CN115803341A - 结合α-突触核蛋白原纤维的抗体 - Google Patents
结合α-突触核蛋白原纤维的抗体 Download PDFInfo
- Publication number
- CN115803341A CN115803341A CN202180041047.0A CN202180041047A CN115803341A CN 115803341 A CN115803341 A CN 115803341A CN 202180041047 A CN202180041047 A CN 202180041047A CN 115803341 A CN115803341 A CN 115803341A
- Authority
- CN
- China
- Prior art keywords
- antibody
- seq
- ser
- synuclein
- ban0805
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 102000003802 alpha-Synuclein Human genes 0.000 title claims abstract description 46
- 108090000185 alpha-Synuclein Proteins 0.000 title claims abstract description 46
- 150000007523 nucleic acids Chemical class 0.000 claims description 33
- 108020004707 nucleic acids Proteins 0.000 claims description 30
- 102000039446 nucleic acids Human genes 0.000 claims description 30
- 125000003275 alpha amino acid group Chemical group 0.000 claims description 29
- 239000013598 vector Substances 0.000 claims description 14
- 229920001184 polypeptide Polymers 0.000 claims description 6
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 6
- 102000004196 processed proteins & peptides Human genes 0.000 claims description 6
- 239000000203 mixture Substances 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 2
- 101000834898 Homo sapiens Alpha-synuclein Proteins 0.000 abstract description 15
- 229940126619 mouse monoclonal antibody Drugs 0.000 abstract 1
- 239000000178 monomer Substances 0.000 description 46
- 108090000623 proteins and genes Proteins 0.000 description 18
- 238000002198 surface plasmon resonance spectroscopy Methods 0.000 description 16
- 238000002965 ELISA Methods 0.000 description 15
- 230000005764 inhibitory process Effects 0.000 description 14
- NFGXHKASABOEEW-UHFFFAOYSA-N 1-methylethyl 11-methoxy-3,7,11-trimethyl-2,4-dodecadienoate Chemical compound COC(C)(C)CCCC(C)CC=CC(C)=CC(=O)OC(C)C NFGXHKASABOEEW-UHFFFAOYSA-N 0.000 description 13
- 102100035360 Cerebellar degeneration-related antigen 1 Human genes 0.000 description 12
- 108010076504 Protein Sorting Signals Proteins 0.000 description 12
- 102000003799 beta-Synuclein Human genes 0.000 description 10
- 108090000182 beta-Synuclein Proteins 0.000 description 10
- 102000004963 gamma-Synuclein Human genes 0.000 description 10
- 108090001121 gamma-Synuclein Proteins 0.000 description 10
- 108020004414 DNA Proteins 0.000 description 9
- 108091028043 Nucleic acid sequence Proteins 0.000 description 8
- 210000004027 cell Anatomy 0.000 description 8
- 230000002776 aggregation Effects 0.000 description 6
- 238000004220 aggregation Methods 0.000 description 6
- 230000009260 cross reactivity Effects 0.000 description 5
- 108010051242 phenylalanylserine Proteins 0.000 description 5
- 102000004169 proteins and genes Human genes 0.000 description 5
- 101150027568 LC gene Proteins 0.000 description 4
- 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 4
- 230000035772 mutation Effects 0.000 description 4
- 108010033670 threonyl-aspartyl-tyrosine Proteins 0.000 description 4
- 108010073969 valyllysine Proteins 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 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
- GGAPHLIUUTVYMX-QWRGUYRKSA-N Gly-Phe-Ser Chemical compound OC[C@@H](C([O-])=O)NC(=O)[C@@H](NC(=O)C[NH3+])CC1=CC=CC=C1 GGAPHLIUUTVYMX-QWRGUYRKSA-N 0.000 description 3
- FULZDMOZUZKGQU-ONGXEEELSA-N Gly-Val-His Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)NC(=O)CN FULZDMOZUZKGQU-ONGXEEELSA-N 0.000 description 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
- 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
- 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
- HNDMFDBQXYZSRM-IHRRRGAJSA-N Ser-Val-Phe Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O HNDMFDBQXYZSRM-IHRRRGAJSA-N 0.000 description 3
- SIEBDTCABMZCLF-XGEHTFHBSA-N Ser-Val-Thr Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O SIEBDTCABMZCLF-XGEHTFHBSA-N 0.000 description 3
- 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 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
- 108010036951 achatin I Proteins 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 230000007423 decrease Effects 0.000 description 3
- 210000004602 germ cell Anatomy 0.000 description 3
- 108010078144 glutaminyl-glycine Proteins 0.000 description 3
- 108010037850 glycylvaline Proteins 0.000 description 3
- 230000008642 heat stress Effects 0.000 description 3
- 238000000569 multi-angle light scattering Methods 0.000 description 3
- 239000000523 sample Substances 0.000 description 3
- 108010069117 seryl-lysyl-aspartic acid Proteins 0.000 description 3
- PIPTUBPKYFRLCP-NHCYSSNCSA-N Ala-Ala-Phe Chemical compound C[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 PIPTUBPKYFRLCP-NHCYSSNCSA-N 0.000 description 2
- BTYTYHBSJKQBQA-GCJQMDKQSA-N Ala-Asp-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CC(=O)O)NC(=O)[C@H](C)N)O BTYTYHBSJKQBQA-GCJQMDKQSA-N 0.000 description 2
- NFDVJAKFMXHJEQ-HERUPUMHSA-N Ala-Asp-Trp Chemical compound C[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](CC1=CNC2=CC=CC=C21)C(=O)O)N NFDVJAKFMXHJEQ-HERUPUMHSA-N 0.000 description 2
- ZDILXFDENZVOTL-BPNCWPANSA-N Ala-Val-Tyr Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O ZDILXFDENZVOTL-BPNCWPANSA-N 0.000 description 2
- 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 2
- OQPAZKMGCWPERI-GUBZILKMSA-N Arg-Ser-Val Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(O)=O OQPAZKMGCWPERI-GUBZILKMSA-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
- 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
- CZIVKMOEXPILDK-SRVKXCTJSA-N Asp-Tyr-Ser Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CO)C(O)=O CZIVKMOEXPILDK-SRVKXCTJSA-N 0.000 description 2
- XWKPSMRPIKKDDU-RCOVLWMOSA-N Asp-Val-Gly Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)NCC(O)=O XWKPSMRPIKKDDU-RCOVLWMOSA-N 0.000 description 2
- 208000034628 Celiac artery compression syndrome Diseases 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
- OHLLDUNVMPPUMD-DCAQKATOSA-N Cys-Leu-Val Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](C(C)C)C(=O)O)NC(=O)[C@H](CS)N OHLLDUNVMPPUMD-DCAQKATOSA-N 0.000 description 2
- 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 2
- WLRYGVYQFXRJDA-DCAQKATOSA-N Gln-Pro-Pro Chemical compound NC(=O)CC[C@H](N)C(=O)N1CCC[C@H]1C(=O)N1[C@H](C(O)=O)CCC1 WLRYGVYQFXRJDA-DCAQKATOSA-N 0.000 description 2
- 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 2
- FITIQFSXXBKFFM-NRPADANISA-N Gln-Val-Ser Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CO)C(O)=O FITIQFSXXBKFFM-NRPADANISA-N 0.000 description 2
- 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 2
- QJVZSVUYZFYLFQ-CIUDSAMLSA-N Glu-Pro-Ala Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](C)C(O)=O QJVZSVUYZFYLFQ-CIUDSAMLSA-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
- 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 2
- KAJAOGBVWCYGHZ-JTQLQIEISA-N Gly-Gly-Phe Chemical compound [NH3+]CC(=O)NCC(=O)N[C@H](C([O-])=O)CC1=CC=CC=C1 KAJAOGBVWCYGHZ-JTQLQIEISA-N 0.000 description 2
- 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 2
- 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 2
- 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 2
- LCRDMSSAKLTKBU-ZDLURKLDSA-N Gly-Ser-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)[C@H](CO)NC(=O)CN LCRDMSSAKLTKBU-ZDLURKLDSA-N 0.000 description 2
- 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 2
- ZVXMEWXHFBYJPI-LSJOCFKGSA-N Gly-Val-Ile Chemical compound [H]NCC(=O)N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O ZVXMEWXHFBYJPI-LSJOCFKGSA-N 0.000 description 2
- 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 2
- 108010065920 Insulin Lispro Proteins 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
- SENJXOPIZNYLHU-UHFFFAOYSA-N L-leucyl-L-arginine Natural products CC(C)CC(N)C(=O)NC(C(O)=O)CCCN=C(N)N SENJXOPIZNYLHU-UHFFFAOYSA-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
- 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 2
- HPBCTWSUJOGJSH-MNXVOIDGSA-N Leu-Glu-Ile Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O HPBCTWSUJOGJSH-MNXVOIDGSA-N 0.000 description 2
- 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 2
- NRFGTHFONZYFNY-MGHWNKPDSA-N Leu-Ile-Tyr Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 NRFGTHFONZYFNY-MGHWNKPDSA-N 0.000 description 2
- BRTVHXHCUSXYRI-CIUDSAMLSA-N Leu-Ser-Ser Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(O)=O BRTVHXHCUSXYRI-CIUDSAMLSA-N 0.000 description 2
- LINKCQUOMUDLKN-KATARQTJSA-N Leu-Thr-Cys Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CS)C(=O)O)NC(=O)[C@H](CC(C)C)N)O LINKCQUOMUDLKN-KATARQTJSA-N 0.000 description 2
- VUBIPAHVHMZHCM-KKUMJFAQSA-N Leu-Tyr-Ser Chemical compound CC(C)C[C@H](N)C(=O)N[C@H](C(=O)N[C@@H](CO)C(O)=O)CC1=CC=C(O)C=C1 VUBIPAHVHMZHCM-KKUMJFAQSA-N 0.000 description 2
- KWUKZRFFKPLUPE-HJGDQZAQSA-N Lys-Asp-Thr Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O KWUKZRFFKPLUPE-HJGDQZAQSA-N 0.000 description 2
- AIRZWUMAHCDDHR-KKUMJFAQSA-N Lys-Leu-Leu Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O AIRZWUMAHCDDHR-KKUMJFAQSA-N 0.000 description 2
- 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 2
- YTJFXEDRUOQGSP-DCAQKATOSA-N Lys-Pro-Ser Chemical compound [H]N[C@@H](CCCCN)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CO)C(O)=O YTJFXEDRUOQGSP-DCAQKATOSA-N 0.000 description 2
- SPSSJSICDYYTQN-HJGDQZAQSA-N Met-Thr-Gln Chemical compound CSCC[C@H](N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@H](C(O)=O)CCC(N)=O SPSSJSICDYYTQN-HJGDQZAQSA-N 0.000 description 2
- IIHMNTBFPMRJCN-RCWTZXSCSA-N Met-Val-Thr Chemical compound CSCC[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O IIHMNTBFPMRJCN-RCWTZXSCSA-N 0.000 description 2
- 241001529936 Murinae Species 0.000 description 2
- 208000018737 Parkinson disease Diseases 0.000 description 2
- YYKZDTVQHTUKDW-RYUDHWBXSA-N Phe-Gly-Gln Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)NCC(=O)N[C@@H](CCC(=O)N)C(=O)O)N YYKZDTVQHTUKDW-RYUDHWBXSA-N 0.000 description 2
- IHCXPSYCHXFXKT-DCAQKATOSA-N Pro-Arg-Glu Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(O)=O IHCXPSYCHXFXKT-DCAQKATOSA-N 0.000 description 2
- HJSCRFZVGXAGNG-SRVKXCTJSA-N Pro-Gln-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H]1CCCN1 HJSCRFZVGXAGNG-SRVKXCTJSA-N 0.000 description 2
- JMVQDLDPDBXAAX-YUMQZZPRSA-N Pro-Gly-Gln Chemical compound NC(=O)CC[C@@H](C(O)=O)NC(=O)CNC(=O)[C@@H]1CCCN1 JMVQDLDPDBXAAX-YUMQZZPRSA-N 0.000 description 2
- YDTUEBLEAVANFH-RCWTZXSCSA-N Pro-Val-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H]1CCCN1 YDTUEBLEAVANFH-RCWTZXSCSA-N 0.000 description 2
- 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
- KJMOINFQVCCSDX-XKBZYTNZSA-N Ser-Gln-Thr Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O KJMOINFQVCCSDX-XKBZYTNZSA-N 0.000 description 2
- KDGARKCAKHBEDB-NKWVEPMBSA-N Ser-Gly-Pro Chemical compound C1C[C@@H](N(C1)C(=O)CNC(=O)[C@H](CO)N)C(=O)O KDGARKCAKHBEDB-NKWVEPMBSA-N 0.000 description 2
- UIGMAMGZOJVTDN-WHFBIAKZSA-N Ser-Gly-Ser Chemical compound OC[C@H](N)C(=O)NCC(=O)N[C@@H](CO)C(O)=O UIGMAMGZOJVTDN-WHFBIAKZSA-N 0.000 description 2
- XXXAXOWMBOKTRN-XPUUQOCRSA-N Ser-Gly-Val Chemical compound [H]N[C@@H](CO)C(=O)NCC(=O)N[C@@H](C(C)C)C(O)=O XXXAXOWMBOKTRN-XPUUQOCRSA-N 0.000 description 2
- 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 2
- XNCUYZKGQOCOQH-YUMQZZPRSA-N Ser-Leu-Gly Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)NCC(O)=O XNCUYZKGQOCOQH-YUMQZZPRSA-N 0.000 description 2
- 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 2
- HDBOEVPDIDDEPC-CIUDSAMLSA-N Ser-Lys-Asn Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(O)=O HDBOEVPDIDDEPC-CIUDSAMLSA-N 0.000 description 2
- FKYWFUYPVKLJLP-DCAQKATOSA-N Ser-Pro-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@@H](N)CO FKYWFUYPVKLJLP-DCAQKATOSA-N 0.000 description 2
- WUXCHQZLUHBSDJ-LKXGYXEUSA-N Ser-Thr-Asp Chemical compound OC[C@H](N)C(=O)N[C@@H]([C@H](O)C)C(=O)N[C@@H](CC(O)=O)C(O)=O WUXCHQZLUHBSDJ-LKXGYXEUSA-N 0.000 description 2
- KRPKYGOFYUNIGM-XVSYOHENSA-N Thr-Asp-Phe Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)O)N)O KRPKYGOFYUNIGM-XVSYOHENSA-N 0.000 description 2
- MECLEFZMPPOEAC-VOAKCMCISA-N Thr-Leu-Lys Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)O)N)O MECLEFZMPPOEAC-VOAKCMCISA-N 0.000 description 2
- YOOAQCZYZHGUAZ-KATARQTJSA-N Thr-Leu-Ser Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(O)=O YOOAQCZYZHGUAZ-KATARQTJSA-N 0.000 description 2
- 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 2
- SCQBNMKLZVCXNX-ZFWWWQNUSA-N Trp-Arg-Gly Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)N[C@@H](CCCN=C(N)N)C(=O)NCC(=O)O)N SCQBNMKLZVCXNX-ZFWWWQNUSA-N 0.000 description 2
- GQHAIUPYZPTADF-FDARSICLSA-N Trp-Ile-Arg Chemical compound C1=CC=C2C(C[C@H](N)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCCN=C(N)N)C(O)=O)=CNC2=C1 GQHAIUPYZPTADF-FDARSICLSA-N 0.000 description 2
- SMLCYZYQFRTLCO-UWJYBYFXSA-N Tyr-Cys-Ala Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CS)C(=O)N[C@@H](C)C(O)=O SMLCYZYQFRTLCO-UWJYBYFXSA-N 0.000 description 2
- VYQQQIRHIFALGE-UWJYBYFXSA-N Tyr-Ser-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 VYQQQIRHIFALGE-UWJYBYFXSA-N 0.000 description 2
- 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 2
- OACSGBOREVRSME-NHCYSSNCSA-N Val-His-Asn Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](Cc1cnc[nH]1)C(=O)N[C@@H](CC(N)=O)C(O)=O OACSGBOREVRSME-NHCYSSNCSA-N 0.000 description 2
- MYLNLEIZWHVENT-VKOGCVSHSA-N Val-Ile-Trp Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC1=CNC2=CC=CC=C21)C(=O)O)NC(=O)[C@H](C(C)C)N MYLNLEIZWHVENT-VKOGCVSHSA-N 0.000 description 2
- 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 2
- DVLWZWNAQUBZBC-ZNSHCXBVSA-N Val-Thr-Pro Chemical compound C[C@H]([C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](C(C)C)N)O DVLWZWNAQUBZBC-ZNSHCXBVSA-N 0.000 description 2
- 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 2
- 108010081404 acein-2 Proteins 0.000 description 2
- 239000000427 antigen Substances 0.000 description 2
- 102000036639 antigens Human genes 0.000 description 2
- 108091007433 antigens Proteins 0.000 description 2
- 108010008355 arginyl-glutamine Proteins 0.000 description 2
- 108010047857 aspartylglycine Proteins 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- 238000010494 dissociation reaction Methods 0.000 description 2
- 230000005593 dissociations Effects 0.000 description 2
- 108010063718 gamma-glutamylaspartic acid Proteins 0.000 description 2
- 108010089804 glycyl-threonine Proteins 0.000 description 2
- 108010000761 leucylarginine Proteins 0.000 description 2
- 108010017391 lysylvaline Proteins 0.000 description 2
- 230000014759 maintenance of location Effects 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 108010087846 prolyl-prolyl-glycine Proteins 0.000 description 2
- 108010031719 prolyl-serine Proteins 0.000 description 2
- 108010029020 prolylglycine Proteins 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- 230000035882 stress Effects 0.000 description 2
- 108010072986 threonyl-seryl-lysine Proteins 0.000 description 2
- 108010038745 tryptophylglycine Proteins 0.000 description 2
- ZCPBEAHAVUJKAE-UHTWSYAYSA-N (2s)-2-[[(2s)-2-[[(2r)-2-[(2-aminoacetyl)amino]-3-phenylpropanoyl]amino]propanoyl]amino]butanedioic acid Chemical compound OC(=O)C[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@H](NC(=O)CN)CC1=CC=CC=C1 ZCPBEAHAVUJKAE-UHTWSYAYSA-N 0.000 description 1
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 1
- CXRCVCURMBFFOL-FXQIFTODSA-N Ala-Ala-Pro Chemical compound C[C@H](N)C(=O)N[C@@H](C)C(=O)N1CCC[C@H]1C(O)=O CXRCVCURMBFFOL-FXQIFTODSA-N 0.000 description 1
- KUDREHRZRIVKHS-UWJYBYFXSA-N Ala-Asp-Tyr Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O KUDREHRZRIVKHS-UWJYBYFXSA-N 0.000 description 1
- MNZHHDPWDWQJCQ-YUMQZZPRSA-N Ala-Leu-Gly Chemical compound C[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)NCC(O)=O MNZHHDPWDWQJCQ-YUMQZZPRSA-N 0.000 description 1
- DPNZTBKGAUAZQU-DLOVCJGASA-N Ala-Leu-His Chemical compound C[C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)N DPNZTBKGAUAZQU-DLOVCJGASA-N 0.000 description 1
- SUHLZMHFRALVSY-YUMQZZPRSA-N Ala-Lys-Gly Chemical compound NCCCC[C@H](NC(=O)[C@@H](N)C)C(=O)NCC(O)=O SUHLZMHFRALVSY-YUMQZZPRSA-N 0.000 description 1
- OINVDEKBKBCPLX-JXUBOQSCSA-N Ala-Lys-Thr Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(O)=O OINVDEKBKBCPLX-JXUBOQSCSA-N 0.000 description 1
- MDNAVFBZPROEHO-UHFFFAOYSA-N Ala-Lys-Val Natural products CC(C)C(C(O)=O)NC(=O)C(NC(=O)C(C)N)CCCCN MDNAVFBZPROEHO-UHFFFAOYSA-N 0.000 description 1
- RNHKOQHGYMTHFR-UBHSHLNASA-N Ala-Phe-Met Chemical compound CSCC[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)[C@H](C)N)CC1=CC=CC=C1 RNHKOQHGYMTHFR-UBHSHLNASA-N 0.000 description 1
- WQKAQKZRDIZYNV-VZFHVOOUSA-N Ala-Ser-Thr Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(O)=O WQKAQKZRDIZYNV-VZFHVOOUSA-N 0.000 description 1
- 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 1
- JEOCWTUOMKEEMF-RHYQMDGZSA-N Arg-Leu-Thr Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O JEOCWTUOMKEEMF-RHYQMDGZSA-N 0.000 description 1
- 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 1
- 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 1
- XRNXPIGJPQHCPC-RCWTZXSCSA-N Arg-Thr-Val Chemical compound CC(C)[C@H](NC(=O)[C@@H](NC(=O)[C@@H](N)CCCNC(N)=N)[C@@H](C)O)C(O)=O XRNXPIGJPQHCPC-RCWTZXSCSA-N 0.000 description 1
- ULBHWNVWSCJLCO-NHCYSSNCSA-N Arg-Val-Glu Chemical compound OC(=O)CC[C@@H](C(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](N)CCCN=C(N)N ULBHWNVWSCJLCO-NHCYSSNCSA-N 0.000 description 1
- XYOVHPDDWCEUDY-CIUDSAMLSA-N Asn-Ala-Leu Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(O)=O XYOVHPDDWCEUDY-CIUDSAMLSA-N 0.000 description 1
- GXMSVVBIAMWMKO-BQBZGAKWSA-N Asn-Arg-Gly Chemical compound NC(=O)C[C@H](N)C(=O)N[C@H](C(=O)NCC(O)=O)CCCN=C(N)N GXMSVVBIAMWMKO-BQBZGAKWSA-N 0.000 description 1
- SRUUBQBAVNQZGJ-LAEOZQHASA-N Asn-Gln-Val Chemical compound CC(C)[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)N)NC(=O)[C@H](CC(=O)N)N SRUUBQBAVNQZGJ-LAEOZQHASA-N 0.000 description 1
- HNXWVVHIGTZTBO-LKXGYXEUSA-N Asn-Ser-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC(N)=O HNXWVVHIGTZTBO-LKXGYXEUSA-N 0.000 description 1
- PUUPMDXIHCOPJU-HJGDQZAQSA-N Asn-Thr-Lys Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CC(=O)N)N)O PUUPMDXIHCOPJU-HJGDQZAQSA-N 0.000 description 1
- QNNBHTFDFFFHGC-KKUMJFAQSA-N Asn-Tyr-Lys Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CC(=O)N)N)O QNNBHTFDFFFHGC-KKUMJFAQSA-N 0.000 description 1
- JZLFYAAGGYMRIK-BYULHYEWSA-N Asn-Val-Asp Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(O)=O)C(O)=O JZLFYAAGGYMRIK-BYULHYEWSA-N 0.000 description 1
- CUQDCPXNZPDYFQ-ZLUOBGJFSA-N Asp-Ser-Asp Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(O)=O)C(O)=O CUQDCPXNZPDYFQ-ZLUOBGJFSA-N 0.000 description 1
- JSNWZMFSLIWAHS-HJGDQZAQSA-N Asp-Thr-Leu Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)O)NC(=O)[C@H](CC(=O)O)N)O JSNWZMFSLIWAHS-HJGDQZAQSA-N 0.000 description 1
- 108020004705 Codon Proteins 0.000 description 1
- VIRYODQIWJNWNU-NRPADANISA-N Cys-Glu-Val Chemical compound CC(C)[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)O)NC(=O)[C@H](CS)N VIRYODQIWJNWNU-NRPADANISA-N 0.000 description 1
- BCFXQBXXDSEHRS-FXQIFTODSA-N Cys-Ser-Arg Chemical compound [H]N[C@@H](CS)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O BCFXQBXXDSEHRS-FXQIFTODSA-N 0.000 description 1
- NDNZRWUDUMTITL-FXQIFTODSA-N Cys-Ser-Val Chemical compound [H]N[C@@H](CS)C(=O)N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(O)=O NDNZRWUDUMTITL-FXQIFTODSA-N 0.000 description 1
- 238000012286 ELISA Assay Methods 0.000 description 1
- SNLOOPZHAQDMJG-CIUDSAMLSA-N Gln-Glu-Glu Chemical compound NC(=O)CC[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(O)=O SNLOOPZHAQDMJG-CIUDSAMLSA-N 0.000 description 1
- IULKWYSYZSURJK-AVGNSLFASA-N Gln-Leu-Lys Chemical compound NC(=O)CC[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(O)=O IULKWYSYZSURJK-AVGNSLFASA-N 0.000 description 1
- ZEEPYMXTJWIMSN-GUBZILKMSA-N Gln-Lys-Ser Chemical compound NCCCC[C@@H](C(=O)N[C@@H](CO)C(O)=O)NC(=O)[C@@H](N)CCC(N)=O ZEEPYMXTJWIMSN-GUBZILKMSA-N 0.000 description 1
- UEILCTONAMOGBR-RWRJDSDZSA-N Gln-Thr-Ile Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O UEILCTONAMOGBR-RWRJDSDZSA-N 0.000 description 1
- JJKKWYQVHRUSDG-GUBZILKMSA-N Glu-Ala-Lys Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCN)C(O)=O JJKKWYQVHRUSDG-GUBZILKMSA-N 0.000 description 1
- CKOFNWCLWRYUHK-XHNCKOQMSA-N Glu-Asp-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CC(=O)O)NC(=O)[C@H](CCC(=O)O)N)C(=O)O CKOFNWCLWRYUHK-XHNCKOQMSA-N 0.000 description 1
- CLROYXHHUZELFX-FXQIFTODSA-N Glu-Gln-Asp Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(O)=O)C(O)=O CLROYXHHUZELFX-FXQIFTODSA-N 0.000 description 1
- RFDHKPSHTXZKLL-IHRRRGAJSA-N Glu-Gln-Phe Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)N)NC(=O)[C@H](CCC(=O)O)N RFDHKPSHTXZKLL-IHRRRGAJSA-N 0.000 description 1
- UHVIQGKBMXEVGN-WDSKDSINSA-N Glu-Gly-Asn Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)NCC(=O)N[C@@H](CC(N)=O)C(O)=O UHVIQGKBMXEVGN-WDSKDSINSA-N 0.000 description 1
- QNJNPKSWAHPYGI-JYJNAYRXSA-N Glu-Phe-Leu Chemical compound OC(=O)CC[C@H](N)C(=O)N[C@H](C(=O)N[C@@H](CC(C)C)C(O)=O)CC1=CC=CC=C1 QNJNPKSWAHPYGI-JYJNAYRXSA-N 0.000 description 1
- JWNZHMSRZXXGTM-XKBZYTNZSA-N Glu-Ser-Thr Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(O)=O JWNZHMSRZXXGTM-XKBZYTNZSA-N 0.000 description 1
- BPCLDCNZBUYGOD-BPUTZDHNSA-N Glu-Trp-Glu Chemical compound C1=CC=C2C(C[C@H](NC(=O)[C@H](CCC(O)=O)N)C(=O)N[C@@H](CCC(O)=O)C(O)=O)=CNC2=C1 BPCLDCNZBUYGOD-BPUTZDHNSA-N 0.000 description 1
- YQPFCZVKMUVZIN-AUTRQRHGSA-N Glu-Val-Gln Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(N)=O)C(O)=O YQPFCZVKMUVZIN-AUTRQRHGSA-N 0.000 description 1
- BUEFQXUHTUZXHR-LURJTMIESA-N Gly-Gly-Pro zwitterion Chemical compound NCC(=O)NCC(=O)N1CCC[C@H]1C(O)=O BUEFQXUHTUZXHR-LURJTMIESA-N 0.000 description 1
- NNCSJUBVFBDDLC-YUMQZZPRSA-N Gly-Leu-Ser Chemical compound NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(O)=O NNCSJUBVFBDDLC-YUMQZZPRSA-N 0.000 description 1
- GMTXWRIDLGTVFC-IUCAKERBSA-N Gly-Lys-Glu Chemical compound [H]NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(O)=O GMTXWRIDLGTVFC-IUCAKERBSA-N 0.000 description 1
- QAMMIGULQSIRCD-IRXDYDNUSA-N Gly-Phe-Tyr Chemical compound C([C@H](NC(=O)C[NH3+])C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C([O-])=O)C1=CC=CC=C1 QAMMIGULQSIRCD-IRXDYDNUSA-N 0.000 description 1
- OOCFXNOVSLSHAB-IUCAKERBSA-N Gly-Pro-Pro Chemical compound NCC(=O)N1CCC[C@H]1C(=O)N1[C@H](C(O)=O)CCC1 OOCFXNOVSLSHAB-IUCAKERBSA-N 0.000 description 1
- SYOJVRNQCXYEOV-XVKPBYJWSA-N Gly-Val-Glu Chemical compound [H]NCC(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(O)=O)C(O)=O SYOJVRNQCXYEOV-XVKPBYJWSA-N 0.000 description 1
- FYVHHKMHFPMBBG-GUBZILKMSA-N His-Gln-Asp Chemical compound C1=C(NC=N1)C[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H](CC(=O)O)C(=O)O)N FYVHHKMHFPMBBG-GUBZILKMSA-N 0.000 description 1
- TTYKEFZRLKQTHH-MELADBBJSA-N His-Lys-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CCCCN)NC(=O)[C@H](CC2=CN=CN2)N)C(=O)O TTYKEFZRLKQTHH-MELADBBJSA-N 0.000 description 1
- CSTDQOOBZBAJKE-BWAGICSOSA-N His-Tyr-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CC1=CC=C(C=C1)O)NC(=O)[C@H](CC2=CN=CN2)N)O CSTDQOOBZBAJKE-BWAGICSOSA-N 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- MKWSZEHGHSLNPF-NAKRPEOUSA-N Ile-Ala-Val Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](C)C(=O)N[C@@H](C(C)C)C(=O)O)N MKWSZEHGHSLNPF-NAKRPEOUSA-N 0.000 description 1
- DFJJAVZIHDFOGQ-MNXVOIDGSA-N Ile-Glu-Lys Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CCCCN)C(=O)O)N DFJJAVZIHDFOGQ-MNXVOIDGSA-N 0.000 description 1
- QQFSKBMCAKWHLG-UHFFFAOYSA-N Ile-Phe-Pro-Pro Chemical compound C1CCC(C(=O)N2C(CCC2)C(O)=O)N1C(=O)C(NC(=O)C(N)C(C)CC)CC1=CC=CC=C1 QQFSKBMCAKWHLG-UHFFFAOYSA-N 0.000 description 1
- TYYLDKGBCJGJGW-UHFFFAOYSA-N L-tryptophan-L-tyrosine Natural products C=1NC2=CC=CC=C2C=1CC(N)C(=O)NC(C(O)=O)CC1=CC=C(O)C=C1 TYYLDKGBCJGJGW-UHFFFAOYSA-N 0.000 description 1
- 241000880493 Leptailurus serval Species 0.000 description 1
- WSGXUIQTEZDVHJ-GARJFASQSA-N Leu-Ala-Pro Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](C)C(=O)N1CCC[C@@H]1C(O)=O WSGXUIQTEZDVHJ-GARJFASQSA-N 0.000 description 1
- DBVWMYGBVFCRBE-CIUDSAMLSA-N Leu-Asn-Asn Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O DBVWMYGBVFCRBE-CIUDSAMLSA-N 0.000 description 1
- DSFYPIUSAMSERP-IHRRRGAJSA-N Leu-Leu-Arg Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](C(O)=O)CCCN=C(N)N DSFYPIUSAMSERP-IHRRRGAJSA-N 0.000 description 1
- XOWMDXHFSBCAKQ-SRVKXCTJSA-N Leu-Ser-Leu Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@H](C(O)=O)CC(C)C XOWMDXHFSBCAKQ-SRVKXCTJSA-N 0.000 description 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
- NTBFKPBULZGXQL-KKUMJFAQSA-N Lys-Asp-Tyr Chemical compound NCCCC[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 NTBFKPBULZGXQL-KKUMJFAQSA-N 0.000 description 1
- GQFDWEDHOQRNLC-QWRGUYRKSA-N Lys-Gly-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)CNC(=O)[C@@H](N)CCCCN GQFDWEDHOQRNLC-QWRGUYRKSA-N 0.000 description 1
- RFQATBGBLDAKGI-VHSXEESVSA-N Lys-Gly-Pro Chemical compound C1C[C@@H](N(C1)C(=O)CNC(=O)[C@H](CCCCN)N)C(=O)O RFQATBGBLDAKGI-VHSXEESVSA-N 0.000 description 1
- FGMHXLULNHTPID-KKUMJFAQSA-N Lys-His-Lys Chemical compound NCCCC[C@H](N)C(=O)N[C@H](C(=O)N[C@@H](CCCCN)C(O)=O)CC1=CN=CN1 FGMHXLULNHTPID-KKUMJFAQSA-N 0.000 description 1
- LUTDBHBIHHREDC-IHRRRGAJSA-N Lys-Pro-Lys Chemical compound NCCCC[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCCCN)C(O)=O LUTDBHBIHHREDC-IHRRRGAJSA-N 0.000 description 1
- SQXZLVXQXWILKW-KKUMJFAQSA-N Lys-Ser-Phe Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O SQXZLVXQXWILKW-KKUMJFAQSA-N 0.000 description 1
- QLFAPXUXEBAWEK-NHCYSSNCSA-N Lys-Val-Asp Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(O)=O)C(O)=O QLFAPXUXEBAWEK-NHCYSSNCSA-N 0.000 description 1
- RKIIYGUHIQJCBW-SRVKXCTJSA-N Met-His-Glu Chemical compound [H]N[C@@H](CCSC)C(=O)N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CCC(O)=O)C(O)=O RKIIYGUHIQJCBW-SRVKXCTJSA-N 0.000 description 1
- FWAHLGXNBLWIKB-NAKRPEOUSA-N Met-Ile-Ser Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H]([C@@H](C)CC)NC(=O)[C@@H](N)CCSC FWAHLGXNBLWIKB-NAKRPEOUSA-N 0.000 description 1
- IHRFZLQEQVHXFA-RHYQMDGZSA-N Met-Thr-Lys Chemical compound CSCC[C@H](N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@H](C(O)=O)CCCCN IHRFZLQEQVHXFA-RHYQMDGZSA-N 0.000 description 1
- SITLTJHOQZFJGG-UHFFFAOYSA-N N-L-alpha-glutamyl-L-valine Natural products CC(C)C(C(O)=O)NC(=O)C(N)CCC(O)=O SITLTJHOQZFJGG-UHFFFAOYSA-N 0.000 description 1
- JOXIIFVCSATTDH-IHPCNDPISA-N Phe-Asn-Trp Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CC2=CNC3=CC=CC=C32)C(=O)O)N JOXIIFVCSATTDH-IHPCNDPISA-N 0.000 description 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
- JDMKQHSHKJHAHR-UHFFFAOYSA-N Phe-Phe-Leu-Tyr Natural products C=1C=C(O)C=CC=1CC(C(O)=O)NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)CC1=CC=CC=C1 JDMKQHSHKJHAHR-UHFFFAOYSA-N 0.000 description 1
- QARPMYDMYVLFMW-KKUMJFAQSA-N Phe-Pro-Glu Chemical compound C([C@H](N)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCC(O)=O)C(O)=O)C1=CC=CC=C1 QARPMYDMYVLFMW-KKUMJFAQSA-N 0.000 description 1
- ZJPGOXWRFNKIQL-JYJNAYRXSA-N Phe-Pro-Pro Chemical compound C([C@H](N)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(O)=O)C1=CC=CC=C1 ZJPGOXWRFNKIQL-JYJNAYRXSA-N 0.000 description 1
- CGBYDGAJHSOGFQ-LPEHRKFASA-N Pro-Ala-Pro Chemical compound C[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@@H]2CCCN2 CGBYDGAJHSOGFQ-LPEHRKFASA-N 0.000 description 1
- UAYHMOIGIQZLFR-NHCYSSNCSA-N Pro-Gln-Val Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](C(C)C)C(O)=O UAYHMOIGIQZLFR-NHCYSSNCSA-N 0.000 description 1
- KIPIKSXPPLABPN-CIUDSAMLSA-N Pro-Glu-Asn Chemical compound NC(=O)C[C@@H](C(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H]1CCCN1 KIPIKSXPPLABPN-CIUDSAMLSA-N 0.000 description 1
- HWLKHNDRXWTFTN-GUBZILKMSA-N Pro-Pro-Cys Chemical compound C1C[C@H](NC1)C(=O)N2CCC[C@H]2C(=O)N[C@@H](CS)C(=O)O HWLKHNDRXWTFTN-GUBZILKMSA-N 0.000 description 1
- FDMKYQQYJKYCLV-GUBZILKMSA-N Pro-Pro-Ser Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@H]1NCCC1 FDMKYQQYJKYCLV-GUBZILKMSA-N 0.000 description 1
- GMJDSFYVTAMIBF-FXQIFTODSA-N Pro-Ser-Asp Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(O)=O)C(O)=O GMJDSFYVTAMIBF-FXQIFTODSA-N 0.000 description 1
- MKGIILKDUGDRRO-FXQIFTODSA-N Pro-Ser-Ser Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H]1CCCN1 MKGIILKDUGDRRO-FXQIFTODSA-N 0.000 description 1
- KHRLUIPIMIQFGT-AVGNSLFASA-N Pro-Val-Leu Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O KHRLUIPIMIQFGT-AVGNSLFASA-N 0.000 description 1
- 102220472894 Receptor-type tyrosine-protein phosphatase beta_R94K_mutation Human genes 0.000 description 1
- HZWAHWQZPSXNCB-BPUTZDHNSA-N Ser-Arg-Trp Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC1=CNC2=C1C=CC=C2)C(O)=O HZWAHWQZPSXNCB-BPUTZDHNSA-N 0.000 description 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
- FTVRVZNYIYWJGB-ACZMJKKPSA-N Ser-Asp-Glu Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(O)=O FTVRVZNYIYWJGB-ACZMJKKPSA-N 0.000 description 1
- ZOHGLPQGEHSLPD-FXQIFTODSA-N Ser-Gln-Glu Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(O)=O ZOHGLPQGEHSLPD-FXQIFTODSA-N 0.000 description 1
- 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 1
- BPMRXBZYPGYPJN-WHFBIAKZSA-N Ser-Gly-Asn Chemical compound [H]N[C@@H](CO)C(=O)NCC(=O)N[C@@H](CC(N)=O)C(O)=O BPMRXBZYPGYPJN-WHFBIAKZSA-N 0.000 description 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
- 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 1
- PPNPDKGQRFSCAC-CIUDSAMLSA-N Ser-Lys-Asp Chemical compound NCCCC[C@H](NC(=O)[C@@H](N)CO)C(=O)N[C@@H](CC(O)=O)C(O)=O PPNPDKGQRFSCAC-CIUDSAMLSA-N 0.000 description 1
- QJKPECIAWNNKIT-KKUMJFAQSA-N Ser-Lys-Tyr Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O QJKPECIAWNNKIT-KKUMJFAQSA-N 0.000 description 1
- RRVFEDGUXSYWOW-BZSNNMDCSA-N Ser-Phe-Phe Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O RRVFEDGUXSYWOW-BZSNNMDCSA-N 0.000 description 1
- SRSPTFBENMJHMR-WHFBIAKZSA-N Ser-Ser-Gly Chemical compound OC[C@H](N)C(=O)N[C@@H](CO)C(=O)NCC(O)=O SRSPTFBENMJHMR-WHFBIAKZSA-N 0.000 description 1
- SNXUIBACCONSOH-BWBBJGPYSA-N Ser-Thr-Ser Chemical compound OC[C@H](N)C(=O)N[C@@H]([C@H](O)C)C(=O)N[C@@H](CO)C(O)=O SNXUIBACCONSOH-BWBBJGPYSA-N 0.000 description 1
- FHXGMDRKJHKLKW-QWRGUYRKSA-N Ser-Tyr-Gly Chemical compound OC[C@H](N)C(=O)N[C@H](C(=O)NCC(O)=O)CC1=CC=C(O)C=C1 FHXGMDRKJHKLKW-QWRGUYRKSA-N 0.000 description 1
- JZRYFUGREMECBH-XPUUQOCRSA-N Ser-Val-Gly Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(=O)NCC(O)=O JZRYFUGREMECBH-XPUUQOCRSA-N 0.000 description 1
- 108091081024 Start codon Proteins 0.000 description 1
- CYVQBKQYQGEELV-NKIYYHGXSA-N Thr-His-Gln Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)N[C@@H](CCC(=O)N)C(=O)O)N)O CYVQBKQYQGEELV-NKIYYHGXSA-N 0.000 description 1
- VRUFCJZQDACGLH-UVOCVTCTSA-N Thr-Leu-Thr Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O VRUFCJZQDACGLH-UVOCVTCTSA-N 0.000 description 1
- JWQNAFHCXKVZKZ-UVOCVTCTSA-N Thr-Lys-Thr Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(O)=O JWQNAFHCXKVZKZ-UVOCVTCTSA-N 0.000 description 1
- JMBRNXUOLJFURW-BEAPCOKYSA-N Thr-Phe-Pro Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N2CCC[C@@H]2C(=O)O)N)O JMBRNXUOLJFURW-BEAPCOKYSA-N 0.000 description 1
- ZESGVALRVJIVLZ-VFCFLDTKSA-N Thr-Thr-Pro Chemical compound C[C@H]([C@@H](C(=O)N[C@@H]([C@@H](C)O)C(=O)N1CCC[C@@H]1C(=O)O)N)O ZESGVALRVJIVLZ-VFCFLDTKSA-N 0.000 description 1
- CYCGARJWIQWPQM-YJRXYDGGSA-N Thr-Tyr-Ser Chemical compound C[C@@H](O)[C@H]([NH3+])C(=O)N[C@H](C(=O)N[C@@H](CO)C([O-])=O)CC1=CC=C(O)C=C1 CYCGARJWIQWPQM-YJRXYDGGSA-N 0.000 description 1
- BKVICMPZWRNWOC-RHYQMDGZSA-N Thr-Val-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](N)[C@@H](C)O BKVICMPZWRNWOC-RHYQMDGZSA-N 0.000 description 1
- XGFGVFMXDXALEV-XIRDDKMYSA-N Trp-Leu-Asn Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)O)NC(=O)[C@H](CC1=CNC2=CC=CC=C21)N XGFGVFMXDXALEV-XIRDDKMYSA-N 0.000 description 1
- QYSBJAUCUKHSLU-JYJNAYRXSA-N Tyr-Arg-Val Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C(C)C)C(O)=O QYSBJAUCUKHSLU-JYJNAYRXSA-N 0.000 description 1
- CTDPLKMBVALCGN-JSGCOSHPSA-N Tyr-Gly-Val Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)NCC(=O)N[C@@H](C(C)C)C(O)=O CTDPLKMBVALCGN-JSGCOSHPSA-N 0.000 description 1
- GZUIDWDVMWZSMI-KKUMJFAQSA-N Tyr-Lys-Cys Chemical compound NCCCC[C@@H](C(=O)N[C@@H](CS)C(O)=O)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 GZUIDWDVMWZSMI-KKUMJFAQSA-N 0.000 description 1
- AUZADXNWQMBZOO-JYJNAYRXSA-N Tyr-Pro-Arg Chemical compound C([C@H](N)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCN=C(N)N)C(O)=O)C1=CC=C(O)C=C1 AUZADXNWQMBZOO-JYJNAYRXSA-N 0.000 description 1
- QFHRUCJIRVILCK-YJRXYDGGSA-N Tyr-Thr-Cys Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CS)C(=O)O)NC(=O)[C@H](CC1=CC=C(C=C1)O)N)O QFHRUCJIRVILCK-YJRXYDGGSA-N 0.000 description 1
- 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 1
- SQUMHUZLJDUROQ-YDHLFZDLSA-N Tyr-Val-Asp Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(O)=O)C(O)=O SQUMHUZLJDUROQ-YDHLFZDLSA-N 0.000 description 1
- LHADRQBREKTRLR-DCAQKATOSA-N Val-Cys-Leu Chemical compound CC(C)C[C@@H](C(=O)O)NC(=O)[C@H](CS)NC(=O)[C@H](C(C)C)N LHADRQBREKTRLR-DCAQKATOSA-N 0.000 description 1
- OXVPMZVGCAPFIG-BQFCYCMXSA-N Val-Gln-Trp Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H](CC1=CNC2=CC=CC=C21)C(=O)O)N OXVPMZVGCAPFIG-BQFCYCMXSA-N 0.000 description 1
- HGJRMXOWUWVUOA-GVXVVHGQSA-N Val-Leu-Gln Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)O)NC(=O)[C@H](C(C)C)N HGJRMXOWUWVUOA-GVXVVHGQSA-N 0.000 description 1
- KISFXYYRKKNLOP-IHRRRGAJSA-N Val-Phe-Ser Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CO)C(=O)O)N KISFXYYRKKNLOP-IHRRRGAJSA-N 0.000 description 1
- SSYBNWFXCFNRFN-GUBZILKMSA-N Val-Pro-Ser Chemical compound CC(C)[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CO)C(O)=O SSYBNWFXCFNRFN-GUBZILKMSA-N 0.000 description 1
- KSFXWENSJABBFI-ZKWXMUAHSA-N Val-Ser-Asn Chemical compound [H]N[C@@H](C(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(O)=O KSFXWENSJABBFI-ZKWXMUAHSA-N 0.000 description 1
- RYHUIHUOYRNNIE-NRPADANISA-N Val-Ser-Gln Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(=O)N)C(=O)O)N RYHUIHUOYRNNIE-NRPADANISA-N 0.000 description 1
- SDHZOOIGIUEPDY-JYJNAYRXSA-N Val-Ser-Trp Chemical compound C1=CC=C2C(C[C@H](NC(=O)[C@H](CO)NC(=O)[C@@H](N)C(C)C)C(O)=O)=CNC2=C1 SDHZOOIGIUEPDY-JYJNAYRXSA-N 0.000 description 1
- NZYNRRGJJVSSTJ-GUBZILKMSA-N Val-Ser-Val Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(O)=O NZYNRRGJJVSSTJ-GUBZILKMSA-N 0.000 description 1
- BZDGLJPROOOUOZ-XGEHTFHBSA-N Val-Thr-Cys Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CS)C(=O)O)NC(=O)[C@H](C(C)C)N)O BZDGLJPROOOUOZ-XGEHTFHBSA-N 0.000 description 1
- QPJSIBAOZBVELU-BPNCWPANSA-N Val-Tyr-Ala Chemical compound C[C@@H](C(=O)O)NC(=O)[C@H](CC1=CC=C(C=C1)O)NC(=O)[C@H](C(C)C)N QPJSIBAOZBVELU-BPNCWPANSA-N 0.000 description 1
- ZLNYBMWGPOKSLW-LSJOCFKGSA-N Val-Val-Asp Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(O)=O)C(O)=O ZLNYBMWGPOKSLW-LSJOCFKGSA-N 0.000 description 1
- JVGDAEKKZKKZFO-RCWTZXSCSA-N Val-Val-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](C(C)C)NC(=O)[C@H](C(C)C)N)O JVGDAEKKZKKZFO-RCWTZXSCSA-N 0.000 description 1
- 238000001042 affinity chromatography Methods 0.000 description 1
- KOSRFJWDECSPRO-UHFFFAOYSA-N alpha-L-glutamyl-L-glutamic acid Natural products OC(=O)CCC(N)C(=O)NC(CCC(O)=O)C(O)=O KOSRFJWDECSPRO-UHFFFAOYSA-N 0.000 description 1
- 108010009111 arginyl-glycyl-glutamic acid Proteins 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 210000003719 b-lymphocyte Anatomy 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 210000004978 chinese hamster ovary cell Anatomy 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000010367 cloning Methods 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 108010060199 cysteinylproline Proteins 0.000 description 1
- 230000007717 exclusion Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000013604 expression vector Substances 0.000 description 1
- 108010013768 glutamyl-aspartyl-proline Proteins 0.000 description 1
- 108010055341 glutamyl-glutamic acid Proteins 0.000 description 1
- 108010049041 glutamylalanine Proteins 0.000 description 1
- 108010000434 glycyl-alanyl-leucine Proteins 0.000 description 1
- 108010050475 glycyl-leucyl-tyrosine Proteins 0.000 description 1
- 108010010147 glycylglutamine Proteins 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 210000005260 human cell Anatomy 0.000 description 1
- 210000004408 hybridoma Anatomy 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000003780 insertion Methods 0.000 description 1
- 230000037431 insertion Effects 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 108010044311 leucyl-glycyl-glycine Proteins 0.000 description 1
- 108010073472 leucyl-prolyl-proline Proteins 0.000 description 1
- 108010091871 leucylmethionine Proteins 0.000 description 1
- 108010057821 leucylproline Proteins 0.000 description 1
- 108010003700 lysyl aspartic acid Proteins 0.000 description 1
- 210000004962 mammalian cell Anatomy 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000004770 neurodegeneration Effects 0.000 description 1
- 208000015122 neurodegenerative disease Diseases 0.000 description 1
- 239000002773 nucleotide Substances 0.000 description 1
- 125000003729 nucleotide group Chemical group 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 108010024654 phenylalanyl-prolyl-alanine Proteins 0.000 description 1
- 108010077112 prolyl-proline Proteins 0.000 description 1
- 108010070643 prolylglutamic acid Proteins 0.000 description 1
- 230000004850 protein–protein interaction Effects 0.000 description 1
- 239000012521 purified sample Substances 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 238000002849 thermal shift Methods 0.000 description 1
- 108010044292 tryptophyltyrosine Proteins 0.000 description 1
- 108010079202 tyrosyl-alanyl-cysteine Proteins 0.000 description 1
- 108010020532 tyrosyl-proline Proteins 0.000 description 1
- 108010071635 tyrosyl-prolyl-arginine Proteins 0.000 description 1
Images
Classifications
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
- C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
- C07K2317/33—Crossreactivity, e.g. for species or epitope, or lack of said crossreactivity
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
- C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
- C07K2317/92—Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Immunology (AREA)
- Biochemistry (AREA)
- Biophysics (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Biomedical Technology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Peptides Or Proteins (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Micro-Organisms Or Cultivation Processes Thereof (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
Abstract
本披露内容部分地基于发现选择性靶向比如寡聚物/原纤维等人α‑突触核蛋白聚集体的抗体,比如BAN0805。与小鼠单克隆抗体mAb47相比,BAN0805与不期望的单体α‑突触核蛋白靶标结合的倾向较低。
Description
相关申请的交叉引用
本申请要求于2020年6月26日提交的美国临时申请号63/044881和2020年8月27日提交的美国临时申请号63/071150的权益,这些临时申请各自的全部内容通过援引并入本文。
参考序列表
名称为Sequence_Listing_AVR-71925_ST25.txt、包含SEQ ID NO:1至SEQ ID NO:20的序列表的全部内容通过援引并入本文,该序列表包括本文所披露的核酸和氨基酸序列。该序列表已通过EFS以ASCII文本格式以电子方式提交。该序列表于2021年6月17日首次创建,并且大小为18,417个字节。
背景技术
国际专利申请号WO 2011/104696 A1(其通过援引并入本文)披露了一种与α-突触核蛋白的原纤维(protofibril)形式结合的鼠单克隆IgG抗体mAb47。仍然需要适用于人类的与α-突触核蛋白的原纤维形式选择性结合的抗体。
发明内容
本披露内容涉及对人α-突触核蛋白原纤维具有高亲和力并且对α-突触核蛋白单体具有低亲和力的抗体。在一些实施方案中,本文所述的抗体选择性靶向比如寡聚物/原纤维等人α-突触核蛋白聚集体,即,与单体相比,与α-突触核蛋白原纤维的结合要强得多。在一些实施方案中,当比较α-突触核蛋白原纤维相对于单体的结合比时,本文所述的抗体具有比mAb47更好的选择性。在一些实施方案中,本文所述的抗体为抗α-突触核蛋白抗体。
在一个方面,本披露内容涉及BAN0805,即一种单克隆抗体,其包含含有SEQ IDNO:3所示的氨基酸序列的重链和含有SEQ ID NO:4所示的氨基酸序列的轻链;该单克隆抗体选择性靶向比如寡聚物/原纤维等人α-突触核蛋白聚集体,对人α-突触核蛋白原纤维具有高亲和力并且对α-突触核蛋白单体具有低亲和力。有趣的是,BAN0805相比于mAb47还表现出较低的α-突触核蛋白单体结合,使得当比较α-突触核蛋白原纤维相对于单体的结合比时,BAN0805比mAb47的选择性更好。此外,未检测到BAN0805与β-突触核蛋白单体和γ-突触核蛋白单体或Aβ-原纤维的结合。
本披露内容进一步涉及用于在治疗具有α-突触核蛋白病状的神经退行性疾病方面进行改善的抗体,这些神经退行性疾病包括但不限于帕金森病(PD)。
附图说明
专利或申请文件包含至少一幅彩色附图。在提出请求并支付必要的费用后,专利局将提供带有一幅或多幅彩图的本专利或专利申请公布的副本。
图1示出BAN0805的热应激数据。将1mg/mL纯化候选抗体的样品暴露于a)4℃、b)25℃、c)37℃和d)50℃的温度持续两周。然后通过SEC-MALS分析了样品以检查聚集情况。数据表明,BAN0805不存在由热应激引起的聚集问题。
图2示出BAN0805在与α-突触核蛋白单体和原纤维(PF)结合时进行的抑制ELISA,以IC50值表示。与仅具有340倍选择性的mAb47相比(未示出),BAN0805对α-突触核蛋白的原纤维形式具有910倍的更好的选择性。原纤维水平在浓度方面表示为与单体水平相当,并且不考虑原纤维的大小。通过将单体结合的IC50值与PF结合的IC50值相除来计算倍数选择性。
图3示出使用Biacore SPR测得的BAN0805相比于mAb47的结合和选择性。mAb47和BAN0805对α-突触核蛋白原纤维的KD值相似,这表明mAb47的修饰不影响与α-突触核蛋白原纤维的强结合,确认了从抑制ELISA得到的结果。用SPR测得的KD值使得BAN0805和mAb47对PF相对于单体分别具有110,000倍和18,000倍的选择性。示出了在Biacore 8K上得到的mAb47和BAN0805 SPR测量结果的代表性传感图。
图4示出使用抑制ELISA测得的BAN0805(在本文中称为hu47-IgG4)对α-突触核蛋白单体、β-突触核蛋白单体、γ-突触核蛋白单体和Aβ-原纤维的交叉反应性。结果表明,与β-突触核蛋白单体或γ-突触核蛋白单体或Aβ-原纤维未发生可检测的结合。
具体实施方式
本披露内容涉及对人α-突触核蛋白原纤维具有高亲和力并且对α-突触核蛋白单体具有低亲和力的抗体。
如本文所披露,本披露内容涉及以下实施方案。
实施方案1.一种抗体,其包含含有SEQ ID NO:1的氨基酸序列的重链和含有SEQID NO:2的氨基酸序列的轻链。
实施方案2.如实施方案1所述的抗体,其中该抗体属于IgG同种型。
实施方案3.如实施方案1所述的抗体,其中该抗体属于IgG4同种型。
实施方案4.如实施方案1至3中任一项所述的抗体,其中该抗体结合α-突触核蛋白的原纤维形式的KD值是结合α-突触核蛋白的单体形式的KD值的至多1/110,000。
实施方案5.如实施方案1至3中任一项所述的抗体,其中该抗体结合α-突触核蛋白的该原纤维形式的KD值为至多18pM,并且结合α-突触核蛋白的该单体形式的KD值为至少2200nM。
实施方案6.如实施方案4或5所述的抗体,其中所述抗体与α-突触核蛋白结合的该原纤维形式的KD以及所述抗体与α-突触核蛋白结合的该单体形式的KD通过SPR来测量。
实施方案7.一种抗体,其包含含有SEQ ID NO:3的氨基酸序列的重链和含有SEQID NO:4的氨基酸序列的轻链。
实施方案8.如实施方案7所述的抗体,其中该抗体包含两条重链和两条轻链。
实施方案9.一种核酸,其编码包含选自由SEQ ID NO:1-4组成的组的氨基酸序列的多肽。
实施方案10.如实施方案9所述的核酸,其包含选自由SEQ ID NO:11-14和17-20组成的组的序列。
实施方案11.一种或多种核酸,其编码如实施方案1至8中任一项所述的抗体。
实施方案12.如实施方案11所述的一种或多种核酸,其中
(a)该一种或多种核酸包含SEQ ID NO:11和12的序列,
(b)该一种或多种核酸包含SEQ ID NO:13和14的序列,
(c)该一种或多种核酸包含SEQ ID NO:17和18的序列,或
(d)该一种或多种核酸包含SEQ ID NO:19和20的序列。
实施方案13.一种或多种载体,其包含如实施方案9、10、11或12中任一项所述的一种或多种核酸。
实施方案14.一种宿主细胞,其包含如实施方案9至12中任一项所述的一种或多种核酸。
实施方案15.一种宿主细胞,其包含如实施方案13所述的一种或多种载体。
实施方案16.一种宿主细胞,其表达如实施方案1至8中任一项所述的抗体。
实施方案17.一种组合物,其包含如实施方案1至8中任一项所述的至少一种抗体和药学上可接受的载剂。
在一个方面,本披露内容涉及一种抗体,该抗体对人α-突触核蛋白原纤维具有高亲和力并且对α-突触核蛋白单体具有低亲和力,并且包含含有SEQ ID NO:1的氨基酸序列的重链和含有SEQ ID NO:2的氨基酸序列的轻链。
在一个实施方案中,本文所提供的抗体包含含有SEQ ID NO:1的氨基酸序列的重链和含有SEQ ID NO:2的氨基酸序列的轻链。
在一个实施方案中,本文所提供的抗体包含含有SEQ ID NO:3的氨基酸序列的重链和含有SEQ ID NO:4的氨基酸序列的轻链。在一些实施方案中,本文所提供的抗体包含两条重链和两条轻链。
在一个实施方案中,本披露内容所述的抗体属于IgG同种型,尤其是人IgG同种型。在另一实施方案中,该抗体属于IgG4同种型。
在本披露内容内,对人α-突触核蛋白原纤维的高亲和力是指对人α-突触核蛋白原纤维的解离常数KD小于10-7M。因此,在一个实施方案中,本披露内容所述的抗体对人α-突触核蛋白原纤维具有小于10-8M、10-9M、10-10M、10-11M或10-12M的KD。在特别的实施方案中,抗体包含含有SEQ ID NO:1所示的氨基酸序列的重链和含有SEQ ID NO:2所示的氨基酸序列的轻链,并且该抗体对人α-突触核蛋白原纤维具有11.2pM至25.8pM的KD。
在另一实施方案中,抗体包含含有SEQ ID NO:1的氨基酸序列的重链和含有SEQID NO:2的氨基酸序列的轻链,并且该抗体对人α-突触核蛋白单体具有低亲和力。例如,本披露内容所述的抗体与α-突触核蛋白的单体形式结合的KD为至少1500nM、至少1600nM、至少1700nM、至少1800nM、至少1900nM、至少2000nM、至少2100nM、至少2200nM、至少2300nM、至少2400nM、至少2500nM、至少2600nM、至少2700nM、至少2800nM、至少2900nM或至少3000nM。在特别的实施方案中,抗体包含含有SEQ ID NO:1所示的氨基酸序列的重链和含有SEQ IDNO:2所示的氨基酸序列的轻链,并且该抗体对人α-突触核蛋白单体具有1650nM至2730nM的KD。
在一个实施方案中,抗体包含含有SEQ ID NO:1的氨基酸序列的重链和含有SEQID NO:2的氨基酸序列的轻链,并且该抗体对人α-突触核蛋白原纤维的选择性是对单体α-突触核蛋白的选择性的80,000倍、90,000倍、100,000倍、110,000倍或120,000倍。在特别的实施方案中,抗体包含含有SEQ ID NO:1所示的氨基酸序列的重链和含有SEQ ID NO:2所示的氨基酸序列的轻链,并且该抗体对人α-突触核蛋白原纤维的选择性是对单体α-突触核蛋白的选择性的64,000倍至244,000倍。
在一个实施方案中,这些结合亲和力使用抑制ELISA来测量,例如,如实施例3中所述。在另一实施方案中,这些结合亲和力使用表面等离子体共振(SPR)来测量,例如,如实施例3中所述。
在另一方面,本文提供了核酸,该核酸编码至少一种包含选自由SEQ ID NO:1-4组成的组的氨基酸序列的多肽。该核酸可以是DNA或RNA。该核酸可包含选自由SEQ ID NO:11-14和17-20组成的组的序列。
在另一方面,本文提供了编码本发明的抗体的一种或多种核酸。在一个实施方案中,该一种或多种核酸包含SEQ ID NO:11和12的序列。在另一实施方案中,该一种或多种核酸包含SEQ ID NO:13和14的序列。在一个实施方案中,该一种或多种核酸包含SEQ ID NO:17和18的序列。在一个实施方案中,该一种或多种核酸包含SEQ ID NO:19和20的序列。
在另一方面,本文提供了载体,该载体包含编码至少一种包含选自由SEQ ID NO:1-4组成的组的氨基酸序列的多肽的核酸。此类载体包括但不限于克隆载体或表达载体。在一个方面,提供了编码本发明的抗体的一种或多种载体。在一个实施方案中,该一种或多种载体包含SEQ ID NO:11和12的序列。在另一实施方案中,该一种或多种载体包含SEQ IDNO:13和14的序列。在一个实施方案中,该一种或多种载体包含SEQ ID NO:17和18的序列。在一个实施方案中,该一种或多种载体包含SEQ ID NO:19和20的序列。
在另一方面,本文提供了宿主细胞,该宿主细胞包含编码至少一种包含选自由SEQID NO:1-4组成的组的氨基酸序列的多肽的核酸。在一个实施方案中,宿主细胞包含编码本发明的抗体的一种或多种核酸。本文所述的宿主细胞可为比如B细胞、杂交瘤或CHO细胞等哺乳动物细胞。在一个实施方案中,本文所述的宿主细胞为人细胞。
在另一方面,本文提供了一种组合物,该组合物包含本发明的抗体和药学上可接受的赋形剂。
实施例
实施例1-抗体候选物的生成
mAb47的初始变异体是通过将mAb47 CDR直接移植到人框架序列并且在不同位置对小鼠残基进行回复突变来生成的。初始变异体均未显示出所期望的与α-突触核蛋白的结合特性。因此,构建了新的模型并且加以分析,以找到更多用于生成新变异体的可能的突变。
在第二次尝试改良mAb47时,检查了与靶标相互作用的可能性较小的残基以及距所确定的CDR处的残基。生成具有SEQ ID NO:3所示的重链序列和SEQ ID NO:4所示的轻链序列的抗体变异体,并且将其命名为BAN0805。结果发现,回复突变V71K和R94K虽然同时存在于BAN0805中,但对这些抗体的结合能力至关重要,因为在其他变异体中去除这些回复突变导致结合丧失。
由于BAN0805的回复突变比类似的变异体少一个,并且已经显示出对原纤维的结合和选择性超过对单体物质的结合和选择性,因此选择BAN0805作为先导候选物。
实施例2-抗体候选物的表征
为确定热稳定性,抗体经受较高温度10分钟,冷却至4℃,并且在每种候选物的EC80浓度(通常为5ng/mL至50ng/mL)下用于ELISA测定。BAN0805是稳定的,保持其与α-突触核蛋白的结合能力,直至达到75℃,此时其结合能力开始下降,而嵌合小鼠抗体c47或cmAb47(组合人IgG4以及mAb47的可变区的嵌合体)的结合提早约5℃急剧下降。
为确定抗体的解链温度,在热位移测定中,相对于BAN0805,对cmAb47进行了测试。解链温度数据表明,BAN0805的Tm计算结果为65℃至65.4℃,低于嵌合抗体的70℃。
此外,将1mg/mL的纯化样品以0.4mL/min进样至HPLC系统中的体积排阻柱中,并且通过多角度光散射进行分析以确定绝对摩尔质量并且检查聚集情况。数据表明,BAN0805不存在聚集问题。BAN0805是单分散的(Mw/Mn<1.05)。质量回收率为100%(计算质量比进样质量),表明蛋白质回收率良好。
使用大量纯化的人多克隆IgG的交叉相互作用色谱是一种监测非特异性蛋白质-蛋白质相互作用的技术,并且可用于区分可溶性抗体与不溶性抗体。升高的保留指数(k′)表明自身相互作用倾向和低溶解度。BAN0805显示出0.025的保留指数,该保留指数低于cmAb47的0.035,表明非特异性相互作用的倾向低并且溶解度良好。
对于冻/融应激分析,1mg/mL纯化候选抗体的样品经受10次如下循环:在-80℃冷冻15分钟,然后在室温解冻15分钟。对于热诱导应激分析,将1mg/mL纯化候选抗体的样品暴露于a)4℃、b)25℃、c)37℃和d)50℃的温度持续两周。然后通过SEC-MALS分析了样品以检查聚集情况。数据表明,冻融循环和热应激不会引起BAN0805中的聚集。见图1。
按照IMGT CDR定义和DomainGapAlign工具,对BAN0805进行了分析,并且与最接近的种系(对于HK为IGVH4-59*03/IGHJ3*01,并且对于KA为IGVK2-28*01/IGKJ2*02)进行了比较。对于轻链,与人种系的总体同一性为86.5%,高于85%的截止值,因此在该分析中将其视为人源化的。对于重链,在移植CDR并且引入两个小鼠回复突变后,与人种系的百分比同一性下降至略低于81%。这可以被解释为IMGT CDR2明显短于本文所用的Kabat定义,其导致在框架3的开始处插入更多数量的小鼠残基。
实施例3-BAN0805与人α-突触核蛋白原纤维的选择性结合
BAN0805对人α-突触核蛋白原纤维的结合选择性通过抑制ELISA和表面等离子体共振(SPR)两者来测量。
mAb47和BAN0805对α-突触核蛋白原纤维的IC50值非常接近(分别为2.7nM和2.2nM),这表明人源化后,对原纤维的结合特性没有改变。相比之下,与α-突触核蛋白单体的结合发生改变,导致BAN0805与α-突触核蛋白单体的结合强度降低。这使得与mAb47(340倍)相比,BAN0805(910倍)对α-突触核蛋白原纤维相对于单体具有更好的选择性。见图2。
然而,由于检测的局限性,不可能进一步降低抗体浓度以使其能够检测更低的IC50值并因此接近″真实″IC50值。因此,已经根据已用于所有mAb47和BAN0805批次的抑制ELISA的现行程序获得了所呈现的IC50值,认为对原纤维的IC50值可能被高估(即,结合强度可能被低估)。使用如下所述的SPR获得了更准确的结合,并因此获得了更准确的选择性。
mAb47和BAN0805的结合选择性使用Biacore 8K仪器(GE医疗(GE Healthcare))通过SPR得到确认。由于靶抗原的复杂性与抗体的显著的亲合力依赖性相结合所引起的可行性问题,分别使用不同的测定设置来评定α-突触核蛋白原纤维和单体结合。为测量与单体的结合,对于mAb47和BAN0805,分别用抗小鼠抗体或抗人抗体包被芯片。然后在表面上捕获0.25μg/ml至1.5μg/ml的mAb47或BAN0805,然后进行α-突触核蛋白单体的5倍稀释单循环动力学注射。为测量与原纤维(PF)的结合,用0.5μg/ml PF包被芯片,并且使用单循环动力学来注射mAb47或BAN0805的2倍稀释液。mAb47和BAN0805的代表性传感图如图3中所示。
mAb47和BAN0805对α-突触核蛋白原纤维的KD值相似,这表明mAb47的修饰不影响与α-突触核蛋白原纤维的强结合(表1),确认了来自抑制ELISA的结果。但是,KD值是在pM范围内,确认了抑制ELISA的上述局限性。重要的是,通过SPR确认,与mAb47相比,BAN0805对α-突触核蛋白单体的亲和力降低。用SPR测得的KD值使得BAN0805和mAb47对PF相对于单体分别具有110,000倍和18,000倍的选择性。mAb47和BAN0805对α-突触核蛋白单体和原纤维的平均KD值如表1中所示。
表1.通过Biacore SPR测得的mAb47和BAN0805与α-突触核蛋白原纤维(PF)和单体(M)结合的KD值。
数据呈现为平均值±标准偏差(n=实验次数)
KD:解离常数
使用直接ELISA(其中致密涂层模拟聚集形式的包被蛋白质)以及抑制ELISA两者测试了比如β-突触核蛋白或γ-突触核蛋白等同源蛋白质和其他易聚集蛋白质(如Aβ)的交叉反应性。在本文中,通过抑制ELISA并行分析mAb47和BAN0805的交叉反应性。用β-突触核蛋白单体、γ-突触核蛋白单体和Aβ-原纤维作为抗原进行抑制ELISA。结果表明,BAN0805与β-突触核蛋白单体或γ-突触核蛋白单体或Aβ-原纤维未发生可检测的结合。抑制ELISA中BAN0805对β-突触核蛋白或γ-突触核蛋白的代表性交叉反应性测试如图4中所示。数据呈现于表2中。
表2.mAb47和BAN0805对β-突触核蛋白单体、γ-突触核蛋白单体和Aβ-原纤维的交叉反应性。
n.b.=无结合
抑制ELISA的结果和表面等离子体共振(SPR)Biacore数据均显示,与mAb47相比,BAN0805对α-突触核蛋白单体的亲和力降低,表明BAN0805的选择性相比于mAb47更好。此外,在测试的浓度(高达μM范围)下,未见BAN0805与β-突触核蛋白单体和γ-突触核蛋白单体或Aβ-原纤维的结合。
因此,本披露内容涉及一种抗体,该抗体对α-突触核蛋白原纤维具有高亲和力并且对α-突触核蛋白单体具有低亲和力,并且与鼠mAb47相比具有以下特性:
(1)与单体相比,BAN0805与α-突触核蛋白原纤维的结合要强得多;
(2)抑制ELISA和SPR Biacore数据均表明,与BAN0805相比,mAb47的α-突触核蛋白单体结合更强,使得当比较α-突触核蛋白原纤维相对于单体的结合比时,BAN0805具有比mAb47更好的选择性(即,与mAb47相比,BAN0805与不期望的单体α-突触核蛋白靶标结合的倾向较低);以及
(3)在测试的浓度(高达μM范围)下,未见BAN0805与β-突触核蛋白单体和γ-突触核蛋白单体或Aβ-原纤维的结合。
实施例4-BAN0805的生产
为生产BAN0805,合成了编码BAN0805 VH(SEQ ID NO:13)和VL(SEQ ID NO:14)(包括信号肽)的优化DNA序列,并且将其分别克隆到GS载体pXC-IgG4Pro(deltaK)和pXC-Kappa(龙沙(Lonza)公司)中。然后使用所得HC和LC SGV生成含有HC和LC基因两者的双基因载体(DGV)。编码BAN0805重链(HC)和轻链(LC)的优化DNA序列分别如SEQ ID NO:11和12所示。编码BAN0805重链可变区(VH)和轻链可变区(VL)的优化DNA序列分别如SEQ ID NO:13和14所示。SEQ ID NO:11-14均包括编码信号肽的核苷酸序列(见表3B)。与BAN0805 HC、LC、VH和VL(排除信号肽)的氨基酸序列相对应的核苷酸序列分别如SEQ ID NO:17、18、19和20所示。BAN0805的CDR序列列于表3A中。根据Chothia命名法的重链CDR(VH-CDR)1至3的氨基酸序列分别如SEQ ID NO:5、6和7所示。根据Rabat命名法的重链CDR(VH-CDR)1至3的氨基酸序列分别如SEQ ID NO:15、16和7所示。根据Chothia和Rabat命名法的重链CDR(VH-CDR-3)的氨基酸序列相同,并且如SEQ ID NO:7所示。根据Chothia和Rabat命名法的轻链CDR(VL-CDR)1至3的氨基酸序列相同,并且分别如SEQ ID NO:8、9和10所示。
然后将所得DGV(称为pBAN0805/DGV)瞬时转染至CHOK1SV GS-KO细胞,并且在引起组装的抗体分泌的条件下培养。然后通过蛋白A亲和色谱纯化分泌的抗体。
表3.序列表
A.BAN0805
VH:
VL:
重链
轻链
CDR
VH-CDR-1(Chothia):GFSLTSYGVH(SEQ ID NO:5)
VH-CDR-1(Rabat):SYGVH(SEQ ID NO:15)
VH-CDR-2(Chothia):VIWRGGSTDYSAAF(SEQ ID NO:6)
VH-CDR-2(Kabat):VIWRGGSTDYSAAFMS(SEQ ID NO:16)
VH-CDR-3(Kabat/Chothia):LLRSVGGFAD(SEQ ID NO:7)
VL-CDR-1(Kabat/Chothia):RSSQTIVHNNGNTYLE(SEQ ID NO:8)
VL-CDR-2(Kabat/Chothia):KVSNRFS(SEQ ID NO:9)
VL-CDR-3(Kabat/Chothia):FQGSHVPFT(SEQ ID NO:10)
表3A列出的带有下划线的序列为根据Chothia命名法的CDR序列,并且以粗体显示的序列为根据Kabat命名法的CDR序列。CDR1、CDR2和CDR3按标准出现顺序从左(N-末端)到右(C-末端)显示。
B.编码BAN0805重链和轻链的核苷酸序列
具有信号序列的BAN0805 HC基因(SEQ ID NO:11)
具有信号序列的BAN0805 LC基因(SEQ ID NO:12)
具有信号序列的BAN0805 VH基因(SEQ ID NO:13)
具有信号序列的BAN0805 VL基因(SEQ ID NO:14)
BAN0805 HC基因(SEQ ID NO:17)
BAN0805 LC基因(SEQ ID NO:18)
BAN0805 VH基因(SEQ ID NO:19)
BAN0805 VL基因(SEQ ID NO:20)
编码信号肽的序列加下划线。起始密码子以粗体显示,并且终止密码子以斜体显示。
序列表
<110> 生命北极公司
<120> 结合α-突触核蛋白原纤维的抗体
<130> AVR-71925
<150> 63/071,150
<151> 2020-08-27
<150> 63/044,881
<151> 2020-06-26
<160> 20
<170> PatentIn 3.5版
<210> 1
<211> 118
<212> PRT
<213> 人工
<220>
<223> BAN0805 VH
<400> 1
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Ser Tyr
20 25 30
Gly Val His Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Val Ile Trp Arg Gly Gly Ser Thr Asp Tyr Ser Ala Ala Phe Met
50 55 60
Ser Arg Leu Thr Ile Ser Lys Asp Thr Ser Lys Asn Gln Val Ser Leu
65 70 75 80
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Lys Leu Leu Arg Ser Val Gly Gly Phe Ala Asp Trp Gly Gln Gly Thr
100 105 110
Met Val Thr Val Ser Ser
115
<210> 2
<211> 112
<212> PRT
<213> 人工
<220>
<223> BAN0805 VL
<400> 2
Asp Ile Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Pro Gly
1 5 10 15
Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Thr Ile Val His Asn
20 25 30
Asn Gly Asn Thr Tyr Leu Glu Trp Tyr Leu Gln Lys Pro Gly Gln Ser
35 40 45
Pro Gln Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Phe Gln Gly
85 90 95
Ser His Val Pro Phe Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 3
<211> 444
<212> PRT
<213> 人工
<220>
<223> BAN0805重链
<400> 3
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Ser Tyr
20 25 30
Gly Val His Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Val Ile Trp Arg Gly Gly Ser Thr Asp Tyr Ser Ala Ala Phe Met
50 55 60
Ser Arg Leu Thr Ile Ser Lys Asp Thr Ser Lys Asn Gln Val Ser Leu
65 70 75 80
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Lys Leu Leu Arg Ser Val Gly Gly Phe Ala Asp Trp Gly Gln Gly Thr
100 105 110
Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro
115 120 125
Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly
130 135 140
Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn
145 150 155 160
Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln
165 170 175
Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser
180 185 190
Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser
195 200 205
Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys
210 215 220
Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu
225 230 235 240
Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu
245 250 255
Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln
260 265 270
Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys
275 280 285
Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu
290 295 300
Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys
305 310 315 320
Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys
325 330 335
Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser
340 345 350
Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys
355 360 365
Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln
370 375 380
Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly
385 390 395 400
Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln
405 410 415
Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn
420 425 430
His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly
435 440
<210> 4
<211> 219
<212> PRT
<213> 人工
<220>
<223> BAN0805轻链
<400> 4
Asp Ile Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Pro Gly
1 5 10 15
Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Thr Ile Val His Asn
20 25 30
Asn Gly Asn Thr Tyr Leu Glu Trp Tyr Leu Gln Lys Pro Gly Gln Ser
35 40 45
Pro Gln Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Phe Gln Gly
85 90 95
Ser His Val Pro Phe Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105 110
Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu
115 120 125
Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe
130 135 140
Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln
145 150 155 160
Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
165 170 175
Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu
180 185 190
Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser
195 200 205
Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 5
<211> 10
<212> PRT
<213> 人工
<220>
<223> BAN0805 VH-CDR-1(Chothia)
<400> 5
Gly Phe Ser Leu Thr Ser Tyr Gly Val His
1 5 10
<210> 6
<211> 14
<212> PRT
<213> 人工
<220>
<223> BAN0805 VH-CDR-2(Chothia)
<400> 6
Val Ile Trp Arg Gly Gly Ser Thr Asp Tyr Ser Ala Ala Phe
1 5 10
<210> 7
<211> 10
<212> PRT
<213> 人工
<220>
<223> BAN0805 VH-CDR-3(Kabat/Chothia)
<400> 7
Leu Leu Arg Ser Val Gly Gly Phe Ala Asp
1 5 10
<210> 8
<211> 16
<212> PRT
<213> 人工
<220>
<223> BAN0805 VL-CDR-1(Kabat/Chothia)
<400> 8
Arg Ser Ser Gln Thr Ile Val His Asn Asn Gly Asn Thr Tyr Leu Glu
1 5 10 15
<210> 9
<211> 7
<212> PRT
<213> 人工
<220>
<223> BAN0805 VL-CDR-2(Kabat/Chothia)
<400> 9
Lys Val Ser Asn Arg Phe Ser
1 5
<210> 10
<211> 9
<212> PRT
<213> 人工
<220>
<223> BAN0805 VL-CDR-3(Kabat/Chothia)
<400> 10
Phe Gln Gly Ser His Val Pro Phe Thr
1 5
<210> 11
<211> 1395
<212> DNA
<213> 人工
<220>
<223> 具有信号序列的BAN0805 HC基因
<400> 11
atggaatggt cctgggtgtt cctgttcttc ctgtccgtga ccaccggcgt gcactctcag 60
gttcagctgc aagagtctgg ccctggcctg gtcaagcctt ccgaaacact gtctctgacc 120
tgcaccgtgt ccggcttctc cctgacatct tatggggtgc actggatcag acagcctcca 180
ggcaaaggcc tggaatggat cggagtgatt tggagaggcg gctccaccga ttactccgcc 240
gccttcatgt cccggctgac catctctaag gacacctcca agaaccaggt gtccctgaag 300
ctgtcctctg tgaccgctgc tgataccgcc gtgtactact gtgccaagct gctgagatct 360
gtcggcggct ttgctgattg gggccagggc acaatggtca ccgtgtctag cgcttctaca 420
aagggcccaa gcgtgttccc cctggccccc tgctccagaa gcaccagcga gagcacagcc 480
gccctgggct gcctggtgaa ggactacttc cccgagcccg tgaccgtgtc ctggaacagc 540
ggagccctga ccagcggcgt gcacaccttc cccgccgtgc tgcagagcag cggcctgtac 600
agcctgagca gcgtggtgac cgtgcccagc agcagcctgg gcaccaagac ctacacctgt 660
aacgtggacc acaagcccag caacaccaag gtggacaaga gggtggagag caagtacggc 720
ccaccctgcc ccccctgccc agcccccgag ttcctgggcg gacccagcgt gttcctgttc 780
ccccccaagc ccaaggacac cctgatgatc agcagaaccc ccgaggtgac ctgtgtggtg 840
gtggacgtgt cccaggagga ccccgaggtc cagttcaact ggtacgtgga cggcgtggag 900
gtgcacaacg ccaagaccaa gcccagagag gagcagttta acagcaccta ccgggtggtg 960
tccgtgctga ccgtgctgca ccaggactgg ctgaacggca aagagtacaa gtgtaaggtc 1020
tccaacaagg gcctgccaag cagcatcgaa aagaccatca gcaaggccaa gggccagcct 1080
agagagcccc aggtctacac cctgccaccc agccaagagg agatgaccaa gaaccaggtg 1140
tccctgacct gtctggtgaa gggcttctac ccaagcgaca tcgccgtgga gtgggagagc 1200
aacggccagc ccgagaacaa ctacaagacc acccccccag tgctggacag cgacggcagc 1260
ttcttcctgt acagcaggct gaccgtggac aagtccagat ggcaggaggg caacgtcttt 1320
agctgctccg tgatgcacga ggccctgcac aaccactaca cccagaagag cctgagcctg 1380
tccctgggct gatga 1395
<210> 12
<211> 723
<212> DNA
<213> 人工
<220>
<223> 具有信号序列的BAN0805 LC基因
<400> 12
atgtctgtgc ctacacaggt tctgggactg ctgctgctgt ggctgaccga cgccagatgc 60
gacatcgtga tgacccagtc tccactgagc ctgcctgtga cacctggcga gcctgcttcc 120
atctcctgca gatcctctca gaccatcgtg cacaacaacg gcaacaccta cctggaatgg 180
tatctgcaga agcccggcca gtctcctcag ctgctgatct acaaggtgtc caaccggttc 240
tctggcgtgc ccgacagatt ttccggctct ggctctggca ccgacttcac cctgaagatc 300
tccagagtgg aagccgagga cgtgggcgtg tactactgct tccaaggctc tcacgtgccc 360
ttcacctttg gccagggcac caagctggaa atcaagcgta cggtggccgc tcccagcgtg 420
ttcatcttcc ccccaagcga cgagcagctg aagagcggca ccgccagcgt ggtgtgtctg 480
ctgaacaact tctaccccag ggaggccaag gtgcagtgga aggtggacaa cgccctgcag 540
agcggcaaca gccaggagag cgtcaccgag caggacagca aggactccac ctacagcctg 600
agcagcaccc tgaccctgag caaggccgac tacgagaagc acaaggtgta cgcctgtgag 660
gtgacccacc agggcctgtc cagccccgtg accaagagct tcaacagggg cgagtgctga 720
tga 723
<210> 13
<211> 413
<212> DNA
<213> 人工
<220>
<223> 具有信号序列的BAN0805 VH基因
<400> 13
atggaatggt cctgggtgtt cctgttcttc ctgtccgtga ccaccggcgt gcactctcag 60
gttcagctgc aagagtctgg ccctggcctg gtcaagcctt ccgaaacact gtctctgacc 120
tgcaccgtgt ccggcttctc cctgacatct tatggggtgc actggatcag acagcctcca 180
ggcaaaggcc tggaatggat cggagtgatt tggagaggcg gctccaccga ttactccgcc 240
gccttcatgt cccggctgac catctctaag gacacctcca agaaccaggt gtccctgaag 300
ctgtcctctg tgaccgctgc tgataccgcc gtgtactact gtgccaagct gctgagatct 360
gtcggcggct ttgctgattg gggccagggc acaatggtca ccgtgtctag cgc 413
<210> 14
<211> 396
<212> DNA
<213> 人工
<220>
<223> 具有信号序列的BAN0805 VL基因
<400> 14
atgtctgtgc ctacacaggt tctgggactg ctgctgctgt ggctgaccga cgccagatgc 60
gacatcgtga tgacccagtc tccactgagc ctgcctgtga cacctggcga gcctgcttcc 120
atctcctgca gatcctctca gaccatcgtg cacaacaacg gcaacaccta cctggaatgg 180
tatctgcaga agcccggcca gtctcctcag ctgctgatct acaaggtgtc caaccggttc 240
tctggcgtgc ccgacagatt ttccggctct ggctctggca ccgacttcac cctgaagatc 300
tccagagtgg aagccgagga cgtgggcgtg tactactgct tccaaggctc tcacgtgccc 360
ttcacctttg gccagggcac caagctggaa atcaag 396
<210> 15
<211> 5
<212> PRT
<213> 人工
<220>
<223> BAN0805 VH-CDR-1(Kabat)
<400> 15
Ser Tyr Gly Val His
1 5
<210> 16
<211> 16
<212> PRT
<213> 人工
<220>
<223> BAN0805 VH-CDR-2(Kabat)
<400> 16
Val Ile Trp Arg Gly Gly Ser Thr Asp Tyr Ser Ala Ala Phe Met Ser
1 5 10 15
<210> 17
<211> 1335
<212> DNA
<213> 人工
<220>
<223> BAN0805 HC基因
<400> 17
caggttcagc tgcaagagtc tggccctggc ctggtcaagc cttccgaaac actgtctctg 60
acctgcaccg tgtccggctt ctccctgaca tcttatgggg tgcactggat cagacagcct 120
ccaggcaaag gcctggaatg gatcggagtg atttggagag gcggctccac cgattactcc 180
gccgccttca tgtcccggct gaccatctct aaggacacct ccaagaacca ggtgtccctg 240
aagctgtcct ctgtgaccgc tgctgatacc gccgtgtact actgtgccaa gctgctgaga 300
tctgtcggcg gctttgctga ttggggccag ggcacaatgg tcaccgtgtc tagcgcttct 360
acaaagggcc caagcgtgtt ccccctggcc ccctgctcca gaagcaccag cgagagcaca 420
gccgccctgg gctgcctggt gaaggactac ttccccgagc ccgtgaccgt gtcctggaac 480
agcggagccc tgaccagcgg cgtgcacacc ttccccgccg tgctgcagag cagcggcctg 540
tacagcctga gcagcgtggt gaccgtgccc agcagcagcc tgggcaccaa gacctacacc 600
tgtaacgtgg accacaagcc cagcaacacc aaggtggaca agagggtgga gagcaagtac 660
ggcccaccct gccccccctg cccagccccc gagttcctgg gcggacccag cgtgttcctg 720
ttccccccca agcccaagga caccctgatg atcagcagaa cccccgaggt gacctgtgtg 780
gtggtggacg tgtcccagga ggaccccgag gtccagttca actggtacgt ggacggcgtg 840
gaggtgcaca acgccaagac caagcccaga gaggagcagt ttaacagcac ctaccgggtg 900
gtgtccgtgc tgaccgtgct gcaccaggac tggctgaacg gcaaagagta caagtgtaag 960
gtctccaaca agggcctgcc aagcagcatc gaaaagacca tcagcaaggc caagggccag 1020
cctagagagc cccaggtcta caccctgcca cccagccaag aggagatgac caagaaccag 1080
gtgtccctga cctgtctggt gaagggcttc tacccaagcg acatcgccgt ggagtgggag 1140
agcaacggcc agcccgagaa caactacaag accacccccc cagtgctgga cagcgacggc 1200
agcttcttcc tgtacagcag gctgaccgtg gacaagtcca gatggcagga gggcaacgtc 1260
tttagctgct ccgtgatgca cgaggccctg cacaaccact acacccagaa gagcctgagc 1320
ctgtccctgg gctga 1335
<210> 18
<211> 660
<212> DNA
<213> 人工
<220>
<223> BAN0805 LC基因
<400> 18
gacatcgtga tgacccagtc tccactgagc ctgcctgtga cacctggcga gcctgcttcc 60
atctcctgca gatcctctca gaccatcgtg cacaacaacg gcaacaccta cctggaatgg 120
tatctgcaga agcccggcca gtctcctcag ctgctgatct acaaggtgtc caaccggttc 180
tctggcgtgc ccgacagatt ttccggctct ggctctggca ccgacttcac cctgaagatc 240
tccagagtgg aagccgagga cgtgggcgtg tactactgct tccaaggctc tcacgtgccc 300
ttcacctttg gccagggcac caagctggaa atcaagcgta cggtggccgc tcccagcgtg 360
ttcatcttcc ccccaagcga cgagcagctg aagagcggca ccgccagcgt ggtgtgtctg 420
ctgaacaact tctaccccag ggaggccaag gtgcagtgga aggtggacaa cgccctgcag 480
agcggcaaca gccaggagag cgtcaccgag caggacagca aggactccac ctacagcctg 540
agcagcaccc tgaccctgag caaggccgac tacgagaagc acaaggtgta cgcctgtgag 600
gtgacccacc agggcctgtc cagccccgtg accaagagct tcaacagggg cgagtgctga 660
<210> 19
<211> 356
<212> DNA
<213> 人工
<220>
<223> BAN0805 VH基因
<400> 19
caggttcagc tgcaagagtc tggccctggc ctggtcaagc cttccgaaac actgtctctg 60
acctgcaccg tgtccggctt ctccctgaca tcttatgggg tgcactggat cagacagcct 120
ccaggcaaag gcctggaatg gatcggagtg atttggagag gcggctccac cgattactcc 180
gccgccttca tgtcccggct gaccatctct aaggacacct ccaagaacca ggtgtccctg 240
aagctgtcct ctgtgaccgc tgctgatacc gccgtgtact actgtgccaa gctgctgaga 300
tctgtcggcg gctttgctga ttggggccag ggcacaatgg tcaccgtgtc tagcgc 356
<210> 20
<211> 336
<212> DNA
<213> 人工
<220>
<223> BAN0805 VL基因
<400> 20
gacatcgtga tgacccagtc tccactgagc ctgcctgtga cacctggcga gcctgcttcc 60
atctcctgca gatcctctca gaccatcgtg cacaacaacg gcaacaccta cctggaatgg 120
tatctgcaga agcccggcca gtctcctcag ctgctgatct acaaggtgtc caaccggttc 180
tctggcgtgc ccgacagatt ttccggctct ggctctggca ccgacttcac cctgaagatc 240
tccagagtgg aagccgagga cgtgggcgtg tactactgct tccaaggctc tcacgtgccc 300
ttcacctttg gccagggcac caagctggaa atcaag 336
Claims (17)
1.一种抗体,其包含含有SEQ ID NO:1的氨基酸序列的重链和含有SEQ ID NO:2的氨基酸序列的轻链。
2.如权利要求1所述的抗体,其中该抗体属于IgG同种型。
3.如权利要求1所述的抗体,其中该抗体属于IgG4同种型。
4.如权利要求1至3中任一项所述的抗体,其中该抗体结合α-突触核蛋白的原纤维形式的KD值是结合α-突触核蛋白的单体形式的KD值的至多1/110,000。
5.如权利要求1至3中任一项所述的抗体,其中该抗体结合α-突触核蛋白的该原纤维形式的KD值为至多18pM,并且结合α-突触核蛋白的该单体形式的KD值为至少2200nM。
6.如权利要求4或5所述的抗体,其中所述抗体与α-突触核蛋白的该原纤维形式结合的KD以及所述抗体与α-突触核蛋白的该单体形式结合的KD通过SPR来测量。
7.一种抗体,其包含含有SEQ ID NO:3的氨基酸序列的重链和含有SEQ ID NO:4的氨基酸序列的轻链。
8.如权利要求7所述的抗体,其中该抗体包含两条重链和两条轻链。
9.一种核酸,其编码包含选自由SEQ ID NO:1-4组成的组的氨基酸序列的多肽。
10.如权利要求9所述的核酸,其包含选自由SEQ ID NO:11-14和17-20组成的组的序列。
11.一种或多种核酸,其编码如权利要求1至8中任一项所述的抗体。
12.如权利要求11所述的一种或多种核酸,其中
(a)该一种或多种核酸包含SEQ ID NO:11和12的序列,
(b)该一种或多种核酸包含SEQ ID NO:13和14的序列,
(c)该一种或多种核酸包含SEQ ID NO:17和18的序列,或
(d)该一种或多种核酸包含SEQ ID NO:19和20的序列。
13.一种或多种载体,其包含如权利要求9至12中任一项所述的一种或多种核酸。
14.一种宿主细胞,其包含如权利要求9至12中任一项所述的一种或多种核酸。
15.一种宿主细胞,其包含如权利要求13所述的一种或多种载体。
16.一种宿主细胞,其表达如权利要求1至8中任一项所述的抗体。
17.一种组合物,其包含如权利要求1至8中任一项所述的抗体和药学上可接受的载剂。
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US202063044881P | 2020-06-26 | 2020-06-26 | |
US63/044,881 | 2020-06-26 | ||
US202063071150P | 2020-08-27 | 2020-08-27 | |
US63/071,150 | 2020-08-27 | ||
PCT/IB2021/000440 WO2021260434A1 (en) | 2020-06-26 | 2021-06-25 | α-SYNUCLEIN PROTOFIBRIL-BINDING ANTIBODIES |
Publications (1)
Publication Number | Publication Date |
---|---|
CN115803341A true CN115803341A (zh) | 2023-03-14 |
Family
ID=77627146
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202180041047.0A Pending CN115803341A (zh) | 2020-06-26 | 2021-06-25 | 结合α-突触核蛋白原纤维的抗体 |
Country Status (13)
Country | Link |
---|---|
US (2) | US11339212B2 (zh) |
EP (1) | EP4172199A1 (zh) |
JP (2) | JP7337959B2 (zh) |
KR (1) | KR20230027095A (zh) |
CN (1) | CN115803341A (zh) |
AU (1) | AU2021298222A1 (zh) |
CA (1) | CA3181207A1 (zh) |
IL (1) | IL298584B1 (zh) |
MX (1) | MX2022016005A (zh) |
TW (1) | TW202212357A (zh) |
UY (1) | UY39295A (zh) |
WO (1) | WO2021260434A1 (zh) |
ZA (1) | ZA202211843B (zh) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
IL298584B1 (en) | 2020-06-26 | 2024-06-01 | Bioarctic Ab | Antibodies against protofibril-binding alpha-synuclein |
Family Cites Families (23)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
ATE312349T1 (de) | 1998-07-03 | 2005-12-15 | Innogenetics Nv | Differentielle diagnose von neurodegeneration |
AU2001268005A1 (en) | 2000-07-07 | 2002-01-21 | Lars Lannfelt | Prevention and treatment of alzheimer's disease |
US20060018918A1 (en) | 2000-12-27 | 2006-01-26 | Board Of Regents, The University Of Texas System | Production of stabilized conformational isomers of disease associated proteins |
TW200509968A (en) | 2002-11-01 | 2005-03-16 | Elan Pharm Inc | Prevention and treatment of synucleinopathic disease |
US8506959B2 (en) | 2002-11-01 | 2013-08-13 | Neotope Biosciences Limited | Prevention and treatment of synucleinopathic and amyloidogenic disease |
US20080014194A1 (en) | 2003-10-31 | 2008-01-17 | Elan Pharmaceuticals, Inc. | Prevention and Treatment of Synucleinopathic and Amyloidogenic Disease |
US7358331B2 (en) | 2003-05-19 | 2008-04-15 | Elan Pharmaceuticals, Inc. | Truncated fragments of alpha-synuclein in Lewy body disease |
US7674599B2 (en) | 2003-11-08 | 2010-03-09 | Elan Pharmaceuticals, Inc. | Methods of using antibodies to detect alpha-synuclein in fluid samples |
US20050203010A1 (en) | 2003-11-14 | 2005-09-15 | Atgen Co., Ltd. | Novel peptides conferring environmental stress resistance and fusion proteins including said peptides |
SE0401601D0 (sv) | 2004-06-21 | 2004-06-21 | Bioarctic Neuroscience Ab | Protofibril specific antibodies and uses thereof |
JP2009525046A (ja) | 2006-01-31 | 2009-07-09 | エラン ファーマシューティカルズ,インコーポレイテッド | アルファ−シヌクレインキナーゼ |
CN101421303B (zh) | 2006-03-23 | 2013-06-12 | 生命北极神经科学公司 | 改进的初原纤维选择性抗体及其用途 |
PL2282758T3 (pl) * | 2008-04-29 | 2019-04-30 | Bioarctic Ab | Przeciwciała i szczepionki do zastosowania w terapeutycznych i diagnostycznych sposobach dla zaburzeń związanych z alfa-synukleiną |
JP5810413B2 (ja) * | 2008-12-19 | 2015-11-11 | バイオジェン インターナショナル ニューロサイエンス ゲーエムベーハー | ヒト抗アルファシヌクレイン自己抗体 |
DK2448968T3 (da) | 2009-06-29 | 2021-04-12 | Bioarctic Ab | ANTISTOFFER SOM ER SELEKTIVE FOR N-TERMINAL-TRUNKEREDE AMYLOID-ß PROTOFIBRILLER/OLIGOMERER |
RS57029B1 (sr) * | 2010-02-26 | 2018-05-31 | Bioartic Ab | Protofibril-vezujuća antitela i njihova upotreba u terapeutskim i dijagnostičkim postupcima za parkinsonovu bolest, demenciju sa levi telima i drugim alfa-sinukleinopatijama |
TWI560199B (en) * | 2010-08-31 | 2016-12-01 | Sanofi Sa | Peptide or peptide complex binding to α2 integrin and methods and uses involving the same |
WO2012177972A1 (en) * | 2011-06-23 | 2012-12-27 | Biogen Idec International Neuroscience Gmbh | Anti-alpha synuclein binding molecules |
US9534044B2 (en) * | 2013-02-28 | 2017-01-03 | United Arab Emirates University | Alpha-synuclein antibodies and uses thereof |
MX369173B (es) * | 2013-12-24 | 2019-10-30 | Janssen Pharmaceutica Nv | Anticuerpos y fragmentos anti-vista. |
US11773166B2 (en) * | 2014-11-04 | 2023-10-03 | Ichnos Sciences SA | CD3/CD38 T cell retargeting hetero-dimeric immunoglobulins and methods of their production |
CN117069841A (zh) * | 2015-10-06 | 2023-11-17 | 艾利妥 | 抗trem2抗体及其使用方法 |
IL298584B1 (en) | 2020-06-26 | 2024-06-01 | Bioarctic Ab | Antibodies against protofibril-binding alpha-synuclein |
-
2021
- 2021-06-25 IL IL298584A patent/IL298584B1/en unknown
- 2021-06-25 WO PCT/IB2021/000440 patent/WO2021260434A1/en active Application Filing
- 2021-06-25 CA CA3181207A patent/CA3181207A1/en active Pending
- 2021-06-25 CN CN202180041047.0A patent/CN115803341A/zh active Pending
- 2021-06-25 US US17/359,212 patent/US11339212B2/en active Active
- 2021-06-25 TW TW110123445A patent/TW202212357A/zh unknown
- 2021-06-25 KR KR1020227046153A patent/KR20230027095A/ko active Search and Examination
- 2021-06-25 UY UY0001039295A patent/UY39295A/es unknown
- 2021-06-25 EP EP21765693.3A patent/EP4172199A1/en active Pending
- 2021-06-25 MX MX2022016005A patent/MX2022016005A/es unknown
- 2021-06-25 JP JP2021570377A patent/JP7337959B2/ja active Active
- 2021-06-25 AU AU2021298222A patent/AU2021298222A1/en active Pending
-
2022
- 2022-04-21 US US17/726,144 patent/US20230080536A1/en active Pending
- 2022-10-31 ZA ZA2022/11843A patent/ZA202211843B/en unknown
-
2023
- 2023-08-22 JP JP2023134451A patent/JP2023159299A/ja active Pending
Also Published As
Publication number | Publication date |
---|---|
MX2022016005A (es) | 2023-02-02 |
ZA202211843B (en) | 2024-02-28 |
JP2023525174A (ja) | 2023-06-15 |
IL298584B1 (en) | 2024-06-01 |
JP7337959B2 (ja) | 2023-09-04 |
JP2023159299A (ja) | 2023-10-31 |
KR20230027095A (ko) | 2023-02-27 |
WO2021260434A1 (en) | 2021-12-30 |
US20230080536A1 (en) | 2023-03-16 |
EP4172199A1 (en) | 2023-05-03 |
US20210403542A1 (en) | 2021-12-30 |
US11339212B2 (en) | 2022-05-24 |
TW202212357A (zh) | 2022-04-01 |
UY39295A (es) | 2022-01-31 |
IL298584A (en) | 2023-01-01 |
AU2021298222A1 (en) | 2022-12-15 |
CA3181207A1 (en) | 2021-12-30 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
IL307767A (en) | G protein-coupled receptor-directed antibodies and methods of use | |
JP2018521691A (ja) | 増殖性および炎症性疾患の処置における抗TfR抗体およびその使用 | |
DK2814842T3 (en) | ANTIBODIES BINDING PEPTIDOGLYCAN RECOGNITION PROTEIN 1 | |
WO2021219048A1 (zh) | 一种靶向nkg2a和pd-l1的双特异性抗体及应用 | |
JP2023509212A (ja) | 新型ポリペプチド複合物 | |
AU2021390121A1 (en) | Anti-human b7-h3 antibody and application thereof | |
CA3148956A1 (en) | Anti-cd47 monoclonal antibody and use thereof | |
JP2023159299A (ja) | α-シヌクレインプロトフィブリル結合抗体 | |
WO2021143914A1 (zh) | 一种激活型抗ox40抗体、生产方法及应用 | |
JPWO2020004492A5 (zh) | ||
IL303610A (en) | GUCY2C binding molecules and their uses | |
KR20220057526A (ko) | 항-pd-l1 항체 | |
US20240209114A1 (en) | Anti-masp2 antibody, antigen-binding fragment thereof and medical use thereof | |
RU2810587C1 (ru) | Антитела, связывающиеся с протофибриллами α-синуклеина | |
CN106519031B (zh) | 一种与旁路途径相关的cfh抗体 | |
WO2022037528A1 (zh) | 结合bcma的单可变结构域及抗原结合分子 | |
TWI724393B (zh) | 抗糖皮質激素誘導的腫瘤壞死因子受體(gitr)的小型化抗體、其聚合物及應用 | |
WO2024061021A1 (zh) | 检测抗CD19 Car表达水平的单克隆抗体及其在激活CD19 CAR-T细胞中的应用 | |
WO2023016516A1 (zh) | 抗vegf a和vegf c双特异性抗体及其用途 | |
WO2023020507A1 (zh) | 一种抗b7-h4抗体及其制备方法和应用 | |
WO2023186120A1 (zh) | 抗血清白蛋白纳米抗体及其衍生物 | |
WO2024078558A1 (zh) | 抗cd100抗体及其用途 | |
TW202302641A (zh) | 針對IL-13Rα2的抗體及其應用 | |
EP3519434A1 (en) | Tenascin epitope and antibodies thereto |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination |