CC(O)=O YRJOLUDFVAUXLI-GSSVUCPTSA-N 0.000 description 3
- UMFLBPIPAJMNIM-LYARXQMPSA-N Thr-Trp-Phe Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC1=CNC2=CC=CC=C21)C(=O)N[C@@H](CC3=CC=CC=C3)C(=O)O)N)O UMFLBPIPAJMNIM-LYARXQMPSA-N 0.000 description 3
- SCQBNMKLZVCXNX-ZFWWWQNUSA-N Trp-Arg-Gly Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)N[C@@H](CCCN=C(N)N)C(=O)NCC(=O)O)N SCQBNMKLZVCXNX-ZFWWWQNUSA-N 0.000 description 3
- AZBIIKDSDLVJAK-VHWLVUOQSA-N Trp-Ile-Asn Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)O)NC(=O)[C@H](CC1=CNC2=CC=CC=C21)N AZBIIKDSDLVJAK-VHWLVUOQSA-N 0.000 description 3
- NLWCSMOXNKBRLC-WDSOQIARSA-N Trp-Lys-Val Chemical compound [H]N[C@@H](CC1=CNC2=C1C=CC=C2)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C(C)C)C(O)=O NLWCSMOXNKBRLC-WDSOQIARSA-N 0.000 description 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
- QOIKZODVIPOPDD-AVGNSLFASA-N Tyr-Cys-Gln Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCC(N)=O)C(O)=O QOIKZODVIPOPDD-AVGNSLFASA-N 0.000 description 3
- QUILOGWWLXMSAT-IHRRRGAJSA-N Tyr-Gln-Gln Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(O)=O QUILOGWWLXMSAT-IHRRRGAJSA-N 0.000 description 3
- YYLHVUCSTXXKBS-IHRRRGAJSA-N Tyr-Pro-Ser Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CO)C(O)=O YYLHVUCSTXXKBS-IHRRRGAJSA-N 0.000 description 3
- CVUDMNSZAIZFAE-UHFFFAOYSA-N Val-Arg-Pro Natural products NC(N)=NCCCC(NC(=O)C(N)C(C)C)C(=O)N1CCCC1C(O)=O CVUDMNSZAIZFAE-UHFFFAOYSA-N 0.000 description 3
- 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 3
- PZTZYZUTCPZWJH-FXQIFTODSA-N Val-Ser-Ser Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)O)N PZTZYZUTCPZWJH-FXQIFTODSA-N 0.000 description 3
- TVGWMCTYUFBXAP-QTKMDUPCSA-N Val-Thr-His Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)NC(=O)[C@H](C(C)C)N)O TVGWMCTYUFBXAP-QTKMDUPCSA-N 0.000 description 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
- ZHWZDZFWBXWPDW-GUBZILKMSA-N Val-Val-Cys Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CS)C(O)=O ZHWZDZFWBXWPDW-GUBZILKMSA-N 0.000 description 3
- 230000009471 action Effects 0.000 description 3
- 208000037842 advanced-stage tumor Diseases 0.000 description 3
- 108010005233 alanylglutamic acid Proteins 0.000 description 3
- 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 3
- 229960000723 ampicillin Drugs 0.000 description 3
- 108010008355 arginyl-glutamine Proteins 0.000 description 3
- 108010009111 arginyl-glycyl-glutamic acid Proteins 0.000 description 3
- 108010069205 aspartyl-phenylalanine Proteins 0.000 description 3
- 238000003776 cleavage reaction Methods 0.000 description 3
- 238000011161 development Methods 0.000 description 3
- 230000018109 developmental process Effects 0.000 description 3
- 230000029087 digestion Effects 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 108010057083 glutamyl-aspartyl-leucine Proteins 0.000 description 3
- 108010049041 glutamylalanine Proteins 0.000 description 3
- 102000056003 human IL15 Human genes 0.000 description 3
- 210000000987 immune system Anatomy 0.000 description 3
- 229940072221 immunoglobulins Drugs 0.000 description 3
- 108010044374 isoleucyl-tyrosine Proteins 0.000 description 3
- 108010024607 phenylalanylalanine Proteins 0.000 description 3
- 108091033319 polynucleotide Proteins 0.000 description 3
- 102000040430 polynucleotide Human genes 0.000 description 3
- 239000002157 polynucleotide Substances 0.000 description 3
- 239000013641 positive control Substances 0.000 description 3
- 108010029020 prolylglycine Proteins 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 230000007017 scission Effects 0.000 description 3
- 108010069117 seryl-lysyl-aspartic acid Proteins 0.000 description 3
- 238000003998 size exclusion chromatography high performance liquid chromatography Methods 0.000 description 3
- 230000002195 synergetic effect Effects 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- 210000001519 tissue Anatomy 0.000 description 3
- 230000005909 tumor killing Effects 0.000 description 3
- 108010071635 tyrosyl-prolyl-arginine Proteins 0.000 description 3
- 239000013603 viral vector Substances 0.000 description 3
- FZRPRRCXGGAZEW-HSZRJFAPSA-N (2r)-n-(6-aminohexyl)-1-tridecanoylpiperidine-2-carboxamide Chemical compound CCCCCCCCCCCCC(=O)N1CCCC[C@@H]1C(=O)NCCCCCCN FZRPRRCXGGAZEW-HSZRJFAPSA-N 0.000 description 2
- RVNZEJNWTUDQSC-JOCHJYFZSA-N (2r)-n-(6-aminohexyl)-1-tridecanoylpyrrolidine-2-carboxamide Chemical compound CCCCCCCCCCCCC(=O)N1CCC[C@@H]1C(=O)NCCCCCCN RVNZEJNWTUDQSC-JOCHJYFZSA-N 0.000 description 2
- ZQJHYRVSKHGGJY-YPKJBDGSSA-N (2s,3r)-2-[[(2s)-2-[[(2s)-1-[(2s)-2-amino-3-(4-hydroxyphenyl)propanoyl]pyrrolidine-2-carbonyl]amino]-3-phenylpropanoyl]amino]-3-hydroxybutanoic acid Chemical compound C([C@@H](C(=O)N[C@@H]([C@H](O)C)C(O)=O)NC(=O)[C@H]1N(CCC1)C(=O)[C@@H](N)CC=1C=CC(O)=CC=1)C1=CC=CC=C1 ZQJHYRVSKHGGJY-YPKJBDGSSA-N 0.000 description 2
- NVKAWKQGWWIWPM-ABEVXSGRSA-N 17-β-hydroxy-5-α-Androstan-3-one Chemical compound C1C(=O)CC[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CC[C@H]21 NVKAWKQGWWIWPM-ABEVXSGRSA-N 0.000 description 2
- CXRCVCURMBFFOL-FXQIFTODSA-N Ala-Ala-Pro Chemical compound C[C@H](N)C(=O)N[C@@H](C)C(=O)N1CCC[C@H]1C(O)=O CXRCVCURMBFFOL-FXQIFTODSA-N 0.000 description 2
- GFBLJMHGHAXGNY-ZLUOBGJFSA-N Ala-Asn-Asp Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(O)=O)C(O)=O GFBLJMHGHAXGNY-ZLUOBGJFSA-N 0.000 description 2
- RGQCNKIDEQJEBT-CQDKDKBSSA-N Ala-Leu-Tyr Chemical compound C[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 RGQCNKIDEQJEBT-CQDKDKBSSA-N 0.000 description 2
- SUHLZMHFRALVSY-YUMQZZPRSA-N Ala-Lys-Gly Chemical compound NCCCC[C@H](NC(=O)[C@@H](N)C)C(=O)NCC(O)=O SUHLZMHFRALVSY-YUMQZZPRSA-N 0.000 description 2
- VCSABYLVNWQYQE-UHFFFAOYSA-N Ala-Lys-Lys Natural products NCCCCC(NC(=O)C(N)C)C(=O)NC(CCCCN)C(O)=O VCSABYLVNWQYQE-UHFFFAOYSA-N 0.000 description 2
- MDNAVFBZPROEHO-UHFFFAOYSA-N Ala-Lys-Val Natural products CC(C)C(C(O)=O)NC(=O)C(NC(=O)C(C)N)CCCCN MDNAVFBZPROEHO-UHFFFAOYSA-N 0.000 description 2
- MAZZQZWCCYJQGZ-GUBZILKMSA-N Ala-Pro-Arg Chemical compound [H]N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCCNC(N)=N)C(O)=O MAZZQZWCCYJQGZ-GUBZILKMSA-N 0.000 description 2
- DYXOFPBJBAHWFY-JBDRJPRFSA-N Ala-Ser-Ile Chemical compound CC[C@H](C)[C@@H](C(O)=O)NC(=O)[C@H](CO)NC(=O)[C@H](C)N DYXOFPBJBAHWFY-JBDRJPRFSA-N 0.000 description 2
- XQNRANMFRPCFFW-GCJQMDKQSA-N Ala-Thr-Asn Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)O)NC(=O)[C@H](C)N)O XQNRANMFRPCFFW-GCJQMDKQSA-N 0.000 description 2
- QDGMZAOSMNGBLP-MRFFXTKBSA-N Ala-Trp-Tyr Chemical compound C[C@@H](C(=O)N[C@@H](CC1=CNC2=CC=CC=C21)C(=O)N[C@@H](CC3=CC=C(C=C3)O)C(=O)O)N QDGMZAOSMNGBLP-MRFFXTKBSA-N 0.000 description 2
- ZDILXFDENZVOTL-BPNCWPANSA-N Ala-Val-Tyr Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O ZDILXFDENZVOTL-BPNCWPANSA-N 0.000 description 2
- GIVATXIGCXFQQA-FXQIFTODSA-N Arg-Ala-Ser Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CCCN=C(N)N GIVATXIGCXFQQA-FXQIFTODSA-N 0.000 description 2
- OTOXOKCIIQLMFH-KZVJFYERSA-N Arg-Ala-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CCCN=C(N)N OTOXOKCIIQLMFH-KZVJFYERSA-N 0.000 description 2
- HPKSHFSEXICTLI-CIUDSAMLSA-N Arg-Glu-Ala Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(O)=O HPKSHFSEXICTLI-CIUDSAMLSA-N 0.000 description 2
- QAODJPUKWNNNRP-DCAQKATOSA-N Arg-Glu-Arg Chemical compound NC(N)=NCCC[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCN=C(N)N)C(O)=O QAODJPUKWNNNRP-DCAQKATOSA-N 0.000 description 2
- 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 2
- ZUVMUOOHJYNJPP-XIRDDKMYSA-N Arg-Trp-Gln Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC1=CNC2=C1C=CC=C2)C(=O)N[C@@H](CCC(N)=O)C(O)=O ZUVMUOOHJYNJPP-XIRDDKMYSA-N 0.000 description 2
- UVTGNSWSRSCPLP-UHFFFAOYSA-N Arg-Tyr Natural products NC(CCNC(=N)N)C(=O)NC(Cc1ccc(O)cc1)C(=O)O UVTGNSWSRSCPLP-UHFFFAOYSA-N 0.000 description 2
- QJWLLRZTJFPCHA-STECZYCISA-N Arg-Tyr-Ile Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O QJWLLRZTJFPCHA-STECZYCISA-N 0.000 description 2
- VYZBPPBKFCHCIS-WPRPVWTQSA-N Arg-Val-Gly Chemical compound OC(=O)CNC(=O)[C@H](C(C)C)NC(=O)[C@@H](N)CCCN=C(N)N VYZBPPBKFCHCIS-WPRPVWTQSA-N 0.000 description 2
- SRUUBQBAVNQZGJ-LAEOZQHASA-N Asn-Gln-Val Chemical compound CC(C)[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)N)NC(=O)[C@H](CC(=O)N)N SRUUBQBAVNQZGJ-LAEOZQHASA-N 0.000 description 2
- WONGRTVAMHFGBE-WDSKDSINSA-N Asn-Gly-Gln Chemical compound C(CC(=O)N)[C@@H](C(=O)O)NC(=O)CNC(=O)[C@H](CC(=O)N)N WONGRTVAMHFGBE-WDSKDSINSA-N 0.000 description 2
- 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 2
- AMGQTNHANMRPOE-LKXGYXEUSA-N Asn-Thr-Ser Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(O)=O AMGQTNHANMRPOE-LKXGYXEUSA-N 0.000 description 2
- QNNBHTFDFFFHGC-KKUMJFAQSA-N Asn-Tyr-Lys Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CC(=O)N)N)O QNNBHTFDFFFHGC-KKUMJFAQSA-N 0.000 description 2
- CBWCQCANJSGUOH-ZKWXMUAHSA-N Asn-Val-Ala Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C)C(O)=O CBWCQCANJSGUOH-ZKWXMUAHSA-N 0.000 description 2
- KVMPVNGOKHTUHZ-GCJQMDKQSA-N Asp-Ala-Thr Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O KVMPVNGOKHTUHZ-GCJQMDKQSA-N 0.000 description 2
- UZNSWMFLKVKJLI-VHWLVUOQSA-N Asp-Ile-Trp Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC1=CNC2=C1C=CC=C2)C(O)=O UZNSWMFLKVKJLI-VHWLVUOQSA-N 0.000 description 2
- GYWQGGUCMDCUJE-DLOVCJGASA-N Asp-Phe-Ala Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](C)C(O)=O GYWQGGUCMDCUJE-DLOVCJGASA-N 0.000 description 2
- JSNWZMFSLIWAHS-HJGDQZAQSA-N Asp-Thr-Leu Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)O)NC(=O)[C@H](CC(=O)O)N)O JSNWZMFSLIWAHS-HJGDQZAQSA-N 0.000 description 2
- CZIVKMOEXPILDK-SRVKXCTJSA-N Asp-Tyr-Ser Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CO)C(O)=O CZIVKMOEXPILDK-SRVKXCTJSA-N 0.000 description 2
- BPAUXFVCSYQDQX-JRQIVUDYSA-N Asp-Tyr-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CC1=CC=C(C=C1)O)NC(=O)[C@H](CC(=O)O)N)O BPAUXFVCSYQDQX-JRQIVUDYSA-N 0.000 description 2
- GYNUXDMCDILYIQ-QRTARXTBSA-N Asp-Val-Trp Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC1=CNC2=CC=CC=C21)C(=O)O)NC(=O)[C@H](CC(=O)O)N GYNUXDMCDILYIQ-QRTARXTBSA-N 0.000 description 2
- 241000894006 Bacteria Species 0.000 description 2
- 210000001239 CD8-positive, alpha-beta cytotoxic T lymphocyte Anatomy 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- 241000282693 Cercopithecidae Species 0.000 description 2
- 108091026890 Coding region Proteins 0.000 description 2
- TVYMKYUSZSVOAG-ZLUOBGJFSA-N Cys-Ala-Ala Chemical compound [H]N[C@@H](CS)C(=O)N[C@@H](C)C(=O)N[C@@H](C)C(O)=O TVYMKYUSZSVOAG-ZLUOBGJFSA-N 0.000 description 2
- CPTUXCUWQIBZIF-ZLUOBGJFSA-N Cys-Asn-Ser Chemical compound SC[C@H](N)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CO)C(O)=O CPTUXCUWQIBZIF-ZLUOBGJFSA-N 0.000 description 2
- YMBAVNPKBWHDAW-CIUDSAMLSA-N Cys-Asp-Lys Chemical compound C(CCN)C[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)O)NC(=O)[C@H](CS)N YMBAVNPKBWHDAW-CIUDSAMLSA-N 0.000 description 2
- MWZSCEAYQCMROW-GUBZILKMSA-N Cys-Gln-His Chemical compound C1=C(NC=N1)C[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)N)NC(=O)[C@H](CS)N MWZSCEAYQCMROW-GUBZILKMSA-N 0.000 description 2
- UVZFZTWNHOQWNK-NAKRPEOUSA-N Cys-Ile-Arg Chemical compound [H]N[C@@H](CS)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O UVZFZTWNHOQWNK-NAKRPEOUSA-N 0.000 description 2
- NIXHTNJAGGFBAW-CIUDSAMLSA-N Cys-Lys-Ser Chemical compound C(CCN)C[C@@H](C(=O)N[C@@H](CO)C(=O)O)NC(=O)[C@H](CS)N NIXHTNJAGGFBAW-CIUDSAMLSA-N 0.000 description 2
- ZXCAQANTQWBICD-DCAQKATOSA-N Cys-Lys-Val Chemical compound CC(C)[C@@H](C(=O)O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CS)N ZXCAQANTQWBICD-DCAQKATOSA-N 0.000 description 2
- NDNZRWUDUMTITL-FXQIFTODSA-N Cys-Ser-Val Chemical compound [H]N[C@@H](CS)C(=O)N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(O)=O NDNZRWUDUMTITL-FXQIFTODSA-N 0.000 description 2
- KZZYVYWSXMFYEC-DCAQKATOSA-N Cys-Val-Leu Chemical compound [H]N[C@@H](CS)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O KZZYVYWSXMFYEC-DCAQKATOSA-N 0.000 description 2
- 241000287828 Gallus gallus Species 0.000 description 2
- MADFVRSKEIEZHZ-DCAQKATOSA-N Gln-Gln-Lys Chemical compound C(CCN)C[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)N)NC(=O)[C@H](CCC(=O)N)N MADFVRSKEIEZHZ-DCAQKATOSA-N 0.000 description 2
- XKBASPWPBXNVLQ-WDSKDSINSA-N Gln-Gly-Asn Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)NCC(=O)N[C@@H](CC(N)=O)C(O)=O XKBASPWPBXNVLQ-WDSKDSINSA-N 0.000 description 2
- ZEEPYMXTJWIMSN-GUBZILKMSA-N Gln-Lys-Ser Chemical compound NCCCC[C@@H](C(=O)N[C@@H](CO)C(O)=O)NC(=O)[C@@H](N)CCC(N)=O ZEEPYMXTJWIMSN-GUBZILKMSA-N 0.000 description 2
- 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 2
- DFRYZTUPVZNRLG-KKUMJFAQSA-N Gln-Met-Phe Chemical compound CSCC[C@@H](C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)O)NC(=O)[C@H](CCC(=O)N)N DFRYZTUPVZNRLG-KKUMJFAQSA-N 0.000 description 2
- RWQCWSGOOOEGPB-FXQIFTODSA-N Gln-Ser-Glu Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(O)=O)C(O)=O RWQCWSGOOOEGPB-FXQIFTODSA-N 0.000 description 2
- OSCLNNWLKKIQJM-WDSKDSINSA-N Gln-Ser-Gly Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CO)C(=O)NCC(O)=O OSCLNNWLKKIQJM-WDSKDSINSA-N 0.000 description 2
- OTQSTOXRUBVWAP-NRPADANISA-N Gln-Ser-Val Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(O)=O OTQSTOXRUBVWAP-NRPADANISA-N 0.000 description 2
- SDSMVVSHLAAOJL-UKJIMTQDSA-N Gln-Val-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)[C@H](C(C)C)NC(=O)[C@H](CCC(=O)N)N SDSMVVSHLAAOJL-UKJIMTQDSA-N 0.000 description 2
- ZOXBSICWUDAOHX-GUBZILKMSA-N Glu-Asn-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](N)CCC(O)=O ZOXBSICWUDAOHX-GUBZILKMSA-N 0.000 description 2
- CKOFNWCLWRYUHK-XHNCKOQMSA-N Glu-Asp-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CC(=O)O)NC(=O)[C@H](CCC(=O)O)N)C(=O)O CKOFNWCLWRYUHK-XHNCKOQMSA-N 0.000 description 2
- SBCYJMOOHUDWDA-NUMRIWBASA-N Glu-Asp-Thr Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O SBCYJMOOHUDWDA-NUMRIWBASA-N 0.000 description 2
- PVBBEKPHARMPHX-DCAQKATOSA-N Glu-Gln-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](N)CCC(O)=O PVBBEKPHARMPHX-DCAQKATOSA-N 0.000 description 2
- HUFCEIHAFNVSNR-IHRRRGAJSA-N Glu-Gln-Tyr Chemical compound OC(=O)CC[C@H](N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 HUFCEIHAFNVSNR-IHRRRGAJSA-N 0.000 description 2
- MUSGDMDGNGXULI-DCAQKATOSA-N Glu-Glu-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](N)CCC(O)=O MUSGDMDGNGXULI-DCAQKATOSA-N 0.000 description 2
- LGYZYFFDELZWRS-DCAQKATOSA-N Glu-Glu-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](N)CCC(O)=O LGYZYFFDELZWRS-DCAQKATOSA-N 0.000 description 2
- VXQOONWNIWFOCS-HGNGGELXSA-N Glu-His-Ala Chemical compound C[C@@H](C(=O)O)NC(=O)[C@H](CC1=CN=CN1)NC(=O)[C@H](CCC(=O)O)N VXQOONWNIWFOCS-HGNGGELXSA-N 0.000 description 2
- MWMJCGBSIORNCD-AVGNSLFASA-N Glu-Leu-Leu Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O MWMJCGBSIORNCD-AVGNSLFASA-N 0.000 description 2
- YGLCLCMAYUYZSG-AVGNSLFASA-N Glu-Lys-His Chemical compound OC(=O)CC[C@H](N)C(=O)N[C@@H](CCCCN)C(=O)N[C@H](C(O)=O)CC1=CN=CN1 YGLCLCMAYUYZSG-AVGNSLFASA-N 0.000 description 2
- SUIAHERNFYRBDZ-GVXVVHGQSA-N Glu-Lys-Val Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C(C)C)C(O)=O SUIAHERNFYRBDZ-GVXVVHGQSA-N 0.000 description 2
- MRWYPDWDZSLWJM-ACZMJKKPSA-N Glu-Ser-Asp Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(O)=O)C(O)=O MRWYPDWDZSLWJM-ACZMJKKPSA-N 0.000 description 2
- RFTVTKBHDXCEEX-WDSKDSINSA-N Glu-Ser-Gly Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(=O)NCC(O)=O RFTVTKBHDXCEEX-WDSKDSINSA-N 0.000 description 2
- 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 2
- LJPIRKICOISLKN-WHFBIAKZSA-N Gly-Ala-Ser Chemical compound NCC(=O)N[C@@H](C)C(=O)N[C@@H](CO)C(O)=O LJPIRKICOISLKN-WHFBIAKZSA-N 0.000 description 2
- 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 2
- GWCRIHNSVMOBEQ-BQBZGAKWSA-N Gly-Arg-Ser Chemical compound [H]NCC(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(O)=O GWCRIHNSVMOBEQ-BQBZGAKWSA-N 0.000 description 2
- WJZLEENECIOOSA-WDSKDSINSA-N Gly-Asn-Gln Chemical compound NCC(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)O WJZLEENECIOOSA-WDSKDSINSA-N 0.000 description 2
- XPJBQTCXPJNIFE-ZETCQYMHSA-N Gly-Gly-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)CNC(=O)CN XPJBQTCXPJNIFE-ZETCQYMHSA-N 0.000 description 2
- BUEFQXUHTUZXHR-LURJTMIESA-N Gly-Gly-Pro zwitterion Chemical compound NCC(=O)NCC(=O)N1CCC[C@H]1C(O)=O BUEFQXUHTUZXHR-LURJTMIESA-N 0.000 description 2
- HAXARWKYFIIHKD-ZKWXMUAHSA-N Gly-Ile-Ser Chemical compound NCC(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(O)=O HAXARWKYFIIHKD-ZKWXMUAHSA-N 0.000 description 2
- ULZCYBYDTUMHNF-IUCAKERBSA-N Gly-Leu-Glu Chemical compound NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(O)=O ULZCYBYDTUMHNF-IUCAKERBSA-N 0.000 description 2
- GMTXWRIDLGTVFC-IUCAKERBSA-N Gly-Lys-Glu Chemical compound [H]NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(O)=O GMTXWRIDLGTVFC-IUCAKERBSA-N 0.000 description 2
- VNNRLUNBJSWZPF-ZKWXMUAHSA-N Gly-Ser-Ile Chemical compound [H]NCC(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O VNNRLUNBJSWZPF-ZKWXMUAHSA-N 0.000 description 2
- NVTPVQLIZCOJFK-FOHZUACHSA-N Gly-Thr-Asp Chemical compound [H]NCC(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(O)=O)C(O)=O NVTPVQLIZCOJFK-FOHZUACHSA-N 0.000 description 2
- SYOJVRNQCXYEOV-XVKPBYJWSA-N Gly-Val-Glu Chemical compound [H]NCC(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(O)=O)C(O)=O SYOJVRNQCXYEOV-XVKPBYJWSA-N 0.000 description 2
- KZTLOHBDLMIFSH-XVYDVKMFSA-N His-Ala-Asp Chemical compound [H]N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(O)=O)C(O)=O KZTLOHBDLMIFSH-XVYDVKMFSA-N 0.000 description 2
- YOSQCYUFZGPIPC-PBCZWWQYSA-N His-Asp-Thr Chemical compound [H]N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O YOSQCYUFZGPIPC-PBCZWWQYSA-N 0.000 description 2
- FYVHHKMHFPMBBG-GUBZILKMSA-N His-Gln-Asp Chemical compound C1=C(NC=N1)C[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H](CC(=O)O)C(=O)O)N FYVHHKMHFPMBBG-GUBZILKMSA-N 0.000 description 2
- IWXMHXYOACDSIA-PYJNHQTQSA-N His-Ile-Val Chemical compound [H]N[C@@H](CC1=CNC=N1)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C(C)C)C(O)=O IWXMHXYOACDSIA-PYJNHQTQSA-N 0.000 description 2
- YEKYGQZUBCRNGH-DCAQKATOSA-N His-Pro-Ser Chemical compound C1C[C@H](N(C1)C(=O)[C@H](CC2=CN=CN2)N)C(=O)N[C@@H](CO)C(=O)O YEKYGQZUBCRNGH-DCAQKATOSA-N 0.000 description 2
- HZWWOGWOBQBETJ-CUJWVEQBSA-N His-Thr-Cys Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CS)C(=O)O)NC(=O)[C@H](CC1=CN=CN1)N)O HZWWOGWOBQBETJ-CUJWVEQBSA-N 0.000 description 2
- YERBCFWVWITTEJ-NAZCDGGXSA-N His-Trp-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CC1=CNC2=CC=CC=C21)NC(=O)[C@H](CC3=CN=CN3)N)O YERBCFWVWITTEJ-NAZCDGGXSA-N 0.000 description 2
- CSTDQOOBZBAJKE-BWAGICSOSA-N His-Tyr-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CC1=CC=C(C=C1)O)NC(=O)[C@H](CC2=CN=CN2)N)O CSTDQOOBZBAJKE-BWAGICSOSA-N 0.000 description 2
- HIJIJPFILYPTFR-ACRUOGEOSA-N His-Tyr-Tyr Chemical compound [H]N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O HIJIJPFILYPTFR-ACRUOGEOSA-N 0.000 description 2
- 101000917858 Homo sapiens Low affinity immunoglobulin gamma Fc region receptor III-A Proteins 0.000 description 2
- 101000917839 Homo sapiens Low affinity immunoglobulin gamma Fc region receptor III-B Proteins 0.000 description 2
- YBJWJQQBWRARLT-KBIXCLLPSA-N Ile-Gln-Ser Chemical compound CC[C@H](C)[C@H](N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CO)C(O)=O YBJWJQQBWRARLT-KBIXCLLPSA-N 0.000 description 2
- KIMHKBDJQQYLHU-PEFMBERDSA-N Ile-Glu-Asp Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CC(=O)O)C(=O)O)N KIMHKBDJQQYLHU-PEFMBERDSA-N 0.000 description 2
- DFJJAVZIHDFOGQ-MNXVOIDGSA-N Ile-Glu-Lys Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CCCCN)C(=O)O)N DFJJAVZIHDFOGQ-MNXVOIDGSA-N 0.000 description 2
- TWPSALMCEHCIOY-YTFOTSKYSA-N Ile-Ile-Leu Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(C)C)C(=O)O)N TWPSALMCEHCIOY-YTFOTSKYSA-N 0.000 description 2
- ADDYYRVQQZFIMW-MNXVOIDGSA-N Ile-Lys-Glu Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(=O)O)C(=O)O)N ADDYYRVQQZFIMW-MNXVOIDGSA-N 0.000 description 2
- QQFSKBMCAKWHLG-UHFFFAOYSA-N Ile-Phe-Pro-Pro Chemical compound C1CCC(C(=O)N2C(CCC2)C(O)=O)N1C(=O)C(NC(=O)C(N)C(C)CC)CC1=CC=CC=C1 QQFSKBMCAKWHLG-UHFFFAOYSA-N 0.000 description 2
- VGSPNSSCMOHRRR-BJDJZHNGSA-N Ile-Ser-Lys Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCCN)C(=O)O)N VGSPNSSCMOHRRR-BJDJZHNGSA-N 0.000 description 2
- RKQAYOWLSFLJEE-SVSWQMSJSA-N Ile-Thr-Cys Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CS)C(=O)O)N RKQAYOWLSFLJEE-SVSWQMSJSA-N 0.000 description 2
- ZSESFIFAYQEKRD-CYDGBPFRSA-N Ile-Val-Met Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCSC)C(=O)O)N ZSESFIFAYQEKRD-CYDGBPFRSA-N 0.000 description 2
- 108010065920 Insulin Lispro Proteins 0.000 description 2
- DCXYFEDJOCDNAF-REOHCLBHSA-N L-asparagine Chemical compound OC(=O)[C@@H](N)CC(N)=O DCXYFEDJOCDNAF-REOHCLBHSA-N 0.000 description 2
- POJPZSMTTMLSTG-SRVKXCTJSA-N Leu-Asn-Lys Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CCCCN)C(=O)O)N POJPZSMTTMLSTG-SRVKXCTJSA-N 0.000 description 2
- GPICTNQYKHHHTH-GUBZILKMSA-N Leu-Gln-Ser Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CO)C(O)=O GPICTNQYKHHHTH-GUBZILKMSA-N 0.000 description 2
- 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
- BTNXKBVLWJBTNR-SRVKXCTJSA-N Leu-His-Asn Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CC(N)=O)C(O)=O BTNXKBVLWJBTNR-SRVKXCTJSA-N 0.000 description 2
- 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 2
- QNBVTHNJGCOVFA-AVGNSLFASA-N Leu-Leu-Glu Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](C(O)=O)CCC(O)=O QNBVTHNJGCOVFA-AVGNSLFASA-N 0.000 description 2
- FAELBUXXFQLUAX-AJNGGQMLSA-N Leu-Leu-Ile Chemical compound CC[C@H](C)[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CC(C)C FAELBUXXFQLUAX-AJNGGQMLSA-N 0.000 description 2
- DCGXHWINSHEPIR-SRVKXCTJSA-N Leu-Lys-Cys Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CS)C(=O)O)N DCGXHWINSHEPIR-SRVKXCTJSA-N 0.000 description 2
- KPYAOIVPJKPIOU-KKUMJFAQSA-N Leu-Lys-Lys Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(O)=O KPYAOIVPJKPIOU-KKUMJFAQSA-N 0.000 description 2
- SBANPBVRHYIMRR-UHFFFAOYSA-N Leu-Ser-Pro Natural products CC(C)CC(N)C(=O)NC(CO)C(=O)N1CCCC1C(O)=O SBANPBVRHYIMRR-UHFFFAOYSA-N 0.000 description 2
- SVBJIZVVYJYGLA-DCAQKATOSA-N Leu-Ser-Val Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(O)=O SVBJIZVVYJYGLA-DCAQKATOSA-N 0.000 description 2
- LFSQWRSVPNKJGP-WDCWCFNPSA-N Leu-Thr-Glu Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@H](C(O)=O)CCC(O)=O LFSQWRSVPNKJGP-WDCWCFNPSA-N 0.000 description 2
- RNYLNYTYMXACRI-VFAJRCTISA-N Leu-Thr-Trp Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CNC2=C1C=CC=C2)C(O)=O RNYLNYTYMXACRI-VFAJRCTISA-N 0.000 description 2
- 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 2
- BGGTYDNTOYRTTR-MEYUZBJRSA-N Leu-Tyr-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CC1=CC=C(C=C1)O)NC(=O)[C@H](CC(C)C)N)O BGGTYDNTOYRTTR-MEYUZBJRSA-N 0.000 description 2
- YQFZRHYZLARWDY-IHRRRGAJSA-N Leu-Val-Lys Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@H](C(O)=O)CCCCN YQFZRHYZLARWDY-IHRRRGAJSA-N 0.000 description 2
- 102100029185 Low affinity immunoglobulin gamma Fc region receptor III-B Human genes 0.000 description 2
- XFIHDSBIPWEYJJ-YUMQZZPRSA-N Lys-Ala-Gly Chemical compound OC(=O)CNC(=O)[C@H](C)NC(=O)[C@@H](N)CCCCN XFIHDSBIPWEYJJ-YUMQZZPRSA-N 0.000 description 2
- 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 2
- KNKHAVVBVXKOGX-JXUBOQSCSA-N Lys-Ala-Thr Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O KNKHAVVBVXKOGX-JXUBOQSCSA-N 0.000 description 2
- SJNZALDHDUYDBU-IHRRRGAJSA-N Lys-Arg-Lys Chemical compound NCCCC[C@H](N)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CCCCN)C(O)=O SJNZALDHDUYDBU-IHRRRGAJSA-N 0.000 description 2
- SWWCDAGDQHTKIE-RHYQMDGZSA-N Lys-Arg-Thr Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(O)=O SWWCDAGDQHTKIE-RHYQMDGZSA-N 0.000 description 2
- PXHCFKXNSBJSTQ-KKUMJFAQSA-N Lys-Asn-Tyr Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)N)NC(=O)[C@H](CCCCN)N)O PXHCFKXNSBJSTQ-KKUMJFAQSA-N 0.000 description 2
- KPJJOZUXFOLGMQ-CIUDSAMLSA-N Lys-Asp-Asn Chemical compound C(CCN)C[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](CC(=O)N)C(=O)O)N KPJJOZUXFOLGMQ-CIUDSAMLSA-N 0.000 description 2
- MWVUEPNEPWMFBD-SRVKXCTJSA-N Lys-Cys-Lys Chemical compound NCCCC[C@H](N)C(=O)N[C@@H](CS)C(=O)N[C@H](C(O)=O)CCCCN MWVUEPNEPWMFBD-SRVKXCTJSA-N 0.000 description 2
- AIPHUKOBUXJNKM-KKUMJFAQSA-N Lys-Cys-Phe Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CS)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O AIPHUKOBUXJNKM-KKUMJFAQSA-N 0.000 description 2
- CRNNMTHBMRFQNG-GUBZILKMSA-N Lys-Glu-Cys Chemical compound C(CCN)C[C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CS)C(=O)O)N CRNNMTHBMRFQNG-GUBZILKMSA-N 0.000 description 2
- ISHNZELVUVPCHY-ZETCQYMHSA-N Lys-Gly-Gly Chemical compound NCCCC[C@H](N)C(=O)NCC(=O)NCC(O)=O ISHNZELVUVPCHY-ZETCQYMHSA-N 0.000 description 2
- OIQSIMFSVLLWBX-VOAKCMCISA-N Lys-Leu-Thr Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O OIQSIMFSVLLWBX-VOAKCMCISA-N 0.000 description 2
- YDDDRTIPNTWGIG-SRVKXCTJSA-N Lys-Lys-Ser Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CO)C(O)=O YDDDRTIPNTWGIG-SRVKXCTJSA-N 0.000 description 2
- LUTDBHBIHHREDC-IHRRRGAJSA-N Lys-Pro-Lys Chemical compound NCCCC[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCCCN)C(O)=O LUTDBHBIHHREDC-IHRRRGAJSA-N 0.000 description 2
- SBQDRNOLGSYHQA-YUMQZZPRSA-N Lys-Ser-Gly Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CO)C(=O)NCC(O)=O SBQDRNOLGSYHQA-YUMQZZPRSA-N 0.000 description 2
- YRNRVKTYDSLKMD-KKUMJFAQSA-N Lys-Ser-Tyr Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O YRNRVKTYDSLKMD-KKUMJFAQSA-N 0.000 description 2
- YKBSXQFZWFXFIB-VOAKCMCISA-N Lys-Thr-Lys Chemical compound NCCCC[C@H](N)C(=O)N[C@@H]([C@H](O)C)C(=O)N[C@@H](CCCCN)C(O)=O YKBSXQFZWFXFIB-VOAKCMCISA-N 0.000 description 2
- HMZPYMSEAALNAE-ULQDDVLXSA-N Lys-Val-Tyr Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O HMZPYMSEAALNAE-ULQDDVLXSA-N 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- RKIIYGUHIQJCBW-SRVKXCTJSA-N Met-His-Glu Chemical compound [H]N[C@@H](CCSC)C(=O)N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CCC(O)=O)C(O)=O RKIIYGUHIQJCBW-SRVKXCTJSA-N 0.000 description 2
- NHDMNXBBSGVYGP-PYJNHQTQSA-N Met-His-Ile Chemical compound CSCC[C@H](N)C(=O)N[C@H](C(=O)N[C@@H]([C@@H](C)CC)C(O)=O)CC1=CN=CN1 NHDMNXBBSGVYGP-PYJNHQTQSA-N 0.000 description 2
- ABHVWYPPHDYFNY-WDSOQIARSA-N Met-His-Trp Chemical compound C([C@H](NC(=O)[C@@H](N)CCSC)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(O)=O)C1=CN=CN1 ABHVWYPPHDYFNY-WDSOQIARSA-N 0.000 description 2
- FWAHLGXNBLWIKB-NAKRPEOUSA-N Met-Ile-Ser Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H]([C@@H](C)CC)NC(=O)[C@@H](N)CCSC FWAHLGXNBLWIKB-NAKRPEOUSA-N 0.000 description 2
- GGXZOTSDJJTDGB-GUBZILKMSA-N Met-Ser-Val Chemical compound [H]N[C@@H](CCSC)C(=O)N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(O)=O GGXZOTSDJJTDGB-GUBZILKMSA-N 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- XMBSYZWANAQXEV-UHFFFAOYSA-N N-alpha-L-glutamyl-L-phenylalanine Natural products OC(=O)CCC(N)C(=O)NC(C(O)=O)CC1=CC=CC=C1 XMBSYZWANAQXEV-UHFFFAOYSA-N 0.000 description 2
- 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 2
- 241000282579 Pan Species 0.000 description 2
- JOXIIFVCSATTDH-IHPCNDPISA-N Phe-Asn-Trp Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CC2=CNC3=CC=CC=C32)C(=O)O)N JOXIIFVCSATTDH-IHPCNDPISA-N 0.000 description 2
- NAXPHWZXEXNDIW-JTQLQIEISA-N Phe-Gly-Gly Chemical compound OC(=O)CNC(=O)CNC(=O)[C@@H](N)CC1=CC=CC=C1 NAXPHWZXEXNDIW-JTQLQIEISA-N 0.000 description 2
- 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 2
- KXUZHWXENMYOHC-QEJZJMRPSA-N Phe-Leu-Ala Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C)C(O)=O KXUZHWXENMYOHC-QEJZJMRPSA-N 0.000 description 2
- RSPUIENXSJYZQO-JYJNAYRXSA-N Phe-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=CC=C1 RSPUIENXSJYZQO-JYJNAYRXSA-N 0.000 description 2
- DMEYUTSDVRCWRS-ULQDDVLXSA-N Phe-Lys-Arg Chemical compound NC(=N)NCCC[C@@H](C(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](N)CC1=CC=CC=C1 DMEYUTSDVRCWRS-ULQDDVLXSA-N 0.000 description 2
- ZJPGOXWRFNKIQL-JYJNAYRXSA-N Phe-Pro-Pro Chemical compound C([C@H](N)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(O)=O)C1=CC=CC=C1 ZJPGOXWRFNKIQL-JYJNAYRXSA-N 0.000 description 2
- BSKMOCNNLNDIMU-CDMKHQONSA-N Phe-Thr-Gly Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(O)=O BSKMOCNNLNDIMU-CDMKHQONSA-N 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- VXCHGLYSIOOZIS-GUBZILKMSA-N Pro-Ala-Arg Chemical compound NC(N)=NCCC[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H]1CCCN1 VXCHGLYSIOOZIS-GUBZILKMSA-N 0.000 description 2
- HFZNNDWPHBRNPV-KZVJFYERSA-N Pro-Ala-Thr Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O HFZNNDWPHBRNPV-KZVJFYERSA-N 0.000 description 2
- JARJPEMLQAWNBR-GUBZILKMSA-N Pro-Asp-Arg Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O JARJPEMLQAWNBR-GUBZILKMSA-N 0.000 description 2
- UAYHMOIGIQZLFR-NHCYSSNCSA-N Pro-Gln-Val Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](C(C)C)C(O)=O UAYHMOIGIQZLFR-NHCYSSNCSA-N 0.000 description 2
- KIPIKSXPPLABPN-CIUDSAMLSA-N Pro-Glu-Asn Chemical compound NC(=O)C[C@@H](C(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H]1CCCN1 KIPIKSXPPLABPN-CIUDSAMLSA-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
- VYWNORHENYEQDW-YUMQZZPRSA-N Pro-Gly-Glu Chemical compound OC(=O)CC[C@@H](C(O)=O)NC(=O)CNC(=O)[C@@H]1CCCN1 VYWNORHENYEQDW-YUMQZZPRSA-N 0.000 description 2
- UIMCLYYSUCIUJM-UWVGGRQHSA-N Pro-Gly-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)CNC(=O)[C@@H]1CCCN1 UIMCLYYSUCIUJM-UWVGGRQHSA-N 0.000 description 2
- VTFXTWDFPTWNJY-RHYQMDGZSA-N Pro-Leu-Thr Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O VTFXTWDFPTWNJY-RHYQMDGZSA-N 0.000 description 2
- MHHQQZIFLWFZGR-DCAQKATOSA-N Pro-Lys-Ser Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CO)C(O)=O MHHQQZIFLWFZGR-DCAQKATOSA-N 0.000 description 2
- HWLKHNDRXWTFTN-GUBZILKMSA-N Pro-Pro-Cys Chemical compound C1C[C@H](NC1)C(=O)N2CCC[C@H]2C(=O)N[C@@H](CS)C(=O)O HWLKHNDRXWTFTN-GUBZILKMSA-N 0.000 description 2
- PCWLNNZTBJTZRN-AVGNSLFASA-N Pro-Pro-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@H]1NCCC1 PCWLNNZTBJTZRN-AVGNSLFASA-N 0.000 description 2
- QAAYIXYLEMRULP-SRVKXCTJSA-N Pro-Pro-Met Chemical compound CSCC[C@@H](C(O)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@H]1NCCC1 QAAYIXYLEMRULP-SRVKXCTJSA-N 0.000 description 2
- SBVPYBFMIGDIDX-SRVKXCTJSA-N Pro-Pro-Pro Chemical compound OC(=O)[C@@H]1CCCN1C(=O)[C@H]1N(C(=O)[C@H]2NCCC2)CCC1 SBVPYBFMIGDIDX-SRVKXCTJSA-N 0.000 description 2
- LNICFEXCAHIJOR-DCAQKATOSA-N Pro-Ser-Leu Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(O)=O LNICFEXCAHIJOR-DCAQKATOSA-N 0.000 description 2
- KHRLUIPIMIQFGT-AVGNSLFASA-N Pro-Val-Leu Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O KHRLUIPIMIQFGT-AVGNSLFASA-N 0.000 description 2
- YUSRGTQIPCJNHQ-CIUDSAMLSA-N Ser-Arg-Glu Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(O)=O YUSRGTQIPCJNHQ-CIUDSAMLSA-N 0.000 description 2
- FIDMVVBUOCMMJG-CIUDSAMLSA-N Ser-Asn-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](N)CO FIDMVVBUOCMMJG-CIUDSAMLSA-N 0.000 description 2
- CTLVSHXLRVEILB-UBHSHLNASA-N Ser-Asn-Trp Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)N)NC(=O)[C@H](CO)N CTLVSHXLRVEILB-UBHSHLNASA-N 0.000 description 2
- BNFVPSRLHHPQKS-WHFBIAKZSA-N Ser-Asp-Gly Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC(O)=O)C(=O)NCC(O)=O BNFVPSRLHHPQKS-WHFBIAKZSA-N 0.000 description 2
- MUARUIBTKQJKFY-WHFBIAKZSA-N Ser-Gly-Asp Chemical compound [H]N[C@@H](CO)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(O)=O MUARUIBTKQJKFY-WHFBIAKZSA-N 0.000 description 2
- SVWQEIRZHHNBIO-WHFBIAKZSA-N Ser-Gly-Cys Chemical compound [H]N[C@@H](CO)C(=O)NCC(=O)N[C@@H](CS)C(O)=O SVWQEIRZHHNBIO-WHFBIAKZSA-N 0.000 description 2
- OQPNSDWGAMFJNU-QWRGUYRKSA-N Ser-Gly-Tyr Chemical compound OC[C@H](N)C(=O)NCC(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 OQPNSDWGAMFJNU-QWRGUYRKSA-N 0.000 description 2
- IFPBAGJBHSNYPR-ZKWXMUAHSA-N Ser-Ile-Gly Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(O)=O IFPBAGJBHSNYPR-ZKWXMUAHSA-N 0.000 description 2
- 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 2
- ZIFYDQAFEMIZII-GUBZILKMSA-N Ser-Leu-Glu Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(O)=O ZIFYDQAFEMIZII-GUBZILKMSA-N 0.000 description 2
- JWOBLHJRDADHLN-KKUMJFAQSA-N Ser-Leu-Tyr Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O JWOBLHJRDADHLN-KKUMJFAQSA-N 0.000 description 2
- RRVFEDGUXSYWOW-BZSNNMDCSA-N Ser-Phe-Phe Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O RRVFEDGUXSYWOW-BZSNNMDCSA-N 0.000 description 2
- QMCDMHWAKMUGJE-IHRRRGAJSA-N Ser-Phe-Val Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](C(C)C)C(O)=O QMCDMHWAKMUGJE-IHRRRGAJSA-N 0.000 description 2
- RHAPJNVNWDBFQI-BQBZGAKWSA-N Ser-Pro-Gly Chemical compound OC[C@H](N)C(=O)N1CCC[C@H]1C(=O)NCC(O)=O RHAPJNVNWDBFQI-BQBZGAKWSA-N 0.000 description 2
- AZWNCEBQZXELEZ-FXQIFTODSA-N Ser-Pro-Ser Chemical compound OC[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CO)C(O)=O AZWNCEBQZXELEZ-FXQIFTODSA-N 0.000 description 2
- CKDXFSPMIDSMGV-GUBZILKMSA-N Ser-Pro-Val Chemical compound [H]N[C@@H](CO)C(=O)N1CCC[C@H]1C(=O)N[C@@H](C(C)C)C(O)=O CKDXFSPMIDSMGV-GUBZILKMSA-N 0.000 description 2
- BMKNXTJLHFIAAH-CIUDSAMLSA-N Ser-Ser-Leu Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(O)=O BMKNXTJLHFIAAH-CIUDSAMLSA-N 0.000 description 2
- RXUOAOOZIWABBW-XGEHTFHBSA-N Ser-Thr-Arg Chemical compound OC[C@H](N)C(=O)N[C@@H]([C@H](O)C)C(=O)N[C@H](C(O)=O)CCCN=C(N)N RXUOAOOZIWABBW-XGEHTFHBSA-N 0.000 description 2
- ZKOKTQPHFMRSJP-YJRXYDGGSA-N Ser-Thr-Tyr Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O ZKOKTQPHFMRSJP-YJRXYDGGSA-N 0.000 description 2
- VVKVHAOOUGNDPJ-SRVKXCTJSA-N Ser-Tyr-Ser Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CO)C(O)=O VVKVHAOOUGNDPJ-SRVKXCTJSA-N 0.000 description 2
- YEDSOSIKVUMIJE-DCAQKATOSA-N Ser-Val-Leu Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O YEDSOSIKVUMIJE-DCAQKATOSA-N 0.000 description 2
- 108010087230 Sincalide Proteins 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 241000282887 Suidae Species 0.000 description 2
- GFDUZZACIWNMPE-KZVJFYERSA-N Thr-Ala-Met Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C)C(=O)N[C@@H](CCSC)C(O)=O GFDUZZACIWNMPE-KZVJFYERSA-N 0.000 description 2
- CAGTXGDOIFXLPC-KZVJFYERSA-N Thr-Arg-Ala Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@H](C(=O)N[C@@H](C)C(O)=O)CCCN=C(N)N CAGTXGDOIFXLPC-KZVJFYERSA-N 0.000 description 2
- KWQBJOUOSNJDRR-XAVMHZPKSA-N Thr-Cys-Pro Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CS)C(=O)N1CCC[C@@H]1C(=O)O)N)O KWQBJOUOSNJDRR-XAVMHZPKSA-N 0.000 description 2
- LIXBDERDAGNVAV-XKBZYTNZSA-N Thr-Gln-Ser Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CO)C(O)=O LIXBDERDAGNVAV-XKBZYTNZSA-N 0.000 description 2
- VOHWDZNIESHTFW-XKBZYTNZSA-N Thr-Glu-Cys Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CS)C(=O)O)N)O VOHWDZNIESHTFW-XKBZYTNZSA-N 0.000 description 2
- OQCXTUQTKQFDCX-HTUGSXCWSA-N Thr-Glu-Phe Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)O)N)O OQCXTUQTKQFDCX-HTUGSXCWSA-N 0.000 description 2
- IMULJHHGAUZZFE-MBLNEYKQSA-N Thr-Gly-Ile Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)NCC(=O)N[C@@H]([C@@H](C)CC)C(O)=O IMULJHHGAUZZFE-MBLNEYKQSA-N 0.000 description 2
- XSEPSRUDSPHMPX-KATARQTJSA-N Thr-Lys-Ser Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CO)C(O)=O XSEPSRUDSPHMPX-KATARQTJSA-N 0.000 description 2
- WRUWXBBEFUTJOU-XGEHTFHBSA-N Thr-Met-Ser Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CO)C(=O)O)N)O WRUWXBBEFUTJOU-XGEHTFHBSA-N 0.000 description 2
- WYLAVUAWOUVUCA-XVSYOHENSA-N Thr-Phe-Asp Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CC(O)=O)C(O)=O WYLAVUAWOUVUCA-XVSYOHENSA-N 0.000 description 2
- XKWABWFMQXMUMT-HJGDQZAQSA-N Thr-Pro-Glu Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCC(O)=O)C(O)=O XKWABWFMQXMUMT-HJGDQZAQSA-N 0.000 description 2
- KERCOYANYUPLHJ-XGEHTFHBSA-N Thr-Pro-Ser Chemical compound C[C@@H](O)[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CO)C(O)=O KERCOYANYUPLHJ-XGEHTFHBSA-N 0.000 description 2
- ZESGVALRVJIVLZ-VFCFLDTKSA-N Thr-Thr-Pro Chemical compound C[C@H]([C@@H](C(=O)N[C@@H]([C@@H](C)O)C(=O)N1CCC[C@@H]1C(=O)O)N)O ZESGVALRVJIVLZ-VFCFLDTKSA-N 0.000 description 2
- LECUEEHKUFYOOV-ZJDVBMNYSA-N Thr-Thr-Val Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@@H](N)[C@@H](C)O LECUEEHKUFYOOV-ZJDVBMNYSA-N 0.000 description 2
- BKVICMPZWRNWOC-RHYQMDGZSA-N Thr-Val-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](N)[C@@H](C)O BKVICMPZWRNWOC-RHYQMDGZSA-N 0.000 description 2
- UKINEYBQXPMOJO-UBHSHLNASA-N Trp-Asn-Ser Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CO)C(=O)O)N UKINEYBQXPMOJO-UBHSHLNASA-N 0.000 description 2
- UDCHKDYNMRJYMI-QEJZJMRPSA-N Trp-Glu-Ser Chemical compound [H]N[C@@H](CC1=CNC2=C1C=CC=C2)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(O)=O UDCHKDYNMRJYMI-QEJZJMRPSA-N 0.000 description 2
- 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 2
- UPUNWAXSLPBMRK-XTWBLICNSA-N Trp-Thr-Thr Chemical compound [H]N[C@@H](CC1=CNC2=C1C=CC=C2)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O UPUNWAXSLPBMRK-XTWBLICNSA-N 0.000 description 2
- BABINGWMZBWXIX-BPUTZDHNSA-N Trp-Val-Ser Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CO)C(=O)O)NC(=O)[C@H](CC1=CNC2=CC=CC=C21)N BABINGWMZBWXIX-BPUTZDHNSA-N 0.000 description 2
- BURPTJBFWIOHEY-UWJYBYFXSA-N Tyr-Ala-Asp Chemical compound OC(=O)C[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 BURPTJBFWIOHEY-UWJYBYFXSA-N 0.000 description 2
- 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 2
- OLWFDNLLBWQWCP-STQMWFEESA-N Tyr-Gly-Met Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)NCC(=O)N[C@@H](CCSC)C(O)=O OLWFDNLLBWQWCP-STQMWFEESA-N 0.000 description 2
- NXRGXTBPMOGFID-CFMVVWHZSA-N Tyr-Ile-Asn Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(N)=O)C(O)=O NXRGXTBPMOGFID-CFMVVWHZSA-N 0.000 description 2
- PWKMJDQXKCENMF-MEYUZBJRSA-N Tyr-Thr-Leu Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(O)=O PWKMJDQXKCENMF-MEYUZBJRSA-N 0.000 description 2
- ZYVAAYAOTVJBSS-GMVOTWDCSA-N Tyr-Trp-Ala Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC1=CNC2=C1C=CC=C2)C(=O)N[C@@H](C)C(O)=O ZYVAAYAOTVJBSS-GMVOTWDCSA-N 0.000 description 2
- SQUMHUZLJDUROQ-YDHLFZDLSA-N Tyr-Val-Asp Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(O)=O)C(O)=O SQUMHUZLJDUROQ-YDHLFZDLSA-N 0.000 description 2
- REJBPZVUHYNMEN-LSJOCFKGSA-N Val-Ala-His Chemical compound C[C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)NC(=O)[C@H](C(C)C)N REJBPZVUHYNMEN-LSJOCFKGSA-N 0.000 description 2
- AZSHAZJLOZQYAY-FXQIFTODSA-N Val-Ala-Ser Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](CO)C(O)=O AZSHAZJLOZQYAY-FXQIFTODSA-N 0.000 description 2
- 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 2
- DBOXBUDEAJVKRE-LSJOCFKGSA-N Val-Asn-Val Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](C(C)C)C(=O)O)N DBOXBUDEAJVKRE-LSJOCFKGSA-N 0.000 description 2
- CFSSLXZJEMERJY-NRPADANISA-N Val-Gln-Ala Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](C)C(O)=O CFSSLXZJEMERJY-NRPADANISA-N 0.000 description 2
- VFOHXOLPLACADK-GVXVVHGQSA-N Val-Gln-Leu Chemical compound CC(C)C[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)N)NC(=O)[C@H](C(C)C)N VFOHXOLPLACADK-GVXVVHGQSA-N 0.000 description 2
- 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 2
- VCAWFLIWYNMHQP-UKJIMTQDSA-N Val-Glu-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)O)NC(=O)[C@H](C(C)C)N VCAWFLIWYNMHQP-UKJIMTQDSA-N 0.000 description 2
- 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 2
- OACSGBOREVRSME-NHCYSSNCSA-N Val-His-Asn Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](Cc1cnc[nH]1)C(=O)N[C@@H](CC(N)=O)C(O)=O OACSGBOREVRSME-NHCYSSNCSA-N 0.000 description 2
- HJSLDXZAZGFPDK-ULQDDVLXSA-N Val-Phe-Leu Chemical compound CC(C)C[C@@H](C(=O)O)NC(=O)[C@H](CC1=CC=CC=C1)NC(=O)[C@H](C(C)C)N HJSLDXZAZGFPDK-ULQDDVLXSA-N 0.000 description 2
- KISFXYYRKKNLOP-IHRRRGAJSA-N Val-Phe-Ser Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CO)C(=O)O)N KISFXYYRKKNLOP-IHRRRGAJSA-N 0.000 description 2
- 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 2
- KRAHMIJVUPUOTQ-DCAQKATOSA-N Val-Ser-His Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)N KRAHMIJVUPUOTQ-DCAQKATOSA-N 0.000 description 2
- CEKSLIVSNNGOKH-KZVJFYERSA-N Val-Thr-Ala Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](C)C(=O)O)NC(=O)[C@H](C(C)C)N)O CEKSLIVSNNGOKH-KZVJFYERSA-N 0.000 description 2
- BZDGLJPROOOUOZ-XGEHTFHBSA-N Val-Thr-Cys Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CS)C(=O)O)NC(=O)[C@H](C(C)C)N)O BZDGLJPROOOUOZ-XGEHTFHBSA-N 0.000 description 2
- UVHFONIHVHLDDQ-IFFSRLJSSA-N Val-Thr-Glu Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)O)NC(=O)[C@H](C(C)C)N)O UVHFONIHVHLDDQ-IFFSRLJSSA-N 0.000 description 2
- ZLNYBMWGPOKSLW-LSJOCFKGSA-N Val-Val-Asp Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(O)=O)C(O)=O ZLNYBMWGPOKSLW-LSJOCFKGSA-N 0.000 description 2
- 238000001042 affinity chromatography Methods 0.000 description 2
- 108010008685 alanyl-glutamyl-aspartic acid Proteins 0.000 description 2
- 108010047495 alanylglycine Proteins 0.000 description 2
- 108010070944 alanylhistidine Proteins 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 108010013835 arginine glutamate Proteins 0.000 description 2
- 108010062796 arginyllysine Proteins 0.000 description 2
- 210000004436 artificial bacterial chromosome Anatomy 0.000 description 2
- 210000004507 artificial chromosome Anatomy 0.000 description 2
- 210000001106 artificial yeast chromosome Anatomy 0.000 description 2
- 108010040443 aspartyl-aspartic acid Proteins 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 239000007853 buffer solution Substances 0.000 description 2
- 238000010609 cell counting kit-8 assay Methods 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 235000013330 chicken meat Nutrition 0.000 description 2
- 238000010367 cloning Methods 0.000 description 2
- 238000010276 construction Methods 0.000 description 2
- 230000008094 contradictory effect Effects 0.000 description 2
- 108010081447 cytochrophin-4 Proteins 0.000 description 2
- 210000004405 cytokine-induced killer cell Anatomy 0.000 description 2
- OPTASPLRGRRNAP-UHFFFAOYSA-N cytosine Chemical compound NC=1C=CNC(=O)N=1 OPTASPLRGRRNAP-UHFFFAOYSA-N 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 238000010586 diagram Methods 0.000 description 2
- 238000007865 diluting Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003937 drug carrier Substances 0.000 description 2
- 239000003623 enhancer Substances 0.000 description 2
- 238000001976 enzyme digestion Methods 0.000 description 2
- 210000003527 eukaryotic cell Anatomy 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 238000005206 flow analysis Methods 0.000 description 2
- 238000000684 flow cytometry Methods 0.000 description 2
- 230000005714 functional activity Effects 0.000 description 2
- 108010013768 glutamyl-aspartyl-proline Proteins 0.000 description 2
- 230000013595 glycosylation Effects 0.000 description 2
- 238000006206 glycosylation reaction Methods 0.000 description 2
- 108010026364 glycyl-glycyl-leucine Proteins 0.000 description 2
- 108010048994 glycyl-tyrosyl-alanine Proteins 0.000 description 2
- 108010045126 glycyl-tyrosyl-glycine Proteins 0.000 description 2
- 108010015792 glycyllysine Proteins 0.000 description 2
- 108010037850 glycylvaline Proteins 0.000 description 2
- 230000012010 growth Effects 0.000 description 2
- UYTPUPDQBNUYGX-UHFFFAOYSA-N guanine Chemical compound O=C1NC(N)=NC2=C1N=CN2 UYTPUPDQBNUYGX-UHFFFAOYSA-N 0.000 description 2
- 210000002443 helper t lymphocyte Anatomy 0.000 description 2
- 230000003053 immunization Effects 0.000 description 2
- 238000002649 immunization Methods 0.000 description 2
- 230000003308 immunostimulating effect Effects 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 238000003780 insertion Methods 0.000 description 2
- 230000037431 insertion Effects 0.000 description 2
- 150000002500 ions Chemical class 0.000 description 2
- 108010027338 isoleucylcysteine Proteins 0.000 description 2
- 210000003292 kidney cell Anatomy 0.000 description 2
- 108010091871 leucylmethionine Proteins 0.000 description 2
- 108010057821 leucylproline Proteins 0.000 description 2
- 239000002502 liposome Substances 0.000 description 2
- 108010003700 lysyl aspartic acid Proteins 0.000 description 2
- 108020004999 messenger RNA Proteins 0.000 description 2
- 238000005457 optimization Methods 0.000 description 2
- 210000000056 organ Anatomy 0.000 description 2
- 230000008506 pathogenesis Effects 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 239000000825 pharmaceutical preparation Substances 0.000 description 2
- 108010070409 phenylalanyl-glycyl-glycine Proteins 0.000 description 2
- 108010073025 phenylalanylphenylalanine Proteins 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 238000004393 prognosis Methods 0.000 description 2
- 230000002035 prolonged effect Effects 0.000 description 2
- 230000006798 recombination Effects 0.000 description 2
- 238000005215 recombination Methods 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 239000012898 sample dilution Substances 0.000 description 2
- 108010048397 seryl-lysyl-leucine Proteins 0.000 description 2
- 108010026333 seryl-proline Proteins 0.000 description 2
- 108010071207 serylmethionine Proteins 0.000 description 2
- IZTQOLKUZKXIRV-YRVFCXMDSA-N sincalide Chemical compound C([C@@H](C(=O)N[C@@H](CCSC)C(=O)NCC(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@@H](N)CC(O)=O)C1=CC=C(OS(O)(=O)=O)C=C1 IZTQOLKUZKXIRV-YRVFCXMDSA-N 0.000 description 2
- 238000002415 sodium dodecyl sulfate polyacrylamide gel electrophoresis Methods 0.000 description 2
- 230000004083 survival effect Effects 0.000 description 2
- 230000002459 sustained effect Effects 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 230000010474 transient expression Effects 0.000 description 2
- 238000013519 translation Methods 0.000 description 2
- 108010079202 tyrosyl-alanyl-cysteine Proteins 0.000 description 2
- 101150028074 2 gene Proteins 0.000 description 1
- GKAZXNDATBWNBI-DCAQKATOSA-N Ala-Met-Lys Chemical compound C[C@@H](C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCCCN)C(=O)O)N GKAZXNDATBWNBI-DCAQKATOSA-N 0.000 description 1
- OLVCTPPSXNRGKV-GUBZILKMSA-N Ala-Pro-Pro Chemical compound C[C@H](N)C(=O)N1CCC[C@H]1C(=O)N1[C@H](C(O)=O)CCC1 OLVCTPPSXNRGKV-GUBZILKMSA-N 0.000 description 1
- WNHNMKOFKCHKKD-BFHQHQDPSA-N Ala-Thr-Gly Chemical compound [H]N[C@@H](C)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(O)=O WNHNMKOFKCHKKD-BFHQHQDPSA-N 0.000 description 1
- OZNSCVPYWZRQPY-CIUDSAMLSA-N Arg-Asp-Glu Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(O)=O OZNSCVPYWZRQPY-CIUDSAMLSA-N 0.000 description 1
- MFAMTAVAFBPXDC-LPEHRKFASA-N Arg-Asp-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CC(=O)O)NC(=O)[C@H](CCCN=C(N)N)N)C(=O)O MFAMTAVAFBPXDC-LPEHRKFASA-N 0.000 description 1
- PNQWAUXQDBIJDY-GUBZILKMSA-N Arg-Glu-Glu Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(O)=O PNQWAUXQDBIJDY-GUBZILKMSA-N 0.000 description 1
- 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 1
- 239000004475 Arginine Substances 0.000 description 1
- VYLVOMUVLMGCRF-ZLUOBGJFSA-N Asn-Asp-Ser Chemical compound NC(=O)C[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(O)=O VYLVOMUVLMGCRF-ZLUOBGJFSA-N 0.000 description 1
- DXVMJJNAOVECBA-WHFBIAKZSA-N Asn-Gly-Asn Chemical compound NC(=O)C[C@H](N)C(=O)NCC(=O)N[C@@H](CC(N)=O)C(O)=O DXVMJJNAOVECBA-WHFBIAKZSA-N 0.000 description 1
- GWNMUVANAWDZTI-YUMQZZPRSA-N Asn-Gly-His Chemical compound C1=C(NC=N1)C[C@@H](C(=O)O)NC(=O)CNC(=O)[C@H](CC(=O)N)N GWNMUVANAWDZTI-YUMQZZPRSA-N 0.000 description 1
- BZWRLDPIWKOVKB-ZPFDUUQYSA-N Asn-Leu-Ile Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O BZWRLDPIWKOVKB-ZPFDUUQYSA-N 0.000 description 1
- RBOBTTLFPRSXKZ-BZSNNMDCSA-N Asn-Phe-Tyr Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O RBOBTTLFPRSXKZ-BZSNNMDCSA-N 0.000 description 1
- YQPSDMUGFKJZHR-QRTARXTBSA-N Asn-Trp-Val Chemical compound CC(C)[C@@H](C(=O)O)NC(=O)[C@H](CC1=CNC2=CC=CC=C21)NC(=O)[C@H](CC(=O)N)N YQPSDMUGFKJZHR-QRTARXTBSA-N 0.000 description 1
- JNCRAQVYJZGIOW-QSFUFRPTSA-N Asn-Val-Ile Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O JNCRAQVYJZGIOW-QSFUFRPTSA-N 0.000 description 1
- XYBJLTKSGFBLCS-QXEWZRGKSA-N Asp-Arg-Val Chemical compound NC(N)=NCCC[C@@H](C(=O)N[C@@H](C(C)C)C(O)=O)NC(=O)[C@@H](N)CC(O)=O XYBJLTKSGFBLCS-QXEWZRGKSA-N 0.000 description 1
- HSWYMWGDMPLTTH-FXQIFTODSA-N Asp-Glu-Gln Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(N)=O)C(O)=O HSWYMWGDMPLTTH-FXQIFTODSA-N 0.000 description 1
- YIDFBWRHIYOYAA-LKXGYXEUSA-N Asp-Ser-Thr Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(O)=O YIDFBWRHIYOYAA-LKXGYXEUSA-N 0.000 description 1
- ITGFVUYOLWBPQW-KKHAAJSZSA-N Asp-Thr-Val Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(O)=O ITGFVUYOLWBPQW-KKHAAJSZSA-N 0.000 description 1
- DCXYFEDJOCDNAF-UHFFFAOYSA-N Asparagine Natural products OC(=O)C(N)CC(N)=O DCXYFEDJOCDNAF-UHFFFAOYSA-N 0.000 description 1
- 208000003950 B-cell lymphoma Diseases 0.000 description 1
- 206010004593 Bile duct cancer Diseases 0.000 description 1
- 206010005003 Bladder cancer Diseases 0.000 description 1
- 210000001266 CD8-positive T-lymphocyte Anatomy 0.000 description 1
- 206010008342 Cervix carcinoma Diseases 0.000 description 1
- 208000005243 Chondrosarcoma Diseases 0.000 description 1
- 102100038449 Claudin-6 Human genes 0.000 description 1
- 108090000229 Claudin-6 Proteins 0.000 description 1
- 108700010070 Codon Usage Proteins 0.000 description 1
- 206010009944 Colon cancer Diseases 0.000 description 1
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 1
- 208000035473 Communicable disease Diseases 0.000 description 1
- 108091029523 CpG island Proteins 0.000 description 1
- 241000699802 Cricetulus griseus Species 0.000 description 1
- SZQCDCKIGWQAQN-FXQIFTODSA-N Cys-Arg-Ala Chemical compound [H]N[C@@H](CS)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(O)=O SZQCDCKIGWQAQN-FXQIFTODSA-N 0.000 description 1
- RESAHOSBQHMOKH-KKUMJFAQSA-N Cys-Phe-Leu Chemical compound CC(C)C[C@@H](C(=O)O)NC(=O)[C@H](CC1=CC=CC=C1)NC(=O)[C@H](CS)N RESAHOSBQHMOKH-KKUMJFAQSA-N 0.000 description 1
- 102000012410 DNA Ligases Human genes 0.000 description 1
- 108010061982 DNA Ligases Proteins 0.000 description 1
- BWGNESOTFCXPMA-UHFFFAOYSA-N Dihydrogen disulfide Chemical compound SS BWGNESOTFCXPMA-UHFFFAOYSA-N 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 206010014733 Endometrial cancer Diseases 0.000 description 1
- 206010014759 Endometrial neoplasm Diseases 0.000 description 1
- 241000701959 Escherichia virus Lambda Species 0.000 description 1
- 108091006020 Fc-tagged proteins Proteins 0.000 description 1
- OKQLXOYFUPVEHI-CIUDSAMLSA-N Gln-Ser-Met Chemical compound CSCC[C@@H](C(=O)O)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(=O)N)N OKQLXOYFUPVEHI-CIUDSAMLSA-N 0.000 description 1
- YRHZWVKUFWCEPW-GLLZPBPUSA-N Gln-Thr-Gln Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)O)NC(=O)[C@H](CCC(=O)N)N)O YRHZWVKUFWCEPW-GLLZPBPUSA-N 0.000 description 1
- 102000006395 Globulins Human genes 0.000 description 1
- 108010044091 Globulins Proteins 0.000 description 1
- WATXSTJXNBOHKD-LAEOZQHASA-N Glu-Asp-Val Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](C(C)C)C(O)=O WATXSTJXNBOHKD-LAEOZQHASA-N 0.000 description 1
- PKYAVRMYTBBRLS-FXQIFTODSA-N Glu-Cys-Glu Chemical compound OC(=O)CC[C@H](N)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCC(O)=O)C(O)=O PKYAVRMYTBBRLS-FXQIFTODSA-N 0.000 description 1
- IRXNJYPKBVERCW-DCAQKATOSA-N Glu-Leu-Glu Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(O)=O IRXNJYPKBVERCW-DCAQKATOSA-N 0.000 description 1
- SWRVAQHFBRZVNX-GUBZILKMSA-N Glu-Lys-Asn Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(O)=O SWRVAQHFBRZVNX-GUBZILKMSA-N 0.000 description 1
- HMJULNMJWOZNFI-XHNCKOQMSA-N Glu-Ser-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CO)NC(=O)[C@H](CCC(=O)O)N)C(=O)O HMJULNMJWOZNFI-XHNCKOQMSA-N 0.000 description 1
- XCLCVBYNGXEVDU-WHFBIAKZSA-N Gly-Asn-Ser Chemical compound NCC(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CO)C(O)=O XCLCVBYNGXEVDU-WHFBIAKZSA-N 0.000 description 1
- KQDMENMTYNBWMR-WHFBIAKZSA-N Gly-Asp-Ala Chemical compound [H]NCC(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](C)C(O)=O KQDMENMTYNBWMR-WHFBIAKZSA-N 0.000 description 1
- LGQZOQRDEUIZJY-YUMQZZPRSA-N Gly-Cys-Lys Chemical compound NCCCC[C@H](NC(=O)[C@H](CS)NC(=O)CN)C(O)=O LGQZOQRDEUIZJY-YUMQZZPRSA-N 0.000 description 1
- OHUKZZYSJBKFRR-WHFBIAKZSA-N Gly-Ser-Asp Chemical compound [H]NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(O)=O)C(O)=O OHUKZZYSJBKFRR-WHFBIAKZSA-N 0.000 description 1
- ZKJZBRHRWKLVSJ-ZDLURKLDSA-N Gly-Thr-Cys Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CS)C(=O)O)NC(=O)CN)O ZKJZBRHRWKLVSJ-ZDLURKLDSA-N 0.000 description 1
- IZVICCORZOSGPT-JSGCOSHPSA-N Gly-Val-Tyr Chemical compound [H]NCC(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O IZVICCORZOSGPT-JSGCOSHPSA-N 0.000 description 1
- 241000696272 Gull adenovirus Species 0.000 description 1
- 241000238631 Hexapoda Species 0.000 description 1
- VTZYMXGGXOFBMX-DJFWLOJKSA-N His-Ile-Asp Chemical compound [H]N[C@@H](CC1=CNC=N1)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(O)=O)C(O)=O VTZYMXGGXOFBMX-DJFWLOJKSA-N 0.000 description 1
- TVMNTHXFRSXZGR-IHRRRGAJSA-N His-Lys-Val Chemical compound [H]N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C(C)C)C(O)=O TVMNTHXFRSXZGR-IHRRRGAJSA-N 0.000 description 1
- KLBVGHCGHUNHEA-BJDJZHNGSA-N Ile-Leu-Ala Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C)C(=O)O)N KLBVGHCGHUNHEA-BJDJZHNGSA-N 0.000 description 1
- IOVUXUSIGXCREV-DKIMLUQUSA-N Ile-Leu-Phe Chemical compound CC[C@H](C)[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 IOVUXUSIGXCREV-DKIMLUQUSA-N 0.000 description 1
- CAHCWMVNBZJVAW-NAKRPEOUSA-N Ile-Pro-Ser Chemical compound CC[C@H](C)[C@@H](C(=O)N1CCC[C@H]1C(=O)N[C@@H](CO)C(=O)O)N CAHCWMVNBZJVAW-NAKRPEOUSA-N 0.000 description 1
- ZLFNNVATRMCAKN-ZKWXMUAHSA-N Ile-Ser-Gly Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CO)C(=O)NCC(=O)O)N ZLFNNVATRMCAKN-ZKWXMUAHSA-N 0.000 description 1
- AUIYHFRUOOKTGX-UKJIMTQDSA-N Ile-Val-Gln Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(=O)N)C(=O)O)N AUIYHFRUOOKTGX-UKJIMTQDSA-N 0.000 description 1
- 206010061598 Immunodeficiency Diseases 0.000 description 1
- 102000018071 Immunoglobulin Fc Fragments Human genes 0.000 description 1
- 108010091135 Immunoglobulin Fc Fragments Proteins 0.000 description 1
- 108010021625 Immunoglobulin Fragments Proteins 0.000 description 1
- 102000008394 Immunoglobulin Fragments Human genes 0.000 description 1
- 208000008839 Kidney Neoplasms Diseases 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
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-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
- 206010023825 Laryngeal cancer Diseases 0.000 description 1
- QVFGXCVIXXBFHO-AVGNSLFASA-N Leu-Glu-Leu Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(O)=O QVFGXCVIXXBFHO-AVGNSLFASA-N 0.000 description 1
- WQWSMEOYXJTFRU-GUBZILKMSA-N Leu-Glu-Ser Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(O)=O WQWSMEOYXJTFRU-GUBZILKMSA-N 0.000 description 1
- LKXANTUNFMVCNF-IHPCNDPISA-N Leu-His-Trp Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CC1=CNC2=C1C=CC=C2)C(O)=O LKXANTUNFMVCNF-IHPCNDPISA-N 0.000 description 1
- JLWZLIQRYCTYBD-IHRRRGAJSA-N Leu-Lys-Arg Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O JLWZLIQRYCTYBD-IHRRRGAJSA-N 0.000 description 1
- VCHVSKNMTXWIIP-SRVKXCTJSA-N Leu-Lys-Ser Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CO)C(O)=O VCHVSKNMTXWIIP-SRVKXCTJSA-N 0.000 description 1
- HDHQQEDVWQGBEE-DCAQKATOSA-N Leu-Met-Ser Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CO)C(O)=O HDHQQEDVWQGBEE-DCAQKATOSA-N 0.000 description 1
- MAXILRZVORNXBE-PMVMPFDFSA-N Leu-Phe-Trp Chemical compound C([C@H](NC(=O)[C@@H](N)CC(C)C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(O)=O)C1=CC=CC=C1 MAXILRZVORNXBE-PMVMPFDFSA-N 0.000 description 1
- DAYQSYGBCUKVKT-VOAKCMCISA-N Leu-Thr-Lys Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCCN)C(O)=O DAYQSYGBCUKVKT-VOAKCMCISA-N 0.000 description 1
- 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 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
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- DUTMKEAPLLUGNO-JYJNAYRXSA-N Lys-Glu-Phe Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O DUTMKEAPLLUGNO-JYJNAYRXSA-N 0.000 description 1
- SKRGVGLIRUGANF-AVGNSLFASA-N Lys-Leu-Glu Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(O)=O SKRGVGLIRUGANF-AVGNSLFASA-N 0.000 description 1
- GAHJXEMYXKLZRQ-AJNGGQMLSA-N Lys-Lys-Ile Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O GAHJXEMYXKLZRQ-AJNGGQMLSA-N 0.000 description 1
- LKDXINHHSWFFJC-SRVKXCTJSA-N Lys-Ser-His Chemical compound C1=C(NC=N1)C[C@@H](C(=O)O)NC(=O)[C@H](CO)NC(=O)[C@H](CCCCN)N LKDXINHHSWFFJC-SRVKXCTJSA-N 0.000 description 1
- SUZVLFWOCKHWET-CQDKDKBSSA-N Lys-Tyr-Ala Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](C)C(O)=O SUZVLFWOCKHWET-CQDKDKBSSA-N 0.000 description 1
- UGCIQUYEJIEHKX-GVXVVHGQSA-N Lys-Val-Glu Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(O)=O)C(O)=O UGCIQUYEJIEHKX-GVXVVHGQSA-N 0.000 description 1
- RIPJMCFGQHGHNP-RHYQMDGZSA-N Lys-Val-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](C(C)C)NC(=O)[C@H](CCCCN)N)O RIPJMCFGQHGHNP-RHYQMDGZSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- 208000006644 Malignant Fibrous Histiocytoma Diseases 0.000 description 1
- HLQWFLJOJRFXHO-CIUDSAMLSA-N Met-Glu-Ser Chemical compound [H]N[C@@H](CCSC)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(O)=O HLQWFLJOJRFXHO-CIUDSAMLSA-N 0.000 description 1
- MHQXIBRPDKXDGZ-ZFWWWQNUSA-N Met-Gly-Trp Chemical compound C1=CC=C2C(C[C@H](NC(=O)CNC(=O)[C@@H](N)CCSC)C(O)=O)=CNC2=C1 MHQXIBRPDKXDGZ-ZFWWWQNUSA-N 0.000 description 1
- RSOMVHWMIAZNLE-HJWJTTGWSA-N Met-Phe-Ile Chemical compound [H]N[C@@H](CCSC)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O RSOMVHWMIAZNLE-HJWJTTGWSA-N 0.000 description 1
- IHRFZLQEQVHXFA-RHYQMDGZSA-N Met-Thr-Lys Chemical compound CSCC[C@H](N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@H](C(O)=O)CCCCN IHRFZLQEQVHXFA-RHYQMDGZSA-N 0.000 description 1
- 206010027476 Metastases Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 208000003445 Mouth Neoplasms Diseases 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 208000012902 Nervous system disease Diseases 0.000 description 1
- 208000025966 Neurological disease Diseases 0.000 description 1
- 206010033128 Ovarian cancer Diseases 0.000 description 1
- 206010061535 Ovarian neoplasm Diseases 0.000 description 1
- 108090000526 Papain Proteins 0.000 description 1
- 229930040373 Paraformaldehyde Natural products 0.000 description 1
- BWTKUQPNOMMKMA-FIRPJDEBSA-N Phe-Ile-Phe Chemical compound C([C@H](N)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)C1=CC=CC=C1 BWTKUQPNOMMKMA-FIRPJDEBSA-N 0.000 description 1
- FXEKNHAJIMHRFJ-ULQDDVLXSA-N Phe-Val-His Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)NC(=O)[C@H](CC2=CC=CC=C2)N FXEKNHAJIMHRFJ-ULQDDVLXSA-N 0.000 description 1
- CZCCVJUUWBMISW-FXQIFTODSA-N Pro-Ser-Cys Chemical compound C1C[C@H](NC1)C(=O)N[C@@H](CO)C(=O)N[C@@H](CS)C(=O)O CZCCVJUUWBMISW-FXQIFTODSA-N 0.000 description 1
- PRKWBYCXBBSLSK-GUBZILKMSA-N Pro-Ser-Val Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(O)=O PRKWBYCXBBSLSK-GUBZILKMSA-N 0.000 description 1
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
- 239000004365 Protease Substances 0.000 description 1
- 206010038389 Renal cancer Diseases 0.000 description 1
- 108091081062 Repeated sequence (DNA) Proteins 0.000 description 1
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 1
- 208000004337 Salivary Gland Neoplasms Diseases 0.000 description 1
- 206010061934 Salivary gland cancer Diseases 0.000 description 1
- BGOWRLSWJCVYAQ-CIUDSAMLSA-N Ser-Asp-Leu Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(O)=O BGOWRLSWJCVYAQ-CIUDSAMLSA-N 0.000 description 1
- SWSRFJZZMNLMLY-ZKWXMUAHSA-N Ser-Asp-Val Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](C(C)C)C(O)=O SWSRFJZZMNLMLY-ZKWXMUAHSA-N 0.000 description 1
- INCNPLPRPOYTJI-JBDRJPRFSA-N Ser-Cys-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)[C@H](CS)NC(=O)[C@H](CO)N INCNPLPRPOYTJI-JBDRJPRFSA-N 0.000 description 1
- LQESNKGTTNHZPZ-GHCJXIJMSA-N Ser-Ile-Asn Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(N)=O)C(O)=O LQESNKGTTNHZPZ-GHCJXIJMSA-N 0.000 description 1
- BEAFYHFQTOTVFS-VGDYDELISA-N Ser-Ile-His Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)NC(=O)[C@H](CO)N BEAFYHFQTOTVFS-VGDYDELISA-N 0.000 description 1
- RWDVVSKYZBNDCO-MELADBBJSA-N Ser-Phe-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CC2=CC=CC=C2)NC(=O)[C@H](CO)N)C(=O)O RWDVVSKYZBNDCO-MELADBBJSA-N 0.000 description 1
- ADJDNJCSPNFFPI-FXQIFTODSA-N Ser-Pro-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@@H]1CCCN1C(=O)[C@@H](N)CO ADJDNJCSPNFFPI-FXQIFTODSA-N 0.000 description 1
- 208000024313 Testicular Neoplasms Diseases 0.000 description 1
- 206010057644 Testis cancer Diseases 0.000 description 1
- ONNSECRQFSTMCC-XKBZYTNZSA-N Thr-Glu-Ser Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(O)=O ONNSECRQFSTMCC-XKBZYTNZSA-N 0.000 description 1
- BIBYEFRASCNLAA-CDMKHQONSA-N Thr-Phe-Gly Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@H](C(=O)NCC(O)=O)CC1=CC=CC=C1 BIBYEFRASCNLAA-CDMKHQONSA-N 0.000 description 1
- GXDLGHLJTHMDII-WISUUJSJSA-N Thr-Ser Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@@H](CO)C(O)=O GXDLGHLJTHMDII-WISUUJSJSA-N 0.000 description 1
- OGOYMQWIWHGTGH-KZVJFYERSA-N Thr-Val-Ala Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C)C(O)=O OGOYMQWIWHGTGH-KZVJFYERSA-N 0.000 description 1
- 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
- 208000000728 Thymus Neoplasms Diseases 0.000 description 1
- 206010052779 Transplant rejections Diseases 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- 102000004142 Trypsin Human genes 0.000 description 1
- 108090000631 Trypsin Proteins 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
- SLCSPPCQWUHPPO-JYJNAYRXSA-N Tyr-Glu-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 SLCSPPCQWUHPPO-JYJNAYRXSA-N 0.000 description 1
- MQGGXGKQSVEQHR-KKUMJFAQSA-N Tyr-Ser-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 MQGGXGKQSVEQHR-KKUMJFAQSA-N 0.000 description 1
- LVFZXRQQQDTBQH-IRIUXVKKSA-N Tyr-Thr-Glu Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCC(O)=O)C(O)=O LVFZXRQQQDTBQH-IRIUXVKKSA-N 0.000 description 1
- 208000015778 Undifferentiated pleomorphic sarcoma Diseases 0.000 description 1
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 description 1
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 description 1
- 208000002495 Uterine Neoplasms Diseases 0.000 description 1
- SLLKXDSRVAOREO-KZVJFYERSA-N Val-Ala-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](C)NC(=O)[C@H](C(C)C)N)O SLLKXDSRVAOREO-KZVJFYERSA-N 0.000 description 1
- 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 1
- OVBMCNDKCWAXMZ-NAKRPEOUSA-N Val-Ile-Ser Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CO)C(=O)O)NC(=O)[C@H](C(C)C)N OVBMCNDKCWAXMZ-NAKRPEOUSA-N 0.000 description 1
- GVNLOVJNNDZUHS-RHYQMDGZSA-N Val-Thr-Lys Chemical compound [H]N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCCN)C(O)=O GVNLOVJNNDZUHS-RHYQMDGZSA-N 0.000 description 1
- DVLWZWNAQUBZBC-ZNSHCXBVSA-N Val-Thr-Pro Chemical compound C[C@H]([C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](C(C)C)N)O DVLWZWNAQUBZBC-ZNSHCXBVSA-N 0.000 description 1
- KZSNJWFQEVHDMF-UHFFFAOYSA-N Valine Natural products CC(C)C(N)C(O)=O KZSNJWFQEVHDMF-UHFFFAOYSA-N 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 201000005188 adrenal gland cancer Diseases 0.000 description 1
- 208000024447 adrenal gland neoplasm Diseases 0.000 description 1
- 235000004279 alanine Nutrition 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 238000005349 anion exchange Methods 0.000 description 1
- 238000011091 antibody purification Methods 0.000 description 1
- 230000010056 antibody-dependent cellular cytotoxicity Effects 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 208000021780 appendiceal neoplasm Diseases 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 235000009582 asparagine Nutrition 0.000 description 1
- 229960001230 asparagine Drugs 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- 108010068265 aspartyltyrosine Proteins 0.000 description 1
- 230000005784 autoimmunity Effects 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 102000012740 beta Adrenergic Receptors Human genes 0.000 description 1
- 108010079452 beta Adrenergic Receptors Proteins 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- 208000026900 bile duct neoplasm Diseases 0.000 description 1
- 229960000074 biopharmaceutical Drugs 0.000 description 1
- 238000001815 biotherapy Methods 0.000 description 1
- 201000000220 brain stem cancer Diseases 0.000 description 1
- 210000004899 c-terminal region Anatomy 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 238000005341 cation exchange Methods 0.000 description 1
- 230000020411 cell activation Effects 0.000 description 1
- 239000012930 cell culture fluid Substances 0.000 description 1
- 238000001516 cell proliferation assay Methods 0.000 description 1
- 239000002458 cell surface marker Substances 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 201000007455 central nervous system cancer Diseases 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 201000010881 cervical cancer Diseases 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 210000004978 chinese hamster ovary cell Anatomy 0.000 description 1
- 208000006990 cholangiocarcinoma Diseases 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 208000024207 chronic leukemia Diseases 0.000 description 1
- 239000013599 cloning vector Substances 0.000 description 1
- 229940000425 combination drug Drugs 0.000 description 1
- 239000002299 complementary DNA Substances 0.000 description 1
- 239000013601 cosmid vector Substances 0.000 description 1
- 239000012228 culture supernatant Substances 0.000 description 1
- 235000018417 cysteine Nutrition 0.000 description 1
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 1
- 108010016616 cysteinylglycine Proteins 0.000 description 1
- 230000009089 cytolysis Effects 0.000 description 1
- 229940104302 cytosine Drugs 0.000 description 1
- 210000001151 cytotoxic T lymphocyte Anatomy 0.000 description 1
- 229940127089 cytotoxic agent Drugs 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 238000007405 data analysis Methods 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 210000003162 effector t lymphocyte Anatomy 0.000 description 1
- 238000001962 electrophoresis Methods 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 239000012149 elution buffer Substances 0.000 description 1
- 238000012407 engineering method Methods 0.000 description 1
- 239000006167 equilibration buffer Substances 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- MHMNJMPURVTYEJ-UHFFFAOYSA-N fluorescein-5-isothiocyanate Chemical compound O1C(=O)C2=CC(N=C=S)=CC=C2C21C1=CC=C(O)C=C1OC1=CC(O)=CC=C21 MHMNJMPURVTYEJ-UHFFFAOYSA-N 0.000 description 1
- 230000004927 fusion Effects 0.000 description 1
- 230000002068 genetic effect Effects 0.000 description 1
- 238000010353 genetic engineering Methods 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 1
- 108010028188 glycyl-histidyl-serine Proteins 0.000 description 1
- 231100000086 high 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
- 230000006801 homologous recombination Effects 0.000 description 1
- 238000002744 homologous recombination Methods 0.000 description 1
- 210000004408 hybridoma Anatomy 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 210000002865 immune cell Anatomy 0.000 description 1
- 230000036737 immune function Effects 0.000 description 1
- 230000005847 immunogenicity Effects 0.000 description 1
- 230000020287 immunological synapse formation Effects 0.000 description 1
- 230000004957 immunoregulator effect Effects 0.000 description 1
- 239000003547 immunosorbent Substances 0.000 description 1
- 230000001506 immunosuppresive effect Effects 0.000 description 1
- 238000009169 immunotherapy Methods 0.000 description 1
- 230000008595 infiltration Effects 0.000 description 1
- 238000001764 infiltration Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000009545 invasion Effects 0.000 description 1
- 238000004255 ion exchange chromatography 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
- 201000010982 kidney cancer Diseases 0.000 description 1
- 206010023841 laryngeal neoplasm Diseases 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 230000031700 light absorption Effects 0.000 description 1
- 208000012987 lip and oral cavity carcinoma Diseases 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 201000007270 liver cancer Diseases 0.000 description 1
- 208000019423 liver disease Diseases 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- 108010009298 lysylglutamic acid Proteins 0.000 description 1
- 210000004962 mammalian cell Anatomy 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 201000001441 melanoma Diseases 0.000 description 1
- 230000009401 metastasis Effects 0.000 description 1
- 229930182817 methionine Natural products 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000010369 molecular cloning Methods 0.000 description 1
- 230000000869 mutational effect Effects 0.000 description 1
- 230000001613 neoplastic effect Effects 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 201000008968 osteosarcoma Diseases 0.000 description 1
- 210000001672 ovary Anatomy 0.000 description 1
- 229940055729 papain Drugs 0.000 description 1
- 235000019834 papain Nutrition 0.000 description 1
- 229920002866 paraformaldehyde Polymers 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 208000029255 peripheral nervous system cancer Diseases 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
- 239000008055 phosphate buffer solution Substances 0.000 description 1
- 230000026731 phosphorylation Effects 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- 239000013600 plasmid vector Substances 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 230000002028 premature Effects 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 210000001236 prokaryotic cell Anatomy 0.000 description 1
- 230000009465 prokaryotic expression Effects 0.000 description 1
- 108010090894 prolylleucine Proteins 0.000 description 1
- 238000007670 refining Methods 0.000 description 1
- 230000010076 replication Effects 0.000 description 1
- 108091008146 restriction endonucleases Proteins 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 239000010147 shenghe Substances 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 230000009870 specific binding Effects 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 201000003120 testicular cancer Diseases 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 201000009377 thymus cancer Diseases 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 239000012588 trypsin Substances 0.000 description 1
- 230000005748 tumor development Effects 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 230000005751 tumor progression Effects 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
- 108010003137 tyrosyltyrosine Proteins 0.000 description 1
- 241000701447 unidentified baculovirus Species 0.000 description 1
- 201000005112 urinary bladder cancer Diseases 0.000 description 1
- 206010046766 uterine cancer Diseases 0.000 description 1
- 239000004474 valine Substances 0.000 description 1
- 238000012795 verification Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/52—Cytokines; Lymphokines; Interferons
- C07K14/54—Interleukins [IL]
- C07K14/5443—IL-15
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
- C07K14/715—Receptors; Cell surface antigens; Cell surface determinants for cytokines; for lymphokines; for interferons
- C07K14/7155—Receptors; Cell surface antigens; Cell surface determinants for cytokines; for lymphokines; for interferons for interleukins [IL]
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
- C07K16/2809—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against the T-cell receptor (TcR)-CD3 complex
-
- 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
- C07K16/30—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants from tumour cells
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
- C12N15/09—Recombinant DNA-technology
- C12N15/63—Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
- C12N15/79—Vectors or expression systems specially adapted for eukaryotic hosts
- C12N15/85—Vectors or expression systems specially adapted for eukaryotic hosts for animal cells
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/51—Complete heavy chain or Fd fragment, i.e. VH + CH1
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/60—Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments
- C07K2317/62—Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments comprising only variable region components
- C07K2317/622—Single chain antibody (scFv)
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2319/00—Fusion polypeptide
- C07K2319/30—Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2319/00—Fusion polypeptide
- C07K2319/31—Fusion polypeptide fusions, other than Fc, for prolonged plasma life, e.g. albumin
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2800/00—Nucleic acids vectors
- C12N2800/10—Plasmid DNA
- C12N2800/106—Plasmid DNA for vertebrates
- C12N2800/107—Plasmid DNA for vertebrates for mammalian
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2800/00—Nucleic acids vectors
- C12N2800/22—Vectors comprising a coding region that has been codon optimised for expression in a respective host
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Organic Chemistry (AREA)
- Immunology (AREA)
- Genetics & Genomics (AREA)
- General Health & Medical Sciences (AREA)
- Biophysics (AREA)
- Medicinal Chemistry (AREA)
- Molecular Biology (AREA)
- Biochemistry (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Zoology (AREA)
- Engineering & Computer Science (AREA)
- General Engineering & Computer Science (AREA)
- Cell Biology (AREA)
- Biomedical Technology (AREA)
- Gastroenterology & Hepatology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biotechnology (AREA)
- Wood Science & Technology (AREA)
- Toxicology (AREA)
- Microbiology (AREA)
- Physics & Mathematics (AREA)
- Plant Pathology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Peptides Or Proteins (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
Abstract
本发明提供了一种多功能融合蛋白,具体提供了一种靶向TAA与CD3,同时具有IL‑15/IL‑15Rα复合物的生物学效应的多功能融合蛋白。所述多功能融合蛋白可解决单靶点抗体药物的耐药和复发问题,降低起效剂量,更加有效地杀伤肿瘤细胞,延长IL‑15/IL‑15Rα血清半衰期并提高肿瘤靶向性,降低其毒副作用。利用CD3抗体与肿瘤靶向抗体的组合,可定向肿瘤并招募T细胞接近肿瘤细胞,起到介导T细胞杀伤肿瘤细胞的作用。通过免疫突触的形成,抗体功能位点与抗原之间的相对距离等结构设计,使该融合蛋白结构更加稳定。IL‑15/IL‑15Rα复合物促进了对T细胞和NK细胞持久的招募和激活作用。
Description
技术领域
本发明属于生物技术领域,具体涉及一种多功能融合蛋白,尤其涉及靶向TAA与CD3,同时具有IL-15/IL-15Rα复合物的生物学效应的多功能融合蛋白。
背景技术
肿瘤的发生和发展都伴随着对免疫系统的入侵,免疫功能不全的个体常常有较高的癌症发生率和较差的预后。细胞因子(cytokine,CK)属于免疫调节分子,根据其性质、给药浓度和活性发挥部位的不同,对免疫系统具有一定的激活或者抑制作用。因此给予免疫刺激性的细胞因子治疗的这种方式,可以达到提高癌症患者免疫功能的作用。
细胞因子作为免疫疗法,虽然有一定益处,但在临床上的使用存在着单药给药靶向性差的缺点,只有高浓度给药才可以达到抗肿瘤作用,而高浓度给药会产生免疫抑制作用和高毒性。并且,非靶向性细胞因子对于免疫系统的激活是系统性的,免疫系统被广泛的激活,具有致命的副作用。此外,由于细胞因子属于小分子量蛋白,不具备抗体的体内循环保护机制,单纯的细胞因子往往半衰期较短,需要短时间重复高剂量给药。目前临床研究药物多采用PEG化或者Fc融合来提高细胞因子的半衰期,虽然半衰期得以延长,但仍无法解决细胞因子的靶向性差的问题。目前已在多种小鼠肿瘤模型中验证了NK细胞和T细胞,尤其是细胞毒性T细胞在肿瘤免疫过程中的作用。多个临床试验正在评估某些细胞因子单用,或者与多种化疗药物和肿瘤靶向的单克隆抗体和其他细胞因子联用的抗癌疗效。但是,诸如IL-15等细胞因子存在的高剂量用药下的毒性以及半衰期短而导致的短时间重复给药问题仍然存在,成为联用策略的一大制约因素。
CD3是由肽链以非共价键组成的复合分子,在成熟T细胞表面表达,对阻断急性同种异体排斥反应起主要作用,且具有稳定TCR结构和传递活化信号的作用。针对CD3分子的单克隆抗体能够激活T细胞增殖及活化,在其他细胞因子IL-15、IL-15Rα等共同作用下,产生具有增殖速度快、杀瘤活性高、杀瘤谱广及非MHC限制性杀瘤特点的CIK细胞,对癌症、慢性白血病、肝病及神经性疾病等多种疾病治疗具有显著疗效。因此利用CD3抗体与肿瘤靶向抗体进行组合,所构建的双特异性抗体可招募T细胞接近肿瘤细胞,起到介导T细胞杀伤肿瘤细胞的作用。
双特异性抗体在临床上有望成为针对癌症、自身免疫和传染病的下一代生物疗法,具有单一靶点抗体无法达到的功能。双特性抗体为细化抗体药物作用机制、探索多机制协同效应提供了很好的途径。
专利CN110023336A公开了包含至少三个结合结构域的结合剂,其中第一结合结构域与T细胞特异性抗原结合,并且第二结合结构域和第三结合结构域与密蛋白(Claudin6或Claudin18.2)结合。其首次报道了包含密蛋白的两个结合结构域和靶向T细胞特异性抗原(例如CD3)的另一个结合结构域的结合剂可诱导强效的T细胞介导的裂解并且在治疗肿瘤疾病中有效。而此抗体结构没有细胞因子的加入,对T细胞和NK细胞的的激活作用不能达到很好的效果。
而随着抗体工程技术的发展和治疗机制研究的深入,三特异性抗体和多特异性抗体也在大量涌现。这些多功能抗体常常以细胞因子或CD3等靶点作为辅助抗肿瘤抗原的免疫刺激或抑制剂,达到单抗或联合用药不具备的机理或超过其疗效。
专利CN109496217A公开了一种包含至少两种可溶性融合蛋白的可溶性融合蛋白复合体,例如,第一融合蛋白是共价连接至白介素-15(IL-15)多肽或其功能性片段的抗-CD3抗体。第二融合蛋白包含识别疾病抗原的结合域,其中,这一域共价链接至可溶性白介素-15受体α(IL-15Rα)多肽或其功能性片段。虽然此结构抗体能够激活效应T细胞和NK细胞并引导其活性以对抗疾病细胞为目标,从而导致疾病特异性的细胞毒性。但是,由于IL-15和IL-15Rα很容易被体内酶降解,且在体外难表达,因此,此抗体在稳定性方面不尽人意。
因此靶点设计组合达到良好的多机制协同作用是优选的一种策略,然而多靶点设计同样带来结构设计上的难题。在行业经验中,不同的架构设计,对抗体的成药性乃至机制发挥有莫大的关系。免疫突触的形成,抗体功能位点与抗原之间的相对距离等等都与架构设计息息相关。
发明内容
为了克服现有技术的不足,解决现有技术中存在的上述问题,满足多功能融合蛋白架构设计需求,提高多功能融合蛋白的稳定性,改善肿瘤预后,兼具良好的成药性。本发明设计了一种结构,主要由抗TAA/CD3及IL-15/IL-15α复合物组成。本文叙述以多功能融合蛋白CCI(抗Claudin18.2与CD3,外加IL-15/IL-15α的多功能融合蛋白)和BCI(抗B7H3与CD3,外加IL-15/IL-15α的多功能融合蛋白)作为示例,使用该种架构设计与靶点组合,公开了通过基因工程技术获得的靶向Claudin18.2(或B7H3)与CD3,同时具有IL-15/IL-15Rα复合物的生物学效应的多功能融合蛋白,并公开了编码所述多功能融合蛋白的氨基酸序列、架构设计、以及包含所述重组载体的重组细胞以及所述多功能融合蛋白的制备方法及其医药用途。具体而言,本发明采用的技术方案如下:
本发明涉及一种多功能融合蛋白,其包含第一重链、第二重链和第一轻链、第二轻链,所述第一重链包含特异性结合靶标的VH和CH1,细胞因子和其受体,以及免疫球蛋白Fc部分;所述第二重链包含特异性结合靶标的VH和CH1,特异性结合靶标的scFv或Fab,以及免疫球蛋白Fc部分;第一轻链与第一重链,第二轻链与第二重链分别特异性配对。
进一步地,所述第一重链和第二重链包含的VH和CH1可以特异性结合TAA抗原,所述TAA抗原为Claudin18.2、CA125、AFP、CEA、EGFR、HER2、B7H3、B7H6、MUC1、MUC16、GPC3、CD24其中的一种或几种,优选的,所述TAA抗原为Claudin18.2或B7H3。
进一步地,所述第一重链包含的细胞因子和其受体分别为IL-15和IL-15受体。
进一步地,所述第二重链包含的scFv或Fab可以特异性激活T细胞、NK细胞和巨噬细胞,优选的,所述第二重链包含的scFv或Fab特异性靶向CD3。
进一步地,所述第一重链和第二重链的免疫球蛋白Fc部分选自IgG1、IgG2、IgG3、IgG4的恒定区氨基酸序列,优选选自IgG1或IgG4的恒定区氨基酸序列。
进一步地,所述第一重链和第二重链的Fc部分还包含一个或多个选自由以下组成的组的氨基酸替换:S228P、L234F、L235E、P331S、D356K、T366W、K392D、D399K、Y407A、和K409D,优选S228P、T366W和/或Y407A。
进一步地,所述第一重链中的IL-15与其受体和第二重链中的scFv或Fab可以分别嵌合于所述第一重链和所述第二重链的Fc部分内部,也可以存在于Fc部分外部,优选位于所述相应重链的CH1和CH2功能区之间。
进一步地,所述第一重链中的IL-15与其受体、第二重链中的scFv或Fab单独或与额外的连接肽一起共价结合于所述链中;所述连接肽包含甘氨酸(G)和丝氨酸(S)残基,优选包含GGGGS重复,更优选包含1-2个GGGGS重复。
进一步地,所述IL-15选自天然的IL-15或其变体,所述变体包含选自N1D、N4D、D30N、E64Q、N65D、N72D、N79A、Q108E和N112A的组的一个或多个氨基酸突变,优选包含选自N4D、N65D、N72D、N79A和N112A的组的一个或多个氨基酸突变;所述IL-15受体片段选自IL-15Rα或其变体,优选IL-15Rα变体,更优选IL-15RαSushi结构域。
进一步地,所述第一重链氨基酸序列选自SEQ ID NO:1;所述多功能融合蛋白的第二重链氨基酸序列选自SEQ ID NO:2;所述多功能融合蛋白的第一轻链和第二轻链的氨基酸序列选自SEQ ID NO:3。
进一步地,所述第一重链氨基酸序列选自SEQ ID NO:14;所述多功能融合蛋白的第二重链氨基酸序列选自SEQ ID NO:15;所述多功能融合蛋白的第一轻链和第二轻链的氨基酸序列选自SEQ ID NO:16。
本发明还涉及编码所述多功能融合蛋白的核酸分子,其包含编码第一轻链和第二轻链的核苷酸序列,或者包含编码第一重链的核苷酸序列,或者包含编码第二重链的核苷酸序列。
进一步地,所述编码第一重链的核苷酸序列选自SEQ ID NO:4;所述编码第二重链的核苷酸序列选自SEQ ID NO:5;所述编码第一轻链和第二轻链的核苷酸序列选自SEQ IDNO:6。
进一步地,所述编码第一重链的核苷酸序列选自SEQ ID NO:17;所述编码第二重链的核苷酸序列选自SEQ ID NO:18;所述编码第一轻链和第二轻链的核苷酸序列选自SEQID NO:19。
进一步地,可以将此类核苷酸序列与编码对于初始抗体而言天然的信号肽或异源信号肽的多核苷酸融合。具体而言,所述核酸分子可在编码其轻链的核苷酸序列和编码其重链的核苷酸序列的5’端分别进一步包含编码信号肽的核苷酸序列,所述信号肽可以是天然的信号肽,也可以是异源信号肽;在编码轻链的核苷酸序列和编码重链的核苷酸序列的3’端分别进一步包含终止密码子。
更进一步地,所述信号肽选自氨基酸序列SEQ ID NO:7和SEQ ID NO:9,编码所述信号肽的核苷酸序列选自SEQ ID NO:8和SEQ ID NO:10。
本发明还涉及一种重组载体,例如表达载体,其包含编码所述多功能融合蛋白的第一重链、和/或第二重链、和/或第一轻链、和/或第二轻链的核苷酸序列。在此类载体中,本发明的核苷酸序列可以与一种或多种调节元件可操作连接。其中,所述调节元件选自表达调控序列,如启动子、增强子等。
本发明的载体包括一段与编码所述多功能融合蛋白的第一重链、第二重链、第一轻链和/或第二轻链的核酸序列可操作性连接的调控元件(例如启动子或增强子)。“可操作性连接”是指所构成的核酸序列的布置使得可执行其正常功能。因此,与编码所述第一重链、第二重链、第一轻链或第二轻链的核苷酸序列可操作性连接的调控元件能够指导转录、复制和/或翻译而得到所述多功能融合蛋白。在一种实施方案中,该载体编码所述多功能融合蛋白的第一重链、第二重链、第一轻链或第二轻链的氨基酸序列。
在本发明中,所述表达载体例如为原核表达载体、真核表达载体、噬菌体载体或病毒载体。进一步地,所述载体选自真核载体。融合蛋白的重链和轻链可以分别在载体中表达。
在本发明的一个具体实施方案中,在编码第一轻链和/或第二轻链的核苷酸序列(SEQ ID NO:6)的5’端分别依次加上HindIII酶切位点、kozak序列和信号肽序列,在3’端加上终止密码子及XhoI酶切位点,通过酶切连接插入到pcDNA3.4-G418;在编码第一重链的核苷酸序列(SEQ ID NO:4)和第二重链的核苷酸序列(SEQ ID NO:5)的5’端分别依次加上HindIII酶切位点、kozak序列和信号肽序列序列,在3’端加上终止密码子和XhoI酶切位点,通过酶切连接插入到载体中。
本发明还涉及一种重组细胞,其含有本发明第三方面任一项的重组载体。进一步地,所述细胞包括人胚肾细胞HEK293或HEK293T、HEK293E、HEK293修饰的HEK293F、中国仓鼠卵巢细胞(CHO)、CHO-S、CHO-DHFR-、CHO/DG44、ExpiCHO、CHO修饰的ExpiCHO,和其组合。
本发明还涉及所述多功能融合蛋白的制备方法,其具体包括:在足以表达本发明第一方面所述多功能融合蛋白的条件下,培养本发明第四方面所述的重组细胞;表达并纯化所述的多功能融合蛋白。
本发明还涉及一种含有所述多功能融合蛋白作为活性成分的药物,所述药物任选含有药学上可接受的载体或赋形剂。
本发明还涉及所述多功能融合蛋白在制备预防或治疗与TAA有关的疾病或病症如肿瘤的药物中的用途。
优选地,所述肿瘤为对Claudin18.2单独治疗无效的肿瘤或晚期肿瘤,更优选为对抗Claudin18.2抗体单独治疗产生抗性或无效的肿瘤;进一步优选为胃癌、食道癌、胰腺癌等。
优选地,所述肿瘤为对B7H3单独治疗无效的肿瘤或晚期肿瘤,更优选为对抗B7H3抗体单独治疗产生抗性或无效的肿瘤;进一步优选为胃癌、食道癌、胰腺癌等。
本发明还提供了一种治疗肿瘤的方法,其包括向癌症患者施用治疗有效量的所述多功能融合蛋白。所述肿瘤为与发病机制相关的肿瘤,优选为对Claudin18.2单独治疗无效的肿瘤或晚期肿瘤,更优选为对抗Claudin18.2抗体单独治疗产生抗性或无效的肿瘤;进一步优选胃癌、食道癌、胰腺癌。
本发明还提供了一种治疗肿瘤的方法,其包括向癌症患者施用治疗有效量的所述多功能融合蛋白。所述肿瘤为与发病机制相关的肿瘤,优选为对B7H3单独治疗无效的肿瘤或晚期肿瘤,更优选为对抗B7H3抗体单独治疗产生抗性或无效的肿瘤;进一步优选胃癌、食道癌、胰腺癌。
本发明还涉及含有如上所述的多功能融合蛋白作为活性成分的药物制剂、药用组合物或试剂盒。
因此,本发明涉及以下实施方案:
1、一种多功能融合蛋白,其特征在于,其包含第一重链、第二重链和第一轻链、第二轻链,所述第一重链包含特异性结合靶标的VH和CH1,细胞因子和其受体,以及免疫球蛋白Fc部分;所述第二重链包含特异性结合靶标的VH和CH1,特异性结合靶标的scFv或Fab,以及免疫球蛋白Fc部分;第一轻链与第一重链,第二轻链与第二重链分别特异性配对。
2、如方案1所述的多功能融合蛋白,其中所述第一重链和第二重链包含的VH和CH1可以特异性结合TAA抗原,所述TAA抗原为Claudin18.2、CA125、AFP、CEA、EGFR、HER2、B7H3、B7H6、MUC1、MUC16、GPC3、CD24其中的一种或几种,优选的,所述TAA抗原为Claudin18.2或B7H3。
3、如方案1-2任一所述的多功能融合蛋白,其中所述第一重链包含的细胞因子和其受体分别为IL-15和IL-15受体。
4、如方案1-3任一所述的多功能融合蛋白,其中所述第二重链包含的scFv或Fab可以特异性激活T细胞、NK细胞和巨噬细胞,优选的,所述第二重链包含的scFv或Fab特异性靶向CD3。
5、如方案1-4任一所述的多功能融合蛋白,其中所述第一重链和第二重链的免疫球蛋白Fc部分选自IgG1、IgG2、IgG3、IgG4的恒定区氨基酸序列,优选选自IgG1或IgG4的恒定区氨基酸序列。
6、如方案1-5任一所述的多功能融合蛋白,其中所述第一重链和第二重链的Fc部分还包含一个或多个选自由以下组成的组的氨基酸替换:S228P、L234F、L235E、P331S、D356K、T366W、K392D、D399K、Y407A、和K409D,优选S228P、T366W和/或Y407A。
7、如方案3所述的多功能融合蛋白,其中所述第一重链中的IL-15与其受体和第二重链中的scFv或Fab可以分别嵌合于所述第一重链和所述第二重链的Fc部分内部,也可以存在于Fc部分外部,优选位于所述相应重链的CH1和CH2功能区之间。
8、如方案3所述的多功能融合蛋白,其中所述第一重链中的IL-15与其受体、第二重链中的scFv或Fab单独或与额外的连接肽一起共价结合于所述链中;所述连接肽包含甘氨酸(G)和丝氨酸(S)残基,优选包含GGGGS重复,更优选包含1-2个GGGGS重复。
9、如方案3所述的多功能融合蛋白,其中所述IL-15选自天然的IL-15或其变体,所述变体包含选自N1D、N4D、D30N、E64Q、N65D、N72D、N79A、Q108E和N112A的组的一个或多个氨基酸突变,优选包含选自N4D、N65D、N72D、N79A和N112A的组的一个或多个氨基酸突变;所述IL-15受体选自IL-15Rα或其变体。
10、如方案1-9任一所述的多功能融合蛋白,其中所述第一重链氨基酸序列选自SEQ ID NO:1;所述多功能融合蛋白的第二重链氨基酸序列选自SEQ ID NO:2;所述多功能融合蛋白的第一轻链和第二轻链的氨基酸序列选自SEQ ID NO:3。
11、如方案1-9任一所述的多功能融合蛋白,其中所述第一重链氨基酸序列选自SEQ ID NO:14;所述多功能融合蛋白的第二重链氨基酸序列选自SEQ ID NO:15;所述多功能融合蛋白的第一轻链和第二轻链的氨基酸序列选自SEQ ID NO:16。
12、一种编码如方案1-11任一项所述多功能融合蛋白的核酸分子,其特征在于包含编码第一轻链和第二轻链的核苷酸序列,或者包含编码第一重链的核苷酸序列,或者包含编码第二重链的核苷酸序列。
13、如方案12所述的核酸分子,其中所述编码第一重链的核苷酸序列选自SEQ IDNO:4;所述编码第二重链的核苷酸序列选自SEQ ID NO:5;所述编码第一轻链和第二轻链的核苷酸序列选自SEQ ID NO:6。
14、如方案12所述的核酸分子,其中所述编码第一重链的核苷酸序列选自SEQ IDNO:17;所述编码第二重链的核苷酸序列选自SEQ ID NO:18;所述编码第一轻链和第二轻链的核苷酸序列选自SEQ ID NO:19。
15、如方案12所述的核酸分子,其中所述核酸分子可在编码其轻链的核苷酸序列和编码其重链的核苷酸序列的5’端分别进一步包含编码信号肽的核苷酸序列,在编码轻链的核苷酸序列和编码重链的核苷酸序列的3’端分别进一步包含终止密码子。
16、如方案15所述的核酸分子,其中所述信号肽选自氨基酸序列SEQ ID NO:7和SEQ ID NO:9,编码所述信号肽的核苷酸序列选自SEQ ID NO:8和SEQ ID NO:10。
17、一种重组载体,其包含编码方案1-11任一项所述多功能融合蛋白的第一重链、和/或第二重链、和/或第一轻链、和/或第二轻链的核苷酸序列。
18、一种重组细胞,其含有方案17所述的重组载体,优选地,所述细胞包括人胚肾细胞HEK293或HEK293T、HEK293E、HEK293修饰的HEK293F、中国仓鼠卵巢细胞(CHO)、CHO-S、CHO-dhfr-、CHO/DG44、ExpiCHO、CHO修饰的ExpiCHO,和其组合。
19、一种制备如方案1-11任一项所述多功能融合蛋白的方法,其具体包括:
在足以表达方案1-11任一项所述多功能融合蛋白的条件下,培养方案18所述的重组细胞,表达并纯化所述的多功能融合蛋白。
20、如方案1-11任一项所述多功能融合蛋白作为活性成分的药物,所述药物任选含有药学上可接受的载体或赋形剂。
21、如方案1-11任一项所述多功能融合蛋白在制备预防或治疗与TAA有关的疾病或病症如肿瘤的药物中的用途。
22、如方案21所述的用途,所述肿瘤为对Claudin18.2单独治疗无效的肿瘤或晚期肿瘤,更优选为对抗Claudin18.2抗体单独治疗产生抗性或无效的肿瘤;进一步优选为胃癌、食道癌、胰腺癌等。
23、如方案21所述的用途,所述肿瘤为对B7H3单独治疗无效的肿瘤或晚期肿瘤,更优选为对抗B7H3抗体单独治疗产生抗性或无效的肿瘤;进一步优选为胃癌、食道癌、胰腺癌等。
24、如方案1-11任一项所述的多功能融合蛋白作为活性成分的药物制剂、药用组合物或试剂盒。
有益效果
本发明在已有的异源二聚体开发经验的基础上通过基因重组、密码子优化和分子生物学等技术,设计获得了一种靶向肿瘤相关抗原与CD3,同时具有IL-15/IL-15Rα复合物的生物学效应的多功能融合蛋白。该多功能融合蛋白在靶向肿瘤抗原的基础上,利用IL-15/IL-15Rα复合物可以有效地扩增和活化PMBC中的T细胞及NK细胞,并使得免疫细胞数目以及杀伤性细胞因子的释放增加,从而解决单靶点抗体药物的耐药和复发问题,同时也可降低有效剂量,更加有效地杀伤肿瘤细胞,且较IL-15或IL-15/IL-15受体复合物而言,延长了血清半衰期并提高了肿瘤靶向性,降低其毒副作用。同时利用CD3抗体与肿瘤靶向抗体的组合,可定向肿瘤并招募T细胞接近肿瘤细胞,起到介导T细胞杀伤肿瘤细胞的作用。
由于IL-15和IL-15Rα很容易被体内酶降解,且在体外难表达,因此,本发明人利用天然抗体在体内的稳定性,创新性的将IL-15和IL-15Rα的融合蛋白设计在多功能融合蛋白结构内部,将其被保护在多功能融合蛋白内部,免于暴露而被体内酶降解,同时降低了表达难度。此种设计的CCI多功能融合蛋白经实验证明具有极高的表达能力和稳定性。
同时,通过将IL-15和IL-15Rα通过接头(linker)连接,即IL-15的受体IL-15Rα内含一个sushi结构域,能与IL-15结合,使得CCI多功能融合蛋白结构更稳定。
另外,本发明合理设计TAA、CD3和IL-15融合蛋白的相对距离,理论上为最佳接触距离,既保留了识别TAA端抗体的识别位点,又保证识别特异性抗体端与IL-15融合蛋白功能发挥,多功能融合蛋白CCI可以全方位接触抗原,并保持其他协同功能活性。
经所述示例试验验证,本发明所获得的多功能融合蛋白具有高效的Claudin18.2抗原亲和力和IL-15亲和力,以及与CD3较好的结合效果,此外还具有较好的纯度、稳定性以及生物活性,在常用的抗体表达宿主细胞CHO上,也可得到较好的表达量。
因此使用该靶点组合或结构设计,不影响功能域的功能发挥,增加了多功能融合蛋白结构的稳定性,且有良好协同作用机制,可应用于免疫或肿瘤治疗。
为了更容易理解本发明,以下具体定义了某些技术和科学术语。除显而易见在本文件的它处另有明确定义,否则本文中使用的所有其他技术和科学术语都具有本发明所属技术领域的一般技术人员通常理解的含义。
术语
在本说明书中,术语“抗体”是指天然的免疫球蛋白或者通过部分或完全合成而制备的免疫球蛋白。抗体可从天然存在该抗体的血浆或血清等的天然资源、或者产生抗体的杂交瘤细胞的培养上清中、动物免疫血清中、噬菌体文库筛选进行重建得到分离。备选地,可通过使用基因重组等的技术部分或完全地合成。优选的抗体包括,例如,免疫球蛋白的同种型或这些同种型的亚类的抗体。已知人免疫球蛋白包括IgGl、IgG2、IgG3、IgG4、IgAl、IgA2、IgD、IgE、IgM这9种类别(同种型)。在这些同种型中,本发明的抗体可以包括IgGl、IgG2、IgG3、IgG4。
术语“多功能融合蛋白”是指包含两个或更多个抗原结合结构域,能够结合两个或更多个不同的表位(例如,两个、三个或更多个不同的表位),表位可以在相同或不同的抗原上的融合蛋白,多功能融合蛋白还可以包含细胞因子(例如IL-15、IL-15Rα等)等。本发明中“多功能融合蛋白CCI”、“抗体CCI”、“CCI多功能融合蛋白”、“CCI抗体”、“CCI”并不矛盾,可互换使用。本发明中“多功能融合蛋白BCI”、“抗体BCI”、“BCI多功能融合蛋白”、“BCI抗体”、“BCI”并不矛盾,可互换使用。
本发明中“Claudin18.2”和“CLDN18.2”具有相同的含义,可以互换使用。
抗体的“可变区”或“可变域”指抗体重链或轻链的氨基末端结构域。重链和轻链的可变域可以分别称为“VH”和“VL”。这些结构域一般是抗体的最可变部分(相对于其他同类抗体)并含有抗原结合位点。
术语“scFv”和“单链抗体”均指单个多肽链的抗体片段,其含有源自重链和轻链的可变区,但没有恒定区。通常,单链抗体还在VH和VL结构域之间含有多肽接头,这使得能够形成被认为允许抗原结合的所需结构。"The Pharmacology of Monoclonal Antibodies,Vol.113,Rosenburg and Moore,eds.,Springer-Verlag,New York,269-315(1994)"中详细讨论了单链抗体。还可参见国际专利WO1988/001649、美国专利US4946778和US5260203。在具体实施方案中,单链抗体可以是双特异性的和/或人源化的。
术语“多肽”是指任何长度的氨基酸链,而与修饰(例如磷酸化或糖基化)无关。术语多肽包括蛋白质及其片段。多肽可以是“外源的”,意指它们是“异源的”,即是所利用的宿主细胞外来的,例如由细菌细胞产生的人多肽。本文将多肽公开为氨基酸残基序列。那些序列按氨基末端到羧基末端的方向从左到右书写。根据标准命名法,氨基酸残基序列以三字母或单字母代码命名,如下所示:丙氨酸(Ala,A)、精氨酸(Arg,R)、天冬酰胺(Asn,N)、天冬氨酸(Asp,D)、半胱氨酸(Cys,C)、谷氨酰胺(Gln,Q)、谷氨酸(Glu,E)、甘氨酸(Gly,G)、组氨酸(His,H)、异亮氨酸(Ile,I)、亮氨酸(Leu,L)、赖氨酸(Lys,K)、甲硫氨酸(Met,M)、苯丙氨酸(Phe,F)、脯氨酸(Pro,P)、丝氨酸(Ser,S)、苏氨酸(Thr,T)、色氨酸(Trp,W)、酪氨酸(Tyr,Y)和缬氨酸(Val,V)。
术语“变体”是指与参与多肽或多核苷酸不同但保持基本特性的多肽或多核苷酸。多肽的典型变体在氨基酸序列方面与另一参考多肽不同。通常,差异是有限的,使得参与多肽和变体的序列总体上非常相似,并且在许多区域中是相同的。变体和参考多肽可以在氨基酸序列方面因一个或多个修饰(例如,取代、添加和/或缺失)而不同。取代或插入的氨基酸残基可以是或可以不是由遗传密码编码的氨基酸残基。多肽的变体可以是天然存在的,诸如等位基因变体,或者可以是不知道会天然存在的变体。
术语“特异性”表示参与特异性结合的分子之一不显示任何与不同于结合分子中的一个或数个的分子的显著结合。此外,在含抗体可变区的结构域对抗原中的多个表位中的特定表位具有特异性时,也使用该术语。当含抗体可变区的结构域所结合的表位被包含在数个不同抗原中时,包含含抗体可变区的结构域的抗原结合分子可以结合具有所述表位的各种抗原。
术语“肿瘤相关抗原(TAA)”优选涉及在正常条件下在有限数目的组织和/或器官中或在特定发育阶段中特异性表达以及在一个或更多个肿瘤或癌症组织中表达或异常表达的蛋白质。在本发明的上下文中,肿瘤相关抗原优选与癌细胞的细胞表面缔合,并且优选不在或仅很少在正常组织中表达。
本发明所用氨基酸三字母代码和单字母代码如J.Boil.Chem.,243,p3558(1968)中所述。本发明中第一重链的Fc或其变体和第二重链的Fc或其变体之间的“相互作用”指的是Fc间作用或Fc变体间作用。“Fc变体”指通过在Fc的合适位点处存在一个或多个氨基酸替换、插入或缺失突变引起Fc结构或功能的变化。“Fc变体间作用”指经突变设计的Fc变体之间可以形成空间填充效应、静电转向、氢键作用、疏水作用等。Fc变体间相互作用有助于形成稳定的异源二聚体。优选的突变设计为“Knob-in-hole”形式的突变设计。此外,本发明所述Fc上还可以存在其他导致其功能变化的突变,例如糖基化改造突变、FcγR结合区域突变(以调整ADCC活性)和改善抗体稳定性的氨基酸突变等。
术语“IL-15”或“IL-15片段”可以是任何IL-15或其突变体,如人IL-15或非人哺乳动物或非哺乳动物的IL-15。示例性非人哺乳动物如猪、兔、猴、猩猩、鼠等,非哺乳动物如鸡等;优选人的白介素15成熟分子(见数据库UniProtKB,登录号P40933,49-162aa)。术语“IL-15变体”指通过一个或多个氨基酸替换、增加或者缺失突变获得的对IL-15与其受体间亲和力提高或者降低,或其刺激T细胞或者NK细胞活性增加或者降低的突变体分子。本发明所述“IL-15片段”优选其变体形式,更优选为IL-15N72D(SEQ ID NO:11)。本发明“IL-15”和“IL-15片段”可以互换使用,并不矛盾。
术语“IL-15Rα”可以是任何物种的IL-15Rα或者其功能性片段,如人IL-15Rα或非人哺乳动物IL-15Rα或非哺乳动物IL-15Rα。示例性非人哺乳动物如猪、兔、猴、猩猩、鼠等,非哺乳动物如鸡等。优选人的IL-15Rα,更优选人IL-15Rα胞外域片段,简称IL-15RαECD(见数据库UniProtKB,登录号Q13261,31-205aa)。术语“IL-15Rα变体”指在IL-15Rα上通过一个或者多个氨基酸缺失、插入或替换突变形成的具有与其配体分子如IL-15结合能力的功能性突变体,优选人的IL-15Rα分子更优选人的IL-15Rα胞外域片段的缩短形式,即从胞外域片段C端开始通过一个或多个氨基酸缺失突变所得的具有人IL-15受体α活性的分子,优选保留65-120个氨基酸的缺失突变形式,更优选保留65-102个氨基酸的缺失突变缩短形式,比如IL-15RαSushi(65)(SEQ ID NO:12)或IL-15RαSushi(77)(SEQ ID NO:13)。
本发明中“与额外的连接肽一起共价结合”是指两个或多个基因的编码区之间可由编码连接肽的序列于一个或数个位置发生共价结合。
术语“免疫球蛋白”指具有抗体活性或化学结构与抗体分子相似的球蛋白,存在五种主要类别的免疫球蛋白:IgA、IgD、IgE、IgG和IgM,这些中的几种可以进一步划分为亚类(同种型),例如IgG1、IgG2、IgG3和IgG4、IgA1和IgA2。对应于不同类别免疫球蛋白的重链恒定结构域分别称为α、δ、ε、γ和μ。
术语“免疫球蛋白Fc部分”指免疫球蛋白的C端区域,无抗原结合活性,是抗体分子与效应分子和细胞相互作用的部位,是包含两个二硫化物连接的抗体重链Fc区多肽的二聚体分子。Fc区可以通过木瓜蛋白酶消化或IdeS消化成胰蛋白酶消化完整(全长)抗体来产生或可以重组产生。“Fc部分”优选包括至少一个免疫球蛋白铰链区,以及IgG的CH2和CH3区。
Fc变体的突变设计技术在本领域内已经较为广泛的应用于制备双特异性抗体或者异源二聚的Fc融合蛋白形式。代表性的有Cater等人(Protein Engineeringvol.9no.7pp617-621,1996)提出的“Knob-in-Hole”形式;Amgen公司技术人员利用静电转向(Electronic Steering)形成含Fc的异源二聚体形式(US2010286374A1);JonathanH.Davis等人(Protein Engineering,Design&Selection pp.1–8,2010)提出的通过IgG/IgA链交换形成的异源二聚体形式(SEEDbodies);Genmab公司DuoBody(Science,2007.317(5844))平台技术形成的双特异性分子;Xencor公司的技术人员综合结构计算及Fc氨基酸突变,综合不同作用方式形成异源二聚体蛋白形式(mAbs3:6,546-557;November/December2011);苏州康宁杰瑞公司的基于电荷网络的Fc改造方法(CN201110459100.7)得到异源二聚体蛋白形式;以及其它基于Fc氨基酸变化或者功能改造手段,达到形成异源二聚体功能蛋白的基因工程方法。本发明所述的Fc变体片段上的Knob-in-Hole结构指两条Fc片段各自突变,突变后可以通过“Knob-in-Hole”形式进行结合。优选用Cater等人的“Knob-in-Hole”模型在Fc区上进行位点突变的改造,以使得到的第一Fc变体和第二Fc变体能以“Knob-in-Hole”的形式结合在一起形成异源二聚体。从特定的免疫球蛋白类别和亚类中选择特定的免疫球蛋白Fc区在本领域技术人员所掌握的范围之内。优选人类抗体IgG1、IgG2、IgG3、IgG4的Fc区,更优选人抗体IgG1和IgG4的Fc区。随机任选第一Fc变体或第二Fc变体中一个做knob的突变,另一个做hole的突变。在实施例中,所述的第一Fc变体做knob的突变;所述的第二Fc变体做hole的突变。
术语“连接肽”在本发明中用于将IL-15与IL-15Rα、CD3的VH与VL连接至相应的重链中,以保证蛋白的正确折叠和肽稳定性。本发明的“连接肽”优选为(GGGGS)n,其中n可以为0、1、2、3、4、5或者更多,优选n为1-2。如果连接肽序列太短,可能影响两蛋白高级结构的折叠,从而相互干扰;如果连接肽序列太长,又涉及免疫原性的问题,因为连接肽序列本身就是新的抗原。
术语的“异源二聚体”优选为基因共表达的产物。如在原核细胞在大肠杆菌中共表达;或在真核细胞,如293、CHO中共表达。所述“共表达”指在一个细胞中多个基因一起表达,同时出现它们的产物。这些基因可以是同时存在而分别或共同地受控表达。在本发明中,优选在一个真核细胞中共表达三种基因。共表达得到的基因表达产物有利于高效、简单地形成复合物;在本发明中,有利于形成异源二聚体。
术语“核酸”旨在包括DNA和RNA,例如基因组DNA、cDNA、mRNA、重组产生和化学合成的分子。核酸可是单链或双链。RNA包括体外转录的RNA(IVT RNA)或合成的RNA。
核酸可包含在载体中。本文中术语“载体”包括技术人员已知的任何载体,其包括质粒载体、黏粒载体、噬菌体载体(例如λ噬菌体)、病毒载体(例如腺病毒或杆状病毒载体),或人工染色体载体(例如细菌人工染色体(BAC)、酵母人工染色体(YAC)或P1人工染色体(PAC))。所述载体包括表达载体以及克隆载体。表达载体包括质粒和病毒载体且一般含有用于在特定宿主生物体(例如,细菌、酵母、植物、昆虫或哺乳动物)或者在体外表达系统中可操作地连接的编码序列之表达所必需的期望编码序列和合适的DNA序列。克隆载体一般用于改造和扩增某期望DNA片段,并可缺乏表达所期望DNA片段所需要的功能性序列。
本发明所述的“治疗有效量”是指达到治疗目的的疾病或病况(例如肿瘤,例如用于使肿瘤消退或减小其大小)所需的本发明的多功能融合蛋白,或者所述药物制剂、药用组合物、试剂盒中有效成分的量。可以通过实践、按照常规的方式出于特定的目的而确定所述有效量。特别地,所述治疗有效量可以是达到下述目的所需的量:减少癌细胞的数目;减少肿瘤大小;抑制(即减缓或停止)癌细胞浸润到外周器官中;抑制(即减缓或停止)肿瘤转移;抑制肿瘤生长;和/或缓解与癌症相关的一种或多种症状。
本发明所述“肿瘤”可选自B细胞淋巴瘤、肺癌、支气管癌、结肠直肠癌、前列腺癌、乳腺癌、胰腺癌、胃癌、卵巢癌、膀胱癌、脑或中枢神经系统癌症、外周神经系统癌症、食道癌、宫颈癌、黑色素瘤、子宫或子宫内膜癌、口腔癌或喉癌、肝癌、肾癌、胆管癌、小肠癌或阑尾癌、唾液腺癌、胸腺癌、肾上腺癌、骨肉瘤、软骨肉瘤、脂肪瘤、睾丸癌以及恶性纤维组织细胞瘤等。
附图说明
图1为以Claudin18.2/CD3/IL-15为例的示例性多功能融合蛋白CCI结构图。
图2a为非还原条件下CCI的CE-SDS图,图2b为还原条件下CCI的CE-SDS图。
图3为多功能融合蛋白CCI反复冻融5次后的SEC-HPLC图。
图4为多功能融合蛋白CCI与Claudin18.2结合活性。
图5为多功能融合蛋白CCI与受体IL-2Rβ的结合活性。
图6为多功能融合蛋白CCI与CD3的结合活性。
图7为多功能融合蛋白CCI对PBMC细胞的增殖图。
图8为PBMC增殖实验细胞流式鉴定分型图。
图9为CCI介导的Claudin18.2-CHO-K1细胞杀伤。
图10为多功能融合蛋白BCI对B7H3的结合活性。
图11为多功能融合蛋白BCI对CD3的结合活性。
图12a-12b为流式细胞术检测MCF-7细胞B7H3表达丰度。
图13为多功能融合蛋白BCI与受体IL-2Rβ的结合活性。
图14为多功能融合蛋白BCI的抗肿瘤活性。
具体实施方式
以下结合附图与具体实施例对本发明做进一步的描述,本发明的保护内容不局限于以下实施例。还应该理解,本发明实施例中使用的术语是为了描述特定的具体实施方案,而不是为了限制本发明的保护范围。在不背离发明构思的精神和范围下,本领域技术人员能够想到的变化和优点都被包括在本发明中,并且以所附的权利要求及其任何等同物为本发明的保护范围。在本发明的说明书和权利要求书中,除非文中另外明确指出,单数形式“一个”、“一”和“这个”包括复数形式。实施本发明的过程、条件、试剂、实验方法等,除以下专门提及的内容之外,均为本领域技术人员的普遍知识和公知常识,本发明没有特别限制内容。
本发明实施例中Claudin18.2抗体的重链氨基酸序列为SEQ ID NO:21,轻链氨基酸序列为SEQ ID NO:22。
本发明实施例中B7H3嵌合抗体的重链氨基酸序列为SEQ ID NO:20,轻链氨基酸序列为SEQ ID NO:16。
实施例1核苷酸序列的获得与优化
多功能融合蛋白CCI(或BCI)的轻链和重链氨基酸序列信息选自公开的或自研Claudin18.2(或B7H3)靶点单抗序列信息,分析获得该序列的可变区和恒定区信息。将天然IL-15与IL-15Rα复合物变体序列插入一条重链的氨基酸序列中,并在另一条重链的相应位置插入CD3抗体的scFv序列。根据需要,调整所述多功能融合蛋白氨基酸序列的Fc为其他IgG类型,如IgG4等,并进一步在各重链中设计所需形式的氨基酸突变,由此得到目标多功能融合蛋白的氨基酸序列,为:
多功能融合蛋白CCI—第一重链为SEQ ID NO:1,第二重链为SEQ ID NO:2,第一轻链和第二轻链为SEQ ID NO:3;
多功能融合蛋白BCI—第一重链为SEQ ID NO:14,第二重链为SEQ ID NO:15,第一轻链和第二轻链为SEQ ID NO:16。
将上述各目标氨基酸序列转化为核苷酸序列,并针对可能影响抗体在哺乳动物细胞中表达的一系列参数:密码子偏好性、GC含量(即DNA的4种碱基中鸟嘌呤G和胞嘧啶C所占的比率)、CpG岛(即CpG双核苷酸在基因组中密度较高的区域)、mRNA的二级结构、拼接位点、前成熟PolyA位点、内部Chi位点(基因组中一段短的DNA片段,在该位点附近发生同源重组的几率增加)或者核糖体结合位点、RNA不稳定序列、反向重复序列及可能干扰克隆的限制性酶切位点等进行优化;同时增加了可能会提高翻译效率的相关序列,例如Kozak序列、SD序列,以及终止密码子。设计得到分别编码上述多功能融合蛋白CCI的重链基因和轻链基因,另外在重链和轻链的5’端分别设计上根据氨基酸序列优化而得的编码信号肽的核苷酸序列;此外,还对轻链和重链核苷酸序列的3’端分别加上终止密码子。
最终优化获得抗体核苷酸序列为:
CCI—第一重链为SEQ ID NO:4,第二重链为SEQ ID NO:5,第一轻链和第二轻链为SEQ ID NO:6;
BCI—第一重链为SEQ ID NO:17,第二重链为SEQ ID NO:18,第一轻链和第二轻链为SEQ ID NO:19。
本发明设计的CCI的理论分子数据如表1所示。
表1 CCI的理论分子数据
实施例2基因合成与表达载体的构建
采用pcDNA3.1-G418载体作为表达所述多功能抗体的轻链和重链的专用载体。pcDNA3.1-G418载体含有重链所使用的启动子CMVPromoter、真核筛选标记G418标签和原核筛选标签氨苄西林(Ampicilline)。基因合成得到多功能融合蛋白CCI和BCI的抗体表达轻链和重链的核苷酸序列,用HindIII和XhoI对载体和目的片段进行双酶切,回收后通过DNA连接酶进行酶连,并转化大肠杆菌感受态细胞DH5α,挑选出阳性克隆并进行质粒提取和酶切验证,获得含所述融合蛋白CCI的全长第一重链、第二重链、第一轻链和第二轻链的重组质粒,分别为CCI-1(第一重链)、CCI-2(第二重链)和CCI-3(第一轻链和第二轻链相同);获得所述融合蛋白BCI的全长第一重链、第二重链、第一轻链和第二轻链的重组质粒,分别为BCI-1(第一重链)、BCI-2(第二重链)和BCI-3(第一轻链和第二轻链相同)。
实施例3质粒抽提
根据《分子克隆实验指南》(2002年,科学出版社)所述方法将含有上述各目的基因的重组质粒转化至大肠杆菌感受态细胞DH5α中,将转化细菌涂布在含100μg/mL氨苄青霉素的LB平板上培养,挑选质粒克隆至液体LB培养基中培养,260rpm摇菌14小时,由无内毒素质粒大抽试剂盒抽提质粒,用无菌水溶解并用核酸蛋白定量仪进行浓度测定。
实施例4质粒转染、瞬转表达与抗体纯化
在37℃、8%CO2、100rpm下培养ExpiCHO至细胞密度6×106个/mL。使用脂质体分别将构建的载体CCI-1、CCI-2和CCI-3;以及BCI-1、BCI-2和BCI-3转染到上述细胞中,转染质粒浓度为1mg/ml,脂质体浓度参照ExpiCHOTM Expression System试剂盒确定,在32℃、5%CO2,100rpm下培养7-10天。转染18-22h之后和第5天之间分别补料一次。4000g离心上述培养产物,0.22μm滤膜过滤并收集培养基上清液,采用ProteinA、离子柱纯化所得的抗体6蛋白并收集洗脱液。
ProteinA、离子柱纯化的具体操作步骤为:细胞培养液经过高速离心后取上清,利用GE的ProteinA层析柱进行亲和层析。层析使用平衡缓冲液为1×PBS(pH7.4),细胞上清上样结合后利用PBS洗涤至紫外线回到基线,然后利用洗脱缓冲液0.1M甘氨酸(pH3.0)洗脱目的蛋白,利用Tris调节pH至中性保存。将亲和层析所得产物调节pH至低于或者高于pI1-2个pH单位,适当稀释以控制样本电导在5ms/cm以下。利用合适的对应pH缓冲液如磷酸缓冲液、醋酸缓冲液等条件,利用本领域内常规的离子交换层析方法如阴离子交换或者阳离子交换进行对应pH条件下NaCl梯度洗脱,根据SDS-PAGE选择目的蛋白所在的收集管合并保存。
然后,将纯化后所得的洗脱液超滤换液至缓冲液中。通过SDS-聚丙烯酰胺凝胶电泳测定检测蛋白质。
经CE-SDS测定证明,非还原CE-SDS条件为1个峰,还原CE-SDS下目标抗体被还原成3个峰,即位置在LC、1、2位置,对应于所需抗体的两个不同的重链以及相同的轻链。因此,经所述质粒转染、瞬转表达和纯化,证明所得到的抗体融合蛋白CCI和BCI结构正确,且纯度较高。多功能融合蛋白CCI相应的CE-SDS电泳图分别如图2a、图2b所示。然后对所得到的抗体CCI进行质量、体外结合活性、细胞生物活性试验分析。
实施例5稳定性研究
将多功能融合蛋白CCI(或BCI)放于特定配方成分的制剂中,记为DR0,放入-80℃1h后转至室温融化,反复操作两次视为冻融2次,本发明研究了DR0、DR2与DR5,即反复冻融2次与五次,结果如表2所示,反复冻融SEC数据均稳定在92%,表明该结构稳定,冻融第五次的SEC-HPLC数据如图3所示。
表2 CCI冻融稳定性SEC-HPLC数据
实施例6多功能融合蛋白CCI与Claudin18.2-CHO-K1细胞的结合活性
使用对数期生长的构建的稳定表达Claudin18.2抗原的Claudin18.2-CHO-K1细胞铺板,以0.8×105/孔铺96孔板,37℃、5%CO2放入二氧化碳培养箱培养48h;固定:吸除多余培养基,使用1X PBST 200μL/孔加入孔板中,清洗2次,4%多聚甲醛100μL/孔,-20℃放置15分钟,移液枪吸除固定液,使用PBST清洗2次;用含2%BSA封闭液放入37℃孵育封闭1小时后,PBST洗3次后;将CCI用0.5%BSA样品稀释液稀释至0.3μg/mL,以此为起始浓度,进行3倍梯度稀释,共7个梯度,并设阴性对照,每孔100μL,37℃孵育1h;再用PBST洗板3次,将HRP标记的山羊抗人IgG Fc用样品稀释液按1:20000稀释,每孔加入100μL,室温孵育45min;PBST洗板4次后,每孔加入100μL TMB底物,室温避光孵育10分钟,每孔加入100μL 1M盐酸液终止显色反应;在多功能酶标仪上选择波长450nm;将多功能融合蛋白CCI的浓度取对数后作为横坐标,测得的每孔吸光值为纵坐标,选用Sigmoidaldose-response(Variable Slope)方式(GraphPad Prism软件,GraphPad Software,SanDiego,California)进行非线性回归,得到CCI与Claudin18.2-CHO-K1的结合曲线。结果如图4所示,其中IgG1为无关抗体,Claudin18.2抗体为Claudin18.2阳性参照,结果表明CCI的结合能力与Claudin18.2抗体相当,该架构的CCI不会影响与Claudin18.2的结合能力。
实施例7多功能融合蛋白CCI与IL-2Rβ的结合活性
采用pH7.4的PBS缓冲液将IL-2Rβ受体稀释至4μg/mL,每孔100μL加入到96孔ELISA板中,4度包被过夜。用1%BSA封闭液封闭1小时后。PBST洗板3次后,将CCI用0.5%BSA样品稀释液稀释至4μg/mL,以此为起始浓度,进行3倍梯度稀释,共7个梯度,并设阴性对照,每孔100μL,37℃孵育1h。再用PBST洗板3次,将HRP标记的山羊抗人IgG Fc用样品稀释液按1:10000稀释,每孔加入100μL,室温孵育1小时。PBST洗板4次后,每孔加入100μL TMB底物,室温避光孵育10分钟,每孔加入100μL 1M HCl液终止显色反应。在多功能酶标仪上选择波长450nm,参比波长570nm测定96孔板中各孔的吸光值,每孔吸光值(OD)=OD450nm-OD570nm。将CCI的浓度取对数后作为横坐标,测得的每孔吸光值为纵坐标,选用Sigmoidaldose-response(Variable Slope)方式(GraphPad Prism软件,GraphPad Software,SanDiego,California)进行非线性回归,得到多功能融合蛋白CCI与IL-2Rβ的结合曲线。
多功能融合蛋白CCI的ELISA结果如图5所示,所述多功能融合蛋白CCI在各浓度下均可与IL-2Rβ结合,表明所述结构的CCI与IL-2Rβ有较好的结合能力。
实施例8多功能融合蛋白CCI与CD3的结合活性
采用pH7.4的PBS缓冲液将多功能融合蛋白CCI、CD3抗体、无关抗体IgG稀释至1.5μg/mL,每孔100μL加入到96孔ELISA板中,4度包被过夜。用1%BSA封闭液封闭1小时后。PBST洗板3次后,将CD3用1%BSA样品稀释液稀释至10μg/mL,以此为起始浓度,进行3倍梯度稀释,共7个梯度,并设阴性对照,每孔100μL,37℃孵育1h。再用PBST洗板3次,将HRP标记的兔抗6*His抗体用样品稀释液按1:20000稀释,每孔加入100μL,室温孵育1小时。PBST洗板4次后,每孔加入100μL TMB底物,室温避光孵育10分钟,每孔加入100μL 1M HCl液终止显色反应。在多功能酶标仪上选择波长450nm,检测每孔吸光值OD450nm。将多功能融合蛋白CCI的浓度取Log10后作为横坐标,测得的每孔吸光值为纵坐标,选用Sigmoidaldose-response(Variable Slope)方式(GraphPad Prism软件,GraphPad Software,SanDiego,California)进行非线性回归,得到CCI与CD3的结合曲线。
多功能融合蛋白CCI的ELISA结果如图6所示,所述多功能融合蛋白CCI在各浓度下均可与CD3结合,IgG1与CD3无结合,与设计效果是一致的,理论上同样浓度下,单抗CD3的效价为CCI的一半。
实施例9多功能融合蛋白CCI对PBMC增殖实验
使用商品化的PBMC细胞,复苏后,以1×106个/mL加入24孔板中,每孔添加抗CD3抗体OKT3 1μg/mL进行激活,继续培养,每隔2天,加入相应浓度的不同抗体(CCI或IL-15)继续持续刺激,每次计数细胞总数。
结果如图7所示,无IL-15持续刺激下,PBMC无法存活;使用OKT3激活+IL-15持续刺激可使PBMC增殖。CCI激活+IL-15持续刺激或OKT3激活+CCI持续刺激与阳性对照OKT3激活+IL-15持续刺激有同等效果,细胞数差别不大;仅仅使用CCI进行激活,细胞数与增殖速度同样与阳性对照差别不大。实验证明,CCI同时具有CD3抗体与IL-15的功能活性。
实施例10 PBMC增殖实验细胞分型流式分析
使用流式抗体对抗体刺激PBMC增殖的细胞进行细胞表面标记分析。流式抗体包含PerCp-cy5.5-CD3(Cat:552852;BD)、APC-CD56(Cat:555518;BD)、PE-CD4(Cat:550630;BD)、PE-cy7-CD16(557744;BD);以1×106/实验,分别加入流式抗体孵育37℃孵育1h,2000r/分钟离心5分钟,而后使用1mL PBS重悬清洗,重复清洗操作两次,最后使用200μL PBS重悬细胞,使用流式细胞仪进行分析,以无添加流式抗体作为空白对照,即Blank。结果统计如表3所示,流式分析如图8所示。图8中,A、D、G为不同刺激条件下PBMC增殖的CD3标记流式分析,B、E、H为不同刺激条件下PBMC增殖的CD16标记流式分析,C、F、I为不同刺激条件下PBMC增殖的CD56标记流式分析,其中A、B、C为CCI激活+无持续刺激,D、E、F为CCI激活+CCI持续刺激,G、H、L为OKT3激活+IL-15持续刺激。
由数据分析得到,刺激增殖的细胞90%以上为CD3阳性细胞,表示增殖的细胞大部分为T细胞,其中CD4+与CD8+被包含在CD3阳性细胞中,其中CD8+细胞高于CD4+细胞,其中CD4+为辅助T细胞,CD8+为杀伤T细胞,表明CD3抗体与IL-15刺激下,杀伤T细胞比例大于辅助T细胞;CD16阳性与CD56阳性各条件下无明显区别,表示维持了NK细胞存活。
由此证明,CCI维持存活的细胞基本为T细胞和NK细胞群体,与设计效果一致。CCI既拥有CD3刺激PBMC细胞活化的功能,也能维持T细胞和NK细胞存活,CCI同时具有CD3抗体功能以及IL-15细胞因子功能,与设计效果一致。
表3细胞表面标记分析
实施例11 CCI介导的Claudin18.2-CHO-K1细胞杀伤实验
使用构建工程细胞株Claudin18.2-CHO-K1,3×104/孔铺于96孔板,培养24h后,加入CCI抗体和无关抗体10μg/mL起始,10倍稀释,共5个浓度梯度,同时加入由CCI激活与持续刺激PBMC得到的效应细胞1.5×105/孔,使效靶比为5:1,孵育24h后,PBS润洗次,洗去效应细胞。加入含10%CCK-8(Cat:CK04)培养基100uL,于培养箱孵育2h后,于酶标仪OD值450nm进行检测。计算细胞杀伤率,公式为细胞杀伤率(%)=(样品孔OD值-blankOD值)/(阴性孔OD值-blankOD值)×100%。
由图9可知,与无关抗体相比,CCI抗体组对Claudin18.2-CHO-K1细胞具有杀伤作用,而无关抗体不具有杀伤作用,说明此杀伤为靶点特异;同时,CCI介导的效应细胞为CCI激活与持续刺激PBMC的细胞,说明CCI激活与持续刺激PBMC的细胞可杀伤抗体介导的靶细胞。所以CCI可激活与持续刺激PBMC细胞,并且作为效应细胞特异杀伤抗体介导的靶细胞。
实施例12多功能融合蛋白BCI与B7H3的结合活性
采用pH7.4的PBS缓冲液将huB7H3-his受体稀释至0.5μg/mL,每孔100μL加入到96孔ELISA板中,4度包被过夜。用1%BSA封闭液封闭1小时后。PBST洗板3次后,将多功能融合蛋白BCI用0.5%BSA样品稀释液稀释至10μg/mL,以此为起始浓度,进行3倍梯度稀释,共11个梯度,并设无关抗体阴性对照与阳性对照B7H3嵌合抗体,每孔100μL,37℃孵育1h。再用PBST洗板3次,将HRP标记的山羊抗人IgGFc用样品稀释液按1:20000稀释,每孔加入100μL,室温孵育1小时。PBST洗板4次后,每孔加入100μL TMB底物,室温避光孵育10分钟,每孔加入100μL 1M HCl液终止显色反应。在多功能酶标仪上选择波长450nm,参比波长570nm测定96孔板中各孔的吸光值,每孔吸光值(OD)=OD450nm-OD570nm。将抗体的浓度取对数后作为横坐标,测得的每孔吸光值为纵坐标,选用Sigmoidaldose-response(Variable Slope)方式(GraphPad Prism软件,GraphPad Software,SanDiego,California)进行非线性回归,得到目标抗体与B7H3蛋白的结合曲线。多功能融合蛋白BCI的结合活性由图10所示。
由图10可知,BCI在各浓度下均与B7H3有很好的结合能力。
实施例13多功能融合蛋白BCI与CD3的结合活性
采用pH7.4的PBS缓冲液将huCD3-his受体稀释至1μg/mL,每孔100μL加入到96孔ELISA板中,4℃包被过夜。用1%BSA封闭液封闭1小时。PBST洗板3次后,将BCI、CD3抗体、无关抗体IgG样品稀释液稀释至10μg/mL,以此为起始浓度,进行3倍梯度稀释,共11个梯度,每孔100μL,37℃孵育1h。再用PBST洗板3次,将HRP标记的山羊抗人IgG Fc用样品稀释液按1:10000稀释,每孔加入100μL,室温孵育1小时。PBST洗板4次后,每孔加入100μL TMB底物,室温避光孵育10分钟,每孔加入100μL 1M HCl液终止显色反应。在多功能酶标仪上选择波长450nm,参比波长570nm测定96孔板中各孔的吸光值,每孔吸光值(OD)=OD450nm-OD570nm。将抗体的浓度取对数后作为横坐标,测得的每孔吸光值为纵坐标,选用Sigmoidaldose-response(Variable Slope)方式(GraphPad Prism软件,GraphPad Software,SanDiego,California)进行非线性回归,得到BCI与CD3蛋白的结合曲线。
由图11可知,BCI在各浓度下均与CD3有很好的结合能力。
实施例14流式细胞术检测MCF-7细胞B7H3表达丰度
取细胞状态良好并处于对数期生长的MCF-7细胞悬液800g,室温离心3分钟,去掉上清,使用PBS洗涤细胞2次后,PBS重悬细胞至2×105/ml,按照1ml/离心管分成若干份。加入100μl使用PBS稀释至20ug/ml的B7H3抗体,并设空白对照组(Blank),阴性对照组(NC),充分混匀后,室温孵育半小时。800g室温离心5分钟,去掉含有抗体的上清,使用PBS洗涤细胞3次。取100ul重悬细胞,加入0.5uL FITC标记的F(ab’)2山羊抗人IgG(Biolegend398006),充分混匀后,室温避光孵育30min;800g室温离心5分钟,去掉含有二抗的上清,使用PBS洗涤细胞3次;使用100uLPBS重悬细胞,进行流式分析。结果如图12a-12b所示。
由图12b可知,跟MCF-7阴性峰相比,MCF-7-B7H3抗体的峰沿X轴显著右移,表明MCF-7细胞高表达B7H3。
实施例15多功能融合蛋白与IL-2Rβ的结合活性
依照实施例7的方法检测多功能融合蛋白与IL-2Rβ的结合活性,结果如图13所示。所述多功能融合蛋白在各浓度下均可与IL-2Rβ结合,表明所述多功能融合蛋白与IL-2Rβ有较好的结合能力。
实施例16多功能融合蛋白BCI的抗肿瘤活性
使用B7H3阳性的乳腺癌细胞MCF-7以2×104/孔铺于96孔板,培养24h后,加入多功能融合蛋白BCI和无关抗体20μg/mL起始,5倍稀释,共10个浓度梯度,同时加入CIK(CD3+CD56+细胞)效应细胞4×104/孔,并设置空白对照(稀释液)、阴性对照(MCF-7+CIK,无抗体)、无关抗体组,于细胞培养箱孵育24h后,PBS润洗次,洗去效应细胞。加入含10%CCK-8(Cat:CK04)培养基100μL,于培养箱孵育3h后,于酶标仪OD值450nm进行检测。计算细胞杀伤率,公式为细胞杀伤率(%)=(样品孔OD值-空白OD值)/(阴性孔OD值-空白OD值)×100%。
由图14可知,BCI可杀伤B7H3阳性的乳腺癌细胞MCF-7,而无关抗体不具有杀伤作用,说明BCI介导CIK细胞特异性杀伤B7H3阳性的MCF-7细胞。
本发明的保护内容不局限于以上实施例。在不背离发明构思的精神和范围下,本领域技术人员能够想到的变化和优点都被包括在本发明中,并且以所附的权利要求为保护范围。
序列表
<110> 盛禾(中国)生物制药有限公司
<120> 一种多功能融合蛋白及其用途
<160> 22
<170> SIPOSequenceListing 1.0
<210> 1
<211> 689
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 1
Gln Val Gln Leu Gln Gln Pro Gly Ala Glu Leu Val Arg Pro Gly Ala
1 5 10 15
Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Trp Ile Asn Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Asn Ile Tyr Pro Ser Asp Ser Tyr Thr Asn Tyr Asn Gln Lys Phe
50 55 60
Lys Asp Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Gln Leu Ser Ser Pro Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Thr Arg Ser Trp Arg Gly Asn Ser Phe Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Thr Leu Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro
115 120 125
Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly
130 135 140
Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn
145 150 155 160
Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln
165 170 175
Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser
180 185 190
Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser
195 200 205
Asn Thr Lys Val Asp Lys Arg Val Gly Gly Gly Gly Ser Gly Gly Gly
210 215 220
Gly Ser Ile Thr Cys Pro Pro Pro Met Ser Val Glu His Ala Asp Ile
225 230 235 240
Trp Val Lys Ser Tyr Ser Leu Tyr Ser Arg Glu Arg Tyr Ile Cys Asn
245 250 255
Ser Gly Phe Lys Arg Lys Ala Gly Thr Ser Ser Leu Thr Glu Cys Val
260 265 270
Leu Asn Lys Ala Thr Asn Val Ala His Trp Thr Thr Pro Ser Leu Lys
275 280 285
Cys Ile Arg Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
290 295 300
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
305 310 315 320
Ser Asn Trp Val Asn Val Ile Ser Asp Leu Lys Lys Ile Glu Asp Leu
325 330 335
Ile Gln Ser Met His Ile Asp Ala Thr Leu Tyr Thr Glu Ser Asp Val
340 345 350
His Pro Ser Cys Lys Val Thr Ala Met Lys Cys Phe Leu Leu Glu Leu
355 360 365
Gln Val Ile Ser Leu Glu Ser Gly Asp Ala Ser Ile His Asp Thr Val
370 375 380
Glu Asn Leu Ile Ile Leu Ala Asn Asp Ser Leu Ser Ser Asn Gly Asn
385 390 395 400
Val Thr Glu Ser Gly Cys Lys Glu Cys Glu Glu Leu Glu Glu Lys Asn
405 410 415
Ile Lys Glu Phe Leu Gln Ser Phe Val His Ile Val Gln Met Phe Ile
420 425 430
Asn Thr Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
435 440 445
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Ser Lys Tyr
450 455 460
Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro
465 470 475 480
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
485 490 495
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp
500 505 510
Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
515 520 525
Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val
530 535 540
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
545 550 555 560
Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys
565 570 575
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
580 585 590
Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr
595 600 605
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
610 615 620
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
625 630 635 640
Asp Ser Asp Gly Ser Phe Phe Leu Ala Ser Arg Leu Thr Val Asp Lys
645 650 655
Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu
660 665 670
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly
675 680 685
Lys
<210> 2
<211> 705
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 2
Gln Val Gln Leu Gln Gln Pro Gly Ala Glu Leu Val Arg Pro Gly Ala
1 5 10 15
Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Trp Ile Asn Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Asn Ile Tyr Pro Ser Asp Ser Tyr Thr Asn Tyr Asn Gln Lys Phe
50 55 60
Lys Asp Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Gln Leu Ser Ser Pro Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Thr Arg Ser Trp Arg Gly Asn Ser Phe Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Thr Leu Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro
115 120 125
Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly
130 135 140
Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn
145 150 155 160
Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln
165 170 175
Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser
180 185 190
Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser
195 200 205
Asn Thr Lys Val Asp Lys Arg Val Glu Val Gln Leu Val Glu Ser Gly
210 215 220
Gly Gly Leu Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Ala Ala
225 230 235 240
Ser Gly Phe Thr Phe Asp Asp Tyr Thr Met His Trp Val Arg Gln Ala
245 250 255
Pro Gly Lys Gly Leu Glu Trp Val Ser Gly Ile Ser Trp Asn Ser Gly
260 265 270
Ser Ile Gly Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg
275 280 285
Asp Asn Ala Lys Lys Ser Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala
290 295 300
Glu Asp Thr Ala Leu Tyr Tyr Cys Ala Lys Asp Asn Ser Gly Tyr Gly
305 310 315 320
His Tyr Tyr Tyr Gly Met Asp Val Trp Gly Gln Gly Thr Thr Val Thr
325 330 335
Val Ala Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
340 345 350
Gly Ser Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser
355 360 365
Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser
370 375 380
Ser Asn Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu
385 390 395 400
Leu Ile Tyr Gly Ala Ser Thr Arg Ala Thr Gly Ile Pro Ala Arg Phe
405 410 415
Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu
420 425 430
Gln Ser Glu Asp Phe Ala Val Tyr Tyr Cys Gln His Tyr Ile Asn Trp
435 440 445
Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Gly Gly Gly
450 455 460
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Ser Lys Tyr
465 470 475 480
Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro
485 490 495
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
500 505 510
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp
515 520 525
Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
530 535 540
Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val
545 550 555 560
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
565 570 575
Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys
580 585 590
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
595 600 605
Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Trp
610 615 620
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
625 630 635 640
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
645 650 655
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys
660 665 670
Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu
675 680 685
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly
690 695 700
Lys
705
<210> 3
<211> 220
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 3
Asp Ile Val Met Thr Gln Ser Pro Ser Ser Leu Thr Val Thr Ala Gly
1 5 10 15
Glu Lys Val Thr Met Ser Cys Lys Ser Ser Gln Ser Leu Leu Asn Ser
20 25 30
Gly Asn Gln Lys Asn Tyr Leu Thr Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val
50 55 60
Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Val Gln Ala Glu Asp Leu Ala Val Tyr Tyr Cys Gln Asn
85 90 95
Asp Tyr Ser Tyr Pro Phe Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile
100 105 110
Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp
115 120 125
Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn
130 135 140
Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu
145 150 155 160
Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp
165 170 175
Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr
180 185 190
Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser
195 200 205
Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215 220
<210> 4
<211> 2070
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 4
caggtgcagc tgcagcagcc aggagctgag ctggtgaggc ctggagctag cgtgaagctg 60
tcttgtaagg cctccggcta caccttcaca agctattgga tcaactgggt gaagcagagg 120
cctggacagg gactggagtg gatcggcaat atctacccaa gcgactctta caccaactat 180
aatcagaagt ttaaggacaa ggccaccctg acagtggata agtccagctc taccgcttac 240
atgcagctgt ccagccccac atctgaggac tccgccgtgt actattgcac aagaagctgg 300
cgcggcaact ctttcgatta ttggggccag ggcaccacac tgaccgtgtc ttccgcctcc 360
acaaagggcc ctagcgtgtt tccactggct cccagctcta agtccaccag cggaggaaca 420
gccgctctgg gctgtctggt gaaggattac ttccctgagc cagtgaccgt gagctggaac 480
tctggcgccc tgaccagcgg agtgcacaca tttcctgctg tgctgcagtc cagcggcctg 540
tactctctgt cttccgtggt gacagtgcct agctcttccc tgggcaccca gacatatatc 600
tgcaacgtga atcacaagcc atccaacacc aaggtggaca agagggtggg aggaggagga 660
tctggaggag gaggatccat cacatgtcca cctccaatga gcgtggagca tgccgatatc 720
tgggtgaagt cttactccct gtattccagg gagcggtaca tctgcaatag cggcttcaag 780
agaaaggctg gcaccagctc tctgacagag tgcgtgctga acaaggccac caatgtggct 840
cattggacca cacctagcct gaagtgcatc aggggaggag gaggaagcgg cggaggaggc 900
agcggcggcg gcggctccgg cggcggcggc agcggtggcg gcggttccgg cggcggcggc 960
tccaactggg tgaatgtgat ctctgacctg aagaagatcg aggatctgat ccagtccatg 1020
cacatcgacg ccaccctgta tacagagagc gatgtgcatc catcttgcaa ggtgaccgct 1080
atgaagtgtt ttctgctgga gctgcaggtc atctccctgg agagcggcga cgcctctatc 1140
cacgataccg tggagaacct gatcatcctg gctaatgaca gcctgtccag caacggcaat 1200
gtgacagagt ctggctgcaa ggagtgtgag gagctggagg agaagaacat caaggagttc 1260
ctgcagtcct ttgtgcatat cgtgcagatg ttcatcaata cctccggcgg cggcggttct 1320
ggcggcggcg gatccggtgg tggtggttct ggtggcggcg gcagcggagg aggaggaagc 1380
gagtctaagt acggaccacc ttgcccacca tgtccagctc ctgagtttct gggaggacca 1440
tccgtgttcc tgtttcctcc aaagcccaag gacaccctga tgatcagcag gaccccagag 1500
gtgacatgcg tggtggtgga cgtgtctcag gaggatcccg aggtgcagtt caactggtac 1560
gtggatggcg tggaggtgca caatgctaag accaagccaa gagaggagca gtttaactct 1620
acctaccgcg tggtgtccgt gctgacagtg ctgcatcagg attggctgaa cggcaaggag 1680
tataagtgca aggtgtccaa taagggcctg ccctcttcca tcgagaagac catcagcaag 1740
gctaagggac agcctcggga gccacaggtg tacacactgc ccccttccca ggaggagatg 1800
accaagaacc aggtgagcct gacatgtctg gtgaagggct tctacccctc tgacatcgct 1860
gtggagtggg agtccaatgg ccagcctgag aacaattata agaccacacc acccgtgctg 1920
gactctgatg gctccttctt tctggccagc aggctgaccg tggataagtc tcggtggcag 1980
gagggcaacg tgttttcctg tagcgtgatg catgaggctc tgcacaatca ttatacacag 2040
aagtctctgt ccctgagcct gggcaagtga 2070
<210> 5
<211> 2118
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 5
caggtgcagc tgcagcagcc aggagctgag ctggtgagac caggagcttc tgtgaagctg 60
tcctgtaagg ctagcggcta taccttcaca tcctactgga tcaactgggt gaagcagagg 120
ccaggacagg gactggagtg gatcggcaat atctatccca gcgactctta taccaactac 180
aatcagaagt ttaaggacaa ggccaccctg acagtggata agtccagctc taccgcttat 240
atgcagctgt ccagcccaac atccgaggac agcgccgtgt actattgcac aaggtcttgg 300
cggggcaact ccttcgatta ctggggccag ggcaccacac tgaccgtgtc ttccgccagc 360
acaaagggac catccgtgtt cccactggct cccagctcta agtccaccag cggaggaaca 420
gccgctctgg gctgtctggt gaaggactac ttccctgagc cagtgaccgt gtcttggaac 480
tccggcgccc tgacctccgg agtgcacaca tttcccgctg tgctgcagtc cagcggcctg 540
tatagcctgt cttccgtggt gaccgtgcca agctcttccc tgggcaccca gacatacatc 600
tgcaacgtga atcataagcc ctctaataca aaggtggata agagggtgga ggtgcagctg 660
gtggagtccg gaggaggact ggtgcagcct ggcagatctc tgcgcctgtc ctgtgccgct 720
agcggcttca cctttgacga ttatacaatg cactgggtgc ggcaggctcc aggcaaggga 780
ctggagtggg tgagcggaat ctcttggaac tctggctcca tcggctatgc cgacagcgtg 840
aagggcaggt tcaccatctc tcgggataac gctaagaagt ccctgtacct gcagatgaat 900
agcctgaggg ccgaggacac agctctgtac tattgcgcca aggataattc tggctacggc 960
cattactatt acggaatgga cgtgtgggga cagggaacca cagtgaccgt ggcttccgga 1020
ggaggaggaa gcggaggagg aggatctgga ggaggaggat ccgagatcgt gatgacccag 1080
agccctgcca cactgagcgt gtctccaggc gagagagcca cactgtcttg tcgcgcttcc 1140
cagagcgtga gctctaacct ggcctggtat cagcagaagc ccggccaggc tcctaggctg 1200
ctgatctacg gcgcctctac cagggctaca ggcatcccag ctcggttctc tggatccgga 1260
agcggcaccg agtttaccct gacaatctcc agcctgcagt ccgaggattt cgccgtgtac 1320
tactgccagc actatatcaa ttggcctctg acctttggcg gcggcacaaa ggtggagatc 1380
aagggcggcg gcggctctgg cggcggcggc tccggaggag gaggatctga gtccaagtac 1440
ggaccacctt gcccaccatg tccagctcct gagtttctgg gaggaccaag cgtgttcctg 1500
tttcctccaa agcctaagga caccctgatg atctctagaa cccccgaggt gacatgcgtg 1560
gtggtggacg tgtcccagga ggatcctgag gtgcagttca actggtacgt ggatggcgtg 1620
gaggtgcaca atgccaagac caagcctagg gaggagcagt ttaactccac ctatcgggtg 1680
gtgagcgtgc tgacagtgct gcatcaggat tggctgaacg gcaaggagta caagtgcaag 1740
gtgagcaata agggcctgcc atcttccatc gagaagacca tctctaaggc taagggccag 1800
cctcgcgagc cacaggtgta taccctgccc ccttcccagg aggagatgac aaagaaccag 1860
gtgagcctgt ggtgtctggt gaagggcttc taccctagcg acatcgccgt ggagtgggag 1920
tctaatggcc agccagagaa caattataag accacaccac ccgtgctgga ctccgatggc 1980
agcttctttc tgtactctag actgaccgtg gataagtccc gctggcagga gggcaacgtg 2040
tttagctgct ctgtgatgca tgaggccctg cacaatcatt acacacagaa gtccctgagc 2100
ctgtctctgg gcaagtga 2118
<210> 6
<211> 669
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 6
gacatcgtga tgacacagtc cccctccagc ctgaccgtga cagctggaga gaaggtgacc 60
atgagctgta agtcttccca gtccctgctg aacagcggca atcagaagaa ctacctgacc 120
tggtatcagc agaagcccgg ccagccccct aagctgctga tctactgggc ttctacaagg 180
gagtccggag tgcctgaccg gttcaccgga agcggatctg gcacagactt caccctgaca 240
atcagctctg tgcaggccga ggacctggcc gtgtactatt gccagaatga ttactcttat 300
cctttcacct ttggctccgg cacaaagctg gagatcaaga gaaccgtggc cgctccaagc 360
gtgttcatct ttccaccctc tgacgagcag ctgaagagcg gcacagcctc tgtggtgtgc 420
ctgctgaaca atttctaccc acgcgaggcc aaggtgcagt ggaaggtgga taatgctctg 480
cagtccggca acagccagga gtctgtgacc gagcaggact ccaaggatag cacatattct 540
ctgtccagca ccctgacact gtctaaggcc gattacgaga agcacaaggt gtatgcttgc 600
gaggtgaccc atcagggcct gtcttccccc gtgacaaagt cctttaacag gggcgagtgt 660
tgactcgag 669
<210> 7
<211> 19
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 7
Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly
1 5 10 15
Val His Ser
<210> 8
<211> 57
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 8
atgggctggt cctgcatcat cctgttcctg gtggccaccg ctacaggcgt gcacagc 57
<210> 9
<211> 20
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 9
Met Glu Ser Gln Thr Gln Val Leu Met Ser Leu Leu Phe Trp Val Ser
1 5 10 15
Gly Thr Cys Gly
20
<210> 10
<211> 60
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 10
atggagtccc agacccaggt gctgatgtcc ctgctgttct gggtgagcgg cacctgcggc 60
<210> 11
<211> 114
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 11
Asn Trp Val Asn Val Ile Ser Asp Leu Lys Lys Ile Glu Asp Leu Ile
1 5 10 15
Gln Ser Met His Ile Asp Ala Thr Leu Tyr Thr Glu Ser Asp Val His
20 25 30
Pro Ser Cys Lys Val Thr Ala Met Lys Cys Phe Leu Leu Glu Leu Gln
35 40 45
Val Ile Ser Leu Glu Ser Gly Asp Ala Ser Ile His Asp Thr Val Glu
50 55 60
Asn Leu Ile Ile Leu Ala Asn Asp Ser Leu Ser Ser Asn Gly Asn Val
65 70 75 80
Thr Glu Ser Gly Cys Lys Glu Cys Glu Glu Leu Glu Glu Lys Asn Ile
85 90 95
Lys Glu Phe Leu Gln Ser Phe Val His Ile Val Gln Met Phe Ile Asn
100 105 110
Thr Ser
<210> 12
<211> 65
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 12
Ile Thr Cys Pro Pro Pro Met Ser Val Glu His Ala Asp Ile Trp Val
1 5 10 15
Lys Ser Tyr Ser Leu Tyr Ser Arg Glu Arg Tyr Ile Cys Asn Ser Gly
20 25 30
Phe Lys Arg Lys Ala Gly Thr Ser Ser Leu Thr Glu Cys Val Leu Asn
35 40 45
Lys Ala Thr Asn Val Ala His Trp Thr Thr Pro Ser Leu Lys Cys Ile
50 55 60
Arg
65
<210> 13
<211> 77
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 13
Ile Thr Cys Pro Pro Pro Met Ser Val Glu His Ala Asp Ile Trp Val
1 5 10 15
Lys Ser Tyr Ser Leu Tyr Ser Arg Glu Arg Tyr Ile Cys Asn Ser Gly
20 25 30
Phe Lys Arg Lys Ala Gly Thr Ser Ser Leu Thr Glu Cys Val Leu Asn
35 40 45
Lys Ala Thr Asn Val Ala His Trp Thr Thr Pro Ser Leu Lys Cys Ile
50 55 60
Arg Asp Pro Ala Leu Val His Gln Arg Pro Ala Pro Pro
65 70 75
<210> 14
<211> 689
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 14
Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Asp Ile Asn Trp Val Arg Gln Arg Pro Glu Gln Gly Leu Glu Trp Ile
35 40 45
Gly Trp Ile Phe Pro Gly Asp Gly Ser Thr Gln Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Thr Asp Thr Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Gln Leu Ser Arg Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys
85 90 95
Ala Arg Gln Thr Thr Ala Thr Trp Phe Ala Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ala Ala Ser Thr Lys Gly Pro Ser Val Phe Pro
115 120 125
Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly
130 135 140
Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn
145 150 155 160
Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln
165 170 175
Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser
180 185 190
Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser
195 200 205
Asn Thr Lys Val Asp Lys Arg Val Gly Gly Gly Gly Ser Gly Gly Gly
210 215 220
Gly Ser Ile Thr Cys Pro Pro Pro Met Ser Val Glu His Ala Asp Ile
225 230 235 240
Trp Val Lys Ser Tyr Ser Leu Tyr Ser Arg Glu Arg Tyr Ile Cys Asn
245 250 255
Ser Gly Phe Lys Arg Lys Ala Gly Thr Ser Ser Leu Thr Glu Cys Val
260 265 270
Leu Asn Lys Ala Thr Asn Val Ala His Trp Thr Thr Pro Ser Leu Lys
275 280 285
Cys Ile Arg Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
290 295 300
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
305 310 315 320
Ser Asn Trp Val Asn Val Ile Ser Asp Leu Lys Lys Ile Glu Asp Leu
325 330 335
Ile Gln Ser Met His Ile Asp Ala Thr Leu Tyr Thr Glu Ser Asp Val
340 345 350
His Pro Ser Cys Lys Val Thr Ala Met Lys Cys Phe Leu Leu Glu Leu
355 360 365
Gln Val Ile Ser Leu Glu Ser Gly Asp Ala Ser Ile His Asp Thr Val
370 375 380
Glu Asn Leu Ile Ile Leu Ala Asn Asp Ser Leu Ser Ser Asn Gly Asn
385 390 395 400
Val Thr Glu Ser Gly Cys Lys Glu Cys Glu Glu Leu Glu Glu Lys Asn
405 410 415
Ile Lys Glu Phe Leu Gln Ser Phe Val His Ile Val Gln Met Phe Ile
420 425 430
Asn Thr Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
435 440 445
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Ser Lys Tyr
450 455 460
Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro
465 470 475 480
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
485 490 495
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp
500 505 510
Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
515 520 525
Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val
530 535 540
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
545 550 555 560
Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys
565 570 575
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
580 585 590
Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr
595 600 605
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
610 615 620
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
625 630 635 640
Asp Ser Asp Gly Ser Phe Phe Leu Ala Ser Arg Leu Thr Val Asp Lys
645 650 655
Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu
660 665 670
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly
675 680 685
Lys
<210> 15
<211> 705
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 15
Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Asp Ile Asn Trp Val Arg Gln Arg Pro Glu Gln Gly Leu Glu Trp Ile
35 40 45
Gly Trp Ile Phe Pro Gly Asp Gly Ser Thr Gln Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Thr Asp Thr Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Gln Leu Ser Arg Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys
85 90 95
Ala Arg Gln Thr Thr Ala Thr Trp Phe Ala Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ala Ala Ser Thr Lys Gly Pro Ser Val Phe Pro
115 120 125
Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly
130 135 140
Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn
145 150 155 160
Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln
165 170 175
Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser
180 185 190
Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser
195 200 205
Asn Thr Lys Val Asp Lys Arg Val Glu Val Gln Leu Val Glu Ser Gly
210 215 220
Gly Gly Leu Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Ala Ala
225 230 235 240
Ser Gly Phe Thr Phe Asp Asp Tyr Thr Met His Trp Val Arg Gln Ala
245 250 255
Pro Gly Lys Gly Leu Glu Trp Val Ser Gly Ile Ser Trp Asn Ser Gly
260 265 270
Ser Ile Gly Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg
275 280 285
Asp Asn Ala Lys Lys Ser Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala
290 295 300
Glu Asp Thr Ala Leu Tyr Tyr Cys Ala Lys Asp Asn Ser Gly Tyr Gly
305 310 315 320
His Tyr Tyr Tyr Gly Met Asp Val Trp Gly Gln Gly Thr Thr Val Thr
325 330 335
Val Ala Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
340 345 350
Gly Ser Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser
355 360 365
Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser
370 375 380
Ser Asn Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu
385 390 395 400
Leu Ile Tyr Gly Ala Ser Thr Arg Ala Thr Gly Ile Pro Ala Arg Phe
405 410 415
Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu
420 425 430
Gln Ser Glu Asp Phe Ala Val Tyr Tyr Cys Gln His Tyr Ile Asn Trp
435 440 445
Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Gly Gly Gly
450 455 460
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Ser Lys Tyr
465 470 475 480
Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro
485 490 495
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
500 505 510
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp
515 520 525
Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
530 535 540
Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val
545 550 555 560
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
565 570 575
Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys
580 585 590
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
595 600 605
Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Trp
610 615 620
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
625 630 635 640
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
645 650 655
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys
660 665 670
Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu
675 680 685
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly
690 695 700
Lys
705
<210> 16
<211> 214
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 16
Asp Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Thr Pro Gly
1 5 10 15
Asp Arg Val Ser Leu Ser Cys Arg Ala Ser Gln Ser Ile Ser Asp Tyr
20 25 30
Leu His Trp Tyr Gln Gln Lys Ser His Glu Ser Pro Arg Leu Leu Ile
35 40 45
Lys Tyr Ala Ser Gln Ser Ile Ser Gly Ile Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Ser Asp Phe Thr Leu Ser Ile Asn Ser Val Glu Pro
65 70 75 80
Glu Asp Val Gly Val Tyr Tyr Cys Gln Asn Gly His Ser Phe Pro Leu
85 90 95
Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys
210
<210> 17
<211> 2067
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 17
caggtccagc tgcaacagtc tggagcagaa ttggtcaaac ctggtgccag cgtgaagctc 60
tcctgcaaag cctcaggtta tacattcacc aactatgata tcaactgggt ccgccagcga 120
cctgaacagg gcttggagtg gatcggctgg atctttcctg gagatggatc tacccagtac 180
aacgaaaaat ttaaaggaaa ggccacgctg acaaccgaca cgagctccag caccgcttac 240
atgcaattga gtcggctgac ctccgaggac agtgctgtgt atttctgtgc acgccagact 300
accgccacat ggttcgctta ctggggtcag ggaacccttg tcaccgtttc tgccgcttca 360
actaaaggcc caagtgtgtt tcccctggct ccaagctcta aaagcacatc cggggggaca 420
gctgcactgg gttgtctggt gaaggattat ttccccgagc ctgtcaccgt gagctggaac 480
tcaggagcac tgacctccgg agtccacacc ttccctgccg tgctgcagtc atccggattg 540
tattccctga gcagcgtggt gacagtcccg agctcttcac tcggcacgca gacctacata 600
tgcaacgtca accacaaacc gagcaatact aaggtggata agcgagttgg tggcggcgga 660
tctggaggtg gaggatcaat cacctgtcct ccacctatgt ccgttgaaca cgctgatatc 720
tgggtgaaga gctactcact gtacagtcga gaacggtaca tttgtaattc agggtttaag 780
agaaaggccg gaacatcatc cctcactgag tgcgtcttga acaaagccac taacgtggct 840
cattggacta ctccttcact gaaatgcata agaggtggtg gaggcagtgg aggtggggga 900
tctggtggtg gaggttctgg tggaggtgga agtggaggtg gaggatcagg gggaggtggt 960
tctaattggg taaacgtcat tagcgatttg aaaaaaatcg aggatcttat tcagagcatg 1020
catattgacg ccaccctgta caccgagagc gatgtgcatc ctagctgcaa agtcacggca 1080
atgaagtgct tccttctcga attgcaggtg atatcactgg aatcaggcga cgcatctatt 1140
catgacacag tggaaaacct gataatcctc gccaatgact ctctttcctc aaacggaaac 1200
gtgacagaga gcggttgtaa agagtgcgag gagctggagg aaaagaatat caaggagttc 1260
ctgcagagct tcgtccacat cgtgcagatg tttatcaaca catctggagg tggcggatca 1320
ggaggtggtg gaagcggtgg aggaggtagt ggaggaggcg gaagtggcgg aggaggaagt 1380
gaaagtaagt acggcccacc ttgtcctccc tgtccagctc cagagttcct gggaggcccc 1440
agtgtgttcc ttttcccacc gaagccaaag gacacactca tgatatctag gacacccgag 1500
gtgacctgtg tcgtagttga cgtctcccaa gaggacccag aagtacaatt taactggtat 1560
gtagacggag tggaagtcca taacgccaag accaaaccaa gagaggaaca gtttaattct 1620
acgtaccgcg ttgtgagcgt gttgacagtc ctgcatcagg actggctcaa cggcaaggag 1680
tacaaatgca aggttagcaa taaaggactg ccatcatcca ttgaaaaaac catctctaag 1740
gccaagggac agcctaggga acctcaggtt tacacactcc ccccctctca agaggaaatg 1800
actaagaacc aagtgagcct tacttgcctt gtaaagggct tttacccatc cgacatcgct 1860
gttgagtggg agagcaacgg ccagcccgaa aacaactata agaccactcc tcctgtgttg 1920
gactctgatg gttccttttt tctggccagc aggctgaccg tagataagag ccggtggcag 1980
gaaggaaacg tgttttcttg ctctgtaatg catgaggcac ttcataatca ctatactcag 2040
aagagtctgt cactgtcttt gggtaag 2067
<210> 18
<211> 2115
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 18
caagtccagc tgcaacaaag cggtgctgag ctggttaaac ctggagcttc agttaagctc 60
agttgtaagg ccagcgggta caccttcact aactatgata ttaattgggt gaggcagagg 120
ccagaacagg ggctggaatg gattggttgg atcttccccg gagacgggtc aacccagtat 180
aacgagaagt ttaagggaaa agccaccctg accacagata cctcctcttc cacagcttat 240
atgcagctgt caagattgac tagcgaggat tctgccgtgt atttttgcgc ccgccagacc 300
actgccacct ggtttgctta ttggggacaa gggacattgg taacagtttc cgcagcctcc 360
accaagggcc cttcagtgtt tccattggct cccagctcta agtcaaccag tgggggcact 420
gccgctttgg gttgtctggt caaagattat ttccccgaac ccgtgactgt gagctggaac 480
agtggcgcac tcacttcagg agttcacacc tttcccgcag ttcttcaaag ttccggcctc 540
tatagtcttt ctagcgtcgt tacagtgccc agcagttctc tggggactca gacctatatc 600
tgtaacgtca atcacaaacc cagcaacact aaagttgata agagggttga agtgcagctg 660
gttgagtctg gaggaggcct ggtgcagcca ggaaggagtc tcagattgtc ctgtgctgcc 720
agtggcttca cattcgatga ttacaccatg cactgggtga ggcaggctcc tggaaaagga 780
cttgagtggg tgtctggtat cagttggaat tccggctcca ttggatacgc agattcagtg 840
aagggtcggt tcacaatctc cagggataac gctaagaagt cactgtactt gcagatgaat 900
tcactgagag ctgaggacac agccctgtat tattgtgcca aagataacag cggatacggg 960
cactattact atgggatgga cgtgtggggc cagggaacaa ctgtcacggt ggcttctgga 1020
ggtggagggt ctggtggtgg aggcagtgga ggaggtgggt ctgagatcgt gatgactcag 1080
agccccgcca ccttgagtgt gtcaccaggc gaaagagcaa ccctctcatg cagggccagc 1140
cagtcagtgt cctccaacct cgcttggtac cagcagaaac ctggtcaagc cccccgcctc 1200
ctgatatacg gagcaagcac cagagccact ggaatccctg ctaggttctc tggaagcggc 1260
tccggcacag agtttaccct gacgatctcc tctctccagt ccgaggattt cgccgtctac 1320
tactgccagc actacattaa ttggcccctc acctttggag gcggtactaa ggttgaaatc 1380
aaaggtggag gtggatctgg tggaggagga tctggggggg gaggatcaga gagcaaatat 1440
ggacctccat gtccaccctg tcccgctcct gagttcctgg gtggtccatc agtcttcttg 1500
tttcccccaa agcctaaaga caccttgatg atttcccgga cgccagaggt tacgtgcgta 1560
gttgtagacg tttcccaaga ggaccccgag gtgcagttta actggtacgt cgacggggtc 1620
gaagtgcaca acgctaagac taaacctcgg gaggaacagt tcaattccac gtaccgggtg 1680
gtgtctgtcc ttaccgtcct tcatcaggat tggctgaacg gtaaagaata taagtgcaaa 1740
gtgtctaata aggggctccc tagctctata gagaagacaa tctccaaagc taagggccag 1800
cctagggagc cgcaggttta tactctgcct ccatctcagg aagagatgac caagaatcag 1860
gtctccttgt ggtgtctggt caagggcttc tacccaagcg atatcgctgt ggagtgggaa 1920
agcaacggcc aaccagagaa caactataag acaacgccac ccgtgctcga tagtgacggt 1980
agctttttcc tgtattcacg gcttaccgtg gacaagagcc ggtggcaaga gggcaatgtg 2040
tttagttgct ctgtcatgca cgaagccttg cacaaccact acacacaaaa gtcactgtct 2100
ttgagcctgg gtaag 2115
<210> 19
<211> 642
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 19
gatattgtca tgactcagag ccccgccaca ttgtccgtga ctcctggaga tcgagtctct 60
ttgtcctgcc gggccagcca gtccattagc gattatctcc attggtacca gcagaagagt 120
cacgagagtc caagattgct cattaagtac gctagtcaga gtattagtgg aattcccagt 180
agattttccg gtagcggatc cggcagtgat ttcactctgt ctatcaacag cgttgagcca 240
gaggacgtcg gcgtgtatta ctgccagaat gggcatagct ttcccctgac ttttggggct 300
ggaacaaagc tggaactgaa aagaactgtg gctgccccct ctgtcttcat cttccccccc 360
agcgatgagc agctgaagag tggaactgcc agcgtagtgt gtctgctgaa caatttttac 420
cccagggagg ctaaggtcca gtggaaagtc gataatgctc tgcaatctgg aaacagtcag 480
gaaagtgtaa ctgagcagga ctctaaagac tccacatatt cactgtcatc caccctcacc 540
ctctctaagg ccgactatga aaaacacaag gtgtacgcct gcgaagtaac acaccaagga 600
ctgtcttccc ctgtcacaaa gagctttaac cggggggaat gc 642
<210> 20
<211> 448
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 20
Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Asp Ile Asn Trp Val Arg Gln Arg Pro Glu Gln Gly Leu Glu Trp Ile
35 40 45
Gly Trp Ile Phe Pro Gly Asp Gly Ser Thr Gln Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Thr Asp Thr Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Gln Leu Ser Arg Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys
85 90 95
Ala Arg Gln Thr Thr Ala Thr Trp Phe Ala Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ala Ala Ser Thr Lys Gly Pro Ser Val Phe Pro
115 120 125
Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly
130 135 140
Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn
145 150 155 160
Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln
165 170 175
Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser
180 185 190
Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser
195 200 205
Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr
210 215 220
His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser
225 230 235 240
Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
245 250 255
Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro
260 265 270
Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
275 280 285
Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val
290 295 300
Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
305 310 315 320
Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr
325 330 335
Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
340 345 350
Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys
355 360 365
Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
370 375 380
Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
385 390 395 400
Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser
405 410 415
Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
420 425 430
Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
435 440 445
<210> 21
<211> 448
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 21
Gln Val Gln Leu Gln Gln Pro Gly Ala Glu Leu Val Arg Pro Gly Ala
1 5 10 15
Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Trp Ile Asn Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Asn Ile Tyr Pro Ser Asp Ser Tyr Thr Asn Tyr Asn Gln Lys Phe
50 55 60
Lys Asp Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Gln Leu Ser Ser Pro Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Thr Arg Ser Trp Arg Gly Asn Ser Phe Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Thr Leu Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro
115 120 125
Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly
130 135 140
Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn
145 150 155 160
Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln
165 170 175
Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser
180 185 190
Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser
195 200 205
Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr
210 215 220
His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser
225 230 235 240
Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
245 250 255
Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro
260 265 270
Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
275 280 285
Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val
290 295 300
Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
305 310 315 320
Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr
325 330 335
Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
340 345 350
Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys
355 360 365
Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
370 375 380
Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
385 390 395 400
Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser
405 410 415
Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
420 425 430
Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
435 440 445
<210> 22
<211> 220
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 22
Asp Ile Val Met Thr Gln Ser Pro Ser Ser Leu Thr Val Thr Ala Gly
1 5 10 15
Glu Lys Val Thr Met Ser Cys Lys Ser Ser Gln Ser Leu Leu Asn Ser
20 25 30
Gly Asn Gln Lys Asn Tyr Leu Thr Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val
50 55 60
Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Val Gln Ala Glu Asp Leu Ala Val Tyr Tyr Cys Gln Asn
85 90 95
Asp Tyr Ser Tyr Pro Phe Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile
100 105 110
Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp
115 120 125
Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn
130 135 140
Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu
145 150 155 160
Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp
165 170 175
Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr
180 185 190
Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser
195 200 205
Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215 220
Claims (10)
1.一种多功能融合蛋白,其特征在于,其包含第一重链、第二重链和第一轻链、第二轻链,所述第一重链包含特异性结合靶标的VH和CH1,细胞因子和其受体,以及免疫球蛋白Fc部分;所述第二重链包含特异性结合靶标的VH和CH1,特异性结合靶标的scFv或Fab,以及免疫球蛋白Fc部分;第一轻链与第一重链,第二轻链与第二重链分别特异性配对。
2.如权利要求1所述的多功能融合蛋白,其中所述第一重链和第二重链包含的VH和CH1可以特异性结合TAA抗原,所述TAA抗原为Claudin18.2、CA125、AFP、CEA、EGFR、HER2、B7H3、B7H6、MUC1、MUC16、GPC3、CD24其中的一种或几种,优选的,所述TAA抗原为Claudin18.2或B7H3。
3.如权利要求1-2任一所述的多功能融合蛋白,其中所述第一重链包含的细胞因子和其受体分别为IL-15和IL-15受体。
4.如权利要求1-3任一所述的多功能融合蛋白,其中所述第二重链包含的scFv或Fab可以特异性激活T细胞、NK细胞和巨噬细胞,优选的,所述第二重链包含的scFv或Fab特异性靶向CD3。
5.如权利要求1-4任一所述的多功能融合蛋白,其中所述第一重链和第二重链的免疫球蛋白Fc部分选自IgG1、IgG2、IgG3、IgG4的恒定区氨基酸序列,优选选自IgG1或IgG4的恒定区氨基酸序列。
6.如权利要求1-5任一所述的多功能融合蛋白,其中所述第一重链和第二重链的Fc部分还包含一个或多个选自由以下组成的组的氨基酸替换:S228P、L234F、L235E、P331S、D356K、T366W、K392D、D399K、Y407A、和K409D,优选S228P、T366W和/或Y407A。
7.如权利要求3所述的多功能融合蛋白,其中所述第一重链中的IL-15与其受体和第二重链中的scFv或Fab可以分别嵌合于所述第一重链和所述第二重链的Fc部分内部,也可以存在于Fc部分外部,优选位于所述相应重链的CH1和CH2功能区之间。
8.如权利要求3所述的多功能融合蛋白,其中所述第一重链中的IL-15与其受体、第二重链中的scFv或Fab单独或与额外的连接肽一起共价结合于所述链中;所述连接肽包含甘氨酸(G)和丝氨酸(S)残基,优选包含GGGGS重复,更优选包含1-2个GGGGS重复。
9.如权利要求3所述的多功能融合蛋白,其中所述IL-15选自天然的IL-15或其变体,所述变体包含选自N1D、N4D、D30N、E64Q、N65D、N72D、N79A、Q108E和N112A的组的一个或多个氨基酸突变,优选包含选自N4D、N65D、N72D、N79A和N112A的组的一个或多个氨基酸突变;所述IL-15受体选自IL-15Rα或其变体。
10.如权利要求1-9任一所述的多功能融合蛋白,其中所述第一重链氨基酸序列选自SEQ ID NO:1;所述多功能融合蛋白的第二重链氨基酸序列选自SEQ ID NO:2;所述多功能融合蛋白的第一轻链和第二轻链的氨基酸序列选自SEQ ID NO:3。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
PCT/CN2021/114408 WO2022042576A1 (zh) | 2020-08-27 | 2021-08-25 | 一种多功能融合蛋白及其用途 |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202010876525 | 2020-08-27 | ||
CN2020108765257 | 2020-08-27 |
Publications (1)
Publication Number | Publication Date |
---|---|
CN114106195A true CN114106195A (zh) | 2022-03-01 |
Family
ID=80440904
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202110971791.2A Pending CN114106195A (zh) | 2020-08-27 | 2021-08-24 | 一种多功能融合蛋白及其用途 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN114106195A (zh) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN114805473A (zh) * | 2022-04-21 | 2022-07-29 | 盛禾(中国)生物制药有限公司 | 一种纯化非对称融合蛋白的方法 |
WO2022253248A1 (zh) * | 2021-06-02 | 2022-12-08 | 启愈生物技术(上海)有限公司 | 抗cd3抗体变异体、融合蛋白及应用 |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN107207610A (zh) * | 2014-11-26 | 2017-09-26 | 森科股份有限公司 | 结合cd3和肿瘤抗原的异二聚体抗体 |
CN109496217A (zh) * | 2016-05-27 | 2019-03-19 | 阿尔托生物科学有限公司 | 具有cd3结合域的基于多聚体il-15的分子的构造和表征 |
CN110023336A (zh) * | 2016-09-23 | 2019-07-16 | 生物技术公司 | 用于治疗表达密蛋白之癌症疾病的与密蛋白6或密蛋白18.2和cd3结合的双特异性三价抗体 |
WO2019204665A1 (en) * | 2018-04-18 | 2019-10-24 | Xencor, Inc. | Pd-1 targeted heterodimeric fusion proteins containing il-15/il-15ra fc-fusion proteins and pd-1 antigen binding domains and uses thereof |
CN111132733A (zh) * | 2017-06-30 | 2020-05-08 | Xencor股份有限公司 | 含有IL-15/IL-15Rα和抗原结合结构域的靶向异源二聚体Fc融合蛋白 |
-
2021
- 2021-08-24 CN CN202110971791.2A patent/CN114106195A/zh active Pending
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN107207610A (zh) * | 2014-11-26 | 2017-09-26 | 森科股份有限公司 | 结合cd3和肿瘤抗原的异二聚体抗体 |
CN109496217A (zh) * | 2016-05-27 | 2019-03-19 | 阿尔托生物科学有限公司 | 具有cd3结合域的基于多聚体il-15的分子的构造和表征 |
CN110023336A (zh) * | 2016-09-23 | 2019-07-16 | 生物技术公司 | 用于治疗表达密蛋白之癌症疾病的与密蛋白6或密蛋白18.2和cd3结合的双特异性三价抗体 |
CN111132733A (zh) * | 2017-06-30 | 2020-05-08 | Xencor股份有限公司 | 含有IL-15/IL-15Rα和抗原结合结构域的靶向异源二聚体Fc融合蛋白 |
WO2019204665A1 (en) * | 2018-04-18 | 2019-10-24 | Xencor, Inc. | Pd-1 targeted heterodimeric fusion proteins containing il-15/il-15ra fc-fusion proteins and pd-1 antigen binding domains and uses thereof |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2022253248A1 (zh) * | 2021-06-02 | 2022-12-08 | 启愈生物技术(上海)有限公司 | 抗cd3抗体变异体、融合蛋白及应用 |
CN114805473A (zh) * | 2022-04-21 | 2022-07-29 | 盛禾(中国)生物制药有限公司 | 一种纯化非对称融合蛋白的方法 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP6783886B2 (ja) | 抗ctla4モノクローナル抗体またはその抗原結合断片、医薬組成物および使用 | |
US11060097B2 (en) | Immunotherapy methods using anti-PD-L1 antibodies in combination with EGFR1 targeted-TGF-beta immunomodulatory fusion proteins | |
CN107151269B (zh) | 一种pdl-1抗体、其药物组合物及其用途 | |
EP2970512B1 (en) | Fusion immunomodulatory proteins and methods for making same | |
JP2023082067A (ja) | 改良された抗原結合受容体 | |
TW201806972A (zh) | 雙特異性結合蛋白 | |
CN116041516A (zh) | 全人源的抗b细胞成熟抗原(bcma)单链抗体及其应用 | |
KR20210010862A (ko) | IL-15/IL-15Rα Fc-융합 단백질 및 PD-1 항원 결합 도메인을 함유하는 PD-1 표적화 이종이량체 융합 단백질 및 이의 용도 | |
EP3805264A1 (en) | Anti-interleukin-17a antibody, pharmaceutical composition thereof and use thereof | |
JP2022513383A (ja) | 二重特異性抗体及びその作製方法と使用 | |
CN114106195A (zh) | 一种多功能融合蛋白及其用途 | |
KR20230024252A (ko) | 차폐된 il12 융합 단백질 및 이의 사용 방법 | |
KR20080039843A (ko) | 만성 림프구성 백혈병의 치료를 위한 cd52 에 대한모노클로날 항체의 제조를 위한 재조합 방법 | |
KR20210076918A (ko) | 4-1bb 및 종양-관련 항원에 결합하는 항체 작제물 및 이의 용도 | |
KR101963230B1 (ko) | 복수개의 단일 항체를 포함하는 단백질 복합체 | |
KR20240046224A (ko) | 이중특이성 항체 및 그 용도 | |
WO2022042576A1 (zh) | 一种多功能融合蛋白及其用途 | |
CN111201242A (zh) | 不对称异二聚fc-scfv融合抗globo h及抗cd3双特异性抗体及其在癌症治疗上的用途 | |
CN112409484B (zh) | 多功能抗体、其制备及其用途 | |
CN115716875A (zh) | 一种多功能融合蛋白及其用途 | |
WO2024051223A1 (zh) | 药物组合及用途 | |
EP4357367A1 (en) | Pharmaceutical composition and use thereof | |
CN113004416B (zh) | 靶向her2-cd137双特异性抗体的构建及其应用 | |
WO2023045977A1 (zh) | 白介素2突变体以及其融合蛋白 | |
CN115246885A (zh) | 一种双特异性抗体及其应用 |
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 |