KR102460843B1 - 고도로 글리코실화된 cea인 mg7에 특이적으로 결합하는 단일쇄 항체 및 검출 및 치료에서 이의 용도 - Google Patents
고도로 글리코실화된 cea인 mg7에 특이적으로 결합하는 단일쇄 항체 및 검출 및 치료에서 이의 용도 Download PDFInfo
- Publication number
- KR102460843B1 KR102460843B1 KR1020197006047A KR20197006047A KR102460843B1 KR 102460843 B1 KR102460843 B1 KR 102460843B1 KR 1020197006047 A KR1020197006047 A KR 1020197006047A KR 20197006047 A KR20197006047 A KR 20197006047A KR 102460843 B1 KR102460843 B1 KR 102460843B1
- Authority
- KR
- South Korea
- Prior art keywords
- ser
- gly
- seq
- thr
- leu
- Prior art date
Links
- 238000001514 detection method Methods 0.000 title description 12
- 238000002560 therapeutic procedure Methods 0.000 title description 3
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 57
- 108010019670 Chimeric Antigen Receptors Proteins 0.000 claims abstract description 44
- 230000008685 targeting Effects 0.000 claims abstract description 4
- 210000004027 cell Anatomy 0.000 claims description 107
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 39
- 210000001744 T-lymphocyte Anatomy 0.000 claims description 38
- 239000000427 antigen Substances 0.000 claims description 31
- 108091007433 antigens Proteins 0.000 claims description 31
- 102000036639 antigens Human genes 0.000 claims description 31
- 229920001184 polypeptide Polymers 0.000 claims description 27
- 102000004196 processed proteins & peptides Human genes 0.000 claims description 27
- 238000000034 method Methods 0.000 claims description 26
- 239000012634 fragment Substances 0.000 claims description 25
- 210000000822 natural killer cell Anatomy 0.000 claims description 20
- 101000914514 Homo sapiens T-cell-specific surface glycoprotein CD28 Proteins 0.000 claims description 19
- 102100027213 T-cell-specific surface glycoprotein CD28 Human genes 0.000 claims description 19
- 230000027455 binding Effects 0.000 claims description 14
- 208000005718 Stomach Neoplasms Diseases 0.000 claims description 13
- 206010017758 gastric cancer Diseases 0.000 claims description 13
- 201000011549 stomach cancer Diseases 0.000 claims description 13
- 101000851370 Homo sapiens Tumor necrosis factor receptor superfamily member 9 Proteins 0.000 claims description 9
- 102100036856 Tumor necrosis factor receptor superfamily member 9 Human genes 0.000 claims description 9
- 206010009944 Colon cancer Diseases 0.000 claims description 8
- 208000000461 Esophageal Neoplasms Diseases 0.000 claims description 7
- 206010030155 Oesophageal carcinoma Diseases 0.000 claims description 7
- 230000000139 costimulatory effect Effects 0.000 claims description 7
- 201000004101 esophageal cancer Diseases 0.000 claims description 7
- 208000001333 Colorectal Neoplasms Diseases 0.000 claims description 6
- 230000004068 intracellular signaling Effects 0.000 claims description 6
- 150000007523 nucleic acids Chemical class 0.000 claims description 6
- 230000003834 intracellular effect Effects 0.000 claims description 5
- 208000002699 Digestive System Neoplasms Diseases 0.000 claims description 4
- 210000001035 gastrointestinal tract Anatomy 0.000 claims description 4
- 210000003719 b-lymphocyte Anatomy 0.000 claims description 3
- 108020004707 nucleic acids Proteins 0.000 claims description 3
- 102000039446 nucleic acids Human genes 0.000 claims description 3
- 108010083359 Antigen Receptors Proteins 0.000 claims description 2
- 102000006306 Antigen Receptors Human genes 0.000 claims description 2
- 238000012546 transfer Methods 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims 4
- 125000003275 alpha amino acid group Chemical group 0.000 claims 2
- 238000003745 diagnosis Methods 0.000 abstract description 3
- 239000003814 drug Substances 0.000 abstract description 2
- 238000004519 manufacturing process Methods 0.000 abstract description 2
- 239000003795 chemical substances by application Substances 0.000 abstract 1
- 108020004414 DNA Proteins 0.000 description 139
- 102100025475 Carcinoembryonic antigen-related cell adhesion molecule 5 Human genes 0.000 description 48
- 108010022366 Carcinoembryonic Antigen Proteins 0.000 description 45
- XKUKSGPZAADMRA-UHFFFAOYSA-N glycyl-glycyl-glycine Natural products NCC(=O)NCC(=O)NCC(O)=O XKUKSGPZAADMRA-UHFFFAOYSA-N 0.000 description 35
- 108091007741 Chimeric antigen receptor T cells Proteins 0.000 description 28
- 102000004127 Cytokines Human genes 0.000 description 20
- 108090000695 Cytokines Proteins 0.000 description 20
- 239000013598 vector Substances 0.000 description 17
- 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 16
- 238000012047 cause and effect analysis Methods 0.000 description 16
- 238000012043 cost effectiveness analysis Methods 0.000 description 16
- 108010065920 Insulin Lispro Proteins 0.000 description 15
- 108010086434 alanyl-seryl-glycine Proteins 0.000 description 15
- 239000000872 buffer Substances 0.000 description 15
- 241000713666 Lentivirus Species 0.000 description 13
- 108010067216 glycyl-glycyl-glycine Proteins 0.000 description 13
- 210000001519 tissue Anatomy 0.000 description 13
- HKZAAJSTFUZYTO-LURJTMIESA-N (2s)-2-[[2-[[2-[[2-[(2-aminoacetyl)amino]acetyl]amino]acetyl]amino]acetyl]amino]-3-hydroxypropanoic acid Chemical compound NCC(=O)NCC(=O)NCC(=O)NCC(=O)N[C@@H](CO)C(O)=O HKZAAJSTFUZYTO-LURJTMIESA-N 0.000 description 12
- 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 12
- 150000001413 amino acids Chemical group 0.000 description 12
- 108010068265 aspartyltyrosine Proteins 0.000 description 12
- 239000006228 supernatant Substances 0.000 description 12
- 108010089804 glycyl-threonine Proteins 0.000 description 11
- 108010051242 phenylalanylserine Proteins 0.000 description 11
- 108090000623 proteins and genes Proteins 0.000 description 11
- 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 10
- 102000003855 L-lactate dehydrogenase Human genes 0.000 description 10
- 108700023483 L-lactate dehydrogenases Proteins 0.000 description 10
- 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 10
- 239000012636 effector Substances 0.000 description 10
- 208000015181 infectious disease Diseases 0.000 description 10
- 108010034529 leucyl-lysine Proteins 0.000 description 10
- 108010003137 tyrosyltyrosine Proteins 0.000 description 10
- 101100505161 Caenorhabditis elegans mel-32 gene Proteins 0.000 description 9
- 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 9
- 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 9
- 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 9
- VPZXBVLAVMBEQI-UHFFFAOYSA-N glycyl-DL-alpha-alanine Natural products OC(=O)C(C)NC(=O)CN VPZXBVLAVMBEQI-UHFFFAOYSA-N 0.000 description 9
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 9
- 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 8
- 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 8
- 108010001064 glycyl-glycyl-glycyl-glycine Proteins 0.000 description 8
- 239000002609 medium Substances 0.000 description 8
- 210000005259 peripheral blood Anatomy 0.000 description 8
- 239000011886 peripheral blood Substances 0.000 description 8
- 108010070409 phenylalanyl-glycyl-glycine Proteins 0.000 description 8
- 230000028327 secretion Effects 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
- 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 7
- 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 7
- 241000880493 Leptailurus serval Species 0.000 description 7
- 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 7
- 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 7
- 241000699666 Mus <mouse, genus> Species 0.000 description 7
- 241000699670 Mus sp. Species 0.000 description 7
- 230000004913 activation Effects 0.000 description 7
- 238000003776 cleavage reaction Methods 0.000 description 7
- 230000000694 effects Effects 0.000 description 7
- 108010078144 glutaminyl-glycine Proteins 0.000 description 7
- 238000011084 recovery Methods 0.000 description 7
- 108091008146 restriction endonucleases Proteins 0.000 description 7
- 230000007017 scission Effects 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- 101100315624 Caenorhabditis elegans tyr-1 gene Proteins 0.000 description 6
- 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 6
- ZYRXTRTUCAVNBQ-GVXVVHGQSA-N Glu-Val-Lys Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CCC(=O)O)N ZYRXTRTUCAVNBQ-GVXVVHGQSA-N 0.000 description 6
- GBYYQVBXFVDJPJ-WLTAIBSBSA-N Gly-Tyr-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CC1=CC=C(C=C1)O)NC(=O)CN)O GBYYQVBXFVDJPJ-WLTAIBSBSA-N 0.000 description 6
- UWKNTTJNVSYXPC-CIUDSAMLSA-N Lys-Ala-Ser Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CCCCN UWKNTTJNVSYXPC-CIUDSAMLSA-N 0.000 description 6
- 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 6
- 241000124008 Mammalia Species 0.000 description 6
- 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 6
- 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 6
- UIPXCLNLUUAMJU-JBDRJPRFSA-N Ser-Ile-Ser Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(O)=O UIPXCLNLUUAMJU-JBDRJPRFSA-N 0.000 description 6
- 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 6
- 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 6
- 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 6
- 201000011510 cancer Diseases 0.000 description 6
- 239000000499 gel Substances 0.000 description 6
- 230000002147 killing effect Effects 0.000 description 6
- 108010038320 lysylphenylalanine Proteins 0.000 description 6
- 238000002360 preparation method Methods 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 108010038745 tryptophylglycine Proteins 0.000 description 6
- 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 5
- 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 5
- 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 5
- 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 5
- 108010047041 Complementarity Determining Regions Proteins 0.000 description 5
- 241000588724 Escherichia coli Species 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
- 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 5
- 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 5
- 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 5
- 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 5
- 102100029360 Hematopoietic cell signal transducer Human genes 0.000 description 5
- 101000990188 Homo sapiens Hematopoietic cell signal transducer Proteins 0.000 description 5
- 108010002350 Interleukin-2 Proteins 0.000 description 5
- 102000000588 Interleukin-2 Human genes 0.000 description 5
- 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 5
- 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 5
- MIXPUVSPPOWTCR-FXQIFTODSA-N Met-Ser-Ser Chemical compound [H]N[C@@H](CCSC)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(O)=O MIXPUVSPPOWTCR-FXQIFTODSA-N 0.000 description 5
- 108010079364 N-glycylalanine Proteins 0.000 description 5
- 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 5
- XQJCEKXQUJQNNK-ZLUOBGJFSA-N Ser-Ser-Ser Chemical compound OC[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(O)=O XQJCEKXQUJQNNK-ZLUOBGJFSA-N 0.000 description 5
- 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 5
- VRUFCJZQDACGLH-UVOCVTCTSA-N Thr-Leu-Thr Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O VRUFCJZQDACGLH-UVOCVTCTSA-N 0.000 description 5
- 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 5
- 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 5
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 5
- 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 description 5
- CNLKDWSAORJEMW-KWQFWETISA-N Tyr-Gly-Ala Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)NCC(=O)N[C@@H](C)C(O)=O CNLKDWSAORJEMW-KWQFWETISA-N 0.000 description 5
- 239000011324 bead Substances 0.000 description 5
- 238000012217 deletion Methods 0.000 description 5
- 230000037430 deletion Effects 0.000 description 5
- 108010048367 enhanced green fluorescent protein Proteins 0.000 description 5
- 238000002474 experimental method Methods 0.000 description 5
- 239000013604 expression vector Substances 0.000 description 5
- 108010057083 glutamyl-aspartyl-leucine Proteins 0.000 description 5
- 108010050848 glycylleucine Proteins 0.000 description 5
- 238000011534 incubation Methods 0.000 description 5
- 108010044374 isoleucyl-tyrosine Proteins 0.000 description 5
- 108010017391 lysylvaline Proteins 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 239000013612 plasmid Substances 0.000 description 5
- 108010026333 seryl-proline Proteins 0.000 description 5
- 238000001890 transfection Methods 0.000 description 5
- 108010044292 tryptophyltyrosine Proteins 0.000 description 5
- 210000004881 tumor cell Anatomy 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 4
- CREYEAPXISDKSB-FQPOAREZSA-N Ala-Thr-Tyr Chemical compound [H]N[C@@H](C)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O CREYEAPXISDKSB-FQPOAREZSA-N 0.000 description 4
- MAISCYVJLBBRNU-DCAQKATOSA-N Arg-Asn-Lys Chemical compound C(CCN)C[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)N)NC(=O)[C@H](CCCN=C(N)N)N MAISCYVJLBBRNU-DCAQKATOSA-N 0.000 description 4
- HUZGPXBILPMCHM-IHRRRGAJSA-N Asn-Arg-Phe Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O HUZGPXBILPMCHM-IHRRRGAJSA-N 0.000 description 4
- DJIMLSXHXKWADV-CIUDSAMLSA-N Asn-Leu-Ser Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CC(N)=O DJIMLSXHXKWADV-CIUDSAMLSA-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
- WMLFFCRUSPNENW-ZLUOBGJFSA-N Asp-Ser-Ala Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](C)C(O)=O WMLFFCRUSPNENW-ZLUOBGJFSA-N 0.000 description 4
- 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 4
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 4
- XPJBQTCXPJNIFE-ZETCQYMHSA-N Gly-Gly-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)CNC(=O)CN XPJBQTCXPJNIFE-ZETCQYMHSA-N 0.000 description 4
- 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 4
- 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 4
- 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 4
- -1 ICOS Proteins 0.000 description 4
- 108060003951 Immunoglobulin Proteins 0.000 description 4
- 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 4
- JGKHAFUAPZCCDU-BZSNNMDCSA-N Leu-Tyr-Leu Chemical compound CC(C)C[C@H]([NH3+])C(=O)N[C@H](C(=O)N[C@@H](CC(C)C)C([O-])=O)CC1=CC=C(O)C=C1 JGKHAFUAPZCCDU-BZSNNMDCSA-N 0.000 description 4
- SKRGVGLIRUGANF-AVGNSLFASA-N Lys-Leu-Glu Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(O)=O SKRGVGLIRUGANF-AVGNSLFASA-N 0.000 description 4
- 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 4
- 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 4
- 108091028043 Nucleic acid sequence Proteins 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
- JMVQDLDPDBXAAX-YUMQZZPRSA-N Pro-Gly-Gln Chemical compound NC(=O)CC[C@@H](C(O)=O)NC(=O)CNC(=O)[C@@H]1CCCN1 JMVQDLDPDBXAAX-YUMQZZPRSA-N 0.000 description 4
- 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 4
- 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 4
- MUJQWSAWLLRJCE-KATARQTJSA-N Ser-Leu-Thr Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O MUJQWSAWLLRJCE-KATARQTJSA-N 0.000 description 4
- ADJDNJCSPNFFPI-FXQIFTODSA-N Ser-Pro-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@@H]1CCCN1C(=O)[C@@H](N)CO ADJDNJCSPNFFPI-FXQIFTODSA-N 0.000 description 4
- 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 4
- 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 4
- SPVHQURZJCUDQC-VOAKCMCISA-N Thr-Lys-Leu Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(O)=O SPVHQURZJCUDQC-VOAKCMCISA-N 0.000 description 4
- SVGAWGVHFIYAEE-JSGCOSHPSA-N Trp-Gly-Gln Chemical compound C1=CC=C2C(C[C@H](N)C(=O)NCC(=O)N[C@@H](CCC(N)=O)C(O)=O)=CNC2=C1 SVGAWGVHFIYAEE-JSGCOSHPSA-N 0.000 description 4
- 102100022153 Tumor necrosis factor receptor superfamily member 4 Human genes 0.000 description 4
- 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 4
- TYGHOWWWMTWVKM-HJOGWXRNSA-N Tyr-Tyr-Phe 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=CC=1)C(O)=O)C1=CC=C(O)C=C1 TYGHOWWWMTWVKM-HJOGWXRNSA-N 0.000 description 4
- ZRSZTKTVPNSUNA-IHRRRGAJSA-N Val-Lys-Leu Chemical compound CC(C)C[C@H](NC(=O)[C@H](CCCCN)NC(=O)[C@@H](N)C(C)C)C(O)=O ZRSZTKTVPNSUNA-IHRRRGAJSA-N 0.000 description 4
- 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 4
- 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 4
- 241000700605 Viruses Species 0.000 description 4
- 125000000539 amino acid group Chemical group 0.000 description 4
- 230000006907 apoptotic process Effects 0.000 description 4
- 108010092854 aspartyllysine Proteins 0.000 description 4
- 238000005119 centrifugation Methods 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 4
- 238000000684 flow cytometry Methods 0.000 description 4
- 108010063718 gamma-glutamylaspartic acid Proteins 0.000 description 4
- 108010026364 glycyl-glycyl-leucine Proteins 0.000 description 4
- 102000018358 immunoglobulin Human genes 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 108010020755 prolyl-glycyl-glycine Proteins 0.000 description 4
- 102000004169 proteins and genes Human genes 0.000 description 4
- RXWNCPJZOCPEPQ-NVWDDTSBSA-N puromycin Chemical compound C1=CC(OC)=CC=C1C[C@H](N)C(=O)N[C@H]1[C@@H](O)[C@H](N2C3=NC=NC(=C3N=C2)N(C)C)O[C@@H]1CO RXWNCPJZOCPEPQ-NVWDDTSBSA-N 0.000 description 4
- 108020003175 receptors Proteins 0.000 description 4
- 102000005962 receptors Human genes 0.000 description 4
- 108010033670 threonyl-aspartyl-tyrosine Proteins 0.000 description 4
- 108010073969 valyllysine Proteins 0.000 description 4
- MZOFCQQQCNRIBI-VMXHOPILSA-N (3s)-4-[[(2s)-1-[[(2s)-1-[[(1s)-1-carboxy-2-hydroxyethyl]amino]-4-methyl-1-oxopentan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-3-[[2-[[(2s)-2,6-diaminohexanoyl]amino]acetyl]amino]-4-oxobutanoic acid Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@@H](N)CCCCN MZOFCQQQCNRIBI-VMXHOPILSA-N 0.000 description 3
- RGQCNKIDEQJEBT-CQDKDKBSSA-N Ala-Leu-Tyr Chemical compound C[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 RGQCNKIDEQJEBT-CQDKDKBSSA-N 0.000 description 3
- XWFWAXPOLRTDFZ-FXQIFTODSA-N Ala-Pro-Ser Chemical compound C[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CO)C(O)=O XWFWAXPOLRTDFZ-FXQIFTODSA-N 0.000 description 3
- 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 3
- VQBULXOHAZSTQY-GKCIPKSASA-N Ala-Trp-Phe Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CC1=CNC2=C1C=CC=C2)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O VQBULXOHAZSTQY-GKCIPKSASA-N 0.000 description 3
- BIOCIVSVEDFKDJ-GUBZILKMSA-N Arg-Arg-Asp Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(O)=O BIOCIVSVEDFKDJ-GUBZILKMSA-N 0.000 description 3
- IASNWHAGGYTEKX-IUCAKERBSA-N Arg-Arg-Gly Chemical compound NC(N)=NCCC[C@H](N)C(=O)N[C@@H](CCCN=C(N)N)C(=O)NCC(O)=O IASNWHAGGYTEKX-IUCAKERBSA-N 0.000 description 3
- SQKPKIJVWHAWNF-DCAQKATOSA-N Arg-Asp-Lys Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCCN)C(O)=O SQKPKIJVWHAWNF-DCAQKATOSA-N 0.000 description 3
- YHQGEARSFILVHL-HJGDQZAQSA-N Arg-Gln-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)N)NC(=O)[C@H](CCCN=C(N)N)N)O YHQGEARSFILVHL-HJGDQZAQSA-N 0.000 description 3
- AOHKLEBWKMKITA-IHRRRGAJSA-N Arg-Phe-Ser Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)N[C@@H](CO)C(=O)O)NC(=O)[C@H](CCCN=C(N)N)N AOHKLEBWKMKITA-IHRRRGAJSA-N 0.000 description 3
- 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 3
- 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 3
- CIBWFJFMOBIFTE-CIUDSAMLSA-N Asn-Arg-Gln Chemical compound C(C[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)O)NC(=O)[C@H](CC(=O)N)N)CN=C(N)N CIBWFJFMOBIFTE-CIUDSAMLSA-N 0.000 description 3
- DXVMJJNAOVECBA-WHFBIAKZSA-N Asn-Gly-Asn Chemical compound NC(=O)C[C@H](N)C(=O)NCC(=O)N[C@@H](CC(N)=O)C(O)=O DXVMJJNAOVECBA-WHFBIAKZSA-N 0.000 description 3
- MDDXKBHIMYYJLW-FXQIFTODSA-N Asn-Met-Asp Chemical compound CSCC[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)O)NC(=O)[C@H](CC(=O)N)N MDDXKBHIMYYJLW-FXQIFTODSA-N 0.000 description 3
- 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 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
- CBHVAFXKOYAHOY-NHCYSSNCSA-N Asn-Val-Leu Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O CBHVAFXKOYAHOY-NHCYSSNCSA-N 0.000 description 3
- 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 3
- PXLNPFOJZQMXAT-BYULHYEWSA-N Asp-Asp-Val Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@@H](N)CC(O)=O PXLNPFOJZQMXAT-BYULHYEWSA-N 0.000 description 3
- WBDWQKRLTVCDSY-WHFBIAKZSA-N Asp-Gly-Asp Chemical compound OC(=O)C[C@H](N)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(O)=O WBDWQKRLTVCDSY-WHFBIAKZSA-N 0.000 description 3
- 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 3
- 108010083946 Asp-Tyr-Leu-Lys Proteins 0.000 description 3
- 102000017420 CD3 protein, epsilon/gamma/delta subunit Human genes 0.000 description 3
- 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 3
- WXKWQSDHEXKKNC-ZKWXMUAHSA-N Cys-Asp-Val Chemical compound CC(C)[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)O)NC(=O)[C@H](CS)N WXKWQSDHEXKKNC-ZKWXMUAHSA-N 0.000 description 3
- CVLIHKBUPSFRQP-WHFBIAKZSA-N Cys-Gly-Ala Chemical compound [H]N[C@@H](CS)C(=O)NCC(=O)N[C@@H](C)C(O)=O CVLIHKBUPSFRQP-WHFBIAKZSA-N 0.000 description 3
- BBQIWFFTTQTNOC-AVGNSLFASA-N Cys-Phe-Gln Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)O)NC(=O)[C@H](CS)N BBQIWFFTTQTNOC-AVGNSLFASA-N 0.000 description 3
- 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 3
- JXFLPKSDLDEOQK-JHEQGTHGSA-N Gln-Gly-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)CNC(=O)[C@@H](N)CCC(N)=O JXFLPKSDLDEOQK-JHEQGTHGSA-N 0.000 description 3
- MSHXWFKYXJTLEZ-CIUDSAMLSA-N Gln-Met-Asn Chemical compound CSCC[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)O)NC(=O)[C@H](CCC(=O)N)N MSHXWFKYXJTLEZ-CIUDSAMLSA-N 0.000 description 3
- WLRYGVYQFXRJDA-DCAQKATOSA-N Gln-Pro-Pro Chemical compound NC(=O)CC[C@H](N)C(=O)N1CCC[C@H]1C(=O)N1[C@H](C(O)=O)CCC1 WLRYGVYQFXRJDA-DCAQKATOSA-N 0.000 description 3
- 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 3
- 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 3
- 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 3
- 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 3
- JVSBYEDSSRZQGV-GUBZILKMSA-N Glu-Asp-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@@H](N)CCC(O)=O JVSBYEDSSRZQGV-GUBZILKMSA-N 0.000 description 3
- SBCYJMOOHUDWDA-NUMRIWBASA-N Glu-Asp-Thr Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O SBCYJMOOHUDWDA-NUMRIWBASA-N 0.000 description 3
- 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 3
- DLISPGXMKZTWQG-IFFSRLJSSA-N Glu-Thr-Val Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(O)=O DLISPGXMKZTWQG-IFFSRLJSSA-N 0.000 description 3
- KRRMJKMGWWXWDW-STQMWFEESA-N Gly-Arg-Phe Chemical compound NC(=N)NCCC[C@H](NC(=O)CN)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 KRRMJKMGWWXWDW-STQMWFEESA-N 0.000 description 3
- XBWMTPAIUQIWKA-BYULHYEWSA-N Gly-Asp-Ile Chemical compound CC[C@H](C)[C@@H](C(O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)CN XBWMTPAIUQIWKA-BYULHYEWSA-N 0.000 description 3
- 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 3
- SWQALSGKVLYKDT-UHFFFAOYSA-N Gly-Ile-Ala Natural products NCC(=O)NC(C(C)CC)C(=O)NC(C)C(O)=O SWQALSGKVLYKDT-UHFFFAOYSA-N 0.000 description 3
- CCBIBMKQNXHNIN-ZETCQYMHSA-N Gly-Leu-Gly Chemical compound NCC(=O)N[C@@H](CC(C)C)C(=O)NCC(O)=O CCBIBMKQNXHNIN-ZETCQYMHSA-N 0.000 description 3
- 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 3
- IBYOLNARKHMLBG-WHOFXGATSA-N Gly-Phe-Ile Chemical compound CC[C@H](C)[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)CN)CC1=CC=CC=C1 IBYOLNARKHMLBG-WHOFXGATSA-N 0.000 description 3
- 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 3
- 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 3
- NGRPGJGKJMUGDM-XVKPBYJWSA-N Gly-Val-Gln Chemical compound NCC(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(N)=O)C(O)=O NGRPGJGKJMUGDM-XVKPBYJWSA-N 0.000 description 3
- 101000914324 Homo sapiens Carcinoembryonic antigen-related cell adhesion molecule 5 Proteins 0.000 description 3
- HERITAGIPLEJMT-GVARAGBVSA-N Ile-Ala-Tyr Chemical compound CC[C@H](C)[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 HERITAGIPLEJMT-GVARAGBVSA-N 0.000 description 3
- JODPUDMBQBIWCK-GHCJXIJMSA-N Ile-Ser-Asn Chemical compound [H]N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(O)=O JODPUDMBQBIWCK-GHCJXIJMSA-N 0.000 description 3
- 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 3
- PXKACEXYLPBMAD-JBDRJPRFSA-N Ile-Ser-Ser Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)O)N PXKACEXYLPBMAD-JBDRJPRFSA-N 0.000 description 3
- 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 3
- JCGMFFQQHJQASB-PYJNHQTQSA-N Ile-Val-His Chemical compound N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC1=CNC=N1)C(=O)O JCGMFFQQHJQASB-PYJNHQTQSA-N 0.000 description 3
- 102100037850 Interferon gamma Human genes 0.000 description 3
- 108010074328 Interferon-gamma Proteins 0.000 description 3
- 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 3
- 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 3
- 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 3
- FQZPTCNSNPWHLJ-AVGNSLFASA-N Leu-Gln-Lys Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCCN)C(O)=O FQZPTCNSNPWHLJ-AVGNSLFASA-N 0.000 description 3
- HVHRPWQEQHIQJF-AVGNSLFASA-N Leu-Lys-Glu Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(O)=O HVHRPWQEQHIQJF-AVGNSLFASA-N 0.000 description 3
- 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 3
- 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 3
- 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 3
- VSRXPEHZMHSFKU-IUCAKERBSA-N Lys-Gln-Gly Chemical compound NCCCC[C@H](N)C(=O)N[C@@H](CCC(N)=O)C(=O)NCC(O)=O VSRXPEHZMHSFKU-IUCAKERBSA-N 0.000 description 3
- 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 3
- WRODMZBHNNPRLN-SRVKXCTJSA-N Lys-Leu-Ser Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(O)=O WRODMZBHNNPRLN-SRVKXCTJSA-N 0.000 description 3
- LJADEBULDNKJNK-IHRRRGAJSA-N Lys-Leu-Val Chemical compound CC(C)C[C@H](NC(=O)[C@@H](N)CCCCN)C(=O)N[C@@H](C(C)C)C(O)=O LJADEBULDNKJNK-IHRRRGAJSA-N 0.000 description 3
- WZVSHTFTCYOFPL-GARJFASQSA-N Lys-Ser-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CO)NC(=O)[C@H](CCCCN)N)C(=O)O WZVSHTFTCYOFPL-GARJFASQSA-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
- 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 3
- 238000012408 PCR amplification Methods 0.000 description 3
- HCTXJGRYAACKOB-SRVKXCTJSA-N Phe-Asn-Asp Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CC(=O)O)C(=O)O)N HCTXJGRYAACKOB-SRVKXCTJSA-N 0.000 description 3
- JJHVFCUWLSKADD-ONGXEEELSA-N Phe-Gly-Ala Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)NCC(=O)N[C@@H](C)C(O)=O JJHVFCUWLSKADD-ONGXEEELSA-N 0.000 description 3
- WEDZFLRYSIDIRX-IHRRRGAJSA-N Phe-Ser-Arg Chemical compound NC(=N)NCCC[C@@H](C(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC1=CC=CC=C1 WEDZFLRYSIDIRX-IHRRRGAJSA-N 0.000 description 3
- IAOZOFPONWDXNT-IXOXFDKPSA-N Phe-Ser-Thr Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(O)=O IAOZOFPONWDXNT-IXOXFDKPSA-N 0.000 description 3
- RAGOJJCBGXARPO-XVSYOHENSA-N Phe-Thr-Asp Chemical compound OC(=O)C[C@@H](C(O)=O)NC(=O)[C@H]([C@H](O)C)NC(=O)[C@@H](N)CC1=CC=CC=C1 RAGOJJCBGXARPO-XVSYOHENSA-N 0.000 description 3
- VOZIBWWZSBIXQN-SRVKXCTJSA-N Pro-Glu-Lys Chemical compound NCCCC[C@H](NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H]1CCCN1)C(O)=O VOZIBWWZSBIXQN-SRVKXCTJSA-N 0.000 description 3
- 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 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
- 108010076504 Protein Sorting Signals Proteins 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
- SQBLRDDJTUJDMV-ACZMJKKPSA-N Ser-Glu-Asn Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O SQBLRDDJTUJDMV-ACZMJKKPSA-N 0.000 description 3
- 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 3
- 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 3
- ZUDXUJSYCCNZQJ-DCAQKATOSA-N Ser-His-Val Chemical compound CC(C)[C@@H](C(=O)O)NC(=O)[C@H](CC1=CN=CN1)NC(=O)[C@H](CO)N ZUDXUJSYCCNZQJ-DCAQKATOSA-N 0.000 description 3
- 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 3
- 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 3
- KCGIREHVWRXNDH-GARJFASQSA-N Ser-Leu-Pro Chemical compound CC(C)C[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](CO)N KCGIREHVWRXNDH-GARJFASQSA-N 0.000 description 3
- YUJLIIRMIAGMCQ-CIUDSAMLSA-N Ser-Leu-Ser Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(O)=O YUJLIIRMIAGMCQ-CIUDSAMLSA-N 0.000 description 3
- FPCGZYMRFFIYIH-CIUDSAMLSA-N Ser-Lys-Ser Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CO)C(O)=O FPCGZYMRFFIYIH-CIUDSAMLSA-N 0.000 description 3
- 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 3
- 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 3
- HAUVENOGHPECML-BPUTZDHNSA-N Ser-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](N)CO)=CNC2=C1 HAUVENOGHPECML-BPUTZDHNSA-N 0.000 description 3
- MQCPGOZXFSYJPS-KZVJFYERSA-N Thr-Ala-Arg Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O MQCPGOZXFSYJPS-KZVJFYERSA-N 0.000 description 3
- 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 3
- OQCXTUQTKQFDCX-HTUGSXCWSA-N Thr-Glu-Phe Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)O)N)O OQCXTUQTKQFDCX-HTUGSXCWSA-N 0.000 description 3
- 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 3
- IHAPJUHCZXBPHR-WZLNRYEVSA-N Thr-Ile-Tyr Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC1=CC=C(C=C1)O)C(=O)O)NC(=O)[C@H]([C@@H](C)O)N IHAPJUHCZXBPHR-WZLNRYEVSA-N 0.000 description 3
- MECLEFZMPPOEAC-VOAKCMCISA-N Thr-Leu-Lys Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)O)N)O MECLEFZMPPOEAC-VOAKCMCISA-N 0.000 description 3
- 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 3
- 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 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
- 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 3
- SEXRBCGSZRCIPE-LYSGOOTNSA-N Trp-Thr-Gly Chemical compound C[C@H]([C@@H](C(=O)NCC(=O)O)NC(=O)[C@H](CC1=CNC2=CC=CC=C21)N)O SEXRBCGSZRCIPE-LYSGOOTNSA-N 0.000 description 3
- 101710165473 Tumor necrosis factor receptor superfamily member 4 Proteins 0.000 description 3
- JWHOIHCOHMZSAR-QWRGUYRKSA-N Tyr-Asp-Gly Chemical compound OC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 JWHOIHCOHMZSAR-QWRGUYRKSA-N 0.000 description 3
- VFJIWSJKZJTQII-SRVKXCTJSA-N Tyr-Asp-Ser 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](CO)C(O)=O VFJIWSJKZJTQII-SRVKXCTJSA-N 0.000 description 3
- SMLCYZYQFRTLCO-UWJYBYFXSA-N Tyr-Cys-Ala Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CS)C(=O)N[C@@H](C)C(O)=O SMLCYZYQFRTLCO-UWJYBYFXSA-N 0.000 description 3
- ARPONUQDNWLXOZ-KKUMJFAQSA-N Tyr-Gln-Arg 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](CCCNC(N)=N)C(O)=O ARPONUQDNWLXOZ-KKUMJFAQSA-N 0.000 description 3
- LMKKMCGTDANZTR-BZSNNMDCSA-N Tyr-Phe-Asp Chemical compound C([C@H](N)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC(O)=O)C(O)=O)C1=CC=C(O)C=C1 LMKKMCGTDANZTR-BZSNNMDCSA-N 0.000 description 3
- 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 3
- MQGGXGKQSVEQHR-KKUMJFAQSA-N Tyr-Ser-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 MQGGXGKQSVEQHR-KKUMJFAQSA-N 0.000 description 3
- 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 3
- 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 3
- 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 3
- UDNYEPLJTRDMEJ-RCOVLWMOSA-N Val-Asn-Gly Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)NCC(=O)O)N UDNYEPLJTRDMEJ-RCOVLWMOSA-N 0.000 description 3
- 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 3
- 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 3
- 108010076324 alanyl-glycyl-glycine Proteins 0.000 description 3
- 108010050025 alpha-glutamyltryptophan Proteins 0.000 description 3
- 230000005809 anti-tumor immunity Effects 0.000 description 3
- 108010062796 arginyllysine Proteins 0.000 description 3
- 238000003556 assay Methods 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 238000004113 cell culture Methods 0.000 description 3
- 230000008859 change Effects 0.000 description 3
- 230000034994 death Effects 0.000 description 3
- 231100000517 death Toxicity 0.000 description 3
- 230000007423 decrease Effects 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 230000006870 function Effects 0.000 description 3
- 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 3
- 108010010147 glycylglutamine Proteins 0.000 description 3
- 108010018006 histidylserine Proteins 0.000 description 3
- 229940072221 immunoglobulins Drugs 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 238000003780 insertion Methods 0.000 description 3
- 230000037431 insertion Effects 0.000 description 3
- 230000003993 interaction Effects 0.000 description 3
- 210000000265 leukocyte Anatomy 0.000 description 3
- 210000004698 lymphocyte Anatomy 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 210000004379 membrane Anatomy 0.000 description 3
- 239000012528 membrane Substances 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- 239000002773 nucleotide Substances 0.000 description 3
- 125000003729 nucleotide group Chemical group 0.000 description 3
- 238000004806 packaging method and process Methods 0.000 description 3
- 210000003819 peripheral blood mononuclear cell Anatomy 0.000 description 3
- 239000013600 plasmid vector Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 108010087846 prolyl-prolyl-glycine Proteins 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 210000002966 serum Anatomy 0.000 description 3
- 239000008223 sterile water Substances 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 108010061238 threonyl-glycine Proteins 0.000 description 3
- 230000009466 transformation Effects 0.000 description 3
- 230000004614 tumor growth Effects 0.000 description 3
- 108010077037 tyrosyl-tyrosyl-phenylalanine Proteins 0.000 description 3
- GJLXVWOMRRWCIB-MERZOTPQSA-N (2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-acetamido-5-(diaminomethylideneamino)pentanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-5-(diaminomethylideneamino)pentanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-6-aminohexanoyl]amino]-6-aminohexanoyl]amino]-6-aminohexanoyl]amino]-6-aminohexanoyl]amino]-6-aminohexanoyl]amino]-6-aminohexanoyl]amino]-6-aminohexanamide Chemical compound C([C@H](NC(=O)[C@H](CCCN=C(N)N)NC(=O)C)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(N)=O)C1=CC=C(O)C=C1 GJLXVWOMRRWCIB-MERZOTPQSA-N 0.000 description 2
- JBGSZRYCXBPWGX-BQBZGAKWSA-N Ala-Arg-Gly Chemical compound OC(=O)CNC(=O)[C@@H](NC(=O)[C@@H](N)C)CCCN=C(N)N JBGSZRYCXBPWGX-BQBZGAKWSA-N 0.000 description 2
- KIUYPHAMDKDICO-WHFBIAKZSA-N Ala-Asp-Gly Chemical compound C[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)NCC(O)=O KIUYPHAMDKDICO-WHFBIAKZSA-N 0.000 description 2
- VGPWRRFOPXVGOH-BYPYZUCNSA-N Ala-Gly-Gly Chemical compound C[C@H](N)C(=O)NCC(=O)NCC(O)=O VGPWRRFOPXVGOH-BYPYZUCNSA-N 0.000 description 2
- IFKQPMZRDQZSHI-GHCJXIJMSA-N Ala-Ile-Asn Chemical compound [H]N[C@@H](C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(N)=O)C(O)=O IFKQPMZRDQZSHI-GHCJXIJMSA-N 0.000 description 2
- CCDFBRZVTDDJNM-GUBZILKMSA-N Ala-Leu-Glu Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(O)=O CCDFBRZVTDDJNM-GUBZILKMSA-N 0.000 description 2
- DHBKYZYFEXXUAK-ONGXEEELSA-N Ala-Phe-Gly Chemical compound OC(=O)CNC(=O)[C@@H](NC(=O)[C@@H](N)C)CC1=CC=CC=C1 DHBKYZYFEXXUAK-ONGXEEELSA-N 0.000 description 2
- MSWSRLGNLKHDEI-ACZMJKKPSA-N Ala-Ser-Glu Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(O)=O)C(O)=O MSWSRLGNLKHDEI-ACZMJKKPSA-N 0.000 description 2
- 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 2
- JSHVMZANPXCDTL-GMOBBJLQSA-N Arg-Asp-Ile Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O JSHVMZANPXCDTL-GMOBBJLQSA-N 0.000 description 2
- 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 2
- 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 2
- FRBAHXABMQXSJQ-FXQIFTODSA-N Arg-Ser-Ser Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(O)=O FRBAHXABMQXSJQ-FXQIFTODSA-N 0.000 description 2
- ZJBUILVYSXQNSW-YTWAJWBKSA-N Arg-Thr-Pro Chemical compound C[C@H]([C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](CCCN=C(N)N)N)O ZJBUILVYSXQNSW-YTWAJWBKSA-N 0.000 description 2
- 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 2
- 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 2
- BYLSYQASFJJBCL-DCAQKATOSA-N Asn-Pro-Leu Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CC(C)C)C(O)=O BYLSYQASFJJBCL-DCAQKATOSA-N 0.000 description 2
- 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 2
- 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 2
- 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 2
- NYQHSUGFEWDWPD-ACZMJKKPSA-N Asp-Gln-Ala Chemical compound C[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)N)NC(=O)[C@H](CC(=O)O)N NYQHSUGFEWDWPD-ACZMJKKPSA-N 0.000 description 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
- 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 2
- 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 2
- JNNVNVRBYUJYGS-CIUDSAMLSA-N Asp-Leu-Ala Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C)C(O)=O JNNVNVRBYUJYGS-CIUDSAMLSA-N 0.000 description 2
- AYFVRYXNDHBECD-YUMQZZPRSA-N Asp-Leu-Gly Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)NCC(O)=O AYFVRYXNDHBECD-YUMQZZPRSA-N 0.000 description 2
- XXAMCEGRCZQGEM-ZLUOBGJFSA-N Asp-Ser-Asn Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(O)=O XXAMCEGRCZQGEM-ZLUOBGJFSA-N 0.000 description 2
- RSMZEHCMIOKNMW-GSSVUCPTSA-N Asp-Thr-Thr Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O RSMZEHCMIOKNMW-GSSVUCPTSA-N 0.000 description 2
- 244000063299 Bacillus subtilis Species 0.000 description 2
- 235000014469 Bacillus subtilis Nutrition 0.000 description 2
- 102100021277 Beta-secretase 2 Human genes 0.000 description 2
- 101710150190 Beta-secretase 2 Proteins 0.000 description 2
- 102100027207 CD27 antigen Human genes 0.000 description 2
- 241000283707 Capra Species 0.000 description 2
- 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 2
- 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 2
- OZHXXYOHPLLLMI-CIUDSAMLSA-N Cys-Lys-Ala Chemical compound [H]N[C@@H](CS)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(O)=O OZHXXYOHPLLLMI-CIUDSAMLSA-N 0.000 description 2
- NRVQLLDIJJEIIZ-VZFHVOOUSA-N Cys-Thr-Ala Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](C)C(=O)O)NC(=O)[C@H](CS)N)O NRVQLLDIJJEIIZ-VZFHVOOUSA-N 0.000 description 2
- YWEHYKGJWHPGPY-XGEHTFHBSA-N Cys-Thr-Arg Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCCN=C(N)N)C(=O)O)NC(=O)[C@H](CS)N)O YWEHYKGJWHPGPY-XGEHTFHBSA-N 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-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
- 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 2
- 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 2
- 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 2
- FQCILXROGNOZON-YUMQZZPRSA-N Gln-Pro-Gly Chemical compound NC(=O)CC[C@H](N)C(=O)N1CCC[C@H]1C(=O)NCC(O)=O FQCILXROGNOZON-YUMQZZPRSA-N 0.000 description 2
- KVQOVQVGVKDZNW-GUBZILKMSA-N Gln-Ser-His Chemical compound C1=C(NC=N1)C[C@@H](C(=O)O)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(=O)N)N KVQOVQVGVKDZNW-GUBZILKMSA-N 0.000 description 2
- SXFPZRRVWSUYII-KBIXCLLPSA-N Gln-Ser-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(=O)N)N SXFPZRRVWSUYII-KBIXCLLPSA-N 0.000 description 2
- 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 2
- 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 2
- JVZLZVJTIXVIHK-SXNHZJKMSA-N Glu-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](CCC(=O)O)N JVZLZVJTIXVIHK-SXNHZJKMSA-N 0.000 description 2
- CGWHAXBNGYQBBK-JBACZVJFSA-N Glu-Trp-Tyr Chemical compound C([C@H](NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CCC(O)=O)N)C(O)=O)C1=CC=C(O)C=C1 CGWHAXBNGYQBBK-JBACZVJFSA-N 0.000 description 2
- VXEFAWJTFAUDJK-AVGNSLFASA-N Glu-Tyr-Ser Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)N[C@@H](CO)C(=O)O)NC(=O)[C@H](CCC(=O)O)N)O VXEFAWJTFAUDJK-AVGNSLFASA-N 0.000 description 2
- SWQALSGKVLYKDT-ZKWXMUAHSA-N Gly-Ile-Ala Chemical compound NCC(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(O)=O SWQALSGKVLYKDT-ZKWXMUAHSA-N 0.000 description 2
- AAHSHTLISQUZJL-QSFUFRPTSA-N Gly-Ile-Ile Chemical compound [H]NCC(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O AAHSHTLISQUZJL-QSFUFRPTSA-N 0.000 description 2
- 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 2
- NTBOEZICHOSJEE-YUMQZZPRSA-N Gly-Lys-Ser Chemical compound [H]NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CO)C(O)=O NTBOEZICHOSJEE-YUMQZZPRSA-N 0.000 description 2
- 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 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
- NVTPVQLIZCOJFK-FOHZUACHSA-N Gly-Thr-Asp Chemical compound [H]NCC(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(O)=O)C(O)=O NVTPVQLIZCOJFK-FOHZUACHSA-N 0.000 description 2
- HUFUVTYGPOUCBN-MBLNEYKQSA-N Gly-Thr-Ile Chemical compound [H]NCC(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O HUFUVTYGPOUCBN-MBLNEYKQSA-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
- FOCSWPCHUDVNLP-PMVMPFDFSA-N His-Trp-Tyr Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)N[C@@H](CC3=CC=C(C=C3)O)C(=O)O)NC(=O)[C@H](CC4=CN=CN4)N FOCSWPCHUDVNLP-PMVMPFDFSA-N 0.000 description 2
- 101000914511 Homo sapiens CD27 antigen Proteins 0.000 description 2
- 101001012157 Homo sapiens Receptor tyrosine-protein kinase erbB-2 Proteins 0.000 description 2
- IOVUXUSIGXCREV-DKIMLUQUSA-N Ile-Leu-Phe Chemical compound CC[C@H](C)[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 IOVUXUSIGXCREV-DKIMLUQUSA-N 0.000 description 2
- PARSHQDZROHERM-NHCYSSNCSA-N Ile-Lys-Gly Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)O)N PARSHQDZROHERM-NHCYSSNCSA-N 0.000 description 2
- PRTZQMBYUZFSFA-XEGUGMAKSA-N Ile-Tyr-Gly Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC1=CC=C(C=C1)O)C(=O)NCC(=O)O)N PRTZQMBYUZFSFA-XEGUGMAKSA-N 0.000 description 2
- 102000018071 Immunoglobulin Fc Fragments Human genes 0.000 description 2
- 108010091135 Immunoglobulin Fc Fragments Proteins 0.000 description 2
- PWWVAXIEGOYWEE-UHFFFAOYSA-N Isophenergan Chemical compound C1=CC=C2N(CC(C)N(C)C)C3=CC=CC=C3SC2=C1 PWWVAXIEGOYWEE-UHFFFAOYSA-N 0.000 description 2
- 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 2
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 2
- KAFOIVJDVSZUMD-DCAQKATOSA-N Leu-Gln-Gln Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(O)=O KAFOIVJDVSZUMD-DCAQKATOSA-N 0.000 description 2
- 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
- QVFGXCVIXXBFHO-AVGNSLFASA-N Leu-Glu-Leu Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(O)=O QVFGXCVIXXBFHO-AVGNSLFASA-N 0.000 description 2
- 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 2
- HDHQQEDVWQGBEE-DCAQKATOSA-N Leu-Met-Ser Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CO)C(O)=O HDHQQEDVWQGBEE-DCAQKATOSA-N 0.000 description 2
- 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 2
- 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 2
- 102000003960 Ligases Human genes 0.000 description 2
- 108090000364 Ligases Proteins 0.000 description 2
- ISHNZELVUVPCHY-ZETCQYMHSA-N Lys-Gly-Gly Chemical compound NCCCC[C@H](N)C(=O)NCC(=O)NCC(O)=O ISHNZELVUVPCHY-ZETCQYMHSA-N 0.000 description 2
- 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 2
- DRRXXZBXDMLGFC-IHRRRGAJSA-N Lys-Val-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](N)CCCCN DRRXXZBXDMLGFC-IHRRRGAJSA-N 0.000 description 2
- VOOINLQYUZOREH-SRVKXCTJSA-N Met-Gln-Leu Chemical compound CC(C)C[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)N)NC(=O)[C@H](CCSC)N VOOINLQYUZOREH-SRVKXCTJSA-N 0.000 description 2
- GHQFLTYXGUETFD-UFYCRDLUSA-N Met-Tyr-Tyr Chemical compound CSCC[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 GHQFLTYXGUETFD-UFYCRDLUSA-N 0.000 description 2
- 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 2
- PESQCPHRXOFIPX-UHFFFAOYSA-N N-L-methionyl-L-tyrosine Natural products CSCCC(N)C(=O)NC(C(O)=O)CC1=CC=C(O)C=C1 PESQCPHRXOFIPX-UHFFFAOYSA-N 0.000 description 2
- 101100068676 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) gln-1 gene Proteins 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
- FQUUYTNBMIBOHS-IHRRRGAJSA-N Phe-Met-Ser Chemical compound CSCC[C@@H](C(=O)N[C@@H](CO)C(=O)O)NC(=O)[C@H](CC1=CC=CC=C1)N FQUUYTNBMIBOHS-IHRRRGAJSA-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
- VXCHGLYSIOOZIS-GUBZILKMSA-N Pro-Ala-Arg Chemical compound NC(N)=NCCC[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H]1CCCN1 VXCHGLYSIOOZIS-GUBZILKMSA-N 0.000 description 2
- 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 2
- JARJPEMLQAWNBR-GUBZILKMSA-N Pro-Asp-Arg Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O JARJPEMLQAWNBR-GUBZILKMSA-N 0.000 description 2
- 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 2
- UIMCLYYSUCIUJM-UWVGGRQHSA-N Pro-Gly-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)CNC(=O)[C@@H]1CCCN1 UIMCLYYSUCIUJM-UWVGGRQHSA-N 0.000 description 2
- 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
- VTFXTWDFPTWNJY-RHYQMDGZSA-N Pro-Leu-Thr Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O VTFXTWDFPTWNJY-RHYQMDGZSA-N 0.000 description 2
- PKHDJFHFMGQMPS-RCWTZXSCSA-N Pro-Thr-Arg Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O PKHDJFHFMGQMPS-RCWTZXSCSA-N 0.000 description 2
- 239000012980 RPMI-1640 medium Substances 0.000 description 2
- 102100030086 Receptor tyrosine-protein kinase erbB-2 Human genes 0.000 description 2
- JPIDMRXXNMIVKY-VZFHVOOUSA-N Ser-Ala-Thr Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O JPIDMRXXNMIVKY-VZFHVOOUSA-N 0.000 description 2
- HBZBPFLJNDXRAY-FXQIFTODSA-N Ser-Ala-Val Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](C)C(=O)N[C@@H](C(C)C)C(O)=O HBZBPFLJNDXRAY-FXQIFTODSA-N 0.000 description 2
- WDXYVIIVDIDOSX-DCAQKATOSA-N Ser-Arg-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)CO)CCCN=C(N)N WDXYVIIVDIDOSX-DCAQKATOSA-N 0.000 description 2
- 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 2
- 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 2
- 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 2
- CLKKNZQUQMZDGD-SRVKXCTJSA-N Ser-His-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)CO)CC1=CN=CN1 CLKKNZQUQMZDGD-SRVKXCTJSA-N 0.000 description 2
- 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 2
- IUXGJEIKJBYKOO-SRVKXCTJSA-N Ser-Leu-His Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)NC(=O)[C@H](CO)N IUXGJEIKJBYKOO-SRVKXCTJSA-N 0.000 description 2
- PTWIYDNFWPXQSD-GARJFASQSA-N Ser-Lys-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CCCCN)NC(=O)[C@H](CO)N)C(=O)O PTWIYDNFWPXQSD-GARJFASQSA-N 0.000 description 2
- RHAPJNVNWDBFQI-BQBZGAKWSA-N Ser-Pro-Gly Chemical compound OC[C@H](N)C(=O)N1CCC[C@H]1C(=O)NCC(O)=O RHAPJNVNWDBFQI-BQBZGAKWSA-N 0.000 description 2
- BMKNXTJLHFIAAH-CIUDSAMLSA-N Ser-Ser-Leu Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(O)=O BMKNXTJLHFIAAH-CIUDSAMLSA-N 0.000 description 2
- RXUOAOOZIWABBW-XGEHTFHBSA-N Ser-Thr-Arg Chemical compound OC[C@H](N)C(=O)N[C@@H]([C@H](O)C)C(=O)N[C@H](C(O)=O)CCCN=C(N)N RXUOAOOZIWABBW-XGEHTFHBSA-N 0.000 description 2
- 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 2
- BIWBTRRBHIEVAH-IHPCNDPISA-N Ser-Tyr-Trp Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC1=CNC2=C1C=CC=C2)C(O)=O BIWBTRRBHIEVAH-IHPCNDPISA-N 0.000 description 2
- LLSLRQOEAFCZLW-NRPADANISA-N Ser-Val-Gln Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(N)=O)C(O)=O LLSLRQOEAFCZLW-NRPADANISA-N 0.000 description 2
- NJEMRSFGDNECGF-GCJQMDKQSA-N Thr-Ala-Asp Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@H](C(O)=O)CC(O)=O NJEMRSFGDNECGF-GCJQMDKQSA-N 0.000 description 2
- 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 2
- 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 2
- 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 2
- 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 2
- LAFLAXHTDVNVEL-WDCWCFNPSA-N Thr-Gln-Lys Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H](CCCCN)C(=O)O)N)O LAFLAXHTDVNVEL-WDCWCFNPSA-N 0.000 description 2
- LIXBDERDAGNVAV-XKBZYTNZSA-N Thr-Gln-Ser Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CO)C(O)=O LIXBDERDAGNVAV-XKBZYTNZSA-N 0.000 description 2
- LGNBRHZANHMZHK-NUMRIWBASA-N Thr-Glu-Asp Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CC(=O)O)C(=O)O)N)O LGNBRHZANHMZHK-NUMRIWBASA-N 0.000 description 2
- AMXMBCAXAZUCFA-RHYQMDGZSA-N Thr-Leu-Arg Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O AMXMBCAXAZUCFA-RHYQMDGZSA-N 0.000 description 2
- 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 2
- MXDOAJQRJBMGMO-FJXKBIBVSA-N Thr-Pro-Gly Chemical compound C[C@@H](O)[C@H](N)C(=O)N1CCC[C@H]1C(=O)NCC(O)=O MXDOAJQRJBMGMO-FJXKBIBVSA-N 0.000 description 2
- DEGCBBCMYWNJNA-RHYQMDGZSA-N Thr-Pro-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@@H](N)[C@@H](C)O DEGCBBCMYWNJNA-RHYQMDGZSA-N 0.000 description 2
- 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 2
- 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 2
- 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 2
- 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 2
- LTLBNCDNXQCOLB-UBHSHLNASA-N Trp-Asp-Ser Chemical compound C1=CC=C2C(C[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(O)=O)=CNC2=C1 LTLBNCDNXQCOLB-UBHSHLNASA-N 0.000 description 2
- VOCHZIJXPRBVSI-XIRDDKMYSA-N Trp-Met-Gln Chemical compound CSCC[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)O)NC(=O)[C@H](CC1=CNC2=CC=CC=C21)N VOCHZIJXPRBVSI-XIRDDKMYSA-N 0.000 description 2
- 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 2
- 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 2
- 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 2
- 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 2
- NMKJPMCEKQHRPD-IRXDYDNUSA-N Tyr-Gly-Tyr Chemical compound C([C@H](N)C(=O)NCC(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(O)=O)C1=CC=C(O)C=C1 NMKJPMCEKQHRPD-IRXDYDNUSA-N 0.000 description 2
- 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 2
- KYPMKDGKAYQCHO-RYUDHWBXSA-N Tyr-Met Chemical compound CSCC[C@@H](C(O)=O)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 KYPMKDGKAYQCHO-RYUDHWBXSA-N 0.000 description 2
- PWKMJDQXKCENMF-MEYUZBJRSA-N Tyr-Thr-Leu Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(O)=O PWKMJDQXKCENMF-MEYUZBJRSA-N 0.000 description 2
- 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 2
- LDKDSFQSEUOCOO-RPTUDFQQSA-N Tyr-Thr-Phe Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O LDKDSFQSEUOCOO-RPTUDFQQSA-N 0.000 description 2
- SLLKXDSRVAOREO-KZVJFYERSA-N Val-Ala-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](C)NC(=O)[C@H](C(C)C)N)O SLLKXDSRVAOREO-KZVJFYERSA-N 0.000 description 2
- 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 2
- 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 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
- JAIZPWVHPQRYOU-ZJDVBMNYSA-N Val-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](C(C)C)N)O JAIZPWVHPQRYOU-ZJDVBMNYSA-N 0.000 description 2
- 239000011543 agarose gel Substances 0.000 description 2
- 108010008685 alanyl-glutamyl-aspartic acid Proteins 0.000 description 2
- 108010005233 alanylglutamic acid Proteins 0.000 description 2
- 108010070944 alanylhistidine Proteins 0.000 description 2
- 108010070783 alanyltyrosine Proteins 0.000 description 2
- 108010008355 arginyl-glutamine Proteins 0.000 description 2
- 108010069926 arginyl-glycyl-serine Proteins 0.000 description 2
- 108010077245 asparaginyl-proline Proteins 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 238000004140 cleaning Methods 0.000 description 2
- 238000010367 cloning Methods 0.000 description 2
- 208000029742 colonic neoplasm Diseases 0.000 description 2
- 238000010276 construction Methods 0.000 description 2
- 210000001100 crypt cell Anatomy 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000035475 disorder Diseases 0.000 description 2
- 238000001976 enzyme digestion Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000001943 fluorescence-activated cell sorting Methods 0.000 description 2
- 230000004927 fusion Effects 0.000 description 2
- 230000002496 gastric effect Effects 0.000 description 2
- 230000002068 genetic effect Effects 0.000 description 2
- 108010000434 glycyl-alanyl-leucine Proteins 0.000 description 2
- 108010015792 glycyllysine Proteins 0.000 description 2
- 108010037850 glycylvaline Proteins 0.000 description 2
- 108010085325 histidylproline Proteins 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 238000001802 infusion Methods 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 210000000936 intestine Anatomy 0.000 description 2
- 208000021601 lentivirus infection Diseases 0.000 description 2
- 108010012058 leucyltyrosine Proteins 0.000 description 2
- 239000003446 ligand Substances 0.000 description 2
- 108010057952 lysyl-phenylalanyl-lysine Proteins 0.000 description 2
- 108010054155 lysyllysine Proteins 0.000 description 2
- 238000002826 magnetic-activated cell sorting Methods 0.000 description 2
- 230000036210 malignancy Effects 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 210000001236 prokaryotic cell Anatomy 0.000 description 2
- 108010004914 prolylarginine Proteins 0.000 description 2
- 238000000159 protein binding assay Methods 0.000 description 2
- 229950010131 puromycin Drugs 0.000 description 2
- 230000002285 radioactive effect Effects 0.000 description 2
- 230000006798 recombination Effects 0.000 description 2
- 238000005215 recombination Methods 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 230000035945 sensitivity Effects 0.000 description 2
- 108010069117 seryl-lysyl-aspartic acid Proteins 0.000 description 2
- 108010071207 serylmethionine Proteins 0.000 description 2
- 230000002269 spontaneous effect Effects 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 230000009261 transgenic effect Effects 0.000 description 2
- 230000005909 tumor killing Effects 0.000 description 2
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 2
- 238000011144 upstream manufacturing Methods 0.000 description 2
- 108010009962 valyltyrosine Proteins 0.000 description 2
- 239000013603 viral vector Substances 0.000 description 2
- 239000002699 waste material Substances 0.000 description 2
- FWMNVWWHGCHHJJ-SKKKGAJSSA-N 4-amino-1-[(2r)-6-amino-2-[[(2r)-2-[[(2r)-2-[[(2r)-2-amino-3-phenylpropanoyl]amino]-3-phenylpropanoyl]amino]-4-methylpentanoyl]amino]hexanoyl]piperidine-4-carboxylic acid Chemical compound C([C@H](C(=O)N[C@H](CC(C)C)C(=O)N[C@H](CCCCN)C(=O)N1CCC(N)(CC1)C(O)=O)NC(=O)[C@H](N)CC=1C=CC=CC=1)C1=CC=CC=C1 FWMNVWWHGCHHJJ-SKKKGAJSSA-N 0.000 description 1
- 108010044087 AS-I toxin Proteins 0.000 description 1
- 229920000936 Agarose Polymers 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
- LSLIRHLIUDVNBN-CIUDSAMLSA-N Ala-Asp-Lys Chemical compound C[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@H](C(O)=O)CCCCN LSLIRHLIUDVNBN-CIUDSAMLSA-N 0.000 description 1
- KXEVYGKATAMXJJ-ACZMJKKPSA-N Ala-Glu-Asp Chemical compound C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(O)=O KXEVYGKATAMXJJ-ACZMJKKPSA-N 0.000 description 1
- TZDNWXDLYFIFPT-BJDJZHNGSA-N Ala-Ile-Leu Chemical compound [H]N[C@@H](C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(C)C)C(O)=O TZDNWXDLYFIFPT-BJDJZHNGSA-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
- DYXOFPBJBAHWFY-JBDRJPRFSA-N Ala-Ser-Ile Chemical compound CC[C@H](C)[C@@H](C(O)=O)NC(=O)[C@H](CO)NC(=O)[C@H](C)N DYXOFPBJBAHWFY-JBDRJPRFSA-N 0.000 description 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
- 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 1
- 101000878581 Aplysia californica Feeding circuit activating peptides Proteins 0.000 description 1
- 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 1
- FBLMOFHNVQBKRR-IHRRRGAJSA-N Arg-Asp-Tyr Chemical compound NC(N)=NCCC[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 FBLMOFHNVQBKRR-IHRRRGAJSA-N 0.000 description 1
- AQPVUEJJARLJHB-BQBZGAKWSA-N Arg-Gly-Ala Chemical compound OC(=O)[C@H](C)NC(=O)CNC(=O)[C@@H](N)CCCN=C(N)N AQPVUEJJARLJHB-BQBZGAKWSA-N 0.000 description 1
- CYXCAHZVPFREJD-LURJTMIESA-N Arg-Gly-Gly Chemical compound NC(=N)NCCC[C@H](N)C(=O)NCC(=O)NCC(O)=O CYXCAHZVPFREJD-LURJTMIESA-N 0.000 description 1
- OTZMRMHZCMZOJZ-SRVKXCTJSA-N Arg-Leu-Glu Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(O)=O OTZMRMHZCMZOJZ-SRVKXCTJSA-N 0.000 description 1
- VIINVRPKMUZYOI-DCAQKATOSA-N Arg-Met-Glu Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCC(O)=O)C(O)=O VIINVRPKMUZYOI-DCAQKATOSA-N 0.000 description 1
- 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 1
- CPTXATAOUQJQRO-GUBZILKMSA-N Arg-Val-Ser Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CO)C(O)=O CPTXATAOUQJQRO-GUBZILKMSA-N 0.000 description 1
- PAXHINASXXXILC-SRVKXCTJSA-N Asn-Asp-Tyr Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)O)NC(=O)[C@H](CC(=O)N)N)O PAXHINASXXXILC-SRVKXCTJSA-N 0.000 description 1
- 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 1
- 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 1
- 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 1
- YNCHFVRXEQFPBY-BQBZGAKWSA-N Asp-Gly-Arg Chemical compound OC(=O)C[C@H](N)C(=O)NCC(=O)N[C@H](C(O)=O)CCCN=C(N)N YNCHFVRXEQFPBY-BQBZGAKWSA-N 0.000 description 1
- RQYMKRMRZWJGHC-BQBZGAKWSA-N Asp-Gly-Met Chemical compound CSCC[C@@H](C(=O)O)NC(=O)CNC(=O)[C@H](CC(=O)O)N RQYMKRMRZWJGHC-BQBZGAKWSA-N 0.000 description 1
- 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 1
- LBOVBQONZJRWPV-YUMQZZPRSA-N Asp-Lys-Gly Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)NCC(O)=O LBOVBQONZJRWPV-YUMQZZPRSA-N 0.000 description 1
- YIDFBWRHIYOYAA-LKXGYXEUSA-N Asp-Ser-Thr Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(O)=O YIDFBWRHIYOYAA-LKXGYXEUSA-N 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- 101150045267 CEA gene Proteins 0.000 description 1
- 101100506090 Caenorhabditis elegans hil-2 gene Proteins 0.000 description 1
- 108091026890 Coding region Proteins 0.000 description 1
- 108020004705 Codon Proteins 0.000 description 1
- 206010050685 Cytokine storm Diseases 0.000 description 1
- 150000008574 D-amino acids Chemical class 0.000 description 1
- 108700039887 Essential Genes Proteins 0.000 description 1
- 206010017993 Gastrointestinal neoplasms Diseases 0.000 description 1
- 206010018338 Glioma Diseases 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
- AAOBFSKXAVIORT-GUBZILKMSA-N Gln-Asn-Leu Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(O)=O AAOBFSKXAVIORT-GUBZILKMSA-N 0.000 description 1
- LMPBBFWHCRURJD-LAEOZQHASA-N Gln-Asn-Val Chemical compound CC(C)[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)N)NC(=O)[C@H](CCC(=O)N)N LMPBBFWHCRURJD-LAEOZQHASA-N 0.000 description 1
- 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 1
- RBWKVOSARCFSQQ-FXQIFTODSA-N Gln-Gln-Ser Chemical compound NC(=O)CC[C@H](N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CO)C(O)=O RBWKVOSARCFSQQ-FXQIFTODSA-N 0.000 description 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
- FGYPOQPQTUNESW-IUCAKERBSA-N Gln-Gly-Leu Chemical compound CC(C)C[C@@H](C(=O)O)NC(=O)CNC(=O)[C@H](CCC(=O)N)N FGYPOQPQTUNESW-IUCAKERBSA-N 0.000 description 1
- YPMDZWPZFOZYFG-GUBZILKMSA-N Gln-Leu-Ser Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(O)=O YPMDZWPZFOZYFG-GUBZILKMSA-N 0.000 description 1
- XZLLTYBONVKGLO-SDDRHHMPSA-N Gln-Lys-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CCCCN)NC(=O)[C@H](CCC(=O)N)N)C(=O)O XZLLTYBONVKGLO-SDDRHHMPSA-N 0.000 description 1
- 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
- AFODTOLGSZQDSL-PEFMBERDSA-N Glu-Asn-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)N)NC(=O)[C@H](CCC(=O)O)N AFODTOLGSZQDSL-PEFMBERDSA-N 0.000 description 1
- JRCUFCXYZLPSDZ-ACZMJKKPSA-N Glu-Asp-Ser Chemical compound OC(=O)CC[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(O)=O JRCUFCXYZLPSDZ-ACZMJKKPSA-N 0.000 description 1
- IVGJYOOGJLFKQE-AVGNSLFASA-N Glu-Leu-Lys Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CCC(=O)O)N IVGJYOOGJLFKQE-AVGNSLFASA-N 0.000 description 1
- HGJREIGJLUQBTJ-SZMVWBNQSA-N Glu-Trp-Leu Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC1=CNC2=C1C=CC=C2)C(=O)N[C@@H](CC(C)C)C(O)=O HGJREIGJLUQBTJ-SZMVWBNQSA-N 0.000 description 1
- RLFSBAPJTYKSLG-WHFBIAKZSA-N Gly-Ala-Asp Chemical compound NCC(=O)N[C@@H](C)C(=O)N[C@@H](CC(O)=O)C(O)=O RLFSBAPJTYKSLG-WHFBIAKZSA-N 0.000 description 1
- MFVQGXGQRIXBPK-WDSKDSINSA-N Gly-Ala-Glu Chemical compound NCC(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(O)=O MFVQGXGQRIXBPK-WDSKDSINSA-N 0.000 description 1
- LJPIRKICOISLKN-WHFBIAKZSA-N Gly-Ala-Ser Chemical compound NCC(=O)N[C@@H](C)C(=O)N[C@@H](CO)C(O)=O LJPIRKICOISLKN-WHFBIAKZSA-N 0.000 description 1
- QSDKBRMVXSWAQE-BFHQHQDPSA-N Gly-Ala-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)CN QSDKBRMVXSWAQE-BFHQHQDPSA-N 0.000 description 1
- XEJTYSCIXKYSHR-WDSKDSINSA-N Gly-Asp-Gln Chemical compound C(CC(=O)N)[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)O)NC(=O)CN XEJTYSCIXKYSHR-WDSKDSINSA-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
- 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
- CSMYMGFCEJWALV-WDSKDSINSA-N Gly-Ser-Gln Chemical compound NCC(=O)N[C@@H](CO)C(=O)N[C@H](C(O)=O)CCC(N)=O CSMYMGFCEJWALV-WDSKDSINSA-N 0.000 description 1
- MKIAPEZXQDILRR-YUMQZZPRSA-N Gly-Ser-His Chemical compound C1=C(NC=N1)C[C@@H](C(=O)O)NC(=O)[C@H](CO)NC(=O)CN MKIAPEZXQDILRR-YUMQZZPRSA-N 0.000 description 1
- FKYQEVBRZSFAMJ-QWRGUYRKSA-N Gly-Ser-Tyr Chemical compound NCC(=O)N[C@@H](CO)C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 FKYQEVBRZSFAMJ-QWRGUYRKSA-N 0.000 description 1
- GNNJKUYDWFIBTK-QWRGUYRKSA-N Gly-Tyr-Asp Chemical compound [H]NCC(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC(O)=O)C(O)=O GNNJKUYDWFIBTK-QWRGUYRKSA-N 0.000 description 1
- 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 1
- IZVICCORZOSGPT-JSGCOSHPSA-N Gly-Val-Tyr Chemical compound [H]NCC(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O IZVICCORZOSGPT-JSGCOSHPSA-N 0.000 description 1
- 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 1
- 206010066476 Haematological malignancy Diseases 0.000 description 1
- 208000002250 Hematologic Neoplasms Diseases 0.000 description 1
- 241000238631 Hexapoda Species 0.000 description 1
- IGBBXBFSLKRHJB-BZSNNMDCSA-N His-Lys-Phe Chemical compound C([C@H](N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)C1=CN=CN1 IGBBXBFSLKRHJB-BZSNNMDCSA-N 0.000 description 1
- 101001002657 Homo sapiens Interleukin-2 Proteins 0.000 description 1
- 101000917858 Homo sapiens Low affinity immunoglobulin gamma Fc region receptor III-A Proteins 0.000 description 1
- 101000917839 Homo sapiens Low affinity immunoglobulin gamma Fc region receptor III-B Proteins 0.000 description 1
- 101000581981 Homo sapiens Neural cell adhesion molecule 1 Proteins 0.000 description 1
- UASTVUQJMLZWGG-PEXQALLHSA-N Ile-His-Gly Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)NCC(=O)O)N UASTVUQJMLZWGG-PEXQALLHSA-N 0.000 description 1
- FCWFBHMAJZGWRY-XUXIUFHCSA-N Ile-Leu-Met Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)O)N FCWFBHMAJZGWRY-XUXIUFHCSA-N 0.000 description 1
- UWBDLNOCIDGPQE-GUBZILKMSA-N Ile-Lys Chemical compound CC[C@H](C)[C@H](N)C(=O)N[C@H](C(O)=O)CCCCN UWBDLNOCIDGPQE-GUBZILKMSA-N 0.000 description 1
- ZLFNNVATRMCAKN-ZKWXMUAHSA-N Ile-Ser-Gly Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CO)C(=O)NCC(=O)O)N ZLFNNVATRMCAKN-ZKWXMUAHSA-N 0.000 description 1
- OAQJOXZPGHTJNA-NGTWOADLSA-N Ile-Trp-Thr Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC1=CNC2=CC=CC=C21)C(=O)N[C@@H]([C@@H](C)O)C(=O)O)N OAQJOXZPGHTJNA-NGTWOADLSA-N 0.000 description 1
- FXJLRZFMKGHYJP-CFMVVWHZSA-N Ile-Tyr-Asn 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)N)C(=O)O)N FXJLRZFMKGHYJP-CFMVVWHZSA-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
- 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 1
- 108010021625 Immunoglobulin Fragments Proteins 0.000 description 1
- 102000008394 Immunoglobulin Fragments Human genes 0.000 description 1
- 102000002698 KIR Receptors Human genes 0.000 description 1
- 108010043610 KIR Receptors Proteins 0.000 description 1
- 150000008575 L-amino acids Chemical class 0.000 description 1
- 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 1
- KFKWRHQBZQICHA-STQMWFEESA-N L-leucyl-L-phenylalanine Natural products CC(C)C[C@H](N)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 KFKWRHQBZQICHA-STQMWFEESA-N 0.000 description 1
- 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 1
- XBBKIIGCUMBKCO-JXUBOQSCSA-N Leu-Ala-Thr Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O XBBKIIGCUMBKCO-JXUBOQSCSA-N 0.000 description 1
- STAVRDQLZOTNKJ-RHYQMDGZSA-N Leu-Arg-Thr Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(O)=O STAVRDQLZOTNKJ-RHYQMDGZSA-N 0.000 description 1
- CCQLQKZTXZBXTN-NHCYSSNCSA-N Leu-Gly-Ile Chemical compound [H]N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H]([C@@H](C)CC)C(O)=O CCQLQKZTXZBXTN-NHCYSSNCSA-N 0.000 description 1
- WRLPVDVHNWSSCL-MELADBBJSA-N Leu-His-Pro Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)N2CCC[C@@H]2C(=O)O)N WRLPVDVHNWSSCL-MELADBBJSA-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
- 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 1
- 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 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
- 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 1
- PPGBXYKMUMHFBF-KATARQTJSA-N Leu-Ser-Thr Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(O)=O PPGBXYKMUMHFBF-KATARQTJSA-N 0.000 description 1
- 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 1
- YIRIDPUGZKHMHT-ACRUOGEOSA-N Leu-Tyr-Tyr Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O YIRIDPUGZKHMHT-ACRUOGEOSA-N 0.000 description 1
- 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 1
- YQFZRHYZLARWDY-IHRRRGAJSA-N Leu-Val-Lys Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@H](C(O)=O)CCCCN YQFZRHYZLARWDY-IHRRRGAJSA-N 0.000 description 1
- 102100029185 Low affinity immunoglobulin gamma Fc region receptor III-B Human genes 0.000 description 1
- KCXUCYYZNZFGLL-SRVKXCTJSA-N Lys-Ala-Leu Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(O)=O KCXUCYYZNZFGLL-SRVKXCTJSA-N 0.000 description 1
- QUCDKEKDPYISNX-HJGDQZAQSA-N Lys-Asn-Thr Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O QUCDKEKDPYISNX-HJGDQZAQSA-N 0.000 description 1
- 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 1
- 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 1
- XFANQCRHTMOEAP-WDSOQIARSA-N Lys-Pro-Trp Chemical compound [H]N[C@@H](CCCCN)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CC1=CNC2=C1C=CC=C2)C(O)=O XFANQCRHTMOEAP-WDSOQIARSA-N 0.000 description 1
- MIROMRNASYKZNL-ULQDDVLXSA-N Lys-Pro-Tyr Chemical compound NCCCC[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 MIROMRNASYKZNL-ULQDDVLXSA-N 0.000 description 1
- WQDKIVRHTQYJSN-DCAQKATOSA-N Lys-Ser-Arg Chemical compound C(CCN)C[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCN=C(N)N)C(=O)O)N WQDKIVRHTQYJSN-DCAQKATOSA-N 0.000 description 1
- 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
- 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
- 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 1
- IECZNARPMKQGJC-XIRDDKMYSA-N Met-Gln-Trp Chemical compound CSCC[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H](CC1=CNC2=CC=CC=C21)C(=O)O)N IECZNARPMKQGJC-XIRDDKMYSA-N 0.000 description 1
- CIDICGYKRUTYLE-FXQIFTODSA-N Met-Ser-Ala Chemical compound CSCC[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@@H](C)C(O)=O CIDICGYKRUTYLE-FXQIFTODSA-N 0.000 description 1
- DBMLDOWSVHMQQN-XGEHTFHBSA-N Met-Ser-Thr Chemical compound CSCC[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(O)=O DBMLDOWSVHMQQN-XGEHTFHBSA-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
- 241001465754 Metazoa Species 0.000 description 1
- YBAFDPFAUTYYRW-UHFFFAOYSA-N N-L-alpha-glutamyl-L-leucine Natural products CC(C)CC(C(O)=O)NC(=O)C(N)CCC(O)=O YBAFDPFAUTYYRW-UHFFFAOYSA-N 0.000 description 1
- 108010002311 N-glycylglutamic acid Proteins 0.000 description 1
- 230000006051 NK cell activation Effects 0.000 description 1
- 102100027347 Neural cell adhesion molecule 1 Human genes 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 1
- UHRNIXJAGGLKHP-DLOVCJGASA-N Phe-Ala-Ser Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](C)C(=O)N[C@@H](CO)C(O)=O UHRNIXJAGGLKHP-DLOVCJGASA-N 0.000 description 1
- LLGTYVHITPVGKR-RYUDHWBXSA-N Phe-Gln-Gly Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CCC(N)=O)C(=O)NCC(O)=O LLGTYVHITPVGKR-RYUDHWBXSA-N 0.000 description 1
- BPIMVBKDLSBKIJ-FCLVOEFKSA-N Phe-Thr-Phe Chemical compound C([C@H](N)C(=O)N[C@@H]([C@H](O)C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)C1=CC=CC=C1 BPIMVBKDLSBKIJ-FCLVOEFKSA-N 0.000 description 1
- IFMDQWDAJUMMJC-DCAQKATOSA-N Pro-Ala-Leu Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(O)=O IFMDQWDAJUMMJC-DCAQKATOSA-N 0.000 description 1
- 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 1
- ULIWFCCJIOEHMU-BQBZGAKWSA-N Pro-Gly-Asp Chemical compound OC(=O)C[C@@H](C(O)=O)NC(=O)CNC(=O)[C@@H]1CCCN1 ULIWFCCJIOEHMU-BQBZGAKWSA-N 0.000 description 1
- VYWNORHENYEQDW-YUMQZZPRSA-N Pro-Gly-Glu Chemical compound OC(=O)CC[C@@H](C(O)=O)NC(=O)CNC(=O)[C@@H]1CCCN1 VYWNORHENYEQDW-YUMQZZPRSA-N 0.000 description 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
- BRJGUPWVFXKBQI-XUXIUFHCSA-N Pro-Leu-Ile Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O BRJGUPWVFXKBQI-XUXIUFHCSA-N 0.000 description 1
- DLZBBDSPTJBOOD-BPNCWPANSA-N Pro-Tyr-Ala Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](C)C(O)=O DLZBBDSPTJBOOD-BPNCWPANSA-N 0.000 description 1
- 101710130181 Protochlorophyllide reductase A, chloroplastic Proteins 0.000 description 1
- 108010008281 Recombinant Fusion Proteins Proteins 0.000 description 1
- 102000007056 Recombinant Fusion Proteins Human genes 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
- 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
- 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 1
- 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 1
- 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 1
- KMWFXJCGRXBQAC-CIUDSAMLSA-N Ser-Cys-Lys Chemical compound C(CCN)C[C@@H](C(=O)O)NC(=O)[C@H](CS)NC(=O)[C@H](CO)N KMWFXJCGRXBQAC-CIUDSAMLSA-N 0.000 description 1
- 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 1
- QGAHMVHBORDHDC-YUMQZZPRSA-N Ser-His-Gly Chemical compound OC[C@H](N)C(=O)N[C@H](C(=O)NCC(O)=O)CC1=CN=CN1 QGAHMVHBORDHDC-YUMQZZPRSA-N 0.000 description 1
- 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 1
- XZKQVQKUZMAADP-IMJSIDKUSA-N Ser-Ser Chemical compound OC[C@H](N)C(=O)N[C@@H](CO)C(O)=O XZKQVQKUZMAADP-IMJSIDKUSA-N 0.000 description 1
- KQNDIKOYWZTZIX-FXQIFTODSA-N Ser-Ser-Arg Chemical compound OC[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@H](C(O)=O)CCCNC(N)=N KQNDIKOYWZTZIX-FXQIFTODSA-N 0.000 description 1
- 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 1
- AABIBDJHSKIMJK-FXQIFTODSA-N Ser-Ser-Met Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCSC)C(O)=O AABIBDJHSKIMJK-FXQIFTODSA-N 0.000 description 1
- CUXJENOFJXOSOZ-BIIVOSGPSA-N Ser-Ser-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CO)NC(=O)[C@H](CO)N)C(=O)O CUXJENOFJXOSOZ-BIIVOSGPSA-N 0.000 description 1
- JURQXQBJKUHGJS-UHFFFAOYSA-N Ser-Ser-Ser-Ser Chemical compound OCC(N)C(=O)NC(CO)C(=O)NC(CO)C(=O)NC(CO)C(O)=O JURQXQBJKUHGJS-UHFFFAOYSA-N 0.000 description 1
- DYEGLQRVMBWQLD-IXOXFDKPSA-N Ser-Thr-Phe Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)O)NC(=O)[C@H](CO)N)O DYEGLQRVMBWQLD-IXOXFDKPSA-N 0.000 description 1
- 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 1
- 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 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
- 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
- 230000006044 T cell activation Effects 0.000 description 1
- 108091008874 T cell receptors Proteins 0.000 description 1
- 102000016266 T-Cell Antigen Receptors Human genes 0.000 description 1
- STGXWWBXWXZOER-MBLNEYKQSA-N Thr-Ala-His Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@H](C(O)=O)CC1=CN=CN1 STGXWWBXWXZOER-MBLNEYKQSA-N 0.000 description 1
- DGDCHPCRMWEOJR-FQPOAREZSA-N Thr-Ala-Tyr Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 DGDCHPCRMWEOJR-FQPOAREZSA-N 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
- UTSWGQNAQRIHAI-UNQGMJICSA-N Thr-Arg-Phe Chemical compound NC(N)=NCCC[C@H](NC(=O)[C@@H](N)[C@H](O)C)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 UTSWGQNAQRIHAI-UNQGMJICSA-N 0.000 description 1
- 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 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
- ABWNZPOIUJMNKT-IXOXFDKPSA-N Thr-Phe-Ser Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CO)C(O)=O ABWNZPOIUJMNKT-IXOXFDKPSA-N 0.000 description 1
- MUAFDCVOHYAFNG-RCWTZXSCSA-N Thr-Pro-Arg Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCCNC(N)=N)C(O)=O MUAFDCVOHYAFNG-RCWTZXSCSA-N 0.000 description 1
- STUAPCLEDMKXKL-LKXGYXEUSA-N Thr-Ser-Asn Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(O)=O STUAPCLEDMKXKL-LKXGYXEUSA-N 0.000 description 1
- 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
- VBMOVTMNHWPZJR-SUSMZKCASA-N Thr-Thr-Glu Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCC(O)=O)C(O)=O VBMOVTMNHWPZJR-SUSMZKCASA-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
- GIAMKIPJSRZVJB-IHPCNDPISA-N Trp-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](CC2=CNC3=CC=CC=C32)N GIAMKIPJSRZVJB-IHPCNDPISA-N 0.000 description 1
- 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 1
- UGFOSENEZHEQKX-PJODQICGSA-N Trp-Val-Ala Chemical compound CC(C)[C@H](NC(=O)[C@@H](N)Cc1c[nH]c2ccccc12)C(=O)N[C@@H](C)C(O)=O UGFOSENEZHEQKX-PJODQICGSA-N 0.000 description 1
- NSOMQRHZMJMZIE-GVARAGBVSA-N Tyr-Ala-Ile Chemical compound CC[C@H](C)[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 NSOMQRHZMJMZIE-GVARAGBVSA-N 0.000 description 1
- MICSYKFECRFCTJ-IHRRRGAJSA-N Tyr-Arg-Asp Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CC(=O)O)C(=O)O)N)O MICSYKFECRFCTJ-IHRRRGAJSA-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
- NLMXVDDEQFKQQU-CFMVVWHZSA-N Tyr-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)CC1=CC=C(O)C=C1 NLMXVDDEQFKQQU-CFMVVWHZSA-N 0.000 description 1
- UMXSDHPSMROQRB-YJRXYDGGSA-N Tyr-Cys-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CS)NC(=O)[C@H](CC1=CC=C(C=C1)O)N)O UMXSDHPSMROQRB-YJRXYDGGSA-N 0.000 description 1
- 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 1
- 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 1
- BMPPMAOOKQJYIP-WMZOPIPTSA-N Tyr-Trp Chemical compound C([C@H]([NH3+])C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C([O-])=O)C1=CC=C(O)C=C1 BMPPMAOOKQJYIP-WMZOPIPTSA-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
- WYOBRXPIZVKNMF-IRXDYDNUSA-N Tyr-Tyr-Gly Chemical compound C([C@H](N)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)NCC(O)=O)C1=CC=C(O)C=C1 WYOBRXPIZVKNMF-IRXDYDNUSA-N 0.000 description 1
- JIODCDXKCJRMEH-NHCYSSNCSA-N Val-Arg-Gln Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CCC(=O)N)C(=O)O)N JIODCDXKCJRMEH-NHCYSSNCSA-N 0.000 description 1
- 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 1
- 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 1
- OQWNEUXPKHIEJO-NRPADANISA-N Val-Glu-Ser Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CO)C(=O)O)N OQWNEUXPKHIEJO-NRPADANISA-N 0.000 description 1
- 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 1
- HQYVQDRYODWONX-DCAQKATOSA-N Val-His-Ser Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)N[C@@H](CO)C(=O)O)N HQYVQDRYODWONX-DCAQKATOSA-N 0.000 description 1
- WBAJDGWKRIHOAC-GVXVVHGQSA-N Val-Lys-Gln Chemical compound [H]N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(N)=O)C(O)=O WBAJDGWKRIHOAC-GVXVVHGQSA-N 0.000 description 1
- CXWJFWAZIVWBOS-XQQFMLRXSA-N Val-Lys-Pro Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCCCN)C(=O)N1CCC[C@@H]1C(=O)O)N CXWJFWAZIVWBOS-XQQFMLRXSA-N 0.000 description 1
- XBJKAZATRJBDCU-GUBZILKMSA-N Val-Pro-Ala Chemical compound CC(C)[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](C)C(O)=O XBJKAZATRJBDCU-GUBZILKMSA-N 0.000 description 1
- QIVPZSWBBHRNBA-JYJNAYRXSA-N Val-Pro-Phe Chemical compound CC(C)[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](Cc1ccccc1)C(O)=O QIVPZSWBBHRNBA-JYJNAYRXSA-N 0.000 description 1
- 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 1
- 108010081404 acein-2 Proteins 0.000 description 1
- 238000011467 adoptive cell therapy Methods 0.000 description 1
- 238000000246 agarose gel electrophoresis Methods 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 238000000137 annealing Methods 0.000 description 1
- 238000002617 apheresis Methods 0.000 description 1
- 108010068380 arginylarginine Proteins 0.000 description 1
- 108010047857 aspartylglycine Proteins 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 150000001576 beta-amino acids Chemical class 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000008827 biological function Effects 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 210000004899 c-terminal region Anatomy 0.000 description 1
- 230000002308 calcification Effects 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 239000006143 cell culture medium Substances 0.000 description 1
- 230000030833 cell death Effects 0.000 description 1
- 230000003915 cell function Effects 0.000 description 1
- 230000022534 cell killing Effects 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 210000004978 chinese hamster ovary cell Anatomy 0.000 description 1
- 239000007979 citrate buffer Substances 0.000 description 1
- 238000003501 co-culture Methods 0.000 description 1
- 210000002808 connective tissue Anatomy 0.000 description 1
- 238000011109 contamination Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 206010052015 cytokine release syndrome Diseases 0.000 description 1
- 238000003568 cytokine secretion assay Methods 0.000 description 1
- 230000009089 cytolysis Effects 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 238000002784 cytotoxicity assay Methods 0.000 description 1
- 231100000263 cytotoxicity test Toxicity 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 239000008367 deionised water Substances 0.000 description 1
- 229910021641 deionized water Inorganic materials 0.000 description 1
- 238000004925 denaturation Methods 0.000 description 1
- 230000036425 denaturation Effects 0.000 description 1
- 238000011033 desalting Methods 0.000 description 1
- 230000029087 digestion Effects 0.000 description 1
- 238000013399 early diagnosis Methods 0.000 description 1
- 238000001962 electrophoresis Methods 0.000 description 1
- 239000012149 elution buffer Substances 0.000 description 1
- 230000006862 enzymatic digestion Effects 0.000 description 1
- 238000011067 equilibration Methods 0.000 description 1
- 210000003527 eukaryotic cell Anatomy 0.000 description 1
- 230000017188 evasion or tolerance of host immune response Effects 0.000 description 1
- 210000003754 fetus Anatomy 0.000 description 1
- MHMNJMPURVTYEJ-UHFFFAOYSA-N fluorescein-5-isothiocyanate Chemical compound O1C(=O)C2=CC(N=C=S)=CC=C2C21C1=CC=C(O)C=C1OC1=CC(O)=CC=C21 MHMNJMPURVTYEJ-UHFFFAOYSA-N 0.000 description 1
- 108020001507 fusion proteins Proteins 0.000 description 1
- 102000037865 fusion proteins Human genes 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 108010080575 glutamyl-aspartyl-alanine Proteins 0.000 description 1
- 230000013595 glycosylation Effects 0.000 description 1
- 238000006206 glycosylation reaction Methods 0.000 description 1
- 108010072405 glycyl-aspartyl-glycine Proteins 0.000 description 1
- 108010081551 glycylphenylalanine Proteins 0.000 description 1
- 108010087823 glycyltyrosine Proteins 0.000 description 1
- 208000024908 graft versus host disease Diseases 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 208000029824 high grade glioma Diseases 0.000 description 1
- 238000009169 immunotherapy Methods 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000015788 innate immune response Effects 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- BPHPUYQFMNQIOC-NXRLNHOXSA-N isopropyl beta-D-thiogalactopyranoside Chemical compound CC(C)S[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O BPHPUYQFMNQIOC-NXRLNHOXSA-N 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 108010051673 leucyl-glycyl-phenylalanine Proteins 0.000 description 1
- 108010044056 leucyl-phenylalanine Proteins 0.000 description 1
- 229940057995 liquid paraffin Drugs 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 201000011614 malignant glioma Diseases 0.000 description 1
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 238000010369 molecular cloning Methods 0.000 description 1
- 238000000329 molecular dynamics simulation Methods 0.000 description 1
- 238000010172 mouse model Methods 0.000 description 1
- 239000003471 mutagenic agent Substances 0.000 description 1
- 231100000707 mutagenic chemical Toxicity 0.000 description 1
- VMGAPWLDMVPYIA-HIDZBRGKSA-N n'-amino-n-iminomethanimidamide Chemical compound N\N=C\N=N VMGAPWLDMVPYIA-HIDZBRGKSA-N 0.000 description 1
- 230000001338 necrotic effect Effects 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 230000009437 off-target effect Effects 0.000 description 1
- 210000000496 pancreas Anatomy 0.000 description 1
- 201000002528 pancreatic cancer Diseases 0.000 description 1
- 208000008443 pancreatic carcinoma Diseases 0.000 description 1
- MXHCPCSDRGLRER-UHFFFAOYSA-N pentaglycine Chemical compound NCC(=O)NCC(=O)NCC(=O)NCC(=O)NCC(O)=O MXHCPCSDRGLRER-UHFFFAOYSA-N 0.000 description 1
- 108010083476 phenylalanyltryptophan Proteins 0.000 description 1
- 229920001983 poloxamer Polymers 0.000 description 1
- 238000010837 poor prognosis Methods 0.000 description 1
- 238000012257 pre-denaturation Methods 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 238000004393 prognosis Methods 0.000 description 1
- 108010090894 prolylleucine Proteins 0.000 description 1
- 238000002708 random mutagenesis Methods 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- BOLDJAUMGUJJKM-LSDHHAIUSA-N renifolin D Natural products CC(=C)[C@@H]1Cc2c(O)c(O)ccc2[C@H]1CC(=O)c3ccc(O)cc3O BOLDJAUMGUJJKM-LSDHHAIUSA-N 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 201000004193 respiratory failure Diseases 0.000 description 1
- 108010056030 retronectin Proteins 0.000 description 1
- 230000003248 secreting effect Effects 0.000 description 1
- 108010048818 seryl-histidine Proteins 0.000 description 1
- 230000011664 signaling Effects 0.000 description 1
- 238000002741 site-directed mutagenesis Methods 0.000 description 1
- 230000009870 specific binding Effects 0.000 description 1
- 238000011895 specific detection Methods 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 238000002626 targeted therapy Methods 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- 238000013519 translation Methods 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 230000001960 triggered effect Effects 0.000 description 1
- 108010025432 tyrosyl-alanyl-phenylalanyl-glycine Proteins 0.000 description 1
- 238000005199 ultracentrifugation Methods 0.000 description 1
- 238000009281 ultraviolet germicidal irradiation Methods 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- 239000011534 wash buffer Substances 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
- 210000005253 yeast cell Anatomy 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
- A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
- A61K35/14—Blood; Artificial blood
- A61K35/17—Lymphocytes; B-cells; T-cells; Natural killer cells; Interferon-activated or cytokine-activated lymphocytes
-
- 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
-
- 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
- A61K39/4631—Chimeric Antigen Receptors [CAR]
-
- 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
- A61K39/46448—Cancer antigens from embryonic or fetal origin
- A61K39/464482—Carcinoembryonic antigen [CEA]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
- C07K14/70503—Immunoglobulin superfamily
- C07K14/7051—T-cell receptor (TcR)-CD3 complex
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
- C07K14/70503—Immunoglobulin superfamily
- C07K14/70517—CD8
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
- C07K14/70503—Immunoglobulin superfamily
- C07K14/70521—CD28, CD152
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
- C07K14/70575—NGF/TNF-superfamily, e.g. CD70, CD95L, CD153, CD154
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
- C07K14/70596—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
- C07K16/40—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against enzymes
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K19/00—Hybrid peptides, i.e. peptides covalently bound to nucleic acids, or non-covalently bound protein-protein complexes
-
- 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
- C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
- C12N15/62—DNA sequences coding for fusion proteins
-
- 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
-
- 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
- C12N5/10—Cells modified by introduction of foreign genetic material
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
- G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
-
- 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
- A61K2239/00—Indexing codes associated with cellular immunotherapy of group A61K39/46
- A61K2239/46—Indexing codes associated with cellular immunotherapy of group A61K39/46 characterised by the cancer treated
- A61K2239/51—Stomach
-
- 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
- C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
- C07K2317/73—Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2319/00—Fusion polypeptide
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2319/00—Fusion polypeptide
- C07K2319/01—Fusion polypeptide containing a localisation/targetting motif
- C07K2319/02—Fusion polypeptide containing a localisation/targetting motif containing a signal sequence
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2319/00—Fusion polypeptide
- C07K2319/01—Fusion polypeptide containing a localisation/targetting motif
- C07K2319/03—Fusion polypeptide containing a localisation/targetting motif containing a transmembrane segment
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2319/00—Fusion polypeptide
- C07K2319/33—Fusion polypeptide fusions for targeting to specific cell types, e.g. tissue specific targeting, targeting of a bacterial subspecies
-
- 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
- C12N2510/00—Genetically modified cells
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
- G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
- G01N2333/46—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans from vertebrates
- G01N2333/47—Assays involving proteins of known structure or function as defined in the subgroups
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Immunology (AREA)
- Organic Chemistry (AREA)
- Genetics & Genomics (AREA)
- General Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Cell Biology (AREA)
- Medicinal Chemistry (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- Zoology (AREA)
- Biomedical Technology (AREA)
- Biophysics (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Microbiology (AREA)
- Biotechnology (AREA)
- Wood Science & Technology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Gastroenterology & Hepatology (AREA)
- Toxicology (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Hematology (AREA)
- Epidemiology (AREA)
- General Engineering & Computer Science (AREA)
- Mycology (AREA)
- Oncology (AREA)
- Urology & Nephrology (AREA)
- Physics & Mathematics (AREA)
- Pathology (AREA)
- Hospice & Palliative Care (AREA)
- Food Science & Technology (AREA)
- Analytical Chemistry (AREA)
- General Physics & Mathematics (AREA)
- Reproductive Health (AREA)
- Pregnancy & Childbirth (AREA)
Abstract
글리코실화된 CEA를 과발현하는 종양의 진단 또는 치료를 위한 제제 또는 약제의 제조에 이용될 수 있는, 글리코실화된 CEA를 표적하는 키메라 항원 수용체 (chimeric antigen receptor, CAR), 및 글리코실화된 CEA-특이적 단일쇄 항체가 개시된다.
Description
본 발명은 종양 면역요법(tumor immunotherapy) 분야에 관한 것으로, 특히, 본 발명은 글리코실화된 CEA-특이적 단일쇄 항체, 및 글리코실화된 CEA를 과발현하는 종양에 대한 형질전환 변형 입양 T 림프구 치료(transgenic modified adoptive T lymphocyte therapy) 분야에 관한 것이다.
위암(gastric cancer) 발생률은 중국 내 소화관 악성 종양에서 1위를 차지하고, 세계에서는 2위를 차지한다. 연간 사망은 악성 종양 사망의 약 24%를 차지하고, 5년 생존율(five-year survival rate)은 단지 약 27%에 불과하다. 위암 환자의 진단은 흔히 느려서, 예후가 극도로 좋지 못하다. 위암에 대한 효과적인 표적 치료는 존재하지 않는다. 암배아 항원(carcinoembryonic antigen, CEA)은 막 결합 단백질로, 일반적으로 태아의 간, 장 및 췌장에서 발현된다. 정상적으로는, 이는 장으로 분비되고, 이의 혈청 수준은 낮다. 세포가 암성(cancerous)인 경우에, 혈청 수준은 상승하는데, 이는 췌장암 및 결장암의 조기 진단에 대한 보조적인 중요성(auxiliary significance)을 가지며, 종양 확산, 치료 효과, 재발 및 예후에 대한 특정한 참고 값(reference value)을 가진다. 제4군의대학(Fourth Military Medical University)의 판 다이밍(Fan Daiming) 교수는 글리코실화된 CEA가 다양한 소화관 암에 고감도(highly sensitive)이고 고도로 특이적(highly specific)임을 밝혀냈다. 임상 연구는 위암 조직에서 글리코실화된 CEA의 양성률(positive rate)이 80%를 초과하고, 결장암에서 양성률이 40%를 초과하며, 위의 전암성 병변(gastric precancerous lesion)에서 양성률이 30%를 초과하고, 식도암 조직에서 양성률이 18% 이상임을 제시하였다. 동시에, 임상 시험의 결과는 28명의 위암 환자에서 혈청 글리코실화된 CEA의 양성률이 수술 전의 양성률에 비해서 현저하게 감소되었다는 것을 나타냈으며, 이는 글리코실화된 CEA와 위암 사이에 밀접한 관계가 있다는 것을 제시한다 (Gadler et al., Int J Cancer 25 ( 1): 91-4, 1980).
현재, 표적된 입양 세포 치료 기술(targeted adoptive cell therapy technology)을 이용한 신생의 키메라 항원 수용체 T 세포 (chimeric antigen receptor T cell, CAR-T)는 다양한 악성 종양의 치료에서 중요한 역할을 한다. CAR-T는 단일쇄 항체와 같은 종양-관련 항원(TAA)-특이적 인식 펩티드[tumor-associated antigen (TAA)-specific recognition peptide], CD3제타와 같은 T 세포 활성화 신호를 수반한 특이적 수용체의 융합이고, 융합 단백질은 렌티바이러스(lentivirus) 등에 의해 T 세포 표면상에 특이적으로 발현되는데, 이는 변형된 T 세포가 종양 세포를 특이적으로 인식하고 사멸시키도록 하며, 주조직 적합성 항원(major histocompatibility antigen, MHC)과 독립적이고, MHC 결실로 인한 종양 면역 회피(tumor immune escape)를 피할 수 있다.
키메라 항원 수용체는 세포 외 항원 표적 및 인식 영역, 힌지 영역, 막 관통 영역, 및 세포 내 공동 자극 신호전달 영역을 포함한다. 항원 인식 영역은 대부분 단일쇄 항체 또는 특이적인 수용체로, 변형 T 세포가 표적 세포를 특이적으로 인식할 수 있고, 표적 세포를 특이적으로 사멸시키도록 활성화될 수 있는 것을 보장하며; 힌지 영역은, T 세포가 표적 세포에 접촉하고 T 세포 작용에 영향을 미치는 것을 보장하는 CD8α, CD28ECD, IgG Fc 단편 등을 일반적으로 채용하고(adopting); 세포 내 신호 영역은 면역수용체 티로신 활성화 모티프 (immunoreceptor tyrosine activation motif, ITAM), 예를 들어, CD3제타 및 CD28, CD137, CD27, ICOS, OX40, DAP10 등과 같은 공동 자극 신호를 채용한다 (Sadelain et al., Cancer Discov 3(4): 388-98, 2013).
CAR-T가 혈액 악성 종양(hematological malignancy)의 치료에서 좋은 응용 가치를 보였으나, CAR-T는 흔히 고형 종양(solid tumor)의 치료에서 기대되는 결과를 달성하지 못한다. 일부 임상 연구에서조차, CAR-T는 비표적 효과(off-target effect)로 인한 독성을 보일 수 있다. 고형 종양에서, 효과적이지 않으며 특이적이지 않은 표적이 종종 존재하는 것이 중요한 이유다. 많은 종양-관련 항원의 경우에, 정상 조직 내 특정한 발현 정도(degree of expression)가 흔히 존재한다. 예를 들어, HER2는 악성 교종(malignant glioma) 및 유방암과 같은 악성 종양에 대한 중요한 표적이나, HER2 표적에 대한 CAR-T 임상 시험에서, 환자는 CAR-T 재주입(re-infusion) 후에, 폐부전(pulmonary failure)을 겪었고, "사이토카인 폭풍(cytokine storm)"이 촉발되어, 단시간에 환자의 죽음을 야기했다. 그러므로, 고형 종양의 고도로 특이적이며 고감도인 표적을 발견하는 것은 고형 종양에서 CAR-T 치료 적용의 중요한 요점이다 (Morgan et al., Mol Ther 18(4): 843-51, 2010).
NK 세포는 CD16와 CD56을 발현하는 림프구 및 선천성 면역(innate immunity)의 중요한 구성요소이다. NK 세포는 MHC-결실 표적 세포를 사멸시킬 수 있다. T 세포에 비해, NK 세포는 T-세포 수용체를 발현하지 않고, 따라서 이식편대 숙주반응(graft versus host response, GVHD)을 겪지 않는다. NK 세포 활성화는 살해 활성화 수용체(Killer Activation Receptor, KAR) 및 살해 저해 수용체(Killer Inhibition Receptor, KIR)에 대한 신호의 평형 상태에 있다. 생체 내 주요 KIR 리간드는 MHC이다. KIR 리간드의 불일치나 결실의 경우, 이는 NK 세포의 활성화를 야기할 것이다. CAR-NK 기술은, 암치료를 위한 NK 세포 또는 NK 세포주 (NK92와 같은) 표면상의 CAR 구조 발현(CAR structure expression)을 이용하는 신생 기술로, 이의 이점은 NK 세포가 IL6를 분비하지 않고, NK 세포가 말초 혈액에서 매우 짧은 순환 반감기(circulating half-life)를 가지며, NK 세포가 높은 형질주입 효율 (비-바이러스성 벡터)을 가지고, NK 세포주가 GMP 수준의 거대한 규모에서 배양될 수 있다는 것이다. NK 세포 또는 NK 세포주의 표면 상에서 CAR 구조 발현은 NK 세포에게 표적화 능력(targeting ability)을 부여할 수 있다. 동시에, CAR-NK 동종이식(allograft)에서, KIR 수용체의 불일치는 NK 세포의 활성화를 강화시켜 더 나은 종양 제거를 달성할 수 있다. 생체 내 NK 세포주의 순환 시간은 매우 짧고, 따라서 안전 고려사항(safety consideration)을 제공한다 (Han et al., Sci Rep 5: 11483, 2015).
제1 측면에 있어서, 본 발명은
i) 글리코실화된 CEA를 표적하는 항원-결합 도메인;
ii) 막 관통 도메인; 및
iii) 공동자극 도메인(costimulatory domain)을 포함하는 세포 내 신호전달 도메인;을 포함하는 키메라 항원 수용체 (chimeric antigen receptor, CAR)로서,
상기 글리코실화된 CEA를 표적하는 항원-결합 도메인은, 하기 조합 중 어느 하나로부터 선택되는 것을 특징으로 하는 중쇄 가변영역 및 경쇄 가변영역을 포함하는 것인, 키메라 항원 수용체를 제공한다:
a. SEQ ID NO: 1에 제시된 CDR-H1, SEQ ID NO: 2에 제시된 CDR-H2, 또는 SEQ ID NO: 3에 제시된 CDR-H3로 기술된 하나 이상의 CDR을 포함하는 중쇄 가변영역, 및 SEQ ID NO: 4에 제시된 CDR-L1, SEQ ID NO: 5에 제시된 CDR-L2, 또는 SEQ ID NO: 6에 제시된 CDR-L3로 기술된 하나 이상의 CDR을 포함하는 경쇄 가변영역;
b. SEQ ID NO:7에 제시된 CDR-H1, SEQ ID NO:8에 제시된 CDR-H2, 또는 SEQ ID NO:9에 제시된 CDR-H3로 기술된 하나 이상의 CDR을 포함하는 중쇄 가변영역, 및 SEQ ID NO: 10에 제시된 CDR-L1, SEQ ID NO: 11에 제시된 CDR-L2, 또는 SEQ ID NO: 12에 제시된 CDR-L3으로 기술된 하나 이상의 CDR을 포함하는 경쇄 가변영역;
c. SEQ ID NO: 13에 제시된 CDR-H1, SEQ ID NO: 14에 제시된 CDR-H2, 또는 SEQ ID NO: 15에 제시된 CDR-H3으로 기술된 하나 이상의 CDR을 포함하는 중쇄 가변영역, 및 SEQ ID NO: 16에 제시된 CDR-L1, SEQ ID NO: 17에 제시된 CDR-L2, 또는 SEQ ID NO: 18에 제시된 CDR-L3으로 기술된 하나 이상의 CDR을 포함하는 경쇄 가변영역;
d. SEQ ID NO: 19에 제시된 CDR-H1, SEQ ID NO: 20에 제시된 CDR-H2, 또는 SEQ ID NO: 21에 제시된 CDR-H3으로 기술된 하나 이상의 CDR을 포함하는 중쇄 가변영역, 및 SEQ ID NO: 22에 제시된 CDR-L1, SEQ ID NO: 23에 제시된 CDR-L2, 또는 SEQ ID NO: 24에 제시된 CDR-L3으로 기술된 하나 이상의 CDR을 포함하는 경쇄 가변영역; 또는
e. SEQ ID NO: 25에 제시된 CDR-H1, SEQ ID NO: 26에 제시된 CDR-H2, 또는 SEQ ID NO: 27에 제시된 CDR-H3으로 기술된 하나 이상의 CDR을 포함하는 중쇄 가변영역, 및 SEQ ID NO: 28에 제시된 CDR-L1, SEQ ID NO: 29에 제시된 CDR-L2, 또는 SEQ ID NO:30에 제시된 CDR-L3으로 기술된 하나 이상의 CDR을 포함하는 경쇄 가변영역.
특정 양태에서, 상기 중쇄 가변영역 및 경쇄 가변영역은 하기 조합 중 어느 하나로부터 선택된다: a) SEQ ID NO: 31에 제시된 폴리펩티드 단편을 포함하는 중쇄 가변영역, 및 SEQ ID NO: 32에 제시된 폴리펩티드 단편을 포함하는 경쇄 가변영역; b) SEQ ID NO: 33에 제시된 폴리펩티드 단편을 포함하는 중쇄 가변영역, 및 SEQ ID NO: 34에 제시된 폴리펩티드 단편을 포함하는 경쇄 가변영역; c) SEQ ID NO: 35에 제시된 폴리펩티드 단편을 포함하는 중쇄 가변영역, 및 SEQ ID NO: 36에 제시된 폴리펩티드 단편을 포함하는 경쇄 가변영역; d) SEQ ID NO: 37에 제시된 폴리펩티드 단편을 포함하는 중쇄 가변영역, 및 SEQ ID NO: 38에 제시된 폴리펩티드 단편을 포함하는 경쇄 가변영역; 또는 e) SEQ ID NO: 39에 제시된 폴리펩티드 단편을 포함하는 중쇄 가변영역, 및 SEQ ID NO:40에 제시된 폴리펩티드 단편을 포함하는 경쇄 가변영역.
다른 양태에서, 본 발명의 항원-결합 도메인은 글리코실화된 CEA(glycosylated CEA)를 특이적으로 인식하는 단일쇄 항체(single-chain antibody)이고, 상기 단일쇄 항체의 아미노산 서열은 SEQ ID NO: 171-180 중 어느 하나에 제시되며, 가장 바람직하게는 상기 단일쇄 항체의 아미노산 서열은 SEQ ID NO: 173 또는 SEQ ID NO: 178이다.
바람직하게는, 본 발명의 키메라 항원 수용체에서, 상기 막 관통 도메인은 CD8α 및/또는 CD28을 포함하고, 상기 세포 내 신호전달 도메인은 CD28, CD137, 및 CD3제타 중 하나 이상을 포함하나, CD8α 힌지 영역은 SEQ ID NO: 52에 제시된 서열에 의해 암호화되고, CD8α 막 관통 영역은 SEQ ID NO:54에 제시된 서열에 의해 암호화되며, CD28 힌지 영역은 SEQ ID NO:53에 제시된 서열에 의해 암호화되고, CD28 막 관통 영역은 SEQ ID NO: 55에 제시된 서열에 의해 암호화되며, CD28 공동자극 도메인은 SEQ ID NO:56에 제시된 서열에 의해 암호화되고, CD137 공동자극 도메인은 SEQ ID NO:57에 제시된 서열에 의해 암호화되며, 상기 CD3제타는 SEQ ID NO:58에 제시된 서열에 의해 암호화된다.
다른 측면에서, 본 발명은 본 발명의 키메라 항원 수용체를 암호화하는 핵산 분자를 제공한다.
다른 측면에서, 본 발명은 본 발명의 키메라 항원 수용체를 발현하는 세포를 제공하고, 바람직하게는 상기 세포는 T 세포, NK 세포 및 B 세포로 이루어진 군으로부터 선택되고, 더욱 바람직하게는 상기 세포는 T 세포이다.
다른 측면에서, 본 발명은 순서대로 연결되어 있는 세포 외 표적된 인식 항원 서열, 힌지 영역 서열, 막 관통 영역 서열, 및 세포 내 신호 서열을 포함하는; 키메라 항원 수용체를 발현하는 림프구를 제공한다. 세포 외 인식 항원 서열은 상기와 같이 정의된 본 발명에서 기술된 글리코실화된 CEA를 특이적으로 인식하는 단일쇄 항체이다. 힌지 영역은 CD8α, CD28ECD, 및 IgG Fc 단편으로 이루어진 군으로부터 선택된다. 세포 내 신호 영역은 CD3제타와 같은 면역수용체 티로신 활성화 모티프(immunoreceptor tyrosine activation motif, ITAM) 및 CD28, CD137, CD27, ICOS, OX40, DAP10과 같은 공동자극 신호를 이용할 수 있다. 한 양태에서, 키메라 항원 수용체 내 힌지 영역 서열은 SEQ ID NO: 52 또는 SEQ ID NO: 53에 각각 제시된 서열에 의해 암호화되는 CD8α 또는 CD28를 포함하고; 키메라 항원 수용체 내 막 관통 영역 서열은 SEQ ID NO: 54 또는 SEQ ID NO: 55에 각각 제시된 서열에 의해 암호화되는 CD8α 또는 CD28를 포함하며; 키메라 항원 수용체 내 세포 내 신호 서열은 CD28, CD137, CD3제타 및 이의 조합을 포함하고, CD28은 SEQ ID NO: 56에 제시된 서열에 의해 암호화되며, CD137은 SEQ ID NO: 57에 제시된 서열에 의해 암호화되고, CD3제타는 SEQ ID NO:58에 제시된 서열에 의해 암호화된다. 한 양태에서, 백혈구는 T 세포, B 세포 또는 NK 세포 등 일 수 있다. 특정 양태에서, 백혈구는 T 세포이고, 키메라 항원수용체는 하기와 같이 발현된다:
scFv-CD8α-CD137-CD3제타,
scFv-CD28-CD28-CD137-CD3제타, 및
scFv-CD28-CD28-CD3제타.
바람직한 양태에서, 본 발명에서 제작된 키메라 항원 수용체는 SEQ ID NO: 69-128에 제시된 서열을 가진다.
키메라 항원 수용체의 항원-결합 도메인이 이의 대응하는 항원에 결합하는 경우에, 키메라 항원 수용체를 포함하는 세포는 항-종양 면역을 보인다.
본 발명은 일련의 글리코실화된 CEA에 대한 단일쇄 항체를 제작한다. 본 발명의 단일쇄 항체는 위암, 대장암, 및 식도암과 같은 종양의 검출 및 치료에 이용될 수 있다. 이러한 단일쇄 항체는 T 세포 및 NK 세포와 같은 백혈구의 표면 상에 발현되어, 글리코실화된 CEA 발현-양성 세포 및 조직을 특이적으로 사멸시키기 위한 글리코실화된 CEA에 대한 키메라 항원 수용체 T 세포 또는 키메라 항원 수용체 NK 세포를 제작 및 형성할 수 있다.
제2 측면에서, 본 발명은 각각 FM2, FM3, FM4, FM5, FM6인, 글리코실화된 CEA에 대한 단일쇄 항체를 제공하며, 이들의 중쇄 가변 영역 및 경쇄 가변 영역의 CDR 서열은 SEQ ID NO : 1~30이고, 이들의 암호화 뉴클레오티드는 각각 SEQ ID NO: 129-158인데, 서열 목록을 참고한다.
본 발명은 각각 FM2, FM3, FM4, FM5, FM6인 글리코실화된 CEA에 대한 단일쇄 항체를 제공하고, 이들의 중쇄 가변 영역은 각각 SEQ ID NO: 31, SEQ ID NO: 33, SEQ ID NO: 35. SEQ ID NO: 37 또는 SEQ ID NO: 39이며; 이들의 경쇄 가변 영역은 각각 SEQ ID NO: 32, SEQ ID NO: 34, SEQ ID NO: 36, SEQ ID NO: 38 또는 SEQ ID NO: 40이다. 한 양태에서, 본 발명은 VH-링커-VL 또는 VL-링커-VH의 형태로 배열된 글리코실화된 CEA에 대한 단일쇄 항체를 제공하며, VH는 상기 기술된 중쇄 가변 영역 서열로부터 선택되고, VL은 상기 기술된 경쇄 가변 영역 서열로부터 선택된다. 바람직한 양태에서, 링커, 즉, 링커 펩티드는 SEQ ID NO:41에 제시된 서열이다.
본 발명은 본 발명의 단일쇄 항체를 암호화하는 분리된 핵산 분자를 제공한다. 한 양태에서, 단일쇄 항체의 중쇄 가변 영역을 암호화하는 뉴클레오티드 서열은 SEQ ID NO: 42, SEQ ID NO: 44, SEQ ID NO: 46, SEQ ID NO: 48 또는 SEQ ID NO: 50이다. 한 양태에서, 단일쇄 항체의 경쇄 가변 영역을 암호화하는 핵산 서열은 SEQ ID NO: 43, SEQ ID NO: 45, SEQ ID NO: 47, SEQ ID NO: 49 또는 SEQ ID NO: 51이다.
본 발명은 키메라 항원 수용체를 암호화하는 핵산 서열을 포함하는 벡터를 또한 제공한다. 특정 양태에서, 벡터는 pGC-EIF1α-MCS (CV185, 진켐) 및 pGC-EIF1α-MCS-2A-EGFP (CV178, 진켐)이다.
종양의 진단을 위한 시약 또는 종양의 치료를 위한 약제의 제조에서, 바람직하게는 상기 종양은 소화관 종양, 더욱 바람직하게는 위암, 대장암, 및 식도암으로 이루어진 군으로부터 선택되는 것인, 본 발명에 따른 키메라 항원 수용체 및 단일쇄 항체의 용도.
본 발명은 포유류에서 항-종양 면역을 제공하는 방법을 또한 제공한다. 한 양태에서, 이 방법은 포유류에게 본 발명의 키메라 항원 수용체 T 세포의 유효량을 투여하여, 포유류에서 항-종양 면역을 제공하는 단계를 포함한다.
본 발명은 증가된 종양 항원 발현과 관련 있는 질병, 질환 또는 병태를 가지는 포유류의 치료방법, 예를 들어, CEA의 고발현(high expression)이 있는 위장관 종양의 치료를 또한 포함한다. 한 양태에서, 상기 방법은 포유류에게 본 발명의 키메라 항원 수용체 T 세포의 유효량을 투여하여, 포유류에서 종양을 치료하는 단계를 포함한다.
본 발명은 증가된 종양 항원 발현과 관련 있는 질병, 질환, 또는 병태의 진단방법, 예를 들어, 높은 CEA 발현이 있는 소화관 종양을 진단하는 것을 또한 포함한다. 한 양태에서, 상기 방법은 종양 및 종양의 주변 조직을 검출하기 위한 상당한 양의 글리코실화된 CEA의 발현을 포함한다.
도 1. 유세포 분석에 의한 SW620-CEA 내 CEA 발현의 검출.
도 2. FM2(VL→VH), FM4( VL → VH ), FM5( VL → VH ), FM6( VL → VH )는 구조 scFv-CD8α-CD137-CD3제타 및 렌티바이러스로 감염된 인간 T 세포에 따라 설계되었고, 10일까지 배양되었으며, 도면 내 표적 세포(SW620-CEA, LOVO, KATO3)와 함께 16시간 동안 배양되었고, IL2 방출이 측정되었다.
도 3. FM2(VL→VH), FM4( VL → VH ), FM5( VL → VH ), FM6( VL → VH )는 구조 scFv-CD8α-CD137-CD3제타 및 렌티바이러스로 감염된 인간 T 세포에 따라 설계되었고, 10일까지 배양되었으며, 도면 내 표적 세포(SW620-CEA, LOVO, KATO3)와 함께 16시간 동안 배양되었고, TNFα 방출이 측정되었다.
도 4. FM2(VL→VH), FM4( VL → VH ), FM5( VL → VH ), FM6( VL → VH )는 구조 scFv-CD8α-CD137-CD3제타 및 렌티바이러스로 감염된 인간 T 세포에 따라 설계되었고, 10일까지 배양되었으며, 도면 내 표적 세포(SW620-CEA, LOVO, KATO3)와 함께 16시간 동안 배양되었고, INFγ 방출이 측정되었다.
도 5. FM2( VL → VH ), FM4( VL → VH )는 구조 scFv-CD28-CD28-CD3제타 및 렌티바이러스로 감염된 인간 T 세포에 따라 설계되었고, 10일까지 배양되었으며, 도면 내 표적 세포(SW620, SW620-CEA, LOVO, KATO3, CRYPT)와 함께 16시간 동안 배양되었고, IL2 방출이 측정되었다.
도 6. FM2(VL→VH), FM4( VL → VH )는 구조 scFv-CD28-CD28-CD3제타 및 렌티바이러스로 감염된 인간 T 세포에 따라 설계되었고, 10일까지 배양되었으며, 도면 내 표적 세포(SW620, SW620-CEA, LOVO, KATO3, CRYPT)와 함께 16시간 동안 배양되었고, TNFα 방출이 측정되었다.
도 7. FM2(VL→VH), FM4( VL → VH )는 구조 scFv-CD28-CD28-CD3제타 및 렌티바이러스로 감염된 인간 T 세포에 따라 설계되었고, 10일까지 배양되었으며, 도면 내 표적 세포(SW620, SW620-CEA, LOVO, KATO3, CRYPT)와 함께 16시간 동안 배양되었고, INFγ 방출이 측정되었다.
도 8. FM2(VL→VH)-BBz가 표적 세포와 E:T 비율로 4시간 동안 혼합되었고, 상청액 내 LDH 방출이 측정되어 FM2( VL → VH )-BBz에 의한 표적 세포의 사멸을 측정하였다.
도 9. FM4(VL→VH)-BBz가 표적 세포와 E:T 비율로 4시간 동안 혼합되었고, 상청액 내 LDH 방출이 측정되어 FM4( VL → VH )-BBz에 의한 표적 세포의 사멸을 측정하였다.
도 10. PDX 모델 마우스의 말초 혈액내 IFNγ 방출의 검출.
도 11. PDX 모델의 종양 성장 곡선.
도 12. FM4(VL→VH)-BBz-NK92 사이토카인 분비 검정.
도 13. FM4(VL→VH)-BBz-NK92 세포 사멸 검정.
도 14. 종양 모델의 마우스에서 INFγ 방출의 검출.
도 15. 종양 모델의 마우스에서 종양 사멸 효과.
도 2. FM2(VL→VH), FM4( VL → VH ), FM5( VL → VH ), FM6( VL → VH )는 구조 scFv-CD8α-CD137-CD3제타 및 렌티바이러스로 감염된 인간 T 세포에 따라 설계되었고, 10일까지 배양되었으며, 도면 내 표적 세포(SW620-CEA, LOVO, KATO3)와 함께 16시간 동안 배양되었고, IL2 방출이 측정되었다.
도 3. FM2(VL→VH), FM4( VL → VH ), FM5( VL → VH ), FM6( VL → VH )는 구조 scFv-CD8α-CD137-CD3제타 및 렌티바이러스로 감염된 인간 T 세포에 따라 설계되었고, 10일까지 배양되었으며, 도면 내 표적 세포(SW620-CEA, LOVO, KATO3)와 함께 16시간 동안 배양되었고, TNFα 방출이 측정되었다.
도 4. FM2(VL→VH), FM4( VL → VH ), FM5( VL → VH ), FM6( VL → VH )는 구조 scFv-CD8α-CD137-CD3제타 및 렌티바이러스로 감염된 인간 T 세포에 따라 설계되었고, 10일까지 배양되었으며, 도면 내 표적 세포(SW620-CEA, LOVO, KATO3)와 함께 16시간 동안 배양되었고, INFγ 방출이 측정되었다.
도 5. FM2( VL → VH ), FM4( VL → VH )는 구조 scFv-CD28-CD28-CD3제타 및 렌티바이러스로 감염된 인간 T 세포에 따라 설계되었고, 10일까지 배양되었으며, 도면 내 표적 세포(SW620, SW620-CEA, LOVO, KATO3, CRYPT)와 함께 16시간 동안 배양되었고, IL2 방출이 측정되었다.
도 6. FM2(VL→VH), FM4( VL → VH )는 구조 scFv-CD28-CD28-CD3제타 및 렌티바이러스로 감염된 인간 T 세포에 따라 설계되었고, 10일까지 배양되었으며, 도면 내 표적 세포(SW620, SW620-CEA, LOVO, KATO3, CRYPT)와 함께 16시간 동안 배양되었고, TNFα 방출이 측정되었다.
도 7. FM2(VL→VH), FM4( VL → VH )는 구조 scFv-CD28-CD28-CD3제타 및 렌티바이러스로 감염된 인간 T 세포에 따라 설계되었고, 10일까지 배양되었으며, 도면 내 표적 세포(SW620, SW620-CEA, LOVO, KATO3, CRYPT)와 함께 16시간 동안 배양되었고, INFγ 방출이 측정되었다.
도 8. FM2(VL→VH)-BBz가 표적 세포와 E:T 비율로 4시간 동안 혼합되었고, 상청액 내 LDH 방출이 측정되어 FM2( VL → VH )-BBz에 의한 표적 세포의 사멸을 측정하였다.
도 9. FM4(VL→VH)-BBz가 표적 세포와 E:T 비율로 4시간 동안 혼합되었고, 상청액 내 LDH 방출이 측정되어 FM4( VL → VH )-BBz에 의한 표적 세포의 사멸을 측정하였다.
도 10. PDX 모델 마우스의 말초 혈액내 IFNγ 방출의 검출.
도 11. PDX 모델의 종양 성장 곡선.
도 12. FM4(VL→VH)-BBz-NK92 사이토카인 분비 검정.
도 13. FM4(VL→VH)-BBz-NK92 세포 사멸 검정.
도 14. 종양 모델의 마우스에서 INFγ 방출의 검출.
도 15. 종양 모델의 마우스에서 종양 사멸 효과.
우선, 본 발명이 더욱 용이하게 이해될 수 있도록 특정 용어들이 정의된다. 본원에서 사용된 모든 기술적 용어 및 특정한 용어는, 달리 명시되지 않는 한, 본 발명이 속하는 기술분야의 통상적인 기술자에 의해 통상적으로 이해된 것과 동일한 의미를 가진다. 본원에서 기술된 방법 및 재료와 유사하거나 등가적인 것이 본 발명의 실행 또는 테스트에서 이용될 수 있으나, 적합한 방법 및 재료가 하기에 기술된다. 본원에 인용된 모든 출판물, 특허 명세서, 특허, 및 다른 참고문헌은 이들의 전체 기재내용이 참고로 본원에 포함된다. 상충의 경우에, 본 명세서 (정의를 포함하는)가 우위에 있을 것이다. 또한, 재료, 방법, 및 예시는 단지 설명적인 것이며 제한적인 것이 아니다.
단일쇄
항체 (single-chain antibody)
본 명세서에서 사용되는 "단일쇄 항체 (단일쇄 Fv, scFv)"는 면역글로불린의 중쇄 가변영역 (heavy chain variable region, VH)과 경쇄 가변영역 (light chain variable region, VL)을 라이게이션 펩티드(ligation peptide)를 통해 연결하여 형성된 재조합 단백질로, 완전한 항원 결합 부위를 갖는 가장 작은 항체 단편이다. 인간 면역글로불린 (Ig)은 IgA, IgD, IgM, IgE 및 IgG의 5개의 하위 유형을 포함하는데, 이 중 IgG가 인간 면역글로불린의 75%를 차지한다; IgG는 두 개의 중쇄 IgH 및 두 개의 경쇄 IgL이 사슬 간 이황화결합(interchain disulfide bond)을 통해 형성된 "Y"형 항체 구조이고; 여기서, IgH는 중쇄 가변영역 (VH) 및 불변영역 (Constant Region)을 포함하며; IgL은 경쇄 가변영역 (VL) 및 불변 영역 (Constant Region)을 포함한다. VH 및 VL의 다양성은 면역글로불린이 항원에 결합하는 것에 대한 근거가 된다. VH 및 VL은 프레임 영역(frame region, FR)과 상보성 결정 영역(complementary determining region, CDR)으로 구성되고, CDR 영역은 고도로 가변적인(highly variable)며 항원 및 항체의 특이적인 결합을 결정한다; 여기서, VH는 CDRH1, CDRH2, CDRH3로 표기된 세 개의 CDR 영역을 포함하고; VL은 CDRL1, CDRL2, CDRL3로 표기된 CDR 영역을 포함한다.
본 발명은 단일쇄 항체의 변이체, 유도체, 및 유사체를 또한 포함한다. 본문에서 사용된 용어 "변이체", "유도체" 및" "유사체"는 본 발명의 단일쇄 항체의 동일한 생물학적 기능 또는 활성을 실질적으로 보유하는 폴리펩티드를 의미한다. 본 발명의 폴리펩티드 변이체, 유도체 또는 유사체는 (i) 하나 이상의 보존적이거나 비-보전적인 아미노산 잔기 (바람직하게는 보존적 아미노산 잔기)가 치환되고, 이러한 치환된 아미노산 잔기가 유전적 암호에 의해 암호화되거나 암호화되지 않을 수 있는 폴리펩티드, 또는 (ii) 하나 이상의 아미노산 잔기가 치환 그룹(substituent group)을 갖는 폴리펩티드, 또는 (iii) 추가의 아미노산 서열을 폴리펩티드 서열 (선도 서열 또는 분비서열 또는 폴리펩티드의 정제에 이용되는 서열 또는 폴리펩티드 서열, 또는 융합 폴리펩티드와 같은)을 융합하여 형성된 폴리펩티드일 수 있다. 이러한 변이체, 유도체 및 유사체는 본원의 정의에 따라서 통상적인 기술자의 이해의 범위 내에 있다.
본 발명의 "단일쇄 항체"는 글리코실화된 CEA에 특이적으로 결합하는 폴리펩티드를 의미한다. 용어는 글리코실화된 CEA에 특이적으로 결합할 수 있는 폴리펩티드 서열을 가지는 변이체 형태를 또한 포함할 수 있다. 이러한 변이체는 C-말단 및/또는 N-말단에서 일부(대개 1-50, 바람직하게는 1-30, 더욱 바람직하게는 1-20, 가장 바람직하게는 1-10, 더욱 더 바람직하게는 1-8 또는 1-5) 아미노산의 결실, 삽입 및/또는 치환, 및 하나 이상의 (대개 20 이내, 바람직하게는 10 이내, 더욱 바람직하게는 5 이하) 아미노산의 삽입 또는 결실을 포함한다 (그러나, 이에 제한되는 것은 아님). 예를 들어, 기술분야에서, 가깝거나 유사한 특성의 아미노산과의 치환은 대개 단백질의 기능을 변화시키지 않는다. 다른 예로서, C-말단 및/또는 N-말단에서 하나 이상의 아미노산의 삽입 또는 결실도 또한 일반적으로 단백질의 기능을 변화시키지 않는다.
본 발명은 단일쇄 항체의 유사체를 또한 제공한다. 이러한 유사체와 자연적인 단일쇄 항체 사이의 차이점은 아미노산 서열의 차이, 서열에 영향을 끼치지 않는 변형 형태의 차이, 또는 이의 조합일 수 있다. 이러한 폴리펩티드는 자연적이거나 유도된 유전적 변이체를 포함한다. 유도된 변이체는 방사선 조사 또는 돌연변이원에 대한 노출에 의한 무작위 돌연변이 유발(random mutagenesis), 또는 부위-지정 돌연변이 유발(site-directed mutagenesis) 또는 분자 생물학의 다른 공지된 기법과 같은 다양한 기법에 의해 수득될 수 있다. 유사체는 자연적인 L-아미노산 (예, D-아미노산) 외의 잔기를 갖는 유사체 뿐만 아니라 비-자연적으로 발생하거나 합성인 아미노산(예를 들어, β-아미노산, γ-아미노산)을 갖는 유사체를 또한 포함한다. 본 발명의 폴리펩티드가 상기 예시된 대표적인 폴리펩티드에 한정되는 것이 나이라는 것을 이해해야 할 것이다.
또한, 본 발명의 단일쇄 항체의 활성, 발현량 및 안정성에 실질적으로 영향을 미치지 않는 다른 아미노산 서열이 단일쇄 항체의 아미노 말단 또는 카르복시 말단에 추가될 수 있다. 바람직하게는, 이러한 추가된 아미노산 서열은 발현 (예, 신호 펩티드)을 용이하게 하거나, 정제 (예, 6 x His 서열), 또는 단일쇄 항체의 활성, 발현 또는 안정성을 촉진하는 다른 서열을 용이하게 한다.
본 발명은 본 발명의 단일쇄 항체 또는 이의 변이체, 유도체를 암호화하는 DNA 분자를 또한 포함한다. DNA 분자는 모두 PCR 증폭에 의해 인공적으로 합성될 수 있거나 수득될 수 있다.
숙주 세포의 발현 수준을 더 증가시키기 위해, 본 발명의 단일쇄 항체의 암호화 서열을, 예를 들어, 숙주 세포-선호 코돈(host cell-preferred codon)을 이용해 조작하여 유전자 전사 및 번역에 도움이 되지 않는 서열을 제거할 수 있다.
단일쇄
항체의 발현
본 발명의 신규한 단일쇄 항체 또는 이의 변이체 또는 유도체를 암호화하는 DNA 서열을 수득한 후에, 이는 적합한 발현 벡터로 클로닝되고, 적합한 숙주 세포로 도입된다. 마침내, 형질전환된 숙주 세포가 배양되고, 본 발명의 신규한 단일쇄 항체는 분리 및 정제에 의해 수득된다.
본원에 사용된 용어 "벡터"는 플라스미드, 코스미드, 발현 벡터, 클로닝 벡터, 바이러스 벡터 등을 포함한다.
본 발명에서, 기술분야에 공지된 다양한 벡터가 이용될 수 있다. 예를 들어, 시판 벡터가 선택된 다음, 본 발명의 신규한 단일쇄 항체를 암호화하는 뉴클레오티드 서열이 발현 조절 서열에 작동 가능하게(operably) 연결되어 발현 벡터를 형성한다.
본 발명에서, 용어 "숙주 세포"는 원핵 세포 및 진핵 세포를 포함한다. 통상적으로 이용되는 원핵 숙주 세포의 예시는 에스체리치아 콜라이 ( Escherichia coli), 바실러스 서브틸리스 (Bacillus subtilis ) 등을 포함한다. 단일쇄 항체를 발현하기 위한 숙주 세포는 에스체리치아 콜라이, 효모 세포, 곤충 세포, COS 세포, CHO 세포 등을 포함한다. 바람직하게는, 숙주 세포는 원핵 세포, 더욱 바람직하게는 E. coli 세포이다.
형질전환된 숙주 세포를 수득한 후에, 상기 세포는 본 발명의 단일쇄 항체의 발현에 적합한 조건 하에서 배양되어 단일쇄 항체를 발현할 수 있고; 이어서, 발현된 단일쇄 항체는 분리될 수 있다.
링커 펩티드(Linker peptide)
본원에서 사용된 용어 "링커 펩티드" (링커)는 항체(또는 이의 변이체)의 중쇄 가변영역 및 항체(또는 이의 변이체)의 경쇄 가변영역 사이의 짧은 펩티드를 의미하는데, 이는 링커로 작용하고, 중쇄 및 경쇄 가변영역이 자유롭게 폴딩(folding)하도록 하며, 이로써 항원 결합 부위를 분자 동력학(molecular dynamics)의 변화를 야기하지 않고, 적절한 구성에 둘 수 있다. 일반적으로, 링커 펩티드는 중쇄 가변영역 (VH) 및 경쇄 가변영역 (VL)의 아미노산 서열의 올바른 폴딩 및 공간적 구조의 형성에 영향을 끼치지 않거나 현저하게 영향을 끼치지 않는다; 대안적으로는, 링커 펩티드는 중쇄 가변영역 (VH)과 경쇄 가변영역 (VL) 사이의 유연한 연결부를 구성하며, 이는 이들의 정상적인 폴딩을 용이하게 한다. 링커 펩티드의 길이는, 길이가 중쇄 및 경쇄 가변영역이 자유롭게 폴딩되도록 허용되고, 항원 결합 부위가 분자 동력학의 변화를 야기하지 않고 적절한 구성에 있는 것이 허용되는 한, 특별히 제한되지 않는다. 예를 들어, 링커 펩티드의 길이는 4-30 aa일 수도 있다. 바람직하게는, 본 발명의 링커 펩티드의 서열은 SEQ ID NO: 1에 제시된다.
키메라
항원 수용체 (Chimeric antigen receptor, CAR)
본 발명의 단일쇄 항체는 위암(gastric cancer), 대장암(colorectal cancer), 및 식도암(esophageal cancer)과 같은 종양의 검출 및 치료에 이용될 수 있다. 본 발명의 단일쇄 항체는 T 세포의 표면상에 특이적으로 발현되어 글리코실화된 CEA에 대한 키메라 항원 수용체 T 세포를 제작할 수 있고, 글리코실화된 CEA 발현-양성 세포 및 조직을 특이적으로 사멸시킬 수 있다. 본 발명의 단일쇄 항체 각각에 대하여, 세 구조의 CAR-T가 별도로 제작될 수 있고, 각 항체하에서 이 세 구조의 기능적 차이를 비교하여, 적절한 CAR-T 구조를 적합한 표적 세포로 채용한다. 세 구조의 CAR-T는 각각 하기와 같다:
scFv-CD8α-CD137-CD3제타,
scFv-CD28-CD28-CD137-CD3제타, 및
scFv-CD28-CD28-CD3제타.
본 발명의 키메라 항원 수용체 구조에서:
힌지 영역은 CD8α, CD28, 인간 IgG1 Fc, 인간 IgG4 Fc, DAP10 등으로 이루어진 군으로부터 선택된 세포 외 영역일 수 있다.
막 관통 영역은 CD8α, CD28, DAP10 등으로 이루어진 군으로부터 선택된 막 관통 영역일 수 있다.
공동자극 도메인은 CD28, CD134 (OX40), CD137 (4-1BB), ICOS, DAP10 등으로 이루어진 군으로부터 선택된 세포 내 영역일 수 있다.
필수적인 신호 도메인은 CD3제타로부터 선택될 수 있다.
실시예
본 발명은 특정 실시예 및 첨부한 도면과 함께 아래에서 더 기술되나, 이는 본 발명을 제한하려는 의도는 아니다. 조건이 특정하게 기술되지 않은 하기 실시예의 실험방법은 J. Sambrook et al., Molecular Cloning Experiment Guide, Science Press, 2002에 의해 기술된 조건과 같은 통상의 조건 또는 제조자의 추천 조건에 따라서 수행한다. 다르게 명시되지 않는 한, 퍼센트(percentage) 및 파트(part)는 중량 퍼센트 및 중량부이다.
[
실시예
1:
단일쇄
항체의 제작]
[표 1]
단일쇄 항체의 발현 방법
각각의 합성된 뉴클레오티드 서열 FM2, 3, 4, 5, 및 6을 3'-말단의 8개의 His (CACCATCACCATCACCATCACCAT)와 함께 추가하였고, 증폭된 단편은 이의 양 말단의 sfiI 및 NotI 제한 부위와 함께 추가한 다음에, pCANTAB5E 벡터 (GE 헬스케어)에 삽입하였다. 제작된 pCANTAB5E (GE) 벡터는 E. coli-HB2151 균주로 형질전환하였고, IPTG에 의해 유도하여 밤새 발현시켰다. 세포를 PBS 완충액에서 재현탁하였고, 얼음 위에서 10분 동안 초음파 분쇄하였다(sonicated). 원심분리 후에, 상청액을 히스 트랩 컬럼(His Trap Column) (GE)으로 정제하였고, 20 mM 이미다졸을 함유한 PBS 완충액을 이용하여 5-10 컬럼 부피(column volume) 동안 세척한 다음에, 500 mM 이미다졸을 함유하는 PBS를 이용하여 용출시켰다; 그 후의 이미다졸은 탈염 G25 컬럼(Desalting G25 column) (GE)을 이용하여 탈염시켜 PBS에 용해된 단일쇄 항체를 수득하였다.
[
실시예
2: CAR 재조합
렌티바이러스
벡터의 제작]
본 발명에서 제작된 바이러스는 표 2에 제시된다.
[표 2]
1. 렌티바이러스 플라스미드 벡터의 제작
1) 유전자 서열의 전장 유전자 합성(Whole gene synthesis)
표 2의 렌티바이러스를 제작하기 위해, 표 2에 제시된 구조에 따라서, 필수 유전자 서열을 전장 유전자 합성하였다.
2) 핵산 단편의 증폭
SEQ ID NO. 69-78, 89-98, 109-118으로 넘버링한(numbering) 합성된 유전자 생성물을 상류 프라이머 (SEQ ID NO. 159-168) 및 하류 프라이머 (SEQ ID NO. 169)를 이용하여 증폭시켰다. PCR 증폭 조건은 다음과 같다: 전-변성: 95°C, 5분; 변성: 95°C, 30초; 어닐링: 55°C, 30초; 신장: 72°C, 1분, 35 사이클; 마지막 신장: 72°C, 10분.
SEQ ID NO. 79-88, 99-108, 119-128로 넘버링된 합성된 유전자 생성물을 상류 프라이머 (SEQ ID NO. 159-168) 및 하류 프라이머 (SEQ ID NO. 170)를 이용하여 증폭시켰다. PCR 증폭 조건은 상기 조건과 같다.
3) 바이러스 플라스미드 벡터의 제작
a) SEQ ID NO. 79-88, 99-108, 119-128의 증폭된 단편을 제한 내부핵산 가수분해효소 절단(restriction endonuclease digestion)하였다. 이용된 제한효소는 BamHI과 EcoRI이었고, 절단 시스템은 다음과 같았다: 20 μl까지 멸균수가 보충된, BamHI 0.5 μl, EcoRI 0.5 μl, 완충액 2 μl, BSA 2 μl, 및 증폭된 단편 2 μg. 37°C에서 2시간 동안 인큐베이팅(incubating) 시킨 후에, 효소 절단 시스템을 DNA 클리닝 및 회수(DNA cleaning and recovery)하였다. 회수 방법은 다음과 같았다: 80 μl의 완충액 PCR-A를 절단 시스템에 추가한 후에, 혼합물을 준비 튜브(preparation tube)로 옮겼고, 준비 튜브를 2 ml 원심분리 튜브(centrifuge tube)에 꽂았으며, 12,000 Х g에서 1분 동안 원심분리하였고, 여과물을 버렸다. 준비 튜브를 2 ml 원심분리 튜브에 다시 꽂았고, 700 μl의 완충액 W2를 추가하였으며, 12,000 Х g에서 1분 동안 원심분리하였고, 여과물을 버렸다. 준비 튜브를 깨끗한 1.5 ml 원심분리 튜브에 꽂았고, 25-30 μl의 용출액 또는 탈이온화수(deionized water)를 준비 튜브의 멤브레인 중앙에 추가하였고, 1분 동안 실온에 두었다. DNA를 12,000 Х g에서 1분 동안 원심분리에 의해 용출시켰다.
SEQ ID NO. 69-78, 89-98, 109-118의 증폭된 단편을 제한 내부핵산 가수분해효소 절단하였다. 사용된 제한 내부핵산 가수분해 효소는 BamHI이었다. 절단 시스템은 다음과 같았다: 20 μl까지 멸균수가 보충된 0.5 μl의 BamHI, 0.5 μl의 EcoRI, 2 μl의 완충액, 2 μl의 BSA, 및 2 μg의 증폭 단편. 2시간 동안 37°C에서 인큐베이팅(incubating) 시킨 후에, 효소 절단 시스템을 DNA 클리닝 및 회수(DNA cleaning and recovery)하였다. 회수 방법은 상기 회수 방법과 같았다.
b) 벡터 단편을 제한 내부핵산 가수분해효소 절단했고, 효소 절단 시스템 및 방법은 상기에 제시된 것과 같았다. 절단 후에, 시스템을 DNA 아가로오스 겔 전기영동(DNA agarose gel electrophoresis)하였고, 벡터 단편 (약 8 Kb)를 겔에 의해 회수하였다. 회수 시스템은 다음과 같다: 관심 있는 DNA 단편을 아가로오스 전기영동에 의해 다른 DNA 밴드로부터 분리한 다음에, 회수될 DNA를 함유하는 아가로오스 겔 블록을 깨끗한 메스로 절제하였고, 미리 넘버링된 1.5 ml EP 튜브에 넣었다. 아가로오스 겔 블록은 가능한 한 얇게 절제되어야 하고, 자외선 조사 시간은 가능한 한 짧아야 한다. 500 μl의 겔 용액(gel solution)을 각 튜브에 추가하였고, 65°C의 웜 배쓰(warm bath)에서, 5분 내지 10분 동안 인큐베이팅(incubating)시켰는데, 이 시간 동안에 혼합물을 2분 마다 인버팅(inverting)시켜서 겔을 완전히 녹였다. 용해된 겔을 수조(water bath)에서 꺼내서, 겔이 실온으로 식을 때까지 2분 동안 실온에 두었다. A UNIQ-10 회수 컬럼(UNIQ-10 recovery column)을 500 μl의 평형 용액(equilibration solution)과 함께 추가하였고, 12,000 rpm에서 1분 동안 원심분리 하였으며, 수집 용액(collection solution)을 제거하였고, 따로 보관하였다(set aside). 이 액체를 UNIQ-10 컬럼으로 옮기고, 1분 동안 실온에 두었으며, 8,000 rpm에서 1분 동안 원심분리했다. UNIQ-10 컬럼을 내렸고(get down), 수집 튜브(collection tube) 내 폐액(waste liquid)을 버렸고 (표적 스트립이 매우 가벼운 경우에, 수집 튜브의 용액을 UNIQ-10 컬럼에 다시 통과시킬 수 있다), UNIQ-10 컬럼을 동일한 수집 튜브에 꽂고, 700 μl의 세척 완충액(Wash buffer)을 추가하였으며, 10,000 rpm에서 30초 동안 원심분리시켰는데, 이 과정을 한번 더 반복하였다. UNIQ-10 컬럼을 내렸고, 수집 튜브 내 폐액을 제거하였고, UNIQ-10 컬럼을 동일한 수집 튜브에 꽂았으며, 12,000 rpm에서 2분 동안 원심분리시켰다. UNIQ-10 컬럼을 새 1.5 ml EP 튜브에 꽂았고, UNIQ-10 컬럼의 뚜껑을 열어서, 65°C의 오븐에 10분 동안 두어, 에탄올을 충분히 증발시켰다. 40 μl의 용출 완충액을 컬럼 멤브레인 중앙에 추가하였고 (주의: 팁(tip)을 교체하여 오염을 피해야한다), UNIQ-10 컬럼의 뚜껑을 닫아서, 65°C의 오븐에 2분 동안 두었다. 관심 있는 DNA를 12,000 rpm에서 1분 동안 원심분리시켜 회수하였다.
EGFP 발현 벡터를 제한 내부핵산 가수분해효소 절단하였는데, 사용한 제한 효소는 BamHI이었고, 효소 절단 시스템 및 겔 회수 방법은 상기 기술된 것과 같았다.
c) 관심 있는 플라스미드 벡터 및 단편의 라이게이션
SEQ ID NO. 79-88, 99-108, 119-128의 절단 생성물을 EGFP 발현-프리 벡터 (CV185, 진켐)[EGFP expression-free vector (CV185, Genechem)]에 라이게이션하였고; SEQ ID NO. 69-78, 89-98, 109-118의 증폭된 절단 생성물을 EGFP 발현 벡터 (CV178, 진켐)으로 라이게이션하였다.
라이게이션 시스템은 다음과 같았다: 20 μl까지 멸균수가 보충된, 25 ng의 삽입 단편, 100 ng의 벡터 단편, 2 μl의 T4 리가아제 완충액, 1 μl의 T4 리가아제, 및 22°C에서 1시간 동안 라이게이션.
2. 렌티바이러스 패키징(Lentiviral packaging)
3세대 렌티바이러스 패키징 시스템(third generation of lentiviral packaging system)을 이용하였다: 전달 플라스미드(transfer plasmid): CV178 또는 CV185 (진켐), 엔벨롭 플라스미드(Envelop plasmid): H1 (진켐), 패키징 플라스미드: H2 (진켐) (Zufferey et al., J Virol 72 ( 12): 9873-80, 1998).
HEK-293T 세포를 24시간 계대 주기(24h passage period)에 따라 보충했고, 배지를 형질주입 전에 교체하였다. 각 플레이트의 세포를 전자 피펫(electric pipette)을 이용하여 2% FBS를 함유한 DMEM 배지 5 ml로 교체하였다. HBW, H1 (12μg/플레이트, 이 플레이트는 10cm 세포 배양 접시(dish)를 의미하며, 이하 마찬가지임), 재조합 H2 (10μg/플레이트), 벡터 (24μg/플레이트), CaCl2 (50μl/플레이트)를 차례로 추가하였고, 2 x HBS (500 μl/디스크)를 적가하여, 마지막으로 볼텍스 오실레이터(vortex oscillator) 상에서 진동을 가했으며(oscillated), 형질주입 시스템은 1 ml/플레이트였다. 이들 중, 벡터는 단계 1에서 제작된 벡터였다. 혼합 후에, 형질주입 시스템을 조심스럽게 피페팅하였고, 1000 μl의 혼합물을 취해 293T 세포에 적가하였으며, 작업을 계속 안정하게 유지하였고, 형질전환 시스템을 10 cm 플레이트 상에 균등하게 분배하였다. 이 플레이트를 평평하게(level) 유지하여 플레이트 내 액체를 각각의 전, 후, 좌, 우 방향에서 10회 교반시킨 다음에-이 혼합 과정은 충분해야 하나, 플레이트 밖으로 엎지르거나 넘치는 액체는 없어야 한다-37°C, 5% CO2 배양기에 두었다. 형질전환 후 8시간 후에, 상청액을 버리고, DMEM 배지를 전자 피펫을 이용하여 교체하였다. 형질전환의 종료 후 28시간 내지 30시간 사이에, 상청액을 처음으로 수집하였고, 10 ml의 DMEM 배지를 보충을 위해 추가하였다. 형질전환의 종료 후 48시간 내지 50시간 사이에, 상청액을 두번째로 수집하였다. 초원심분리 후에, 나중에 사용하기 위해, 이를 100 μl의 DMEM에 재현탁하였다.
[
실시예
3: 재조합
렌티바이러스를
이용한 T 림프구의 감염]
감염 실험을 통상적인 기술자에게 공지된 통상의 방법에 따라 수행하였다. 감염 단계를 다음과 같이 간단히 기술하였다:
1. 말초 혈액 단핵 림프구(Peripheral blood mononuclear lymphocyte, PBMC)를 수득하였고, >1 x 107 세포를 성분 수혈 시스템(blood apheresis system)에 의해 수득하였다.
2. 세포 배양 접시의 실험 항-인간 CD3/CD28 항체 처리.
항-인간 CD3 항체 (OKT3 클론, MACS) 및 항-인간 CD28 항체 (15E8 클론, MACS)를 최종 농도 1 μg/ml으로 PBS로 희석하였고, 희석된 항체 혼합물을 세포 배양 접시로 추가하여, 접시 내 배양물을 도말하였다. 실온에서 2시간 동안의 배양 후에, 접시를 PBS로 1회 세척하였고, 따로 보관하였다.
3. T 림프구의 활성화
분리된 PBMC를 T 림프구 배양 배지 (TexMACS medium + 10% FBS + 30 IU/재조합 인간 IL-2)에서 1*106 세포/ml의 최종 농도로 재현탁하였고, 단계 2에서 처리된 접시에 놓고 배양시켰다. 배양 조건은 37°C + 5% CO2였고, 배양 시간은 24시간이었다.
4. 활성화된 T 림프구의 감염
1) 감염 시약의 준비
특정 양의 T 세포 배양 배지를 취하여, 신퍼로닉(synperonic) F108과 함께 추가하여 최종 농도 1 mg/ml에 도달시켰고, 충분히 혼합하였으며, 수조에서 37°C로 가열시켰고, 따로 보관하였다.
2) 배양 플레이트의 처리
1 mg/ml CD3 및 0.5 mg/ml CD28 항체를 취하여, 적합한 양의 PBS 완충액에 대한 1:1000 부피비로 희석시켰고, 레트로넥틴 시약 (다카라, Cat. No. T100A)을 취하여, PBS 완충액에 대해 1:40의 부피비로 희석시켰다. 충분히 혼합한 후에, 완충액을 균등하게 세포 접시에 도말하였고 실온에서 2시간 동안 배양시켰다. 2시간 후에, 접시를 PBS로 세척하였고, 따로 보관하였다.
3) 렌티바이러스를 이용한 T 림프구의 감염 및 T 림프구 유지(maintaining)
1)에서 준비된 감염 시약을 이용하여 활성화된 T림프구를 희석하였고, 렌티바이러스를 MOI=3에 따라서 추가하였으며, 혼합하였다. 혼합물을 2)에서 처리된 접시에 균등하게 도말하였다.
감염 후에, 세포 밀도를 모니터링하여, 세포를 1*106 세포/ml로 유지시켰고; 통상적으로, 14일 후에, 세포는 30-100배 증폭되었다.
[
실시예
4: 소화관 공급원의 암 세포주 내 글리코실화된 C
EA
발현의 검출]
유세포 분석을 이용하여 다양한 표적 세포에서의 글리코실화된 CEA의 발현 수준을 검출하였다. 특이적인 검출 방법은 다음과 같았다:
1. 표 3에 제시된 6*105 세포/그룹을 취해서 200g에서 5분 동안 원심분리하였고, 상청액을 버렸다;
2. 200 μl PBS에서 재현탁한 후에, 재현탁된 세포를 두 개의 그룹으로 나누었는데, 이 중 한 그룹을 본 발명의 글리코실화된 CEA에 대한 단일쇄 항체 1 μg과 함께 추가하였고, 4°C에서 2시간 동안 배양시켰다;
3. 1 ml의 PBS를 각 그룹에 추가하였고, 혼합하였으며, 200 g에서 5 분 동안 원심분리하였고, 상청액은 버렸다; 세포를 100 μl의 PBS로 재현탁하였고, 5 μl의 고트(goat) 항-마우스 IgG1 FITC-표지 2차 항체를 세포 현탁액에 추가하였으며, 4 °C에서 1시간 동안 배양시켰다;
4. 세포를 PBS로 3회 세척하였고, 유세포 분석으로 측정 및 분석하였다.
결과는 표 3에 제시된다. 글리코실화된 CEA 항원의 발현은 SW620에서는 검출되지 않으나, CEA를 과발현하는 LOVO 세포주 및 SW620-CEA 뿐만 아니라, KATO3, CRYPT에서도 상이한 정도의 글리코실화된 CEA 발현이 검출되었다.
SW620-CEA 세포주의 제작 방법: 10% FBS와 함께 추가된 1640 배지에서 SW620 세포를 유지 및 배양시켰다; 전체 길이의 CEA 유전자 (CEACAM5, NM-004363)를 전장 유전자 합성에 의해 수득하였다; GV348 벡터(진켐)에 클로닝한 후에, 두 헬퍼 플라스미드(helper plasmid)와 함께 유전자를 인산 칼슘을 이용하여 293T 세포로 형질주입하였고, 패키징하여 렌티바이러스를 구성하였다. SW620 세포를 24-웰 플레이트로, 105/웰 접종하였고, 밤새 배양시켰다; SW620를 CEA-발현 렌티바이러스를 이용해 MOI=3에 따라서 감염시켰고, 푸로마이신(puromycin)을 추가하여, 감염 후 24 시간 후에 최종 농도를 1 μg/ml에 도달시켰다; 세포를 푸로마이신을 이용해 스크리닝하여, 단일항체를 수득하였다. CEA 발현을 FACS로 검출하였다. 결과는 도 1에 제시된다.
[표 3]
[
실시예
4a: FM4
단일쇄
항체 및
CEA
항체를 이용한 종양 시료에서
CEA
발현의 검출]
환자의 위암 종양 조직 시료를 액체 파라핀에 포매시켰고 동결하였으며, 절편(section)을 유리 슬라이드에 고정시켰다; 크실렌을 이용해 탈랍(dewaxing)시킨 후에, 시트르산 완충액을 이용하여 항원 회수를 수행하였다; 회수된 시료를 5% FBS를 이용하여 PBS 완충액에서 30분 동안 블로킹시켰고, 2 μg/ml의 본 발명의 FM4 단일쇄 항체 또는 CEA 항체 (클론 CB30) [이바이오사이어스(ebioscience), Cat. No. 14-0669-82]를 4°C의 냉장고에서 밤새 추가하였다; 조직 슬라이드를 PBS로 3회 세척하였고, 2차 항체와 함께 추가하였으며, 발색 전개시켰다(color development).
FM4 단일쇄 항체는 더 높은 감도 및 조직 특이성을 보였다 (표 4에 제시됨).
[표 4]
[
실시예
5: 글리코실화된 C
EA
양성 세포 상의 CAR-T의
특이성에 대한 연구
]
CAR-T가 글리코실화된 CEA-양성 세포 (항원의 낮은 수준의 발현이 있는 SW620-CEA, CRYPT, KATO3, 및 LoVo)내 특이적 기능을 특이적으로 인식 및 생성하는지에 대한 여부를 조사하기 위해, 본 발명의 실험실은, 4개의 제작된 CAR-T, 즉, FM2(VL→VH)-BBz, FM4( VL → VH )-BBz, FM5( VL → VH )-BBz, 및 FM6( VL → VH )-BBz (SEQ ID NO. 80, SEQ ID NO. 84, SEQ ID NO. 86, SEQ ID NO. 88)의 표적 세포-특이적인 사멸 및 특이적인 사이토카인 방출을, 표적 세포와 공동 배양한 후에, 유사한 감염 효율(infection efficiency) 하에서, CAR 바이러스로 감염되지 않은 T 림프구를 대조군으로 이용하여 검출하였다.
1. CAR-T 감염 효율의 플로우 검출(Flow detection)
EGFP 단백질 및 CAR 단백질이 CAR-T 세포에서 공동 발현(co-expressed)되기 때문에, 유세포 분석에 의해 검출된 EGFP-양성 세포의 백분율은 CAR-양성 세포를 나타낼 수 있다. CAR 바이러스로 감염되지 않은 T세포를 대조군으로 이용하였고, 테스트 결과를 하기 표(표 5)에 제시하였다.
[표 5]
2. 표적 세포와 CAR-T의 상호작용 후, 사이토카인 분비 수준
표적 세포는 SW620, SW620-CEA, LoVo, 및 KATO3 세포였다. 이펙터 세포는 표 5에서 언급된 5개의 세포였고, 사이토카인 분비를 CAR 바이러스 감염 후 10일 째에서 검출하였다.
방법은 다음과 같았다: 1*105 표적 세포를 이펙터 세포와 1:1의 비율로 100 μl의 RPMI 1640+2% FBS 배지에서 별도로 혼합하였고, 약 16 시간 동안 37°C의 5% CO2 배양기에서 배양시켰다. 16시간 후에, 원심분리를 5분 동안 200 g에서 수행하였고, 상청액을 취해 상청액 내 사이토카인의 분비 수준을 측정하였다. 사이토카인 함량을 BD 컴퍼니가 생산한 HU TH1-TH2 CBA 키트로 측정하였다. 측정 메커니즘은, 반응 용액 내 사이토카인이 대응하는 비드 상의 항체와 결합할 수 있고, 각 사이토카인에 대응하는 비드는 상이한 강도의 APC 형광수준을 가지며; 사이토카인이 비드에 결합된 후에, 비드에 결합된 사이토카인은 다른 PE 형광 표지 항체로 더 표지되었고, 사이토카인 함량은 PE의 형광 강도를 측정함으로써 측정되었으며, 상이한 사이토카인 종류가 APC 형광 광도의 차이에 의해 구별되었다는 것이다. 이 연구에서, 세 사이토카인, 즉, IL-2, IFN-γ 및 TNF-α의 분비 수준을 측정하였다. 특이적인 테스트 방법은 키트 지시사항을 의미했다. 테스트 결과를 FCAP 어레이 v3 소프트웨어에 의해 분석하였고, 결과는 도 2, 도 3, 도 4, 도 5, 도 6, 및 도 7에 제시된다.
결과는 FM2( VL → VH )-BBz 및 FM4( VL → VH )-BBz가 표적 세포와 상호작용한 후에, IL-2, TNF-α, IFN-γ 및 다른 사이토카인이 현저히 증가한 것을 제시하였다.
3. CAR-T와 표적 세포의 상호작용 후에 표적 세포에 대한 시험관 내 사멸 독성(killing toxicity)
글리코실화된 CEA-양성 표적 세포에 대한 CAR-T의 사멸 효과를 확인하기 위해, 낮은 수준의 항원 발현이 있는 SW620-CEA 뿐만 아니라, 항원 발현-양성 세포 LoVo, KATO3 및 CRYPT도 이 연구에서 이용되었다. 사용된 키트는 사이토톡스96 비-방사성 세포독성 검정 키트(프로메가) [Cytotox96 non-radioactive cytotoxicity assay kit (Promega)]였다. 이 방법의 메커니즘은 통상의 방사성 원소가 세포에서 안정적으로 발현되고 분비되지 않는 젖산 탈수소효소(lactate dehydrogenase, LDH)로 대체되고; 세포의 세포사멸(apoptosis)이 발생되는 경우에, LDH가 세포 외로 방출되면, LDH에 산화된 포르마잔(formazan)의 함량이 검출되어 상청액 내 효소의 수준을 측정함으로써, 세포사멸의 수준을 측정하는 것이다. 이펙터 세포는 FM4( VL → VH )-28z였고, 이펙터 세포의 표적 세포에 대한 비율은 각각 1:2, 1:5, 1:10, 1:20, 1:30이었다. 표적 세포의 수는 10,000 세포/웰이었고, 두 개의 부수적인 웰(accessory well)이 각 그룹에 설정되었으며, 검출 시간은 상호작용 후 4시간이었다.
이들 중에서, 각각의 실험 그룹 및 대조 그룹은 다음과 같이 설정하였다:
실험 그룹: 표적 세포 및 상이한 표적 세포에 대한 이펙터 세포의 상이한 비율의 CAR-T 세포;
대조 그룹 1: 표적 세포의 LDH의 방출 중 LDH의 최대 방출이 있는 그룹;
대조 그룹 2: 표적 세포의 LDH의 방출 중 자발적인 LDH의 방출이 있는 그룹; 및
대조 그룹 3: 이펙터 세포의 방출에서 자발적인 방출이 있는 그룹.
특정한 실험 방법은 키트 지시사항을 의미했다. 세포독성은 하기의 식에 의해 산출되었다:
특이적 용해(Specific lysis) = (실험 그룹 - 대조 그룹 2 - 대조 그룹 3) / (대조 그룹 1 - 대조 그룹 2).
결과는 FM4( VL → VH )-28z가 LoVo, KATO3 및 CRYPT 세포에 대한 강한 사멸 효과를 가지나, SW620-CEA에 대해서는 사멸 효과를 거의 가지지 않는 것을 제시하였다. 관련 결과는 도 8 및 도 9에 제시된다.
이 연구는 FM4( VL → VH )-28z가 글리코실화된 CEA 항원을 특이적으로 인식하고, 낮은 정도의 글리코실화가 있는 CEA 항원에 대해서는 감도가 낮은 것을 입증하였다.
[
실시예
6: 글리코실화된 C
EA
-양성
PDX
종양 모델에 대한 CAR-T의 효과]
NCG 마우스 [난징 대학교의 모델 생물학 연구소(Institute of Model Biology)로부터 구입함]에게 글리코실화된 CEA 항원-양성 환자-유래의 종양 세포를 피하로 주사하였다. 환자의 종양 조직을 제거한 후에, 표면상의 결합 조직 및 혈관을 제거하였고; 종양 덩어리를 정중선(midline)을 따라 절제하였으며, 괴사 조직(necrotic tissue), 큰 석회화 지점(large calcification point) 및 분비물(secretion)을 제거하였고, 조심스러운 세척(cleaning) 후에, 양질(good quality) 및 좋은 단단함(good toughness)을 가진 종양 조직을 신선한, 아주 차가운(ice-cold) RPMI-1640 배지로 옮겼다. 종양 조직을 약 3Х3 mm2의 작은 종양 덩어리로 절제하여 NSG 마우스에 일측으로 이식하였다(transplanted unilaterally). 평균적인 종양 부피가 160-180 mm3에 도달되는 경우에, 모델 동물에게 이펙터 세포를 종양내로(intratumorally) 주사하였다.
이 연구에 이용된 이펙터 세포는 FM4( VL → VH )-BBz였고, 대조 그룹은 CAR로 형질주입되지 않은 T 세포 및 동일한 양의 동일한 양의 PBS였다. 주사 전에, 이펙터 세포를 PBS로 2회 세척하였고, PBS에서 재현탁하여 각각 3E7/ml 및 1E8/ml에 달하게 했고, 각각 저용량 그룹(low dose group) 및 고용량 그룹(high dose group)으로 기록하였다. 각 마우스에게 30 μl의 이펙터 세포/PBS를 종양내로 주사하였다.
이 연구의 연구 내용(research content)은 다음을 포함하였다:
마우스 체중 및 종양 부피 / 3 일 / 시간;
마우스 말초 혈액 사이토카인 검출 / 7 일 / 시간; 및
마우스 말초 혈액 CAR 카피 수(copy number) / 7 일 / 시간.
종양 부피 결과는 도 11에 제시된다. CAR-T의 주사 후 4일째부터, FM4( VL →VH)-BBz 고용량 그룹의 종양 부피는 감소하기 시작 한 반면, 공 T-세포 그룹(empty T-cell group) 및 PBS 그룹은 하락세를 보이지 않았다. 이는 CAR-T가 글리코실화된 CEA-양성 종양에 대한 현저한 저해 효과를 가지는 것을 나타낸다. CAR-T의 주사 후에, 공 T 세포 그룹 및 PBS 대조 그룹에 비해서, CAR-T가 주사된 마우스의 현저한 체중 변화는 없었다.
말초 혈액 내 사이토카인 분비 경향은 도 10에 제시된다. CAR-T 주입 그룹에서, 다양한 인간 사이토카인(IL-2, TNF-α, IFN-γ)의 분비는 말초 혈액에서 검출되었고, 사이토카인의 분비량은 종양 부피의 감소와 함께 점진적으로 감소되었는데, 이는 CAR-T이 종양 세포에 대한 현저한 활성화 반응을 생성하는 것을 증명하였다.
[
실시예
6a: 마우스 종양 모델]
NSG 마우스 (NOD scid IL2Rγnull)에게 1E7/마우스의 Lovo 세포 (CCL229, ATCC)를 피하로 접종하여 200mm3-300mm3 부피의 종양을 형성시켰다. 종양을 대조군으로서 PBMC와 함께 주사하였고, FM4(VL→VH)-BBz, 및 특이적 그룹은 다음과 같다:
PBMC 또는 FM4BBz T 세포로 수혈된 NSG 마우스를 꼬리 혈관(tail vein)을 통해 40 μl (3일째 및 7일째)를 채혈했고, 시료를 동일한 부피의 PBS에 재현탁 및 원심분리하였고, 상청액을 사이토카인 방출 검정 [BD 사이토메트릭 비드 검정(BD Cytometric Bead Array)]에 이용하였다. 결과는 도 14에 제시된다.
도 14에 제시된 바와 같이, 고용량 또는 저용량 FM4BBz-수혈 그룹 모두에서, IFNγ가 말초 혈액에서 검출되었는데, 이는 FM4BBz가 종양 세포를 접촉하였고, 사이토카인의 방출을 야기한 반면, 대조 그룹에서는 PBMC가 사이토 카인의 방출을 유도하지 않았다는 것을 제시하였다(FM4BBzH/L vs. PBMC 그룹, p 값 <0.001). 종양 부피를 35일 동안 주 2회 측정하였고, 종양 성장 곡선이 도 15에 제시된다.
도 15에 제시된 바와 같이, 고용량 및 저용량 FM4BBz 그룹 모두가 종양 성장에 대한 현저한 저해를 보이는데, 이는 FM4BBz가 종양을 사멸시키는 효과를 가지는 것을 제시한다.
[
실시예
7: FM4
(
VL
→
VH
)
-
BBz
렌티바이러스를
이용한 NK92 세포의 감염]
NK92 세포를 20% FBS, 150 IU/ml hIL-2를 함유한 1640 배지에서 배양시켰다. 실시예 3의 방법에 따라서, NK92 세포주를 FM4( VL → VH )-BBz CAR 바이러스로 감염시켰고, 10일 동안 지속해서 배양시켰다. FM4(VL→VH)-BBz-NK92 세포를 사멸 실험(killing experiment) 및 사이토카인 방출 검정에 이용하였고, 결과를 도 12 및 도 13에 제시하였다.
[
실시예
8: 항체-세포 결합 검정]
항체 FM2, FM4, FM5, 및 FM6를 1% BSA를 함유하는 PBS 완충액으로 희석시켰고, SW620-CEA 또는 CRYPT 세포와 1시간 동안 실온에서 배양시켰고 (최종 농도: 50 μg/ml, 5 μg/ml, 0.5 μg/ml, 0.05 μg/ml, 0.005 μg/ml, 0.0005 μg/ml); 세포를 1% BSA를 함유하는 PBS 완충액으로 2회 세척한 다음, 고트 항 마우스 IgG-APC(Goat Anti Mouse IgG-APC)와 함께 1시간 동안 배양시켰으며; 세포를 1% BSA를 함유하는 PBS 완충액으로 2회 세척하였고, PBS 완충액에서 재현탁하였으며; 세포의 APC 형광 값(fluorescence value)을 BD Accuri C6 FACS를 이용하여 판독하였다.
중간 형광 값(median fluorescence value, MFI)을 세로 좌표로 이용하고 항체 농도를 (μg/ml) 가로 좌표로 이용하여, S-곡선을 로지스틱 방정식(logistic equation)을 이용해 피팅하여 항체 결합 EC50를 계산하였다, 결과는 하기 표에 제시된다:
[표 6]
[결론]
SW620-CEA는 SW620 세포주 (CEACAM5)에서 과발현된 CEA이고, 이의 표면 CEA는 비-글리코실화 상태이다; CRYPT는 글리코실화된 CEA를 발현하는 종양 세포주이다.
항체-세포 결합 검정에 따라 계산된 항체의 EC50값으로부터, 항체 FM4가 글리코실화된 CEA에 특이적으로 결합하고, 높은 특이성 [선택성있음(selective) > 100배)]을 가진다는 것을 결론 내릴 수 있다.
SEQUENCE LISTING
<110> The fourth military medical university;
Shanghai Genechem CO., LTD
<120> Single-chain antibody specifically binding MG7, highly glycosylated CEA and use thereof in detection and therapy
<130> IEC160056PCT
<160> 180
<170> PatentIn version 3.5
<210> 1
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 1
Gly Phe Thr Phe Ser Arg Tyr
1 5
<210> 2
<211> 6
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 2
Ser Asn Ser Gly Ser Tyr
1 5
<210> 3
<211> 3
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 3
Gly Ser Pro
1
<210> 4
<211> 11
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 4
Gly Ala Ser Glu Asn Ile Tyr Gly Ala Leu Asn
1 5 10
<210> 5
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 5
Gly Ala Thr Lys Leu Ala Asp
1 5
<210> 6
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 6
Gln Asn Val Leu Ser Lys Pro Tyr Ala
1 5
<210> 7
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 7
Gly Tyr Thr Phe Ser Thr Tyr
1 5
<210> 8
<211> 6
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 8
Tyr Pro Gly Asp Gly Asp
1 5
<210> 9
<211> 11
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 9
Gly Gly Leu Tyr Tyr Gly Tyr Asp Ile Ala Tyr
1 5 10
<210> 10
<211> 16
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 10
Arg Ser Ser Gln Ser Ile Val His Ser Asn Gly Asn Thr Tyr Leu Glu
1 5 10 15
<210> 11
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 11
Lys Val Ser Asn Arg Phe Ser
1 5
<210> 12
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 12
Phe Gln Gly Ser His Val Pro Phe Thr
1 5
<210> 13
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 13
Gly Phe Thr Phe Thr Asp Tyr
1 5
<210> 14
<211> 8
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 14
Arg Asn Lys Val Asn Gly Asp Thr
1 5
<210> 15
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 15
Asp Lys Gly Ile Ala Tyr Tyr Phe Asp Tyr
1 5 10
<210> 16
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 16
Arg Ala Ser Ser Ser Val Ser Tyr Ile His
1 5 10
<210> 17
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 17
Gly Thr Ser Asn Leu Ala Ser
1 5
<210> 18
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 18
Gln Gln Trp Ser Ser Asn Leu Ser Thr
1 5
<210> 19
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 19
Gly Phe Ser Leu Thr Ser Tyr
1 5
<210> 20
<211> 5
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 20
Trp Thr Gly Gly Gly
1 5
<210> 21
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 21
Gly Val Tyr Tyr Phe Asp Tyr
1 5
<210> 22
<211> 11
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 22
Lys Ala Ser Gln Asp Val Thr Thr Ala Val Ala
1 5 10
<210> 23
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 23
Trp Ala Ser Thr Arg His Thr
1 5
<210> 24
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 24
Gln Gln Tyr Tyr Arg Thr Pro Arg Thr
1 5
<210> 25
<211> 11
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 25
Gly Tyr Thr Phe Asn Asp Tyr Asn Met Asp Tyr
1 5 10
<210> 26
<211> 6
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 26
Asn Pro Asn Tyr Asp Ser
1 5
<210> 27
<211> 13
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 27
Arg Asp Tyr Asp Gly Arg Arg Gly Ala Trp Phe Ser Tyr
1 5 10
<210> 28
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 28
Thr Ala Ser Ser Ser Val Ser Tyr Met Tyr Trp Tyr
1 5 10
<210> 29
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 29
Leu Thr Ser Asn Leu Ala Ser
1 5
<210> 30
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 30
Gln Gln Trp Asp Ser Asn Pro Leu Thr
1 5
<210> 31
<211> 116
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 31
Gly Val Gln Cys Asp Val Lys Leu Val Glu Ser Gly Gly Gly Leu Val
1 5 10 15
Lys Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr
20 25 30
Phe Ser Arg Tyr Thr Met Ser Trp Val Arg Gln Thr Pro Glu Lys Arg
35 40 45
Leu Glu Trp Val Ala Thr Ile Ser Asn Ser Gly Ser Tyr Thr Tyr Tyr
50 55 60
Arg Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys
65 70 75 80
Asn Thr Leu Tyr Leu Gln Met Ser Ser Leu Lys Ser Glu Asp Thr Ala
85 90 95
Met Tyr Tyr Cys Thr Arg Gly Ser Pro Trp Gly Gln Gly Thr Leu Val
100 105 110
Thr Val Ser Ala
115
<210> 32
<211> 107
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 32
Asp Ile Gln Met Thr Gln Ser Pro Asp Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Glu Thr Val Thr Ile Thr Cys Gly Ala Ser Glu Asn Ile Tyr Gly Ala
20 25 30
Leu Asn Trp Tyr Gln Arg Lys Gln Gly Lys Ser Pro Gln Leu Leu Ile
35 40 45
Tyr Gly Ala Thr Lys Leu Ala Asp Gly Met Ser Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Asn Arg Gln Tyr Ser Leu Lys Ile Ser Ser Leu His Pro
65 70 75 80
Asp Asp Val Ala Thr Tyr Tyr Cys Gln Asn Val Leu Ser Lys Pro Tyr
85 90 95
Ala Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 33
<211> 120
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 33
Glu Val Lys Leu Gln Gln Ser Gly Ala Asp Leu Ala Thr Pro Gly Ala
1 5 10 15
Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Ser Thr Tyr
20 25 30
Trp Met Gln Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Thr Ile Tyr Pro Gly Asp Gly Asp Thr Arg Tyr Thr Gln Lys Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala His
65 70 75 80
Met Gln Leu Ser Ser Leu Ala Ser Glu Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Gly Leu Tyr Tyr Gly Tyr Asp Ile Ala Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ala
115 120
<210> 34
<211> 112
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 34
Asp Ile Leu Met Thr Gln Thr Pro Leu Ser Leu Pro Val Ser Leu Gly
1 5 10 15
Asp Gln Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Ile Val His Ser
20 25 30
Asn Gly Asn Thr Tyr Leu Glu Trp Tyr Leu Gln Lys Pro Gly Gln Ser
35 40 45
Pro Lys Pro Leu Ile Lys Lys Val Ser Asn Arg Phe Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Tyr Cys Phe Gln Gly
85 90 95
Ser His Val Pro Phe Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 35
<211> 121
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 35
Glu Val Lys Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ser Ile Ser Gly Phe Thr Phe Thr Asp Tyr
20 25 30
Tyr Met Asn Trp Val Arg Gln Ser Pro Gly Lys Ala Leu Glu Trp Leu
35 40 45
Gly Phe Ile Arg Asn Lys Val Asn Gly Asp Thr Thr Glu Tyr Ser Ala
50 55 60
Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Ile Ser Gln Ser Ile
65 70 75 80
Leu Tyr Leu Gln Met Asn Thr Leu Arg Thr Glu Asp Ser Ala Thr Tyr
85 90 95
Tyr Cys Ala Arg Asp Lys Gly Ile Ala Tyr Tyr Phe Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Thr Leu Thr Val Ser Ser
115 120
<210> 36
<211> 106
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 36
Gln Ile Val Leu Ser Gln Ser Pro Ala Ile Leu Phe 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 Tyr Gln Gln Lys Pro Gly Ser Ser Pro Lys Pro Trp Ile His
35 40 45
Gly Thr Ser Asn Leu Ala Ser Gly Val Pro Ala Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Arg Met Glu Ala Glu
65 70 75 80
Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser Asn Leu Ser Thr
85 90 95
Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 37
<211> 115
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 37
Gln Val Gln Leu Lys Glu Ser Gly Pro Gly Leu Val Ala Pro Ser Gln
1 5 10 15
Asn Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Ser Tyr
20 25 30
Ala Ile Asn Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Leu
35 40 45
Gly Ile Ile Trp Thr Gly Gly Gly Thr Asn Tyr Asn Ser Ala Leu Lys
50 55 60
Ser Arg Leu Ser Ile Ser 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 Arg Tyr Tyr Cys Ala
85 90 95
Ser Gly Val Tyr Tyr Phe Asp Tyr Trp Gly Leu Gly Thr Thr Leu Thr
100 105 110
Val Ser Ser
115
<210> 38
<211> 107
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 38
Asp Ile Val Met Thr Gln Ser His Lys Phe Met Ser Thr Ser Val Gly
1 5 10 15
Asp Arg Val Ser Ile Thr Cys Lys Ala Ser Gln Asp Val Thr Thr Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Lys Val Leu Ile
35 40 45
Phe Trp Ala Ser Thr Arg His Thr Gly Val Pro Asp Arg Phe Thr Gly
50 55 60
Ser Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Val Gln Ala
65 70 75 80
Glu Asp Leu Ala Leu Tyr Tyr Cys Gln Gln Tyr Tyr Arg Thr Pro Arg
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 39
<211> 122
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 39
Glu Val Lys Leu Gln Glu Ser Gly Ala Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Asn Asp Tyr
20 25 30
Asn Met Asp Tyr Leu Lys Gln Ser His Gly Lys Ser Leu Glu Trp Ile
35 40 45
Gly Asp Ile Asn Pro Asn Tyr Asp Ser Thr Ile Tyr Asn Gln Lys Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Arg Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Arg Asp Tyr Asp Gly Arg Arg Gly Ala Trp Phe Ser Tyr Trp
100 105 110
Gly Gln Gly Thr Leu Val Thr Val Ser Ala
115 120
<210> 40
<211> 106
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 40
Gln Ile Val Leu Thr Gln Ser Pro Ala Leu Met Ser Ala Ser Pro Gly
1 5 10 15
Glu Lys Val Thr Val Thr Cys Thr Ala Ser Ser Ser Val Ser Tyr Met
20 25 30
Tyr Trp Tyr Gln Gln Lys Pro Arg Ser Ser Pro Lys Pro Trp Ile Tyr
35 40 45
Leu Thr Ser Asn Leu Ala Ser Gly Val Pro Thr Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Ser Met Glu Ala Glu
65 70 75 80
Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Asp Ser Asn Pro Leu Thr
85 90 95
Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys
100 105
<210> 41
<211> 15
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 41
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
1 5 10 15
<210> 42
<211> 348
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 42
ggtgtccagt gtgacgtgaa gttggtggag tctgggggag gcttagtgaa gcctggaggg 60
tccctgaaac tctcctgtgc agcctctgga ttcactttca gtagatacac catgtcttgg 120
gttcgccaga ctccggagaa gaggctggag tgggtcgcaa ccattagtaa tagtggtagt 180
tatacctact atcgagacag tgtgaagggc cgattcacca tctccagaga caatgccaag 240
aacaccctgt acctgcaaat gagcagtctg aagtctgagg acacagccat gtattactgt 300
acaagggggt cgccctgggg ccaagggact ctggtcactg tctctgca 348
<210> 43
<211> 321
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 43
gacatccaga tgactcagtc tccagattca ctgtctgcat ctgtgggaga aactgtcacc 60
atcacatgtg gagcaagtga gaacatttac ggtgctttaa attggtatca gcggaaacag 120
ggaaaatctc ctcagctcct gatctatggt gcaaccaagt tggcagatgg catgtcatcg 180
aggttcagtg gcagtggatc taatagacag tattctctca agatcagtag cctgcatcct 240
gacgatgttg caacgtatta ctgtcaaaat gtgttaagta agccgtacgc gttcggaggg 300
gggaccaaac tggaaataaa a 321
<210> 44
<211> 360
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 44
gaggtgaagc tgcagcaatc aggggctgac ctggcaacac ctggggcttc agtgaagttg 60
tcctgcaagg cttctggcta tacctttagt acctactgga tgcagtgggt aaaacagagg 120
cctggacagg gtctggaatg gattgggact atttatcctg gagatggtga tactaggtac 180
actcagaagt tcaagggcaa ggccacattg actgcagata aatcctccag tacagcccac 240
atgcaactca gcagcttggc atctgaggac tctgcggtct attattgtgc aagaggggga 300
ctctattatg gttacgacat tgcttactgg ggccaaggga ctctggtcac tgtctctgca 360
<210> 45
<211> 336
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 45
gatattttga tgacccaaac tccactctcc ctgcctgtca gtcttggaga tcaagcctcc 60
atctcttgca gatctagtca gagcattgta catagtaatg gaaacaccta tttagaatgg 120
tacctgcaga aaccaggcca gtctccaaag cccctgataa agaaagtctc caaccgattt 180
tctggggtcc cagacaggtt cagtggcagt ggatcaggga cagaattcac actcaagatc 240
agcagagtgg aggctgagga tctgggagtt tattactgct ttcaaggttc acatgttcca 300
ttcacgttcg gctcggggac aaagttggaa ataaaa 336
<210> 46
<211> 363
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 46
gaggtgaagc tggtggagtc tggaggaggc ttggtccagc cgggggggtc tctgagactc 60
tcctgttcaa tttctggatt caccttcact gattactaca tgaactgggt ccgccagtct 120
ccaggaaagg cacttgagtg gttgggtttt attagaaaca aagttaatgg tgacacaaca 180
gaatatagtg catctgtgaa gggtcggttc accatctcca gagatatttc ccagagcatc 240
ctctatcttc aaatgaacac cctgagaact gaggacagtg ccacttatta ctgtgcgaga 300
gataagggaa tagcgtacta ctttgactat tggggccaag gcaccactct cacagtctcc 360
tca 363
<210> 47
<211> 318
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 47
caaattgttc tctcccagtc tccagcaatc ctgtttgcat ctccagggga gaaggtcaca 60
atgacttgta gggccagctc aagtgtaagt tacattcact ggtaccagca gaagccagga 120
tcctccccca aaccctggat tcatggcaca tccaacctgg cttctggagt ccctgctcgc 180
ttcagtggca gtgggtctgg gacctcttac tctctcacaa tcagcagaat ggaggctgaa 240
gatgccgcca catattactg ccagcagtgg agtagtaatt tatccacgtt cggagggggg 300
accaagctgg aaataaaa 318
<210> 48
<211> 345
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 48
caggtgcagc tgaaggagtc aggacctggc ctggtggcgc cctcacagaa cctgtccatc 60
acatgcactg tctctgggtt ctcattaacc agctatgcta taaactgggt tcgccagcca 120
ccaggaaagg gtctggagtg gcttggaata atatggactg gtggaggcac aaattataat 180
tcagctctca aatccagact gagcatcagc aaagacaact ccaagagtca agttttctta 240
aaaatgaaca gtctgcaaac tgatgacaca gccaggtact actgtgcctc gggggtgtac 300
tactttgact actggggcct aggcaccact ctcacagtct cctca 345
<210> 49
<211> 321
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 49
gacattgtga tgacccagtc tcacaaattc atgtccacat cagtaggaga cagggtcagc 60
atcacctgca aggccagtca ggatgtgact actgctgtag cctggtatca acaaaaacca 120
gggcaatctc ctaaagtact gattttctgg gcatccaccc ggcacactgg agtccctgat 180
cgcttcacag gcagtggatc tgggacagat tatactctca ccatcagcag tgtgcaggct 240
gaagacctgg cactttatta ctgtcagcaa tattatagaa ctcctcggac gttcggtgga 300
ggcaccaaac tggaaatcaa a 321
<210> 50
<211> 366
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 50
gaggtgaagc tgcaggaatc tggagctgag ctggtgaagc ctggggcttc agtgaagatc 60
tcctgcaagg cttctggcta cacattcaat gactacaaca tggactatct gaagcagagc 120
catggaaaga gccttgagtg gattggagat attaatccta actatgatag cactatctac 180
aaccagaagt tcaagggcaa ggccacattg actgtagaca agtcctccag cacagcctac 240
atggagctcc gcagcctgac atctgaggac tctgcagtct attactgtgc aagacgagac 300
tacgatggta ggaggggggc ctggttttct tactggggcc aagggactct ggtcactgtc 360
tctgca 366
<210> 51
<211> 318
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 51
caaattgttc tcacccagtc tccagcactc atgtctgcat ctccagggga gaaggtcacc 60
gtgacctgca ctgccagctc aagtgtaagt tacatgtact ggtaccagca gaagccaaga 120
tcctccccca aaccctggat ttatctcaca tccaacctgg cttctggagt ccctactcgc 180
ttcagtggca gtgggtctgg gacctcttat tctctcacaa tcagcagcat ggaggctgaa 240
gatgctgcca cttattactg ccagcagtgg gatagtaacc cgctcacgtt cggtgctggg 300
accaaactgg agctgaaa 318
<210> 52
<211> 135
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 52
accacgacgc cagcgccgcg accaccaaca ccggcgccca ccatcgcgtc gcagcccctg 60
tccctgcgcc cagaggcgtg ccggccagcg gcggggggcg cagtgcacac gagggggctg 120
gacttcgcct gtgat 135
<210> 53
<211> 117
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 53
attgaagtta tgtatcctcc tccttaccta gacaatgaga agagcaatgg aaccattatc 60
catgtgaaag ggaaacacct ttgtccaagt cccctatttc ccggaccttc taagccc 117
<210> 54
<211> 72
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 54
atctacatct gggcgccctt ggccgggact tgtggggtcc ttctcctgtc actggttatc 60
accctttact gc 72
<210> 55
<211> 81
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 55
ttttgggtgc tggtggtggt tgggggagtc ctggcttgct atagcttgct agtaacagtg 60
gcctttatta ttttctgggt g 81
<210> 56
<211> 123
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 56
aggagtaaga ggagcaggct cctgcacagt gactacatga acatgactcc ccgccgcccc 60
gggcccaccc gcaagcatta ccagccctat gccccaccac gcgacttcgc agcctatcgc 120
tcc 123
<210> 57
<211> 123
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 57
aaacggggca gaaagaaact cctgtatata ttcaaacaac catttatgag accagtacaa 60
actactcaag aggaagatgg ctgtagctgc cgatttccag aagaagaaga aggaggatgt 120
gaa 123
<210> 58
<211> 342
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 58
ctgagagtga agttcagcag gagcgcagac gcccccgcgt accagcaggg ccagaaccag 60
ctctataacg agctcaatct aggacgaaga gaggagtacg atgttttgga caagagacgt 120
ggccgggacc ctgagatggg gggaaagccg agaaggaaga accctcagga aggcctgtac 180
aatgaactgc agaaagataa gatggcggag gcctacagtg agattgggat gaaaggcgag 240
cgccggaggg gcaaggggca cgatggcctt taccagggtc tcagtacagc caccaaggac 300
acctacgacg cccttcacat gcaggccctg ccccctcgct aa 342
<210> 59
<211> 714
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 59
ggtgtccagt gtgacgtgaa gttggtggag tctgggggag gcttagtgaa gcctggaggg 60
tccctgaaac tctcctgtgc agcctctgga ttcactttca gtagatacac catgtcttgg 120
gttcgccaga ctccggagaa gaggctggag tgggtcgcaa ccattagtaa tagtggtagt 180
tatacctact atcgagacag tgtgaagggc cgattcacca tctccagaga caatgccaag 240
aacaccctgt acctgcaaat gagcagtctg aagtctgagg acacagccat gtattactgt 300
acaagggggt cgccctgggg ccaagggact ctggtcactg tctctgcagg tggcggtggc 360
tcgggcggtg gtgggtcggg tggcggcgga tctgacatcc agatgactca gtctccagat 420
tcactgtctg catctgtggg agaaactgtc accatcacat gtggagcaag tgagaacatt 480
tacggtgctt taaattggta tcagcggaaa cagggaaaat ctcctcagct cctgatctat 540
ggtgcaacca agttggcaga tggcatgtca tcgaggttca gtggcagtgg atctaataga 600
cagtattctc tcaagatcag tagcctgcat cctgacgatg ttgcaacgta ttactgtcaa 660
aatgtgttaa gtaagccgta cgcgttcgga ggggggacca aactggaaat aaaa 714
<210> 60
<211> 741
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 60
gaggtgaagc tgcagcaatc aggggctgac ctggcaacac ctggggcttc agtgaagttg 60
tcctgcaagg cttctggcta tacctttagt acctactgga tgcagtgggt aaaacagagg 120
cctggacagg gtctggaatg gattgggact atttatcctg gagatggtga tactaggtac 180
actcagaagt tcaagggcaa ggccacattg actgcagata aatcctccag tacagcccac 240
atgcaactca gcagcttggc atctgaggac tctgcggtct attattgtgc aagaggggga 300
ctctattatg gttacgacat tgcttactgg ggccaaggga ctctggtcac tgtctctgca 360
ggtggcggtg gctcgggcgg tggtgggtcg ggtggcggcg gatctgatat tttgatgacc 420
caaactccac tctccctgcc tgtcagtctt ggagatcaag cctccatctc ttgcagatct 480
agtcagagca ttgtacatag taatggaaac acctatttag aatggtacct gcagaaacca 540
ggccagtctc caaagcccct gataaagaaa gtctccaacc gattttctgg ggtcccagac 600
aggttcagtg gcagtggatc agggacagaa ttcacactca agatcagcag agtggaggct 660
gaggatctgg gagtttatta ctgctttcaa ggttcacatg ttccattcac gttcggctcg 720
gggacaaagt tggaaataaa a 741
<210> 61
<211> 726
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 61
gaggtgaagc tggtggagtc tggaggaggc ttggtccagc cgggggggtc tctgagactc 60
tcctgttcaa tttctggatt caccttcact gattactaca tgaactgggt ccgccagtct 120
ccaggaaagg cacttgagtg gttgggtttt attagaaaca aagttaatgg tgacacaaca 180
gaatatagtg catctgtgaa gggtcggttc accatctcca gagatatttc ccagagcatc 240
ctctatcttc aaatgaacac cctgagaact gaggacagtg ccacttatta ctgtgcgaga 300
gataagggaa tagcgtacta ctttgactat tggggccaag gcaccactct cacagtctcc 360
tcaggtggcg gtggctcggg cggtggtggg tcgggtggcg gcggatctca aattgttctc 420
tcccagtctc cagcaatcct gtttgcatct ccaggggaga aggtcacaat gacttgtagg 480
gccagctcaa gtgtaagtta cattcactgg taccagcaga agccaggatc ctcccccaaa 540
ccctggattc atggcacatc caacctggct tctggagtcc ctgctcgctt cagtggcagt 600
gggtctggga cctcttactc tctcacaatc agcagaatgg aggctgaaga tgccgccaca 660
tattactgcc agcagtggag tagtaattta tccacgttcg gaggggggac caagctggaa 720
ataaaa 726
<210> 62
<211> 711
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 62
caggtgcagc tgaaggagtc aggacctggc ctggtggcgc cctcacagaa cctgtccatc 60
acatgcactg tctctgggtt ctcattaacc agctatgcta taaactgggt tcgccagcca 120
ccaggaaagg gtctggagtg gcttggaata atatggactg gtggaggcac aaattataat 180
tcagctctca aatccagact gagcatcagc aaagacaact ccaagagtca agttttctta 240
aaaatgaaca gtctgcaaac tgatgacaca gccaggtact actgtgcctc gggggtgtac 300
tactttgact actggggcct aggcaccact ctcacagtct cctcaggtgg cggtggctcg 360
ggcggtggtg ggtcgggtgg cggcggatct gacattgtga tgacccagtc tcacaaattc 420
atgtccacat cagtaggaga cagggtcagc atcacctgca aggccagtca ggatgtgact 480
actgctgtag cctggtatca acaaaaacca gggcaatctc ctaaagtact gattttctgg 540
gcatccaccc ggcacactgg agtccctgat cgcttcacag gcagtggatc tgggacagat 600
tatactctca ccatcagcag tgtgcaggct gaagacctgg cactttatta ctgtcagcaa 660
tattatagaa ctcctcggac gttcggtgga ggcaccaaac tggaaatcaa a 711
<210> 63
<211> 729
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 63
gaggtgaagc tgcaggaatc tggagctgag ctggtgaagc ctggggcttc agtgaagatc 60
tcctgcaagg cttctggcta cacattcaat gactacaaca tggactatct gaagcagagc 120
catggaaaga gccttgagtg gattggagat attaatccta actatgatag cactatctac 180
aaccagaagt tcaagggcaa ggccacattg actgtagaca agtcctccag cacagcctac 240
atggagctcc gcagcctgac atctgaggac tctgcagtct attactgtgc aagacgagac 300
tacgatggta ggaggggggc ctggttttct tactggggcc aagggactct ggtcactgtc 360
tctgcaggtg gcggtggctc gggcggtggt gggtcgggtg gcggcggatc tcaaattgtt 420
ctcacccagt ctccagcact catgtctgca tctccagggg agaaggtcac cgtgacctgc 480
actgccagct caagtgtaag ttacatgtac tggtaccagc agaagccaag atcctccccc 540
aaaccctgga tttatctcac atccaacctg gcttctggag tccctactcg cttcagtggc 600
agtgggtctg ggacctctta ttctctcaca atcagcagca tggaggctga agatgctgcc 660
acttattact gccagcagtg ggatagtaac ccgctcacgt tcggtgctgg gaccaaactg 720
gagctgaaa 729
<210> 64
<211> 714
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 64
gacatccaga tgactcagtc tccagattca ctgtctgcat ctgtgggaga aactgtcacc 60
atcacatgtg gagcaagtga gaacatttac ggtgctttaa attggtatca gcggaaacag 120
ggaaaatctc ctcagctcct gatctatggt gcaaccaagt tggcagatgg catgtcatcg 180
aggttcagtg gcagtggatc taatagacag tattctctca agatcagtag cctgcatcct 240
gacgatgttg caacgtatta ctgtcaaaat gtgttaagta agccgtacgc gttcggaggg 300
gggaccaaac tggaaataaa aggtggcggt ggctcgggcg gtggtgggtc gggtggcggc 360
ggatctggtg tccagtgtga cgtgaagttg gtggagtctg ggggaggctt agtgaagcct 420
ggagggtccc tgaaactctc ctgtgcagcc tctggattca ctttcagtag atacaccatg 480
tcttgggttc gccagactcc ggagaagagg ctggagtggg tcgcaaccat tagtaatagt 540
ggtagttata cctactatcg agacagtgtg aagggccgat tcaccatctc cagagacaat 600
gccaagaaca ccctgtacct gcaaatgagc agtctgaagt ctgaggacac agccatgtat 660
tactgtacaa gggggtcgcc ctggggccaa gggactctgg tcactgtctc tgca 714
<210> 65
<211> 741
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 65
gatattttga tgacccaaac tccactctcc ctgcctgtca gtcttggaga tcaagcctcc 60
atctcttgca gatctagtca gagcattgta catagtaatg gaaacaccta tttagaatgg 120
tacctgcaga aaccaggcca gtctccaaag cccctgataa agaaagtctc caaccgattt 180
tctggggtcc cagacaggtt cagtggcagt ggatcaggga cagaattcac actcaagatc 240
agcagagtgg aggctgagga tctgggagtt tattactgct ttcaaggttc acatgttcca 300
ttcacgttcg gctcggggac aaagttggaa ataaaaggtg gcggtggctc gggcggtggt 360
gggtcgggtg gcggcggatc tgaggtgaag ctgcagcaat caggggctga cctggcaaca 420
cctggggctt cagtgaagtt gtcctgcaag gcttctggct atacctttag tacctactgg 480
atgcagtggg taaaacagag gcctggacag ggtctggaat ggattgggac tatttatcct 540
ggagatggtg atactaggta cactcagaag ttcaagggca aggccacatt gactgcagat 600
aaatcctcca gtacagccca catgcaactc agcagcttgg catctgagga ctctgcggtc 660
tattattgtg caagaggggg actctattat ggttacgaca ttgcttactg gggccaaggg 720
actctggtca ctgtctctgc a 741
<210> 66
<211> 726
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 66
caaattgttc tctcccagtc tccagcaatc ctgtttgcat ctccagggga gaaggtcaca 60
atgacttgta gggccagctc aagtgtaagt tacattcact ggtaccagca gaagccagga 120
tcctccccca aaccctggat tcatggcaca tccaacctgg cttctggagt ccctgctcgc 180
ttcagtggca gtgggtctgg gacctcttac tctctcacaa tcagcagaat ggaggctgaa 240
gatgccgcca catattactg ccagcagtgg agtagtaatt tatccacgtt cggagggggg 300
accaagctgg aaataaaagg tggcggtggc tcgggcggtg gtgggtcggg tggcggcgga 360
tctgaggtga agctggtgga gtctggagga ggcttggtcc agccgggggg gtctctgaga 420
ctctcctgtt caatttctgg attcaccttc actgattact acatgaactg ggtccgccag 480
tctccaggaa aggcacttga gtggttgggt tttattagaa acaaagttaa tggtgacaca 540
acagaatata gtgcatctgt gaagggtcgg ttcaccatct ccagagatat ttcccagagc 600
atcctctatc ttcaaatgaa caccctgaga actgaggaca gtgccactta ttactgtgcg 660
agagataagg gaatagcgta ctactttgac tattggggcc aaggcaccac tctcacagtc 720
tcctca 726
<210> 67
<211> 711
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 67
gacattgtga tgacccagtc tcacaaattc atgtccacat cagtaggaga cagggtcagc 60
atcacctgca aggccagtca ggatgtgact actgctgtag cctggtatca acaaaaacca 120
gggcaatctc ctaaagtact gattttctgg gcatccaccc ggcacactgg agtccctgat 180
cgcttcacag gcagtggatc tgggacagat tatactctca ccatcagcag tgtgcaggct 240
gaagacctgg cactttatta ctgtcagcaa tattatagaa ctcctcggac gttcggtgga 300
ggcaccaaac tggaaatcaa aggtggcggt ggctcgggcg gtggtgggtc gggtggcggc 360
ggatctcagg tgcagctgaa ggagtcagga cctggcctgg tggcgccctc acagaacctg 420
tccatcacat gcactgtctc tgggttctca ttaaccagct atgctataaa ctgggttcgc 480
cagccaccag gaaagggtct ggagtggctt ggaataatat ggactggtgg aggcacaaat 540
tataattcag ctctcaaatc cagactgagc atcagcaaag acaactccaa gagtcaagtt 600
ttcttaaaaa tgaacagtct gcaaactgat gacacagcca ggtactactg tgcctcgggg 660
gtgtactact ttgactactg gggcctaggc accactctca cagtctcctc a 711
<210> 68
<211> 729
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 68
caaattgttc tcacccagtc tccagcactc atgtctgcat ctccagggga gaaggtcacc 60
gtgacctgca ctgccagctc aagtgtaagt tacatgtact ggtaccagca gaagccaaga 120
tcctccccca aaccctggat ttatctcaca tccaacctgg cttctggagt ccctactcgc 180
ttcagtggca gtgggtctgg gacctcttat tctctcacaa tcagcagcat ggaggctgaa 240
gatgctgcca cttattactg ccagcagtgg gatagtaacc cgctcacgtt cggtgctggg 300
accaaactgg agctgaaagg tggcggtggc tcgggcggtg gtgggtcggg tggcggcgga 360
tctgaggtga agctgcagga atctggagct gagctggtga agcctggggc ttcagtgaag 420
atctcctgca aggcttctgg ctacacattc aatgactaca acatggacta tctgaagcag 480
agccatggaa agagccttga gtggattgga gatattaatc ctaactatga tagcactatc 540
tacaaccaga agttcaaggg caaggccaca ttgactgtag acaagtcctc cagcacagcc 600
tacatggagc tccgcagcct gacatctgag gactctgcag tctattactg tgcaagacga 660
gactacgatg gtaggagggg ggcctggttt tcttactggg gccaagggac tctggtcact 720
gtctctgca 729
<210> 69
<211> 2169
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 69
ggtgtccagt gtgacgtgaa gttggtggag tctgggggag gcttagtgaa gcctggaggg 60
tccctgaaac tctcctgtgc agcctctgga ttcactttca gtagatacac catgtcttgg 120
gttcgccaga ctccggagaa gaggctggag tgggtcgcaa ccattagtaa tagtggtagt 180
tatacctact atcgagacag tgtgaagggc cgattcacca tctccagaga caatgccaag 240
aacaccctgt acctgcaaat gagcagtctg aagtctgagg acacagccat gtattactgt 300
acaagggggt cgccctgggg ccaagggact ctggtcactg tctctgcagg tggcggtggc 360
tcgggcggtg gtgggtcggg tggcggcgga tctgacatcc agatgactca gtctccagat 420
tcactgtctg catctgtggg agaaactgtc accatcacat gtggagcaag tgagaacatt 480
tacggtgctt taaattggta tcagcggaaa cagggaaaat ctcctcagct cctgatctat 540
ggtgcaacca agttggcaga tggcatgtca tcgaggttca gtggcagtgg atctaataga 600
cagtattctc tcaagatcag tagcctgcat cctgacgatg ttgcaacgta ttactgtcaa 660
aatgtgttaa gtaagccgta cgcgttcgga ggggggacca aactggaaat aaaaaccacg 720
acgccagcgc cgcgaccacc aacaccggcg cccaccatcg cgtcgcagcc cctgtccctg 780
cgcccagagg cgtgccggcc agcggcgggg ggcgcagtgc acacgagggg gctggacttc 840
gcctgtgata tctacatctg ggcgcccttg gccgggactt gtggggtcct tctcctgtca 900
ctggttatca ccctttactg caaacggggc agaaagaaac tcctgtatat attcaaacaa 960
ccatttatga gaccagtaca aactactcaa gaggaagatg gctgtagctg ccgatttcca 1020
gaagaagaag aaggaggatg tgaactgaga gtgaagttca gcaggagcgc agacgccccc 1080
gcgtaccagc agggccagaa ccagctctat aacgagctca atctaggacg aagagaggag 1140
tacgatgttt tggacaagag acgtggccgg gaccctgaga tggggggaaa gccgagaagg 1200
aagaaccctc aggaaggcct gtacaatgaa ctgcagaaag ataagatggc ggaggcctac 1260
agtgagattg ggatgaaagg cgagcgccgg aggggcaagg ggcacgatgg cctttaccag 1320
ggtctcagta cagccaccaa ggacacctac gacgcccttc acatgcaggc cctgccccct 1380
cgcggatctg gcgccaccaa cttctctctg ctgaagcagg ccggcgacgt ggaggagaac 1440
ccaggcccaa tggtgagcaa gggcgaggag ctgttcaccg gggtggtgcc catcctggtc 1500
gagctggacg gcgacgtaaa cggccacaag ttcagcgtgt ccggcgaggg cgagggcgat 1560
gccacctacg gcaagctgac cctgaagttc atctgcacca ccggcaagct gcccgtgccc 1620
tggcccaccc tcgtgaccac cctgacctac ggcgtgcagt gcttcagccg ctaccccgac 1680
cacatgaagc agcacgactt cttcaagtcc gccatgcccg aaggctacgt ccaggagcgc 1740
accatcttct tcaaggacga cggcaactac aagacccgcg ccgaggtgaa gttcgagggc 1800
gacaccctgg tgaaccgcat cgagctgaag ggcatcgact tcaaggagga cggcaacatc 1860
ctggggcaca agctggagta caactacaac agccacaacg tctatatcat ggccgacaag 1920
cagaagaacg gcatcaaggt gaacttcaag atccgccaca acatcgagga cggcagcgtg 1980
cagctcgccg accactacca gcagaacacc cccatcggcg acggccccgt gctgctgccc 2040
gacaaccact acctgagcac ccagtccgcc ctgagcaaag accccaacga gaagcgcgat 2100
cacatggtcc tgctggagtt cgtgaccgcc gccgggatca ctctcggcat ggacgagctg 2160
tacaagtaa 2169
<210> 70
<211> 2169
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 70
gacatccaga tgactcagtc tccagattca ctgtctgcat ctgtgggaga aactgtcacc 60
atcacatgtg gagcaagtga gaacatttac ggtgctttaa attggtatca gcggaaacag 120
ggaaaatctc ctcagctcct gatctatggt gcaaccaagt tggcagatgg catgtcatcg 180
aggttcagtg gcagtggatc taatagacag tattctctca agatcagtag cctgcatcct 240
gacgatgttg caacgtatta ctgtcaaaat gtgttaagta agccgtacgc gttcggaggg 300
gggaccaaac tggaaataaa aggtggcggt ggctcgggcg gtggtgggtc gggtggcggc 360
ggatctggtg tccagtgtga cgtgaagttg gtggagtctg ggggaggctt agtgaagcct 420
ggagggtccc tgaaactctc ctgtgcagcc tctggattca ctttcagtag atacaccatg 480
tcttgggttc gccagactcc ggagaagagg ctggagtggg tcgcaaccat tagtaatagt 540
ggtagttata cctactatcg agacagtgtg aagggccgat tcaccatctc cagagacaat 600
gccaagaaca ccctgtacct gcaaatgagc agtctgaagt ctgaggacac agccatgtat 660
tactgtacaa gggggtcgcc ctggggccaa gggactctgg tcactgtctc tgcaaccacg 720
acgccagcgc cgcgaccacc aacaccggcg cccaccatcg cgtcgcagcc cctgtccctg 780
cgcccagagg cgtgccggcc agcggcgggg ggcgcagtgc acacgagggg gctggacttc 840
gcctgtgata tctacatctg ggcgcccttg gccgggactt gtggggtcct tctcctgtca 900
ctggttatca ccctttactg caaacggggc agaaagaaac tcctgtatat attcaaacaa 960
ccatttatga gaccagtaca aactactcaa gaggaagatg gctgtagctg ccgatttcca 1020
gaagaagaag aaggaggatg tgaactgaga gtgaagttca gcaggagcgc agacgccccc 1080
gcgtaccagc agggccagaa ccagctctat aacgagctca atctaggacg aagagaggag 1140
tacgatgttt tggacaagag acgtggccgg gaccctgaga tggggggaaa gccgagaagg 1200
aagaaccctc aggaaggcct gtacaatgaa ctgcagaaag ataagatggc ggaggcctac 1260
agtgagattg ggatgaaagg cgagcgccgg aggggcaagg ggcacgatgg cctttaccag 1320
ggtctcagta cagccaccaa ggacacctac gacgcccttc acatgcaggc cctgccccct 1380
cgcggatctg gcgccaccaa cttctctctg ctgaagcagg ccggcgacgt ggaggagaac 1440
ccaggcccaa tggtgagcaa gggcgaggag ctgttcaccg gggtggtgcc catcctggtc 1500
gagctggacg gcgacgtaaa cggccacaag ttcagcgtgt ccggcgaggg cgagggcgat 1560
gccacctacg gcaagctgac cctgaagttc atctgcacca ccggcaagct gcccgtgccc 1620
tggcccaccc tcgtgaccac cctgacctac ggcgtgcagt gcttcagccg ctaccccgac 1680
cacatgaagc agcacgactt cttcaagtcc gccatgcccg aaggctacgt ccaggagcgc 1740
accatcttct tcaaggacga cggcaactac aagacccgcg ccgaggtgaa gttcgagggc 1800
gacaccctgg tgaaccgcat cgagctgaag ggcatcgact tcaaggagga cggcaacatc 1860
ctggggcaca agctggagta caactacaac agccacaacg tctatatcat ggccgacaag 1920
cagaagaacg gcatcaaggt gaacttcaag atccgccaca acatcgagga cggcagcgtg 1980
cagctcgccg accactacca gcagaacacc cccatcggcg acggccccgt gctgctgccc 2040
gacaaccact acctgagcac ccagtccgcc ctgagcaaag accccaacga gaagcgcgat 2100
cacatggtcc tgctggagtt cgtgaccgcc gccgggatca ctctcggcat ggacgagctg 2160
tacaagtaa 2169
<210> 71
<211> 2196
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 71
gaggtgaagc tgcagcaatc aggggctgac ctggcaacac ctggggcttc agtgaagttg 60
tcctgcaagg cttctggcta tacctttagt acctactgga tgcagtgggt aaaacagagg 120
cctggacagg gtctggaatg gattgggact atttatcctg gagatggtga tactaggtac 180
actcagaagt tcaagggcaa ggccacattg actgcagata aatcctccag tacagcccac 240
atgcaactca gcagcttggc atctgaggac tctgcggtct attattgtgc aagaggggga 300
ctctattatg gttacgacat tgcttactgg ggccaaggga ctctggtcac tgtctctgca 360
ggtggcggtg gctcgggcgg tggtgggtcg ggtggcggcg gatctgatat tttgatgacc 420
caaactccac tctccctgcc tgtcagtctt ggagatcaag cctccatctc ttgcagatct 480
agtcagagca ttgtacatag taatggaaac acctatttag aatggtacct gcagaaacca 540
ggccagtctc caaagcccct gataaagaaa gtctccaacc gattttctgg ggtcccagac 600
aggttcagtg gcagtggatc agggacagaa ttcacactca agatcagcag agtggaggct 660
gaggatctgg gagtttatta ctgctttcaa ggttcacatg ttccattcac gttcggctcg 720
gggacaaagt tggaaataaa aaccacgacg ccagcgccgc gaccaccaac accggcgccc 780
accatcgcgt cgcagcccct gtccctgcgc ccagaggcgt gccggccagc ggcggggggc 840
gcagtgcaca cgagggggct ggacttcgcc tgtgatatct acatctgggc gcccttggcc 900
gggacttgtg gggtccttct cctgtcactg gttatcaccc tttactgcaa acggggcaga 960
aagaaactcc tgtatatatt caaacaacca tttatgagac cagtacaaac tactcaagag 1020
gaagatggct gtagctgccg atttccagaa gaagaagaag gaggatgtga actgagagtg 1080
aagttcagca ggagcgcaga cgcccccgcg taccagcagg gccagaacca gctctataac 1140
gagctcaatc taggacgaag agaggagtac gatgttttgg acaagagacg tggccgggac 1200
cctgagatgg ggggaaagcc gagaaggaag aaccctcagg aaggcctgta caatgaactg 1260
cagaaagata agatggcgga ggcctacagt gagattggga tgaaaggcga gcgccggagg 1320
ggcaaggggc acgatggcct ttaccagggt ctcagtacag ccaccaagga cacctacgac 1380
gcccttcaca tgcaggccct gccccctcgc ggatctggcg ccaccaactt ctctctgctg 1440
aagcaggccg gcgacgtgga ggagaaccca ggcccaatgg tgagcaaggg cgaggagctg 1500
ttcaccgggg tggtgcccat cctggtcgag ctggacggcg acgtaaacgg ccacaagttc 1560
agcgtgtccg gcgagggcga gggcgatgcc acctacggca agctgaccct gaagttcatc 1620
tgcaccaccg gcaagctgcc cgtgccctgg cccaccctcg tgaccaccct gacctacggc 1680
gtgcagtgct tcagccgcta ccccgaccac atgaagcagc acgacttctt caagtccgcc 1740
atgcccgaag gctacgtcca ggagcgcacc atcttcttca aggacgacgg caactacaag 1800
acccgcgccg aggtgaagtt cgagggcgac accctggtga accgcatcga gctgaagggc 1860
atcgacttca aggaggacgg caacatcctg gggcacaagc tggagtacaa ctacaacagc 1920
cacaacgtct atatcatggc cgacaagcag aagaacggca tcaaggtgaa cttcaagatc 1980
cgccacaaca tcgaggacgg cagcgtgcag ctcgccgacc actaccagca gaacaccccc 2040
atcggcgacg gccccgtgct gctgcccgac aaccactacc tgagcaccca gtccgccctg 2100
agcaaagacc ccaacgagaa gcgcgatcac atggtcctgc tggagttcgt gaccgccgcc 2160
gggatcactc tcggcatgga cgagctgtac aagtaa 2196
<210> 72
<211> 2196
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 72
gatattttga tgacccaaac tccactctcc ctgcctgtca gtcttggaga tcaagcctcc 60
atctcttgca gatctagtca gagcattgta catagtaatg gaaacaccta tttagaatgg 120
tacctgcaga aaccaggcca gtctccaaag cccctgataa agaaagtctc caaccgattt 180
tctggggtcc cagacaggtt cagtggcagt ggatcaggga cagaattcac actcaagatc 240
agcagagtgg aggctgagga tctgggagtt tattactgct ttcaaggttc acatgttcca 300
ttcacgttcg gctcggggac aaagttggaa ataaaaggtg gcggtggctc gggcggtggt 360
gggtcgggtg gcggcggatc tgaggtgaag ctgcagcaat caggggctga cctggcaaca 420
cctggggctt cagtgaagtt gtcctgcaag gcttctggct atacctttag tacctactgg 480
atgcagtggg taaaacagag gcctggacag ggtctggaat ggattgggac tatttatcct 540
ggagatggtg atactaggta cactcagaag ttcaagggca aggccacatt gactgcagat 600
aaatcctcca gtacagccca catgcaactc agcagcttgg catctgagga ctctgcggtc 660
tattattgtg caagaggggg actctattat ggttacgaca ttgcttactg gggccaaggg 720
actctggtca ctgtctctgc aaccacgacg ccagcgccgc gaccaccaac accggcgccc 780
accatcgcgt cgcagcccct gtccctgcgc ccagaggcgt gccggccagc ggcggggggc 840
gcagtgcaca cgagggggct ggacttcgcc tgtgatatct acatctgggc gcccttggcc 900
gggacttgtg gggtccttct cctgtcactg gttatcaccc tttactgcaa acggggcaga 960
aagaaactcc tgtatatatt caaacaacca tttatgagac cagtacaaac tactcaagag 1020
gaagatggct gtagctgccg atttccagaa gaagaagaag gaggatgtga actgagagtg 1080
aagttcagca ggagcgcaga cgcccccgcg taccagcagg gccagaacca gctctataac 1140
gagctcaatc taggacgaag agaggagtac gatgttttgg acaagagacg tggccgggac 1200
cctgagatgg ggggaaagcc gagaaggaag aaccctcagg aaggcctgta caatgaactg 1260
cagaaagata agatggcgga ggcctacagt gagattggga tgaaaggcga gcgccggagg 1320
ggcaaggggc acgatggcct ttaccagggt ctcagtacag ccaccaagga cacctacgac 1380
gcccttcaca tgcaggccct gccccctcgc ggatctggcg ccaccaactt ctctctgctg 1440
aagcaggccg gcgacgtgga ggagaaccca ggcccaatgg tgagcaaggg cgaggagctg 1500
ttcaccgggg tggtgcccat cctggtcgag ctggacggcg acgtaaacgg ccacaagttc 1560
agcgtgtccg gcgagggcga gggcgatgcc acctacggca agctgaccct gaagttcatc 1620
tgcaccaccg gcaagctgcc cgtgccctgg cccaccctcg tgaccaccct gacctacggc 1680
gtgcagtgct tcagccgcta ccccgaccac atgaagcagc acgacttctt caagtccgcc 1740
atgcccgaag gctacgtcca ggagcgcacc atcttcttca aggacgacgg caactacaag 1800
acccgcgccg aggtgaagtt cgagggcgac accctggtga accgcatcga gctgaagggc 1860
atcgacttca aggaggacgg caacatcctg gggcacaagc tggagtacaa ctacaacagc 1920
cacaacgtct atatcatggc cgacaagcag aagaacggca tcaaggtgaa cttcaagatc 1980
cgccacaaca tcgaggacgg cagcgtgcag ctcgccgacc actaccagca gaacaccccc 2040
atcggcgacg gccccgtgct gctgcccgac aaccactacc tgagcaccca gtccgccctg 2100
agcaaagacc ccaacgagaa gcgcgatcac atggtcctgc tggagttcgt gaccgccgcc 2160
gggatcactc tcggcatgga cgagctgtac aagtaa 2196
<210> 73
<211> 2181
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 73
gaggtgaagc tggtggagtc tggaggaggc ttggtccagc cgggggggtc tctgagactc 60
tcctgttcaa tttctggatt caccttcact gattactaca tgaactgggt ccgccagtct 120
ccaggaaagg cacttgagtg gttgggtttt attagaaaca aagttaatgg tgacacaaca 180
gaatatagtg catctgtgaa gggtcggttc accatctcca gagatatttc ccagagcatc 240
ctctatcttc aaatgaacac cctgagaact gaggacagtg ccacttatta ctgtgcgaga 300
gataagggaa tagcgtacta ctttgactat tggggccaag gcaccactct cacagtctcc 360
tcaggtggcg gtggctcggg cggtggtggg tcgggtggcg gcggatctca aattgttctc 420
tcccagtctc cagcaatcct gtttgcatct ccaggggaga aggtcacaat gacttgtagg 480
gccagctcaa gtgtaagtta cattcactgg taccagcaga agccaggatc ctcccccaaa 540
ccctggattc atggcacatc caacctggct tctggagtcc ctgctcgctt cagtggcagt 600
gggtctggga cctcttactc tctcacaatc agcagaatgg aggctgaaga tgccgccaca 660
tattactgcc agcagtggag tagtaattta tccacgttcg gaggggggac caagctggaa 720
ataaaaacca cgacgccagc gccgcgacca ccaacaccgg cgcccaccat cgcgtcgcag 780
cccctgtccc tgcgcccaga ggcgtgccgg ccagcggcgg ggggcgcagt gcacacgagg 840
gggctggact tcgcctgtga tatctacatc tgggcgccct tggccgggac ttgtggggtc 900
cttctcctgt cactggttat caccctttac tgcaaacggg gcagaaagaa actcctgtat 960
atattcaaac aaccatttat gagaccagta caaactactc aagaggaaga tggctgtagc 1020
tgccgatttc cagaagaaga agaaggagga tgtgaactga gagtgaagtt cagcaggagc 1080
gcagacgccc ccgcgtacca gcagggccag aaccagctct ataacgagct caatctagga 1140
cgaagagagg agtacgatgt tttggacaag agacgtggcc gggaccctga gatgggggga 1200
aagccgagaa ggaagaaccc tcaggaaggc ctgtacaatg aactgcagaa agataagatg 1260
gcggaggcct acagtgagat tgggatgaaa ggcgagcgcc ggaggggcaa ggggcacgat 1320
ggcctttacc agggtctcag tacagccacc aaggacacct acgacgccct tcacatgcag 1380
gccctgcccc ctcgcggatc tggcgccacc aacttctctc tgctgaagca ggccggcgac 1440
gtggaggaga acccaggccc aatggtgagc aagggcgagg agctgttcac cggggtggtg 1500
cccatcctgg tcgagctgga cggcgacgta aacggccaca agttcagcgt gtccggcgag 1560
ggcgagggcg atgccaccta cggcaagctg accctgaagt tcatctgcac caccggcaag 1620
ctgcccgtgc cctggcccac cctcgtgacc accctgacct acggcgtgca gtgcttcagc 1680
cgctaccccg accacatgaa gcagcacgac ttcttcaagt ccgccatgcc cgaaggctac 1740
gtccaggagc gcaccatctt cttcaaggac gacggcaact acaagacccg cgccgaggtg 1800
aagttcgagg gcgacaccct ggtgaaccgc atcgagctga agggcatcga cttcaaggag 1860
gacggcaaca tcctggggca caagctggag tacaactaca acagccacaa cgtctatatc 1920
atggccgaca agcagaagaa cggcatcaag gtgaacttca agatccgcca caacatcgag 1980
gacggcagcg tgcagctcgc cgaccactac cagcagaaca cccccatcgg cgacggcccc 2040
gtgctgctgc ccgacaacca ctacctgagc acccagtccg ccctgagcaa agaccccaac 2100
gagaagcgcg atcacatggt cctgctggag ttcgtgaccg ccgccgggat cactctcggc 2160
atggacgagc tgtacaagta a 2181
<210> 74
<211> 2181
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 74
caaattgttc tctcccagtc tccagcaatc ctgtttgcat ctccagggga gaaggtcaca 60
atgacttgta gggccagctc aagtgtaagt tacattcact ggtaccagca gaagccagga 120
tcctccccca aaccctggat tcatggcaca tccaacctgg cttctggagt ccctgctcgc 180
ttcagtggca gtgggtctgg gacctcttac tctctcacaa tcagcagaat ggaggctgaa 240
gatgccgcca catattactg ccagcagtgg agtagtaatt tatccacgtt cggagggggg 300
accaagctgg aaataaaagg tggcggtggc tcgggcggtg gtgggtcggg tggcggcgga 360
tctgaggtga agctggtgga gtctggagga ggcttggtcc agccgggggg gtctctgaga 420
ctctcctgtt caatttctgg attcaccttc actgattact acatgaactg ggtccgccag 480
tctccaggaa aggcacttga gtggttgggt tttattagaa acaaagttaa tggtgacaca 540
acagaatata gtgcatctgt gaagggtcgg ttcaccatct ccagagatat ttcccagagc 600
atcctctatc ttcaaatgaa caccctgaga actgaggaca gtgccactta ttactgtgcg 660
agagataagg gaatagcgta ctactttgac tattggggcc aaggcaccac tctcacagtc 720
tcctcaacca cgacgccagc gccgcgacca ccaacaccgg cgcccaccat cgcgtcgcag 780
cccctgtccc tgcgcccaga ggcgtgccgg ccagcggcgg ggggcgcagt gcacacgagg 840
gggctggact tcgcctgtga tatctacatc tgggcgccct tggccgggac ttgtggggtc 900
cttctcctgt cactggttat caccctttac tgcaaacggg gcagaaagaa actcctgtat 960
atattcaaac aaccatttat gagaccagta caaactactc aagaggaaga tggctgtagc 1020
tgccgatttc cagaagaaga agaaggagga tgtgaactga gagtgaagtt cagcaggagc 1080
gcagacgccc ccgcgtacca gcagggccag aaccagctct ataacgagct caatctagga 1140
cgaagagagg agtacgatgt tttggacaag agacgtggcc gggaccctga gatgggggga 1200
aagccgagaa ggaagaaccc tcaggaaggc ctgtacaatg aactgcagaa agataagatg 1260
gcggaggcct acagtgagat tgggatgaaa ggcgagcgcc ggaggggcaa ggggcacgat 1320
ggcctttacc agggtctcag tacagccacc aaggacacct acgacgccct tcacatgcag 1380
gccctgcccc ctcgcggatc tggcgccacc aacttctctc tgctgaagca ggccggcgac 1440
gtggaggaga acccaggccc aatggtgagc aagggcgagg agctgttcac cggggtggtg 1500
cccatcctgg tcgagctgga cggcgacgta aacggccaca agttcagcgt gtccggcgag 1560
ggcgagggcg atgccaccta cggcaagctg accctgaagt tcatctgcac caccggcaag 1620
ctgcccgtgc cctggcccac cctcgtgacc accctgacct acggcgtgca gtgcttcagc 1680
cgctaccccg accacatgaa gcagcacgac ttcttcaagt ccgccatgcc cgaaggctac 1740
gtccaggagc gcaccatctt cttcaaggac gacggcaact acaagacccg cgccgaggtg 1800
aagttcgagg gcgacaccct ggtgaaccgc atcgagctga agggcatcga cttcaaggag 1860
gacggcaaca tcctggggca caagctggag tacaactaca acagccacaa cgtctatatc 1920
atggccgaca agcagaagaa cggcatcaag gtgaacttca agatccgcca caacatcgag 1980
gacggcagcg tgcagctcgc cgaccactac cagcagaaca cccccatcgg cgacggcccc 2040
gtgctgctgc ccgacaacca ctacctgagc acccagtccg ccctgagcaa agaccccaac 2100
gagaagcgcg atcacatggt cctgctggag ttcgtgaccg ccgccgggat cactctcggc 2160
atggacgagc tgtacaagta a 2181
<210> 75
<211> 2166
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 75
caggtgcagc tgaaggagtc aggacctggc ctggtggcgc cctcacagaa cctgtccatc 60
acatgcactg tctctgggtt ctcattaacc agctatgcta taaactgggt tcgccagcca 120
ccaggaaagg gtctggagtg gcttggaata atatggactg gtggaggcac aaattataat 180
tcagctctca aatccagact gagcatcagc aaagacaact ccaagagtca agttttctta 240
aaaatgaaca gtctgcaaac tgatgacaca gccaggtact actgtgcctc gggggtgtac 300
tactttgact actggggcct aggcaccact ctcacagtct cctcaggtgg cggtggctcg 360
ggcggtggtg ggtcgggtgg cggcggatct gacattgtga tgacccagtc tcacaaattc 420
atgtccacat cagtaggaga cagggtcagc atcacctgca aggccagtca ggatgtgact 480
actgctgtag cctggtatca acaaaaacca gggcaatctc ctaaagtact gattttctgg 540
gcatccaccc ggcacactgg agtccctgat cgcttcacag gcagtggatc tgggacagat 600
tatactctca ccatcagcag tgtgcaggct gaagacctgg cactttatta ctgtcagcaa 660
tattatagaa ctcctcggac gttcggtgga ggcaccaaac tggaaatcaa aaccacgacg 720
ccagcgccgc gaccaccaac accggcgccc accatcgcgt cgcagcccct gtccctgcgc 780
ccagaggcgt gccggccagc ggcggggggc gcagtgcaca cgagggggct ggacttcgcc 840
tgtgatatct acatctgggc gcccttggcc gggacttgtg gggtccttct cctgtcactg 900
gttatcaccc tttactgcaa acggggcaga aagaaactcc tgtatatatt caaacaacca 960
tttatgagac cagtacaaac tactcaagag gaagatggct gtagctgccg atttccagaa 1020
gaagaagaag gaggatgtga actgagagtg aagttcagca ggagcgcaga cgcccccgcg 1080
taccagcagg gccagaacca gctctataac gagctcaatc taggacgaag agaggagtac 1140
gatgttttgg acaagagacg tggccgggac cctgagatgg ggggaaagcc gagaaggaag 1200
aaccctcagg aaggcctgta caatgaactg cagaaagata agatggcgga ggcctacagt 1260
gagattggga tgaaaggcga gcgccggagg ggcaaggggc acgatggcct ttaccagggt 1320
ctcagtacag ccaccaagga cacctacgac gcccttcaca tgcaggccct gccccctcgc 1380
ggatctggcg ccaccaactt ctctctgctg aagcaggccg gcgacgtgga ggagaaccca 1440
ggcccaatgg tgagcaaggg cgaggagctg ttcaccgggg tggtgcccat cctggtcgag 1500
ctggacggcg acgtaaacgg ccacaagttc agcgtgtccg gcgagggcga gggcgatgcc 1560
acctacggca agctgaccct gaagttcatc tgcaccaccg gcaagctgcc cgtgccctgg 1620
cccaccctcg tgaccaccct gacctacggc gtgcagtgct tcagccgcta ccccgaccac 1680
atgaagcagc acgacttctt caagtccgcc atgcccgaag gctacgtcca ggagcgcacc 1740
atcttcttca aggacgacgg caactacaag acccgcgccg aggtgaagtt cgagggcgac 1800
accctggtga accgcatcga gctgaagggc atcgacttca aggaggacgg caacatcctg 1860
gggcacaagc tggagtacaa ctacaacagc cacaacgtct atatcatggc cgacaagcag 1920
aagaacggca tcaaggtgaa cttcaagatc cgccacaaca tcgaggacgg cagcgtgcag 1980
ctcgccgacc actaccagca gaacaccccc atcggcgacg gccccgtgct gctgcccgac 2040
aaccactacc tgagcaccca gtccgccctg agcaaagacc ccaacgagaa gcgcgatcac 2100
atggtcctgc tggagttcgt gaccgccgcc gggatcactc tcggcatgga cgagctgtac 2160
aagtaa 2166
<210> 76
<211> 2166
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 76
gacattgtga tgacccagtc tcacaaattc atgtccacat cagtaggaga cagggtcagc 60
atcacctgca aggccagtca ggatgtgact actgctgtag cctggtatca acaaaaacca 120
gggcaatctc ctaaagtact gattttctgg gcatccaccc ggcacactgg agtccctgat 180
cgcttcacag gcagtggatc tgggacagat tatactctca ccatcagcag tgtgcaggct 240
gaagacctgg cactttatta ctgtcagcaa tattatagaa ctcctcggac gttcggtgga 300
ggcaccaaac tggaaatcaa aggtggcggt ggctcgggcg gtggtgggtc gggtggcggc 360
ggatctcagg tgcagctgaa ggagtcagga cctggcctgg tggcgccctc acagaacctg 420
tccatcacat gcactgtctc tgggttctca ttaaccagct atgctataaa ctgggttcgc 480
cagccaccag gaaagggtct ggagtggctt ggaataatat ggactggtgg aggcacaaat 540
tataattcag ctctcaaatc cagactgagc atcagcaaag acaactccaa gagtcaagtt 600
ttcttaaaaa tgaacagtct gcaaactgat gacacagcca ggtactactg tgcctcgggg 660
gtgtactact ttgactactg gggcctaggc accactctca cagtctcctc aaccacgacg 720
ccagcgccgc gaccaccaac accggcgccc accatcgcgt cgcagcccct gtccctgcgc 780
ccagaggcgt gccggccagc ggcggggggc gcagtgcaca cgagggggct ggacttcgcc 840
tgtgatatct acatctgggc gcccttggcc gggacttgtg gggtccttct cctgtcactg 900
gttatcaccc tttactgcaa acggggcaga aagaaactcc tgtatatatt caaacaacca 960
tttatgagac cagtacaaac tactcaagag gaagatggct gtagctgccg atttccagaa 1020
gaagaagaag gaggatgtga actgagagtg aagttcagca ggagcgcaga cgcccccgcg 1080
taccagcagg gccagaacca gctctataac gagctcaatc taggacgaag agaggagtac 1140
gatgttttgg acaagagacg tggccgggac cctgagatgg ggggaaagcc gagaaggaag 1200
aaccctcagg aaggcctgta caatgaactg cagaaagata agatggcgga ggcctacagt 1260
gagattggga tgaaaggcga gcgccggagg ggcaaggggc acgatggcct ttaccagggt 1320
ctcagtacag ccaccaagga cacctacgac gcccttcaca tgcaggccct gccccctcgc 1380
ggatctggcg ccaccaactt ctctctgctg aagcaggccg gcgacgtgga ggagaaccca 1440
ggcccaatgg tgagcaaggg cgaggagctg ttcaccgggg tggtgcccat cctggtcgag 1500
ctggacggcg acgtaaacgg ccacaagttc agcgtgtccg gcgagggcga gggcgatgcc 1560
acctacggca agctgaccct gaagttcatc tgcaccaccg gcaagctgcc cgtgccctgg 1620
cccaccctcg tgaccaccct gacctacggc gtgcagtgct tcagccgcta ccccgaccac 1680
atgaagcagc acgacttctt caagtccgcc atgcccgaag gctacgtcca ggagcgcacc 1740
atcttcttca aggacgacgg caactacaag acccgcgccg aggtgaagtt cgagggcgac 1800
accctggtga accgcatcga gctgaagggc atcgacttca aggaggacgg caacatcctg 1860
gggcacaagc tggagtacaa ctacaacagc cacaacgtct atatcatggc cgacaagcag 1920
aagaacggca tcaaggtgaa cttcaagatc cgccacaaca tcgaggacgg cagcgtgcag 1980
ctcgccgacc actaccagca gaacaccccc atcggcgacg gccccgtgct gctgcccgac 2040
aaccactacc tgagcaccca gtccgccctg agcaaagacc ccaacgagaa gcgcgatcac 2100
atggtcctgc tggagttcgt gaccgccgcc gggatcactc tcggcatgga cgagctgtac 2160
aagtaa 2166
<210> 77
<211> 2184
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 77
gaggtgaagc tgcaggaatc tggagctgag ctggtgaagc ctggggcttc agtgaagatc 60
tcctgcaagg cttctggcta cacattcaat gactacaaca tggactatct gaagcagagc 120
catggaaaga gccttgagtg gattggagat attaatccta actatgatag cactatctac 180
aaccagaagt tcaagggcaa ggccacattg actgtagaca agtcctccag cacagcctac 240
atggagctcc gcagcctgac atctgaggac tctgcagtct attactgtgc aagacgagac 300
tacgatggta ggaggggggc ctggttttct tactggggcc aagggactct ggtcactgtc 360
tctgcaggtg gcggtggctc gggcggtggt gggtcgggtg gcggcggatc tcaaattgtt 420
ctcacccagt ctccagcact catgtctgca tctccagggg agaaggtcac cgtgacctgc 480
actgccagct caagtgtaag ttacatgtac tggtaccagc agaagccaag atcctccccc 540
aaaccctgga tttatctcac atccaacctg gcttctggag tccctactcg cttcagtggc 600
agtgggtctg ggacctctta ttctctcaca atcagcagca tggaggctga agatgctgcc 660
acttattact gccagcagtg ggatagtaac ccgctcacgt tcggtgctgg gaccaaactg 720
gagctgaaaa ccacgacgcc agcgccgcga ccaccaacac cggcgcccac catcgcgtcg 780
cagcccctgt ccctgcgccc agaggcgtgc cggccagcgg cggggggcgc agtgcacacg 840
agggggctgg acttcgcctg tgatatctac atctgggcgc ccttggccgg gacttgtggg 900
gtccttctcc tgtcactggt tatcaccctt tactgcaaac ggggcagaaa gaaactcctg 960
tatatattca aacaaccatt tatgagacca gtacaaacta ctcaagagga agatggctgt 1020
agctgccgat ttccagaaga agaagaagga ggatgtgaac tgagagtgaa gttcagcagg 1080
agcgcagacg cccccgcgta ccagcagggc cagaaccagc tctataacga gctcaatcta 1140
ggacgaagag aggagtacga tgttttggac aagagacgtg gccgggaccc tgagatgggg 1200
ggaaagccga gaaggaagaa ccctcaggaa ggcctgtaca atgaactgca gaaagataag 1260
atggcggagg cctacagtga gattgggatg aaaggcgagc gccggagggg caaggggcac 1320
gatggccttt accagggtct cagtacagcc accaaggaca cctacgacgc ccttcacatg 1380
caggccctgc cccctcgcgg atctggcgcc accaacttct ctctgctgaa gcaggccggc 1440
gacgtggagg agaacccagg cccaatggtg agcaagggcg aggagctgtt caccggggtg 1500
gtgcccatcc tggtcgagct ggacggcgac gtaaacggcc acaagttcag cgtgtccggc 1560
gagggcgagg gcgatgccac ctacggcaag ctgaccctga agttcatctg caccaccggc 1620
aagctgcccg tgccctggcc caccctcgtg accaccctga cctacggcgt gcagtgcttc 1680
agccgctacc ccgaccacat gaagcagcac gacttcttca agtccgccat gcccgaaggc 1740
tacgtccagg agcgcaccat cttcttcaag gacgacggca actacaagac ccgcgccgag 1800
gtgaagttcg agggcgacac cctggtgaac cgcatcgagc tgaagggcat cgacttcaag 1860
gaggacggca acatcctggg gcacaagctg gagtacaact acaacagcca caacgtctat 1920
atcatggccg acaagcagaa gaacggcatc aaggtgaact tcaagatccg ccacaacatc 1980
gaggacggca gcgtgcagct cgccgaccac taccagcaga acacccccat cggcgacggc 2040
cccgtgctgc tgcccgacaa ccactacctg agcacccagt ccgccctgag caaagacccc 2100
aacgagaagc gcgatcacat ggtcctgctg gagttcgtga ccgccgccgg gatcactctc 2160
ggcatggacg agctgtacaa gtaa 2184
<210> 78
<211> 2184
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 78
caaattgttc tcacccagtc tccagcactc atgtctgcat ctccagggga gaaggtcacc 60
gtgacctgca ctgccagctc aagtgtaagt tacatgtact ggtaccagca gaagccaaga 120
tcctccccca aaccctggat ttatctcaca tccaacctgg cttctggagt ccctactcgc 180
ttcagtggca gtgggtctgg gacctcttat tctctcacaa tcagcagcat ggaggctgaa 240
gatgctgcca cttattactg ccagcagtgg gatagtaacc cgctcacgtt cggtgctggg 300
accaaactgg agctgaaagg tggcggtggc tcgggcggtg gtgggtcggg tggcggcgga 360
tctgaggtga agctgcagga atctggagct gagctggtga agcctggggc ttcagtgaag 420
atctcctgca aggcttctgg ctacacattc aatgactaca acatggacta tctgaagcag 480
agccatggaa agagccttga gtggattgga gatattaatc ctaactatga tagcactatc 540
tacaaccaga agttcaaggg caaggccaca ttgactgtag acaagtcctc cagcacagcc 600
tacatggagc tccgcagcct gacatctgag gactctgcag tctattactg tgcaagacga 660
gactacgatg gtaggagggg ggcctggttt tcttactggg gccaagggac tctggtcact 720
gtctctgcaa ccacgacgcc agcgccgcga ccaccaacac cggcgcccac catcgcgtcg 780
cagcccctgt ccctgcgccc agaggcgtgc cggccagcgg cggggggcgc agtgcacacg 840
agggggctgg acttcgcctg tgatatctac atctgggcgc ccttggccgg gacttgtggg 900
gtccttctcc tgtcactggt tatcaccctt tactgcaaac ggggcagaaa gaaactcctg 960
tatatattca aacaaccatt tatgagacca gtacaaacta ctcaagagga agatggctgt 1020
agctgccgat ttccagaaga agaagaagga ggatgtgaac tgagagtgaa gttcagcagg 1080
agcgcagacg cccccgcgta ccagcagggc cagaaccagc tctataacga gctcaatcta 1140
ggacgaagag aggagtacga tgttttggac aagagacgtg gccgggaccc tgagatgggg 1200
ggaaagccga gaaggaagaa ccctcaggaa ggcctgtaca atgaactgca gaaagataag 1260
atggcggagg cctacagtga gattgggatg aaaggcgagc gccggagggg caaggggcac 1320
gatggccttt accagggtct cagtacagcc accaaggaca cctacgacgc ccttcacatg 1380
caggccctgc cccctcgcgg atctggcgcc accaacttct ctctgctgaa gcaggccggc 1440
gacgtggagg agaacccagg cccaatggtg agcaagggcg aggagctgtt caccggggtg 1500
gtgcccatcc tggtcgagct ggacggcgac gtaaacggcc acaagttcag cgtgtccggc 1560
gagggcgagg gcgatgccac ctacggcaag ctgaccctga agttcatctg caccaccggc 1620
aagctgcccg tgccctggcc caccctcgtg accaccctga cctacggcgt gcagtgcttc 1680
agccgctacc ccgaccacat gaagcagcac gacttcttca agtccgccat gcccgaaggc 1740
tacgtccagg agcgcaccat cttcttcaag gacgacggca actacaagac ccgcgccgag 1800
gtgaagttcg agggcgacac cctggtgaac cgcatcgagc tgaagggcat cgacttcaag 1860
gaggacggca acatcctggg gcacaagctg gagtacaact acaacagcca caacgtctat 1920
atcatggccg acaagcagaa gaacggcatc aaggtgaact tcaagatccg ccacaacatc 1980
gaggacggca gcgtgcagct cgccgaccac taccagcaga acacccccat cggcgacggc 2040
cccgtgctgc tgcccgacaa ccactacctg agcacccagt ccgccctgag caaagacccc 2100
aacgagaagc gcgatcacat ggtcctgctg gagttcgtga ccgccgccgg gatcactctc 2160
ggcatggacg agctgtacaa gtaa 2184
<210> 79
<211> 1386
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 79
ggtgtccagt gtgacgtgaa gttggtggag tctgggggag gcttagtgaa gcctggaggg 60
tccctgaaac tctcctgtgc agcctctgga ttcactttca gtagatacac catgtcttgg 120
gttcgccaga ctccggagaa gaggctggag tgggtcgcaa ccattagtaa tagtggtagt 180
tatacctact atcgagacag tgtgaagggc cgattcacca tctccagaga caatgccaag 240
aacaccctgt acctgcaaat gagcagtctg aagtctgagg acacagccat gtattactgt 300
acaagggggt cgccctgggg ccaagggact ctggtcactg tctctgcagg tggcggtggc 360
tcgggcggtg gtgggtcggg tggcggcgga tctgacatcc agatgactca gtctccagat 420
tcactgtctg catctgtggg agaaactgtc accatcacat gtggagcaag tgagaacatt 480
tacggtgctt taaattggta tcagcggaaa cagggaaaat ctcctcagct cctgatctat 540
ggtgcaacca agttggcaga tggcatgtca tcgaggttca gtggcagtgg atctaataga 600
cagtattctc tcaagatcag tagcctgcat cctgacgatg ttgcaacgta ttactgtcaa 660
aatgtgttaa gtaagccgta cgcgttcgga ggggggacca aactggaaat aaaaaccacg 720
acgccagcgc cgcgaccacc aacaccggcg cccaccatcg cgtcgcagcc cctgtccctg 780
cgcccagagg cgtgccggcc agcggcgggg ggcgcagtgc acacgagggg gctggacttc 840
gcctgtgata tctacatctg ggcgcccttg gccgggactt gtggggtcct tctcctgtca 900
ctggttatca ccctttactg caaacggggc agaaagaaac tcctgtatat attcaaacaa 960
ccatttatga gaccagtaca aactactcaa gaggaagatg gctgtagctg ccgatttcca 1020
gaagaagaag aaggaggatg tgaactgaga gtgaagttca gcaggagcgc agacgccccc 1080
gcgtaccagc agggccagaa ccagctctat aacgagctca atctaggacg aagagaggag 1140
tacgatgttt tggacaagag acgtggccgg gaccctgaga tggggggaaa gccgagaagg 1200
aagaaccctc aggaaggcct gtacaatgaa ctgcagaaag ataagatggc ggaggcctac 1260
agtgagattg ggatgaaagg cgagcgccgg aggggcaagg ggcacgatgg cctttaccag 1320
ggtctcagta cagccaccaa ggacacctac gacgcccttc acatgcaggc cctgccccct 1380
cgctaa 1386
<210> 80
<211> 1386
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 80
gacatccaga tgactcagtc tccagattca ctgtctgcat ctgtgggaga aactgtcacc 60
atcacatgtg gagcaagtga gaacatttac ggtgctttaa attggtatca gcggaaacag 120
ggaaaatctc ctcagctcct gatctatggt gcaaccaagt tggcagatgg catgtcatcg 180
aggttcagtg gcagtggatc taatagacag tattctctca agatcagtag cctgcatcct 240
gacgatgttg caacgtatta ctgtcaaaat gtgttaagta agccgtacgc gttcggaggg 300
gggaccaaac tggaaataaa aggtggcggt ggctcgggcg gtggtgggtc gggtggcggc 360
ggatctggtg tccagtgtga cgtgaagttg gtggagtctg ggggaggctt agtgaagcct 420
ggagggtccc tgaaactctc ctgtgcagcc tctggattca ctttcagtag atacaccatg 480
tcttgggttc gccagactcc ggagaagagg ctggagtggg tcgcaaccat tagtaatagt 540
ggtagttata cctactatcg agacagtgtg aagggccgat tcaccatctc cagagacaat 600
gccaagaaca ccctgtacct gcaaatgagc agtctgaagt ctgaggacac agccatgtat 660
tactgtacaa gggggtcgcc ctggggccaa gggactctgg tcactgtctc tgcaaccacg 720
acgccagcgc cgcgaccacc aacaccggcg cccaccatcg cgtcgcagcc cctgtccctg 780
cgcccagagg cgtgccggcc agcggcgggg ggcgcagtgc acacgagggg gctggacttc 840
gcctgtgata tctacatctg ggcgcccttg gccgggactt gtggggtcct tctcctgtca 900
ctggttatca ccctttactg caaacggggc agaaagaaac tcctgtatat attcaaacaa 960
ccatttatga gaccagtaca aactactcaa gaggaagatg gctgtagctg ccgatttcca 1020
gaagaagaag aaggaggatg tgaactgaga gtgaagttca gcaggagcgc agacgccccc 1080
gcgtaccagc agggccagaa ccagctctat aacgagctca atctaggacg aagagaggag 1140
tacgatgttt tggacaagag acgtggccgg gaccctgaga tggggggaaa gccgagaagg 1200
aagaaccctc aggaaggcct gtacaatgaa ctgcagaaag ataagatggc ggaggcctac 1260
agtgagattg ggatgaaagg cgagcgccgg aggggcaagg ggcacgatgg cctttaccag 1320
ggtctcagta cagccaccaa ggacacctac gacgcccttc acatgcaggc cctgccccct 1380
cgctaa 1386
<210> 81
<211> 1413
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 81
gaggtgaagc tgcagcaatc aggggctgac ctggcaacac ctggggcttc agtgaagttg 60
tcctgcaagg cttctggcta tacctttagt acctactgga tgcagtgggt aaaacagagg 120
cctggacagg gtctggaatg gattgggact atttatcctg gagatggtga tactaggtac 180
actcagaagt tcaagggcaa ggccacattg actgcagata aatcctccag tacagcccac 240
atgcaactca gcagcttggc atctgaggac tctgcggtct attattgtgc aagaggggga 300
ctctattatg gttacgacat tgcttactgg ggccaaggga ctctggtcac tgtctctgca 360
ggtggcggtg gctcgggcgg tggtgggtcg ggtggcggcg gatctgatat tttgatgacc 420
caaactccac tctccctgcc tgtcagtctt ggagatcaag cctccatctc ttgcagatct 480
agtcagagca ttgtacatag taatggaaac acctatttag aatggtacct gcagaaacca 540
ggccagtctc caaagcccct gataaagaaa gtctccaacc gattttctgg ggtcccagac 600
aggttcagtg gcagtggatc agggacagaa ttcacactca agatcagcag agtggaggct 660
gaggatctgg gagtttatta ctgctttcaa ggttcacatg ttccattcac gttcggctcg 720
gggacaaagt tggaaataaa aaccacgacg ccagcgccgc gaccaccaac accggcgccc 780
accatcgcgt cgcagcccct gtccctgcgc ccagaggcgt gccggccagc ggcggggggc 840
gcagtgcaca cgagggggct ggacttcgcc tgtgatatct acatctgggc gcccttggcc 900
gggacttgtg gggtccttct cctgtcactg gttatcaccc tttactgcaa acggggcaga 960
aagaaactcc tgtatatatt caaacaacca tttatgagac cagtacaaac tactcaagag 1020
gaagatggct gtagctgccg atttccagaa gaagaagaag gaggatgtga actgagagtg 1080
aagttcagca ggagcgcaga cgcccccgcg taccagcagg gccagaacca gctctataac 1140
gagctcaatc taggacgaag agaggagtac gatgttttgg acaagagacg tggccgggac 1200
cctgagatgg ggggaaagcc gagaaggaag aaccctcagg aaggcctgta caatgaactg 1260
cagaaagata agatggcgga ggcctacagt gagattggga tgaaaggcga gcgccggagg 1320
ggcaaggggc acgatggcct ttaccagggt ctcagtacag ccaccaagga cacctacgac 1380
gcccttcaca tgcaggccct gccccctcgc taa 1413
<210> 82
<211> 1413
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 82
gatattttga tgacccaaac tccactctcc ctgcctgtca gtcttggaga tcaagcctcc 60
atctcttgca gatctagtca gagcattgta catagtaatg gaaacaccta tttagaatgg 120
tacctgcaga aaccaggcca gtctccaaag cccctgataa agaaagtctc caaccgattt 180
tctggggtcc cagacaggtt cagtggcagt ggatcaggga cagaattcac actcaagatc 240
agcagagtgg aggctgagga tctgggagtt tattactgct ttcaaggttc acatgttcca 300
ttcacgttcg gctcggggac aaagttggaa ataaaaggtg gcggtggctc gggcggtggt 360
gggtcgggtg gcggcggatc tgaggtgaag ctgcagcaat caggggctga cctggcaaca 420
cctggggctt cagtgaagtt gtcctgcaag gcttctggct atacctttag tacctactgg 480
atgcagtggg taaaacagag gcctggacag ggtctggaat ggattgggac tatttatcct 540
ggagatggtg atactaggta cactcagaag ttcaagggca aggccacatt gactgcagat 600
aaatcctcca gtacagccca catgcaactc agcagcttgg catctgagga ctctgcggtc 660
tattattgtg caagaggggg actctattat ggttacgaca ttgcttactg gggccaaggg 720
actctggtca ctgtctctgc aaccacgacg ccagcgccgc gaccaccaac accggcgccc 780
accatcgcgt cgcagcccct gtccctgcgc ccagaggcgt gccggccagc ggcggggggc 840
gcagtgcaca cgagggggct ggacttcgcc tgtgatatct acatctgggc gcccttggcc 900
gggacttgtg gggtccttct cctgtcactg gttatcaccc tttactgcaa acggggcaga 960
aagaaactcc tgtatatatt caaacaacca tttatgagac cagtacaaac tactcaagag 1020
gaagatggct gtagctgccg atttccagaa gaagaagaag gaggatgtga actgagagtg 1080
aagttcagca ggagcgcaga cgcccccgcg taccagcagg gccagaacca gctctataac 1140
gagctcaatc taggacgaag agaggagtac gatgttttgg acaagagacg tggccgggac 1200
cctgagatgg ggggaaagcc gagaaggaag aaccctcagg aaggcctgta caatgaactg 1260
cagaaagata agatggcgga ggcctacagt gagattggga tgaaaggcga gcgccggagg 1320
ggcaaggggc acgatggcct ttaccagggt ctcagtacag ccaccaagga cacctacgac 1380
gcccttcaca tgcaggccct gccccctcgc taa 1413
<210> 83
<211> 1398
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 83
gaggtgaagc tggtggagtc tggaggaggc ttggtccagc cgggggggtc tctgagactc 60
tcctgttcaa tttctggatt caccttcact gattactaca tgaactgggt ccgccagtct 120
ccaggaaagg cacttgagtg gttgggtttt attagaaaca aagttaatgg tgacacaaca 180
gaatatagtg catctgtgaa gggtcggttc accatctcca gagatatttc ccagagcatc 240
ctctatcttc aaatgaacac cctgagaact gaggacagtg ccacttatta ctgtgcgaga 300
gataagggaa tagcgtacta ctttgactat tggggccaag gcaccactct cacagtctcc 360
tcaggtggcg gtggctcggg cggtggtggg tcgggtggcg gcggatctca aattgttctc 420
tcccagtctc cagcaatcct gtttgcatct ccaggggaga aggtcacaat gacttgtagg 480
gccagctcaa gtgtaagtta cattcactgg taccagcaga agccaggatc ctcccccaaa 540
ccctggattc atggcacatc caacctggct tctggagtcc ctgctcgctt cagtggcagt 600
gggtctggga cctcttactc tctcacaatc agcagaatgg aggctgaaga tgccgccaca 660
tattactgcc agcagtggag tagtaattta tccacgttcg gaggggggac caagctggaa 720
ataaaaacca cgacgccagc gccgcgacca ccaacaccgg cgcccaccat cgcgtcgcag 780
cccctgtccc tgcgcccaga ggcgtgccgg ccagcggcgg ggggcgcagt gcacacgagg 840
gggctggact tcgcctgtga tatctacatc tgggcgccct tggccgggac ttgtggggtc 900
cttctcctgt cactggttat caccctttac tgcaaacggg gcagaaagaa actcctgtat 960
atattcaaac aaccatttat gagaccagta caaactactc aagaggaaga tggctgtagc 1020
tgccgatttc cagaagaaga agaaggagga tgtgaactga gagtgaagtt cagcaggagc 1080
gcagacgccc ccgcgtacca gcagggccag aaccagctct ataacgagct caatctagga 1140
cgaagagagg agtacgatgt tttggacaag agacgtggcc gggaccctga gatgggggga 1200
aagccgagaa ggaagaaccc tcaggaaggc ctgtacaatg aactgcagaa agataagatg 1260
gcggaggcct acagtgagat tgggatgaaa ggcgagcgcc ggaggggcaa ggggcacgat 1320
ggcctttacc agggtctcag tacagccacc aaggacacct acgacgccct tcacatgcag 1380
gccctgcccc ctcgctaa 1398
<210> 84
<211> 1398
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 84
caaattgttc tctcccagtc tccagcaatc ctgtttgcat ctccagggga gaaggtcaca 60
atgacttgta gggccagctc aagtgtaagt tacattcact ggtaccagca gaagccagga 120
tcctccccca aaccctggat tcatggcaca tccaacctgg cttctggagt ccctgctcgc 180
ttcagtggca gtgggtctgg gacctcttac tctctcacaa tcagcagaat ggaggctgaa 240
gatgccgcca catattactg ccagcagtgg agtagtaatt tatccacgtt cggagggggg 300
accaagctgg aaataaaagg tggcggtggc tcgggcggtg gtgggtcggg tggcggcgga 360
tctgaggtga agctggtgga gtctggagga ggcttggtcc agccgggggg gtctctgaga 420
ctctcctgtt caatttctgg attcaccttc actgattact acatgaactg ggtccgccag 480
tctccaggaa aggcacttga gtggttgggt tttattagaa acaaagttaa tggtgacaca 540
acagaatata gtgcatctgt gaagggtcgg ttcaccatct ccagagatat ttcccagagc 600
atcctctatc ttcaaatgaa caccctgaga actgaggaca gtgccactta ttactgtgcg 660
agagataagg gaatagcgta ctactttgac tattggggcc aaggcaccac tctcacagtc 720
tcctcaacca cgacgccagc gccgcgacca ccaacaccgg cgcccaccat cgcgtcgcag 780
cccctgtccc tgcgcccaga ggcgtgccgg ccagcggcgg ggggcgcagt gcacacgagg 840
gggctggact tcgcctgtga tatctacatc tgggcgccct tggccgggac ttgtggggtc 900
cttctcctgt cactggttat caccctttac tgcaaacggg gcagaaagaa actcctgtat 960
atattcaaac aaccatttat gagaccagta caaactactc aagaggaaga tggctgtagc 1020
tgccgatttc cagaagaaga agaaggagga tgtgaactga gagtgaagtt cagcaggagc 1080
gcagacgccc ccgcgtacca gcagggccag aaccagctct ataacgagct caatctagga 1140
cgaagagagg agtacgatgt tttggacaag agacgtggcc gggaccctga gatgggggga 1200
aagccgagaa ggaagaaccc tcaggaaggc ctgtacaatg aactgcagaa agataagatg 1260
gcggaggcct acagtgagat tgggatgaaa ggcgagcgcc ggaggggcaa ggggcacgat 1320
ggcctttacc agggtctcag tacagccacc aaggacacct acgacgccct tcacatgcag 1380
gccctgcccc ctcgctaa 1398
<210> 85
<211> 1383
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 85
caggtgcagc tgaaggagtc aggacctggc ctggtggcgc cctcacagaa cctgtccatc 60
acatgcactg tctctgggtt ctcattaacc agctatgcta taaactgggt tcgccagcca 120
ccaggaaagg gtctggagtg gcttggaata atatggactg gtggaggcac aaattataat 180
tcagctctca aatccagact gagcatcagc aaagacaact ccaagagtca agttttctta 240
aaaatgaaca gtctgcaaac tgatgacaca gccaggtact actgtgcctc gggggtgtac 300
tactttgact actggggcct aggcaccact ctcacagtct cctcaggtgg cggtggctcg 360
ggcggtggtg ggtcgggtgg cggcggatct gacattgtga tgacccagtc tcacaaattc 420
atgtccacat cagtaggaga cagggtcagc atcacctgca aggccagtca ggatgtgact 480
actgctgtag cctggtatca acaaaaacca gggcaatctc ctaaagtact gattttctgg 540
gcatccaccc ggcacactgg agtccctgat cgcttcacag gcagtggatc tgggacagat 600
tatactctca ccatcagcag tgtgcaggct gaagacctgg cactttatta ctgtcagcaa 660
tattatagaa ctcctcggac gttcggtgga ggcaccaaac tggaaatcaa aaccacgacg 720
ccagcgccgc gaccaccaac accggcgccc accatcgcgt cgcagcccct gtccctgcgc 780
ccagaggcgt gccggccagc ggcggggggc gcagtgcaca cgagggggct ggacttcgcc 840
tgtgatatct acatctgggc gcccttggcc gggacttgtg gggtccttct cctgtcactg 900
gttatcaccc tttactgcaa acggggcaga aagaaactcc tgtatatatt caaacaacca 960
tttatgagac cagtacaaac tactcaagag gaagatggct gtagctgccg atttccagaa 1020
gaagaagaag gaggatgtga actgagagtg aagttcagca ggagcgcaga cgcccccgcg 1080
taccagcagg gccagaacca gctctataac gagctcaatc taggacgaag agaggagtac 1140
gatgttttgg acaagagacg tggccgggac cctgagatgg ggggaaagcc gagaaggaag 1200
aaccctcagg aaggcctgta caatgaactg cagaaagata agatggcgga ggcctacagt 1260
gagattggga tgaaaggcga gcgccggagg ggcaaggggc acgatggcct ttaccagggt 1320
ctcagtacag ccaccaagga cacctacgac gcccttcaca tgcaggccct gccccctcgc 1380
taa 1383
<210> 86
<211> 1383
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 86
gacattgtga tgacccagtc tcacaaattc atgtccacat cagtaggaga cagggtcagc 60
atcacctgca aggccagtca ggatgtgact actgctgtag cctggtatca acaaaaacca 120
gggcaatctc ctaaagtact gattttctgg gcatccaccc ggcacactgg agtccctgat 180
cgcttcacag gcagtggatc tgggacagat tatactctca ccatcagcag tgtgcaggct 240
gaagacctgg cactttatta ctgtcagcaa tattatagaa ctcctcggac gttcggtgga 300
ggcaccaaac tggaaatcaa aggtggcggt ggctcgggcg gtggtgggtc gggtggcggc 360
ggatctcagg tgcagctgaa ggagtcagga cctggcctgg tggcgccctc acagaacctg 420
tccatcacat gcactgtctc tgggttctca ttaaccagct atgctataaa ctgggttcgc 480
cagccaccag gaaagggtct ggagtggctt ggaataatat ggactggtgg aggcacaaat 540
tataattcag ctctcaaatc cagactgagc atcagcaaag acaactccaa gagtcaagtt 600
ttcttaaaaa tgaacagtct gcaaactgat gacacagcca ggtactactg tgcctcgggg 660
gtgtactact ttgactactg gggcctaggc accactctca cagtctcctc aaccacgacg 720
ccagcgccgc gaccaccaac accggcgccc accatcgcgt cgcagcccct gtccctgcgc 780
ccagaggcgt gccggccagc ggcggggggc gcagtgcaca cgagggggct ggacttcgcc 840
tgtgatatct acatctgggc gcccttggcc gggacttgtg gggtccttct cctgtcactg 900
gttatcaccc tttactgcaa acggggcaga aagaaactcc tgtatatatt caaacaacca 960
tttatgagac cagtacaaac tactcaagag gaagatggct gtagctgccg atttccagaa 1020
gaagaagaag gaggatgtga actgagagtg aagttcagca ggagcgcaga cgcccccgcg 1080
taccagcagg gccagaacca gctctataac gagctcaatc taggacgaag agaggagtac 1140
gatgttttgg acaagagacg tggccgggac cctgagatgg ggggaaagcc gagaaggaag 1200
aaccctcagg aaggcctgta caatgaactg cagaaagata agatggcgga ggcctacagt 1260
gagattggga tgaaaggcga gcgccggagg ggcaaggggc acgatggcct ttaccagggt 1320
ctcagtacag ccaccaagga cacctacgac gcccttcaca tgcaggccct gccccctcgc 1380
taa 1383
<210> 87
<211> 1401
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 87
gaggtgaagc tgcaggaatc tggagctgag ctggtgaagc ctggggcttc agtgaagatc 60
tcctgcaagg cttctggcta cacattcaat gactacaaca tggactatct gaagcagagc 120
catggaaaga gccttgagtg gattggagat attaatccta actatgatag cactatctac 180
aaccagaagt tcaagggcaa ggccacattg actgtagaca agtcctccag cacagcctac 240
atggagctcc gcagcctgac atctgaggac tctgcagtct attactgtgc aagacgagac 300
tacgatggta ggaggggggc ctggttttct tactggggcc aagggactct ggtcactgtc 360
tctgcaggtg gcggtggctc gggcggtggt gggtcgggtg gcggcggatc tcaaattgtt 420
ctcacccagt ctccagcact catgtctgca tctccagggg agaaggtcac cgtgacctgc 480
actgccagct caagtgtaag ttacatgtac tggtaccagc agaagccaag atcctccccc 540
aaaccctgga tttatctcac atccaacctg gcttctggag tccctactcg cttcagtggc 600
agtgggtctg ggacctctta ttctctcaca atcagcagca tggaggctga agatgctgcc 660
acttattact gccagcagtg ggatagtaac ccgctcacgt tcggtgctgg gaccaaactg 720
gagctgaaaa ccacgacgcc agcgccgcga ccaccaacac cggcgcccac catcgcgtcg 780
cagcccctgt ccctgcgccc agaggcgtgc cggccagcgg cggggggcgc agtgcacacg 840
agggggctgg acttcgcctg tgatatctac atctgggcgc ccttggccgg gacttgtggg 900
gtccttctcc tgtcactggt tatcaccctt tactgcaaac ggggcagaaa gaaactcctg 960
tatatattca aacaaccatt tatgagacca gtacaaacta ctcaagagga agatggctgt 1020
agctgccgat ttccagaaga agaagaagga ggatgtgaac tgagagtgaa gttcagcagg 1080
agcgcagacg cccccgcgta ccagcagggc cagaaccagc tctataacga gctcaatcta 1140
ggacgaagag aggagtacga tgttttggac aagagacgtg gccgggaccc tgagatgggg 1200
ggaaagccga gaaggaagaa ccctcaggaa ggcctgtaca atgaactgca gaaagataag 1260
atggcggagg cctacagtga gattgggatg aaaggcgagc gccggagggg caaggggcac 1320
gatggccttt accagggtct cagtacagcc accaaggaca cctacgacgc ccttcacatg 1380
caggccctgc cccctcgcta a 1401
<210> 88
<211> 1401
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 88
caaattgttc tcacccagtc tccagcactc atgtctgcat ctccagggga gaaggtcacc 60
gtgacctgca ctgccagctc aagtgtaagt tacatgtact ggtaccagca gaagccaaga 120
tcctccccca aaccctggat ttatctcaca tccaacctgg cttctggagt ccctactcgc 180
ttcagtggca gtgggtctgg gacctcttat tctctcacaa tcagcagcat ggaggctgaa 240
gatgctgcca cttattactg ccagcagtgg gatagtaacc cgctcacgtt cggtgctggg 300
accaaactgg agctgaaagg tggcggtggc tcgggcggtg gtgggtcggg tggcggcgga 360
tctgaggtga agctgcagga atctggagct gagctggtga agcctggggc ttcagtgaag 420
atctcctgca aggcttctgg ctacacattc aatgactaca acatggacta tctgaagcag 480
agccatggaa agagccttga gtggattgga gatattaatc ctaactatga tagcactatc 540
tacaaccaga agttcaaggg caaggccaca ttgactgtag acaagtcctc cagcacagcc 600
tacatggagc tccgcagcct gacatctgag gactctgcag tctattactg tgcaagacga 660
gactacgatg gtaggagggg ggcctggttt tcttactggg gccaagggac tctggtcact 720
gtctctgcaa ccacgacgcc agcgccgcga ccaccaacac cggcgcccac catcgcgtcg 780
cagcccctgt ccctgcgccc agaggcgtgc cggccagcgg cggggggcgc agtgcacacg 840
agggggctgg acttcgcctg tgatatctac atctgggcgc ccttggccgg gacttgtggg 900
gtccttctcc tgtcactggt tatcaccctt tactgcaaac ggggcagaaa gaaactcctg 960
tatatattca aacaaccatt tatgagacca gtacaaacta ctcaagagga agatggctgt 1020
agctgccgat ttccagaaga agaagaagga ggatgtgaac tgagagtgaa gttcagcagg 1080
agcgcagacg cccccgcgta ccagcagggc cagaaccagc tctataacga gctcaatcta 1140
ggacgaagag aggagtacga tgttttggac aagagacgtg gccgggaccc tgagatgggg 1200
ggaaagccga gaaggaagaa ccctcaggaa ggcctgtaca atgaactgca gaaagataag 1260
atggcggagg cctacagtga gattgggatg aaaggcgagc gccggagggg caaggggcac 1320
gatggccttt accagggtct cagtacagcc accaaggaca cctacgacgc ccttcacatg 1380
caggccctgc cccctcgcta a 1401
<210> 89
<211> 2160
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 89
ggtgtccagt gtgacgtgaa gttggtggag tctgggggag gcttagtgaa gcctggaggg 60
tccctgaaac tctcctgtgc agcctctgga ttcactttca gtagatacac catgtcttgg 120
gttcgccaga ctccggagaa gaggctggag tgggtcgcaa ccattagtaa tagtggtagt 180
tatacctact atcgagacag tgtgaagggc cgattcacca tctccagaga caatgccaag 240
aacaccctgt acctgcaaat gagcagtctg aagtctgagg acacagccat gtattactgt 300
acaagggggt cgccctgggg ccaagggact ctggtcactg tctctgcagg tggcggtggc 360
tcgggcggtg gtgggtcggg tggcggcgga tctgacatcc agatgactca gtctccagat 420
tcactgtctg catctgtggg agaaactgtc accatcacat gtggagcaag tgagaacatt 480
tacggtgctt taaattggta tcagcggaaa cagggaaaat ctcctcagct cctgatctat 540
ggtgcaacca agttggcaga tggcatgtca tcgaggttca gtggcagtgg atctaataga 600
cagtattctc tcaagatcag tagcctgcat cctgacgatg ttgcaacgta ttactgtcaa 660
aatgtgttaa gtaagccgta cgcgttcgga ggggggacca aactggaaat aaaaattgaa 720
gttatgtatc ctcctcctta cctagacaat gagaagagca atggaaccat tatccatgtg 780
aaagggaaac acctttgtcc aagtccccta tttcccggac cttctaagcc cttttgggtg 840
ctggtggtgg ttgggggagt cctggcttgc tatagcttgc tagtaacagt ggcctttatt 900
attttctggg tgaaacgggg cagaaagaaa ctcctgtata tattcaaaca accatttatg 960
agaccagtac aaactactca agaggaagat ggctgtagct gccgatttcc agaagaagaa 1020
gaaggaggat gtgaactgag agtgaagttc agcaggagcg cagacgcccc cgcgtaccag 1080
cagggccaga accagctcta taacgagctc aatctaggac gaagagagga gtacgatgtt 1140
ttggacaaga gacgtggccg ggaccctgag atggggggaa agccgagaag gaagaaccct 1200
caggaaggcc tgtacaatga actgcagaaa gataagatgg cggaggccta cagtgagatt 1260
gggatgaaag gcgagcgccg gaggggcaag gggcacgatg gcctttacca gggtctcagt 1320
acagccacca aggacaccta cgacgccctt cacatgcagg ccctgccccc tcgcggatct 1380
ggcgccacca acttctctct gctgaagcag gccggcgacg tggaggagaa cccaggccca 1440
atggtgagca agggcgagga gctgttcacc ggggtggtgc ccatcctggt cgagctggac 1500
ggcgacgtaa acggccacaa gttcagcgtg tccggcgagg gcgagggcga tgccacctac 1560
ggcaagctga ccctgaagtt catctgcacc accggcaagc tgcccgtgcc ctggcccacc 1620
ctcgtgacca ccctgaccta cggcgtgcag tgcttcagcc gctaccccga ccacatgaag 1680
cagcacgact tcttcaagtc cgccatgccc gaaggctacg tccaggagcg caccatcttc 1740
ttcaaggacg acggcaacta caagacccgc gccgaggtga agttcgaggg cgacaccctg 1800
gtgaaccgca tcgagctgaa gggcatcgac ttcaaggagg acggcaacat cctggggcac 1860
aagctggagt acaactacaa cagccacaac gtctatatca tggccgacaa gcagaagaac 1920
ggcatcaagg tgaacttcaa gatccgccac aacatcgagg acggcagcgt gcagctcgcc 1980
gaccactacc agcagaacac ccccatcggc gacggccccg tgctgctgcc cgacaaccac 2040
tacctgagca cccagtccgc cctgagcaaa gaccccaacg agaagcgcga tcacatggtc 2100
ctgctggagt tcgtgaccgc cgccgggatc actctcggca tggacgagct gtacaagtaa 2160
<210> 90
<211> 2160
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 90
gacatccaga tgactcagtc tccagattca ctgtctgcat ctgtgggaga aactgtcacc 60
atcacatgtg gagcaagtga gaacatttac ggtgctttaa attggtatca gcggaaacag 120
ggaaaatctc ctcagctcct gatctatggt gcaaccaagt tggcagatgg catgtcatcg 180
aggttcagtg gcagtggatc taatagacag tattctctca agatcagtag cctgcatcct 240
gacgatgttg caacgtatta ctgtcaaaat gtgttaagta agccgtacgc gttcggaggg 300
gggaccaaac tggaaataaa aggtggcggt ggctcgggcg gtggtgggtc gggtggcggc 360
ggatctggtg tccagtgtga cgtgaagttg gtggagtctg ggggaggctt agtgaagcct 420
ggagggtccc tgaaactctc ctgtgcagcc tctggattca ctttcagtag atacaccatg 480
tcttgggttc gccagactcc ggagaagagg ctggagtggg tcgcaaccat tagtaatagt 540
ggtagttata cctactatcg agacagtgtg aagggccgat tcaccatctc cagagacaat 600
gccaagaaca ccctgtacct gcaaatgagc agtctgaagt ctgaggacac agccatgtat 660
tactgtacaa gggggtcgcc ctggggccaa gggactctgg tcactgtctc tgcaattgaa 720
gttatgtatc ctcctcctta cctagacaat gagaagagca atggaaccat tatccatgtg 780
aaagggaaac acctttgtcc aagtccccta tttcccggac cttctaagcc cttttgggtg 840
ctggtggtgg ttgggggagt cctggcttgc tatagcttgc tagtaacagt ggcctttatt 900
attttctggg tgaaacgggg cagaaagaaa ctcctgtata tattcaaaca accatttatg 960
agaccagtac aaactactca agaggaagat ggctgtagct gccgatttcc agaagaagaa 1020
gaaggaggat gtgaactgag agtgaagttc agcaggagcg cagacgcccc cgcgtaccag 1080
cagggccaga accagctcta taacgagctc aatctaggac gaagagagga gtacgatgtt 1140
ttggacaaga gacgtggccg ggaccctgag atggggggaa agccgagaag gaagaaccct 1200
caggaaggcc tgtacaatga actgcagaaa gataagatgg cggaggccta cagtgagatt 1260
gggatgaaag gcgagcgccg gaggggcaag gggcacgatg gcctttacca gggtctcagt 1320
acagccacca aggacaccta cgacgccctt cacatgcagg ccctgccccc tcgcggatct 1380
ggcgccacca acttctctct gctgaagcag gccggcgacg tggaggagaa cccaggccca 1440
atggtgagca agggcgagga gctgttcacc ggggtggtgc ccatcctggt cgagctggac 1500
ggcgacgtaa acggccacaa gttcagcgtg tccggcgagg gcgagggcga tgccacctac 1560
ggcaagctga ccctgaagtt catctgcacc accggcaagc tgcccgtgcc ctggcccacc 1620
ctcgtgacca ccctgaccta cggcgtgcag tgcttcagcc gctaccccga ccacatgaag 1680
cagcacgact tcttcaagtc cgccatgccc gaaggctacg tccaggagcg caccatcttc 1740
ttcaaggacg acggcaacta caagacccgc gccgaggtga agttcgaggg cgacaccctg 1800
gtgaaccgca tcgagctgaa gggcatcgac ttcaaggagg acggcaacat cctggggcac 1860
aagctggagt acaactacaa cagccacaac gtctatatca tggccgacaa gcagaagaac 1920
ggcatcaagg tgaacttcaa gatccgccac aacatcgagg acggcagcgt gcagctcgcc 1980
gaccactacc agcagaacac ccccatcggc gacggccccg tgctgctgcc cgacaaccac 2040
tacctgagca cccagtccgc cctgagcaaa gaccccaacg agaagcgcga tcacatggtc 2100
ctgctggagt tcgtgaccgc cgccgggatc actctcggca tggacgagct gtacaagtaa 2160
<210> 91
<211> 2187
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 91
gaggtgaagc tgcagcaatc aggggctgac ctggcaacac ctggggcttc agtgaagttg 60
tcctgcaagg cttctggcta tacctttagt acctactgga tgcagtgggt aaaacagagg 120
cctggacagg gtctggaatg gattgggact atttatcctg gagatggtga tactaggtac 180
actcagaagt tcaagggcaa ggccacattg actgcagata aatcctccag tacagcccac 240
atgcaactca gcagcttggc atctgaggac tctgcggtct attattgtgc aagaggggga 300
ctctattatg gttacgacat tgcttactgg ggccaaggga ctctggtcac tgtctctgca 360
ggtggcggtg gctcgggcgg tggtgggtcg ggtggcggcg gatctgatat tttgatgacc 420
caaactccac tctccctgcc tgtcagtctt ggagatcaag cctccatctc ttgcagatct 480
agtcagagca ttgtacatag taatggaaac acctatttag aatggtacct gcagaaacca 540
ggccagtctc caaagcccct gataaagaaa gtctccaacc gattttctgg ggtcccagac 600
aggttcagtg gcagtggatc agggacagaa ttcacactca agatcagcag agtggaggct 660
gaggatctgg gagtttatta ctgctttcaa ggttcacatg ttccattcac gttcggctcg 720
gggacaaagt tggaaataaa aattgaagtt atgtatcctc ctccttacct agacaatgag 780
aagagcaatg gaaccattat ccatgtgaaa gggaaacacc tttgtccaag tcccctattt 840
cccggacctt ctaagccctt ttgggtgctg gtggtggttg ggggagtcct ggcttgctat 900
agcttgctag taacagtggc ctttattatt ttctgggtga aacggggcag aaagaaactc 960
ctgtatatat tcaaacaacc atttatgaga ccagtacaaa ctactcaaga ggaagatggc 1020
tgtagctgcc gatttccaga agaagaagaa ggaggatgtg aactgagagt gaagttcagc 1080
aggagcgcag acgcccccgc gtaccagcag ggccagaacc agctctataa cgagctcaat 1140
ctaggacgaa gagaggagta cgatgttttg gacaagagac gtggccggga ccctgagatg 1200
gggggaaagc cgagaaggaa gaaccctcag gaaggcctgt acaatgaact gcagaaagat 1260
aagatggcgg aggcctacag tgagattggg atgaaaggcg agcgccggag gggcaagggg 1320
cacgatggcc tttaccaggg tctcagtaca gccaccaagg acacctacga cgcccttcac 1380
atgcaggccc tgccccctcg cggatctggc gccaccaact tctctctgct gaagcaggcc 1440
ggcgacgtgg aggagaaccc aggcccaatg gtgagcaagg gcgaggagct gttcaccggg 1500
gtggtgccca tcctggtcga gctggacggc gacgtaaacg gccacaagtt cagcgtgtcc 1560
ggcgagggcg agggcgatgc cacctacggc aagctgaccc tgaagttcat ctgcaccacc 1620
ggcaagctgc ccgtgccctg gcccaccctc gtgaccaccc tgacctacgg cgtgcagtgc 1680
ttcagccgct accccgacca catgaagcag cacgacttct tcaagtccgc catgcccgaa 1740
ggctacgtcc aggagcgcac catcttcttc aaggacgacg gcaactacaa gacccgcgcc 1800
gaggtgaagt tcgagggcga caccctggtg aaccgcatcg agctgaaggg catcgacttc 1860
aaggaggacg gcaacatcct ggggcacaag ctggagtaca actacaacag ccacaacgtc 1920
tatatcatgg ccgacaagca gaagaacggc atcaaggtga acttcaagat ccgccacaac 1980
atcgaggacg gcagcgtgca gctcgccgac cactaccagc agaacacccc catcggcgac 2040
ggccccgtgc tgctgcccga caaccactac ctgagcaccc agtccgccct gagcaaagac 2100
cccaacgaga agcgcgatca catggtcctg ctggagttcg tgaccgccgc cgggatcact 2160
ctcggcatgg acgagctgta caagtaa 2187
<210> 92
<211> 2187
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 92
gatattttga tgacccaaac tccactctcc ctgcctgtca gtcttggaga tcaagcctcc 60
atctcttgca gatctagtca gagcattgta catagtaatg gaaacaccta tttagaatgg 120
tacctgcaga aaccaggcca gtctccaaag cccctgataa agaaagtctc caaccgattt 180
tctggggtcc cagacaggtt cagtggcagt ggatcaggga cagaattcac actcaagatc 240
agcagagtgg aggctgagga tctgggagtt tattactgct ttcaaggttc acatgttcca 300
ttcacgttcg gctcggggac aaagttggaa ataaaaggtg gcggtggctc gggcggtggt 360
gggtcgggtg gcggcggatc tgaggtgaag ctgcagcaat caggggctga cctggcaaca 420
cctggggctt cagtgaagtt gtcctgcaag gcttctggct atacctttag tacctactgg 480
atgcagtggg taaaacagag gcctggacag ggtctggaat ggattgggac tatttatcct 540
ggagatggtg atactaggta cactcagaag ttcaagggca aggccacatt gactgcagat 600
aaatcctcca gtacagccca catgcaactc agcagcttgg catctgagga ctctgcggtc 660
tattattgtg caagaggggg actctattat ggttacgaca ttgcttactg gggccaaggg 720
actctggtca ctgtctctgc aattgaagtt atgtatcctc ctccttacct agacaatgag 780
aagagcaatg gaaccattat ccatgtgaaa gggaaacacc tttgtccaag tcccctattt 840
cccggacctt ctaagccctt ttgggtgctg gtggtggttg ggggagtcct ggcttgctat 900
agcttgctag taacagtggc ctttattatt ttctgggtga aacggggcag aaagaaactc 960
ctgtatatat tcaaacaacc atttatgaga ccagtacaaa ctactcaaga ggaagatggc 1020
tgtagctgcc gatttccaga agaagaagaa ggaggatgtg aactgagagt gaagttcagc 1080
aggagcgcag acgcccccgc gtaccagcag ggccagaacc agctctataa cgagctcaat 1140
ctaggacgaa gagaggagta cgatgttttg gacaagagac gtggccggga ccctgagatg 1200
gggggaaagc cgagaaggaa gaaccctcag gaaggcctgt acaatgaact gcagaaagat 1260
aagatggcgg aggcctacag tgagattggg atgaaaggcg agcgccggag gggcaagggg 1320
cacgatggcc tttaccaggg tctcagtaca gccaccaagg acacctacga cgcccttcac 1380
atgcaggccc tgccccctcg cggatctggc gccaccaact tctctctgct gaagcaggcc 1440
ggcgacgtgg aggagaaccc aggcccaatg gtgagcaagg gcgaggagct gttcaccggg 1500
gtggtgccca tcctggtcga gctggacggc gacgtaaacg gccacaagtt cagcgtgtcc 1560
ggcgagggcg agggcgatgc cacctacggc aagctgaccc tgaagttcat ctgcaccacc 1620
ggcaagctgc ccgtgccctg gcccaccctc gtgaccaccc tgacctacgg cgtgcagtgc 1680
ttcagccgct accccgacca catgaagcag cacgacttct tcaagtccgc catgcccgaa 1740
ggctacgtcc aggagcgcac catcttcttc aaggacgacg gcaactacaa gacccgcgcc 1800
gaggtgaagt tcgagggcga caccctggtg aaccgcatcg agctgaaggg catcgacttc 1860
aaggaggacg gcaacatcct ggggcacaag ctggagtaca actacaacag ccacaacgtc 1920
tatatcatgg ccgacaagca gaagaacggc atcaaggtga acttcaagat ccgccacaac 1980
atcgaggacg gcagcgtgca gctcgccgac cactaccagc agaacacccc catcggcgac 2040
ggccccgtgc tgctgcccga caaccactac ctgagcaccc agtccgccct gagcaaagac 2100
cccaacgaga agcgcgatca catggtcctg ctggagttcg tgaccgccgc cgggatcact 2160
ctcggcatgg acgagctgta caagtaa 2187
<210> 93
<211> 2172
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 93
gaggtgaagc tggtggagtc tggaggaggc ttggtccagc cgggggggtc tctgagactc 60
tcctgttcaa tttctggatt caccttcact gattactaca tgaactgggt ccgccagtct 120
ccaggaaagg cacttgagtg gttgggtttt attagaaaca aagttaatgg tgacacaaca 180
gaatatagtg catctgtgaa gggtcggttc accatctcca gagatatttc ccagagcatc 240
ctctatcttc aaatgaacac cctgagaact gaggacagtg ccacttatta ctgtgcgaga 300
gataagggaa tagcgtacta ctttgactat tggggccaag gcaccactct cacagtctcc 360
tcaggtggcg gtggctcggg cggtggtggg tcgggtggcg gcggatctca aattgttctc 420
tcccagtctc cagcaatcct gtttgcatct ccaggggaga aggtcacaat gacttgtagg 480
gccagctcaa gtgtaagtta cattcactgg taccagcaga agccaggatc ctcccccaaa 540
ccctggattc atggcacatc caacctggct tctggagtcc ctgctcgctt cagtggcagt 600
gggtctggga cctcttactc tctcacaatc agcagaatgg aggctgaaga tgccgccaca 660
tattactgcc agcagtggag tagtaattta tccacgttcg gaggggggac caagctggaa 720
ataaaaattg aagttatgta tcctcctcct tacctagaca atgagaagag caatggaacc 780
attatccatg tgaaagggaa acacctttgt ccaagtcccc tatttcccgg accttctaag 840
cccttttggg tgctggtggt ggttggggga gtcctggctt gctatagctt gctagtaaca 900
gtggccttta ttattttctg ggtgaaacgg ggcagaaaga aactcctgta tatattcaaa 960
caaccattta tgagaccagt acaaactact caagaggaag atggctgtag ctgccgattt 1020
ccagaagaag aagaaggagg atgtgaactg agagtgaagt tcagcaggag cgcagacgcc 1080
cccgcgtacc agcagggcca gaaccagctc tataacgagc tcaatctagg acgaagagag 1140
gagtacgatg ttttggacaa gagacgtggc cgggaccctg agatgggggg aaagccgaga 1200
aggaagaacc ctcaggaagg cctgtacaat gaactgcaga aagataagat ggcggaggcc 1260
tacagtgaga ttgggatgaa aggcgagcgc cggaggggca aggggcacga tggcctttac 1320
cagggtctca gtacagccac caaggacacc tacgacgccc ttcacatgca ggccctgccc 1380
cctcgcggat ctggcgccac caacttctct ctgctgaagc aggccggcga cgtggaggag 1440
aacccaggcc caatggtgag caagggcgag gagctgttca ccggggtggt gcccatcctg 1500
gtcgagctgg acggcgacgt aaacggccac aagttcagcg tgtccggcga gggcgagggc 1560
gatgccacct acggcaagct gaccctgaag ttcatctgca ccaccggcaa gctgcccgtg 1620
ccctggccca ccctcgtgac caccctgacc tacggcgtgc agtgcttcag ccgctacccc 1680
gaccacatga agcagcacga cttcttcaag tccgccatgc ccgaaggcta cgtccaggag 1740
cgcaccatct tcttcaagga cgacggcaac tacaagaccc gcgccgaggt gaagttcgag 1800
ggcgacaccc tggtgaaccg catcgagctg aagggcatcg acttcaagga ggacggcaac 1860
atcctggggc acaagctgga gtacaactac aacagccaca acgtctatat catggccgac 1920
aagcagaaga acggcatcaa ggtgaacttc aagatccgcc acaacatcga ggacggcagc 1980
gtgcagctcg ccgaccacta ccagcagaac acccccatcg gcgacggccc cgtgctgctg 2040
cccgacaacc actacctgag cacccagtcc gccctgagca aagaccccaa cgagaagcgc 2100
gatcacatgg tcctgctgga gttcgtgacc gccgccggga tcactctcgg catggacgag 2160
ctgtacaagt aa 2172
<210> 94
<211> 2172
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 94
caaattgttc tctcccagtc tccagcaatc ctgtttgcat ctccagggga gaaggtcaca 60
atgacttgta gggccagctc aagtgtaagt tacattcact ggtaccagca gaagccagga 120
tcctccccca aaccctggat tcatggcaca tccaacctgg cttctggagt ccctgctcgc 180
ttcagtggca gtgggtctgg gacctcttac tctctcacaa tcagcagaat ggaggctgaa 240
gatgccgcca catattactg ccagcagtgg agtagtaatt tatccacgtt cggagggggg 300
accaagctgg aaataaaagg tggcggtggc tcgggcggtg gtgggtcggg tggcggcgga 360
tctgaggtga agctggtgga gtctggagga ggcttggtcc agccgggggg gtctctgaga 420
ctctcctgtt caatttctgg attcaccttc actgattact acatgaactg ggtccgccag 480
tctccaggaa aggcacttga gtggttgggt tttattagaa acaaagttaa tggtgacaca 540
acagaatata gtgcatctgt gaagggtcgg ttcaccatct ccagagatat ttcccagagc 600
atcctctatc ttcaaatgaa caccctgaga actgaggaca gtgccactta ttactgtgcg 660
agagataagg gaatagcgta ctactttgac tattggggcc aaggcaccac tctcacagtc 720
tcctcaattg aagttatgta tcctcctcct tacctagaca atgagaagag caatggaacc 780
attatccatg tgaaagggaa acacctttgt ccaagtcccc tatttcccgg accttctaag 840
cccttttggg tgctggtggt ggttggggga gtcctggctt gctatagctt gctagtaaca 900
gtggccttta ttattttctg ggtgaaacgg ggcagaaaga aactcctgta tatattcaaa 960
caaccattta tgagaccagt acaaactact caagaggaag atggctgtag ctgccgattt 1020
ccagaagaag aagaaggagg atgtgaactg agagtgaagt tcagcaggag cgcagacgcc 1080
cccgcgtacc agcagggcca gaaccagctc tataacgagc tcaatctagg acgaagagag 1140
gagtacgatg ttttggacaa gagacgtggc cgggaccctg agatgggggg aaagccgaga 1200
aggaagaacc ctcaggaagg cctgtacaat gaactgcaga aagataagat ggcggaggcc 1260
tacagtgaga ttgggatgaa aggcgagcgc cggaggggca aggggcacga tggcctttac 1320
cagggtctca gtacagccac caaggacacc tacgacgccc ttcacatgca ggccctgccc 1380
cctcgcggat ctggcgccac caacttctct ctgctgaagc aggccggcga cgtggaggag 1440
aacccaggcc caatggtgag caagggcgag gagctgttca ccggggtggt gcccatcctg 1500
gtcgagctgg acggcgacgt aaacggccac aagttcagcg tgtccggcga gggcgagggc 1560
gatgccacct acggcaagct gaccctgaag ttcatctgca ccaccggcaa gctgcccgtg 1620
ccctggccca ccctcgtgac caccctgacc tacggcgtgc agtgcttcag ccgctacccc 1680
gaccacatga agcagcacga cttcttcaag tccgccatgc ccgaaggcta cgtccaggag 1740
cgcaccatct tcttcaagga cgacggcaac tacaagaccc gcgccgaggt gaagttcgag 1800
ggcgacaccc tggtgaaccg catcgagctg aagggcatcg acttcaagga ggacggcaac 1860
atcctggggc acaagctgga gtacaactac aacagccaca acgtctatat catggccgac 1920
aagcagaaga acggcatcaa ggtgaacttc aagatccgcc acaacatcga ggacggcagc 1980
gtgcagctcg ccgaccacta ccagcagaac acccccatcg gcgacggccc cgtgctgctg 2040
cccgacaacc actacctgag cacccagtcc gccctgagca aagaccccaa cgagaagcgc 2100
gatcacatgg tcctgctgga gttcgtgacc gccgccggga tcactctcgg catggacgag 2160
ctgtacaagt aa 2172
<210> 95
<211> 2157
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 95
caggtgcagc tgaaggagtc aggacctggc ctggtggcgc cctcacagaa cctgtccatc 60
acatgcactg tctctgggtt ctcattaacc agctatgcta taaactgggt tcgccagcca 120
ccaggaaagg gtctggagtg gcttggaata atatggactg gtggaggcac aaattataat 180
tcagctctca aatccagact gagcatcagc aaagacaact ccaagagtca agttttctta 240
aaaatgaaca gtctgcaaac tgatgacaca gccaggtact actgtgcctc gggggtgtac 300
tactttgact actggggcct aggcaccact ctcacagtct cctcaggtgg cggtggctcg 360
ggcggtggtg ggtcgggtgg cggcggatct gacattgtga tgacccagtc tcacaaattc 420
atgtccacat cagtaggaga cagggtcagc atcacctgca aggccagtca ggatgtgact 480
actgctgtag cctggtatca acaaaaacca gggcaatctc ctaaagtact gattttctgg 540
gcatccaccc ggcacactgg agtccctgat cgcttcacag gcagtggatc tgggacagat 600
tatactctca ccatcagcag tgtgcaggct gaagacctgg cactttatta ctgtcagcaa 660
tattatagaa ctcctcggac gttcggtgga ggcaccaaac tggaaatcaa aattgaagtt 720
atgtatcctc ctccttacct agacaatgag aagagcaatg gaaccattat ccatgtgaaa 780
gggaaacacc tttgtccaag tcccctattt cccggacctt ctaagccctt ttgggtgctg 840
gtggtggttg ggggagtcct ggcttgctat agcttgctag taacagtggc ctttattatt 900
ttctgggtga aacggggcag aaagaaactc ctgtatatat tcaaacaacc atttatgaga 960
ccagtacaaa ctactcaaga ggaagatggc tgtagctgcc gatttccaga agaagaagaa 1020
ggaggatgtg aactgagagt gaagttcagc aggagcgcag acgcccccgc gtaccagcag 1080
ggccagaacc agctctataa cgagctcaat ctaggacgaa gagaggagta cgatgttttg 1140
gacaagagac gtggccggga ccctgagatg gggggaaagc cgagaaggaa gaaccctcag 1200
gaaggcctgt acaatgaact gcagaaagat aagatggcgg aggcctacag tgagattggg 1260
atgaaaggcg agcgccggag gggcaagggg cacgatggcc tttaccaggg tctcagtaca 1320
gccaccaagg acacctacga cgcccttcac atgcaggccc tgccccctcg cggatctggc 1380
gccaccaact tctctctgct gaagcaggcc ggcgacgtgg aggagaaccc aggcccaatg 1440
gtgagcaagg gcgaggagct gttcaccggg gtggtgccca tcctggtcga gctggacggc 1500
gacgtaaacg gccacaagtt cagcgtgtcc ggcgagggcg agggcgatgc cacctacggc 1560
aagctgaccc tgaagttcat ctgcaccacc ggcaagctgc ccgtgccctg gcccaccctc 1620
gtgaccaccc tgacctacgg cgtgcagtgc ttcagccgct accccgacca catgaagcag 1680
cacgacttct tcaagtccgc catgcccgaa ggctacgtcc aggagcgcac catcttcttc 1740
aaggacgacg gcaactacaa gacccgcgcc gaggtgaagt tcgagggcga caccctggtg 1800
aaccgcatcg agctgaaggg catcgacttc aaggaggacg gcaacatcct ggggcacaag 1860
ctggagtaca actacaacag ccacaacgtc tatatcatgg ccgacaagca gaagaacggc 1920
atcaaggtga acttcaagat ccgccacaac atcgaggacg gcagcgtgca gctcgccgac 1980
cactaccagc agaacacccc catcggcgac ggccccgtgc tgctgcccga caaccactac 2040
ctgagcaccc agtccgccct gagcaaagac cccaacgaga agcgcgatca catggtcctg 2100
ctggagttcg tgaccgccgc cgggatcact ctcggcatgg acgagctgta caagtaa 2157
<210> 96
<211> 2157
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 96
gacattgtga tgacccagtc tcacaaattc atgtccacat cagtaggaga cagggtcagc 60
atcacctgca aggccagtca ggatgtgact actgctgtag cctggtatca acaaaaacca 120
gggcaatctc ctaaagtact gattttctgg gcatccaccc ggcacactgg agtccctgat 180
cgcttcacag gcagtggatc tgggacagat tatactctca ccatcagcag tgtgcaggct 240
gaagacctgg cactttatta ctgtcagcaa tattatagaa ctcctcggac gttcggtgga 300
ggcaccaaac tggaaatcaa aggtggcggt ggctcgggcg gtggtgggtc gggtggcggc 360
ggatctcagg tgcagctgaa ggagtcagga cctggcctgg tggcgccctc acagaacctg 420
tccatcacat gcactgtctc tgggttctca ttaaccagct atgctataaa ctgggttcgc 480
cagccaccag gaaagggtct ggagtggctt ggaataatat ggactggtgg aggcacaaat 540
tataattcag ctctcaaatc cagactgagc atcagcaaag acaactccaa gagtcaagtt 600
ttcttaaaaa tgaacagtct gcaaactgat gacacagcca ggtactactg tgcctcgggg 660
gtgtactact ttgactactg gggcctaggc accactctca cagtctcctc aattgaagtt 720
atgtatcctc ctccttacct agacaatgag aagagcaatg gaaccattat ccatgtgaaa 780
gggaaacacc tttgtccaag tcccctattt cccggacctt ctaagccctt ttgggtgctg 840
gtggtggttg ggggagtcct ggcttgctat agcttgctag taacagtggc ctttattatt 900
ttctgggtga aacggggcag aaagaaactc ctgtatatat tcaaacaacc atttatgaga 960
ccagtacaaa ctactcaaga ggaagatggc tgtagctgcc gatttccaga agaagaagaa 1020
ggaggatgtg aactgagagt gaagttcagc aggagcgcag acgcccccgc gtaccagcag 1080
ggccagaacc agctctataa cgagctcaat ctaggacgaa gagaggagta cgatgttttg 1140
gacaagagac gtggccggga ccctgagatg gggggaaagc cgagaaggaa gaaccctcag 1200
gaaggcctgt acaatgaact gcagaaagat aagatggcgg aggcctacag tgagattggg 1260
atgaaaggcg agcgccggag gggcaagggg cacgatggcc tttaccaggg tctcagtaca 1320
gccaccaagg acacctacga cgcccttcac atgcaggccc tgccccctcg cggatctggc 1380
gccaccaact tctctctgct gaagcaggcc ggcgacgtgg aggagaaccc aggcccaatg 1440
gtgagcaagg gcgaggagct gttcaccggg gtggtgccca tcctggtcga gctggacggc 1500
gacgtaaacg gccacaagtt cagcgtgtcc ggcgagggcg agggcgatgc cacctacggc 1560
aagctgaccc tgaagttcat ctgcaccacc ggcaagctgc ccgtgccctg gcccaccctc 1620
gtgaccaccc tgacctacgg cgtgcagtgc ttcagccgct accccgacca catgaagcag 1680
cacgacttct tcaagtccgc catgcccgaa ggctacgtcc aggagcgcac catcttcttc 1740
aaggacgacg gcaactacaa gacccgcgcc gaggtgaagt tcgagggcga caccctggtg 1800
aaccgcatcg agctgaaggg catcgacttc aaggaggacg gcaacatcct ggggcacaag 1860
ctggagtaca actacaacag ccacaacgtc tatatcatgg ccgacaagca gaagaacggc 1920
atcaaggtga acttcaagat ccgccacaac atcgaggacg gcagcgtgca gctcgccgac 1980
cactaccagc agaacacccc catcggcgac ggccccgtgc tgctgcccga caaccactac 2040
ctgagcaccc agtccgccct gagcaaagac cccaacgaga agcgcgatca catggtcctg 2100
ctggagttcg tgaccgccgc cgggatcact ctcggcatgg acgagctgta caagtaa 2157
<210> 97
<211> 2175
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 97
gaggtgaagc tgcaggaatc tggagctgag ctggtgaagc ctggggcttc agtgaagatc 60
tcctgcaagg cttctggcta cacattcaat gactacaaca tggactatct gaagcagagc 120
catggaaaga gccttgagtg gattggagat attaatccta actatgatag cactatctac 180
aaccagaagt tcaagggcaa ggccacattg actgtagaca agtcctccag cacagcctac 240
atggagctcc gcagcctgac atctgaggac tctgcagtct attactgtgc aagacgagac 300
tacgatggta ggaggggggc ctggttttct tactggggcc aagggactct ggtcactgtc 360
tctgcaggtg gcggtggctc gggcggtggt gggtcgggtg gcggcggatc tcaaattgtt 420
ctcacccagt ctccagcact catgtctgca tctccagggg agaaggtcac cgtgacctgc 480
actgccagct caagtgtaag ttacatgtac tggtaccagc agaagccaag atcctccccc 540
aaaccctgga tttatctcac atccaacctg gcttctggag tccctactcg cttcagtggc 600
agtgggtctg ggacctctta ttctctcaca atcagcagca tggaggctga agatgctgcc 660
acttattact gccagcagtg ggatagtaac ccgctcacgt tcggtgctgg gaccaaactg 720
gagctgaaaa ttgaagttat gtatcctcct ccttacctag acaatgagaa gagcaatgga 780
accattatcc atgtgaaagg gaaacacctt tgtccaagtc ccctatttcc cggaccttct 840
aagccctttt gggtgctggt ggtggttggg ggagtcctgg cttgctatag cttgctagta 900
acagtggcct ttattatttt ctgggtgaaa cggggcagaa agaaactcct gtatatattc 960
aaacaaccat ttatgagacc agtacaaact actcaagagg aagatggctg tagctgccga 1020
tttccagaag aagaagaagg aggatgtgaa ctgagagtga agttcagcag gagcgcagac 1080
gcccccgcgt accagcaggg ccagaaccag ctctataacg agctcaatct aggacgaaga 1140
gaggagtacg atgttttgga caagagacgt ggccgggacc ctgagatggg gggaaagccg 1200
agaaggaaga accctcagga aggcctgtac aatgaactgc agaaagataa gatggcggag 1260
gcctacagtg agattgggat gaaaggcgag cgccggaggg gcaaggggca cgatggcctt 1320
taccagggtc tcagtacagc caccaaggac acctacgacg cccttcacat gcaggccctg 1380
ccccctcgcg gatctggcgc caccaacttc tctctgctga agcaggccgg cgacgtggag 1440
gagaacccag gcccaatggt gagcaagggc gaggagctgt tcaccggggt ggtgcccatc 1500
ctggtcgagc tggacggcga cgtaaacggc cacaagttca gcgtgtccgg cgagggcgag 1560
ggcgatgcca cctacggcaa gctgaccctg aagttcatct gcaccaccgg caagctgccc 1620
gtgccctggc ccaccctcgt gaccaccctg acctacggcg tgcagtgctt cagccgctac 1680
cccgaccaca tgaagcagca cgacttcttc aagtccgcca tgcccgaagg ctacgtccag 1740
gagcgcacca tcttcttcaa ggacgacggc aactacaaga cccgcgccga ggtgaagttc 1800
gagggcgaca ccctggtgaa ccgcatcgag ctgaagggca tcgacttcaa ggaggacggc 1860
aacatcctgg ggcacaagct ggagtacaac tacaacagcc acaacgtcta tatcatggcc 1920
gacaagcaga agaacggcat caaggtgaac ttcaagatcc gccacaacat cgaggacggc 1980
agcgtgcagc tcgccgacca ctaccagcag aacaccccca tcggcgacgg ccccgtgctg 2040
ctgcccgaca accactacct gagcacccag tccgccctga gcaaagaccc caacgagaag 2100
cgcgatcaca tggtcctgct ggagttcgtg accgccgccg ggatcactct cggcatggac 2160
gagctgtaca agtaa 2175
<210> 98
<211> 2175
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 98
caaattgttc tcacccagtc tccagcactc atgtctgcat ctccagggga gaaggtcacc 60
gtgacctgca ctgccagctc aagtgtaagt tacatgtact ggtaccagca gaagccaaga 120
tcctccccca aaccctggat ttatctcaca tccaacctgg cttctggagt ccctactcgc 180
ttcagtggca gtgggtctgg gacctcttat tctctcacaa tcagcagcat ggaggctgaa 240
gatgctgcca cttattactg ccagcagtgg gatagtaacc cgctcacgtt cggtgctggg 300
accaaactgg agctgaaagg tggcggtggc tcgggcggtg gtgggtcggg tggcggcgga 360
tctgaggtga agctgcagga atctggagct gagctggtga agcctggggc ttcagtgaag 420
atctcctgca aggcttctgg ctacacattc aatgactaca acatggacta tctgaagcag 480
agccatggaa agagccttga gtggattgga gatattaatc ctaactatga tagcactatc 540
tacaaccaga agttcaaggg caaggccaca ttgactgtag acaagtcctc cagcacagcc 600
tacatggagc tccgcagcct gacatctgag gactctgcag tctattactg tgcaagacga 660
gactacgatg gtaggagggg ggcctggttt tcttactggg gccaagggac tctggtcact 720
gtctctgcaa ttgaagttat gtatcctcct ccttacctag acaatgagaa gagcaatgga 780
accattatcc atgtgaaagg gaaacacctt tgtccaagtc ccctatttcc cggaccttct 840
aagccctttt gggtgctggt ggtggttggg ggagtcctgg cttgctatag cttgctagta 900
acagtggcct ttattatttt ctgggtgaaa cggggcagaa agaaactcct gtatatattc 960
aaacaaccat ttatgagacc agtacaaact actcaagagg aagatggctg tagctgccga 1020
tttccagaag aagaagaagg aggatgtgaa ctgagagtga agttcagcag gagcgcagac 1080
gcccccgcgt accagcaggg ccagaaccag ctctataacg agctcaatct aggacgaaga 1140
gaggagtacg atgttttgga caagagacgt ggccgggacc ctgagatggg gggaaagccg 1200
agaaggaaga accctcagga aggcctgtac aatgaactgc agaaagataa gatggcggag 1260
gcctacagtg agattgggat gaaaggcgag cgccggaggg gcaaggggca cgatggcctt 1320
taccagggtc tcagtacagc caccaaggac acctacgacg cccttcacat gcaggccctg 1380
ccccctcgcg gatctggcgc caccaacttc tctctgctga agcaggccgg cgacgtggag 1440
gagaacccag gcccaatggt gagcaagggc gaggagctgt tcaccggggt ggtgcccatc 1500
ctggtcgagc tggacggcga cgtaaacggc cacaagttca gcgtgtccgg cgagggcgag 1560
ggcgatgcca cctacggcaa gctgaccctg aagttcatct gcaccaccgg caagctgccc 1620
gtgccctggc ccaccctcgt gaccaccctg acctacggcg tgcagtgctt cagccgctac 1680
cccgaccaca tgaagcagca cgacttcttc aagtccgcca tgcccgaagg ctacgtccag 1740
gagcgcacca tcttcttcaa ggacgacggc aactacaaga cccgcgccga ggtgaagttc 1800
gagggcgaca ccctggtgaa ccgcatcgag ctgaagggca tcgacttcaa ggaggacggc 1860
aacatcctgg ggcacaagct ggagtacaac tacaacagcc acaacgtcta tatcatggcc 1920
gacaagcaga agaacggcat caaggtgaac ttcaagatcc gccacaacat cgaggacggc 1980
agcgtgcagc tcgccgacca ctaccagcag aacaccccca tcggcgacgg ccccgtgctg 2040
ctgcccgaca accactacct gagcacccag tccgccctga gcaaagaccc caacgagaag 2100
cgcgatcaca tggtcctgct ggagttcgtg accgccgccg ggatcactct cggcatggac 2160
gagctgtaca agtaa 2175
<210> 99
<211> 1377
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 99
ggtgtccagt gtgacgtgaa gttggtggag tctgggggag gcttagtgaa gcctggaggg 60
tccctgaaac tctcctgtgc agcctctgga ttcactttca gtagatacac catgtcttgg 120
gttcgccaga ctccggagaa gaggctggag tgggtcgcaa ccattagtaa tagtggtagt 180
tatacctact atcgagacag tgtgaagggc cgattcacca tctccagaga caatgccaag 240
aacaccctgt acctgcaaat gagcagtctg aagtctgagg acacagccat gtattactgt 300
acaagggggt cgccctgggg ccaagggact ctggtcactg tctctgcagg tggcggtggc 360
tcgggcggtg gtgggtcggg tggcggcgga tctgacatcc agatgactca gtctccagat 420
tcactgtctg catctgtggg agaaactgtc accatcacat gtggagcaag tgagaacatt 480
tacggtgctt taaattggta tcagcggaaa cagggaaaat ctcctcagct cctgatctat 540
ggtgcaacca agttggcaga tggcatgtca tcgaggttca gtggcagtgg atctaataga 600
cagtattctc tcaagatcag tagcctgcat cctgacgatg ttgcaacgta ttactgtcaa 660
aatgtgttaa gtaagccgta cgcgttcgga ggggggacca aactggaaat aaaaattgaa 720
gttatgtatc ctcctcctta cctagacaat gagaagagca atggaaccat tatccatgtg 780
aaagggaaac acctttgtcc aagtccccta tttcccggac cttctaagcc cttttgggtg 840
ctggtggtgg ttgggggagt cctggcttgc tatagcttgc tagtaacagt ggcctttatt 900
attttctggg tgaaacgggg cagaaagaaa ctcctgtata tattcaaaca accatttatg 960
agaccagtac aaactactca agaggaagat ggctgtagct gccgatttcc agaagaagaa 1020
gaaggaggat gtgaactgag agtgaagttc agcaggagcg cagacgcccc cgcgtaccag 1080
cagggccaga accagctcta taacgagctc aatctaggac gaagagagga gtacgatgtt 1140
ttggacaaga gacgtggccg ggaccctgag atggggggaa agccgagaag gaagaaccct 1200
caggaaggcc tgtacaatga actgcagaaa gataagatgg cggaggccta cagtgagatt 1260
gggatgaaag gcgagcgccg gaggggcaag gggcacgatg gcctttacca gggtctcagt 1320
acagccacca aggacaccta cgacgccctt cacatgcagg ccctgccccc tcgctaa 1377
<210> 100
<211> 1377
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 100
gacatccaga tgactcagtc tccagattca ctgtctgcat ctgtgggaga aactgtcacc 60
atcacatgtg gagcaagtga gaacatttac ggtgctttaa attggtatca gcggaaacag 120
ggaaaatctc ctcagctcct gatctatggt gcaaccaagt tggcagatgg catgtcatcg 180
aggttcagtg gcagtggatc taatagacag tattctctca agatcagtag cctgcatcct 240
gacgatgttg caacgtatta ctgtcaaaat gtgttaagta agccgtacgc gttcggaggg 300
gggaccaaac tggaaataaa aggtggcggt ggctcgggcg gtggtgggtc gggtggcggc 360
ggatctggtg tccagtgtga cgtgaagttg gtggagtctg ggggaggctt agtgaagcct 420
ggagggtccc tgaaactctc ctgtgcagcc tctggattca ctttcagtag atacaccatg 480
tcttgggttc gccagactcc ggagaagagg ctggagtggg tcgcaaccat tagtaatagt 540
ggtagttata cctactatcg agacagtgtg aagggccgat tcaccatctc cagagacaat 600
gccaagaaca ccctgtacct gcaaatgagc agtctgaagt ctgaggacac agccatgtat 660
tactgtacaa gggggtcgcc ctggggccaa gggactctgg tcactgtctc tgcaattgaa 720
gttatgtatc ctcctcctta cctagacaat gagaagagca atggaaccat tatccatgtg 780
aaagggaaac acctttgtcc aagtccccta tttcccggac cttctaagcc cttttgggtg 840
ctggtggtgg ttgggggagt cctggcttgc tatagcttgc tagtaacagt ggcctttatt 900
attttctggg tgaaacgggg cagaaagaaa ctcctgtata tattcaaaca accatttatg 960
agaccagtac aaactactca agaggaagat ggctgtagct gccgatttcc agaagaagaa 1020
gaaggaggat gtgaactgag agtgaagttc agcaggagcg cagacgcccc cgcgtaccag 1080
cagggccaga accagctcta taacgagctc aatctaggac gaagagagga gtacgatgtt 1140
ttggacaaga gacgtggccg ggaccctgag atggggggaa agccgagaag gaagaaccct 1200
caggaaggcc tgtacaatga actgcagaaa gataagatgg cggaggccta cagtgagatt 1260
gggatgaaag gcgagcgccg gaggggcaag gggcacgatg gcctttacca gggtctcagt 1320
acagccacca aggacaccta cgacgccctt cacatgcagg ccctgccccc tcgctaa 1377
<210> 101
<211> 1404
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 101
gaggtgaagc tgcagcaatc aggggctgac ctggcaacac ctggggcttc agtgaagttg 60
tcctgcaagg cttctggcta tacctttagt acctactgga tgcagtgggt aaaacagagg 120
cctggacagg gtctggaatg gattgggact atttatcctg gagatggtga tactaggtac 180
actcagaagt tcaagggcaa ggccacattg actgcagata aatcctccag tacagcccac 240
atgcaactca gcagcttggc atctgaggac tctgcggtct attattgtgc aagaggggga 300
ctctattatg gttacgacat tgcttactgg ggccaaggga ctctggtcac tgtctctgca 360
ggtggcggtg gctcgggcgg tggtgggtcg ggtggcggcg gatctgatat tttgatgacc 420
caaactccac tctccctgcc tgtcagtctt ggagatcaag cctccatctc ttgcagatct 480
agtcagagca ttgtacatag taatggaaac acctatttag aatggtacct gcagaaacca 540
ggccagtctc caaagcccct gataaagaaa gtctccaacc gattttctgg ggtcccagac 600
aggttcagtg gcagtggatc agggacagaa ttcacactca agatcagcag agtggaggct 660
gaggatctgg gagtttatta ctgctttcaa ggttcacatg ttccattcac gttcggctcg 720
gggacaaagt tggaaataaa aattgaagtt atgtatcctc ctccttacct agacaatgag 780
aagagcaatg gaaccattat ccatgtgaaa gggaaacacc tttgtccaag tcccctattt 840
cccggacctt ctaagccctt ttgggtgctg gtggtggttg ggggagtcct ggcttgctat 900
agcttgctag taacagtggc ctttattatt ttctgggtga aacggggcag aaagaaactc 960
ctgtatatat tcaaacaacc atttatgaga ccagtacaaa ctactcaaga ggaagatggc 1020
tgtagctgcc gatttccaga agaagaagaa ggaggatgtg aactgagagt gaagttcagc 1080
aggagcgcag acgcccccgc gtaccagcag ggccagaacc agctctataa cgagctcaat 1140
ctaggacgaa gagaggagta cgatgttttg gacaagagac gtggccggga ccctgagatg 1200
gggggaaagc cgagaaggaa gaaccctcag gaaggcctgt acaatgaact gcagaaagat 1260
aagatggcgg aggcctacag tgagattggg atgaaaggcg agcgccggag gggcaagggg 1320
cacgatggcc tttaccaggg tctcagtaca gccaccaagg acacctacga cgcccttcac 1380
atgcaggccc tgccccctcg ctaa 1404
<210> 102
<211> 1404
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 102
gatattttga tgacccaaac tccactctcc ctgcctgtca gtcttggaga tcaagcctcc 60
atctcttgca gatctagtca gagcattgta catagtaatg gaaacaccta tttagaatgg 120
tacctgcaga aaccaggcca gtctccaaag cccctgataa agaaagtctc caaccgattt 180
tctggggtcc cagacaggtt cagtggcagt ggatcaggga cagaattcac actcaagatc 240
agcagagtgg aggctgagga tctgggagtt tattactgct ttcaaggttc acatgttcca 300
ttcacgttcg gctcggggac aaagttggaa ataaaaggtg gcggtggctc gggcggtggt 360
gggtcgggtg gcggcggatc tgaggtgaag ctgcagcaat caggggctga cctggcaaca 420
cctggggctt cagtgaagtt gtcctgcaag gcttctggct atacctttag tacctactgg 480
atgcagtggg taaaacagag gcctggacag ggtctggaat ggattgggac tatttatcct 540
ggagatggtg atactaggta cactcagaag ttcaagggca aggccacatt gactgcagat 600
aaatcctcca gtacagccca catgcaactc agcagcttgg catctgagga ctctgcggtc 660
tattattgtg caagaggggg actctattat ggttacgaca ttgcttactg gggccaaggg 720
actctggtca ctgtctctgc aattgaagtt atgtatcctc ctccttacct agacaatgag 780
aagagcaatg gaaccattat ccatgtgaaa gggaaacacc tttgtccaag tcccctattt 840
cccggacctt ctaagccctt ttgggtgctg gtggtggttg ggggagtcct ggcttgctat 900
agcttgctag taacagtggc ctttattatt ttctgggtga aacggggcag aaagaaactc 960
ctgtatatat tcaaacaacc atttatgaga ccagtacaaa ctactcaaga ggaagatggc 1020
tgtagctgcc gatttccaga agaagaagaa ggaggatgtg aactgagagt gaagttcagc 1080
aggagcgcag acgcccccgc gtaccagcag ggccagaacc agctctataa cgagctcaat 1140
ctaggacgaa gagaggagta cgatgttttg gacaagagac gtggccggga ccctgagatg 1200
gggggaaagc cgagaaggaa gaaccctcag gaaggcctgt acaatgaact gcagaaagat 1260
aagatggcgg aggcctacag tgagattggg atgaaaggcg agcgccggag gggcaagggg 1320
cacgatggcc tttaccaggg tctcagtaca gccaccaagg acacctacga cgcccttcac 1380
atgcaggccc tgccccctcg ctaa 1404
<210> 103
<211> 1389
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 103
gaggtgaagc tggtggagtc tggaggaggc ttggtccagc cgggggggtc tctgagactc 60
tcctgttcaa tttctggatt caccttcact gattactaca tgaactgggt ccgccagtct 120
ccaggaaagg cacttgagtg gttgggtttt attagaaaca aagttaatgg tgacacaaca 180
gaatatagtg catctgtgaa gggtcggttc accatctcca gagatatttc ccagagcatc 240
ctctatcttc aaatgaacac cctgagaact gaggacagtg ccacttatta ctgtgcgaga 300
gataagggaa tagcgtacta ctttgactat tggggccaag gcaccactct cacagtctcc 360
tcaggtggcg gtggctcggg cggtggtggg tcgggtggcg gcggatctca aattgttctc 420
tcccagtctc cagcaatcct gtttgcatct ccaggggaga aggtcacaat gacttgtagg 480
gccagctcaa gtgtaagtta cattcactgg taccagcaga agccaggatc ctcccccaaa 540
ccctggattc atggcacatc caacctggct tctggagtcc ctgctcgctt cagtggcagt 600
gggtctggga cctcttactc tctcacaatc agcagaatgg aggctgaaga tgccgccaca 660
tattactgcc agcagtggag tagtaattta tccacgttcg gaggggggac caagctggaa 720
ataaaaattg aagttatgta tcctcctcct tacctagaca atgagaagag caatggaacc 780
attatccatg tgaaagggaa acacctttgt ccaagtcccc tatttcccgg accttctaag 840
cccttttggg tgctggtggt ggttggggga gtcctggctt gctatagctt gctagtaaca 900
gtggccttta ttattttctg ggtgaaacgg ggcagaaaga aactcctgta tatattcaaa 960
caaccattta tgagaccagt acaaactact caagaggaag atggctgtag ctgccgattt 1020
ccagaagaag aagaaggagg atgtgaactg agagtgaagt tcagcaggag cgcagacgcc 1080
cccgcgtacc agcagggcca gaaccagctc tataacgagc tcaatctagg acgaagagag 1140
gagtacgatg ttttggacaa gagacgtggc cgggaccctg agatgggggg aaagccgaga 1200
aggaagaacc ctcaggaagg cctgtacaat gaactgcaga aagataagat ggcggaggcc 1260
tacagtgaga ttgggatgaa aggcgagcgc cggaggggca aggggcacga tggcctttac 1320
cagggtctca gtacagccac caaggacacc tacgacgccc ttcacatgca ggccctgccc 1380
cctcgctaa 1389
<210> 104
<211> 1389
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 104
caaattgttc tctcccagtc tccagcaatc ctgtttgcat ctccagggga gaaggtcaca 60
atgacttgta gggccagctc aagtgtaagt tacattcact ggtaccagca gaagccagga 120
tcctccccca aaccctggat tcatggcaca tccaacctgg cttctggagt ccctgctcgc 180
ttcagtggca gtgggtctgg gacctcttac tctctcacaa tcagcagaat ggaggctgaa 240
gatgccgcca catattactg ccagcagtgg agtagtaatt tatccacgtt cggagggggg 300
accaagctgg aaataaaagg tggcggtggc tcgggcggtg gtgggtcggg tggcggcgga 360
tctgaggtga agctggtgga gtctggagga ggcttggtcc agccgggggg gtctctgaga 420
ctctcctgtt caatttctgg attcaccttc actgattact acatgaactg ggtccgccag 480
tctccaggaa aggcacttga gtggttgggt tttattagaa acaaagttaa tggtgacaca 540
acagaatata gtgcatctgt gaagggtcgg ttcaccatct ccagagatat ttcccagagc 600
atcctctatc ttcaaatgaa caccctgaga actgaggaca gtgccactta ttactgtgcg 660
agagataagg gaatagcgta ctactttgac tattggggcc aaggcaccac tctcacagtc 720
tcctcaattg aagttatgta tcctcctcct tacctagaca atgagaagag caatggaacc 780
attatccatg tgaaagggaa acacctttgt ccaagtcccc tatttcccgg accttctaag 840
cccttttggg tgctggtggt ggttggggga gtcctggctt gctatagctt gctagtaaca 900
gtggccttta ttattttctg ggtgaaacgg ggcagaaaga aactcctgta tatattcaaa 960
caaccattta tgagaccagt acaaactact caagaggaag atggctgtag ctgccgattt 1020
ccagaagaag aagaaggagg atgtgaactg agagtgaagt tcagcaggag cgcagacgcc 1080
cccgcgtacc agcagggcca gaaccagctc tataacgagc tcaatctagg acgaagagag 1140
gagtacgatg ttttggacaa gagacgtggc cgggaccctg agatgggggg aaagccgaga 1200
aggaagaacc ctcaggaagg cctgtacaat gaactgcaga aagataagat ggcggaggcc 1260
tacagtgaga ttgggatgaa aggcgagcgc cggaggggca aggggcacga tggcctttac 1320
cagggtctca gtacagccac caaggacacc tacgacgccc ttcacatgca ggccctgccc 1380
cctcgctaa 1389
<210> 105
<211> 1374
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 105
caggtgcagc tgaaggagtc aggacctggc ctggtggcgc cctcacagaa cctgtccatc 60
acatgcactg tctctgggtt ctcattaacc agctatgcta taaactgggt tcgccagcca 120
ccaggaaagg gtctggagtg gcttggaata atatggactg gtggaggcac aaattataat 180
tcagctctca aatccagact gagcatcagc aaagacaact ccaagagtca agttttctta 240
aaaatgaaca gtctgcaaac tgatgacaca gccaggtact actgtgcctc gggggtgtac 300
tactttgact actggggcct aggcaccact ctcacagtct cctcaggtgg cggtggctcg 360
ggcggtggtg ggtcgggtgg cggcggatct gacattgtga tgacccagtc tcacaaattc 420
atgtccacat cagtaggaga cagggtcagc atcacctgca aggccagtca ggatgtgact 480
actgctgtag cctggtatca acaaaaacca gggcaatctc ctaaagtact gattttctgg 540
gcatccaccc ggcacactgg agtccctgat cgcttcacag gcagtggatc tgggacagat 600
tatactctca ccatcagcag tgtgcaggct gaagacctgg cactttatta ctgtcagcaa 660
tattatagaa ctcctcggac gttcggtgga ggcaccaaac tggaaatcaa aattgaagtt 720
atgtatcctc ctccttacct agacaatgag aagagcaatg gaaccattat ccatgtgaaa 780
gggaaacacc tttgtccaag tcccctattt cccggacctt ctaagccctt ttgggtgctg 840
gtggtggttg ggggagtcct ggcttgctat agcttgctag taacagtggc ctttattatt 900
ttctgggtga aacggggcag aaagaaactc ctgtatatat tcaaacaacc atttatgaga 960
ccagtacaaa ctactcaaga ggaagatggc tgtagctgcc gatttccaga agaagaagaa 1020
ggaggatgtg aactgagagt gaagttcagc aggagcgcag acgcccccgc gtaccagcag 1080
ggccagaacc agctctataa cgagctcaat ctaggacgaa gagaggagta cgatgttttg 1140
gacaagagac gtggccggga ccctgagatg gggggaaagc cgagaaggaa gaaccctcag 1200
gaaggcctgt acaatgaact gcagaaagat aagatggcgg aggcctacag tgagattggg 1260
atgaaaggcg agcgccggag gggcaagggg cacgatggcc tttaccaggg tctcagtaca 1320
gccaccaagg acacctacga cgcccttcac atgcaggccc tgccccctcg ctaa 1374
<210> 106
<211> 1374
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 106
gacattgtga tgacccagtc tcacaaattc atgtccacat cagtaggaga cagggtcagc 60
atcacctgca aggccagtca ggatgtgact actgctgtag cctggtatca acaaaaacca 120
gggcaatctc ctaaagtact gattttctgg gcatccaccc ggcacactgg agtccctgat 180
cgcttcacag gcagtggatc tgggacagat tatactctca ccatcagcag tgtgcaggct 240
gaagacctgg cactttatta ctgtcagcaa tattatagaa ctcctcggac gttcggtgga 300
ggcaccaaac tggaaatcaa aggtggcggt ggctcgggcg gtggtgggtc gggtggcggc 360
ggatctcagg tgcagctgaa ggagtcagga cctggcctgg tggcgccctc acagaacctg 420
tccatcacat gcactgtctc tgggttctca ttaaccagct atgctataaa ctgggttcgc 480
cagccaccag gaaagggtct ggagtggctt ggaataatat ggactggtgg aggcacaaat 540
tataattcag ctctcaaatc cagactgagc atcagcaaag acaactccaa gagtcaagtt 600
ttcttaaaaa tgaacagtct gcaaactgat gacacagcca ggtactactg tgcctcgggg 660
gtgtactact ttgactactg gggcctaggc accactctca cagtctcctc aattgaagtt 720
atgtatcctc ctccttacct agacaatgag aagagcaatg gaaccattat ccatgtgaaa 780
gggaaacacc tttgtccaag tcccctattt cccggacctt ctaagccctt ttgggtgctg 840
gtggtggttg ggggagtcct ggcttgctat agcttgctag taacagtggc ctttattatt 900
ttctgggtga aacggggcag aaagaaactc ctgtatatat tcaaacaacc atttatgaga 960
ccagtacaaa ctactcaaga ggaagatggc tgtagctgcc gatttccaga agaagaagaa 1020
ggaggatgtg aactgagagt gaagttcagc aggagcgcag acgcccccgc gtaccagcag 1080
ggccagaacc agctctataa cgagctcaat ctaggacgaa gagaggagta cgatgttttg 1140
gacaagagac gtggccggga ccctgagatg gggggaaagc cgagaaggaa gaaccctcag 1200
gaaggcctgt acaatgaact gcagaaagat aagatggcgg aggcctacag tgagattggg 1260
atgaaaggcg agcgccggag gggcaagggg cacgatggcc tttaccaggg tctcagtaca 1320
gccaccaagg acacctacga cgcccttcac atgcaggccc tgccccctcg ctaa 1374
<210> 107
<211> 1392
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 107
gaggtgaagc tgcaggaatc tggagctgag ctggtgaagc ctggggcttc agtgaagatc 60
tcctgcaagg cttctggcta cacattcaat gactacaaca tggactatct gaagcagagc 120
catggaaaga gccttgagtg gattggagat attaatccta actatgatag cactatctac 180
aaccagaagt tcaagggcaa ggccacattg actgtagaca agtcctccag cacagcctac 240
atggagctcc gcagcctgac atctgaggac tctgcagtct attactgtgc aagacgagac 300
tacgatggta ggaggggggc ctggttttct tactggggcc aagggactct ggtcactgtc 360
tctgcaggtg gcggtggctc gggcggtggt gggtcgggtg gcggcggatc tcaaattgtt 420
ctcacccagt ctccagcact catgtctgca tctccagggg agaaggtcac cgtgacctgc 480
actgccagct caagtgtaag ttacatgtac tggtaccagc agaagccaag atcctccccc 540
aaaccctgga tttatctcac atccaacctg gcttctggag tccctactcg cttcagtggc 600
agtgggtctg ggacctctta ttctctcaca atcagcagca tggaggctga agatgctgcc 660
acttattact gccagcagtg ggatagtaac ccgctcacgt tcggtgctgg gaccaaactg 720
gagctgaaaa ttgaagttat gtatcctcct ccttacctag acaatgagaa gagcaatgga 780
accattatcc atgtgaaagg gaaacacctt tgtccaagtc ccctatttcc cggaccttct 840
aagccctttt gggtgctggt ggtggttggg ggagtcctgg cttgctatag cttgctagta 900
acagtggcct ttattatttt ctgggtgaaa cggggcagaa agaaactcct gtatatattc 960
aaacaaccat ttatgagacc agtacaaact actcaagagg aagatggctg tagctgccga 1020
tttccagaag aagaagaagg aggatgtgaa ctgagagtga agttcagcag gagcgcagac 1080
gcccccgcgt accagcaggg ccagaaccag ctctataacg agctcaatct aggacgaaga 1140
gaggagtacg atgttttgga caagagacgt ggccgggacc ctgagatggg gggaaagccg 1200
agaaggaaga accctcagga aggcctgtac aatgaactgc agaaagataa gatggcggag 1260
gcctacagtg agattgggat gaaaggcgag cgccggaggg gcaaggggca cgatggcctt 1320
taccagggtc tcagtacagc caccaaggac acctacgacg cccttcacat gcaggccctg 1380
ccccctcgct aa 1392
<210> 108
<211> 1392
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 108
caaattgttc tcacccagtc tccagcactc atgtctgcat ctccagggga gaaggtcacc 60
gtgacctgca ctgccagctc aagtgtaagt tacatgtact ggtaccagca gaagccaaga 120
tcctccccca aaccctggat ttatctcaca tccaacctgg cttctggagt ccctactcgc 180
ttcagtggca gtgggtctgg gacctcttat tctctcacaa tcagcagcat ggaggctgaa 240
gatgctgcca cttattactg ccagcagtgg gatagtaacc cgctcacgtt cggtgctggg 300
accaaactgg agctgaaagg tggcggtggc tcgggcggtg gtgggtcggg tggcggcgga 360
tctgaggtga agctgcagga atctggagct gagctggtga agcctggggc ttcagtgaag 420
atctcctgca aggcttctgg ctacacattc aatgactaca acatggacta tctgaagcag 480
agccatggaa agagccttga gtggattgga gatattaatc ctaactatga tagcactatc 540
tacaaccaga agttcaaggg caaggccaca ttgactgtag acaagtcctc cagcacagcc 600
tacatggagc tccgcagcct gacatctgag gactctgcag tctattactg tgcaagacga 660
gactacgatg gtaggagggg ggcctggttt tcttactggg gccaagggac tctggtcact 720
gtctctgcaa ttgaagttat gtatcctcct ccttacctag acaatgagaa gagcaatgga 780
accattatcc atgtgaaagg gaaacacctt tgtccaagtc ccctatttcc cggaccttct 840
aagccctttt gggtgctggt ggtggttggg ggagtcctgg cttgctatag cttgctagta 900
acagtggcct ttattatttt ctgggtgaaa cggggcagaa agaaactcct gtatatattc 960
aaacaaccat ttatgagacc agtacaaact actcaagagg aagatggctg tagctgccga 1020
tttccagaag aagaagaagg aggatgtgaa ctgagagtga agttcagcag gagcgcagac 1080
gcccccgcgt accagcaggg ccagaaccag ctctataacg agctcaatct aggacgaaga 1140
gaggagtacg atgttttgga caagagacgt ggccgggacc ctgagatggg gggaaagccg 1200
agaaggaaga accctcagga aggcctgtac aatgaactgc agaaagataa gatggcggag 1260
gcctacagtg agattgggat gaaaggcgag cgccggaggg gcaaggggca cgatggcctt 1320
taccagggtc tcagtacagc caccaaggac acctacgacg cccttcacat gcaggccctg 1380
ccccctcgct aa 1392
<210> 109
<211> 2160
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 109
ggtgtccagt gtgacgtgaa gttggtggag tctgggggag gcttagtgaa gcctggaggg 60
tccctgaaac tctcctgtgc agcctctgga ttcactttca gtagatacac catgtcttgg 120
gttcgccaga ctccggagaa gaggctggag tgggtcgcaa ccattagtaa tagtggtagt 180
tatacctact atcgagacag tgtgaagggc cgattcacca tctccagaga caatgccaag 240
aacaccctgt acctgcaaat gagcagtctg aagtctgagg acacagccat gtattactgt 300
acaagggggt cgccctgggg ccaagggact ctggtcactg tctctgcagg tggcggtggc 360
tcgggcggtg gtgggtcggg tggcggcgga tctgacatcc agatgactca gtctccagat 420
tcactgtctg catctgtggg agaaactgtc accatcacat gtggagcaag tgagaacatt 480
tacggtgctt taaattggta tcagcggaaa cagggaaaat ctcctcagct cctgatctat 540
ggtgcaacca agttggcaga tggcatgtca tcgaggttca gtggcagtgg atctaataga 600
cagtattctc tcaagatcag tagcctgcat cctgacgatg ttgcaacgta ttactgtcaa 660
aatgtgttaa gtaagccgta cgcgttcgga ggggggacca aactggaaat aaaaattgaa 720
gttatgtatc ctcctcctta cctagacaat gagaagagca atggaaccat tatccatgtg 780
aaagggaaac acctttgtcc aagtccccta tttcccggac cttctaagcc cttttgggtg 840
ctggtggtgg ttgggggagt cctggcttgc tatagcttgc tagtaacagt ggcctttatt 900
attttctggg tgaggagtaa gaggagcagg ctcctgcaca gtgactacat gaacatgact 960
ccccgccgcc ccgggcccac ccgcaagcat taccagccct atgccccacc acgcgacttc 1020
gcagcctatc gctccctgag agtgaagttc agcaggagcg cagacgcccc cgcgtaccag 1080
cagggccaga accagctcta taacgagctc aatctaggac gaagagagga gtacgatgtt 1140
ttggacaaga gacgtggccg ggaccctgag atggggggaa agccgagaag gaagaaccct 1200
caggaaggcc tgtacaatga actgcagaaa gataagatgg cggaggccta cagtgagatt 1260
gggatgaaag gcgagcgccg gaggggcaag gggcacgatg gcctttacca gggtctcagt 1320
acagccacca aggacaccta cgacgccctt cacatgcagg ccctgccccc tcgcggatct 1380
ggcgccacca acttctctct gctgaagcag gccggcgacg tggaggagaa cccaggccca 1440
atggtgagca agggcgagga gctgttcacc ggggtggtgc ccatcctggt cgagctggac 1500
ggcgacgtaa acggccacaa gttcagcgtg tccggcgagg gcgagggcga tgccacctac 1560
ggcaagctga ccctgaagtt catctgcacc accggcaagc tgcccgtgcc ctggcccacc 1620
ctcgtgacca ccctgaccta cggcgtgcag tgcttcagcc gctaccccga ccacatgaag 1680
cagcacgact tcttcaagtc cgccatgccc gaaggctacg tccaggagcg caccatcttc 1740
ttcaaggacg acggcaacta caagacccgc gccgaggtga agttcgaggg cgacaccctg 1800
gtgaaccgca tcgagctgaa gggcatcgac ttcaaggagg acggcaacat cctggggcac 1860
aagctggagt acaactacaa cagccacaac gtctatatca tggccgacaa gcagaagaac 1920
ggcatcaagg tgaacttcaa gatccgccac aacatcgagg acggcagcgt gcagctcgcc 1980
gaccactacc agcagaacac ccccatcggc gacggccccg tgctgctgcc cgacaaccac 2040
tacctgagca cccagtccgc cctgagcaaa gaccccaacg agaagcgcga tcacatggtc 2100
ctgctggagt tcgtgaccgc cgccgggatc actctcggca tggacgagct gtacaagtaa 2160
<210> 110
<211> 2169
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 110
gacatccaga tgactcagtc tccagattca ctgtctgcat ctgtgggaga aactgtcacc 60
atcacatgtg gagcaagtga gaacatttac ggtgctttaa attggtatca gcggaaacag 120
ggaaaatctc ctcagctcct gatctatggt gcaaccaagt tggcagatgg catgtcatcg 180
aggttcagtg gcagtggatc taatagacag tattctctca agatcagtag cctgcatcct 240
gacgatgttg caacgtatta ctgtcaaaat gtgttaagta agccgtacgc gttcggaggg 300
gggaccaaac tggaaataaa aggtggcggt ggctcgggcg gtggtgggtc gggtggcggc 360
ggatctggtg tccagtgtga cgtgaagttg gtggagtctg ggggaggctt agtgaagcct 420
ggagggtccc tgaaactctc ctgtgcagcc tctggattca ctttcagtag atacaccatg 480
tcttgggttc gccagactcc ggagaagagg ctggagtggg tcgcaaccat tagtaatagt 540
ggtagttata cctactatcg agacagtgtg aagggccgat tcaccatctc cagagacaat 600
gccaagaaca ccctgtacct gcaaatgagc agtctgaagt ctgaggacac agccatgtat 660
tactgtacaa gggggtcgcc ctggggccaa gggactctgg tcactgtctc tgcaaccacg 720
acgccagcgc cgcgaccacc aacaccggcg cccaccatcg cgtcgcagcc cctgtccctg 780
cgcccagagg cgtgccggcc agcggcgggg ggcgcagtgc acacgagggg gctggacttc 840
gcctgtgata tctacatctg ggcgcccttg gccgggactt gtggggtcct tctcctgtca 900
ctggttatca ccctttactg caaacggggc agaaagaaac tcctgtatat attcaaacaa 960
ccatttatga gaccagtaca aactactcaa gaggaagatg gctgtagctg ccgatttcca 1020
gaagaagaag aaggaggatg tgaactgaga gtgaagttca gcaggagcgc agacgccccc 1080
gcgtaccagc agggccagaa ccagctctat aacgagctca atctaggacg aagagaggag 1140
tacgatgttt tggacaagag acgtggccgg gaccctgaga tggggggaaa gccgagaagg 1200
aagaaccctc aggaaggcct gtacaatgaa ctgcagaaag ataagatggc ggaggcctac 1260
agtgagattg ggatgaaagg cgagcgccgg aggggcaagg ggcacgatgg cctttaccag 1320
ggtctcagta cagccaccaa ggacacctac gacgcccttc acatgcaggc cctgccccct 1380
cgcggatctg gcgccaccaa cttctctctg ctgaagcagg ccggcgacgt ggaggagaac 1440
ccaggcccaa tggtgagcaa gggcgaggag ctgttcaccg gggtggtgcc catcctggtc 1500
gagctggacg gcgacgtaaa cggccacaag ttcagcgtgt ccggcgaggg cgagggcgat 1560
gccacctacg gcaagctgac cctgaagttc atctgcacca ccggcaagct gcccgtgccc 1620
tggcccaccc tcgtgaccac cctgacctac ggcgtgcagt gcttcagccg ctaccccgac 1680
cacatgaagc agcacgactt cttcaagtcc gccatgcccg aaggctacgt ccaggagcgc 1740
accatcttct tcaaggacga cggcaactac aagacccgcg ccgaggtgaa gttcgagggc 1800
gacaccctgg tgaaccgcat cgagctgaag ggcatcgact tcaaggagga cggcaacatc 1860
ctggggcaca agctggagta caactacaac agccacaacg tctatatcat ggccgacaag 1920
cagaagaacg gcatcaaggt gaacttcaag atccgccaca acatcgagga cggcagcgtg 1980
cagctcgccg accactacca gcagaacacc cccatcggcg acggccccgt gctgctgccc 2040
gacaaccact acctgagcac ccagtccgcc ctgagcaaag accccaacga gaagcgcgat 2100
cacatggtcc tgctggagtt cgtgaccgcc gccgggatca ctctcggcat ggacgagctg 2160
tacaagtaa 2169
<210> 111
<211> 2187
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 111
gaggtgaagc tgcagcaatc aggggctgac ctggcaacac ctggggcttc agtgaagttg 60
tcctgcaagg cttctggcta tacctttagt acctactgga tgcagtgggt aaaacagagg 120
cctggacagg gtctggaatg gattgggact atttatcctg gagatggtga tactaggtac 180
actcagaagt tcaagggcaa ggccacattg actgcagata aatcctccag tacagcccac 240
atgcaactca gcagcttggc atctgaggac tctgcggtct attattgtgc aagaggggga 300
ctctattatg gttacgacat tgcttactgg ggccaaggga ctctggtcac tgtctctgca 360
ggtggcggtg gctcgggcgg tggtgggtcg ggtggcggcg gatctgatat tttgatgacc 420
caaactccac tctccctgcc tgtcagtctt ggagatcaag cctccatctc ttgcagatct 480
agtcagagca ttgtacatag taatggaaac acctatttag aatggtacct gcagaaacca 540
ggccagtctc caaagcccct gataaagaaa gtctccaacc gattttctgg ggtcccagac 600
aggttcagtg gcagtggatc agggacagaa ttcacactca agatcagcag agtggaggct 660
gaggatctgg gagtttatta ctgctttcaa ggttcacatg ttccattcac gttcggctcg 720
gggacaaagt tggaaataaa aattgaagtt atgtatcctc ctccttacct agacaatgag 780
aagagcaatg gaaccattat ccatgtgaaa gggaaacacc tttgtccaag tcccctattt 840
cccggacctt ctaagccctt ttgggtgctg gtggtggttg ggggagtcct ggcttgctat 900
agcttgctag taacagtggc ctttattatt ttctgggtga ggagtaagag gagcaggctc 960
ctgcacagtg actacatgaa catgactccc cgccgccccg ggcccacccg caagcattac 1020
cagccctatg ccccaccacg cgacttcgca gcctatcgct ccctgagagt gaagttcagc 1080
aggagcgcag acgcccccgc gtaccagcag ggccagaacc agctctataa cgagctcaat 1140
ctaggacgaa gagaggagta cgatgttttg gacaagagac gtggccggga ccctgagatg 1200
gggggaaagc cgagaaggaa gaaccctcag gaaggcctgt acaatgaact gcagaaagat 1260
aagatggcgg aggcctacag tgagattggg atgaaaggcg agcgccggag gggcaagggg 1320
cacgatggcc tttaccaggg tctcagtaca gccaccaagg acacctacga cgcccttcac 1380
atgcaggccc tgccccctcg cggatctggc gccaccaact tctctctgct gaagcaggcc 1440
ggcgacgtgg aggagaaccc aggcccaatg gtgagcaagg gcgaggagct gttcaccggg 1500
gtggtgccca tcctggtcga gctggacggc gacgtaaacg gccacaagtt cagcgtgtcc 1560
ggcgagggcg agggcgatgc cacctacggc aagctgaccc tgaagttcat ctgcaccacc 1620
ggcaagctgc ccgtgccctg gcccaccctc gtgaccaccc tgacctacgg cgtgcagtgc 1680
ttcagccgct accccgacca catgaagcag cacgacttct tcaagtccgc catgcccgaa 1740
ggctacgtcc aggagcgcac catcttcttc aaggacgacg gcaactacaa gacccgcgcc 1800
gaggtgaagt tcgagggcga caccctggtg aaccgcatcg agctgaaggg catcgacttc 1860
aaggaggacg gcaacatcct ggggcacaag ctggagtaca actacaacag ccacaacgtc 1920
tatatcatgg ccgacaagca gaagaacggc atcaaggtga acttcaagat ccgccacaac 1980
atcgaggacg gcagcgtgca gctcgccgac cactaccagc agaacacccc catcggcgac 2040
ggccccgtgc tgctgcccga caaccactac ctgagcaccc agtccgccct gagcaaagac 2100
cccaacgaga agcgcgatca catggtcctg ctggagttcg tgaccgccgc cgggatcact 2160
ctcggcatgg acgagctgta caagtaa 2187
<210> 112
<211> 2187
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 112
gatattttga tgacccaaac tccactctcc ctgcctgtca gtcttggaga tcaagcctcc 60
atctcttgca gatctagtca gagcattgta catagtaatg gaaacaccta tttagaatgg 120
tacctgcaga aaccaggcca gtctccaaag cccctgataa agaaagtctc caaccgattt 180
tctggggtcc cagacaggtt cagtggcagt ggatcaggga cagaattcac actcaagatc 240
agcagagtgg aggctgagga tctgggagtt tattactgct ttcaaggttc acatgttcca 300
ttcacgttcg gctcggggac aaagttggaa ataaaaggtg gcggtggctc gggcggtggt 360
gggtcgggtg gcggcggatc tgaggtgaag ctgcagcaat caggggctga cctggcaaca 420
cctggggctt cagtgaagtt gtcctgcaag gcttctggct atacctttag tacctactgg 480
atgcagtggg taaaacagag gcctggacag ggtctggaat ggattgggac tatttatcct 540
ggagatggtg atactaggta cactcagaag ttcaagggca aggccacatt gactgcagat 600
aaatcctcca gtacagccca catgcaactc agcagcttgg catctgagga ctctgcggtc 660
tattattgtg caagaggggg actctattat ggttacgaca ttgcttactg gggccaaggg 720
actctggtca ctgtctctgc aattgaagtt atgtatcctc ctccttacct agacaatgag 780
aagagcaatg gaaccattat ccatgtgaaa gggaaacacc tttgtccaag tcccctattt 840
cccggacctt ctaagccctt ttgggtgctg gtggtggttg ggggagtcct ggcttgctat 900
agcttgctag taacagtggc ctttattatt ttctgggtga ggagtaagag gagcaggctc 960
ctgcacagtg actacatgaa catgactccc cgccgccccg ggcccacccg caagcattac 1020
cagccctatg ccccaccacg cgacttcgca gcctatcgct ccctgagagt gaagttcagc 1080
aggagcgcag acgcccccgc gtaccagcag ggccagaacc agctctataa cgagctcaat 1140
ctaggacgaa gagaggagta cgatgttttg gacaagagac gtggccggga ccctgagatg 1200
gggggaaagc cgagaaggaa gaaccctcag gaaggcctgt acaatgaact gcagaaagat 1260
aagatggcgg aggcctacag tgagattggg atgaaaggcg agcgccggag gggcaagggg 1320
cacgatggcc tttaccaggg tctcagtaca gccaccaagg acacctacga cgcccttcac 1380
atgcaggccc tgccccctcg cggatctggc gccaccaact tctctctgct gaagcaggcc 1440
ggcgacgtgg aggagaaccc aggcccaatg gtgagcaagg gcgaggagct gttcaccggg 1500
gtggtgccca tcctggtcga gctggacggc gacgtaaacg gccacaagtt cagcgtgtcc 1560
ggcgagggcg agggcgatgc cacctacggc aagctgaccc tgaagttcat ctgcaccacc 1620
ggcaagctgc ccgtgccctg gcccaccctc gtgaccaccc tgacctacgg cgtgcagtgc 1680
ttcagccgct accccgacca catgaagcag cacgacttct tcaagtccgc catgcccgaa 1740
ggctacgtcc aggagcgcac catcttcttc aaggacgacg gcaactacaa gacccgcgcc 1800
gaggtgaagt tcgagggcga caccctggtg aaccgcatcg agctgaaggg catcgacttc 1860
aaggaggacg gcaacatcct ggggcacaag ctggagtaca actacaacag ccacaacgtc 1920
tatatcatgg ccgacaagca gaagaacggc atcaaggtga acttcaagat ccgccacaac 1980
atcgaggacg gcagcgtgca gctcgccgac cactaccagc agaacacccc catcggcgac 2040
ggccccgtgc tgctgcccga caaccactac ctgagcaccc agtccgccct gagcaaagac 2100
cccaacgaga agcgcgatca catggtcctg ctggagttcg tgaccgccgc cgggatcact 2160
ctcggcatgg acgagctgta caagtaa 2187
<210> 113
<211> 2172
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 113
gaggtgaagc tggtggagtc tggaggaggc ttggtccagc cgggggggtc tctgagactc 60
tcctgttcaa tttctggatt caccttcact gattactaca tgaactgggt ccgccagtct 120
ccaggaaagg cacttgagtg gttgggtttt attagaaaca aagttaatgg tgacacaaca 180
gaatatagtg catctgtgaa gggtcggttc accatctcca gagatatttc ccagagcatc 240
ctctatcttc aaatgaacac cctgagaact gaggacagtg ccacttatta ctgtgcgaga 300
gataagggaa tagcgtacta ctttgactat tggggccaag gcaccactct cacagtctcc 360
tcaggtggcg gtggctcggg cggtggtggg tcgggtggcg gcggatctca aattgttctc 420
tcccagtctc cagcaatcct gtttgcatct ccaggggaga aggtcacaat gacttgtagg 480
gccagctcaa gtgtaagtta cattcactgg taccagcaga agccaggatc ctcccccaaa 540
ccctggattc atggcacatc caacctggct tctggagtcc ctgctcgctt cagtggcagt 600
gggtctggga cctcttactc tctcacaatc agcagaatgg aggctgaaga tgccgccaca 660
tattactgcc agcagtggag tagtaattta tccacgttcg gaggggggac caagctggaa 720
ataaaaattg aagttatgta tcctcctcct tacctagaca atgagaagag caatggaacc 780
attatccatg tgaaagggaa acacctttgt ccaagtcccc tatttcccgg accttctaag 840
cccttttggg tgctggtggt ggttggggga gtcctggctt gctatagctt gctagtaaca 900
gtggccttta ttattttctg ggtgaggagt aagaggagca ggctcctgca cagtgactac 960
atgaacatga ctccccgccg ccccgggccc acccgcaagc attaccagcc ctatgcccca 1020
ccacgcgact tcgcagccta tcgctccctg agagtgaagt tcagcaggag cgcagacgcc 1080
cccgcgtacc agcagggcca gaaccagctc tataacgagc tcaatctagg acgaagagag 1140
gagtacgatg ttttggacaa gagacgtggc cgggaccctg agatgggggg aaagccgaga 1200
aggaagaacc ctcaggaagg cctgtacaat gaactgcaga aagataagat ggcggaggcc 1260
tacagtgaga ttgggatgaa aggcgagcgc cggaggggca aggggcacga tggcctttac 1320
cagggtctca gtacagccac caaggacacc tacgacgccc ttcacatgca ggccctgccc 1380
cctcgcggat ctggcgccac caacttctct ctgctgaagc aggccggcga cgtggaggag 1440
aacccaggcc caatggtgag caagggcgag gagctgttca ccggggtggt gcccatcctg 1500
gtcgagctgg acggcgacgt aaacggccac aagttcagcg tgtccggcga gggcgagggc 1560
gatgccacct acggcaagct gaccctgaag ttcatctgca ccaccggcaa gctgcccgtg 1620
ccctggccca ccctcgtgac caccctgacc tacggcgtgc agtgcttcag ccgctacccc 1680
gaccacatga agcagcacga cttcttcaag tccgccatgc ccgaaggcta cgtccaggag 1740
cgcaccatct tcttcaagga cgacggcaac tacaagaccc gcgccgaggt gaagttcgag 1800
ggcgacaccc tggtgaaccg catcgagctg aagggcatcg acttcaagga ggacggcaac 1860
atcctggggc acaagctgga gtacaactac aacagccaca acgtctatat catggccgac 1920
aagcagaaga acggcatcaa ggtgaacttc aagatccgcc acaacatcga ggacggcagc 1980
gtgcagctcg ccgaccacta ccagcagaac acccccatcg gcgacggccc cgtgctgctg 2040
cccgacaacc actacctgag cacccagtcc gccctgagca aagaccccaa cgagaagcgc 2100
gatcacatgg tcctgctgga gttcgtgacc gccgccggga tcactctcgg catggacgag 2160
ctgtacaagt aa 2172
<210> 114
<211> 2181
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 114
caaattgttc tctcccagtc tccagcaatc ctgtttgcat ctccagggga gaaggtcaca 60
atgacttgta gggccagctc aagtgtaagt tacattcact ggtaccagca gaagccagga 120
tcctccccca aaccctggat tcatggcaca tccaacctgg cttctggagt ccctgctcgc 180
ttcagtggca gtgggtctgg gacctcttac tctctcacaa tcagcagaat ggaggctgaa 240
gatgccgcca catattactg ccagcagtgg agtagtaatt tatccacgtt cggagggggg 300
accaagctgg aaataaaagg tggcggtggc tcgggcggtg gtgggtcggg tggcggcgga 360
tctgaggtga agctggtgga gtctggagga ggcttggtcc agccgggggg gtctctgaga 420
ctctcctgtt caatttctgg attcaccttc actgattact acatgaactg ggtccgccag 480
tctccaggaa aggcacttga gtggttgggt tttattagaa acaaagttaa tggtgacaca 540
acagaatata gtgcatctgt gaagggtcgg ttcaccatct ccagagatat ttcccagagc 600
atcctctatc ttcaaatgaa caccctgaga actgaggaca gtgccactta ttactgtgcg 660
agagataagg gaatagcgta ctactttgac tattggggcc aaggcaccac tctcacagtc 720
tcctcaacca cgacgccagc gccgcgacca ccaacaccgg cgcccaccat cgcgtcgcag 780
cccctgtccc tgcgcccaga ggcgtgccgg ccagcggcgg ggggcgcagt gcacacgagg 840
gggctggact tcgcctgtga tatctacatc tgggcgccct tggccgggac ttgtggggtc 900
cttctcctgt cactggttat caccctttac tgcaaacggg gcagaaagaa actcctgtat 960
atattcaaac aaccatttat gagaccagta caaactactc aagaggaaga tggctgtagc 1020
tgccgatttc cagaagaaga agaaggagga tgtgaactga gagtgaagtt cagcaggagc 1080
gcagacgccc ccgcgtacca gcagggccag aaccagctct ataacgagct caatctagga 1140
cgaagagagg agtacgatgt tttggacaag agacgtggcc gggaccctga gatgggggga 1200
aagccgagaa ggaagaaccc tcaggaaggc ctgtacaatg aactgcagaa agataagatg 1260
gcggaggcct acagtgagat tgggatgaaa ggcgagcgcc ggaggggcaa ggggcacgat 1320
ggcctttacc agggtctcag tacagccacc aaggacacct acgacgccct tcacatgcag 1380
gccctgcccc ctcgcggatc tggcgccacc aacttctctc tgctgaagca ggccggcgac 1440
gtggaggaga acccaggccc aatggtgagc aagggcgagg agctgttcac cggggtggtg 1500
cccatcctgg tcgagctgga cggcgacgta aacggccaca agttcagcgt gtccggcgag 1560
ggcgagggcg atgccaccta cggcaagctg accctgaagt tcatctgcac caccggcaag 1620
ctgcccgtgc cctggcccac cctcgtgacc accctgacct acggcgtgca gtgcttcagc 1680
cgctaccccg accacatgaa gcagcacgac ttcttcaagt ccgccatgcc cgaaggctac 1740
gtccaggagc gcaccatctt cttcaaggac gacggcaact acaagacccg cgccgaggtg 1800
aagttcgagg gcgacaccct ggtgaaccgc atcgagctga agggcatcga cttcaaggag 1860
gacggcaaca tcctggggca caagctggag tacaactaca acagccacaa cgtctatatc 1920
atggccgaca agcagaagaa cggcatcaag gtgaacttca agatccgcca caacatcgag 1980
gacggcagcg tgcagctcgc cgaccactac cagcagaaca cccccatcgg cgacggcccc 2040
gtgctgctgc ccgacaacca ctacctgagc acccagtccg ccctgagcaa agaccccaac 2100
gagaagcgcg atcacatggt cctgctggag ttcgtgaccg ccgccgggat cactctcggc 2160
atggacgagc tgtacaagta a 2181
<210> 115
<211> 2157
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 115
caggtgcagc tgaaggagtc aggacctggc ctggtggcgc cctcacagaa cctgtccatc 60
acatgcactg tctctgggtt ctcattaacc agctatgcta taaactgggt tcgccagcca 120
ccaggaaagg gtctggagtg gcttggaata atatggactg gtggaggcac aaattataat 180
tcagctctca aatccagact gagcatcagc aaagacaact ccaagagtca agttttctta 240
aaaatgaaca gtctgcaaac tgatgacaca gccaggtact actgtgcctc gggggtgtac 300
tactttgact actggggcct aggcaccact ctcacagtct cctcaggtgg cggtggctcg 360
ggcggtggtg ggtcgggtgg cggcggatct gacattgtga tgacccagtc tcacaaattc 420
atgtccacat cagtaggaga cagggtcagc atcacctgca aggccagtca ggatgtgact 480
actgctgtag cctggtatca acaaaaacca gggcaatctc ctaaagtact gattttctgg 540
gcatccaccc ggcacactgg agtccctgat cgcttcacag gcagtggatc tgggacagat 600
tatactctca ccatcagcag tgtgcaggct gaagacctgg cactttatta ctgtcagcaa 660
tattatagaa ctcctcggac gttcggtgga ggcaccaaac tggaaatcaa aattgaagtt 720
atgtatcctc ctccttacct agacaatgag aagagcaatg gaaccattat ccatgtgaaa 780
gggaaacacc tttgtccaag tcccctattt cccggacctt ctaagccctt ttgggtgctg 840
gtggtggttg ggggagtcct ggcttgctat agcttgctag taacagtggc ctttattatt 900
ttctgggtga ggagtaagag gagcaggctc ctgcacagtg actacatgaa catgactccc 960
cgccgccccg ggcccacccg caagcattac cagccctatg ccccaccacg cgacttcgca 1020
gcctatcgct ccctgagagt gaagttcagc aggagcgcag acgcccccgc gtaccagcag 1080
ggccagaacc agctctataa cgagctcaat ctaggacgaa gagaggagta cgatgttttg 1140
gacaagagac gtggccggga ccctgagatg gggggaaagc cgagaaggaa gaaccctcag 1200
gaaggcctgt acaatgaact gcagaaagat aagatggcgg aggcctacag tgagattggg 1260
atgaaaggcg agcgccggag gggcaagggg cacgatggcc tttaccaggg tctcagtaca 1320
gccaccaagg acacctacga cgcccttcac atgcaggccc tgccccctcg cggatctggc 1380
gccaccaact tctctctgct gaagcaggcc ggcgacgtgg aggagaaccc aggcccaatg 1440
gtgagcaagg gcgaggagct gttcaccggg gtggtgccca tcctggtcga gctggacggc 1500
gacgtaaacg gccacaagtt cagcgtgtcc ggcgagggcg agggcgatgc cacctacggc 1560
aagctgaccc tgaagttcat ctgcaccacc ggcaagctgc ccgtgccctg gcccaccctc 1620
gtgaccaccc tgacctacgg cgtgcagtgc ttcagccgct accccgacca catgaagcag 1680
cacgacttct tcaagtccgc catgcccgaa ggctacgtcc aggagcgcac catcttcttc 1740
aaggacgacg gcaactacaa gacccgcgcc gaggtgaagt tcgagggcga caccctggtg 1800
aaccgcatcg agctgaaggg catcgacttc aaggaggacg gcaacatcct ggggcacaag 1860
ctggagtaca actacaacag ccacaacgtc tatatcatgg ccgacaagca gaagaacggc 1920
atcaaggtga acttcaagat ccgccacaac atcgaggacg gcagcgtgca gctcgccgac 1980
cactaccagc agaacacccc catcggcgac ggccccgtgc tgctgcccga caaccactac 2040
ctgagcaccc agtccgccct gagcaaagac cccaacgaga agcgcgatca catggtcctg 2100
ctggagttcg tgaccgccgc cgggatcact ctcggcatgg acgagctgta caagtaa 2157
<210> 116
<211> 2166
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 116
gacattgtga tgacccagtc tcacaaattc atgtccacat cagtaggaga cagggtcagc 60
atcacctgca aggccagtca ggatgtgact actgctgtag cctggtatca acaaaaacca 120
gggcaatctc ctaaagtact gattttctgg gcatccaccc ggcacactgg agtccctgat 180
cgcttcacag gcagtggatc tgggacagat tatactctca ccatcagcag tgtgcaggct 240
gaagacctgg cactttatta ctgtcagcaa tattatagaa ctcctcggac gttcggtgga 300
ggcaccaaac tggaaatcaa aggtggcggt ggctcgggcg gtggtgggtc gggtggcggc 360
ggatctcagg tgcagctgaa ggagtcagga cctggcctgg tggcgccctc acagaacctg 420
tccatcacat gcactgtctc tgggttctca ttaaccagct atgctataaa ctgggttcgc 480
cagccaccag gaaagggtct ggagtggctt ggaataatat ggactggtgg aggcacaaat 540
tataattcag ctctcaaatc cagactgagc atcagcaaag acaactccaa gagtcaagtt 600
ttcttaaaaa tgaacagtct gcaaactgat gacacagcca ggtactactg tgcctcgggg 660
gtgtactact ttgactactg gggcctaggc accactctca cagtctcctc aaccacgacg 720
ccagcgccgc gaccaccaac accggcgccc accatcgcgt cgcagcccct gtccctgcgc 780
ccagaggcgt gccggccagc ggcggggggc gcagtgcaca cgagggggct ggacttcgcc 840
tgtgatatct acatctgggc gcccttggcc gggacttgtg gggtccttct cctgtcactg 900
gttatcaccc tttactgcaa acggggcaga aagaaactcc tgtatatatt caaacaacca 960
tttatgagac cagtacaaac tactcaagag gaagatggct gtagctgccg atttccagaa 1020
gaagaagaag gaggatgtga actgagagtg aagttcagca ggagcgcaga cgcccccgcg 1080
taccagcagg gccagaacca gctctataac gagctcaatc taggacgaag agaggagtac 1140
gatgttttgg acaagagacg tggccgggac cctgagatgg ggggaaagcc gagaaggaag 1200
aaccctcagg aaggcctgta caatgaactg cagaaagata agatggcgga ggcctacagt 1260
gagattggga tgaaaggcga gcgccggagg ggcaaggggc acgatggcct ttaccagggt 1320
ctcagtacag ccaccaagga cacctacgac gcccttcaca tgcaggccct gccccctcgc 1380
ggatctggcg ccaccaactt ctctctgctg aagcaggccg gcgacgtgga ggagaaccca 1440
ggcccaatgg tgagcaaggg cgaggagctg ttcaccgggg tggtgcccat cctggtcgag 1500
ctggacggcg acgtaaacgg ccacaagttc agcgtgtccg gcgagggcga gggcgatgcc 1560
acctacggca agctgaccct gaagttcatc tgcaccaccg gcaagctgcc cgtgccctgg 1620
cccaccctcg tgaccaccct gacctacggc gtgcagtgct tcagccgcta ccccgaccac 1680
atgaagcagc acgacttctt caagtccgcc atgcccgaag gctacgtcca ggagcgcacc 1740
atcttcttca aggacgacgg caactacaag acccgcgccg aggtgaagtt cgagggcgac 1800
accctggtga accgcatcga gctgaagggc atcgacttca aggaggacgg caacatcctg 1860
gggcacaagc tggagtacaa ctacaacagc cacaacgtct atatcatggc cgacaagcag 1920
aagaacggca tcaaggtgaa cttcaagatc cgccacaaca tcgaggacgg cagcgtgcag 1980
ctcgccgacc actaccagca gaacaccccc atcggcgacg gccccgtgct gctgcccgac 2040
aaccactacc tgagcaccca gtccgccctg agcaaagacc ccaacgagaa gcgcgatcac 2100
atggtcctgc tggagttcgt gaccgccgcc gggatcactc tcggcatgga cgagctgtac 2160
aagtaa 2166
<210> 117
<211> 2175
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 117
gaggtgaagc tgcaggaatc tggagctgag ctggtgaagc ctggggcttc agtgaagatc 60
tcctgcaagg cttctggcta cacattcaat gactacaaca tggactatct gaagcagagc 120
catggaaaga gccttgagtg gattggagat attaatccta actatgatag cactatctac 180
aaccagaagt tcaagggcaa ggccacattg actgtagaca agtcctccag cacagcctac 240
atggagctcc gcagcctgac atctgaggac tctgcagtct attactgtgc aagacgagac 300
tacgatggta ggaggggggc ctggttttct tactggggcc aagggactct ggtcactgtc 360
tctgcaggtg gcggtggctc gggcggtggt gggtcgggtg gcggcggatc tcaaattgtt 420
ctcacccagt ctccagcact catgtctgca tctccagggg agaaggtcac cgtgacctgc 480
actgccagct caagtgtaag ttacatgtac tggtaccagc agaagccaag atcctccccc 540
aaaccctgga tttatctcac atccaacctg gcttctggag tccctactcg cttcagtggc 600
agtgggtctg ggacctctta ttctctcaca atcagcagca tggaggctga agatgctgcc 660
acttattact gccagcagtg ggatagtaac ccgctcacgt tcggtgctgg gaccaaactg 720
gagctgaaaa ttgaagttat gtatcctcct ccttacctag acaatgagaa gagcaatgga 780
accattatcc atgtgaaagg gaaacacctt tgtccaagtc ccctatttcc cggaccttct 840
aagccctttt gggtgctggt ggtggttggg ggagtcctgg cttgctatag cttgctagta 900
acagtggcct ttattatttt ctgggtgagg agtaagagga gcaggctcct gcacagtgac 960
tacatgaaca tgactccccg ccgccccggg cccacccgca agcattacca gccctatgcc 1020
ccaccacgcg acttcgcagc ctatcgctcc ctgagagtga agttcagcag gagcgcagac 1080
gcccccgcgt accagcaggg ccagaaccag ctctataacg agctcaatct aggacgaaga 1140
gaggagtacg atgttttgga caagagacgt ggccgggacc ctgagatggg gggaaagccg 1200
agaaggaaga accctcagga aggcctgtac aatgaactgc agaaagataa gatggcggag 1260
gcctacagtg agattgggat gaaaggcgag cgccggaggg gcaaggggca cgatggcctt 1320
taccagggtc tcagtacagc caccaaggac acctacgacg cccttcacat gcaggccctg 1380
ccccctcgcg gatctggcgc caccaacttc tctctgctga agcaggccgg cgacgtggag 1440
gagaacccag gcccaatggt gagcaagggc gaggagctgt tcaccggggt ggtgcccatc 1500
ctggtcgagc tggacggcga cgtaaacggc cacaagttca gcgtgtccgg cgagggcgag 1560
ggcgatgcca cctacggcaa gctgaccctg aagttcatct gcaccaccgg caagctgccc 1620
gtgccctggc ccaccctcgt gaccaccctg acctacggcg tgcagtgctt cagccgctac 1680
cccgaccaca tgaagcagca cgacttcttc aagtccgcca tgcccgaagg ctacgtccag 1740
gagcgcacca tcttcttcaa ggacgacggc aactacaaga cccgcgccga ggtgaagttc 1800
gagggcgaca ccctggtgaa ccgcatcgag ctgaagggca tcgacttcaa ggaggacggc 1860
aacatcctgg ggcacaagct ggagtacaac tacaacagcc acaacgtcta tatcatggcc 1920
gacaagcaga agaacggcat caaggtgaac ttcaagatcc gccacaacat cgaggacggc 1980
agcgtgcagc tcgccgacca ctaccagcag aacaccccca tcggcgacgg ccccgtgctg 2040
ctgcccgaca accactacct gagcacccag tccgccctga gcaaagaccc caacgagaag 2100
cgcgatcaca tggtcctgct ggagttcgtg accgccgccg ggatcactct cggcatggac 2160
gagctgtaca agtaa 2175
<210> 118
<211> 2184
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 118
caaattgttc tcacccagtc tccagcactc atgtctgcat ctccagggga gaaggtcacc 60
gtgacctgca ctgccagctc aagtgtaagt tacatgtact ggtaccagca gaagccaaga 120
tcctccccca aaccctggat ttatctcaca tccaacctgg cttctggagt ccctactcgc 180
ttcagtggca gtgggtctgg gacctcttat tctctcacaa tcagcagcat ggaggctgaa 240
gatgctgcca cttattactg ccagcagtgg gatagtaacc cgctcacgtt cggtgctggg 300
accaaactgg agctgaaagg tggcggtggc tcgggcggtg gtgggtcggg tggcggcgga 360
tctgaggtga agctgcagga atctggagct gagctggtga agcctggggc ttcagtgaag 420
atctcctgca aggcttctgg ctacacattc aatgactaca acatggacta tctgaagcag 480
agccatggaa agagccttga gtggattgga gatattaatc ctaactatga tagcactatc 540
tacaaccaga agttcaaggg caaggccaca ttgactgtag acaagtcctc cagcacagcc 600
tacatggagc tccgcagcct gacatctgag gactctgcag tctattactg tgcaagacga 660
gactacgatg gtaggagggg ggcctggttt tcttactggg gccaagggac tctggtcact 720
gtctctgcaa ccacgacgcc agcgccgcga ccaccaacac cggcgcccac catcgcgtcg 780
cagcccctgt ccctgcgccc agaggcgtgc cggccagcgg cggggggcgc agtgcacacg 840
agggggctgg acttcgcctg tgatatctac atctgggcgc ccttggccgg gacttgtggg 900
gtccttctcc tgtcactggt tatcaccctt tactgcaaac ggggcagaaa gaaactcctg 960
tatatattca aacaaccatt tatgagacca gtacaaacta ctcaagagga agatggctgt 1020
agctgccgat ttccagaaga agaagaagga ggatgtgaac tgagagtgaa gttcagcagg 1080
agcgcagacg cccccgcgta ccagcagggc cagaaccagc tctataacga gctcaatcta 1140
ggacgaagag aggagtacga tgttttggac aagagacgtg gccgggaccc tgagatgggg 1200
ggaaagccga gaaggaagaa ccctcaggaa ggcctgtaca atgaactgca gaaagataag 1260
atggcggagg cctacagtga gattgggatg aaaggcgagc gccggagggg caaggggcac 1320
gatggccttt accagggtct cagtacagcc accaaggaca cctacgacgc ccttcacatg 1380
caggccctgc cccctcgcgg atctggcgcc accaacttct ctctgctgaa gcaggccggc 1440
gacgtggagg agaacccagg cccaatggtg agcaagggcg aggagctgtt caccggggtg 1500
gtgcccatcc tggtcgagct ggacggcgac gtaaacggcc acaagttcag cgtgtccggc 1560
gagggcgagg gcgatgccac ctacggcaag ctgaccctga agttcatctg caccaccggc 1620
aagctgcccg tgccctggcc caccctcgtg accaccctga cctacggcgt gcagtgcttc 1680
agccgctacc ccgaccacat gaagcagcac gacttcttca agtccgccat gcccgaaggc 1740
tacgtccagg agcgcaccat cttcttcaag gacgacggca actacaagac ccgcgccgag 1800
gtgaagttcg agggcgacac cctggtgaac cgcatcgagc tgaagggcat cgacttcaag 1860
gaggacggca acatcctggg gcacaagctg gagtacaact acaacagcca caacgtctat 1920
atcatggccg acaagcagaa gaacggcatc aaggtgaact tcaagatccg ccacaacatc 1980
gaggacggca gcgtgcagct cgccgaccac taccagcaga acacccccat cggcgacggc 2040
cccgtgctgc tgcccgacaa ccactacctg agcacccagt ccgccctgag caaagacccc 2100
aacgagaagc gcgatcacat ggtcctgctg gagttcgtga ccgccgccgg gatcactctc 2160
ggcatggacg agctgtacaa gtaa 2184
<210> 119
<211> 1377
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 119
ggtgtccagt gtgacgtgaa gttggtggag tctgggggag gcttagtgaa gcctggaggg 60
tccctgaaac tctcctgtgc agcctctgga ttcactttca gtagatacac catgtcttgg 120
gttcgccaga ctccggagaa gaggctggag tgggtcgcaa ccattagtaa tagtggtagt 180
tatacctact atcgagacag tgtgaagggc cgattcacca tctccagaga caatgccaag 240
aacaccctgt acctgcaaat gagcagtctg aagtctgagg acacagccat gtattactgt 300
acaagggggt cgccctgggg ccaagggact ctggtcactg tctctgcagg tggcggtggc 360
tcgggcggtg gtgggtcggg tggcggcgga tctgacatcc agatgactca gtctccagat 420
tcactgtctg catctgtggg agaaactgtc accatcacat gtggagcaag tgagaacatt 480
tacggtgctt taaattggta tcagcggaaa cagggaaaat ctcctcagct cctgatctat 540
ggtgcaacca agttggcaga tggcatgtca tcgaggttca gtggcagtgg atctaataga 600
cagtattctc tcaagatcag tagcctgcat cctgacgatg ttgcaacgta ttactgtcaa 660
aatgtgttaa gtaagccgta cgcgttcgga ggggggacca aactggaaat aaaaattgaa 720
gttatgtatc ctcctcctta cctagacaat gagaagagca atggaaccat tatccatgtg 780
aaagggaaac acctttgtcc aagtccccta tttcccggac cttctaagcc cttttgggtg 840
ctggtggtgg ttgggggagt cctggcttgc tatagcttgc tagtaacagt ggcctttatt 900
attttctggg tgaggagtaa gaggagcagg ctcctgcaca gtgactacat gaacatgact 960
ccccgccgcc ccgggcccac ccgcaagcat taccagccct atgccccacc acgcgacttc 1020
gcagcctatc gctccctgag agtgaagttc agcaggagcg cagacgcccc cgcgtaccag 1080
cagggccaga accagctcta taacgagctc aatctaggac gaagagagga gtacgatgtt 1140
ttggacaaga gacgtggccg ggaccctgag atggggggaa agccgagaag gaagaaccct 1200
caggaaggcc tgtacaatga actgcagaaa gataagatgg cggaggccta cagtgagatt 1260
gggatgaaag gcgagcgccg gaggggcaag gggcacgatg gcctttacca gggtctcagt 1320
acagccacca aggacaccta cgacgccctt cacatgcagg ccctgccccc tcgctaa 1377
<210> 120
<211> 1377
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 120
gacatccaga tgactcagtc tccagattca ctgtctgcat ctgtgggaga aactgtcacc 60
atcacatgtg gagcaagtga gaacatttac ggtgctttaa attggtatca gcggaaacag 120
ggaaaatctc ctcagctcct gatctatggt gcaaccaagt tggcagatgg catgtcatcg 180
aggttcagtg gcagtggatc taatagacag tattctctca agatcagtag cctgcatcct 240
gacgatgttg caacgtatta ctgtcaaaat gtgttaagta agccgtacgc gttcggaggg 300
gggaccaaac tggaaataaa aggtggcggt ggctcgggcg gtggtgggtc gggtggcggc 360
ggatctggtg tccagtgtga cgtgaagttg gtggagtctg ggggaggctt agtgaagcct 420
ggagggtccc tgaaactctc ctgtgcagcc tctggattca ctttcagtag atacaccatg 480
tcttgggttc gccagactcc ggagaagagg ctggagtggg tcgcaaccat tagtaatagt 540
ggtagttata cctactatcg agacagtgtg aagggccgat tcaccatctc cagagacaat 600
gccaagaaca ccctgtacct gcaaatgagc agtctgaagt ctgaggacac agccatgtat 660
tactgtacaa gggggtcgcc ctggggccaa gggactctgg tcactgtctc tgcaattgaa 720
gttatgtatc ctcctcctta cctagacaat gagaagagca atggaaccat tatccatgtg 780
aaagggaaac acctttgtcc aagtccccta tttcccggac cttctaagcc cttttgggtg 840
ctggtggtgg ttgggggagt cctggcttgc tatagcttgc tagtaacagt ggcctttatt 900
attttctggg tgaggagtaa gaggagcagg ctcctgcaca gtgactacat gaacatgact 960
ccccgccgcc ccgggcccac ccgcaagcat taccagccct atgccccacc acgcgacttc 1020
gcagcctatc gctccctgag agtgaagttc agcaggagcg cagacgcccc cgcgtaccag 1080
cagggccaga accagctcta taacgagctc aatctaggac gaagagagga gtacgatgtt 1140
ttggacaaga gacgtggccg ggaccctgag atggggggaa agccgagaag gaagaaccct 1200
caggaaggcc tgtacaatga actgcagaaa gataagatgg cggaggccta cagtgagatt 1260
gggatgaaag gcgagcgccg gaggggcaag gggcacgatg gcctttacca gggtctcagt 1320
acagccacca aggacaccta cgacgccctt cacatgcagg ccctgccccc tcgctaa 1377
<210> 121
<211> 1404
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 121
gaggtgaagc tgcagcaatc aggggctgac ctggcaacac ctggggcttc agtgaagttg 60
tcctgcaagg cttctggcta tacctttagt acctactgga tgcagtgggt aaaacagagg 120
cctggacagg gtctggaatg gattgggact atttatcctg gagatggtga tactaggtac 180
actcagaagt tcaagggcaa ggccacattg actgcagata aatcctccag tacagcccac 240
atgcaactca gcagcttggc atctgaggac tctgcggtct attattgtgc aagaggggga 300
ctctattatg gttacgacat tgcttactgg ggccaaggga ctctggtcac tgtctctgca 360
ggtggcggtg gctcgggcgg tggtgggtcg ggtggcggcg gatctgatat tttgatgacc 420
caaactccac tctccctgcc tgtcagtctt ggagatcaag cctccatctc ttgcagatct 480
agtcagagca ttgtacatag taatggaaac acctatttag aatggtacct gcagaaacca 540
ggccagtctc caaagcccct gataaagaaa gtctccaacc gattttctgg ggtcccagac 600
aggttcagtg gcagtggatc agggacagaa ttcacactca agatcagcag agtggaggct 660
gaggatctgg gagtttatta ctgctttcaa ggttcacatg ttccattcac gttcggctcg 720
gggacaaagt tggaaataaa aattgaagtt atgtatcctc ctccttacct agacaatgag 780
aagagcaatg gaaccattat ccatgtgaaa gggaaacacc tttgtccaag tcccctattt 840
cccggacctt ctaagccctt ttgggtgctg gtggtggttg ggggagtcct ggcttgctat 900
agcttgctag taacagtggc ctttattatt ttctgggtga ggagtaagag gagcaggctc 960
ctgcacagtg actacatgaa catgactccc cgccgccccg ggcccacccg caagcattac 1020
cagccctatg ccccaccacg cgacttcgca gcctatcgct ccctgagagt gaagttcagc 1080
aggagcgcag acgcccccgc gtaccagcag ggccagaacc agctctataa cgagctcaat 1140
ctaggacgaa gagaggagta cgatgttttg gacaagagac gtggccggga ccctgagatg 1200
gggggaaagc cgagaaggaa gaaccctcag gaaggcctgt acaatgaact gcagaaagat 1260
aagatggcgg aggcctacag tgagattggg atgaaaggcg agcgccggag gggcaagggg 1320
cacgatggcc tttaccaggg tctcagtaca gccaccaagg acacctacga cgcccttcac 1380
atgcaggccc tgccccctcg ctaa 1404
<210> 122
<211> 1404
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 122
gatattttga tgacccaaac tccactctcc ctgcctgtca gtcttggaga tcaagcctcc 60
atctcttgca gatctagtca gagcattgta catagtaatg gaaacaccta tttagaatgg 120
tacctgcaga aaccaggcca gtctccaaag cccctgataa agaaagtctc caaccgattt 180
tctggggtcc cagacaggtt cagtggcagt ggatcaggga cagaattcac actcaagatc 240
agcagagtgg aggctgagga tctgggagtt tattactgct ttcaaggttc acatgttcca 300
ttcacgttcg gctcggggac aaagttggaa ataaaaggtg gcggtggctc gggcggtggt 360
gggtcgggtg gcggcggatc tgaggtgaag ctgcagcaat caggggctga cctggcaaca 420
cctggggctt cagtgaagtt gtcctgcaag gcttctggct atacctttag tacctactgg 480
atgcagtggg taaaacagag gcctggacag ggtctggaat ggattgggac tatttatcct 540
ggagatggtg atactaggta cactcagaag ttcaagggca aggccacatt gactgcagat 600
aaatcctcca gtacagccca catgcaactc agcagcttgg catctgagga ctctgcggtc 660
tattattgtg caagaggggg actctattat ggttacgaca ttgcttactg gggccaaggg 720
actctggtca ctgtctctgc aattgaagtt atgtatcctc ctccttacct agacaatgag 780
aagagcaatg gaaccattat ccatgtgaaa gggaaacacc tttgtccaag tcccctattt 840
cccggacctt ctaagccctt ttgggtgctg gtggtggttg ggggagtcct ggcttgctat 900
agcttgctag taacagtggc ctttattatt ttctgggtga ggagtaagag gagcaggctc 960
ctgcacagtg actacatgaa catgactccc cgccgccccg ggcccacccg caagcattac 1020
cagccctatg ccccaccacg cgacttcgca gcctatcgct ccctgagagt gaagttcagc 1080
aggagcgcag acgcccccgc gtaccagcag ggccagaacc agctctataa cgagctcaat 1140
ctaggacgaa gagaggagta cgatgttttg gacaagagac gtggccggga ccctgagatg 1200
gggggaaagc cgagaaggaa gaaccctcag gaaggcctgt acaatgaact gcagaaagat 1260
aagatggcgg aggcctacag tgagattggg atgaaaggcg agcgccggag gggcaagggg 1320
cacgatggcc tttaccaggg tctcagtaca gccaccaagg acacctacga cgcccttcac 1380
atgcaggccc tgccccctcg ctaa 1404
<210> 123
<211> 1389
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 123
gaggtgaagc tggtggagtc tggaggaggc ttggtccagc cgggggggtc tctgagactc 60
tcctgttcaa tttctggatt caccttcact gattactaca tgaactgggt ccgccagtct 120
ccaggaaagg cacttgagtg gttgggtttt attagaaaca aagttaatgg tgacacaaca 180
gaatatagtg catctgtgaa gggtcggttc accatctcca gagatatttc ccagagcatc 240
ctctatcttc aaatgaacac cctgagaact gaggacagtg ccacttatta ctgtgcgaga 300
gataagggaa tagcgtacta ctttgactat tggggccaag gcaccactct cacagtctcc 360
tcaggtggcg gtggctcggg cggtggtggg tcgggtggcg gcggatctca aattgttctc 420
tcccagtctc cagcaatcct gtttgcatct ccaggggaga aggtcacaat gacttgtagg 480
gccagctcaa gtgtaagtta cattcactgg taccagcaga agccaggatc ctcccccaaa 540
ccctggattc atggcacatc caacctggct tctggagtcc ctgctcgctt cagtggcagt 600
gggtctggga cctcttactc tctcacaatc agcagaatgg aggctgaaga tgccgccaca 660
tattactgcc agcagtggag tagtaattta tccacgttcg gaggggggac caagctggaa 720
ataaaaattg aagttatgta tcctcctcct tacctagaca atgagaagag caatggaacc 780
attatccatg tgaaagggaa acacctttgt ccaagtcccc tatttcccgg accttctaag 840
cccttttggg tgctggtggt ggttggggga gtcctggctt gctatagctt gctagtaaca 900
gtggccttta ttattttctg ggtgaggagt aagaggagca ggctcctgca cagtgactac 960
atgaacatga ctccccgccg ccccgggccc acccgcaagc attaccagcc ctatgcccca 1020
ccacgcgact tcgcagccta tcgctccctg agagtgaagt tcagcaggag cgcagacgcc 1080
cccgcgtacc agcagggcca gaaccagctc tataacgagc tcaatctagg acgaagagag 1140
gagtacgatg ttttggacaa gagacgtggc cgggaccctg agatgggggg aaagccgaga 1200
aggaagaacc ctcaggaagg cctgtacaat gaactgcaga aagataagat ggcggaggcc 1260
tacagtgaga ttgggatgaa aggcgagcgc cggaggggca aggggcacga tggcctttac 1320
cagggtctca gtacagccac caaggacacc tacgacgccc ttcacatgca ggccctgccc 1380
cctcgctaa 1389
<210> 124
<211> 1389
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 124
caaattgttc tctcccagtc tccagcaatc ctgtttgcat ctccagggga gaaggtcaca 60
atgacttgta gggccagctc aagtgtaagt tacattcact ggtaccagca gaagccagga 120
tcctccccca aaccctggat tcatggcaca tccaacctgg cttctggagt ccctgctcgc 180
ttcagtggca gtgggtctgg gacctcttac tctctcacaa tcagcagaat ggaggctgaa 240
gatgccgcca catattactg ccagcagtgg agtagtaatt tatccacgtt cggagggggg 300
accaagctgg aaataaaagg tggcggtggc tcgggcggtg gtgggtcggg tggcggcgga 360
tctgaggtga agctggtgga gtctggagga ggcttggtcc agccgggggg gtctctgaga 420
ctctcctgtt caatttctgg attcaccttc actgattact acatgaactg ggtccgccag 480
tctccaggaa aggcacttga gtggttgggt tttattagaa acaaagttaa tggtgacaca 540
acagaatata gtgcatctgt gaagggtcgg ttcaccatct ccagagatat ttcccagagc 600
atcctctatc ttcaaatgaa caccctgaga actgaggaca gtgccactta ttactgtgcg 660
agagataagg gaatagcgta ctactttgac tattggggcc aaggcaccac tctcacagtc 720
tcctcaattg aagttatgta tcctcctcct tacctagaca atgagaagag caatggaacc 780
attatccatg tgaaagggaa acacctttgt ccaagtcccc tatttcccgg accttctaag 840
cccttttggg tgctggtggt ggttggggga gtcctggctt gctatagctt gctagtaaca 900
gtggccttta ttattttctg ggtgaggagt aagaggagca ggctcctgca cagtgactac 960
atgaacatga ctccccgccg ccccgggccc acccgcaagc attaccagcc ctatgcccca 1020
ccacgcgact tcgcagccta tcgctccctg agagtgaagt tcagcaggag cgcagacgcc 1080
cccgcgtacc agcagggcca gaaccagctc tataacgagc tcaatctagg acgaagagag 1140
gagtacgatg ttttggacaa gagacgtggc cgggaccctg agatgggggg aaagccgaga 1200
aggaagaacc ctcaggaagg cctgtacaat gaactgcaga aagataagat ggcggaggcc 1260
tacagtgaga ttgggatgaa aggcgagcgc cggaggggca aggggcacga tggcctttac 1320
cagggtctca gtacagccac caaggacacc tacgacgccc ttcacatgca ggccctgccc 1380
cctcgctaa 1389
<210> 125
<211> 1374
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 125
caggtgcagc tgaaggagtc aggacctggc ctggtggcgc cctcacagaa cctgtccatc 60
acatgcactg tctctgggtt ctcattaacc agctatgcta taaactgggt tcgccagcca 120
ccaggaaagg gtctggagtg gcttggaata atatggactg gtggaggcac aaattataat 180
tcagctctca aatccagact gagcatcagc aaagacaact ccaagagtca agttttctta 240
aaaatgaaca gtctgcaaac tgatgacaca gccaggtact actgtgcctc gggggtgtac 300
tactttgact actggggcct aggcaccact ctcacagtct cctcaggtgg cggtggctcg 360
ggcggtggtg ggtcgggtgg cggcggatct gacattgtga tgacccagtc tcacaaattc 420
atgtccacat cagtaggaga cagggtcagc atcacctgca aggccagtca ggatgtgact 480
actgctgtag cctggtatca acaaaaacca gggcaatctc ctaaagtact gattttctgg 540
gcatccaccc ggcacactgg agtccctgat cgcttcacag gcagtggatc tgggacagat 600
tatactctca ccatcagcag tgtgcaggct gaagacctgg cactttatta ctgtcagcaa 660
tattatagaa ctcctcggac gttcggtgga ggcaccaaac tggaaatcaa aattgaagtt 720
atgtatcctc ctccttacct agacaatgag aagagcaatg gaaccattat ccatgtgaaa 780
gggaaacacc tttgtccaag tcccctattt cccggacctt ctaagccctt ttgggtgctg 840
gtggtggttg ggggagtcct ggcttgctat agcttgctag taacagtggc ctttattatt 900
ttctgggtga ggagtaagag gagcaggctc ctgcacagtg actacatgaa catgactccc 960
cgccgccccg ggcccacccg caagcattac cagccctatg ccccaccacg cgacttcgca 1020
gcctatcgct ccctgagagt gaagttcagc aggagcgcag acgcccccgc gtaccagcag 1080
ggccagaacc agctctataa cgagctcaat ctaggacgaa gagaggagta cgatgttttg 1140
gacaagagac gtggccggga ccctgagatg gggggaaagc cgagaaggaa gaaccctcag 1200
gaaggcctgt acaatgaact gcagaaagat aagatggcgg aggcctacag tgagattggg 1260
atgaaaggcg agcgccggag gggcaagggg cacgatggcc tttaccaggg tctcagtaca 1320
gccaccaagg acacctacga cgcccttcac atgcaggccc tgccccctcg ctaa 1374
<210> 126
<211> 1374
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 126
gacattgtga tgacccagtc tcacaaattc atgtccacat cagtaggaga cagggtcagc 60
atcacctgca aggccagtca ggatgtgact actgctgtag cctggtatca acaaaaacca 120
gggcaatctc ctaaagtact gattttctgg gcatccaccc ggcacactgg agtccctgat 180
cgcttcacag gcagtggatc tgggacagat tatactctca ccatcagcag tgtgcaggct 240
gaagacctgg cactttatta ctgtcagcaa tattatagaa ctcctcggac gttcggtgga 300
ggcaccaaac tggaaatcaa aggtggcggt ggctcgggcg gtggtgggtc gggtggcggc 360
ggatctcagg tgcagctgaa ggagtcagga cctggcctgg tggcgccctc acagaacctg 420
tccatcacat gcactgtctc tgggttctca ttaaccagct atgctataaa ctgggttcgc 480
cagccaccag gaaagggtct ggagtggctt ggaataatat ggactggtgg aggcacaaat 540
tataattcag ctctcaaatc cagactgagc atcagcaaag acaactccaa gagtcaagtt 600
ttcttaaaaa tgaacagtct gcaaactgat gacacagcca ggtactactg tgcctcgggg 660
gtgtactact ttgactactg gggcctaggc accactctca cagtctcctc aattgaagtt 720
atgtatcctc ctccttacct agacaatgag aagagcaatg gaaccattat ccatgtgaaa 780
gggaaacacc tttgtccaag tcccctattt cccggacctt ctaagccctt ttgggtgctg 840
gtggtggttg ggggagtcct ggcttgctat agcttgctag taacagtggc ctttattatt 900
ttctgggtga ggagtaagag gagcaggctc ctgcacagtg actacatgaa catgactccc 960
cgccgccccg ggcccacccg caagcattac cagccctatg ccccaccacg cgacttcgca 1020
gcctatcgct ccctgagagt gaagttcagc aggagcgcag acgcccccgc gtaccagcag 1080
ggccagaacc agctctataa cgagctcaat ctaggacgaa gagaggagta cgatgttttg 1140
gacaagagac gtggccggga ccctgagatg gggggaaagc cgagaaggaa gaaccctcag 1200
gaaggcctgt acaatgaact gcagaaagat aagatggcgg aggcctacag tgagattggg 1260
atgaaaggcg agcgccggag gggcaagggg cacgatggcc tttaccaggg tctcagtaca 1320
gccaccaagg acacctacga cgcccttcac atgcaggccc tgccccctcg ctaa 1374
<210> 127
<211> 1392
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 127
gaggtgaagc tgcaggaatc tggagctgag ctggtgaagc ctggggcttc agtgaagatc 60
tcctgcaagg cttctggcta cacattcaat gactacaaca tggactatct gaagcagagc 120
catggaaaga gccttgagtg gattggagat attaatccta actatgatag cactatctac 180
aaccagaagt tcaagggcaa ggccacattg actgtagaca agtcctccag cacagcctac 240
atggagctcc gcagcctgac atctgaggac tctgcagtct attactgtgc aagacgagac 300
tacgatggta ggaggggggc ctggttttct tactggggcc aagggactct ggtcactgtc 360
tctgcaggtg gcggtggctc gggcggtggt gggtcgggtg gcggcggatc tcaaattgtt 420
ctcacccagt ctccagcact catgtctgca tctccagggg agaaggtcac cgtgacctgc 480
actgccagct caagtgtaag ttacatgtac tggtaccagc agaagccaag atcctccccc 540
aaaccctgga tttatctcac atccaacctg gcttctggag tccctactcg cttcagtggc 600
agtgggtctg ggacctctta ttctctcaca atcagcagca tggaggctga agatgctgcc 660
acttattact gccagcagtg ggatagtaac ccgctcacgt tcggtgctgg gaccaaactg 720
gagctgaaaa ttgaagttat gtatcctcct ccttacctag acaatgagaa gagcaatgga 780
accattatcc atgtgaaagg gaaacacctt tgtccaagtc ccctatttcc cggaccttct 840
aagccctttt gggtgctggt ggtggttggg ggagtcctgg cttgctatag cttgctagta 900
acagtggcct ttattatttt ctgggtgagg agtaagagga gcaggctcct gcacagtgac 960
tacatgaaca tgactccccg ccgccccggg cccacccgca agcattacca gccctatgcc 1020
ccaccacgcg acttcgcagc ctatcgctcc ctgagagtga agttcagcag gagcgcagac 1080
gcccccgcgt accagcaggg ccagaaccag ctctataacg agctcaatct aggacgaaga 1140
gaggagtacg atgttttgga caagagacgt ggccgggacc ctgagatggg gggaaagccg 1200
agaaggaaga accctcagga aggcctgtac aatgaactgc agaaagataa gatggcggag 1260
gcctacagtg agattgggat gaaaggcgag cgccggaggg gcaaggggca cgatggcctt 1320
taccagggtc tcagtacagc caccaaggac acctacgacg cccttcacat gcaggccctg 1380
ccccctcgct aa 1392
<210> 128
<211> 1392
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 128
caaattgttc tcacccagtc tccagcactc atgtctgcat ctccagggga gaaggtcacc 60
gtgacctgca ctgccagctc aagtgtaagt tacatgtact ggtaccagca gaagccaaga 120
tcctccccca aaccctggat ttatctcaca tccaacctgg cttctggagt ccctactcgc 180
ttcagtggca gtgggtctgg gacctcttat tctctcacaa tcagcagcat ggaggctgaa 240
gatgctgcca cttattactg ccagcagtgg gatagtaacc cgctcacgtt cggtgctggg 300
accaaactgg agctgaaagg tggcggtggc tcgggcggtg gtgggtcggg tggcggcgga 360
tctgaggtga agctgcagga atctggagct gagctggtga agcctggggc ttcagtgaag 420
atctcctgca aggcttctgg ctacacattc aatgactaca acatggacta tctgaagcag 480
agccatggaa agagccttga gtggattgga gatattaatc ctaactatga tagcactatc 540
tacaaccaga agttcaaggg caaggccaca ttgactgtag acaagtcctc cagcacagcc 600
tacatggagc tccgcagcct gacatctgag gactctgcag tctattactg tgcaagacga 660
gactacgatg gtaggagggg ggcctggttt tcttactggg gccaagggac tctggtcact 720
gtctctgcaa ttgaagttat gtatcctcct ccttacctag acaatgagaa gagcaatgga 780
accattatcc atgtgaaagg gaaacacctt tgtccaagtc ccctatttcc cggaccttct 840
aagccctttt gggtgctggt ggtggttggg ggagtcctgg cttgctatag cttgctagta 900
acagtggcct ttattatttt ctgggtgagg agtaagagga gcaggctcct gcacagtgac 960
tacatgaaca tgactccccg ccgccccggg cccacccgca agcattacca gccctatgcc 1020
ccaccacgcg acttcgcagc ctatcgctcc ctgagagtga agttcagcag gagcgcagac 1080
gcccccgcgt accagcaggg ccagaaccag ctctataacg agctcaatct aggacgaaga 1140
gaggagtacg atgttttgga caagagacgt ggccgggacc ctgagatggg gggaaagccg 1200
agaaggaaga accctcagga aggcctgtac aatgaactgc agaaagataa gatggcggag 1260
gcctacagtg agattgggat gaaaggcgag cgccggaggg gcaaggggca cgatggcctt 1320
taccagggtc tcagtacagc caccaaggac acctacgacg cccttcacat gcaggccctg 1380
ccccctcgct aa 1392
<210> 129
<211> 21
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 129
ggattcactt tcagtagata c 21
<210> 130
<211> 18
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 130
agtaatagtg gtagttat 18
<210> 131
<211> 9
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 131
gggtcgccc 9
<210> 132
<211> 33
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 132
ggagcaagtg agaacattta cggtgcttta aat 33
<210> 133
<211> 21
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 133
ggtgcaacca agttggcaga t 21
<210> 134
<211> 27
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 134
caaaatgtgt taagtaagcc gtacgcg 27
<210> 135
<211> 21
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 135
ggctatacct ttagtaccta c 21
<210> 136
<211> 18
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 136
tatcctggag atggtgat 18
<210> 137
<211> 33
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 137
gggggactct attatggtta cgacattgct tac 33
<210> 138
<211> 48
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 138
agatctagtc agagcattgt acatagtaat ggaaacacct atttagaa 48
<210> 139
<211> 21
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 139
aaagtctcca accgattttc t 21
<210> 140
<211> 27
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 140
tttcaaggtt cacatgttcc attcacg 27
<210> 141
<211> 21
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 141
ggattcacct tcactgatta c 21
<210> 142
<211> 24
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 142
agaaacaaag ttaatggtga caca 24
<210> 143
<211> 30
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 143
gataagggaa tagcgtacta ctttgactat 30
<210> 144
<211> 30
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 144
agggccagct caagtgtaag ttacattcac 30
<210> 145
<211> 21
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 145
ggcacatcca acctggcttc t 21
<210> 146
<211> 27
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 146
cagcagtgga gtagtaattt atccacg 27
<210> 147
<211> 21
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 147
gggttctcat taaccagcta t 21
<210> 148
<211> 15
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 148
tggactggtg gaggc 15
<210> 149
<211> 21
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 149
ggggtgtact actttgacta c 21
<210> 150
<211> 33
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 150
aaggccagtc aggatgtgac tactgctgta gcc 33
<210> 151
<211> 21
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 151
tgggcatcca cccggcacac t 21
<210> 152
<211> 27
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 152
cagcaatatt atagaactcc tcggacg 27
<210> 153
<211> 21
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 153
ggctacacat tcaatgacta c 21
<210> 154
<211> 18
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 154
aatcctaact atgatagc 18
<210> 155
<211> 39
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 155
cgagactacg atggtaggag gggggcctgg ttttcttac 39
<210> 156
<211> 30
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 156
actgccagct caagtgtaag ttacatgtac 30
<210> 157
<211> 21
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 157
ctcacatcca acctggcttc t 21
<210> 158
<211> 27
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 158
cagcagtggg atagtaaccc gctcacg 27
<210> 159
<211> 29
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 159
gcggatccgg tgtccagtgt gacgtgaag 29
<210> 160
<211> 28
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 160
gcggatccga catccagatg actcagtc 28
<210> 161
<211> 28
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 161
gcggatccga ggtgaagctg cagcaatc 28
<210> 162
<211> 28
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 162
gcggatccga tattttgatg acccaaac 28
<210> 163
<211> 30
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 163
gcggatccga ggtgaagctg gtggagtctg 30
<210> 164
<211> 28
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 164
gcggatccca aattgttctc tcccagtc 28
<210> 165
<211> 30
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 165
gcggatccca ggtgcagctg aaggagtcag 30
<210> 166
<211> 28
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 166
gcggatccca aattgttctc tcccagtc 28
<210> 167
<211> 30
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 167
gcggatccga ggtgaagctg caggaatctg 30
<210> 168
<211> 28
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 168
gcggatccca aattgttctc acccagtc 28
<210> 169
<211> 29
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 169
gcgaattctt acttgtacag ctcgtccat 29
<210> 170
<211> 29
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 170
gcgaattctt agcgaggggg cagggcctg 29
<210> 171
<211> 238
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 171
Gly Val Gln Cys Asp Val Lys Leu Val Glu Ser Gly Gly Gly Leu Val
1 5 10 15
Lys Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr
20 25 30
Phe Ser Arg Tyr Thr Met Ser Trp Val Arg Gln Thr Pro Glu Lys Arg
35 40 45
Leu Glu Trp Val Ala Thr Ile Ser Asn Ser Gly Ser Tyr Thr Tyr Tyr
50 55 60
Arg Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys
65 70 75 80
Asn Thr Leu Tyr Leu Gln Met Ser Ser Leu Lys Ser Glu Asp Thr Ala
85 90 95
Met Tyr Tyr Cys Thr Arg Gly Ser Pro Trp Gly Gln Gly Thr Leu Val
100 105 110
Thr Val Ser Ala Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
115 120 125
Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Asp Ser Leu Ser Ala
130 135 140
Ser Val Gly Glu Thr Val Thr Ile Thr Cys Gly Ala Ser Glu Asn Ile
145 150 155 160
Tyr Gly Ala Leu Asn Trp Tyr Gln Arg Lys Gln Gly Lys Ser Pro Gln
165 170 175
Leu Leu Ile Tyr Gly Ala Thr Lys Leu Ala Asp Gly Met Ser Ser Arg
180 185 190
Phe Ser Gly Ser Gly Ser Asn Arg Gln Tyr Ser Leu Lys Ile Ser Ser
195 200 205
Leu His Pro Asp Asp Val Ala Thr Tyr Tyr Cys Gln Asn Val Leu Ser
210 215 220
Lys Pro Tyr Ala Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
225 230 235
<210> 172
<211> 247
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 172
Glu Val Lys Leu Gln Gln Ser Gly Ala Asp Leu Ala Thr Pro Gly Ala
1 5 10 15
Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Ser Thr Tyr
20 25 30
Trp Met Gln Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Thr Ile Tyr Pro Gly Asp Gly Asp Thr Arg Tyr Thr Gln Lys Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala His
65 70 75 80
Met Gln Leu Ser Ser Leu Ala Ser Glu Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Gly Leu Tyr Tyr Gly Tyr Asp Ile Ala Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ala Gly Gly Gly Gly Ser Gly Gly Gly
115 120 125
Gly Ser Gly Gly Gly Gly Ser Asp Ile Leu Met Thr Gln Thr Pro Leu
130 135 140
Ser Leu Pro Val Ser Leu Gly Asp Gln Ala Ser Ile Ser Cys Arg Ser
145 150 155 160
Ser Gln Ser Ile Val His Ser Asn Gly Asn Thr Tyr Leu Glu Trp Tyr
165 170 175
Leu Gln Lys Pro Gly Gln Ser Pro Lys Pro Leu Ile Lys 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 Glu Phe Thr Leu Lys Ile Ser Arg Val Glu Ala Glu Asp Leu Gly
210 215 220
Val Tyr Tyr Cys Phe Gln Gly Ser His Val Pro Phe Thr Phe Gly Ser
225 230 235 240
Gly Thr Lys Leu Glu Ile Lys
245
<210> 173
<211> 242
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 173
Glu Val Lys Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ser Ile Ser Gly Phe Thr Phe Thr Asp Tyr
20 25 30
Tyr Met Asn Trp Val Arg Gln Ser Pro Gly Lys Ala Leu Glu Trp Leu
35 40 45
Gly Phe Ile Arg Asn Lys Val Asn Gly Asp Thr Thr Glu Tyr Ser Ala
50 55 60
Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Ile Ser Gln Ser Ile
65 70 75 80
Leu Tyr Leu Gln Met Asn Thr Leu Arg Thr Glu Asp Ser Ala Thr Tyr
85 90 95
Tyr Cys Ala Arg Asp Lys Gly Ile Ala Tyr Tyr Phe Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Thr Leu Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly
115 120 125
Gly Gly Ser Gly Gly Gly Gly Ser Gln Ile Val Leu Ser Gln Ser Pro
130 135 140
Ala Ile Leu Phe Ala Ser Pro Gly Glu Lys Val Thr Met Thr Cys Arg
145 150 155 160
Ala Ser Ser Ser Val Ser Tyr Ile His Trp Tyr Gln Gln Lys Pro Gly
165 170 175
Ser Ser Pro Lys Pro Trp Ile His Gly Thr Ser Asn Leu Ala Ser Gly
180 185 190
Val Pro Ala Arg Phe Ser Gly Ser Gly Ser Gly Thr Ser Tyr Ser Leu
195 200 205
Thr Ile Ser Arg Met Glu Ala Glu Asp Ala Ala Thr Tyr Tyr Cys Gln
210 215 220
Gln Trp Ser Ser Asn Leu Ser Thr Phe Gly Gly Gly Thr Lys Leu Glu
225 230 235 240
Ile Lys
<210> 174
<211> 237
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 174
Gln Val Gln Leu Lys Glu Ser Gly Pro Gly Leu Val Ala Pro Ser Gln
1 5 10 15
Asn Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Ser Tyr
20 25 30
Ala Ile Asn Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Leu
35 40 45
Gly Ile Ile Trp Thr Gly Gly Gly Thr Asn Tyr Asn Ser Ala Leu Lys
50 55 60
Ser Arg Leu Ser Ile Ser 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 Arg Tyr Tyr Cys Ala
85 90 95
Ser Gly Val Tyr Tyr Phe Asp Tyr Trp Gly Leu Gly Thr Thr Leu Thr
100 105 110
Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
115 120 125
Gly Ser Asp Ile Val Met Thr Gln Ser His Lys Phe Met Ser Thr Ser
130 135 140
Val Gly Asp Arg Val Ser Ile Thr Cys Lys Ala Ser Gln Asp Val Thr
145 150 155 160
Thr Ala Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Lys Val
165 170 175
Leu Ile Phe Trp Ala Ser Thr Arg His Thr Gly Val Pro Asp Arg Phe
180 185 190
Thr Gly Ser Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Val
195 200 205
Gln Ala Glu Asp Leu Ala Leu Tyr Tyr Cys Gln Gln Tyr Tyr Arg Thr
210 215 220
Pro Arg Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
225 230 235
<210> 175
<211> 243
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 175
Glu Val Lys Leu Gln Glu Ser Gly Ala Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Asn Asp Tyr
20 25 30
Asn Met Asp Tyr Leu Lys Gln Ser His Gly Lys Ser Leu Glu Trp Ile
35 40 45
Gly Asp Ile Asn Pro Asn Tyr Asp Ser Thr Ile Tyr Asn Gln Lys Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Arg Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Arg Asp Tyr Asp Gly Arg Arg Gly Ala Trp Phe Ser Tyr Trp
100 105 110
Gly Gln Gly Thr Leu Val Thr Val Ser Ala Gly Gly Gly Gly Ser Gly
115 120 125
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Ile Val Leu Thr Gln Ser
130 135 140
Pro Ala Leu Met Ser Ala Ser Pro Gly Glu Lys Val Thr Val Thr Cys
145 150 155 160
Thr Ala Ser Ser Ser Val Ser Tyr Met Tyr Trp Tyr Gln Gln Lys Pro
165 170 175
Arg Ser Ser Pro Lys Pro Trp Ile Tyr Leu Thr Ser Asn Leu Ala Ser
180 185 190
Gly Val Pro Thr Arg Phe Ser Gly Ser Gly Ser Gly Thr Ser Tyr Ser
195 200 205
Leu Thr Ile Ser Ser Met Glu Ala Glu Asp Ala Ala Thr Tyr Tyr Cys
210 215 220
Gln Gln Trp Asp Ser Asn Pro Leu Thr Phe Gly Ala Gly Thr Lys Leu
225 230 235 240
Glu Leu Lys
<210> 176
<211> 238
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 176
Asp Ile Gln Met Thr Gln Ser Pro Asp Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Glu Thr Val Thr Ile Thr Cys Gly Ala Ser Glu Asn Ile Tyr Gly Ala
20 25 30
Leu Asn Trp Tyr Gln Arg Lys Gln Gly Lys Ser Pro Gln Leu Leu Ile
35 40 45
Tyr Gly Ala Thr Lys Leu Ala Asp Gly Met Ser Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Asn Arg Gln Tyr Ser Leu Lys Ile Ser Ser Leu His Pro
65 70 75 80
Asp Asp Val Ala Thr Tyr Tyr Cys Gln Asn Val Leu Ser Lys Pro Tyr
85 90 95
Ala Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly Gly Ser
100 105 110
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Val Gln Cys Asp Val
115 120 125
Lys Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly Ser Leu
130 135 140
Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Arg Tyr Thr Met
145 150 155 160
Ser Trp Val Arg Gln Thr Pro Glu Lys Arg Leu Glu Trp Val Ala Thr
165 170 175
Ile Ser Asn Ser Gly Ser Tyr Thr Tyr Tyr Arg Asp Ser Val Lys Gly
180 185 190
Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr Leu Gln
195 200 205
Met Ser Ser Leu Lys Ser Glu Asp Thr Ala Met Tyr Tyr Cys Thr Arg
210 215 220
Gly Ser Pro Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ala
225 230 235
<210> 177
<211> 247
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 177
Asp Ile Leu Met Thr Gln Thr Pro Leu Ser Leu Pro Val Ser Leu Gly
1 5 10 15
Asp Gln Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Ile Val His Ser
20 25 30
Asn Gly Asn Thr Tyr Leu Glu Trp Tyr Leu Gln Lys Pro Gly Gln Ser
35 40 45
Pro Lys Pro Leu Ile Lys Lys Val Ser Asn Arg Phe Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Tyr Cys Phe Gln Gly
85 90 95
Ser His Val Pro Phe Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys
100 105 110
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu
115 120 125
Val Lys Leu Gln Gln Ser Gly Ala Asp Leu Ala Thr Pro Gly Ala Ser
130 135 140
Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Ser Thr Tyr Trp
145 150 155 160
Met Gln Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile Gly
165 170 175
Thr Ile Tyr Pro Gly Asp Gly Asp Thr Arg Tyr Thr Gln Lys Phe Lys
180 185 190
Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala His Met
195 200 205
Gln Leu Ser Ser Leu Ala Ser Glu Asp Ser Ala Val Tyr Tyr Cys Ala
210 215 220
Arg Gly Gly Leu Tyr Tyr Gly Tyr Asp Ile Ala Tyr Trp Gly Gln Gly
225 230 235 240
Thr Leu Val Thr Val Ser Ala
245
<210> 178
<211> 242
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 178
Gln Ile Val Leu Ser Gln Ser Pro Ala Ile Leu Phe 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 Tyr Gln Gln Lys Pro Gly Ser Ser Pro Lys Pro Trp Ile His
35 40 45
Gly Thr Ser Asn Leu Ala Ser Gly Val Pro Ala Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Arg Met Glu Ala Glu
65 70 75 80
Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser Asn Leu Ser Thr
85 90 95
Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly Gly Ser Gly
100 105 110
Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Lys Leu Val Glu Ser
115 120 125
Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ser
130 135 140
Ile Ser Gly Phe Thr Phe Thr Asp Tyr Tyr Met Asn Trp Val Arg Gln
145 150 155 160
Ser Pro Gly Lys Ala Leu Glu Trp Leu Gly Phe Ile Arg Asn Lys Val
165 170 175
Asn Gly Asp Thr Thr Glu Tyr Ser Ala Ser Val Lys Gly Arg Phe Thr
180 185 190
Ile Ser Arg Asp Ile Ser Gln Ser Ile Leu Tyr Leu Gln Met Asn Thr
195 200 205
Leu Arg Thr Glu Asp Ser Ala Thr Tyr Tyr Cys Ala Arg Asp Lys Gly
210 215 220
Ile Ala Tyr Tyr Phe Asp Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val
225 230 235 240
Ser Ser
<210> 179
<211> 237
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 179
Asp Ile Val Met Thr Gln Ser His Lys Phe Met Ser Thr Ser Val Gly
1 5 10 15
Asp Arg Val Ser Ile Thr Cys Lys Ala Ser Gln Asp Val Thr Thr Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Lys Val Leu Ile
35 40 45
Phe Trp Ala Ser Thr Arg His Thr Gly Val Pro Asp Arg Phe Thr Gly
50 55 60
Ser Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Val Gln Ala
65 70 75 80
Glu Asp Leu Ala Leu Tyr Tyr Cys Gln Gln Tyr Tyr Arg Thr Pro Arg
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly Gly Ser
100 105 110
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Val Gln Leu Lys Glu
115 120 125
Ser Gly Pro Gly Leu Val Ala Pro Ser Gln Asn Leu Ser Ile Thr Cys
130 135 140
Thr Val Ser Gly Phe Ser Leu Thr Ser Tyr Ala Ile Asn Trp Val Arg
145 150 155 160
Gln Pro Pro Gly Lys Gly Leu Glu Trp Leu Gly Ile Ile Trp Thr Gly
165 170 175
Gly Gly Thr Asn Tyr Asn Ser Ala Leu Lys Ser Arg Leu Ser Ile Ser
180 185 190
Lys Asp Asn Ser Lys Ser Gln Val Phe Leu Lys Met Asn Ser Leu Gln
195 200 205
Thr Asp Asp Thr Ala Arg Tyr Tyr Cys Ala Ser Gly Val Tyr Tyr Phe
210 215 220
Asp Tyr Trp Gly Leu Gly Thr Thr Leu Thr Val Ser Ser
225 230 235
<210> 180
<211> 243
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic
<400> 180
Gln Ile Val Leu Thr Gln Ser Pro Ala Leu Met Ser Ala Ser Pro Gly
1 5 10 15
Glu Lys Val Thr Val Thr Cys Thr Ala Ser Ser Ser Val Ser Tyr Met
20 25 30
Tyr Trp Tyr Gln Gln Lys Pro Arg Ser Ser Pro Lys Pro Trp Ile Tyr
35 40 45
Leu Thr Ser Asn Leu Ala Ser Gly Val Pro Thr Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Ser Met Glu Ala Glu
65 70 75 80
Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Asp Ser Asn Pro Leu Thr
85 90 95
Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Gly Gly Gly Gly Ser Gly
100 105 110
Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Lys Leu Gln Glu Ser
115 120 125
Gly Ala Glu Leu Val Lys Pro Gly Ala Ser Val Lys Ile Ser Cys Lys
130 135 140
Ala Ser Gly Tyr Thr Phe Asn Asp Tyr Asn Met Asp Tyr Leu Lys Gln
145 150 155 160
Ser His Gly Lys Ser Leu Glu Trp Ile Gly Asp Ile Asn Pro Asn Tyr
165 170 175
Asp Ser Thr Ile Tyr Asn Gln Lys Phe Lys Gly Lys Ala Thr Leu Thr
180 185 190
Val Asp Lys Ser Ser Ser Thr Ala Tyr Met Glu Leu Arg Ser Leu Thr
195 200 205
Ser Glu Asp Ser Ala Val Tyr Tyr Cys Ala Arg Arg Asp Tyr Asp Gly
210 215 220
Arg Arg Gly Ala Trp Phe Ser Tyr Trp Gly Gln Gly Thr Leu Val Thr
225 230 235 240
Val Ser Ala
Claims (13)
- i) 글리코실화된 CEA를 표적하는 항원-결합 도메인;
ii) 막 관통 도메인; 및
iii) 공동자극 도메인(costimulatory domain)을 포함하는 세포 내 신호전달 도메인;을 포함하는 키메라 항원 수용체 (chimeric antigen receptor, CAR)로서,
상기 글리코실화된 CEA를 표적하는 항원-결합 도메인은 중쇄 가변영역 및 경쇄 가변영역을 포함하되, 상기 중쇄 가변영역은 SEQ ID NO: 13에 제시된 CDR-H1, SEQ ID NO: 14에 제시된 CDR-H2, 및 SEQ ID NO: 15에 제시된 CDR-H3을 포함하고, 상기 경쇄 가변영역은 SEQ ID NO: 16에 제시된 CDR-L1, SEQ ID NO: 17에 제시된 CDR-L2, 및 SEQ ID NO: 18에 제시된 CDR-L3을 포함하는 것을 특징으로 하는, 키메라 항원 수용체.
- 제1항에 있어서,
상기 중쇄 가변영역은 SEQ ID NO: 35에 제시된 폴리펩티드 단편을 포함하고, 상기 경쇄 가변영역은 SEQ ID NO: 36에 제시된 폴리펩티드 단편을 포함하는 것인, 키메라 항원 수용체.
- 제1항에 있어서,
상기 항원-결합 도메인은 인간 글리코실화된 CEA(human glycosylated CEA)를 특이적으로 인식하는 단일쇄 항체(single-chain antibody)이고, 상기 단일쇄 항체의 아미노산 서열은 SEQ ID NO: 173 또는 SEQ ID NO: 178인 것인, 키메라 항원 수용체.
- 제1항에 있어서,
상기 키메라 항원 수용체는 힌지 영역을 더 포함하고, 상기 막 관통 도메인은 CD8α 및/또는 CD28을 포함하며, 상기 세포 내 신호전달 도메인은 CD28, CD137, 및 CD3제타 중 하나 이상을 포함하는 것인, 키메라 항원 수용체.
- 제4항에 있어서,
상기 힌지 영역은 SEQ ID NO: 52 또는 SEQ ID NO:53에 제시된 서열에 의해 암호화되고, 막 관통 영역은 SEQ ID NO:54 또는 SEQ ID NO: 55에 제시된 서열에 의해 암호화되며, 상기 세포 내 신호전달 도메인은 SEQ ID NO:56 또는 SEQ ID NO:57 또는 SEQ ID NO:58에 제시된 서열에 의해 암호화되는 것인, 키메라 항원 수용체.
- 제1항 내지 제5항 중 어느 한 항에 기재된 키메라 항원 수용체를 암호화하는, 핵산 분자.
- 제1항 내지 제5항 중 어느 한 항에 기재된 키메라 항원 수용체를 발현하는 세포로서, 상기 세포는 T 세포, NK 세포 및 B 세포로 이루어진 군으로부터 선택되는 것인, 키메라 항원 수용체를 발현하는 세포.
- 인간 글리코실화된 CEA에 특이적으로 결합하는 단일쇄 항체로서, 상기 단일쇄 항체는 중쇄 가변영역 및 경쇄 가변영역을 포함하되,
상기 중쇄 가변영역은 SEQ ID NO: 13에 제시된 CDR-H1, SEQ ID NO: 14에 제시된 CDR-H2, 및 SEQ ID NO: 15에 제시된 CDR-H3을 포함하고, 상기 경쇄 가변영역은 SEQ ID NO: 16에 제시된 CDR-L1, SEQ ID NO: 17에 제시된 CDR-L2, 및 SEQ ID NO: 18에 제시된 CDR-L3을 포함하는 것을 특징으로 하는, 단일쇄 항체.
- 제8항에 있어서,
상기 중쇄 가변영역은 SEQ ID NO: 35에 제시된 폴리펩티드 단편을 포함하고, 상기 경쇄 가변영역은 SEQ ID NO: 36에 제시된 폴리펩티드 단편을 포함하는 것인, 단일쇄 항체.
- 제8항 또는 제9항에 있어서,
상기 단일쇄 항체의 아미노산 서열은 SEQ ID NO:173 또는 SEQ ID NO:178인 것인, 단일쇄 항체.
- 제1항 내지 제5항 중 어느 한 항에 기재된 키메라 항원 수용체를 포함하는 종양 치료용 약제학적 조성물로서, 상기 종양은 위암(gastric cancer), 대장암(colorectal cancer), 및 식도암(esophageal cancer)으로 이루어진 군으로부터 선택되는 소화관 종양(digestive tract tumor)인 것인, 약제학적 조성물.
- 제7항에 기재된 세포를 포함하는 종양 치료용 약제학적 조성물로서, 상기 종양은 위암, 대장암, 및 식도암으로 이루어진 군으로부터 선택되는 소화관 종양인 것인, 약제학적 조성물.
- 제8항 또는 제9항에 기재된 단일쇄 항체를 포함하는 종양 치료용 약제학적 조성물로서, 상기 종양은 위암, 대장암, 및 식도암으로 이루어진 군으로부터 선택되는 소화관 종양인 것인, 약제학적 조성물.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201610614701.3A CN107663240B (zh) | 2016-07-29 | 2016-07-29 | 高度糖基化cea特异性结合的单链抗体及其在检测和治疗上的应用 |
CN201610614701.3 | 2016-07-29 | ||
PCT/CN2017/094755 WO2018019275A1 (zh) | 2016-07-29 | 2017-07-27 | Mg7,高度糖基化cea特异性结合的单链抗体及其在检测和治疗上的应用 |
Publications (2)
Publication Number | Publication Date |
---|---|
KR20190034626A KR20190034626A (ko) | 2019-04-02 |
KR102460843B1 true KR102460843B1 (ko) | 2022-10-31 |
Family
ID=61017506
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
KR1020197006047A KR102460843B1 (ko) | 2016-07-29 | 2017-07-27 | 고도로 글리코실화된 cea인 mg7에 특이적으로 결합하는 단일쇄 항체 및 검출 및 치료에서 이의 용도 |
Country Status (7)
Country | Link |
---|---|
US (1) | US11266688B2 (ko) |
EP (1) | EP3492497B1 (ko) |
JP (1) | JP7195253B2 (ko) |
KR (1) | KR102460843B1 (ko) |
CN (2) | CN107663240B (ko) |
AU (1) | AU2017303944C1 (ko) |
WO (1) | WO2018019275A1 (ko) |
Families Citing this family (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US11786551B2 (en) | 2017-09-26 | 2023-10-17 | The Trustees Of The University Of Pennsylvania | Methods for treating heart disease via redirected T cell immunotherapies |
CN109517798B (zh) * | 2018-11-28 | 2022-05-10 | 北京康爱瑞浩生物科技股份有限公司 | 一种嵌合cea抗原受体的nk细胞及其制备方法与应用 |
EP4041290A4 (en) * | 2019-09-23 | 2024-02-07 | The Trustees of the University of Pennsylvania | MONOCLONAL ANTIBODIES TO DOG FIBROBLAST ACTIVATION PROTEIN CROSS-REACTING WITH MOUSE AND HUMAN FIBROBLAST ACTIVATION PROTEIN (FAP). |
US20210087295A1 (en) * | 2019-09-23 | 2021-03-25 | The Trustees Of The University Of Pennsylvania | Disrupting tumor tissues by targeting fibroblast activation protein (fap) |
CN116348593A (zh) * | 2020-08-21 | 2023-06-27 | 上海吉倍生物技术有限公司 | 特异性结合糖基化ceacam5的抗体 |
TWI804099B (zh) * | 2021-12-10 | 2023-06-01 | 大陸商上海吉倍生物技術有限公司 | 特異性結合糖基化ceacam5的抗體及其製備方法 |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2007146172A2 (en) * | 2006-06-07 | 2007-12-21 | Bioalliance C.V. | Antibodies recognizing a carbohydrate containing epitope on cd-43 and cea expressed on cancer cells and methods using same |
Family Cites Families (17)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5872215A (en) * | 1991-12-02 | 1999-02-16 | Medical Research Council | Specific binding members, materials and methods |
AU665221B2 (en) * | 1991-12-02 | 1995-12-21 | Cambridge Antibody Technology Limited | Production of anti-self antibodies from antibody segment repertoires and displayed on phage |
CU23228A1 (en) * | 2002-04-29 | 2007-09-26 | Ct Ingenieria Genetica Biotech | FRAGMENTS OF SPECIFIC ANTIBODIES FOR THE HUMAN CARCINOEMBRIONARY ANTIGEN (CEA) SEQUENCES OF ITS VARIABLE REGIONS AND VECTORS FOR THE MICROBIAL EXPRESSION OF THE SAME |
CN101658672B (zh) | 2002-10-08 | 2017-09-26 | 免疫医疗公司 | 用iii类抗cea单克隆抗体和治疗剂进行联合治疗 |
US20090226444A1 (en) * | 2005-12-21 | 2009-09-10 | Micromet Ag | Pharmaceutical antibody compositions with resistance to soluble cea |
RU2426743C2 (ru) | 2005-12-21 | 2011-08-20 | Микромет Аг | Фармацевтические композиции с устойчивостью к растворимому сеа |
EP2280997A2 (en) * | 2008-04-18 | 2011-02-09 | Xencor, Inc. | Human equivalent monoclonal antibodies engineered from nonhuman variable regions |
SG178567A1 (en) | 2009-08-31 | 2012-04-27 | Roche Glycart Ag | Affinity-matured humanized anti cea monoclonal antibodies |
EP3327035A1 (en) | 2010-06-22 | 2018-05-30 | Precision Biologics Inc. | Colon and pancreas cancer specific antigens and antibodies |
CN104371019B (zh) | 2013-08-13 | 2019-09-10 | 鸿运华宁(杭州)生物医药有限公司 | 一种能与glp-1r特异性结合的抗体及其与glp-1的融合蛋白质 |
WO2015153685A1 (en) | 2014-03-31 | 2015-10-08 | Board Of Regents, The University Of Texas System | Humanized pertussis antibodies and uses thereof |
US20170158749A1 (en) * | 2014-04-23 | 2017-06-08 | Board Of Regents, The University Of Texas System | Chimeric antigen receptors (car) and methods for making and using the same |
CN104628859A (zh) | 2015-01-26 | 2015-05-20 | 佳德资本投资管理(Bvi)有限公司 | 抗人癌胚抗原抗体及其编码基因和应用 |
CN104829733B (zh) | 2015-05-25 | 2018-06-05 | 广州百暨基因科技有限公司 | 抗原结合单元稳定的嵌合抗原受体及制备方法与应用 |
CN104910279B (zh) | 2015-06-05 | 2019-02-22 | 重庆精准生物技术有限公司 | 靶向癌胚抗原的嵌合抗原受体、慢病毒表达载体及其制备方法和应用 |
CN105331585A (zh) * | 2015-11-13 | 2016-02-17 | 科济生物医药(上海)有限公司 | 携带pd-l1阻断剂的嵌合抗原受体修饰的免疫效应细胞 |
CN105330750B (zh) * | 2015-11-20 | 2019-02-01 | 上海细胞治疗研究院 | 一种快速中止car-t细胞杀伤作用的分子刹车及其用途 |
-
2016
- 2016-07-29 CN CN201610614701.3A patent/CN107663240B/zh active Active
-
2017
- 2017-07-27 KR KR1020197006047A patent/KR102460843B1/ko active IP Right Grant
- 2017-07-27 EP EP17833578.2A patent/EP3492497B1/en active Active
- 2017-07-27 CN CN201780045050.3A patent/CN110072892B/zh active Active
- 2017-07-27 US US16/321,529 patent/US11266688B2/en active Active
- 2017-07-27 WO PCT/CN2017/094755 patent/WO2018019275A1/zh unknown
- 2017-07-27 AU AU2017303944A patent/AU2017303944C1/en active Active
- 2017-07-27 JP JP2019526356A patent/JP7195253B2/ja active Active
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2007146172A2 (en) * | 2006-06-07 | 2007-12-21 | Bioalliance C.V. | Antibodies recognizing a carbohydrate containing epitope on cd-43 and cea expressed on cancer cells and methods using same |
JP2009539380A (ja) | 2006-06-07 | 2009-11-19 | バイオアライアンス セー.フェー. | 癌細胞で発現するcd−43およびceaの炭水化物含有エピトープを認識する抗体およびそれを使用する方法 |
Non-Patent Citations (1)
Title |
---|
Dotti G. et al, Immunological Reviews 257:pp.107~126 (2014.)* |
Also Published As
Publication number | Publication date |
---|---|
US11266688B2 (en) | 2022-03-08 |
AU2017303944C1 (en) | 2022-09-08 |
EP3492497B1 (en) | 2023-09-06 |
US20190167721A1 (en) | 2019-06-06 |
AU2017303944B2 (en) | 2022-03-31 |
CN107663240A (zh) | 2018-02-06 |
CN107663240B (zh) | 2021-01-12 |
JP7195253B2 (ja) | 2022-12-23 |
JP2019526275A (ja) | 2019-09-19 |
WO2018019275A1 (zh) | 2018-02-01 |
KR20190034626A (ko) | 2019-04-02 |
EP3492497A1 (en) | 2019-06-05 |
EP3492497A4 (en) | 2020-06-17 |
CN110072892A (zh) | 2019-07-30 |
CN110072892B (zh) | 2023-08-29 |
AU2017303944A1 (en) | 2019-02-21 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
KR102460843B1 (ko) | 고도로 글리코실화된 cea인 mg7에 특이적으로 결합하는 단일쇄 항체 및 검출 및 치료에서 이의 용도 | |
RU2744245C2 (ru) | Антитело против глипикана-3 и его применение | |
CN110662771B (zh) | 一种结合bcma的嵌合抗原受体(car)及其应用 | |
KR101837053B1 (ko) | 종간 특이적 PSCAxCD3, CD19xCD3, c-METxCD3, 엔도시알린xCD3, EpCAMxCD3, IGF-1RxCD3 또는 FAPαxCD3 이중특이적 단일쇄 항체 | |
KR20220133318A (ko) | 선택적 단백질 발현을 위한 조성물 및 방법 | |
KR102099073B1 (ko) | 항 sez6 항체들 및 사용 방법 | |
CN116082518A (zh) | 一种结合bcma的嵌合抗原受体(car)及其应用 | |
CA3032581A1 (en) | Treatment of cancer using a chimeric antigen receptor in combination with an inhibitor of a pro-m2 macrophage molecule | |
CN112638947B (zh) | 用于治疗实体瘤的嵌合抗原受体细胞 | |
KR20220016083A (ko) | 키메라 수용체 및 이의 사용 방법 | |
CN114585645A (zh) | 对杂合性丧失作出响应的细胞表面受体 | |
JP2018523686A (ja) | B7‐h3及びcd3に結合できる二重特異性1価ダイアボディ並びにその使用 | |
KR20220018081A (ko) | Cd20 결합 분자 및 그의 용도 | |
CN111247168A (zh) | 靶向多种抗原的复合嵌合抗原受体(cCAR)及其组成和使用方法 | |
KR102520550B1 (ko) | Cd19 및 cd20을 표적화하는 조합된 키메라 항원 수용체 및 그의 적용 | |
JP2018528786A (ja) | 腫瘍特異的抗egfr抗体およびその使用 | |
CN112390892B (zh) | 一种嵌合抗原受体以及表达该嵌抗原受体的免疫效应细胞 | |
CN114008079A (zh) | 抗adam12抗体和嵌合抗原受体以及包含其的组合物和方法 | |
CN113164538A (zh) | 修饰的溶瘤病毒、其组合物和用途 | |
WO2015172341A1 (zh) | 针对磷脂酰肌醇蛋白多糖-3和t细胞抗原的双特异性抗体 | |
CN112661857B (zh) | 一种嵌合抗原受体及其用途 | |
WO2024128219A1 (ja) | キメラ抗原受容体 | |
RU2795467C2 (ru) | Композиции и способы для избирательной экспрессии белка | |
CN111971303B (zh) | 抗cd27抗体及其用途 | |
CN116390941A (zh) | 多特异性嵌合抗原受体及其用途 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A201 | Request for examination | ||
E902 | Notification of reason for refusal | ||
E701 | Decision to grant or registration of patent right | ||
GRNT | Written decision to grant |