CN114573690A - 抗sar-cov-2全人源单克隆抗体及其制法与应用 - Google Patents
抗sar-cov-2全人源单克隆抗体及其制法与应用 Download PDFInfo
- Publication number
- CN114573690A CN114573690A CN202011390806.8A CN202011390806A CN114573690A CN 114573690 A CN114573690 A CN 114573690A CN 202011390806 A CN202011390806 A CN 202011390806A CN 114573690 A CN114573690 A CN 114573690A
- Authority
- CN
- China
- Prior art keywords
- seq
- antibody
- variable region
- gly
- chain variable
- 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.)
- Granted
Links
- 238000002360 preparation method Methods 0.000 title description 7
- 239000012634 fragment Substances 0.000 claims abstract description 43
- 239000000427 antigen Substances 0.000 claims abstract description 37
- 102000036639 antigens Human genes 0.000 claims abstract description 36
- 108091007433 antigens Proteins 0.000 claims abstract description 36
- 108010047041 Complementarity Determining Regions Proteins 0.000 claims abstract description 7
- 239000002773 nucleotide Substances 0.000 claims description 30
- 125000003729 nucleotide group Chemical group 0.000 claims description 30
- 239000003814 drug Substances 0.000 claims description 19
- 238000002965 ELISA Methods 0.000 claims description 8
- 239000008194 pharmaceutical composition Substances 0.000 claims description 8
- 239000013598 vector Substances 0.000 claims description 8
- 241000711573 Coronaviridae Species 0.000 claims description 7
- 239000003153 chemical reaction reagent Substances 0.000 claims description 7
- 238000001514 detection method Methods 0.000 claims description 7
- 238000004519 manufacturing process Methods 0.000 claims description 6
- 208000024891 symptom Diseases 0.000 claims description 6
- 208000015181 infectious disease Diseases 0.000 claims description 5
- 206010035664 Pneumonia Diseases 0.000 claims description 4
- 206010040070 Septic Shock Diseases 0.000 claims description 4
- 230000036303 septic shock Effects 0.000 claims description 4
- 230000002055 immunohistochemical effect Effects 0.000 claims description 3
- 208000010444 Acidosis Diseases 0.000 claims description 2
- 206010001052 Acute respiratory distress syndrome Diseases 0.000 claims description 2
- 206010002383 Angina Pectoris Diseases 0.000 claims description 2
- 206010011224 Cough Diseases 0.000 claims description 2
- 206010012735 Diarrhoea Diseases 0.000 claims description 2
- 208000000059 Dyspnea Diseases 0.000 claims description 2
- 206010013975 Dyspnoeas Diseases 0.000 claims description 2
- 206010021143 Hypoxia Diseases 0.000 claims description 2
- 206010027417 Metabolic acidosis Diseases 0.000 claims description 2
- 206010053159 Organ failure Diseases 0.000 claims description 2
- 206010037660 Pyrexia Diseases 0.000 claims description 2
- 208000013616 Respiratory Distress Syndrome Diseases 0.000 claims description 2
- 206010039101 Rhinorrhoea Diseases 0.000 claims description 2
- 201000000028 adult respiratory distress syndrome Diseases 0.000 claims description 2
- 238000003556 assay Methods 0.000 claims description 2
- 230000015271 coagulation Effects 0.000 claims description 2
- 238000005345 coagulation Methods 0.000 claims description 2
- 230000004064 dysfunction Effects 0.000 claims description 2
- 238000000684 flow cytometry Methods 0.000 claims description 2
- 208000018875 hypoxemia Diseases 0.000 claims description 2
- 238000003119 immunoblot Methods 0.000 claims description 2
- 208000010753 nasal discharge Diseases 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- 206010028748 Nasal obstruction Diseases 0.000 claims 1
- 208000027418 Wounds and injury Diseases 0.000 claims 1
- 230000006378 damage Effects 0.000 claims 1
- 208000014674 injury Diseases 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 7
- 125000003275 alpha amino acid group Chemical group 0.000 description 31
- 210000004027 cell Anatomy 0.000 description 30
- 241000700605 Viruses Species 0.000 description 25
- 108090000623 proteins and genes Proteins 0.000 description 19
- XKUKSGPZAADMRA-UHFFFAOYSA-N glycyl-glycyl-glycine Natural products NCC(=O)NCC(=O)NCC(O)=O XKUKSGPZAADMRA-UHFFFAOYSA-N 0.000 description 17
- 102100031673 Corneodesmosin Human genes 0.000 description 14
- 101710139375 Corneodesmosin Proteins 0.000 description 12
- 238000000034 method Methods 0.000 description 11
- 150000001413 amino acids Chemical class 0.000 description 10
- 229940079593 drug Drugs 0.000 description 9
- VPZXBVLAVMBEQI-UHFFFAOYSA-N glycyl-DL-alpha-alanine Natural products OC(=O)C(C)NC(=O)CN VPZXBVLAVMBEQI-UHFFFAOYSA-N 0.000 description 9
- ALNKNYKSZPSLBD-ZDLURKLDSA-N Cys-Thr-Gly Chemical compound [H]N[C@@H](CS)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(O)=O ALNKNYKSZPSLBD-ZDLURKLDSA-N 0.000 description 8
- 108010004073 cysteinylcysteine Proteins 0.000 description 8
- 230000006870 function Effects 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- 108020004414 DNA Proteins 0.000 description 7
- 108010086434 alanyl-seryl-glycine Proteins 0.000 description 7
- 108010047495 alanylglycine Proteins 0.000 description 7
- 238000005516 engineering process Methods 0.000 description 7
- 238000002474 experimental method Methods 0.000 description 7
- 229940125645 monoclonal antibody drug Drugs 0.000 description 7
- WNZOCXUOGVYYBJ-CDMKHQONSA-N Gly-Phe-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CC1=CC=CC=C1)NC(=O)CN)O WNZOCXUOGVYYBJ-CDMKHQONSA-N 0.000 description 6
- 108010076324 alanyl-glycyl-glycine Proteins 0.000 description 6
- 210000003719 b-lymphocyte Anatomy 0.000 description 6
- 108010067216 glycyl-glycyl-glycine Proteins 0.000 description 6
- TVYMKYUSZSVOAG-ZLUOBGJFSA-N Cys-Ala-Ala Chemical compound [H]N[C@@H](CS)C(=O)N[C@@H](C)C(=O)N[C@@H](C)C(O)=O TVYMKYUSZSVOAG-ZLUOBGJFSA-N 0.000 description 5
- AEJSNWMRPXAKCW-WHFBIAKZSA-N Cys-Ala-Gly Chemical compound SC[C@H](N)C(=O)N[C@@H](C)C(=O)NCC(O)=O AEJSNWMRPXAKCW-WHFBIAKZSA-N 0.000 description 5
- 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 5
- 241000880493 Leptailurus serval Species 0.000 description 5
- 239000002299 complementary DNA Substances 0.000 description 5
- 210000001806 memory b lymphocyte Anatomy 0.000 description 5
- 210000003819 peripheral blood mononuclear cell Anatomy 0.000 description 5
- 102000005962 receptors Human genes 0.000 description 5
- 108020003175 receptors Proteins 0.000 description 5
- 239000006228 supernatant Substances 0.000 description 5
- YBJHBAHKTGYVGT-ZKWXMUAHSA-N (+)-Biotin Chemical compound N1C(=O)N[C@@H]2[C@H](CCCCC(=O)O)SC[C@@H]21 YBJHBAHKTGYVGT-ZKWXMUAHSA-N 0.000 description 4
- WNHNMKOFKCHKKD-BFHQHQDPSA-N Ala-Thr-Gly Chemical compound [H]N[C@@H](C)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(O)=O WNHNMKOFKCHKKD-BFHQHQDPSA-N 0.000 description 4
- MKJBPDLENBUHQU-CIUDSAMLSA-N Asn-Ser-Leu Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(O)=O MKJBPDLENBUHQU-CIUDSAMLSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- NRVQLLDIJJEIIZ-VZFHVOOUSA-N Cys-Thr-Ala Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](C)C(=O)O)NC(=O)[C@H](CS)N)O NRVQLLDIJJEIIZ-VZFHVOOUSA-N 0.000 description 4
- FQCILXROGNOZON-YUMQZZPRSA-N Gln-Pro-Gly Chemical compound NC(=O)CC[C@H](N)C(=O)N1CCC[C@H]1C(=O)NCC(O)=O FQCILXROGNOZON-YUMQZZPRSA-N 0.000 description 4
- IDOGEHIWMJMAHT-BYPYZUCNSA-N Gly-Gly-Cys Chemical compound NCC(=O)NCC(=O)N[C@@H](CS)C(O)=O IDOGEHIWMJMAHT-BYPYZUCNSA-N 0.000 description 4
- 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 4
- 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 4
- KIZIOFNVSOSKJI-CIUDSAMLSA-N Leu-Ser-Cys Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CS)C(=O)O)N KIZIOFNVSOSKJI-CIUDSAMLSA-N 0.000 description 4
- GQZMPWBZQALKJO-UWVGGRQHSA-N Lys-Gly-Arg Chemical compound [H]N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(O)=O GQZMPWBZQALKJO-UWVGGRQHSA-N 0.000 description 4
- 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 4
- 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 4
- QYSFWUIXDFJUDW-DCAQKATOSA-N Ser-Leu-Arg Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O QYSFWUIXDFJUDW-DCAQKATOSA-N 0.000 description 4
- MBLJBGZWLHTJBH-SZMVWBNQSA-N Trp-Val-Arg Chemical compound C1=CC=C2C(C[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCN=C(N)N)C(O)=O)=CNC2=C1 MBLJBGZWLHTJBH-SZMVWBNQSA-N 0.000 description 4
- 108010069020 alanyl-prolyl-glycine Proteins 0.000 description 4
- 108010008355 arginyl-glutamine Proteins 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- UQLDLKMNUJERMK-UHFFFAOYSA-L di(octadecanoyloxy)lead Chemical compound [Pb+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O UQLDLKMNUJERMK-UHFFFAOYSA-L 0.000 description 4
- 108010089804 glycyl-threonine Proteins 0.000 description 4
- 241000894007 species Species 0.000 description 4
- 108010061238 threonyl-glycine Proteins 0.000 description 4
- YYSWCHMLFJLLBJ-ZLUOBGJFSA-N Ala-Ala-Ser Chemical compound C[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](CO)C(O)=O YYSWCHMLFJLLBJ-ZLUOBGJFSA-N 0.000 description 3
- VKKYFICVTYKFIO-CIUDSAMLSA-N Arg-Ala-Glu Chemical compound OC(=O)CC[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CCCN=C(N)N VKKYFICVTYKFIO-CIUDSAMLSA-N 0.000 description 3
- MNQMTYSEKZHIDF-GCJQMDKQSA-N Asp-Thr-Ala Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C)C(O)=O MNQMTYSEKZHIDF-GCJQMDKQSA-N 0.000 description 3
- 208000025721 COVID-19 Diseases 0.000 description 3
- CVOZXIPULQQFNY-ZLUOBGJFSA-N Cys-Ala-Cys Chemical compound C[C@H](NC(=O)[C@@H](N)CS)C(=O)N[C@@H](CS)C(O)=O CVOZXIPULQQFNY-ZLUOBGJFSA-N 0.000 description 3
- FTTZLFIEUQHLHH-BWBBJGPYSA-N Cys-Thr-Cys Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CS)C(=O)O)NC(=O)[C@H](CS)N)O FTTZLFIEUQHLHH-BWBBJGPYSA-N 0.000 description 3
- 102000004190 Enzymes Human genes 0.000 description 3
- 108090000790 Enzymes Proteins 0.000 description 3
- 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 3
- CEXINUGNTZFNRY-BYPYZUCNSA-N Gly-Cys-Gly Chemical compound [NH3+]CC(=O)N[C@@H](CS)C(=O)NCC([O-])=O CEXINUGNTZFNRY-BYPYZUCNSA-N 0.000 description 3
- UQJNXZSSGQIPIQ-FBCQKBJTSA-N Gly-Gly-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)CNC(=O)CN UQJNXZSSGQIPIQ-FBCQKBJTSA-N 0.000 description 3
- 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 3
- 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 3
- JQFILXICXLDTRR-FBCQKBJTSA-N Gly-Thr-Gly Chemical compound NCC(=O)N[C@@H]([C@H](O)C)C(=O)NCC(O)=O JQFILXICXLDTRR-FBCQKBJTSA-N 0.000 description 3
- 108010001336 Horseradish Peroxidase Proteins 0.000 description 3
- PXKACEXYLPBMAD-JBDRJPRFSA-N Ile-Ser-Ser Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)O)N PXKACEXYLPBMAD-JBDRJPRFSA-N 0.000 description 3
- 241000713666 Lentivirus Species 0.000 description 3
- HXWALXSAVBLTPK-NUTKFTJISA-N Leu-Ala-Trp Chemical compound C[C@@H](C(=O)N[C@@H](CC1=CNC2=CC=CC=C21)C(=O)O)NC(=O)[C@H](CC(C)C)N HXWALXSAVBLTPK-NUTKFTJISA-N 0.000 description 3
- AXZGZMGRBDQTEY-SRVKXCTJSA-N Leu-Gln-Met Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCSC)C(O)=O AXZGZMGRBDQTEY-SRVKXCTJSA-N 0.000 description 3
- 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 3
- AIMGJYMCTAABEN-GVXVVHGQSA-N Leu-Val-Glu Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(O)=O)C(O)=O AIMGJYMCTAABEN-GVXVVHGQSA-N 0.000 description 3
- 108010079364 N-glycylalanine Proteins 0.000 description 3
- IAOZOFPONWDXNT-IXOXFDKPSA-N Phe-Ser-Thr Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(O)=O IAOZOFPONWDXNT-IXOXFDKPSA-N 0.000 description 3
- KLYYKKGCPOGDPE-OEAJRASXSA-N Phe-Thr-Leu Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(O)=O KLYYKKGCPOGDPE-OEAJRASXSA-N 0.000 description 3
- 229940096437 Protein S Drugs 0.000 description 3
- QEDMOZUJTGEIBF-FXQIFTODSA-N Ser-Arg-Asp Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(O)=O QEDMOZUJTGEIBF-FXQIFTODSA-N 0.000 description 3
- FMDHKPRACUXATF-ACZMJKKPSA-N Ser-Gln-Ser Chemical compound OC[C@H](N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CO)C(O)=O FMDHKPRACUXATF-ACZMJKKPSA-N 0.000 description 3
- 101710198474 Spike protein Proteins 0.000 description 3
- XPNSAQMEAVSQRD-FBCQKBJTSA-N Thr-Gly-Gly Chemical compound C[C@@H](O)[C@H](N)C(=O)NCC(=O)NCC(O)=O XPNSAQMEAVSQRD-FBCQKBJTSA-N 0.000 description 3
- 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 3
- AZSHAZJLOZQYAY-FXQIFTODSA-N Val-Ala-Ser Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](CO)C(O)=O AZSHAZJLOZQYAY-FXQIFTODSA-N 0.000 description 3
- 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 3
- 108010008685 alanyl-glutamyl-aspartic acid Proteins 0.000 description 3
- 108010040443 aspartyl-aspartic acid Proteins 0.000 description 3
- 238000012258 culturing Methods 0.000 description 3
- 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 3
- 239000007788 liquid Substances 0.000 description 3
- 108010070409 phenylalanyl-glycyl-glycine Proteins 0.000 description 3
- 108010020755 prolyl-glycyl-glycine Proteins 0.000 description 3
- 238000010839 reverse transcription Methods 0.000 description 3
- 230000003248 secreting effect Effects 0.000 description 3
- 239000012192 staining solution Substances 0.000 description 3
- 108010044292 tryptophyltyrosine Proteins 0.000 description 3
- 241000712461 unidentified influenza virus Species 0.000 description 3
- JBVSSSZFNTXJDX-YTLHQDLWSA-N Ala-Ala-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@H](C)N JBVSSSZFNTXJDX-YTLHQDLWSA-N 0.000 description 2
- JBGSZRYCXBPWGX-BQBZGAKWSA-N Ala-Arg-Gly Chemical compound OC(=O)CNC(=O)[C@@H](NC(=O)[C@@H](N)C)CCCN=C(N)N JBGSZRYCXBPWGX-BQBZGAKWSA-N 0.000 description 2
- BUDNAJYVCUHLSV-ZLUOBGJFSA-N Ala-Asp-Ser Chemical compound C[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(O)=O BUDNAJYVCUHLSV-ZLUOBGJFSA-N 0.000 description 2
- RCQRKPUXJAGEEC-ZLUOBGJFSA-N Ala-Cys-Cys Chemical compound C[C@H](N)C(=O)N[C@@H](CS)C(=O)N[C@@H](CS)C(O)=O RCQRKPUXJAGEEC-ZLUOBGJFSA-N 0.000 description 2
- KRHRBKYBJXMYBB-WHFBIAKZSA-N Ala-Cys-Gly Chemical compound C[C@H](N)C(=O)N[C@@H](CS)C(=O)NCC(O)=O KRHRBKYBJXMYBB-WHFBIAKZSA-N 0.000 description 2
- ZVFVBBGVOILKPO-WHFBIAKZSA-N Ala-Gly-Ala Chemical compound C[C@H](N)C(=O)NCC(=O)N[C@@H](C)C(O)=O ZVFVBBGVOILKPO-WHFBIAKZSA-N 0.000 description 2
- LJFNNUBZSZCZFN-WHFBIAKZSA-N Ala-Gly-Cys Chemical compound N[C@@H](C)C(=O)NCC(=O)N[C@@H](CS)C(=O)O LJFNNUBZSZCZFN-WHFBIAKZSA-N 0.000 description 2
- VGPWRRFOPXVGOH-BYPYZUCNSA-N Ala-Gly-Gly Chemical compound C[C@H](N)C(=O)NCC(=O)NCC(O)=O VGPWRRFOPXVGOH-BYPYZUCNSA-N 0.000 description 2
- OBVSBEYOMDWLRJ-BFHQHQDPSA-N Ala-Gly-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)CNC(=O)[C@H](C)N OBVSBEYOMDWLRJ-BFHQHQDPSA-N 0.000 description 2
- BDQNLQSWRAPHGU-DLOVCJGASA-N Ala-Phe-Cys Chemical compound C[C@@H](C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CS)C(=O)O)N BDQNLQSWRAPHGU-DLOVCJGASA-N 0.000 description 2
- KUFVXLQLDHJVOG-SHGPDSBTSA-N Ala-Thr-Thr Chemical compound C[C@H]([C@@H](C(=O)N[C@@H]([C@@H](C)O)C(=O)O)NC(=O)[C@H](C)N)O KUFVXLQLDHJVOG-SHGPDSBTSA-N 0.000 description 2
- 102000002260 Alkaline Phosphatase Human genes 0.000 description 2
- 108020004774 Alkaline Phosphatase Proteins 0.000 description 2
- 102100035765 Angiotensin-converting enzyme 2 Human genes 0.000 description 2
- 108090000975 Angiotensin-converting enzyme 2 Proteins 0.000 description 2
- MFAMTAVAFBPXDC-LPEHRKFASA-N Arg-Asp-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CC(=O)O)NC(=O)[C@H](CCCN=C(N)N)N)C(=O)O MFAMTAVAFBPXDC-LPEHRKFASA-N 0.000 description 2
- OGSQONVYSTZIJB-WDSOQIARSA-N Arg-Leu-Trp Chemical compound CC(C)C[C@H](NC(=O)[C@@H](N)CCCN=C(N)N)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(O)=O OGSQONVYSTZIJB-WDSOQIARSA-N 0.000 description 2
- UGXYFDQFLVCDFC-CIUDSAMLSA-N Asn-Ser-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC(N)=O UGXYFDQFLVCDFC-CIUDSAMLSA-N 0.000 description 2
- JBDLMLZNDRLDIX-HJGDQZAQSA-N Asn-Thr-Leu Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(O)=O JBDLMLZNDRLDIX-HJGDQZAQSA-N 0.000 description 2
- FHCRKXCTKSHNOE-QEJZJMRPSA-N Asn-Trp-Glu Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)O)NC(=O)[C@H](CC(=O)N)N FHCRKXCTKSHNOE-QEJZJMRPSA-N 0.000 description 2
- 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 2
- CTWCFPWFIGRAEP-CIUDSAMLSA-N Asp-Lys-Asp Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(O)=O)C(O)=O CTWCFPWFIGRAEP-CIUDSAMLSA-N 0.000 description 2
- 108010029697 CD40 Ligand Proteins 0.000 description 2
- 102100032937 CD40 ligand Human genes 0.000 description 2
- 241001678559 COVID-19 virus Species 0.000 description 2
- 108010001857 Cell Surface Receptors Proteins 0.000 description 2
- SZQCDCKIGWQAQN-FXQIFTODSA-N Cys-Arg-Ala Chemical compound [H]N[C@@H](CS)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(O)=O SZQCDCKIGWQAQN-FXQIFTODSA-N 0.000 description 2
- HYKFOHGZGLOCAY-ZLUOBGJFSA-N Cys-Cys-Ala Chemical compound [H]N[C@@H](CS)C(=O)N[C@@H](CS)C(=O)N[C@@H](C)C(O)=O HYKFOHGZGLOCAY-ZLUOBGJFSA-N 0.000 description 2
- KOHBWQDSVCARMI-BWBBJGPYSA-N Cys-Cys-Thr Chemical compound [H]N[C@@H](CS)C(=O)N[C@@H](CS)C(=O)N[C@@H]([C@@H](C)O)C(O)=O KOHBWQDSVCARMI-BWBBJGPYSA-N 0.000 description 2
- CVLIHKBUPSFRQP-WHFBIAKZSA-N Cys-Gly-Ala Chemical compound [H]N[C@@H](CS)C(=O)NCC(=O)N[C@@H](C)C(O)=O CVLIHKBUPSFRQP-WHFBIAKZSA-N 0.000 description 2
- OXOQBEVULIBOSH-ZDLURKLDSA-N Cys-Gly-Thr Chemical compound [H]N[C@@H](CS)C(=O)NCC(=O)N[C@@H]([C@@H](C)O)C(O)=O OXOQBEVULIBOSH-ZDLURKLDSA-N 0.000 description 2
- JXFLPKSDLDEOQK-JHEQGTHGSA-N Gln-Gly-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)CNC(=O)[C@@H](N)CCC(N)=O JXFLPKSDLDEOQK-JHEQGTHGSA-N 0.000 description 2
- OTQSTOXRUBVWAP-NRPADANISA-N Gln-Ser-Val Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(O)=O OTQSTOXRUBVWAP-NRPADANISA-N 0.000 description 2
- AVZHGSCDKIQZPQ-CIUDSAMLSA-N Glu-Arg-Ala Chemical compound C[C@H](NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@@H](N)CCC(O)=O)C(O)=O AVZHGSCDKIQZPQ-CIUDSAMLSA-N 0.000 description 2
- PYTZFYUXZZHOAD-WHFBIAKZSA-N Gly-Ala-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)CN PYTZFYUXZZHOAD-WHFBIAKZSA-N 0.000 description 2
- GVVKYKCOFMMTKZ-WHFBIAKZSA-N Gly-Cys-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@H](CS)NC(=O)CN GVVKYKCOFMMTKZ-WHFBIAKZSA-N 0.000 description 2
- NMROINAYXCACKF-WHFBIAKZSA-N Gly-Cys-Cys Chemical compound NCC(=O)N[C@@H](CS)C(=O)N[C@@H](CS)C(O)=O NMROINAYXCACKF-WHFBIAKZSA-N 0.000 description 2
- CCQOOWAONKGYKQ-BYPYZUCNSA-N Gly-Gly-Ala Chemical compound OC(=O)[C@H](C)NC(=O)CNC(=O)CN CCQOOWAONKGYKQ-BYPYZUCNSA-N 0.000 description 2
- UFPXDFOYHVEIPI-BYPYZUCNSA-N Gly-Gly-Asp Chemical compound NCC(=O)NCC(=O)N[C@H](C(O)=O)CC(O)=O UFPXDFOYHVEIPI-BYPYZUCNSA-N 0.000 description 2
- NVTPVQLIZCOJFK-FOHZUACHSA-N Gly-Thr-Asp Chemical compound [H]NCC(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(O)=O)C(O)=O NVTPVQLIZCOJFK-FOHZUACHSA-N 0.000 description 2
- ZKJZBRHRWKLVSJ-ZDLURKLDSA-N Gly-Thr-Cys Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CS)C(=O)O)NC(=O)CN)O ZKJZBRHRWKLVSJ-ZDLURKLDSA-N 0.000 description 2
- NXRNRBOKDBIVKQ-CXTHYWKRSA-N Ile-Tyr-Tyr Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC1=CC=C(C=C1)O)C(=O)N[C@@H](CC2=CC=C(C=C2)O)C(=O)O)N NXRNRBOKDBIVKQ-CXTHYWKRSA-N 0.000 description 2
- 108060003951 Immunoglobulin Proteins 0.000 description 2
- 108010021625 Immunoglobulin Fragments Proteins 0.000 description 2
- 102000008394 Immunoglobulin Fragments Human genes 0.000 description 2
- CQGSYZCULZMEDE-UHFFFAOYSA-N Leu-Gln-Pro Natural products CC(C)CC(N)C(=O)NC(CCC(N)=O)C(=O)N1CCCC1C(O)=O CQGSYZCULZMEDE-UHFFFAOYSA-N 0.000 description 2
- POZULHZYLPGXMR-ONGXEEELSA-N Leu-Gly-Val Chemical compound CC(C)C[C@H](N)C(=O)NCC(=O)N[C@@H](C(C)C)C(O)=O POZULHZYLPGXMR-ONGXEEELSA-N 0.000 description 2
- SIGZKCWZEBFNAK-QAETUUGQSA-N Leu-Ser-Ser-Tyr Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 SIGZKCWZEBFNAK-QAETUUGQSA-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
- UCRJTSIIAYHOHE-ULQDDVLXSA-N Leu-Tyr-Arg Chemical compound CC(C)C[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 UCRJTSIIAYHOHE-ULQDDVLXSA-N 0.000 description 2
- PXHCFKXNSBJSTQ-KKUMJFAQSA-N Lys-Asn-Tyr Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)N)NC(=O)[C@H](CCCCN)N)O PXHCFKXNSBJSTQ-KKUMJFAQSA-N 0.000 description 2
- GZGWILAQHOVXTD-DCAQKATOSA-N Lys-Met-Asp Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(O)=O GZGWILAQHOVXTD-DCAQKATOSA-N 0.000 description 2
- 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 2
- SBQDRNOLGSYHQA-YUMQZZPRSA-N Lys-Ser-Gly Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CO)C(=O)NCC(O)=O SBQDRNOLGSYHQA-YUMQZZPRSA-N 0.000 description 2
- 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 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
- YMIZSYUAZJSOFL-SRVKXCTJSA-N Phe-Ser-Asn Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(O)=O YMIZSYUAZJSOFL-SRVKXCTJSA-N 0.000 description 2
- FGWUALWGCZJQDJ-URLPEUOOSA-N Phe-Thr-Ile Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O FGWUALWGCZJQDJ-URLPEUOOSA-N 0.000 description 2
- JARJPEMLQAWNBR-GUBZILKMSA-N Pro-Asp-Arg Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O JARJPEMLQAWNBR-GUBZILKMSA-N 0.000 description 2
- RDFQNDHEHVSONI-ZLUOBGJFSA-N Ser-Asn-Ser Chemical compound OC[C@H](N)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CO)C(O)=O RDFQNDHEHVSONI-ZLUOBGJFSA-N 0.000 description 2
- 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 2
- OLKICIBQRVSQMA-SRVKXCTJSA-N Ser-Ser-Tyr Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O OLKICIBQRVSQMA-SRVKXCTJSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 101710137302 Surface antigen S Proteins 0.000 description 2
- CAJFZCICSVBOJK-SHGPDSBTSA-N Thr-Ala-Thr Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O CAJFZCICSVBOJK-SHGPDSBTSA-N 0.000 description 2
- DGOJNGCGEYOBKN-BWBBJGPYSA-N Thr-Cys-Cys Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CS)C(=O)O)N)O DGOJNGCGEYOBKN-BWBBJGPYSA-N 0.000 description 2
- UZJDBCHMIQXLOQ-HEIBUPTGSA-N Thr-Cys-Thr Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CS)C(=O)N[C@@H]([C@@H](C)O)C(=O)O)N)O UZJDBCHMIQXLOQ-HEIBUPTGSA-N 0.000 description 2
- SLUWOCTZVGMURC-BFHQHQDPSA-N Thr-Gly-Ala Chemical compound C[C@@H](O)[C@H](N)C(=O)NCC(=O)N[C@@H](C)C(O)=O SLUWOCTZVGMURC-BFHQHQDPSA-N 0.000 description 2
- 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 2
- BIBYEFRASCNLAA-CDMKHQONSA-N Thr-Phe-Gly Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@H](C(=O)NCC(O)=O)CC1=CC=CC=C1 BIBYEFRASCNLAA-CDMKHQONSA-N 0.000 description 2
- QOIKZODVIPOPDD-AVGNSLFASA-N Tyr-Cys-Gln Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCC(N)=O)C(O)=O QOIKZODVIPOPDD-AVGNSLFASA-N 0.000 description 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
- 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
- JAIZPWVHPQRYOU-ZJDVBMNYSA-N Val-Thr-Thr Chemical compound C[C@H]([C@@H](C(=O)N[C@@H]([C@@H](C)O)C(=O)O)NC(=O)[C@H](C(C)C)N)O JAIZPWVHPQRYOU-ZJDVBMNYSA-N 0.000 description 2
- 108010069205 aspartyl-phenylalanine Proteins 0.000 description 2
- 230000001588 bifunctional effect Effects 0.000 description 2
- 230000000975 bioactive effect Effects 0.000 description 2
- 229960002685 biotin Drugs 0.000 description 2
- 235000020958 biotin Nutrition 0.000 description 2
- 239000011616 biotin Substances 0.000 description 2
- 238000010367 cloning Methods 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 238000013461 design Methods 0.000 description 2
- 230000008014 freezing Effects 0.000 description 2
- 238000007710 freezing Methods 0.000 description 2
- 210000004602 germ cell Anatomy 0.000 description 2
- 108010084264 glycyl-glycyl-cysteine Proteins 0.000 description 2
- 108010001064 glycyl-glycyl-glycyl-glycine Proteins 0.000 description 2
- 108010010147 glycylglutamine Proteins 0.000 description 2
- 108010050848 glycylleucine Proteins 0.000 description 2
- 108010037850 glycylvaline Proteins 0.000 description 2
- 229940048921 humira Drugs 0.000 description 2
- 102000018358 immunoglobulin Human genes 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- 206010022000 influenza Diseases 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 239000002609 medium Substances 0.000 description 2
- 102000006240 membrane receptors Human genes 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 230000035772 mutation Effects 0.000 description 2
- 230000003472 neutralizing effect Effects 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 238000002823 phage display Methods 0.000 description 2
- 108090000765 processed proteins & peptides Proteins 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 238000001179 sorption measurement Methods 0.000 description 2
- 229940124597 therapeutic agent Drugs 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- 108010038745 tryptophylglycine Proteins 0.000 description 2
- 108010003137 tyrosyltyrosine Proteins 0.000 description 2
- 229960005486 vaccine Drugs 0.000 description 2
- WOJJIRYPFAZEPF-YFKPBYRVSA-N 2-[[(2s)-2-[[2-[(2-azaniumylacetyl)amino]acetyl]amino]propanoyl]amino]acetate Chemical compound OC(=O)CNC(=O)[C@H](C)NC(=O)CNC(=O)CN WOJJIRYPFAZEPF-YFKPBYRVSA-N 0.000 description 1
- QMOQBVOBWVNSNO-UHFFFAOYSA-N 2-[[2-[[2-[(2-azaniumylacetyl)amino]acetyl]amino]acetyl]amino]acetate Chemical compound NCC(=O)NCC(=O)NCC(=O)NCC(O)=O QMOQBVOBWVNSNO-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
- 206010069754 Acquired gene mutation Diseases 0.000 description 1
- 229920000936 Agarose Polymers 0.000 description 1
- SBGXWWCLHIOABR-UHFFFAOYSA-N Ala Ala Gly Ala Chemical compound CC(N)C(=O)NC(C)C(=O)NCC(=O)NC(C)C(O)=O SBGXWWCLHIOABR-UHFFFAOYSA-N 0.000 description 1
- UWQJHXKARZWDIJ-ZLUOBGJFSA-N Ala-Ala-Cys Chemical compound C[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](CS)C(O)=O UWQJHXKARZWDIJ-ZLUOBGJFSA-N 0.000 description 1
- RLMISHABBKUNFO-WHFBIAKZSA-N Ala-Ala-Gly Chemical compound C[C@H](N)C(=O)N[C@@H](C)C(=O)NCC(O)=O RLMISHABBKUNFO-WHFBIAKZSA-N 0.000 description 1
- FXKNPWNXPQZLES-ZLUOBGJFSA-N Ala-Asn-Ser Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CO)C(O)=O FXKNPWNXPQZLES-ZLUOBGJFSA-N 0.000 description 1
- XQJAFSDFQZPYCU-UWJYBYFXSA-N Ala-Asn-Tyr Chemical compound C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CC1=CC=C(C=C1)O)C(=O)O)N XQJAFSDFQZPYCU-UWJYBYFXSA-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
- LGFCAXJBAZESCF-ACZMJKKPSA-N Ala-Gln-Ala Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](C)C(O)=O LGFCAXJBAZESCF-ACZMJKKPSA-N 0.000 description 1
- VWEWCZSUWOEEFM-WDSKDSINSA-N Ala-Gly-Ala-Gly Chemical compound C[C@H](N)C(=O)NCC(=O)N[C@@H](C)C(=O)NCC(O)=O VWEWCZSUWOEEFM-WDSKDSINSA-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
- RAAWHFXHAACDFT-FXQIFTODSA-N Ala-Met-Asn Chemical compound CSCC[C@H](NC(=O)[C@H](C)N)C(=O)N[C@@H](CC(N)=O)C(O)=O RAAWHFXHAACDFT-FXQIFTODSA-N 0.000 description 1
- GFEDXKNBZMPEDM-KZVJFYERSA-N Ala-Met-Thr Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H]([C@@H](C)O)C(O)=O GFEDXKNBZMPEDM-KZVJFYERSA-N 0.000 description 1
- ADSGHMXEAZJJNF-DCAQKATOSA-N Ala-Pro-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@H](C)N ADSGHMXEAZJJNF-DCAQKATOSA-N 0.000 description 1
- BTRULDJUUVGRNE-DCAQKATOSA-N Ala-Pro-Lys Chemical compound C[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCCCN)C(O)=O BTRULDJUUVGRNE-DCAQKATOSA-N 0.000 description 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
- OEVCHROQUIVQFZ-YTLHQDLWSA-N Ala-Thr-Ala Chemical compound C[C@H](N)C(=O)N[C@@H]([C@H](O)C)C(=O)N[C@@H](C)C(O)=O OEVCHROQUIVQFZ-YTLHQDLWSA-N 0.000 description 1
- YMIYZAOBQDRCPP-UHFFFAOYSA-N Ala-Thr-Cys-Cys Chemical compound CC(N)C(=O)NC(C(O)C)C(=O)NC(CS)C(=O)NC(CS)C(O)=O YMIYZAOBQDRCPP-UHFFFAOYSA-N 0.000 description 1
- CREYEAPXISDKSB-FQPOAREZSA-N Ala-Thr-Tyr Chemical compound [H]N[C@@H](C)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O CREYEAPXISDKSB-FQPOAREZSA-N 0.000 description 1
- 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 1
- 102100030988 Angiotensin-converting enzyme Human genes 0.000 description 1
- HKRXJBBCQBAGIM-FXQIFTODSA-N Arg-Asp-Ser Chemical compound C(C[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](CO)C(=O)O)N)CN=C(N)N HKRXJBBCQBAGIM-FXQIFTODSA-N 0.000 description 1
- AOHKLEBWKMKITA-IHRRRGAJSA-N Arg-Phe-Ser Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)N[C@@H](CO)C(=O)O)NC(=O)[C@H](CCCN=C(N)N)N AOHKLEBWKMKITA-IHRRRGAJSA-N 0.000 description 1
- 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
- JJGRJMKUOYXZRA-LPEHRKFASA-N Asn-Arg-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC(=O)N)N)C(=O)O JJGRJMKUOYXZRA-LPEHRKFASA-N 0.000 description 1
- GQRDIVQPSMPQME-ZPFDUUQYSA-N Asn-Ile-Leu Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(C)C)C(O)=O GQRDIVQPSMPQME-ZPFDUUQYSA-N 0.000 description 1
- OOXUBGLNDRGOKT-FXQIFTODSA-N Asn-Ser-Arg Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O OOXUBGLNDRGOKT-FXQIFTODSA-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
- XYBJLTKSGFBLCS-QXEWZRGKSA-N Asp-Arg-Val Chemical compound NC(N)=NCCC[C@@H](C(=O)N[C@@H](C(C)C)C(O)=O)NC(=O)[C@@H](N)CC(O)=O XYBJLTKSGFBLCS-QXEWZRGKSA-N 0.000 description 1
- ICTXFVKYAGQURS-UBHSHLNASA-N Asp-Asn-Trp Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC1=CNC2=C1C=CC=C2)C(O)=O ICTXFVKYAGQURS-UBHSHLNASA-N 0.000 description 1
- SVFOIXMRMLROHO-SRVKXCTJSA-N Asp-Asp-Phe Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 SVFOIXMRMLROHO-SRVKXCTJSA-N 0.000 description 1
- VAWNQIGQPUOPQW-ACZMJKKPSA-N Asp-Glu-Ala Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(O)=O VAWNQIGQPUOPQW-ACZMJKKPSA-N 0.000 description 1
- QNFRBNZGVVKBNJ-PEFMBERDSA-N Asp-Ile-Gln Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)O)NC(=O)[C@H](CC(=O)O)N QNFRBNZGVVKBNJ-PEFMBERDSA-N 0.000 description 1
- 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 1
- 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 1
- VNXQRBXEQXLERQ-CIUDSAMLSA-N Asp-Ser-Lys Chemical compound C(CCN)C[C@@H](C(=O)O)NC(=O)[C@H](CO)NC(=O)[C@H](CC(=O)O)N VNXQRBXEQXLERQ-CIUDSAMLSA-N 0.000 description 1
- MGSVBZIBCCKGCY-ZLUOBGJFSA-N Asp-Ser-Ser Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(O)=O MGSVBZIBCCKGCY-ZLUOBGJFSA-N 0.000 description 1
- JSHWXQIZOCVWIA-ZKWXMUAHSA-N Asp-Ser-Val Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(O)=O JSHWXQIZOCVWIA-ZKWXMUAHSA-N 0.000 description 1
- GCACQYDBDHRVGE-LKXGYXEUSA-N Asp-Thr-Ser Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H]([C@H](O)C)NC(=O)[C@@H](N)CC(O)=O GCACQYDBDHRVGE-LKXGYXEUSA-N 0.000 description 1
- HTSSXFASOUSJQG-IHPCNDPISA-N Asp-Tyr-Trp Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC1=CNC2=C1C=CC=C2)C(O)=O HTSSXFASOUSJQG-IHPCNDPISA-N 0.000 description 1
- ALMIMUZAWTUNIO-BZSNNMDCSA-N Asp-Tyr-Tyr 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=C(O)C=C1)C(O)=O ALMIMUZAWTUNIO-BZSNNMDCSA-N 0.000 description 1
- 102100024222 B-lymphocyte antigen CD19 Human genes 0.000 description 1
- 208000035473 Communicable disease Diseases 0.000 description 1
- CPTUXCUWQIBZIF-ZLUOBGJFSA-N Cys-Asn-Ser Chemical compound SC[C@H](N)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CO)C(O)=O CPTUXCUWQIBZIF-ZLUOBGJFSA-N 0.000 description 1
- ZJBWJHQDOIMVLM-WHFBIAKZSA-N Cys-Cys-Gly Chemical compound SC[C@H](N)C(=O)N[C@@H](CS)C(=O)NCC(O)=O ZJBWJHQDOIMVLM-WHFBIAKZSA-N 0.000 description 1
- DZLQXIFVQFTFJY-BYPYZUCNSA-N Cys-Gly-Gly Chemical compound SC[C@H](N)C(=O)NCC(=O)NCC(O)=O DZLQXIFVQFTFJY-BYPYZUCNSA-N 0.000 description 1
- NIXHTNJAGGFBAW-CIUDSAMLSA-N Cys-Lys-Ser Chemical compound C(CCN)C[C@@H](C(=O)N[C@@H](CO)C(=O)O)NC(=O)[C@H](CS)N NIXHTNJAGGFBAW-CIUDSAMLSA-N 0.000 description 1
- NAPULYCVEVVFRB-HEIBUPTGSA-N Cys-Thr-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@@H](N)CS NAPULYCVEVVFRB-HEIBUPTGSA-N 0.000 description 1
- BWGNESOTFCXPMA-UHFFFAOYSA-N Dihydrogen disulfide Chemical compound SS BWGNESOTFCXPMA-UHFFFAOYSA-N 0.000 description 1
- JESJDAAGXULQOP-CIUDSAMLSA-N Gln-Arg-Ser Chemical compound C(C[C@@H](C(=O)N[C@@H](CO)C(=O)O)NC(=O)[C@H](CCC(=O)N)N)CN=C(N)N JESJDAAGXULQOP-CIUDSAMLSA-N 0.000 description 1
- LOJYQMFIIJVETK-WDSKDSINSA-N Gln-Gln Chemical compound NC(=O)CC[C@H](N)C(=O)N[C@@H](CCC(N)=O)C(O)=O LOJYQMFIIJVETK-WDSKDSINSA-N 0.000 description 1
- NKCZYEDZTKOFBG-GUBZILKMSA-N Gln-Gln-Arg Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O NKCZYEDZTKOFBG-GUBZILKMSA-N 0.000 description 1
- MADFVRSKEIEZHZ-DCAQKATOSA-N Gln-Gln-Lys Chemical compound C(CCN)C[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)N)NC(=O)[C@H](CCC(=O)N)N MADFVRSKEIEZHZ-DCAQKATOSA-N 0.000 description 1
- SXFPZRRVWSUYII-KBIXCLLPSA-N Gln-Ser-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(=O)N)N SXFPZRRVWSUYII-KBIXCLLPSA-N 0.000 description 1
- WPJDPEOQUIXXOY-AVGNSLFASA-N Gln-Tyr-Asn Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)O)NC(=O)[C@H](CCC(=O)N)N)O WPJDPEOQUIXXOY-AVGNSLFASA-N 0.000 description 1
- 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 1
- MXOODARRORARSU-ACZMJKKPSA-N Glu-Ala-Ser Chemical compound C[C@@H](C(=O)N[C@@H](CO)C(=O)O)NC(=O)[C@H](CCC(=O)O)N MXOODARRORARSU-ACZMJKKPSA-N 0.000 description 1
- PAQUJCSYVIBPLC-AVGNSLFASA-N Glu-Asp-Phe Chemical compound OC(=O)CC[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 PAQUJCSYVIBPLC-AVGNSLFASA-N 0.000 description 1
- WATXSTJXNBOHKD-LAEOZQHASA-N Glu-Asp-Val Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](C(C)C)C(O)=O WATXSTJXNBOHKD-LAEOZQHASA-N 0.000 description 1
- XTZDZAXYPDISRR-MNXVOIDGSA-N Glu-Ile-Lys Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CCC(=O)O)N XTZDZAXYPDISRR-MNXVOIDGSA-N 0.000 description 1
- INGJLBQKTRJLFO-UKJIMTQDSA-N Glu-Ile-Val Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)[C@H]([C@@H](C)CC)NC(=O)[C@@H](N)CCC(O)=O INGJLBQKTRJLFO-UKJIMTQDSA-N 0.000 description 1
- RFTVTKBHDXCEEX-WDSKDSINSA-N Glu-Ser-Gly Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(=O)NCC(O)=O RFTVTKBHDXCEEX-WDSKDSINSA-N 0.000 description 1
- QSDKBRMVXSWAQE-BFHQHQDPSA-N Gly-Ala-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)CN QSDKBRMVXSWAQE-BFHQHQDPSA-N 0.000 description 1
- DUYYPIRFTLOAJQ-YUMQZZPRSA-N Gly-Asn-His Chemical compound C1=C(NC=N1)C[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)N)NC(=O)CN DUYYPIRFTLOAJQ-YUMQZZPRSA-N 0.000 description 1
- LCNXZQROPKFGQK-WHFBIAKZSA-N Gly-Asp-Ser Chemical compound NCC(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(O)=O LCNXZQROPKFGQK-WHFBIAKZSA-N 0.000 description 1
- 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 1
- RVGMVLVBDRQVKB-UWVGGRQHSA-N Gly-Met-His Chemical compound CSCC[C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)NC(=O)CN RVGMVLVBDRQVKB-UWVGGRQHSA-N 0.000 description 1
- OMOZPGCHVWOXHN-BQBZGAKWSA-N Gly-Met-Ser Chemical compound CSCC[C@@H](C(=O)N[C@@H](CO)C(=O)O)NC(=O)CN OMOZPGCHVWOXHN-BQBZGAKWSA-N 0.000 description 1
- WMGHDYWNHNLGBV-ONGXEEELSA-N Gly-Phe-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)CN)CC1=CC=CC=C1 WMGHDYWNHNLGBV-ONGXEEELSA-N 0.000 description 1
- WCORRBXVISTKQL-WHFBIAKZSA-N Gly-Ser-Ser Chemical compound NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(O)=O WCORRBXVISTKQL-WHFBIAKZSA-N 0.000 description 1
- DBUNZBWUWCIELX-JHEQGTHGSA-N Gly-Thr-Glu Chemical compound [H]NCC(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCC(O)=O)C(O)=O DBUNZBWUWCIELX-JHEQGTHGSA-N 0.000 description 1
- 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 1
- TVTZEOHWHUVYCG-KYNKHSRBSA-N Gly-Thr-Thr Chemical compound [H]NCC(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O TVTZEOHWHUVYCG-KYNKHSRBSA-N 0.000 description 1
- DNAZKGFYFRGZIH-QWRGUYRKSA-N Gly-Tyr-Ser Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)CN)CC1=CC=C(O)C=C1 DNAZKGFYFRGZIH-QWRGUYRKSA-N 0.000 description 1
- KSOBNUBCYHGUKH-UWVGGRQHSA-N Gly-Val-Val Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)[C@H](C(C)C)NC(=O)CN KSOBNUBCYHGUKH-UWVGGRQHSA-N 0.000 description 1
- 108090000288 Glycoproteins Proteins 0.000 description 1
- 102000003886 Glycoproteins Human genes 0.000 description 1
- JATYGDHMDRAISQ-KKUMJFAQSA-N His-Tyr-Ser Chemical compound [H]N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CO)C(O)=O JATYGDHMDRAISQ-KKUMJFAQSA-N 0.000 description 1
- 101000980825 Homo sapiens B-lymphocyte antigen CD19 Proteins 0.000 description 1
- ZLFNNVATRMCAKN-ZKWXMUAHSA-N Ile-Ser-Gly Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CO)C(=O)NCC(=O)O)N ZLFNNVATRMCAKN-ZKWXMUAHSA-N 0.000 description 1
- YBKKLDBBPFIXBQ-MBLNEYKQSA-N Ile-Thr-Gly Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(=O)O)N YBKKLDBBPFIXBQ-MBLNEYKQSA-N 0.000 description 1
- BQIIHAGJIYOQBP-YFYLHZKVSA-N Ile-Trp-Pro Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC1=CNC2=CC=CC=C21)C(=O)N3CCC[C@@H]3C(=O)O)N BQIIHAGJIYOQBP-YFYLHZKVSA-N 0.000 description 1
- MITYXXNZSZLHGG-OBAATPRFSA-N Ile-Trp-Tyr Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC1=CNC2=CC=CC=C21)C(=O)N[C@@H](CC3=CC=C(C=C3)O)C(=O)O)N MITYXXNZSZLHGG-OBAATPRFSA-N 0.000 description 1
- 108010065920 Insulin Lispro Proteins 0.000 description 1
- 102100034343 Integrase Human genes 0.000 description 1
- 108010002350 Interleukin-2 Proteins 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
- GBDMISNMNXVTNV-XIRDDKMYSA-N Leu-Asp-Trp Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC1=CNC2=C1C=CC=C2)C(O)=O GBDMISNMNXVTNV-XIRDDKMYSA-N 0.000 description 1
- BOFAFKVZQUMTID-AVGNSLFASA-N Leu-Gln-His Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)N BOFAFKVZQUMTID-AVGNSLFASA-N 0.000 description 1
- CQGSYZCULZMEDE-SRVKXCTJSA-N Leu-Gln-Pro Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CCC(N)=O)C(=O)N1CCC[C@H]1C(O)=O CQGSYZCULZMEDE-SRVKXCTJSA-N 0.000 description 1
- UCDHVOALNXENLC-KBPBESRZSA-N Leu-Gly-Tyr Chemical compound CC(C)C[C@H]([NH3+])C(=O)NCC(=O)N[C@H](C([O-])=O)CC1=CC=C(O)C=C1 UCDHVOALNXENLC-KBPBESRZSA-N 0.000 description 1
- QNBVTHNJGCOVFA-AVGNSLFASA-N Leu-Leu-Glu Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](C(O)=O)CCC(O)=O QNBVTHNJGCOVFA-AVGNSLFASA-N 0.000 description 1
- FAELBUXXFQLUAX-AJNGGQMLSA-N Leu-Leu-Ile Chemical compound CC[C@H](C)[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CC(C)C FAELBUXXFQLUAX-AJNGGQMLSA-N 0.000 description 1
- INCJJHQRZGQLFC-KBPBESRZSA-N Leu-Phe-Gly Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)NCC(O)=O INCJJHQRZGQLFC-KBPBESRZSA-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
- ODRREERHVHMIPT-OEAJRASXSA-N Leu-Thr-Phe 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)CC1=CC=CC=C1 ODRREERHVHMIPT-OEAJRASXSA-N 0.000 description 1
- FMFNIDICDKEMOE-XUXIUFHCSA-N Leu-Val-Ile Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O FMFNIDICDKEMOE-XUXIUFHCSA-N 0.000 description 1
- QESXLSQLQHHTIX-RHYQMDGZSA-N Leu-Val-Thr Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O QESXLSQLQHHTIX-RHYQMDGZSA-N 0.000 description 1
- IXHKPDJKKCUKHS-GARJFASQSA-N Lys-Ala-Pro Chemical compound C[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](CCCCN)N IXHKPDJKKCUKHS-GARJFASQSA-N 0.000 description 1
- SKRGVGLIRUGANF-AVGNSLFASA-N Lys-Leu-Glu Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(O)=O SKRGVGLIRUGANF-AVGNSLFASA-N 0.000 description 1
- 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 1
- OIQSIMFSVLLWBX-VOAKCMCISA-N Lys-Leu-Thr Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O OIQSIMFSVLLWBX-VOAKCMCISA-N 0.000 description 1
- VKCPHIOZDWUFSW-ONGXEEELSA-N Lys-Val-Gly Chemical compound OC(=O)CNC(=O)[C@H](C(C)C)NC(=O)[C@@H](N)CCCCN VKCPHIOZDWUFSW-ONGXEEELSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 241001529936 Murinae Species 0.000 description 1
- YBAFDPFAUTYYRW-UHFFFAOYSA-N N-L-alpha-glutamyl-L-leucine Natural products CC(C)CC(C(O)=O)NC(=O)C(N)CCC(O)=O YBAFDPFAUTYYRW-UHFFFAOYSA-N 0.000 description 1
- XMBSYZWANAQXEV-UHFFFAOYSA-N N-alpha-L-glutamyl-L-phenylalanine Natural products OC(=O)CCC(N)C(=O)NC(C(O)=O)CC1=CC=CC=C1 XMBSYZWANAQXEV-UHFFFAOYSA-N 0.000 description 1
- KZNQNBZMBZJQJO-UHFFFAOYSA-N N-glycyl-L-proline Natural products NCC(=O)N1CCCC1C(O)=O KZNQNBZMBZJQJO-UHFFFAOYSA-N 0.000 description 1
- 206010028735 Nasal congestion Diseases 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 108091028043 Nucleic acid sequence Proteins 0.000 description 1
- IILUKIJNFMUBNF-IHRRRGAJSA-N Phe-Gln-Gln Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(O)=O IILUKIJNFMUBNF-IHRRRGAJSA-N 0.000 description 1
- CKJACGQPCPMWIT-UFYCRDLUSA-N Phe-Pro-Phe Chemical compound C([C@H](N)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)C1=CC=CC=C1 CKJACGQPCPMWIT-UFYCRDLUSA-N 0.000 description 1
- AFNJAQVMTIQTCB-DLOVCJGASA-N Phe-Ser-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC1=CC=CC=C1 AFNJAQVMTIQTCB-DLOVCJGASA-N 0.000 description 1
- BPCLGWHVPVTTFM-QWRGUYRKSA-N Phe-Ser-Gly Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CO)C(=O)NCC(O)=O BPCLGWHVPVTTFM-QWRGUYRKSA-N 0.000 description 1
- MSSXKZBDKZAHCX-UNQGMJICSA-N Phe-Thr-Val Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(O)=O MSSXKZBDKZAHCX-UNQGMJICSA-N 0.000 description 1
- 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 1
- AFXCXDQNRXTSBD-FJXKBIBVSA-N Pro-Gly-Thr Chemical compound [H]N1CCC[C@H]1C(=O)NCC(=O)N[C@@H]([C@@H](C)O)C(O)=O AFXCXDQNRXTSBD-FJXKBIBVSA-N 0.000 description 1
- VTFXTWDFPTWNJY-RHYQMDGZSA-N Pro-Leu-Thr Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O VTFXTWDFPTWNJY-RHYQMDGZSA-N 0.000 description 1
- 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 1
- 108010092799 RNA-directed DNA polymerase Proteins 0.000 description 1
- BNFVPSRLHHPQKS-WHFBIAKZSA-N Ser-Asp-Gly Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC(O)=O)C(=O)NCC(O)=O BNFVPSRLHHPQKS-WHFBIAKZSA-N 0.000 description 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
- MUARUIBTKQJKFY-WHFBIAKZSA-N Ser-Gly-Asp Chemical compound [H]N[C@@H](CO)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(O)=O MUARUIBTKQJKFY-WHFBIAKZSA-N 0.000 description 1
- IOVHBRCQOGWAQH-ZKWXMUAHSA-N Ser-Gly-Ile Chemical compound [H]N[C@@H](CO)C(=O)NCC(=O)N[C@@H]([C@@H](C)CC)C(O)=O IOVHBRCQOGWAQH-ZKWXMUAHSA-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
- WEQAYODCJHZSJZ-KKUMJFAQSA-N Ser-His-Tyr Chemical compound C([C@H](NC(=O)[C@H](CO)N)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(O)=O)C1=CN=CN1 WEQAYODCJHZSJZ-KKUMJFAQSA-N 0.000 description 1
- FKZSXTKZLPPHQU-GQGQLFGLSA-N Ser-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](CO)N FKZSXTKZLPPHQU-GQGQLFGLSA-N 0.000 description 1
- GJFYFGOEWLDQGW-GUBZILKMSA-N Ser-Leu-Gln Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)O)NC(=O)[C@H](CO)N GJFYFGOEWLDQGW-GUBZILKMSA-N 0.000 description 1
- ZIFYDQAFEMIZII-GUBZILKMSA-N Ser-Leu-Glu Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(O)=O ZIFYDQAFEMIZII-GUBZILKMSA-N 0.000 description 1
- 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 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
- NNFMANHDYSVNIO-DCAQKATOSA-N Ser-Lys-Arg Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O NNFMANHDYSVNIO-DCAQKATOSA-N 0.000 description 1
- ADJDNJCSPNFFPI-FXQIFTODSA-N Ser-Pro-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@@H]1CCCN1C(=O)[C@@H](N)CO ADJDNJCSPNFFPI-FXQIFTODSA-N 0.000 description 1
- QUGRFWPMPVIAPW-IHRRRGAJSA-N Ser-Pro-Phe Chemical compound OC[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 QUGRFWPMPVIAPW-IHRRRGAJSA-N 0.000 description 1
- AZWNCEBQZXELEZ-FXQIFTODSA-N Ser-Pro-Ser Chemical compound OC[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CO)C(O)=O AZWNCEBQZXELEZ-FXQIFTODSA-N 0.000 description 1
- PPCZVWHJWJFTFN-ZLUOBGJFSA-N Ser-Ser-Asp Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(O)=O)C(O)=O PPCZVWHJWJFTFN-ZLUOBGJFSA-N 0.000 description 1
- 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 1
- BMKNXTJLHFIAAH-CIUDSAMLSA-N Ser-Ser-Leu Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(O)=O BMKNXTJLHFIAAH-CIUDSAMLSA-N 0.000 description 1
- OZPDGESCTGGNAD-CIUDSAMLSA-N Ser-Ser-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CO OZPDGESCTGGNAD-CIUDSAMLSA-N 0.000 description 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
- DKGRNFUXVTYRAS-UBHSHLNASA-N Ser-Ser-Trp Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC1=CNC2=C1C=CC=C2)C(O)=O DKGRNFUXVTYRAS-UBHSHLNASA-N 0.000 description 1
- XJDMUQCLVSCRSJ-VZFHVOOUSA-N Ser-Thr-Ala Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C)C(O)=O XJDMUQCLVSCRSJ-VZFHVOOUSA-N 0.000 description 1
- RXUOAOOZIWABBW-XGEHTFHBSA-N Ser-Thr-Arg Chemical compound OC[C@H](N)C(=O)N[C@@H]([C@H](O)C)C(=O)N[C@H](C(O)=O)CCCN=C(N)N RXUOAOOZIWABBW-XGEHTFHBSA-N 0.000 description 1
- FLMYSKVSDVHLEW-SVSWQMSJSA-N Ser-Thr-Ile Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O FLMYSKVSDVHLEW-SVSWQMSJSA-N 0.000 description 1
- PIQRHJQWEPWFJG-UWJYBYFXSA-N Ser-Tyr-Ala Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](C)C(O)=O PIQRHJQWEPWFJG-UWJYBYFXSA-N 0.000 description 1
- UBTNVMGPMYDYIU-HJPIBITLSA-N Ser-Tyr-Ile Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O UBTNVMGPMYDYIU-HJPIBITLSA-N 0.000 description 1
- VVKVHAOOUGNDPJ-SRVKXCTJSA-N Ser-Tyr-Ser Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CO)C(O)=O VVKVHAOOUGNDPJ-SRVKXCTJSA-N 0.000 description 1
- 108010003723 Single-Domain Antibodies Proteins 0.000 description 1
- YRNBANYVJJBGDI-VZFHVOOUSA-N Thr-Ala-Cys Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](C)C(=O)N[C@@H](CS)C(=O)O)N)O YRNBANYVJJBGDI-VZFHVOOUSA-N 0.000 description 1
- WYKJENSCCRJLRC-ZDLURKLDSA-N Thr-Gly-Cys Chemical compound C[C@H]([C@@H](C(=O)NCC(=O)N[C@@H](CS)C(=O)O)N)O WYKJENSCCRJLRC-ZDLURKLDSA-N 0.000 description 1
- KBBRNEDOYWMIJP-KYNKHSRBSA-N Thr-Gly-Thr Chemical compound C[C@H]([C@@H](C(=O)NCC(=O)N[C@@H]([C@@H](C)O)C(=O)O)N)O KBBRNEDOYWMIJP-KYNKHSRBSA-N 0.000 description 1
- PAXANSWUSVPFNK-IUKAMOBKSA-N Thr-Ile-Asn Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)O)NC(=O)[C@H]([C@@H](C)O)N PAXANSWUSVPFNK-IUKAMOBKSA-N 0.000 description 1
- 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 1
- KZSYAEWQMJEGRZ-RHYQMDGZSA-N Thr-Leu-Val Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(O)=O KZSYAEWQMJEGRZ-RHYQMDGZSA-N 0.000 description 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
- ABWNZPOIUJMNKT-IXOXFDKPSA-N Thr-Phe-Ser Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CO)C(O)=O ABWNZPOIUJMNKT-IXOXFDKPSA-N 0.000 description 1
- WTMPKZWHRCMMMT-KZVJFYERSA-N Thr-Pro-Ala Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](C)C(O)=O WTMPKZWHRCMMMT-KZVJFYERSA-N 0.000 description 1
- NDZYTIMDOZMECO-SHGPDSBTSA-N Thr-Thr-Ala Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C)C(O)=O NDZYTIMDOZMECO-SHGPDSBTSA-N 0.000 description 1
- TZQWJCGVCIJDMU-HEIBUPTGSA-N Thr-Thr-Cys Chemical compound C[C@H]([C@@H](C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CS)C(=O)O)N)O TZQWJCGVCIJDMU-HEIBUPTGSA-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
- KZTLZZQTJMCGIP-ZJDVBMNYSA-N Thr-Val-Thr Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O KZTLZZQTJMCGIP-ZJDVBMNYSA-N 0.000 description 1
- AVYVKJMBNLPWRX-WFBYXXMGSA-N Trp-Ala-Ser Chemical compound C1=CC=C2C(C[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](CO)C(O)=O)=CNC2=C1 AVYVKJMBNLPWRX-WFBYXXMGSA-N 0.000 description 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
- JWHOIHCOHMZSAR-QWRGUYRKSA-N Tyr-Asp-Gly Chemical compound OC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 JWHOIHCOHMZSAR-QWRGUYRKSA-N 0.000 description 1
- MNMYOSZWCKYEDI-JRQIVUDYSA-N Tyr-Asp-Thr Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O MNMYOSZWCKYEDI-JRQIVUDYSA-N 0.000 description 1
- YLRLHDFMMWDYTK-KKUMJFAQSA-N Tyr-Cys-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](CS)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 YLRLHDFMMWDYTK-KKUMJFAQSA-N 0.000 description 1
- NQJDICVXXIMMMB-XDTLVQLUSA-N Tyr-Glu-Ala Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(O)=O NQJDICVXXIMMMB-XDTLVQLUSA-N 0.000 description 1
- HRHYJNLMIJWGLF-BZSNNMDCSA-N Tyr-Ser-Phe Chemical compound C([C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)C1=CC=C(O)C=C1 HRHYJNLMIJWGLF-BZSNNMDCSA-N 0.000 description 1
- UMSZZGTXGKHTFJ-SRVKXCTJSA-N Tyr-Ser-Ser Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 UMSZZGTXGKHTFJ-SRVKXCTJSA-N 0.000 description 1
- ZYVAAYAOTVJBSS-GMVOTWDCSA-N Tyr-Trp-Ala Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC1=CNC2=C1C=CC=C2)C(=O)N[C@@H](C)C(O)=O ZYVAAYAOTVJBSS-GMVOTWDCSA-N 0.000 description 1
- VHRLUTIMTDOVCG-PEDHHIEDSA-N Val-Ile-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)O)NC(=O)[C@H](C(C)C)N VHRLUTIMTDOVCG-PEDHHIEDSA-N 0.000 description 1
- 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 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
- KRAHMIJVUPUOTQ-DCAQKATOSA-N Val-Ser-His Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)N KRAHMIJVUPUOTQ-DCAQKATOSA-N 0.000 description 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
- 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
- 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 1
- QHSSPPHOHJSTML-HOCLYGCPSA-N Val-Trp-Gly Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC1=CNC2=CC=CC=C21)C(=O)NCC(=O)O)N QHSSPPHOHJSTML-HOCLYGCPSA-N 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 108010081404 acein-2 Proteins 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 239000011543 agarose gel Substances 0.000 description 1
- 230000008484 agonism Effects 0.000 description 1
- 108010041407 alanylaspartic acid Proteins 0.000 description 1
- 108010005233 alanylglutamic acid Proteins 0.000 description 1
- 230000008382 alveolar damage Effects 0.000 description 1
- 125000000539 amino acid group Chemical group 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000008485 antagonism Effects 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 229940124599 anti-inflammatory drug Drugs 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 229940125644 antibody drug Drugs 0.000 description 1
- 230000000890 antigenic effect Effects 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 239000003443 antiviral agent Substances 0.000 description 1
- 108010062796 arginyllysine Proteins 0.000 description 1
- 108010036533 arginylvaline Proteins 0.000 description 1
- 206010003246 arthritis Diseases 0.000 description 1
- 239000011324 bead Substances 0.000 description 1
- 230000004071 biological 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
- 201000011510 cancer Diseases 0.000 description 1
- 230000007910 cell fusion Effects 0.000 description 1
- 230000001413 cellular effect Effects 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
- 239000003246 corticosteroid Substances 0.000 description 1
- 229960001334 corticosteroids Drugs 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 235000015872 dietary supplement Nutrition 0.000 description 1
- 230000029087 digestion Effects 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 230000002884 effect on inflammation Effects 0.000 description 1
- 239000013604 expression vector Substances 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 238000001943 fluorescence-activated cell sorting Methods 0.000 description 1
- 108010015792 glycyllysine Proteins 0.000 description 1
- 108010077515 glycylproline Proteins 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 229940022353 herceptin Drugs 0.000 description 1
- 108010040030 histidinoalanine Proteins 0.000 description 1
- 108010025306 histidylleucine Proteins 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
- 238000010324 immunological assay Methods 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 108010044374 isoleucyl-tyrosine Proteins 0.000 description 1
- 210000002751 lymph Anatomy 0.000 description 1
- 239000006166 lysate Substances 0.000 description 1
- 210000004962 mammalian cell Anatomy 0.000 description 1
- 230000003278 mimic effect Effects 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000003607 modifier Substances 0.000 description 1
- 229940126619 mouse monoclonal antibody Drugs 0.000 description 1
- 239000013642 negative control Substances 0.000 description 1
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 238000002638 palliative care Methods 0.000 description 1
- 108010051242 phenylalanylserine Proteins 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 108010070643 prolylglutamic acid Proteins 0.000 description 1
- 230000002285 radioactive effect Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 230000000241 respiratory effect Effects 0.000 description 1
- 229960004641 rituximab Drugs 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000012163 sequencing technique Methods 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 238000002741 site-directed mutagenesis Methods 0.000 description 1
- 235000020183 skimmed milk Nutrition 0.000 description 1
- 230000037439 somatic mutation Effects 0.000 description 1
- 238000010186 staining Methods 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 239000012089 stop solution Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000010257 thawing Methods 0.000 description 1
- 108010072986 threonyl-seryl-lysine Proteins 0.000 description 1
- 238000001890 transfection Methods 0.000 description 1
- 108010084932 tryptophyl-proline Proteins 0.000 description 1
- 210000005239 tubule Anatomy 0.000 description 1
- 230000005909 tumor killing Effects 0.000 description 1
- 108010035534 tyrosyl-leucyl-alanine Proteins 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 238000001262 western blot Methods 0.000 description 1
- 210000005253 yeast cell Anatomy 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- 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
-
- 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
-
- 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
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
- G01N2333/005—Assays involving biological materials from specific organisms or of a specific nature from viruses
- G01N2333/08—RNA viruses
- G01N2333/165—Coronaviridae, e.g. avian infectious bronchitis virus
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2469/00—Immunoassays for the detection of microorganisms
- G01N2469/10—Detection of antigens from microorganism in sample from host
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Virology (AREA)
- Molecular Biology (AREA)
- Immunology (AREA)
- Engineering & Computer Science (AREA)
- General Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Medicinal Chemistry (AREA)
- Hematology (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Biomedical Technology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Biochemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Urology & Nephrology (AREA)
- Cell Biology (AREA)
- Analytical Chemistry (AREA)
- Biotechnology (AREA)
- Biophysics (AREA)
- Pathology (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Microbiology (AREA)
- Peptides Or Proteins (AREA)
- Physics & Mathematics (AREA)
- General Physics & Mathematics (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Tropical Medicine & Parasitology (AREA)
- Genetics & Genomics (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pulmonology (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Food Science & Technology (AREA)
Abstract
本发明涉及抗SAR‑COV‑2抗体或其抗原结合片段及其应用，具体公开了，抗体2I3、2I3、3I15和4E17重链和轻链互补决定区以及重链和轻链可变区序列。本发明的抗体为人源化抗体，其副作用低，亲和力和特异性高。
Description
技术领域
本发明属于免疫学领域，具体地涉及抗SAR-COV-2(COVID-19)全人源单克隆抗体及 其制法与应用。
背景技术
在2018年全球十大畅销药中，有8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6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Orth℃lone 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、流行性感冒特别是冠状病毒等方面具有高特异性的 显著疗效。COVID-19是由一种SAR-COV-2冠状病毒引起的急性呼吸道传染病，至今仍然缺 乏有效的药物和疫苗。新冠状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SAR-COV-2流行性感冒。
发明内容
为解决上述问题，本发明提供一种抗SAR-COV-2的抗体或其抗原结合片段，其特异性结 合SAR-COV-2的S蛋白。
本发明一方面提供一种分离的抗SAR-COV-2的抗体或其抗原结合片段；其具有如下任一 组的三个重链可变区的互补决定区(HCDR)和三个轻链可变区的互补决定区(LCDR)：
抗体2E5
2E5-HCDR1：GFTFSTYG SEQ ID No：1；
2E5-HCDR2：IWYDGSSK SEQ ID No：2；
2E5-HCDR3：ARDPKTTVTTKMDV SEQ ID No：3；
2E5-LCDR1：SLRLYY SEQ ID No：4；
2E5-LCDR:2：DKD SEQ ID No：5；以及
2E5-LCDR3：NSRDSSGNHLGVL SEQ ID No：6；
或者
抗体2I3
2I3-HCDR1：GFTFSNHA SEQ ID No：11；
2I3-HCDR2：ISGSDGSA SEQ ID No：12；
2I3-HCDR3：ARGNWESSYAFCDN SEQ ID No：13；
2I3-LCDR1：QSVLYRSNSKNY SEQ ID No：14；
2I3-LCDR:2：WAS SEQ ID No：15；以及
2I3-LCDR3：LQHYSFPFT SEQ ID No：16；
或者
抗体3I15
3I15-HCDR1：GFTLSSYG SEQ ID No：21；
3I15-HCDR2：LGYSGDSI SEQ ID No：22；
3I15-HCDR3：ARLWVASGGDDY SEQ ID No：23；
3I15-LCDR1：QSVSHY SEQ ID No：24；
3I15-LCDR:2：DTS SEQ ID No：25；以及
3I15-LCDR3：QQRSIWPLT SEQ ID No：26；
或者
抗体4E17
4E17-HCDR1：GFAFSTYA SEQ ID No：31；
4E17-HCDR2：ISSGSSTI SEQ ID No：32；
4E17-HCDR3：ARGRSYALADLPY SEQ ID No：33；
4E17-LCDR1：QSISSW SEQ ID No：34；
4E17-LCDR:2：EAS SEQ ID No：35；以及
4E17-LCDR3：QQYNSYSSLT SEQ ID No：36。
本发明另一个方面提供了一种分离的抗SAR-COV-2的抗体或其抗原结合片段，其中，抗 体抗体2E5的重链可变区和轻链可变区为：
2E5重链可变区：
QVQLVESGGGVVQPGRSLRLSCAASGFTFSTYGMHWVRQAPGKGLEWVAVIWYDGSSKSYADSVKGRFTVSSDDSKNILYLQMNSLRAEDTAVYYCARDPKTTVTTKMDVWGQGTT VTVSS SEQ ID No：7
2E5轻链可变区：
SSELTQDPAVSVALGQTVRITCQGDSLRLYYANWYQQKPGQAPLLVIYDKDNRPSGIPD RFSGSSSGSTASLTITGAQAEDEADYYCNSRDSSGNHLGVLFGGGTKLTVT SEQ ID No：8；
或者，抗体2I3重链可变区和轻链可变区为：
2I3重链可变区：
EVQLLESGGGLVQPGGSLRLSCVASGFTFSNHAMTWVRQAPGKGLDWVSTISGSDGSANYADSVKGRVIISRDNSKNTLYLQMNSLRAEDTAVYYCARGNWESSYAFCDNWGQGTLV TVSS SEQ ID No：17
2I3轻链可变区：
DIVMTQSPFSLPVSLGERATINCKSSQSVLYRSNSKNYLAWYQQKPGQAPKLLIYWAST RKSGVPDRFSASGSGTDFTLTISSLQPEDVADYYCLQHYSFPFTFGPGTKVGLR SEQ ID No:18；
或者，抗体3I15重链可变区和轻链可变区为：
3I15重链可变区：
EVQLVESGGGLVQPGGSLRLSCAASGFTLSSYGMSWVRQAPGKGLEWVSGLGYSGDSIYYADSVKGRFTISRDNSKNTLYLQMNSLRAADTAVYYCARLWVASGGDDYWGQGTLVTV SS SEQ ID No：27
3I15轻链可变区：
EIVLTQSPATLSLSPGERATLSCRASQSVSHYLAWFQQKSGQAPRLLIYDTSKRATGTPA TFSGSGSGTDFTLTISSLEPEDFAVYYCQQRSIWPLTFGGGTKLEIK SEQ ID No:28
或者，抗体4E17重链可变区和轻链可变区为：
4E17重链可变区：
EVQLVESGGGLVQPGGSLRLSCAASGFAFSTYAMNWVRQAPGKGLEWVSYISSGSSTI YYANSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARGRSYALADLPYWGQGTLVTV SS SEQ ID No：37
4E17轻链可变区：
DIQMTQSPSTLSASVGDRVTITCRASQSISSWLAWYQQKPGKAPKLLIYEASSLESGVP SRFSGSGSGTEFTLTISSLQPDDFATYYCQQYNSYSSLTFGGGTKVEIK SEQ ID No:38
在本发明的技术方案中，所述的抗体或其抗原结合片段为人源化抗体，更优选为全人源 化抗体。
在本发明的技术方案中，所述的抗体为IgG1抗体。
在本发明的技术方案中，所述的抗体或其抗原结合片段特异性结合SAR-COV-2表面S 蛋白。
在本发明的技术方案中，所述的抗体为单克隆抗体或多克隆抗体，优选为单克隆抗体。
在本发明的技术方案中，所述的抗体或其抗原结合片段特异性结合SAR-COV-2表面S 蛋白。
本发明再一个方面提供了一种核苷酸序列，其编码如前述的抗体或其抗原结合片段。
本发明再一个方面提供了一种载体，包含前述的核苷酸序列。
本发明再一个方面提供了一种宿主细胞，包含前述载体或载体组，优选地，所述宿主细 胞是原核的或真核的，更优选的选自酵母细胞、哺乳动物细胞或适用于制备抗体或其抗原结 合片段的其它细胞。
本发明再一个方面提供了一种试剂盒，所述试剂盒包含如前述的抗体或其抗原结合片段。
本发明再一个方面提供了一种检测试剂，所述检测试剂包含如前述的抗体或其抗原结合 片段。
本发明再一个方面提供了上述抗体或其抗原结合片段作为检测试剂的用途，所述试剂用 于以下用途的试剂：酶联免疫吸附检测(ELISA)、免疫印迹(Western Blot)、流式细胞术 (FACS)、免疫组织化学(IHC)检测或者免疫PCR。
在上述在免疫学检测中，抗体或其抗原结合片段可单独或与通过化学键偶联，静电吸附 或者亲疏水性吸附，而连接缀合物包括辣根过氧化物酶(HRP)，碱性磷酸酶(AP)，生物素 (Biotin)，异硫氰酸荧光素(FITC)，Cy3、Cy5、磁珠和琼脂糖等缀合物连接。
在本发明的技术方案中，检测试剂可用于非诊断或治疗目的检测。
本发明再一个方面提供了一种药物组合物，其如前所述的分离的抗体或其抗原结合片段 和药物上可接受辅料。
在本发明的技术方案中，其中所述抗体或其抗原结合片段阻断或降低SAR-COV-2的S 蛋白与受试者的细胞表面受体结合，所述细胞表面受体优选为细胞血管紧张素转化酶相关性 羧肽酶(ACE2)。
本发明再一个方面提供了一种抗SAR-COV-2的抗体或其抗原结合片段在制备预防、治疗 或缓解SAR-COV-2感染的至少一种症状或适应症的药物中的用途。
在本发明的技术方案中，所述的药物为口服或注射制剂。
本发明再一个方面提供了一种预防、治疗或缓解SAR-COV-2感染的至少一种症状或适应 症的方法，所述方法包括将前述任一项的抗体或其抗原结合片段或前述药物组合物施用于受 试者。
在本发明的技术方案中，其中所述至少一种症状或适应症选自下组：肺部炎症、肺泡损 伤、发热、咳嗽、呼吸困难、低血氧症、急性呼吸窘迫综合征、脓毒症休克、凝血功能障碍、 代谢性酸中毒、鼻塞、流涕、咽痛、腹泻、器官衰竭、败血性休克和死亡。
在本发明的技术方案中，其中所述药物组合物或所述抗体或其抗原结合片段与第二治疗 剂组合施用。其中所述第二治疗剂选自下组：抗炎症药物(如皮质类固醇和非甾体抗炎症药 物)、抗病毒药物、针对SAR-COV-2的S蛋白的不同的抗体、对于SAR-COV-2的疫苗、抗生 素、膳食补充剂如抗氧化剂和治疗SAR-COV-2感染的任何其他姑息疗法、缓解上述症状或适 应症的药物。
在本发明的技术方案中，其中所述药物组合物或所述抗体或其抗原结合片段通过皮下、 静脉内、皮内、腹膜内、口服、肌内或颅内施用。
有益效果
(1)本发明所述抗SAR-COV-2抗体可以靶向结合SAR-COV-2病毒的S蛋白，特异性高， 能有效阻断SAR-COV-2病毒表面S蛋白与受试者细胞表面受体的结合。
(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SAR-COV-2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SAR-COV-2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1ELISA实验结果图。
具体实施方式
为了使本发明的上述目的、特征和优点能够更加明显易懂，下面对本发明的具体实施方 式做详细的说明，但不能理解为对本发明的可实施范围的限定。
为了对本发明的技术特征、目的和有益效果有更加清楚的理解，现结合具体实施例对本 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。
如本文所用，术语“抗体”是指包含至少一个抗原结合位点的分子，所述抗原结合位点 免疫特异性地结合至特定的目标抗原靶标。因此，术语“抗体”包括但不限于全长抗体和/或 其变体，其片段，肽体及其变体，单克隆抗体(包括全长单克隆抗体)、多克隆抗体、由至少 两个完整的抗体形成的多特异性抗体(例如双特异性抗体)、人抗体、人源化抗体和模拟抗体 的结构和/或功能的抗体模拟物或其指定片段或部分，包括单链抗体及其片段。抗体与靶标的 结合可引起多种作用，例如但不限于这种结合在体外、原位和/或体内调节、减少、增加、拮 抗、激动、减轻、减缓、阻断、抑制、消除和/或干扰至少一种靶标活性或结合，或受体活性 或结合。因此，本公开的抗体涵盖能够结合生物分子(例如抗原或受体)或其部分的抗体片段， 包括但不限于Fab、Fab'和F(ab')2、pFc'、Fd、单结构域抗体(sdAb)、可变片段(Fv)、单链可 变片段(scFv)或二硫化物连接的Fv(sdFv)；双功能抗体或二价双功能抗体；线性抗体；单链抗 体分子；由抗体片段形成的多特异性抗体。抗体可以是任何类型(例如IgG、IgE、IgM、IgD、 IgA和IgY)，类别(例如IgG1、IgG2、IgG3、IgG4、IgA1和IgA2)或亚类。
如本文所用，术语“单克隆抗体”是指得自一群基本上同种的抗体的抗体，即除了可能 存在少量可能天然发生的突变之外，构成群体的各个抗体是相同的。单克隆抗体是高度特异 性的，针对单个抗原位点。此外，与包含针对不同决定簇(表位)的不同抗体的多克隆抗体制 备物相反，每个单克隆抗体针对抗原上的单一决定簇。除了其特异性之外，单克隆抗体的优 点还在于其可以未污染其它抗体而合成。修饰语“单克隆”不应解释为需要通过任何特定方 法产生抗体。
如本文所用，术语HCDR与重链互补决定区含义相同，LCDR与轻链互补决定区含义相 同。
如本文所用，单克隆抗体包括“嵌合”抗体，其中重链和/或轻链的一部分与衍生自特定 物种或属于特定抗类别或亚类的抗体中的相应序列相同或同源，而所述链剩余的与衍生自另 一物种或属于另一抗体类别或亚类的抗体中的相应序列相同或同源，且这些抗体的片段，表 现出所需的生物活性。
如本文所用，术语“SAR-COV-2”也称作“新型冠状病毒”，指新发生的引起新型冠状病 毒肺炎(COVID-19)的病毒。
如本文所用，S蛋白指冠状病毒上的刺突蛋白(Spike protein)，SARS-CoV-2通过病毒表 面的刺突蛋白识别人体内细胞表面的ACE2并侵染宿主细胞。通过阻断冠状病毒SARS-CoV-2 表面的S蛋白可以有效抑制病毒黏附靶细胞受体，防止病毒侵入细胞。
如本文使用的术语"人源化抗体"包括具有源自人种系免疫球蛋白序列的可变和恒定区的 抗体。本发明的人人源化抗体可包括不由人种系免疫球蛋白序列编码的氨基酸残基(例如由随 机或体外位点特异性诱变或通过体内体细胞突变引入的突变)。
如本文使用的术语抗"抗原结合片段"等包括任何天然存在的、酶学可获得的、合成的或 基因工程的特异性结合抗原以形成复合物的多肽或糖蛋白。如本文使用的术语抗体的"抗原结 合片段"与SAR-COV-2的S蛋白具有结合能力的一个或多个片段。
一方面，本发明提供抗SAR-COV-2全人源单克隆抗体或来源于该单克隆抗体的能够特异 性结合SAR-COV-2的生物活性片段，其中，抗体的重轻链CDR1、CDR2及CDR3区的氨基酸序列分别如下所示：
抗体2E5
2E5-HCDR1：GFTFSTYG SEQ ID No：1；
2E5-HCDR2：IWYDGSSK SEQ ID No：2；
2E5-HCDR3：ARDPKTTVTTKMDV SEQ ID No：3；
2E5-LCDR1：SLRLYY SEQ ID No：4；
2E5-LCDR:2：DKD SEQ ID No：5；以及
2E5-LCDR3：NSRDSSGNHLGVL SEQ ID No：6；
或者
抗体2I3
2I3-HCDR1：GFTFSNHA SEQ ID No：11；
2I3-HCDR2：ISGSDGSA SEQ ID No：12；
2I3-HCDR3：ARGNWESSYAFCDN SEQ ID No：13；
2I3-LCDR1：QSVLYRSNSKNY SEQ ID No：14；
2I3-LCDR:2：WAS SEQ ID No：15；以及
2I3-LCDR3：LQHYSFPFT SEQ ID No：16；
或者
抗体3I15
3I15-HCDR1：GFTLSSYG SEQ ID No：21；
3I15-HCDR2：LGYSGDSI SEQ ID No：22；
3I15-HCDR3：ARLWVASGGDDY SEQ ID No：23；
3I15-LCDR1：QSVSHY SEQ ID No：24；
3I15-LCDR:2：DTS SEQ ID No：25；以及
3I15-LCDR3：QQRSIWPLT SEQ ID No：26；
或者
抗体4E17
4E17-HCDR1：GFAFSTYA SEQ ID No：31；
4E17-HCDR2：ISSGSSTI SEQ ID No：32；
4E17-HCDR3：ARGRSYALADLPY SEQ ID No：33；
4E17-LCDR1：QSISSW SEQ ID No：34；
4E17-LCDR:2：EAS SEQ ID No：35；以及
4E17-LCDR3：QQYNSYSSLT SEQ ID No：36。
在一些实施方式中，该抗体2E5的重链可变区氨基酸序列如SEQ ID NO:7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；
QVQLVESGGGVVQPGRSLRLSCAASGFTFSTYGMHWVRQAPGKGLEWVAVIWYDGSSKSYADSVKGRFTVSSDDSKNILYLQMNSLRAEDTAVYYCARDPKTTVTTKMDVWGQGTT VTVSS SEQ ID No：7
且
该抗体的轻链可变区氨基酸序列如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 SSELTQDPAVSVALGQTVRITCQGDSLRLYYANWYQQKPGQAPLLVIYDKDNRPSGIPDRFS GSSSGSTASLTITGAQAEDEADYYCNSRDSSGNHLGVLFGGGTKLTVT SEQ ID No：8。
在一些实施方式中，该抗体2I3的重链可变区氨基酸序列如SEQ ID NO:17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；
EVQLLESGGGLVQPGGSLRLSCVASGFTFSNHAMTWVRQAPGKGLDWVSTISGSDGS ANYADSVKGRVIISRDNSKNTLYLQMNSLRAEDTAVYYCARGNWESSYAFCDNWGQGTLV TVSS SEQ ID NO:17
且
该抗体的轻链可变区氨基酸序列如SEQ ID NO:18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。
DIVMTQSPFSLPVSLGERATINCKSSQSVLYRSNSKNYLAWYQQKPGQAPKLLIYWAST RKSGVPDRFSASGSGTDFTLTISSLQPEDVADYYCLQHYSFPFTFGPGTKVGLR SEQ ID NO:18。
在一些实施方式中，该抗体3I15的重链可变区氨基酸序列如SEQ ID NO:27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；
EVQLVESGGGLVQPGGSLRLSCAASGFTLSSYGMSWVRQAPGKGLEWVSGLGYSGDS IYYADSVKGRFTISRDNSKNTLYLQMNSLRAADTAVYYCARLWVASGGDDYWGQGTLVTV SS SEQ ID NO:27
且
该抗体的轻链可变区氨基酸序列如SEQ ID NO:28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
EIVLTQSPATLSLSPGERATLSCRASQSVSHYLAWFQQKSGQAPRLLIYDTSKRATGTPA TFSGSGSGTDFTLTISSLEPEDFAVYYCQQRSIWPLTFGGGTKLEIK SEQ ID NO:28。
在一些实施方式中，该抗体4E17的重链可变区氨基酸序列如SEQ ID NO:37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；
EVQLVESGGGLVQPGGSLRLSCAASGFAFSTYAMNWVRQAPGKGLEWVSYISSGSSTI YYANSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARGRSYALADLPYWGQGTLVTV SS SEQ ID NO:37
且
该抗体的轻链可变区氨基酸序列如SEQ ID NO:38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
DIQMTQSPSTLSASVGDRVTITCRASQSISSWLAWYQQKPGKAPKLLIYEASSLESGVP SRFSGSGSGTEFTLTISSLQPDDFATYYCQQYNSYSSLTFGGGTKVEIK SEQ ID NO:38。
经ELISA实验验证，本发明所述抗SAR-COV-2全人源单克隆抗体可以靶向结合SAR-COV-2病毒的S蛋白。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SAR-COV-2全人源单克隆抗体的基因。在一 些实施方式中，所述基因包含编码具有上述所示的氨基酸的核苷酸序列。
在一些具体实施方式中，该核苷酸序列如下所示(以下序列仅为示例性，本领域技术人 员根据具体的氨基酸序列，可以设计其他可以翻译为所需氨基酸序列的核苷酸序列)：
编码抗体2E5重链可变区的核苷酸序列为：
CagGTGCagctggtggagtctgggggaggcgtggtccagcctgggaggtccctgagactctcctgtgcagcctctggattcaccttcagtacctatggcatgcactgggtccgccaggctccaggcaaggggctggagtgggtggcagttatatggtatgatggaagtagtaaatcctat gcagactccgtgaagggccgattcaccgtctccagcgacgattccaagaatatattgtatctgcaaatgaacagcctgagagccgaggacacg gctgtctattactgtgcgaga gatccaaagacaacggtgactacaaaaatggacgtctggggccaagggaccacggtcaccgtctcctca SEQ IDNo：9
编码抗体2E5轻链可变区的核苷酸序列为：
tcgtctgagctgactcaggaccctgctgtgtctgtggccttgggacagacagtcaggatcacatgccaaggagacagcctcagactctattatgcaaactggtaccaacagaagccaggacaggcccctctacttgtcatctatgataaagacaaccggccctcagggatcccagaccgattct ctggctccagctcaggaagcacagcttccttgaccatcactggggctcaggcggaagatgaggctgactattactgtaactcccgggacagcagtggtaaccatctggggg ttctcttcggcggcgggaccaagctgaccgtcacagta SEQ ID No：10。
编码抗体2I3重链可变区的核苷酸序列为：
gaggtgcagctgttggagtctgggggaggcctggtgcagccgggggggtccctgagactctcctgtgtcgcctctggattcacctttagcaaccatgccatgacgtgggtccgccaggctccaggaaagggactggattgggtctcaactataagcggcagtgatggaagcgcaaattacg cagactccgtgaagggccgggttatcatctccagagacaattccaagaacacactgtatctgcaaatgaacagcctgagagccgaagacacgg ccgtatattactgtgcgagg gggaattgggagagttcttatgccttctgtgataactggggccagggaaccctggtcaccgtctcctca SEQ IDNo：19
编码抗体2I3轻链可变区的核苷酸序列为：
gacAtcgTgatgacccagtctccattctccctgcctgtgtctctgggcgagagggccaccatcaactgcaagtccagccagagtgttttatacaggtccaacagtaagaactacttagcttggtatcagcagaaaccaggacaggctcctaagttgctcatttactgggcctctacccgtaaatcc ggggtccctgaccgattcagtgccagcgggtctgggacagatttcactctcaccataagcagcctgcaacctgaggatgtggcagattattactg ccttcaacattat agttttcctttcacttttggccctgggaccaaagtgggcctcaga SEQ ID No：20。
编码抗体3I15重链可变区的核苷酸序列为：
GaGgtgcagctggtggagtctgggggaggcttggtacagcctggggggtcccttagactctcctgtgcagcctctggattcacccttagttcctatggcatgagttgggtccgccaggctccagggaaggggctggagtgggtctcaggccttggttatagtggtgatagtatatactacgcag actccgtgaagggccggttcaccatctccagagacaattccaagaacacgctgtatctccaaatgaacagcctgagagccgcggacacggcc gtatattattgtgcgaga ctttgggtcgcaagtggtggagatgactactggggccagggaaccctggtcaccgtctcctca SEQ ID No： 29
编码抗体3I15轻链可变区的核苷酸序列为：
gaAatTgTgTtgaCacagtctccaGCcAccctgtcgttgtctccaggggagagagccaccctctcctgcagggccagtcagagtgttagccactacttagcgtggtttcaacagaaatctggccaggctcccaggctcctcatctatgatacatccaagagggccactggcaccccagc cacattcagtggcagtgggtctgggacagacttcactctcaccatcagcagcctagagcctgaagattttgcggtttattactgccagcagcgtagcatctggcctctcactttcggcggagggaccaaactggagatcaaa SEQ ID No：30。
编码抗体4E17重链可变区的核苷酸序列为：
gaggtgcagctggtggagtctgggggaggcttggtacagcctggggggtccctgagactctcctgtgcagcctctggattcgccttcagtacctatgccatgaactgggtccgccaggctccagggaaggggctggagtgggtttcatacattagtagtggtagtagtaccatatactacgcaa actctgtgaagggccgattcaccatctccagagacaacgccaagaactcactgtatctgcaaatgaacagcctgagagccgaggacacggctg tgtattactgtgcgaga ggtcggagttacgcattagctgacttgccgtactggggccagggaaccctggtcaccgtctcctca SEQ ID No：39
编码抗体4E17轻链可变区的核苷酸序列为：
gacatccAgatgaCccagtctccatccaccctgtctgcatctgtaggagacagagtcaccatcacttgccgggccagtcagagtattagtagctggttggcctggtatcagcagaaaccagggaaagcccctaagctcctgatctatgaggcgtctagtttagaaagtggggtcccatcaaggt tcagcggcagtggatctgggacagaattcactctcaccatcagcagcctgcagcctgatgactttgcaacttattactgccaacagtataatagttattcttcgctcactttcggcggagggaccaaggtggagatcaaacga SEQ ID No：40。
本发明抗体的重链可变区和轻链可变区序列中，其中下划线部分区域中的显示的是CDR 区。
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SAR-COV-2全人源单克隆抗体或来源于该单克隆 抗体的能够特异性结合SAR-COV-2的生物活性片段的方法，该方法包括培养含编码抗 SAR-COV-2全人源单克隆抗体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SAR-COV-2全人源单克隆抗体。
现有技术中存在采用噬菌体展示技术制备抗SAR-COV-2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SAR-COV-2全人源单克 隆抗体或来源于该单克隆抗体的能够特异性结合SAR-COV-2的生物活性片段。
另一方面，本发明提供所述的抗SAR-COV-2全人源单克隆抗体或来源于该单克隆抗体的 能够特异性结合SAR-COV-2的生物活性片段或所述的药物组合物在制备用于治疗由 SAR-COV-2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SAR-COV-2病毒水平的试剂盒，其含有本发明所述的抗SAR-COV-2全人源单克隆抗体或来源于该单克隆抗体的能够特异性结合SAR-COV-2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的抗抗体。
为了对本发明的技术特征、目的和有益效果有更加清楚的理解，现结合具体实施例对本 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，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SAR-COV-2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，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，获得人源单克隆抗体。
(3)人源单克隆抗体结合SAR-COV-2病毒的表面抗原S蛋白实验
表面抗原S蛋白购自义翘神州公司，具有免疫原性，抗S蛋白抗体可以SAR-COV-2流感病毒。对上述获得的上清液人源单克隆抗体进行ELISA实验，具体地：
(1)将100ng/100μL的SAR-COV-2病毒的HA蛋白包被在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)或上清液，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1所示，ELISA实验表明本发明获得的人源单克隆抗体可以靶向结合SAR-COV-2病 毒的S蛋白。
实施例2人源化单克隆抗体基因的克隆
将实施例1获得的能够分泌结合SAR-COV-2病毒的抗体的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，并且送金唯智公司测序。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 IgepalCA-630(Sigma, I3021-50ML),4U RNAsin(Promega),6U Prime RNAse Inhibitor(Eppendorf)and 50U 
III reverse transcriptase(Invitrogen,18080-044)，补DEPC水至14μL/孔。
(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:
(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)，4μL 2mM 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。
(9)抗体基因重链可变区PCR产物测序结果如下，其中：
抗体2E5的重链可变区核苷酸序列为如SEQ ID No:9所示序列：
CagGTGCagctggtggagtctgggggaggcgtggtccagcctgggaggtccctgagactctcctgtgcagcctctggattcaccttcagtacctatggcatgcactgggtccgccaggctccaggcaaggggctggagtgggtggcagttatatggtatgatggaagtagtaaatcctat gcagactccgtgaagggccgattcaccgtctccagcgacgattccaagaatatattgtatctgcaaatgaacagcctgagagccgaggacacg gctgtctattactgtgcgaga gatccaaagacaacggtgactacaaaaatggacgtctggggccaagggaccacggtcaccgtctcctca SEQ IDNo：9；
抗体2E5重链可变区氨基酸序列为如SEQ ID No:7所示序列:
QVQLVESGGGVVQPGRSLRLSCAASGFTFSTYGMHWVRQAPGKGLEWVAVIWYDGSSKSYADSVKGRFTVSSDDSKNILYLQMNSLRAEDTAVYYCARDPKTTVTTKMDVWGQGTT VTVSS SEQ ID No：7；
抗体2E5轻链可变区核苷酸序列为如SEQ ID No:10所示序列，
tcgtctgagctgactcaggaccctgctgtgtctgtggccttgggacagacagtcaggatcacatgccaaggagacagcctcagactctattatgcaaactggtaccaacagaagccaggacaggcccctctacttgtcatctatgataaagacaaccggccctcagggatcccagaccgattct ctggctccagctcaggaagcacagcttccttgaccatcactggggctcaggcggaagatgaggctgactattactgtaactcccgggacagcagtggtaaccatctggggg ttctcttcggcggcgggaccaagctgaccgtcacagta SEQ ID No：10；
抗体2E5轻链可变区的氨基酸序列如SEQ ID No:8所示序列
SSELTQDPAVSVALGQTVRITCQGDSLRLYYANWYQQKPGQAPLLVIYDKDNRPSGIPD RFSGSSSGSTASLTITGAQAEDEADYYCNSRDSSGNHLGVLFGGGTKLTVT SEQ ID No：8。
抗体2I3的重链可变区核苷酸序列为如SEQ ID No:19所示序列：
gaggtgcagctgttggagtctgggggaggcctggtgcagccgggggggtccctgagactctcctgtgtcgcctctggattcacctttagcaaccatgccatgacgtgggtccgccaggctccaggaaagggactggattgggtctcaactataagcggcagtgatggaagcgcaaattacg cagactccgtgaagggccgggttatcatctccagagacaattccaagaacacactgtatctgcaaatgaacagcctgagagccgaagacacgg ccgtatattactgtgcgagg gggaattgggagagttcttatgccttctgtgataactggggccagggaaccctggtcaccgtctcctca SEQ IDNo：19；
抗体2I3重链可变区氨基酸序列为如SEQ ID No:17所示序列
EVQLLESGGGLVQPGGSLRLSCVASGFTFSNHAMTWVRQAPGKGLDWVSTISGSDGS ANYADSVKGRVIISRDNSKNTLYLQMNSLRAEDTAVYYCARGNWESSYAFCDNWGQGTLV TVSS SEQ ID NO:17；
抗体2I3轻链可变区核苷酸序列为如SEQ ID No:20所示序列，
gacAtcgTgatgacccagtctccattctccctgcctgtgtctctgggcgagagggccaccatcaactgcaagtccagccagagtgttttatacaggtccaacagtaagaactacttagcttggtatcagcagaaaccaggacaggctcctaagttgctcatttactgggcctctacccgtaaatcc ggggtccctgaccgattcagtgccagcgggtctgggacagatttcactctcaccataagcagcctgcaacctgaggatgtggcagattattactg ccttcaacattat agttttcctttcacttttggccctgggaccaaagtgggcctcaga SEQ ID No：20；
抗体2I3轻链可变区的氨基酸序列如SEQ ID No:18所示序列
DIVMTQSPFSLPVSLGERATINCKSSQSVLYRSNSKNYLAWYQQKPGQAPKLLIYWAST RKSGVPDRFSASGSGTDFTLTISSLQPEDVADYYCLQHYSFPFTFGPGTKVGLR SEQ ID NO:18。
抗体3I15的重链可变区核苷酸序列为如SEQ ID No:29所示序列：
GaGgtgcagctggtggagtctgggggaggcttggtacagcctggggggtcccttagactctcctgtgcagcctctggattcacccttagttcctatggcatgagttgggtccgccaggctccagggaaggggctggagtgggtctcaggccttggttatagtggtgatagtatatactacgcag actccgtgaagggccggttcaccatctccagagacaattccaagaacacgctgtatctccaaatgaacagcctgagagccgcggacacggcc gtatattattgtgcgaga ctttgggtcgcaagtggtggagatgactactggggccagggaaccctggtcaccgtctcctca SEQ ID No：29；
抗体3I15重链可变区氨基酸序列为如SEQ ID No:27所示序列
EVQLVESGGGLVQPGGSLRLSCAASGFTLSSYGMSWVRQAPGKGLEWVSGLGYSGDS IYYADSVKGRFTISRDNSKNTLYLQMNSLRAADTAVYYCARLWVASGGDDYWGQGTLVTV SS SEQ ID NO:27；
抗体3I15轻链可变区核苷酸序列为如SEQ ID No:30所示序列，
gaAatTgTgTtgaCacagtctccaGCcAccctgtcgttgtctccaggggagagagccaccctctcctgcagggccagtcagagtgttagccactacttagcgtggtttcaacagaaatctggccaggctcccaggctcctcatctatgatacatccaagagggccactggcaccccagc cacattcagtggcagtgggtctgggacagacttcactctcaccatcagcagcctagagcctgaagattttgcggtttattactgccagcagcgtagcatctggcctctcactttcggcggagggaccaaactggagatcaaa SEQ ID No：30；
抗体3I15轻链可变区的氨基酸序列如SEQ ID No:28所示序列。
EIVLTQSPATLSLSPGERATLSCRASQSVSHYLAWFQQKSGQAPRLLIYDTSKRATGTPA TFSGSGSGTDFTLTISSLEPEDFAVYYCQQRSIWPLTFGGGTKLEIK SEQ ID NO:28。
抗体4E17的重链可变区核苷酸序列为如SEQ ID No:39所示序列：
gaggtgcagctggtggagtctgggggaggcttggtacagcctggggggtccctgagactctcctgtgcagcctctggattcgccttcagtacctatgccatgaactgggtccgccaggctccagggaaggggctggagtgggtttcatacattagtagtggtagtagtaccatatactacgcaa actctgtgaagggccgattcaccatctccagagacaacgccaagaactcactgtatctgcaaatgaacagcctgagagccgaggacacggctg tgtattactgtgcgaga ggtcggagttacgcattagctgacttgccgtactggggccagggaaccctggtcaccgtctcctca SEQ ID No：39；
抗体4E17重链可变区氨基酸序列为如SEQ ID No:37所示序列
EVQLVESGGGLVQPGGSLRLSCAASGFAFSTYAMNWVRQAPGKGLEWVSYISSGSSTI YYANSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARGRSYALADLPYWGQGTLVTV SS SEQ ID NO:37；
抗体4E17轻链可变区核苷酸序列为如SEQ ID No:40所示序列，
gacatccAgatgaCccagtctccatccaccctgtctgcatctgtaggagacagagtcaccatcacttgccgggccagtcagagtattagtagctggttggcctggtatcagcagaaaccagggaaagcccctaagctcctgatctatgaggcgtctagtttagaaagtggggtcccatcaaggt tcagcggcagtggatctgggacagaattcactctcaccatcagcagcctgcagcctgatgactttgcaacttattactgccaacagtataatagttattcttcgctcactttcggcggagggaccaaggtggagatcaaacga SEQ ID No：40；
抗体4E17轻链可变区的氨基酸序列如SEQ ID No:38所示序列
DIQMTQSPSTLSASVGDRVTITCRASQSISSWLAWYQQKPGKAPKLLIYEASSLESGVP SRFSGSGSGTEFTLTISSLQPDDFATYYCQQYNSYSSLTFGGGTKVEIK SEQ ID NO:38。
对应地，各抗体的CDR区序列如下所示：
抗体2E5
2E5-HCDR1：GFTFSTYG SEQ ID No：1；
2E5-HCDR2：IWYDGSSK SEQ ID No：2；
2E5-HCDR3：ARDPKTTVTTKMDV SEQ ID No：3；
2E5-LCDR1：SLRLYY SEQ ID No：4；
2E5-LCDR:2：DKD SEQ ID No：5；以及
2E5-LCDR3：NSRDSSGNHLGVL SEQ ID No：6；
或者
抗体2I3
2I3-HCDR1：GFTFSNHA SEQ ID No：11；
2I3-HCDR2：ISGSDGSA SEQ ID No：12；
2I3-HCDR3：ARGNWESSYAFCDN SEQ ID No：13；
2I3-LCDR1：QSVLYRSNSKNY SEQ ID No：14；
2I3-LCDR:2：WAS SEQ ID No：15；以及
2I3-LCDR3：LQHYSFPFT SEQ ID No：16；
或者
抗体3I15
3I15-HCDR1：GFTLSSYGSEQ ID No：21；
3I15-HCDR2：LGYSGDSI SEQ ID No：22；
3I15-HCDR3：ARLWVASGGDDY SEQ ID No：23；
3I15-LCDR1：QSVSHY SEQ ID No：24；
3I15-LCDR:2：DTS SEQ ID No：25；以及
3I15-LCDR3：QQRSIWPLT SEQ ID No：26；
或者
抗体4E17
4E17-HCDR1：GFAFSTYA SEQ ID No：31；
4E17-HCDR2：ISSGSSTI SEQ ID No：32；
4E17-HCDR3：ARGRSYALADLPY SEQ ID No：33；
4E17-LCDR1：QSISSW SEQ ID No：34；
4E17-LCDR:2：EAS SEQ ID No：35；以及
4E17-LCDR3：QQYNSYSSLT SEQ ID No：36。
上述结果显示上清液中含有能够结合SAR-COV-2病毒的抗体。
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。
SEQUENCE LISTING
<110> 深圳先进技术研究院
<120> 抗SAR-COV-2全人源单克隆抗体及其制法与应用
<130> CP120010923C
<160> 40
<170> PatentIn version 3.3
<210> 1
<211> 8
<212> PRT
<213> 2E5-HCDR1
<400> 1
Gly Phe Thr Phe Ser Thr Tyr Gly
1 5
<210> 2
<211> 8
<212> PRT
<213> 2E5-HCDR2
<400> 2
Ile Trp Tyr Asp Gly Ser Ser Lys
1 5
<210> 3
<211> 14
<212> PRT
<213> 2E5-HCDR3
<400> 3
Ala Arg Asp Pro Lys Thr Thr Val Thr Thr Lys Met Asp Val
1 5 10
<210> 4
<211> 6
<212> PRT
<213> 2E5-LCDR1
<400> 4
Ser Leu Arg Leu Tyr Tyr
1 5
<210> 5
<211> 3
<212> PRT
<213> 2E5-LCDR2
<400> 5
Asp Lys Asp
1
<210> 6
<211> 13
<212> PRT
<213> 2E5-LCDR3
<400> 6
Asn Ser Arg Asp Ser Ser Gly Asn His Leu Gly Val Leu
1 5 10
<210> 7
<211> 121
<212> PRT
<213> 2E5重链可变区
<400> 7
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Thr Tyr
20 25 30
Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Val Ile Trp Tyr Asp Gly Ser Ser Lys Ser Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Val Ser Ser Asp Asp Ser Lys Asn Ile Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Pro Lys Thr Thr Val Thr Thr Lys Met Asp Val Trp Gly
100 105 110
Gln Gly Thr Thr Val Thr Val Ser Ser
115 120
<210> 8
<211> 110
<212> PRT
<213> 2E5轻链可变区
<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 Ser Leu Arg Leu Tyr Tyr Ala
20 25 30
Asn Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Leu Leu Val Ile Tyr
35 40 45
Asp Lys Asp Asn Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser
50 55 60
Ser Ser Gly Ser Thr Ala Ser Leu Thr Ile Thr Gly Ala Gln Ala Glu
65 70 75 80
Asp Glu Ala Asp Tyr Tyr Cys Asn Ser Arg Asp Ser Ser Gly Asn His
85 90 95
Leu Gly Val Leu Phe Gly Gly Gly Thr Lys Leu Thr Val Thr
100 105 110
<210> 9
<211> 363
<212> PRT
<213> 编码抗体2E5重链可变区的核苷酸序列
<400> 9
Cys Ala Gly Gly Thr Gly Cys Ala Gly Cys Thr Gly Gly Thr Gly Gly
1 5 10 15
Ala Gly Thr Cys Thr Gly Gly Gly Gly Gly Ala Gly Gly Cys Gly Thr
20 25 30
Gly Gly Thr Cys Cys Ala Gly Cys Cys Thr Gly Gly Gly Ala Gly Gly
35 40 45
Thr Cys Cys Cys Thr Gly Ala Gly Ala Cys Thr Cys Thr Cys Cys Thr
50 55 60
Gly Thr Gly Cys Ala Gly Cys Cys Thr Cys Thr Gly Gly Ala Thr Thr
65 70 75 80
Cys Ala Cys Cys Thr Thr Cys Ala Gly Thr Ala Cys Cys Thr Ala Thr
85 90 95
Gly Gly Cys Ala Thr Gly Cys Ala Cys Thr Gly Gly Gly Thr Cys Cys
100 105 110
Gly Cys Cys Ala Gly Gly Cys Thr Cys Cys Ala Gly Gly Cys Ala Ala
115 120 125
Gly Gly Gly Gly Cys Thr Gly Gly Ala Gly Thr Gly Gly Gly Thr Gly
130 135 140
Gly Cys Ala Gly Thr Thr Ala Thr Ala Thr Gly Gly Thr Ala Thr Gly
145 150 155 160
Ala Thr Gly Gly Ala Ala Gly Thr Ala Gly Thr Ala Ala Ala Thr Cys
165 170 175
Cys Thr Ala Thr Gly Cys Ala Gly Ala Cys Thr Cys Cys Gly Thr Gly
180 185 190
Ala Ala Gly Gly Gly Cys Cys Gly Ala Thr Thr Cys Ala Cys Cys Gly
195 200 205
Thr Cys Thr Cys Cys Ala Gly Cys Gly Ala Cys Gly Ala Thr Thr Cys
210 215 220
Cys Ala Ala Gly Ala Ala Thr Ala Thr Ala Thr Thr Gly Thr Ala Thr
225 230 235 240
Cys Thr Gly Cys Ala Ala Ala Thr Gly Ala Ala Cys Ala Gly Cys Cys
245 250 255
Thr Gly Ala Gly Ala Gly Cys Cys Gly Ala Gly Gly Ala Cys Ala Cys
260 265 270
Gly Gly Cys Thr Gly Thr Cys Thr Ala Thr Thr Ala Cys Thr Gly Thr
275 280 285
Gly Cys Gly Ala Gly Ala Gly Ala Thr Cys Cys Ala Ala Ala Gly Ala
290 295 300
Cys Ala Ala Cys Gly Gly Thr Gly Ala Cys Thr Ala Cys Ala Ala Ala
305 310 315 320
Ala Ala Thr Gly Gly Ala Cys Gly Thr Cys Thr Gly Gly Gly Gly Cys
325 330 335
Cys Ala Ala Gly Gly Gly Ala Cys Cys Ala Cys Gly Gly Thr Cys Ala
340 345 350
Cys Cys Gly Thr Cys Thr Cys Cys Thr Cys Ala
355 360
<210> 10
<211> 333
<212> DNA
<213> 编码抗体2E5轻链可变区的核苷酸序列
<400> 10
tcgtctgagc tgactcagga ccctgctgtg tctgtggcct tgggacagac agtcaggatc 60
acatgccaag gagacagcct cagactctat tatgcaaact ggtaccaaca gaagccagga 120
caggcccctc tacttgtcat ctatgataaa gacaaccggc cctcagggat cccagaccga 180
ttctctggct ccagctcagg aagcacagct tccttgacca tcactggggc tcaggcggaa 240
gatgaggctg actattactg taactcccgg gacagcagtg gtaaccatct gggggttctc 300
ttcggcggcg ggaccaagct gaccgtcaca gta 333
<210> 11
<211> 8
<212> PRT
<213> 2I3-HCDR1
<400> 11
Gly Phe Thr Phe Ser Asn His Ala
1 5
<210> 12
<211> 8
<212> PRT
<213> 2I3-HCDR2
<400> 12
Ile Ser Gly Ser Asp Gly Ser Ala
1 5
<210> 13
<211> 14
<212> PRT
<213> 2I3-HCDR3
<400> 13
Ala Arg Gly Asn Trp Glu Ser Ser Tyr Ala Phe Cys Asp Asn
1 5 10
<210> 14
<211> 12
<212> PRT
<213> 2I3-LCDR1
<400> 14
Gln Ser Val Leu Tyr Arg Ser Asn Ser Lys Asn Tyr
1 5 10
<210> 15
<211> 3
<212> PRT
<213> 2I3-LCDR1
<400> 15
Trp Ala Ser
1
<210> 16
<211> 9
<212> PRT
<213> 2I3-LCDR
<400> 16
Leu Gln His Tyr Ser Phe Pro Phe Thr
1 5
<210> 17
<211> 121
<212> PRT
<213> 2I3重链可变区
<400> 17
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Val Ala Ser Gly Phe Thr Phe Ser Asn His
20 25 30
Ala Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Asp Trp Val
35 40 45
Ser Thr Ile Ser Gly Ser Asp Gly Ser Ala Asn Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Val Ile Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Asn Trp Glu Ser Ser Tyr Ala Phe Cys Asp Asn Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 18
<211> 113
<212> PRT
<213> 2I3轻链可变区
<400> 18
Asp Ile Val Met Thr Gln Ser Pro Phe Ser Leu Pro Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Val Leu Tyr Arg
20 25 30
Ser Asn Ser Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Ala Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Lys Ser Gly Val
50 55 60
Pro Asp Arg Phe Ser Ala Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Leu Gln Pro Glu Asp Val Ala Asp Tyr Tyr Cys Leu Gln
85 90 95
His Tyr Ser Phe Pro Phe Thr Phe Gly Pro Gly Thr Lys Val Gly Leu
100 105 110
Arg
<210> 19
<211> 363
<212> DNA
<213> 编码抗体2I3重链可变区的核苷酸序列
<400> 19
gaggtgcagc tgttggagtc tgggggaggc ctggtgcagc cgggggggtc cctgagactc 60
tcctgtgtcg cctctggatt cacctttagc aaccatgcca tgacgtgggt ccgccaggct 120
ccaggaaagg gactggattg ggtctcaact ataagcggca gtgatggaag cgcaaattac 180
gcagactccg tgaagggccg ggttatcatc tccagagaca attccaagaa cacactgtat 240
ctgcaaatga acagcctgag agccgaagac acggccgtat attactgtgc gagggggaat 300
tgggagagtt cttatgcctt ctgtgataac tggggccagg gaaccctggt caccgtctcc 360
tca 363
<210> 20
<211> 339
<212> DNA
<213> 编码抗体2I3轻链可变区的核苷酸序列
<400> 20
gacatcgtga tgacccagtc tccattctcc ctgcctgtgt ctctgggcga gagggccacc 60
atcaactgca agtccagcca gagtgtttta tacaggtcca acagtaagaa ctacttagct 120
tggtatcagc agaaaccagg acaggctcct aagttgctca tttactgggc ctctacccgt 180
aaatccgggg tccctgaccg attcagtgcc agcgggtctg ggacagattt cactctcacc 240
ataagcagcc tgcaacctga ggatgtggca gattattact gccttcaaca ttatagtttt 300
cctttcactt ttggccctgg gaccaaagtg ggcctcaga 339
<210> 21
<211> 8
<212> PRT
<213> 3I15-HCDR1
<400> 21
Gly Phe Thr Leu Ser Ser Tyr Gly
1 5
<210> 22
<211> 8
<212> PRT
<213> 3I15-HCDR2
<400> 22
Leu Gly Tyr Ser Gly Asp Ser Ile
1 5
<210> 23
<211> 12
<212> PRT
<213> 3I15-HCDR3
<400> 23
Ala Arg Leu Trp Val Ala Ser Gly Gly Asp Asp Tyr
1 5 10
<210> 24
<211> 6
<212> PRT
<213> 3I15-LCDR1
<400> 24
Gln Ser Val Ser His Tyr
1 5
<210> 25
<211> 3
<212> PRT
<213> 3I15-LCDR2
<400> 25
Asp Thr Ser
1
<210> 26
<211> 9
<212> PRT
<213> 3I15-LCDR3
<400> 26
Gln Gln Arg Ser Ile Trp Pro Leu Thr
1 5
<210> 27
<211> 119
<212> PRT
<213> 3I15的重链可变区氨基酸序列
<400> 27
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Leu Ser Ser Tyr
20 25 30
Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Gly Leu Gly Tyr Ser Gly Asp Ser Ile Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Ala Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Leu Trp Val Ala Ser Gly Gly Asp Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 28
<211> 107
<212> PRT
<213> 3I15的轻链可变区氨基酸序列
<400> 28
Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser His Tyr
20 25 30
Leu Ala Trp Phe Gln Gln Lys Ser Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Tyr Asp Thr Ser Lys Arg Ala Thr Gly Thr Pro Ala Thr Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro
65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Arg Ser Ile Trp Pro Leu
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 29
<211> 357
<212> DNA
<213> 抗体3I15的重链可变区核苷酸序列
<400> 29
gaggtgcagc tggtggagtc tgggggaggc ttggtacagc ctggggggtc ccttagactc 60
tcctgtgcag cctctggatt cacccttagt tcctatggca tgagttgggt ccgccaggct 120
ccagggaagg ggctggagtg ggtctcaggc cttggttata gtggtgatag tatatactac 180
gcagactccg tgaagggccg gttcaccatc tccagagaca attccaagaa cacgctgtat 240
ctccaaatga acagcctgag agccgcggac acggccgtat attattgtgc gagactttgg 300
gtcgcaagtg gtggagatga ctactggggc cagggaaccc tggtcaccgt ctcctca 357
<210> 30
<211> 321
<212> DNA
<213> 抗体3I15轻链可变区核苷酸序列
<400> 30
gaaattgtgt tgacacagtc tccagccacc ctgtcgttgt ctccagggga gagagccacc 60
ctctcctgca gggccagtca gagtgttagc cactacttag cgtggtttca acagaaatct 120
ggccaggctc ccaggctcct catctatgat acatccaaga gggccactgg caccccagcc 180
acattcagtg gcagtgggtc tgggacagac ttcactctca ccatcagcag cctagagcct 240
gaagattttg cggtttatta ctgccagcag cgtagcatct ggcctctcac tttcggcgga 300
gggaccaaac tggagatcaa a 321
<210> 31
<211> 8
<212> PRT
<213> 4E17-HCDR1
<400> 31
Gly Phe Ala Phe Ser Thr Tyr Ala
1 5
<210> 32
<211> 8
<212> PRT
<213> 4E17-HCDR2
<400> 32
Ile Ser Ser Gly Ser Ser Thr Ile
1 5
<210> 33
<211> 13
<212> PRT
<213> 4E17-HCDR3
<400> 33
Ala Arg Gly Arg Ser Tyr Ala Leu Ala Asp Leu Pro Tyr
1 5 10
<210> 34
<211> 6
<212> PRT
<213> 4E17-LCDR1
<400> 34
Gln Ser Ile Ser Ser Trp
1 5
<210> 35
<211> 3
<212> PRT
<213> 4E17-LCDR2
<400> 35
Glu Ala Ser
1
<210> 36
<211> 10
<212> PRT
<213> 4E17-LCDR3
<400> 36
Gln Gln Tyr Asn Ser Tyr Ser Ser Leu Thr
1 5 10
<210> 37
<211> 120
<212> PRT
<213> 抗体4E17重链可变区氨基酸序列
<400> 37
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ala Phe Ser Thr Tyr
20 25 30
Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Tyr Ile Ser Ser Gly Ser Ser Thr Ile Tyr Tyr Ala Asn Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Arg Ser Tyr Ala Leu Ala Asp Leu Pro Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 38
<211> 108
<212> PRT
<213> 抗体4E17轻链可变区的氨基酸序列
<400> 38
Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Trp
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Glu Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asn Ser Tyr Ser Ser
85 90 95
Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 39
<211> 360
<212> DNA
<213> 抗体4E17的重链可变区核苷酸序列
<400> 39
gaggtgcagc tggtggagtc tgggggaggc ttggtacagc ctggggggtc cctgagactc 60
tcctgtgcag cctctggatt cgccttcagt acctatgcca tgaactgggt ccgccaggct 120
ccagggaagg ggctggagtg ggtttcatac attagtagtg gtagtagtac catatactac 180
gcaaactctg tgaagggccg attcaccatc tccagagaca acgccaagaa ctcactgtat 240
ctgcaaatga acagcctgag agccgaggac acggctgtgt attactgtgc gagaggtcgg 300
agttacgcat tagctgactt gccgtactgg ggccagggaa ccctggtcac cgtctcctca 360
<210> 40
<211> 327
<212> DNA
<213> 抗体4E17轻链可变区核苷酸序列
<400> 40
gacatccaga tgacccagtc tccatccacc ctgtctgcat ctgtaggaga cagagtcacc 60
atcacttgcc gggccagtca gagtattagt agctggttgg cctggtatca gcagaaacca 120
gggaaagccc ctaagctcct gatctatgag gcgtctagtt tagaaagtgg ggtcccatca 180
aggttcagcg gcagtggatc tgggacagaa ttcactctca ccatcagcag cctgcagcct 240
gatgactttg caacttatta ctgccaacag tataatagtt attcttcgct cactttcggc 300
ggagggacca aggtggagat caaacga 327
Claims (11)
1.一种分离的抗SAR-COV-2的抗体或其抗原结合片段，其具有如下任一组的三个重链互补决定区和三个轻链互补决定区：
抗体2E5
2E5-HCDR1：GFTFSTYG SEQ ID No：1；
2E5-HCDR2：IWYDGSSK SEQ ID No：2；
2E5-HCDR3：ARDPKTTVTTKMDV SEQ ID No：3；
2E5-LCDR1：SLRLYY SEQ ID No：4；
2E5-LCDR:2：DKD SEQ ID No：5；以及
2E5-LCDR3：NSRDSSGNHLGVL SEQ ID No：6；
或者
抗体2I3
2I3-HCDR1：GFTFSNHA SEQ ID No：11；
2I3-HCDR2：ISGSDGSA SEQ ID No：12；
2I3-HCDR3：ARGNWESSYAFCDN SEQ ID No：13；
2I3-LCDR1：QSVLYRSNSKNY SEQ ID No：14；
2I3-LCDR:2：WAS SEQ ID No：15；以及
2I3-LCDR3：LQHYSFPFT SEQ ID No：16；
或者
抗体3I15
3I15-HCDR1：GFTLSSYG SEQ ID No：21；
3I15-HCDR2：LGYSGDSI SEQ ID No：22；
3I15-HCDR3：ARLWVASGGDDY SEQ ID No：23；
3I15-LCDR1：QSVSHY SEQ ID No：24；
3I15-LCDR:2：DTS SEQ ID No：25；以及
3I15-LCDR3：QQRSIWPLT SEQ ID No：26；
或者
抗体4E17
4E17-HCDR1：GFAFSTYA SEQ ID No：31；
4E17-HCDR2：ISSGSSTI SEQ ID No：32；
4E17-HCDR3：ARGRSYALADLPY SEQ ID No：33；
4E17-LCDR1：QSISSW SEQ ID No：34；
4E17-LCDR:2：EAS SEQ ID No：35；以及
4E17-LCDR3：QQYNSYSSLT SEQ ID No：36。
2.根据权利要求1所述的分离的抗SAR-COV-2的抗体或其抗原结合片段，抗体2E5的重链可变区和轻链可变区的序列分别为；
2E5重链可变区：
QVQLVESGGGVVQPGRSLRLSCAASGFTFSTYGMHWVRQAPGKGLEWVAVIWYDGSSKSYADSVKGRFTVSSDDSKNILYLQMNSLRAEDTAVYYCARDPKTTVTTKMDVWGQGTTVTVSS SEQ ID No：7，
2E5轻链可变区：
SSELTQDPAVSVALGQTVRITCQGDSLRLYYANWYQQKPGQAPLLVIYDKDNRPSGIPDRFSGSSSGSTASLTITGAQAEDEADYYCNSRDSSGNHLGVLFGGGTKLTVT SEQ ID No：8；
或者，抗体2I3的重链可变区和轻链可变区的序列分别为；
2I3重链可变区：
EVQLLESGGGLVQPGGSLRLSCVASGFTFSNHAMTWVRQAPGKGLDWVSTISGSDGSANYADSVKGRVIISRDNSKNTLYLQMNSLRAEDTAVYYCARGNWESSYAFCDNWGQGTLVTVSS SEQ ID NO:17，
2I3轻链可变区：
DIVMTQSPFSLPVSLGERATINCKSSQSVLYRSNSKNYLAWYQQKPGQAPKLLIYWASTRKSGVPDRFSASGSGTDFTLTISSLQPEDVADYYCLQHYSFPFTFGPGTKVGLR SEQ ID NO:18；
或者，抗体3I15的重链可变区和轻链可变区的序列分别为；
3I15重链可变区：
EVQLVESGGGLVQPGGSLRLSCAASGFTLSSYGMSWVRQAPGKGLEWVSGLGYSGDSIYYADSVKGRFTISRDNSKNTLYLQMNSLRAADTAVYYCARLWVASGGDDYWGQGTLVTVSS SEQ ID NO:27，
3I15轻链可变区
EIVLTQSPATLSLSPGERATLSCRASQSVSHYLAWFQQKSGQAPRLLIYDTSKRATGTPATFSGSGSGTDFTLTISSLEPEDFAVYYCQQRSIWPLTFGGGTKLEIK SEQ ID NO:28；
或者，抗体4E17的重链可变区和轻链可变区的序列分别为；
4E17重链可变区：
EVQLVESGGGLVQPGGSLRLSCAASGFAFSTYAMNWVRQAPGKGLEWVSYISSGSSTIYYANSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARGRSYALADLPYWGQGTLVTVSS SEQ ID NO:37，
4E17轻链可变区
DIQMTQSPSTLSASVGDRVTITCRASQSISSWLAWYQQKPGKAPKLLIYEASSLESGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQQYNSYSSLTFGGGTKVEIK SEQ ID NO:38。
3.根据权利要求1或权利要求2任一项所述的抗体或其抗原结合片段，所述的抗体或其抗原结合片段为人源化的抗体或其抗原结合片段。
4.一种核苷酸序列，其特征在于：其编码如权利要求1-3任一项所述的抗体或其抗原结合片段。
5.一种载体，其特征在于：包含权利要求4所述的核苷酸序列。
6.一种宿主细胞，其特征在于：包含权利要求5所述载体。
7.一种试剂盒，所述试剂盒包含如权利要求1-3任一项所述的抗体或其抗原结合片段。
8.一种检测试剂，所述检测试剂包含如权利要求1-3任一项所述的抗体或其抗原结合片段。
9.如权利要求1-3任一项所述的抗体或其抗原结合片段作为检测试剂的用途，所述试剂用于以下用途的试剂：酶联免疫吸附检测、免疫印迹、流式细胞术、免疫组织化学检测或者免疫PCR。
10.一种药物组合物，其如权利要求1-3任一项所述的分离的抗体或其抗原结合片段和药物上可接受辅料。
11.权利要求1-3任一项所述的抗SAR-COV-2的抗体或其抗原结合片段，或权利要求10所述的药物组合物在制备预防、治疗或缓解SAR-COV-2感染的至少一种症状或适应症的药物中的用途；
优选地，所述至少一种症状或适应症选自下组：新型冠状病毒肺炎、肺部炎症、肺泡损伤、发热、咳嗽、呼吸困难、低血氧症、急性呼吸窘迫综合征、脓毒症休克、凝血功能障碍、代谢性酸中毒、鼻塞、流涕、咽痛、腹泻、器官衰竭、败血性休克和死亡。
Priority Applications (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202311623596.6A CN117924466A (zh) | 2020-12-02 | 2020-12-02 | 广谱抗冠状病毒全人源单克隆抗体及其制法与应用 |
| CN202011390806.8A CN114573690B (zh) | 2020-12-02 | 2020-12-02 | 抗sar-cov-2全人源单克隆抗体及其制法与应用 |
| CN202311623600.9A CN117924467A (zh) | 2020-12-02 | 2020-12-02 | 广谱抗冠状病毒全人源单克隆抗体及其制法与应用 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202011390806.8A CN114573690B (zh) | 2020-12-02 | 2020-12-02 | 抗sar-cov-2全人源单克隆抗体及其制法与应用 |
Related Child Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202311623600.9A Division CN117924467A (zh) | 2020-12-02 | 2020-12-02 | 广谱抗冠状病毒全人源单克隆抗体及其制法与应用 |
| CN202311623596.6A Division CN117924466A (zh) | 2020-12-02 | 2020-12-02 | 广谱抗冠状病毒全人源单克隆抗体及其制法与应用 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN114573690A true CN114573690A (zh) | 2022-06-03 |
| CN114573690B CN114573690B (zh) | 2023-12-12 |
Family
ID=81768828
Family Applications (3)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202311623596.6A Pending CN117924466A (zh) | 2020-12-02 | 2020-12-02 | 广谱抗冠状病毒全人源单克隆抗体及其制法与应用 |
| CN202011390806.8A Active CN114573690B (zh) | 2020-12-02 | 2020-12-02 | 抗sar-cov-2全人源单克隆抗体及其制法与应用 |
| CN202311623600.9A Pending CN117924467A (zh) | 2020-12-02 | 2020-12-02 | 广谱抗冠状病毒全人源单克隆抗体及其制法与应用 |
Family Applications Before (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202311623596.6A Pending CN117924466A (zh) | 2020-12-02 | 2020-12-02 | 广谱抗冠状病毒全人源单克隆抗体及其制法与应用 |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202311623600.9A Pending CN117924467A (zh) | 2020-12-02 | 2020-12-02 | 广谱抗冠状病毒全人源单克隆抗体及其制法与应用 |
Country Status (1)
| Country | Link |
|---|---|
| CN (3) | CN117924466A (zh) |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111592594A (zh) * | 2020-03-13 | 2020-08-28 | 北京大学 | 一种抗新型冠状病毒的单克隆抗体及其应用 |
| CN111620945A (zh) * | 2020-05-09 | 2020-09-04 | 江苏省疾病预防控制中心(江苏省公共卫生研究院) | 一种抗新型冠状病毒的单克隆抗体或其衍生体 |
| CN111690059A (zh) * | 2020-06-19 | 2020-09-22 | 武汉生物制品研究所有限责任公司 | 一种抗SARS-CoV-2的单克隆抗体1D7 |
| CN111718411A (zh) * | 2020-06-19 | 2020-09-29 | 武汉生物制品研究所有限责任公司 | 一种抗SARS-CoV-2的单克隆抗体1F2 |
| CN111995675A (zh) * | 2020-05-15 | 2020-11-27 | 潍坊医学院 | 一种针对新冠病毒SARS-CoV-2棘突蛋白RBD区的单克隆抗体及其应用 |
-
2020
- 2020-12-02 CN CN202311623596.6A patent/CN117924466A/zh active Pending
- 2020-12-02 CN CN202011390806.8A patent/CN114573690B/zh active Active
- 2020-12-02 CN CN202311623600.9A patent/CN117924467A/zh active Pending
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111592594A (zh) * | 2020-03-13 | 2020-08-28 | 北京大学 | 一种抗新型冠状病毒的单克隆抗体及其应用 |
| CN111620945A (zh) * | 2020-05-09 | 2020-09-04 | 江苏省疾病预防控制中心(江苏省公共卫生研究院) | 一种抗新型冠状病毒的单克隆抗体或其衍生体 |
| CN111995675A (zh) * | 2020-05-15 | 2020-11-27 | 潍坊医学院 | 一种针对新冠病毒SARS-CoV-2棘突蛋白RBD区的单克隆抗体及其应用 |
| CN112010966A (zh) * | 2020-05-15 | 2020-12-01 | 潍坊医学院 | 一种针对新冠病毒棘突蛋白非rbd区的单克隆抗体及其应用 |
| CN111690059A (zh) * | 2020-06-19 | 2020-09-22 | 武汉生物制品研究所有限责任公司 | 一种抗SARS-CoV-2的单克隆抗体1D7 |
| CN111718411A (zh) * | 2020-06-19 | 2020-09-29 | 武汉生物制品研究所有限责任公司 | 一种抗SARS-CoV-2的单克隆抗体1F2 |
Non-Patent Citations (2)
| Title |
|---|
| ROGERS T.F.等: "Isolation of potent SARS-CoV-2 neutralizing antibodies and protection from disease in a small animal model", SCIENCE * |
| 杜剑晖 等: "新型冠状病毒中和抗体的研发策略及研究进展", 中国生物制品学杂志 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN117924466A (zh) | 2024-04-26 |
| CN117924467A (zh) | 2024-04-26 |
| CN114573690B (zh) | 2023-12-12 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN108640989B (zh) | 可结合并中和b型流感病毒的人类结合分子及其用途 | |
| KR101732056B1 (ko) | 중화 항-인플루엔자 ａ 바이러스 항체 및 이의 용도 | |
| CN101522716B (zh) | 抗人il-4受体的高亲和力人抗体 | |
| CA2759848C (en) | Anti-il-17f antibodies and methods of use thereof | |
| CN112574300B (zh) | 抗sar-cov-2全人源单克隆抗体及其制法与应用 | |
| CN113354732A (zh) | 针对埃博拉病毒糖蛋白的人抗体 | |
| KR20140014067A (ko) | 항-cd48 항체 및 그의 용도 | |
| CA2508375A1 (en) | Antibodies directed to tumor necrosis factor and uses thereof | |
| KR20110052585A (ko) | 인간 사이토메갈바이러스 중화 항체 및 이의 용도 | |
| KR20150061041A (ko) | 인간 ｏｘ４０ 수용체에 대한 결합 분자 | |
| TW201233796A (en) | Human antibodies to human TNF-like ligand 1A (TL1A) | |
| HUE031725T2 (en) | High Human Human Protease Activated Receptor-2 Affinity | |
| KR20190103147A (ko) | 항-호흡기 세포융합 바이러스 항체, 그리고 이의 생성 방법 및 사용 방법 | |
| AU2017237543A1 (en) | Antibody that binds to envelope glycoprotein of severe fever with thrombocytopenia syndrome virus, and use for same | |
| KR20240064051A (ko) | 항-cd115 항체 | |
| CN114685652B (zh) | 针对SARS-CoV-2和SARS-CoV的全人广谱交叉中和抗体及其应用 | |
| CN107922939B (zh) | 中和全部种类埃博拉病毒的感染性的单克隆抗体 | |
| KR20220038415A (ko) | 엔테로바이러스 d68에 대한 인간 모노클로날 항체 | |
| KR20190077306A (ko) | 항-o2 항체 및 이의 용도 | |
| TW202235432A (zh) | 中和抗ｓａｒｓ－ｃｏｖ－２抗體 | |
| KR20230042598A (ko) | SARS-CoV-2 중화 항체 또는 그 단편 | |
| CN113896788B (zh) | 抗sar-cov-2（covid-19）全人源单克隆抗体及其制法与应用 | |
| CN114573690B (zh) | 抗sar-cov-2全人源单克隆抗体及其制法与应用 | |
| WO2021248276A1 (zh) | 一种抗sar-cov-2抗体或其抗原结合片段及其应用 | |
| KR20240006575A (ko) | SARS-CoV-2에 대한 사람 중화 모노클로날 항체 및 이의 용도 |
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 |