CN111434683B - 抗h7n9全人源单克隆抗体8d11及其制备方法与应用 - Google Patents
抗h7n9全人源单克隆抗体8d11及其制备方法与应用 Download PDFInfo
- Publication number
- CN111434683B CN111434683B CN201910035567.5A CN201910035567A CN111434683B CN 111434683 B CN111434683 B CN 111434683B CN 201910035567 A CN201910035567 A CN 201910035567A CN 111434683 B CN111434683 B CN 111434683B
- Authority
- CN
- China
- Prior art keywords
- seq
- antibody
- monoclonal antibody
- amino acid
- fully human
- 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.)
- Active
Links
- 241000282414 Homo sapiens Species 0.000 title claims abstract description 58
- 238000002360 preparation method Methods 0.000 title abstract description 11
- 238000000034 method Methods 0.000 claims abstract description 14
- 239000003814 drug Substances 0.000 claims abstract description 8
- 108090000623 proteins and genes Proteins 0.000 claims description 37
- 150000001413 amino acids Chemical class 0.000 claims description 34
- 239000002773 nucleotide Substances 0.000 claims description 18
- 125000003729 nucleotide group Chemical group 0.000 claims description 18
- 239000012634 fragment Substances 0.000 claims description 17
- 239000013598 vector Substances 0.000 claims description 14
- 239000008194 pharmaceutical composition Substances 0.000 claims description 6
- 108090000790 Enzymes Proteins 0.000 claims description 5
- 102000004190 Enzymes Human genes 0.000 claims description 5
- 239000000872 buffer Substances 0.000 claims description 5
- 238000012258 culturing Methods 0.000 claims description 5
- 238000001514 detection method Methods 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 201000010099 disease Diseases 0.000 claims description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 2
- 230000002285 radioactive effect Effects 0.000 claims description 2
- 125000003275 alpha amino acid group Chemical group 0.000 claims 13
- 241000712461 unidentified influenza virus Species 0.000 abstract description 9
- 230000003472 neutralizing effect Effects 0.000 abstract description 8
- 239000000185 hemagglutinin Substances 0.000 abstract description 7
- 101710154606 Hemagglutinin Proteins 0.000 abstract description 6
- 101710093908 Outer capsid protein VP4 Proteins 0.000 abstract description 6
- 101710135467 Outer capsid protein sigma-1 Proteins 0.000 abstract description 6
- 101710176177 Protein A56 Proteins 0.000 abstract description 6
- 229940079593 drug Drugs 0.000 abstract description 5
- 230000000694 effects Effects 0.000 abstract description 5
- 210000001806 memory b lymphocyte Anatomy 0.000 abstract description 5
- 230000009385 viral infection Effects 0.000 abstract description 5
- 241001529936 Murinae Species 0.000 abstract description 4
- 231100000331 toxic Toxicity 0.000 abstract description 3
- 230000002588 toxic effect Effects 0.000 abstract description 3
- 210000004027 cell Anatomy 0.000 description 43
- 241000700605 Viruses Species 0.000 description 14
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 12
- 229940125645 monoclonal antibody drug Drugs 0.000 description 12
- 239000002953 phosphate buffered saline Substances 0.000 description 12
- 238000002965 ELISA Methods 0.000 description 10
- 239000000243 solution Substances 0.000 description 10
- 238000002474 experimental method Methods 0.000 description 9
- 101100112922 Candida albicans CDR3 gene Proteins 0.000 description 8
- 102100035360 Cerebellar degeneration-related antigen 1 Human genes 0.000 description 8
- 102100035361 Cerebellar degeneration-related protein 2 Human genes 0.000 description 8
- 101000737793 Homo sapiens Cerebellar degeneration-related antigen 1 Proteins 0.000 description 8
- 101000737796 Homo sapiens Cerebellar degeneration-related protein 2 Proteins 0.000 description 8
- 210000003719 b-lymphocyte Anatomy 0.000 description 8
- 238000005516 engineering process Methods 0.000 description 7
- UQLDLKMNUJERMK-UHFFFAOYSA-L di(octadecanoyloxy)lead Chemical compound [Pb+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O UQLDLKMNUJERMK-UHFFFAOYSA-L 0.000 description 6
- 239000006228 supernatant Substances 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 5
- 239000002299 complementary DNA Substances 0.000 description 5
- 230000006870 function Effects 0.000 description 5
- 108010078144 glutaminyl-glycine Proteins 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 210000003819 peripheral blood mononuclear cell Anatomy 0.000 description 5
- 238000005406 washing Methods 0.000 description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 241000880493 Leptailurus serval Species 0.000 description 4
- 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 4
- YBAFDPFAUTYYRW-UHFFFAOYSA-N N-L-alpha-glutamyl-L-leucine Natural products CC(C)CC(C(O)=O)NC(=O)C(N)CCC(O)=O YBAFDPFAUTYYRW-UHFFFAOYSA-N 0.000 description 4
- 238000004113 cell culture Methods 0.000 description 4
- 229940088598 enzyme Drugs 0.000 description 4
- 101150118163 h gene Proteins 0.000 description 4
- 238000012423 maintenance Methods 0.000 description 4
- 239000002609 medium Substances 0.000 description 4
- 238000006386 neutralization reaction Methods 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 230000003248 secreting effect Effects 0.000 description 4
- 108010061238 threonyl-glycine Proteins 0.000 description 4
- 108010029697 CD40 Ligand Proteins 0.000 description 3
- 102100032937 CD40 ligand Human genes 0.000 description 3
- 101150062031 L gene Proteins 0.000 description 3
- 241000713666 Lentivirus Species 0.000 description 3
- 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 3
- OYEDZGNMSBZCIM-XGEHTFHBSA-N Ser-Arg-Thr Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(O)=O OYEDZGNMSBZCIM-XGEHTFHBSA-N 0.000 description 3
- 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 3
- 229940125644 antibody drug Drugs 0.000 description 3
- 239000000427 antigen Substances 0.000 description 3
- 102000036639 antigens Human genes 0.000 description 3
- 108091007433 antigens Proteins 0.000 description 3
- 238000003556 assay Methods 0.000 description 3
- 238000010367 cloning Methods 0.000 description 3
- 238000010790 dilution Methods 0.000 description 3
- 239000012895 dilution Substances 0.000 description 3
- 206010022000 influenza Diseases 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 238000010839 reverse transcription Methods 0.000 description 3
- 239000012192 staining solution Substances 0.000 description 3
- NVKAWKQGWWIWPM-ABEVXSGRSA-N 17-β-hydroxy-5-α-Androstan-3-one Chemical compound C1C(=O)CC[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CC[C@H]21 NVKAWKQGWWIWPM-ABEVXSGRSA-N 0.000 description 2
- 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 2
- 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 2
- 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 2
- HOVPGJUNRLMIOZ-CIUDSAMLSA-N Ala-Ser-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](CO)NC(=O)[C@H](C)N HOVPGJUNRLMIOZ-CIUDSAMLSA-N 0.000 description 2
- UCDOXFBTMLKASE-HERUPUMHSA-N Ala-Ser-Trp Chemical compound C[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CC1=CNC2=CC=CC=C21)C(=O)O)N UCDOXFBTMLKASE-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
- FEZJJKXNPSEYEV-CIUDSAMLSA-N Arg-Gln-Ala Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](C)C(O)=O FEZJJKXNPSEYEV-CIUDSAMLSA-N 0.000 description 2
- LVMUGODRNHFGRA-AVGNSLFASA-N Arg-Leu-Arg Chemical compound NC(N)=NCCC[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCN=C(N)N)C(O)=O LVMUGODRNHFGRA-AVGNSLFASA-N 0.000 description 2
- 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 2
- QLSRIZIDQXDQHK-RCWTZXSCSA-N Arg-Val-Thr Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O QLSRIZIDQXDQHK-RCWTZXSCSA-N 0.000 description 2
- HAJWYALLJIATCX-FXQIFTODSA-N Asn-Asn-Arg Chemical compound C(C[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)N)NC(=O)[C@H](CC(=O)N)N)CN=C(N)N HAJWYALLJIATCX-FXQIFTODSA-N 0.000 description 2
- AMGQTNHANMRPOE-LKXGYXEUSA-N Asn-Thr-Ser Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(O)=O AMGQTNHANMRPOE-LKXGYXEUSA-N 0.000 description 2
- 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 2
- NURJSGZGBVJFAD-ZLUOBGJFSA-N Asp-Cys-Ser Chemical compound C([C@@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CO)C(=O)O)N)C(=O)O NURJSGZGBVJFAD-ZLUOBGJFSA-N 0.000 description 2
- KPSHWSWFPUDEGF-FXQIFTODSA-N Asp-Pro-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@@H]1CCCN1C(=O)[C@@H](N)CC(O)=O KPSHWSWFPUDEGF-FXQIFTODSA-N 0.000 description 2
- KGHLGJAXYSVNJP-WHFBIAKZSA-N Asp-Ser-Gly Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CO)C(=O)NCC(O)=O KGHLGJAXYSVNJP-WHFBIAKZSA-N 0.000 description 2
- JJQGZGOEDSSHTE-FOHZUACHSA-N Asp-Thr-Gly Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(O)=O JJQGZGOEDSSHTE-FOHZUACHSA-N 0.000 description 2
- 241000282465 Canis Species 0.000 description 2
- YFXFOZPXVFPBDH-VZFHVOOUSA-N Cys-Ala-Thr Chemical compound C[C@@H](O)[C@H](NC(=O)[C@H](C)NC(=O)[C@@H](N)CS)C(O)=O YFXFOZPXVFPBDH-VZFHVOOUSA-N 0.000 description 2
- IWVNIQXKTIQXCT-SRVKXCTJSA-N Cys-Tyr-Asn Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)O)NC(=O)[C@H](CS)N)O IWVNIQXKTIQXCT-SRVKXCTJSA-N 0.000 description 2
- 238000012286 ELISA Assay Methods 0.000 description 2
- OYTPNWYZORARHL-XHNCKOQMSA-N Gln-Ala-Pro Chemical compound C[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](CCC(=O)N)N OYTPNWYZORARHL-XHNCKOQMSA-N 0.000 description 2
- NSNUZSPSADIMJQ-WDSKDSINSA-N Gln-Gly-Asp Chemical compound NC(=O)CC[C@H](N)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(O)=O NSNUZSPSADIMJQ-WDSKDSINSA-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
- XXCDTYBVGMPIOA-FXQIFTODSA-N Glu-Asp-Glu Chemical compound OC(=O)CC[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(O)=O XXCDTYBVGMPIOA-FXQIFTODSA-N 0.000 description 2
- SBCYJMOOHUDWDA-NUMRIWBASA-N Glu-Asp-Thr Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O SBCYJMOOHUDWDA-NUMRIWBASA-N 0.000 description 2
- ZYRXTRTUCAVNBQ-GVXVVHGQSA-N Glu-Val-Lys Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CCC(=O)O)N ZYRXTRTUCAVNBQ-GVXVVHGQSA-N 0.000 description 2
- GZUKEVBTYNNUQF-WDSKDSINSA-N Gly-Ala-Gln Chemical compound NCC(=O)N[C@@H](C)C(=O)N[C@@H](CCC(N)=O)C(O)=O GZUKEVBTYNNUQF-WDSKDSINSA-N 0.000 description 2
- UXJHNZODTMHWRD-WHFBIAKZSA-N Gly-Asn-Ala Chemical compound [H]NCC(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](C)C(O)=O UXJHNZODTMHWRD-WHFBIAKZSA-N 0.000 description 2
- FMNHBTKMRFVGRO-FOHZUACHSA-N Gly-Asn-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)[C@H](CC(N)=O)NC(=O)CN FMNHBTKMRFVGRO-FOHZUACHSA-N 0.000 description 2
- 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 2
- ULZCYBYDTUMHNF-IUCAKERBSA-N Gly-Leu-Glu Chemical compound NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(O)=O ULZCYBYDTUMHNF-IUCAKERBSA-N 0.000 description 2
- 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 2
- KOYUSMBPJOVSOO-XEGUGMAKSA-N Gly-Tyr-Ile Chemical compound [H]NCC(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O KOYUSMBPJOVSOO-XEGUGMAKSA-N 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- 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 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- OWSWUWDMSNXTNE-GMOBBJLQSA-N Ile-Pro-Asp Chemical compound CC[C@H](C)[C@@H](C(=O)N1CCC[C@H]1C(=O)N[C@@H](CC(=O)O)C(=O)O)N OWSWUWDMSNXTNE-GMOBBJLQSA-N 0.000 description 2
- RKQAYOWLSFLJEE-SVSWQMSJSA-N Ile-Thr-Cys Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CS)C(=O)O)N RKQAYOWLSFLJEE-SVSWQMSJSA-N 0.000 description 2
- NURNJECQNNCRBK-FLBSBUHZSA-N Ile-Thr-Thr Chemical compound CC[C@H](C)[C@H](N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O NURNJECQNNCRBK-FLBSBUHZSA-N 0.000 description 2
- 108010065920 Insulin Lispro Proteins 0.000 description 2
- 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 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
- 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 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
- 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 2
- IHITVQKJXQQGLJ-LPEHRKFASA-N Met-Asn-Pro Chemical compound CSCC[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N1CCC[C@@H]1C(=O)O)N IHITVQKJXQQGLJ-LPEHRKFASA-N 0.000 description 2
- MHQXIBRPDKXDGZ-ZFWWWQNUSA-N Met-Gly-Trp Chemical compound C1=CC=C2C(C[C@H](NC(=O)CNC(=O)[C@@H](N)CCSC)C(O)=O)=CNC2=C1 MHQXIBRPDKXDGZ-ZFWWWQNUSA-N 0.000 description 2
- KSIPKXNIQOWMIC-RCWTZXSCSA-N Met-Thr-Arg Chemical compound CSCC[C@H](N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@H](C(O)=O)CCCNC(N)=N KSIPKXNIQOWMIC-RCWTZXSCSA-N 0.000 description 2
- KZNQNBZMBZJQJO-UHFFFAOYSA-N N-glycyl-L-proline Natural products NCC(=O)N1CCCC1C(O)=O KZNQNBZMBZJQJO-UHFFFAOYSA-N 0.000 description 2
- 108010079364 N-glycylalanine Proteins 0.000 description 2
- AJOKKVTWEMXZHC-DRZSPHRISA-N Phe-Ala-Gln Chemical compound NC(=O)CC[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC1=CC=CC=C1 AJOKKVTWEMXZHC-DRZSPHRISA-N 0.000 description 2
- MQVFHOPCKNTHGT-MELADBBJSA-N Phe-Asp-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CC(=O)O)NC(=O)[C@H](CC2=CC=CC=C2)N)C(=O)O MQVFHOPCKNTHGT-MELADBBJSA-N 0.000 description 2
- 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 2
- MGLBSROLWAWCKN-FCLVOEFKSA-N Phe-Phe-Thr Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H]([C@@H](C)O)C(O)=O MGLBSROLWAWCKN-FCLVOEFKSA-N 0.000 description 2
- BGWKULMLUIUPKY-BQBZGAKWSA-N Pro-Ser-Gly Chemical compound OC(=O)CNC(=O)[C@H](CO)NC(=O)[C@@H]1CCCN1 BGWKULMLUIUPKY-BQBZGAKWSA-N 0.000 description 2
- PRKWBYCXBBSLSK-GUBZILKMSA-N Pro-Ser-Val Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(O)=O PRKWBYCXBBSLSK-GUBZILKMSA-N 0.000 description 2
- 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 2
- OQPNSDWGAMFJNU-QWRGUYRKSA-N Ser-Gly-Tyr Chemical compound OC[C@H](N)C(=O)NCC(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 OQPNSDWGAMFJNU-QWRGUYRKSA-N 0.000 description 2
- GZSZPKSBVAOGIE-CIUDSAMLSA-N Ser-Lys-Ala Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(O)=O GZSZPKSBVAOGIE-CIUDSAMLSA-N 0.000 description 2
- GYDFRTRSSXOZCR-ACZMJKKPSA-N Ser-Ser-Glu Chemical compound OC[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@H](C(O)=O)CCC(O)=O GYDFRTRSSXOZCR-ACZMJKKPSA-N 0.000 description 2
- OQSQCUWQOIHECT-YJRXYDGGSA-N Ser-Tyr-Thr Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H]([C@@H](C)O)C(O)=O OQSQCUWQOIHECT-YJRXYDGGSA-N 0.000 description 2
- 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 2
- HSWXBJCBYSWBPT-GUBZILKMSA-N Ser-Val-Val Chemical compound CC(C)[C@H](NC(=O)[C@@H](NC(=O)[C@@H](N)CO)C(C)C)C(O)=O HSWXBJCBYSWBPT-GUBZILKMSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- VYEHBMMAJFVTOI-JHEQGTHGSA-N Thr-Gly-Gln Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)NCC(=O)N[C@@H](CCC(N)=O)C(O)=O VYEHBMMAJFVTOI-JHEQGTHGSA-N 0.000 description 2
- 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 2
- XGFYGMKZKFRGAI-RCWTZXSCSA-N Thr-Val-Arg Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@H](C(O)=O)CCCN=C(N)N XGFYGMKZKFRGAI-RCWTZXSCSA-N 0.000 description 2
- SVGAWGVHFIYAEE-JSGCOSHPSA-N Trp-Gly-Gln Chemical compound C1=CC=C2C(C[C@H](N)C(=O)NCC(=O)N[C@@H](CCC(N)=O)C(O)=O)=CNC2=C1 SVGAWGVHFIYAEE-JSGCOSHPSA-N 0.000 description 2
- 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 2
- XBWKCYFGRXKWGO-SRVKXCTJSA-N Tyr-Cys-Asn Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(N)=O)C(O)=O XBWKCYFGRXKWGO-SRVKXCTJSA-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
- JKUZFODWJGEQAP-KBPBESRZSA-N Tyr-Gly-Lys Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)O)N)O JKUZFODWJGEQAP-KBPBESRZSA-N 0.000 description 2
- XDGPTBVOSHKDFT-KKUMJFAQSA-N Tyr-Met-Glu Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCC(O)=O)C(O)=O XDGPTBVOSHKDFT-KKUMJFAQSA-N 0.000 description 2
- JQTYTBPCSOAZHI-FXQIFTODSA-N Val-Ser-Cys Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CS)C(=O)O)N JQTYTBPCSOAZHI-FXQIFTODSA-N 0.000 description 2
- 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 2
- 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 2
- 108010086434 alanyl-seryl-glycine Proteins 0.000 description 2
- 108010050025 alpha-glutamyltryptophan Proteins 0.000 description 2
- 108010060035 arginylproline Proteins 0.000 description 2
- 108010092854 aspartyllysine Proteins 0.000 description 2
- 206010064097 avian influenza Diseases 0.000 description 2
- 238000005520 cutting process Methods 0.000 description 2
- 238000001976 enzyme digestion Methods 0.000 description 2
- 239000000834 fixative Substances 0.000 description 2
- 238000000684 flow cytometry Methods 0.000 description 2
- 239000012530 fluid Substances 0.000 description 2
- 108010049041 glutamylalanine Proteins 0.000 description 2
- VPZXBVLAVMBEQI-UHFFFAOYSA-N glycyl-DL-alpha-alanine Natural products OC(=O)C(C)NC(=O)CN VPZXBVLAVMBEQI-UHFFFAOYSA-N 0.000 description 2
- 108010010147 glycylglutamine Proteins 0.000 description 2
- 229940048921 humira Drugs 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 210000003292 kidney cell Anatomy 0.000 description 2
- 108010017391 lysylvaline Proteins 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 239000013642 negative control Substances 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 238000002823 phage display Methods 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 108010031719 prolyl-serine Proteins 0.000 description 2
- 238000012163 sequencing technique Methods 0.000 description 2
- 210000002966 serum Anatomy 0.000 description 2
- 235000020183 skimmed milk Nutrition 0.000 description 2
- 241000894007 species Species 0.000 description 2
- 108010044292 tryptophyltyrosine Proteins 0.000 description 2
- IESDGNYHXIOKRW-YXMSTPNBSA-N (2s)-2-[[(2s)-1-[(2s)-6-amino-2-[[(2s,3r)-2-amino-3-hydroxybutanoyl]amino]hexanoyl]pyrrolidine-2-carbonyl]amino]-5-(diaminomethylideneamino)pentanoic acid Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@@H](CCCCN)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCCNC(N)=N)C(O)=O IESDGNYHXIOKRW-YXMSTPNBSA-N 0.000 description 1
- DIBLBAURNYJYBF-XLXZRNDBSA-N (2s)-2-[[(2s)-2-[[2-[[(2s)-6-amino-2-[[(2s)-2-amino-3-methylbutanoyl]amino]hexanoyl]amino]acetyl]amino]-3-phenylpropanoyl]amino]-3-(4-hydroxyphenyl)propanoic acid Chemical compound C([C@H](NC(=O)CNC(=O)[C@H](CCCCN)NC(=O)[C@@H](N)C(C)C)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(O)=O)C1=CC=CC=C1 DIBLBAURNYJYBF-XLXZRNDBSA-N 0.000 description 1
- UBCHPRBFMUDMNC-UHFFFAOYSA-N 1-(1-adamantyl)ethanamine Chemical compound C1C(C2)CC3CC2CC1(C(N)C)C3 UBCHPRBFMUDMNC-UHFFFAOYSA-N 0.000 description 1
- UAIUNKRWKOVEES-UHFFFAOYSA-N 3,3',5,5'-tetramethylbenzidine Chemical compound CC1=C(N)C(C)=CC(C=2C=C(C)C(N)=C(C)C=2)=C1 UAIUNKRWKOVEES-UHFFFAOYSA-N 0.000 description 1
- UZOVYGYOLBIAJR-UHFFFAOYSA-N 4-isocyanato-4'-methyldiphenylmethane Chemical compound C1=CC(C)=CC=C1CC1=CC=C(N=C=O)C=C1 UZOVYGYOLBIAJR-UHFFFAOYSA-N 0.000 description 1
- SUMYEVXWCAYLLJ-GUBZILKMSA-N Ala-Leu-Gln Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(O)=O SUMYEVXWCAYLLJ-GUBZILKMSA-N 0.000 description 1
- MDNAVFBZPROEHO-DCAQKATOSA-N Ala-Lys-Val Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C(C)C)C(O)=O MDNAVFBZPROEHO-DCAQKATOSA-N 0.000 description 1
- 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
- HPSVTWMFWCHKFN-GARJFASQSA-N Arg-Glu-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CCC(=O)O)NC(=O)[C@H](CCCN=C(N)N)N)C(=O)O HPSVTWMFWCHKFN-GARJFASQSA-N 0.000 description 1
- AUFHLLPVPSMEOG-YUMQZZPRSA-N Arg-Gly-Glu Chemical compound NC(N)=NCCC[C@H](N)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(O)=O AUFHLLPVPSMEOG-YUMQZZPRSA-N 0.000 description 1
- SLKLLQWZQHXYSV-CIUDSAMLSA-N Asn-Ala-Lys Chemical compound NC(=O)C[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCN)C(O)=O SLKLLQWZQHXYSV-CIUDSAMLSA-N 0.000 description 1
- NVGWESORMHFISY-SRVKXCTJSA-N Asn-Asn-Phe Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O NVGWESORMHFISY-SRVKXCTJSA-N 0.000 description 1
- OLVIPTLKNSAYRJ-YUMQZZPRSA-N Asn-Gly-Lys Chemical compound C(CCN)C[C@@H](C(=O)O)NC(=O)CNC(=O)[C@H](CC(=O)N)N OLVIPTLKNSAYRJ-YUMQZZPRSA-N 0.000 description 1
- QUAWOKPCAKCHQL-SRVKXCTJSA-N Asn-His-Lys Chemical compound C1=C(NC=N1)C[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CC(=O)N)N QUAWOKPCAKCHQL-SRVKXCTJSA-N 0.000 description 1
- LGCVSPFCFXWUEY-IHPCNDPISA-N Asn-Trp-Tyr Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)N[C@@H](CC3=CC=C(C=C3)O)C(=O)O)NC(=O)[C@H](CC(=O)N)N LGCVSPFCFXWUEY-IHPCNDPISA-N 0.000 description 1
- HSWYMWGDMPLTTH-FXQIFTODSA-N Asp-Glu-Gln Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(N)=O)C(O)=O HSWYMWGDMPLTTH-FXQIFTODSA-N 0.000 description 1
- PDECQIHABNQRHN-GUBZILKMSA-N Asp-Glu-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](N)CC(O)=O PDECQIHABNQRHN-GUBZILKMSA-N 0.000 description 1
- SNDBKTFJWVEVPO-WHFBIAKZSA-N Asp-Gly-Ser Chemical compound [H]N[C@@H](CC(O)=O)C(=O)NCC(=O)N[C@@H](CO)C(O)=O SNDBKTFJWVEVPO-WHFBIAKZSA-N 0.000 description 1
- WSGVTKZFVJSJOG-RCOVLWMOSA-N Asp-Gly-Val Chemical compound [H]N[C@@H](CC(O)=O)C(=O)NCC(=O)N[C@@H](C(C)C)C(O)=O WSGVTKZFVJSJOG-RCOVLWMOSA-N 0.000 description 1
- 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 1
- UZFHNLYQWMGUHU-DCAQKATOSA-N Asp-Lys-Arg Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O UZFHNLYQWMGUHU-DCAQKATOSA-N 0.000 description 1
- AHWRSSLYSGLBGD-CIUDSAMLSA-N Asp-Pro-Glu Chemical compound OC(=O)C[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCC(O)=O)C(O)=O AHWRSSLYSGLBGD-CIUDSAMLSA-N 0.000 description 1
- YUELDQUPTAYEGM-XIRDDKMYSA-N Asp-Trp-Leu Chemical compound CC(C)C[C@@H](C(=O)O)NC(=O)[C@H](CC1=CNC2=CC=CC=C21)NC(=O)[C@H](CC(=O)O)N YUELDQUPTAYEGM-XIRDDKMYSA-N 0.000 description 1
- KNDCWFXCFKSEBM-AVGNSLFASA-N Asp-Tyr-Glu Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CCC(O)=O)C(O)=O KNDCWFXCFKSEBM-AVGNSLFASA-N 0.000 description 1
- SQIARYGNVQWOSB-BZSNNMDCSA-N Asp-Tyr-Phe Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O SQIARYGNVQWOSB-BZSNNMDCSA-N 0.000 description 1
- 102100024222 B-lymphocyte antigen CD19 Human genes 0.000 description 1
- 241000700199 Cavia porcellus Species 0.000 description 1
- 208000035473 Communicable disease Diseases 0.000 description 1
- NDUSUIGBMZCOIL-ZKWXMUAHSA-N Cys-Asn-Val Chemical compound CC(C)[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)N)NC(=O)[C@H](CS)N NDUSUIGBMZCOIL-ZKWXMUAHSA-N 0.000 description 1
- WVLZTXGTNGHPBO-SRVKXCTJSA-N Cys-Leu-Leu Chemical compound [H]N[C@@H](CS)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O WVLZTXGTNGHPBO-SRVKXCTJSA-N 0.000 description 1
- ZXCAQANTQWBICD-DCAQKATOSA-N Cys-Lys-Val Chemical compound CC(C)[C@@H](C(=O)O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CS)N ZXCAQANTQWBICD-DCAQKATOSA-N 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 241000287828 Gallus gallus Species 0.000 description 1
- WLODHVXYKYHLJD-ACZMJKKPSA-N Gln-Asp-Ser Chemical compound C(CC(=O)N)[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](CO)C(=O)O)N WLODHVXYKYHLJD-ACZMJKKPSA-N 0.000 description 1
- 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
- XKPACHRGOWQHFH-IRIUXVKKSA-N Gln-Thr-Tyr Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O XKPACHRGOWQHFH-IRIUXVKKSA-N 0.000 description 1
- BETSEXMYBWCDAE-SZMVWBNQSA-N Gln-Trp-Lys Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CCC(=O)N)N BETSEXMYBWCDAE-SZMVWBNQSA-N 0.000 description 1
- CSMHMEATMDCQNY-DZKIICNBSA-N Gln-Val-Tyr Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O CSMHMEATMDCQNY-DZKIICNBSA-N 0.000 description 1
- ITYRYNUZHPNCIK-GUBZILKMSA-N Glu-Ala-Leu Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(O)=O ITYRYNUZHPNCIK-GUBZILKMSA-N 0.000 description 1
- GLWXKFRTOHKGIT-ACZMJKKPSA-N Glu-Asn-Asn Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O GLWXKFRTOHKGIT-ACZMJKKPSA-N 0.000 description 1
- HNVFSTLPVJWIDV-CIUDSAMLSA-N Glu-Glu-Gln Chemical compound OC(=O)CC[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(N)=O)C(O)=O HNVFSTLPVJWIDV-CIUDSAMLSA-N 0.000 description 1
- BFEZQZKEPRKKHV-SRVKXCTJSA-N Glu-Pro-Lys Chemical compound C1C[C@H](N(C1)C(=O)[C@H](CCC(=O)O)N)C(=O)N[C@@H](CCCCN)C(=O)O BFEZQZKEPRKKHV-SRVKXCTJSA-N 0.000 description 1
- NNQDRRUXFJYCCJ-NHCYSSNCSA-N Glu-Pro-Val Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](C(C)C)C(O)=O NNQDRRUXFJYCCJ-NHCYSSNCSA-N 0.000 description 1
- ALMBZBOCGSVSAI-ACZMJKKPSA-N Glu-Ser-Asn Chemical compound C(CC(=O)O)[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(=O)N)C(=O)O)N ALMBZBOCGSVSAI-ACZMJKKPSA-N 0.000 description 1
- MFYLRRCYBBJYPI-JYJNAYRXSA-N Glu-Tyr-Lys Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CCC(=O)O)N)O MFYLRRCYBBJYPI-JYJNAYRXSA-N 0.000 description 1
- ZALGPUWUVHOGAE-GVXVVHGQSA-N Glu-Val-His Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)NC(=O)[C@H](CCC(=O)O)N ZALGPUWUVHOGAE-GVXVVHGQSA-N 0.000 description 1
- WGYHAAXZWPEBDQ-IFFSRLJSSA-N Glu-Val-Thr Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O WGYHAAXZWPEBDQ-IFFSRLJSSA-N 0.000 description 1
- VSVZIEVNUYDAFR-YUMQZZPRSA-N Gly-Ala-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)CN VSVZIEVNUYDAFR-YUMQZZPRSA-N 0.000 description 1
- GRIRDMVMJJDZKV-RCOVLWMOSA-N Gly-Asn-Val Chemical compound [H]NCC(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](C(C)C)C(O)=O GRIRDMVMJJDZKV-RCOVLWMOSA-N 0.000 description 1
- PABFFPWEJMEVEC-JGVFFNPUSA-N Gly-Gln-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CCC(=O)N)NC(=O)CN)C(=O)O PABFFPWEJMEVEC-JGVFFNPUSA-N 0.000 description 1
- FFJQHWKSGAWSTJ-BFHQHQDPSA-N Gly-Thr-Ala Chemical compound [H]NCC(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C)C(O)=O FFJQHWKSGAWSTJ-BFHQHQDPSA-N 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- WMKXFMUJRCEGRP-SRVKXCTJSA-N His-Asn-His Chemical compound C1=C(NC=N1)C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CC2=CN=CN2)C(=O)O)N WMKXFMUJRCEGRP-SRVKXCTJSA-N 0.000 description 1
- HVCRQRQPIIRNLY-IUCAKERBSA-N His-Gln-Gly Chemical compound C1=C(NC=N1)C[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)NCC(=O)O)N HVCRQRQPIIRNLY-IUCAKERBSA-N 0.000 description 1
- ALPXXNRQBMRCPZ-MEYUZBJRSA-N His-Thr-Phe Chemical compound [H]N[C@@H](CC1=CNC=N1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O ALPXXNRQBMRCPZ-MEYUZBJRSA-N 0.000 description 1
- 101000980825 Homo sapiens B-lymphocyte antigen CD19 Proteins 0.000 description 1
- 101000934346 Homo sapiens T-cell surface antigen CD2 Proteins 0.000 description 1
- 108010002350 Interleukin-2 Proteins 0.000 description 1
- PVMPDMIKUVNOBD-CIUDSAMLSA-N Leu-Asp-Ser Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(O)=O PVMPDMIKUVNOBD-CIUDSAMLSA-N 0.000 description 1
- GPICTNQYKHHHTH-GUBZILKMSA-N Leu-Gln-Ser Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CO)C(O)=O GPICTNQYKHHHTH-GUBZILKMSA-N 0.000 description 1
- QJUWBDPGGYVRHY-YUMQZZPRSA-N Leu-Gly-Cys Chemical compound CC(C)C[C@@H](C(=O)NCC(=O)N[C@@H](CS)C(=O)O)N QJUWBDPGGYVRHY-YUMQZZPRSA-N 0.000 description 1
- VWHGTYCRDRBSFI-ZETCQYMHSA-N Leu-Gly-Gly Chemical compound CC(C)C[C@H](N)C(=O)NCC(=O)NCC(O)=O VWHGTYCRDRBSFI-ZETCQYMHSA-N 0.000 description 1
- HYMLKESRWLZDBR-WEDXCCLWSA-N Leu-Gly-Thr Chemical compound CC(C)C[C@H](N)C(=O)NCC(=O)N[C@@H]([C@@H](C)O)C(O)=O HYMLKESRWLZDBR-WEDXCCLWSA-N 0.000 description 1
- VCHVSKNMTXWIIP-SRVKXCTJSA-N Leu-Lys-Ser Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CO)C(O)=O VCHVSKNMTXWIIP-SRVKXCTJSA-N 0.000 description 1
- AUNMOHYWTAPQLA-XUXIUFHCSA-N Leu-Met-Ile Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O AUNMOHYWTAPQLA-XUXIUFHCSA-N 0.000 description 1
- WMIOEVKKYIMVKI-DCAQKATOSA-N Leu-Pro-Ala Chemical compound [H]N[C@@H](CC(C)C)C(=O)N1CCC[C@H]1C(=O)N[C@@H](C)C(O)=O WMIOEVKKYIMVKI-DCAQKATOSA-N 0.000 description 1
- SBANPBVRHYIMRR-GARJFASQSA-N Leu-Ser-Pro Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CO)C(=O)N1CCC[C@@H]1C(=O)O)N SBANPBVRHYIMRR-GARJFASQSA-N 0.000 description 1
- SBANPBVRHYIMRR-UHFFFAOYSA-N Leu-Ser-Pro Natural products CC(C)CC(N)C(=O)NC(CO)C(=O)N1CCCC1C(O)=O SBANPBVRHYIMRR-UHFFFAOYSA-N 0.000 description 1
- QWWPYKKLXWOITQ-VOAKCMCISA-N Leu-Thr-Leu Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@H](C(O)=O)CC(C)C QWWPYKKLXWOITQ-VOAKCMCISA-N 0.000 description 1
- 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
- YKIRNDPUWONXQN-GUBZILKMSA-N Lys-Asn-Gln Chemical compound C(CCN)C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CCC(=O)N)C(=O)O)N YKIRNDPUWONXQN-GUBZILKMSA-N 0.000 description 1
- NRQRKMYZONPCTM-CIUDSAMLSA-N Lys-Asp-Ser Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(O)=O NRQRKMYZONPCTM-CIUDSAMLSA-N 0.000 description 1
- 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 1
- XNKDCYABMBBEKN-IUCAKERBSA-N Lys-Gly-Gln Chemical compound NCCCC[C@H](N)C(=O)NCC(=O)N[C@H](C(O)=O)CCC(N)=O XNKDCYABMBBEKN-IUCAKERBSA-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
- 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
- IEVXCWPVBYCJRZ-IXOXFDKPSA-N Lys-Thr-His Chemical compound NCCCC[C@H](N)C(=O)N[C@@H]([C@H](O)C)C(=O)N[C@H](C(O)=O)CC1=CN=CN1 IEVXCWPVBYCJRZ-IXOXFDKPSA-N 0.000 description 1
- DLCAXBGXGOVUCD-PPCPHDFISA-N Lys-Thr-Ile Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O DLCAXBGXGOVUCD-PPCPHDFISA-N 0.000 description 1
- CAVRAQIDHUPECU-UVOCVTCTSA-N Lys-Thr-Thr Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O CAVRAQIDHUPECU-UVOCVTCTSA-N 0.000 description 1
- 241001465754 Metazoa Species 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
- 206010028980 Neoplasm Diseases 0.000 description 1
- 108010019160 Pancreatin Proteins 0.000 description 1
- MSHZERMPZKCODG-ACRUOGEOSA-N Phe-Leu-Phe Chemical compound C([C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)C1=CC=CC=C1 MSHZERMPZKCODG-ACRUOGEOSA-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
- WWPAHTZOWURIMR-ULQDDVLXSA-N Phe-Pro-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@@H](N)CC1=CC=CC=C1 WWPAHTZOWURIMR-ULQDDVLXSA-N 0.000 description 1
- OOLOTUZJUBOMAX-GUBZILKMSA-N Pro-Ala-Val Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](C)C(=O)N[C@@H](C(C)C)C(O)=O OOLOTUZJUBOMAX-GUBZILKMSA-N 0.000 description 1
- TUYWCHPXKQTISF-LPEHRKFASA-N Pro-Cys-Pro Chemical compound C1C[C@H](NC1)C(=O)N[C@@H](CS)C(=O)N2CCC[C@@H]2C(=O)O TUYWCHPXKQTISF-LPEHRKFASA-N 0.000 description 1
- NXEYSLRNNPWCRN-SRVKXCTJSA-N Pro-Glu-Leu Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(O)=O NXEYSLRNNPWCRN-SRVKXCTJSA-N 0.000 description 1
- VPEVBAUSTBWQHN-NHCYSSNCSA-N Pro-Glu-Val Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(O)=O VPEVBAUSTBWQHN-NHCYSSNCSA-N 0.000 description 1
- KWMUAKQOVYCQJQ-ZPFDUUQYSA-N Pro-Ile-Glu Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)O)NC(=O)[C@@H]1CCCN1 KWMUAKQOVYCQJQ-ZPFDUUQYSA-N 0.000 description 1
- PCWLNNZTBJTZRN-AVGNSLFASA-N Pro-Pro-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@H]1NCCC1 PCWLNNZTBJTZRN-AVGNSLFASA-N 0.000 description 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
- KBUAPZAZPWNYSW-SRVKXCTJSA-N Pro-Pro-Val Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@H]1NCCC1 KBUAPZAZPWNYSW-SRVKXCTJSA-N 0.000 description 1
- GOMUXSCOIWIJFP-GUBZILKMSA-N Pro-Ser-Arg Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O GOMUXSCOIWIJFP-GUBZILKMSA-N 0.000 description 1
- OWQXAJQZLWHPBH-FXQIFTODSA-N Pro-Ser-Asn Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(O)=O OWQXAJQZLWHPBH-FXQIFTODSA-N 0.000 description 1
- 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 1
- 108010076504 Protein Sorting Signals Proteins 0.000 description 1
- VGNYHOBZJKWRGI-CIUDSAMLSA-N Ser-Asn-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](N)CO VGNYHOBZJKWRGI-CIUDSAMLSA-N 0.000 description 1
- KNCJWSPMTFFJII-ZLUOBGJFSA-N Ser-Cys-Asp Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(O)=O)C(O)=O KNCJWSPMTFFJII-ZLUOBGJFSA-N 0.000 description 1
- MOVJSUIKUNCVMG-ZLUOBGJFSA-N Ser-Cys-Ser Chemical compound C([C@@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CO)C(=O)O)N)O MOVJSUIKUNCVMG-ZLUOBGJFSA-N 0.000 description 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
- 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 1
- GZFAWAQTEYDKII-YUMQZZPRSA-N Ser-Gly-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)CNC(=O)[C@@H](N)CO GZFAWAQTEYDKII-YUMQZZPRSA-N 0.000 description 1
- HMRAQFJFTOLDKW-GUBZILKMSA-N Ser-His-Glu Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CCC(O)=O)C(O)=O HMRAQFJFTOLDKW-GUBZILKMSA-N 0.000 description 1
- 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 1
- XUDRHBPSPAPDJP-SRVKXCTJSA-N Ser-Lys-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](N)CO XUDRHBPSPAPDJP-SRVKXCTJSA-N 0.000 description 1
- 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 1
- GDUZTEQRAOXYJS-SRVKXCTJSA-N Ser-Phe-Asn Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)O)NC(=O)[C@H](CO)N GDUZTEQRAOXYJS-SRVKXCTJSA-N 0.000 description 1
- HHJFMHQYEAAOBM-ZLUOBGJFSA-N Ser-Ser-Ala Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H](C)C(O)=O HHJFMHQYEAAOBM-ZLUOBGJFSA-N 0.000 description 1
- PYTKULIABVRXSC-BWBBJGPYSA-N Ser-Ser-Thr Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(O)=O PYTKULIABVRXSC-BWBBJGPYSA-N 0.000 description 1
- 102100025237 T-cell surface antigen CD2 Human genes 0.000 description 1
- IGROJMCBGRFRGI-YTLHQDLWSA-N Thr-Ala-Ala Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](C)C(O)=O IGROJMCBGRFRGI-YTLHQDLWSA-N 0.000 description 1
- ASJDFGOPDCVXTG-KATARQTJSA-N Thr-Cys-Leu Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(C)C)C(O)=O ASJDFGOPDCVXTG-KATARQTJSA-N 0.000 description 1
- KWQBJOUOSNJDRR-XAVMHZPKSA-N Thr-Cys-Pro Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CS)C(=O)N1CCC[C@@H]1C(=O)O)N)O KWQBJOUOSNJDRR-XAVMHZPKSA-N 0.000 description 1
- DSLHSTIUAPKERR-XGEHTFHBSA-N Thr-Cys-Val Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CS)C(=O)N[C@@H](C(C)C)C(O)=O DSLHSTIUAPKERR-XGEHTFHBSA-N 0.000 description 1
- NCXVJIQMWSGRHY-KXNHARMFSA-N Thr-Leu-Pro Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N1CCC[C@@H]1C(=O)O)N)O NCXVJIQMWSGRHY-KXNHARMFSA-N 0.000 description 1
- JLNMFGCJODTXDH-WEDXCCLWSA-N Thr-Lys-Gly Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCCN)C(=O)NCC(O)=O JLNMFGCJODTXDH-WEDXCCLWSA-N 0.000 description 1
- DXPURPNJDFCKKO-RHYQMDGZSA-N Thr-Lys-Val Chemical compound CC(C)[C@H](NC(=O)[C@H](CCCCN)NC(=O)[C@@H](N)[C@@H](C)O)C(O)=O DXPURPNJDFCKKO-RHYQMDGZSA-N 0.000 description 1
- SGAOHNPSEPVAFP-ZDLURKLDSA-N Thr-Ser-Gly Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(=O)NCC(O)=O SGAOHNPSEPVAFP-ZDLURKLDSA-N 0.000 description 1
- BEZTUFWTPVOROW-KJEVXHAQSA-N Thr-Tyr-Arg Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC1=CC=C(C=C1)O)C(=O)N[C@@H](CCCN=C(N)N)C(=O)O)N)O BEZTUFWTPVOROW-KJEVXHAQSA-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
- 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 1
- QNXZCKMXHPULME-ZNSHCXBVSA-N Thr-Val-Pro Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@@H]1C(=O)O)N)O QNXZCKMXHPULME-ZNSHCXBVSA-N 0.000 description 1
- 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 1
- UKINEYBQXPMOJO-UBHSHLNASA-N Trp-Asn-Ser Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CO)C(=O)O)N UKINEYBQXPMOJO-UBHSHLNASA-N 0.000 description 1
- DQDXHYIEITXNJY-BPUTZDHNSA-N Trp-Gln-Gln Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H](CCC(=O)N)C(=O)O)N DQDXHYIEITXNJY-BPUTZDHNSA-N 0.000 description 1
- QJBWZNTWJSZUOY-UWJYBYFXSA-N Tyr-Ala-Cys Chemical compound C[C@@H](C(=O)N[C@@H](CS)C(=O)O)NC(=O)[C@H](CC1=CC=C(C=C1)O)N QJBWZNTWJSZUOY-UWJYBYFXSA-N 0.000 description 1
- SCCKSNREWHMKOJ-SRVKXCTJSA-N Tyr-Asn-Ser Chemical compound N[C@@H](Cc1ccc(O)cc1)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CO)C(O)=O SCCKSNREWHMKOJ-SRVKXCTJSA-N 0.000 description 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
- MQGGXGKQSVEQHR-KKUMJFAQSA-N Tyr-Ser-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 MQGGXGKQSVEQHR-KKUMJFAQSA-N 0.000 description 1
- RIVVDNTUSRVTQT-IRIUXVKKSA-N Tyr-Thr-Gln Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)O)NC(=O)[C@H](CC1=CC=C(C=C1)O)N)O RIVVDNTUSRVTQT-IRIUXVKKSA-N 0.000 description 1
- CGGVNFJRZJUVAE-BYULHYEWSA-N Val-Asp-Asn Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](CC(=O)N)C(=O)O)N CGGVNFJRZJUVAE-BYULHYEWSA-N 0.000 description 1
- SCBITHMBEJNRHC-LSJOCFKGSA-N Val-Asp-Val Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](C(C)C)C(=O)O)N SCBITHMBEJNRHC-LSJOCFKGSA-N 0.000 description 1
- RKIGNDAHUOOIMJ-BQFCYCMXSA-N Val-Glu-Trp Chemical compound C1=CC=C2C(C[C@H](NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](N)C(C)C)C(O)=O)=CNC2=C1 RKIGNDAHUOOIMJ-BQFCYCMXSA-N 0.000 description 1
- XTDDIVQWDXMRJL-IHRRRGAJSA-N Val-Leu-His Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)NC(=O)[C@H](C(C)C)N XTDDIVQWDXMRJL-IHRRRGAJSA-N 0.000 description 1
- SYSWVVCYSXBVJG-RHYQMDGZSA-N Val-Leu-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](C(C)C)N)O SYSWVVCYSXBVJG-RHYQMDGZSA-N 0.000 description 1
- HPANGHISDXDUQY-ULQDDVLXSA-N Val-Lys-Phe Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)O)N HPANGHISDXDUQY-ULQDDVLXSA-N 0.000 description 1
- SBJCTAZFSZXWSR-AVGNSLFASA-N Val-Met-His Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)N SBJCTAZFSZXWSR-AVGNSLFASA-N 0.000 description 1
- FMQGYTMERWBMSI-HJWJTTGWSA-N Val-Phe-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)[C@H](CC1=CC=CC=C1)NC(=O)[C@H](C(C)C)N FMQGYTMERWBMSI-HJWJTTGWSA-N 0.000 description 1
- 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 1
- UVHFONIHVHLDDQ-IFFSRLJSSA-N Val-Thr-Glu Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)O)NC(=O)[C@H](C(C)C)N)O UVHFONIHVHLDDQ-IFFSRLJSSA-N 0.000 description 1
- LLJLBRRXKZTTRD-GUBZILKMSA-N Val-Val-Ser Chemical compound CC(C)[C@@H](C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CO)C(=O)O)N LLJLBRRXKZTTRD-GUBZILKMSA-N 0.000 description 1
- 108010003533 Viral Envelope Proteins Proteins 0.000 description 1
- 208000036142 Viral infection Diseases 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 239000011543 agarose gel Substances 0.000 description 1
- 230000004520 agglutination Effects 0.000 description 1
- 108010041407 alanylaspartic acid Proteins 0.000 description 1
- 108010087924 alanylproline Proteins 0.000 description 1
- DKNWSYNQZKUICI-UHFFFAOYSA-N amantadine Chemical compound C1C(C2)CC3CC2CC1(N)C3 DKNWSYNQZKUICI-UHFFFAOYSA-N 0.000 description 1
- 229960003805 amantadine Drugs 0.000 description 1
- 239000003443 antiviral agent Substances 0.000 description 1
- 108010052670 arginyl-glutamyl-glutamic acid Proteins 0.000 description 1
- 108010009111 arginyl-glycyl-glutamic acid Proteins 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 238000007664 blowing Methods 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 230000007910 cell fusion Effects 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000005138 cryopreservation Methods 0.000 description 1
- 239000012228 culture supernatant Substances 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000000502 dialysis Methods 0.000 description 1
- 230000029087 digestion Effects 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- FSXRLASFHBWESK-UHFFFAOYSA-N dipeptide phenylalanyl-tyrosine Natural products C=1C=C(O)C=CC=1CC(C(O)=O)NC(=O)C(N)CC1=CC=CC=C1 FSXRLASFHBWESK-UHFFFAOYSA-N 0.000 description 1
- 238000010494 dissociation reaction Methods 0.000 description 1
- 230000005593 dissociations Effects 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 230000002884 effect on inflammation Effects 0.000 description 1
- 210000003743 erythrocyte Anatomy 0.000 description 1
- 210000003527 eukaryotic cell Anatomy 0.000 description 1
- 239000013604 expression vector Substances 0.000 description 1
- 239000000284 extract Substances 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
- 238000007710 freezing Methods 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- 108010013768 glutamyl-aspartyl-proline Proteins 0.000 description 1
- 108010000434 glycyl-alanyl-leucine Proteins 0.000 description 1
- 108010050475 glycyl-leucyl-tyrosine Proteins 0.000 description 1
- 108010089804 glycyl-threonine Proteins 0.000 description 1
- 108010015792 glycyllysine Proteins 0.000 description 1
- 108010037850 glycylvaline Proteins 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 229940022353 herceptin Drugs 0.000 description 1
- 210000005260 human cell Anatomy 0.000 description 1
- 230000003053 immunization Effects 0.000 description 1
- 238000002649 immunization Methods 0.000 description 1
- 230000005847 immunogenicity Effects 0.000 description 1
- 230000016784 immunoglobulin production Effects 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 108010044311 leucyl-glycyl-glycine Proteins 0.000 description 1
- 108010073472 leucyl-prolyl-proline Proteins 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 210000002751 lymph Anatomy 0.000 description 1
- 239000006166 lysate Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 229940029358 orthoclone okt3 Drugs 0.000 description 1
- 229940055695 pancreatin Drugs 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 108010024654 phenylalanyl-prolyl-alanine Proteins 0.000 description 1
- 238000007747 plating Methods 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 108010070643 prolylglutamic acid Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 230000006798 recombination Effects 0.000 description 1
- 238000005215 recombination Methods 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 229960000888 rimantadine Drugs 0.000 description 1
- 229960004641 rituximab Drugs 0.000 description 1
- 230000001932 seasonal effect Effects 0.000 description 1
- 108010069117 seryl-lysyl-aspartic acid Proteins 0.000 description 1
- 108010048397 seryl-lysyl-leucine Proteins 0.000 description 1
- 108010026333 seryl-proline Proteins 0.000 description 1
- 238000007619 statistical method Methods 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 239000012089 stop solution Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000010257 thawing Methods 0.000 description 1
- 238000001890 transfection Methods 0.000 description 1
- 210000005239 tubule Anatomy 0.000 description 1
- 230000005909 tumor killing Effects 0.000 description 1
- 108010079202 tyrosyl-alanyl-cysteine Proteins 0.000 description 1
- 108010071635 tyrosyl-prolyl-arginine Proteins 0.000 description 1
- 108010052774 valyl-lysyl-glycyl-phenylalanyl-tyrosine 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
- C07K16/08—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from viruses
- C07K16/10—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from viruses from RNA viruses
- C07K16/1018—Orthomyxoviridae, e.g. influenza virus
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
-
- 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
- G01N33/569—Immunoassay; Biospecific binding assay; Materials therefor for microorganisms, e.g. protozoa, bacteria, viruses
- G01N33/56983—Viruses
-
- 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
- G01N33/577—Immunoassay; Biospecific binding assay; Materials therefor involving monoclonal antibodies binding reaction mechanisms characterised by the use of monoclonal antibodies; monoclonal antibodies per se are classified with their corresponding antigens
-
- 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
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
- C07K2317/565—Complementarity determining region [CDR]
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/70—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
- C07K2317/92—Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Immunology (AREA)
- Virology (AREA)
- Molecular Biology (AREA)
- Engineering & Computer Science (AREA)
- Hematology (AREA)
- Urology & Nephrology (AREA)
- Biomedical Technology (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Biochemistry (AREA)
- Analytical Chemistry (AREA)
- Biotechnology (AREA)
- Physics & Mathematics (AREA)
- Food Science & Technology (AREA)
- General Physics & Mathematics (AREA)
- Pathology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Microbiology (AREA)
- Pulmonology (AREA)
- Communicable Diseases (AREA)
- Cell Biology (AREA)
- Oncology (AREA)
- General Chemical & Material Sciences (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Genetics & Genomics (AREA)
- Biophysics (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Tropical Medicine & Parasitology (AREA)
- Peptides Or Proteins (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
Abstract
本发明涉及抗H7N9全人源单克隆抗体8D11及其制备方法与应用。利用记忆B细胞PCR方法快速筛选全人源单克隆抗体8D11，不含任何鼠源成分。本发明抗体可靶向结合H7N9病毒的血凝素HA，具有显著地抗H7N9病毒感染的中和活性；本发明抗体不发生抗鼠抗抗体等毒副作用，具有更好的生物相容性，更适合和更有潜力成为治疗流感病毒的大分子药物。
Description
技术领域
本发明属于免疫学领域，具体地涉及一种抗H7N9全人源单克隆抗体8D11及其制备方法与应用。
背景技术
在2015年全球十大畅销药中，有6个是全人源或人源化单克隆抗体药物。排名第一的是艾伯维公司治疗关节炎的抗TNFa单克隆抗体Humira，这是一个全人源单克隆抗体，已经是连续3年销售额100亿以上的药王。从1986年第一个单克隆抗体药物上市开始，单抗药物经历了鼠源单抗药物(如Orthoclone OKT3)、嵌合单抗药物(Rituximab)、人源化单抗药物(Herceptin)和全人源单抗药物(Humira)等阶段。由于人体出现抗鼠抗体反应(HAMA)，鼠源单抗药物、嵌合单抗药物已经逐渐被淘汰，目前占据市场的单克隆抗体药物全都是人源化单克隆抗体药物。与国际先进的人源抗体生产技术相比，深圳乃至全中国都有很大差距，主要表现在人源抗体药物领域的创新能力薄弱，自主研发的品种少，目前还没有原创人源化单克隆抗体药物上市的报道，庞大的抗体药物市场被国外药企占领。我国要改变落后局面，争夺消费潜力巨大的国内外抗体药物市场，亟需攻克全人源单克隆抗体技术。
人源单克隆抗体在治疗炎症、癌症特别是流行性感冒方面具有高特异性的显著疗效。流行性感冒是由流感病毒引起的传染性疾病，严重威胁人类健康。全球每年约有10亿人受季节性流感病毒感染，其中有25-50万人死亡。H7N9病毒是一种流感病毒，对传统的抗病毒药金刚烷胺(amantadine)和金刚烷乙胺(rimantadine)有耐药性，目前尚没有有效治疗手段。H7N9病毒在入侵细胞时需要依赖病毒自身表达的特定分子与人细胞上的受体结合，才能感染细胞，并进一步扩增。中和病毒的人源抗体是人B淋巴细胞产生的某些特异抗体，能够与病毒表面的抗原结合，从而阻止该病毒黏附靶细胞受体，防止病毒侵入细胞，能够高效防治H7N9流行性感冒。
发明内容
一方面，本发明涉及抗H7N9全人源单克隆抗体8D11或来源于该单克隆抗体的能够中和H7N9病毒的生物活性片段。
另一方面，本发明涉及编码所述抗H7N9全人源单克隆抗体8D11或来源于该单克隆抗体的能够特异性结合H7N9的生物活性片段的基因及含该基因的载体或细胞。
另一方面，本发明涉及产生所述抗H7N9全人源单克隆抗体8D11的方法。
另一方面，本发明涉及包含所述的抗H7N9全人源单克隆抗体8D11或来源于该单克隆抗体的能够特异性结合H7N9的生物活性片段的药物组合物。
另一方面，本发明涉及本发明所述的抗H7N9全人源单克隆抗体8D11或来源于该单克隆抗体的能够特异性结合H7N9的生物活性片段或所述药物组合物的应用。
另一方面，本发明涉及一种检测H7N9病毒的试剂盒。
具体地，一方面，本发明提供抗H7N9全人源单克隆抗体8D11或来源于该单克隆抗体的能够特异性结合H7N9的生物活性片段，其中，该抗体的重轻链CDR1、CDR2及CDR3区的氨基酸序列分别如下所示：
重链CDR1:GYIFFTSYD；
重链CDR2:MNPDSGDT；
重链CDR3:ATGNADCSGGSCYNWFDP；
轻链CDR1:RLRSYTY；
轻链CDR2:GKN；
轻链CDR3:NSRTSGYHLV。
在一些实施方式中，该抗体的重链可变区氨基酸序列如SEQ ID NO:2所示，或该序列经替换、缺失或添加一个或几个氨基酸形成的具有同等功能的氨基酸序列；和/或
该抗体的轻链可变区氨基酸序列如SEQ ID NO:4所示，或该序列经替换、缺失或添加一个或几个氨基酸形成的具有同等功能的氨基酸序列。
在一些实施方式中，该抗体的重链氨基酸序列如SEQ ID NO:6所示，或该序列经替换、缺失或添加一个或几个氨基酸形成的具有同等功能的氨基酸序列；和/或
该抗体的轻链氨基酸序列如SEQ ID NO:8所示，或该序列经替换、缺失或添加一个或几个氨基酸形成的具有同等功能的氨基酸序列。
经ELISA实验验证，本发明所述抗H7N9全人源单克隆抗体8D11可以靶向结合H7N9病毒的血凝素HA，亲和力为8.30×10-9M；在病毒感染细胞模型中，其IC50值仅为0.89uM左右。本发明所述抗体为全人源性单克隆抗体，相比鼠源抗体，全人源抗体的基因完全来源于人的基因，没有其他种属的成分，在人体内不发生抗鼠抗抗体等毒副作用，具有更好的生物相容性，更适合和更有潜力成为治疗流感病毒的大分子药物。
另一方面，本发明提供编码本发明所述的抗H7N9全人源单克隆抗体8D11的基因。在一些实施方式中，所述基因包含编码具有SEQ ID NO:2所示的氨基酸的核苷酸序列，在一些实施方式中，该核苷酸序列如SEQ ID NO:1所示；和/或
所述基因包含编码具有SEQ ID NO:4所示的氨基酸的核苷酸序列，在一些实施方式中，该核苷酸序列如SEQ ID NO:3所示。
在一些体实施方式中，所述基因包含编码具有SEQ ID NO:6的氨基酸的核苷酸序列，在一些实施方式中，该核苷酸序列如SEQ ID NO:5所示；和/或
所述基因包含编码具有SEQ ID NO:8所示的氨基酸的核苷酸序列，在一些实施方式中，该核苷酸序列如SEQ ID NO:7所示。
本发明SEQ ID NO:1～8的序列如序列表所示，其中：
(1)SEQ ID NO:1中第76～102位序列以及SEQ ID NO:5中第124～150位序列：用于编码重链CDR1区序列；
(2)SEQ ID NO:1中第154～177位序列以及SEQ ID NO:5中第202～225位序列：用于编码重链CDR2区序列；
(3)SEQ ID NO:1中第292～345位序列以及SEQ ID NO:5中第340～393位序列：用于编码重链CDR3区序列；
(4)SEQ ID NO:3中第76～96位序列以及SEQ ID NO:7中第124～144位序列：用于编码轻链CDR1区序列；
(5)SEQ ID NO:3中第148～156位序列以及SEQ ID NO:7中第196～204位序列：用于编码轻链CDR2区序列；
(6)SEQ ID NO:3中第265～294位序列以及SEQ ID NO:7中第313～342位序列：用于编码轻链CDR3区序列；
(7)SEQ ID NO:5和SEQ ID NO:7中的第1～48位序列为用于编码信号肽的序列。
(8)SEQ ID NO:2和SEQ ID NO:6中的第26-34位氨基酸序列为重链CDR1序列；SEQID NO:2和SEQ ID NO:6中的第52-59位氨基酸序列为重链CDR2序列；SEQ ID NO:2和SEQIDNO:6中第98-115位氨基酸序列为重链CDR3序列。
(9)SEQ ID NO:4和SEQ ID NO:8中的第26-32位氨基酸序列为轻链CDR1序列；SEQID NO:4和SEQ ID NO:8中的第50-52位氨基酸序列为轻链CDR2序列；SEQ ID NO:4和SEQIDNO:8中的第89-98位氨基酸序列为轻链CDR3序列。
另一方面，本发明提供含如上所述基因的载体。
再一方面，本发明提供含如上所述基因或如上所述载体的细胞。
再一方面，本发明提供一种产生所述抗H7N9全人源单克隆抗体8D11或来源于该单克隆抗体的能够特异性结合H7N9的生物活性片段的方法，该方法包括培养含编码抗H7N9全人源单克隆抗体8D11的重轻链的上述基因或上述载体的基因工程细胞或直接培养上述细胞，收集，纯化得所述抗H7N9全人源单克隆抗体8D11。
现有技术中存在采用噬菌体展示技术制备抗H7N9病毒人源单克隆抗体的方法，尽管该方法具有生产成本低、不经过免疫和细胞融合等繁琐工作的优点，但是其缺点也比较明显，从非免疫抗体库中获得的抗体往往亲和力不足、受外源基因转化率的限制、抗体库的库容量不足以涵盖动物的抗体多样性等。本发明从病人的血液中分离分泌功能抗体的B细胞，然后提取RNA和合成cDNA，从中克隆分泌目的抗体的基因，最后重组和表达全人源单克隆抗体。该技术操作简单快捷，生产的人源抗体具有高亲和力和特异性，此外，可进一步采用改进的从记忆B细胞中分离具有中和病毒功能或杀伤肿瘤功能的本发明所述单克隆抗体技术，更是大大减少了繁琐操作和成本。
另一方面，本发明提供一种药物组合物，其包含本发明所述的抗H7N9全人源单克隆抗体8D11或来源于该单克隆抗体的能够特异性结合H7N9的生物活性片段。
另一方面，本发明提供所述的抗H7N9全人源单克隆抗体8D11或来源于该单克隆抗体的能够特异性结合H7N9的生物活性片段或所述的药物组合物在制备用于治疗由H7N9病毒引起的疾病的药物中的应用。
另一方面，本发明提供一种检测H7N9病毒水平的试剂盒，其含有本发明所述的抗H7N9全人源单克隆抗体8D11或来源于该单克隆抗体的能够特异性结合H7N9的生物活性片段；在一些实施方式中，所述的试剂盒还含有第二抗体和用于检测的酶或荧光或放射标记物，以及缓冲液；所述第二抗体例如为抗本发明所述单克隆抗体8D11的抗抗体。
与现有技术相比，本发明具有如下有益效果：
(1)本发明所述抗H7N9全人源单克隆抗体8D11可以靶向结合H7N9病毒的血凝素HA，具有显著抗H7N9病毒感染的中和活性。
(2)相比鼠源抗体，本发明全人源抗体的基因完全来源于人的基因，没有其他种属的成分，在人体内不发生抗鼠抗抗体等毒副作用，具有更好的生物相容性，更适合和更有潜力成为治疗流感病毒的大分子药物。
(3)相较于现有技术提供的噬菌体展示技术制备抗H7N9病毒人源单克隆抗体的方法，本发明采用的单个B细胞开发抗H7N9病毒的抗体具有操作简单快捷，生产的人源抗体具有高亲和力和特异性等优点。
附图说明
图1为实施例1中NTH-3T3表达CD40L的流式检测结果图。
图2为实施例1中流式细胞仪分选记忆B细胞结果图。
图3为实施例1中ELISA实验结果图。
图4为实施例3中和实验结果图。
具体实施方式
例对本发明的技术方案进行以下详细说明，应理解这些实例仅用于说明本发明而不用于限制本发明的范围。实施例中，各原始试剂材料均可商购获得，未注明具体条件的实验方法为所属领域熟知的常规方法和常规条件，或按照仪器制造商所建议的条件。
实施例1
(1)构建稳定表达CD40L的NTH-3T3细胞系(3T3-CD40L)
利用慢病毒建立3T3-CD40L饲养细胞。构建慢病毒表达载体pLVX-CD40L，转染293T细胞，转染第四天收集病毒上清液。活化NIH-3T3细胞，培养3代后用慢病毒感染，继续培养并传代3次。利用流式细胞仪进行分选FITC荧光强度在MFI附近的细胞，重新加入至培养瓶中，37℃，5％CO2培养箱中培养和检测，检测结果如图1所示，其是将表达CD40L的3T3细胞和空载体pLVX(带有ZxGreen)转染的3T3细胞分别用带有APC的抗CD40L染色，然后上流式细胞仪分析。结果发现，所有3T3-CD40L饲养细胞都表达CD40L。当细胞长到80％～90％时，消化收集细胞，浓度为每毫升1×107细胞。置于辐射仪中进行5000rads辐射，冻存液重悬细胞，浓度为每毫升3.5×107细胞，分装1ml在冷冻小管，液氮冻存(可以保存2年)。
(2)记忆B细胞的分选和活化
用淋巴分离液分离和冻存曾经感染H7N9病毒的康复病人的PBMC，每管10～50×106细胞，冻存在液氮罐中。配制PBMC流式染色液，其成分如下表1所示
表1 PBMC流式染色液
| 抗体 | 体积(μL) |
| CD19-PE-Cy7 | 0.5 |
| IgM-PE | 1.0 |
| IgA-APC | 2.5 |
| IgD-FITC | 2.5 |
| PBS-1％(wt/vol)BSA | 43.5 |
解冻PBMC，加入上述PBMC流式染色液并在流式细胞仪上分选，结果如图2所示，分选出CD19+IgM-IgA-IgD-的记忆B细胞，细胞纯度需在90％以上，若低于90％，重复分选过程。配制激活B细胞的混合培养基，如下表2所示：
表2
| 组分 | 体积 |
| 完全IMDM培养基 | 336mL |
| IL-2(10，000U mL<sup>-1</sup>) | 3.5mL |
| IL-21(100μg mL<sup>-1</sup>) | 175μL |
| 步骤(1)中得到的3T3-CD40L | 10mL |
将记忆B细胞加入到混合培养基中，混匀后有限稀释在384孔板，每孔1个细胞，体积为50μl，置于37℃，5％CO2培养箱中静置培养。13天后，取上清液进行ELISA。
(3)获得人源单克隆抗体8D11
流感病毒血凝素HA是病毒包膜表面柱状抗原，能与人、鸡、豚鼠等多种红细胞受体结合引起红细胞凝集，具有免疫原性，抗血凝素抗体可以中和流感病毒。本发明中，通过ELISA发现了能够分泌结合H7N9病毒的抗体8D11的B细胞，其分泌的人源单克隆抗体8D11可以靶向结合H7N9病毒的血凝素HA(图3)。
ELISA实验具体操作：
(1)将100ng/100μl的H7N9病毒的HA蛋白(购自ACROBiosystems)包被在96孔酶标板中，每孔100μl；
(2)放置4℃冰箱过夜；
(3)用PBST溶液洗涤三遍，每孔加5％的脱脂奶粉溶液200μl，37℃孵育1小时；
(4)用PBST溶液洗涤三遍，加100μl没有感染病毒的正常人血清(阴性对照)或加感染病毒的病人血清或抗H7N9全人源单克隆抗体8D11，各三个重复；
(5)37℃孵育1小时后用PBST溶液洗涤三遍；
(6)以1:5000稀释带HRP的抗人IgG抗体(abcam)，加入酶标版中，每孔100μl；
(7)37℃孵育1小时后用PBST溶液洗涤三遍；
(8)每孔加100μl TMB底物溶液(Thermo Scientific)，37℃5分钟；
(9)每孔加终止溶液2M硫酸100μl，立刻在酶标仪中450nm波长检测吸光值。其结果如图3所示，ELISA实验表明本发明获得的人源单克隆抗体8D11可以靶向结合H7N9病毒的血凝素HA。
实施例2人源化单克隆抗体8D11基因的克隆、重组、表达和纯化
将实施例1获得的能够分泌结合H7N9病毒的8D11抗体的B细胞进行裂解，取裂解液进行RNA的反转录，获得人源抗体基因的PCR模板cDNA。设计和合成克隆抗体基因的引物，以cDNA为模板克隆抗体的重链和轻链的基因，并且重组在真核细胞293F或HEK293中进行表达和纯化。具体地：
(1)将裂解后的B细胞液转移至96孔板(Eppendorf，030133366)。
(2)反转录体系：150ng随机引物(invitrogen,48190-011),0.5μl 10mM dNTP(Invitrogen,18427-088),1μl 0.1M DTT(Invitrogen,18080-044),0.5％v/v Igepal CA-630(Sigma,I3021-50ML),4U RNAsin(Promega),6U Prime RNAse Inhibitor(Eppendorf)and 50UIII reverse transcriptase(Invitrogen,18080-044)，补DEPC水至14μl/well。
(3)反转录反应程序：42℃，10min；25℃，10min；50℃，60min；94℃，5min。
(4)cDNA保存在-20℃。
(5)引物的设计和合成:
正向引物5′-3′序列(Forward Primer 5′-3′sequence)
重链可变区PCR引物:
5′VH1 CTGCAACCGGTGTACATTCCCAGGTGCAGCTGGTGCAG(SEQ ID NO:9)
5′VH1/5CTGCAACCGGTGTACATTCCGAGGTGCAGCTGGTGCAG(SEQ ID NO:10)
5′VH3 CTGCAACCGGTGTACATTCTGAGGTGCAGCTGGTGGAG(SEQ ID NO:11)
5′VH3-23CTGCAACCGGTGTACATTCTGAGGTGCAGCTGTTGGAG(SEQ ID NO:12)
5′VH4 CTGCAACCGGTGTACATTCCCAGGTGCAGCTGCAGGAG(SEQ ID NO:13)
5′VH 4-34CTGCAACCGGTGTACATTCCCAGGTGCAGCTACAGCAGTG(SEQ ID NO:14)
5′VH 1-18CTGCAACCGGTGTACATTCCCAGGTTCAGCTGGTGCAG(SEQ ID NO:15)
5′VH 1-24CTGCAACCGGTGTACATTCCCAGGTCCAGCTGGTACAG(SEQ ID NO:16)
5′VH3-33CTGCAACCGGTGTACATTCTCAGGTGCAGCTGGTGGAG(SEQ ID NO:17)
5′VH 3-9CTGCAACCGGTGTACATTCTGAAGTGCAGCTGGTGGAG(SEQ ID NO:18)
5′VH4-39CTGCAACCGGTGTACATTCCCAGCTGCAGCTGCAGGAG(SEQ ID NO:19)
5′VH 6-1CTGCAACCGGTGTACATTCCCAGGTACAGCTGCAGCAG(SEQ ID NO:20)
3′JH 1/2/4/5TGCGAAGTCGACGCTGAGGAGACGGTGACCAG(SEQ ID NO:21)
3′JH 3TGCGAAGTCGACGCTGAAGAGACGGTGACCATTG(SEQ ID NO:22)
3′JH 6TGCGAAGTCGACGCTGAGGAGACGGTGACCGTG(SEQ ID NO:23)
κ轻链可变区PCR产物
5′Vκ1-5CTGCAACCGGTGTACATTCTGACATCCAGATGACCCAGTC(SEQID NO:24)
5′Vκ1-9TTGTGCTGCAACCGGTGTACATTCAGACATCCAGTTGACCCAGTCT(SEQ ID NO:25)
5′Vκ1D-43CTGCAACCGGTGTACATTGTGCCATCCGGATGACCCAGTC(SEQ ID NO:26)
5′Vκ2-24CTGCAACCGGTGTACATGGGGATATTGTGATGACCCAGAC(SEQ ID NO:27)
5′Vκ2-28CTGCAACCGGTGTACATGGGGATATTGTGATGACTCAGTC(SEQ ID NO:28)
5′Vκ2-30CTGCAACCGGTGTACATGGGGATGTTGTGATGACTCAGTC(SEQ ID NO:29)
5′Vκ3-11
TTGTGCTGCAACCGGTGTACATTCAGAAATTGTGTTGACACAGTC(SEQ ID NO:30)
5′Vκ3-15CTGCAACCGGTGTACATTCAGAAATAGTGATGACGCAGTC(SEQ ID NO:31)
5′Vκ3-20TTGTGCTGCAACCGGTGTACATTCAGAAATTGTGTTGACGCAGTCT(SEQ ID NO:32)
5′Vκ4-1CTGCAACCGGTGTACATTCGGACATCGTGATGACCCAGTC(SEQ ID NO:33)
3′Jκ1/4GCCACCGTACGTTTGATYTCCACCTTGGTC(SEQ ID NO:34)
3′Jκ2GCCACCGTACGTTTGATCTCCAGCTTGGTC(SEQ ID NO:35)
3′Jκ3GCCACCGTACGTTTGATATCCACTTTGGTC(SEQ ID NO:36)
3′Jκ5GCCACCGTACGTTTAATCTCCAGTCGTGTC(SEQ ID NO:37)
(6)用KOD-Plus-Neo(TOYOBO，KOD401)试剂盒PCR分别扩增抗体基因的重链和轻链，40μL体系：3.5μL cDNA，20nM混合引物，4μL缓冲液(buffer)，4μL2mM dNTPs，2.4μLMgSO4，1μL KOD。
(7)反应程序：94℃，2min；45个循环：98℃,10s；58℃,30s；68℃,28s。
(8)对扩增产物进行琼脂糖凝胶，结果发现，抗体轻链大小为327bp，重链大小是375bp。
(9)抗体基因重链可变区PCR产物测序结果如SEQ ID NO:1所示序列，其相应的氨基酸序列如SEQ ID NO:2所示序列。抗体基因轻链可变区PCR产物测序结果如SEQ ID NO:3所示序列，其相应的氨基酸序列如SEQ ID NO:4所示序列。
依据所得重轻链可变区序列，设计并委托Invitrogen公司合成抗体基因重链全长H基因，其带有BamH1/EcoR1双酶切位点；及抗体基因轻链全长L基因，其带有Not1/Xho1双酶切位点。
(10)将H基因和pcDNA3.1分别进行BamH1/EcoR1双酶切后相连，形成pcDNA3.1-H载体。
(11)将L基因和pcDNA3.1分别进行Notl/Xho1双酶切后相连，形成pcDNA3.1-L载体。
(12)培养293F细胞。
(13)20μg pcDNA3.1-H(该H基因的核苷酸序列如SEQ ID NO：5所示)载体和10μgpcDNA3.1-L(该L基因的核苷酸序列如SEQ ID NO：7所示)载体共转染293F细胞，培养96小时。
(14)取上清液进行ELISA(ABC是上清液，DEF是阳性对照，GH是阴性对照)；ELISA具体的实验步骤如前所述，ELISA实验结果如下表3和图3所示：
表3
| 数据 | 450nm | 数据 | 450nm |
| A | 0.956 | E | 1.185 |
| B | 0.981 | F | 1.201 |
| C | 0.742 | G | 0.0675 |
| D | 1.114 | H | 0.0554 |
由表3和图3数据可知：上清液中含有能够结合H7N9病毒的抗体。
(15)纯化过程，具体地，全人源单克隆抗体8D11的纯化过程为：
(a)200μg pcDNA3.1-L载体和100μg pcDNA3.1-H载体共转染300ml 293F细胞，培养96小时。
(b)收集上清液，加入proteinA亲和层析柱，用10倍PBS清洗，加入2ml pH3.0，0.1M甘氨酸收集抗体。收集管中加入100μl中和缓冲液(1M Tri-HCL)，以便及时中和洗脱所得抗体液的pH值。
(c)在磷酸盐缓冲液(PBS)中透析，透析完后，近期用的存放在4℃，长期储存在-20℃。共获得500μg 8D11纯抗体，其重链氨基酸序列如SEQ ID NO：6所示，轻链氨基酸序列如SEQ ID NO：8所示。
实施例3纯化后的全人源单克隆抗体8D11的中和实验及抗体亲和力实验
(1)实验目的
使用病毒感染细胞模型(犬肾细胞MDCK)，通过微量中和-ELISA实验评价8D11抗体对H7N9流感病毒的抑制作用和效果，检测抗体抗流感病毒活性。
(2)实验步骤
(2.1)细胞铺板
胰酶消化对数生长期MDCK犬肾细胞，终止后离心收集，吹散均匀，制备单细胞悬液；用细胞培养液将细胞浓度调整至5×104个/ml，接种于96孔细胞培养板，细胞置于37℃、5％CO2培养箱中培养过夜。
(2.2)8D11抗体与H7N9病毒(该病毒A/Anhui/1/2013取自于中国科学院微生物研究所)预处理
8D11抗体设立10个浓度梯度，依次为10-1010倍稀释，各组各浓度均设3个平行孔。
(2.3)病毒感染
弃步骤(2.1)培养的细胞培养上清，PBS洗3遍。将预混的抗体-病毒混合液(以102μg/ml的8D11单克隆抗体依次以10-1010倍稀释，将每个浓度的8D11抗体分别与等体积的100TCID50病毒混合得该混合液)。加入96孔细胞培养板，37℃孵育1h，吸弃混合液，PBS洗2遍。
(2.4)配置维持液
用无血清DMEM中加入终浓度为2μg/ml的TPCK-胰蛋白酶(TPCK-Trypsin)(维持液)。弃去96孔板中的PBS，每孔加入100μl维持液，置于37℃，5％CO2培养箱培养20h。
(2.5)中和实验-ELISA法
(2.5.1)弃去微量培养板中的维持液；
(2.5.2)100μl PBS洗细胞一次；
(2.5.3)弃去PBS(不要让细胞干燥)，加入50μl/孔固定液(体积比为丙酮：无水乙醇＝2：3)；
(2.5.4)覆盖微量培养板，于室温固定细胞10min；
(2.5.5)弃去固定液，用100μl PBS液洗涤细胞，重复洗涤3次(轻轻晃动，避免强烈清洗)，以去除残余的丙酮。
(2.5.6)用5％脱脂奶粉于室温封闭细胞1h，用100μl PBS液洗涤细胞1次；
(2.5.7)用PBS 1：2000稀释1抗(商购抗H7N9的NP单克隆抗体)每孔加入稀释后的50μl，室温作用1小时。
(2.5.8)用100μl PBST洗板5次以除去1抗；
(2.5.9)用PBS 1:2000稀释2抗(带HRP的抗鼠IgG抗体)，每孔加入50μl，室温作用1小时。
(2.5.10)用100μl PBST洗涤板6次以除去2抗。
(2.5.11)每孔加TMB显色液50μl。
(2.5.12)室温避光放10分钟左右显色后，每孔加2M盐酸50μl终止反应。
(2.5.13)在ELISA测定仪上(450纳米)读出每孔OD值。
(3)统计分析
使用GraphPad Prism 6.0.1对数据进行分析和绘制剂量-效应曲线，并计算IC50。抑制率计算公式：
抑制率＝[(OD病毒孔-OD阴性细胞对照孔)-(OD药物孔-OD阴性细胞对照孔)]/(OD病毒孔-OD阴性细胞对照孔)×100％。
所得结构如图4所示，从图4中可以看出8D11的IC50＝0.89ug/mL。
从实施例3可以看出，本发明8D11对H7N9有良好的IC50值，证明8D11的中和病毒能力好。
本发明对比了2016年05年10日向中国国家知识产权局递交的申请号为“201610303416.X”、发明名称为“抗H7N9全人源单克隆抗体2L11及其制法与应用”中的单克隆抗体2L11，及2016年05月03日向中国国家知识产权局递交的申请号为“201610288358.8”、发明名称为“抗H7N9全人源单克隆抗体2J17及其制法与应用”中的单克隆抗体2J17。本发明8D11中和活性的IC50为0.89μg/mL，而2L11及2J17抗体没有中和活性。研究组2018年07月24日提交了一件“抗H7N9全人源单克隆抗体hIg311及其制法与应用”的申请(申请号：201810818233.0)，目前该申请尚未公开，本发明是在该申请内容的基础上针对重轻链CDR1、CDR2及CDR3区的氨基酸进行了部分氨基酸的改变，以研究其相关功能。
抗体亲和力检测：
亲和力检测的仪器为PALL的Fortebio。配制200μl 50μg/ml 8D11抗体，结合proteinA传感器120秒，HA抗原配制100nM、50nM、2.5nM、12.5nM和、6.25nM和0nM浓度溶液，结合抗体120秒，解离时间为5分钟，显示8D11对H7N9病毒有较高亲和力，KD＝8.30×10-9M。
最后说明的是：以上实施例仅用于说明本发明的实施过程和特点，而非限制本发明的技术方案，尽管参照上述实施例对本发明进行了详细说明，本领域的普通技术人员应当理解：依然可以对本发明进行修改或者等同替换，而不脱离本发明的精神和范围的任何修改或局部替换，均应涵盖在本发明的保护范围当中。
序列表
<110> 中国科学院深圳先进技术研究院
<120> 抗H7N9全人源单克隆抗体8D11及其制法与应用
<130> GAI18CN6777
<160> 37
<170> SIPOSequenceListing 1.0
<210> 1
<211> 378
<212> DNA
<213> 人工序列()
<400> 1
caagtgcagc tggtggagtc tggggctgag gtgaagaagc ctggggcctc agtgaaggtc 60
tcctgcaagg cttctggata catattcttc accagttatg atatcaactg ggtgcgacag 120
gccactggcc aagggcttga gtggatggga tggatgaacc ctgacagtgg tgacacaggc 180
tttgcacaga agttccaggg cagagtcacc atgaccagga acacctccat aaccacagcc 240
tacatggagc tgagcagcct gacttctgag gacacggccg tgtattactg tgcgacagga 300
aatgcggatt gtagtggtgg tagctgctac aattggttcg acccctgggg ccagggaacc 360
ctggtcaccg tctcctca 378
<210> 2
<211> 126
<212> PRT
<213> 人工序列()
<400> 2
Gln Val Gln Leu Val Glu Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ile Phe Phe Thr Ser
20 25 30
Tyr Asp Ile Asn Trp Val Arg Gln Ala Thr Gly Gln Gly Leu Glu Trp
35 40 45
Met Gly Trp Met Asn Pro Asp Ser Gly Asp Thr Gly Phe Ala Gln Lys
50 55 60
Phe Gln Gly Arg Val Thr Met Thr Arg Asn Thr Ser Ile Thr Thr Ala
65 70 75 80
Tyr Met Glu Leu Ser Ser Leu Thr Ser Glu Asp Thr Ala Val Tyr Tyr
85 90 95
Cys Ala Thr Gly Asn Ala Asp Cys Ser Gly Gly Ser Cys Tyr Asn Trp
100 105 110
Phe Asp Pro Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120 125
<210> 3
<211> 327
<212> DNA
<213> 人工序列()
<400> 3
tcgtctgagc tgactcagga ccctgctgtg tctgtggcct tgggacagac agtcaggatc 60
acatgccaag gagacagact cagaagctat acttatgcaa gctggtacca gcagaagcca 120
ggacaggccc ctgtacttgt catctatggt aaaaacaacc ggccctcagg gatcccagac 180
cgattctctg gctccagctc aggaaacaca gcttccttga ccatcactgg ggctcaggcg 240
gaagatgagg ctgactatta ctgtaactcc cggaccagtg gttaccatct ggtgttcggc 300
ggagggacca agctgaccgt cctagta 327
<210> 4
<211> 109
<212> PRT
<213> 人工序列()
<400> 4
Ser Ser Glu Leu Thr Gln Asp Pro Ala Val Ser Val Ala Leu Gly Gln
1 5 10 15
Thr Val Arg Ile Thr Cys Gln Gly Asp Arg Leu Arg Ser Tyr Thr Tyr
20 25 30
Ala Ser Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Val Leu Val Ile
35 40 45
Tyr Gly Lys Asn Asn Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser Gly
50 55 60
Ser Ser Ser Gly Asn Thr Ala Ser Leu Thr Ile Thr Gly Ala Gln Ala
65 70 75 80
Glu Asp Glu Ala Asp Tyr Tyr Cys Asn Ser Arg Thr Ser Gly Tyr His
85 90 95
Leu Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Val
100 105
<210> 5
<211> 1419
<212> DNA
<213> 人工序列()
<400> 5
atgggctggt cctgcatcat cctgttcctg gtggccaccg ccaccggcca agtgcagctg 60
gtggagtctg gggctgaggt gaagaagcct ggggcctcag tgaaggtctc ctgcaaggct 120
tctggataca tattcttcac cagttatgat atcaactggg tgcgacaggc cactggccaa 180
gggcttgagt ggatgggatg gatgaaccct gacagtggtg acacaggctt tgcacagaag 240
ttccagggca gagtcaccat gaccaggaac acctccataa ccacagccta catggagctg 300
agcagcctga cttctgagga cacggccgtg tattactgtg cgacaggaaa tgcggattgt 360
agtggtggta gctgctacaa ttggttcgac ccctggggcc agggaaccct ggtcaccgtc 420
tcctcagcta gcaccaaggg cccatcggtc ttccccctgg caccctcctc caagagcacc 480
tctgggggca cagcggccct gggctgcctg gtcaaggact acttccccga accggtgacg 540
gtgtcgtgga actcaggcgc cctgaccagc ggcgtgcaca ccttcccggc cgtcctacag 600
tcctcaggac tctactccct cagcagcgtg gtgaccgtgc cctccagcag cttgggcacc 660
cagacctaca tctgcaacgt gaatcacaag cccagcaaca ccaaggtgga caagagagtt 720
gagcccaaat cttgtgacaa aactcacaca tgcccaccgt gcccagcacc tgaactcctg 780
gggggaccgt cagtcttcct cttcccccca aaacccaagg acaccctcat gatctcccgg 840
acccctgagg tcacatgcgt ggtggtggac gtgagccacg aagaccctga ggtcaagttc 900
aactggtacg tggacggcgt ggaggtgcat aatgccaaga caaagccgcg ggaggagcag 960
tacaacagca cgtaccgtgt ggtcagcgtc ctcaccgtcc tgcaccagga ctggctgaat 1020
ggcaaggagt acaagtgcaa ggtctccaac aaagccctcc cagcccccat cgagaaaacc 1080
atctccaaag ccaaagggca gccccgagaa ccacaggtgt acaccctgcc cccatcccgg 1140
gatgagctga ccaagaacca ggtcagcctg acctgcctgg tcaaaggctt ctatcccagc 1200
gacatcgccg tggagtggga gagcaatggg cagccggaga acaactacaa gaccacgcct 1260
cccgtgctgg actccgacgg ctccttcttc ctctacagca agctcaccgt ggacaagagc 1320
aggtggcagc aggggaacgt cttctcatgc tccgtgatgc atgaggctct gcacaaccac 1380
tacacgcaga agagcctctc cctgtctccg ggtaaatga 1419
<210> 6
<211> 456
<212> PRT
<213> 人工序列()
<400> 6
Gln Val Gln Leu Val Glu Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ile Phe Phe Thr Ser
20 25 30
Tyr Asp Ile Asn Trp Val Arg Gln Ala Thr Gly Gln Gly Leu Glu Trp
35 40 45
Met Gly Trp Met Asn Pro Asp Ser Gly Asp Thr Gly Phe Ala Gln Lys
50 55 60
Phe Gln Gly Arg Val Thr Met Thr Arg Asn Thr Ser Ile Thr Thr Ala
65 70 75 80
Tyr Met Glu Leu Ser Ser Leu Thr Ser Glu Asp Thr Ala Val Tyr Tyr
85 90 95
Cys Ala Thr Gly Asn Ala Asp Cys Ser Gly Gly Ser Cys Tyr Asn Trp
100 105 110
Phe Asp Pro Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser
115 120 125
Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr
130 135 140
Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro
145 150 155 160
Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val
165 170 175
His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser
180 185 190
Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile
195 200 205
Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val
210 215 220
Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala
225 230 235 240
Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
245 250 255
Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
260 265 270
Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val
275 280 285
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln
290 295 300
Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln
305 310 315 320
Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala
325 330 335
Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
340 345 350
Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr
355 360 365
Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser
370 375 380
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
385 390 395 400
Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr
405 410 415
Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe
420 425 430
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
435 440 445
Ser Leu Ser Leu Ser Pro Gly Lys
450 455
<210> 7
<211> 696
<212> DNA
<213> 人工序列()
<400> 7
atgggctggt cctgcatcat cctgttcctg gtggccaccg ccaccggctc gtctgagctg 60
actcaggacc ctgctgtgtc tgtggccttg ggacagacag tcaggatcac atgccaagga 120
gacagactca gaagctatac ttatgcaagc tggtaccagc agaagccagg acaggcccct 180
gtacttgtca tctatggtaa aaacaaccgg ccctcaggga tcccagaccg attctctggc 240
tccagctcag gaaacacagc ttccttgacc atcactgggg ctcaggcgga agatgaggct 300
gactattact gtaactcccg gaccagtggt taccatctgg tgttcggcgg agggaccaag 360
ctgaccgtcc tagtaaccgt ggccgccccc tccgtgttca tcttcccccc ctccgacgag 420
cagctgaagt ccggcaccgc ctccgtggtg tgcctgctga acaacttcta cccccgggag 480
gccaaggtgc agtggaaggt ggacaacgcc ctgcagtccg gcaactccca ggagtccgtg 540
accgagcagg actccaagga ctccacctac tccctgtcct ccaccctgac cctgtccaag 600
gccgactacg agaagcacaa ggtgtacgcc tgcgaggtta cccaccaggg cctgtcctcc 660
cccgtgacca agtccttcaa ccggggcgag tgctag 696
<210> 8
<211> 215
<212> PRT
<213> 人工序列()
<400> 8
Ser Ser Glu Leu Thr Gln Asp Pro Ala Val Ser Val Ala Leu Gly Gln
1 5 10 15
Thr Val Arg Ile Thr Cys Gln Gly Asp Arg Leu Arg Ser Tyr Thr Tyr
20 25 30
Ala Ser Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Val Leu Val Ile
35 40 45
Tyr Gly Lys Asn Asn Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser Gly
50 55 60
Ser Ser Ser Gly Asn Thr Ala Ser Leu Thr Ile Thr Gly Ala Gln Ala
65 70 75 80
Glu Asp Glu Ala Asp Tyr Tyr Cys Asn Ser Arg Thr Ser Gly Tyr His
85 90 95
Leu Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Val Thr Val Ala
100 105 110
Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser
115 120 125
Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu
130 135 140
Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser
145 150 155 160
Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu
165 170 175
Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val
180 185 190
Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys
195 200 205
Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 9
<211> 38
<212> DNA
<213> 人工序列()
<400> 9
ctgcaaccgg tgtacattcc caggtgcagc tggtgcag 38
<210> 10
<211> 38
<212> DNA
<213> 人工序列()
<400> 10
ctgcaaccgg tgtacattcc gaggtgcagc tggtgcag 38
<210> 11
<211> 38
<212> DNA
<213> 人工序列()
<400> 11
ctgcaaccgg tgtacattct gaggtgcagc tggtggag 38
<210> 12
<211> 38
<212> DNA
<213> 人工序列()
<400> 12
ctgcaaccgg tgtacattct gaggtgcagc tgttggag 38
<210> 13
<211> 38
<212> DNA
<213> 人工序列()
<400> 13
ctgcaaccgg tgtacattcc caggtgcagc tgcaggag 38
<210> 14
<211> 40
<212> DNA
<213> 人工序列()
<400> 14
ctgcaaccgg tgtacattcc caggtgcagc tacagcagtg 40
<210> 15
<211> 38
<212> DNA
<213> 人工序列()
<400> 15
ctgcaaccgg tgtacattcc caggttcagc tggtgcag 38
<210> 16
<211> 38
<212> DNA
<213> 人工序列()
<400> 16
ctgcaaccgg tgtacattcc caggtccagc tggtacag 38
<210> 17
<211> 38
<212> DNA
<213> 人工序列()
<400> 17
ctgcaaccgg tgtacattct caggtgcagc tggtggag 38
<210> 18
<211> 38
<212> DNA
<213> 人工序列()
<400> 18
ctgcaaccgg tgtacattct gaagtgcagc tggtggag 38
<210> 19
<211> 38
<212> DNA
<213> 人工序列()
<400> 19
ctgcaaccgg tgtacattcc cagctgcagc tgcaggag 38
<210> 20
<211> 38
<212> DNA
<213> 人工序列()
<400> 20
ctgcaaccgg tgtacattcc caggtacagc tgcagcag 38
<210> 21
<211> 32
<212> DNA
<213> 人工序列()
<400> 21
tgcgaagtcg acgctgagga gacggtgacc ag 32
<210> 22
<211> 34
<212> DNA
<213> 人工序列()
<400> 22
tgcgaagtcg acgctgaaga gacggtgacc attg 34
<210> 23
<211> 33
<212> DNA
<213> 人工序列()
<400> 23
tgcgaagtcg acgctgagga gacggtgacc gtg 33
<210> 24
<211> 40
<212> DNA
<213> 人工序列()
<400> 24
ctgcaaccgg tgtacattct gacatccaga tgacccagtc 40
<210> 25
<211> 46
<212> DNA
<213> 人工序列()
<400> 25
ttgtgctgca accggtgtac attcagacat ccagttgacc cagtct 46
<210> 26
<211> 40
<212> DNA
<213> 人工序列()
<400> 26
ctgcaaccgg tgtacattgt gccatccgga tgacccagtc 40
<210> 27
<211> 40
<212> DNA
<213> 人工序列()
<400> 27
ctgcaaccgg tgtacatggg gatattgtga tgacccagac 40
<210> 28
<211> 40
<212> DNA
<213> 人工序列()
<400> 28
ctgcaaccgg tgtacatggg gatattgtga tgactcagtc 40
<210> 29
<211> 40
<212> DNA
<213> 人工序列()
<400> 29
ctgcaaccgg tgtacatggg gatgttgtga tgactcagtc 40
<210> 30
<211> 45
<212> DNA
<213> 人工序列()
<400> 30
ttgtgctgca accggtgtac attcagaaat tgtgttgaca cagtc 45
<210> 31
<211> 40
<212> DNA
<213> 人工序列()
<400> 31
ctgcaaccgg tgtacattca gaaatagtga tgacgcagtc 40
<210> 32
<211> 46
<212> DNA
<213> 人工序列()
<400> 32
ttgtgctgca accggtgtac attcagaaat tgtgttgacg cagtct 46
<210> 33
<211> 40
<212> DNA
<213> 人工序列()
<400> 33
ctgcaaccgg tgtacattcg gacatcgtga tgacccagtc 40
<210> 34
<211> 30
<212> DNA
<213> 人工序列()
<400> 34
gccaccgtac gtttgatytc caccttggtc 30
<210> 35
<211> 30
<212> DNA
<213> 人工序列()
<400> 35
gccaccgtac gtttgatctc cagcttggtc 30
<210> 36
<211> 30
<212> DNA
<213> 人工序列()
<400> 36
gccaccgtac gtttgatatc cactttggtc 30
<210> 37
<211> 30
<212> DNA
<213> 人工序列()
<400> 37
gccaccgtac gtttaatctc cagtcgtgtc 30
Claims (16)
1.抗H7N9全人源单克隆抗体8D11或来源于该单克隆抗体的能够特异性结合H7N9的生物活性片段，其中，所述抗体的重轻链CDR1、CDR2及CDR3区的氨基酸序列分别如下所示：
重链CDR1:GYIFFTSYD；
重链CDR2:MNPDSGDT；
重链CDR3:ATGNADCSGGSCYNWFDP；
轻链CDR1:RLRSYTY；
轻链CDR2:GKN；
轻链CDR3:NSRTSGYHLV。
2.根据权利要求1所述的抗H7N9全人源单克隆抗体8D11或来源于该单克隆抗体的能够特异性结合H7N9的生物活性片段，其中，所述抗体的重链可变区氨基酸序列如SEQ ID NO:2所示；和/或
所述抗体的轻链可变区氨基酸序列如SEQ ID NO:4所示。
3.根据权利要求2所述的抗H7N9全人源单克隆抗体8D11或来源于该单克隆抗体的能够特异性结合H7N9的生物活性片段，其中，所述抗体的重链氨基酸序列如SEQ ID NO:6所示；和/或
所述抗体的轻链氨基酸序列如SEQ ID NO:8所示。
4.编码权利要求1或2所述的抗H7N9全人源单克隆抗体8D11或来源于该单克隆抗体的能够特异性结合H7N9的生物活性片段的基因。
5.根据权利要求4所述的基因，其中，所述基因包含编码具有SEQ ID NO:2所示的氨基酸的核苷酸序列；和/或
所述基因包含编码具有SEQ ID NO:4所示的氨基酸的核苷酸序列。
6.根据权利要求5所述的基因，其中，编码具有SEQ ID NO:2所示的氨基酸的核苷酸序列如SEQ ID NO:1所示；编码具有SEQ ID NO:4所示的氨基酸的核苷酸序列如SEQ ID NO:3所示。
7.根据权利要求4所述的基因，其中，所述基因包含编码具有SEQ ID NO:6所示的氨基酸的核苷酸序列；和/或
所述基因包含编码具有SEQ ID NO:8所示的氨基酸的核苷酸序列。
8.根据权利要求7所述的基因，其中，编码具有SEQ ID NO:6所示的氨基酸的核苷酸序列如SEQ ID NO:5所示；编码具有SEQ ID NO:8所示的氨基酸的核苷酸序列如SEQ ID NO:7所示。
9.一种载体，其包含权利要求4-8任一项所述的基因。
10.一种细胞，其含有权利要求4-8任一项所述的基因、或含有权利要求9所述的载体。
11.一种产生权利要求1-3任一项所述抗H7N9全人源单克隆抗体8D11或来源于该单克隆抗体的能够特异性结合H7N9的生物活性片段的方法，该方法包括：培养含编码抗H7N9全人源单克隆抗体8D11的重轻链的权利要求4-8任一项所述的基因或权利要求9所述的载体的基因工程细胞，或直接培养权利要求10所述的细胞；收集，纯化得所述抗H7N9全人源单克隆抗体8D11。
12.一种药物组合物，其包含权利要求1-3任一项所述的抗H7N9全人源单克隆抗体8D11或来源于该单克隆抗体的能够特异性结合H7N9的生物活性片段。
13.权利要求1-3任一项所述的抗H7N9全人源单克隆抗体8D11或来源于该单克隆抗体的能够特异性结合H7N9的生物活性片段、或权利要求12所述的药物组合物在制备用于治疗由H7N9病毒引起的疾病的药物中的应用。
14.一种检测H7N9病毒水平的试剂盒，其含有权利要求1-3任一项所述的抗H7N9全人源单克隆抗体8D11或来源于该单克隆抗体的能够特异性结合H7N9的生物活性片段。
15.根据权利要求14所述的检测H7N9病毒水平的试剂盒，所述的试剂盒还含有：第二抗体和用于检测的酶或荧光或放射标记物，以及缓冲液。
16.根据权利要求15所述的检测H7N9病毒水平的试剂盒，所述第二抗体为抗权利要求1-3任一项所述单克隆抗体8D11的抗抗体。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910035567.5A CN111434683B (zh) | 2019-01-15 | 2019-01-15 | 抗h7n9全人源单克隆抗体8d11及其制备方法与应用 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910035567.5A CN111434683B (zh) | 2019-01-15 | 2019-01-15 | 抗h7n9全人源单克隆抗体8d11及其制备方法与应用 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN111434683A CN111434683A (zh) | 2020-07-21 |
| CN111434683B true CN111434683B (zh) | 2022-03-25 |
Family
ID=71580811
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201910035567.5A Active CN111434683B (zh) | 2019-01-15 | 2019-01-15 | 抗h7n9全人源单克隆抗体8d11及其制备方法与应用 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN111434683B (zh) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112079918B (zh) * | 2020-09-01 | 2021-05-18 | 武汉珈创生物技术股份有限公司 | 一种h7n9病毒特异性识别抗体p51c05及检测试剂盒 |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107098968A (zh) * | 2017-04-10 | 2017-08-29 | 江苏省疾病预防控制中心 | 单克隆抗体mAb910及其应用 |
| CN107353340A (zh) * | 2016-05-10 | 2017-11-17 | 深圳先进技术研究院 | 抗h7n9全人源单克隆抗体2l11及其制法与应用 |
| WO2018086599A1 (zh) * | 2016-11-11 | 2018-05-17 | 深圳先进技术研究院 | 抗h7n9全人源单克隆抗体5j13及其制法与应用 |
-
2019
- 2019-01-15 CN CN201910035567.5A patent/CN111434683B/zh active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107353340A (zh) * | 2016-05-10 | 2017-11-17 | 深圳先进技术研究院 | 抗h7n9全人源单克隆抗体2l11及其制法与应用 |
| WO2018086599A1 (zh) * | 2016-11-11 | 2018-05-17 | 深圳先进技术研究院 | 抗h7n9全人源单克隆抗体5j13及其制法与应用 |
| CN107098968A (zh) * | 2017-04-10 | 2017-08-29 | 江苏省疾病预防控制中心 | 单克隆抗体mAb910及其应用 |
Non-Patent Citations (2)
| Title |
|---|
| A broadly neutralizing human monoclonal antibody is effective against H7N9;Kannan Tharakaraman;《Proc Natl Acad Sci U S A.》;20150930;第112卷(第35期);第10890-10895页 * |
| 人源抗H7N9 血凝素中和抗体IgG 的制备及鉴定;陈雅;《南京医科大学学报（自然科学版）》;20160731;第36卷(第7期);第874-879页 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN111434683A (zh) | 2020-07-21 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN106519027B (zh) | 抗h7n9全人源单克隆抗体5j13及其制法与应用 | |
| WO2021244089A1 (zh) | 新型冠状病毒（sars-cov-2）刺突蛋白结合分子及其应用 | |
| CN111875700B (zh) | 抗sars-cov-2病毒n蛋白的单链抗体及其用途 | |
| CN113264998B (zh) | 抗新冠病毒SARS-CoV-2表面S1蛋白的单链抗体及其应用 | |
| CN111825762A (zh) | 抗sars-cov-2病毒s蛋白rbd结构域的纳米抗体及其用途 | |
| CN112409479B (zh) | 人源抗新冠病毒中和性抗体nCoV-121及其应用 | |
| CN101627115A (zh) | 抗人巨细胞病毒（hcmv）的抗体 | |
| US20230331824A1 (en) | Single-domain antibodies that bind sars-cov-2 | |
| CN111320687B (zh) | 抗h7n9全人源单克隆抗体4e18及其制备方法与应用 | |
| CN113150129B (zh) | 抗新冠病毒SARS-CoV-2表面S2蛋白的单链抗体及其应用 | |
| CN109206517A (zh) | St2抗原结合蛋白 | |
| KR20210158420A (ko) | 항-cd137 항체 | |
| KR20150030706A (ko) | 이중 수용체 길항 항원-결합 단백질 및 그것의 사용 | |
| KR20120113175A (ko) | Ｄｌｋ１ 특이적 인간 항체 및 이를 포함하는 약학적 조성물 | |
| CN111320685B (zh) | 抗h7n9全人源单克隆抗体3f12及其制备方法与应用 | |
| CN114031688B (zh) | 一种人源化抗体及其应用 | |
| CN111051343B (zh) | Il-6r抗体、其抗原结合片段及医药用途 | |
| CN104592390B (zh) | 一类双特异重组抗HBsAg抗体、其制备方法及用途 | |
| CN111434683B (zh) | 抗h7n9全人源单克隆抗体8d11及其制备方法与应用 | |
| CN114456261B (zh) | 抗sars-cov-2病毒s蛋白rbd结构域的纳米抗体及其用途 | |
| CN108484772A (zh) | 抗her2抗原的人源化抗体h5l5及其应用 | |
| CN111875704B (zh) | 一种egfr抗体及其应用 | |
| KR20230121120A (ko) | 인자 xi 및/또는 인자 xia 항체에 대한 항-약물 항체의검출 방법 | |
| CN112794906B (zh) | 抗4-1bb的单链抗体及其应用 | |
| CN113493513B (zh) | 抗人il-33中和性自身抗体及其制备方法和应用 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |