CN115551890A - 用于产生武装免疫细胞的双特异性抗体 - Google Patents
用于产生武装免疫细胞的双特异性抗体 Download PDFInfo
- Publication number
- CN115551890A CN115551890A CN202180029464.3A CN202180029464A CN115551890A CN 115551890 A CN115551890 A CN 115551890A CN 202180029464 A CN202180029464 A CN 202180029464A CN 115551890 A CN115551890 A CN 115551890A
- Authority
- CN
- China
- Prior art keywords
- ser
- thr
- gly
- val
- 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
- 210000002865 immune cell Anatomy 0.000 title claims abstract description 118
- 238000004519 manufacturing process Methods 0.000 title claims description 10
- 230000027455 binding Effects 0.000 claims abstract description 259
- 238000009739 binding Methods 0.000 claims abstract description 237
- 239000000427 antigen Substances 0.000 claims abstract description 80
- 108091007433 antigens Proteins 0.000 claims abstract description 80
- 102000036639 antigens Human genes 0.000 claims abstract description 80
- 238000000034 method Methods 0.000 claims abstract description 79
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 78
- 201000011510 cancer Diseases 0.000 claims abstract description 55
- 108010047041 Complementarity Determining Regions Proteins 0.000 claims description 206
- 210000004027 cell Anatomy 0.000 claims description 193
- 210000001744 T-lymphocyte Anatomy 0.000 claims description 186
- 150000001413 amino acids Chemical class 0.000 claims description 136
- 241000282414 Homo sapiens Species 0.000 claims description 67
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 59
- 239000012634 fragment Substances 0.000 claims description 52
- 210000003819 peripheral blood mononuclear cell Anatomy 0.000 claims description 31
- 102100024222 B-lymphocyte antigen CD19 Human genes 0.000 claims description 26
- 101000980825 Homo sapiens B-lymphocyte antigen CD19 Proteins 0.000 claims description 26
- 229920001184 polypeptide Polymers 0.000 claims description 24
- 102000004196 processed proteins & peptides Human genes 0.000 claims description 24
- 125000003275 alpha amino acid group Chemical group 0.000 claims description 23
- 150000007523 nucleic acids Chemical class 0.000 claims description 22
- 108020004707 nucleic acids Proteins 0.000 claims description 21
- 102000039446 nucleic acids Human genes 0.000 claims description 21
- 108010054477 Immunoglobulin Fab Fragments Proteins 0.000 claims description 19
- 102000001706 Immunoglobulin Fab Fragments Human genes 0.000 claims description 19
- 206010009944 Colon cancer Diseases 0.000 claims description 18
- 102000052116 epidermal growth factor receptor activity proteins Human genes 0.000 claims description 18
- 108700015053 epidermal growth factor receptor activity proteins Proteins 0.000 claims description 18
- 230000014509 gene expression Effects 0.000 claims description 18
- 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 18
- 210000000581 natural killer T-cell Anatomy 0.000 claims description 17
- 102100023832 Prolyl endopeptidase FAP Human genes 0.000 claims description 16
- 239000013604 expression vector Substances 0.000 claims description 16
- 239000013598 vector Substances 0.000 claims description 16
- 206010006187 Breast cancer Diseases 0.000 claims description 15
- 208000026310 Breast neoplasm Diseases 0.000 claims description 15
- 208000029742 colonic neoplasm Diseases 0.000 claims description 14
- 102100041003 Glutamate carboxypeptidase 2 Human genes 0.000 claims description 13
- 101000892862 Homo sapiens Glutamate carboxypeptidase 2 Proteins 0.000 claims description 13
- 206010060862 Prostate cancer Diseases 0.000 claims description 13
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 13
- 102100031585 ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase 1 Human genes 0.000 claims description 11
- 101000777636 Homo sapiens ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase 1 Proteins 0.000 claims description 11
- 101000868279 Homo sapiens Leukocyte surface antigen CD47 Proteins 0.000 claims description 11
- 101000934338 Homo sapiens Myeloid cell surface antigen CD33 Proteins 0.000 claims description 11
- 101001012157 Homo sapiens Receptor tyrosine-protein kinase erbB-2 Proteins 0.000 claims description 11
- 102100032913 Leukocyte surface antigen CD47 Human genes 0.000 claims description 11
- 102100025243 Myeloid cell surface antigen CD33 Human genes 0.000 claims description 11
- 102100024216 Programmed cell death 1 ligand 1 Human genes 0.000 claims description 11
- 102100030086 Receptor tyrosine-protein kinase erbB-2 Human genes 0.000 claims description 11
- 238000000338 in vitro Methods 0.000 claims description 11
- 238000012258 culturing Methods 0.000 claims description 9
- 101000610604 Homo sapiens Tumor necrosis factor receptor superfamily member 10B Proteins 0.000 claims description 8
- 108010002350 Interleukin-2 Proteins 0.000 claims description 8
- 102000000588 Interleukin-2 Human genes 0.000 claims description 8
- 210000004962 mammalian cell Anatomy 0.000 claims description 8
- 210000000130 stem cell Anatomy 0.000 claims description 8
- 102000003735 Mesothelin Human genes 0.000 claims description 7
- 108090000015 Mesothelin Proteins 0.000 claims description 7
- 102100040112 Tumor necrosis factor receptor superfamily member 10B Human genes 0.000 claims description 7
- 210000003719 b-lymphocyte Anatomy 0.000 claims description 7
- 108010002586 Interleukin-7 Proteins 0.000 claims description 6
- 210000004263 induced pluripotent stem cell Anatomy 0.000 claims description 6
- 229940100994 interleukin-7 Drugs 0.000 claims description 6
- 102100022005 B-lymphocyte antigen CD20 Human genes 0.000 claims description 5
- 101000897405 Homo sapiens B-lymphocyte antigen CD20 Proteins 0.000 claims description 5
- 206010035226 Plasma cell myeloma Diseases 0.000 claims description 5
- 210000002540 macrophage Anatomy 0.000 claims description 5
- 210000001616 monocyte Anatomy 0.000 claims description 5
- 208000002154 non-small cell lung carcinoma Diseases 0.000 claims description 5
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 claims description 5
- 108010074708 B7-H1 Antigen Proteins 0.000 claims description 4
- 206010005003 Bladder cancer Diseases 0.000 claims description 4
- 208000001333 Colorectal Neoplasms Diseases 0.000 claims description 4
- 101150084967 EPCAM gene Proteins 0.000 claims description 4
- 206010025323 Lymphomas Diseases 0.000 claims description 4
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims description 4
- 208000015634 Rectal Neoplasms Diseases 0.000 claims description 4
- 206010041067 Small cell lung cancer Diseases 0.000 claims description 4
- 208000005718 Stomach Neoplasms Diseases 0.000 claims description 4
- 208000024313 Testicular Neoplasms Diseases 0.000 claims description 4
- 206010057644 Testis cancer Diseases 0.000 claims description 4
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 claims description 4
- 210000004700 fetal blood Anatomy 0.000 claims description 4
- 206010017758 gastric cancer Diseases 0.000 claims description 4
- 210000003958 hematopoietic stem cell Anatomy 0.000 claims description 4
- 208000032839 leukemia Diseases 0.000 claims description 4
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims description 4
- 201000000050 myeloid neoplasm Diseases 0.000 claims description 4
- 201000002528 pancreatic cancer Diseases 0.000 claims description 4
- 208000008443 pancreatic carcinoma Diseases 0.000 claims description 4
- 206010038038 rectal cancer Diseases 0.000 claims description 4
- 201000001275 rectum cancer Diseases 0.000 claims description 4
- 210000003289 regulatory T cell Anatomy 0.000 claims description 4
- 208000000587 small cell lung carcinoma Diseases 0.000 claims description 4
- 201000011549 stomach cancer Diseases 0.000 claims description 4
- 201000003120 testicular cancer Diseases 0.000 claims description 4
- 201000005112 urinary bladder cancer Diseases 0.000 claims description 4
- 208000003174 Brain Neoplasms Diseases 0.000 claims description 3
- 102000004127 Cytokines Human genes 0.000 claims description 3
- 108090000695 Cytokines Proteins 0.000 claims description 3
- 208000000461 Esophageal Neoplasms Diseases 0.000 claims description 3
- 101710088083 Glomulin Proteins 0.000 claims description 3
- 208000008839 Kidney Neoplasms Diseases 0.000 claims description 3
- 206010030155 Oesophageal carcinoma Diseases 0.000 claims description 3
- 206010033128 Ovarian cancer Diseases 0.000 claims description 3
- 206010061535 Ovarian neoplasm Diseases 0.000 claims description 3
- 206010038389 Renal cancer Diseases 0.000 claims description 3
- 208000000102 Squamous Cell Carcinoma of Head and Neck Diseases 0.000 claims description 3
- 208000024770 Thyroid neoplasm Diseases 0.000 claims description 3
- 102000004887 Transforming Growth Factor beta Human genes 0.000 claims description 3
- 108090001012 Transforming Growth Factor beta Proteins 0.000 claims description 3
- 230000000735 allogeneic effect Effects 0.000 claims description 3
- -1 cMET Proteins 0.000 claims description 3
- 201000004101 esophageal cancer Diseases 0.000 claims description 3
- 201000000459 head and neck squamous cell carcinoma Diseases 0.000 claims description 3
- 206010073071 hepatocellular carcinoma Diseases 0.000 claims description 3
- 201000010982 kidney cancer Diseases 0.000 claims description 3
- 208000014018 liver neoplasm Diseases 0.000 claims description 3
- 201000001441 melanoma Diseases 0.000 claims description 3
- ZRKFYGHZFMAOKI-QMGMOQQFSA-N tgfbeta Chemical compound C([C@H](NC(=O)[C@H](C(C)C)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CC(C)C)NC(=O)CNC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CCSC)C(C)C)[C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O)C1=CC=C(O)C=C1 ZRKFYGHZFMAOKI-QMGMOQQFSA-N 0.000 claims description 3
- 201000002510 thyroid cancer Diseases 0.000 claims description 3
- 230000001580 bacterial effect Effects 0.000 claims description 2
- 230000003993 interaction Effects 0.000 claims description 2
- 210000005253 yeast cell Anatomy 0.000 claims description 2
- 102000000704 Interleukin-7 Human genes 0.000 claims 2
- 101000914324 Homo sapiens Carcinoembryonic antigen-related cell adhesion molecule 5 Proteins 0.000 claims 1
- 101000914321 Homo sapiens Carcinoembryonic antigen-related cell adhesion molecule 7 Proteins 0.000 claims 1
- 101000617725 Homo sapiens Pregnancy-specific beta-1-glycoprotein 2 Proteins 0.000 claims 1
- 102100022019 Pregnancy-specific beta-1-glycoprotein 2 Human genes 0.000 claims 1
- 229920001481 poly(stearyl methacrylate) Polymers 0.000 claims 1
- 238000011282 treatment Methods 0.000 abstract description 18
- 230000001225 therapeutic effect Effects 0.000 abstract description 7
- 230000015572 biosynthetic process Effects 0.000 description 153
- 238000003786 synthesis reaction Methods 0.000 description 145
- XKUKSGPZAADMRA-UHFFFAOYSA-N glycyl-glycyl-glycine Chemical compound NCC(=O)NCC(=O)NCC(O)=O XKUKSGPZAADMRA-UHFFFAOYSA-N 0.000 description 87
- 102000017420 CD3 protein, epsilon/gamma/delta subunit Human genes 0.000 description 59
- 108050005493 CD3 protein, epsilon/gamma/delta subunit Proteins 0.000 description 59
- 241000880493 Leptailurus serval Species 0.000 description 50
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 48
- 108010067216 glycyl-glycyl-glycine Proteins 0.000 description 46
- 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 38
- YMTLKLXDFCSCNX-BYPYZUCNSA-N Ser-Gly-Gly Chemical compound OC[C@H](N)C(=O)NCC(=O)NCC(O)=O YMTLKLXDFCSCNX-BYPYZUCNSA-N 0.000 description 37
- 108010086434 alanyl-seryl-glycine Proteins 0.000 description 34
- 201000010099 disease Diseases 0.000 description 34
- 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 31
- 108010050848 glycylleucine Proteins 0.000 description 31
- 108010073969 valyllysine Proteins 0.000 description 29
- 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 26
- VPZXBVLAVMBEQI-UHFFFAOYSA-N glycyl-DL-alpha-alanine Natural products OC(=O)C(C)NC(=O)CN VPZXBVLAVMBEQI-UHFFFAOYSA-N 0.000 description 26
- ARHJJAAWNWOACN-FXQIFTODSA-N Ala-Ser-Val Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(O)=O ARHJJAAWNWOACN-FXQIFTODSA-N 0.000 description 25
- 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 25
- 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 25
- 108010068265 aspartyltyrosine Proteins 0.000 description 25
- 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 24
- 108090000623 proteins and genes Proteins 0.000 description 24
- 208000003950 B-cell lymphoma Diseases 0.000 description 23
- 108010079364 N-glycylalanine Proteins 0.000 description 22
- MNYNCKZAEIAONY-XGEHTFHBSA-N Thr-Val-Ser Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CO)C(O)=O MNYNCKZAEIAONY-XGEHTFHBSA-N 0.000 description 22
- HTONZBWRYUKUKC-RCWTZXSCSA-N Val-Thr-Val Chemical compound CC(C)[C@H](N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(O)=O HTONZBWRYUKUKC-RCWTZXSCSA-N 0.000 description 22
- 108010089804 glycyl-threonine Proteins 0.000 description 22
- QNFRBNZGVVKBNJ-PEFMBERDSA-N Asp-Ile-Gln Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)O)NC(=O)[C@H](CC(=O)O)N QNFRBNZGVVKBNJ-PEFMBERDSA-N 0.000 description 21
- MNQMTYSEKZHIDF-GCJQMDKQSA-N Asp-Thr-Ala Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C)C(O)=O MNQMTYSEKZHIDF-GCJQMDKQSA-N 0.000 description 21
- SOEGEPHNZOISMT-BYPYZUCNSA-N Gly-Ser-Gly Chemical compound NCC(=O)N[C@@H](CO)C(=O)NCC(O)=O SOEGEPHNZOISMT-BYPYZUCNSA-N 0.000 description 21
- 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 21
- SVGAWGVHFIYAEE-JSGCOSHPSA-N Trp-Gly-Gln Chemical compound C1=CC=C2C(C[C@H](N)C(=O)NCC(=O)N[C@@H](CCC(N)=O)C(O)=O)=CNC2=C1 SVGAWGVHFIYAEE-JSGCOSHPSA-N 0.000 description 21
- 108010092854 aspartyllysine Proteins 0.000 description 21
- 108010078144 glutaminyl-glycine Proteins 0.000 description 21
- 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 20
- 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 20
- YOPQYBJJNSIQGZ-JNPHEJMOSA-N Thr-Tyr-Tyr Chemical compound C([C@H](NC(=O)[C@@H](N)[C@H](O)C)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(O)=O)C1=CC=C(O)C=C1 YOPQYBJJNSIQGZ-JNPHEJMOSA-N 0.000 description 20
- 108010063718 gamma-glutamylaspartic acid Proteins 0.000 description 20
- 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 19
- 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 19
- 238000000684 flow cytometry Methods 0.000 description 19
- 108010003137 tyrosyltyrosine Proteins 0.000 description 19
- 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 18
- MIIVFRCYJABHTQ-ONGXEEELSA-N Gly-Leu-Val Chemical compound [H]NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(O)=O MIIVFRCYJABHTQ-ONGXEEELSA-N 0.000 description 18
- PDUHNKAFQXQNLH-ZETCQYMHSA-N Gly-Lys-Gly Chemical compound NCCCC[C@H](NC(=O)CN)C(=O)NCC(O)=O PDUHNKAFQXQNLH-ZETCQYMHSA-N 0.000 description 18
- CQGSYZCULZMEDE-UHFFFAOYSA-N Leu-Gln-Pro Natural products CC(C)CC(N)C(=O)NC(CCC(N)=O)C(=O)N1CCCC1C(O)=O CQGSYZCULZMEDE-UHFFFAOYSA-N 0.000 description 18
- XXXAXOWMBOKTRN-XPUUQOCRSA-N Ser-Gly-Val Chemical compound [H]N[C@@H](CO)C(=O)NCC(=O)N[C@@H](C(C)C)C(O)=O XXXAXOWMBOKTRN-XPUUQOCRSA-N 0.000 description 18
- 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 17
- 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 17
- 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 17
- 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 17
- 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 17
- 102000004169 proteins and genes Human genes 0.000 description 17
- 108010044292 tryptophyltyrosine Proteins 0.000 description 17
- 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 16
- 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 16
- 230000000259 anti-tumor effect Effects 0.000 description 16
- 108010008355 arginyl-glutamine Proteins 0.000 description 16
- 108010044374 isoleucyl-tyrosine Proteins 0.000 description 16
- 108010070409 phenylalanyl-glycyl-glycine Proteins 0.000 description 16
- 108010051242 phenylalanylserine Proteins 0.000 description 16
- 108010065920 Insulin Lispro Proteins 0.000 description 15
- XQJCEKXQUJQNNK-ZLUOBGJFSA-N Ser-Ser-Ser Chemical compound OC[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(O)=O XQJCEKXQUJQNNK-ZLUOBGJFSA-N 0.000 description 15
- 108010087924 alanylproline Proteins 0.000 description 15
- 108010037850 glycylvaline Proteins 0.000 description 15
- 108010017391 lysylvaline Proteins 0.000 description 15
- OYTPNWYZORARHL-XHNCKOQMSA-N Gln-Ala-Pro Chemical compound C[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](CCC(=O)N)N OYTPNWYZORARHL-XHNCKOQMSA-N 0.000 description 14
- FQCILXROGNOZON-YUMQZZPRSA-N Gln-Pro-Gly Chemical compound NC(=O)CC[C@H](N)C(=O)N1CCC[C@H]1C(=O)NCC(O)=O FQCILXROGNOZON-YUMQZZPRSA-N 0.000 description 14
- 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 14
- 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 14
- GXUWHVZYDAHFSV-FLBSBUHZSA-N Thr-Ile-Thr Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(O)=O GXUWHVZYDAHFSV-FLBSBUHZSA-N 0.000 description 14
- 108010069020 alanyl-prolyl-glycine Proteins 0.000 description 14
- 125000000539 amino acid group Chemical group 0.000 description 14
- 108010069205 aspartyl-phenylalanine Proteins 0.000 description 14
- 238000004113 cell culture Methods 0.000 description 14
- 208000035475 disorder Diseases 0.000 description 14
- 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 13
- 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 13
- 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 13
- 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 13
- 108010001064 glycyl-glycyl-glycyl-glycine Proteins 0.000 description 13
- 108010070643 prolylglutamic acid Proteins 0.000 description 13
- 210000004881 tumor cell Anatomy 0.000 description 13
- CREYEAPXISDKSB-FQPOAREZSA-N Ala-Thr-Tyr Chemical compound [H]N[C@@H](C)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O CREYEAPXISDKSB-FQPOAREZSA-N 0.000 description 12
- 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 12
- 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 12
- 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 12
- 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 12
- MVJRBCJCRYGCKV-GVXVVHGQSA-N Leu-Val-Gln Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(N)=O)C(O)=O MVJRBCJCRYGCKV-GVXVVHGQSA-N 0.000 description 12
- 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 12
- YQHZVYJAGWMHES-ZLUOBGJFSA-N Ser-Ala-Ser Chemical compound OC[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](CO)C(O)=O YQHZVYJAGWMHES-ZLUOBGJFSA-N 0.000 description 12
- SFTZWNJFZYOLBD-ZDLURKLDSA-N Ser-Gly-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)CNC(=O)[C@@H](N)CO SFTZWNJFZYOLBD-ZDLURKLDSA-N 0.000 description 12
- 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 12
- 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 12
- 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 12
- 108010081404 acein-2 Proteins 0.000 description 12
- 108010008685 alanyl-glutamyl-aspartic acid Proteins 0.000 description 12
- 108010034529 leucyl-lysine Proteins 0.000 description 12
- 108010024654 phenylalanyl-prolyl-alanine Proteins 0.000 description 12
- 108010026333 seryl-proline Proteins 0.000 description 12
- 108010072986 threonyl-seryl-lysine Proteins 0.000 description 12
- 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 11
- BPHKULHWEIUDOB-FXQIFTODSA-N Cys-Gln-Gln Chemical compound SC[C@H](N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(O)=O BPHKULHWEIUDOB-FXQIFTODSA-N 0.000 description 11
- JXFLPKSDLDEOQK-JHEQGTHGSA-N Gln-Gly-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)CNC(=O)[C@@H](N)CCC(N)=O JXFLPKSDLDEOQK-JHEQGTHGSA-N 0.000 description 11
- 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 11
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 11
- 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 11
- 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 11
- LCNASHSOFMRYFO-WDCWCFNPSA-N Leu-Thr-Gln Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@H](C(O)=O)CCC(N)=O LCNASHSOFMRYFO-WDCWCFNPSA-N 0.000 description 11
- MYZMQWHPDAYKIE-SRVKXCTJSA-N Lys-Leu-Ala Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C)C(O)=O MYZMQWHPDAYKIE-SRVKXCTJSA-N 0.000 description 11
- 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 11
- GJFYFGOEWLDQGW-GUBZILKMSA-N Ser-Leu-Gln Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)O)NC(=O)[C@H](CO)N GJFYFGOEWLDQGW-GUBZILKMSA-N 0.000 description 11
- 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 11
- 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 11
- 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 11
- 108010040443 aspartyl-aspartic acid Proteins 0.000 description 11
- 230000001472 cytotoxic effect Effects 0.000 description 11
- 108010031719 prolyl-serine Proteins 0.000 description 11
- 108010069117 seryl-lysyl-aspartic acid Proteins 0.000 description 11
- YYSWCHMLFJLLBJ-ZLUOBGJFSA-N Ala-Ala-Ser Chemical compound C[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](CO)C(O)=O YYSWCHMLFJLLBJ-ZLUOBGJFSA-N 0.000 description 10
- KUDREHRZRIVKHS-UWJYBYFXSA-N Ala-Asp-Tyr Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O KUDREHRZRIVKHS-UWJYBYFXSA-N 0.000 description 10
- XWFWAXPOLRTDFZ-FXQIFTODSA-N Ala-Pro-Ser Chemical compound C[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CO)C(O)=O XWFWAXPOLRTDFZ-FXQIFTODSA-N 0.000 description 10
- MKJBPDLENBUHQU-CIUDSAMLSA-N Asn-Ser-Leu Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(O)=O MKJBPDLENBUHQU-CIUDSAMLSA-N 0.000 description 10
- ZZWUYQXMIFTIIY-WEDXCCLWSA-N Gly-Thr-Leu Chemical compound [H]NCC(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(O)=O ZZWUYQXMIFTIIY-WEDXCCLWSA-N 0.000 description 10
- YGHSQRJSHKYUJY-SCZZXKLOSA-N Gly-Val-Pro Chemical compound CC(C)[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)CN YGHSQRJSHKYUJY-SCZZXKLOSA-N 0.000 description 10
- 108020004684 Internal Ribosome Entry Sites Proteins 0.000 description 10
- GQZMPWBZQALKJO-UWVGGRQHSA-N Lys-Gly-Arg Chemical compound [H]N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(O)=O GQZMPWBZQALKJO-UWVGGRQHSA-N 0.000 description 10
- 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 10
- AIRZWUMAHCDDHR-KKUMJFAQSA-N Lys-Leu-Leu Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O AIRZWUMAHCDDHR-KKUMJFAQSA-N 0.000 description 10
- BPCLGWHVPVTTFM-QWRGUYRKSA-N Phe-Ser-Gly Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CO)C(=O)NCC(O)=O BPCLGWHVPVTTFM-QWRGUYRKSA-N 0.000 description 10
- 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 10
- FPCGZYMRFFIYIH-CIUDSAMLSA-N Ser-Lys-Ser Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CO)C(O)=O FPCGZYMRFFIYIH-CIUDSAMLSA-N 0.000 description 10
- 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 10
- ANHVRCNNGJMJNG-BZSNNMDCSA-N Tyr-Tyr-Cys Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)N[C@@H](CC2=CC=C(C=C2)O)C(=O)N[C@@H](CS)C(=O)O)N)O ANHVRCNNGJMJNG-BZSNNMDCSA-N 0.000 description 10
- HWNYVQMOLCYHEA-IHRRRGAJSA-N Val-Ser-Tyr Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CC1=CC=C(C=C1)O)C(=O)O)N HWNYVQMOLCYHEA-IHRRRGAJSA-N 0.000 description 10
- 108010009111 arginyl-glycyl-glutamic acid Proteins 0.000 description 10
- 108010077245 asparaginyl-proline Proteins 0.000 description 10
- 108010047857 aspartylglycine Proteins 0.000 description 10
- 108010050475 glycyl-leucyl-tyrosine Proteins 0.000 description 10
- 239000001963 growth medium Substances 0.000 description 10
- 230000035772 mutation Effects 0.000 description 10
- 108010020755 prolyl-glycyl-glycine Proteins 0.000 description 10
- 238000006467 substitution reaction Methods 0.000 description 10
- 108010071635 tyrosyl-prolyl-arginine Proteins 0.000 description 10
- VKKYFICVTYKFIO-CIUDSAMLSA-N Arg-Ala-Glu Chemical compound OC(=O)CC[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CCCN=C(N)N VKKYFICVTYKFIO-CIUDSAMLSA-N 0.000 description 9
- GCACQYDBDHRVGE-LKXGYXEUSA-N Asp-Thr-Ser Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H]([C@H](O)C)NC(=O)[C@@H](N)CC(O)=O GCACQYDBDHRVGE-LKXGYXEUSA-N 0.000 description 9
- 101100314454 Caenorhabditis elegans tra-1 gene Proteins 0.000 description 9
- OZHXXYOHPLLLMI-CIUDSAMLSA-N Cys-Lys-Ala Chemical compound [H]N[C@@H](CS)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(O)=O OZHXXYOHPLLLMI-CIUDSAMLSA-N 0.000 description 9
- YQPFCZVKMUVZIN-AUTRQRHGSA-N Glu-Val-Gln Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(N)=O)C(O)=O YQPFCZVKMUVZIN-AUTRQRHGSA-N 0.000 description 9
- 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 9
- LJBVRCDPWOJOEK-PPCPHDFISA-N Leu-Thr-Ile Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O LJBVRCDPWOJOEK-PPCPHDFISA-N 0.000 description 9
- QLFAPXUXEBAWEK-NHCYSSNCSA-N Lys-Val-Asp Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(O)=O)C(O)=O QLFAPXUXEBAWEK-NHCYSSNCSA-N 0.000 description 9
- 241000699666 Mus <mouse, genus> Species 0.000 description 9
- KZNQNBZMBZJQJO-UHFFFAOYSA-N N-glycyl-L-proline Natural products NCC(=O)N1CCCC1C(O)=O KZNQNBZMBZJQJO-UHFFFAOYSA-N 0.000 description 9
- XNQMZHLAYFWSGJ-HTUGSXCWSA-N Phe-Thr-Glu Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCC(O)=O)C(O)=O XNQMZHLAYFWSGJ-HTUGSXCWSA-N 0.000 description 9
- GOMUXSCOIWIJFP-GUBZILKMSA-N Pro-Ser-Arg Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O GOMUXSCOIWIJFP-GUBZILKMSA-N 0.000 description 9
- MKGIILKDUGDRRO-FXQIFTODSA-N Pro-Ser-Ser Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H]1CCCN1 MKGIILKDUGDRRO-FXQIFTODSA-N 0.000 description 9
- 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 9
- 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 9
- SIEBDTCABMZCLF-XGEHTFHBSA-N Ser-Val-Thr Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O SIEBDTCABMZCLF-XGEHTFHBSA-N 0.000 description 9
- JRAUIKJSEAKTGD-TUBUOCAGSA-N Thr-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]([C@@H](C)O)N JRAUIKJSEAKTGD-TUBUOCAGSA-N 0.000 description 9
- 208000003721 Triple Negative Breast Neoplasms Diseases 0.000 description 9
- PKZIWSHDJYIPRH-JBACZVJFSA-N Trp-Tyr-Gln Chemical compound [H]N[C@@H](CC1=CNC2=C1C=CC=C2)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CCC(N)=O)C(O)=O PKZIWSHDJYIPRH-JBACZVJFSA-N 0.000 description 9
- 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 9
- 238000007796 conventional method Methods 0.000 description 9
- 108010000434 glycyl-alanyl-leucine Proteins 0.000 description 9
- 108010010147 glycylglutamine Proteins 0.000 description 9
- 208000022679 triple-negative breast carcinoma Diseases 0.000 description 9
- 108010038745 tryptophylglycine Proteins 0.000 description 9
- BUDNAJYVCUHLSV-ZLUOBGJFSA-N Ala-Asp-Ser Chemical compound C[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(O)=O BUDNAJYVCUHLSV-ZLUOBGJFSA-N 0.000 description 8
- MEFILNJXAVSUTO-JXUBOQSCSA-N Ala-Leu-Thr Chemical compound C[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O MEFILNJXAVSUTO-JXUBOQSCSA-N 0.000 description 8
- REAQAWSENITKJL-DDWPSWQVSA-N Ala-Met-Asp-Tyr Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O REAQAWSENITKJL-DDWPSWQVSA-N 0.000 description 8
- BTRULDJUUVGRNE-DCAQKATOSA-N Ala-Pro-Lys Chemical compound C[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCCCN)C(O)=O BTRULDJUUVGRNE-DCAQKATOSA-N 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 8
- 108010022366 Carcinoembryonic Antigen Proteins 0.000 description 8
- 102100025475 Carcinoembryonic antigen-related cell adhesion molecule 5 Human genes 0.000 description 8
- CMYVIUWVYHOLRD-ZLUOBGJFSA-N Cys-Ser-Ala Chemical compound [H]N[C@@H](CS)C(=O)N[C@@H](CO)C(=O)N[C@@H](C)C(O)=O CMYVIUWVYHOLRD-ZLUOBGJFSA-N 0.000 description 8
- 102000018651 Epithelial Cell Adhesion Molecule Human genes 0.000 description 8
- 108010066687 Epithelial Cell Adhesion Molecule Proteins 0.000 description 8
- ZMXZGYLINVNTKH-DZKIICNBSA-N Gln-Val-Phe Chemical compound NC(=O)CC[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 ZMXZGYLINVNTKH-DZKIICNBSA-N 0.000 description 8
- 102100022623 Hepatocyte growth factor receptor Human genes 0.000 description 8
- ZNTSGDNUITWTRA-WDSOQIARSA-N His-Trp-Val Chemical compound [H]N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CC1=CNC2=C1C=CC=C2)C(=O)N[C@@H](C(C)C)C(O)=O ZNTSGDNUITWTRA-WDSOQIARSA-N 0.000 description 8
- 101000972946 Homo sapiens Hepatocyte growth factor receptor Proteins 0.000 description 8
- 102000008394 Immunoglobulin Fragments Human genes 0.000 description 8
- 108010021625 Immunoglobulin Fragments Proteins 0.000 description 8
- CQGSYZCULZMEDE-SRVKXCTJSA-N Leu-Gln-Pro Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CCC(N)=O)C(=O)N1CCC[C@H]1C(O)=O CQGSYZCULZMEDE-SRVKXCTJSA-N 0.000 description 8
- 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 8
- 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 8
- 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 8
- 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 8
- ULVMNZOKDBHKKI-ACZMJKKPSA-N Ser-Gln-Asp Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(O)=O)C(O)=O ULVMNZOKDBHKKI-ACZMJKKPSA-N 0.000 description 8
- BPMRXBZYPGYPJN-WHFBIAKZSA-N Ser-Gly-Asn Chemical compound [H]N[C@@H](CO)C(=O)NCC(=O)N[C@@H](CC(N)=O)C(O)=O BPMRXBZYPGYPJN-WHFBIAKZSA-N 0.000 description 8
- XNCUYZKGQOCOQH-YUMQZZPRSA-N Ser-Leu-Gly Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)NCC(O)=O XNCUYZKGQOCOQH-YUMQZZPRSA-N 0.000 description 8
- VGQVAVQWKJLIRM-FXQIFTODSA-N Ser-Ser-Val Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(O)=O VGQVAVQWKJLIRM-FXQIFTODSA-N 0.000 description 8
- PXQUBKWZENPDGE-CIQUZCHMSA-N Thr-Ala-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)[C@H](C)NC(=O)[C@H]([C@@H](C)O)N PXQUBKWZENPDGE-CIQUZCHMSA-N 0.000 description 8
- 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 8
- HUPLKEHTTQBXSC-YJRXYDGGSA-N Thr-Ser-Tyr Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 HUPLKEHTTQBXSC-YJRXYDGGSA-N 0.000 description 8
- ARKBYVBCEOWRNR-UBHSHLNASA-N Trp-Ser-Ser Chemical compound [H]N[C@@H](CC1=CNC2=C1C=CC=C2)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(O)=O ARKBYVBCEOWRNR-UBHSHLNASA-N 0.000 description 8
- 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 8
- 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 8
- OJCISMMNNUNNJA-BZSNNMDCSA-N Tyr-Tyr-Asp Chemical compound C([C@H](N)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CC(O)=O)C(O)=O)C1=CC=C(O)C=C1 OJCISMMNNUNNJA-BZSNNMDCSA-N 0.000 description 8
- WUFHZIRMAZZWRS-OSUNSFLBSA-N Val-Thr-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](C(C)C)N WUFHZIRMAZZWRS-OSUNSFLBSA-N 0.000 description 8
- 108010070783 alanyltyrosine Proteins 0.000 description 8
- 230000037396 body weight Effects 0.000 description 8
- 238000011161 development Methods 0.000 description 8
- XBGGUPMXALFZOT-UHFFFAOYSA-N glycyl-L-tyrosine hemihydrate Natural products NCC(=O)NC(C(O)=O)CC1=CC=C(O)C=C1 XBGGUPMXALFZOT-UHFFFAOYSA-N 0.000 description 8
- 108010015792 glycyllysine Proteins 0.000 description 8
- 108010087823 glycyltyrosine Proteins 0.000 description 8
- 108010038320 lysylphenylalanine Proteins 0.000 description 8
- 239000000203 mixture Substances 0.000 description 8
- 108010027345 wheylin-1 peptide Proteins 0.000 description 8
- PNHQRQTVBRDIEF-CIUDSAMLSA-N Asn-Leu-Ala Chemical compound C[C@@H](C(=O)O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(=O)N)N PNHQRQTVBRDIEF-CIUDSAMLSA-N 0.000 description 7
- JBDLMLZNDRLDIX-HJGDQZAQSA-N Asn-Thr-Leu Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(O)=O JBDLMLZNDRLDIX-HJGDQZAQSA-N 0.000 description 7
- VAWNQIGQPUOPQW-ACZMJKKPSA-N Asp-Glu-Ala Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(O)=O VAWNQIGQPUOPQW-ACZMJKKPSA-N 0.000 description 7
- 241000283707 Capra Species 0.000 description 7
- 108020004414 DNA Proteins 0.000 description 7
- IOFDDSNZJDIGPB-GVXVVHGQSA-N Gln-Leu-Val Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(O)=O IOFDDSNZJDIGPB-GVXVVHGQSA-N 0.000 description 7
- IESFZVCAVACGPH-PEFMBERDSA-N Glu-Asp-Ile Chemical compound CC[C@H](C)[C@@H](C(O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@@H](N)CCC(O)=O IESFZVCAVACGPH-PEFMBERDSA-N 0.000 description 7
- PAQUJCSYVIBPLC-AVGNSLFASA-N Glu-Asp-Phe Chemical compound OC(=O)CC[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 PAQUJCSYVIBPLC-AVGNSLFASA-N 0.000 description 7
- 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 7
- QPDUVFSVVAOUHE-XVKPBYJWSA-N Gly-Gln-Val Chemical compound CC(C)[C@H](NC(=O)[C@H](CCC(N)=O)NC(=O)CN)C(O)=O QPDUVFSVVAOUHE-XVKPBYJWSA-N 0.000 description 7
- JSNNHGHYGYMVCK-XVKPBYJWSA-N Gly-Glu-Val Chemical compound [H]NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(O)=O JSNNHGHYGYMVCK-XVKPBYJWSA-N 0.000 description 7
- YWAQATDNEKZFFK-BYPYZUCNSA-N Gly-Gly-Ser Chemical compound NCC(=O)NCC(=O)N[C@@H](CO)C(O)=O YWAQATDNEKZFFK-BYPYZUCNSA-N 0.000 description 7
- 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 7
- SBVMXEZQJVUARN-XPUUQOCRSA-N Gly-Val-Ser Chemical compound NCC(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CO)C(O)=O SBVMXEZQJVUARN-XPUUQOCRSA-N 0.000 description 7
- 101001117317 Homo sapiens Programmed cell death 1 ligand 1 Proteins 0.000 description 7
- RSFGIMMPWAXNML-MNXVOIDGSA-N Leu-Gln-Ile Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O RSFGIMMPWAXNML-MNXVOIDGSA-N 0.000 description 7
- IXHKPDJKKCUKHS-GARJFASQSA-N Lys-Ala-Pro Chemical compound C[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](CCCCN)N IXHKPDJKKCUKHS-GARJFASQSA-N 0.000 description 7
- MIFFFXHMAHFACR-KATARQTJSA-N Lys-Ser-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CCCCN MIFFFXHMAHFACR-KATARQTJSA-N 0.000 description 7
- 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 7
- 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 7
- 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 7
- KRPKYGOFYUNIGM-XVSYOHENSA-N Thr-Asp-Phe Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)O)N)O KRPKYGOFYUNIGM-XVSYOHENSA-N 0.000 description 7
- KZSYAEWQMJEGRZ-RHYQMDGZSA-N Thr-Leu-Val Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(O)=O KZSYAEWQMJEGRZ-RHYQMDGZSA-N 0.000 description 7
- BIWVVOHTKDLRMP-ULQDDVLXSA-N Tyr-Pro-Leu Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CC(C)C)C(O)=O BIWVVOHTKDLRMP-ULQDDVLXSA-N 0.000 description 7
- ZLFHAAGHGQBQQN-GUBZILKMSA-N Val-Ala-Pro Natural products CC(C)[C@H](N)C(=O)N[C@@H](C)C(=O)N1CCC[C@H]1C(O)=O ZLFHAAGHGQBQQN-GUBZILKMSA-N 0.000 description 7
- 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 7
- 238000002784 cytotoxicity assay Methods 0.000 description 7
- 231100000263 cytotoxicity test Toxicity 0.000 description 7
- 238000011534 incubation Methods 0.000 description 7
- 210000001519 tissue Anatomy 0.000 description 7
- 108010017949 tyrosyl-glycyl-glycine Proteins 0.000 description 7
- FEZJJKXNPSEYEV-CIUDSAMLSA-N Arg-Gln-Ala Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](C)C(O)=O FEZJJKXNPSEYEV-CIUDSAMLSA-N 0.000 description 6
- PRLPSDIHSRITSF-UNQGMJICSA-N Arg-Phe-Thr Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H]([C@@H](C)O)C(O)=O PRLPSDIHSRITSF-UNQGMJICSA-N 0.000 description 6
- ISJWBVIYRBAXEB-CIUDSAMLSA-N Arg-Ser-Glu Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(O)=O)C(O)=O ISJWBVIYRBAXEB-CIUDSAMLSA-N 0.000 description 6
- POZKLUIXMHIULG-FDARSICLSA-N Arg-Trp-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)[C@H](CC1=CNC2=CC=CC=C21)NC(=O)[C@H](CCCN=C(N)N)N POZKLUIXMHIULG-FDARSICLSA-N 0.000 description 6
- SZNGQSBRHFMZLT-IHRRRGAJSA-N Asn-Pro-Phe Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O SZNGQSBRHFMZLT-IHRRRGAJSA-N 0.000 description 6
- UGXYFDQFLVCDFC-CIUDSAMLSA-N Asn-Ser-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC(N)=O UGXYFDQFLVCDFC-CIUDSAMLSA-N 0.000 description 6
- WLVLIYYBPPONRJ-GCJQMDKQSA-N Asn-Thr-Ala Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C)C(O)=O WLVLIYYBPPONRJ-GCJQMDKQSA-N 0.000 description 6
- LGCVSPFCFXWUEY-IHPCNDPISA-N Asn-Trp-Tyr Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)N[C@@H](CC3=CC=C(C=C3)O)C(=O)O)NC(=O)[C@H](CC(=O)N)N LGCVSPFCFXWUEY-IHPCNDPISA-N 0.000 description 6
- MRQQMVZUHXUPEV-IHRRRGAJSA-N Asp-Arg-Phe Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O MRQQMVZUHXUPEV-IHRRRGAJSA-N 0.000 description 6
- 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 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
- AMRLSQGGERHDHJ-FXQIFTODSA-N Cys-Ala-Arg Chemical compound [H]N[C@@H](CS)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O AMRLSQGGERHDHJ-FXQIFTODSA-N 0.000 description 6
- ILKYYKRAULNYMS-JYJNAYRXSA-N Gln-Lys-Phe Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O ILKYYKRAULNYMS-JYJNAYRXSA-N 0.000 description 6
- LPIKVBWNNVFHCQ-GUBZILKMSA-N Gln-Ser-Leu Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(O)=O LPIKVBWNNVFHCQ-GUBZILKMSA-N 0.000 description 6
- KOYUSMBPJOVSOO-XEGUGMAKSA-N Gly-Tyr-Ile Chemical compound [H]NCC(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O KOYUSMBPJOVSOO-XEGUGMAKSA-N 0.000 description 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
- BEWFWZRGBDVXRP-PEFMBERDSA-N Ile-Glu-Asn Chemical compound [H]N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O BEWFWZRGBDVXRP-PEFMBERDSA-N 0.000 description 6
- RMNMUUCYTMLWNA-ZPFDUUQYSA-N Ile-Lys-Asp Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(=O)O)C(=O)O)N RMNMUUCYTMLWNA-ZPFDUUQYSA-N 0.000 description 6
- 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 6
- 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 6
- QLQHWWCSCLZUMA-KKUMJFAQSA-N Leu-Asp-Tyr Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 QLQHWWCSCLZUMA-KKUMJFAQSA-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
- AXZGZMGRBDQTEY-SRVKXCTJSA-N Leu-Gln-Met Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCSC)C(O)=O AXZGZMGRBDQTEY-SRVKXCTJSA-N 0.000 description 6
- NRFGTHFONZYFNY-MGHWNKPDSA-N Leu-Ile-Tyr Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 NRFGTHFONZYFNY-MGHWNKPDSA-N 0.000 description 6
- 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 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
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 6
- SJDQOYTYNGZZJX-SRVKXCTJSA-N Met-Glu-Leu Chemical compound CSCC[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(O)=O SJDQOYTYNGZZJX-SRVKXCTJSA-N 0.000 description 6
- 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 6
- CUMXHKAOHNWRFQ-BZSNNMDCSA-N Phe-Asp-Tyr Chemical compound C([C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(O)=O)C1=CC=CC=C1 CUMXHKAOHNWRFQ-BZSNNMDCSA-N 0.000 description 6
- FSPGBMWPNMRWDB-AVGNSLFASA-N Phe-Cys-Gln Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CCC(=O)N)C(=O)O)N FSPGBMWPNMRWDB-AVGNSLFASA-N 0.000 description 6
- LTAWNJXSRUCFAN-UNQGMJICSA-N Phe-Thr-Arg Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O LTAWNJXSRUCFAN-UNQGMJICSA-N 0.000 description 6
- FGWUALWGCZJQDJ-URLPEUOOSA-N Phe-Thr-Ile Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O FGWUALWGCZJQDJ-URLPEUOOSA-N 0.000 description 6
- GZNYIXWOIUFLGO-ZJDVBMNYSA-N Pro-Thr-Thr Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O GZNYIXWOIUFLGO-ZJDVBMNYSA-N 0.000 description 6
- QGMLKFGTGXWAHF-IHRRRGAJSA-N Ser-Arg-Phe Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O QGMLKFGTGXWAHF-IHRRRGAJSA-N 0.000 description 6
- KDGARKCAKHBEDB-NKWVEPMBSA-N Ser-Gly-Pro Chemical compound C1C[C@@H](N(C1)C(=O)CNC(=O)[C@H](CO)N)C(=O)O KDGARKCAKHBEDB-NKWVEPMBSA-N 0.000 description 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
- 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 6
- 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 6
- SPVHQURZJCUDQC-VOAKCMCISA-N Thr-Lys-Leu Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(O)=O SPVHQURZJCUDQC-VOAKCMCISA-N 0.000 description 6
- LHNNQVXITHUCAB-QTKMDUPCSA-N Thr-Met-His Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)N)O LHNNQVXITHUCAB-QTKMDUPCSA-N 0.000 description 6
- FWTFAZKJORVTIR-VZFHVOOUSA-N Thr-Ser-Ala Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(=O)N[C@@H](C)C(O)=O FWTFAZKJORVTIR-VZFHVOOUSA-N 0.000 description 6
- SGAOHNPSEPVAFP-ZDLURKLDSA-N Thr-Ser-Gly Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(=O)NCC(O)=O SGAOHNPSEPVAFP-ZDLURKLDSA-N 0.000 description 6
- 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 6
- JQTYTBPCSOAZHI-FXQIFTODSA-N Val-Ser-Cys Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CS)C(=O)O)N JQTYTBPCSOAZHI-FXQIFTODSA-N 0.000 description 6
- UJMCYJKPDFQLHX-XGEHTFHBSA-N Val-Ser-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CO)NC(=O)[C@H](C(C)C)N)O UJMCYJKPDFQLHX-XGEHTFHBSA-N 0.000 description 6
- 238000013459 approach Methods 0.000 description 6
- 231100000433 cytotoxic Toxicity 0.000 description 6
- 230000003013 cytotoxicity Effects 0.000 description 6
- 231100000135 cytotoxicity Toxicity 0.000 description 6
- 210000002950 fibroblast Anatomy 0.000 description 6
- 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 6
- 238000001727 in vivo Methods 0.000 description 6
- 201000005202 lung cancer Diseases 0.000 description 6
- 208000020816 lung neoplasm Diseases 0.000 description 6
- 108010057952 lysyl-phenylalanyl-lysine Proteins 0.000 description 6
- 108010024607 phenylalanylalanine Proteins 0.000 description 6
- 108010077112 prolyl-proline Proteins 0.000 description 6
- 208000024891 symptom Diseases 0.000 description 6
- NFGXHKASABOEEW-UHFFFAOYSA-N 1-methylethyl 11-methoxy-3,7,11-trimethyl-2,4-dodecadienoate Chemical compound COC(C)(C)CCCC(C)CC=CC(C)=CC(=O)OC(C)C NFGXHKASABOEEW-UHFFFAOYSA-N 0.000 description 5
- 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 5
- 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 5
- 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 5
- ZBLQIYPCUWZSRZ-QEJZJMRPSA-N Ala-Phe-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)[C@H](C)N)CC1=CC=CC=C1 ZBLQIYPCUWZSRZ-QEJZJMRPSA-N 0.000 description 5
- NZGRHTKZFSVPAN-BIIVOSGPSA-N Ala-Ser-Pro Chemical compound C[C@@H](C(=O)N[C@@H](CO)C(=O)N1CCC[C@@H]1C(=O)O)N NZGRHTKZFSVPAN-BIIVOSGPSA-N 0.000 description 5
- NGTYEHIRESTSRX-UWVGGRQHSA-N Arg-Lys-Gly Chemical compound NCCCC[C@@H](C(=O)NCC(O)=O)NC(=O)[C@@H](N)CCCN=C(N)N NGTYEHIRESTSRX-UWVGGRQHSA-N 0.000 description 5
- IZSMEUDYADKZTJ-KJEVXHAQSA-N Arg-Tyr-Thr 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)O)C(O)=O IZSMEUDYADKZTJ-KJEVXHAQSA-N 0.000 description 5
- PBSQFBAJKPLRJY-BYULHYEWSA-N Asn-Gly-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)CNC(=O)[C@H](CC(=O)N)N PBSQFBAJKPLRJY-BYULHYEWSA-N 0.000 description 5
- HDHZCEDPLTVHFZ-GUBZILKMSA-N Asn-Leu-Glu Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(O)=O HDHZCEDPLTVHFZ-GUBZILKMSA-N 0.000 description 5
- HPBNLFLSSQDFQW-WHFBIAKZSA-N Asn-Ser-Gly Chemical compound NC(=O)C[C@H](N)C(=O)N[C@@H](CO)C(=O)NCC(O)=O HPBNLFLSSQDFQW-WHFBIAKZSA-N 0.000 description 5
- 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 5
- FAEIQWHBRBWUBN-FXQIFTODSA-N Asp-Arg-Ser Chemical compound C(C[C@@H](C(=O)N[C@@H](CO)C(=O)O)NC(=O)[C@H](CC(=O)O)N)CN=C(N)N FAEIQWHBRBWUBN-FXQIFTODSA-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
- CELPEWWLSXMVPH-CIUDSAMLSA-N Asp-Asp-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@@H](N)CC(O)=O CELPEWWLSXMVPH-CIUDSAMLSA-N 0.000 description 5
- 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 5
- 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 5
- NDUSUIGBMZCOIL-ZKWXMUAHSA-N Cys-Asn-Val Chemical compound CC(C)[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)N)NC(=O)[C@H](CS)N NDUSUIGBMZCOIL-ZKWXMUAHSA-N 0.000 description 5
- QFJPFPCSXOXMKI-BPUTZDHNSA-N Gln-Gln-Trp Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)N)NC(=O)[C@H](CCC(=O)N)N QFJPFPCSXOXMKI-BPUTZDHNSA-N 0.000 description 5
- 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 5
- FFVXLVGUJBCKRX-UKJIMTQDSA-N Gln-Ile-Val Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](C(C)C)C(=O)O)NC(=O)[C@H](CCC(=O)N)N FFVXLVGUJBCKRX-UKJIMTQDSA-N 0.000 description 5
- IULKWYSYZSURJK-AVGNSLFASA-N Gln-Leu-Lys Chemical compound NC(=O)CC[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(O)=O IULKWYSYZSURJK-AVGNSLFASA-N 0.000 description 5
- XZLLTYBONVKGLO-SDDRHHMPSA-N Gln-Lys-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CCCCN)NC(=O)[C@H](CCC(=O)N)N)C(=O)O XZLLTYBONVKGLO-SDDRHHMPSA-N 0.000 description 5
- ROHVCXBMIAAASL-HJGDQZAQSA-N Gln-Met-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CCSC)NC(=O)[C@H](CCC(=O)N)N)O ROHVCXBMIAAASL-HJGDQZAQSA-N 0.000 description 5
- XTZDZAXYPDISRR-MNXVOIDGSA-N Glu-Ile-Lys Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CCC(=O)O)N XTZDZAXYPDISRR-MNXVOIDGSA-N 0.000 description 5
- NNQDRRUXFJYCCJ-NHCYSSNCSA-N Glu-Pro-Val Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](C(C)C)C(O)=O NNQDRRUXFJYCCJ-NHCYSSNCSA-N 0.000 description 5
- 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 5
- 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 5
- 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 5
- FFJQHWKSGAWSTJ-BFHQHQDPSA-N Gly-Thr-Ala Chemical compound [H]NCC(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C)C(O)=O FFJQHWKSGAWSTJ-BFHQHQDPSA-N 0.000 description 5
- CQMFNTVQVLQRLT-JHEQGTHGSA-N Gly-Thr-Gln Chemical compound [H]NCC(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCC(N)=O)C(O)=O CQMFNTVQVLQRLT-JHEQGTHGSA-N 0.000 description 5
- FFALDIDGPLUDKV-ZDLURKLDSA-N Gly-Thr-Ser Chemical compound [H]NCC(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(O)=O FFALDIDGPLUDKV-ZDLURKLDSA-N 0.000 description 5
- ALPXXNRQBMRCPZ-MEYUZBJRSA-N His-Thr-Phe Chemical compound [H]N[C@@H](CC1=CNC=N1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O ALPXXNRQBMRCPZ-MEYUZBJRSA-N 0.000 description 5
- UKTUOMWSJPXODT-GUDRVLHUSA-N Ile-Asn-Pro Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N1CCC[C@@H]1C(=O)O)N UKTUOMWSJPXODT-GUDRVLHUSA-N 0.000 description 5
- GVKKVHNRTUFCCE-BJDJZHNGSA-N Ile-Leu-Ser Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)O)N GVKKVHNRTUFCCE-BJDJZHNGSA-N 0.000 description 5
- OMDWJWGZGMCQND-CFMVVWHZSA-N Ile-Tyr-Asp Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC1=CC=C(C=C1)O)C(=O)N[C@@H](CC(=O)O)C(=O)O)N OMDWJWGZGMCQND-CFMVVWHZSA-N 0.000 description 5
- 108060003951 Immunoglobulin Proteins 0.000 description 5
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 5
- DBVWMYGBVFCRBE-CIUDSAMLSA-N Leu-Asn-Asn Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O DBVWMYGBVFCRBE-CIUDSAMLSA-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
- 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 5
- BMVFXOQHDQZAQU-DCAQKATOSA-N Leu-Pro-Asp Chemical compound CC(C)C[C@@H](C(=O)N1CCC[C@H]1C(=O)N[C@@H](CC(=O)O)C(=O)O)N BMVFXOQHDQZAQU-DCAQKATOSA-N 0.000 description 5
- VJGQRELPQWNURN-JYJNAYRXSA-N Leu-Tyr-Glu Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CCC(O)=O)C(O)=O VJGQRELPQWNURN-JYJNAYRXSA-N 0.000 description 5
- 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 5
- 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 5
- 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 5
- 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 5
- 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 5
- 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 5
- YYKZDTVQHTUKDW-RYUDHWBXSA-N Phe-Gly-Gln Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)NCC(=O)N[C@@H](CCC(=O)N)C(=O)O)N YYKZDTVQHTUKDW-RYUDHWBXSA-N 0.000 description 5
- 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 5
- OOLOTUZJUBOMAX-GUBZILKMSA-N Pro-Ala-Val Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](C)C(=O)N[C@@H](C(C)C)C(O)=O OOLOTUZJUBOMAX-GUBZILKMSA-N 0.000 description 5
- FUVBEZJCRMHWEM-FXQIFTODSA-N Pro-Asn-Ser Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CO)C(O)=O FUVBEZJCRMHWEM-FXQIFTODSA-N 0.000 description 5
- FMLRRBDLBJLJIK-DCAQKATOSA-N Pro-Leu-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H]1CCCN1 FMLRRBDLBJLJIK-DCAQKATOSA-N 0.000 description 5
- 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 5
- RCYUBVHMVUHEBM-RCWTZXSCSA-N Pro-Pro-Thr Chemical compound [H]N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)N[C@@H]([C@@H](C)O)C(O)=O RCYUBVHMVUHEBM-RCWTZXSCSA-N 0.000 description 5
- 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 5
- RDFQNDHEHVSONI-ZLUOBGJFSA-N Ser-Asn-Ser Chemical compound OC[C@H](N)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CO)C(O)=O RDFQNDHEHVSONI-ZLUOBGJFSA-N 0.000 description 5
- UGJRQLURDVGULT-LKXGYXEUSA-N Ser-Asn-Thr Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O UGJRQLURDVGULT-LKXGYXEUSA-N 0.000 description 5
- 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 5
- PPNPDKGQRFSCAC-CIUDSAMLSA-N Ser-Lys-Asp Chemical compound NCCCC[C@H](NC(=O)[C@@H](N)CO)C(=O)N[C@@H](CC(O)=O)C(O)=O PPNPDKGQRFSCAC-CIUDSAMLSA-N 0.000 description 5
- GDUZTEQRAOXYJS-SRVKXCTJSA-N Ser-Phe-Asn Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)O)NC(=O)[C@H](CO)N GDUZTEQRAOXYJS-SRVKXCTJSA-N 0.000 description 5
- 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 5
- NMZXJDSKEGFDLJ-DCAQKATOSA-N Ser-Pro-Lys Chemical compound C1C[C@H](N(C1)C(=O)[C@H](CO)N)C(=O)N[C@@H](CCCCN)C(=O)O NMZXJDSKEGFDLJ-DCAQKATOSA-N 0.000 description 5
- 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 5
- 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 5
- HSWXBJCBYSWBPT-GUBZILKMSA-N Ser-Val-Val Chemical compound CC(C)[C@H](NC(=O)[C@@H](NC(=O)[C@@H](N)CO)C(C)C)C(O)=O HSWXBJCBYSWBPT-GUBZILKMSA-N 0.000 description 5
- 102100034922 T-cell surface glycoprotein CD8 alpha chain Human genes 0.000 description 5
- 239000004098 Tetracycline Substances 0.000 description 5
- 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 5
- 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 5
- KPNSNVTUVKSBFL-ZJDVBMNYSA-N Thr-Met-Thr Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCSC)C(=O)N[C@@H]([C@@H](C)O)C(=O)O)N)O KPNSNVTUVKSBFL-ZJDVBMNYSA-N 0.000 description 5
- 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 5
- 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 5
- RPECVQBNONKZAT-WZLNRYEVSA-N Thr-Tyr-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)[C@H](CC1=CC=C(C=C1)O)NC(=O)[C@H]([C@@H](C)O)N RPECVQBNONKZAT-WZLNRYEVSA-N 0.000 description 5
- 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 5
- WURLIFOWSMBUAR-SLFFLAALSA-N Tyr-Phe-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CC2=CC=CC=C2)NC(=O)[C@H](CC3=CC=C(C=C3)O)N)C(=O)O WURLIFOWSMBUAR-SLFFLAALSA-N 0.000 description 5
- NUQZCPSZHGIYTA-HKUYNNGSSA-N Tyr-Trp-Gly Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)NCC(=O)O)NC(=O)[C@H](CC3=CC=C(C=C3)O)N NUQZCPSZHGIYTA-HKUYNNGSSA-N 0.000 description 5
- 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 5
- OTJMMKPMLUNTQT-AVGNSLFASA-N Val-Leu-Arg Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CCCN=C(N)N)C(=O)O)NC(=O)[C@H](C(C)C)N OTJMMKPMLUNTQT-AVGNSLFASA-N 0.000 description 5
- KTEZUXISLQTDDQ-NHCYSSNCSA-N Val-Lys-Asp Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(=O)O)C(=O)O)N KTEZUXISLQTDDQ-NHCYSSNCSA-N 0.000 description 5
- CKTMJBPRVQWPHU-JSGCOSHPSA-N Val-Phe-Gly Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)NCC(=O)O)N CKTMJBPRVQWPHU-JSGCOSHPSA-N 0.000 description 5
- 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 5
- 108010005233 alanylglutamic acid Proteins 0.000 description 5
- 238000010586 diagram Methods 0.000 description 5
- FSXRLASFHBWESK-UHFFFAOYSA-N dipeptide phenylalanyl-tyrosine Natural products C=1C=C(O)C=CC=1CC(C(O)=O)NC(=O)C(N)CC1=CC=CC=C1 FSXRLASFHBWESK-UHFFFAOYSA-N 0.000 description 5
- 239000012636 effector Substances 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 108010049041 glutamylalanine Proteins 0.000 description 5
- 108010077515 glycylproline Proteins 0.000 description 5
- 108010018006 histidylserine Proteins 0.000 description 5
- 102000018358 immunoglobulin Human genes 0.000 description 5
- 230000001939 inductive effect Effects 0.000 description 5
- 239000008101 lactose Substances 0.000 description 5
- 108010064235 lysylglycine Proteins 0.000 description 5
- 230000014759 maintenance of location Effects 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- 239000008194 pharmaceutical composition Substances 0.000 description 5
- 108010053725 prolylvaline Proteins 0.000 description 5
- 238000003259 recombinant expression Methods 0.000 description 5
- 230000008685 targeting Effects 0.000 description 5
- 229960002180 tetracycline Drugs 0.000 description 5
- 229930101283 tetracycline Natural products 0.000 description 5
- 235000019364 tetracycline Nutrition 0.000 description 5
- 150000003522 tetracyclines Chemical class 0.000 description 5
- 238000013518 transcription Methods 0.000 description 5
- 230000035897 transcription Effects 0.000 description 5
- 108010035534 tyrosyl-leucyl-alanine Proteins 0.000 description 5
- 208000031261 Acute myeloid leukaemia Diseases 0.000 description 4
- TTXMOJWKNRJWQJ-FXQIFTODSA-N Ala-Arg-Ser Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)C)CCCN=C(N)N TTXMOJWKNRJWQJ-FXQIFTODSA-N 0.000 description 4
- WYPUMLRSQMKIJU-BPNCWPANSA-N Ala-Arg-Tyr Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O WYPUMLRSQMKIJU-BPNCWPANSA-N 0.000 description 4
- CKLDHDOIYBVUNP-KBIXCLLPSA-N Ala-Ile-Glu Chemical compound [H]N[C@@H](C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCC(O)=O)C(O)=O CKLDHDOIYBVUNP-KBIXCLLPSA-N 0.000 description 4
- 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 4
- YYAVDNKUWLAFCV-ACZMJKKPSA-N Ala-Ser-Gln Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(O)=O YYAVDNKUWLAFCV-ACZMJKKPSA-N 0.000 description 4
- HOVPGJUNRLMIOZ-CIUDSAMLSA-N Ala-Ser-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](CO)NC(=O)[C@H](C)N HOVPGJUNRLMIOZ-CIUDSAMLSA-N 0.000 description 4
- 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 4
- 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 4
- 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 4
- ZZZWQALDSQQBEW-STQMWFEESA-N Arg-Gly-Tyr Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)NCC(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O ZZZWQALDSQQBEW-STQMWFEESA-N 0.000 description 4
- OVQJAKFLFTZDNC-GUBZILKMSA-N Arg-Pro-Asp Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CC(O)=O)C(O)=O OVQJAKFLFTZDNC-GUBZILKMSA-N 0.000 description 4
- XYOVHPDDWCEUDY-CIUDSAMLSA-N Asn-Ala-Leu Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(O)=O XYOVHPDDWCEUDY-CIUDSAMLSA-N 0.000 description 4
- GXMSVVBIAMWMKO-BQBZGAKWSA-N Asn-Arg-Gly Chemical compound NC(=O)C[C@H](N)C(=O)N[C@H](C(=O)NCC(O)=O)CCCN=C(N)N GXMSVVBIAMWMKO-BQBZGAKWSA-N 0.000 description 4
- QUAWOKPCAKCHQL-SRVKXCTJSA-N Asn-His-Lys Chemical compound C1=C(NC=N1)C[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CC(=O)N)N QUAWOKPCAKCHQL-SRVKXCTJSA-N 0.000 description 4
- 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 4
- JTXVXGXTRXMOFJ-FXQIFTODSA-N Asn-Pro-Asn Chemical compound NC(=O)C[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CC(N)=O)C(O)=O JTXVXGXTRXMOFJ-FXQIFTODSA-N 0.000 description 4
- VCJCPARXDBEGNE-GUBZILKMSA-N Asn-Pro-Pro Chemical compound NC(=O)C[C@H](N)C(=O)N1CCC[C@H]1C(=O)N1[C@H](C(O)=O)CCC1 VCJCPARXDBEGNE-GUBZILKMSA-N 0.000 description 4
- GMUOCGCDOYYWPD-FXQIFTODSA-N Asn-Pro-Ser Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CO)C(O)=O GMUOCGCDOYYWPD-FXQIFTODSA-N 0.000 description 4
- JWQWPRCDYWNVNM-ACZMJKKPSA-N Asn-Ser-Gln Chemical compound C(CC(=O)N)[C@@H](C(=O)O)NC(=O)[C@H](CO)NC(=O)[C@H](CC(=O)N)N JWQWPRCDYWNVNM-ACZMJKKPSA-N 0.000 description 4
- QXNGSPZMGFEZNO-QRTARXTBSA-N Asn-Val-Trp Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC1=CNC2=C1C=CC=C2)C(O)=O QXNGSPZMGFEZNO-QRTARXTBSA-N 0.000 description 4
- KRXIWXCXOARFNT-ZLUOBGJFSA-N Asp-Ala-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC(O)=O KRXIWXCXOARFNT-ZLUOBGJFSA-N 0.000 description 4
- SWTQDYFZVOJVLL-KKUMJFAQSA-N Asp-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)O)N)O SWTQDYFZVOJVLL-KKUMJFAQSA-N 0.000 description 4
- 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 4
- 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 4
- 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 4
- VIRYODQIWJNWNU-NRPADANISA-N Cys-Glu-Val Chemical compound CC(C)[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)O)NC(=O)[C@H](CS)N VIRYODQIWJNWNU-NRPADANISA-N 0.000 description 4
- WAJDEKCJRKGRPG-CIUDSAMLSA-N Cys-His-Ser Chemical compound C1=C(NC=N1)C[C@@H](C(=O)N[C@@H](CO)C(=O)O)NC(=O)[C@H](CS)N WAJDEKCJRKGRPG-CIUDSAMLSA-N 0.000 description 4
- 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 4
- KFYPRIGJTICABD-XGEHTFHBSA-N Cys-Thr-Val Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](C(C)C)C(=O)O)NC(=O)[C@H](CS)N)O KFYPRIGJTICABD-XGEHTFHBSA-N 0.000 description 4
- 241000588724 Escherichia coli Species 0.000 description 4
- NVEASDQHBRZPSU-BQBZGAKWSA-N Gln-Gln-Gly Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)NCC(O)=O NVEASDQHBRZPSU-BQBZGAKWSA-N 0.000 description 4
- 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 4
- LHMWTCWZARHLPV-CIUDSAMLSA-N Gln-Met-Ser Chemical compound CSCC[C@@H](C(=O)N[C@@H](CO)C(=O)O)NC(=O)[C@H](CCC(=O)N)N LHMWTCWZARHLPV-CIUDSAMLSA-N 0.000 description 4
- SYZZMPFLOLSMHL-XHNCKOQMSA-N Gln-Ser-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CO)NC(=O)[C@H](CCC(=O)N)N)C(=O)O SYZZMPFLOLSMHL-XHNCKOQMSA-N 0.000 description 4
- CLROYXHHUZELFX-FXQIFTODSA-N Glu-Gln-Asp Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(O)=O)C(O)=O CLROYXHHUZELFX-FXQIFTODSA-N 0.000 description 4
- 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 4
- 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 4
- BFEZQZKEPRKKHV-SRVKXCTJSA-N Glu-Pro-Lys Chemical compound C1C[C@H](N(C1)C(=O)[C@H](CCC(=O)O)N)C(=O)N[C@@H](CCCCN)C(=O)O BFEZQZKEPRKKHV-SRVKXCTJSA-N 0.000 description 4
- 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 4
- IXKRSKPKSLXIHN-YUMQZZPRSA-N Gly-Cys-Leu Chemical compound [H]NCC(=O)N[C@@H](CS)C(=O)N[C@@H](CC(C)C)C(O)=O IXKRSKPKSLXIHN-YUMQZZPRSA-N 0.000 description 4
- UFPXDFOYHVEIPI-BYPYZUCNSA-N Gly-Gly-Asp Chemical compound NCC(=O)NCC(=O)N[C@H](C(O)=O)CC(O)=O UFPXDFOYHVEIPI-BYPYZUCNSA-N 0.000 description 4
- NNCSJUBVFBDDLC-YUMQZZPRSA-N Gly-Leu-Ser Chemical compound NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(O)=O NNCSJUBVFBDDLC-YUMQZZPRSA-N 0.000 description 4
- AFWYPMDMDYCKMD-KBPBESRZSA-N Gly-Leu-Tyr Chemical compound NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 AFWYPMDMDYCKMD-KBPBESRZSA-N 0.000 description 4
- ICUTTWWCDIIIEE-BQBZGAKWSA-N Gly-Met-Asn Chemical compound CSCC[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)O)NC(=O)CN ICUTTWWCDIIIEE-BQBZGAKWSA-N 0.000 description 4
- HAOUOFNNJJLVNS-BQBZGAKWSA-N Gly-Pro-Ser Chemical compound NCC(=O)N1CCC[C@H]1C(=O)N[C@@H](CO)C(O)=O HAOUOFNNJJLVNS-BQBZGAKWSA-N 0.000 description 4
- 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 4
- 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 4
- ZVXMEWXHFBYJPI-LSJOCFKGSA-N Gly-Val-Ile Chemical compound [H]NCC(=O)N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O ZVXMEWXHFBYJPI-LSJOCFKGSA-N 0.000 description 4
- UXSATKFPUVZVDK-KKUMJFAQSA-N His-Lys-Leu Chemical compound CC(C)C[C@@H](C(=O)O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CC1=CN=CN1)N UXSATKFPUVZVDK-KKUMJFAQSA-N 0.000 description 4
- ZHHLTWUOWXHVQJ-YUMQZZPRSA-N His-Ser-Gly Chemical compound C1=C(NC=N1)C[C@@H](C(=O)N[C@@H](CO)C(=O)NCC(=O)O)N ZHHLTWUOWXHVQJ-YUMQZZPRSA-N 0.000 description 4
- YKUAGFAXQRYUQW-KKUMJFAQSA-N His-Tyr-Cys Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)N[C@@H](CS)C(=O)O)NC(=O)[C@H](CC2=CN=CN2)N)O YKUAGFAXQRYUQW-KKUMJFAQSA-N 0.000 description 4
- JHNJNTMTZHEDLJ-NAKRPEOUSA-N Ile-Ser-Arg Chemical compound CC[C@H](C)[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCN=C(N)N)C(O)=O JHNJNTMTZHEDLJ-NAKRPEOUSA-N 0.000 description 4
- FBGXMKUWQFPHFB-JBDRJPRFSA-N Ile-Ser-Cys Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CS)C(=O)O)N FBGXMKUWQFPHFB-JBDRJPRFSA-N 0.000 description 4
- 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 4
- 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 4
- DZMWFIRHFFVBHS-ZEWNOJEFSA-N Ile-Tyr-Phe Chemical compound CC[C@H](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 DZMWFIRHFFVBHS-ZEWNOJEFSA-N 0.000 description 4
- 102100021592 Interleukin-7 Human genes 0.000 description 4
- USTCFDAQCLDPBD-XIRDDKMYSA-N Leu-Asn-Trp Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CC1=CNC2=CC=CC=C21)C(=O)O)N USTCFDAQCLDPBD-XIRDDKMYSA-N 0.000 description 4
- VQPPIMUZCZCOIL-GUBZILKMSA-N Leu-Gln-Ala Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](C)C(O)=O VQPPIMUZCZCOIL-GUBZILKMSA-N 0.000 description 4
- 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 4
- QJUWBDPGGYVRHY-YUMQZZPRSA-N Leu-Gly-Cys Chemical compound CC(C)C[C@@H](C(=O)NCC(=O)N[C@@H](CS)C(=O)O)N QJUWBDPGGYVRHY-YUMQZZPRSA-N 0.000 description 4
- POZULHZYLPGXMR-ONGXEEELSA-N Leu-Gly-Val Chemical compound CC(C)C[C@H](N)C(=O)NCC(=O)N[C@@H](C(C)C)C(O)=O POZULHZYLPGXMR-ONGXEEELSA-N 0.000 description 4
- OYQUOLRTJHWVSQ-SRVKXCTJSA-N Leu-His-Ser Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CO)C(O)=O OYQUOLRTJHWVSQ-SRVKXCTJSA-N 0.000 description 4
- AMSSKPUHBUQBOQ-SRVKXCTJSA-N Leu-Ser-Lys Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCCN)C(=O)O)N AMSSKPUHBUQBOQ-SRVKXCTJSA-N 0.000 description 4
- 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 4
- 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 4
- 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 4
- GOVDTWNJCBRRBJ-DCAQKATOSA-N Lys-Met-Asn Chemical compound CSCC[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)O)NC(=O)[C@H](CCCCN)N GOVDTWNJCBRRBJ-DCAQKATOSA-N 0.000 description 4
- RMOKGALPSPOYKE-KATARQTJSA-N Lys-Thr-Ser Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(O)=O RMOKGALPSPOYKE-KATARQTJSA-N 0.000 description 4
- 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 4
- WRXOPYNEKGZWAZ-FXQIFTODSA-N Met-Ser-Cys Chemical compound CSCC[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CS)C(O)=O WRXOPYNEKGZWAZ-FXQIFTODSA-N 0.000 description 4
- 241000699670 Mus sp. Species 0.000 description 4
- 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 4
- 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 4
- AUJWXNGCAQWLEI-KBPBESRZSA-N Phe-Lys-Gly Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CCCCN)C(=O)NCC(O)=O AUJWXNGCAQWLEI-KBPBESRZSA-N 0.000 description 4
- JLLJTMHNXQTMCK-UBHSHLNASA-N Phe-Pro-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@@H]1CCCN1C(=O)[C@@H](N)CC1=CC=CC=C1 JLLJTMHNXQTMCK-UBHSHLNASA-N 0.000 description 4
- 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 4
- WWPAHTZOWURIMR-ULQDDVLXSA-N Phe-Pro-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@@H](N)CC1=CC=CC=C1 WWPAHTZOWURIMR-ULQDDVLXSA-N 0.000 description 4
- MCIXMYKSPQUMJG-SRVKXCTJSA-N Phe-Ser-Ser Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(O)=O MCIXMYKSPQUMJG-SRVKXCTJSA-N 0.000 description 4
- BPIMVBKDLSBKIJ-FCLVOEFKSA-N Phe-Thr-Phe Chemical compound C([C@H](N)C(=O)N[C@@H]([C@H](O)C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)C1=CC=CC=C1 BPIMVBKDLSBKIJ-FCLVOEFKSA-N 0.000 description 4
- 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 4
- 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 4
- RMODQFBNDDENCP-IHRRRGAJSA-N Pro-Lys-Leu Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(O)=O RMODQFBNDDENCP-IHRRRGAJSA-N 0.000 description 4
- QKWYXRPICJEQAJ-KJEVXHAQSA-N Pro-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]2CCCN2)O QKWYXRPICJEQAJ-KJEVXHAQSA-N 0.000 description 4
- QEDMOZUJTGEIBF-FXQIFTODSA-N Ser-Arg-Asp Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(O)=O QEDMOZUJTGEIBF-FXQIFTODSA-N 0.000 description 4
- FTVRVZNYIYWJGB-ACZMJKKPSA-N Ser-Asp-Glu Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(O)=O FTVRVZNYIYWJGB-ACZMJKKPSA-N 0.000 description 4
- NLOAIFSWUUFQFR-CIUDSAMLSA-N Ser-Leu-Asp Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(O)=O)C(O)=O NLOAIFSWUUFQFR-CIUDSAMLSA-N 0.000 description 4
- 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 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
- PCJLFYBAQZQOFE-KATARQTJSA-N Ser-Thr-Lys Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CO)N)O PCJLFYBAQZQOFE-KATARQTJSA-N 0.000 description 4
- IGROJMCBGRFRGI-YTLHQDLWSA-N Thr-Ala-Ala Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](C)C(O)=O IGROJMCBGRFRGI-YTLHQDLWSA-N 0.000 description 4
- NJEMRSFGDNECGF-GCJQMDKQSA-N Thr-Ala-Asp Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@H](C(O)=O)CC(O)=O NJEMRSFGDNECGF-GCJQMDKQSA-N 0.000 description 4
- KGKWKSSSQGGYAU-SUSMZKCASA-N Thr-Gln-Thr Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H]([C@@H](C)O)C(=O)O)N)O KGKWKSSSQGGYAU-SUSMZKCASA-N 0.000 description 4
- CYVQBKQYQGEELV-NKIYYHGXSA-N Thr-His-Gln Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)N[C@@H](CCC(=O)N)C(=O)O)N)O CYVQBKQYQGEELV-NKIYYHGXSA-N 0.000 description 4
- NCXVJIQMWSGRHY-KXNHARMFSA-N Thr-Leu-Pro Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N1CCC[C@@H]1C(=O)O)N)O NCXVJIQMWSGRHY-KXNHARMFSA-N 0.000 description 4
- JLNMFGCJODTXDH-WEDXCCLWSA-N Thr-Lys-Gly Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCCN)C(=O)NCC(O)=O JLNMFGCJODTXDH-WEDXCCLWSA-N 0.000 description 4
- PRTHQBSMXILLPC-XGEHTFHBSA-N Thr-Ser-Arg Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O PRTHQBSMXILLPC-XGEHTFHBSA-N 0.000 description 4
- ZMYCLHFLHRVOEA-HEIBUPTGSA-N Thr-Thr-Ser Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(O)=O ZMYCLHFLHRVOEA-HEIBUPTGSA-N 0.000 description 4
- 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 4
- PWONLXBUSVIZPH-RHYQMDGZSA-N Thr-Val-Lys Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)O)N)O PWONLXBUSVIZPH-RHYQMDGZSA-N 0.000 description 4
- QNXZCKMXHPULME-ZNSHCXBVSA-N Thr-Val-Pro Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@@H]1C(=O)O)N)O QNXZCKMXHPULME-ZNSHCXBVSA-N 0.000 description 4
- KZTLZZQTJMCGIP-ZJDVBMNYSA-N Thr-Val-Thr Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O KZTLZZQTJMCGIP-ZJDVBMNYSA-N 0.000 description 4
- 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 4
- SCCKSNREWHMKOJ-SRVKXCTJSA-N Tyr-Asn-Ser Chemical compound N[C@@H](Cc1ccc(O)cc1)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CO)C(O)=O SCCKSNREWHMKOJ-SRVKXCTJSA-N 0.000 description 4
- BEIGSKUPTIFYRZ-SRVKXCTJSA-N Tyr-Asp-Asp Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](CC(=O)O)C(=O)O)N)O BEIGSKUPTIFYRZ-SRVKXCTJSA-N 0.000 description 4
- TZXFLDNBYYGLKA-BZSNNMDCSA-N Tyr-Asp-Tyr Chemical compound C([C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(O)=O)C1=CC=C(O)C=C1 TZXFLDNBYYGLKA-BZSNNMDCSA-N 0.000 description 4
- 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 4
- CTDPLKMBVALCGN-JSGCOSHPSA-N Tyr-Gly-Val Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)NCC(=O)N[C@@H](C(C)C)C(O)=O CTDPLKMBVALCGN-JSGCOSHPSA-N 0.000 description 4
- CVXURBLRELTJKO-BWAGICSOSA-N Tyr-His-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CC1=CN=CN1)NC(=O)[C@H](CC2=CC=C(C=C2)O)N)O CVXURBLRELTJKO-BWAGICSOSA-N 0.000 description 4
- 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 4
- NKUGCYDFQKFVOJ-JYJNAYRXSA-N Tyr-Leu-Gln Chemical compound NC(=O)CC[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 NKUGCYDFQKFVOJ-JYJNAYRXSA-N 0.000 description 4
- NVZVJIUDICCMHZ-BZSNNMDCSA-N Tyr-Phe-Ser Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CO)C(O)=O NVZVJIUDICCMHZ-BZSNNMDCSA-N 0.000 description 4
- ZPFLBLFITJCBTP-QWRGUYRKSA-N Tyr-Ser-Gly Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CO)C(=O)NCC(O)=O ZPFLBLFITJCBTP-QWRGUYRKSA-N 0.000 description 4
- NXPDPYYCIRDUHO-ULQDDVLXSA-N Tyr-Val-His Chemical compound C([C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1NC=NC=1)C(O)=O)C1=CC=C(O)C=C1 NXPDPYYCIRDUHO-ULQDDVLXSA-N 0.000 description 4
- RVGVIWNHABGIFH-IHRRRGAJSA-N Tyr-Val-Ser 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](CO)C(O)=O RVGVIWNHABGIFH-IHRRRGAJSA-N 0.000 description 4
- VJOWWOGRNXRQMF-UVBJJODRSA-N Val-Ala-Trp Chemical compound C1=CC=C2C(C[C@H](NC(=O)[C@H](C)NC(=O)[C@@H](N)C(C)C)C(O)=O)=CNC2=C1 VJOWWOGRNXRQMF-UVBJJODRSA-N 0.000 description 4
- LHADRQBREKTRLR-DCAQKATOSA-N Val-Cys-Leu Chemical compound CC(C)C[C@@H](C(=O)O)NC(=O)[C@H](CS)NC(=O)[C@H](C(C)C)N LHADRQBREKTRLR-DCAQKATOSA-N 0.000 description 4
- OXVPMZVGCAPFIG-BQFCYCMXSA-N Val-Gln-Trp Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H](CC1=CNC2=CC=CC=C21)C(=O)O)N OXVPMZVGCAPFIG-BQFCYCMXSA-N 0.000 description 4
- 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 4
- DEGUERSKQBRZMZ-FXQIFTODSA-N Val-Ser-Ala Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@@H](C)C(O)=O DEGUERSKQBRZMZ-FXQIFTODSA-N 0.000 description 4
- 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 4
- 239000013543 active substance Substances 0.000 description 4
- 108010038850 arginyl-isoleucyl-tyrosine Proteins 0.000 description 4
- 230000008901 benefit Effects 0.000 description 4
- 239000006143 cell culture medium Substances 0.000 description 4
- 230000030833 cell death Effects 0.000 description 4
- 238000005119 centrifugation Methods 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 102000037865 fusion proteins Human genes 0.000 description 4
- 108020001507 fusion proteins Proteins 0.000 description 4
- 108010062266 glycyl-glycyl-argininal Proteins 0.000 description 4
- 230000001900 immune effect Effects 0.000 description 4
- 230000005764 inhibitory process Effects 0.000 description 4
- 238000001990 intravenous administration Methods 0.000 description 4
- 108010027338 isoleucylcysteine Proteins 0.000 description 4
- 108010057821 leucylproline Proteins 0.000 description 4
- 230000004048 modification Effects 0.000 description 4
- 238000012986 modification Methods 0.000 description 4
- 239000000546 pharmaceutical excipient Substances 0.000 description 4
- 230000008488 polyadenylation Effects 0.000 description 4
- 238000010188 recombinant method Methods 0.000 description 4
- 238000002415 sodium dodecyl sulfate polyacrylamide gel electrophoresis Methods 0.000 description 4
- 230000004083 survival effect Effects 0.000 description 4
- 108010033670 threonyl-aspartyl-tyrosine Proteins 0.000 description 4
- 108010058119 tryptophyl-glycyl-glycine Proteins 0.000 description 4
- OQWQTGBOFPJOIF-DLOVCJGASA-N Ala-Lys-His Chemical compound C[C@@H](C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)N OQWQTGBOFPJOIF-DLOVCJGASA-N 0.000 description 3
- 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 3
- KTXKIYXZQFWJKB-VZFHVOOUSA-N Ala-Thr-Ser Chemical compound [H]N[C@@H](C)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(O)=O KTXKIYXZQFWJKB-VZFHVOOUSA-N 0.000 description 3
- PGNNQOJOEGFAOR-KWQFWETISA-N Ala-Tyr-Gly Chemical compound OC(=O)CNC(=O)[C@@H](NC(=O)[C@@H](N)C)CC1=CC=C(O)C=C1 PGNNQOJOEGFAOR-KWQFWETISA-N 0.000 description 3
- 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 3
- BHSYMWWMVRPCPA-CYDGBPFRSA-N Arg-Arg-Ile Chemical compound CC[C@H](C)[C@@H](C(O)=O)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@@H](N)CCCN=C(N)N BHSYMWWMVRPCPA-CYDGBPFRSA-N 0.000 description 3
- CPSHGRGUPZBMOK-CIUDSAMLSA-N Arg-Asn-Gln Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(O)=O CPSHGRGUPZBMOK-CIUDSAMLSA-N 0.000 description 3
- HKRXJBBCQBAGIM-FXQIFTODSA-N Arg-Asp-Ser Chemical compound C(C[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](CO)C(=O)O)N)CN=C(N)N HKRXJBBCQBAGIM-FXQIFTODSA-N 0.000 description 3
- ZEAYJGRKRUBDOB-GARJFASQSA-N Arg-Gln-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CCC(=O)N)NC(=O)[C@H](CCCN=C(N)N)N)C(=O)O ZEAYJGRKRUBDOB-GARJFASQSA-N 0.000 description 3
- 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 3
- XSPKAHFVDKRGRL-DCAQKATOSA-N Arg-Pro-Glu Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCC(O)=O)C(O)=O XSPKAHFVDKRGRL-DCAQKATOSA-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
- SYFHFLGAROUHNT-VEVYYDQMSA-N Arg-Thr-Asn Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(O)=O SYFHFLGAROUHNT-VEVYYDQMSA-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
- ANRZCQXIXGDXLR-CWRNSKLLSA-N Asn-Trp-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CC2=CNC3=CC=CC=C32)NC(=O)[C@H](CC(=O)N)N)C(=O)O ANRZCQXIXGDXLR-CWRNSKLLSA-N 0.000 description 3
- RTFXPCYMDYBZNQ-SRVKXCTJSA-N Asn-Tyr-Asn Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC(N)=O)C(O)=O RTFXPCYMDYBZNQ-SRVKXCTJSA-N 0.000 description 3
- 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 3
- KHGPWGKPYHPOIK-QWRGUYRKSA-N Asp-Gly-Phe Chemical compound [H]N[C@@H](CC(O)=O)C(=O)NCC(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O KHGPWGKPYHPOIK-QWRGUYRKSA-N 0.000 description 3
- HOBNTSHITVVNBN-ZPFDUUQYSA-N Asp-Ile-Leu Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC(C)C)C(=O)O)NC(=O)[C@H](CC(=O)O)N HOBNTSHITVVNBN-ZPFDUUQYSA-N 0.000 description 3
- KLYPOCBLKMPBIQ-GHCJXIJMSA-N Asp-Ile-Ser Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CO)C(=O)O)NC(=O)[C@H](CC(=O)O)N KLYPOCBLKMPBIQ-GHCJXIJMSA-N 0.000 description 3
- JSHWXQIZOCVWIA-ZKWXMUAHSA-N Asp-Ser-Val Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(O)=O JSHWXQIZOCVWIA-ZKWXMUAHSA-N 0.000 description 3
- JJQGZGOEDSSHTE-FOHZUACHSA-N Asp-Thr-Gly Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(O)=O JJQGZGOEDSSHTE-FOHZUACHSA-N 0.000 description 3
- NJLLRXWFPQQPHV-SRVKXCTJSA-N Asp-Tyr-Asn 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](CC(N)=O)C(O)=O NJLLRXWFPQQPHV-SRVKXCTJSA-N 0.000 description 3
- SQIARYGNVQWOSB-BZSNNMDCSA-N Asp-Tyr-Phe Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O SQIARYGNVQWOSB-BZSNNMDCSA-N 0.000 description 3
- 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 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
- 108091026890 Coding region Proteins 0.000 description 3
- XMTDCXXLDZKAGI-ACZMJKKPSA-N Cys-Ala-Gln Chemical compound C[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)O)NC(=O)[C@H](CS)N XMTDCXXLDZKAGI-ACZMJKKPSA-N 0.000 description 3
- GEEXORWTBTUOHC-FXQIFTODSA-N Cys-Arg-Ser Chemical compound C(C[C@@H](C(=O)N[C@@H](CO)C(=O)O)NC(=O)[C@H](CS)N)CN=C(N)N GEEXORWTBTUOHC-FXQIFTODSA-N 0.000 description 3
- 241000701022 Cytomegalovirus Species 0.000 description 3
- SOBBAYVQSNXYPQ-ACZMJKKPSA-N Gln-Asn-Asn Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O SOBBAYVQSNXYPQ-ACZMJKKPSA-N 0.000 description 3
- LOJYQMFIIJVETK-WDSKDSINSA-N Gln-Gln Chemical compound NC(=O)CC[C@H](N)C(=O)N[C@@H](CCC(N)=O)C(O)=O LOJYQMFIIJVETK-WDSKDSINSA-N 0.000 description 3
- NPTGGVQJYRSMCM-GLLZPBPUSA-N Gln-Gln-Thr Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O NPTGGVQJYRSMCM-GLLZPBPUSA-N 0.000 description 3
- 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 3
- VNTGPISAOMAXRK-CIUDSAMLSA-N Gln-Pro-Ser Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CO)C(O)=O VNTGPISAOMAXRK-CIUDSAMLSA-N 0.000 description 3
- JILRMFFFCHUUTJ-ACZMJKKPSA-N Gln-Ser-Ser Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(O)=O JILRMFFFCHUUTJ-ACZMJKKPSA-N 0.000 description 3
- VOUSELYGTNGEPB-NUMRIWBASA-N Gln-Thr-Asp Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(O)=O)C(O)=O VOUSELYGTNGEPB-NUMRIWBASA-N 0.000 description 3
- STHSGOZLFLFGSS-SUSMZKCASA-N Gln-Thr-Thr Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O STHSGOZLFLFGSS-SUSMZKCASA-N 0.000 description 3
- XHUCVVHRLNPZSZ-CIUDSAMLSA-N Glu-Gln-Glu Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(O)=O XHUCVVHRLNPZSZ-CIUDSAMLSA-N 0.000 description 3
- ZSWGJYOZWBHROQ-RWRJDSDZSA-N Glu-Ile-Thr Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(O)=O ZSWGJYOZWBHROQ-RWRJDSDZSA-N 0.000 description 3
- HVYWQYLBVXMXSV-GUBZILKMSA-N Glu-Leu-Ala Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C)C(O)=O HVYWQYLBVXMXSV-GUBZILKMSA-N 0.000 description 3
- IVGJYOOGJLFKQE-AVGNSLFASA-N Glu-Leu-Lys Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CCC(=O)O)N IVGJYOOGJLFKQE-AVGNSLFASA-N 0.000 description 3
- GJBUAAAIZSRCDC-GVXVVHGQSA-N Glu-Leu-Val Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(O)=O GJBUAAAIZSRCDC-GVXVVHGQSA-N 0.000 description 3
- VSVZIEVNUYDAFR-YUMQZZPRSA-N Gly-Ala-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)CN VSVZIEVNUYDAFR-YUMQZZPRSA-N 0.000 description 3
- RJIVPOXLQFJRTG-LURJTMIESA-N Gly-Arg-Gly Chemical compound OC(=O)CNC(=O)[C@@H](NC(=O)CN)CCCN=C(N)N RJIVPOXLQFJRTG-LURJTMIESA-N 0.000 description 3
- DTRUBYPMMVPQPD-YUMQZZPRSA-N Gly-Gln-Arg Chemical compound [H]NCC(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O DTRUBYPMMVPQPD-YUMQZZPRSA-N 0.000 description 3
- FQKKPCWTZZEDIC-XPUUQOCRSA-N Gly-His-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)CN)CC1=CN=CN1 FQKKPCWTZZEDIC-XPUUQOCRSA-N 0.000 description 3
- WMGHDYWNHNLGBV-ONGXEEELSA-N Gly-Phe-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)CN)CC1=CC=CC=C1 WMGHDYWNHNLGBV-ONGXEEELSA-N 0.000 description 3
- MTBIKIMYHUWBRX-QWRGUYRKSA-N Gly-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)CN MTBIKIMYHUWBRX-QWRGUYRKSA-N 0.000 description 3
- GGAPHLIUUTVYMX-QWRGUYRKSA-N Gly-Phe-Ser Chemical compound OC[C@@H](C([O-])=O)NC(=O)[C@@H](NC(=O)C[NH3+])CC1=CC=CC=C1 GGAPHLIUUTVYMX-QWRGUYRKSA-N 0.000 description 3
- WNZOCXUOGVYYBJ-CDMKHQONSA-N Gly-Phe-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CC1=CC=CC=C1)NC(=O)CN)O WNZOCXUOGVYYBJ-CDMKHQONSA-N 0.000 description 3
- ABPRMMYHROQBLY-NKWVEPMBSA-N Gly-Ser-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CO)NC(=O)CN)C(=O)O ABPRMMYHROQBLY-NKWVEPMBSA-N 0.000 description 3
- CUVBTVWFVIIDOC-YEPSODPASA-N Gly-Thr-Val Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)[C@H]([C@@H](C)O)NC(=O)CN CUVBTVWFVIIDOC-YEPSODPASA-N 0.000 description 3
- KSOBNUBCYHGUKH-UWVGGRQHSA-N Gly-Val-Val Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)[C@H](C(C)C)NC(=O)CN KSOBNUBCYHGUKH-UWVGGRQHSA-N 0.000 description 3
- JBCLFWXMTIKCCB-UHFFFAOYSA-N H-Gly-Phe-OH Natural products NCC(=O)NC(C(O)=O)CC1=CC=CC=C1 JBCLFWXMTIKCCB-UHFFFAOYSA-N 0.000 description 3
- 101000581981 Homo sapiens Neural cell adhesion molecule 1 Proteins 0.000 description 3
- CYHYBSGMHMHKOA-CIQUZCHMSA-N Ile-Ala-Thr Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](C)C(=O)N[C@@H]([C@@H](C)O)C(=O)O)N CYHYBSGMHMHKOA-CIQUZCHMSA-N 0.000 description 3
- DFFTXLCCDFYRKD-MBLNEYKQSA-N Ile-Gly-Thr Chemical compound CC[C@H](C)[C@@H](C(=O)NCC(=O)N[C@@H]([C@@H](C)O)C(=O)O)N DFFTXLCCDFYRKD-MBLNEYKQSA-N 0.000 description 3
- NPAYJTAXWXJKLO-NAKRPEOUSA-N Ile-Met-Ser Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CO)C(=O)O)N NPAYJTAXWXJKLO-NAKRPEOUSA-N 0.000 description 3
- 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 3
- WKSHBPRUIRGWRZ-KCTSRDHCSA-N Ile-Trp-Gly Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC1=CNC2=CC=CC=C21)C(=O)NCC(=O)O)N WKSHBPRUIRGWRZ-KCTSRDHCSA-N 0.000 description 3
- IBMVEYRWAWIOTN-UHFFFAOYSA-N L-Leucyl-L-Arginyl-L-Proline Natural products CC(C)CC(N)C(=O)NC(CCCN=C(N)N)C(=O)N1CCCC1C(O)=O IBMVEYRWAWIOTN-UHFFFAOYSA-N 0.000 description 3
- SITWEMZOJNKJCH-UHFFFAOYSA-N L-alanine-L-arginine Natural products CC(N)C(=O)NC(C(O)=O)CCCNC(N)=N SITWEMZOJNKJCH-UHFFFAOYSA-N 0.000 description 3
- 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 3
- 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 3
- UCOCBWDBHCUPQP-DCAQKATOSA-N Leu-Arg-Ser Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(O)=O UCOCBWDBHCUPQP-DCAQKATOSA-N 0.000 description 3
- LAPSXOAUPNOINL-YUMQZZPRSA-N Leu-Gly-Asp Chemical compound CC(C)C[C@H](N)C(=O)NCC(=O)N[C@H](C(O)=O)CC(O)=O LAPSXOAUPNOINL-YUMQZZPRSA-N 0.000 description 3
- KYIIALJHAOIAHF-KKUMJFAQSA-N Leu-Leu-His Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](C(O)=O)CC1=CN=CN1 KYIIALJHAOIAHF-KKUMJFAQSA-N 0.000 description 3
- VVQJGYPTIYOFBR-IHRRRGAJSA-N Leu-Lys-Met Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCSC)C(=O)O)N VVQJGYPTIYOFBR-IHRRRGAJSA-N 0.000 description 3
- IRMLZWSRWSGTOP-CIUDSAMLSA-N Leu-Ser-Ala Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@@H](C)C(O)=O IRMLZWSRWSGTOP-CIUDSAMLSA-N 0.000 description 3
- AEDWWMMHUGYIFD-HJGDQZAQSA-N Leu-Thr-Asn Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(O)=O AEDWWMMHUGYIFD-HJGDQZAQSA-N 0.000 description 3
- 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 3
- AIMGJYMCTAABEN-GVXVVHGQSA-N Leu-Val-Glu Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(O)=O)C(O)=O AIMGJYMCTAABEN-GVXVVHGQSA-N 0.000 description 3
- 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 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
- PNPYKQFJGRFYJE-GUBZILKMSA-N Lys-Ala-Glu Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(O)=O PNPYKQFJGRFYJE-GUBZILKMSA-N 0.000 description 3
- 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 3
- 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 3
- 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 3
- 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 3
- ONPDTSFZAIWMDI-AVGNSLFASA-N Lys-Leu-Gln Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(O)=O ONPDTSFZAIWMDI-AVGNSLFASA-N 0.000 description 3
- WGILOYIKJVQUPT-DCAQKATOSA-N Lys-Pro-Asp Chemical compound [H]N[C@@H](CCCCN)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CC(O)=O)C(O)=O WGILOYIKJVQUPT-DCAQKATOSA-N 0.000 description 3
- YTJFXEDRUOQGSP-DCAQKATOSA-N Lys-Pro-Ser Chemical compound [H]N[C@@H](CCCCN)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CO)C(O)=O YTJFXEDRUOQGSP-DCAQKATOSA-N 0.000 description 3
- HKXSZKJMDBHOTG-CIUDSAMLSA-N Lys-Ser-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CCCCN HKXSZKJMDBHOTG-CIUDSAMLSA-N 0.000 description 3
- WQDKIVRHTQYJSN-DCAQKATOSA-N Lys-Ser-Arg Chemical compound C(CCN)C[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCN=C(N)N)C(=O)O)N WQDKIVRHTQYJSN-DCAQKATOSA-N 0.000 description 3
- CTJUSALVKAWFFU-CIUDSAMLSA-N Lys-Ser-Cys Chemical compound C(CCN)C[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CS)C(=O)O)N CTJUSALVKAWFFU-CIUDSAMLSA-N 0.000 description 3
- MIMXMVDLMDMOJD-BZSNNMDCSA-N Lys-Tyr-Leu Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC(C)C)C(O)=O MIMXMVDLMDMOJD-BZSNNMDCSA-N 0.000 description 3
- 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 3
- 241000124008 Mammalia Species 0.000 description 3
- QWTGQXGNNMIUCW-BPUTZDHNSA-N Met-Asn-Trp Chemical compound [H]N[C@@H](CCSC)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC1=CNC2=C1C=CC=C2)C(O)=O QWTGQXGNNMIUCW-BPUTZDHNSA-N 0.000 description 3
- UYAKZHGIPRCGPF-CIUDSAMLSA-N Met-Glu-Ala Chemical compound C[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)O)NC(=O)[C@H](CCSC)N UYAKZHGIPRCGPF-CIUDSAMLSA-N 0.000 description 3
- RUTZUJXAVNWLQP-BVSLBCMMSA-N Met-Tyr-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=CC=C(O)C=C1 RUTZUJXAVNWLQP-BVSLBCMMSA-N 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- 208000033776 Myeloid Acute Leukemia Diseases 0.000 description 3
- 102100027347 Neural cell adhesion molecule 1 Human genes 0.000 description 3
- CGOMLCQJEMWMCE-STQMWFEESA-N Phe-Arg-Gly Chemical compound NC(N)=NCCC[C@@H](C(=O)NCC(O)=O)NC(=O)[C@@H](N)CC1=CC=CC=C1 CGOMLCQJEMWMCE-STQMWFEESA-N 0.000 description 3
- CWFGECHCRMGPPT-MXAVVETBSA-N Phe-Ile-Ser Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(O)=O CWFGECHCRMGPPT-MXAVVETBSA-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
- 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
- FCCBQBZXIAZNIG-LSJOCFKGSA-N Pro-Ala-His Chemical compound C[C@H](NC(=O)[C@@H]1CCCN1)C(=O)N[C@@H](Cc1cnc[nH]1)C(O)=O FCCBQBZXIAZNIG-LSJOCFKGSA-N 0.000 description 3
- ZSKJPKFTPQCPIH-RCWTZXSCSA-N Pro-Arg-Thr Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(O)=O ZSKJPKFTPQCPIH-RCWTZXSCSA-N 0.000 description 3
- MLQVJYMFASXBGZ-IHRRRGAJSA-N Pro-Asn-Tyr Chemical compound C1C[C@H](NC1)C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CC2=CC=C(C=C2)O)C(=O)O MLQVJYMFASXBGZ-IHRRRGAJSA-N 0.000 description 3
- 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 3
- LGSANCBHSMDFDY-GARJFASQSA-N Pro-Glu-Pro Chemical compound C1C[C@H](NC1)C(=O)N[C@@H](CCC(=O)O)C(=O)N2CCC[C@@H]2C(=O)O LGSANCBHSMDFDY-GARJFASQSA-N 0.000 description 3
- 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 3
- SPLBRAKYXGOFSO-UNQGMJICSA-N Pro-Phe-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CC1=CC=CC=C1)NC(=O)[C@@H]2CCCN2)O SPLBRAKYXGOFSO-UNQGMJICSA-N 0.000 description 3
- OWQXAJQZLWHPBH-FXQIFTODSA-N Pro-Ser-Asn Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(O)=O OWQXAJQZLWHPBH-FXQIFTODSA-N 0.000 description 3
- ZUGXSSFMTXKHJS-ZLUOBGJFSA-N Ser-Ala-Ala Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](C)C(=O)N[C@@H](C)C(O)=O ZUGXSSFMTXKHJS-ZLUOBGJFSA-N 0.000 description 3
- HRNQLKCLPVKZNE-CIUDSAMLSA-N Ser-Ala-Leu Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(O)=O HRNQLKCLPVKZNE-CIUDSAMLSA-N 0.000 description 3
- QVOGDCQNGLBNCR-FXQIFTODSA-N Ser-Arg-Ser Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(O)=O QVOGDCQNGLBNCR-FXQIFTODSA-N 0.000 description 3
- 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 3
- BLPYXIXXCFVIIF-FXQIFTODSA-N Ser-Cys-Arg Chemical compound C(C[C@@H](C(=O)O)NC(=O)[C@H](CS)NC(=O)[C@H](CO)N)CN=C(N)N BLPYXIXXCFVIIF-FXQIFTODSA-N 0.000 description 3
- VQBCMLMPEWPUTB-ACZMJKKPSA-N Ser-Glu-Ser Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(O)=O VQBCMLMPEWPUTB-ACZMJKKPSA-N 0.000 description 3
- GZBKRJVCRMZAST-XKBZYTNZSA-N Ser-Glu-Thr Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O GZBKRJVCRMZAST-XKBZYTNZSA-N 0.000 description 3
- GZFAWAQTEYDKII-YUMQZZPRSA-N Ser-Gly-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)CNC(=O)[C@@H](N)CO GZFAWAQTEYDKII-YUMQZZPRSA-N 0.000 description 3
- MQUZANJDFOQOBX-SRVKXCTJSA-N Ser-Phe-Ser Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CO)C(O)=O MQUZANJDFOQOBX-SRVKXCTJSA-N 0.000 description 3
- HHJFMHQYEAAOBM-ZLUOBGJFSA-N Ser-Ser-Ala Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H](C)C(O)=O HHJFMHQYEAAOBM-ZLUOBGJFSA-N 0.000 description 3
- WLJPJRGQRNCIQS-ZLUOBGJFSA-N Ser-Ser-Asn Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(O)=O WLJPJRGQRNCIQS-ZLUOBGJFSA-N 0.000 description 3
- GYDFRTRSSXOZCR-ACZMJKKPSA-N Ser-Ser-Glu Chemical compound OC[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@H](C(O)=O)CCC(O)=O GYDFRTRSSXOZCR-ACZMJKKPSA-N 0.000 description 3
- AXKJPUBALUNJEO-UBHSHLNASA-N Ser-Trp-Asn Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC1=CNC2=C1C=CC=C2)C(=O)N[C@@H](CC(N)=O)C(O)=O AXKJPUBALUNJEO-UBHSHLNASA-N 0.000 description 3
- ATEQEHCGZKBEMU-GQGQLFGLSA-N Ser-Trp-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)[C@H](CC1=CNC2=CC=CC=C21)NC(=O)[C@H](CO)N ATEQEHCGZKBEMU-GQGQLFGLSA-N 0.000 description 3
- YXGCIEUDOHILKR-IHRRRGAJSA-N Ser-Tyr-Met Chemical compound CSCC[C@@H](C(=O)O)NC(=O)[C@H](CC1=CC=C(C=C1)O)NC(=O)[C@H](CO)N YXGCIEUDOHILKR-IHRRRGAJSA-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
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 3
- UNURFMVMXLENAZ-KJEVXHAQSA-N Thr-Arg-Tyr Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O UNURFMVMXLENAZ-KJEVXHAQSA-N 0.000 description 3
- DCLBXIWHLVEPMQ-JRQIVUDYSA-N Thr-Asp-Tyr Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 DCLBXIWHLVEPMQ-JRQIVUDYSA-N 0.000 description 3
- 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 3
- YDWLCDQXLCILCZ-BWAGICSOSA-N Thr-His-Tyr Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O YDWLCDQXLCILCZ-BWAGICSOSA-N 0.000 description 3
- DXPURPNJDFCKKO-RHYQMDGZSA-N Thr-Lys-Val Chemical compound CC(C)[C@H](NC(=O)[C@H](CCCCN)NC(=O)[C@@H](N)[C@@H](C)O)C(O)=O DXPURPNJDFCKKO-RHYQMDGZSA-N 0.000 description 3
- 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 3
- MXNAOGFNFNKUPD-JHYOHUSXSA-N Thr-Phe-Thr Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H]([C@@H](C)O)C(O)=O MXNAOGFNFNKUPD-JHYOHUSXSA-N 0.000 description 3
- OLFOOYQTTQSSRK-UNQGMJICSA-N Thr-Pro-Phe Chemical compound C[C@@H](O)[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 OLFOOYQTTQSSRK-UNQGMJICSA-N 0.000 description 3
- STUAPCLEDMKXKL-LKXGYXEUSA-N Thr-Ser-Asn Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(O)=O STUAPCLEDMKXKL-LKXGYXEUSA-N 0.000 description 3
- IQPWNQRRAJHOKV-KATARQTJSA-N Thr-Ser-Lys Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@H](C(O)=O)CCCCN IQPWNQRRAJHOKV-KATARQTJSA-N 0.000 description 3
- IEZVHOULSUULHD-XGEHTFHBSA-N Thr-Ser-Val Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(O)=O IEZVHOULSUULHD-XGEHTFHBSA-N 0.000 description 3
- NJGMALCNYAMYCB-JRQIVUDYSA-N Thr-Tyr-Asn Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC(N)=O)C(O)=O NJGMALCNYAMYCB-JRQIVUDYSA-N 0.000 description 3
- JAWUQFCGNVEDRN-MEYUZBJRSA-N Thr-Tyr-Leu Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC1=CC=C(C=C1)O)C(=O)N[C@@H](CC(C)C)C(=O)O)N)O JAWUQFCGNVEDRN-MEYUZBJRSA-N 0.000 description 3
- AVYVKJMBNLPWRX-WFBYXXMGSA-N Trp-Ala-Ser Chemical compound C1=CC=C2C(C[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](CO)C(O)=O)=CNC2=C1 AVYVKJMBNLPWRX-WFBYXXMGSA-N 0.000 description 3
- UIRVSEPRMWDVEW-RNXOBYDBSA-N Trp-Tyr-Phe Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)O)NC(=O)[C@H](CC2=CC=C(C=C2)O)NC(=O)[C@H](CC3=CNC4=CC=CC=C43)N UIRVSEPRMWDVEW-RNXOBYDBSA-N 0.000 description 3
- YGKVNUAKYPGORG-AVGNSLFASA-N Tyr-Asp-Glu Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(O)=O YGKVNUAKYPGORG-AVGNSLFASA-N 0.000 description 3
- HDSKHCBAVVWPCQ-FHWLQOOXSA-N Tyr-Glu-Phe Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O HDSKHCBAVVWPCQ-FHWLQOOXSA-N 0.000 description 3
- HIINQLBHPIQYHN-JTQLQIEISA-N Tyr-Gly-Gly Chemical compound OC(=O)CNC(=O)CNC(=O)[C@@H](N)CC1=CC=C(O)C=C1 HIINQLBHPIQYHN-JTQLQIEISA-N 0.000 description 3
- 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 3
- XDGPTBVOSHKDFT-KKUMJFAQSA-N Tyr-Met-Glu Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCC(O)=O)C(O)=O XDGPTBVOSHKDFT-KKUMJFAQSA-N 0.000 description 3
- UPODKYBYUBTWSV-BZSNNMDCSA-N Tyr-Phe-Cys Chemical compound C([C@H](N)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CS)C(O)=O)C1=CC=C(O)C=C1 UPODKYBYUBTWSV-BZSNNMDCSA-N 0.000 description 3
- XFEMMSGONWQACR-KJEVXHAQSA-N Tyr-Thr-Met Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCSC)C(=O)O)NC(=O)[C@H](CC1=CC=C(C=C1)O)N)O XFEMMSGONWQACR-KJEVXHAQSA-N 0.000 description 3
- 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 3
- RZAGEHHVNYESNR-RNXOBYDBSA-N Tyr-Trp-Tyr 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](CC1=CC=C(O)C=C1)C(O)=O RZAGEHHVNYESNR-RNXOBYDBSA-N 0.000 description 3
- GZWPQZDVTBZVEP-BZSNNMDCSA-N Tyr-Tyr-Asn Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC(N)=O)C(O)=O GZWPQZDVTBZVEP-BZSNNMDCSA-N 0.000 description 3
- RMRFSFXLFWWAJZ-HJOGWXRNSA-N Tyr-Tyr-Tyr Chemical compound C([C@H](N)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(O)=O)C1=CC=C(O)C=C1 RMRFSFXLFWWAJZ-HJOGWXRNSA-N 0.000 description 3
- GNWUWQAVVJQREM-NHCYSSNCSA-N Val-Asn-His Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)N GNWUWQAVVJQREM-NHCYSSNCSA-N 0.000 description 3
- XKVXSCHXGJOQND-ZOBUZTSGSA-N Val-Asp-Trp Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](CC1=CNC2=CC=CC=C21)C(=O)O)N XKVXSCHXGJOQND-ZOBUZTSGSA-N 0.000 description 3
- SZTTYWIUCGSURQ-AUTRQRHGSA-N Val-Glu-Glu Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(O)=O SZTTYWIUCGSURQ-AUTRQRHGSA-N 0.000 description 3
- ROLGIBMFNMZANA-GVXVVHGQSA-N Val-Glu-Leu Chemical compound CC(C)C[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)O)NC(=O)[C@H](C(C)C)N ROLGIBMFNMZANA-GVXVVHGQSA-N 0.000 description 3
- ZIGZPYJXIWLQFC-QTKMDUPCSA-N Val-His-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CC1=CN=CN1)NC(=O)[C@H](C(C)C)N)O ZIGZPYJXIWLQFC-QTKMDUPCSA-N 0.000 description 3
- DIOSYUIWOQCXNR-ONGXEEELSA-N Val-Lys-Gly Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](CCCCN)C(=O)NCC(O)=O DIOSYUIWOQCXNR-ONGXEEELSA-N 0.000 description 3
- ZRSZTKTVPNSUNA-IHRRRGAJSA-N Val-Lys-Leu Chemical compound CC(C)C[C@H](NC(=O)[C@H](CCCCN)NC(=O)[C@@H](N)C(C)C)C(O)=O ZRSZTKTVPNSUNA-IHRRRGAJSA-N 0.000 description 3
- VCIYTVOBLZHFSC-XHSDSOJGSA-N Val-Phe-Pro Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N2CCC[C@@H]2C(=O)O)N VCIYTVOBLZHFSC-XHSDSOJGSA-N 0.000 description 3
- GBIUHAYJGWVNLN-AEJSXWLSSA-N Val-Ser-Pro Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CO)C(=O)N1CCC[C@@H]1C(=O)O)N GBIUHAYJGWVNLN-AEJSXWLSSA-N 0.000 description 3
- GBIUHAYJGWVNLN-UHFFFAOYSA-N Val-Ser-Pro Natural products CC(C)C(N)C(=O)NC(CO)C(=O)N1CCCC1C(O)=O GBIUHAYJGWVNLN-UHFFFAOYSA-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
- 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 3
- 230000009471 action Effects 0.000 description 3
- 230000004913 activation Effects 0.000 description 3
- 239000000556 agonist Substances 0.000 description 3
- 108010069926 arginyl-glycyl-serine Proteins 0.000 description 3
- 239000000872 buffer Substances 0.000 description 3
- 238000010367 cloning Methods 0.000 description 3
- 238000010276 construction Methods 0.000 description 3
- 230000003247 decreasing effect Effects 0.000 description 3
- 239000002552 dosage form Substances 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 230000006870 function Effects 0.000 description 3
- 238000001415 gene therapy Methods 0.000 description 3
- 108010090037 glycyl-alanyl-isoleucine Proteins 0.000 description 3
- 108010019832 glycyl-asparaginyl-glycine Proteins 0.000 description 3
- 108010077435 glycyl-phenylalanyl-glycine Proteins 0.000 description 3
- 108010081551 glycylphenylalanine Proteins 0.000 description 3
- 230000036541 health Effects 0.000 description 3
- 238000009169 immunotherapy Methods 0.000 description 3
- 230000001965 increasing effect Effects 0.000 description 3
- 238000001802 infusion Methods 0.000 description 3
- 238000010369 molecular cloning Methods 0.000 description 3
- 239000004570 mortar (masonry) Substances 0.000 description 3
- 239000002773 nucleotide Substances 0.000 description 3
- 125000003729 nucleotide group Chemical group 0.000 description 3
- 210000000056 organ Anatomy 0.000 description 3
- 238000004806 packaging method and process Methods 0.000 description 3
- 108010073025 phenylalanylphenylalanine Proteins 0.000 description 3
- 108010025488 pinealon Proteins 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 108010090894 prolylleucine Proteins 0.000 description 3
- 108010061238 threonyl-glycine Proteins 0.000 description 3
- 230000001988 toxicity Effects 0.000 description 3
- 231100000419 toxicity Toxicity 0.000 description 3
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 2
- RLMISHABBKUNFO-WHFBIAKZSA-N Ala-Ala-Gly Chemical compound C[C@H](N)C(=O)N[C@@H](C)C(=O)NCC(O)=O RLMISHABBKUNFO-WHFBIAKZSA-N 0.000 description 2
- SKHCUBQVZJHOFM-NAKRPEOUSA-N Ala-Arg-Ile Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O SKHCUBQVZJHOFM-NAKRPEOUSA-N 0.000 description 2
- YWWATNIVMOCSAV-UBHSHLNASA-N Ala-Arg-Phe Chemical compound NC(=N)NCCC[C@H](NC(=O)[C@@H](N)C)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 YWWATNIVMOCSAV-UBHSHLNASA-N 0.000 description 2
- DWINFPQUSSHSFS-UVBJJODRSA-N Ala-Arg-Trp Chemical compound N[C@@H](C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC1=CNC2=CC=CC=C12)C(=O)O DWINFPQUSSHSFS-UVBJJODRSA-N 0.000 description 2
- SMCGQGDVTPFXKB-XPUUQOCRSA-N Ala-Gly-Val Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)CNC(=O)[C@H](C)N SMCGQGDVTPFXKB-XPUUQOCRSA-N 0.000 description 2
- RZZMZYZXNJRPOJ-BJDJZHNGSA-N Ala-Ile-Lys Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](C)N RZZMZYZXNJRPOJ-BJDJZHNGSA-N 0.000 description 2
- QQACQIHVWCVBBR-GVARAGBVSA-N Ala-Ile-Tyr Chemical compound [H]N[C@@H](C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O QQACQIHVWCVBBR-GVARAGBVSA-N 0.000 description 2
- AWZKCUCQJNTBAD-SRVKXCTJSA-N Ala-Leu-Lys Chemical compound C[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](C(O)=O)CCCCN AWZKCUCQJNTBAD-SRVKXCTJSA-N 0.000 description 2
- BLTRAARCJYVJKV-QEJZJMRPSA-N Ala-Lys-Phe Chemical compound C[C@H](N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](Cc1ccccc1)C(O)=O BLTRAARCJYVJKV-QEJZJMRPSA-N 0.000 description 2
- PHQXWZGXKAFWAZ-ZLIFDBKOSA-N Ala-Trp-Lys Chemical compound C1=CC=C2C(C[C@H](NC(=O)[C@@H](N)C)C(=O)N[C@@H](CCCCN)C(O)=O)=CNC2=C1 PHQXWZGXKAFWAZ-ZLIFDBKOSA-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
- 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 2
- MUGAESARFRGOTQ-IGNZVWTISA-N Ala-Tyr-Tyr Chemical compound 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 MUGAESARFRGOTQ-IGNZVWTISA-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
- MTANSHNQTWPZKP-KKUMJFAQSA-N Arg-Gln-Tyr Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)N)NC(=O)[C@H](CCCN=C(N)N)N)O MTANSHNQTWPZKP-KKUMJFAQSA-N 0.000 description 2
- DNUKXVMPARLPFN-XUXIUFHCSA-N Arg-Leu-Ile Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O DNUKXVMPARLPFN-XUXIUFHCSA-N 0.000 description 2
- BECXEHHOZNFFFX-IHRRRGAJSA-N Arg-Ser-Tyr Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O BECXEHHOZNFFFX-IHRRRGAJSA-N 0.000 description 2
- XRNXPIGJPQHCPC-RCWTZXSCSA-N Arg-Thr-Val Chemical compound CC(C)[C@H](NC(=O)[C@@H](NC(=O)[C@@H](N)CCCNC(N)=N)[C@@H](C)O)C(O)=O XRNXPIGJPQHCPC-RCWTZXSCSA-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
- QLSRIZIDQXDQHK-RCWTZXSCSA-N Arg-Val-Thr Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O QLSRIZIDQXDQHK-RCWTZXSCSA-N 0.000 description 2
- PCKRJVZAQZWNKM-WHFBIAKZSA-N Asn-Asn-Gly Chemical compound NC(=O)C[C@H](N)C(=O)N[C@@H](CC(N)=O)C(=O)NCC(O)=O PCKRJVZAQZWNKM-WHFBIAKZSA-N 0.000 description 2
- APHUDFFMXFYRKP-CIUDSAMLSA-N Asn-Asn-Lys Chemical compound C(CCN)C[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)N)NC(=O)[C@H](CC(=O)N)N APHUDFFMXFYRKP-CIUDSAMLSA-N 0.000 description 2
- IICZCLFBILYRCU-WHFBIAKZSA-N Asn-Gly-Asp Chemical compound [H]N[C@@H](CC(N)=O)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(O)=O IICZCLFBILYRCU-WHFBIAKZSA-N 0.000 description 2
- UDSVWSUXKYXSTR-QWRGUYRKSA-N Asn-Gly-Tyr Chemical compound [H]N[C@@H](CC(N)=O)C(=O)NCC(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O UDSVWSUXKYXSTR-QWRGUYRKSA-N 0.000 description 2
- RCFGLXMZDYNRSC-CIUDSAMLSA-N Asn-Lys-Ala Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(O)=O RCFGLXMZDYNRSC-CIUDSAMLSA-N 0.000 description 2
- VOKWBBBXJONREA-DCAQKATOSA-N Asn-Met-His Chemical compound CSCC[C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)NC(=O)[C@H](CC(=O)N)N VOKWBBBXJONREA-DCAQKATOSA-N 0.000 description 2
- QXOPPIDJKPEKCW-GUBZILKMSA-N Asn-Pro-Arg Chemical compound C1C[C@H](N(C1)C(=O)[C@H](CC(=O)N)N)C(=O)N[C@@H](CCCN=C(N)N)C(=O)O QXOPPIDJKPEKCW-GUBZILKMSA-N 0.000 description 2
- KZYSHAMXEBPJBD-JRQIVUDYSA-N Asn-Thr-Tyr Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O KZYSHAMXEBPJBD-JRQIVUDYSA-N 0.000 description 2
- YSYTWUMRHSFODC-QWRGUYRKSA-N Asn-Tyr-Gly Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)NCC(O)=O YSYTWUMRHSFODC-QWRGUYRKSA-N 0.000 description 2
- DPSUVAPLRQDWAO-YDHLFZDLSA-N Asn-Tyr-Val Chemical compound CC(C)[C@@H](C(=O)O)NC(=O)[C@H](CC1=CC=C(C=C1)O)NC(=O)[C@H](CC(=O)N)N DPSUVAPLRQDWAO-YDHLFZDLSA-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
- VPSHHQXIWLGVDD-ZLUOBGJFSA-N Asp-Asp-Asp Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(O)=O)C(O)=O VPSHHQXIWLGVDD-ZLUOBGJFSA-N 0.000 description 2
- KTTCQQNRRLCIBC-GHCJXIJMSA-N Asp-Ile-Ala 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(O)=O KTTCQQNRRLCIBC-GHCJXIJMSA-N 0.000 description 2
- UZFHNLYQWMGUHU-DCAQKATOSA-N Asp-Lys-Arg Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O UZFHNLYQWMGUHU-DCAQKATOSA-N 0.000 description 2
- NONWUQAWAANERO-BZSNNMDCSA-N Asp-Phe-Tyr Chemical compound C([C@H](NC(=O)[C@H](CC(O)=O)N)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(O)=O)C1=CC=CC=C1 NONWUQAWAANERO-BZSNNMDCSA-N 0.000 description 2
- QSFHZPQUAAQHAQ-CIUDSAMLSA-N Asp-Ser-Leu Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(O)=O QSFHZPQUAAQHAQ-CIUDSAMLSA-N 0.000 description 2
- USENATHVGFXRNO-SRVKXCTJSA-N Asp-Tyr-Asp Chemical compound OC(=O)C[C@H](N)C(=O)N[C@H](C(=O)N[C@@H](CC(O)=O)C(O)=O)CC1=CC=C(O)C=C1 USENATHVGFXRNO-SRVKXCTJSA-N 0.000 description 2
- BYLPQJAWXJWUCJ-YDHLFZDLSA-N Asp-Tyr-Val 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](C(C)C)C(O)=O BYLPQJAWXJWUCJ-YDHLFZDLSA-N 0.000 description 2
- 208000023275 Autoimmune disease Diseases 0.000 description 2
- 229940045513 CTLA4 antagonist Drugs 0.000 description 2
- 102000000905 Cadherin Human genes 0.000 description 2
- 108050007957 Cadherin Proteins 0.000 description 2
- 241000282472 Canis lupus familiaris Species 0.000 description 2
- 241000282693 Cercopithecidae Species 0.000 description 2
- BLGNLNRBABWDST-CIUDSAMLSA-N Cys-Leu-Asp Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)O)NC(=O)[C@H](CS)N BLGNLNRBABWDST-CIUDSAMLSA-N 0.000 description 2
- VPQZSNQICFCCSO-BJDJZHNGSA-N Cys-Leu-Ile Chemical compound [H]N[C@@H](CS)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O VPQZSNQICFCCSO-BJDJZHNGSA-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
- MXZYQNJCBVJHSR-KATARQTJSA-N Cys-Lys-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CS)N)O MXZYQNJCBVJHSR-KATARQTJSA-N 0.000 description 2
- 102100039498 Cytotoxic T-lymphocyte protein 4 Human genes 0.000 description 2
- WQZGKKKJIJFFOK-QTVWNMPRSA-N D-mannopyranose Chemical compound OC[C@H]1OC(O)[C@@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-QTVWNMPRSA-N 0.000 description 2
- 238000002965 ELISA Methods 0.000 description 2
- 241000282326 Felis catus Species 0.000 description 2
- 102100037362 Fibronectin Human genes 0.000 description 2
- 108010067306 Fibronectins Proteins 0.000 description 2
- SHERTACNJPYHAR-ACZMJKKPSA-N Gln-Ala-Ser Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CCC(N)=O SHERTACNJPYHAR-ACZMJKKPSA-N 0.000 description 2
- 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 2
- GPISLLFQNHELLK-DCAQKATOSA-N Gln-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](CCC(=O)N)N GPISLLFQNHELLK-DCAQKATOSA-N 0.000 description 2
- OOLCSQQPSLIETN-JYJNAYRXSA-N Gln-His-Tyr Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)O)NC(=O)[C@H](CC2=CN=CN2)NC(=O)[C@H](CCC(=O)N)N)O OOLCSQQPSLIETN-JYJNAYRXSA-N 0.000 description 2
- LGIKBBLQVSWUGK-DCAQKATOSA-N Gln-Leu-Gln Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(O)=O LGIKBBLQVSWUGK-DCAQKATOSA-N 0.000 description 2
- WLRYGVYQFXRJDA-DCAQKATOSA-N Gln-Pro-Pro Chemical compound NC(=O)CC[C@H](N)C(=O)N1CCC[C@H]1C(=O)N1[C@H](C(O)=O)CCC1 WLRYGVYQFXRJDA-DCAQKATOSA-N 0.000 description 2
- VLOLPWWCNKWRNB-LOKLDPHHSA-N Gln-Thr-Pro Chemical compound C[C@H]([C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](CCC(=O)N)N)O VLOLPWWCNKWRNB-LOKLDPHHSA-N 0.000 description 2
- XKPACHRGOWQHFH-IRIUXVKKSA-N Gln-Thr-Tyr Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O XKPACHRGOWQHFH-IRIUXVKKSA-N 0.000 description 2
- HLRLXVPRJJITSK-IFFSRLJSSA-N Gln-Thr-Val Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(O)=O HLRLXVPRJJITSK-IFFSRLJSSA-N 0.000 description 2
- WPJDPEOQUIXXOY-AVGNSLFASA-N Gln-Tyr-Asn Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)O)NC(=O)[C@H](CCC(=O)N)N)O WPJDPEOQUIXXOY-AVGNSLFASA-N 0.000 description 2
- HPBKQFJXDUVNQV-FHWLQOOXSA-N Gln-Tyr-Tyr Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)N[C@@H](CC2=CC=C(C=C2)O)C(=O)O)NC(=O)[C@H](CCC(=O)N)N)O HPBKQFJXDUVNQV-FHWLQOOXSA-N 0.000 description 2
- AVZHGSCDKIQZPQ-CIUDSAMLSA-N Glu-Arg-Ala Chemical compound C[C@H](NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@@H](N)CCC(O)=O)C(O)=O AVZHGSCDKIQZPQ-CIUDSAMLSA-N 0.000 description 2
- DYFJZDDQPNIPAB-NHCYSSNCSA-N Glu-Arg-Val Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C(C)C)C(O)=O DYFJZDDQPNIPAB-NHCYSSNCSA-N 0.000 description 2
- QPRZKNOOOBWXSU-CIUDSAMLSA-N Glu-Asp-Arg Chemical compound OC(=O)CC[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@H](C(O)=O)CCCN=C(N)N QPRZKNOOOBWXSU-CIUDSAMLSA-N 0.000 description 2
- 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 2
- RAUDKMVXNOWDLS-WDSKDSINSA-N Glu-Gly-Ser Chemical compound OC(=O)CC[C@H](N)C(=O)NCC(=O)N[C@@H](CO)C(O)=O RAUDKMVXNOWDLS-WDSKDSINSA-N 0.000 description 2
- CAQXJMUDOLSBPF-SUSMZKCASA-N Glu-Thr-Thr Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O CAQXJMUDOLSBPF-SUSMZKCASA-N 0.000 description 2
- UQULNJAARAXSPO-ZCWPNWOLSA-N Glu-Thr-Thr-Tyr Chemical compound OC(=O)CC[C@H](N)C(=O)N[C@@H]([C@H](O)C)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 UQULNJAARAXSPO-ZCWPNWOLSA-N 0.000 description 2
- BKMOHWJHXQLFEX-IRIUXVKKSA-N Glu-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](CCC(=O)O)N)O BKMOHWJHXQLFEX-IRIUXVKKSA-N 0.000 description 2
- YMUFWNJHVPQNQD-ZKWXMUAHSA-N Gly-Ala-Ile Chemical compound CC[C@H](C)[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)CN YMUFWNJHVPQNQD-ZKWXMUAHSA-N 0.000 description 2
- 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 2
- FMNHBTKMRFVGRO-FOHZUACHSA-N Gly-Asn-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)[C@H](CC(N)=O)NC(=O)CN FMNHBTKMRFVGRO-FOHZUACHSA-N 0.000 description 2
- IWAXHBCACVWNHT-BQBZGAKWSA-N Gly-Asp-Arg Chemical compound NCC(=O)N[C@@H](CC(O)=O)C(=O)N[C@H](C(O)=O)CCCN=C(N)N IWAXHBCACVWNHT-BQBZGAKWSA-N 0.000 description 2
- QGZSAHIZRQHCEQ-QWRGUYRKSA-N Gly-Asp-Tyr Chemical compound NCC(=O)N[C@@H](CC(O)=O)C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 QGZSAHIZRQHCEQ-QWRGUYRKSA-N 0.000 description 2
- HQRHFUYMGCHHJS-LURJTMIESA-N Gly-Gly-Arg Chemical compound NCC(=O)NCC(=O)N[C@H](C(O)=O)CCCN=C(N)N HQRHFUYMGCHHJS-LURJTMIESA-N 0.000 description 2
- XMPXVJIDADUOQB-RCOVLWMOSA-N Gly-Gly-Ile Chemical compound CC[C@H](C)[C@@H](C([O-])=O)NC(=O)CNC(=O)C[NH3+] XMPXVJIDADUOQB-RCOVLWMOSA-N 0.000 description 2
- QAMMIGULQSIRCD-IRXDYDNUSA-N Gly-Phe-Tyr Chemical compound C([C@H](NC(=O)C[NH3+])C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C([O-])=O)C1=CC=CC=C1 QAMMIGULQSIRCD-IRXDYDNUSA-N 0.000 description 2
- 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 2
- WNGHUXFWEWTKAO-YUMQZZPRSA-N Gly-Ser-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](CO)NC(=O)CN WNGHUXFWEWTKAO-YUMQZZPRSA-N 0.000 description 2
- FKYQEVBRZSFAMJ-QWRGUYRKSA-N Gly-Ser-Tyr Chemical compound NCC(=O)N[C@@H](CO)C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 FKYQEVBRZSFAMJ-QWRGUYRKSA-N 0.000 description 2
- JKSMZVCGQWVTBW-STQMWFEESA-N Gly-Trp-Asn Chemical compound [H]NCC(=O)N[C@@H](CC1=CNC2=C1C=CC=C2)C(=O)N[C@@H](CC(N)=O)C(O)=O JKSMZVCGQWVTBW-STQMWFEESA-N 0.000 description 2
- 239000004471 Glycine Substances 0.000 description 2
- 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 2
- MDOBWSFNSNPENN-PMVVWTBXSA-N His-Thr-Gly Chemical compound [H]N[C@@H](CC1=CNC=N1)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(O)=O MDOBWSFNSNPENN-PMVVWTBXSA-N 0.000 description 2
- KECFCPNPPYCGBL-PMVMPFDFSA-N His-Trp-Phe Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)O)NC(=O)[C@H](CC2=CNC3=CC=CC=C32)NC(=O)[C@H](CC4=CN=CN4)N KECFCPNPPYCGBL-PMVMPFDFSA-N 0.000 description 2
- 101000889276 Homo sapiens Cytotoxic T-lymphocyte protein 4 Proteins 0.000 description 2
- 101000851181 Homo sapiens Epidermal growth factor receptor Proteins 0.000 description 2
- 101001057504 Homo sapiens Interferon-stimulated gene 20 kDa protein Proteins 0.000 description 2
- 101001055144 Homo sapiens Interleukin-2 receptor subunit alpha Proteins 0.000 description 2
- NCSIQAFSIPHVAN-IUKAMOBKSA-N Ile-Asn-Thr Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H]([C@@H](C)O)C(=O)O)N NCSIQAFSIPHVAN-IUKAMOBKSA-N 0.000 description 2
- FADXGVVLSPPEQY-GHCJXIJMSA-N Ile-Cys-Asn Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(=O)N)C(=O)O)N FADXGVVLSPPEQY-GHCJXIJMSA-N 0.000 description 2
- UAQSZXGJGLHMNV-XEGUGMAKSA-N Ile-Gly-Tyr Chemical compound CC[C@H](C)[C@@H](C(=O)NCC(=O)N[C@@H](CC1=CC=C(C=C1)O)C(=O)O)N UAQSZXGJGLHMNV-XEGUGMAKSA-N 0.000 description 2
- GTSAALPQZASLPW-KJYZGMDISA-N Ile-His-Trp Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)N[C@@H](CC2=CNC3=CC=CC=C32)C(=O)O)N GTSAALPQZASLPW-KJYZGMDISA-N 0.000 description 2
- NZGTYCMLUGYMCV-XUXIUFHCSA-N Ile-Lys-Arg Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCN=C(N)N)C(=O)O)N NZGTYCMLUGYMCV-XUXIUFHCSA-N 0.000 description 2
- NSPNUMNLZNOPAQ-SJWGOKEGSA-N Ile-Tyr-Pro Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC1=CC=C(C=C1)O)C(=O)N2CCC[C@@H]2C(=O)O)N NSPNUMNLZNOPAQ-SJWGOKEGSA-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
- 102100026878 Interleukin-2 receptor subunit alpha Human genes 0.000 description 2
- FADYJNXDPBKVCA-UHFFFAOYSA-N L-Phenylalanyl-L-lysin Natural products NCCCCC(C(O)=O)NC(=O)C(N)CC1=CC=CC=C1 FADYJNXDPBKVCA-UHFFFAOYSA-N 0.000 description 2
- BQSLGJHIAGOZCD-CIUDSAMLSA-N Leu-Ala-Ser Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](CO)C(O)=O BQSLGJHIAGOZCD-CIUDSAMLSA-N 0.000 description 2
- HXWALXSAVBLTPK-NUTKFTJISA-N Leu-Ala-Trp Chemical compound C[C@@H](C(=O)N[C@@H](CC1=CNC2=CC=CC=C21)C(=O)O)NC(=O)[C@H](CC(C)C)N HXWALXSAVBLTPK-NUTKFTJISA-N 0.000 description 2
- ZTLGVASZOIKNIX-DCAQKATOSA-N Leu-Gln-Glu Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H](CCC(=O)O)C(=O)O)N ZTLGVASZOIKNIX-DCAQKATOSA-N 0.000 description 2
- HYMLKESRWLZDBR-WEDXCCLWSA-N Leu-Gly-Thr Chemical compound CC(C)C[C@H](N)C(=O)NCC(=O)N[C@@H]([C@@H](C)O)C(O)=O HYMLKESRWLZDBR-WEDXCCLWSA-N 0.000 description 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
- ZGUMORRUBUCXEH-AVGNSLFASA-N Leu-Lys-Gln Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(N)=O)C(O)=O ZGUMORRUBUCXEH-AVGNSLFASA-N 0.000 description 2
- AKVBOOKXVAMKSS-GUBZILKMSA-N Leu-Ser-Gln Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(O)=O AKVBOOKXVAMKSS-GUBZILKMSA-N 0.000 description 2
- ZJZNLRVCZWUONM-JXUBOQSCSA-N Leu-Thr-Ala Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C)C(O)=O ZJZNLRVCZWUONM-JXUBOQSCSA-N 0.000 description 2
- FUKDBQGFSJUXGX-RWMBFGLXSA-N Lys-Arg-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CCCCN)N)C(=O)O FUKDBQGFSJUXGX-RWMBFGLXSA-N 0.000 description 2
- NTSPQIONFJUMJV-AVGNSLFASA-N Lys-Arg-Val Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C(C)C)C(O)=O NTSPQIONFJUMJV-AVGNSLFASA-N 0.000 description 2
- FLCMXEFCTLXBTL-DCAQKATOSA-N Lys-Asp-Arg Chemical compound C(CCN)C[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](CCCN=C(N)N)C(=O)O)N FLCMXEFCTLXBTL-DCAQKATOSA-N 0.000 description 2
- DFXQCCBKGUNYGG-GUBZILKMSA-N Lys-Gln-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](N)CCCCN DFXQCCBKGUNYGG-GUBZILKMSA-N 0.000 description 2
- NNCDAORZCMPZPX-GUBZILKMSA-N Lys-Gln-Ser Chemical compound C(CCN)C[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H](CO)C(=O)O)N NNCDAORZCMPZPX-GUBZILKMSA-N 0.000 description 2
- GPJGFSFYBJGYRX-YUMQZZPRSA-N Lys-Gly-Asp Chemical compound NCCCC[C@H](N)C(=O)NCC(=O)N[C@H](C(O)=O)CC(O)=O GPJGFSFYBJGYRX-YUMQZZPRSA-N 0.000 description 2
- 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 2
- FGMHXLULNHTPID-KKUMJFAQSA-N Lys-His-Lys Chemical compound NCCCC[C@H](N)C(=O)N[C@H](C(=O)N[C@@H](CCCCN)C(O)=O)CC1=CN=CN1 FGMHXLULNHTPID-KKUMJFAQSA-N 0.000 description 2
- OIYWBDBHEGAVST-BZSNNMDCSA-N Lys-His-Tyr Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O OIYWBDBHEGAVST-BZSNNMDCSA-N 0.000 description 2
- VUTWYNQUSJWBHO-BZSNNMDCSA-N Lys-Leu-Tyr Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O VUTWYNQUSJWBHO-BZSNNMDCSA-N 0.000 description 2
- QQPSCXKFDSORFT-IHRRRGAJSA-N Lys-Lys-Val Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](N)CCCCN QQPSCXKFDSORFT-IHRRRGAJSA-N 0.000 description 2
- JYVCOTWSRGFABJ-DCAQKATOSA-N Lys-Met-Ser Chemical compound CSCC[C@@H](C(=O)N[C@@H](CO)C(=O)O)NC(=O)[C@H](CCCCN)N JYVCOTWSRGFABJ-DCAQKATOSA-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
- 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 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
- 102000000440 Melanoma-associated antigen Human genes 0.000 description 2
- 108050008953 Melanoma-associated antigen Proteins 0.000 description 2
- 102100027159 Membrane primary amine oxidase Human genes 0.000 description 2
- 101710132836 Membrane primary amine oxidase Proteins 0.000 description 2
- CAODKDAPYGUMLK-FXQIFTODSA-N Met-Asn-Ser Chemical compound CSCC[C@H](N)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CO)C(O)=O CAODKDAPYGUMLK-FXQIFTODSA-N 0.000 description 2
- 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 2
- 241001529936 Murinae Species 0.000 description 2
- WUGMRIBZSVSJNP-UHFFFAOYSA-N N-L-alanyl-L-tryptophan Natural products C1=CC=C2C(CC(NC(=O)C(N)C)C(O)=O)=CNC2=C1 WUGMRIBZSVSJNP-UHFFFAOYSA-N 0.000 description 2
- AJHCSUXXECOXOY-UHFFFAOYSA-N N-glycyl-L-tryptophan Natural products C1=CC=C2C(CC(NC(=O)CN)C(O)=O)=CNC2=C1 AJHCSUXXECOXOY-UHFFFAOYSA-N 0.000 description 2
- 108010002311 N-glycylglutamic acid Proteins 0.000 description 2
- 102000019315 Nicotinic acetylcholine receptors Human genes 0.000 description 2
- 108050006807 Nicotinic acetylcholine receptors Proteins 0.000 description 2
- 108091028043 Nucleic acid sequence Proteins 0.000 description 2
- DFEVBOYEUQJGER-JURCDPSOSA-N Phe-Ala-Ile Chemical compound N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)O DFEVBOYEUQJGER-JURCDPSOSA-N 0.000 description 2
- XWBJLKDCHJVKAK-KKUMJFAQSA-N Phe-Arg-Gln Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CCC(=O)N)C(=O)O)N XWBJLKDCHJVKAK-KKUMJFAQSA-N 0.000 description 2
- JIYJYFIXQTYDNF-YDHLFZDLSA-N Phe-Asn-Val Chemical compound CC(C)[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)N)NC(=O)[C@H](CC1=CC=CC=C1)N JIYJYFIXQTYDNF-YDHLFZDLSA-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
- 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
- UNBFGVQVQGXXCK-KKUMJFAQSA-N Phe-Ser-Leu Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(O)=O UNBFGVQVQGXXCK-KKUMJFAQSA-N 0.000 description 2
- BPIFSOUEUYDJRM-DCPHZVHLSA-N Phe-Trp-Ala Chemical compound C([C@H](N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](C)C(O)=O)C1=CC=CC=C1 BPIFSOUEUYDJRM-DCPHZVHLSA-N 0.000 description 2
- VDTYRPWRWRCROL-UFYCRDLUSA-N Phe-Val-Phe Chemical compound C([C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)C1=CC=CC=C1 VDTYRPWRWRCROL-UFYCRDLUSA-N 0.000 description 2
- WWAQEUOYCYMGHB-FXQIFTODSA-N Pro-Asn-Asn Chemical compound NC(=O)C[C@@H](C(O)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H]1CCCN1 WWAQEUOYCYMGHB-FXQIFTODSA-N 0.000 description 2
- VDGTVWFMRXVQCT-GUBZILKMSA-N Pro-Glu-Gln Chemical compound NC(=O)CC[C@@H](C(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H]1CCCN1 VDGTVWFMRXVQCT-GUBZILKMSA-N 0.000 description 2
- DXTOOBDIIAJZBJ-BQBZGAKWSA-N Pro-Gly-Ser Chemical compound [H]N1CCC[C@H]1C(=O)NCC(=O)N[C@@H](CO)C(O)=O DXTOOBDIIAJZBJ-BQBZGAKWSA-N 0.000 description 2
- OFGUOWQVEGTVNU-DCAQKATOSA-N Pro-Lys-Ala Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(O)=O OFGUOWQVEGTVNU-DCAQKATOSA-N 0.000 description 2
- HBBBLSVBQGZKOZ-GUBZILKMSA-N Pro-Met-Ala Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCSC)C(=O)N[C@@H](C)C(O)=O HBBBLSVBQGZKOZ-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
- IURWWZYKYPEANQ-HJGDQZAQSA-N Pro-Thr-Glu Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCC(O)=O)C(O)=O IURWWZYKYPEANQ-HJGDQZAQSA-N 0.000 description 2
- VVEQUISRWJDGMX-VKOGCVSHSA-N Pro-Trp-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)[C@H](CC1=CNC2=CC=CC=C21)NC(=O)[C@@H]3CCCN3 VVEQUISRWJDGMX-VKOGCVSHSA-N 0.000 description 2
- WWXNZNWZNZPDIF-SRVKXCTJSA-N Pro-Val-Arg Chemical compound NC(N)=NCCC[C@@H](C(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H]1CCCN1 WWXNZNWZNZPDIF-SRVKXCTJSA-N 0.000 description 2
- 102100040678 Programmed cell death protein 1 Human genes 0.000 description 2
- 101710089372 Programmed cell death protein 1 Proteins 0.000 description 2
- 101710120463 Prostate stem cell antigen Proteins 0.000 description 2
- 102100036735 Prostate stem cell antigen Human genes 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- 238000011579 SCID mouse model Methods 0.000 description 2
- MWMKFWJYRRGXOR-ZLUOBGJFSA-N Ser-Ala-Asn Chemical compound N[C@H](C(=O)N[C@H](C(=O)N[C@H](C(=O)O)CC(N)=O)C)CO MWMKFWJYRRGXOR-ZLUOBGJFSA-N 0.000 description 2
- LVVBAKCGXXUHFO-ZLUOBGJFSA-N Ser-Ala-Asp Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(O)=O)C(O)=O LVVBAKCGXXUHFO-ZLUOBGJFSA-N 0.000 description 2
- PZZJMBYSYAKYPK-UWJYBYFXSA-N Ser-Ala-Tyr Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](C)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O PZZJMBYSYAKYPK-UWJYBYFXSA-N 0.000 description 2
- HQTKVSCNCDLXSX-BQBZGAKWSA-N Ser-Arg-Gly Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(O)=O HQTKVSCNCDLXSX-BQBZGAKWSA-N 0.000 description 2
- 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 2
- UBRXAVQWXOWRSJ-ZLUOBGJFSA-N Ser-Asn-Asp Chemical compound C([C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)O)NC(=O)[C@H](CO)N)C(=O)N UBRXAVQWXOWRSJ-ZLUOBGJFSA-N 0.000 description 2
- OLIJLNWFEQEFDM-SRVKXCTJSA-N Ser-Asp-Phe Chemical compound OC[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 OLIJLNWFEQEFDM-SRVKXCTJSA-N 0.000 description 2
- KNCJWSPMTFFJII-ZLUOBGJFSA-N Ser-Cys-Asp Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(O)=O)C(O)=O KNCJWSPMTFFJII-ZLUOBGJFSA-N 0.000 description 2
- TUYBIWUZWJUZDD-ACZMJKKPSA-N Ser-Cys-Gln Chemical compound OC[C@H](N)C(=O)N[C@@H](CS)C(=O)N[C@H](C(O)=O)CCC(N)=O TUYBIWUZWJUZDD-ACZMJKKPSA-N 0.000 description 2
- KJMOINFQVCCSDX-XKBZYTNZSA-N Ser-Gln-Thr Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O KJMOINFQVCCSDX-XKBZYTNZSA-N 0.000 description 2
- MIJWOJAXARLEHA-WDSKDSINSA-N Ser-Gly-Glu Chemical compound OC[C@H](N)C(=O)NCC(=O)N[C@H](C(O)=O)CCC(O)=O MIJWOJAXARLEHA-WDSKDSINSA-N 0.000 description 2
- 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 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
- FUMGHWDRRFCKEP-CIUDSAMLSA-N Ser-Leu-Ala Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C)C(O)=O FUMGHWDRRFCKEP-CIUDSAMLSA-N 0.000 description 2
- UPLYXVPQLJVWMM-KKUMJFAQSA-N Ser-Phe-Leu Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CC(C)C)C(O)=O UPLYXVPQLJVWMM-KKUMJFAQSA-N 0.000 description 2
- PJIQEIFXZPCWOJ-FXQIFTODSA-N Ser-Pro-Asp Chemical compound [H]N[C@@H](CO)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CC(O)=O)C(O)=O PJIQEIFXZPCWOJ-FXQIFTODSA-N 0.000 description 2
- FLMYSKVSDVHLEW-SVSWQMSJSA-N Ser-Thr-Ile Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O FLMYSKVSDVHLEW-SVSWQMSJSA-N 0.000 description 2
- FGBLCMLXHRPVOF-IHRRRGAJSA-N Ser-Tyr-Arg Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O FGBLCMLXHRPVOF-IHRRRGAJSA-N 0.000 description 2
- PQEQXWRVHQAAKS-SRVKXCTJSA-N Ser-Tyr-Asn Chemical compound NC(=O)C[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CO)N)CC1=CC=C(O)C=C1 PQEQXWRVHQAAKS-SRVKXCTJSA-N 0.000 description 2
- UBTNVMGPMYDYIU-HJPIBITLSA-N Ser-Tyr-Ile Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O UBTNVMGPMYDYIU-HJPIBITLSA-N 0.000 description 2
- PLQWGQUNUPMNOD-KKUMJFAQSA-N Ser-Tyr-Leu Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC(C)C)C(O)=O PLQWGQUNUPMNOD-KKUMJFAQSA-N 0.000 description 2
- KIEIJCFVGZCUAS-MELADBBJSA-N Ser-Tyr-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CC2=CC=C(C=C2)O)NC(=O)[C@H](CO)N)C(=O)O KIEIJCFVGZCUAS-MELADBBJSA-N 0.000 description 2
- IAOHCSQDQDWRQU-GUBZILKMSA-N Ser-Val-Arg Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O IAOHCSQDQDWRQU-GUBZILKMSA-N 0.000 description 2
- JZRYFUGREMECBH-XPUUQOCRSA-N Ser-Val-Gly Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(=O)NCC(O)=O JZRYFUGREMECBH-XPUUQOCRSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 102000007000 Tenascin Human genes 0.000 description 2
- 108010008125 Tenascin Proteins 0.000 description 2
- UKBSDLHIKIXJKH-HJGDQZAQSA-N Thr-Arg-Glu Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(O)=O UKBSDLHIKIXJKH-HJGDQZAQSA-N 0.000 description 2
- YOSLMIPKOUAHKI-OLHMAJIHSA-N Thr-Asp-Asp Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(O)=O)C(O)=O YOSLMIPKOUAHKI-OLHMAJIHSA-N 0.000 description 2
- AQAMPXBRJJWPNI-JHEQGTHGSA-N Thr-Gly-Glu Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(O)=O AQAMPXBRJJWPNI-JHEQGTHGSA-N 0.000 description 2
- PAXANSWUSVPFNK-IUKAMOBKSA-N Thr-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]([C@@H](C)O)N PAXANSWUSVPFNK-IUKAMOBKSA-N 0.000 description 2
- GMXIJHCBTZDAPD-QPHKQPEJSA-N Thr-Ile-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)O)NC(=O)[C@H]([C@@H](C)O)N GMXIJHCBTZDAPD-QPHKQPEJSA-N 0.000 description 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
- YGCDFAJJCRVQKU-RCWTZXSCSA-N Thr-Pro-Val Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@@H](N)[C@@H](C)O YGCDFAJJCRVQKU-RCWTZXSCSA-N 0.000 description 2
- 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 2
- BBPCSGKKPJUYRB-UVOCVTCTSA-N Thr-Thr-Leu Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(O)=O BBPCSGKKPJUYRB-UVOCVTCTSA-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
- DIHPMRTXPYMDJZ-KAOXEZKKSA-N Thr-Tyr-Pro Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC1=CC=C(C=C1)O)C(=O)N2CCC[C@@H]2C(=O)O)N)O DIHPMRTXPYMDJZ-KAOXEZKKSA-N 0.000 description 2
- CYCGARJWIQWPQM-YJRXYDGGSA-N Thr-Tyr-Ser Chemical compound C[C@@H](O)[C@H]([NH3+])C(=O)N[C@H](C(=O)N[C@@H](CO)C([O-])=O)CC1=CC=C(O)C=C1 CYCGARJWIQWPQM-YJRXYDGGSA-N 0.000 description 2
- LVRFMARKDGGZMX-IZPVPAKOSA-N Thr-Tyr-Thr Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@H](C(=O)N[C@@H]([C@@H](C)O)C(O)=O)CC1=CC=C(O)C=C1 LVRFMARKDGGZMX-IZPVPAKOSA-N 0.000 description 2
- KPMIQCXJDVKWKO-IFFSRLJSSA-N Thr-Val-Glu Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(O)=O)C(O)=O KPMIQCXJDVKWKO-IFFSRLJSSA-N 0.000 description 2
- 102000040945 Transcription factor Human genes 0.000 description 2
- 108091023040 Transcription factor Proteins 0.000 description 2
- UTQBQJNSNXJNIH-IHPCNDPISA-N Trp-Asn-Phe Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)N)NC(=O)[C@H](CC2=CNC3=CC=CC=C32)N UTQBQJNSNXJNIH-IHPCNDPISA-N 0.000 description 2
- ZCPCXVJOMUPIDD-IHPCNDPISA-N Trp-Asp-Phe Chemical compound C([C@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)N)C(O)=O)C1=CC=CC=C1 ZCPCXVJOMUPIDD-IHPCNDPISA-N 0.000 description 2
- JVTHMUDOKPQBOT-NSHDSACASA-N Trp-Gly-Gly Chemical compound C1=CC=C2C(C[C@H]([NH3+])C(=O)NCC(=O)NCC([O-])=O)=CNC2=C1 JVTHMUDOKPQBOT-NSHDSACASA-N 0.000 description 2
- NXQAOORHSYJRGH-AAEUAGOBSA-N Trp-Gly-Ser Chemical compound C1=CC=C2C(C[C@H](N)C(=O)NCC(=O)N[C@@H](CO)C(O)=O)=CNC2=C1 NXQAOORHSYJRGH-AAEUAGOBSA-N 0.000 description 2
- GQHAIUPYZPTADF-FDARSICLSA-N Trp-Ile-Arg Chemical compound C1=CC=C2C(C[C@H](N)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCCN=C(N)N)C(O)=O)=CNC2=C1 GQHAIUPYZPTADF-FDARSICLSA-N 0.000 description 2
- 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 2
- ULHASJWZGUEUNN-XIRDDKMYSA-N Trp-Lys-Ser Chemical compound [H]N[C@@H](CC1=CNC2=C1C=CC=C2)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CO)C(O)=O ULHASJWZGUEUNN-XIRDDKMYSA-N 0.000 description 2
- UJGDFQRPYGJBEH-AAEUAGOBSA-N Trp-Ser-Gly Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)N[C@@H](CO)C(=O)NCC(=O)O)N UJGDFQRPYGJBEH-AAEUAGOBSA-N 0.000 description 2
- VMXLNDRJXVAJFT-JYBASQMISA-N Trp-Thr-Ser Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CO)C(=O)O)NC(=O)[C@H](CC1=CNC2=CC=CC=C21)N)O VMXLNDRJXVAJFT-JYBASQMISA-N 0.000 description 2
- 102100036922 Tumor necrosis factor ligand superfamily member 13B Human genes 0.000 description 2
- AKXBNSZMYAOGLS-STQMWFEESA-N Tyr-Arg-Gly Chemical compound NC(N)=NCCC[C@@H](C(=O)NCC(O)=O)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 AKXBNSZMYAOGLS-STQMWFEESA-N 0.000 description 2
- MNMYOSZWCKYEDI-JRQIVUDYSA-N Tyr-Asp-Thr Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O MNMYOSZWCKYEDI-JRQIVUDYSA-N 0.000 description 2
- BVOCLAPFOBSJHR-KKUMJFAQSA-N Tyr-Cys-His Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CC2=CN=CN2)C(=O)O)N)O BVOCLAPFOBSJHR-KKUMJFAQSA-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
- DZKFGCNKEVMXFA-JUKXBJQTSA-N Tyr-Ile-His Chemical compound CC[C@H](C)[C@H](NC(=O)[C@@H](N)Cc1ccc(O)cc1)C(=O)N[C@@H](Cc1cnc[nH]1)C(O)=O DZKFGCNKEVMXFA-JUKXBJQTSA-N 0.000 description 2
- GULIUBBXCYPDJU-CQDKDKBSSA-N Tyr-Leu-Ala Chemical compound [O-]C(=O)[C@H](C)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H]([NH3+])CC1=CC=C(O)C=C1 GULIUBBXCYPDJU-CQDKDKBSSA-N 0.000 description 2
- QPBJXNYYQTUTDD-KKUMJFAQSA-N Tyr-Met-Gln Chemical compound CSCC[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)O)NC(=O)[C@H](CC1=CC=C(C=C1)O)N QPBJXNYYQTUTDD-KKUMJFAQSA-N 0.000 description 2
- AUZADXNWQMBZOO-JYJNAYRXSA-N Tyr-Pro-Arg Chemical compound C([C@H](N)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCN=C(N)N)C(O)=O)C1=CC=C(O)C=C1 AUZADXNWQMBZOO-JYJNAYRXSA-N 0.000 description 2
- SZEIFUXUTBBQFQ-STQMWFEESA-N Tyr-Pro-Gly Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N1CCC[C@H]1C(=O)NCC(O)=O SZEIFUXUTBBQFQ-STQMWFEESA-N 0.000 description 2
- XGZBEGGGAUQBMB-KJEVXHAQSA-N Tyr-Pro-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@@H]1CCCN1C(=O)[C@H](CC2=CC=C(C=C2)O)N)O XGZBEGGGAUQBMB-KJEVXHAQSA-N 0.000 description 2
- VYQQQIRHIFALGE-UWJYBYFXSA-N Tyr-Ser-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 VYQQQIRHIFALGE-UWJYBYFXSA-N 0.000 description 2
- NZBSVMQZQMEUHI-WZLNRYEVSA-N Tyr-Thr-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CC1=CC=C(C=C1)O)N NZBSVMQZQMEUHI-WZLNRYEVSA-N 0.000 description 2
- KLQPIEVIKOQRAW-IZPVPAKOSA-N Tyr-Thr-Thr Chemical compound C[C@H]([C@@H](C(=O)N[C@@H]([C@@H](C)O)C(=O)O)NC(=O)[C@H](CC1=CC=C(C=C1)O)N)O KLQPIEVIKOQRAW-IZPVPAKOSA-N 0.000 description 2
- WYOBRXPIZVKNMF-IRXDYDNUSA-N Tyr-Tyr-Gly Chemical compound C([C@H](N)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)NCC(O)=O)C1=CC=C(O)C=C1 WYOBRXPIZVKNMF-IRXDYDNUSA-N 0.000 description 2
- PVPAOIGJYHVWBT-KKHAAJSZSA-N Val-Asn-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CC(=O)N)NC(=O)[C@H](C(C)C)N)O PVPAOIGJYHVWBT-KKHAAJSZSA-N 0.000 description 2
- XGJLNBNZNMVJRS-NRPADANISA-N Val-Glu-Ala Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(O)=O XGJLNBNZNMVJRS-NRPADANISA-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
- WDIGUPHXPBMODF-UMNHJUIQSA-N Val-Glu-Pro Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)N1CCC[C@@H]1C(=O)O)N WDIGUPHXPBMODF-UMNHJUIQSA-N 0.000 description 2
- DJEVQCWNMQOABE-RCOVLWMOSA-N Val-Gly-Asp Chemical compound CC(C)[C@@H](C(=O)NCC(=O)N[C@@H](CC(=O)O)C(=O)O)N DJEVQCWNMQOABE-RCOVLWMOSA-N 0.000 description 2
- KZKMBGXCNLPYKD-YEPSODPASA-N Val-Gly-Thr Chemical compound CC(C)[C@H](N)C(=O)NCC(=O)N[C@@H]([C@@H](C)O)C(O)=O KZKMBGXCNLPYKD-YEPSODPASA-N 0.000 description 2
- MYLNLEIZWHVENT-VKOGCVSHSA-N Val-Ile-Trp Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC1=CNC2=CC=CC=C21)C(=O)O)NC(=O)[C@H](C(C)C)N MYLNLEIZWHVENT-VKOGCVSHSA-N 0.000 description 2
- ZXYPHBKIZLAQTL-QXEWZRGKSA-N Val-Pro-Asp Chemical compound CC(C)[C@@H](C(=O)N1CCC[C@H]1C(=O)N[C@@H](CC(=O)O)C(=O)O)N ZXYPHBKIZLAQTL-QXEWZRGKSA-N 0.000 description 2
- VHIZXDZMTDVFGX-DCAQKATOSA-N Val-Ser-Leu Chemical compound CC(C)C[C@@H](C(=O)O)NC(=O)[C@H](CO)NC(=O)[C@H](C(C)C)N VHIZXDZMTDVFGX-DCAQKATOSA-N 0.000 description 2
- 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
- LCHZBEUVGAVMKS-RHYQMDGZSA-N Val-Thr-Leu Chemical compound CC(C)C[C@H](NC(=O)[C@@H](NC(=O)[C@@H](N)C(C)C)[C@@H](C)O)C(O)=O LCHZBEUVGAVMKS-RHYQMDGZSA-N 0.000 description 2
- HVRRJRMULCPNRO-BZSNNMDCSA-N Val-Trp-Arg Chemical compound C1=CC=C2C(C[C@H](NC(=O)[C@@H](N)C(C)C)C(=O)N[C@@H](CCCN=C(N)N)C(O)=O)=CNC2=C1 HVRRJRMULCPNRO-BZSNNMDCSA-N 0.000 description 2
- 108010053096 Vascular Endothelial Growth Factor Receptor-1 Proteins 0.000 description 2
- 102100033178 Vascular endothelial growth factor receptor 1 Human genes 0.000 description 2
- 241000700605 Viruses Species 0.000 description 2
- 102000013529 alpha-Fetoproteins Human genes 0.000 description 2
- 108010026331 alpha-Fetoproteins Proteins 0.000 description 2
- 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 2
- 238000004458 analytical method Methods 0.000 description 2
- 210000004102 animal cell Anatomy 0.000 description 2
- 230000001093 anti-cancer Effects 0.000 description 2
- 239000002246 antineoplastic agent Substances 0.000 description 2
- 108010013835 arginine glutamate Proteins 0.000 description 2
- 210000002798 bone marrow cell Anatomy 0.000 description 2
- 239000001506 calcium phosphate Substances 0.000 description 2
- 229910000389 calcium phosphate Inorganic materials 0.000 description 2
- 235000011010 calcium phosphates Nutrition 0.000 description 2
- 150000001720 carbohydrates Chemical class 0.000 description 2
- 235000014633 carbohydrates Nutrition 0.000 description 2
- 230000022534 cell killing Effects 0.000 description 2
- 238000002512 chemotherapy Methods 0.000 description 2
- 230000000295 complement effect Effects 0.000 description 2
- 206010052015 cytokine release syndrome Diseases 0.000 description 2
- 230000034994 death Effects 0.000 description 2
- 231100000517 death Toxicity 0.000 description 2
- 230000007423 decrease Effects 0.000 description 2
- 230000004069 differentiation Effects 0.000 description 2
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 230000001605 fetal effect Effects 0.000 description 2
- 150000002270 gangliosides Chemical class 0.000 description 2
- 238000010353 genetic engineering Methods 0.000 description 2
- 108010055341 glutamyl-glutamic acid Proteins 0.000 description 2
- 230000012010 growth Effects 0.000 description 2
- 208000010726 hind limb paralysis Diseases 0.000 description 2
- 230000028993 immune response Effects 0.000 description 2
- 210000000987 immune system Anatomy 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 230000002147 killing effect Effects 0.000 description 2
- 230000000670 limiting effect Effects 0.000 description 2
- 108010025153 lysyl-alanyl-alanine Proteins 0.000 description 2
- 230000001404 mediated effect Effects 0.000 description 2
- 239000002609 medium Substances 0.000 description 2
- 238000001823 molecular biology technique Methods 0.000 description 2
- 238000007899 nucleic acid hybridization Methods 0.000 description 2
- 239000002953 phosphate buffered saline Substances 0.000 description 2
- 238000003752 polymerase chain reaction Methods 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 108010029020 prolylglycine Proteins 0.000 description 2
- 229940127293 prostanoid Drugs 0.000 description 2
- 150000003814 prostanoids Chemical class 0.000 description 2
- 238000001959 radiotherapy Methods 0.000 description 2
- ZAHRKKWIAAJSAO-UHFFFAOYSA-N rapamycin Natural products COCC(O)C(=C/C(C)C(=O)CC(OC(=O)C1CCCCN1C(=O)C(=O)C2(O)OC(CC(OC)C(=CC=CC=CC(C)CC(C)C(=O)C)C)CCC2C)C(C)CC3CCC(O)C(C3)OC)C ZAHRKKWIAAJSAO-UHFFFAOYSA-N 0.000 description 2
- 102000005962 receptors Human genes 0.000 description 2
- 108020003175 receptors Proteins 0.000 description 2
- 102220285225 rs1198168331 Human genes 0.000 description 2
- 102200060276 rs137853102 Human genes 0.000 description 2
- 102220058913 rs374396150 Human genes 0.000 description 2
- 102220058920 rs761960690 Human genes 0.000 description 2
- 108010048818 seryl-histidine Proteins 0.000 description 2
- 229960002930 sirolimus Drugs 0.000 description 2
- QFJCIRLUMZQUOT-HPLJOQBZSA-N sirolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 QFJCIRLUMZQUOT-HPLJOQBZSA-N 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 230000009870 specific binding Effects 0.000 description 2
- 230000000087 stabilizing effect Effects 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000001356 surgical procedure Methods 0.000 description 2
- 229940124597 therapeutic agent Drugs 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- 230000002103 transcriptional effect Effects 0.000 description 2
- 238000001890 transfection Methods 0.000 description 2
- 238000012546 transfer Methods 0.000 description 2
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 2
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 2
- 108010084932 tryptophyl-proline Proteins 0.000 description 2
- HDTRYLNUVZCQOY-UHFFFAOYSA-N α-D-glucopyranosyl-α-D-glucopyranoside Natural products OC1C(O)C(O)C(CO)OC1OC1C(O)C(O)C(O)C(CO)O1 HDTRYLNUVZCQOY-UHFFFAOYSA-N 0.000 description 1
- BJHCYTJNPVGSBZ-YXSASFKJSA-N 1-[4-[6-amino-5-[(Z)-methoxyiminomethyl]pyrimidin-4-yl]oxy-2-chlorophenyl]-3-ethylurea Chemical compound CCNC(=O)Nc1ccc(Oc2ncnc(N)c2\C=N/OC)cc1Cl BJHCYTJNPVGSBZ-YXSASFKJSA-N 0.000 description 1
- VOXZDWNPVJITMN-ZBRFXRBCSA-N 17β-estradiol Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 VOXZDWNPVJITMN-ZBRFXRBCSA-N 0.000 description 1
- XKZQKPRCPNGNFR-UHFFFAOYSA-N 2-(3-hydroxyphenyl)phenol Chemical compound OC1=CC=CC(C=2C(=CC=CC=2)O)=C1 XKZQKPRCPNGNFR-UHFFFAOYSA-N 0.000 description 1
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 1
- 102100033400 4F2 cell-surface antigen heavy chain Human genes 0.000 description 1
- SQDAZGGFXASXDW-UHFFFAOYSA-N 5-bromo-2-(trifluoromethoxy)pyridine Chemical compound FC(F)(F)OC1=CC=C(Br)C=N1 SQDAZGGFXASXDW-UHFFFAOYSA-N 0.000 description 1
- JBVSSSZFNTXJDX-YTLHQDLWSA-N Ala-Ala-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@H](C)N JBVSSSZFNTXJDX-YTLHQDLWSA-N 0.000 description 1
- CSAHOYQKNHGDHX-ACZMJKKPSA-N Ala-Gln-Asn Chemical compound C[C@H](N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O CSAHOYQKNHGDHX-ACZMJKKPSA-N 0.000 description 1
- LNNSWWRRYJLGNI-NAKRPEOUSA-N Ala-Ile-Val Chemical compound C[C@H](N)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C(C)C)C(O)=O LNNSWWRRYJLGNI-NAKRPEOUSA-N 0.000 description 1
- SUMYEVXWCAYLLJ-GUBZILKMSA-N Ala-Leu-Gln Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(O)=O SUMYEVXWCAYLLJ-GUBZILKMSA-N 0.000 description 1
- MDNAVFBZPROEHO-DCAQKATOSA-N Ala-Lys-Val Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C(C)C)C(O)=O MDNAVFBZPROEHO-DCAQKATOSA-N 0.000 description 1
- FVNAUOZKIPAYNA-BPNCWPANSA-N Ala-Met-Tyr Chemical compound CSCC[C@H](NC(=O)[C@H](C)N)C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 FVNAUOZKIPAYNA-BPNCWPANSA-N 0.000 description 1
- DYJJJCHDHLEFDW-FXQIFTODSA-N Ala-Pro-Cys Chemical compound C[C@@H](C(=O)N1CCC[C@H]1C(=O)N[C@@H](CS)C(=O)O)N DYJJJCHDHLEFDW-FXQIFTODSA-N 0.000 description 1
- RTZCUEHYUQZIDE-WHFBIAKZSA-N Ala-Ser-Gly Chemical compound C[C@H](N)C(=O)N[C@@H](CO)C(=O)NCC(O)=O RTZCUEHYUQZIDE-WHFBIAKZSA-N 0.000 description 1
- PEEYDECOOVQKRZ-DLOVCJGASA-N Ala-Ser-Phe Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O PEEYDECOOVQKRZ-DLOVCJGASA-N 0.000 description 1
- NCQMBSJGJMYKCK-ZLUOBGJFSA-N Ala-Ser-Ser Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(O)=O NCQMBSJGJMYKCK-ZLUOBGJFSA-N 0.000 description 1
- IETUUAHKCHOQHP-KZVJFYERSA-N Ala-Thr-Val Chemical compound CC(C)[C@H](NC(=O)[C@@H](NC(=O)[C@H](C)N)[C@@H](C)O)C(O)=O IETUUAHKCHOQHP-KZVJFYERSA-N 0.000 description 1
- XPBVBZPVNFIHOA-UVBJJODRSA-N Ala-Trp-Val Chemical compound C1=CC=C2C(C[C@@H](C(=O)N[C@@H](C(C)C)C(O)=O)NC(=O)[C@H](C)N)=CNC2=C1 XPBVBZPVNFIHOA-UVBJJODRSA-N 0.000 description 1
- NLYYHIKRBRMAJV-AEJSXWLSSA-N Ala-Val-Pro Chemical compound C[C@@H](C(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@@H]1C(=O)O)N NLYYHIKRBRMAJV-AEJSXWLSSA-N 0.000 description 1
- REWSWYIDQIELBE-FXQIFTODSA-N Ala-Val-Ser Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CO)C(O)=O REWSWYIDQIELBE-FXQIFTODSA-N 0.000 description 1
- 108020005544 Antisense RNA Proteins 0.000 description 1
- SNBHMYQRNCJSOJ-CIUDSAMLSA-N Arg-Gln-Asn Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O SNBHMYQRNCJSOJ-CIUDSAMLSA-N 0.000 description 1
- BEXGZLUHRXTZCC-CIUDSAMLSA-N Arg-Gln-Ser Chemical compound C(C[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H](CO)C(=O)O)N)CN=C(N)N BEXGZLUHRXTZCC-CIUDSAMLSA-N 0.000 description 1
- AUFHLLPVPSMEOG-YUMQZZPRSA-N Arg-Gly-Glu Chemical compound NC(N)=NCCC[C@H](N)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(O)=O AUFHLLPVPSMEOG-YUMQZZPRSA-N 0.000 description 1
- NKNILFJYKKHBKE-WPRPVWTQSA-N Arg-Gly-Val Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)NCC(=O)N[C@@H](C(C)C)C(O)=O NKNILFJYKKHBKE-WPRPVWTQSA-N 0.000 description 1
- PCQXGEUALSFGIA-WDSOQIARSA-N Arg-His-Trp Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CC1=CNC2=C1C=CC=C2)C(O)=O PCQXGEUALSFGIA-WDSOQIARSA-N 0.000 description 1
- GXXWTNKNFFKTJB-NAKRPEOUSA-N Arg-Ile-Ser Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(O)=O GXXWTNKNFFKTJB-NAKRPEOUSA-N 0.000 description 1
- FNXCAFKDGBROCU-STECZYCISA-N Arg-Ile-Tyr Chemical compound NC(N)=NCCC[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 FNXCAFKDGBROCU-STECZYCISA-N 0.000 description 1
- WMEVEPXNCMKNGH-IHRRRGAJSA-N Arg-Leu-His Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)NC(=O)[C@H](CCCN=C(N)N)N WMEVEPXNCMKNGH-IHRRRGAJSA-N 0.000 description 1
- SLQQPJBDBVPVQV-JYJNAYRXSA-N Arg-Phe-Val Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](C(C)C)C(O)=O SLQQPJBDBVPVQV-JYJNAYRXSA-N 0.000 description 1
- DNLQVHBBMPZUGJ-BQBZGAKWSA-N Arg-Ser-Gly Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)NCC(O)=O DNLQVHBBMPZUGJ-BQBZGAKWSA-N 0.000 description 1
- KMFPQTITXUKJOV-DCAQKATOSA-N Arg-Ser-Leu Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(O)=O KMFPQTITXUKJOV-DCAQKATOSA-N 0.000 description 1
- LRPZJPMQGKGHSG-XGEHTFHBSA-N Arg-Ser-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CO)NC(=O)[C@H](CCCN=C(N)N)N)O LRPZJPMQGKGHSG-XGEHTFHBSA-N 0.000 description 1
- NVPHRWNWTKYIST-BPNCWPANSA-N Arg-Tyr-Ala Chemical compound NC(N)=NCCC[C@H](N)C(=O)N[C@H](C(=O)N[C@@H](C)C(O)=O)CC1=CC=C(O)C=C1 NVPHRWNWTKYIST-BPNCWPANSA-N 0.000 description 1
- VDCIPFYVCICPEC-FXQIFTODSA-N Asn-Arg-Ala Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(O)=O VDCIPFYVCICPEC-FXQIFTODSA-N 0.000 description 1
- XHFXZQHTLJVZBN-FXQIFTODSA-N Asn-Arg-Asn Chemical compound C(C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)O)NC(=O)[C@H](CC(=O)N)N)CN=C(N)N XHFXZQHTLJVZBN-FXQIFTODSA-N 0.000 description 1
- NVGWESORMHFISY-SRVKXCTJSA-N Asn-Asn-Phe Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O NVGWESORMHFISY-SRVKXCTJSA-N 0.000 description 1
- JRVABKHPWDRUJF-UBHSHLNASA-N Asn-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](CC(=O)N)N JRVABKHPWDRUJF-UBHSHLNASA-N 0.000 description 1
- PTSDPWIHOYMRGR-UGYAYLCHSA-N Asn-Ile-Asn Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(N)=O)C(O)=O PTSDPWIHOYMRGR-UGYAYLCHSA-N 0.000 description 1
- KMCRKVOLRCOMBG-DJFWLOJKSA-N Asn-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](CC(=O)N)N KMCRKVOLRCOMBG-DJFWLOJKSA-N 0.000 description 1
- FTSAJSADJCMDHH-CIUDSAMLSA-N Asn-Lys-Asp Chemical compound C(CCN)C[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)O)NC(=O)[C@H](CC(=O)N)N FTSAJSADJCMDHH-CIUDSAMLSA-N 0.000 description 1
- XTMZYFMTYJNABC-ZLUOBGJFSA-N Asn-Ser-Ala Chemical compound C[C@@H](C(=O)O)NC(=O)[C@H](CO)NC(=O)[C@H](CC(=O)N)N XTMZYFMTYJNABC-ZLUOBGJFSA-N 0.000 description 1
- MYTHOBCLNIOFBL-SRVKXCTJSA-N Asn-Ser-Tyr Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O MYTHOBCLNIOFBL-SRVKXCTJSA-N 0.000 description 1
- HPASIOLTWSNMFB-OLHMAJIHSA-N Asn-Thr-Asp Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(O)=O)C(O)=O HPASIOLTWSNMFB-OLHMAJIHSA-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
- DATSKXOXPUAOLK-KKUMJFAQSA-N Asn-Tyr-Leu Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC(C)C)C(O)=O DATSKXOXPUAOLK-KKUMJFAQSA-N 0.000 description 1
- 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 1
- BKXPJCBEHWFSTF-ACZMJKKPSA-N Asp-Gln-Asp Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(O)=O)C(O)=O BKXPJCBEHWFSTF-ACZMJKKPSA-N 0.000 description 1
- VFUXXFVCYZPOQG-WDSKDSINSA-N Asp-Glu-Gly Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)NCC(O)=O VFUXXFVCYZPOQG-WDSKDSINSA-N 0.000 description 1
- RRKCPMGSRIDLNC-AVGNSLFASA-N Asp-Glu-Tyr Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O RRKCPMGSRIDLNC-AVGNSLFASA-N 0.000 description 1
- SVABRQFIHCSNCI-FOHZUACHSA-N Asp-Gly-Thr Chemical compound [H]N[C@@H](CC(O)=O)C(=O)NCC(=O)N[C@@H]([C@@H](C)O)C(O)=O SVABRQFIHCSNCI-FOHZUACHSA-N 0.000 description 1
- OAMLVOVXNKILLQ-BQBZGAKWSA-N Asp-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@@H](N)CC(O)=O OAMLVOVXNKILLQ-BQBZGAKWSA-N 0.000 description 1
- USNJAPJZSGTTPX-XVSYOHENSA-N Asp-Phe-Thr Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H]([C@@H](C)O)C(O)=O USNJAPJZSGTTPX-XVSYOHENSA-N 0.000 description 1
- ZQFRDAZBTSFGGW-SRVKXCTJSA-N Asp-Ser-Phe Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O ZQFRDAZBTSFGGW-SRVKXCTJSA-N 0.000 description 1
- OZBXOELNJBSJOA-UBHSHLNASA-N Asp-Ser-Trp Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)O)NC(=O)[C@H](CO)NC(=O)[C@H](CC(=O)O)N OZBXOELNJBSJOA-UBHSHLNASA-N 0.000 description 1
- JDDYEZGPYBBPBN-JRQIVUDYSA-N Asp-Thr-Tyr Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O JDDYEZGPYBBPBN-JRQIVUDYSA-N 0.000 description 1
- GHAHOJDCBRXAKC-IHPCNDPISA-N Asp-Trp-Tyr Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)N[C@@H](CC3=CC=C(C=C3)O)C(=O)O)NC(=O)[C@H](CC(=O)O)N GHAHOJDCBRXAKC-IHPCNDPISA-N 0.000 description 1
- KNDCWFXCFKSEBM-AVGNSLFASA-N Asp-Tyr-Glu 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](CCC(O)=O)C(O)=O KNDCWFXCFKSEBM-AVGNSLFASA-N 0.000 description 1
- AWPWHMVCSISSQK-QWRGUYRKSA-N Asp-Tyr-Gly Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)NCC(O)=O AWPWHMVCSISSQK-QWRGUYRKSA-N 0.000 description 1
- PLOKOIJSGCISHE-BYULHYEWSA-N Asp-Val-Asn Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(N)=O)C(O)=O PLOKOIJSGCISHE-BYULHYEWSA-N 0.000 description 1
- 102100035526 B melanoma antigen 1 Human genes 0.000 description 1
- 108010028006 B-Cell Activating Factor Proteins 0.000 description 1
- 208000025324 B-cell acute lymphoblastic leukemia Diseases 0.000 description 1
- 208000028564 B-cell non-Hodgkin lymphoma Diseases 0.000 description 1
- 102100038080 B-cell receptor CD22 Human genes 0.000 description 1
- 229930185605 Bisphenol Natural products 0.000 description 1
- 229920002799 BoPET Polymers 0.000 description 1
- 102100024217 CAMPATH-1 antigen Human genes 0.000 description 1
- 102100027207 CD27 antigen Human genes 0.000 description 1
- 101150013553 CD40 gene Proteins 0.000 description 1
- 108010058905 CD44v6 antigen Proteins 0.000 description 1
- 108010065524 CD52 Antigen Proteins 0.000 description 1
- 102100025222 CD63 antigen Human genes 0.000 description 1
- 210000001266 CD8-positive T-lymphocyte Anatomy 0.000 description 1
- 101100123850 Caenorhabditis elegans her-1 gene Proteins 0.000 description 1
- 101100463133 Caenorhabditis elegans pdl-1 gene Proteins 0.000 description 1
- 102000014914 Carrier Proteins Human genes 0.000 description 1
- 102100034231 Cell surface A33 antigen Human genes 0.000 description 1
- 101710165668 Cell surface A33 antigen Proteins 0.000 description 1
- 229920002567 Chondroitin Polymers 0.000 description 1
- 229920001287 Chondroitin sulfate Polymers 0.000 description 1
- 102000008186 Collagen Human genes 0.000 description 1
- 108010035532 Collagen Proteins 0.000 description 1
- 102000012422 Collagen Type I Human genes 0.000 description 1
- 108010022452 Collagen Type I Proteins 0.000 description 1
- 241000699802 Cricetulus griseus Species 0.000 description 1
- DCJNIJAWIRPPBB-CIUDSAMLSA-N Cys-Ala-Lys Chemical compound C[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CS)N DCJNIJAWIRPPBB-CIUDSAMLSA-N 0.000 description 1
- 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 1
- YUZPQIQWXLRFBW-ACZMJKKPSA-N Cys-Glu-Ala Chemical compound [H]N[C@@H](CS)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(O)=O YUZPQIQWXLRFBW-ACZMJKKPSA-N 0.000 description 1
- VTJLJQGUMBWHBP-GUBZILKMSA-N Cys-His-Gln Chemical compound C1=C(NC=N1)C[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)O)NC(=O)[C@H](CS)N VTJLJQGUMBWHBP-GUBZILKMSA-N 0.000 description 1
- WVLZTXGTNGHPBO-SRVKXCTJSA-N Cys-Leu-Leu Chemical compound [H]N[C@@H](CS)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O WVLZTXGTNGHPBO-SRVKXCTJSA-N 0.000 description 1
- BCFXQBXXDSEHRS-FXQIFTODSA-N Cys-Ser-Arg Chemical compound [H]N[C@@H](CS)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O BCFXQBXXDSEHRS-FXQIFTODSA-N 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- 102100040481 Desmocollin-2 Human genes 0.000 description 1
- 101710157873 Desmocollin-2 Proteins 0.000 description 1
- 206010012735 Diarrhoea Diseases 0.000 description 1
- 101150076616 EPHA2 gene Proteins 0.000 description 1
- 101150016325 EPHA3 gene Proteins 0.000 description 1
- 241000976823 Embernagra platensis Species 0.000 description 1
- 108010055211 EphA1 Receptor Proteins 0.000 description 1
- 108010055323 EphB4 Receptor Proteins 0.000 description 1
- 101150078651 Epha4 gene Proteins 0.000 description 1
- 102100030322 Ephrin type-A receptor 1 Human genes 0.000 description 1
- 102100021600 Ephrin type-A receptor 10 Human genes 0.000 description 1
- 102100030340 Ephrin type-A receptor 2 Human genes 0.000 description 1
- 102100030324 Ephrin type-A receptor 3 Human genes 0.000 description 1
- 102100021616 Ephrin type-A receptor 4 Human genes 0.000 description 1
- 102100021606 Ephrin type-A receptor 7 Human genes 0.000 description 1
- 102100021601 Ephrin type-A receptor 8 Human genes 0.000 description 1
- 102100031983 Ephrin type-B receptor 4 Human genes 0.000 description 1
- 241000283086 Equidae Species 0.000 description 1
- 241000283073 Equus caballus Species 0.000 description 1
- 238000012413 Fluorescence activated cell sorting analysis Methods 0.000 description 1
- RZSLYUUFFVHFRQ-FXQIFTODSA-N Gln-Ala-Glu Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(O)=O RZSLYUUFFVHFRQ-FXQIFTODSA-N 0.000 description 1
- CRRFJBGUGNNOCS-PEFMBERDSA-N Gln-Asp-Ile Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O CRRFJBGUGNNOCS-PEFMBERDSA-N 0.000 description 1
- WLODHVXYKYHLJD-ACZMJKKPSA-N Gln-Asp-Ser Chemical compound C(CC(=O)N)[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](CO)C(=O)O)N WLODHVXYKYHLJD-ACZMJKKPSA-N 0.000 description 1
- IXFVOPOHSRKJNG-LAEOZQHASA-N Gln-Asp-Val Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](C(C)C)C(O)=O IXFVOPOHSRKJNG-LAEOZQHASA-N 0.000 description 1
- CITDWMLWXNUQKD-FXQIFTODSA-N Gln-Gln-Asn Chemical compound C(CC(=O)N)[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H](CC(=O)N)C(=O)O)N CITDWMLWXNUQKD-FXQIFTODSA-N 0.000 description 1
- ZNZPKVQURDQFFS-FXQIFTODSA-N Gln-Glu-Ser Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(O)=O ZNZPKVQURDQFFS-FXQIFTODSA-N 0.000 description 1
- XFAUJGNLHIGXET-AVGNSLFASA-N Gln-Leu-Leu Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O XFAUJGNLHIGXET-AVGNSLFASA-N 0.000 description 1
- MLSKFHLRFVGNLL-WDCWCFNPSA-N Gln-Leu-Thr Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O MLSKFHLRFVGNLL-WDCWCFNPSA-N 0.000 description 1
- FKXCBKCOSVIGCT-AVGNSLFASA-N Gln-Lys-Leu Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(O)=O FKXCBKCOSVIGCT-AVGNSLFASA-N 0.000 description 1
- QKWBEMCLYTYBNI-GVXVVHGQSA-N Gln-Lys-Val Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](N)CCC(N)=O QKWBEMCLYTYBNI-GVXVVHGQSA-N 0.000 description 1
- OKARHJKJTKFQBM-ACZMJKKPSA-N Gln-Ser-Asn Chemical compound C(CC(=O)N)[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(=O)N)C(=O)O)N OKARHJKJTKFQBM-ACZMJKKPSA-N 0.000 description 1
- UTOQQOMEJDPDMX-ACZMJKKPSA-N Gln-Ser-Asp Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(O)=O)C(O)=O UTOQQOMEJDPDMX-ACZMJKKPSA-N 0.000 description 1
- SXFPZRRVWSUYII-KBIXCLLPSA-N Gln-Ser-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(=O)N)N SXFPZRRVWSUYII-KBIXCLLPSA-N 0.000 description 1
- BETSEXMYBWCDAE-SZMVWBNQSA-N Gln-Trp-Lys Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CCC(=O)N)N BETSEXMYBWCDAE-SZMVWBNQSA-N 0.000 description 1
- CVRUVYDNRPSKBM-QEJZJMRPSA-N Gln-Trp-Ser Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)N[C@@H](CO)C(=O)O)NC(=O)[C@H](CCC(=O)N)N CVRUVYDNRPSKBM-QEJZJMRPSA-N 0.000 description 1
- LKDIBBOKUAASNP-FXQIFTODSA-N Glu-Ala-Glu Chemical compound OC(=O)CC[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(O)=O LKDIBBOKUAASNP-FXQIFTODSA-N 0.000 description 1
- JJKKWYQVHRUSDG-GUBZILKMSA-N Glu-Ala-Lys Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCN)C(O)=O JJKKWYQVHRUSDG-GUBZILKMSA-N 0.000 description 1
- PBEQPAZRHDVJQI-SRVKXCTJSA-N Glu-Arg-His Chemical compound C1=C(NC=N1)C[C@@H](C(=O)O)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CCC(=O)O)N PBEQPAZRHDVJQI-SRVKXCTJSA-N 0.000 description 1
- RDPOETHPAQEGDP-ACZMJKKPSA-N Glu-Asp-Ala Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](C)C(O)=O RDPOETHPAQEGDP-ACZMJKKPSA-N 0.000 description 1
- XXCDTYBVGMPIOA-FXQIFTODSA-N Glu-Asp-Glu Chemical compound OC(=O)CC[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(O)=O XXCDTYBVGMPIOA-FXQIFTODSA-N 0.000 description 1
- 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 1
- YLJHCWNDBKKOEB-IHRRRGAJSA-N Glu-Glu-Phe Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O YLJHCWNDBKKOEB-IHRRRGAJSA-N 0.000 description 1
- HPJLZFTUUJKWAJ-JHEQGTHGSA-N Glu-Gly-Thr Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)NCC(=O)N[C@@H]([C@@H](C)O)C(O)=O HPJLZFTUUJKWAJ-JHEQGTHGSA-N 0.000 description 1
- SYAYROHMAIHWFB-KBIXCLLPSA-N Glu-Ser-Ile Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O SYAYROHMAIHWFB-KBIXCLLPSA-N 0.000 description 1
- HAGKYCXGTRUUFI-RYUDHWBXSA-N Glu-Tyr-Gly Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)NCC(=O)O)NC(=O)[C@H](CCC(=O)O)N)O HAGKYCXGTRUUFI-RYUDHWBXSA-N 0.000 description 1
- 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 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- UGVQELHRNUDMAA-BYPYZUCNSA-N Gly-Ala-Gly Chemical compound [NH3+]CC(=O)N[C@@H](C)C(=O)NCC([O-])=O UGVQELHRNUDMAA-BYPYZUCNSA-N 0.000 description 1
- DTPOVRRYXPJJAZ-FJXKBIBVSA-N Gly-Arg-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)CN)CCCN=C(N)N DTPOVRRYXPJJAZ-FJXKBIBVSA-N 0.000 description 1
- GGEJHJIXRBTJPD-BYPYZUCNSA-N Gly-Asn-Gly Chemical compound NCC(=O)N[C@@H](CC(N)=O)C(=O)NCC(O)=O GGEJHJIXRBTJPD-BYPYZUCNSA-N 0.000 description 1
- PMNHJLASAAWELO-FOHZUACHSA-N Gly-Asp-Thr Chemical compound [H]NCC(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O PMNHJLASAAWELO-FOHZUACHSA-N 0.000 description 1
- PABFFPWEJMEVEC-JGVFFNPUSA-N Gly-Gln-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CCC(=O)N)NC(=O)CN)C(=O)O PABFFPWEJMEVEC-JGVFFNPUSA-N 0.000 description 1
- MOJKRXIRAZPZLW-WDSKDSINSA-N Gly-Glu-Ala Chemical compound [H]NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(O)=O MOJKRXIRAZPZLW-WDSKDSINSA-N 0.000 description 1
- DHDOADIPGZTAHT-YUMQZZPRSA-N Gly-Glu-Arg Chemical compound NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@H](C(O)=O)CCCN=C(N)N DHDOADIPGZTAHT-YUMQZZPRSA-N 0.000 description 1
- ZQIMMEYPEXIYBB-IUCAKERBSA-N Gly-Glu-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)CN ZQIMMEYPEXIYBB-IUCAKERBSA-N 0.000 description 1
- QSVCIFZPGLOZGH-WDSKDSINSA-N Gly-Glu-Ser Chemical compound NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(O)=O QSVCIFZPGLOZGH-WDSKDSINSA-N 0.000 description 1
- KMSGYZQRXPUKGI-BYPYZUCNSA-N Gly-Gly-Asn Chemical compound NCC(=O)NCC(=O)N[C@H](C(O)=O)CC(N)=O KMSGYZQRXPUKGI-BYPYZUCNSA-N 0.000 description 1
- DGKBSGNCMCLDSL-BYULHYEWSA-N Gly-Ile-Asn Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)O)NC(=O)CN DGKBSGNCMCLDSL-BYULHYEWSA-N 0.000 description 1
- BHPQOIPBLYJNAW-NGZCFLSTSA-N Gly-Ile-Pro Chemical compound CC[C@H](C)[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)CN BHPQOIPBLYJNAW-NGZCFLSTSA-N 0.000 description 1
- VBOBNHSVQKKTOT-YUMQZZPRSA-N Gly-Lys-Ala Chemical compound [H]NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(O)=O VBOBNHSVQKKTOT-YUMQZZPRSA-N 0.000 description 1
- GAFKBWKVXNERFA-QWRGUYRKSA-N Gly-Phe-Asp Chemical compound OC(=O)C[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)CN)CC1=CC=CC=C1 GAFKBWKVXNERFA-QWRGUYRKSA-N 0.000 description 1
- IGOYNRWLWHWAQO-JTQLQIEISA-N Gly-Phe-Gly Chemical compound OC(=O)CNC(=O)[C@@H](NC(=O)CN)CC1=CC=CC=C1 IGOYNRWLWHWAQO-JTQLQIEISA-N 0.000 description 1
- WCORRBXVISTKQL-WHFBIAKZSA-N Gly-Ser-Ser Chemical compound NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(O)=O WCORRBXVISTKQL-WHFBIAKZSA-N 0.000 description 1
- LCRDMSSAKLTKBU-ZDLURKLDSA-N Gly-Ser-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)[C@H](CO)NC(=O)CN LCRDMSSAKLTKBU-ZDLURKLDSA-N 0.000 description 1
- ZLCLYFGMKFCDCN-XPUUQOCRSA-N Gly-Ser-Val Chemical compound CC(C)[C@H](NC(=O)[C@H](CO)NC(=O)CN)C(O)=O ZLCLYFGMKFCDCN-XPUUQOCRSA-N 0.000 description 1
- FKESCSGWBPUTPN-FOHZUACHSA-N Gly-Thr-Asn Chemical compound [H]NCC(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(O)=O FKESCSGWBPUTPN-FOHZUACHSA-N 0.000 description 1
- MYXNLWDWWOTERK-BHNWBGBOSA-N Gly-Thr-Pro Chemical compound C[C@H]([C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)CN)O MYXNLWDWWOTERK-BHNWBGBOSA-N 0.000 description 1
- TVTZEOHWHUVYCG-KYNKHSRBSA-N Gly-Thr-Thr Chemical compound [H]NCC(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O TVTZEOHWHUVYCG-KYNKHSRBSA-N 0.000 description 1
- BAYQNCWLXIDLHX-ONGXEEELSA-N Gly-Val-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](C(C)C)NC(=O)CN BAYQNCWLXIDLHX-ONGXEEELSA-N 0.000 description 1
- 102000003886 Glycoproteins Human genes 0.000 description 1
- 108090000288 Glycoproteins Proteins 0.000 description 1
- 239000007995 HEPES buffer Substances 0.000 description 1
- 102100030595 HLA class II histocompatibility antigen gamma chain Human genes 0.000 description 1
- 102100031573 Hematopoietic progenitor cell antigen CD34 Human genes 0.000 description 1
- 208000032843 Hemorrhage Diseases 0.000 description 1
- 208000009889 Herpes Simplex Diseases 0.000 description 1
- 108010068250 Herpes Simplex Virus Protein Vmw65 Proteins 0.000 description 1
- MBSSHYPAEHPSGY-LSJOCFKGSA-N His-Ala-Met Chemical compound [H]N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](C)C(=O)N[C@@H](CCSC)C(O)=O MBSSHYPAEHPSGY-LSJOCFKGSA-N 0.000 description 1
- HVCRQRQPIIRNLY-IUCAKERBSA-N His-Gln-Gly Chemical compound C1=C(NC=N1)C[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)NCC(=O)O)N HVCRQRQPIIRNLY-IUCAKERBSA-N 0.000 description 1
- FMRKUXFLLPKVPG-JYJNAYRXSA-N His-Gln-Tyr Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)N)NC(=O)[C@H](CC2=CN=CN2)N)O FMRKUXFLLPKVPG-JYJNAYRXSA-N 0.000 description 1
- ZVKDCQVQTGYBQT-LSJOCFKGSA-N His-Pro-Ala Chemical compound [H]N[C@@H](CC1=CNC=N1)C(=O)N1CCC[C@H]1C(=O)N[C@@H](C)C(O)=O ZVKDCQVQTGYBQT-LSJOCFKGSA-N 0.000 description 1
- FFKJUTZARGRVTH-KKUMJFAQSA-N His-Ser-Tyr Chemical compound [H]N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O FFKJUTZARGRVTH-KKUMJFAQSA-N 0.000 description 1
- UWSMZKRTOZEGDD-CUJWVEQBSA-N His-Thr-Ser Chemical compound [H]N[C@@H](CC1=CNC=N1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(O)=O UWSMZKRTOZEGDD-CUJWVEQBSA-N 0.000 description 1
- SWBUZLFWGJETAO-KKUMJFAQSA-N His-Tyr-Asn Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)O)NC(=O)[C@H](CC2=CN=CN2)N)O SWBUZLFWGJETAO-KKUMJFAQSA-N 0.000 description 1
- 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 1
- 101000800023 Homo sapiens 4F2 cell-surface antigen heavy chain Proteins 0.000 description 1
- 101000874316 Homo sapiens B melanoma antigen 1 Proteins 0.000 description 1
- 101000884305 Homo sapiens B-cell receptor CD22 Proteins 0.000 description 1
- 101000914511 Homo sapiens CD27 antigen Proteins 0.000 description 1
- 101000934368 Homo sapiens CD63 antigen Proteins 0.000 description 1
- 101000898673 Homo sapiens Ephrin type-A receptor 10 Proteins 0.000 description 1
- 101000898708 Homo sapiens Ephrin type-A receptor 7 Proteins 0.000 description 1
- 101000898676 Homo sapiens Ephrin type-A receptor 8 Proteins 0.000 description 1
- 101001082627 Homo sapiens HLA class II histocompatibility antigen gamma chain Proteins 0.000 description 1
- 101000777663 Homo sapiens Hematopoietic progenitor cell antigen CD34 Proteins 0.000 description 1
- 101000599862 Homo sapiens Intercellular adhesion molecule 3 Proteins 0.000 description 1
- 101000853002 Homo sapiens Interleukin-25 Proteins 0.000 description 1
- 101000777628 Homo sapiens Leukocyte antigen CD37 Proteins 0.000 description 1
- 101000608935 Homo sapiens Leukosialin Proteins 0.000 description 1
- 101000878605 Homo sapiens Low affinity immunoglobulin epsilon Fc receptor Proteins 0.000 description 1
- 101000576802 Homo sapiens Mesothelin Proteins 0.000 description 1
- 101000628547 Homo sapiens Metalloreductase STEAP1 Proteins 0.000 description 1
- 101001133081 Homo sapiens Mucin-2 Proteins 0.000 description 1
- 101000972284 Homo sapiens Mucin-3A Proteins 0.000 description 1
- 101000972282 Homo sapiens Mucin-5AC Proteins 0.000 description 1
- 101000972276 Homo sapiens Mucin-5B Proteins 0.000 description 1
- 101000972273 Homo sapiens Mucin-7 Proteins 0.000 description 1
- 101001128431 Homo sapiens Myeloid-derived growth factor Proteins 0.000 description 1
- 101000934341 Homo sapiens T-cell surface glycoprotein CD5 Proteins 0.000 description 1
- 101000851376 Homo sapiens Tumor necrosis factor receptor superfamily member 8 Proteins 0.000 description 1
- 241000714260 Human T-lymphotropic virus 1 Species 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- RSDHVTMRXSABSV-GHCJXIJMSA-N Ile-Asn-Cys Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CS)C(=O)O)N RSDHVTMRXSABSV-GHCJXIJMSA-N 0.000 description 1
- HDODQNPMSHDXJT-GHCJXIJMSA-N Ile-Asn-Ser Chemical compound CC[C@H](C)[C@H](N)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CO)C(O)=O HDODQNPMSHDXJT-GHCJXIJMSA-N 0.000 description 1
- WNQKUUQIVDDAFA-ZPFDUUQYSA-N Ile-Gln-Met Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H](CCSC)C(=O)O)N WNQKUUQIVDDAFA-ZPFDUUQYSA-N 0.000 description 1
- NZOCIWKZUVUNDW-ZKWXMUAHSA-N Ile-Gly-Ala Chemical compound CC[C@H](C)[C@H](N)C(=O)NCC(=O)N[C@@H](C)C(O)=O NZOCIWKZUVUNDW-ZKWXMUAHSA-N 0.000 description 1
- SLQVFYWBGNNOTK-BYULHYEWSA-N Ile-Gly-Asn Chemical compound CC[C@H](C)[C@@H](C(=O)NCC(=O)N[C@@H](CC(=O)N)C(=O)O)N SLQVFYWBGNNOTK-BYULHYEWSA-N 0.000 description 1
- CDGLBYSAZFIIJO-RCOVLWMOSA-N Ile-Gly-Gly Chemical compound CC[C@H](C)[C@H]([NH3+])C(=O)NCC(=O)NCC([O-])=O CDGLBYSAZFIIJO-RCOVLWMOSA-N 0.000 description 1
- SVZFKLBRCYCIIY-CYDGBPFRSA-N Ile-Pro-Arg Chemical compound CC[C@H](C)[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCCNC(N)=N)C(O)=O SVZFKLBRCYCIIY-CYDGBPFRSA-N 0.000 description 1
- YKZAMJXNJUWFIK-JBDRJPRFSA-N Ile-Ser-Ala Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](C)C(=O)O)N YKZAMJXNJUWFIK-JBDRJPRFSA-N 0.000 description 1
- RQJUKVXWAKJDBW-SVSWQMSJSA-N Ile-Ser-Thr Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(=O)O)N RQJUKVXWAKJDBW-SVSWQMSJSA-N 0.000 description 1
- PZWBBXHHUSIGKH-OSUNSFLBSA-N Ile-Thr-Arg Chemical compound CC[C@H](C)[C@H](N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@H](C(O)=O)CCCN=C(N)N PZWBBXHHUSIGKH-OSUNSFLBSA-N 0.000 description 1
- DGTOKVBDZXJHNZ-WZLNRYEVSA-N Ile-Thr-Tyr Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CC=C(C=C1)O)C(=O)O)N DGTOKVBDZXJHNZ-WZLNRYEVSA-N 0.000 description 1
- QHUREMVLLMNUAX-OSUNSFLBSA-N Ile-Thr-Val Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(=O)O)N QHUREMVLLMNUAX-OSUNSFLBSA-N 0.000 description 1
- YBHKCXNNNVDYEB-SPOWBLRKSA-N Ile-Trp-Ser Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC1=CNC2=CC=CC=C21)C(=O)N[C@@H](CO)C(=O)O)N YBHKCXNNNVDYEB-SPOWBLRKSA-N 0.000 description 1
- UYODHPPSCXBNCS-XUXIUFHCSA-N Ile-Val-Leu Chemical compound CC[C@H](C)[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@H](C(O)=O)CC(C)C UYODHPPSCXBNCS-XUXIUFHCSA-N 0.000 description 1
- 108700002232 Immediate-Early Genes Proteins 0.000 description 1
- 229940076838 Immune checkpoint inhibitor Drugs 0.000 description 1
- 102000037982 Immune checkpoint proteins Human genes 0.000 description 1
- 108091008036 Immune checkpoint proteins Proteins 0.000 description 1
- 206010021639 Incontinence Diseases 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 102000037984 Inhibitory immune checkpoint proteins Human genes 0.000 description 1
- 108091008026 Inhibitory immune checkpoint proteins Proteins 0.000 description 1
- 108090000723 Insulin-Like Growth Factor I Proteins 0.000 description 1
- 102000014429 Insulin-like growth factor Human genes 0.000 description 1
- 102100037871 Intercellular adhesion molecule 3 Human genes 0.000 description 1
- 108010074328 Interferon-gamma Proteins 0.000 description 1
- 102000008070 Interferon-gamma Human genes 0.000 description 1
- 108090000193 Interleukin-1 beta Proteins 0.000 description 1
- 102000003777 Interleukin-1 beta Human genes 0.000 description 1
- 108010065805 Interleukin-12 Proteins 0.000 description 1
- 108090000171 Interleukin-18 Proteins 0.000 description 1
- 108010065637 Interleukin-23 Proteins 0.000 description 1
- 108010066979 Interleukin-27 Proteins 0.000 description 1
- 101710181613 Interleukin-31 Proteins 0.000 description 1
- 108090000978 Interleukin-4 Proteins 0.000 description 1
- 108090001005 Interleukin-6 Proteins 0.000 description 1
- LHSGPCFBGJHPCY-UHFFFAOYSA-N L-leucine-L-tyrosine Natural products CC(C)CC(N)C(=O)NC(C(O)=O)CC1=CC=C(O)C=C1 LHSGPCFBGJHPCY-UHFFFAOYSA-N 0.000 description 1
- IBMVEYRWAWIOTN-RWMBFGLXSA-N Leu-Arg-Pro Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N1CCC[C@@H]1C(O)=O IBMVEYRWAWIOTN-RWMBFGLXSA-N 0.000 description 1
- KGCLIYGPQXUNLO-IUCAKERBSA-N Leu-Gly-Glu Chemical compound CC(C)C[C@H](N)C(=O)NCC(=O)N[C@H](C(O)=O)CCC(O)=O KGCLIYGPQXUNLO-IUCAKERBSA-N 0.000 description 1
- HNDWYLYAYNBWMP-AJNGGQMLSA-N Leu-Ile-Lys Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CC(C)C)N HNDWYLYAYNBWMP-AJNGGQMLSA-N 0.000 description 1
- QLDHBYRUNQZIJQ-DKIMLUQUSA-N Leu-Ile-Phe Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O QLDHBYRUNQZIJQ-DKIMLUQUSA-N 0.000 description 1
- ZRHDPZAAWLXXIR-SRVKXCTJSA-N Leu-Lys-Ala Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(O)=O ZRHDPZAAWLXXIR-SRVKXCTJSA-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
- RZXLZBIUTDQHJQ-SRVKXCTJSA-N Leu-Lys-Asp Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(O)=O)C(O)=O RZXLZBIUTDQHJQ-SRVKXCTJSA-N 0.000 description 1
- MVHXGBZUJLWZOH-BJDJZHNGSA-N Leu-Ser-Ile Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O MVHXGBZUJLWZOH-BJDJZHNGSA-N 0.000 description 1
- QWWPYKKLXWOITQ-VOAKCMCISA-N Leu-Thr-Leu 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)CC(C)C QWWPYKKLXWOITQ-VOAKCMCISA-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
- GZRABTMNWJXFMH-UVOCVTCTSA-N Leu-Thr-Thr Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O GZRABTMNWJXFMH-UVOCVTCTSA-N 0.000 description 1
- RIHIGSWBLHSGLV-CQDKDKBSSA-N Leu-Tyr-Ala Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](C)C(O)=O RIHIGSWBLHSGLV-CQDKDKBSSA-N 0.000 description 1
- 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 1
- 102100031586 Leukocyte antigen CD37 Human genes 0.000 description 1
- 102100039564 Leukosialin Human genes 0.000 description 1
- 102000003960 Ligases Human genes 0.000 description 1
- 108090000364 Ligases Proteins 0.000 description 1
- 102100038007 Low affinity immunoglobulin epsilon Fc receptor Human genes 0.000 description 1
- YNNPKXBBRZVIRX-IHRRRGAJSA-N Lys-Arg-Leu Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(O)=O YNNPKXBBRZVIRX-IHRRRGAJSA-N 0.000 description 1
- WGCKDDHUFPQSMZ-ZPFDUUQYSA-N Lys-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)CCCCN WGCKDDHUFPQSMZ-ZPFDUUQYSA-N 0.000 description 1
- NRQRKMYZONPCTM-CIUDSAMLSA-N Lys-Asp-Ser Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(O)=O NRQRKMYZONPCTM-CIUDSAMLSA-N 0.000 description 1
- WTZUSCUIVPVCRH-SRVKXCTJSA-N Lys-Gln-Arg Chemical compound NCCCC[C@H](N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@H](C(O)=O)CCCN=C(N)N WTZUSCUIVPVCRH-SRVKXCTJSA-N 0.000 description 1
- HEWWNLVEWBJBKA-WDCWCFNPSA-N Lys-Gln-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](N)CCCCN HEWWNLVEWBJBKA-WDCWCFNPSA-N 0.000 description 1
- IUWMQCZOTYRXPL-ZPFDUUQYSA-N Lys-Ile-Asp Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(O)=O)C(O)=O IUWMQCZOTYRXPL-ZPFDUUQYSA-N 0.000 description 1
- PRSBSVAVOQOAMI-BJDJZHNGSA-N Lys-Ile-Ser Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H]([C@@H](C)CC)NC(=O)[C@@H](N)CCCCN PRSBSVAVOQOAMI-BJDJZHNGSA-N 0.000 description 1
- CNGOEHJCLVCJHN-SRVKXCTJSA-N Lys-Pro-Glu Chemical compound NCCCC[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCC(O)=O)C(O)=O CNGOEHJCLVCJHN-SRVKXCTJSA-N 0.000 description 1
- IOQWIOPSKJOEKI-SRVKXCTJSA-N Lys-Ser-Leu Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(O)=O IOQWIOPSKJOEKI-SRVKXCTJSA-N 0.000 description 1
- SQXZLVXQXWILKW-KKUMJFAQSA-N Lys-Ser-Phe Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O SQXZLVXQXWILKW-KKUMJFAQSA-N 0.000 description 1
- VHTOGMKQXXJOHG-RHYQMDGZSA-N Lys-Thr-Val Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(O)=O VHTOGMKQXXJOHG-RHYQMDGZSA-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
- 229930195725 Mannitol Natural products 0.000 description 1
- 206010027406 Mesothelioma Diseases 0.000 description 1
- TZLYIHDABYBOCJ-FXQIFTODSA-N Met-Asp-Ser Chemical compound CSCC[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(O)=O TZLYIHDABYBOCJ-FXQIFTODSA-N 0.000 description 1
- BCRQJDMZQUHQSV-STQMWFEESA-N Met-Gly-Tyr Chemical compound [H]N[C@@H](CCSC)C(=O)NCC(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O BCRQJDMZQUHQSV-STQMWFEESA-N 0.000 description 1
- AFVOKRHYSSFPHC-STECZYCISA-N Met-Ile-Tyr Chemical compound CSCC[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 AFVOKRHYSSFPHC-STECZYCISA-N 0.000 description 1
- WSPQHZOMTFFWGH-XGEHTFHBSA-N Met-Thr-Cys Chemical compound CSCC[C@H](N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CS)C(O)=O WSPQHZOMTFFWGH-XGEHTFHBSA-N 0.000 description 1
- 102100026712 Metalloreductase STEAP1 Human genes 0.000 description 1
- 102100034256 Mucin-1 Human genes 0.000 description 1
- 108010008707 Mucin-1 Proteins 0.000 description 1
- 102100034263 Mucin-2 Human genes 0.000 description 1
- 102100022497 Mucin-3A Human genes 0.000 description 1
- 102100022494 Mucin-5B Human genes 0.000 description 1
- 102100022492 Mucin-7 Human genes 0.000 description 1
- 102000015728 Mucins Human genes 0.000 description 1
- 108010063954 Mucins Proteins 0.000 description 1
- 208000034578 Multiple myelomas Diseases 0.000 description 1
- 101100346932 Mus musculus Muc1 gene Proteins 0.000 description 1
- 208000029549 Muscle injury Diseases 0.000 description 1
- 239000005041 Mylar™ Substances 0.000 description 1
- 229930193140 Neomycin Natural products 0.000 description 1
- 208000028389 Nerve injury Diseases 0.000 description 1
- 206010029260 Neuroblastoma Diseases 0.000 description 1
- 206010029350 Neurotoxicity Diseases 0.000 description 1
- RMINQIRDFIBNLE-NNRWGFCXSA-N O-[N-acetyl-alpha-neuraminyl-(2->6)-N-acetyl-alpha-D-galactosaminyl]-L-serine Chemical compound O1[C@H](OC[C@H](N)C(O)=O)[C@H](NC(=O)C)[C@@H](O)[C@@H](O)[C@H]1CO[C@@]1(C(O)=O)O[C@@H]([C@H](O)[C@H](O)CO)[C@H](NC(C)=O)[C@@H](O)C1 RMINQIRDFIBNLE-NNRWGFCXSA-N 0.000 description 1
- 108020005187 Oligonucleotide Probes Proteins 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 241000282577 Pan troglodytes Species 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- BKWJQWJPZMUWEG-LFSVMHDDSA-N Phe-Ala-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC1=CC=CC=C1 BKWJQWJPZMUWEG-LFSVMHDDSA-N 0.000 description 1
- NOFBJKKOPKJDCO-KKXDTOCCSA-N Phe-Ala-Tyr Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](C)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O NOFBJKKOPKJDCO-KKXDTOCCSA-N 0.000 description 1
- QEPZQAPZKIPVDV-KKUMJFAQSA-N Phe-Cys-His Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CC2=CN=CN2)C(=O)O)N QEPZQAPZKIPVDV-KKUMJFAQSA-N 0.000 description 1
- MPFGIYLYWUCSJG-AVGNSLFASA-N Phe-Glu-Asp Chemical compound OC(=O)C[C@@H](C(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](N)CC1=CC=CC=C1 MPFGIYLYWUCSJG-AVGNSLFASA-N 0.000 description 1
- 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 1
- KNYPNEYICHHLQL-ACRUOGEOSA-N Phe-Leu-Tyr Chemical compound C([C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(O)=O)C1=CC=CC=C1 KNYPNEYICHHLQL-ACRUOGEOSA-N 0.000 description 1
- OQTDZEJJWWAGJT-KKUMJFAQSA-N Phe-Lys-Asp Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(O)=O)C(O)=O OQTDZEJJWWAGJT-KKUMJFAQSA-N 0.000 description 1
- PHJUFDQVVKVOPU-ULQDDVLXSA-N Phe-Lys-Met Chemical compound CSCC[C@@H](C(=O)O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CC1=CC=CC=C1)N PHJUFDQVVKVOPU-ULQDDVLXSA-N 0.000 description 1
- FKFCKDROTNIVSO-JYJNAYRXSA-N Phe-Pro-Met Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCSC)C(O)=O FKFCKDROTNIVSO-JYJNAYRXSA-N 0.000 description 1
- 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 1
- 241000288906 Primates Species 0.000 description 1
- FZHBZMDRDASUHN-NAKRPEOUSA-N Pro-Ala-Ile Chemical compound CC[C@H](C)[C@H](NC(=O)[C@H](C)NC(=O)[C@@H]1CCCN1)C(O)=O FZHBZMDRDASUHN-NAKRPEOUSA-N 0.000 description 1
- CYQQWUPHIZVCNY-GUBZILKMSA-N Pro-Arg-Ser Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(O)=O CYQQWUPHIZVCNY-GUBZILKMSA-N 0.000 description 1
- ZCXQTRXYZOSGJR-FXQIFTODSA-N Pro-Asp-Ser Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(O)=O ZCXQTRXYZOSGJR-FXQIFTODSA-N 0.000 description 1
- MGDFPGCFVJFITQ-CIUDSAMLSA-N Pro-Glu-Asp Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(O)=O MGDFPGCFVJFITQ-CIUDSAMLSA-N 0.000 description 1
- UUHXBJHVTVGSKM-BQBZGAKWSA-N Pro-Gly-Asn Chemical compound [H]N1CCC[C@H]1C(=O)NCC(=O)N[C@@H](CC(N)=O)C(O)=O UUHXBJHVTVGSKM-BQBZGAKWSA-N 0.000 description 1
- HAAQQNHQZBOWFO-LURJTMIESA-N Pro-Gly-Gly Chemical compound OC(=O)CNC(=O)CNC(=O)[C@@H]1CCCN1 HAAQQNHQZBOWFO-LURJTMIESA-N 0.000 description 1
- DRKAXLDECUGLFE-ULQDDVLXSA-N Pro-Leu-Phe Chemical compound CC(C)C[C@H](NC(=O)[C@@H]1CCCN1)C(=O)N[C@@H](Cc1ccccc1)C(O)=O DRKAXLDECUGLFE-ULQDDVLXSA-N 0.000 description 1
- 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 1
- WVXQQUWOKUZIEG-VEVYYDQMSA-N Pro-Thr-Asn Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(O)=O WVXQQUWOKUZIEG-VEVYYDQMSA-N 0.000 description 1
- JDJMFMVVJHLWDP-UNQGMJICSA-N Pro-Thr-Phe Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O JDJMFMVVJHLWDP-UNQGMJICSA-N 0.000 description 1
- LZHHZYDPMZEMRX-STQMWFEESA-N Pro-Tyr-Gly Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)NCC(O)=O LZHHZYDPMZEMRX-STQMWFEESA-N 0.000 description 1
- STGVYUTZKGPRCI-GUBZILKMSA-N Pro-Val-Cys Chemical compound SC[C@@H](C(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H]1CCCN1 STGVYUTZKGPRCI-GUBZILKMSA-N 0.000 description 1
- 101710100969 Receptor tyrosine-protein kinase erbB-3 Proteins 0.000 description 1
- 102100029986 Receptor tyrosine-protein kinase erbB-3 Human genes 0.000 description 1
- 102100029981 Receptor tyrosine-protein kinase erbB-4 Human genes 0.000 description 1
- 101710100963 Receptor tyrosine-protein kinase erbB-4 Proteins 0.000 description 1
- 241000714474 Rous sarcoma virus Species 0.000 description 1
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 1
- BTKUIVBNGBFTTP-WHFBIAKZSA-N Ser-Ala-Gly Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](C)C(=O)NCC(O)=O BTKUIVBNGBFTTP-WHFBIAKZSA-N 0.000 description 1
- WTUJZHKANPDPIN-CIUDSAMLSA-N Ser-Ala-Lys Chemical compound C[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CO)N WTUJZHKANPDPIN-CIUDSAMLSA-N 0.000 description 1
- HBOABDXGTMMDSE-GUBZILKMSA-N Ser-Arg-Val Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C(C)C)C(O)=O HBOABDXGTMMDSE-GUBZILKMSA-N 0.000 description 1
- 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 1
- KAAPNMOKUUPKOE-SRVKXCTJSA-N Ser-Asn-Phe Chemical compound OC[C@H](N)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 KAAPNMOKUUPKOE-SRVKXCTJSA-N 0.000 description 1
- DKKGAAJTDKHWOD-BIIVOSGPSA-N Ser-Asn-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CC(=O)N)NC(=O)[C@H](CO)N)C(=O)O DKKGAAJTDKHWOD-BIIVOSGPSA-N 0.000 description 1
- 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 1
- HJEBZBMOTCQYDN-ACZMJKKPSA-N Ser-Glu-Asp Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(O)=O HJEBZBMOTCQYDN-ACZMJKKPSA-N 0.000 description 1
- ZOPISOXXPQNOCO-SVSWQMSJSA-N Ser-Ile-Thr Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H]([C@@H](C)O)C(=O)O)NC(=O)[C@H](CO)N ZOPISOXXPQNOCO-SVSWQMSJSA-N 0.000 description 1
- GZSZPKSBVAOGIE-CIUDSAMLSA-N Ser-Lys-Ala Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(O)=O GZSZPKSBVAOGIE-CIUDSAMLSA-N 0.000 description 1
- XUDRHBPSPAPDJP-SRVKXCTJSA-N Ser-Lys-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](N)CO XUDRHBPSPAPDJP-SRVKXCTJSA-N 0.000 description 1
- 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 1
- VIIJCAQMJBHSJH-FXQIFTODSA-N Ser-Met-Ser Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CO)C(O)=O VIIJCAQMJBHSJH-FXQIFTODSA-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
- 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 1
- GZGFSPWOMUKKCV-NAKRPEOUSA-N Ser-Pro-Ile Chemical compound CC[C@H](C)[C@@H](C(O)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@@H](N)CO GZGFSPWOMUKKCV-NAKRPEOUSA-N 0.000 description 1
- ILZAUMFXKSIUEF-SRVKXCTJSA-N Ser-Ser-Phe Chemical compound OC[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 ILZAUMFXKSIUEF-SRVKXCTJSA-N 0.000 description 1
- PYTKULIABVRXSC-BWBBJGPYSA-N Ser-Ser-Thr Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(O)=O PYTKULIABVRXSC-BWBBJGPYSA-N 0.000 description 1
- BDMWLJLPPUCLNV-XGEHTFHBSA-N Ser-Thr-Val Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(O)=O BDMWLJLPPUCLNV-XGEHTFHBSA-N 0.000 description 1
- NERYDXBVARJIQS-JYBASQMISA-N Ser-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](CO)N)O NERYDXBVARJIQS-JYBASQMISA-N 0.000 description 1
- PIQRHJQWEPWFJG-UWJYBYFXSA-N Ser-Tyr-Ala Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](C)C(O)=O PIQRHJQWEPWFJG-UWJYBYFXSA-N 0.000 description 1
- 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 1
- OQSQCUWQOIHECT-YJRXYDGGSA-N Ser-Tyr-Thr Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H]([C@@H](C)O)C(O)=O OQSQCUWQOIHECT-YJRXYDGGSA-N 0.000 description 1
- HAYADTTXNZFUDM-IHRRRGAJSA-N Ser-Tyr-Val Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](C(C)C)C(O)=O HAYADTTXNZFUDM-IHRRRGAJSA-N 0.000 description 1
- JGUWRQWULDWNCM-FXQIFTODSA-N Ser-Val-Ser Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CO)C(O)=O JGUWRQWULDWNCM-FXQIFTODSA-N 0.000 description 1
- 208000000453 Skin Neoplasms Diseases 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 241000282898 Sus scrofa Species 0.000 description 1
- 230000006044 T cell activation Effects 0.000 description 1
- 102100025244 T-cell surface glycoprotein CD5 Human genes 0.000 description 1
- XSLXHSYIVPGEER-KZVJFYERSA-N Thr-Ala-Val Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C)C(=O)N[C@@H](C(C)C)C(O)=O XSLXHSYIVPGEER-KZVJFYERSA-N 0.000 description 1
- PKXHGEXFMIZSER-QTKMDUPCSA-N Thr-Arg-His Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)N)O PKXHGEXFMIZSER-QTKMDUPCSA-N 0.000 description 1
- WFUAUEQXPVNAEF-ZJDVBMNYSA-N Thr-Arg-Thr Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@H](C(=O)N[C@@H]([C@@H](C)O)C(O)=O)CCCN=C(N)N WFUAUEQXPVNAEF-ZJDVBMNYSA-N 0.000 description 1
- TZKPNGDGUVREEB-FOHZUACHSA-N Thr-Asn-Gly Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@@H](CC(N)=O)C(=O)NCC(O)=O TZKPNGDGUVREEB-FOHZUACHSA-N 0.000 description 1
- NRUPKQSXTJNQGD-XGEHTFHBSA-N Thr-Cys-Arg Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O NRUPKQSXTJNQGD-XGEHTFHBSA-N 0.000 description 1
- MMTOHPRBJKEZHT-BWBBJGPYSA-N Thr-Cys-Ser Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CS)C(=O)N[C@@H](CO)C(O)=O MMTOHPRBJKEZHT-BWBBJGPYSA-N 0.000 description 1
- DJDSEDOKJTZBAR-ZDLURKLDSA-N Thr-Gly-Ser Chemical compound C[C@@H](O)[C@H](N)C(=O)NCC(=O)N[C@@H](CO)C(O)=O DJDSEDOKJTZBAR-ZDLURKLDSA-N 0.000 description 1
- JKGGPMOUIAAJAA-YEPSODPASA-N Thr-Gly-Val Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)NCC(=O)N[C@@H](C(C)C)C(O)=O JKGGPMOUIAAJAA-YEPSODPASA-N 0.000 description 1
- FKIGTIXHSRNKJU-IXOXFDKPSA-N Thr-His-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)[C@H](O)C)CC1=CN=CN1 FKIGTIXHSRNKJU-IXOXFDKPSA-N 0.000 description 1
- RVMNUBQWPVOUKH-HEIBUPTGSA-N Thr-Ser-Thr Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(O)=O RVMNUBQWPVOUKH-HEIBUPTGSA-N 0.000 description 1
- 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 1
- QJIODPFLAASXJC-JHYOHUSXSA-N Thr-Thr-Phe Chemical compound C[C@H]([C@@H](C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)O)N)O QJIODPFLAASXJC-JHYOHUSXSA-N 0.000 description 1
- GRIUMVXCJDKVPI-IZPVPAKOSA-N Thr-Thr-Tyr Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O GRIUMVXCJDKVPI-IZPVPAKOSA-N 0.000 description 1
- VGNKUXWYFFDWDH-BEMMVCDISA-N Thr-Trp-Pro Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC1=CNC2=CC=CC=C21)C(=O)N3CCC[C@@H]3C(=O)O)N)O VGNKUXWYFFDWDH-BEMMVCDISA-N 0.000 description 1
- LXXCHJKHJYRMIY-FQPOAREZSA-N Thr-Tyr-Ala Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](C)C(O)=O LXXCHJKHJYRMIY-FQPOAREZSA-N 0.000 description 1
- KVEWWQRTAVMOFT-KJEVXHAQSA-N Thr-Tyr-Val Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](C(C)C)C(O)=O KVEWWQRTAVMOFT-KJEVXHAQSA-N 0.000 description 1
- 208000007536 Thrombosis Diseases 0.000 description 1
- 206010044221 Toxic encephalopathy Diseases 0.000 description 1
- 101710120037 Toxin CcdB Proteins 0.000 description 1
- 108700019146 Transgenes Proteins 0.000 description 1
- 102100034902 Transmembrane 4 L6 family member 1 Human genes 0.000 description 1
- 101710097359 Transmembrane 4 L6 family member 1 Proteins 0.000 description 1
- HDTRYLNUVZCQOY-WSWWMNSNSA-N Trehalose Natural products O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-WSWWMNSNSA-N 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- SAKLWFSRZTZQAJ-GQGQLFGLSA-N Trp-Ile-Ser Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CO)C(=O)O)NC(=O)[C@H](CC1=CNC2=CC=CC=C21)N SAKLWFSRZTZQAJ-GQGQLFGLSA-N 0.000 description 1
- WNZRNOGHEONFMS-PXDAIIFMSA-N Trp-Ile-Tyr Chemical compound [H]N[C@@H](CC1=CNC2=C1C=CC=C2)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O WNZRNOGHEONFMS-PXDAIIFMSA-N 0.000 description 1
- ZHDQRPWESGUDST-JBACZVJFSA-N Trp-Phe-Gln Chemical compound C([C@H](NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)N)C(=O)N[C@@H](CCC(N)=O)C(O)=O)C1=CC=CC=C1 ZHDQRPWESGUDST-JBACZVJFSA-N 0.000 description 1
- 102100040245 Tumor necrosis factor receptor superfamily member 5 Human genes 0.000 description 1
- 102100036857 Tumor necrosis factor receptor superfamily member 8 Human genes 0.000 description 1
- QJBWZNTWJSZUOY-UWJYBYFXSA-N Tyr-Ala-Cys Chemical compound C[C@@H](C(=O)N[C@@H](CS)C(=O)O)NC(=O)[C@H](CC1=CC=C(C=C1)O)N QJBWZNTWJSZUOY-UWJYBYFXSA-N 0.000 description 1
- CDRYEAWHKJSGAF-BPNCWPANSA-N Tyr-Ala-Met Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](C)C(=O)N[C@@H](CCSC)C(O)=O CDRYEAWHKJSGAF-BPNCWPANSA-N 0.000 description 1
- LGEYOIQBBIPHQN-UWJYBYFXSA-N Tyr-Ala-Ser Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 LGEYOIQBBIPHQN-UWJYBYFXSA-N 0.000 description 1
- DYEGCOJHFNJBKB-UFYCRDLUSA-N Tyr-Arg-Tyr Chemical compound C([C@H](N)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(O)=O)C1=CC=C(O)C=C1 DYEGCOJHFNJBKB-UFYCRDLUSA-N 0.000 description 1
- BVWADTBVGZHSLW-IHRRRGAJSA-N Tyr-Asn-Met Chemical compound CSCC[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)N)NC(=O)[C@H](CC1=CC=C(C=C1)O)N BVWADTBVGZHSLW-IHRRRGAJSA-N 0.000 description 1
- ZNFPUOSTMUMUDR-JRQIVUDYSA-N Tyr-Asn-Thr Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O ZNFPUOSTMUMUDR-JRQIVUDYSA-N 0.000 description 1
- RWOKVQUCENPXGE-IHRRRGAJSA-N Tyr-Ser-Arg Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O RWOKVQUCENPXGE-IHRRRGAJSA-N 0.000 description 1
- ZZDYJFVIKVSUFA-WLTAIBSBSA-N Tyr-Thr-Gly Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(O)=O ZZDYJFVIKVSUFA-WLTAIBSBSA-N 0.000 description 1
- GAKBTSMAPGLQFA-JNPHEJMOSA-N Tyr-Thr-Tyr Chemical compound C([C@H](N)C(=O)N[C@@H]([C@H](O)C)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(O)=O)C1=CC=C(O)C=C1 GAKBTSMAPGLQFA-JNPHEJMOSA-N 0.000 description 1
- MWUYSCVVPVITMW-IGNZVWTISA-N Tyr-Tyr-Ala Chemical compound C([C@@H](C(=O)N[C@@H](C)C(O)=O)NC(=O)[C@@H](N)CC=1C=CC(O)=CC=1)C1=CC=C(O)C=C1 MWUYSCVVPVITMW-IGNZVWTISA-N 0.000 description 1
- GPLTZEMVOCZVAV-UFYCRDLUSA-N Tyr-Tyr-Arg Chemical compound C([C@H](N)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CCCN=C(N)N)C(O)=O)C1=CC=C(O)C=C1 GPLTZEMVOCZVAV-UFYCRDLUSA-N 0.000 description 1
- KSGKJSFPWSMJHK-JNPHEJMOSA-N Tyr-Tyr-Thr Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H]([C@@H](C)O)C(O)=O KSGKJSFPWSMJHK-JNPHEJMOSA-N 0.000 description 1
- 244000000188 Vaccinium ovalifolium Species 0.000 description 1
- DDRBQONWVBDQOY-GUBZILKMSA-N Val-Ala-Arg Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCN=C(N)N)C(O)=O DDRBQONWVBDQOY-GUBZILKMSA-N 0.000 description 1
- CGGVNFJRZJUVAE-BYULHYEWSA-N Val-Asp-Asn Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](CC(=O)N)C(=O)O)N CGGVNFJRZJUVAE-BYULHYEWSA-N 0.000 description 1
- VLOYGOZDPGYWFO-LAEOZQHASA-N Val-Asp-Glu Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(O)=O VLOYGOZDPGYWFO-LAEOZQHASA-N 0.000 description 1
- SRWWRLKBEJZFPW-IHRRRGAJSA-N Val-Cys-Phe Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)O)N SRWWRLKBEJZFPW-IHRRRGAJSA-N 0.000 description 1
- JAKHAONCJJZVHT-DCAQKATOSA-N Val-Lys-Ser Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CO)C(=O)O)N JAKHAONCJJZVHT-DCAQKATOSA-N 0.000 description 1
- PHZGFLFMGLXCFG-FHWLQOOXSA-N Val-Lys-Trp Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC1=CNC2=CC=CC=C21)C(=O)O)N PHZGFLFMGLXCFG-FHWLQOOXSA-N 0.000 description 1
- FMQGYTMERWBMSI-HJWJTTGWSA-N Val-Phe-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)[C@H](CC1=CC=CC=C1)NC(=O)[C@H](C(C)C)N FMQGYTMERWBMSI-HJWJTTGWSA-N 0.000 description 1
- 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 1
- 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 1
- OFTXTCGQJXTNQS-XGEHTFHBSA-N Val-Thr-Ser Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CO)C(=O)O)NC(=O)[C@H](C(C)C)N)O OFTXTCGQJXTNQS-XGEHTFHBSA-N 0.000 description 1
- 108010053099 Vascular Endothelial Growth Factor Receptor-2 Proteins 0.000 description 1
- 108010053100 Vascular Endothelial Growth Factor Receptor-3 Proteins 0.000 description 1
- 102100033177 Vascular endothelial growth factor receptor 2 Human genes 0.000 description 1
- 102100033179 Vascular endothelial growth factor receptor 3 Human genes 0.000 description 1
- 206010047700 Vomiting Diseases 0.000 description 1
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 239000008351 acetate buffer Substances 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 238000001042 affinity chromatography Methods 0.000 description 1
- 230000009824 affinity maturation Effects 0.000 description 1
- 238000001261 affinity purification Methods 0.000 description 1
- 108010076324 alanyl-glycyl-glycine Proteins 0.000 description 1
- 108010041407 alanylaspartic acid Proteins 0.000 description 1
- 108010047495 alanylglycine Proteins 0.000 description 1
- 108010070944 alanylhistidine Proteins 0.000 description 1
- 108010011559 alanylphenylalanine Proteins 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 230000007815 allergy Effects 0.000 description 1
- HDTRYLNUVZCQOY-LIZSDCNHSA-N alpha,alpha-trehalose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-LIZSDCNHSA-N 0.000 description 1
- WQZGKKKJIJFFOK-PHYPRBDBSA-N alpha-D-galactose Chemical compound OC[C@H]1O[C@H](O)[C@H](O)[C@@H](O)[C@H]1O WQZGKKKJIJFFOK-PHYPRBDBSA-N 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 238000011319 anticancer therapy Methods 0.000 description 1
- 230000000890 antigenic effect Effects 0.000 description 1
- 239000004599 antimicrobial Substances 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 108010060035 arginylproline Proteins 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 239000011324 bead Substances 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 108091008324 binding proteins Proteins 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000031018 biological processes and functions Effects 0.000 description 1
- IISBACLAFKSPIT-UHFFFAOYSA-N bisphenol A Chemical compound C=1C=C(O)C=CC=1C(C)(C)C1=CC=C(O)C=C1 IISBACLAFKSPIT-UHFFFAOYSA-N 0.000 description 1
- 208000034158 bleeding Diseases 0.000 description 1
- 230000000740 bleeding effect Effects 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004899 c-terminal region Anatomy 0.000 description 1
- BPKIGYQJPYCAOW-FFJTTWKXSA-I calcium;potassium;disodium;(2s)-2-hydroxypropanoate;dichloride;dihydroxide;hydrate Chemical compound O.[OH-].[OH-].[Na+].[Na+].[Cl-].[Cl-].[K+].[Ca+2].C[C@H](O)C([O-])=O BPKIGYQJPYCAOW-FFJTTWKXSA-I 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- DLGJWSVWTWEWBJ-HGGSSLSASA-N chondroitin Chemical compound CC(O)=N[C@@H]1[C@H](O)O[C@H](CO)[C@H](O)[C@@H]1OC1[C@H](O)[C@H](O)C=C(C(O)=O)O1 DLGJWSVWTWEWBJ-HGGSSLSASA-N 0.000 description 1
- 229940059329 chondroitin sulfate Drugs 0.000 description 1
- 239000007979 citrate buffer Substances 0.000 description 1
- 229920001436 collagen Polymers 0.000 description 1
- 210000001072 colon Anatomy 0.000 description 1
- 239000003184 complementary RNA Substances 0.000 description 1
- 238000002591 computed tomography Methods 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 239000012228 culture supernatant Substances 0.000 description 1
- 210000004748 cultured cell Anatomy 0.000 description 1
- 108010016616 cysteinylglycine Proteins 0.000 description 1
- 229940127089 cytotoxic agent Drugs 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 238000000502 dialysis Methods 0.000 description 1
- 238000010494 dissociation reaction Methods 0.000 description 1
- 230000005593 dissociations Effects 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000009510 drug design Methods 0.000 description 1
- 238000001962 electrophoresis Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 239000003623 enhancer Substances 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 230000010502 episomal replication Effects 0.000 description 1
- 229960005309 estradiol Drugs 0.000 description 1
- 229930182833 estradiol Natural products 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 230000035558 fertility Effects 0.000 description 1
- 108010072257 fibroblast activation protein alpha Proteins 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 238000009459 flexible packaging Methods 0.000 description 1
- 238000012921 fluorescence analysis Methods 0.000 description 1
- 238000002825 functional assay Methods 0.000 description 1
- 230000004927 fusion Effects 0.000 description 1
- 229930182830 galactose Natural products 0.000 description 1
- 238000002523 gelfiltration Methods 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 150000004676 glycans Chemical class 0.000 description 1
- 108010020688 glycylhistidine Proteins 0.000 description 1
- 238000005734 heterodimerization reaction Methods 0.000 description 1
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 1
- 102000045108 human EGFR Human genes 0.000 description 1
- 102000053594 human TNFRSF10B Human genes 0.000 description 1
- 210000004408 hybridoma Anatomy 0.000 description 1
- 208000026278 immune system disease Diseases 0.000 description 1
- 239000012274 immune-checkpoint protein inhibitor Substances 0.000 description 1
- 230000016784 immunoglobulin production Effects 0.000 description 1
- 239000002955 immunomodulating agent Substances 0.000 description 1
- 238000000099 in vitro assay Methods 0.000 description 1
- 230000005917 in vivo anti-tumor Effects 0.000 description 1
- 238000005462 in vivo assay Methods 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 229960003130 interferon gamma Drugs 0.000 description 1
- 108010074108 interleukin-21 Proteins 0.000 description 1
- 108010053037 kyotorphin Proteins 0.000 description 1
- 238000009533 lab test Methods 0.000 description 1
- 108010012058 leucyltyrosine Proteins 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 108010003700 lysyl aspartic acid Proteins 0.000 description 1
- 230000036210 malignancy Effects 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 239000003550 marker Substances 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 description 1
- 108020004999 messenger RNA Proteins 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000000897 modulatory effect Effects 0.000 description 1
- 238000010172 mouse model Methods 0.000 description 1
- 239000006199 nebulizer Substances 0.000 description 1
- 229960004927 neomycin Drugs 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 230000007135 neurotoxicity Effects 0.000 description 1
- 231100000228 neurotoxicity Toxicity 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 239000002751 oligonucleotide probe Substances 0.000 description 1
- 238000002515 oligonucleotide synthesis Methods 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 210000001672 ovary Anatomy 0.000 description 1
- 101710135378 pH 6 antigen Proteins 0.000 description 1
- 230000002688 persistence Effects 0.000 description 1
- 238000002823 phage display Methods 0.000 description 1
- 108010073101 phenylalanylleucine Proteins 0.000 description 1
- 108010083476 phenylalanyltryptophan Proteins 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 108091033319 polynucleotide Proteins 0.000 description 1
- 102000040430 polynucleotide Human genes 0.000 description 1
- 239000002157 polynucleotide Substances 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 238000002818 protein evolution Methods 0.000 description 1
- 239000012474 protein marker Substances 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000010076 replication Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 108091008146 restriction endonucleases Proteins 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 238000002702 ribosome display Methods 0.000 description 1
- 108010048397 seryl-lysyl-leucine Proteins 0.000 description 1
- 230000001568 sexual effect Effects 0.000 description 1
- 201000000849 skin cancer Diseases 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 235000010356 sorbitol Nutrition 0.000 description 1
- 238000004611 spectroscopical analysis Methods 0.000 description 1
- 238000010186 staining Methods 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 239000008362 succinate buffer Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 238000002198 surface plasmon resonance spectroscopy Methods 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 101150061166 tetR gene Proteins 0.000 description 1
- 230000001550 time effect Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 230000005030 transcription termination Effects 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 230000001052 transient effect Effects 0.000 description 1
- 238000013519 translation Methods 0.000 description 1
- 230000014616 translation Effects 0.000 description 1
- 238000011269 treatment regimen Methods 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 108010079202 tyrosyl-alanyl-cysteine Proteins 0.000 description 1
- 108010020532 tyrosyl-proline Proteins 0.000 description 1
- 238000002604 ultrasonography Methods 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 239000000811 xylitol Substances 0.000 description 1
- 235000010447 xylitol Nutrition 0.000 description 1
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
- 229960002675 xylitol Drugs 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/46—Cellular immunotherapy
- A61K39/461—Cellular immunotherapy characterised by the cell type used
- A61K39/4611—T-cells, e.g. tumor infiltrating lymphocytes [TIL], lymphokine-activated killer cells [LAK] or regulatory T cells [Treg]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/46—Cellular immunotherapy
- A61K39/463—Cellular immunotherapy characterised by recombinant expression
- A61K39/4633—Antibodies or T cell engagers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/46—Cellular immunotherapy
- A61K39/464—Cellular immunotherapy characterised by the antigen targeted or presented
- A61K39/4643—Vertebrate antigens
- A61K39/4644—Cancer antigens
- A61K39/464402—Receptors, cell surface antigens or cell surface determinants
- A61K39/464403—Receptors for growth factors
- A61K39/464404—Epidermal growth factor receptors [EGFR]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/46—Cellular immunotherapy
- A61K39/464—Cellular immunotherapy characterised by the antigen targeted or presented
- A61K39/4643—Vertebrate antigens
- A61K39/4644—Cancer antigens
- A61K39/464402—Receptors, cell surface antigens or cell surface determinants
- A61K39/464403—Receptors for growth factors
- A61K39/464406—Her-2/neu/ErbB2, Her-3/ErbB3 or Her 4/ ErbB4
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/46—Cellular immunotherapy
- A61K39/464—Cellular immunotherapy characterised by the antigen targeted or presented
- A61K39/4643—Vertebrate antigens
- A61K39/4644—Cancer antigens
- A61K39/464402—Receptors, cell surface antigens or cell surface determinants
- A61K39/464403—Receptors for growth factors
- A61K39/46441—Hepatocyte growth factor receptor [HGFR or c-met]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/46—Cellular immunotherapy
- A61K39/464—Cellular immunotherapy characterised by the antigen targeted or presented
- A61K39/4643—Vertebrate antigens
- A61K39/4644—Cancer antigens
- A61K39/464402—Receptors, cell surface antigens or cell surface determinants
- A61K39/464411—Immunoglobulin superfamily
- A61K39/464412—CD19 or B4
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/46—Cellular immunotherapy
- A61K39/464—Cellular immunotherapy characterised by the antigen targeted or presented
- A61K39/4643—Vertebrate antigens
- A61K39/4644—Cancer antigens
- A61K39/464402—Receptors, cell surface antigens or cell surface determinants
- A61K39/464422—Ephrin Receptors [Eph]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/46—Cellular immunotherapy
- A61K39/464—Cellular immunotherapy characterised by the antigen targeted or presented
- A61K39/4643—Vertebrate antigens
- A61K39/4644—Cancer antigens
- A61K39/464402—Receptors, cell surface antigens or cell surface determinants
- A61K39/464424—CD20
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/46—Cellular immunotherapy
- A61K39/464—Cellular immunotherapy characterised by the antigen targeted or presented
- A61K39/4643—Vertebrate antigens
- A61K39/4644—Cancer antigens
- A61K39/464402—Receptors, cell surface antigens or cell surface determinants
- A61K39/464426—CD38 not IgG
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/46—Cellular immunotherapy
- A61K39/464—Cellular immunotherapy characterised by the antigen targeted or presented
- A61K39/4643—Vertebrate antigens
- A61K39/4644—Cancer antigens
- A61K39/464402—Receptors, cell surface antigens or cell surface determinants
- A61K39/464428—CD44 not IgG
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/46—Cellular immunotherapy
- A61K39/464—Cellular immunotherapy characterised by the antigen targeted or presented
- A61K39/4643—Vertebrate antigens
- A61K39/4644—Cancer antigens
- A61K39/464493—Prostate associated antigens e.g. Prostate stem cell antigen [PSCA]; Prostate carcinoma tumor antigen [PCTA]; Prostatic acid phosphatase [PAP]; Prostate-specific G-protein-coupled receptor [PSGR]
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
- C07K16/2809—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
- C07K16/2863—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against receptors for growth factors, growth regulators
-
- 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
- C07K16/2896—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against molecules with a "CD"-designation, not provided for elsewhere
-
- 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
- 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
- C07K16/3007—Carcino-embryonic Antigens
-
- 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
- C07K16/3069—Reproductive system, e.g. ovaria, uterus, testes, prostate
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/40—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against enzymes
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
- C12N5/06—Animal cells or tissues; Human cells or tissues
- C12N5/0602—Vertebrate cells
- C12N5/0634—Cells from the blood or the immune system
- C12N5/0636—T lymphocytes
- C12N5/0637—Immunosuppressive T lymphocytes, e.g. regulatory T cells or Treg
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/51—Medicinal preparations containing antigens or antibodies comprising whole cells, viruses or DNA/RNA
- A61K2039/515—Animal cells
- A61K2039/5156—Animal cells expressing foreign proteins
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
- C07K16/2827—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against B7 molecules, e.g. CD80, CD86
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- 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
- C07K16/2878—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 NGF-receptor/TNF-receptor superfamily, e.g. CD27, CD30, CD40, CD95
-
- 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
- C07K16/2887—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against CD20
-
- 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
- C07K16/3076—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 against structure-related tumour-associated moieties
- C07K16/3084—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 against structure-related tumour-associated moieties against tumour-associated gangliosides
-
- 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
- C07K16/32—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against translation products of oncogenes
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
- C07K2317/31—Immunoglobulins specific features characterized by aspects of specificity or valency multispecific
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/55—Fab or Fab'
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
- C07K2317/565—Complementarity determining region [CDR]
-
- 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
- C07K2317/00—Immunoglobulins specific features
- C07K2317/60—Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments
- C07K2317/64—Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments comprising a combination of variable region and constant region components
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Immunology (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Genetics & Genomics (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- Biophysics (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Cell Biology (AREA)
- Oncology (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- Microbiology (AREA)
- Epidemiology (AREA)
- Mycology (AREA)
- Engineering & Computer Science (AREA)
- Biomedical Technology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Zoology (AREA)
- Biotechnology (AREA)
- Wood Science & Technology (AREA)
- Hematology (AREA)
- General Engineering & Computer Science (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pregnancy & Childbirth (AREA)
- Reproductive Health (AREA)
- Gynecology & Obstetrics (AREA)
- Physics & Mathematics (AREA)
- Plant Pathology (AREA)
- Developmental Biology & Embryology (AREA)
- Dermatology (AREA)
- Gastroenterology & Hepatology (AREA)
Abstract
本发明提供一种能够结合于CD3和肿瘤相关抗原的双特异性抗体、武装有这类双特异性抗体的免疫细胞以及其在癌症治疗中的治疗用途。本文还提供产生武装有所述双特异性抗体的免疫细胞的方法。
Description
相关申请的交叉引用
本申请要求2020年3月23日提交的美国临时申请第62/993,080号从提交日开始的权益,所述美国临时申请的全部内容以引用的方式并入本文中。
背景技术
癌症为一种以不可控制地分裂并且能够浸润及破坏受试者的正常组织和/或器官的异常细胞为特征的疾病。癌症是全球第二大主要死亡原因,且2018年造成估计960万人死亡,其中最常见的癌症包含肺癌(约209万病例)、乳腺癌(约209万病例)、结肠直肠癌(约180万病例)、前列腺癌(约128万病例)、皮肤癌(约104万病例)及胃癌(约103万病例)。
癌症治疗可能因癌症类型和其进展程度而异。常规癌症治疗包含手术、放射疗法和化学疗法。这类治疗通常引起各种并发症或副作用,例如感染、血块、出血、恶心和呕吐、腹泻、神经或肌肉损伤、失禁以及性与生育问题。免疫疗法提供替代性癌症治疗策略,其旨在经由例如阻断免疫检查点或增强免疫细胞(例如T细胞或B细胞)靶向和破坏癌细胞的能力特异性地刺激受试者对癌细胞的免疫反应。癌症患者已报告与免疫疗法药用过度刺激或非特异性毒性相关的严重副作用,包含神经毒性、细胞因子释放综合症(CRS)、过敏、器官炎症和自体免疫病症。
因此,极其重要的是研发特异性地靶向癌细胞而不影响正常细胞和/或组织的有效癌症治疗。
发明内容
本公开是基于能够结合于CD3(例如人CD3)和肿瘤相关抗原(TAA)的双特异性抗体(BsAb)的研发。这类BsAb能够经由使BsAb中的抗CD3部分结合到细胞表面CD3而结合到CD3阳性免疫细胞的表面以产生武装免疫细胞。
因此,在一些方面,本公开的特征在于一种双特异性抗体,其包括:(a)结合人CD3的第一抗原结合片段,和(b)结合肿瘤相关抗原(TAA)的第二抗原结合片段。所述第一抗原结合片段包括(i)包括第一重链可变区(VH)的第一重链和(ii)包括第一轻链可变区(VL)的第一轻链。在一些实施例中,第一VH包括与第一参考抗体相同的重链互补决定区(CDR)。在其它实施例中,第一VH包括或CDR中的不超过5个相对于第一参考抗体的氨基酸变异。或者或另外,第一VL可以包括与第一参考抗体相同的轻链CDR。在其它实施例中,第一VL可以包括CDR中的不超过5个相对于第一参考抗体的氨基酸变异。在一些实例中,第一参考抗体为CTA.02。在一些实例中,第一参考抗体为CTA.03。在其它实例中,第一参考抗体为CTA.04。在其它实例中,第一参考抗体为CTA.05。这些示范性参考抗体的结构信息提供在下文表1中。在一些实例中,第一重链和第一轻链包括与第一参考抗体相同的VH和VL。
第二抗原结合片段包括第二重链和(ii)第二轻链,所述第二重链包括(i)第二重链可变区(VH),所述第二轻链包括第二轻链可变区(VL)。第二抗原结合片段结合TAA。实例包含CD20、CD19、EGFR、HER2、PSMA、CEA、EpCAM、FAP、PD-L1、CD38、CD33、cMET、CD47、TRAIL-R2、间皮素或GD2。在一些情况下,第二VH包括与第二参考抗体相同的重链互补决定区(CDR)。或者,第二VH可以包括CDR中的不超过五个相对于第二参考抗体的氨基酸变异。或者或另外,第二VL可以包括相同轻链CDR。在其它实例中,第二VL可以包括CDR中的不超过5个相对于第二参考抗体的氨基酸变异。在一些情况下,第二参考抗体为CTAT.01、CTAT.02、CTAT.03、CTAT.04、CTAT.05、CTAT.06、CTAT.07、CTAT.08、CTAT.09、CTAT.10、CTAT.11、CTAT.12、CTAT.13、CTAT.14、CTAT.15或CTAT.16。参见下文表2。在一些实例中,第二抗原结合片段包括与第二参考抗体相同的VH和相同的VL。
在一些实施例中,第一抗原结合片段为Fab片段,且第二抗原结合片段为单链可变片段(scFv)。在一些实例中,Fab片段包括第一重链和第一轻链,所述第一重链包括第一VH和CH1片段,所述第一轻链包括第一VL和轻链恒定区。在特定实例中,Fab片段可以包括第一重链和第一轻链,其分别包括以下氨基酸序列:(a)SEQ ID NO:10和SEQ ID NO:11,(b)SEQID NO:23和SEQ ID NO:24、25或228,(c)SEQ ID NO:35和SEQ ID NO:36,或(d)SEQ ID NO:46和SEQ ID NO:47。在一些实例中,第二抗原结合片段的scFv包括SEQ ID NO:254至271中的任一个氨基酸序列。
在一些情况下,scFv任选地经由肽连接子连接到CH1片段。或者,scFv任选地经由肽连接子连接到轻链恒定区。举例来说,双特异性抗体可以包括第一多肽和第二多肽,第一多肽包括第一轻链,第二多肽从N端到C端包括第一重链、肽连接子和scFv。实例包含SEQ IDNO:229至248中的任一个。这种双特异性抗体可以包括含有选自由SEQ ID NO:24、25和228组成的组的氨基酸序列的第二多肽。参见下文表3。
在其它情况下,第一抗原结合片段为单链可变片段(scFv),且第二抗原结合片段为Fab片段。scFv可以包括SEQ ID NO:250至253中的任一个氨基酸序列。在一些实例中,Fab片段包括第二重链和第二轻链,所述第二重链包括第二VH和CH1片段,所述第二轻链包括第二VL和轻链恒定区。在特定实例中,所述Fab片段包括第一重链和第一轻链,其分别包括以下氨基酸序列:(1)SEQ ID NO:57和SEQ ID NO:58,(2)SEQ ID NO:72和SEQ ID NO:73,(3)SEQ ID NO:83和SEQ ID NO:84,(4)SEQ ID NO:94和SEQ ID NO:95,(5)SEQ ID NO:105和SEQ ID NO:106,(6)SEQ ID NO:116和SEQ ID NO:117,(7)SEQ ID NO:127和SEQ ID NO:128,(8)SEQ ID NO:138和SEQ ID NO:139,(9)SEQ ID NO:149和SEQ ID NO:150,(10)SEQID NO:160和SEQ ID NO:161,(11)SEQ ID NO:171和SEQ ID NO:172,(12)SEQ ID NO:182和SEQ ID NO:183,(13)SEQ ID NO:193和SEQ ID NO:194,(14)SEQ ID NO:204和SEQ ID NO:205,(15)SEQ ID NO:215和SEQ ID NO:216,或(16)SEQ ID NO:226和SEQ ID NO:227。
在一些实例中,scFv任选地经由肽连接子连接到CH1片段。或者,scFv任选地经由肽连接子连接到轻链恒定区。肽连接子中的任一个的长度可以是至少5个氨基酸。
在其它情况下,第一抗原结合片段和第二抗原结合片段都为scFv抗体。在一些实例中,双特异性抗体包括含有两种scFv抗体的多肽。
在其它方面,本公开提供一种武装免疫细胞,其包括表达表面CD3的免疫细胞和本文公开的任何双特异性抗体(例如表1到表3中例示的双特异性抗体)。武装免疫细胞经由双特异性抗体中的第一抗原结合片段与由免疫细胞表达的CD3之间的相互作用将双特异性抗体呈现在表面上。在一些实施例中,所述免疫细胞为T细胞、B细胞、单核细胞、巨噬细胞或其组合。在一些情况下,T细胞可为CD4+T细胞、CD8+T细胞、调节T细胞或自然杀手T细胞。在一些实例中,所述免疫细胞为人免疫细胞,例如,来源于人类供体的免疫细胞。
另外,本文提供一种产生本文公开的武装免疫细胞的方法。所述方法可以包括在本文公开的双特异性抗体存在下培养包括免疫细胞的细胞群体以使双特异性抗体与免疫细胞结合,从而产生武装免疫细胞。由本文公开的任何方法产生的武装免疫细胞也在本公开的范围内。
在一些实施例中,细胞群体包括T细胞、B细胞、单核细胞、巨噬细胞或其组合。在一些实例中,细胞群体包括来源于体外干细胞的外周血单核细胞(PBMC)或免疫细胞。干细胞可以是造血干细胞、脐带血干细胞或诱导性多能干细胞(iPS)细胞。
在一些实施例中,培养步骤在包括细胞因子的培养基中进行,所述细胞因子任选地包括白介素2(IL-2)、白介素7(IL-7)、转化生长因子-β(TGF-β)或其组合。
此外,本文提供一种治疗癌症的方法,其包括向有需要的受试者施用有效量的本文公开的任何武装免疫细胞的群体。受试者患有或怀疑患有TAA阳性的癌症,双特异性抗体的第二抗原结合片段结合所述TAA。在一些实施例中,受试者为人类癌症患者。在一些实施例中,武装免疫细胞为受试者自体的。或者,武装免疫细胞为受试者同种异体的。示范性癌症包含但不限于:黑色素瘤、食道癌、胃癌、脑瘤、小细胞肺癌、非小细胞肺癌、膀胱癌、乳腺癌、胰腺癌、结肠癌、直肠癌、结肠直肠癌、肾癌、肝细胞癌、卵巢癌、前列腺癌、甲状腺癌、睾丸癌、头颈部鳞状细胞癌、白血病、淋巴瘤和骨髓瘤。
在其它方面,本公开的特征在于一种核酸或核酸集合(两种核酸分子),其编码或共同编码本文公开的任何双特异性抗体。在一些实例中,核酸或核酸集合为载体或载体集合,例如表达载体。包括本文公开的核酸或核酸集合中的任一者的宿主细胞(例如细菌细胞、酵母细胞或哺乳动物细胞)也在本公开的范围内。
另外,本公开的特征在于一种用于产生双特异性抗体的方法,其包括:(i)在允许表达双特异性抗体的条件下培养本文公开的宿主细胞;及(ii)收集双特异性抗体。
用于癌症治疗的本文公开的武装免疫细胞或任何武装免疫细胞用于制造治疗目标癌症的药物的用途也在本公开的范围内。
在以下描述中阐述本发明的一个或多个实施例的细节。根据以下附图和几个实施例的具体实施方式以及所附权利要求书,本发明的其它特征或优点将变得显而易见。
附图说明
以下附图形成本说明书的一部分,并且被包含以进一步说明本公开的某些方面,通过参考附图并结合本文呈现的具体实施例的具体实施方式,可以更好地理解本公开的某些方面。
图1A到1N为示范性双特异性抗体型式的示意图。图1A到1D:抗CD3Fab/抗TAA scFv双特异性型式的结构。图1E到1H:抗CD3 scFv/抗TAA Fab双特异性型式的结构。图1I到1L:抗CD3 scFv/抗TAA scFv双特异性型式的结构。图1M:抗CD3杵/抗TAA臼双特异性抗体型式的结构,所述形式包括单价抗CD3抗体及单价抗TAA抗体。图1N:抗CD3杵/抗TAA scFv臼抗体,其包括单价抗CD3抗体及单价抗TAA scFv-Fc融合蛋白。
图2A到2E包含用于表达所说明重组双特异性抗体的DNA构建体的示意图。图2A:用于表达抗CD3Fab/抗TAA scFv双特异性抗体的示范性构建体。图2B:用于表达抗CD3scFv/抗TAA Fab双特异性抗体的示范性构建。图2C:用于表达抗CD3 scFv/抗TAA scFv双特异性抗体的示范性构建体。图2D:用于表达抗CD3杵/抗TAA臼双特异性抗体的示范性构建体。图2E:用于表达抗CD3杵/抗TAA scFv臼抗体的示范性构建体。
图3为展示由流式细胞术测量的示范性双特异性抗体与T细胞的结合亲和力的图表。
图4为描绘武装有示范性双特异性抗体或由针对HT-29癌细胞的OKT3抗体活化的T细胞的细胞毒性作用的图表。
图5为描绘示范性双特异性抗体在T细胞表面上的量的时程的图表。
图6A到6B包含展示示范性双特异性抗体如由SDS-PAGE所指示的在非还原条件(图6A)及还原条件(图6B)下的表达和组装的像片。估计的分子量:完整BsAb=95kDa,重链=60kDa,且轻链=25kDa。泳道1:蛋白质标记物,泳道2:CTA02Fab/CTAT02scFv,泳道3:CTA04Fab/CTAT02scFv。泳道4:CTA03Fab/CTAT02scFv,且泳道5:CTA05Fab/CTAT02scFv。
图7A到7F包含展示示范性抗CD3 Fab/抗肿瘤双特异性抗体如由SDS-PAGE所指示的在还原或非还原条件下的表达和组装的像片。估计的分子量:完整BsAb=95kDa。图7A到7B:非还原条件下的CTA03Fab/抗TAA scFv双特异性抗体。图7C到7D:还原条件下的CTA03Fab/抗TAA scFv双特异性抗体。图7E到7F:分别在非还原和还原条件下的抗CD3scFv/CTAT03Fab双特异性抗体。
图8为展示所指示的各种双特异性抗体与T细胞和与肿瘤细胞的结合活性的图。将CD3+T细胞(Jurkat)和CD19+B细胞淋巴瘤(Raji)分开地用示范性双特异性抗体CTA02Fab/CTAT02scFv、CTA03Fab/CTAT02scFv、CTA04Fab/CTAT02scFv和CTA05Fab/CTAT02scFv BsAb培育,且随后用FITC结合山羊抗人IgG Fab抗体和流式细胞仪分析。
图9A到9L包含展示所指示的示范性抗CD3 Fab/抗肿瘤scFv双特异性抗体与T细胞和与肿瘤细胞的结合活性的图。图9A:CTA03Fab/CTAT02scFv与CD3+T细胞(Jurkat)和CD19+B细胞淋巴瘤细胞(Raji)结合。图9B:CTA03Fab/CTAT03scFv与CD3+T细胞(Jurkat)和EGFR+三阴性乳腺癌细胞(MDA-MB-231)结合。图9C:CTA03Fab/CTAT04scFv与CD3+T细胞(Jurkat)和HER2+乳腺癌细胞(MCF7/HER2)结合。图9D:CTA03Fab/CTAT05scFv与CD3+T细胞(Jurkat)和PSMA+前列腺癌细胞(LNCaP)结合。图9E:CTA03Fab/CTAT07scFv与CD3+T细胞(Jurkat)和EpCAM+前列腺癌细胞(LNCaP)结合。图9F:CTA03Fab/CTAT08scFv与CD3+T细胞(Jurkat)和FAP+小鼠成纤维细胞(3T3/FAP)结合。图9G:CTA03Fab/CTAT09scFv与CD3+T细胞(Jurkat)和PDL1+三阴性乳腺癌细胞(MDA-MB-231)结合。图9H:CTA03Fab/CTAT10scFv与CD3+T细胞(Jurkat)和CD38+B细胞淋巴瘤细胞(Raji)结合。图9I:CTA03Fab/CTAT11scFv与CD3+T细胞(Jurkat)和CD33+人急性骨髓性白血病细胞(HL-60)结合。图9J:CTA03Fab/CTAT12scFv与CD3+T细胞(Jurkat)和HGFR+人肺癌细胞(A549)结合。图9K:CTA03Fab/CTAT13scFv与CD3+T细胞(Jurkat)和CD47+乳腺癌细胞(MCF7/HER2)结合。图9L:BsAb CTA02scFv/CTAT03Fab、CTA03scFv/CTAT03Fab、CTA04scFv/CTAT03Fab和CTA05scFv/CTAT03Fab与CD3+T细胞(Jurkat)(上图)及EGFR+结肠癌细胞(HT-29)(下图)的结合。用FITC结合山羊抗人IgG Fab抗体和流式细胞术分析样本。
图10为展示示范性BsAb在T细胞表面上的留存能力的图表。将人T细胞与带有4种不同抗CD3抗体(CTA01Fab/CTAT02scFv、CTA02Fab/CTAT02scFv、CTA03Fab/CTAT02scFv和CTA05Fab/CTAT02scFv)的Fab的变异抗CD3Fab/抗CD19scFv BsAb一起培育1hr,随后在培养基中培养5min、24hr、48hr和72hr。培养后,用FITC结合山羊抗人IgG Fab抗体使细胞染色,且使用流式细胞术分析BsAb在T细胞表面上的留存。
图11A和11B包含展示武装有本文公开的示范性BsAb的T细胞的形成的图。图11A:从左到右,OKT3、CTA01Fab/CTAT02scFv和CTA02Fab/CTAT02scFv。图11B:CTA03Fab/CTAT02scFv(左)及CTA05Fab/CTAT02scFv(右)。在OKT3或各种BsAb存在下培养PBMC。随后用FITC结合CD8抗体和PE结合山羊抗人IgGFab使细胞培养物染色,随后使用流式细胞术分析。
图12A到12D包含展示武装有所指示的示范性BsAb的T细胞的形成的图。图12A:OKT3、CTA03Fab/CTAT03scFv和CTA03Fab/CTAT04scFv(上图,从左到右),以及CTA03Fab/CTAT09scFv、CTA03Fab/CTAT010scFv和CTA03Fab/CTAT11scFv(下图,从左到右)。图12B:CTA03Fab/CTAT05scFv、CTA03Fab/CTAT07scFv和CTAFab/CTAT08scFv(上图,从左到右),以及CTA03Fab/CTAT12scFv和CTA03Fab/CTAT13scFv(下图,从左到右)。图12C:OKT3、CTA01scFv/CTAT03Fab和CTA02scFv/CTA03Fab(从左到右)。图12D:CTA03scFv/CTAT03Fab、CTA04scFv/CTAT03Fab和CTA05scFv/CTAT03Fab(从左到右)。用抗CD8抗体和山羊抗人IgGFab使细胞培养物染色,随后使用流式细胞术分析。
图13A到13B包含展示由OKT3抗体诱导或武装有针对肿瘤细胞的所指示示范性双特异性抗体的T细胞的细胞毒性活性的图表。图13A:针对B细胞淋巴瘤的抗CD3Fab/抗CD19scFv BsAb。图13B:针对HT29细胞的抗CD3scFv/CTAT03Fab BsAb。用OKT3或所指示的示范性BsAb培养细胞。随后将细胞培养物与CD19+B细胞淋巴瘤(Raji)以几种效细胞:靶细胞比率(3:1、5:1及10:1)一起培育18hr。用CytoTox 非放射性细胞毒性分析(普洛麦格(Promega),G1780)确定肿瘤细胞死亡。
图14A到14G包含展示针对癌细胞的抗CD3Fab/抗EGFRscFv BsAb武装T细胞的体外细胞毒性活性的电荷。图14A:针对HT29细胞(EGFR+结肠癌细胞)的CTA01Fab/CTAT03scFv或CTA03Fab/CTAT03scFv武装T细胞。图14B:针对HCT-116细胞(EGFR+结肠癌细胞)的CTA01Fab/CTAT03scFv或CTA03Fab/CTAT03scFv武装T细胞。图14C:针对HER2+乳腺癌细胞(MCF-7/HER2)的抗CD3Fab/抗HER2scFv(CTA03Fab/CTAT04scFv)武装T细胞。图14D:针对PSMA+前列腺癌细胞(LNCaP)的抗CD3Fab/抗PSMAscFv(CTA03Fab/CTAT05scFv)武装T细胞。图14E:针对EpCAM+前列腺癌细胞(LNCaP)的抗CD3Fab/抗EpCAMscFv(CTA03Fab/CTAT07scFv)武装T细胞。图14F到14G:针对FAP-小鼠成纤维细胞(3T3)(图14F)或FAP+小鼠成纤维细胞(3T3/FAP)(图14G)的抗CD3Fab/抗FAPscFv(CTA03Fab/CTAT08scFv)武装T细胞。将OKT3培养T细胞或武装T细胞与癌细胞以几种效应细胞:靶细胞比率(3:1、5:1和10:1)共同培养18hr。用CytoTox非放射性细胞毒性分析(普洛麦格,G1780)确定肿瘤细胞死亡。
图15A到15E包含展示针对对应癌细胞的示范性抗CD3Fab/抗TAA scFv BsAb的体外细胞毒性活性的图表。图15A:针对三阴性乳腺癌细胞(MDA-MB-231)的抗CD3Fab/抗PDL1scFv(CTA03Fab/CTAT09scFv)武装T细胞。图15B:针对CD38+B细胞淋巴瘤细胞(Raji)的抗CD3Fab/抗CD38scFv(CTA03Fab/CTAT10scFv)武装T细胞。图15C:针对CD33+人急性骨髓性白血病细胞(HL-60)的抗CD3Fab/抗CD33scFv(CTA03Fab/CTAT11scFv)武装T细胞。图15D:针对HGFR+人肺癌细胞(A549)的抗CD3Fab/抗HGFRscFv(CTA03Fab/CTAT12scFv)武装T细胞。图15E:针对CD47+乳腺癌细胞(MCF-7/HER2)的抗CD3Fab/抗CD47scFv(CTA03Fab/CTAT13scFv)武装T细胞。将OKT3培养T细胞或武装T细胞与癌细胞以几种效应细胞:靶细胞比率(3:1、5:1和10:1)共同培养18hr。用CytoTox非放射性细胞毒性分析(普洛麦格,G1780)确定肿瘤细胞死亡。
图16A到16C包含展示示范性抗CD3Fab/抗CD19scFv武装T细胞针对淋巴瘤的体内治疗功效的图式。用CD19+B细胞淋巴瘤细胞(2.5×106个细胞/小鼠)对SCID小鼠进行静脉内接种。3天后,向小鼠静脉内注射T细胞、CTA01Fab/CTAT02scFv武装T细胞和CTA03Fab/CTAT02scFv武装T细胞(5×106个细胞/小鼠,一周一次,4次)。图16A:体重。图16B:存活率。图16C:后肢麻痹发生率。
图17A到17B包含展示示范性CTA03Fab/CTAT03scFv武装T细胞和CTA03Fab/CTAT04scFv武装T细胞针对人三阴性乳腺癌的体内治疗功效的图式。用临床人乳腺瘤组织对ASID小鼠进行皮下接种。19天后,向小鼠静脉内注射T细胞、CTA03Fab/CTAT03scFv武装T细胞和CTA03Fab/CTAT04scFv武装T细胞(5×106个细胞/小鼠,一周一次,4次)。图17A:体重。图17B:肿瘤尺寸。
图18A到18D包含展示含各种抗CD3/抗TAA BsAb的BsAb武装NKT细胞的形成的图式。图18A:OKT3(左)和CTA03Fab/CTAT03scFv(右)。图18B:CTA03Fab/CTAT04scFv(左)和CTA03Fab/CTAT05scFv(右)。图18C:OKT3、CTA01scFv/CTAT03Fab和CTA02scFv/CTAT03Fab(从左到右)。图18D:CTA03scFv/CTAT03Fab、CTA04scFv/CTAT03Fab和CTA05scFv/CTAT03Fab(从左到右)。在OKT3抗体或所指示的BsAb存在下培养及分化NKT细胞(CD8+CD25+)。随后用抗CD8抗体、抗CD56抗体和FITC结合抗人IgGFab抗体使细胞染色。使用流式细胞术分析细胞表面上的BsAb。
图19A到19C包含展示点突变BsAb CTA03Fab/CTAT02scFv的结合活性和毒性的图表。图19A:与CD3+T细胞(Jurkat)的结合活性。图19B:与CD19+B细胞淋巴瘤(Raji)的结合活性。图19C:武装T细胞相对于用OKT3培养的T细胞的细胞毒性使所述细胞包含CTA03Fab/CTAT02scFv、CTA03-01Fab/CTAT02-01scFv、CTA03-01Fab/CTAT02-02scFv、CTA03-02Fab/CTAT02-02scFv和CTA03-02Fab/CTAT02-01scFv BsAb,随后用FITC结合山羊抗人IgG Fab抗体染色。使用流式细胞术检测细胞表面上的荧光信号。针对细胞毒性分析,用OKT3或各种BsAb培养T细胞以形成武装T细胞。随后将所述细胞与CD19+B细胞淋巴瘤(Raji)以几种效应细胞:靶细胞比率(3:1、5:1和10:1)共同培养18hr。用CytoTox非放射性细胞毒性分析(普洛麦格,G1780)确定肿瘤细胞死亡。
具体实施方式
本公开是基于能够结合于CD3(例如人CD3)和肿瘤相关抗原(TAA)的双特异性抗体(BsAb)的研发。这类BsAb能够经由使BsAb中的抗CD3部分结合到细胞表面CD3而结合到CD3阳性免疫细胞的表面以产生武装免疫细胞。如本文所用,术语“武装免疫细胞”指代经由使本文公开的双特异性抗体中的抗CD3部分与细胞表面CD3分子结合来呈现双特异性抗体的免疫细胞。经由细胞表面上的双特异性抗体中的抗TAA部分,武装免疫细胞能够靶向表达TAA的疾病细胞(例如癌细胞),从而引发针对疾病细胞的免疫反应。
据本文报告,本文公开的BsAb显示与CD3+免疫细胞和TAA+癌细胞两者的高结合活性以及在CD3+免疫细胞上的高留存水平保持至少72小时。武装有本文公开的BsAb的免疫细胞展现针对体外和体内表达对应TAA的癌细胞的高细胞毒性。因此,BsAb和本文公开的武装免疫细胞预期会具有高抗癌效应。
因此,本文提供能够结合于CD3和TAA的双特异性抗体、呈现其的武装免疫细胞、使用双特异性抗体产生武装免疫细胞的方法以及使用武装免疫细胞治疗癌症的方法。
I.结合CD3和肿瘤相关抗原的双特异性抗体
在一些方面,本公开提供能够结合于CD3(例如CD3+细胞)和肿瘤相关抗原(TAA)(例如在细胞表面上表达TAA的癌细胞)的双特异性抗体。抗体(与复数形式可互换使用)为能够通过位于免疫球蛋白分子的可变区中的至少一个抗原识别位点特异性结合于例如糖类、聚核苷酸、脂质、多肽等靶标的免疫球蛋白分子。本文所公开的双特异性抗体包括两个抗原结合部分,其中之一结合如人CD3等CD3,且其中的另一个结合肿瘤相关抗原,例如本文公开的那些肿瘤相关抗原。
典型的抗体分子包括重链可变区(VH)和轻链可变区(VL),其通常参与抗原结合。可以将VH和VL区进一步细分为也被称为“互补决定区”(“CDR”)的高变区,穿插有更保守的称为“构架区”(“FR”)的区。每个VH和VL典型地由三个CDR和四个FR构成,按以下顺序从氨基端到羧基端布置:FR1、CDR1、FR2、CDR2、FR3、CDR3、FR4。构架区和CDR的范围可以使用本领域中已知的方法,例如通过均为本领域中众所周知的Kabat定义、Chothia定义、AbM定义和/或contact定义精确地鉴定。参见例如Kabat,E.A.等人(1991)《免疫学所关注的蛋白质的序列(Sequences of Proteins of Immunological Interest)》,第五版,美国卫生与公众服务部(U.S.Department of Health and Human Services),第91-3242号NIH公开案、Chothia等人,(1989)《自然(Nature)》342:877、Chothia,C.等人(1987)《分子生物学杂志(J.Mol.Biol.)》196:901-917、Al-lazikani等人(1997)《分子生物学杂志》273:927-948和Almagro,《分子识别杂志(J.Mol.Recognit.)》17:132-143(2004)。还参见hgmp.mrc.ac.ukand bioinf.org.uk/abs)。
在一些实施例中,本文公开的抗体部分可与参考抗体共有相同重链和/或轻链互补决定区(CDR)或相同VH和/或VL链。两种抗体具有相同VH和/或VL CDR是指当通过相同方法(例如本领域中已知的Kabat法、Chothia法、AbM法、Contact法或IMGT法。参见例如bioinf.org.uk/abs/)确定时,其CDR一致。这类抗CD19抗体可具有与本文描述的示范性抗体相同的VH、相同的VL或两者。
在一些实施例中,本文公开的抗体部分可以与参考序列共有某一水平的序列同一性。使用Karlin和Altschul,《美国国家科学院院刊(Proc.Natl.Acad.Sci.USA)》,87:2264-68,1990的算法来确定两个氨基酸序列的“同一性百分比”,所述算法如Karlin和Altschul,《美国国家科学院院刊》,90:5873-77,1993中那样进行修改。这种算法被结合到Altschul等人在《分子生物学杂志》215:403-10,1990的NBLAST和XBLAST程序(2.0版)中。可以用XBLAST程序(分值=50,字长=3)来执行BLAST蛋白质检索以获得与所关注蛋白质分子同源的氨基酸序列。在两个序列之间存在间隙的情况下,Gapped BLAST可以如Altschul等人在《核酸研究(Nucleic Acids Res.)》25(17):3389-3402,1997中所描述使用。当利用BLAST程序和Gapped BLAST程序时,可以使用相应程序(例如XBLAST和NBLAST)的默认参数。
在一些实施例中,本文公开的抗体部分可具有一或多个相对于参考抗体的氨基酸变异。本公开中公开的氨基酸残基变异(例如构架区中和/或CDR中)可以是保守氨基酸残基取代。如本文所用,“保守氨基酸取代”是指不改变进行氨基酸取代的蛋白质的相对电荷或尺寸特性的氨基酸取代。可以根据本领域普通技术人员已知的改变多肽序列的方法来制备变异体,例如在汇编这类方法的参考文献中所发现的,例如《分子克隆:实验指南(Molecular Cloning:A Laboratory Manual)》,J.Sambrook等人编,第二版,冷泉港实验室出版社(Cold Spring Harbor Laboratory Press),冷泉港(Cold Spring Harbor),纽约(New York),1989或《现代分子生物学实验技术(Current Protocols in MolecularBiology)》,F.M.Ausubel等人编,约翰·威利父子公司(John Wiley&Sons,Inc.),纽约。氨基酸的保守取代包含在以下组内的氨基酸之间进行的取代:(a)M、I、L、V;(b)F、Y、W;(c)K、R、H;(d)A、G;(e)S、T;(f)Q、N;和(g)E、D。
A.双特异性抗体
本文公开的双特异性抗体包括CD3结合部分(抗CD3部分)和TAA结合部分(抗TAA部分)。
(i)CD3结合部分
本文公开的任何双特异性抗体中的抗CD3部分包括对CD3分子(例如人CD3)具特异性的抗原结合片段。在一些实施例中,抗CD3部分包括重链可变区(VH)和轻链可变区(VL)。在一些情况下,抗CD3部分可以来源于参考抗CD3抗体。示范性参考抗CD3抗体包含CTA.02、CTA.03、CTA.04或CTA.05。这些参考抗CD3抗体的结构信息提供于下文表1中(基于Kabat方案的重链和轻链互补决定区(CDR)呈粗体且加下划线)。
表1.参考抗CD3抗体
来源于参考抗体的抗CD3结合部分(和下文公开的抗TAA结合部分)指代具有与参考抗体大体上类似的结构和功能特征的结合部分。结构上,结合部分可以具有与参考抗体相同的重链和/或轻链互补决定区或相同的VH和/或VL链。或者,结合部分可以仅在一个或多个构架区和/或一个或多个CDR中具有数量有限的氨基酸变异,而不会显著影响其相对于参考抗体的结合亲和力和结合特异性。
在一些实施例中,抗CD3结合部分可以包括与抗体CTA.02中的那些重链CDR(其提供于上文表1中)相同的重链CDR。或者或另外,抗CD3结合部分可以具有与抗体CTA.02中的那些轻链CDR(其也提供于上文表1中)相同的轻链CDR。这种抗CD3结合部分可以包括与CTA.02相同的VH和/或VL链。或者,抗CD3结合部分可以在一个或多个构架区中包括相对于CTA.02中的对应构架区的氨基酸变异。举例来说,抗CD3结合部分可以在一个或多个构架区中共同地包括相对于CTA.02中的对应构架区的最多15个氨基酸变异(例如最多12、10、9、8、7、6、5、4、3、2或1个氨基酸变异)。
在一些实施例中,抗CD3部分可以在一个或多个CDR中包括相对于CTA.02的那些CDR的某一水平的变异。举例来说,抗CD3部分可以包括重链CDR,所述重链CDR个别地或共同地与CTA.02的VH CDR具有至少80%(例如85%、90%、95%或98%)序列同一性。或者或另外,抗CD3抗体可以包括轻链CDR,所述轻链CDR个别地或共同地与CTA.02的VL CDR具有至少80%(例如85%、90%、95%或98%)序列同一性。如本文所用,“个别地”是指抗体的一个CDR与参考抗体(例如上文表1中提供的抗CD3参考抗体或下文公开的任何抗TAA参考抗体)的对应CDR共有所指示的序列同一性。“共同地”是指抗体的三个VH或VL CDR的组合与参考抗体的三个对应VH或VL CDR的组合共有所指示的序列同一性。
在一些情况下,抗CD3部分可以在一个或多个重链和轻链CDR中共同地包括相对于CTA.02的CDR的最多10个氨基酸变异(例如最多9、8、7、6、5、4、3、2或1个氨基酸变异)。在一些情况下,抗CD3部分可以包括与CTA.02的重链CDR3相同的重链CDR3且在其它重链和轻链CDR中的一个或多个中包括一个或多个氨基酸变异。
在一些实施例中,抗CD3结合部分可以包括与抗体CTA.03中的那些重链CDR(其提供于上文表1中)相同的重链CDR。或者或另外,抗CD3结合部分可以具有与抗体CTA.03中的那些轻链CDR(其也提供于上文表1中)相同的轻链CDR。这种抗CD3结合部分可以包括与CTA.03相同的VH和/或VL链。或者,抗CD3结合部分可以在一个或多个构架区中包括相对于CTA.03中的对应构架区的氨基酸变异。举例来说,抗CD3结合部分可以在一个或多个构架区中共同地包括相对于CTA.03中的对应构架区的最多15个氨基酸变异(例如最多12、10、9、8、7、6、5、4、3、2或1个氨基酸变异)。在一个特定实例中,本文公开的抗CD3部分在VL链的位置G58处包括相对于CTA.03的突变,例如氨基酸残基取代(例如G58A)。参见例如上文表1中的CTA.03VL-01。
在一些实施例中,抗CD3部分可以在一个或多个CDR中包括相对于CTA.03的那些CDR的某一水平的变异。举例来说,抗CD3部分可以包括重链CDR,所述重链CDR个别地或共同地与CTA.03的VH CDR具有至少80%(例如85%、90%、95%或98%)序列同一性。或者或另外,抗CD3抗体可以包括轻链CDR,所述轻链CDR个别地或共同地与CTA.03的VL CDR具有至少80%(例如85%、90%、95%或98%)序列同一性。
在一些情况下,抗CD3部分可以在一个或多个重链和轻链CDR中共同地包括相对于CTA.03的CDR的最多10个氨基酸变异(例如最多9、8、7、6、5、4、3、2或1个氨基酸变异)。在一些情况下,抗CD3部分可以包括与CTA.03的重链CDR3相同的重链CDR3且在其它重链和轻链CDR中的一个或多个中包括一个或多个氨基酸变异。在特定实例中,本文公开的抗CD3部分可以在VL链的位置D57处包括相对于CTA.03的突变,例如氨基酸残基取代,例如D57E。参见例如表1中的CTA.03VL-02。
在一些实例中,抗CD3结合部分可以包括与抗体CTA.04中的那些重链CDR(其提供于上文表1中)相同的重链CDR。或者或另外,抗CD3结合部分可以具有与抗体CTA.04中的那些轻链CDR(其也提供于上文表1中)相同的轻链CDR。这种抗CD3结合部分可以包括与CTA.04相同的VH和/或VL链。或者,抗CD3结合部分可以在一个或多个构架区中包括相对于CTA.04中的对应构架区的氨基酸变异。举例来说,抗CD3结合部分可以在一个或多个构架区中共同地包括相对于CTA.04中的对应构架区的最多15个氨基酸变异(例如最多12、10、9、8、7、6、5、4、3、2或1个氨基酸变异)。
在一些实施例中,抗CD3部分可以在一个或多个CDR中包括相对于CTA.04的那些CDR的某一水平的变异。举例来说,抗CD3部分可以包括重链CDR,所述重链CDR个别地或共同地与CTA.04的VH CDR具有至少80%(例如85%、90%、95%或98%)序列同一性。或者或另外,抗CD3抗体可以包括轻链CDR,所述轻链CDR个别地或共同地与CTA.04的VL CDR具有至少80%(例如85%、90%、95%或98%)序列同一性。
在一些情况下,抗CD3部分可以在一个或多个重链和轻链CDR中共同地包括相对于CTA.04的CDR的最多10个氨基酸变异(例如最多9、8、7、6、5、4、3、2或1个氨基酸变异)。在一些情况下,抗CD3部分可以包括与CTA.04的重链CDR3相同的重链CDR3且在其它重链和轻链CDR中的一个或多个中包括一个或多个氨基酸变异。
在一些实例中,抗CD3结合部分可以包括与抗体CTA.05中的那些重链CDR(其提供于上文表1中)相同的重链CDR。或者或另外,抗CD3结合部分可以具有与抗体CTA.05中的那些轻链CDR(其也提供于上文表1中)相同的轻链CDR。这种抗CD3结合部分可以包括与CTA.05相同的VH和/或VL链。或者,抗CD3结合部分可以在一个或多个构架区中包括相对于CTA.05中的对应构架区的氨基酸变异。举例来说,抗CD3结合部分可以在一个或多个构架区中共同地包括相对于CTA.05中的对应构架区的最多15个氨基酸变异(例如最多12、10、9、8、7、6、5、4、3、2或1个氨基酸变异)。
在一些实施例中,抗CD3部分可以一个或多个CDR中包括相对于CTA.05的那些CDR的某一水平的变异。举例来说,抗CD3部分可以包括重链CDR,所述重链CDR个别地或共同地与CTA.05的VH CDR具有至少80%(例如85%、90%、95%或98%)序列同一性。或者或另外,抗CD3抗体可以包括轻链CDR,所述轻链CDR个别地或共同地与CTA.05的VL CDR具有至少80%(例如85%、90%、95%或98%)序列同一性。
在一些情况下,抗CD3部分可以在一个或多个重链和轻链CDR中共同地包括相对于CTA.05的CDR的最多10个氨基酸变异(例如最多9、8、7、6、5、4、3、2或1个氨基酸变异)。在一些情况下,抗CD3部分可以包括与CTA.05的重链CDR3相同的重链CDR3且在其它重链和轻链CDR中的一个或多个中包括一个或多个氨基酸变异。
(ii)TAA结合部分
除抗CD3结合部分以外,本文公开的任何双特异性抗体进一步包括对肿瘤相关抗原具特异性的第二结合部分。术语“肿瘤相关抗原”(TAA)在本领域中众所周知,且指代相对于相同细胞类型的非癌性细胞在癌细胞上和/或癌细胞中差异表达的分子。TAA的非限制性实例包含CD5、CD19、CD20、CD22、CD23、CD25、CD27、CD30、CD33、CD34、CD37、CD38、CD40、CD43、CD44v6、CD47、CD50、CD52、CD56、CD63、CD72a、CD74、CD78、CD79a、CD79b、CD86、CD134、CD137、CD138、CD248、CD319、αvβ3、α5β1、人表皮生长因子受体(EGFR或HER1)、HER2、HER3、HER4、血管内皮生长因子受体1(VEGFR-1)、VEGFR-2、VEGFR-3、TRAIL-R2、糖链抗原19-9(CA 19-9)、糖链抗原125(CA 125)、癌胚抗原(CEA)、粘蛋白1(MUC 1)、MUC2、MUC3、MUC4、MUC5、MUC7、神经节苷脂GD2、神经节苷脂GD3、神经节苷脂GM2、碳酸酐酶IX(CAIX)、音猬因子(SHH)、黑色素瘤硫酸软骨素蛋白聚糖(MCSP)、硫酸软骨素蛋白聚糖4(CSPG4)、前列腺六跨膜上皮抗原(six-transmembrane epithelial antigen of prostate;STEAP)、A33抗原、桥粒芯蛋白-2(Dsg2)、Dsg3、Dsg4、E-钙粘蛋白新表位(E-cadherin neoepitope)、胎儿烟碱型乙酰胆碱受体(fetal nicotinic acetylcholine receptor;fnAChR)、苗勒氏抑制物受体II型(muellerian inhibitory substance receptor type II;MISIIR)、肿瘤相关抗原L6(TAL6)、汤姆森-弗雷登雷希(Thomsen-Friedenreich;TF)抗原、EPHA1、EPHA2、EPHA3、EPHA4、EPHA7、EPHA8、EPHA10、EPHB4、睾丸癌抗原(CTA)、NY-BR1、肿瘤相关糖蛋白72(TAG-72)、α-胎蛋白(AFP)、印记位点调节因子类似基因(brother of the regulator of theimprinted site;BORIS)、B细胞活化因子(BAFF)、额外域B纤连蛋白(extradomain-Bfibronectin;EDB-FN)、糖蛋白A33(GPA33)、肌腱蛋白-C(TNC)、黑色素瘤相关抗原(MAGE)、GAGE、BAGE、前列腺干细胞抗原(PSCA)、间皮素、粘蛋白相关Tn、Sialyl Tn、globo H、阶段特异性胚胎抗原-4(SSEA-4)、上皮细胞粘着分子(EpCAM)、细胞毒性T淋巴细胞相关蛋白4(CTLA-4)、程序性细胞死亡1(PD-1)、程序性细胞死亡1配体1(PD-L1)、前列腺特异性膜抗原(PSMA)、成纤维细胞活化蛋白(FAP)、血管细胞粘着蛋白1(VCAM-1)、胰岛素样生长因子受体(IGFR)或肝细胞生长因子受体(HGFR)。
在一些实施例中,抗TAA结合部分包括重链可变区(VH)和轻链可变区(VL)。在一些实例中,抗TAA结合部分对CD20(例如人CD20)具特异性。在一些实例中,抗TAA结合部分对CD19(例如人CD19)具特异性。在一些实例中,抗TAA结合部分对EGFR(例如人EGFR)具特异性。在一些实例中,抗TAA结合部分对HER2(例如人HER2)具特异性。在一些实例中,抗TAA结合部分对PSMA(例如人PSMA)具特异性。在一些实例中,抗TAA结合部分对CEA(例如人CEA)具特异性。在一些实例中,抗TAA结合部分对EpCAM(例如人EpCAM)具特异性。在一些实例中,抗TAA结合部分对FAP(例如人FAP)具特异性。在一些实例中,抗TAA结合部分对PDL1(例如人PDL1)具特异性。在一些实例中,抗TAA结合部分对CD38(例如人CD38)具特异性。在一些实例中,抗TAA结合部分对CD33(例如人CD33)具特异性。在一些实例中,抗TAA结合部分对HGFR(cMET)(例如人cMET)具特异性。在一些实例中,抗TAA结合部分对CD47(例如人CD47)具特异性。在一些实例中,抗TAA结合部分对TRAIL-R2(例如人TRAIL-R2)具特异性。在一些实例中,抗TAA结合部分对间皮素(例如人间皮素)具特异性。在一些实例中,抗TAA结合部分对GD2(例如人GD2)具特异性。
在一些情况下,抗TAA部分可以来源于参考抗TAA抗体。示范性参考抗TAA抗体包含CTAT.01到CTAT.16。这些参考抗CD3抗体的结构信息提供于下文表2中(基于Kabat方案的重链和轻链互补决定区(CDR)呈粗体且加下划线)。
表2.参考抗肿瘤相关抗原抗体
在一些实例中,抗TAA结合部分可以包括与抗体CTAT.01的那些重链CDR(其提供于上文表2中)相同的重链CDR。或者或另外,抗TAA结合部分可以具有与抗体CTAT.01的那些轻链CDR(其也提供于上文表2中)相同的轻链CDR。这种抗TAA结合部分可以包括与CTAT.01相同的VH和/或VL链。或者,抗TAA结合部分可以在一个或多个构架区中包括相对于CTAT.01中的对应构架区的氨基酸变异。举例来说,抗TAA结合部分可以在一个或多个构架区中共同地包括相对于CTAT.01中的对应构架区的最多15个氨基酸变异(例如最多12、10、9、8、7、6、5、4、3、2或1个氨基酸变异)。
在一些实施例中,抗TAA部分可以在一个或多个CDR中包括相对于CTAT.01的那些CDR的某一水平的变异。举例来说,抗TAA部分可以包括重链CDR,所述重链CDR个别地或共同地与CTAT.01的VH CDR具有至少80%(例如85%、90%、95%或98%)序列同一性。或者或另外,抗TAA抗体可以包括轻链CDR,所述轻链CDR个别地或共同地与CTAT.01的VL CDR具有至少80%(例如85%、90%、95%或98%)序列同一性。
在一些情况下,抗TAA部分可以在一个或多个重链和轻链CDR中共同地包括相对于CTAT.01的CDR的最多10个氨基酸变异(例如最多9、8、7、6、5、4、3、2或1个氨基酸变异)。在一些情况下,抗TAA部分可以包括与CTAT.01的重链CDR3相同的重链CDR3,且在其它重链和轻链CDR中的一个或多个中包括一个或多个氨基酸变异。
在一些实例中,抗TAA结合部分可以包括与抗体CTAT.02的那些重链CDR(其提供于上文表2中)相同的重链CDR。或者或另外,抗TAA结合部分可以具有与抗体CTAT.02的那些轻链CDR(其也提供于上文表2中)相同的轻链CDR。这种抗TAA结合部分可以包括与CTAT.02相同的VH和/或VL链。或者,抗TAA结合部分可以在一个或多个构架区中包括相对于CTAT.02中的对应构架区的氨基酸变异。举例来说,抗TAA结合部分可以在一个或多个构架区中共同地包括相对于CTAT.02中的对应构架区的最多15个氨基酸变异(例如最多12、10、9、8、7、6、5、4、3、2或1个氨基酸变异)。
在一个特定实例中,本文公开的抗TAA部分在VL链的位置G42处包括相对于CTAT.02的突变,例如氨基酸残基取代(例如G42A)。参见例如上文表2中的CTAT.02VL-01。在另一特定实例中,本文公开的抗TAA部分在VL链的位置D41处包括相对于CTAT.02的突变,例如氨基酸残基取代(例如D41E)。参见例如上文表2中的CTAT.02VL-02。
在一些实施例中,抗TAA部分可以在一个或多个CDR中包括相对于CTAT.02的那些CDR的某一水平的变异。举例来说,抗TAA部分可以包括重链CDR,所述重链CDR个别地或共同地与CTAT.02的VH CDR具有至少80%(例如85%、90%、95%或98%)序列同一性。或者或另外,抗TAA抗体可以包括轻链CDR,所述轻链CDR个别地或共同地与CTAT.02的VL CDR具有至少80%(例如85%、90%、95%或98%)序列同一性。
在一些情况下,抗TAA部分可以在一个或多个重链和轻链CDR中共同地包括相对于CTAT.02的CDR的最多10个氨基酸变异(例如最多9、8、7、6、5、4、3、2或1个氨基酸变异)。在一些情况下,抗TAA部分可以包括与CTAT.02的重链CDR3相同的重链CDR3,且在其它重链和轻链CDR中的一个或多个中包括一个或多个氨基酸变异。
在一些实例中,抗TAA结合部分可以包括与抗体CTAT.03的那些重链CDR(其提供于上文表2中)相同的重链CDR。或者或另外,抗TAA结合部分可以具有与抗体CTAT.03的那些轻链CDR(其也提供于上文表2中)相同的轻链CDR。这种抗TAA结合部分可以包括与CTAT.03相同的VH和/或VL链。或者,抗TAA结合部分可以在一个或多个构架区中包括相对于CTAT.03中的对应构架区的氨基酸变异。举例来说,抗TAA结合部分可以在一个或多个构架区中共同地包括相对于CTAT.03中的对应构架区的最多15个氨基酸变异(例如最多12、10、9、8、7、6、5、4、3、2或1个氨基酸变异)。
在一些实施例中,抗TAA部分可以在一个或多个CDR中包括相对于CTAT.03的那些CDR的某一水平的变异。举例来说,抗TAA部分可以包括重链CDR,所述重链CDR个别地或共同地与CTAT.03的VH CDR具有至少80%(例如85%、90%、95%或98%)序列同一性。或者或另外,抗TAA抗体可以包括轻链CDR,所述轻链CDR个别地或共同地与CTAT.03的VL CDR具有至少80%(例如85%、90%、95%或98%)序列同一性。
在一些情况下,抗TAA部分可以在一个或多个重链和轻链CDR中共同地包括相对于CTAT.03的CDR的最多10个氨基酸变异(例如最多9、8、7、6、5、4、3、2或1个氨基酸变异)。在一些情况下,抗TAA部分可以包括与CTAT.03的重链CDR3相同的重链CDR3,且在其它重链和轻链CDR中的一个或多个中包括一个或多个氨基酸变异。
在一些实例中,抗TAA结合部分可以包括与抗体CTAT.04的那些重链CDR(其提供于上文表2中)相同的重链CDR。或者或另外,抗TAA结合部分可以具有与抗体CTAT.04的那些轻链CDR(其也提供于上文表2中)相同的轻链CDR。这种抗TAA结合部分可以包括与CTAT.04相同的VH和/或VL链。或者,抗TAA结合部分可以在一个或多个构架区中包括相对于CTAT.04中的对应构架区的氨基酸变异。举例来说,抗TAA结合部分可以在一个或多个构架区中共同地包括相对于CTAT.04中的对应构架区的最多15个氨基酸变异(例如最多12、10、9、8、7、6、5、4、3、2或1个氨基酸变异)。
在一些实施例中,抗TAA部分可以在一个或多个CDR中包括相对于CTAT.04的那些CDR的某一水平的变异。举例来说,抗TAA部分可以包括重链CDR,所述重链CDR个别地或共同地与CTAT.04的VH CDR具有至少80%(例如85%、90%、95%或98%)序列同一性。或者或另外,抗TAA抗体可以包括轻链CDR,所述轻链CDR个别地或共同地与CTAT.04的VL CDR具有至少80%(例如85%、90%、95%或98%)序列同一性。
在一些情况下,抗TAA部分可以在一个或多个重链和轻链CDR中共同地包括相对于CTAT.04的CDR的最多10个氨基酸变异(例如最多9、8、7、6、5、4、3、2或1个氨基酸变异)。在一些情况下,抗TAA部分可以包括与CTAT.04的重链CDR3相同的重链CDR3,且在其它重链和轻链CDR中的一个或多个中包括一个或多个氨基酸变异。
在一些实例中,抗TAA结合部分可以包括与抗体CTAT.05的那些重链CDR(其提供于上文表2中)相同的重链CDR。或者或另外,抗TAA结合部分可以具有与抗体CTAT.05的那些轻链CDR(其也提供于上文表2中)相同的轻链CDR。这种抗TAA结合部分可以包括与CTAT.05相同的VH和/或VL链。或者,抗TAA结合部分可以在一个或多个构架区中包括相对于CTAT.05中的对应构架区的氨基酸变异。举例来说,抗TAA结合部分可以在一个或多个构架区中共同地包括相对于CTAT.05中的对应构架区的最多15个氨基酸变异(例如最多12、10、9、8、7、6、5、4、3、2或1个氨基酸变异)。
在一些实施例中,抗TAA部分可以在一个或多个CDR中包括相对于CTAT.05的那些CDR的某一水平的变异。举例来说,抗TAA部分可以包括重链CDR,所述重链CDR个别地或共同地与CTAT.05的VH CDR具有至少80%(例如85%、90%、95%或98%)序列同一性。或者或另外,抗TAA抗体可以包括轻链CDR,所述轻链CDR个别地或共同地与CTAT.05的VL CDR具有至少80%(例如85%、90%、95%或98%)序列同一性。
在一些情况下,抗TAA部分可以在一个或多个重链和轻链CDR中共同地包括相对于CTAT.05的CDR的最多10个氨基酸变异(例如最多9、8、7、6、5、4、3、2或1个氨基酸变异)。在一些情况下,抗TAA部分可以包括与CTAT.05的重链CDR3相同的重链CDR3,且在其它重链和轻链CDR中的一个或多个中包括一个或多个氨基酸变异。
在一些实例中,抗TAA结合部分可以包括与抗体CTAT.06的那些重链CDR(其提供于上文表2中)相同的重链CDR。或者或另外,抗TAA结合部分可以具有与抗体CTAT.06的那些轻链CDR(其也提供于上文表2中)相同的轻链CDR。这种抗TAA结合部分可以包括与CTAT.06相同的VH和/或VL链。或者,抗TAA结合部分可以在一个或多个构架区中包括相对于CTAT.06中的对应构架区的氨基酸变异。举例来说,抗TAA结合部分可以在一个或多个构架区中共同地包括相对于CTAT.06中的对应构架区的最多15个氨基酸变异(例如最多12、10、9、8、7、6、5、4、3、2或1个氨基酸变异)。
在一些实施例中,抗TAA部分可以在一个或多个CDR中包括相对于CTAT.06的那些CDR的某一水平的变异。举例来说,抗TAA部分可以包括重链CDR,所述重链CDR个别地或共同地与CTAT.06的VH CDR具有至少80%(例如85%、90%、95%或98%)序列同一性。或者或另外,抗TAA抗体可以包括轻链CDR,所述轻链CDR个别地或共同地与CTAT.06的VL CDR具有至少80%(例如85%、90%、95%或98%)序列同一性。
在一些情况下,抗TAA部分可以在一个或多个重链和轻链CDR中共同地包括相对于CTAT.06的CDR的最多10个氨基酸变异(例如最多9、8、7、6、5、4、3、2或1个氨基酸变异)。在一些情况下,抗TAA部分可以包括与CTAT.06的重链CDR3相同的重链CDR3,且在其它重链和轻链CDR中的一个或多个中包括一个或多个氨基酸变异。
在一些实例中,抗TAA结合部分可以包括与抗体CTAT.07的那些重链CDR(其提供于上文表2中)相同的重链CDR。或者或另外,抗TAA结合部分可以具有与抗体CTAT.07的那些轻链CDR(其也提供于上文表2中)相同的轻链CDR。这种抗TAA结合部分可以包括与CTAT.07相同的VH和/或VL链。或者,抗TAA结合部分可以在一个或多个构架区中包括相对于CTAT.07中的对应构架区的氨基酸变异。举例来说,抗TAA结合部分可以在一个或多个构架区中共同地包括相对于CTAT.07中的对应构架区的最多15个氨基酸变异(例如最多12、10、9、8、7、6、5、4、3、2或1个氨基酸变异)。
在一些实施例中,抗TAA部分可以在一个或多个CDR中包括相对于CTAT.07的那些CDR的某一水平的变异。举例来说,抗TAA部分可以包括重链CDR,所述重链CDR个别地或共同地与CTAT.07的VH CDR具有至少80%(例如85%、90%、95%或98%)序列同一性。或者或另外,抗TAA抗体可以包括轻链CDR,所述轻链CDR个别地或共同地与CTAT.07的VL CDR具有至少80%(例如85%、90%、95%或98%)序列同一性。
在一些情况下,抗TAA部分可以在一个或多个重链和轻链CDR中共同地包括相对于CTAT.07的CDR的最多10个氨基酸变异(例如最多9、8、7、6、5、4、3、2或1个氨基酸变异)。在一些情况下,抗TAA部分可以包括与CTAT.07的重链CDR3相同的重链CDR3,且在其它重链和轻链CDR中的一个或多个中包括一个或多个氨基酸变异。
在一些实例中,抗TAA结合部分可以包括与抗体CTAT.08的那些重链CDR(其提供于上文表2中)相同的重链CDR。或者或另外,抗TAA结合部分可以具有与抗体CTAT.08的那些轻链CDR(其也提供于上文表2中)相同的轻链CDR。这种抗TAA结合部分可以包括与CTAT.08相同的VH和/或VL链。或者,抗TAA结合部分可以在一个或多个构架区中包括相对于CTAT.08中的对应构架区的氨基酸变异。举例来说,抗TAA结合部分可以在一个或多个构架区中共同地包括相对于CTAT.08中的对应构架区的最多15个氨基酸变异(例如最多12、10、9、8、7、6、5、4、3、2或1个氨基酸变异)。
在一些实施例中,抗TAA部分可以在一个或多个CDR中包括相对于CTAT.08的那些CDR的某一水平的变异。举例来说,抗TAA部分可以包括重链CDR,所述重链CDR个别地或共同地与CTAT.08的VH CDR具有至少80%(例如85%、90%、95%或98%)序列同一性。或者或另外,抗TAA抗体可以包括轻链CDR,所述轻链CDR个别地或共同地与CTAT.08的VL CDR具有至少80%(例如85%、90%、95%或98%)序列同一性。
在一些情况下,抗TAA部分可以在一个或多个重链和轻链CDR中共同地包括相对于CTAT.08的CDR的最多10个氨基酸变异(例如最多9、8、7、6、5、4、3、2或1个氨基酸变异)。在一些情况下,抗TAA部分可以包括与CTAT.08的重链CDR3相同的重链CDR3,且在其它重链和轻链CDR中的一个或多个中包括一个或多个氨基酸变异。
在一些实例中,抗TAA结合部分可以包括与抗体CTAT.09的那些重链CDR(其提供于上文表2中)相同的重链CDR。或者或另外,抗TAA结合部分可以具有与抗体CTAT.09的那些轻链CDR(其也提供于上文表2中)相同的轻链CDR。这种抗TAA结合部分可以包括与CTAT.09相同的VH和/或VL链。或者,抗TAA结合部分可以在一个或多个构架区中包括相对于CTAT.09中的对应构架区的氨基酸变异。举例来说,抗TAA结合部分可以在一个或多个构架区中共同地包括相对于CTAT.09中的对应构架区的最多15个氨基酸变异(例如最多12、10、9、8、7、6、5、4、3、2或1个氨基酸变异)。
在一些实施例中,抗TAA部分可以在一个或多个CDR中包括相对于CTAT.09的那些CDR的某一水平的变异。举例来说,抗TAA部分可以包括重链CDR,所述重链CDR个别地或共同地与CTAT.09的VH CDR具有至少80%(例如85%、90%、95%或98%)序列同一性。或者或另外,抗TAA抗体可以包括轻链CDR,所述轻链CDR个别地或共同地与CTAT.09的VL CDR具有至少80%(例如85%、90%、95%或98%)序列同一性。
在一些情况下,抗TAA部分可以在一个或多个重链和轻链CDR中共同地包括相对于CTAT.09的CDR的最多10个氨基酸变异(例如最多9、8、7、6、5、4、3、2或1个氨基酸变异)。在一些情况下,抗TAA部分可以包括与CTAT.09的重链CDR3相同的重链CDR3,且在其它重链和轻链CDR中的一个或多个中包括一个或多个氨基酸变异。
在一些实例中,抗TAA结合部分可以包括与抗体CTAT.10的那些重链CDR(其提供于上文表2中)相同的重链CDR。或者或另外,抗TAA结合部分可以具有与抗体CTAT.10的那些轻链CDR(其也提供于上文表2中)相同的轻链CDR。这种抗TAA结合部分可以包括与CTAT.10相同的VH和/或VL链。或者,抗TAA结合部分可以在一个或多个构架区中包括相对于CTAT.10中的对应构架区的氨基酸变异。举例来说,抗TAA结合部分可以在一个或多个构架区中共同地包括相对于CTAT.10中的对应构架区的最多15个氨基酸变异(例如最多12、10、9、8、7、6、5、4、3、2或1个氨基酸变异)。
在一些实施例中,抗TAA部分可以在一个或多个CDR中包括相对于CTAT.10的那些CDR的某一水平的变异。举例来说,抗TAA部分可以包括重链CDR,所述重链CDR个别地或共同地与CTAT.10的VH CDR具有至少80%(例如85%、90%、95%或98%)序列同一性。或者或另外,抗TAA抗体可以包括轻链CDR,所述轻链CDR个别地或共同地与CTAT.10的VL CDR具有至少80%(例如85%、90%、95%或98%)序列同一性。
在一些情况下,抗TAA部分可以在一个或多个重链和轻链CDR中共同地包括相对于CTAT.10的CDR的最多10个氨基酸变异(例如最多9、8、7、6、5、4、3、2或1个氨基酸变异)。在一些情况下,抗TAA部分可以包括与CTAT.10的重链CDR3相同的重链CDR3,且在其它重链和轻链CDR中的一个或多个中包括一个或多个氨基酸变异。
在一些实例中,抗TAA结合部分可以包括与抗体CTAT.11的那些重链CDR(其提供于上文表2中)相同的重链CDR。或者或另外,抗TAA结合部分可以具有与抗体CTAT.11的那些轻链CDR(其也提供于上文表2中)相同的轻链CDR。这种抗TAA结合部分可以包括与CTAT.11相同的VH和/或VL链。或者,抗TAA结合部分可以在一个或多个构架区中包括相对于CTAT.11中的对应构架区的氨基酸变异。举例来说,抗TAA结合部分可以在一个或多个构架区中共同地包括相对于CTAT.11中的对应构架区的最多15个氨基酸变异(例如最多12、10、9、8、7、6、5、4、3、2或1个氨基酸变异)。
在一些实施例中,抗TAA部分可以在一个或多个CDR中包括相对于CTAT.11的那些CDR的某一水平的变异。举例来说,抗TAA部分可以包括重链CDR,所述重链CDR个别地或共同地与CTAT.11的VH CDR具有至少80%(例如85%、90%、95%或98%)序列同一性。或者或另外,抗TAA抗体可以包括轻链CDR,所述轻链CDR个别地或共同地与CTAT.10的VL CDR具有至少80%(例如85%、90%、95%或98%)序列同一性。
在一些情况下,抗TAA部分可以在一个或多个重链和轻链CDR中共同地包括相对于CTAT.11的CDR的最多10个氨基酸变异(例如最多9、8、7、6、5、4、3、2或1个氨基酸变异)。在一些情况下,抗TAA部分可以包括与CTAT.11的重链CDR3相同的重链CDR3,且在其它重链和轻链CDR中的一个或多个中包括一个或多个氨基酸变异。
在一些实例中,抗TAA结合部分可以包括与抗体CTAT.12的那些重链CDR(其提供于上文表2中)相同的重链CDR。或者或另外,抗TAA结合部分可以具有与抗体CTAT.12的那些轻链CDR(其也提供于上文表2中)相同的轻链CDR。这种抗TAA结合部分可以包括与CTAT.12相同的VH和/或VL链。或者,抗TAA结合部分可以在一个或多个构架区中包括相对于CTAT.12中的对应构架区的氨基酸变异。举例来说,抗TAA结合部分可以在一个或多个构架区中共同地包括相对于CTAT.12中的对应构架区的最多15个氨基酸变异(例如最多12、10、9、8、7、6、5、4、3、2或1个氨基酸变异)。
在一些实施例中,抗TAA部分可以在一个或多个CDR中包括相对于CTAT.12的那些CDR的某一水平的变异。举例来说,抗TAA部分可以包括重链CDR,所述重链CDR个别地或共同地与CTAT.12的VH CDR具有至少80%(例如85%、90%、95%或98%)序列同一性。或者或另外,抗TAA抗体可以包括轻链CDR,所述轻链CDR个别地或共同地与CTAT.12的VL CDR具有至少80%(例如85%、90%、95%或98%)序列同一性。
在一些情况下,抗TAA部分可以在一个或多个重链和轻链CDR中共同地包括相对于CTAT.12的CDR的最多10个氨基酸变异(例如最多9、8、7、6、5、4、3、2或1个氨基酸变异)。在一些情况下,抗TAA部分可以包括与CTAT.12的重链CDR3相同的重链CDR3,且在其它重链和轻链CDR中的一个或多个中包括一个或多个氨基酸变异。
在一些实例中,抗TAA结合部分可以包括与抗体CTAT.13的那些重链CDR(其提供于上文表2中)相同的重链CDR。或者或另外,抗TAA结合部分可以具有与抗体CTAT.13的那些轻链CDR(其也提供于上文表2中)相同的轻链CDR。这种抗TAA结合部分可以包括与CTAT.13相同的VH和/或VL链。或者,抗TAA结合部分可以在一个或多个构架区中包括相对于CTAT.13中的对应构架区的氨基酸变异。举例来说,抗TAA结合部分可以在一个或多个构架区中共同地包括相对于CTAT.13中的对应构架区的最多15个氨基酸变异(例如最多12、10、9、8、7、6、5、4、3、2或1个氨基酸变异)。
在一些实施例中,抗TAA部分可以在一个或多个CDR中包括相对于CTAT.13的那些CDR的某一水平的变异。举例来说,抗TAA部分可以包括重链CDR,所述重链CDR个别地或共同地与CTAT.13的VH CDR具有至少80%(例如85%、90%、95%或98%)序列同一性。或者或另外,抗TAA抗体可以包括轻链CDR,所述轻链CDR个别地或共同地与CTAT.13的VL CDR具有至少80%(例如85%、90%、95%或98%)序列同一性。
在一些情况下,抗TAA部分可以在一个或多个重链和轻链CDR中共同地包括相对于CTAT.13的CDR的最多10个氨基酸变异(例如最多9、8、7、6、5、4、3、2或1个氨基酸变异)。在一些情况下,抗TAA部分可以包括与CTAT.13的重链CDR3相同的重链CDR3,且在其它重链和轻链CDR中的一个或多个中包括一个或多个氨基酸变异。
在一些实例中,抗TAA结合部分可以包括与抗体CTAT.14的那些重链CDR(其提供于上文表2中)相同的重链CDR。或者或另外,抗TAA结合部分可以具有与抗体CTAT.14的那些轻链CDR(其也提供于上文表2中)相同的轻链CDR。这种抗TAA结合部分可以包括与CTAT.14相同的VH和/或VL链。或者,抗TAA结合部分可以在一个或多个构架区中包括相对于CTAT.14中的对应构架区的氨基酸变异。举例来说,抗TAA结合部分可以在一个或多个构架区中共同地包括相对于CTAT.14中的对应构架区的最多15个氨基酸变异(例如最多12、10、9、8、7、6、5、4、3、2或1个氨基酸变异)。
在一些实施例中,抗TAA部分可以在一个或多个CDR中包括相对于CTAT.14的那些CDR的某一水平的变异。举例来说,抗TAA部分可以包括重链CDR,所述重链CDR个别地或共同地与CTAT.14的VH CDR具有至少80%(例如85%、90%、95%或98%)序列同一性。或者或另外,抗TAA抗体可以包括轻链CDR,所述轻链CDR个别地或共同地与CTAT.14的VL CDR具有至少80%(例如85%、90%、95%或98%)序列同一性。
在一些情况下,抗TAA部分可以在一个或多个重链和轻链CDR中共同地包括相对于CTAT.14的CDR的最多10个氨基酸变异(例如最多9、8、7、6、5、4、3、2或1个氨基酸变异)。在一些情况下,抗TAA部分可以包括与CTAT.14的重链CDR3相同的重链CDR3,且在其它重链和轻链CDR中的一个或多个中包括一个或多个氨基酸变异。
在一些实例中,抗TAA结合部分可以包括与抗体CTAT.15的那些重链CDR(其提供于上文表2中)相同的重链CDR。或者或另外,抗TAA结合部分可以具有与抗体CTAT.15的那些轻链CDR(其也提供于上文表2中)相同的轻链CDR。这种抗TAA结合部分可以包括与CTAT.15相同的VH和/或VL链。或者,抗TAA结合部分可以在一个或多个构架区中包括相对于CTAT.15中的对应构架区的氨基酸变异。举例来说,抗TAA结合部分可以在一个或多个构架区中共同地包括相对于CTAT.15中的对应构架区的最多15个氨基酸变异(例如最多12、10、9、8、7、6、5、4、3、2或1个氨基酸变异)。
在一些实施例中,抗TAA部分可以在一个或多个CDR中包括相对于CTAT.15的那些CDR的某一水平的变异。举例来说,抗TAA部分可以包括重链CDR,所述重链CDR个别地或共同地与CTAT.15的VH CDR具有至少80%(例如85%、90%、95%或98%)序列同一性。或者或另外,抗TAA抗体可以包括轻链CDR,所述轻链CDR个别地或共同地与CTAT.15的VL CDR具有至少80%(例如85%、90%、95%或98%)序列同一性。
在一些情况下,抗TAA部分可以在一个或多个重链和轻链CDR中共同地包括相对于CTAT.15的CDR的最多10个氨基酸变异(例如最多9、8、7、6、5、4、3、2或1个氨基酸变异)。在一些情况下,抗TAA部分可以包括与CTAT.15的重链CDR3相同的重链CDR3,且在其它重链和轻链CDR中的一个或多个中包括一个或多个氨基酸变异。
在一些实例中,抗TAA结合部分可以包括与抗体CTAT.16的那些重链CDR(其提供于上文表2中)相同的重链CDR。或者或另外,抗TAA结合部分可以具有与抗体CTAT.16的那些轻链CDR(其也提供于上文表2中)相同的轻链CDR。这种抗TAA结合部分可以包括与CTAT.16相同的VH和/或VL链。或者,抗TAA结合部分可以在一个或多个构架区中包括相对于CTAT.16中的对应构架区的氨基酸变异。举例来说,抗TAA结合部分可以在一个或多个构架区中共同地包括相对于CTAT.16中的对应构架区的最多15个氨基酸变异(例如最多12、10、9、8、7、6、5、4、3、2或1个氨基酸变异)。
在一些实施例中,抗TAA部分可以在一个或多个CDR中包括相对于CTAT.16的那些CDR的某一水平的变异。举例来说,抗TAA部分可以包括重链CDR,所述重链CDR个别地或共同地与CTAT.16的VH CDR具有至少80%(例如85%、90%、95%或98%)序列同一性。或者或另外,抗TAA抗体可以包括轻链CDR,所述轻链CDR个别地或共同地与CTAT.16的VL CDR具有至少80%(例如85%、90%、95%或98%)序列同一性。
在一些情况下,抗TAA部分可以在一个或多个重链和轻链CDR中共同地包括相对于CTAT.16的CDR的最多10个氨基酸变异(例如最多9、8、7、6、5、4、3、2或1个氨基酸变异)。在一些情况下,抗TAA部分可以包括与CTAT.16的重链CDR3相同的重链CDR3,且在其它重链和轻链CDR中的一个或多个中包括一个或多个氨基酸变异。
(iii)抗CD3/抗TAA双特异性抗体
本文公开的双特异性抗体可以呈本领域中已知的任何合适型式,例如《分子免疫学(Mol.Immunol.)》67(2):95-106(2015)中公开的那些型式,所述参考文献的相关公开内容以引用的方式并入以用于本文中提及的主题和目的。下文提供一些实例。还参见图1A到1N。
在一些实施例中,本文公开的双特异性抗体可以包括呈Fab型式的一个抗原结合部分和呈单链可变片段(scFv)型式的另一抗原结合部分。这种双特异性抗体可以包括两个多肽,一个包括连接到scFv片段的Fab片段的重链或轻链,且另一个包括未连接到scFv片段的Fab的轻链或重链。
在一些情况下,Fab片段包括两个多肽链,一个包括连接到重链恒定区(例如CH1)的片段的VH域,另一个包括连接到轻链恒定区的VL域。重链恒定区片段可以来自任何Ig子类,例如IgG、IgA、IgE、IgD或IgM。在一些实例中,重链恒定区片段来自IgG分子(例如人IgG分子)。轻链恒定区可以是κ链或λ链(例如人κ或λ链)。scFv片段包括通过肽连接子连接的VH域和VL域。参见例如Bird等人(1988)《科学(Science)》242:423-426;和Huston等人(1988)《美国国家科学院院刊》85:5879-5883。在一些情况下,scFv片段从N端到C端具有VH-连接子-VL定向。或者,scFv片段从N端到C端具有VL-连接子-VH定向。在双特异性抗体中,scFv片段可以连接到Fab片段的重链。或者,scFv可以连接到Fab片段的轻链。参见图1A到1H。
在一些实例中,本文公开的双特异性抗体可以包括呈Fab型式的抗CD3结合部分和呈scFv型式的抗TAA结合部分。示范性图解说明提供于图1A到1D中。抗CD3 Fab包括重链VH-CH1域和轻链VL-Cκ或VL-Cλ域。抗TAA scFv包括VH域和VL域。图1A到1D。在一些情况下,抗CD3 Fab可以经由设置在抗CD3 Fab重链的CH1域与抗肿瘤scFv的VH域之间的肽连接子连接到抗TAA scFv。示范性图解说明提供于图1A中。在其它情况下,抗CD3 Fab重链的CH1域可以如图1B所示连接到抗肿瘤scFv的VL域。在其它情况下,抗TAA scFv可以经由scFv的VL域(图1C)或经由抗肿瘤scFv的VH域(图1D)连接到抗CD3 Fab轻链的Cκ或Cλ域。抗CD3 Fab重链(VH-CH1)和轻链(VL-Ck)的实例以及抗TAA scFv片段的实例分别提供于表1和表2中。这些实例的任何组合都在本公开的范围内。
在一些实例中,本文公开的双特异性抗体可以包括呈Fab型式的抗TAA结合部分和呈scFv型式的抗CD3结合部分。示范性图解说明提供于图1E到1H中。抗TAA Fab包括重链VH-CH1域和轻链VL-Cκ或VL-Cλ域。抗CD3 scFv包括VH域和VL域。图1E到1H。在一些情况下,抗TAA Fab可以经由设置在抗TAA Fab重链的CH1域与抗CD3 scFv的VH域之间的肽连接子连接到抗CD3 scFv。示范性图解说明提供于图1E中。在其它情况下,抗TAA Fab重链的CH1域可以如图1F所示连接到抗CD3 scFv的VL域。在其它情况下,抗CD3 scFv可以经由scFv的VL域(图1G)或经由抗CD3scFv的VH域(图1H)连接到抗TAA Fab轻链的Cκ或Cλ域。抗TAA Fab重链(VH-CH1)和轻链(VL-Ck)的实例以及抗CD3 scFv片段的实例分别提供于表2和表1中。这些实例的任何组合都在本公开的范围内。
在一些实施例中,本文公开的双特异性抗体可以包括呈scFv型式的两个抗原结合部分。示范性图解说明提供于图1I到1L中。
在一些实例中,抗CD3 scFv的VH域可以经由肽连接子连接到抗TAA scFv的VH域(图1I)。在一些实例中,抗CD3 scFv的VH域可以经由肽连接子连接到抗TAA scFv的VL域(图1J)。在一些实例中,抗CD3 scFv的VL域可以经由肽连接子连接到抗TAA scFv的VH域(图1K)。在其它实例中,抗CD3 scFv的VL域可以经由肽连接子连接到抗TAA scFv的VH域(图1L)。示范性抗CD3 scFv片段和示范性抗TAA scFv片段分别提供于表1和表2中。其用于构建双特异性抗体的任何组合在本公开的范围内。
在其它实施例中,本文公开的双特异性抗体可以包括一个或多个Fc区,其可以任选地为“臼包杵”结构,其中第一重链的CH2域、CH3域或两者中的杵是通过用替代氨基酸侧链置换几个氨基酸侧链而产生,且第二重链的CH3域处的相邻位置中的臼是通过用替代氨基酸侧链置换适当氨基酸侧链而产生。示范性图解说明提供于图1M到1N中。
典型地,术语“杵和臼”或“臼包杵”在本文中可互换使用。臼包杵氨基酸变化为本领域中已知用于双特异性IgG抗体产生中重(H)链的异二聚化的合理设计策略。Carter,《免疫学方法杂志(J.Immunol.Methods)》,248(1-2):7-15(2001),其相关公开内容以引用的方式并入本文以用于本文提及的目的和主题。
在一个实例中,“臼包杵”提供例如Ridgway JBB等人(1996)《蛋白质工程(ProteinEngineering)》,9(7):617-21和US 5,731,168中所描述的方法,所述参考文献的相关公开内容以引用的方式并入本文以用于本文提及的目的和主题。已显示这个方法促进第一多肽和第二多肽链的杂二聚体的形成且阻碍对应同二聚体的组装。在一个方面,杵是通过用较大氨基侧链置换CH3域之间的界面处的较小氨基侧链而产生,而臼是通过用较小侧链置换较大侧链而构建。在特定实例中,“杵”突变包括T366W且“臼”突变包括T366S、L368A和Y407V(Atwell S等人(1997)《分子生物学杂志》270:26-35)。
在一些情况下,双特异性抗体可以包括抗CD3结合部分和抗TAA结合部分,所述抗CD3结合部分包括第一VH-CH1-CH2-CH3域和第一VL-Cκ或VL-Cλ域,所述抗TAA结合部分包括第二VH-CH1-CH2-CH3域和第二VL-Cκ或VL-Cλ域。图1M。抗CD3结合部分的重链中的CH2和/或CH3以及抗TAA结合部分的重链中的CH2和/或CH3可以包括杵/臼修饰,允许两条重链之间的结合。在其它情况下,双特异性抗体可以包括抗Cd3结合部分和抗TAA scFv,所述抗Cd3结合部分包括第一VH-CH1-CH2-CH3域和第一VL-Cκ或VL-Cλ域,且抗TAA scFv连接到第二CH2-CH3域。抗CD3结合部分的重链中的CH2和/或CH3以及抗TAA结合部分中的CH2和/或CH3可以包括杵/臼修饰,允许两条重链之间的结合。图1N。在这种情况下,抗CD3结合部分的型式和抗TAA结合部分的型式可以切换。
术语“肽连接子”指代具有用于连接两个多肽的天然或合成氨基酸残基的肽。举例来说,肽连接子可以用于连接一个VH域与一个VL域以形成单链可变片段(例如scFv);连接一个scFv与一个Fab以形成scFv/Fab重组抗体;连接两个scFv以形成scFv/scFv重组抗体;或连接两个单价抗体(例如两个单价IgG)、两个单价抗体片段(例如两个单价scFv-Fc融合蛋白)或一个单价抗体与一个单价抗体片段(例如一个单价IgG和一个单价scFv-Fc融合蛋白),从而形成二价抗体。优选地,肽连接子是长度为至少5个氨基酸残基,例如长度为5到100个氨基酸残基,长度更优选为10到30个氨基酸残基的肽。scFv内的肽连接子是长度为至少5个氨基酸残基,长度优选地为15到20个氨基酸残基的肽。优选地,肽连接子包括序列(GnS)m,其中G=甘氨酸,S=丝氨酸,且n和m独立地为1到4之间的数字。在一个实例中,连接子包括序列(G2S)4。在另一实例中,连接子包括序列(G4S)3。
用于连接第一抗体片段(即抗CD3抗体片段)与第二抗体片段(即抗TAA抗体片段)的肽连接子可以为适合于连接两个多肽的任何肽。根据本公开的某些实施例,肽连接子是长度为至少5个氨基酸残基的肽,例如长度为5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29、30、31、32、33、34、35、36、37、38、39、40、41、42、43、44、45、46、47、48、49、50、51、52、53、54、55、56、57、58、59、60、61、62、63、64、65、66、67、68、69、70、71、72、73、74、75、76、77、78、79、80、81、82、83、84、85、86、87、88、89、90、91、92、93、94、95、96、97、98、99、100或更多个氨基酸残基。优选地,本发明重组抗体的肽连接子由10到30个甘氨酸(G)和/或丝氨酸(S)残基组成。
在一些实施例中,本文所描述的双特异性抗体特异性结合于对应靶抗原(CD3和TAA)或其表位中的一个或两个。与抗原或表位“特异性结合”的抗体是本领域内众所周知的术语。如果分子与特定靶抗原的反应比其与替代靶的反应更频繁、更迅速、持续时间更长和/或具有更大的亲和力,那么称所述分子展现“特异性结合”。如果抗体与靶抗原或表位的结合比其与其它物质的结合具有更大的亲和力、亲合力、更容易和/或持续时间更长,那么所述抗体与靶抗原或表位“特异性结合”。举例来说,与抗原(CD3和/或TAA)或其中的抗原表位特异性(或优先)结合的抗体是其与所述靶抗原的结合比其与其它抗原或同一抗原中的其它表位的结合具有更大的亲和力、亲合力、更容易和/或持续时间更长的抗体。通过这个定义还应理解,例如,与第一靶抗原特异性结合的抗体可能或可能不与第二靶抗原特异性或优先结合。因此,“特异性结合”或“优先结合”不一定需要(尽管其可以包含)排他性结合。在一些实例中,与靶抗原或其表位“特异性结合”的抗体可能不会与其它抗原或同一抗原中的其它表位结合(即在常规方法中仅可检测到基线结合活性)。
在一些实施例中,本文描述的双特异性抗体对靶抗原(例如CD3和TAA)或其抗原表位中的一个或两个具有合适的结合亲和力。如本文所用,“结合亲和力”指代表观缔合常数或KA。KA为解离常数的倒数(KD)。本文描述的双特异性抗体对CD3的结合亲和力(KD)可以是至少100nM、10nM、1nM、0.1nM或更低(例如低于1nM或0.1nM)。或者,本文描述的双特异性抗体对TAA的结合亲和力(KD)可以是至少100nM、10nM、1nM、0.1nM或更低。
结合亲和力增大对应于KD减小。相对于第二抗原,抗体对第一抗原的结合亲和力较高可以由相比结合第二抗原的KA(或数值KD),结合第一抗原的KA较高(或数值KD较小)来指示。在这些情况下,相对于第二抗原(例如,呈第二构形的第一蛋白质或其模拟物;或第二蛋白质),抗体对第一抗原(例如呈第一构形的相同第一蛋白质或其模拟物)具有特异性。结合亲和力的差异(例如对于特异性或其它比较)可以是至少1.5、2、3、4、5、10、15、20、37.5、50、70、80、90、100、500、1000、10,000或105倍。在一些实施例中,用于制备双特异性抗体的任何抗CD3和/或抗TAA抗体可以进一步亲和力成熟,以增大抗体与靶抗原或其抗原表位的结合亲和力。
结合亲和力(或结合特异性)可以通过各种方法测定,包含平衡透析、平衡结合、凝胶过滤、ELISA、表面等离子体共振或光谱学(例如使用荧光分析)。用于评估结合亲和力的示范性条件是在HBS-P缓冲液(10mM HEPES pH7.4、150mM NaCl、0.005%(v/v)表面活性剂P20)中。这些技术可以用于测量结合的结合蛋白随着靶蛋白浓度变化的浓度。结合的结合蛋白的浓度([结合])一般通过以下等式与游离靶蛋白([游离])的浓度相关:
[结合]=[游离]/(Kd+[游离])
并非总是必须准确测定KA,但由于有时获得亲和力的定量测量就足够了,例如使用如ELISA或FACS分析等方法测定的亲和力与KA成比例,因此可以用于比较,例如测定较高亲和力是否高例如2倍,以获得亲和力的定性测量或例如通过功能性分析(例如体外或体内分析)中的活性获得亲和力的推断。
本文公开的示范性双特异性抗体提供于下文表3中(使用来自CTA.03的抗CD3结合部分作为实例)。来自其它抗CD3参考抗体(例如CTA.02、CTA.04和CTA.05)的抗CD3结合部分也在本公开的范围内。
表3.示范性双特异性抗体
本文还提供药物组合物,其包括本文所公开的双特异性抗体(或本文同时公开的武装免疫细胞)中的任一种,其进一步包括药学上可接受的赋形剂。药学上可接受的赋形剂可以是与活性分子(例如双特异性抗体或武装免疫细胞)组合用于制备一种合意或适宜剂型的任何惰性物质。通常,药学上可接受的赋形剂在所用剂量和浓度下对接受者无毒,且与包括重组抗体的调配物的其它成分兼容。适合用于本发明药物组合物中的药学上可接受的赋形剂的实例包含但不限于水、磷酸盐缓冲液、醋酸盐缓冲液、丁二酸盐缓冲液、柠檬酸盐缓冲液、三(羟甲基)氨基甲烷(Tris)缓冲液、磷酸盐缓冲胜利生理盐水(PBS)、林格氏溶液(Ringer's solution)、乳酸盐林格氏溶液和其组合。任选地,药物组合物可以进一步包括用于存储和/或使重组抗体稳定的试剂,例如氨基酸留存(例如,组氨酸(H)或丝氨酸(S)残基)、葡萄糖、半乳糖、木糖醇、山梨糖醇、甘露糖醇、蔗糖、海藻糖或抗氧化剂。还可添加其它试剂,例如抗微生物剂,以防止在存储后腐败,即抑制如酵母和霉菌等微生物生长。
B.产生双特异性抗体的方法
本文描述的任何双特异性抗体可以通过本领域中已知的任何方法制备。参见例如Harlow和Lane,(1998),《抗体:实验室手册(Antibodies:A Laboratory Manual)》,冷泉港实验室,纽约。在一些实施例中,用于制备双特异性抗体的抗CD3抗体和/或抗TAA抗体可以通过常规融合瘤技术产生。或者,抗CD3和/或抗TAA抗体可以从合适库(例如人抗体库)鉴定。在一些情况下,高亲和力完全人CD3和/或TAA结合子可以从人抗体库,例如亲和力成熟库(例如在一个或多个CDR区中具有变异)获得。本领域中已知多种常规方法来鉴定和分离能够结合于本文所描述的靶抗原的抗体,包含噬菌体呈现、酵母呈现、核糖体呈现或哺乳动物呈现技术。
在一些实施例中,本文公开的双特异性抗体可以通过常规重组技术产生。在一个实例中,编码对靶抗原具特异性的单克隆抗体的DNA可以使用常规程序(例如,通过使用能够特异性结合于对单克隆抗体的重链和轻链进行编码的基因的寡核苷酸探针)容易地分离和测序。一经分离,就可以将DNA放入一种或多种表达载体中,随后将所述表达载体转染到如大肠杆菌细胞、猿猴COS细胞、中国仓鼠卵巢(CHO)细胞或不以其它方式产生免疫球蛋白的骨髓瘤细胞等宿主细胞中,以获得重组宿主细胞中单克隆抗体的合成。参见例如第WO87/04462号PCT公开案。随后可以例如通过用编码序列取代代替同源鼠类序列的人重链和轻链恒定域(Morrison等人,(1984)《美国国家科学院院刊》81:6851)或通过使非免疫球蛋白多肽的编码序列的全部或一部分与免疫球蛋白编码序列共价连接来对DNA进行修饰。
在一些情况下,可以将对本文描述的双特异性抗体的一个或两个链进行编码的核酸克隆到一个表达载体中,各核苷酸序列与合适的启动子可操作连接。在一个实例中,编码重链和轻链的各核苷酸序列与不同启动子可操作连接。或者,编码重链和轻链的核苷酸序列可以与单个启动子可操作连接,使得重链和轻链都从同一启动子表达。需要时,可将内部核糖体进入位点(IRES)插入重链与轻链编码序列之间。
在一些实例中,将编码抗体的两个链的核苷酸序列克隆到两个载体中,所述载体可以引入到相同或不同细胞中。当两个链表达于不同细胞中时,其各自可以从表达其的宿主细胞分离,且经分离的重链和轻链可以在允许形成抗体的合适条件下混合和培育。
通常,可以使用本领域中已知的方法将编码抗体的一个或所有链的核酸序列克隆到与合适的启动子可操作连接的合适表达载体中。举例来说,可以使核苷酸序列和载体在合适的条件下与限制酶接触以在各分子上产生互补端,其可以彼此配对且与连接酶接合在一起。或者,可以使合成核酸连接子连接到基因的末端。这些合成连接子含有对应于载体中的特定限制位点的核酸序列。表达载体/启动子的选择将取决于用于产生抗体的宿主细胞的类型。
可以使用多种启动子表达本文所描述的抗体,包含但不限于巨细胞病毒(CMV)中间早期启动子、病毒LTR(例如劳氏肉瘤病毒LTR、HIV-LTR、HTLV-1LTR)、猴病毒40(SV40)早期启动子、大肠杆菌乳糖UV5启动子和单纯性疱疹tk病毒启动子。
也可以使用可调节启动子。这些可调节启动子包含使用来自大肠杆菌的乳糖抑制子作为转录调节剂来调节从携带乳糖操纵子的哺乳动物细胞启动子的转录的那些可调节启动子[Brown,M.等人,《细胞(Cell),49:603-612(1987)]、使用四环素抑制子(tetR)的那些可调节启动子[Gossen,M.,和Bujard,H.,《美国国家科学院院刊》89:5547-5551(1992);Yao,F.等人,《人基因疗法(Human Gene Therapy),9:1939-1950(1998);Shockelt,P.等人,《美国国家科学院院刊》,92:6522-6526(1995)]。其它系统包含FK506二聚体、使用雌二醇(astradiol)的VP16或p65、RU486、双酚鼠李酮(diphenol murislerone)或雷帕霉素(rapamycin)。可诱导系统可以从英杰公司(Invitrogen)、克隆科技公司(Clontech)和阿瑞德公司(Ariad)获得。
可以使用包含具有操纵子的抑制子的可调节启动子。在一个实施例中,来自大肠杆菌的乳糖抑制子可以充当转录调节剂以调节从携带乳糖操纵子的哺乳动物细胞启动子的转录[M.Brown等人,《细胞》49:603-612(1987);Gossen和Bujard(1992);M.Gossen等人,《美国国家科学院院刊,89:5547-5551(1992)],与具有转录活化子(VP 16)的四环素抑制子(tetR)结合以产生tetR-哺乳动物细胞转录活化融合蛋白tTa(tetR-VP 16),具有来源于人巨细胞病毒(hCMV)主要立即早期启动子的携tetO最小启动子以产生tetR-tet操纵子系统以控制哺乳动物细胞中的基因表达。在一个实施例中,使用四环素可诱导开关。单独的四环素抑制子(tetR),而不是tetR-哺乳动物细胞转录因子融合衍生物,可以充当强效反式调节剂以在四环素操纵子适当地位于CMVIE启动子的TATA元件的下游时调节哺乳动物细胞中的基因表达(Yao等人,《人基因疗法》,10(16):1392-1399(2003))。这种四环素可诱导开关的一个特定优点在于其不需要使用四环素抑制子-哺乳动物细胞反式活化子或抑制子融合蛋白,所述蛋白在一些情况下可能对细胞具有毒性(Gossen等人,《美国国家科学院院刊》,89:5547-5551(1992);Shockett等人,《美国国家科学院院刊》,92:6522-6526(1995)),从而实现其可调节作用。
另外,载体可以含有例如以下中的一些或全部:可选标记基因,例如用于选择哺乳动物细胞中的稳定或短暂转染物的新霉素基因;来自人CMV的立即早期基因的用于高水平转录的增强子/启动子序列;来自SV40的用于mRNA稳定性的转录终止与RNA处理信号;用于适当游离型复制的SV40多瘤复制起点和ColE1;内部核糖体结合位点(IRESes)、通用多克隆位点;以及用于正义和反义RNA的体外转录的T7与SP6 RNA启动子。用于产生含有转基因的载体的合适载体和方法在本领域中众所周知且可获得。
适用于实践本文所描述的方法的多腺苷酸化信号的实例包含但不限于人胶原蛋白I聚腺苷酸化信号、人胶原蛋白II聚腺苷酸化信号和SV40聚腺苷酸化信号。
用于产生本文公开的呈各种配置的双特异性抗体的示范性构建体提供于图2A到2E中。
可以将包括编码任何抗体的核酸的一个或多个载体(例如表达载体)引入到适合于产生抗体的宿主细胞中。可以在适合于表达抗体或其任何多肽链的条件下培养宿主细胞。可以经由例如亲和纯化的常规方法由经培养细胞(例如从细胞或培养物上清液)回收这些抗体或其多肽链。需要时,可以将抗体的多肽链在合适条件下培育允许产生抗体的合适时间段。
在一些实施例中,制备本文描述的抗体的方法涉及编码本文所描述的双特异性抗体的两个链的重组表达载体。可以通过常规方法(例如磷酸钙介导的转染)将重组表达载体引入到合适宿主细胞(例如dhfr-CHO细胞)中。可以选择正转化体宿主细胞且在允许表达形成抗体的两个多肽链的合适条件下培养,所述抗体可以从细胞或培养基回收。需要时,可以在允许形成抗体的合适条件下培育从宿主细胞回收的两个链。
在一个实例中,提供两种重组表达载体,其各自编码本文公开的双特异性抗体的一个链。两种重组表达载体都可以通过常规方法(例如磷酸钙介导的转染)引入到合适宿主细胞(例如dhfr-CHO细胞)中。或者,可以将各表达载体引入到合适宿主细胞中。可以选择正转化体且在允许表达抗体的多肽链的合适条件下培养。当将两种表达载体引入到相同宿主细胞中时,可以从宿主细胞或培养基回收其中产生的抗体。需要时,可以从宿主细胞或培养基回收多肽链,随后在允许形成抗体的合适条件下培育。当将两种表达载体引入到不同宿主细胞中时,其各自可以从对应宿主细胞或对应培养基回收。随后可以在用于形成抗体的合适条件下培育两个多肽链。
将标准分子生物学技术用于制备重组表达载体、转染宿主细胞、选择转化体、培养宿主细胞和从培养基回收抗体。举例来说,可通过亲和色谱法用蛋白质A或蛋白质G偶合基质分离一些抗体。
编码本文描述的双特异性抗体的任何核酸、含有其的载体(例如表达载体)以及包括所述载体的宿主细胞在本公开的范围内。用于产生这类双特异性抗体的方法(例如使用宿主细胞经由重组技术)也在本公开的范围内。
II.武装免疫细胞
在另一方面,本文提供武装有本文公开的任何双特异性抗体(例如包括表1和表2中提供的Fab片段和/或scFv链的那些,或上文表3中提供的示范性双特异性抗体)的免疫细胞。双特异性抗体可以经由结合于细胞表面CD3分子来呈现于CD3+免疫细胞的表面。
免疫细胞可以是表达表面CD3的任何类型的免疫细胞(例如人免疫细胞)或其混合物。实例包含但不限于T细胞、B细胞、单核细胞和/或巨噬细胞。在一些情况下,T细胞为传统CD4+和/或CD8+T细胞。在一些情况下,T细胞为调节T细胞(Treg)。在其它情况下,T细胞为自然杀手T细胞(NKT)。免疫细胞可以从例如体液供体的供体(例如健康供体)获得。或者,免疫细胞可以从细胞系获得或从干细胞(例如造血干细胞)、骨髓细胞、脐带血细胞或诱导性多能干细胞分化。
可以通过将合适免疫细胞与本文公开的任何双特异性抗体(例如包括表1和表2中提供的Fab片段和/或scFv链的那些,或上文表3中提供的示范性双特异性抗体)在合适条件下培育合适时间段来产生任何武装免疫细胞。不同于单独的抗CD3抗体(例如OKT3),将本文公开的双特异性抗体与免疫细胞一起培育使得产生双特异性抗体呈现于细胞表面上的武装免疫细胞。双特异性抗体可以诱导免疫细胞增殖和/或分化,例如经由通过其抗CD3结合部分结合于T细胞上的CD3分子而诱导天然T细胞分化成效应细胞。因此产生的武装免疫细胞能够经由通过双特异性抗体的抗TAA结合部分识别癌细胞上表达的TAA分子来靶向癌细胞,所述双特异性抗体呈现于武装免疫细胞的表面上。
在一些实例中,可以使用外周血单核细胞(PBMC)产生本文公开的武装免疫细胞。举例来说,可以使用常规方法从供体(例如人类供体)分离PBMC。适合于从供体分离PBMC的方法包含但不限于密度离心(例如Paque)、细胞制备管(CPT)和SEPMATETM管。在一些实例中,可以根据制造商引导经由密度离心从获自供体的全血样本分离PBMC。随后可以将经分离PBMC与双特异性抗体在合适细胞培养基中培养至少7天,例如7、8、9、10、11、12、13、14或更多天;优选地,至少14天。在一些实施例中,在培养7天后,CD3+免疫细胞,例如T细胞(例如CD4/CD8 T细胞和/或NKT细胞)的数量倍增。在其它实施例中,培养持续14天,且CD3+T细胞的数量增加3倍。
在其它实例中,来自细胞培养物的免疫细胞可以用于制备本文公开的武装免疫细胞。体外培养的免疫细胞可以来自已确定的细胞系。或者,免疫细胞可以遵循常规方法从合适的干细胞(例如造血干细胞)、骨髓细胞、脐带血细胞或诱导性多能干细胞分化。
可以将合适量的免疫细胞(例如3×105个细胞)在合适细胞培养基中、在约500ng至约3,000ng(例如500、600、700、800、900、1,000、1,100、1,200、1,300、1,400、1,500、1,600、1,700、1,800、1,900、2,000、2,100、2,200、2,300、2,400、2,500、2,600、2,700、2,800、2,900或3,000ng)双特异性抗体存在下、在合适条件下培养合适时间段以产生武装免疫细胞。细胞培养基可以包括一个或多个用于维持如T细胞等免疫细胞的生长和/或刺激免疫细胞的活化的细胞因子。实例包含但不限于IL-1β、IL-2、IL-4、IL-6、IL-7、IL-12、IL-18、IL-21、IL-23、IL-25、IL-27、IL-31、干扰素-γ(IFN-γ)、TGF-β或其组合。另外或替代地,培养基可以包括抗体或用于活化用途的糖类,例如抗CD28抗体或甘露糖。
在一些实例中,IL-2可用于培养基中培养PBMC,以产生例如武装CD8+T细胞。在其它实例中,IL-2和IL-7可以用于培养基中培养PBMC,从而产生例如武装CD4+T细胞。为了产生武装Treg细胞,可以将IL-2、抗CD28抗体和甘露糖用于细胞培养基中。
由本文公开的任何方法产生的武装免疫细胞也在本公开的范围内。
III.使用武装免疫细胞的癌症治疗
在另一方面,本公开提供一种使用本文公开的武装免疫细胞治疗癌症的方法。为了实践本文公开的方法,可以经由合适途径,例如静脉内施用,例如呈大丸剂或通过在一段时间内连续输注来向需要治疗的受试者(例如人)施用有效量的武装免疫细胞或包括其的药物组合物。在一些情况下,武装免疫细胞为受试者自体的。在其它情况下,武装免疫细胞为受试者同种异体的。
待通过本文描述的方法治疗的受试者可以是哺乳动物,更优选人或非人灵长类动物。哺乳动物包含但不限于家畜、竞技动物(sport animal)、宠物、灵长类动物、马、狗、猫、小鼠和大鼠。需要治疗的人类受试者可以是出于患上以携带表达靶TAA的肿瘤细胞为特征的目标疾病/病症的危险下或怀疑患有所述目标疾病/病症的人类患者,双特异性抗体结合于所述靶TAA。示范性癌症包含但不限于:黑色素瘤、食道癌、胃癌、脑瘤、小细胞肺癌、非小细胞肺癌、膀胱癌、乳腺癌、胰腺癌、结肠癌、直肠癌、结肠直肠癌、肾癌、肝细胞癌、卵巢癌、前列腺癌、甲状腺癌、睾丸癌、头颈部鳞状细胞癌、白血病、淋巴瘤和骨髓瘤。
本领域中已知由特定类型的癌细胞呈递的特定肿瘤相关抗原。举例来说,B细胞恶性病通常包含CD19+(例如B细胞急性成淋巴细胞性白血病)和/或CD20+癌细胞(例如B细胞非霍奇金氏淋巴瘤(B-cell Non-Hodgkin's lymphoma))。EGFR表达于各种类型的癌症(例如肺癌和结肠癌)上。HER2与例如乳腺癌相关。PSMA与例如前列腺癌相关。CEA与包含结肠癌、直肠癌和胰腺癌的各种类型的癌症相关。EpCAM、FAP、CD47和TRAIL-R2与实体肿瘤相关。PDL1与如膀胱癌、非小细胞肺癌、乳腺癌、小细胞肺癌等的各种癌症相关。CD38与例如多发性骨髓瘤相关。CD33与例如AML相关。cMET(HGFR)与例如非小细胞肺癌相关。间皮素与间皮瘤相关。GD2与成神经细胞瘤相关。因此,选择本文公开的具有合适抗TAA结合部分的双特异性抗体治疗特定类型的癌症是在医学从业者的知识范围内的。
患有目标癌症的受试者可以通过常规医学检查,例如实验室测试、器官功能测试、CT扫描或超声波检查来鉴定。在一些实施例中,待通过本文描述的方法治疗的受试者可以是已经或正在接受抗癌疗法(例如化学疗法、放射疗法、免疫疗法或手术)的人类癌症患者。怀疑患有任何这类目标疾病/病症的受试者可能显示所述疾病/病症的一种或多种症状。处于所述疾病/病症风险下的受试者可以是具有所述疾病/病症的风险因素中的一个或多个的受试者。
如本文所用,“有效量”指代单独或与一种或多种其它活性剂组合赋予受试者治疗作用所需的每种活性剂的量。确定一定量的抗体是否达到治疗作用对本领域的技术人员来说是显而易见的。如本领域的技术人员所认识到的,有效量取决于以下而变化:所治疗的特定病况、病况严重程度、个别患者参数(包含年龄、身体状况、体型、性别和体重)、治疗持续时间、并行疗法(如果存在)的性质、特定施用途径以及健康从业者的知识和专长范围内的类似因素。这些因素是本领域普通技术人员所熟知的,并且可以通过常规实验解决。通常优选的是使用单独的组分或其组合的最大剂量,即根据合理的医学判断的最高安全剂量。
如半衰期等经验考虑因素通常将有助于确定剂量。举例来说,可以使用如人源化抗体或完全人抗体等与人免疫系统兼容的抗体来延长抗体的半衰期并防止抗体受到宿主的免疫系统的攻击。可在疗程中确定和调节施用频率,且通常但未必基于目标疾病/病症的治疗和/或抑制和/或减轻和/或延缓。或者,抗体的持续连续释放调配物可能是适当的。用于实现持续释放的各种调配物和装置为本领域中已知的。
在一个实例中,可以在已经给予了抗体的一次或多次施用的个体中凭经验确定本文所描述的抗体的剂量。给予个体递增剂量的促效剂。为了评定促效剂的功效,可以追踪疾病/病症的指标。
特定给药方案,即剂量、定时和重复次数将取决于特定个体和所述个体的病史,以及个别药剂的特性(例如药剂的半衰期,和本领域中众所周知的其它考虑因素)。
出于本公开的目的,本文描述的武装免疫细胞的适当剂量将取决于免疫细胞上的特定双特异性抗体、所用的免疫细胞(或其组合物)的类型、疾病/病症的类型和严重程度、患者的临床病史和对促效剂的反应以及主治医生的判断。临床医生通常将施用武装免疫细胞,直到达到实现期望结果的剂量为止。确定一个剂量是否得到所需结果的方法对于本领域的技术人员将显而易见。武装免疫细胞的一个或多个剂量的施用可以是连续或间歇的,取决于例如接受者的生理状况、使用的目的是治疗还是预防以及熟练从业者已知的其它因素。武装免疫细胞的施用可以在预选时间段内基本上连续或可以呈一系列间隔开的剂量,例如在罹患目标疾病或病症之前、期间或之后。
在一些实施例中,向受试者施用的如武装T细胞等武装免疫细胞的量可以是每千克受试者体重约1×104至1×107个细胞。在某些实施例中,可以向受试者施用的武装免疫细胞(例如武装T细胞)的量为每千克受试者体重约1×105到1×106个细胞。所述剂量可以呈单个剂量或替代地呈超过一个剂量施用。
如本文所用,术语“治疗”指代向受试者施加或施用包含一种或多种活性剂的组合物,所述受试者患有目标疾病或病症、具有所述疾病/病症的症状或具有疾病/病症易感性,其目的是治疗、治愈、减轻、缓解、改变、补救、改善、改进或影响病症、疾病的症状或对疾病或病症的易感性。
减轻目标疾病/病症包含延迟疾病的发展或进展或者降低疾病严重程度或延长存活期。减轻疾病或延长存活期未必需要治愈性结果。如本文所用,“延迟”目标疾病或病症的发展意味着推迟、阻碍、减缓、延缓、稳定和/或延迟疾病的进展。这一延迟可以具有不同的时间长度,这取决于疾病的历史和/或正在治疗的个体。“延迟”或缓解疾病发展,或延迟疾病发作的方法为相比于不使用所述方法,降低在给定时间范围内出现疾病的一种或多种症状的概率和/或降低在给定时间范围内症状的程度。这种比较通常基于临床研究,使用了足以给出统计学上显著的结果的许多受试者。
疾病的“发展”或“进展”意味着疾病的初始表达和/或后续进展。疾病的发展可以是可检测到的并且可以使用本领域所熟知的标准临床技术进行评定。然而,发展还指代可能无法检测到的进展。出于本公开的目的,发展或进展指代症状的生物学过程。“发展”包含发生、复发和发作。如本文所用,目标疾病或病症的“发作”或“发生”包含初始发作和/或复发。
取决于待治疗的癌症类型或癌症部位,可以使用医学领域的普通技术人员已知的常规方法向受试者施用武装免疫细胞或包括其的药物组合物。在一些情况下,武装免疫细胞可以经由静脉内输注施用。
在一些实施例中,本文公开的武装免疫细胞可以与另一抗癌剂(例如化学治疗剂、免疫治疗剂或其组合)一起使用。举例来说,本文公开的武装免疫细胞可以与免疫检查点抑制剂(例如抗PD-1抗体或抗PDL1抗体)组合使用。如本文所用,术语“组合”和相关术语指代同时或依序施用多种根据本公开的治疗剂。举例来说,本文公开的武装免疫细胞可以与另一治疗剂同时或依序地呈分开的单位剂型或呈单个单位剂型一起施用。
在一个实例中,用于使用本文公开的武装免疫细胞治疗具有表达TAA的癌症细胞的受试者(例如人类癌症患者)的方法可以包括以下步骤:(a)从患者分离PBMC;(b)将步骤(a)的PBMC与本文公开的双特异性抗体一起培养,所述双特异性抗体包括对TAA具特异性的结合部分以便产生武装免疫细胞,例如武装T细胞;和(c)向受试者施用有效量的武装免疫细胞。
在步骤(a)中,可以从受试者分离PBMC。受试者可以是任何哺乳动物,例如人、小鼠、大鼠、黑猩猩、兔、猴、绵羊、山羊、猫、狗、马或猪。优选地,受试者为人。适合于从受试者分离PBMC的方法包含但不限于密度离心(例如Paque)、细胞制备管(CPT)和SEPMATETM管。
在步骤(b)中,将经分离PBMC培养于含有本发明重组抗体的培养基中足够时间段(例如至少7天)以便产生TAA特异性T细胞。双特异性抗体能够通过其抗CD3抗体片段诱导T细胞活化。因此产生的武装T细胞具有结合于其表面上的双特异性抗体,且因此可以经由双特异性抗体的抗TAA抗体片段特异性地靶向癌细胞。
在步骤(c)中,可以向受试者施用在步骤(b)中产生的武装免疫细胞,例如武装T细胞,以便治疗癌症。向受试者施用的T细胞的量为每千克受试者体重约1×104到1×107个细胞。在某些实施例中,向受试者施用的T细胞的量为每千克受试者体重约1×105到1×106个细胞。所述剂量可以呈单个剂量或替代地呈超过一个剂量施用。
任选地,在步骤(c)之前,所述方法可能进一步通过适合于分离或纯化免疫细胞的方法(例如亲和柱或磁珠)从步骤(b)的产物分离T细胞。可以经由例行操作检验治疗功效。
IV.用于癌症治疗的试剂盒
本公开还提供试剂盒,其包括本文公开的任何武装免疫细胞(例如武装T细胞)或任何双特异性抗体。这类试剂盒可以用于治疗或减轻本文公开的目标癌症。这类试剂盒可以包含一个或多个包括武装免疫细胞或双特异性抗体(如本文所描述的那些)的容器。
在一些实施例中,试剂盒可以包括根据本文所述的任何方法的使用说明书。所包含的说明书可以包括关于用以治疗目标疾病(如本文描述的那些)、延迟其发作或使其减轻的武装免疫细胞的施用或产生武装免疫细胞的双特异性抗体的使用的描述。试剂盒可以进一步包括关于基于鉴定个体是否患有目标疾病而选择适合于治疗的个体的描述。在其它实施例中,说明书包括关于向有目标疾病风险的个体施用抗体的描述。
与武装免疫细胞(例如武装T细胞)或双特异性抗体的使用相关的说明书通常包含关于用于预期治疗的剂量、给药时程和施用途径的信息。容器可以是单位剂量、批量包装(例如多剂量包装)或亚单位剂量。本公开的试剂盒中供应的说明书通常是标签或药品说明书(例如试剂盒中包含的纸张)上的书面说明书,但也可接受机器可读指令(例如载于磁性或光学存储磁盘上的指令)。
标签或药品说明书指示组合物用于治疗疾病、延迟其发作和/或使其减轻,所述疾病例如癌症或免疫病症(例如自身免疫疾病)。可提供说明书以用于实践本文所描述的任何方法。
本发明的试剂盒呈适合包装形式。适合的包装包含但不限于小瓶、瓶子、罐、软包装(例如密封聚酯薄膜或塑料袋)等等。还考虑了与特定装置结合使用的包装,所述特定装置例如吸入器、鼻腔施用装置(例如雾化器)或输注装置,例如微型泵。试剂盒可以具有无菌进入端口(例如,容器可以是静脉输液袋或具有可被皮下注射针刺穿的塞子的小瓶)。容器也可以具有无菌进入端口(例如,容器可以是静脉输液袋或具有可被皮下注射针刺穿的塞子的小瓶)。组合物中的至少一种活性剂为武装免疫细胞或双特异性抗体,如本文描述的那些。
试剂盒可以任选地提供额外组分(例如缓冲剂)和说明性信息。通常,试剂盒包括容器和在容器上或与容器结合的标签或药品说明书。在一些实施例中,本发明提供包括上文描述的试剂盒的内含物的制品。
一般技术
除非另外指明,否则本公开的实践将采用本领域技术范围内的分子生物学(包含重组技术)、微生物学、细胞生物学、生物化学和免疫学的常规技术。这些技术在以下文献中进行了充分说明,例如《分子克隆:实验指南(Molecular Cloning:A LaboratoryManual)》,第二版(Sambrook等人,1989)冷泉港出版社;《寡核苷酸合成(OligonucleotideSynthesis)》(M.J.Gait编1984);《分子生物学方法(Methods in Molecular Biology)》,胡马纳出版社(Humana Press);《细胞生物学:实验室笔记(Cell Biology:A LaboratoryNotebook)》(J.E.Cellis编1989)学术出版社(Academic Press);《动物细胞培养(AnimalCell Culture)》(R.I.Freshney编1987);《引入细胞和组织培养物(Introuction to Celland Tissue Culture)》(J.P.Mather和P.E.Roberts,1998)普莱南出版社(Plenum Press);《细胞和组织培养物:实验室程序(Cell and Tissue Culture:Laboratory Procedures)》(A.Doyle、J.B.Griffiths和D.G.Newell编1993-8)威利父子公司(J.Wiley and Sons);《酶学方法(Methods in Enzymology)》(学术出版社公司(Academic Press,Inc.));《实验免疫学手册(Handbook of Experimental Immunology)》(D.M.Weir和C.C.Blackwell编);《哺乳动物细胞的基因转移载体(Gene Transfer Vectors for Mammalian Cells)》(J.M.Miller和M.P.Calos编1987);《现代分子生物学实验技术(Current Protocols in MolecularBiology)》(F.M.Ausubel等人编1987);《PCR:聚合酶链反应(PCR:The Polymerase ChainReaction)》,(Mullis等人编1994);《免疫学最新方案(Current Protocols inImmunology)》(J.E.Coligan等人编1991);《精编分子生物学方案(Short Protocols inMolecular Biology)》(威利父子公司,1999);《免疫生物学(Immunobiology)》(C.A.Janeway和P.Travers,1997);《抗体(Antibodies)》(P.Finch,1997);《抗体:实践方法(Antibodies:a practice approach)》(D.Catty.编,IRL出版社,1988-1989);《单克隆抗体:实践方法(Monoclonal antibodies:a practical approach)》(P.Shepherd和C.Dean编,牛津大学出版社(Oxford University Press),2000);《使用抗体:实验室手册(Usingantibodies:a laboratory manual)》(E.Harlow和D.Lane(冷泉港实验室出版社,1999);《抗体(The Antibodies)》(M.Zanetti和J.D.Capra编哈伍德学术出版设(HarwoodAcademic Publishers),1995);《DNA克隆实用方法(DNA Cloning:A practicalApproach)》,第I和II卷(D.N.Glover编1985);《核酸杂交(Nucleic Acid Hybridization)》(B.D.Hames和S.J.Higgins编(1985>>;《转录和转译Transcription and Translation)》(B.D.Hames和S.J.Higgins编(1984>>;《动物细胞培养(Animal Cell Culture)》(R.I.Freshney编(1986>>;《固定化细胞和酶(Immobilized Cells and Enzymes)》(lRL出版社,(1986>>;以及B.Perbal,《分子克隆实践指南(A practical Guide To MolecularCloning)》(1984);F.M.Ausubel等人(编)。
无需进一步详细阐述,相信本领域技术人员可以基于以上描述在最大程度上利用本发明。因此,以下具体实施例应理解为仅说明性的,而不以任何方式限制本公开的其余部分。本文所引用的所有出版物均通过引用并入以用于本文提及的目的或主题。
实例1:产生重组双特异性抗体
在这个实例中,使用图2A到2E中所示的DNA构建体制备分别具有如图1A到1L所描绘的结构的重组抗体。对于抗CD3 Fab/抗TAA scFv双特异性抗体,构建体从N端到C端包括:(a)Igk前导序列(LS)、抗CD3 VL-Ck域或抗CD3 VL-Cλ域、内部核糖体进入位点(IRES)、LS、抗CD3 VH-CH1域、肽连接子和抗TAA scFv(例如抗EGFR scFv)(图1A到1D和图2A,顶部的两个构建体);或(b)LS、抗CD3 VL-Ck域或抗CD3 VL-Cλ域、肽连接子、抗TAA scFv(例如抗EGFRscFv)、IRES、LS和抗CD3 VH-CH1域(图1B和图2A,底部的两个构建体)。
对于抗CD3 scFv/抗TAA Fab,构建体从N端到C端包括:(a)LS、抗TAA VL-Ck域(例如抗EGFR VL-Ck域)、IRES、LS、抗TAA VH-CH1域(例如抗EGFR VH-CH1域)、肽连接子和抗CD3VH-VL域或抗CD3 VL-VH域(图1E到1H和图2B,顶部的两个构建体);或(b)LS、抗TAA VL-Ck域(例如抗EGFR VL-Ck域)、肽连接子、抗CD3 VH-VL域或抗CD3 VL-VH域、IRES、LS和抗TAA VH-CH1域(例如抗EGFR VH-CH1域)(图1F和图2B,底部的两个构建体)。
对于抗CD3 scFv/抗TAA scFv,构建体从N端到C端包括LS、抗TAA scFv(例如抗EGFR scFv)、肽连接子和抗CD3 VH-VL域或抗CD3 VL-VH域(图1I到IL和图2C)。
对于抗CD3杵/抗TAA臼抗体,抗CD3杵构建体从N端到C端包括LS、抗CD3 VL-Ck域或抗CD3 VL-Cλ域、IRES、LS和抗CD3 VH-CH1-杵Fc,而抗肿瘤臼按顺序包括LS、抗TAA VL-Ck(例如抗EGFR VL-Ck域)、IRES、LS和抗TAA VH-CH1-臼Fc(例如抗EGFR-CH1-臼Fc)(图2D)。
对于抗CD3杵/抗TAA scFv臼抗体,抗CD3杵构建体按顺序包括LS、抗CD3 VL-Ck域或抗CD3 VL-Cλ域、IRES、LS和抗CD3 VH-CH1-杵Fc,而抗肿瘤臼按顺序包括LS、抗TAA scFv(例如抗EGFR scFv)、肽连接子和臼Fc(图2E)。
因此制备分别指定为CTA02scFv/CTAT03Fab(先前命名为抗EGFR Fab/CAT.02scFv)和CTA01scFv/CTAT03Fab(先前命名为抗EGFR Fab/aCD3scFv,其结构信息提供于WO2018177371中,所述文献的相关公开内容以引用方式并入以用于本文提及的主题和目的)的两种重组抗体。CTA02scFv/CTAT03Fab和CTA01scFv/CTAT03Fab都包括抗EGFR Fab和抗CD3 scFv,其中抗EGFR Fab的VH-CH1和VL-Ck域分别具有氨基酸序列SEQ ID NO:83和84。CTA02scFv/CTAT03Fab的抗CD3 scFv具有氨基酸序列SEQ ID NO:9,且CTA01scFv/CTAT03Fab的抗CD3 scFv提供于WO2018177371中(CTA01为在WO2018177371中命名为OKT3的相同抗体)。
实例2:重组双特异性抗体对T细胞的作用
本实例研究本文公开的重组双特异性抗体的生物活性。
结合亲和力
在这个实例中通过流式细胞术检验重组抗体CTA02scFv/CTAT03Fab和CTA01scFv/CTAT03Fab的结合亲和力。CTA02scFv/CTAT03Fab和CTA01scFv/CTAT03Fab都能够结合于CD3阳性T细胞。CTA02scFv/CTAT03Fab的结合亲和力高于theCTA01scFv/CTAT03Fab。图3。结合亲和力结果提供与下文表4中。
表4示范性双特异性抗体的结合亲和力
组 | 荧光信号 |
T细胞 | 0 |
T细胞+1ug/mL CTA01scFv/CTAT03Fab | 24.44 |
T细胞+5ug/mL CTA01scFv/CTAT03Fab | 50.31 |
T细胞+10ug/mL CTA01scFv/CTAT03Fab | 74.97 |
T细胞+1ug/mL CTA02scFv/CTAT03Fab | 57.95 |
T细胞+5ug/mL CTA02scFv/CTAT03Fab | 104.63 |
T细胞+10ug/mL CTA02scFv/CTAT03Fab | 117.25 |
细胞毒性作用
在这个实例中评估重组抗体CTA02scFv/CTAT03Fab或CTA01scFv/CTAT03Fab对癌细胞的细胞毒性作用。发现约2.5%、18.2%和26.9%的HT-29细胞分别以3:1、5:1和10:1的效应细胞与靶细胞比率(E/T比率)被由鼠类OKT3活化的CD3+/CD8+T细胞杀死;约13.8%、34.8%和65.7%的HT-29细胞被武装有CTA01scFv/CTAT03Fab的CD3+/CD8+T细胞杀死,且约28.1%、44.4%和76.7%的HT-29细胞以相同E/T比率被武装有CTA02scFv/CTAT03Fab的T细胞杀死(图4和表5)。
表5指定抗体的细胞毒性作用
数据表明所测试的双特异性抗体都显示相对于OKT3抗体(抗CD3抗体)更高的针对癌细胞的细胞毒性作用,且CTA02scFv/CTAT03Fab显示更好的细胞毒性作用。
对留存在T细胞表面上的抗体量的时间作用
将CTA02scFv/CTAT03Fab和CTA01scFv/CTAT03Fab分别在20% FBS存在下与T细胞一起培育24小时。随后通过流式细胞术分析T细胞以评估T细胞表面上抗体的残余量。这个分析的结果表明T细胞表面上的抗体量随时间推移而下降。图5和下文表6。与CTA01scFv/CTAT03Fab相比,CTA02scFv/CTAT03Fab受降解的影响较小。约84.5%的CTA02scFv/CTAT03Fab在24小时后仍留存在T细胞表面上,而留存在T细胞表面上的CTA01scFv/CTAT03Fab的水平在24小时后降到约40%。
表6.随时间推移,细胞表面上剩余的双特异性抗体的百分比
时间(小时) | CTA02scFv/CTAT03Fab | CTA01scFv/CTAT03Fab |
0 | 100 | 100 |
24 | 84.5±0.6 | 40±1.4 |
总之,本文公开的双特异性抗体(以CTA02scFv/CTAT03Fab抗体例示)展现相对于CTA01scFv/CTAT03Fab对照抗体更高的T细胞结合亲和力、更高的细胞毒性和更高的随时间推移的T细胞结合水平。
实例2:构建变异抗CD3/抗肿瘤双特异性抗体
通过基因工程构建一组各种抗CD3/抗肿瘤相关抗原(TAA)双特异性抗体(BsAb)。这些BsAb来源于4种抗CD3抗体和16种抗TAA抗体(CD20(CTAT01)、CD19(CTAT02)、EGFR(CTAT03)、HER2(CTAT04)、PSMA(CTAT05)、CEA(CTAT06)、EpCAM(CTAT07)、FAP(CTAT08)、PDL1(CTAT09)、CD38(CTAT10)、CD33(CTAT11)、HGFR(CTAT12)、CD47(CTAT13)、TRAIL-R2(CTAT14)、间皮素(CTAT15)和GD2(CTAT16))。参见上文表1和表2。
经由重组技术在哺乳动物宿主细胞中产生BsAb,收集,且通过SDS-PAGE在还原条件和非还原条件下进行检验。简单来说,在非还原条件和还原条件下用8% SDS-PAGE进行蛋白质电泳以分析包括抗CD3片段和抗TAA片段的各种BsAb的结构和分子量。
图6A到6B展示BsAb的表达和组装,所述BsAb各自包括4种不同抗CD3抗体(CTA02、CTA03、CTA04和CTA05;参见上文表1)的Fab和抗CD19 scFv(CTAT02;参见上文表2)。
图7A到7D展示BsAb的表达和组装,所述BsAb各自包括抗CD3 Fab(CTA03;参见上文表1)和16种不同抗肿瘤抗体(CD20(CTAT01)、CD19(CTAT02)、EGFR(CTAT03)、HER2(CTAT04)、PSMA(CTAT05)、CEA(CTAT06)、EpCAM(CTAT07)、FAP(CTAT08)、PDL1(CTAT09)、CD38(CTAT10)、CD33(CTAT11)、HGFR(CTAT12)、CD47(CTAT13)、TRAIL-R2(CTAT14)、间皮素(CTAT15)和GD2(CTAT16);参见上文表2)的scFv。图7E和7F展示BsAb的表达,所述BsAb各自包括四种抗CD3抗体(CTA02到CTA05)中的一种的scFv以及抗EGFR CTAT03的Fab片段。
实例3:抗CD3/抗TAA BsAb结合T细胞且靶向表达TAA的肿瘤细胞
使用流式细胞术分析各种抗CD3/抗肿瘤BsAb与T细胞和肿瘤细胞的结合活性。对CD3和CD19具特异性的BsAb(CTA02Fab/CTAT02scFv、CTA03Fab/CTAT02scFv、CTA04Fab/CTAT02scFv和CTA05Fab/CTAT02scFv)全部显示与CD3+T细胞(Jurkat)和CD19+B细胞淋巴瘤细胞(Raji)的结合活性,表明武装有这类BsAb的T细胞可以用于靶向CD19+疾病细胞,例如CD19+B细胞淋巴瘤细胞。图8。
还研究具有结合片段的BsAb与其它TAA的结合活性。如图9A到10K中所示:
·CTA03Fab/CTAT02scFv显示与CD3+T细胞(Jurkat)和CD19+B细胞淋巴瘤细胞(Raji)的结合活性(图9A);
·CTA03Fab/CTAT03scFv显示与CD3+T细胞(Jurkat)和EGFR+三阴性乳腺癌细胞(MDA-MB-231)的结合活性(图9B);
·CTA03Fab/CTAT04scFv显示与CD3+T细胞(Jurkat)和HER2+乳腺癌细胞(MCF7/HER2)的结合活性(图9C);
·CTA03Fab/CTAT05scFv显示与CD3+T细胞(Jurkat)和PSMA+前列腺癌细胞(LNCaP)的结合活性(图9D);
·CTA03Fab/CTAT07scFv显示与CD3+T细胞(Jurkat)和EpCAM+前列腺癌细胞(LNCaP)的结合活性(图9E);
·CTA03Fab/CTAT08scFv显示与CD3+T细胞(Jurkat)FAP+小鼠成纤维细胞(3T3/FAP)的结合活性(图9F);
·CTA03Fab/CTAT09scFv显示与CD3+T细胞(Jurkat)和PDL1+三阴性乳腺癌(MDA-MB-231)的结合活性(图9G);
·CTA03Fab/CTAT10scFv显示与CD3+T细胞(Jurkat)和CD38+B细胞淋巴瘤细胞(Raji)的结合活性(图9H);
·CTA03Fab/CTAT11scFv与CD3+T细胞(Jurkat)和CD33+人急性骨髓性白血病细胞(HL-60)的结合活性(图9I)。
·CTA03Fab/CTAT12scFv显示与CD3+T细胞(Jurkat)和HGFR+人肺癌细胞(A549)的结合活性(图9J);且
·CTA03Fab/CTAT13scFv显示与CD3+T细胞(Jurkat)和CD47+乳腺癌细胞(MCF7/HER2)的结合活性(图9K)。
此外,使用流式细胞术分析各种抗CD3 scFv/抗肿瘤Fab BsAb与T细胞和肿瘤细胞的结合活性。图9L展示由4种不同抗CD3抗体(CTA02、CTA03、CTA04、CTA05)的scFv和抗EGFRFab(CTAT03)组成的BsAb针对CD3+T细胞(Jurkat)和EGFR+结肠癌细胞(HT-29)的靶向能力。结果表明CTA02scFv/CTAT03Fab、CTA03scFv/CTAT03Fab、CTA04scFv/CTAT03Fab和CTA05scFv/CTAT03Fab全部具有针对CD3+T细胞(Jurkat)和EGFR+结肠癌细胞(HT-29)的靶向能力。
实例4:BsAb在T细胞表面上的留存能力
使用体外培育平台分析BsAb在T细胞表面上的留存时间。简单来说,将人T细胞与各种抗CD3Fab/抗CD19scFv(CTA01Fab/CTAT02scFv、CTA02Fab/CTAT02scFv、CTA03Fab/CTAT02scFv和CTA05Fab/CTAT02scFv)一起培育1hr,且随后在培养基中培养5min、24hr、48hr和72hr。培养后,使用流式细胞术检测T细胞表面上BsAb的残余量。72hr后,在T细胞表面上检测到CTA01Fab/CTAT02scFv、CTA02Fab/CTAT02scFv、CTA03Fab/CTAT02scFv和CTA05Fab/CTAT02scFv全部,且CTA03Fab/CTAT02scFv在T细胞表面上的留存量最高。图10。
实例5:使用BsAb经由单步培育制备武装免疫细胞
在OKT3抗体存在下,或在本文公开的示范性BsAb(使用CTA01Fab/CTAT02scFv、CTA02Fab/CTAT02scFv、CTA03Fab/CTAT02scFv和CTA05Fab/CTAT02scFv作为实例)存在下培养来自健康供体的人外周血单核细胞(PBMC)且使其分化成T细胞。在相同条件下(在具有5% CO2供应和稳定湿度水平的37℃下的培育箱中)培养所有组。7天后,使用流式细胞术分析所有组以测量BsAb武装T细胞的产生。
如图11A和11B中所示,OKT3抗CD3抗体诱导PBMC仅分化成正常T细胞而非武装T细胞。相比之下,CTA01Fab/CTAT02scFv、CTA02Fab/CTAT02scFv、CTA03Fab/CTAT02scFv和CTA05Fab/CTAT02scFvBsAb全部成功地产生武装T细胞。
在另一实验中,用OKT3或示范性抗CD3 Fab/抗肿瘤scFv BsAb(CTA03Fab/CTAT03scFv、CTA03Fab/CTAT04scFv、CTA03Fab/CTAT05scFv、CTA03Fab/CTAT07scFv、CTA03Fab/CTAT08scFv、CTA03Fab/CTAT9scFv、CTA03Fab/CTAT10scFv、CTA03Fab/CTAT11scFv、CTA03Fab/CTAT12scFv和CTA03Fab/CTAT13scFv)培养PBMC且使其分化成T细胞。在相同条件下(在具有5% CO2和稳定湿度水平的37℃下的培育箱中)培养所有组。7天后,使用流式细胞术分析所有组以显示是否成功地产生BsAb武装T细胞。图12A和12B展示OKT3抗体引起PBMC分化成正常T细胞,但不产生武装T细胞。相比之下,CTA03Fab/CTAT03scFv、CTA03Fab/CTAT04scFv、CTA03Fab/CTAT05scFv、CTA03Fab/CTAT07scFv、CTA03Fab/CTAT08scFv、CTA03Fab/CTAT9scFv、CTA03Fab/CTAT10scFv、CTA03Fab/CTAT11scFv、CTA03Fab/CTAT12scFv和CTA03Fab/CTAT13scFv BsAb全部引起武装T细胞产生。
此外,用OKT3或各种抗CD3 scFv/抗肿瘤Fab BsAb(CTA01scFv/CTAT03Fab、CTA02scFv/CTAT03Fab、CTA03scFv/CTAT03Fab、CTA04scFv/CTAT03Fab和CTA05scFv/CTAT03Fab)培养PBMC且使其分化成T细胞。在相同条件下(在具有5% CO2和稳定湿度水平的37℃下的培育箱中)培养所有组。7天后,使用流式细胞术分析所有组以显示是否成功地产生BsAb武装T细胞。图12C和12D展示传统的OKT3方法引起PBMC仅分化成正常T细胞,而非武装T细胞。然而,CTA01scFv/CTAT03Fab、CTA02scFv/CTAT03Fab、CTA03scFv/CTAT03Fab、CTA04scFv/CTAT03Fab和CTA05scFv/CTAT03Fab BsAb全部成功地产生武装T细胞。
实例6:BsAb武装T细胞针对肿瘤细胞的体外毒性
在这个实例中研究武装有抗CD3/抗CD19 BsAb的T细胞针对CD19+B细胞淋巴瘤细胞(Raji)的细胞毒性活性。本文公开的示范性抗CD3/抗CD19BsAb包含CTA01Fab/CTAT02scFv、CTA02Fab/CTAT02scFv、CTA03Fab/CTAT02scFv和CTA05Fab/CTAT02scFv。使用体外细胞毒性分析来分析用OKT3抗体培养的T细胞。没有观察到用OKT3培养的T细胞针对CD19+B细胞淋巴瘤细胞(Raji)的显著细胞毒性。不同的是,用CTA01Fab/CTAT02scFv、CTA02Fab/CTAT02scFv、CTA03Fab/CTAT02scFv或CTA05Fab/CTAT02scFv培养的T细胞有效地杀死CD19+B细胞淋巴瘤细胞(Raji)。在所测试BsAb中,CTA03Fab/CTAT02scFv武装T细胞具有最优细胞毒性活性。图13A。
此外,使用体外细胞毒性分析来分析武装有由5种不同抗CD3 scFv(CTA01scFv/CTAT03Fab、CTA02scFv/CTAT03Fab、CTA03scFv/CTAT03Fab、CTA04scFv/CTAT03Fab和CTA05scFv/CTAT03Fab)组成的抗CD3scFv/抗EGFRFab BsAb的T细胞和用传统OKT3抗体培养的T细胞的EGFR+结肠癌细胞(HT-29)杀灭活性。图13B展示与OKT3一起培育的T细胞没有有效地杀死EGFR+结肠癌细胞(HT-29),但用CTA01scFv/CTAT03Fab、CTA02scFv/CTAT03Fab、CTA03scFv/CTAT03Fab、CTA04scFv/CTAT03Fab和CTA05scFv/CTAT03Fab培养的武装T细胞有效地杀死EGFR+结肠癌细胞(HT-29)。图13B。
在另一实验中,进一步分析用各种抗CD3 Fab/抗肿瘤scFv BsAb(包含CTA03Fab/CTAT03scFv、CTA03Fab/CTAT04scFv、CTA03Fab/CTAT05scFv、CTA03Fab/CTAT07scFv、CTA03Fab/CTAT08scFv、CTA03Fab/CTAT9scFv、CTA03Fab/CTAT10scFv、CTA03Fab/CTAT11scFv、CTA03Fab/CTAT12scFv和CTA03Fab/CTAT13scFv)产生的武装T细胞的肿瘤细胞杀灭活性。如图14A和14B中所示,CTA03Fab/CTAT03scFv武装T细胞有效地杀死EGFR+结肠癌细胞HT29和HCT-116。图14C展示CTA03Fab/CTAT04scFv武装T细胞有效地杀死HER2+乳腺癌细胞(MCF7/HER2)。图14D展示CTA03Fab/CTAT05scFv武装T细胞有效地杀死PSMA+前列腺癌细胞(LNCaP)。图14E展示CTA03Fab/CTAT07scFv武装T细胞有效地杀死EpCAM+前列腺癌细胞(LNCaP)。此外,图14F到14G展示CTA03Fab/CTAT08scFv武装T细胞有效地杀死FAP+小鼠成纤维细胞(3T3/FAP)。
另外,图15A展示CTA03Fab/CTAT09scFv武装T细胞有效地杀死PDL1+三阴性乳腺癌细胞(MDA-MB-231)。图15B展示CTA03Fab/CTAT10scFv武装T细胞有效地杀死CD38+B细胞淋巴瘤细胞(Raji)。图15C展示CTA03Fab/CTAT11scFv武装T细胞有效地杀死CD33+人急性骨髓性白血病细胞(HL-60)。图15D展示CTA03Fab/CTAT12scFv武装T细胞有效地杀死HGFR+人肺癌细胞(A549)。图15E展示CTA03Fab/CTAT13scFv武装T细胞有效地杀死CD47+乳腺癌细胞(MCF7/HER2)。
实例7:CTA03Fab/CTAT02scFv武装T细胞的体内抗癌活性
评估抗CD3Fab/抗CD19scFv(CTA01Fab/CTAT02scFv和CTA03Fab/CTAT02scFv)武装T细胞的体内癌症抑制。将CTA01Fab/CTAT02scFv武装T细胞和CTA03Fab/CTAT02scFv武装T细胞静脉内注射到携带B细胞淋巴瘤(Raji)的SCID小鼠。记录体重、存活率和后肢麻痹发生率。图16A到16C展示CTA03Fab/CTAT02scFv武装T细胞具有有效抑制癌症的最优治疗功效。
实例8:CTA03Fab/CTAT03scFv武装T细胞和CTA03Fab/CTAT04scFv武装T细胞的体内抗肿瘤活性
评估抗CD3Fab/抗EGFRscFv(CTA03Fab/CTAT03scFv)武装T细胞和抗CD3Fab/抗HER2scFv(CTA03Fab/CTAT04scFv)武装T细胞的体内肿瘤抑制。将CTA03Fab/CTAT03scFv武装T细胞和CTA03Fab/CTAT04scFv武装T细胞静脉内注射到携带人三阴性乳腺癌的患者来源的异种移植(PDX)小鼠模型。记录体重和肿瘤尺寸。图17A到17B展示CTA03Fab/CTAT03scFv武装T细胞和CTA03Fab/CTAT04scFv武装T细胞都有效地抑制人三阴性乳腺癌的肿瘤生长。
实例9:使用BsAb从PBMC产生武装NKT细胞的单步培育
用OKT3传统方法或用CTA03Fab/CTAT03scFv、CTA03Fab/CTAT04scFv和CTA03Fab/CTAT05scFv BsAb培养来自健康供体的人外周血单核细胞(PBMC)且使其分化成NKT细胞(CD8+CD56+)。在相同环境下(在具有5%CO2和稳定湿度水平的37℃下的培育箱中)培养所有组。7天后,使用流式细胞术分析所有组以显示是否成功地产生BsAb武装NKT细胞。图18A和18B展示OKT3方法诱导PBMC仅分化成正常NKT细胞,但不形成武装T细胞。不同的是,CTA03Fab/CTAT03scFv、CTA03Fab/CTAT04scFv和CTA03Fab/CTAT05scFv BsAb全部成功地产生武装NKT细胞。
在类似分析中,在OKT抗体存在下或用CTA01scFv/CTAT03Fab、CTA02scFv/CTAT03Fab、CTA03scFv/CTAT03Fab、CTA04scFv/CTAT03Fab和CTA05scFv/CTAT03Fab BsAb培养来自健康供体的人外周血单核细胞(PBMC)且使其分化成NKT细胞(CD8+CD56+)。在相同环境下(在具有5%CO2和稳定湿度水平的37℃下的培育箱中)培养所有组。7天后,使用流式细胞术分析所有组以显示是否成功地产生BsAb武装NKT细胞。图34展示传统的OKT3方法引起PBMC仅分化成正常NKT细胞,而非武装T细胞。然而,CTA01scFv/CTAT03Fab、CTA02scFv/CTAT03Fab、CTA03scFv/CTAT03Fab、CTA04scFv/CTAT03Fab和CTA05scFv/CTAT03FabBsAb全部成功地产生武装NKT细胞。
实例10:具有点突变的CTA03Fab/CTAT02scFv BsAb的构建及其表征
通过基因工程将点突变引入到CTA03Fab/CTAT02scFv BsAb中,产生BsAb CTA03-01Fab/CTAT02-01scFv(CTA03Fab(VLG58A)/CTAT02scFv(VLG42A))、CTA03-01Fab/CTAT02-02scFv(CTA03Fab(VLG58A)/CTAT02scFv(VLD41E))、CTA03-02Fab/CTAT02-02scFv(CTA03Fab(VLD57E)/CTAT02scFv(VLD41E))和CTA03-02Fab/CTAT02-01scFv(CTA03Fab(VLD57E)/CTAT02scFv(VLG42A))。更确切地说,将点突变G58A和D57E引入到CTA03的VL中且将G42A和D41E引入到CTAT02的VL中。参见上文表2。
使用流式细胞术分析BsAb针对CD3+T细胞(Jurkat)和CD19+B细胞淋巴瘤细胞(Raji)的结合能力。图19A到19B展示CTA03-01Fab/CTAT02-01scFv、CTA03-01Fab/CTAT02-02scFv、CTA03-02Fab/CTAT02-02scFv和CTA03-02Fab/CTAT02-01scFv BsAb全部具有针对CD3+T细胞(Jurkat)和CD19+B细胞淋巴瘤细胞(Raji)的靶向能力。另外,BsAbs与靶细胞的结合是以剂量依赖性方式。
将用点突变BsAb(CTA03-01Fab/CTAT02-01scFv、CTA03-01Fab/CTAT02-02scFv、CTA03-02Fab/CTAT02-02scFv和CTA03-02Fab/CTAT02-01scFv)产生的武装T细胞针对CD19+B细胞淋巴瘤细胞的杀灭活性与原始CTA03Fab/CTAT02scFv BsAb武装T细胞的杀灭活性进行比较。图19C展示与OKT3一起培育的T细胞没有显示针对CD19+B细胞淋巴瘤细胞(Raji)的细胞毒性。另一方面,用CTA03-01Fab/CTAT02-01scFv、CTA03-01Fab/CTAT02-02scFv、CTA03-02Fab/CTAT02-02scFv或CTA03-02Fab/CTAT02-01scFv培养的武装T细胞有效地杀死CD19+B细胞淋巴瘤细胞(Raji),且细胞毒性全部优于母体CTA03Fab/CTAT02scFv BsAb。
其它实施例
本说明书中公开的所有特征都可以以任何组合进行组合。本说明书中公开的各个特征可经用于实现相同、等效或类似目的的替代性特征置换。因此,除非另外明确陈述,否则各个公开的特征都只是一系列通用的等效或类似特征的实例。
通过以上描述,本领域技术人员可以很容易地确定本发明的实质特性,并且在不脱离本发明的精神和范围的情况下,可以对本发明进行各种改变和修改以使其适于各种用途和条件。因此,其它实施例也在权利要求书范围内。
等效物
尽管本文中已经描述和说明了多个发明性实施例,但是本领域普通技术人员将容易设想多种用于执行本文描述的功能和/或获得本文描述的结果和/或本文描述的优点中的一个或多个的其它装置和/或结构,并且认为这类变化形式和/或修改中的每一个都在本文描述的发明性实施例的范围内。更一般来讲,本领域的技术人员将容易理解,本文中描述的所有参数、尺寸、材料以及配置意在为示范性的,并且实际参数、尺寸、材料和/或配置将取决于本发明传授内容所用于的一种或多种具体应用。本领域技术人员将认识到或能够仅使用常规实验来确定本文描述的具体发明性实施例的许多等效物。因此,应理解,前述实施例是仅通过实例方式来介绍的,并且在所附权利要求书和其等效物的范围内,发明性实施例可以按与具体描述和要求不同的方式来实践。本公开的发明性实施例涉及本文描述的各个个别特征、系统、物品、材料、套件和/或方法。另外,如果这类特征、系统、物品、材料、套件和/或方法并非互不一致,那么两个或更多个这类特征、系统、物品、材料、套件和/或方法的任何组合包含在本公开的发明性范围内。
应理解,本文中定义和使用的所有定义都优先于辞典定义、以引用的方式并入的文献中的定义和/或定义的术语的普通含义。
本文公开的所有参考文献、专利和专利申请关于其各自被引用的主题以引用的方式并入,在一些情况下,可涵盖整个文献。
除非明确相反指示,否则本文在说明书和权利要求书中所使用的不定冠词“一”应理解为意味着“至少一个”。
本文在说明书和权利要求书中所使用的短语“和/或”应理解为意味着如此联合的要素中的“任一个或两个”,例如,要素在一些情况下结合地存在而在其它情况下分开存在。通过“和/或”列出的多个要素应按相同方式解释,即,如此结合的要素中的“一个或多个”。除通过“和/或”从句具体标识的要素之外,可以任选地存在其它要素,无论与具体标识的那些要素相关还是无关。因此,作为非限制性实例,当结合如“包括”等开放式语言使用时,对“A和/或B”的引用可以在一个实施例中仅指代A(任选地包含除B之外的要素);在另一个实施例中,仅指代B(任选地包含除了A之外的要素);在另一个实施例中,指代A和B两者(任选地包含其它要素);等。
如在本说明书和权利要求书中所使用,“或”应理解为具有与如上所定义的“和/或”相同的含义。举例来说,当在列表中分隔多项时,“或”或“和/或”将解释为包含性的,即,包含至少一个,但也包含多个要素或要素列表中的一个以上和任选地存在的额外未列出项。只有明确相反指示的术语,如“仅仅…中的一个”或“恰好…中的一个”或当在权利要求书中使用时的“由…组成”将指代包含多个要素或要素列表中的恰好一个要素。一般来说,本文中所用的术语“或”在带有例如“任一”、“…中的一个”、“仅…中的一个”或“恰好…中的一个”等排他性术语时,仅应解释为指示排他性替代形式(即,“一个或另一个但并非两个”)。“基本上由…组成”当在权利要求书中使用时,应具有其如专利法领域中所用的普通含义。
术语“约”或“大约”意味着在本领域一般技术人员测定的特定值的可接受误差范围内,其将部分取决于所述值测量或测定的方式,即,测量系统的限制。举例来说,“约”可能意味着根据本领域的实践在可接受的标准偏差内。或者,“约”可以意味着给定值的最高±20%、优选地最高±10%、更优选地最高±5%并且更优选地最高±1%的范围内。或者,特别是对于生物学系统和方法,所述术语可以意味着在值的数量级内,优选地在2倍内。当在本申请和权利要求书中描述特定值时,除非另有说明,否则术语“约”是隐含的并且在这种上下文中意味着在特定值的可接受误差范围内。在一些实施例中,铰链域为天然存在的蛋白质的铰链域。
如本文在说明书和权利要求书中所使用,短语“至少一个”在提及一个或多个要素的列表时,应理解为意味着选自要素列表中的任一个或多个要素中的至少一个要素,而非一定包含要素列表内具体列举的每个要素中的至少一个,并且不排除要素列表中的元素的任何组合。这个定义还允许可以任选地存在除在短语“至少一个”所指的要素列表内具体标识的要素之外的要素,无论是否与具体标识的那些元素相关还是无关。因此,作为非限制性实例,在一个实施例中,“A和B中的至少一个”(或等效地,“A或B中的至少一个”,或等效地“A和/或B中的至少一个”)可以指任选地包含多于一个A,不存在B(并且任选地包含除B以外的要素)的至少一个;在另一实施例中,可以指任选地包含多于一个B,不存在A(并且任选地包含除A以外的要素)的至少一个;在另一个实施例中,可以指任选地包含多于一个A的至少一个,以及任选地包含多于一个B(以及任选地包含其它要素)的至少一个;等。
还应理解,除非明确相反地指示,否则在本文要求的包含一个以上步骤或动作的任何方法中,所述方法的步骤或动作的顺序不必限于其中所列举的方法的步骤或动作的顺序。
序列表
<110> 赛昂生医股份有限公司(CytoArm Co., Ltd.)
<120> 用于产生武装免疫细胞的双特异性抗体
<130> 113122-0014-700WO00
<140> Not Yet Assigned
<141> Concurrently Herewith
<150> US 62/993,080
<151> 2020-03-23
<160> 249
<170> PatentIn version 3.5
<210> 1
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 1
Arg Tyr Thr Met His
1 5
<210> 2
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 2
Tyr Ile Asn Pro Ser Arg Gly Tyr Thr Asn Tyr Asn Gln Lys Phe Lys
1 5 10 15
Asp
<210> 3
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 3
Tyr Tyr Asp Asp His Tyr Cys Leu Asp Tyr
1 5 10
<210> 4
<211> 119
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 4
Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Ala Arg Pro Gly Ala
1 5 10 15
Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Arg Tyr
20 25 30
Thr Met His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Asn Pro Ser Arg Gly Tyr Thr Asn Tyr Asn Gln Lys Phe
50 55 60
Lys Asp Lys Ala Thr Leu Thr Thr Asp Lys Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Tyr Tyr Asp Asp His Tyr Cys Leu Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Thr Leu Thr Val Ser Ser
115
<210> 5
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 5
Ser Ala Ser Ser Ser Val Ser Tyr Met Asn
1 5 10
<210> 6
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 6
Asp Thr Ser Lys Leu Ala Ser
1 5
<210> 7
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 7
Gln Gln Trp Ser Ser Asn Pro Phe Thr
1 5
<210> 8
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 8
Gln Ile Val Leu Thr Gln Ser Pro Ala Ile Met Ser Ala Ser Pro Gly
1 5 10 15
Glu Lys Val Thr Met Thr Cys Ser Ala Ser Ser Ser Val Ser Tyr Met
20 25 30
Asn Trp Tyr Gln Gln Lys Ser Gly Thr Ser Pro Lys Arg Trp Ile Tyr
35 40 45
Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Ala His Phe Arg Gly Ser
50 55 60
Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Gly Met Glu Ala Glu
65 70 75 80
Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser Asn Pro Phe Thr
85 90 95
Phe Gly Ser Gly Thr Lys Leu Glu Ile Asn Arg
100 105
<210> 9
<211> 248
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 9
Gly Gly Gly Ser Gly Gly Gly Gln Val Gln Leu Gln Gln Ser Gly Ala
1 5 10 15
Glu Leu Ala Arg Pro Gly Ala Ser Val Lys Met Ser Cys Lys Ala Ser
20 25 30
Gly Tyr Thr Phe Thr Arg Tyr Thr Met His Trp Val Lys Gln Arg Pro
35 40 45
Gly Gln Gly Leu Glu Trp Ile Gly Tyr Ile Asn Pro Ser Arg Gly Tyr
50 55 60
Thr Asn Tyr Asn Gln Lys Phe Lys Asp Lys Ala Thr Leu Thr Thr Asp
65 70 75 80
Lys Ser Ser Ser Thr Ala Tyr Met Gln Leu Ser Ser Leu Thr Ser Glu
85 90 95
Asp Ser Ala Val Tyr Tyr Cys Ala Arg Tyr Tyr Asp Asp His Tyr Cys
100 105 110
Leu Asp Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val Ser Ser Gly Gly
115 120 125
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Ile Val
130 135 140
Leu Thr Gln Ser Pro Ala Ile Met Ser Ala Ser Pro Gly Glu Lys Val
145 150 155 160
Thr Met Thr Cys Ser Ala Ser Ser Ser Val Ser Tyr Met Asn Trp Tyr
165 170 175
Gln Gln Lys Ser Gly Thr Ser Pro Lys Arg Trp Ile Tyr Asp Thr Ser
180 185 190
Lys Leu Ala Ser Gly Val Pro Ala His Phe Arg Gly Ser Gly Ser Gly
195 200 205
Thr Ser Tyr Ser Leu Thr Ile Ser Gly Met Glu Ala Glu Asp Ala Ala
210 215 220
Thr Tyr Tyr Cys Gln Gln Trp Ser Ser Asn Pro Phe Thr Phe Gly Ser
225 230 235 240
Gly Thr Lys Leu Glu Ile Asn Arg
245
<210> 10
<211> 216
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 10
Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Ala Arg Pro Gly Ala
1 5 10 15
Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Arg Tyr
20 25 30
Thr Met His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Asn Pro Ser Arg Gly Tyr Thr Asn Tyr Asn Gln Lys Phe
50 55 60
Lys Asp Lys Ala Thr Leu Thr Thr Asp Lys Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Tyr Tyr Asp Asp His Tyr Cys Leu Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Thr Leu Thr Val Ser Ser Ala Lys Thr Thr Ala Pro Ser Val Tyr
115 120 125
Pro Leu Ala Pro Val Cys Gly Gly Thr Thr Gly Ser Ser Val Thr Leu
130 135 140
Gly Cys Leu Val Lys Gly Tyr Phe Pro Glu Pro Val Thr Leu Thr Trp
145 150 155 160
Asn Ser Gly Ser Leu Ser Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Asp Leu Tyr Thr Leu Ser Ser Ser Val Thr Val Thr Ser Ser
180 185 190
Thr Trp Pro Ser Gln Ser Ile Thr Cys Asn Val Ala His Pro Ala Ser
195 200 205
Ser Thr Lys Val Asp Lys Lys Ile
210 215
<210> 11
<211> 213
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 11
Gln Ile Val Leu Thr Gln Ser Pro Ala Ile Met Ser Ala Ser Pro Gly
1 5 10 15
Glu Lys Val Thr Met Thr Cys Ser Ala Ser Ser Ser Val Ser Tyr Met
20 25 30
Asn Trp Tyr Gln Gln Lys Ser Gly Thr Ser Pro Lys Arg Trp Ile Tyr
35 40 45
Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Ala His Phe Arg Gly Ser
50 55 60
Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Gly Met Glu Ala Glu
65 70 75 80
Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser Asn Pro Phe Thr
85 90 95
Phe Gly Ser Gly Thr Lys Leu Glu Ile Asn Arg Ala Asp Thr Ala Pro
100 105 110
Thr Val Ser Ile Phe Pro Pro Ser Ser Glu Gln Leu Thr Ser Gly Gly
115 120 125
Ala Ser Val Val Cys Phe Leu Asn Asn Phe Tyr Pro Lys Asp Ile Asn
130 135 140
Val Lys Trp Lys Ile Asp Gly Ser Glu Arg Gln Asn Gly Val Leu Asn
145 150 155 160
Ser Trp Thr Asp Gln Asp Ser Lys Asp Ser Thr Tyr Ser Met Ser Ser
165 170 175
Thr Leu Thr Leu Thr Lys Asp Glu Tyr Glu Arg His Asn Ser Tyr Thr
180 185 190
Cys Glu Ala Thr His Lys Thr Ser Thr Ser Pro Ile Val Lys Ser Phe
195 200 205
Asn Arg Asn Glu Cys
210
<210> 12
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 12
Ser Phe Pro Met Ala
1 5
<210> 13
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 13
Thr Ile Ser Thr Ser Gly Gly Arg Thr Tyr Tyr Arg Asp Ser Val Lys
1 5 10 15
Gly
<210> 14
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 14
Phe Arg Gln Tyr Ser Gly Gly Phe Asp Tyr
1 5 10
<210> 15
<211> 119
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 15
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe
20 25 30
Pro Met Ala Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Thr Ile Ser Thr Ser Gly Gly Arg Thr Tyr Tyr Arg Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Phe Arg Gln Tyr Ser Gly Gly Phe Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 16
<211> 13
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 16
Thr Leu Ser Ser Gly Asn Ile Glu Asn Asn Tyr Val His
1 5 10
<210> 17
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 17
Asp Asp Asp Lys Arg Pro Asp
1 5
<210> 18
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 18
Asp Asp Asp Lys Arg Pro Glu
1 5
<210> 19
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 19
His Ser Tyr Val Ser Ser Phe Asn Val
1 5
<210> 20
<211> 112
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 20
Asp Ile Gln Leu Thr Gln Pro Asn Ser Val Ser Thr Ser Leu Gly Ser
1 5 10 15
Thr Val Lys Leu Ser Cys Thr Leu Ser Ser Gly Asn Ile Glu Asn Asn
20 25 30
Tyr Val His Trp Tyr Gln Leu Tyr Glu Gly Arg Ser Pro Thr Thr Met
35 40 45
Ile Tyr Asp Asp Asp Lys Arg Pro Asp Gly Val Pro Asp Arg Phe Ser
50 55 60
Gly Ser Ile Asp Arg Ser Ser Asn Ser Ala Phe Leu Thr Ile His Asn
65 70 75 80
Val Ala Ile Glu Asp Glu Ala Ile Tyr Phe Cys His Ser Tyr Val Ser
85 90 95
Ser Phe Asn Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Arg Gln
100 105 110
<210> 21
<211> 112
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 21
Asp Ile Gln Leu Thr Gln Pro Asn Ser Val Ser Thr Ser Leu Gly Ser
1 5 10 15
Thr Val Lys Leu Ser Cys Thr Leu Ser Ser Gly Asn Ile Glu Asn Asn
20 25 30
Tyr Val His Trp Tyr Gln Leu Tyr Glu Gly Arg Ser Pro Thr Thr Met
35 40 45
Ile Tyr Asp Asp Asp Lys Arg Pro Asp Ala Val Pro Asp Arg Phe Ser
50 55 60
Gly Ser Ile Asp Arg Ser Ser Asn Ser Ala Phe Leu Thr Ile His Asn
65 70 75 80
Val Ala Ile Glu Asp Glu Ala Ile Tyr Phe Cys His Ser Tyr Val Ser
85 90 95
Ser Phe Asn Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Arg Gln
100 105 110
<210> 22
<211> 253
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 22
Gly Gly Gly Ser Gly Gly Gly Glu Val Gln Leu Leu Glu Ser Gly Gly
1 5 10 15
Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser
20 25 30
Gly Phe Thr Phe Ser Ser Phe Pro Met Ala Trp Val Arg Gln Ala Pro
35 40 45
Gly Lys Gly Leu Glu Trp Val Ser Thr Ile Ser Thr Ser Gly Gly Arg
50 55 60
Thr Tyr Tyr Arg Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp
65 70 75 80
Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu
85 90 95
Asp Thr Ala Val Tyr Tyr Cys Ala Lys Phe Arg Gln Tyr Ser Gly Gly
100 105 110
Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly
115 120 125
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln
130 135 140
Leu Thr Gln Pro Asn Ser Val Ser Thr Ser Leu Gly Ser Thr Val Lys
145 150 155 160
Leu Ser Cys Thr Leu Ser Ser Gly Asn Ile Glu Asn Asn Tyr Val His
165 170 175
Trp Tyr Gln Leu Tyr Glu Gly Arg Ser Pro Thr Thr Met Ile Tyr Asp
180 185 190
Asp Asp Lys Arg Pro Asp Gly Val Pro Asp Arg Phe Ser Gly Ser Ile
195 200 205
Asp Arg Ser Ser Asn Ser Ala Phe Leu Thr Ile His Asn Val Ala Ile
210 215 220
Glu Asp Glu Ala Ile Tyr Phe Cys His Ser Tyr Val Ser Ser Phe Asn
225 230 235 240
Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Arg Gln
245 250
<210> 23
<211> 222
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 23
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe
20 25 30
Pro Met Ala Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Thr Ile Ser Thr Ser Gly Gly Arg Thr Tyr Tyr Arg Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Phe Arg Gln Tyr Ser Gly Gly Phe Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys
210 215 220
<210> 24
<211> 216
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 24
Asp Ile Gln Leu Thr Gln Pro Asn Ser Val Ser Thr Ser Leu Gly Ser
1 5 10 15
Thr Val Lys Leu Ser Cys Thr Leu Ser Ser Gly Asn Ile Glu Asn Asn
20 25 30
Tyr Val His Trp Tyr Gln Leu Tyr Glu Gly Arg Ser Pro Thr Thr Met
35 40 45
Ile Tyr Asp Asp Asp Lys Arg Pro Asp Gly Val Pro Asp Arg Phe Ser
50 55 60
Gly Ser Ile Asp Arg Ser Ser Asn Ser Ala Phe Leu Thr Ile His Asn
65 70 75 80
Val Ala Ile Glu Asp Glu Ala Ile Tyr Phe Cys His Ser Tyr Val Ser
85 90 95
Ser Phe Asn Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Arg Gln
100 105 110
Pro Lys Ala Ala Pro Ser Val Thr Leu Phe Pro Pro Ser Ser Glu Glu
115 120 125
Leu Gln Ala Asn Lys Ala Thr Leu Val Cys Leu Ile Ser Asp Phe Tyr
130 135 140
Pro Gly Ala Val Thr Val Ala Trp Lys Ala Asp Ser Ser Pro Val Lys
145 150 155 160
Ala Gly Val Glu Thr Thr Thr Pro Ser Lys Gln Ser Asn Asn Lys Tyr
165 170 175
Ala Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys Ser His
180 185 190
Arg Ser Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr Val Glu Lys
195 200 205
Thr Val Ala Pro Thr Glu Cys Ser
210 215
<210> 25
<211> 216
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 25
Asp Ile Gln Leu Thr Gln Pro Asn Ser Val Ser Thr Ser Leu Gly Ser
1 5 10 15
Thr Val Lys Leu Ser Cys Thr Leu Ser Ser Gly Asn Ile Glu Asn Asn
20 25 30
Tyr Val His Trp Tyr Gln Leu Tyr Glu Gly Arg Ser Pro Thr Thr Met
35 40 45
Ile Tyr Asp Asp Asp Lys Arg Pro Glu Gly Val Pro Asp Arg Phe Ser
50 55 60
Gly Ser Ile Asp Arg Ser Ser Asn Ser Ala Phe Leu Thr Ile His Asn
65 70 75 80
Val Ala Ile Glu Asp Glu Ala Ile Tyr Phe Cys His Ser Tyr Val Ser
85 90 95
Ser Phe Asn Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Arg Gln
100 105 110
Pro Lys Ala Ala Pro Ser Val Thr Leu Phe Pro Pro Ser Ser Glu Glu
115 120 125
Leu Gln Ala Asn Lys Ala Thr Leu Val Cys Leu Ile Ser Asp Phe Tyr
130 135 140
Pro Gly Ala Val Thr Val Ala Trp Lys Ala Asp Ser Ser Pro Val Lys
145 150 155 160
Ala Gly Val Glu Thr Thr Thr Pro Ser Lys Gln Ser Asn Asn Lys Tyr
165 170 175
Ala Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys Ser His
180 185 190
Arg Ser Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr Val Glu Lys
195 200 205
Thr Val Ala Pro Thr Glu Cys Ser
210 215
<210> 26
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 26
Arg Tyr Thr Met His
1 5
<210> 27
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 27
Tyr Ile Asn Pro Ser Arg Gly Tyr Thr Asn Tyr Asn Gln Lys Val Lys
1 5 10 15
Asp
<210> 28
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 28
Tyr Tyr Asp Asp His Tyr Cys Leu Asp Tyr
1 5 10
<210> 29
<211> 119
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 29
Gln Val Gln Leu Val Gln Ser Gly Gly Gly Val Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Arg Tyr
20 25 30
Thr Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Asn Pro Ser Arg Gly Tyr Thr Asn Tyr Asn Gln Lys Val
50 55 60
Lys Asp Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Ala Phe
65 70 75 80
Leu Gln Met Asp Ser Leu Arg Pro Glu Asp Thr Gly Val Tyr Phe Cys
85 90 95
Ala Arg Tyr Tyr Asp Asp His Tyr Cys Leu Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Pro Val Thr Val Ser Ser
115
<210> 30
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 30
Ser Ala Ser Ser Ser Val Ser Tyr Met Asn
1 5 10
<210> 31
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 31
Asp Thr Ser Lys Leu Ala Ser
1 5
<210> 32
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 32
Gln Gln Trp Ser Ser Asn Pro Phe Thr
1 5
<210> 33
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 33
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Ser Ala Ser Ser Ser Val Ser Tyr Met
20 25 30
Asn Trp Tyr Gln Gln Thr Pro Gly Lys Ala Pro Lys Arg Trp Ile Tyr
35 40 45
Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Asp Tyr Thr Phe Thr Ile Ser Ser Leu Gln Pro Glu
65 70 75 80
Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser Asn Pro Phe Thr
85 90 95
Phe Gly Gln Gly Thr Lys Leu Gln Ile Thr Arg
100 105
<210> 34
<211> 248
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 34
Gly Gly Gly Ser Gly Gly Gly Gln Val Gln Leu Val Gln Ser Gly Gly
1 5 10 15
Gly Val Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Lys Ala Ser
20 25 30
Gly Tyr Thr Phe Thr Arg Tyr Thr Met His Trp Val Arg Gln Ala Pro
35 40 45
Gly Lys Gly Leu Glu Trp Ile Gly Tyr Ile Asn Pro Ser Arg Gly Tyr
50 55 60
Thr Asn Tyr Asn Gln Lys Val Lys Asp Arg Phe Thr Ile Ser Arg Asp
65 70 75 80
Asn Ser Lys Asn Thr Ala Phe Leu Gln Met Asp Ser Leu Arg Pro Glu
85 90 95
Asp Thr Gly Val Tyr Phe Cys Ala Arg Tyr Tyr Asp Asp His Tyr Cys
100 105 110
Leu Asp Tyr Trp Gly Gln Gly Thr Pro Val Thr Val Ser Ser Gly Gly
115 120 125
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln
130 135 140
Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val
145 150 155 160
Thr Ile Thr Cys Ser Ala Ser Ser Ser Val Ser Tyr Met Asn Trp Tyr
165 170 175
Gln Gln Thr Pro Gly Lys Ala Pro Lys Arg Trp Ile Tyr Asp Thr Ser
180 185 190
Lys Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly
195 200 205
Thr Asp Tyr Thr Phe Thr Ile Ser Ser Leu Gln Pro Glu Asp Ile Ala
210 215 220
Thr Tyr Tyr Cys Gln Gln Trp Ser Ser Asn Pro Phe Thr Phe Gly Gln
225 230 235 240
Gly Thr Lys Leu Gln Ile Thr Arg
245
<210> 35
<211> 222
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 35
Gln Val Gln Leu Val Gln Ser Gly Gly Gly Val Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Arg Tyr
20 25 30
Thr Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Asn Pro Ser Arg Gly Tyr Thr Asn Tyr Asn Gln Lys Val
50 55 60
Lys Asp Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Ala Phe
65 70 75 80
Leu Gln Met Asp Ser Leu Arg Pro Glu Asp Thr Gly Val Tyr Phe Cys
85 90 95
Ala Arg Tyr Tyr Asp Asp His Tyr Cys Leu Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Pro Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys
210 215 220
<210> 36
<211> 213
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 36
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Ser Ala Ser Ser Ser Val Ser Tyr Met
20 25 30
Asn Trp Tyr Gln Gln Thr Pro Gly Lys Ala Pro Lys Arg Trp Ile Tyr
35 40 45
Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Asp Tyr Thr Phe Thr Ile Ser Ser Leu Gln Pro Glu
65 70 75 80
Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser Asn Pro Phe Thr
85 90 95
Phe Gly Gln Gly Thr Lys Leu Gln Ile Thr Arg Thr Val Ala Ala Pro
100 105 110
Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr
115 120 125
Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys
130 135 140
Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu
145 150 155 160
Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser
165 170 175
Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala
180 185 190
Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe
195 200 205
Asn Arg Gly Glu Cys
210
<210> 37
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 37
Ser Tyr Thr Met His
1 5
<210> 38
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 38
Tyr Ile Asn Pro Arg Ser Gly Tyr Thr His Tyr Asn Gln Lys Leu Lys
1 5 10 15
Asp
<210> 39
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 39
Ser Ala Tyr Tyr Asp Tyr Asp Gly Phe Ala Tyr
1 5 10
<210> 40
<211> 120
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 40
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Ile Ser Tyr
20 25 30
Thr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Tyr Ile Asn Pro Arg Ser Gly Tyr Thr His Tyr Asn Gln Lys Leu
50 55 60
Lys Asp Lys Ala Thr Leu Thr Ala Asp Lys Ser Ala Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Ala Tyr Tyr Asp Tyr Asp Gly Phe Ala Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 41
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 41
Ser Ala Ser Ser Ser Val Ser Tyr Met Asn
1 5 10
<210> 42
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 42
Asp Thr Ser Lys Leu Ala Ser
1 5
<210> 43
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 43
Gln Gln Trp Ser Ser Asn Pro Pro Thr
1 5
<210> 44
<211> 106
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 44
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Ser Ala Ser Ser Ser Val Ser Tyr Met
20 25 30
Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Leu Ile Tyr
35 40 45
Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu
65 70 75 80
Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser Asn Pro Pro Thr
85 90 95
Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 45
<211> 248
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 45
Gly Gly Gly Ser Gly Gly Gly Gln Val Gln Leu Val Gln Ser Gly Ala
1 5 10 15
Glu Val Lys Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser
20 25 30
Gly Tyr Thr Phe Ile Ser Tyr Thr Met His Trp Val Arg Gln Ala Pro
35 40 45
Gly Gln Gly Leu Glu Trp Met Gly Tyr Ile Asn Pro Arg Ser Gly Tyr
50 55 60
Thr His Tyr Asn Gln Lys Leu Lys Asp Lys Ala Thr Leu Thr Ala Asp
65 70 75 80
Lys Ser Ala Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu
85 90 95
Asp Thr Ala Val Tyr Tyr Cys Ala Arg Ser Ala Tyr Tyr Asp Tyr Asp
100 105 110
Gly Phe Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly
115 120 125
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile
130 135 140
Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg
145 150 155 160
Val Thr Ile Thr Cys Ser Ala Ser Ser Ser Val Ser Tyr Met Asn Trp
165 170 175
Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Leu Ile Tyr Asp Thr
180 185 190
Ser Lys Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser
195 200 205
Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe
210 215 220
Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser Asn Pro Pro Thr Phe Gly
225 230 235 240
Gly Gly Thr Lys Val Glu Ile Lys
245
<210> 46
<211> 220
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 46
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Ile Ser Tyr
20 25 30
Thr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Tyr Ile Asn Pro Arg Ser Gly Tyr Thr His Tyr Asn Gln Lys Leu
50 55 60
Lys Asp Lys Ala Thr Leu Thr Ala Asp Lys Ser Ala Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Ala Tyr Tyr Asp Tyr Asp Gly Phe Ala Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val
115 120 125
Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala
130 135 140
Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
145 150 155 160
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
165 170 175
Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Ala Ile Val Thr
180 185 190
Val Pro Ser Ser Asn Phe Gly Thr Gln Thr Tyr Thr Cys Asn Val Asp
195 200 205
His Lys Pro Ser Asn Thr Lys Val Asp Lys Thr Val
210 215 220
<210> 47
<211> 213
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 47
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Ser Ala Ser Ser Ser Val Ser Tyr Met
20 25 30
Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Leu Ile Tyr
35 40 45
Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu
65 70 75 80
Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser Asn Pro Pro Thr
85 90 95
Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala Pro
100 105 110
Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr
115 120 125
Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys
130 135 140
Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu
145 150 155 160
Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser
165 170 175
Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Leu Tyr Ala
180 185 190
Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe
195 200 205
Asn Arg Gly Glu Cys
210
<210> 48
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 48
Ser Tyr Asn Met His
1 5
<210> 49
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 49
Ala Ile Tyr Pro Gly Asn Gly Asp Thr Ser Tyr Asn Gln Lys Phe Lys
1 5 10 15
Gly
<210> 50
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 50
Ser Thr Tyr Tyr Gly Gly Asp Trp Tyr Phe Asn Val
1 5 10
<210> 51
<211> 121
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 51
Gln Val Gln Leu Gln Gln Pro Gly Ala Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Asn Met His Trp Val Lys Gln Thr Pro Gly Arg Gly Leu Glu Trp Ile
35 40 45
Gly Ala Ile Tyr Pro Gly Asn Gly Asp Thr Ser Tyr Asn Gln Lys Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Thr Tyr Tyr Gly Gly Asp Trp Tyr Phe Asn Val Trp Gly
100 105 110
Ala Gly Thr Thr Val Thr Val Ser Ala
115 120
<210> 52
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 52
Arg Ala Ser Ser Ser Val Ser Tyr Ile His
1 5 10
<210> 53
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 53
Ala Thr Ser Asn Leu Ala Ser
1 5
<210> 54
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 54
Gln Gln Trp Thr Ser Asn Pro Pro Thr
1 5
<210> 55
<211> 106
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 55
Gln Ile Val Leu Ser Gln Ser Pro Ala Ile Leu Ser Ala Ser Pro Gly
1 5 10 15
Glu Lys Val Thr Met Thr Cys Arg Ala Ser Ser Ser Val Ser Tyr Ile
20 25 30
His Trp Phe Gln Gln Lys Pro Gly Ser Ser Pro Lys Pro Trp Ile Tyr
35 40 45
Ala Thr Ser Asn Leu Ala Ser Gly Val Pro Val Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Arg Val Glu Ala Glu
65 70 75 80
Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Thr Ser Asn Pro Pro Thr
85 90 95
Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 56
<211> 249
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 56
Gly Gly Gly Ser Gly Gly Gly Gln Val Gln Leu Gln Gln Pro Gly Ala
1 5 10 15
Glu Leu Val Lys Pro Gly Ala Ser Val Lys Met Ser Cys Lys Ala Ser
20 25 30
Gly Tyr Thr Phe Thr Ser Tyr Asn Met His Trp Val Lys Gln Thr Pro
35 40 45
Gly Arg Gly Leu Glu Trp Ile Gly Ala Ile Tyr Pro Gly Asn Gly Asp
50 55 60
Thr Ser Tyr Asn Gln Lys Phe Lys Gly Lys Ala Thr Leu Thr Ala Asp
65 70 75 80
Lys Ser Ser Ser Thr Ala Tyr Met Gln Leu Ser Ser Leu Thr Ser Glu
85 90 95
Asp Ser Ala Val Tyr Tyr Cys Ala Arg Ser Thr Tyr Tyr Gly Gly Asp
100 105 110
Trp Tyr Phe Asn Val Trp Gly Ala Gly Thr Thr Val Thr Val Ser Ala
115 120 125
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln
130 135 140
Ile Val Leu Ser Gln Ser Pro Ala Ile Leu Ser Ala Ser Pro Gly Glu
145 150 155 160
Lys Val Thr Met Thr Cys Arg Ala Ser Ser Ser Val Ser Tyr Ile His
165 170 175
Trp Phe Gln Gln Lys Pro Gly Ser Ser Pro Lys Pro Trp Ile Tyr Ala
180 185 190
Thr Ser Asn Leu Ala Ser Gly Val Pro Val Arg Phe Ser Gly Ser Gly
195 200 205
Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Arg Val Glu Ala Glu Asp
210 215 220
Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Thr Ser Asn Pro Pro Thr Phe
225 230 235 240
Gly Gly Gly Thr Lys Leu Glu Ile Lys
245
<210> 57
<211> 224
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 57
Gln Val Gln Leu Gln Gln Pro Gly Ala Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Asn Met His Trp Val Lys Gln Thr Pro Gly Arg Gly Leu Glu Trp Ile
35 40 45
Gly Ala Ile Tyr Pro Gly Asn Gly Asp Thr Ser Tyr Asn Gln Lys Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Thr Tyr Tyr Gly Gly Asp Trp Tyr Phe Asn Val Trp Gly
100 105 110
Ala Gly Thr Thr Val Thr Val Ser Ala Ala Ser Thr Lys Gly Pro Ser
115 120 125
Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
130 135 140
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
145 150 155 160
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
165 170 175
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
180 185 190
Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
195 200 205
Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Ala Glu Pro Lys Ser Cys
210 215 220
<210> 58
<211> 213
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 58
Gln Ile Val Leu Ser Gln Ser Pro Ala Ile Leu Ser Ala Ser Pro Gly
1 5 10 15
Glu Lys Val Thr Met Thr Cys Arg Ala Ser Ser Ser Val Ser Tyr Ile
20 25 30
His Trp Phe Gln Gln Lys Pro Gly Ser Ser Pro Lys Pro Trp Ile Tyr
35 40 45
Ala Thr Ser Asn Leu Ala Ser Gly Val Pro Val Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Arg Val Glu Ala Glu
65 70 75 80
Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Thr Ser Asn Pro Pro Thr
85 90 95
Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala Pro
100 105 110
Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr
115 120 125
Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys
130 135 140
Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu
145 150 155 160
Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser
165 170 175
Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala
180 185 190
Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe
195 200 205
Asn Arg Gly Glu Cys
210
<210> 59
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 59
Asp Tyr Gly Val Ser
1 5
<210> 60
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 60
Val Ile Trp Gly Ser Glu Thr Thr Tyr Tyr Asn Ser Ala Leu Lys Ser
1 5 10 15
<210> 61
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 61
His Tyr Tyr Tyr Gly Gly Ser Tyr Ala Met Asp Tyr
1 5 10
<210> 62
<211> 120
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 62
Glu Val Lys Leu Gln Glu Ser Gly Pro Gly Leu Val Ala Pro Ser Gln
1 5 10 15
Ser Leu Ser Val Thr Cys Thr Val Ser Gly Val Ser Leu Pro Asp Tyr
20 25 30
Gly Val Ser Trp Ile Arg Gln Pro Pro Arg Lys Gly Leu Glu Trp Leu
35 40 45
Gly Val Ile Trp Gly Ser Glu Thr Thr Tyr Tyr Asn Ser Ala Leu Lys
50 55 60
Ser Arg Leu Thr Ile Ile Lys Asp Asn Ser Lys Ser Gln Val Phe Leu
65 70 75 80
Lys Met Asn Ser Leu Gln Thr Asp Asp Thr Ala Ile Tyr Tyr Cys Ala
85 90 95
Lys His Tyr Tyr Tyr Gly Gly Ser Tyr Ala Met Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Ser Val Thr Val Ser Ser
115 120
<210> 63
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 63
Arg Ala Ser Gln Asp Ile Ser Lys Tyr Leu Asn
1 5 10
<210> 64
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 64
His Thr Ser Arg Leu His Ser
1 5
<210> 65
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 65
Gln Gln Gly Asn Thr Leu Pro Tyr Thr
1 5
<210> 66
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 66
Asp Ile Gln Met Thr Gln Thr Thr Ser Ser Leu Ser Ala Ser Leu Gly
1 5 10 15
Asp Arg Val Thr Ile Ser Cys Arg Ala Ser Gln Asp Ile Ser Lys Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Asp Gly Thr Val Lys Leu Leu Ile
35 40 45
Tyr His Thr Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile Ser Asn Leu Glu Gln
65 70 75 80
Glu Asp Ile Ala Thr Tyr Phe Cys Gln Gln Gly Asn Thr Leu Pro Tyr
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Thr
100 105
<210> 67
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 67
Asp Ile Gln Met Thr Gln Thr Thr Ser Ser Leu Ser Ala Ser Leu Gly
1 5 10 15
Asp Arg Val Thr Ile Ser Cys Arg Ala Ser Gln Asp Ile Ser Lys Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Asp Ala Thr Val Lys Leu Leu Ile
35 40 45
Tyr His Thr Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile Ser Asn Leu Glu Gln
65 70 75 80
Glu Asp Ile Ala Thr Tyr Phe Cys Gln Gln Gly Asn Thr Leu Pro Tyr
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Thr
100 105
<210> 68
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 68
Asp Ile Gln Met Thr Gln Thr Thr Ser Ser Leu Ser Ala Ser Leu Gly
1 5 10 15
Asp Arg Val Thr Ile Ser Cys Arg Ala Ser Gln Asp Ile Ser Lys Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Glu Gly Thr Val Lys Leu Leu Ile
35 40 45
Tyr His Thr Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile Ser Asn Leu Glu Gln
65 70 75 80
Glu Asp Ile Ala Thr Tyr Phe Cys Gln Gln Gly Asn Thr Leu Pro Tyr
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Thr
100 105
<210> 69
<211> 249
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 69
Gly Gly Gly Ser Gly Gly Gly Glu Val Lys Leu Gln Glu Ser Gly Pro
1 5 10 15
Gly Leu Val Ala Pro Ser Gln Ser Leu Ser Val Thr Cys Thr Val Ser
20 25 30
Gly Val Ser Leu Pro Asp Tyr Gly Val Ser Trp Ile Arg Gln Pro Pro
35 40 45
Arg Lys Gly Leu Glu Trp Leu Gly Val Ile Trp Gly Ser Glu Thr Thr
50 55 60
Tyr Tyr Asn Ser Ala Leu Lys Ser Arg Leu Thr Ile Ile Lys Asp Asn
65 70 75 80
Ser Lys Ser Gln Val Phe Leu Lys Met Asn Ser Leu Gln Thr Asp Asp
85 90 95
Thr Ala Ile Tyr Tyr Cys Ala Lys His Tyr Tyr Tyr Gly Gly Ser Tyr
100 105 110
Ala Met Asp Tyr Trp Gly Gln Gly Thr Ser Val Thr Val Ser Ser Gly
115 120 125
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile
130 135 140
Gln Met Thr Gln Thr Thr Ser Ser Leu Ser Ala Ser Leu Gly Asp Arg
145 150 155 160
Val Thr Ile Ser Cys Arg Ala Ser Gln Asp Ile Ser Lys Tyr Leu Asn
165 170 175
Trp Tyr Gln Gln Lys Pro Asp Gly Thr Val Lys Leu Leu Ile Tyr His
180 185 190
Thr Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly
195 200 205
Ser Gly Thr Asp Tyr Ser Leu Thr Ile Ser Asn Leu Glu Gln Glu Asp
210 215 220
Ile Ala Thr Tyr Phe Cys Gln Gln Gly Asn Thr Leu Pro Tyr Thr Phe
225 230 235 240
Gly Gly Gly Thr Lys Leu Glu Ile Thr
245
<210> 70
<211> 249
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 70
Gly Gly Gly Ser Gly Gly Gly Glu Val Lys Leu Gln Glu Ser Gly Pro
1 5 10 15
Gly Leu Val Ala Pro Ser Gln Ser Leu Ser Val Thr Cys Thr Val Ser
20 25 30
Gly Val Ser Leu Pro Asp Tyr Gly Val Ser Trp Ile Arg Gln Pro Pro
35 40 45
Arg Lys Gly Leu Glu Trp Leu Gly Val Ile Trp Gly Ser Glu Thr Thr
50 55 60
Tyr Tyr Asn Ser Ala Leu Lys Ser Arg Leu Thr Ile Ile Lys Asp Asn
65 70 75 80
Ser Lys Ser Gln Val Phe Leu Lys Met Asn Ser Leu Gln Thr Asp Asp
85 90 95
Thr Ala Ile Tyr Tyr Cys Ala Lys His Tyr Tyr Tyr Gly Gly Ser Tyr
100 105 110
Ala Met Asp Tyr Trp Gly Gln Gly Thr Ser Val Thr Val Ser Ser Gly
115 120 125
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile
130 135 140
Gln Met Thr Gln Thr Thr Ser Ser Leu Ser Ala Ser Leu Gly Asp Arg
145 150 155 160
Val Thr Ile Ser Cys Arg Ala Ser Gln Asp Ile Ser Lys Tyr Leu Asn
165 170 175
Trp Tyr Gln Gln Lys Pro Asp Ala Thr Val Lys Leu Leu Ile Tyr His
180 185 190
Thr Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly
195 200 205
Ser Gly Thr Asp Tyr Ser Leu Thr Ile Ser Asn Leu Glu Gln Glu Asp
210 215 220
Ile Ala Thr Tyr Phe Cys Gln Gln Gly Asn Thr Leu Pro Tyr Thr Phe
225 230 235 240
Gly Gly Gly Thr Lys Leu Glu Ile Thr
245
<210> 71
<211> 249
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 71
Gly Gly Gly Ser Gly Gly Gly Glu Val Lys Leu Gln Glu Ser Gly Pro
1 5 10 15
Gly Leu Val Ala Pro Ser Gln Ser Leu Ser Val Thr Cys Thr Val Ser
20 25 30
Gly Val Ser Leu Pro Asp Tyr Gly Val Ser Trp Ile Arg Gln Pro Pro
35 40 45
Arg Lys Gly Leu Glu Trp Leu Gly Val Ile Trp Gly Ser Glu Thr Thr
50 55 60
Tyr Tyr Asn Ser Ala Leu Lys Ser Arg Leu Thr Ile Ile Lys Asp Asn
65 70 75 80
Ser Lys Ser Gln Val Phe Leu Lys Met Asn Ser Leu Gln Thr Asp Asp
85 90 95
Thr Ala Ile Tyr Tyr Cys Ala Lys His Tyr Tyr Tyr Gly Gly Ser Tyr
100 105 110
Ala Met Asp Tyr Trp Gly Gln Gly Thr Ser Val Thr Val Ser Ser Gly
115 120 125
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile
130 135 140
Gln Met Thr Gln Thr Thr Ser Ser Leu Ser Ala Ser Leu Gly Asp Arg
145 150 155 160
Val Thr Ile Ser Cys Arg Ala Ser Gln Asp Ile Ser Lys Tyr Leu Asn
165 170 175
Trp Tyr Gln Gln Lys Pro Glu Gly Thr Val Lys Leu Leu Ile Tyr His
180 185 190
Thr Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly
195 200 205
Ser Gly Thr Asp Tyr Ser Leu Thr Ile Ser Asn Leu Glu Gln Glu Asp
210 215 220
Ile Ala Thr Tyr Phe Cys Gln Gln Gly Asn Thr Leu Pro Tyr Thr Phe
225 230 235 240
Gly Gly Gly Thr Lys Leu Glu Ile Thr
245
<210> 72
<211> 225
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 72
Glu Val Lys Leu Gln Glu Ser Gly Pro Gly Leu Val Ala Pro Ser Gln
1 5 10 15
Ser Leu Ser Val Thr Cys Thr Val Ser Gly Val Ser Leu Pro Asp Tyr
20 25 30
Gly Val Ser Trp Ile Arg Gln Pro Pro Arg Lys Gly Leu Glu Trp Leu
35 40 45
Gly Val Ile Trp Gly Ser Glu Thr Thr Tyr Tyr Asn Ser Ala Leu Lys
50 55 60
Ser Arg Leu Thr Ile Ile Lys Asp Asn Ser Lys Ser Gln Val Phe Leu
65 70 75 80
Lys Met Asn Ser Leu Gln Thr Asp Asp Thr Ala Ile Tyr Tyr Cys Ala
85 90 95
Lys His Tyr Tyr Tyr Gly Gly Ser Tyr Ala Met Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Ser Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val
115 120 125
Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala
130 135 140
Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
145 150 155 160
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
165 170 175
Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
180 185 190
Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys
195 200 205
Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp
210 215 220
Lys
225
<210> 73
<211> 214
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 73
Asp Ile Gln Met Thr Gln Thr Thr Ser Ser Leu Ser Ala Ser Leu Gly
1 5 10 15
Asp Arg Val Thr Ile Ser Cys Arg Ala Ser Gln Asp Ile Ser Lys Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Asp Gly Thr Val Lys Leu Leu Ile
35 40 45
Tyr His Thr Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile Ser Asn Leu Glu Gln
65 70 75 80
Glu Asp Ile Ala Thr Tyr Phe Cys Gln Gln Gly Asn Thr Leu Pro Tyr
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Thr 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 Leu 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> 74
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 74
Asn Tyr Gly Val His
1 5
<210> 75
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 75
Val Ile Trp Ser Gly Gly Asn Thr Asp Tyr Asn Thr Pro Phe Thr Ser
1 5 10 15
<210> 76
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 76
Ala Leu Thr Tyr Tyr Asp Tyr Glu Phe Ala Tyr
1 5 10
<210> 77
<211> 119
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 77
Gln Val Gln Leu Lys Gln Ser Gly Pro Gly Leu Val Gln Pro Ser Gln
1 5 10 15
Ser Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Asn Tyr
20 25 30
Gly Val His Trp Val Arg Gln Ser Pro Gly Lys Gly Leu Glu Trp Leu
35 40 45
Gly Val Ile Trp Ser Gly Gly Asn Thr Asp Tyr Asn Thr Pro Phe Thr
50 55 60
Ser Arg Leu Ser Ile Asn Lys Asp Asn Ser Lys Ser Gln Val Phe Phe
65 70 75 80
Lys Met Asn Ser Leu Gln Ser Asn Asp Thr Ala Ile Tyr Tyr Cys Ala
85 90 95
Arg Ala Leu Thr Tyr Tyr Asp Tyr Glu Phe Ala Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ala
115
<210> 78
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 78
Arg Ala Ser Gln Ser Ile Gly Thr Asn Ile His
1 5 10
<210> 79
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 79
Tyr Ala Ser Glu Ser Ile Ser
1 5
<210> 80
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 80
Gln Gln Asn Asn Asn Trp Pro Thr Thr
1 5
<210> 81
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 81
Asp Ile Leu Leu Thr Gln Ser Pro Val Ile Leu Ser Val Ser Pro Gly
1 5 10 15
Glu Arg Val Ser Phe Ser Cys Arg Ala Ser Gln Ser Ile Gly Thr Asn
20 25 30
Ile His Trp Tyr Gln Gln Arg Thr Asn Gly Ser Pro Arg Leu Leu Ile
35 40 45
Lys Tyr Ala Ser Glu Ser Ile Ser Gly Ile Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Ser Ile Asn Ser Val Glu Ser
65 70 75 80
Glu Asp Ile Ala Asp Tyr Tyr Cys Gln Gln Asn Asn Asn Trp Pro Thr
85 90 95
Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys
100 105
<210> 82
<211> 248
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 82
Gly Gly Gly Ser Gly Gly Gly Gln Val Gln Leu Lys Gln Ser Gly Pro
1 5 10 15
Gly Leu Val Gln Pro Ser Gln Ser Leu Ser Ile Thr Cys Thr Val Ser
20 25 30
Gly Phe Ser Leu Thr Asn Tyr Gly Val His Trp Val Arg Gln Ser Pro
35 40 45
Gly Lys Gly Leu Glu Trp Leu Gly Val Ile Trp Ser Gly Gly Asn Thr
50 55 60
Asp Tyr Asn Thr Pro Phe Thr Ser Arg Leu Ser Ile Asn Lys Asp Asn
65 70 75 80
Ser Lys Ser Gln Val Phe Phe Lys Met Asn Ser Leu Gln Ser Asn Asp
85 90 95
Thr Ala Ile Tyr Tyr Cys Ala Arg Ala Leu Thr Tyr Tyr Asp Tyr Glu
100 105 110
Phe Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ala Gly Gly
115 120 125
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Leu
130 135 140
Leu Thr Gln Ser Pro Val Ile Leu Ser Val Ser Pro Gly Glu Arg Val
145 150 155 160
Ser Phe Ser Cys Arg Ala Ser Gln Ser Ile Gly Thr Asn Ile His Trp
165 170 175
Tyr Gln Gln Arg Thr Asn Gly Ser Pro Arg Leu Leu Ile Lys Tyr Ala
180 185 190
Ser Glu Ser Ile Ser Gly Ile Pro Ser Arg Phe Ser Gly Ser Gly Ser
195 200 205
Gly Thr Asp Phe Thr Leu Ser Ile Asn Ser Val Glu Ser Glu Asp Ile
210 215 220
Ala Asp Tyr Tyr Cys Gln Gln Asn Asn Asn Trp Pro Thr Thr Phe Gly
225 230 235 240
Ala Gly Thr Lys Leu Glu Leu Lys
245
<210> 83
<211> 224
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 83
Gln Val Gln Leu Lys Gln Ser Gly Pro Gly Leu Val Gln Pro Ser Gln
1 5 10 15
Ser Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Asn Tyr
20 25 30
Gly Val His Trp Val Arg Gln Ser Pro Gly Lys Gly Leu Glu Trp Leu
35 40 45
Gly Val Ile Trp Ser Gly Gly Asn Thr Asp Tyr Asn Thr Pro Phe Thr
50 55 60
Ser Arg Leu Ser Ile Asn Lys Asp Asn Ser Lys Ser Gln Val Phe Phe
65 70 75 80
Lys Met Asn Ser Leu Gln Ser Asn Asp Thr Ala Ile Tyr Tyr Cys Ala
85 90 95
Arg Ala Leu Thr Tyr Tyr Asp Tyr Glu Phe Ala Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ala Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys
210 215 220
<210> 84
<211> 214
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 84
Asp Ile Leu Leu Thr Gln Ser Pro Val Ile Leu Ser Val Ser Pro Gly
1 5 10 15
Glu Arg Val Ser Phe Ser Cys Arg Ala Ser Gln Ser Ile Gly Thr Asn
20 25 30
Ile His Trp Tyr Gln Gln Arg Thr Asn Gly Ser Pro Arg Leu Leu Ile
35 40 45
Lys Tyr Ala Ser Glu Ser Ile Ser Gly Ile Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Ser Ile Asn Ser Val Glu Ser
65 70 75 80
Glu Asp Ile Ala Asp Tyr Tyr Cys Gln Gln Asn Asn Asn Trp Pro Thr
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 Leu 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> 85
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 85
Asp Thr Tyr Ile His
1 5
<210> 86
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 86
Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val Lys
1 5 10 15
Gly
<210> 87
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 87
Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr
1 5 10
<210> 88
<211> 120
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 88
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Ile Lys Asp Thr
20 25 30
Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 89
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 89
Arg Ala Ser Gln Asp Val Asn Thr Ala Val Ala
1 5 10
<210> 90
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 90
Ser Ala Ser Phe Leu Tyr Ser
1 5
<210> 91
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 91
Gln Gln His Tyr Thr Thr Pro Pro Thr
1 5
<210> 92
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 92
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Val Asn Thr Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln His Tyr Thr Thr Pro Pro
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 93
<211> 249
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 93
Gly Gly Gly Ser Gly Gly Gly Glu Val Gln Leu Val Glu Ser Gly Gly
1 5 10 15
Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser
20 25 30
Gly Phe Asn Ile Lys Asp Thr Tyr Ile His Trp Val Arg Gln Ala Pro
35 40 45
Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Tyr Pro Thr Asn Gly Tyr
50 55 60
Thr Arg Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Ala Asp
65 70 75 80
Thr Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu
85 90 95
Asp Thr Ala Val Tyr Tyr Cys Ser Arg Trp Gly Gly Asp Gly Phe Tyr
100 105 110
Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly
115 120 125
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile
130 135 140
Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg
145 150 155 160
Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Val Asn Thr Ala Val Ala
165 170 175
Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ser
180 185 190
Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Arg
195 200 205
Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp
210 215 220
Phe Ala Thr Tyr Tyr Cys Gln Gln His Tyr Thr Thr Pro Pro Thr Phe
225 230 235 240
Gly Gln Gly Thr Lys Val Glu Ile Lys
245
<210> 94
<211> 225
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 94
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Ile Lys Asp Thr
20 25 30
Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val
115 120 125
Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala
130 135 140
Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
145 150 155 160
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
165 170 175
Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
180 185 190
Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys
195 200 205
Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp
210 215 220
Lys
225
<210> 95
<211> 214
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 95
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Val Asn Thr Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln His Tyr Thr Thr Pro Pro
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile 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 Leu 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> 96
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 96
Glu Tyr Thr Ile His
1 5
<210> 97
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 97
Asn Ile Asn Pro Asn Asn Gly Gly Thr Thr Tyr Asn Gln Lys Phe Glu
1 5 10 15
Asp
<210> 98
<211> 6
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 98
Gly Trp Asn Phe Asp Tyr
1 5
<210> 99
<211> 115
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 99
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Ile Ser Cys Lys Thr Ser Gly Tyr Thr Phe Thr Glu Tyr
20 25 30
Thr Ile His Trp Val Lys Gln Ala Ser Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Asn Ile Asn Pro Asn Asn Gly Gly Thr Thr Tyr Asn Gln Lys Phe
50 55 60
Glu Asp Arg Ala Thr Leu Thr Val Asp Lys Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Gly Trp Asn Phe Asp Tyr Trp Gly Gln Gly Thr Thr Val Thr
100 105 110
Val Ser Ser
115
<210> 100
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 100
Lys Ala Ser Gln Asp Val Gly Thr Ala Val Asp
1 5 10
<210> 101
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 101
Trp Ala Ser Thr Arg His Thr
1 5
<210> 102
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 102
Gln Gln Tyr Asn Ser Tyr Pro Leu Thr
1 5
<210> 103
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 103
Asp Ile Val Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asp Val Gly Thr Ala
20 25 30
Val Asp Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Trp Ala Ser Thr Arg His Thr Gly Val Pro Asp Arg Phe Thr Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Asp Tyr Phe Cys Gln Gln Tyr Asn Ser Tyr Pro Leu
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 104
<211> 244
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 104
Gly Gly Gly Ser Gly Gly Gly Glu Val Gln Leu Val Gln Ser Gly Ala
1 5 10 15
Glu Val Lys Lys Pro Gly Ala Ser Val Lys Ile Ser Cys Lys Thr Ser
20 25 30
Gly Tyr Thr Phe Thr Glu Tyr Thr Ile His Trp Val Lys Gln Ala Ser
35 40 45
Gly Lys Gly Leu Glu Trp Ile Gly Asn Ile Asn Pro Asn Asn Gly Gly
50 55 60
Thr Thr Tyr Asn Gln Lys Phe Glu Asp Arg Ala Thr Leu Thr Val Asp
65 70 75 80
Lys Ser Thr Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu
85 90 95
Asp Thr Ala Val Tyr Tyr Cys Ala Ala Gly Trp Asn Phe Asp Tyr Trp
100 105 110
Gly Gln Gly Thr Thr Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly
115 120 125
Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Val Met Thr Gln Ser
130 135 140
Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys
145 150 155 160
Lys Ala Ser Gln Asp Val Gly Thr Ala Val Asp Trp Tyr Gln Gln Lys
165 170 175
Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg His
180 185 190
Thr Gly Val Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe
195 200 205
Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Asp Tyr Phe
210 215 220
Cys Gln Gln Tyr Asn Ser Tyr Pro Leu Thr Phe Gly Gly Gly Thr Lys
225 230 235 240
Leu Glu Ile Lys
<210> 105
<211> 220
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 105
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Ile Ser Cys Lys Thr Ser Gly Tyr Thr Phe Thr Glu Tyr
20 25 30
Thr Ile His Trp Val Lys Gln Ala Ser Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Asn Ile Asn Pro Asn Asn Gly Gly Thr Thr Tyr Asn Gln Lys Phe
50 55 60
Glu Asp Arg Ala Thr Leu Thr Val Asp Lys Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Gly Trp Asn Phe Asp Tyr Trp Gly Gln Gly Thr Thr Val Thr
100 105 110
Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro
115 120 125
Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val
130 135 140
Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala
145 150 155 160
Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly
165 170 175
Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly
180 185 190
Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys
195 200 205
Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys
210 215 220
<210> 106
<211> 214
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 106
Asp Ile Val Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asp Val Gly Thr Ala
20 25 30
Val Asp Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Trp Ala Ser Thr Arg His Thr Gly Val Pro Asp Arg Phe Thr Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Asp Tyr Phe Cys Gln Gln Tyr Asn Ser Tyr Pro Leu
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile 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 Leu 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> 107
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 107
Glu Tyr Gly Met Asn
1 5
<210> 108
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 108
Trp Ile Asn Thr Lys Ser Gly Glu Ala Thr Tyr Val Glu Glu Phe Lys
1 5 10 15
Gly
<210> 109
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 109
Trp Asp Phe Tyr Asp Tyr Val Asp Glu Ala Met Tyr
1 5 10
<210> 110
<211> 121
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 110
Gln Val Gln Leu Val Gln Ser Gly Ser Glu Leu Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Glu Tyr
20 25 30
Gly Met Asn Val Trp Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Trp Ile Asn Thr Lys Ser Gly Glu Ala Thr Tyr Val Glu Glu Phe
50 55 60
Lys Gly Arg Phe Val Phe Ser Leu Asp Thr Ser Val Ser Thr Ala Tyr
65 70 75 80
Leu Gln Ile Ser Ser Leu Lys Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Trp Asp Phe Tyr Asp Tyr Val Asp Glu Ala Met Tyr Trp Gly
100 105 110
Gln Gly Thr Thr Val Thr Val Ser Ser
115 120
<210> 111
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 111
Lys Ala Ser Gln Thr Val Ser Ala Asn Val Ala
1 5 10
<210> 112
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 112
Leu Ala Ser Tyr Arg Tyr Arg
1 5
<210> 113
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 113
His Gln Tyr Tyr Thr Tyr Pro Leu Phe Thr
1 5 10
<210> 114
<211> 108
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 114
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Thr Val Ser Ala Asn
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Leu Ala Ser Tyr Arg Tyr Arg Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys His Gln Tyr Tyr Thr Tyr Pro Leu
85 90 95
Phe Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 115
<211> 251
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 115
Gly Gly Gly Ser Gly Gly Gly Gln Val Gln Leu Val Gln Ser Gly Ser
1 5 10 15
Glu Leu Lys Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser
20 25 30
Gly Tyr Thr Phe Thr Glu Tyr Gly Met Asn Val Trp Arg Gln Ala Pro
35 40 45
Gly Gln Gly Leu Glu Trp Met Gly Trp Ile Asn Thr Lys Ser Gly Glu
50 55 60
Ala Thr Tyr Val Glu Glu Phe Lys Gly Arg Phe Val Phe Ser Leu Asp
65 70 75 80
Thr Ser Val Ser Thr Ala Tyr Leu Gln Ile Ser Ser Leu Lys Ala Glu
85 90 95
Asp Thr Ala Val Tyr Tyr Cys Ala Arg Trp Asp Phe Tyr Asp Tyr Val
100 105 110
Asp Glu Ala Met Tyr Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser
115 120 125
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp
130 135 140
Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp
145 150 155 160
Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Thr Val Ser Ala Asn Val
165 170 175
Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr
180 185 190
Leu Ala Ser Tyr Arg Tyr Arg Gly Val Pro Ser Arg Phe Ser Gly Ser
195 200 205
Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu
210 215 220
Asp Phe Ala Thr Tyr Tyr Cys His Gln Tyr Tyr Thr Tyr Pro Leu Phe
225 230 235 240
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
245 250
<210> 116
<211> 226
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 116
Gln Val Gln Leu Val Gln Ser Gly Ser Glu Leu Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Glu Tyr
20 25 30
Gly Met Asn Val Trp Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Trp Ile Asn Thr Lys Ser Gly Glu Ala Thr Tyr Val Glu Glu Phe
50 55 60
Lys Gly Arg Phe Val Phe Ser Leu Asp Thr Ser Val Ser Thr Ala Tyr
65 70 75 80
Leu Gln Ile Ser Ser Leu Lys Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Trp Asp Phe Tyr Asp Tyr Val Asp Glu Ala Met Tyr Trp Gly
100 105 110
Gln Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
115 120 125
Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
130 135 140
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
145 150 155 160
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
165 170 175
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
180 185 190
Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
195 200 205
Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys
210 215 220
Asp Lys
225
<210> 117
<211> 215
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 117
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Thr Val Ser Ala Asn
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Leu Ala Ser Tyr Arg Tyr Arg Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys His Gln Tyr Tyr Thr Tyr Pro Leu
85 90 95
Phe Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala
100 105 110
Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser
115 120 125
Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu
130 135 140
Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser
145 150 155 160
Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu
165 170 175
Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Leu
180 185 190
Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys
195 200 205
Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 118
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 118
Asn Tyr Gly Met Asn
1 5
<210> 119
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 119
Trp Ile Asn Thr Tyr Thr Gly Glu Ser Thr Tyr Ala Asp Ser Phe Lys
1 5 10 15
Gly
<210> 120
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 120
Phe Ala Ile Lys Gly Asp Tyr
1 5
<210> 121
<211> 116
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 121
Glu Val Gln Leu Val Gln Ser Gly Pro Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Val Arg Ile Ser Cys Ala Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Gly Met Asn Trp Val Lys Gln Ala Pro Gly Lys Gly Leu Glu Trp Met
35 40 45
Gly Trp Ile Asn Thr Tyr Thr Gly Glu Ser Thr Tyr Ala Asp Ser Phe
50 55 60
Lys Gly Arg Phe Thr Phe Ser Leu Asp Thr Ser Ala Ser Ala Ala Tyr
65 70 75 80
Leu Gln Ile Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Phe Ala Ile Lys Gly Asp Tyr Trp Gly Gln Gly Thr Leu Leu
100 105 110
Thr Val Ser Ser
115
<210> 122
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 122
Arg Ser Thr Lys Ser Leu Leu His Ser Asn Gly Ile Thr Tyr Leu Tyr
1 5 10 15
<210> 123
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 123
Gln Met Ser Asn Leu Ala Ser
1 5
<210> 124
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 124
Ala Gln Asn Leu Glu Ile Pro Arg Thr
1 5
<210> 125
<211> 112
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 125
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ser Thr Lys Ser Leu Leu His Ser
20 25 30
Asn Gly Ile Thr Tyr Leu Tyr Trp Tyr Gln Gln Lys Pro Gly Lys Ala
35 40 45
Pro Lys Leu Leu Ile Tyr Gln Met Ser Asn Leu Ala Ser Gly Val Pro
50 55 60
Ser Arg Phe Ser Ser Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile
65 70 75 80
Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Ala Gln Asn
85 90 95
Leu Glu Ile Pro Arg Thr Phe Gly Gln Gly Thr Lys Val Glu Leu Lys
100 105 110
<210> 126
<211> 250
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 126
Gly Gly Gly Ser Gly Gly Gly Glu Val Gln Leu Val Gln Ser Gly Pro
1 5 10 15
Gly Leu Val Gln Pro Gly Gly Ser Val Arg Ile Ser Cys Ala Ala Ser
20 25 30
Gly Tyr Thr Phe Thr Asn Tyr Gly Met Asn Trp Val Lys Gln Ala Pro
35 40 45
Gly Lys Gly Leu Glu Trp Met Gly Trp Ile Asn Thr Tyr Thr Gly Glu
50 55 60
Ser Thr Tyr Ala Asp Ser Phe Lys Gly Arg Phe Thr Phe Ser Leu Asp
65 70 75 80
Thr Ser Ala Ser Ala Ala Tyr Leu Gln Ile Asn Ser Leu Arg Ala Glu
85 90 95
Asp Thr Ala Val Tyr Tyr Cys Ala Arg Phe Ala Ile Lys Gly Asp Tyr
100 105 110
Trp Gly Gln Gly Thr Leu Leu Thr Val Ser Ser Gly Gly Gly Gly Ser
115 120 125
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln
130 135 140
Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr
145 150 155 160
Cys Arg Ser Thr Lys Ser Leu Leu His Ser Asn Gly Ile Thr Tyr Leu
165 170 175
Tyr Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr
180 185 190
Gln Met Ser Asn Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Ser Ser
195 200 205
Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu
210 215 220
Asp Phe Ala Thr Tyr Tyr Cys Ala Gln Asn Leu Glu Ile Pro Arg Thr
225 230 235 240
Phe Gly Gln Gly Thr Lys Val Glu Leu Lys
245 250
<210> 127
<211> 221
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 127
Glu Val Gln Leu Val Gln Ser Gly Pro Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Val Arg Ile Ser Cys Ala Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Gly Met Asn Trp Val Lys Gln Ala Pro Gly Lys Gly Leu Glu Trp Met
35 40 45
Gly Trp Ile Asn Thr Tyr Thr Gly Glu Ser Thr Tyr Ala Asp Ser Phe
50 55 60
Lys Gly Arg Phe Thr Phe Ser Leu Asp Thr Ser Ala Ser Ala Ala Tyr
65 70 75 80
Leu Gln Ile Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Phe Ala Ile Lys Gly Asp Tyr Trp Gly Gln Gly Thr Leu Leu
100 105 110
Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala
115 120 125
Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu
130 135 140
Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly
145 150 155 160
Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser
165 170 175
Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu
180 185 190
Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr
195 200 205
Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys
210 215 220
<210> 128
<211> 219
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 128
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ser Thr Lys Ser Leu Leu His Ser
20 25 30
Asn Gly Ile Thr Tyr Leu Tyr Trp Tyr Gln Gln Lys Pro Gly Lys Ala
35 40 45
Pro Lys Leu Leu Ile Tyr Gln Met Ser Asn Leu Ala Ser Gly Val Pro
50 55 60
Ser Arg Phe Ser Ser Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile
65 70 75 80
Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Ala Gln Asn
85 90 95
Leu Glu Ile Pro Arg Thr Phe Gly Gln Gly Thr Lys Val Glu Leu Lys
100 105 110
Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu
115 120 125
Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe
130 135 140
Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln
145 150 155 160
Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
165 170 175
Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu
180 185 190
Lys His Lys Leu Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser
195 200 205
Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 129
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 129
Glu Tyr Thr Ile His
1 5
<210> 130
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 130
Gly Ile Asn Pro Asn Asn Gly Ile Pro Asn Tyr Asn Gln Lys Phe Lys
1 5 10 15
Gly
<210> 131
<211> 15
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 131
Arg Arg Ile Ala Tyr Gly Tyr Asp Glu Gly His Ala Met Asp Tyr
1 5 10 15
<210> 132
<211> 124
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 132
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Thr Ser Arg Tyr Thr Phe Thr Glu Tyr
20 25 30
Thr Ile His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Ile
35 40 45
Gly Gly Ile Asn Pro Asn Asn Gly Ile Pro Asn Tyr Asn Gln Lys Phe
50 55 60
Lys Gly Arg Val Thr Ile Thr Val Asp Thr Ser Ala Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Arg Arg Ile Ala Tyr Gly Tyr Asp Glu Gly His Ala Met Asp
100 105 110
Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 133
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 133
Lys Ser Ser Gln Ser Leu Leu Tyr Ser Arg Asn Gln Lys Asn Tyr Leu
1 5 10 15
Ala
<210> 134
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 134
Trp Ala Ser Thr Arg Glu Ser
1 5
<210> 135
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 135
Gln Gln Tyr Phe Ser Tyr Pro Leu Thr
1 5
<210> 136
<211> 113
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 136
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Leu Leu Tyr Ser
20 25 30
Arg Asn Gln Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Pro Pro Lys Leu Leu Ile Phe Trp Ala Ser Thr Arg Glu Ser Gly Val
50 55 60
Pro Asp Arg Phe Ser Gly Ser Gly Phe Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln
85 90 95
Tyr Phe Ser Tyr Pro Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile
100 105 110
Lys
<210> 137
<211> 259
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 137
Gly Gly Gly Ser Gly Gly Gly Gln Val Gln Leu Val Gln Ser Gly Ala
1 5 10 15
Glu Val Lys Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Thr Ser
20 25 30
Arg Tyr Thr Phe Thr Glu Tyr Thr Ile His Trp Val Arg Gln Ala Pro
35 40 45
Gly Gln Arg Leu Glu Trp Ile Gly Gly Ile Asn Pro Asn Asn Gly Ile
50 55 60
Pro Asn Tyr Asn Gln Lys Phe Lys Gly Arg Val Thr Ile Thr Val Asp
65 70 75 80
Thr Ser Ala Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu
85 90 95
Asp Thr Ala Val Tyr Tyr Cys Ala Arg Arg Arg Ile Ala Tyr Gly Tyr
100 105 110
Asp Glu Gly His Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr
115 120 125
Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
130 135 140
Gly Ser Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser
145 150 155 160
Leu Gly Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Leu Leu
165 170 175
Tyr Ser Arg Asn Gln Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro
180 185 190
Gly Gln Pro Pro Lys Leu Leu Ile Phe Trp Ala Ser Thr Arg Glu Ser
195 200 205
Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Phe Gly Thr Asp Phe Thr
210 215 220
Leu Thr Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys
225 230 235 240
Gln Gln Tyr Phe Ser Tyr Pro Leu Thr Phe Gly Gln Gly Thr Lys Val
245 250 255
Glu Ile Lys
<210> 138
<211> 229
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 138
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Thr Ser Arg Tyr Thr Phe Thr Glu Tyr
20 25 30
Thr Ile His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Ile
35 40 45
Gly Gly Ile Asn Pro Asn Asn Gly Ile Pro Asn Tyr Asn Gln Lys Phe
50 55 60
Lys Gly Arg Val Thr Ile Thr Val Asp Thr Ser Ala Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Arg Arg Ile Ala Tyr Gly Tyr Asp Glu Gly His Ala Met Asp
100 105 110
Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys
115 120 125
Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly
130 135 140
Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro
145 150 155 160
Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr
165 170 175
Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val
180 185 190
Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn
195 200 205
Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro
210 215 220
Lys Ser Cys Asp Lys
225
<210> 139
<211> 220
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 139
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Leu Leu Tyr Ser
20 25 30
Arg Asn Gln Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Pro Pro Lys Leu Leu Ile Phe Trp Ala Ser Thr Arg Glu Ser Gly Val
50 55 60
Pro Asp Arg Phe Ser Gly Ser Gly Phe Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln
85 90 95
Tyr Phe Ser Tyr Pro Leu Thr Phe Gly Gln Gly Thr Lys Val 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 Leu 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> 140
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 140
Asp Ser Trp Ile His
1 5
<210> 141
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 141
Trp Ile Ser Pro Tyr Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys
1 5 10 15
Gly
<210> 142
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 142
Arg His Trp Pro Gly Gly Phe Asp Tyr
1 5
<210> 143
<211> 118
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 143
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Ser
20 25 30
Trp Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Trp Ile Ser Pro Tyr Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Arg His Trp Pro Gly Gly Phe Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser
115
<210> 144
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 144
Arg Ala Ser Gln Asp Val Ser Thr Ala Val Ala
1 5 10
<210> 145
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 145
Ser Ala Ser Phe Leu Tyr Ser
1 5
<210> 146
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 146
Gln Gln Tyr Leu Tyr His Pro Ala Thr
1 5
<210> 147
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 147
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Val Ser Thr Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Leu Tyr His Pro Ala
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 148
<211> 247
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 148
Gly Gly Gly Ser Gly Gly Gly Glu Val Gln Leu Val Glu Ser Gly Gly
1 5 10 15
Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser
20 25 30
Gly Phe Thr Phe Ser Asp Ser Trp Ile His Trp Val Arg Gln Ala Pro
35 40 45
Gly Lys Gly Leu Glu Trp Val Ala Trp Ile Ser Pro Tyr Gly Gly Ser
50 55 60
Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Ala Asp
65 70 75 80
Thr Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu
85 90 95
Asp Thr Ala Val Tyr Tyr Cys Ala Arg Arg His Trp Pro Gly Gly Phe
100 105 110
Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly
115 120 125
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met
130 135 140
Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr
145 150 155 160
Ile Thr Cys Arg Ala Ser Gln Asp Val Ser Thr Ala Val Ala Trp Tyr
165 170 175
Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ser Ala Ser
180 185 190
Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly
195 200 205
Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala
210 215 220
Thr Tyr Tyr Cys Gln Gln Tyr Leu Tyr His Pro Ala Thr Phe Gly Gln
225 230 235 240
Gly Thr Lys Val Glu Ile Lys
245
<210> 149
<211> 223
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 149
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Ser
20 25 30
Trp Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Trp Ile Ser Pro Tyr Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Arg His Trp Pro Gly Gly Phe Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val 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 Lys Val Glu Pro Lys Ser Cys Asp Lys
210 215 220
<210> 150
<211> 214
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 150
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Val Ser Thr Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Leu Tyr His Pro Ala
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile 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> 151
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 151
Ser Phe Ala Met Ser
1 5
<210> 152
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 152
Ala Ile Ser Gly Ser Gly Gly Gly Thr Tyr Tyr Ala Asp Ser Val Lys
1 5 10 15
Gly
<210> 153
<211> 13
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 153
Asp Lys Ile Leu Trp Phe Gly Glu Pro Val Phe Asp Tyr
1 5 10
<210> 154
<211> 122
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 154
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Phe Thr Phe Asn Ser Phe
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ala Ile Ser Gly Ser Gly Gly Gly Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Phe Cys
85 90 95
Ala Lys Asp Lys Ile Leu Trp Phe Gly Glu Pro Val Phe Asp Tyr Trp
100 105 110
Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 155
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 155
Arg Ala Ser Gln Ser Val Ser Ser Tyr Leu Ala
1 5 10
<210> 156
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 156
Asp Ala Ser Asn Arg Ala Thr
1 5
<210> 157
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 157
Gln Gln Arg Ser Asn Trp Pro Pro Thr
1 5
<210> 158
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 158
Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Tyr
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Tyr Asp Ala Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro
65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Arg Ser Asn Trp Pro Pro
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 159
<211> 251
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 159
Gly Gly Gly Ser Gly Gly Gly Glu Val Gln Leu Leu Glu Ser Gly Gly
1 5 10 15
Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Val Ser
20 25 30
Gly Phe Thr Phe Asn Ser Phe Ala Met Ser Trp Val Arg Gln Ala Pro
35 40 45
Gly Lys Gly Leu Glu Trp Val Ser Ala Ile Ser Gly Ser Gly Gly Gly
50 55 60
Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp
65 70 75 80
Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu
85 90 95
Asp Thr Ala Val Tyr Phe Cys Ala Lys Asp Lys Ile Leu Trp Phe Gly
100 105 110
Glu Pro Val Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser
115 120 125
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
130 135 140
Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly
145 150 155 160
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Tyr
165 170 175
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
180 185 190
Tyr Asp Ala Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly
195 200 205
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro
210 215 220
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Arg Ser Asn Trp Pro Pro
225 230 235 240
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
245 250
<210> 160
<211> 227
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 160
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Phe Thr Phe Asn Ser Phe
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ala Ile Ser Gly Ser Gly Gly Gly Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Phe Cys
85 90 95
Ala Lys Asp Lys Ile Leu Trp Phe Gly Glu Pro Val Phe Asp Tyr Trp
100 105 110
Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro
115 120 125
Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr
130 135 140
Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr
145 150 155 160
Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro
165 170 175
Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr
180 185 190
Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn
195 200 205
His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser
210 215 220
Cys Asp Lys
225
<210> 161
<211> 214
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 161
Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Tyr
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Tyr Asp Ala Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro
65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Arg Ser Asn Trp Pro Pro
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile 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> 162
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 162
Asp Ser Asn Ile His
1 5
<210> 163
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 163
Tyr Ile Tyr Pro Tyr Asn Gly Gly Thr Asp Tyr Asn Gln Lys Phe Lys
1 5 10 15
Asn
<210> 164
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 164
Gly Asn Pro Trp Leu Ala Tyr
1 5
<210> 165
<211> 116
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 165
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Ile Thr Asp Ser
20 25 30
Asn Ile His Trp Val Arg Gln Ala Pro Gly Gln Ser Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Tyr Pro Tyr Asn Gly Gly Thr Asp Tyr Asn Gln Lys Phe
50 55 60
Lys Asn Arg Ala Thr Leu Thr Val Asp Asn Pro Thr Asn Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Phe Tyr Tyr Cys
85 90 95
Val Asn Gly Asn Pro Trp Leu Ala Tyr Trp Gly Gln Gly Thr Leu Val
100 105 110
Thr Val Ser Ser
115
<210> 166
<211> 15
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 166
Arg Ala Ser Glu Ser Leu Asp Asn Tyr Gly Ile Arg Phe Leu Thr
1 5 10 15
<210> 167
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 167
Ala Ala Ser Asn Gln Gly Ser
1 5
<210> 168
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 168
Gln Gln Thr Lys Glu Val Pro Trp Ser
1 5
<210> 169
<211> 111
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 169
Asp Ile Gln Leu Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Glu Ser Leu Asp Asn Tyr
20 25 30
Gly Ile Arg Phe Leu Thr Trp Phe Gln Gln Lys Pro Gly Lys Ala Pro
35 40 45
Lys Leu Leu Met Tyr Ala Ala Ser Asn Gln Gly Ser Gly Val Pro Ser
50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser
65 70 75 80
Ser Leu Gln Pro Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Thr Lys
85 90 95
Glu Val Pro Trp Ser Phe Gly Gln Gly Thr Lys Val Glu Val Lys
100 105 110
<210> 170
<211> 249
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 170
Gly Gly Gly Ser Gly Gly Gly Glu Val Gln Leu Val Gln Ser Gly Ala
1 5 10 15
Glu Val Lys Lys Pro Gly Ser Ser Val Lys Val Ser Cys Lys Ala Ser
20 25 30
Gly Tyr Thr Ile Thr Asp Ser Asn Ile His Trp Val Arg Gln Ala Pro
35 40 45
Gly Gln Ser Leu Glu Trp Ile Gly Tyr Ile Tyr Pro Tyr Asn Gly Gly
50 55 60
Thr Asp Tyr Asn Gln Lys Phe Lys Asn Arg Ala Thr Leu Thr Val Asp
65 70 75 80
Asn Pro Thr Asn Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu
85 90 95
Asp Thr Ala Phe Tyr Tyr Cys Val Asn Gly Asn Pro Trp Leu Ala Tyr
100 105 110
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser
115 120 125
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Leu Thr Gln
130 135 140
Ser Pro Ser Thr Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr
145 150 155 160
Cys Arg Ala Ser Glu Ser Leu Asp Asn Tyr Gly Ile Arg Phe Leu Thr
165 170 175
Trp Phe Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Met Tyr Ala
180 185 190
Ala Ser Asn Gln Gly Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly
195 200 205
Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Asp Asp
210 215 220
Phe Ala Thr Tyr Tyr Cys Gln Gln Thr Lys Glu Val Pro Trp Ser Phe
225 230 235 240
Gly Gln Gly Thr Lys Val Glu Val Lys
245
<210> 171
<211> 214
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 171
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Ile Thr Asp Ser
20 25 30
Asn Ile His Trp Val Arg Gln Ala Pro Gly Gln Ser Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Tyr Pro Tyr Asn Gly Gly Thr Asp Tyr Asn Gln Lys Phe
50 55 60
Lys Asn Arg Ala Thr Leu Thr Val Asp Asn Pro Thr Asn Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Phe Tyr Tyr Cys
85 90 95
Val Asn Gly Asn Pro Trp Leu Ala Tyr Trp Gly Gln Gly Thr Leu Val
100 105 110
Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala
115 120 125
Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu
130 135 140
Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly
145 150 155 160
Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser
165 170 175
Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu
180 185 190
Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr
195 200 205
Lys Val Asp Lys Arg Val
210
<210> 172
<211> 218
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 172
Asp Ile Gln Leu Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Glu Ser Leu Asp Asn Tyr
20 25 30
Gly Ile Arg Phe Leu Thr Trp Phe Gln Gln Lys Pro Gly Lys Ala Pro
35 40 45
Lys Leu Leu Met Tyr Ala Ala Ser Asn Gln Gly Ser Gly Val Pro Ser
50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser
65 70 75 80
Ser Leu Gln Pro Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Thr Lys
85 90 95
Glu Val Pro Trp Ser Phe Gly Gln Gly Thr Lys Val Glu Val Lys Arg
100 105 110
Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln
115 120 125
Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr
130 135 140
Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser
145 150 155 160
Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr
165 170 175
Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys
180 185 190
His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro
195 200 205
Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 173
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 173
Ser Tyr Trp Leu His
1 5
<210> 174
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 174
Met Ile Asp Pro Ser Asn Ser Asp Thr Arg Phe Asn Pro Asn Phe Lys
1 5 10 15
Asp
<210> 175
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 175
Tyr Arg Ser Tyr Val Thr Pro Leu Asp Tyr
1 5 10
<210> 176
<211> 119
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 176
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Trp Leu His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Met Ile Asp Pro Ser Asn Ser Asp Thr Arg Phe Asn Pro Asn Phe
50 55 60
Lys Asp Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Thr Tyr Arg Ser Tyr Val Thr Pro Leu Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 177
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 177
Lys Ser Ser Gln Ser Leu Leu Tyr Thr Ser Ser Gln Lys Asn Tyr Leu
1 5 10 15
Ala
<210> 178
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 178
Trp Ala Ser Thr Arg Glu Ser
1 5
<210> 179
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 179
Gln Gln Tyr Tyr Ala Tyr Pro Trp Thr
1 5
<210> 180
<211> 113
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 180
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Lys Ser Ser Gln Ser Leu Leu Tyr Thr
20 25 30
Ser Ser Gln Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys
35 40 45
Ala Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val
50 55 60
Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln
85 90 95
Tyr Tyr Ala Tyr Pro Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile
100 105 110
Lys
<210> 181
<211> 254
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 181
Gly Gly Gly Ser Gly Gly Gly Glu Val Gln Leu Val Glu Ser Gly Gly
1 5 10 15
Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser
20 25 30
Gly Tyr Thr Phe Thr Ser Tyr Trp Leu His Trp Val Arg Gln Ala Pro
35 40 45
Gly Lys Gly Leu Glu Trp Val Gly Met Ile Asp Pro Ser Asn Ser Asp
50 55 60
Thr Arg Phe Asn Pro Asn Phe Lys Asp Arg Phe Thr Ile Ser Ala Asp
65 70 75 80
Thr Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu
85 90 95
Asp Thr Ala Val Tyr Tyr Cys Ala Thr Tyr Arg Ser Tyr Val Thr Pro
100 105 110
Leu Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly
115 120 125
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln
130 135 140
Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val
145 150 155 160
Thr Ile Thr Cys Lys Ser Ser Gln Ser Leu Leu Tyr Thr Ser Ser Gln
165 170 175
Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys
180 185 190
Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val Pro Ser Arg
195 200 205
Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser
210 215 220
Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Tyr Ala
225 230 235 240
Tyr Pro Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
245 250
<210> 182
<211> 224
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 182
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Trp Leu His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Met Ile Asp Pro Ser Asn Ser Asp Thr Arg Phe Asn Pro Asn Phe
50 55 60
Lys Asp Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Thr Tyr Arg Ser Tyr Val Thr Pro Leu Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys
210 215 220
<210> 183
<211> 220
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 183
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Lys Ser Ser Gln Ser Leu Leu Tyr Thr
20 25 30
Ser Ser Gln Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys
35 40 45
Ala Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val
50 55 60
Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln
85 90 95
Tyr Tyr Ala Tyr Pro Trp Thr Phe Gly Gln Gly Thr Lys Val 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> 184
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 184
Asn Tyr Asn Met His
1 5
<210> 185
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 185
Thr Ile Tyr Pro Gly Asn Asp Asp Thr Ser Tyr Asn Gln Lys Phe Lys
1 5 10 15
Asp
<210> 186
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 186
Gly Gly Tyr Arg Ala Met Asp Tyr
1 5
<210> 187
<211> 117
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 187
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Asn Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
35 40 45
Gly Thr Ile Tyr Pro Gly Asn Asp Asp Thr Ser Tyr Asn Gln Lys Phe
50 55 60
Lys Asp Arg Val Thr Ile Thr Ala Asp Thr Ser Ala Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Gly Tyr Arg Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 188
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 188
Arg Ser Ser Gln Ser Ile Val Tyr Ser Asn Gly Asn Thr Tyr Leu Gly
1 5 10 15
<210> 189
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 189
Lys Val Ser Asn Arg Phe Ser
1 5
<210> 190
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 190
Phe Gln Gly Ser His Val Pro Tyr Thr
1 5
<210> 191
<211> 112
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 191
Asp Ile Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Pro Gly
1 5 10 15
Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Ile Val Tyr Ser
20 25 30
Asn Gly Asn Thr Tyr Leu Gly Trp Tyr Leu Gln Lys Pro Gly Gln Ser
35 40 45
Pro Gln Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Phe Gln Gly
85 90 95
Ser His Val Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 192
<211> 251
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 192
Gly Gly Gly Ser Gly Gly Gly Gln Val Gln Leu Val Gln Ser Gly Ala
1 5 10 15
Glu Val Lys Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser
20 25 30
Gly Tyr Thr Phe Thr Asn Tyr Asn Met His Trp Val Arg Gln Ala Pro
35 40 45
Gly Gln Arg Leu Glu Trp Met Gly Thr Ile Tyr Pro Gly Asn Asp Asp
50 55 60
Thr Ser Tyr Asn Gln Lys Phe Lys Asp Arg Val Thr Ile Thr Ala Asp
65 70 75 80
Thr Ser Ala Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu
85 90 95
Asp Thr Ala Val Tyr Tyr Cys Ala Arg Gly Gly Tyr Arg Ala Met Asp
100 105 110
Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly
115 120 125
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Val Met Thr
130 135 140
Gln Ser Pro Leu Ser Leu Pro Val Thr Pro Gly Glu Pro Ala Ser Ile
145 150 155 160
Ser Cys Arg Ser Ser Gln Ser Ile Val Tyr Ser Asn Gly Asn Thr Tyr
165 170 175
Leu Gly Trp Tyr Leu Gln Lys Pro Gly Gln Ser Pro Gln Leu Leu Ile
180 185 190
Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro Asp Arg Phe Ser Gly
195 200 205
Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile Ser Arg Val Glu Ala
210 215 220
Glu Asp Val Gly Val Tyr Tyr Cys Phe Gln Gly Ser His Val Pro Tyr
225 230 235 240
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
245 250
<210> 193
<211> 222
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 193
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Asn Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
35 40 45
Gly Thr Ile Tyr Pro Gly Asn Asp Asp Thr Ser Tyr Asn Gln Lys Phe
50 55 60
Lys Asp Arg Val Thr Ile Thr Ala Asp Thr Ser Ala Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Gly Tyr Arg Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu
115 120 125
Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys
130 135 140
Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser
145 150 155 160
Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser
165 170 175
Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser
180 185 190
Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn
195 200 205
Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys
210 215 220
<210> 194
<211> 219
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 194
Asp Ile Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Pro Gly
1 5 10 15
Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Ile Val Tyr Ser
20 25 30
Asn Gly Asn Thr Tyr Leu Gly Trp Tyr Leu Gln Lys Pro Gly Gln Ser
35 40 45
Pro Gln Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Phe Gln Gly
85 90 95
Ser His Val Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105 110
Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu
115 120 125
Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe
130 135 140
Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln
145 150 155 160
Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
165 170 175
Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu
180 185 190
Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser
195 200 205
Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 195
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 195
Ser Gly Asp Tyr Phe Trp Ser
1 5
<210> 196
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 196
His Ile His Asn Ser Gly Thr Thr Tyr Tyr Asn Pro Ser Leu Lys Ser
1 5 10 15
<210> 197
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 197
Asp Arg Gly Gly Asp Tyr Tyr Tyr Gly Met Asp Val
1 5 10
<210> 198
<211> 122
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 198
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Gly
20 25 30
Asp Tyr Phe Trp Ser Trp Ile Arg Gln Leu Pro Gly Lys Gly Leu Glu
35 40 45
Trp Ile Gly His Ile His Asn Ser Gly Thr Thr Tyr Tyr Asn Pro Ser
50 55 60
Leu Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Lys Gln Phe
65 70 75 80
Ser Leu Arg Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr
85 90 95
Cys Ala Arg Asp Arg Gly Gly Asp Tyr Tyr Tyr Gly Met Asp Val Trp
100 105 110
Gly Gln Gly Thr Thr Val Thr Val Ser Ser
115 120
<210> 199
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 199
Arg Ala Ser Gln Gly Ile Ser Arg Ser Tyr Leu Ala
1 5 10
<210> 200
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 200
Gly Ala Ser Ser Arg Ala Thr
1 5
<210> 201
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 201
Gln Gln Phe Gly Ser Ser Pro Trp Thr
1 5
<210> 202
<211> 108
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 202
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Gly Ile Ser Arg Ser
20 25 30
Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Ser Leu Leu
35 40 45
Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
65 70 75 80
Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Phe Gly Ser Ser Pro
85 90 95
Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 203
<211> 252
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 203
Gly Gly Gly Ser Gly Gly Gly Gln Val Gln Leu Gln Glu Ser Gly Pro
1 5 10 15
Gly Leu Val Lys Pro Ser Gln Thr Leu Ser Leu Thr Cys Thr Val Ser
20 25 30
Gly Gly Ser Ile Ser Ser Gly Asp Tyr Phe Trp Ser Trp Ile Arg Gln
35 40 45
Leu Pro Gly Lys Gly Leu Glu Trp Ile Gly His Ile His Asn Ser Gly
50 55 60
Thr Thr Tyr Tyr Asn Pro Ser Leu Lys Ser Arg Val Thr Ile Ser Val
65 70 75 80
Asp Thr Ser Lys Lys Gln Phe Ser Leu Arg Leu Ser Ser Val Thr Ala
85 90 95
Ala Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Arg Gly Gly Asp Tyr
100 105 110
Tyr Tyr Gly Met Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser
115 120 125
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
130 135 140
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
145 150 155 160
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Gly Ile Ser Arg Ser
165 170 175
Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Ser Leu Leu
180 185 190
Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser
195 200 205
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
210 215 220
Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Phe Gly Ser Ser Pro
225 230 235 240
Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
245 250
<210> 204
<211> 227
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 204
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Gly
20 25 30
Asp Tyr Phe Trp Ser Trp Ile Arg Gln Leu Pro Gly Lys Gly Leu Glu
35 40 45
Trp Ile Gly His Ile His Asn Ser Gly Thr Thr Tyr Tyr Asn Pro Ser
50 55 60
Leu Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Lys Gln Phe
65 70 75 80
Ser Leu Arg Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr
85 90 95
Cys Ala Arg Asp Arg Gly Gly Asp Tyr Tyr Tyr Gly Met Asp Val Trp
100 105 110
Gly Gln Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro
115 120 125
Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr
130 135 140
Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr
145 150 155 160
Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro
165 170 175
Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr
180 185 190
Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn
195 200 205
His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser
210 215 220
Cys Asp Lys
225
<210> 205
<211> 215
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 205
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Gly Ile Ser Arg Ser
20 25 30
Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Ser Leu Leu
35 40 45
Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
65 70 75 80
Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Phe Gly Ser Ser Pro
85 90 95
Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala
100 105 110
Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser
115 120 125
Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu
130 135 140
Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser
145 150 155 160
Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu
165 170 175
Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val
180 185 190
Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys
195 200 205
Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 206
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 206
Ser Gly Ser Tyr Tyr Trp Ser
1 5
<210> 207
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 207
Tyr Ile Tyr Tyr Ser Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys Ser
1 5 10 15
<210> 208
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 208
Glu Gly Lys Asn Gly Ala Phe Asp Ile
1 5
<210> 209
<211> 119
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 209
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Val Ser Ser Gly
20 25 30
Ser Tyr Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu
35 40 45
Trp Ile Gly Tyr Ile Tyr Tyr Ser Gly Ser Thr Asn Tyr Asn Pro Ser
50 55 60
Leu Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe
65 70 75 80
Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr
85 90 95
Cys Ala Arg Glu Gly Lys Asn Gly Ala Phe Asp Ile Trp Gly Gln Gly
100 105 110
Thr Met Val Thr Val Ser Ser
115
<210> 210
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 210
Arg Ala Ser Gln Ser Ile Ser Ser Tyr Leu Asn
1 5 10
<210> 211
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 211
Ala Ala Ser Ser Leu Gln Ser
1 5
<210> 212
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 212
Gln Gln Ser Tyr Ser Thr Pro Leu Thr
1 5
<210> 213
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 213
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Gly Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ser Thr Pro Leu
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 214
<211> 248
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 214
Gly Gly Gly Ser Gly Gly Gly Gln Val Gln Leu Gln Glu Ser Gly Pro
1 5 10 15
Gly Leu Val Lys Pro Ser Glu Thr Leu Ser Leu Thr Cys Thr Val Ser
20 25 30
Gly Gly Ser Val Ser Ser Gly Ser Tyr Tyr Trp Ser Trp Ile Arg Gln
35 40 45
Pro Pro Gly Lys Gly Leu Glu Trp Ile Gly Tyr Ile Tyr Tyr Ser Gly
50 55 60
Ser Thr Asn Tyr Asn Pro Ser Leu Lys Ser Arg Val Thr Ile Ser Val
65 70 75 80
Asp Thr Ser Lys Asn Gln Phe Ser Leu Lys Leu Ser Ser Val Thr Ala
85 90 95
Ala Asp Thr Ala Val Tyr Tyr Cys Ala Arg Glu Gly Lys Asn Gly Ala
100 105 110
Phe Asp Ile Trp Gly Gln Gly Thr Met Val Thr Val Ser Ser Gly Gly
115 120 125
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln
130 135 140
Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val
145 150 155 160
Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr Leu Asn Trp
165 170 175
Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ala Ala
180 185 190
Ser Ser Leu Gln Ser Gly Val Pro Ser Gly Phe Ser Gly Ser Gly Ser
195 200 205
Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe
210 215 220
Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ser Thr Pro Leu Thr Phe Gly
225 230 235 240
Gly Gly Thr Lys Val Glu Ile Lys
245
<210> 215
<211> 224
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 215
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Val Ser Ser Gly
20 25 30
Ser Tyr Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu
35 40 45
Trp Ile Gly Tyr Ile Tyr Tyr Ser Gly Ser Thr Asn Tyr Asn Pro Ser
50 55 60
Leu Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe
65 70 75 80
Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr
85 90 95
Cys Ala Arg Glu Gly Lys Asn Gly Ala Phe Asp Ile Trp Gly Gln Gly
100 105 110
Thr Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys
210 215 220
<210> 216
<211> 214
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 216
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Gly Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ser Thr Pro Leu
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile 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> 217
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 217
Gly Tyr Asn Met Asn
1 5
<210> 218
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 218
Ala Ile Asp Pro Tyr Tyr Gly Gly Thr Ser Tyr Asn Gln Lys Phe Lys
1 5 10 15
Gly
<210> 219
<211> 4
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 219
Gly Met Glu Tyr
1
<210> 220
<211> 113
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 220
Glu Val Gln Leu Leu Gln Ser Gly Pro Glu Leu Glu Lys Pro Gly Ala
1 5 10 15
Ser Val Met Ile Ser Cys Lys Ala Ser Gly Ser Ser Phe Thr Gly Tyr
20 25 30
Asn Met Asn Trp Val Arg Gln Asn Ile Gly Lys Ser Leu Glu Trp Ile
35 40 45
Gly Ala Ile Asp Pro Tyr Tyr Gly Gly Thr Ser Tyr Asn Gln Lys Phe
50 55 60
Lys Gly Arg Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met His Leu Lys Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Val Ser Gly Met Glu Tyr Trp Gly Gln Gly Thr Ser Val Thr Val Ser
100 105 110
Ser
<210> 221
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 221
Arg Ser Ser Gln Ser Leu Val His Arg Asn Gly Asn Thr Tyr Leu His
1 5 10 15
<210> 222
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 222
Lys Val Ser Asn Arg Phe Ser
1 5
<210> 223
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 223
Ser Gln Ser Thr His Val Pro Pro Leu Thr
1 5 10
<210> 224
<211> 113
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 224
Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ser Ser Gln Ser Leu Val His Arg
20 25 30
Asn Gly Asn Thr Tyr Leu His Trp Tyr Leu Gln Lys Pro Gly Gln Ser
35 40 45
Pro Lys Leu Leu Ile His Lys Val Ser Asn Arg Phe Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Phe Cys Ser Gln Ser
85 90 95
Thr His Val Pro Pro Leu Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu
100 105 110
Lys
<210> 225
<211> 248
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 225
Gly Gly Gly Ser Gly Gly Gly Glu Val Gln Leu Leu Gln Ser Gly Pro
1 5 10 15
Glu Leu Glu Lys Pro Gly Ala Ser Val Met Ile Ser Cys Lys Ala Ser
20 25 30
Gly Ser Ser Phe Thr Gly Tyr Asn Met Asn Trp Val Arg Gln Asn Ile
35 40 45
Gly Lys Ser Leu Glu Trp Ile Gly Ala Ile Asp Pro Tyr Tyr Gly Gly
50 55 60
Thr Ser Tyr Asn Gln Lys Phe Lys Gly Arg Ala Thr Leu Thr Val Asp
65 70 75 80
Lys Ser Ser Ser Thr Ala Tyr Met His Leu Lys Ser Leu Thr Ser Glu
85 90 95
Asp Ser Ala Val Tyr Tyr Cys Val Ser Gly Met Glu Tyr Trp Gly Gln
100 105 110
Gly Thr Ser Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly
115 120 125
Gly Ser Gly Gly Gly Gly Ser Glu Ile Val Met Thr Gln Ser Pro Ala
130 135 140
Thr Leu Ser Val Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg Ser
145 150 155 160
Ser Gln Ser Leu Val His Arg Asn Gly Asn Thr Tyr Leu His Trp Tyr
165 170 175
Leu Gln Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile His Lys Val Ser
180 185 190
Asn Arg Phe Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly
195 200 205
Thr Asp Phe Thr Leu Lys Ile Ser Arg Val Glu Ala Glu Asp Leu Gly
210 215 220
Val Tyr Phe Cys Ser Gln Ser Thr His Val Pro Pro Leu Thr Phe Gly
225 230 235 240
Ala Gly Thr Lys Leu Glu Leu Lys
245
<210> 226
<211> 218
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 226
Glu Val Gln Leu Leu Gln Ser Gly Pro Glu Leu Glu Lys Pro Gly Ala
1 5 10 15
Ser Val Met Ile Ser Cys Lys Ala Ser Gly Ser Ser Phe Thr Gly Tyr
20 25 30
Asn Met Asn Trp Val Arg Gln Asn Ile Gly Lys Ser Leu Glu Trp Ile
35 40 45
Gly Ala Ile Asp Pro Tyr Tyr Gly Gly Thr Ser Tyr Asn Gln Lys Phe
50 55 60
Lys Gly Arg Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met His Leu Lys Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Val Ser Gly Met Glu Tyr Trp Gly Gln Gly Thr Ser Val Thr Val Ser
100 105 110
Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser
115 120 125
Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp
130 135 140
Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr
145 150 155 160
Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr
165 170 175
Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln
180 185 190
Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp
195 200 205
Lys Arg Val Glu Pro Lys Ser Cys Asp Lys
210 215
<210> 227
<211> 220
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 227
Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ser Ser Gln Ser Leu Val His Arg
20 25 30
Asn Gly Asn Thr Tyr Leu His Trp Tyr Leu Gln Lys Pro Gly Gln Ser
35 40 45
Pro Lys Leu Leu Ile His Lys Val Ser Asn Arg Phe Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Phe Cys Ser Gln Ser
85 90 95
Thr His Val Pro Pro Leu Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu
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> 228
<211> 216
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 228
Asp Ile Gln Leu Thr Gln Pro Asn Ser Val Ser Thr Ser Leu Gly Ser
1 5 10 15
Thr Val Lys Leu Ser Cys Thr Leu Ser Ser Gly Asn Ile Glu Asn Asn
20 25 30
Tyr Val His Trp Tyr Gln Leu Tyr Glu Gly Arg Ser Pro Thr Thr Met
35 40 45
Ile Tyr Asp Asp Asp Lys Arg Pro Asp Ala Val Pro Asp Arg Phe Ser
50 55 60
Gly Ser Ile Asp Arg Ser Ser Asn Ser Ala Phe Leu Thr Ile His Asn
65 70 75 80
Val Ala Ile Glu Asp Glu Ala Ile Tyr Phe Cys His Ser Tyr Val Ser
85 90 95
Ser Phe Asn Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Arg Gln
100 105 110
Pro Lys Ala Ala Pro Ser Val Thr Leu Phe Pro Pro Ser Ser Glu Glu
115 120 125
Leu Gln Ala Asn Lys Ala Thr Leu Val Cys Leu Ile Ser Asp Phe Tyr
130 135 140
Pro Gly Ala Val Thr Val Ala Trp Lys Ala Asp Ser Ser Pro Val Lys
145 150 155 160
Ala Gly Val Glu Thr Thr Thr Pro Ser Lys Gln Ser Asn Asn Lys Tyr
165 170 175
Ala Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys Ser His
180 185 190
Arg Ser Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr Val Glu Lys
195 200 205
Thr Val Ala Pro Thr Glu Cys Ser
210 215
<210> 229
<211> 471
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 229
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe
20 25 30
Pro Met Ala Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Thr Ile Ser Thr Ser Gly Gly Arg Thr Tyr Tyr Arg Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Phe Arg Gln Tyr Ser Gly Gly Phe Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Gly Gly
210 215 220
Gly Ser Gly Gly Gly Gln Val Gln Leu Gln Gln Pro Gly Ala Glu Leu
225 230 235 240
Val Lys Pro Gly Ala Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr
245 250 255
Thr Phe Thr Ser Tyr Asn Met His Trp Val Lys Gln Thr Pro Gly Arg
260 265 270
Gly Leu Glu Trp Ile Gly Ala Ile Tyr Pro Gly Asn Gly Asp Thr Ser
275 280 285
Tyr Asn Gln Lys Phe Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser
290 295 300
Ser Ser Thr Ala Tyr Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser
305 310 315 320
Ala Val Tyr Tyr Cys Ala Arg Ser Thr Tyr Tyr Gly Gly Asp Trp Tyr
325 330 335
Phe Asn Val Trp Gly Ala Gly Thr Thr Val Thr Val Ser Ala Gly Gly
340 345 350
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Ile Val
355 360 365
Leu Ser Gln Ser Pro Ala Ile Leu Ser Ala Ser Pro Gly Glu Lys Val
370 375 380
Thr Met Thr Cys Arg Ala Ser Ser Ser Val Ser Tyr Ile His Trp Phe
385 390 395 400
Gln Gln Lys Pro Gly Ser Ser Pro Lys Pro Trp Ile Tyr Ala Thr Ser
405 410 415
Asn Leu Ala Ser Gly Val Pro Val Arg Phe Ser Gly Ser Gly Ser Gly
420 425 430
Thr Ser Tyr Ser Leu Thr Ile Ser Arg Val Glu Ala Glu Asp Ala Ala
435 440 445
Thr Tyr Tyr Cys Gln Gln Trp Thr Ser Asn Pro Pro Thr Phe Gly Gly
450 455 460
Gly Thr Lys Leu Glu Ile Lys
465 470
<210> 230
<211> 471
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 230
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe
20 25 30
Pro Met Ala Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Thr Ile Ser Thr Ser Gly Gly Arg Thr Tyr Tyr Arg Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Phe Arg Gln Tyr Ser Gly Gly Phe Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Gly Gly
210 215 220
Gly Ser Gly Gly Gly Glu Val Lys Leu Gln Glu Ser Gly Pro Gly Leu
225 230 235 240
Val Ala Pro Ser Gln Ser Leu Ser Val Thr Cys Thr Val Ser Gly Val
245 250 255
Ser Leu Pro Asp Tyr Gly Val Ser Trp Ile Arg Gln Pro Pro Arg Lys
260 265 270
Gly Leu Glu Trp Leu Gly Val Ile Trp Gly Ser Glu Thr Thr Tyr Tyr
275 280 285
Asn Ser Ala Leu Lys Ser Arg Leu Thr Ile Ile Lys Asp Asn Ser Lys
290 295 300
Ser Gln Val Phe Leu Lys Met Asn Ser Leu Gln Thr Asp Asp Thr Ala
305 310 315 320
Ile Tyr Tyr Cys Ala Lys His Tyr Tyr Tyr Gly Gly Ser Tyr Ala Met
325 330 335
Asp Tyr Trp Gly Gln Gly Thr Ser Val Thr Val Ser Ser Gly Gly Gly
340 345 350
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met
355 360 365
Thr Gln Thr Thr Ser Ser Leu Ser Ala Ser Leu Gly Asp Arg Val Thr
370 375 380
Ile Ser Cys Arg Ala Ser Gln Asp Ile Ser Lys Tyr Leu Asn Trp Tyr
385 390 395 400
Gln Gln Lys Pro Asp Gly Thr Val Lys Leu Leu Ile Tyr His Thr Ser
405 410 415
Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly
420 425 430
Thr Asp Tyr Ser Leu Thr Ile Ser Asn Leu Glu Gln Glu Asp Ile Ala
435 440 445
Thr Tyr Phe Cys Gln Gln Gly Asn Thr Leu Pro Tyr Thr Phe Gly Gly
450 455 460
Gly Thr Lys Leu Glu Ile Thr
465 470
<210> 231
<211> 470
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 231
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe
20 25 30
Pro Met Ala Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Thr Ile Ser Thr Ser Gly Gly Arg Thr Tyr Tyr Arg Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Phe Arg Gln Tyr Ser Gly Gly Phe Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Gly Gly
210 215 220
Gly Ser Gly Gly Gly Gln Val Gln Leu Lys Gln Ser Gly Pro Gly Leu
225 230 235 240
Val Gln Pro Ser Gln Ser Leu Ser Ile Thr Cys Thr Val Ser Gly Phe
245 250 255
Ser Leu Thr Asn Tyr Gly Val His Trp Val Arg Gln Ser Pro Gly Lys
260 265 270
Gly Leu Glu Trp Leu Gly Val Ile Trp Ser Gly Gly Asn Thr Asp Tyr
275 280 285
Asn Thr Pro Phe Thr Ser Arg Leu Ser Ile Asn Lys Asp Asn Ser Lys
290 295 300
Ser Gln Val Phe Phe Lys Met Asn Ser Leu Gln Ser Asn Asp Thr Ala
305 310 315 320
Ile Tyr Tyr Cys Ala Arg Ala Leu Thr Tyr Tyr Asp Tyr Glu Phe Ala
325 330 335
Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ala Gly Gly Gly Gly
340 345 350
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Leu Leu Thr
355 360 365
Gln Ser Pro Val Ile Leu Ser Val Ser Pro Gly Glu Arg Val Ser Phe
370 375 380
Ser Cys Arg Ala Ser Gln Ser Ile Gly Thr Asn Ile His Trp Tyr Gln
385 390 395 400
Gln Arg Thr Asn Gly Ser Pro Arg Leu Leu Ile Lys Tyr Ala Ser Glu
405 410 415
Ser Ile Ser Gly Ile Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr
420 425 430
Asp Phe Thr Leu Ser Ile Asn Ser Val Glu Ser Glu Asp Ile Ala Asp
435 440 445
Tyr Tyr Cys Gln Gln Asn Asn Asn Trp Pro Thr Thr Phe Gly Ala Gly
450 455 460
Thr Lys Leu Glu Leu Lys
465 470
<210> 232
<211> 471
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 232
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe
20 25 30
Pro Met Ala Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Thr Ile Ser Thr Ser Gly Gly Arg Thr Tyr Tyr Arg Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Phe Arg Gln Tyr Ser Gly Gly Phe Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Gly Gly
210 215 220
Gly Ser Gly Gly Gly Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu
225 230 235 240
Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe
245 250 255
Asn Ile Lys Asp Thr Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys
260 265 270
Gly Leu Glu Trp Val Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg
275 280 285
Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser
290 295 300
Lys Asn Thr Ala Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr
305 310 315 320
Ala Val Tyr Tyr Cys Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met
325 330 335
Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly
340 345 350
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met
355 360 365
Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr
370 375 380
Ile Thr Cys Arg Ala Ser Gln Asp Val Asn Thr Ala Val Ala Trp Tyr
385 390 395 400
Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ser Ala Ser
405 410 415
Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Arg Ser Gly
420 425 430
Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala
435 440 445
Thr Tyr Tyr Cys Gln Gln His Tyr Thr Thr Pro Pro Thr Phe Gly Gln
450 455 460
Gly Thr Lys Val Glu Ile Lys
465 470
<210> 233
<211> 466
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 233
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe
20 25 30
Pro Met Ala Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Thr Ile Ser Thr Ser Gly Gly Arg Thr Tyr Tyr Arg Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Phe Arg Gln Tyr Ser Gly Gly Phe Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Gly Gly
210 215 220
Gly Ser Gly Gly Gly Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val
225 230 235 240
Lys Lys Pro Gly Ala Ser Val Lys Ile Ser Cys Lys Thr Ser Gly Tyr
245 250 255
Thr Phe Thr Glu Tyr Thr Ile His Trp Val Lys Gln Ala Ser Gly Lys
260 265 270
Gly Leu Glu Trp Ile Gly Asn Ile Asn Pro Asn Asn Gly Gly Thr Thr
275 280 285
Tyr Asn Gln Lys Phe Glu Asp Arg Ala Thr Leu Thr Val Asp Lys Ser
290 295 300
Thr Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr
305 310 315 320
Ala Val Tyr Tyr Cys Ala Ala Gly Trp Asn Phe Asp Tyr Trp Gly Gln
325 330 335
Gly Thr Thr Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly
340 345 350
Gly Ser Gly Gly Gly Gly Ser Asp Ile Val Met Thr Gln Ser Pro Ser
355 360 365
Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Lys Ala
370 375 380
Ser Gln Asp Val Gly Thr Ala Val Asp Trp Tyr Gln Gln Lys Pro Gly
385 390 395 400
Lys Ala Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg His Thr Gly
405 410 415
Val Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu
420 425 430
Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Asp Tyr Phe Cys Gln
435 440 445
Gln Tyr Asn Ser Tyr Pro Leu Thr Phe Gly Gly Gly Thr Lys Leu Glu
450 455 460
Ile Lys
465
<210> 234
<211> 473
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 234
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe
20 25 30
Pro Met Ala Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Thr Ile Ser Thr Ser Gly Gly Arg Thr Tyr Tyr Arg Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Phe Arg Gln Tyr Ser Gly Gly Phe Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Gly Gly
210 215 220
Gly Ser Gly Gly Gly Gln Val Gln Leu Val Gln Ser Gly Ser Glu Leu
225 230 235 240
Lys Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr
245 250 255
Thr Phe Thr Glu Tyr Gly Met Asn Val Trp Arg Gln Ala Pro Gly Gln
260 265 270
Gly Leu Glu Trp Met Gly Trp Ile Asn Thr Lys Ser Gly Glu Ala Thr
275 280 285
Tyr Val Glu Glu Phe Lys Gly Arg Phe Val Phe Ser Leu Asp Thr Ser
290 295 300
Val Ser Thr Ala Tyr Leu Gln Ile Ser Ser Leu Lys Ala Glu Asp Thr
305 310 315 320
Ala Val Tyr Tyr Cys Ala Arg Trp Asp Phe Tyr Asp Tyr Val Asp Glu
325 330 335
Ala Met Tyr Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Gly Gly
340 345 350
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln
355 360 365
Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val
370 375 380
Thr Ile Thr Cys Lys Ala Ser Gln Thr Val Ser Ala Asn Val Ala Trp
385 390 395 400
Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Leu Ala
405 410 415
Ser Tyr Arg Tyr Arg Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser
420 425 430
Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe
435 440 445
Ala Thr Tyr Tyr Cys His Gln Tyr Tyr Thr Tyr Pro Leu Phe Thr Phe
450 455 460
Gly Gln Gly Thr Lys Leu Glu Ile Lys
465 470
<210> 235
<211> 472
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 235
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe
20 25 30
Pro Met Ala Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Thr Ile Ser Thr Ser Gly Gly Arg Thr Tyr Tyr Arg Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Phe Arg Gln Tyr Ser Gly Gly Phe Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Gly Gly
210 215 220
Gly Ser Gly Gly Gly Glu Val Gln Leu Val Gln Ser Gly Pro Gly Leu
225 230 235 240
Val Gln Pro Gly Gly Ser Val Arg Ile Ser Cys Ala Ala Ser Gly Tyr
245 250 255
Thr Phe Thr Asn Tyr Gly Met Asn Trp Val Lys Gln Ala Pro Gly Lys
260 265 270
Gly Leu Glu Trp Met Gly Trp Ile Asn Thr Tyr Thr Gly Glu Ser Thr
275 280 285
Tyr Ala Asp Ser Phe Lys Gly Arg Phe Thr Phe Ser Leu Asp Thr Ser
290 295 300
Ala Ser Ala Ala Tyr Leu Gln Ile Asn Ser Leu Arg Ala Glu Asp Thr
305 310 315 320
Ala Val Tyr Tyr Cys Ala Arg Phe Ala Ile Lys Gly Asp Tyr Trp Gly
325 330 335
Gln Gly Thr Leu Leu Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly
340 345 350
Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro
355 360 365
Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg
370 375 380
Ser Thr Lys Ser Leu Leu His Ser Asn Gly Ile Thr Tyr Leu Tyr Trp
385 390 395 400
Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Gln Met
405 410 415
Ser Asn Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Ser Ser Gly Ser
420 425 430
Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe
435 440 445
Ala Thr Tyr Tyr Cys Ala Gln Asn Leu Glu Ile Pro Arg Thr Phe Gly
450 455 460
Gln Gly Thr Lys Val Glu Leu Lys
465 470
<210> 236
<211> 481
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 236
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe
20 25 30
Pro Met Ala Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Thr Ile Ser Thr Ser Gly Gly Arg Thr Tyr Tyr Arg Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Phe Arg Gln Tyr Ser Gly Gly Phe Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Gly Gly
210 215 220
Gly Ser Gly Gly Gly Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val
225 230 235 240
Lys Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Thr Ser Arg Tyr
245 250 255
Thr Phe Thr Glu Tyr Thr Ile His Trp Val Arg Gln Ala Pro Gly Gln
260 265 270
Arg Leu Glu Trp Ile Gly Gly Ile Asn Pro Asn Asn Gly Ile Pro Asn
275 280 285
Tyr Asn Gln Lys Phe Lys Gly Arg Val Thr Ile Thr Val Asp Thr Ser
290 295 300
Ala Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr
305 310 315 320
Ala Val Tyr Tyr Cys Ala Arg Arg Arg Ile Ala Tyr Gly Tyr Asp Glu
325 330 335
Gly His Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser
340 345 350
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
355 360 365
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
370 375 380
Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Leu Leu Tyr Ser
385 390 395 400
Arg Asn Gln Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln
405 410 415
Pro Pro Lys Leu Leu Ile Phe Trp Ala Ser Thr Arg Glu Ser Gly Val
420 425 430
Pro Asp Arg Phe Ser Gly Ser Gly Phe Gly Thr Asp Phe Thr Leu Thr
435 440 445
Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln
450 455 460
Tyr Phe Ser Tyr Pro Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile
465 470 475 480
Lys
<210> 237
<211> 469
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 237
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe
20 25 30
Pro Met Ala Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Thr Ile Ser Thr Ser Gly Gly Arg Thr Tyr Tyr Arg Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Phe Arg Gln Tyr Ser Gly Gly Phe Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Gly Gly
210 215 220
Gly Ser Gly Gly Gly Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu
225 230 235 240
Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe
245 250 255
Thr Phe Ser Asp Ser Trp Ile His Trp Val Arg Gln Ala Pro Gly Lys
260 265 270
Gly Leu Glu Trp Val Ala Trp Ile Ser Pro Tyr Gly Gly Ser Thr Tyr
275 280 285
Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser
290 295 300
Lys Asn Thr Ala Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr
305 310 315 320
Ala Val Tyr Tyr Cys Ala Arg Arg His Trp Pro Gly Gly Phe Asp Tyr
325 330 335
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser
340 345 350
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln
355 360 365
Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr
370 375 380
Cys Arg Ala Ser Gln Asp Val Ser Thr Ala Val Ala Trp Tyr Gln Gln
385 390 395 400
Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ser Ala Ser Phe Leu
405 410 415
Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp
420 425 430
Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr
435 440 445
Tyr Cys Gln Gln Tyr Leu Tyr His Pro Ala Thr Phe Gly Gln Gly Thr
450 455 460
Lys Val Glu Ile Lys
465
<210> 238
<211> 473
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 238
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe
20 25 30
Pro Met Ala Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Thr Ile Ser Thr Ser Gly Gly Arg Thr Tyr Tyr Arg Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Phe Arg Gln Tyr Ser Gly Gly Phe Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Gly Gly
210 215 220
Gly Ser Gly Gly Gly Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu
225 230 235 240
Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Phe
245 250 255
Thr Phe Asn Ser Phe Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys
260 265 270
Gly Leu Glu Trp Val Ser Ala Ile Ser Gly Ser Gly Gly Gly Thr Tyr
275 280 285
Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser
290 295 300
Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr
305 310 315 320
Ala Val Tyr Phe Cys Ala Lys Asp Lys Ile Leu Trp Phe Gly Glu Pro
325 330 335
Val Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly
340 345 350
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Ile
355 360 365
Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly Glu Arg
370 375 380
Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Tyr Leu Ala
385 390 395 400
Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile Tyr Asp
405 410 415
Ala Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly Ser Gly
420 425 430
Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro Glu Asp
435 440 445
Phe Ala Val Tyr Tyr Cys Gln Gln Arg Ser Asn Trp Pro Pro Thr Phe
450 455 460
Gly Gln Gly Thr Lys Val Glu Ile Lys
465 470
<210> 239
<211> 471
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 239
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe
20 25 30
Pro Met Ala Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Thr Ile Ser Thr Ser Gly Gly Arg Thr Tyr Tyr Arg Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Phe Arg Gln Tyr Ser Gly Gly Phe Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Gly Gly
210 215 220
Gly Ser Gly Gly Gly Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val
225 230 235 240
Lys Lys Pro Gly Ser Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr
245 250 255
Thr Ile Thr Asp Ser Asn Ile His Trp Val Arg Gln Ala Pro Gly Gln
260 265 270
Ser Leu Glu Trp Ile Gly Tyr Ile Tyr Pro Tyr Asn Gly Gly Thr Asp
275 280 285
Tyr Asn Gln Lys Phe Lys Asn Arg Ala Thr Leu Thr Val Asp Asn Pro
290 295 300
Thr Asn Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr
305 310 315 320
Ala Phe Tyr Tyr Cys Val Asn Gly Asn Pro Trp Leu Ala Tyr Trp Gly
325 330 335
Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly
340 345 350
Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Leu Thr Gln Ser Pro
355 360 365
Ser Thr Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg
370 375 380
Ala Ser Glu Ser Leu Asp Asn Tyr Gly Ile Arg Phe Leu Thr Trp Phe
385 390 395 400
Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Met Tyr Ala Ala Ser
405 410 415
Asn Gln Gly Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly
420 425 430
Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Asp Asp Phe Ala
435 440 445
Thr Tyr Tyr Cys Gln Gln Thr Lys Glu Val Pro Trp Ser Phe Gly Gln
450 455 460
Gly Thr Lys Val Glu Val Lys
465 470
<210> 240
<211> 476
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 240
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe
20 25 30
Pro Met Ala Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Thr Ile Ser Thr Ser Gly Gly Arg Thr Tyr Tyr Arg Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Phe Arg Gln Tyr Ser Gly Gly Phe Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Gly Gly
210 215 220
Gly Ser Gly Gly Gly Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu
225 230 235 240
Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr
245 250 255
Thr Phe Thr Ser Tyr Trp Leu His Trp Val Arg Gln Ala Pro Gly Lys
260 265 270
Gly Leu Glu Trp Val Gly Met Ile Asp Pro Ser Asn Ser Asp Thr Arg
275 280 285
Phe Asn Pro Asn Phe Lys Asp Arg Phe Thr Ile Ser Ala Asp Thr Ser
290 295 300
Lys Asn Thr Ala Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr
305 310 315 320
Ala Val Tyr Tyr Cys Ala Thr Tyr Arg Ser Tyr Val Thr Pro Leu Asp
325 330 335
Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly
340 345 350
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr
355 360 365
Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile
370 375 380
Thr Cys Lys Ser Ser Gln Ser Leu Leu Tyr Thr Ser Ser Gln Lys Asn
385 390 395 400
Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu
405 410 415
Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val Pro Ser Arg Phe Ser
420 425 430
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln
435 440 445
Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Tyr Ala Tyr Pro
450 455 460
Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
465 470 475
<210> 241
<211> 473
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 241
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe
20 25 30
Pro Met Ala Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Thr Ile Ser Thr Ser Gly Gly Arg Thr Tyr Tyr Arg Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Phe Arg Gln Tyr Ser Gly Gly Phe Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Gly Gly
210 215 220
Gly Ser Gly Gly Gly Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val
225 230 235 240
Lys Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr
245 250 255
Thr Phe Thr Asn Tyr Asn Met His Trp Val Arg Gln Ala Pro Gly Gln
260 265 270
Arg Leu Glu Trp Met Gly Thr Ile Tyr Pro Gly Asn Asp Asp Thr Ser
275 280 285
Tyr Asn Gln Lys Phe Lys Asp Arg Val Thr Ile Thr Ala Asp Thr Ser
290 295 300
Ala Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr
305 310 315 320
Ala Val Tyr Tyr Cys Ala Arg Gly Gly Tyr Arg Ala Met Asp Tyr Trp
325 330 335
Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly
340 345 350
Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Val Met Thr Gln Ser
355 360 365
Pro Leu Ser Leu Pro Val Thr Pro Gly Glu Pro Ala Ser Ile Ser Cys
370 375 380
Arg Ser Ser Gln Ser Ile Val Tyr Ser Asn Gly Asn Thr Tyr Leu Gly
385 390 395 400
Trp Tyr Leu Gln Lys Pro Gly Gln Ser Pro Gln Leu Leu Ile Tyr Lys
405 410 415
Val Ser Asn Arg Phe Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly
420 425 430
Ser Gly Thr Asp Phe Thr Leu Lys Ile Ser Arg Val Glu Ala Glu Asp
435 440 445
Val Gly Val Tyr Tyr Cys Phe Gln Gly Ser His Val Pro Tyr Thr Phe
450 455 460
Gly Gln Gly Thr Lys Leu Glu Ile Lys
465 470
<210> 242
<211> 474
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 242
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe
20 25 30
Pro Met Ala Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Thr Ile Ser Thr Ser Gly Gly Arg Thr Tyr Tyr Arg Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Phe Arg Gln Tyr Ser Gly Gly Phe Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Gly Gly
210 215 220
Gly Ser Gly Gly Gly Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu
225 230 235 240
Val Lys Pro Ser Gln Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly
245 250 255
Ser Ile Ser Ser Gly Asp Tyr Phe Trp Ser Trp Ile Arg Gln Leu Pro
260 265 270
Gly Lys Gly Leu Glu Trp Ile Gly His Ile His Asn Ser Gly Thr Thr
275 280 285
Tyr Tyr Asn Pro Ser Leu Lys Ser Arg Val Thr Ile Ser Val Asp Thr
290 295 300
Ser Lys Lys Gln Phe Ser Leu Arg Leu Ser Ser Val Thr Ala Ala Asp
305 310 315 320
Thr Ala Val Tyr Tyr Cys Ala Arg Asp Arg Gly Gly Asp Tyr Tyr Tyr
325 330 335
Gly Met Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Gly
340 345 350
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Ile
355 360 365
Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly Glu Arg
370 375 380
Ala Thr Leu Ser Cys Arg Ala Ser Gln Gly Ile Ser Arg Ser Tyr Leu
385 390 395 400
Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Ser Leu Leu Ile Tyr
405 410 415
Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser Gly Ser
420 425 430
Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu Pro Glu
435 440 445
Asp Phe Ala Val Tyr Tyr Cys Gln Gln Phe Gly Ser Ser Pro Trp Thr
450 455 460
Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
465 470
<210> 243
<211> 470
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 243
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe
20 25 30
Pro Met Ala Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Thr Ile Ser Thr Ser Gly Gly Arg Thr Tyr Tyr Arg Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Phe Arg Gln Tyr Ser Gly Gly Phe Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Gly Gly
210 215 220
Gly Ser Gly Gly Gly Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu
225 230 235 240
Val Lys Pro Ser Glu Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly
245 250 255
Ser Val Ser Ser Gly Ser Tyr Tyr Trp Ser Trp Ile Arg Gln Pro Pro
260 265 270
Gly Lys Gly Leu Glu Trp Ile Gly Tyr Ile Tyr Tyr Ser Gly Ser Thr
275 280 285
Asn Tyr Asn Pro Ser Leu Lys Ser Arg Val Thr Ile Ser Val Asp Thr
290 295 300
Ser Lys Asn Gln Phe Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp
305 310 315 320
Thr Ala Val Tyr Tyr Cys Ala Arg Glu Gly Lys Asn Gly Ala Phe Asp
325 330 335
Ile Trp Gly Gln Gly Thr Met Val Thr Val Ser Ser Gly Gly Gly Gly
340 345 350
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr
355 360 365
Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile
370 375 380
Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr Leu Asn Trp Tyr Gln
385 390 395 400
Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ala Ala Ser Ser
405 410 415
Leu Gln Ser Gly Val Pro Ser Gly Phe Ser Gly Ser Gly Ser Gly Thr
420 425 430
Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr
435 440 445
Tyr Tyr Cys Gln Gln Ser Tyr Ser Thr Pro Leu Thr Phe Gly Gly Gly
450 455 460
Thr Lys Val Glu Ile Lys
465 470
<210> 244
<211> 470
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 244
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe
20 25 30
Pro Met Ala Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Thr Ile Ser Thr Ser Gly Gly Arg Thr Tyr Tyr Arg Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Phe Arg Gln Tyr Ser Gly Gly Phe Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Gly Gly
210 215 220
Gly Ser Gly Gly Gly Glu Val Gln Leu Leu Gln Ser Gly Pro Glu Leu
225 230 235 240
Glu Lys Pro Gly Ala Ser Val Met Ile Ser Cys Lys Ala Ser Gly Ser
245 250 255
Ser Phe Thr Gly Tyr Asn Met Asn Trp Val Arg Gln Asn Ile Gly Lys
260 265 270
Ser Leu Glu Trp Ile Gly Ala Ile Asp Pro Tyr Tyr Gly Gly Thr Ser
275 280 285
Tyr Asn Gln Lys Phe Lys Gly Arg Ala Thr Leu Thr Val Asp Lys Ser
290 295 300
Ser Ser Thr Ala Tyr Met His Leu Lys Ser Leu Thr Ser Glu Asp Ser
305 310 315 320
Ala Val Tyr Tyr Cys Val Ser Gly Met Glu Tyr Trp Gly Gln Gly Thr
325 330 335
Ser Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
340 345 350
Gly Gly Gly Gly Ser Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu
355 360 365
Ser Val Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg Ser Ser Gln
370 375 380
Ser Leu Val His Arg Asn Gly Asn Thr Tyr Leu His Trp Tyr Leu Gln
385 390 395 400
Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile His Lys Val Ser Asn Arg
405 410 415
Phe Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp
420 425 430
Phe Thr Leu Lys Ile Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr
435 440 445
Phe Cys Ser Gln Ser Thr His Val Pro Pro Leu Thr Phe Gly Ala Gly
450 455 460
Thr Lys Leu Glu Leu Lys
465 470
<210> 245
<211> 471
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 245
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe
20 25 30
Pro Met Ala Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Thr Ile Ser Thr Ser Gly Gly Arg Thr Tyr Tyr Arg Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Phe Arg Gln Tyr Ser Gly Gly Phe Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Gly Gly
210 215 220
Gly Ser Gly Gly Gly Glu Val Lys Leu Gln Glu Ser Gly Pro Gly Leu
225 230 235 240
Val Ala Pro Ser Gln Ser Leu Ser Val Thr Cys Thr Val Ser Gly Val
245 250 255
Ser Leu Pro Asp Tyr Gly Val Ser Trp Ile Arg Gln Pro Pro Arg Lys
260 265 270
Gly Leu Glu Trp Leu Gly Val Ile Trp Gly Ser Glu Thr Thr Tyr Tyr
275 280 285
Asn Ser Ala Leu Lys Ser Arg Leu Thr Ile Ile Lys Asp Asn Ser Lys
290 295 300
Ser Gln Val Phe Leu Lys Met Asn Ser Leu Gln Thr Asp Asp Thr Ala
305 310 315 320
Ile Tyr Tyr Cys Ala Lys His Tyr Tyr Tyr Gly Gly Ser Tyr Ala Met
325 330 335
Asp Tyr Trp Gly Gln Gly Thr Ser Val Thr Val Ser Ser Gly Gly Gly
340 345 350
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met
355 360 365
Thr Gln Thr Thr Ser Ser Leu Ser Ala Ser Leu Gly Asp Arg Val Thr
370 375 380
Ile Ser Cys Arg Ala Ser Gln Asp Ile Ser Lys Tyr Leu Asn Trp Tyr
385 390 395 400
Gln Gln Lys Pro Asp Ala Thr Val Lys Leu Leu Ile Tyr His Thr Ser
405 410 415
Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly
420 425 430
Thr Asp Tyr Ser Leu Thr Ile Ser Asn Leu Glu Gln Glu Asp Ile Ala
435 440 445
Thr Tyr Phe Cys Gln Gln Gly Asn Thr Leu Pro Tyr Thr Phe Gly Gly
450 455 460
Gly Thr Lys Leu Glu Ile Thr
465 470
<210> 246
<211> 471
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 246
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe
20 25 30
Pro Met Ala Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Thr Ile Ser Thr Ser Gly Gly Arg Thr Tyr Tyr Arg Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Phe Arg Gln Tyr Ser Gly Gly Phe Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Gly Gly
210 215 220
Gly Ser Gly Gly Gly Glu Val Lys Leu Gln Glu Ser Gly Pro Gly Leu
225 230 235 240
Val Ala Pro Ser Gln Ser Leu Ser Val Thr Cys Thr Val Ser Gly Val
245 250 255
Ser Leu Pro Asp Tyr Gly Val Ser Trp Ile Arg Gln Pro Pro Arg Lys
260 265 270
Gly Leu Glu Trp Leu Gly Val Ile Trp Gly Ser Glu Thr Thr Tyr Tyr
275 280 285
Asn Ser Ala Leu Lys Ser Arg Leu Thr Ile Ile Lys Asp Asn Ser Lys
290 295 300
Ser Gln Val Phe Leu Lys Met Asn Ser Leu Gln Thr Asp Asp Thr Ala
305 310 315 320
Ile Tyr Tyr Cys Ala Lys His Tyr Tyr Tyr Gly Gly Ser Tyr Ala Met
325 330 335
Asp Tyr Trp Gly Gln Gly Thr Ser Val Thr Val Ser Ser Gly Gly Gly
340 345 350
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met
355 360 365
Thr Gln Thr Thr Ser Ser Leu Ser Ala Ser Leu Gly Asp Arg Val Thr
370 375 380
Ile Ser Cys Arg Ala Ser Gln Asp Ile Ser Lys Tyr Leu Asn Trp Tyr
385 390 395 400
Gln Gln Lys Pro Glu Gly Thr Val Lys Leu Leu Ile Tyr His Thr Ser
405 410 415
Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly
420 425 430
Thr Asp Tyr Ser Leu Thr Ile Ser Asn Leu Glu Gln Glu Asp Ile Ala
435 440 445
Thr Tyr Phe Cys Gln Gln Gly Asn Thr Leu Pro Tyr Thr Phe Gly Gly
450 455 460
Gly Thr Lys Leu Glu Ile Thr
465 470
<210> 247
<211> 471
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 247
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe
20 25 30
Pro Met Ala Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Thr Ile Ser Thr Ser Gly Gly Arg Thr Tyr Tyr Arg Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Phe Arg Gln Tyr Ser Gly Gly Phe Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Gly Gly
210 215 220
Gly Ser Gly Gly Gly Glu Val Lys Leu Gln Glu Ser Gly Pro Gly Leu
225 230 235 240
Val Ala Pro Ser Gln Ser Leu Ser Val Thr Cys Thr Val Ser Gly Val
245 250 255
Ser Leu Pro Asp Tyr Gly Val Ser Trp Ile Arg Gln Pro Pro Arg Lys
260 265 270
Gly Leu Glu Trp Leu Gly Val Ile Trp Gly Ser Glu Thr Thr Tyr Tyr
275 280 285
Asn Ser Ala Leu Lys Ser Arg Leu Thr Ile Ile Lys Asp Asn Ser Lys
290 295 300
Ser Gln Val Phe Leu Lys Met Asn Ser Leu Gln Thr Asp Asp Thr Ala
305 310 315 320
Ile Tyr Tyr Cys Ala Lys His Tyr Tyr Tyr Gly Gly Ser Tyr Ala Met
325 330 335
Asp Tyr Trp Gly Gln Gly Thr Ser Val Thr Val Ser Ser Gly Gly Gly
340 345 350
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met
355 360 365
Thr Gln Thr Thr Ser Ser Leu Ser Ala Ser Leu Gly Asp Arg Val Thr
370 375 380
Ile Ser Cys Arg Ala Ser Gln Asp Ile Ser Lys Tyr Leu Asn Trp Tyr
385 390 395 400
Gln Gln Lys Pro Glu Gly Thr Val Lys Leu Leu Ile Tyr His Thr Ser
405 410 415
Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly
420 425 430
Thr Asp Tyr Ser Leu Thr Ile Ser Asn Leu Glu Gln Glu Asp Ile Ala
435 440 445
Thr Tyr Phe Cys Gln Gln Gly Asn Thr Leu Pro Tyr Thr Phe Gly Gly
450 455 460
Gly Thr Lys Leu Glu Ile Thr
465 470
<210> 248
<211> 471
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 248
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe
20 25 30
Pro Met Ala Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Thr Ile Ser Thr Ser Gly Gly Arg Thr Tyr Tyr Arg Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Phe Arg Gln Tyr Ser Gly Gly Phe Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Gly Gly
210 215 220
Gly Ser Gly Gly Gly Glu Val Lys Leu Gln Glu Ser Gly Pro Gly Leu
225 230 235 240
Val Ala Pro Ser Gln Ser Leu Ser Val Thr Cys Thr Val Ser Gly Val
245 250 255
Ser Leu Pro Asp Tyr Gly Val Ser Trp Ile Arg Gln Pro Pro Arg Lys
260 265 270
Gly Leu Glu Trp Leu Gly Val Ile Trp Gly Ser Glu Thr Thr Tyr Tyr
275 280 285
Asn Ser Ala Leu Lys Ser Arg Leu Thr Ile Ile Lys Asp Asn Ser Lys
290 295 300
Ser Gln Val Phe Leu Lys Met Asn Ser Leu Gln Thr Asp Asp Thr Ala
305 310 315 320
Ile Tyr Tyr Cys Ala Lys His Tyr Tyr Tyr Gly Gly Ser Tyr Ala Met
325 330 335
Asp Tyr Trp Gly Gln Gly Thr Ser Val Thr Val Ser Ser Gly Gly Gly
340 345 350
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met
355 360 365
Thr Gln Thr Thr Ser Ser Leu Ser Ala Ser Leu Gly Asp Arg Val Thr
370 375 380
Ile Ser Cys Arg Ala Ser Gln Asp Ile Ser Lys Tyr Leu Asn Trp Tyr
385 390 395 400
Gln Gln Lys Pro Asp Ala Thr Val Lys Leu Leu Ile Tyr His Thr Ser
405 410 415
Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly
420 425 430
Thr Asp Tyr Ser Leu Thr Ile Ser Asn Leu Glu Gln Glu Asp Ile Ala
435 440 445
Thr Tyr Phe Cys Gln Gln Gly Asn Thr Leu Pro Tyr Thr Phe Gly Gly
450 455 460
Gly Thr Lys Leu Glu Ile Thr
465 470
<210> 249
<211> 112
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 249
Asp Ile Gln Leu Thr Gln Pro Asn Ser Val Ser Thr Ser Leu Gly Ser
1 5 10 15
Thr Val Lys Leu Ser Cys Thr Leu Ser Ser Gly Asn Ile Glu Asn Asn
20 25 30
Tyr Val His Trp Tyr Gln Leu Tyr Glu Gly Arg Ser Pro Thr Thr Met
35 40 45
Ile Tyr Asp Asp Asp Lys Arg Pro Glu Gly Val Pro Asp Arg Phe Ser
50 55 60
Gly Ser Ile Asp Arg Ser Ser Asn Ser Ala Phe Leu Thr Ile His Asn
65 70 75 80
Val Ala Ile Glu Asp Glu Ala Ile Tyr Phe Cys His Ser Tyr Val Ser
85 90 95
Ser Phe Asn Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Arg Gln
100 105 110
Claims (39)
1.一种双特异性抗体,其包括:
(a)第一抗原结合片段,其结合人CD3,其中所述第一抗原结合片段包括第一重链和第一轻链,所述第一重链包括第一重链可变区(VH),所述第一轻链包括第一轻链可变区(VL),其中所述第一VH包括与第一参考抗体相同的重链互补决定区(CDR)或不超过5个相对于第一参考抗体的氨基酸变异,且所述第一VL包括与所述参考抗体相同的轻链CDR或不超过5个相对于所述参考抗体的氨基酸变异,且其中所述第一参考抗体为CTA.02、CTA.03、CTA.04或CTA.05;及
(b)第二抗原结合片段,其结合肿瘤相关抗原(TAA),其中所述第二抗原结合片段包括第二重链和第二轻链,所述第二重链包括第二重链可变区(VH),所述第二轻链包括第二轻链可变区(VL)。
2.根据权利要求1所述的双特异性抗体,其中所述第一重链和所述第一轻链包括与所述第一参考抗体相同的VH和VL。
3.根据权利要求1或权利要求2所述的双特异性抗体,其中所述第二抗原结合片段结合TAA,所述TAA为CD20、CD19、EGFR、HER2、PSMA、CEA、EpCAM、FAP、PD-L1、CD38、CD33、cMET、CD47、TRAIL-R2、间皮素或GD2。
4.根据权利要求3所述的双特异性抗体,其中所述第二VH包括与第二参考抗体相同的重链互补决定区(CDR)或不超过五个相对于第二参考抗体的氨基酸变异,且所述第二VL包括与所述第二参考抗体相同的轻链CDR或不超过5个相对于所述第二参考抗体的氨基酸变异,且其中所述第二参考抗体为CTAT.01、CTAT.02、CTAT.03、CTAT.04、CTAT.05、CTAT.06、CTAT.07、CTAT.08、CTAT.09、CTAT.10、CTAT.11、CTAT.12、CTAT.13、CTAT.14、CTAT.15或CTAT.16。
5.根据权利要求4所述的双特异性抗体,其中所述第二抗原结合片段包括与所述第二参考抗体相同的VH和相同的VL。
6.根据权利要求1至5中任一权利要求所述的双特异性抗体,其中所述第一抗原结合片段为Fab片段,且所述第二抗原结合片段为单链可变片段(scFv),且其中所述Fab片段包括所述第一重链和所述第一轻链,所述第一重链包括所述第一VH和CH1片段,所述第一轻链包括所述第一VL和轻链恒定区。
7.根据权利要求6所述的双特异性抗体,其中所述Fab片段包括所述第一重链和所述第一轻链,其分别包括以下氨基酸序列:(a)SEQ ID NO:10和SEQ ID NO:11,(b)SEQ ID NO:23和SEQ ID NO:24、25或228,(c)SEQ ID NO:35和SEQ ID NO:36,或(d)SEQ ID NO:46和SEQID NO:47。
8.根据权利要求6或权利要求7所述的双特异性抗体,其中所述第二抗原结合片段的所述scFv包括SEQ ID NO:254至271中的任一个氨基酸序列。
9.根据权利要求6至8中任一权利要求所述的双特异性抗体,其中所述scFv经由肽连接子连接到所述CH1片段或所述轻链恒定区。
10.根据权利要求7所述的双特异性抗体,其中所述双特异性抗体包括第一多肽和第二多肽,所述第一多肽包括所述第一轻链,所述第二多肽从N端到C端包括所述第一重链、所述肽连接子和所述scFv。
11.根据权利要求8所述的双特异性抗体,其中所述第一多肽包括选自由SEQ ID NO:229至248组成的组的氨基酸序列。
12.根据权利要求10或权利要求11所述的双特异性抗体,其中所述第二多肽包括选自由SEQ ID NO:24、25和228组成的组的氨基酸序列。
13.根据权利要求1至5中任一权利要求所述的双特异性抗体,其中所述第一抗原结合片段为单链可变片段(scFv),且所述第二抗原结合片段为Fab片段,且其中所述Fab片段包括所述第二重链和所述第二轻链,所述第二重链包括所述第二VH和CH1片段,所述第二轻链包括所述第二VL和轻链恒定区。
14.根据权利要求13所述的双特异性抗体,其中所述scFv包括SEQ ID NO:250至253中的任一个氨基酸序列。
15.根据权利要求13或权利要求14所述的双特异性抗体,其中所述Fab片段包括所述第一重链和所述第一轻链,其分别包括以下氨基酸序列:(1)SEQ ID NO:57和SEQ ID NO:58,(2)SEQ ID NO:72和SEQ ID NO:73,(3)SEQ ID NO:83和SEQ ID NO:84,(4)SEQ ID NO:94和SEQ ID NO:95,(5)SEQ ID NO:105和SEQ ID NO:106,(6)SEQ ID NO:116和SEQ ID NO:117,(7)SEQ ID NO:127和SEQ ID NO:128,(8)SEQ ID NO:138和SEQ ID NO:139,(9)SEQ ID NO:149和SEQ ID NO:150,(10)SEQ ID NO:160和SEQ ID NO:161,(11)SEQ ID NO:171和SEQ IDNO:172,(12)SEQ ID NO:182和SEQ ID NO:183,(13)SEQ ID NO:193和SEQ ID NO:194,(14)SEQ ID NO:204和SEQ ID NO:205,(15)SEQ ID NO:215和SEQ ID NO:216,或(16)SEQ IDNO:226和SEQ ID NO:227。
16.根据权利要求13至15中任一权利要求所述的双特异性抗体,其中所述scFv经由肽连接子连接到所述CH1片段或所述轻链恒定区,所述肽连接子的长度任选地为至少5个氨基酸。
17.根据权利要求1至5中任一权利要求所述的双特异性抗体,其中所述第一抗原结合片段和所述第二抗原结合片段都为scFv抗体。
18.根据权利要求13所述的双特异性抗体,其中所述双特异性抗体包括含有所述两种scFv抗体的多肽。
19.一种武装免疫细胞,其包括表达表面CD3的免疫细胞和根据权利要求1至18中任一权利要求所述的双特异性抗体,其中所述武装免疫细胞经由所述双特异性抗体中的第一抗原结合片段与由所述免疫细胞表达的所述CD3之间的相互作用将所述双特异性抗体呈现在所述表面上。
20.根据权利要求19所述的武装免疫细胞,其中所述免疫细胞为T细胞、B细胞、单核细胞、巨噬细胞或其组合。
21.根据权利要求20所述的武装免疫细胞,其中所述T细胞为CD4+T细胞、CD8+T细胞、调节T细胞或自然杀手T细胞。
22.根据权利要求19至21中任一权利要求所述的武装免疫细胞,其中所述免疫细胞为人免疫细胞。
23.根据权利要求22所述的武装免疫细胞,其中所述人免疫细胞来源于人类供体。
24.一种产生根据权利要求19所述的武装免疫细胞的方法,其包括在双特异性抗体存在下培养包括所述免疫细胞的细胞群体以使所述双特异性抗体与所述免疫细胞结合,从而产生所述武装免疫细胞。
25.根据权利要求24所述的方法,其中所述细胞群体包括T细胞、B细胞、单核细胞、巨噬细胞或其组合。
26.根据权利要求25所述的方法,其中所述细胞群体包括来源于体外干细胞的外周血单核细胞(PBMC)或免疫细胞,且任选地其中所述干细胞为造血干细胞、脐带血干细胞或诱导性多能干细胞(iPS)细胞。
27.根据权利要求24至26中任一权利要求所述的方法,其中所述培养步骤在包括细胞因子的培养基中进行,所述细胞因子任选地包括白介素2(IL-2)、白介素7(IL-7)、转化生长因子-β(TGF-β)或其组合。
28.一种武装免疫细胞群体,其通过根据权利要求24至27中任一权利要求所述的方法产生。
29.一种用于治疗癌症的方法,其包括向有需要的受试者施用有效量的权利要求19至23及28中任一权利要求中所阐述的武装免疫细胞群体,其中所述受试者患有或怀疑患有TAA阳性的癌症,所述双特异性抗体的第二抗原结合片段结合所述TAA。
30.根据权利要求29所述的方法,其中所述受试者为人类癌症患者。
31.根据权利要求29或权利要求30所述的方法,其中所述武装免疫细胞为所述受试者自体的。
32.根据权利要求29或权利要求30所述的方法,其中所述武装免疫细胞为所述受试者同种异体的。
33.根据权利要求29至32中任一权利要求所述的方法,其中所述癌症选自由以下组成的组:黑色素瘤、食道癌、胃癌、脑瘤、小细胞肺癌、非小细胞肺癌、膀胱癌、乳腺癌、胰腺癌、结肠癌、直肠癌、结肠直肠癌、肾癌、肝细胞癌、卵巢癌、前列腺癌、甲状腺癌、睾丸癌、头颈部鳞状细胞癌、白血病、淋巴瘤和骨髓瘤。
34.一种核酸或核酸集合,其编码或共同编码权利要求1至18中任一权利要求中所阐述的双特异性抗体。
35.根据权利要求34所述的核酸或核酸集合,其为载体或载体集合。
36.根据权利要求35所述的核酸或核酸集合,其中所述载体为表达载体。
37.一种宿主细胞,其包括权利要求34至36中任一权利要求中所阐述的核酸或核酸集合。
38.根据权利要求37所述的宿主细胞,其中所述宿主细胞为细菌细胞、酵母细胞或哺乳动物细胞。
39.一种用于产生双特异性抗体的方法,其包括:
(i)在允许表达所述双特异性抗体的条件下培养根据权利要求37或权利要求38所述的宿主细胞;及
(ii)收集所述双特异性抗体。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US202062993080P | 2020-03-23 | 2020-03-23 | |
US62/993,080 | 2020-03-23 | ||
PCT/US2021/023655 WO2021195067A1 (en) | 2020-03-23 | 2021-03-23 | Bi-specific antibodies for use in producing armed immune cells |
Publications (1)
Publication Number | Publication Date |
---|---|
CN115551890A true CN115551890A (zh) | 2022-12-30 |
Family
ID=77892613
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202180029464.3A Pending CN115551890A (zh) | 2020-03-23 | 2021-03-23 | 用于产生武装免疫细胞的双特异性抗体 |
Country Status (8)
Country | Link |
---|---|
US (1) | US20240209084A1 (zh) |
EP (1) | EP4126954A4 (zh) |
JP (1) | JP2023519851A (zh) |
CN (1) | CN115551890A (zh) |
AU (1) | AU2021244375A1 (zh) |
IL (1) | IL296566A (zh) |
TW (1) | TW202202522A (zh) |
WO (1) | WO2021195067A1 (zh) |
Families Citing this family (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2020232247A1 (en) | 2019-05-14 | 2020-11-19 | Provention Bio, Inc. | Methods and compositions for preventing type 1 diabetes |
BR112022025381A2 (pt) | 2020-06-11 | 2023-01-24 | Provention Bio Inc | Métodos e composições para prevenir diabetes tipo 1 |
TW202323295A (zh) * | 2021-08-11 | 2023-06-16 | 賽昂生醫股份有限公司 | 用於產生武裝免疫細胞的方法 |
WO2023143478A1 (en) * | 2022-01-27 | 2023-08-03 | Crown Bioscience Inc. | Novel anti-cd4 and anti-pd-l1 bispecific antibodies |
Family Cites Families (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20030108548A1 (en) * | 1993-06-01 | 2003-06-12 | Bluestone Jeffrey A. | Methods and materials for modulation of the immunosuppressive activity and toxicity of monoclonal antibodies |
US20060134105A1 (en) * | 2004-10-21 | 2006-06-22 | Xencor, Inc. | IgG immunoglobulin variants with optimized effector function |
US9315567B2 (en) * | 2012-08-14 | 2016-04-19 | Ibc Pharmaceuticals, Inc. | T-cell redirecting bispecific antibodies for treatment of disease |
KR102614189B1 (ko) * | 2014-11-17 | 2023-12-18 | 리제너론 파아마슈티컬스, 인크. | Cd3xcd20 이특이적 항체를 이용한 종양의 치료 방법 |
KR102367658B1 (ko) * | 2017-03-29 | 2022-02-25 | 타이페이 메디컬 유니이버시티 | 항원 특이적 t 세포 및 그의 용도 |
WO2019234241A1 (en) * | 2018-06-07 | 2019-12-12 | Oncoone Research & Development Gmbh | ANTI-oxMIF/ANTI-CD3 ANTIBODY FOR CANCER TREATMENT |
-
2021
- 2021-03-23 AU AU2021244375A patent/AU2021244375A1/en active Pending
- 2021-03-23 TW TW110110483A patent/TW202202522A/zh unknown
- 2021-03-23 JP JP2022558065A patent/JP2023519851A/ja active Pending
- 2021-03-23 WO PCT/US2021/023655 patent/WO2021195067A1/en unknown
- 2021-03-23 IL IL296566A patent/IL296566A/en unknown
- 2021-03-23 CN CN202180029464.3A patent/CN115551890A/zh active Pending
- 2021-03-23 EP EP21774346.7A patent/EP4126954A4/en active Pending
- 2021-03-23 US US17/913,775 patent/US20240209084A1/en active Pending
Also Published As
Publication number | Publication date |
---|---|
US20240209084A1 (en) | 2024-06-27 |
JP2023519851A (ja) | 2023-05-15 |
TW202202522A (zh) | 2022-01-16 |
IL296566A (en) | 2022-11-01 |
EP4126954A4 (en) | 2024-08-21 |
WO2021195067A1 (en) | 2021-09-30 |
AU2021244375A1 (en) | 2022-10-13 |
EP4126954A1 (en) | 2023-02-08 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
AU2020203137B2 (en) | Bispecific chimeric antigen receptors and therapeutic uses thereof | |
US11679127B2 (en) | Antigen binding receptors specific for mutated Fc domains | |
CN109096396B (zh) | 一种抗pd-l1人源化纳米抗体及其应用 | |
CN115551890A (zh) | 用于产生武装免疫细胞的双特异性抗体 | |
US20200093861A1 (en) | Antigen binding receptor formats | |
JP2019068855A (ja) | Aprilバリアント | |
EP3875484A1 (en) | Cll1-targeting antibody and application thereof | |
JP2022523781A (ja) | Dll3標的化キメラ抗原受容体および結合剤 | |
CN113784980B (zh) | 人源化抗Claudin18.2嵌合抗原受体及其用途 | |
KR20200021074A (ko) | Hla 제한된 방식으로 hla-a2/tyrd를 결합할 수 있는 항체 및 이의 용도 | |
US20240052031A1 (en) | Cea6 binding molecules and uses thereof | |
US20230265185A1 (en) | Anti-cd22 single domain antibodies and therapeutic constructs | |
US20240084011A1 (en) | Anti-CTLA4 monoclonal antibodies and chimeric antigen receptors | |
WO2022133116A1 (en) | Mesothelin binding molecules and uses thereof | |
JP2023539654A (ja) | 抗ox40抗体、その医薬組成物および応用 | |
WO2023199927A1 (ja) | がん治療におけるpd-1シグナル阻害剤との組み合わせによる抗tspan8-抗cd3二重特異性抗体の使用 | |
TW202323295A (zh) | 用於產生武裝免疫細胞的方法 | |
KR20240043784A (ko) | 염증유발성 시토카인의 방출로부터 t 세포-매개 종양 세포독성을 디커플링시키는 단백질 | |
CN116396388A (zh) | 一种抗b7-h3抗体及其应用 | |
WO2022133110A1 (en) | Epcam binding molecules and uses thereof | |
WO2023177821A2 (en) | Binding domains and methods of use thereof | |
WO2022133074A1 (en) | Muc1 binding molecules and uses thereof |
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 |