CN107207602A - 改良的april结合抗体 - Google Patents
改良的april结合抗体 Download PDFInfo
- Publication number
- CN107207602A CN107207602A CN201680006375.6A CN201680006375A CN107207602A CN 107207602 A CN107207602 A CN 107207602A CN 201680006375 A CN201680006375 A CN 201680006375A CN 107207602 A CN107207602 A CN 107207602A
- Authority
- CN
- China
- Prior art keywords
- antibody
- ser
- val
- thr
- gly
- 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
- 230000027455 binding Effects 0.000 title claims abstract description 48
- 230000006872 improvement Effects 0.000 title description 11
- 239000000427 antigen Substances 0.000 claims abstract description 37
- 108091007433 antigens Proteins 0.000 claims abstract description 37
- 102000036639 antigens Human genes 0.000 claims abstract description 37
- 239000000203 mixture Substances 0.000 claims abstract description 35
- 125000003275 alpha amino acid group Chemical group 0.000 claims description 54
- 108060003951 Immunoglobulin Proteins 0.000 claims description 49
- 210000004027 cell Anatomy 0.000 claims description 49
- 102000018358 immunoglobulin Human genes 0.000 claims description 49
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 45
- 201000010099 disease Diseases 0.000 claims description 41
- 238000000034 method Methods 0.000 claims description 41
- 108091033319 polynucleotide Proteins 0.000 claims description 38
- 102000040430 polynucleotide Human genes 0.000 claims description 38
- 239000002157 polynucleotide Substances 0.000 claims description 38
- 150000001413 amino acids Chemical class 0.000 claims description 34
- 230000014509 gene expression Effects 0.000 claims description 34
- 238000011282 treatment Methods 0.000 claims description 33
- 241000282414 Homo sapiens Species 0.000 claims description 31
- 206010028980 Neoplasm Diseases 0.000 claims description 27
- 238000002965 ELISA Methods 0.000 claims description 24
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 24
- 201000011510 cancer Diseases 0.000 claims description 22
- 108010021625 Immunoglobulin Fragments Proteins 0.000 claims description 21
- 102000008394 Immunoglobulin Fragments Human genes 0.000 claims description 21
- 239000002253 acid Substances 0.000 claims description 19
- 239000002773 nucleotide Substances 0.000 claims description 19
- 125000003729 nucleotide group Chemical group 0.000 claims description 19
- 102000004196 processed proteins & peptides Human genes 0.000 claims description 17
- 238000002560 therapeutic procedure Methods 0.000 claims description 17
- 102000006942 B-Cell Maturation Antigen Human genes 0.000 claims description 16
- 108010008014 B-Cell Maturation Antigen Proteins 0.000 claims description 16
- BGFTWECWAICPDG-UHFFFAOYSA-N 2-[bis(4-chlorophenyl)methyl]-4-n-[3-[bis(4-chlorophenyl)methyl]-4-(dimethylamino)phenyl]-1-n,1-n-dimethylbenzene-1,4-diamine Chemical compound C1=C(C(C=2C=CC(Cl)=CC=2)C=2C=CC(Cl)=CC=2)C(N(C)C)=CC=C1NC(C=1)=CC=C(N(C)C)C=1C(C=1C=CC(Cl)=CC=1)C1=CC=C(Cl)C=C1 BGFTWECWAICPDG-UHFFFAOYSA-N 0.000 claims description 15
- 238000009175 antibody therapy Methods 0.000 claims description 15
- 238000000926 separation method Methods 0.000 claims description 15
- 229920001184 polypeptide Polymers 0.000 claims description 14
- 230000001225 therapeutic effect Effects 0.000 claims description 13
- 101000795167 Homo sapiens Tumor necrosis factor receptor superfamily member 13B Proteins 0.000 claims description 12
- 102100029675 Tumor necrosis factor receptor superfamily member 13B Human genes 0.000 claims description 12
- 230000004083 survival effect Effects 0.000 claims description 12
- -1 Amino Chemical group 0.000 claims description 11
- 239000003795 chemical substances by application Substances 0.000 claims description 11
- 239000013604 expression vector Substances 0.000 claims description 11
- 150000001875 compounds Chemical class 0.000 claims description 10
- 208000023275 Autoimmune disease Diseases 0.000 claims description 9
- 206010061218 Inflammation Diseases 0.000 claims description 9
- 230000004054 inflammatory process Effects 0.000 claims description 9
- 230000008685 targeting Effects 0.000 claims description 9
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 claims description 8
- 238000003745 diagnosis Methods 0.000 claims description 8
- 210000002865 immune cell Anatomy 0.000 claims description 8
- UEJJHQNACJXSKW-UHFFFAOYSA-N 2-(2,6-dioxopiperidin-3-yl)-1H-isoindole-1,3(2H)-dione Chemical class O=C1C2=CC=CC=C2C(=O)N1C1CCC(=O)NC1=O UEJJHQNACJXSKW-UHFFFAOYSA-N 0.000 claims description 7
- 229960003957 dexamethasone Drugs 0.000 claims description 6
- UREBDLICKHMUKA-CXSFZGCWSA-N dexamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-CXSFZGCWSA-N 0.000 claims description 6
- 229960004942 lenalidomide Drugs 0.000 claims description 6
- GOTYRUGSSMKFNF-UHFFFAOYSA-N lenalidomide Chemical compound C1C=2C(N)=CC=CC=2C(=O)N1C1CCC(=O)NC1=O GOTYRUGSSMKFNF-UHFFFAOYSA-N 0.000 claims description 6
- 108090001005 Interleukin-6 Proteins 0.000 claims description 5
- 239000000370 acceptor Substances 0.000 claims description 5
- 239000001963 growth medium Substances 0.000 claims description 5
- 238000000338 in vitro Methods 0.000 claims description 5
- 230000009467 reduction Effects 0.000 claims description 5
- 229960001467 bortezomib Drugs 0.000 claims description 4
- GXJABQQUPOEUTA-RDJZCZTQSA-N bortezomib Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)B(O)O)NC(=O)C=1N=CC=NC=1)C1=CC=CC=C1 GXJABQQUPOEUTA-RDJZCZTQSA-N 0.000 claims description 4
- 239000003085 diluting agent Substances 0.000 claims description 4
- 229960004679 doxorubicin Drugs 0.000 claims description 4
- 229960000688 pomalidomide Drugs 0.000 claims description 4
- UVSMNLNDYGZFPF-UHFFFAOYSA-N pomalidomide Chemical compound O=C1C=2C(N)=CC=CC=2C(=O)N1C1CCC(=O)NC1=O UVSMNLNDYGZFPF-UHFFFAOYSA-N 0.000 claims description 4
- 229960005205 prednisolone Drugs 0.000 claims description 4
- OIGNJSKKLXVSLS-VWUMJDOOSA-N prednisolone Chemical compound O=C1C=C[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 OIGNJSKKLXVSLS-VWUMJDOOSA-N 0.000 claims description 4
- 229960003433 thalidomide Drugs 0.000 claims description 4
- 229960002707 bendamustine Drugs 0.000 claims description 3
- YTKUWDBFDASYHO-UHFFFAOYSA-N bendamustine Chemical compound ClCCN(CCCl)C1=CC=C2N(C)C(CCCC(O)=O)=NC2=C1 YTKUWDBFDASYHO-UHFFFAOYSA-N 0.000 claims description 3
- 229960004630 chlorambucil Drugs 0.000 claims description 3
- JCKYGMPEJWAADB-UHFFFAOYSA-N chlorambucil Chemical compound OC(=O)CCCC1=CC=C(N(CCCl)CCCl)C=C1 JCKYGMPEJWAADB-UHFFFAOYSA-N 0.000 claims description 3
- 239000003246 corticosteroid Substances 0.000 claims description 3
- VJJPUSNTGOMMGY-MRVIYFEKSA-N etoposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@H](C)OC[C@H]4O3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 VJJPUSNTGOMMGY-MRVIYFEKSA-N 0.000 claims description 3
- 229960005420 etoposide Drugs 0.000 claims description 3
- 238000000684 flow cytometry Methods 0.000 claims description 3
- 229960000390 fludarabine Drugs 0.000 claims description 3
- GIUYCYHIANZCFB-FJFJXFQQSA-N fludarabine phosphate Chemical compound C1=NC=2C(N)=NC(F)=NC=2N1[C@@H]1O[C@H](COP(O)(O)=O)[C@@H](O)[C@@H]1O GIUYCYHIANZCFB-FJFJXFQQSA-N 0.000 claims description 3
- 238000002991 immunohistochemical analysis Methods 0.000 claims description 3
- 239000002609 medium Substances 0.000 claims description 3
- 229960001924 melphalan Drugs 0.000 claims description 3
- SGDBTWWWUNNDEQ-LBPRGKRZSA-N melphalan Chemical compound OC(=O)[C@@H](N)CC1=CC=C(N(CCCl)CCCl)C=C1 SGDBTWWWUNNDEQ-LBPRGKRZSA-N 0.000 claims description 3
- WRUUGTRCQOWXEG-UHFFFAOYSA-N pamidronate Chemical compound NCCC(O)(P(O)(O)=O)P(O)(O)=O WRUUGTRCQOWXEG-UHFFFAOYSA-N 0.000 claims description 3
- 229940046231 pamidronate Drugs 0.000 claims description 3
- 229910052697 platinum Inorganic materials 0.000 claims description 3
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Substances [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 claims description 3
- 229960004641 rituximab Drugs 0.000 claims description 3
- 238000001262 western blot Methods 0.000 claims description 3
- 102100031585 ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase 1 Human genes 0.000 claims description 2
- 102100022005 B-lymphocyte antigen CD20 Human genes 0.000 claims description 2
- 102100024217 CAMPATH-1 antigen Human genes 0.000 claims description 2
- 108010065524 CD52 Antigen Proteins 0.000 claims description 2
- 101710178046 Chorismate synthase 1 Proteins 0.000 claims description 2
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 claims description 2
- 101710152695 Cysteine synthase 1 Proteins 0.000 claims description 2
- 101000777636 Homo sapiens ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase 1 Proteins 0.000 claims description 2
- 101000897405 Homo sapiens B-lymphocyte antigen CD20 Proteins 0.000 claims description 2
- 102100032831 Protein ITPRID2 Human genes 0.000 claims description 2
- 241000218636 Thuja Species 0.000 claims description 2
- XQRLCLUYWUNEEH-UHFFFAOYSA-L diphosphonate(2-) Chemical compound [O-]P(=O)OP([O-])=O XQRLCLUYWUNEEH-UHFFFAOYSA-L 0.000 claims description 2
- 239000002955 immunomodulating agent Substances 0.000 claims description 2
- 229940121354 immunomodulator Drugs 0.000 claims description 2
- 230000002584 immunomodulator Effects 0.000 claims description 2
- 229940043355 kinase inhibitor Drugs 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 239000003757 phosphotransferase inhibitor Substances 0.000 claims description 2
- 229960000575 trastuzumab Drugs 0.000 claims description 2
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 claims description 2
- 229960004528 vincristine Drugs 0.000 claims description 2
- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 claims description 2
- 230000001276 controlling effect Effects 0.000 claims 2
- 238000002405 diagnostic procedure Methods 0.000 claims 2
- 230000001105 regulatory effect Effects 0.000 claims 2
- 150000003851 azoles Chemical class 0.000 claims 1
- 150000003009 phosphonic acids Chemical class 0.000 claims 1
- 108020004414 DNA Proteins 0.000 description 60
- 102100035360 Cerebellar degeneration-related antigen 1 Human genes 0.000 description 36
- 235000001014 amino acid Nutrition 0.000 description 33
- 230000008859 change Effects 0.000 description 33
- 229940024606 amino acid Drugs 0.000 description 31
- 239000012634 fragment Substances 0.000 description 25
- PDIDTSZKKFEDMB-UWVGGRQHSA-N Lys-Pro-Gly Chemical compound [H]N[C@@H](CCCCN)C(=O)N1CCC[C@H]1C(=O)NCC(O)=O PDIDTSZKKFEDMB-UWVGGRQHSA-N 0.000 description 23
- 230000000903 blocking effect Effects 0.000 description 22
- 241000699660 Mus musculus Species 0.000 description 21
- 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 20
- 210000002966 serum Anatomy 0.000 description 20
- 241000699666 Mus <mouse, genus> Species 0.000 description 19
- UQFYNFTYDHUIMI-WHFBIAKZSA-N Ser-Gly-Ala Chemical compound OC(=O)[C@H](C)NC(=O)CNC(=O)[C@@H](N)CO UQFYNFTYDHUIMI-WHFBIAKZSA-N 0.000 description 19
- VPZXBVLAVMBEQI-UHFFFAOYSA-N glycyl-DL-alpha-alanine Natural products OC(=O)C(C)NC(=O)CN VPZXBVLAVMBEQI-UHFFFAOYSA-N 0.000 description 19
- 108010050848 glycylleucine Proteins 0.000 description 18
- 108010038320 lysylphenylalanine Proteins 0.000 description 18
- 102000039446 nucleic acids Human genes 0.000 description 18
- 108020004707 nucleic acids Proteins 0.000 description 18
- 150000007523 nucleic acids Chemical class 0.000 description 18
- RGQCNKIDEQJEBT-CQDKDKBSSA-N Ala-Leu-Tyr Chemical compound C[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 RGQCNKIDEQJEBT-CQDKDKBSSA-N 0.000 description 17
- GBYYQVBXFVDJPJ-WLTAIBSBSA-N Gly-Tyr-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CC1=CC=C(C=C1)O)NC(=O)CN)O GBYYQVBXFVDJPJ-WLTAIBSBSA-N 0.000 description 17
- UWKNTTJNVSYXPC-CIUDSAMLSA-N Lys-Ala-Ser Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CCCCN UWKNTTJNVSYXPC-CIUDSAMLSA-N 0.000 description 17
- GNRMAQSIROFNMI-IXOXFDKPSA-N Phe-Thr-Ser Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(O)=O GNRMAQSIROFNMI-IXOXFDKPSA-N 0.000 description 17
- CDRYEAWHKJSGAF-BPNCWPANSA-N Tyr-Ala-Met Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](C)C(=O)N[C@@H](CCSC)C(O)=O CDRYEAWHKJSGAF-BPNCWPANSA-N 0.000 description 17
- 108010048994 glycyl-tyrosyl-alanine Proteins 0.000 description 17
- 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 16
- KXEGPPNPXOKKHK-ZLUOBGJFSA-N Asn-Asp-Ala Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](C)C(O)=O KXEGPPNPXOKKHK-ZLUOBGJFSA-N 0.000 description 16
- OLGCWMNDJTWQAG-GUBZILKMSA-N Asn-Glu-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](N)CC(N)=O OLGCWMNDJTWQAG-GUBZILKMSA-N 0.000 description 16
- SUIJFTJDTJKSRK-IHRRRGAJSA-N Asn-Pro-Tyr Chemical compound NC(=O)C[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 SUIJFTJDTJKSRK-IHRRRGAJSA-N 0.000 description 16
- 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 16
- KOYUSMBPJOVSOO-XEGUGMAKSA-N Gly-Tyr-Ile Chemical compound [H]NCC(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O KOYUSMBPJOVSOO-XEGUGMAKSA-N 0.000 description 16
- 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 16
- 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 16
- SJDQOYTYNGZZJX-SRVKXCTJSA-N Met-Glu-Leu Chemical compound CSCC[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(O)=O SJDQOYTYNGZZJX-SRVKXCTJSA-N 0.000 description 16
- 108010079364 N-glycylalanine Proteins 0.000 description 16
- WCNVGGZRTNHOOS-ULQDDVLXSA-N Pro-Lys-Tyr Chemical compound C1C[C@H](NC1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC2=CC=C(C=C2)O)C(=O)O WCNVGGZRTNHOOS-ULQDDVLXSA-N 0.000 description 16
- LGIMRDKGABDMBN-DCAQKATOSA-N Ser-Val-Lys Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CO)N LGIMRDKGABDMBN-DCAQKATOSA-N 0.000 description 16
- SBJCTAZFSZXWSR-AVGNSLFASA-N Val-Met-His Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)N SBJCTAZFSZXWSR-AVGNSLFASA-N 0.000 description 16
- 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 16
- 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 16
- 108010086434 alanyl-seryl-glycine Proteins 0.000 description 16
- 108010087924 alanylproline Proteins 0.000 description 16
- 235000018102 proteins Nutrition 0.000 description 16
- 108090000623 proteins and genes Proteins 0.000 description 16
- 108010038745 tryptophylglycine Proteins 0.000 description 16
- 101100112922 Candida albicans CDR3 gene Proteins 0.000 description 15
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 15
- 239000003814 drug Substances 0.000 description 15
- 108010031719 prolyl-serine Proteins 0.000 description 15
- 102000004169 proteins and genes Human genes 0.000 description 15
- 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 14
- OYTPNWYZORARHL-XHNCKOQMSA-N Gln-Ala-Pro Chemical compound C[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](CCC(=O)N)N OYTPNWYZORARHL-XHNCKOQMSA-N 0.000 description 14
- ZYRXTRTUCAVNBQ-GVXVVHGQSA-N Glu-Val-Lys Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CCC(=O)O)N ZYRXTRTUCAVNBQ-GVXVVHGQSA-N 0.000 description 14
- 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 14
- 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 14
- MVJRBCJCRYGCKV-GVXVVHGQSA-N Leu-Val-Gln Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(N)=O)C(O)=O MVJRBCJCRYGCKV-GVXVVHGQSA-N 0.000 description 14
- 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 14
- 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 14
- JQTYTBPCSOAZHI-FXQIFTODSA-N Val-Ser-Cys Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CS)C(=O)O)N JQTYTBPCSOAZHI-FXQIFTODSA-N 0.000 description 14
- 108010069020 alanyl-prolyl-glycine Proteins 0.000 description 14
- 108010008355 arginyl-glutamine Proteins 0.000 description 14
- 238000006467 substitution reaction Methods 0.000 description 14
- 108010044292 tryptophyltyrosine Proteins 0.000 description 14
- ZFBBMCKQSNJZSN-AUTRQRHGSA-N Gln-Val-Gln Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(N)=O)C(O)=O ZFBBMCKQSNJZSN-AUTRQRHGSA-N 0.000 description 13
- 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 12
- SITLTJHOQZFJGG-UHFFFAOYSA-N N-L-alpha-glutamyl-L-valine Natural products CC(C)C(C(O)=O)NC(=O)C(N)CCC(O)=O SITLTJHOQZFJGG-UHFFFAOYSA-N 0.000 description 12
- IHCXPSYCHXFXKT-DCAQKATOSA-N Pro-Arg-Glu Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(O)=O IHCXPSYCHXFXKT-DCAQKATOSA-N 0.000 description 12
- 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 12
- 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 12
- 210000003719 b-lymphocyte Anatomy 0.000 description 12
- 108010040443 aspartyl-aspartic acid Proteins 0.000 description 11
- 238000002474 experimental method Methods 0.000 description 11
- 230000006870 function Effects 0.000 description 11
- ADPACBMPYWJJCE-FXQIFTODSA-N Arg-Ser-Asp Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(O)=O)C(O)=O ADPACBMPYWJJCE-FXQIFTODSA-N 0.000 description 10
- 102000006496 Immunoglobulin Heavy Chains Human genes 0.000 description 10
- 108010019476 Immunoglobulin Heavy Chains Proteins 0.000 description 10
- VUBIPAHVHMZHCM-KKUMJFAQSA-N Leu-Tyr-Ser Chemical compound CC(C)C[C@H](N)C(=O)N[C@H](C(=O)N[C@@H](CO)C(O)=O)CC1=CC=C(O)C=C1 VUBIPAHVHMZHCM-KKUMJFAQSA-N 0.000 description 10
- HWLKHNDRXWTFTN-GUBZILKMSA-N Pro-Pro-Cys Chemical compound C1C[C@H](NC1)C(=O)N2CCC[C@H]2C(=O)N[C@@H](CS)C(=O)O HWLKHNDRXWTFTN-GUBZILKMSA-N 0.000 description 10
- MKGIILKDUGDRRO-FXQIFTODSA-N Pro-Ser-Ser Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H]1CCCN1 MKGIILKDUGDRRO-FXQIFTODSA-N 0.000 description 10
- 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 10
- XNCUYZKGQOCOQH-YUMQZZPRSA-N Ser-Leu-Gly Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)NCC(O)=O XNCUYZKGQOCOQH-YUMQZZPRSA-N 0.000 description 10
- BMGOFDMKDVVGJG-NHCYSSNCSA-N Val-Asp-Lys Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](CCCCN)C(=O)O)N BMGOFDMKDVVGJG-NHCYSSNCSA-N 0.000 description 10
- 108010060199 cysteinylproline Proteins 0.000 description 10
- 108010017391 lysylvaline Proteins 0.000 description 10
- 230000035772 mutation Effects 0.000 description 10
- 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 9
- KGHLGJAXYSVNJP-WHFBIAKZSA-N Asp-Ser-Gly Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CO)C(=O)NCC(O)=O KGHLGJAXYSVNJP-WHFBIAKZSA-N 0.000 description 9
- OZHXXYOHPLLLMI-CIUDSAMLSA-N Cys-Lys-Ala Chemical compound [H]N[C@@H](CS)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(O)=O OZHXXYOHPLLLMI-CIUDSAMLSA-N 0.000 description 9
- 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 9
- YQPFCZVKMUVZIN-AUTRQRHGSA-N Glu-Val-Gln Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(N)=O)C(O)=O YQPFCZVKMUVZIN-AUTRQRHGSA-N 0.000 description 9
- NSPNUMNLZNOPAQ-SJWGOKEGSA-N Ile-Tyr-Pro Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC1=CC=C(C=C1)O)C(=O)N2CCC[C@@H]2C(=O)O)N NSPNUMNLZNOPAQ-SJWGOKEGSA-N 0.000 description 9
- 241000880493 Leptailurus serval Species 0.000 description 9
- 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 9
- OBXVZEAMXFSGPU-FXQIFTODSA-N Ser-Asn-Arg Chemical compound C(C[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)N)NC(=O)[C@H](CO)N)CN=C(N)N OBXVZEAMXFSGPU-FXQIFTODSA-N 0.000 description 9
- CDVFZMOFNJPUDD-ACZMJKKPSA-N Ser-Gln-Asn Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O CDVFZMOFNJPUDD-ACZMJKKPSA-N 0.000 description 9
- 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 9
- FWTFAZKJORVTIR-VZFHVOOUSA-N Thr-Ser-Ala Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(=O)N[C@@H](C)C(O)=O FWTFAZKJORVTIR-VZFHVOOUSA-N 0.000 description 9
- 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 9
- VJOWWOGRNXRQMF-UVBJJODRSA-N Val-Ala-Trp Chemical compound C1=CC=C2C(C[C@H](NC(=O)[C@H](C)NC(=O)[C@@H](N)C(C)C)C(O)=O)=CNC2=C1 VJOWWOGRNXRQMF-UVBJJODRSA-N 0.000 description 9
- NXRAUQGGHPCJIB-RCOVLWMOSA-N Val-Gly-Asn Chemical compound CC(C)[C@H](N)C(=O)NCC(=O)N[C@@H](CC(N)=O)C(O)=O NXRAUQGGHPCJIB-RCOVLWMOSA-N 0.000 description 9
- USXYVSTVPHELAF-RCWTZXSCSA-N Val-Thr-Met Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCSC)C(=O)O)NC(=O)[C@H](C(C)C)N)O USXYVSTVPHELAF-RCWTZXSCSA-N 0.000 description 9
- 238000005516 engineering process Methods 0.000 description 9
- 108010037850 glycylvaline Proteins 0.000 description 9
- 230000028327 secretion Effects 0.000 description 9
- 208000024891 symptom Diseases 0.000 description 9
- 208000011580 syndromic disease Diseases 0.000 description 9
- 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 8
- 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 8
- GLQFKOVWXPPFTP-VEVYYDQMSA-N Thr-Arg-Asp Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(O)=O GLQFKOVWXPPFTP-VEVYYDQMSA-N 0.000 description 8
- IVDFVBVIVLJJHR-LKXGYXEUSA-N Thr-Ser-Asp Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(O)=O)C(O)=O IVDFVBVIVLJJHR-LKXGYXEUSA-N 0.000 description 8
- 210000004369 blood Anatomy 0.000 description 8
- 239000008280 blood Substances 0.000 description 8
- 108010010147 glycylglutamine Proteins 0.000 description 8
- 239000011159 matrix material Substances 0.000 description 8
- 229940124597 therapeutic agent Drugs 0.000 description 8
- 108010073969 valyllysine Proteins 0.000 description 8
- 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 7
- 208000010839 B-cell chronic lymphocytic leukemia Diseases 0.000 description 7
- VGSPNSSCMOHRRR-BJDJZHNGSA-N Ile-Ser-Lys Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCCN)C(=O)O)N VGSPNSSCMOHRRR-BJDJZHNGSA-N 0.000 description 7
- FSPGBMWPNMRWDB-AVGNSLFASA-N Phe-Cys-Gln Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CCC(=O)N)C(=O)O)N FSPGBMWPNMRWDB-AVGNSLFASA-N 0.000 description 7
- FDMKYQQYJKYCLV-GUBZILKMSA-N Pro-Pro-Ser Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@H]1NCCC1 FDMKYQQYJKYCLV-GUBZILKMSA-N 0.000 description 7
- 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 7
- 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 7
- 238000004422 calculation algorithm Methods 0.000 description 7
- 230000000694 effects Effects 0.000 description 7
- 108010049041 glutamylalanine Proteins 0.000 description 7
- 108010003700 lysyl aspartic acid Proteins 0.000 description 7
- 108010024654 phenylalanyl-prolyl-alanine Proteins 0.000 description 7
- HNXWVVHIGTZTBO-LKXGYXEUSA-N Asn-Ser-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC(N)=O HNXWVVHIGTZTBO-LKXGYXEUSA-N 0.000 description 6
- QNNBHTFDFFFHGC-KKUMJFAQSA-N Asn-Tyr-Lys Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CC(=O)N)N)O QNNBHTFDFFFHGC-KKUMJFAQSA-N 0.000 description 6
- 206010009944 Colon cancer Diseases 0.000 description 6
- OHLLDUNVMPPUMD-DCAQKATOSA-N Cys-Leu-Val Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](C(C)C)C(=O)O)NC(=O)[C@H](CS)N OHLLDUNVMPPUMD-DCAQKATOSA-N 0.000 description 6
- NDNZRWUDUMTITL-FXQIFTODSA-N Cys-Ser-Val Chemical compound [H]N[C@@H](CS)C(=O)N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(O)=O NDNZRWUDUMTITL-FXQIFTODSA-N 0.000 description 6
- RFDHKPSHTXZKLL-IHRRRGAJSA-N Glu-Gln-Phe Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)N)NC(=O)[C@H](CCC(=O)O)N RFDHKPSHTXZKLL-IHRRRGAJSA-N 0.000 description 6
- GMTXWRIDLGTVFC-IUCAKERBSA-N Gly-Lys-Glu Chemical compound [H]NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(O)=O GMTXWRIDLGTVFC-IUCAKERBSA-N 0.000 description 6
- FULZDMOZUZKGQU-ONGXEEELSA-N Gly-Val-His Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)NC(=O)CN FULZDMOZUZKGQU-ONGXEEELSA-N 0.000 description 6
- FYVHHKMHFPMBBG-GUBZILKMSA-N His-Gln-Asp Chemical compound C1=C(NC=N1)C[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H](CC(=O)O)C(=O)O)N FYVHHKMHFPMBBG-GUBZILKMSA-N 0.000 description 6
- BRTVHXHCUSXYRI-CIUDSAMLSA-N Leu-Ser-Ser Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(O)=O BRTVHXHCUSXYRI-CIUDSAMLSA-N 0.000 description 6
- ILDSIMPXNFWKLH-KATARQTJSA-N Leu-Thr-Ser Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(O)=O ILDSIMPXNFWKLH-KATARQTJSA-N 0.000 description 6
- LUTDBHBIHHREDC-IHRRRGAJSA-N Lys-Pro-Lys Chemical compound NCCCC[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCCCN)C(O)=O LUTDBHBIHHREDC-IHRRRGAJSA-N 0.000 description 6
- 241001465754 Metazoa Species 0.000 description 6
- 208000015914 Non-Hodgkin lymphomas Diseases 0.000 description 6
- QARPMYDMYVLFMW-KKUMJFAQSA-N Phe-Pro-Glu Chemical compound C([C@H](N)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCC(O)=O)C(O)=O)C1=CC=CC=C1 QARPMYDMYVLFMW-KKUMJFAQSA-N 0.000 description 6
- ZJPGOXWRFNKIQL-JYJNAYRXSA-N Phe-Pro-Pro Chemical compound C([C@H](N)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(O)=O)C1=CC=CC=C1 ZJPGOXWRFNKIQL-JYJNAYRXSA-N 0.000 description 6
- YDTUEBLEAVANFH-RCWTZXSCSA-N Pro-Val-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H]1CCCN1 YDTUEBLEAVANFH-RCWTZXSCSA-N 0.000 description 6
- 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 6
- SIEBDTCABMZCLF-XGEHTFHBSA-N Ser-Val-Thr Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O SIEBDTCABMZCLF-XGEHTFHBSA-N 0.000 description 6
- 210000001744 T-lymphocyte Anatomy 0.000 description 6
- JMBRNXUOLJFURW-BEAPCOKYSA-N Thr-Phe-Pro Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N2CCC[C@@H]2C(=O)O)N)O JMBRNXUOLJFURW-BEAPCOKYSA-N 0.000 description 6
- XGFGVFMXDXALEV-XIRDDKMYSA-N Trp-Leu-Asn Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)O)NC(=O)[C@H](CC1=CNC2=CC=CC=C21)N XGFGVFMXDXALEV-XIRDDKMYSA-N 0.000 description 6
- PWKMJDQXKCENMF-MEYUZBJRSA-N Tyr-Thr-Leu Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(O)=O PWKMJDQXKCENMF-MEYUZBJRSA-N 0.000 description 6
- BZDGLJPROOOUOZ-XGEHTFHBSA-N Val-Thr-Cys Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CS)C(=O)O)NC(=O)[C@H](C(C)C)N)O BZDGLJPROOOUOZ-XGEHTFHBSA-N 0.000 description 6
- ZLNYBMWGPOKSLW-LSJOCFKGSA-N Val-Val-Asp Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(O)=O)C(O)=O ZLNYBMWGPOKSLW-LSJOCFKGSA-N 0.000 description 6
- 239000002585 base Substances 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 6
- 239000003153 chemical reaction reagent Substances 0.000 description 6
- 230000008473 connective tissue growth Effects 0.000 description 6
- 108010063718 gamma-glutamylaspartic acid Proteins 0.000 description 6
- 239000003102 growth factor Substances 0.000 description 6
- 238000001727 in vivo Methods 0.000 description 6
- 230000001965 increasing effect Effects 0.000 description 6
- 230000003993 interaction Effects 0.000 description 6
- 239000008194 pharmaceutical composition Substances 0.000 description 6
- YBYRMVIVWMBXKQ-UHFFFAOYSA-N phenylmethanesulfonyl fluoride Chemical compound FS(=O)(=O)CC1=CC=CC=C1 YBYRMVIVWMBXKQ-UHFFFAOYSA-N 0.000 description 6
- 239000013612 plasmid Substances 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
- 210000001519 tissue Anatomy 0.000 description 6
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 description 5
- 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 5
- SUHLZMHFRALVSY-YUMQZZPRSA-N Ala-Lys-Gly Chemical compound NCCCC[C@H](NC(=O)[C@@H](N)C)C(=O)NCC(O)=O SUHLZMHFRALVSY-YUMQZZPRSA-N 0.000 description 5
- WQKAQKZRDIZYNV-VZFHVOOUSA-N Ala-Ser-Thr Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(O)=O WQKAQKZRDIZYNV-VZFHVOOUSA-N 0.000 description 5
- YJHKTAMKPGFJCT-NRPADANISA-N Ala-Val-Glu Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(O)=O)C(O)=O YJHKTAMKPGFJCT-NRPADANISA-N 0.000 description 5
- JEOCWTUOMKEEMF-RHYQMDGZSA-N Arg-Leu-Thr Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O JEOCWTUOMKEEMF-RHYQMDGZSA-N 0.000 description 5
- 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 5
- ZUVMUOOHJYNJPP-XIRDDKMYSA-N Arg-Trp-Gln Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC1=CNC2=C1C=CC=C2)C(=O)N[C@@H](CCC(N)=O)C(O)=O ZUVMUOOHJYNJPP-XIRDDKMYSA-N 0.000 description 5
- ULBHWNVWSCJLCO-NHCYSSNCSA-N Arg-Val-Glu Chemical compound OC(=O)CC[C@@H](C(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](N)CCCN=C(N)N ULBHWNVWSCJLCO-NHCYSSNCSA-N 0.000 description 5
- SRUUBQBAVNQZGJ-LAEOZQHASA-N Asn-Gln-Val Chemical compound CC(C)[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)N)NC(=O)[C@H](CC(=O)N)N SRUUBQBAVNQZGJ-LAEOZQHASA-N 0.000 description 5
- WONGRTVAMHFGBE-WDSKDSINSA-N Asn-Gly-Gln Chemical compound C(CC(=O)N)[C@@H](C(=O)O)NC(=O)CNC(=O)[C@H](CC(=O)N)N WONGRTVAMHFGBE-WDSKDSINSA-N 0.000 description 5
- PUUPMDXIHCOPJU-HJGDQZAQSA-N Asn-Thr-Lys Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CC(=O)N)N)O PUUPMDXIHCOPJU-HJGDQZAQSA-N 0.000 description 5
- JZLFYAAGGYMRIK-BYULHYEWSA-N Asn-Val-Asp Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(O)=O)C(O)=O JZLFYAAGGYMRIK-BYULHYEWSA-N 0.000 description 5
- JSNWZMFSLIWAHS-HJGDQZAQSA-N Asp-Thr-Leu Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)O)NC(=O)[C@H](CC(=O)O)N)O JSNWZMFSLIWAHS-HJGDQZAQSA-N 0.000 description 5
- BCFXQBXXDSEHRS-FXQIFTODSA-N Cys-Ser-Arg Chemical compound [H]N[C@@H](CS)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O BCFXQBXXDSEHRS-FXQIFTODSA-N 0.000 description 5
- SNLOOPZHAQDMJG-CIUDSAMLSA-N Gln-Glu-Glu Chemical compound NC(=O)CC[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(O)=O SNLOOPZHAQDMJG-CIUDSAMLSA-N 0.000 description 5
- ZEEPYMXTJWIMSN-GUBZILKMSA-N Gln-Lys-Ser Chemical compound NCCCC[C@@H](C(=O)N[C@@H](CO)C(O)=O)NC(=O)[C@@H](N)CCC(N)=O ZEEPYMXTJWIMSN-GUBZILKMSA-N 0.000 description 5
- SYZZMPFLOLSMHL-XHNCKOQMSA-N Gln-Ser-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CO)NC(=O)[C@H](CCC(=O)N)N)C(=O)O SYZZMPFLOLSMHL-XHNCKOQMSA-N 0.000 description 5
- JVSBYEDSSRZQGV-GUBZILKMSA-N Glu-Asp-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@@H](N)CCC(O)=O JVSBYEDSSRZQGV-GUBZILKMSA-N 0.000 description 5
- CKOFNWCLWRYUHK-XHNCKOQMSA-N Glu-Asp-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CC(=O)O)NC(=O)[C@H](CCC(=O)O)N)C(=O)O CKOFNWCLWRYUHK-XHNCKOQMSA-N 0.000 description 5
- UHVIQGKBMXEVGN-WDSKDSINSA-N Glu-Gly-Asn Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)NCC(=O)N[C@@H](CC(N)=O)C(O)=O UHVIQGKBMXEVGN-WDSKDSINSA-N 0.000 description 5
- QNJNPKSWAHPYGI-JYJNAYRXSA-N Glu-Phe-Leu Chemical compound OC(=O)CC[C@H](N)C(=O)N[C@H](C(=O)N[C@@H](CC(C)C)C(O)=O)CC1=CC=CC=C1 QNJNPKSWAHPYGI-JYJNAYRXSA-N 0.000 description 5
- JWNZHMSRZXXGTM-XKBZYTNZSA-N Glu-Ser-Thr Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(O)=O JWNZHMSRZXXGTM-XKBZYTNZSA-N 0.000 description 5
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 5
- BUEFQXUHTUZXHR-LURJTMIESA-N Gly-Gly-Pro zwitterion Chemical compound NCC(=O)NCC(=O)N1CCC[C@H]1C(O)=O BUEFQXUHTUZXHR-LURJTMIESA-N 0.000 description 5
- 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 5
- SYOJVRNQCXYEOV-XVKPBYJWSA-N Gly-Val-Glu Chemical compound [H]NCC(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(O)=O)C(O)=O SYOJVRNQCXYEOV-XVKPBYJWSA-N 0.000 description 5
- CSTDQOOBZBAJKE-BWAGICSOSA-N His-Tyr-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CC1=CC=C(C=C1)O)NC(=O)[C@H](CC2=CN=CN2)N)O CSTDQOOBZBAJKE-BWAGICSOSA-N 0.000 description 5
- DFJJAVZIHDFOGQ-MNXVOIDGSA-N Ile-Glu-Lys Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CCCCN)C(=O)O)N DFJJAVZIHDFOGQ-MNXVOIDGSA-N 0.000 description 5
- RCFDOSNHHZGBOY-UHFFFAOYSA-N L-isoleucyl-L-alanine Natural products CCC(C)C(N)C(=O)NC(C)C(O)=O RCFDOSNHHZGBOY-UHFFFAOYSA-N 0.000 description 5
- 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 5
- WSGXUIQTEZDVHJ-GARJFASQSA-N Leu-Ala-Pro Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](C)C(=O)N1CCC[C@@H]1C(O)=O WSGXUIQTEZDVHJ-GARJFASQSA-N 0.000 description 5
- BTNXKBVLWJBTNR-SRVKXCTJSA-N Leu-His-Asn Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CC(N)=O)C(O)=O BTNXKBVLWJBTNR-SRVKXCTJSA-N 0.000 description 5
- XOWMDXHFSBCAKQ-SRVKXCTJSA-N Leu-Ser-Leu Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@H](C(O)=O)CC(C)C XOWMDXHFSBCAKQ-SRVKXCTJSA-N 0.000 description 5
- YQFZRHYZLARWDY-IHRRRGAJSA-N Leu-Val-Lys Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@H](C(O)=O)CCCCN YQFZRHYZLARWDY-IHRRRGAJSA-N 0.000 description 5
- NTBFKPBULZGXQL-KKUMJFAQSA-N Lys-Asp-Tyr Chemical compound NCCCC[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 NTBFKPBULZGXQL-KKUMJFAQSA-N 0.000 description 5
- MWVUEPNEPWMFBD-SRVKXCTJSA-N Lys-Cys-Lys Chemical compound NCCCC[C@H](N)C(=O)N[C@@H](CS)C(=O)N[C@H](C(O)=O)CCCCN MWVUEPNEPWMFBD-SRVKXCTJSA-N 0.000 description 5
- GQFDWEDHOQRNLC-QWRGUYRKSA-N Lys-Gly-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)CNC(=O)[C@@H](N)CCCCN GQFDWEDHOQRNLC-QWRGUYRKSA-N 0.000 description 5
- RFQATBGBLDAKGI-VHSXEESVSA-N Lys-Gly-Pro Chemical compound C1C[C@@H](N(C1)C(=O)CNC(=O)[C@H](CCCCN)N)C(=O)O RFQATBGBLDAKGI-VHSXEESVSA-N 0.000 description 5
- 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 5
- YTJFXEDRUOQGSP-DCAQKATOSA-N Lys-Pro-Ser Chemical compound [H]N[C@@H](CCCCN)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CO)C(O)=O YTJFXEDRUOQGSP-DCAQKATOSA-N 0.000 description 5
- YKBSXQFZWFXFIB-VOAKCMCISA-N Lys-Thr-Lys Chemical compound NCCCC[C@H](N)C(=O)N[C@@H]([C@H](O)C)C(=O)N[C@@H](CCCCN)C(O)=O YKBSXQFZWFXFIB-VOAKCMCISA-N 0.000 description 5
- RKIIYGUHIQJCBW-SRVKXCTJSA-N Met-His-Glu Chemical compound [H]N[C@@H](CCSC)C(=O)N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CCC(O)=O)C(O)=O RKIIYGUHIQJCBW-SRVKXCTJSA-N 0.000 description 5
- FWAHLGXNBLWIKB-NAKRPEOUSA-N Met-Ile-Ser Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H]([C@@H](C)CC)NC(=O)[C@@H](N)CCSC FWAHLGXNBLWIKB-NAKRPEOUSA-N 0.000 description 5
- IHRFZLQEQVHXFA-RHYQMDGZSA-N Met-Thr-Lys Chemical compound CSCC[C@H](N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@H](C(O)=O)CCCCN IHRFZLQEQVHXFA-RHYQMDGZSA-N 0.000 description 5
- 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 5
- JOXIIFVCSATTDH-IHPCNDPISA-N Phe-Asn-Trp Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CC2=CNC3=CC=CC=C32)C(=O)O)N JOXIIFVCSATTDH-IHPCNDPISA-N 0.000 description 5
- JDMKQHSHKJHAHR-UHFFFAOYSA-N Phe-Phe-Leu-Tyr Natural products C=1C=C(O)C=CC=1CC(C(O)=O)NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)CC1=CC=CC=C1 JDMKQHSHKJHAHR-UHFFFAOYSA-N 0.000 description 5
- SJRQWEDYTKYHHL-SLFFLAALSA-N Phe-Tyr-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CC2=CC=C(C=C2)O)NC(=O)[C@H](CC3=CC=CC=C3)N)C(=O)O SJRQWEDYTKYHHL-SLFFLAALSA-N 0.000 description 5
- CGBYDGAJHSOGFQ-LPEHRKFASA-N Pro-Ala-Pro Chemical compound C[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@@H]2CCCN2 CGBYDGAJHSOGFQ-LPEHRKFASA-N 0.000 description 5
- UAYHMOIGIQZLFR-NHCYSSNCSA-N Pro-Gln-Val Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](C(C)C)C(O)=O UAYHMOIGIQZLFR-NHCYSSNCSA-N 0.000 description 5
- KIPIKSXPPLABPN-CIUDSAMLSA-N Pro-Glu-Asn Chemical compound NC(=O)C[C@@H](C(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H]1CCCN1 KIPIKSXPPLABPN-CIUDSAMLSA-N 0.000 description 5
- KHRLUIPIMIQFGT-AVGNSLFASA-N Pro-Val-Leu Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O KHRLUIPIMIQFGT-AVGNSLFASA-N 0.000 description 5
- 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 5
- QPFJSHSJFIYDJZ-GHCJXIJMSA-N Ser-Asp-Ile Chemical compound CC[C@H](C)[C@@H](C(O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@@H](N)CO QPFJSHSJFIYDJZ-GHCJXIJMSA-N 0.000 description 5
- VMVNCJDKFOQOHM-GUBZILKMSA-N Ser-Gln-Lys Chemical compound C(CCN)C[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)N)NC(=O)[C@H](CO)N VMVNCJDKFOQOHM-GUBZILKMSA-N 0.000 description 5
- QJKPECIAWNNKIT-KKUMJFAQSA-N Ser-Lys-Tyr Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O QJKPECIAWNNKIT-KKUMJFAQSA-N 0.000 description 5
- RRVFEDGUXSYWOW-BZSNNMDCSA-N Ser-Phe-Phe Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O RRVFEDGUXSYWOW-BZSNNMDCSA-N 0.000 description 5
- 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 5
- SNXUIBACCONSOH-BWBBJGPYSA-N Ser-Thr-Ser Chemical compound OC[C@H](N)C(=O)N[C@@H]([C@H](O)C)C(=O)N[C@@H](CO)C(O)=O SNXUIBACCONSOH-BWBBJGPYSA-N 0.000 description 5
- AXKJPUBALUNJEO-UBHSHLNASA-N Ser-Trp-Asn Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC1=CNC2=C1C=CC=C2)C(=O)N[C@@H](CC(N)=O)C(O)=O AXKJPUBALUNJEO-UBHSHLNASA-N 0.000 description 5
- YEDSOSIKVUMIJE-DCAQKATOSA-N Ser-Val-Leu Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O YEDSOSIKVUMIJE-DCAQKATOSA-N 0.000 description 5
- JWQNAFHCXKVZKZ-UVOCVTCTSA-N Thr-Lys-Thr Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(O)=O JWQNAFHCXKVZKZ-UVOCVTCTSA-N 0.000 description 5
- XKWABWFMQXMUMT-HJGDQZAQSA-N Thr-Pro-Glu Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCC(O)=O)C(O)=O XKWABWFMQXMUMT-HJGDQZAQSA-N 0.000 description 5
- IEZVHOULSUULHD-XGEHTFHBSA-N Thr-Ser-Val Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(O)=O IEZVHOULSUULHD-XGEHTFHBSA-N 0.000 description 5
- ZESGVALRVJIVLZ-VFCFLDTKSA-N Thr-Thr-Pro Chemical compound C[C@H]([C@@H](C(=O)N[C@@H]([C@@H](C)O)C(=O)N1CCC[C@@H]1C(=O)O)N)O ZESGVALRVJIVLZ-VFCFLDTKSA-N 0.000 description 5
- BKVICMPZWRNWOC-RHYQMDGZSA-N Thr-Val-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](N)[C@@H](C)O BKVICMPZWRNWOC-RHYQMDGZSA-N 0.000 description 5
- UDCHKDYNMRJYMI-QEJZJMRPSA-N Trp-Glu-Ser Chemical compound [H]N[C@@H](CC1=CNC2=C1C=CC=C2)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(O)=O UDCHKDYNMRJYMI-QEJZJMRPSA-N 0.000 description 5
- QYSBJAUCUKHSLU-JYJNAYRXSA-N Tyr-Arg-Val Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C(C)C)C(O)=O QYSBJAUCUKHSLU-JYJNAYRXSA-N 0.000 description 5
- VYQQQIRHIFALGE-UWJYBYFXSA-N Tyr-Ser-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 VYQQQIRHIFALGE-UWJYBYFXSA-N 0.000 description 5
- QFHRUCJIRVILCK-YJRXYDGGSA-N Tyr-Thr-Cys Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CS)C(=O)O)NC(=O)[C@H](CC1=CC=C(C=C1)O)N)O QFHRUCJIRVILCK-YJRXYDGGSA-N 0.000 description 5
- SQUMHUZLJDUROQ-YDHLFZDLSA-N Tyr-Val-Asp Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(O)=O)C(O)=O SQUMHUZLJDUROQ-YDHLFZDLSA-N 0.000 description 5
- OACSGBOREVRSME-NHCYSSNCSA-N Val-His-Asn Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](Cc1cnc[nH]1)C(=O)N[C@@H](CC(N)=O)C(O)=O OACSGBOREVRSME-NHCYSSNCSA-N 0.000 description 5
- HGJRMXOWUWVUOA-GVXVVHGQSA-N Val-Leu-Gln Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)O)NC(=O)[C@H](C(C)C)N HGJRMXOWUWVUOA-GVXVVHGQSA-N 0.000 description 5
- HJSLDXZAZGFPDK-ULQDDVLXSA-N Val-Phe-Leu Chemical compound CC(C)C[C@@H](C(=O)O)NC(=O)[C@H](CC1=CC=CC=C1)NC(=O)[C@H](C(C)C)N HJSLDXZAZGFPDK-ULQDDVLXSA-N 0.000 description 5
- VCIYTVOBLZHFSC-XHSDSOJGSA-N Val-Phe-Pro Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N2CCC[C@@H]2C(=O)O)N VCIYTVOBLZHFSC-XHSDSOJGSA-N 0.000 description 5
- KISFXYYRKKNLOP-IHRRRGAJSA-N Val-Phe-Ser Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CO)C(=O)O)N KISFXYYRKKNLOP-IHRRRGAJSA-N 0.000 description 5
- ZXYPHBKIZLAQTL-QXEWZRGKSA-N Val-Pro-Asp Chemical compound CC(C)[C@@H](C(=O)N1CCC[C@H]1C(=O)N[C@@H](CC(=O)O)C(=O)O)N ZXYPHBKIZLAQTL-QXEWZRGKSA-N 0.000 description 5
- KSFXWENSJABBFI-ZKWXMUAHSA-N Val-Ser-Asn Chemical compound [H]N[C@@H](C(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(O)=O KSFXWENSJABBFI-ZKWXMUAHSA-N 0.000 description 5
- RYHUIHUOYRNNIE-NRPADANISA-N Val-Ser-Gln Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(=O)N)C(=O)O)N RYHUIHUOYRNNIE-NRPADANISA-N 0.000 description 5
- JVGDAEKKZKKZFO-RCWTZXSCSA-N Val-Val-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](C(C)C)NC(=O)[C@H](C(C)C)N)O JVGDAEKKZKKZFO-RCWTZXSCSA-N 0.000 description 5
- 108010050025 alpha-glutamyltryptophan Proteins 0.000 description 5
- 125000000539 amino acid group Chemical group 0.000 description 5
- 108010052670 arginyl-glutamyl-glutamic acid Proteins 0.000 description 5
- 108010069205 aspartyl-phenylalanine Proteins 0.000 description 5
- 108010047857 aspartylglycine Proteins 0.000 description 5
- 238000003556 assay Methods 0.000 description 5
- 230000009286 beneficial effect Effects 0.000 description 5
- 238000004587 chromatography analysis Methods 0.000 description 5
- 108010057083 glutamyl-aspartyl-leucine Proteins 0.000 description 5
- 108010013768 glutamyl-aspartyl-proline Proteins 0.000 description 5
- 108010000434 glycyl-alanyl-leucine Proteins 0.000 description 5
- 108010050475 glycyl-leucyl-tyrosine Proteins 0.000 description 5
- 108010015792 glycyllysine Proteins 0.000 description 5
- 108010044311 leucyl-glycyl-glycine Proteins 0.000 description 5
- 108010091871 leucylmethionine Proteins 0.000 description 5
- 108010057821 leucylproline Proteins 0.000 description 5
- 238000005259 measurement Methods 0.000 description 5
- 108010077112 prolyl-proline Proteins 0.000 description 5
- 108010090894 prolylleucine Proteins 0.000 description 5
- 241000894007 species Species 0.000 description 5
- 108010071097 threonyl-lysyl-proline Proteins 0.000 description 5
- 108010052774 valyl-lysyl-glycyl-phenylalanyl-tyrosine Proteins 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
- 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 4
- CREYEAPXISDKSB-FQPOAREZSA-N Ala-Thr-Tyr Chemical compound [H]N[C@@H](C)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O CREYEAPXISDKSB-FQPOAREZSA-N 0.000 description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- PRLPSDIHSRITSF-UNQGMJICSA-N Arg-Phe-Thr Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H]([C@@H](C)O)C(O)=O PRLPSDIHSRITSF-UNQGMJICSA-N 0.000 description 4
- ISJWBVIYRBAXEB-CIUDSAMLSA-N Arg-Ser-Glu Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(O)=O)C(O)=O ISJWBVIYRBAXEB-CIUDSAMLSA-N 0.000 description 4
- LTDGPJKGJDIBQD-LAEOZQHASA-N Asn-Val-Gln Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(N)=O)C(O)=O LTDGPJKGJDIBQD-LAEOZQHASA-N 0.000 description 4
- 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 4
- 201000009030 Carcinoma Diseases 0.000 description 4
- 108020004705 Codon Proteins 0.000 description 4
- 229920001917 Ficoll Polymers 0.000 description 4
- 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 4
- 208000017604 Hodgkin disease Diseases 0.000 description 4
- 208000010747 Hodgkins lymphoma Diseases 0.000 description 4
- 101000777550 Homo sapiens CCN family member 2 Proteins 0.000 description 4
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 4
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 4
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 4
- 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 4
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 4
- 208000031422 Lymphocytic Chronic B-Cell Leukemia Diseases 0.000 description 4
- KCXUCYYZNZFGLL-SRVKXCTJSA-N Lys-Ala-Leu Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(O)=O KCXUCYYZNZFGLL-SRVKXCTJSA-N 0.000 description 4
- 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 4
- NKKFVJRLCCUJNA-QWRGUYRKSA-N Lys-Gly-Lys Chemical compound NCCCC[C@H](N)C(=O)NCC(=O)N[C@H](C(O)=O)CCCCN NKKFVJRLCCUJNA-QWRGUYRKSA-N 0.000 description 4
- 102220539316 Prostaglandin D2 receptor 2_R72S_mutation Human genes 0.000 description 4
- 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 4
- 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 4
- HHJFMHQYEAAOBM-ZLUOBGJFSA-N Ser-Ser-Ala Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H](C)C(O)=O HHJFMHQYEAAOBM-ZLUOBGJFSA-N 0.000 description 4
- 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 4
- 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 4
- 230000009471 action Effects 0.000 description 4
- 206010003246 arthritis Diseases 0.000 description 4
- 230000001363 autoimmune Effects 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 208000032852 chronic lymphocytic leukemia Diseases 0.000 description 4
- 230000000295 complement effect Effects 0.000 description 4
- 239000002299 complementary DNA Substances 0.000 description 4
- 229940127089 cytotoxic agent Drugs 0.000 description 4
- 239000002254 cytotoxic agent Substances 0.000 description 4
- 238000010790 dilution Methods 0.000 description 4
- 239000012895 dilution Substances 0.000 description 4
- 239000012636 effector Substances 0.000 description 4
- 230000013595 glycosylation Effects 0.000 description 4
- 238000006206 glycosylation reaction Methods 0.000 description 4
- 102000047612 human CCN2 Human genes 0.000 description 4
- 230000036039 immunity Effects 0.000 description 4
- 238000002372 labelling Methods 0.000 description 4
- 201000005202 lung cancer Diseases 0.000 description 4
- 208000020816 lung neoplasm Diseases 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 201000006417 multiple sclerosis Diseases 0.000 description 4
- 238000011160 research Methods 0.000 description 4
- 239000006228 supernatant Substances 0.000 description 4
- 201000000596 systemic lupus erythematosus Diseases 0.000 description 4
- 108010061238 threonyl-glycine Proteins 0.000 description 4
- 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 3
- 108010088751 Albumins Proteins 0.000 description 3
- 102000009027 Albumins Human genes 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 3
- 241000196324 Embryophyta Species 0.000 description 3
- 102000004190 Enzymes Human genes 0.000 description 3
- 108090000790 Enzymes Proteins 0.000 description 3
- 206010018364 Glomerulonephritis Diseases 0.000 description 3
- 108090000288 Glycoproteins Proteins 0.000 description 3
- 102000003886 Glycoproteins Human genes 0.000 description 3
- 208000021519 Hodgkin lymphoma Diseases 0.000 description 3
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 3
- AYFVYJQAPQTCCC-GBXIJSLDSA-N L-threonine Chemical compound C[C@@H](O)[C@H](N)C(O)=O AYFVYJQAPQTCCC-GBXIJSLDSA-N 0.000 description 3
- 201000001263 Psoriatic Arthritis Diseases 0.000 description 3
- 208000036824 Psoriatic arthropathy Diseases 0.000 description 3
- 206010039491 Sarcoma Diseases 0.000 description 3
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 3
- 102100040247 Tumor necrosis factor Human genes 0.000 description 3
- WUFHZIRMAZZWRS-OSUNSFLBSA-N Val-Thr-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](C(C)C)N WUFHZIRMAZZWRS-OSUNSFLBSA-N 0.000 description 3
- 208000033559 Waldenström macroglobulinemia Diseases 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 238000011091 antibody purification Methods 0.000 description 3
- 108010092854 aspartyllysine Proteins 0.000 description 3
- 230000005784 autoimmunity Effects 0.000 description 3
- 238000003776 cleavage reaction Methods 0.000 description 3
- 238000004590 computer program Methods 0.000 description 3
- 230000008878 coupling Effects 0.000 description 3
- 238000010168 coupling process Methods 0.000 description 3
- 238000005859 coupling reaction Methods 0.000 description 3
- 231100000599 cytotoxic agent Toxicity 0.000 description 3
- 239000002552 dosage form Substances 0.000 description 3
- 238000012377 drug delivery Methods 0.000 description 3
- 239000012530 fluid Substances 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 210000004602 germ cell Anatomy 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 230000028993 immune response Effects 0.000 description 3
- 238000003780 insertion Methods 0.000 description 3
- 230000037431 insertion Effects 0.000 description 3
- 239000003446 ligand Substances 0.000 description 3
- 108010057952 lysyl-phenylalanyl-lysine Proteins 0.000 description 3
- 230000003211 malignant effect Effects 0.000 description 3
- 229960000485 methotrexate Drugs 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 210000001616 monocyte Anatomy 0.000 description 3
- 238000002703 mutagenesis Methods 0.000 description 3
- 231100000350 mutagenesis Toxicity 0.000 description 3
- 239000000546 pharmaceutical excipient Substances 0.000 description 3
- 208000005987 polymyositis Diseases 0.000 description 3
- 102000005962 receptors Human genes 0.000 description 3
- 108020003175 receptors Proteins 0.000 description 3
- 230000002829 reductive effect Effects 0.000 description 3
- 108091008146 restriction endonucleases Proteins 0.000 description 3
- 102200004706 rs1060505034 Human genes 0.000 description 3
- 102200118280 rs33918343 Human genes 0.000 description 3
- 230000007017 scission Effects 0.000 description 3
- 238000012216 screening Methods 0.000 description 3
- 238000012163 sequencing technique Methods 0.000 description 3
- 235000004400 serine Nutrition 0.000 description 3
- 108010069117 seryl-lysyl-aspartic acid Proteins 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 238000011830 transgenic mouse model Methods 0.000 description 3
- DWNBOPVKNPVNQG-LURJTMIESA-N (2s)-4-hydroxy-2-(propylamino)butanoic acid Chemical compound CCCN[C@H](C(O)=O)CCO DWNBOPVKNPVNQG-LURJTMIESA-N 0.000 description 2
- MXBCYQUALCBQIJ-RYVPXURESA-N (8s,9s,10r,13s,14s,17r)-13-ethyl-17-ethynyl-11-methylidene-1,2,3,6,7,8,9,10,12,14,15,16-dodecahydrocyclopenta[a]phenanthren-17-ol;(8r,9s,13s,14s,17r)-17-ethynyl-13-methyl-7,8,9,11,12,14,15,16-octahydro-6h-cyclopenta[a]phenanthrene-3,17-diol Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@](CC4)(O)C#C)[C@@H]4[C@@H]3CCC2=C1.C1CC[C@@H]2[C@H]3C(=C)C[C@](CC)([C@](CC4)(O)C#C)[C@@H]4[C@@H]3CCC2=C1 MXBCYQUALCBQIJ-RYVPXURESA-N 0.000 description 2
- QFVHZQCOUORWEI-UHFFFAOYSA-N 4-[(4-anilino-5-sulfonaphthalen-1-yl)diazenyl]-5-hydroxynaphthalene-2,7-disulfonic acid Chemical compound C=12C(O)=CC(S(O)(=O)=O)=CC2=CC(S(O)(=O)=O)=CC=1N=NC(C1=CC=CC(=C11)S(O)(=O)=O)=CC=C1NC1=CC=CC=C1 QFVHZQCOUORWEI-UHFFFAOYSA-N 0.000 description 2
- 101000689231 Aeromonas salmonicida S-layer protein Proteins 0.000 description 2
- 229920000936 Agarose Polymers 0.000 description 2
- 101710186708 Agglutinin Proteins 0.000 description 2
- ROLXPVQSRCPVGK-XDTLVQLUSA-N Ala-Glu-Tyr Chemical compound N[C@@H](C)C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CC1=CC=C(C=C1)O)C(=O)O ROLXPVQSRCPVGK-XDTLVQLUSA-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
- ISCYZXFOCXWUJU-KZVJFYERSA-N Ala-Thr-Met Chemical compound [H]N[C@@H](C)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCSC)C(O)=O ISCYZXFOCXWUJU-KZVJFYERSA-N 0.000 description 2
- IETUUAHKCHOQHP-KZVJFYERSA-N Ala-Thr-Val Chemical compound CC(C)[C@H](NC(=O)[C@@H](NC(=O)[C@H](C)N)[C@@H](C)O)C(O)=O IETUUAHKCHOQHP-KZVJFYERSA-N 0.000 description 2
- 206010002556 Ankylosing Spondylitis Diseases 0.000 description 2
- RBOBTTLFPRSXKZ-BZSNNMDCSA-N Asn-Phe-Tyr Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O RBOBTTLFPRSXKZ-BZSNNMDCSA-N 0.000 description 2
- WMLFFCRUSPNENW-ZLUOBGJFSA-N Asp-Ser-Ala Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](C)C(O)=O WMLFFCRUSPNENW-ZLUOBGJFSA-N 0.000 description 2
- 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 2
- YIDFBWRHIYOYAA-LKXGYXEUSA-N Asp-Ser-Thr Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(O)=O YIDFBWRHIYOYAA-LKXGYXEUSA-N 0.000 description 2
- 206010004146 Basal cell carcinoma Diseases 0.000 description 2
- 208000017897 Carcinoma of esophagus Diseases 0.000 description 2
- 208000006332 Choriocarcinoma Diseases 0.000 description 2
- 208000028399 Critical Illness Diseases 0.000 description 2
- 208000011231 Crohn disease Diseases 0.000 description 2
- 102000004127 Cytokines Human genes 0.000 description 2
- 108090000695 Cytokines Proteins 0.000 description 2
- 201000004624 Dermatitis Diseases 0.000 description 2
- 208000000461 Esophageal Neoplasms Diseases 0.000 description 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 2
- 229930091371 Fructose Natural products 0.000 description 2
- RFSUNEUAIZKAJO-ARQDHWQXSA-N Fructose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O RFSUNEUAIZKAJO-ARQDHWQXSA-N 0.000 description 2
- 239000005715 Fructose Substances 0.000 description 2
- XZLLTYBONVKGLO-SDDRHHMPSA-N Gln-Lys-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CCCCN)NC(=O)[C@H](CCC(=O)N)N)C(=O)O XZLLTYBONVKGLO-SDDRHHMPSA-N 0.000 description 2
- GJBUAAAIZSRCDC-GVXVVHGQSA-N Glu-Leu-Val Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(O)=O GJBUAAAIZSRCDC-GVXVVHGQSA-N 0.000 description 2
- DTRUBYPMMVPQPD-YUMQZZPRSA-N Gly-Gln-Arg Chemical compound [H]NCC(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O DTRUBYPMMVPQPD-YUMQZZPRSA-N 0.000 description 2
- 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 2
- 208000030836 Hashimoto thyroiditis Diseases 0.000 description 2
- 208000031220 Hemophilia Diseases 0.000 description 2
- 208000009292 Hemophilia A Diseases 0.000 description 2
- 102000008055 Heparan Sulfate Proteoglycans Human genes 0.000 description 2
- 229920002971 Heparan sulfate Polymers 0.000 description 2
- 101000998952 Homo sapiens Immunoglobulin heavy variable 1-3 Proteins 0.000 description 2
- 101710146024 Horcolin Proteins 0.000 description 2
- NZGTYCMLUGYMCV-XUXIUFHCSA-N Ile-Lys-Arg Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCN=C(N)N)C(=O)O)N NZGTYCMLUGYMCV-XUXIUFHCSA-N 0.000 description 2
- 102000001706 Immunoglobulin Fab Fragments Human genes 0.000 description 2
- 108010054477 Immunoglobulin Fab Fragments Proteins 0.000 description 2
- 102000017727 Immunoglobulin Variable Region Human genes 0.000 description 2
- 108010067060 Immunoglobulin Variable Region Proteins 0.000 description 2
- 102100036886 Immunoglobulin heavy variable 1-3 Human genes 0.000 description 2
- DCXYFEDJOCDNAF-REOHCLBHSA-N L-asparagine Chemical compound OC(=O)[C@@H](N)CC(N)=O DCXYFEDJOCDNAF-REOHCLBHSA-N 0.000 description 2
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 2
- SENJXOPIZNYLHU-UHFFFAOYSA-N L-leucyl-L-arginine Natural products CC(C)CC(N)C(=O)NC(C(O)=O)CCCN=C(N)N SENJXOPIZNYLHU-UHFFFAOYSA-N 0.000 description 2
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 2
- 101710189395 Lectin Proteins 0.000 description 2
- KAFOIVJDVSZUMD-DCAQKATOSA-N Leu-Gln-Gln Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(O)=O KAFOIVJDVSZUMD-DCAQKATOSA-N 0.000 description 2
- KAFOIVJDVSZUMD-UHFFFAOYSA-N Leu-Gln-Gln Natural products CC(C)CC(N)C(=O)NC(CCC(N)=O)C(=O)NC(CCC(N)=O)C(O)=O KAFOIVJDVSZUMD-UHFFFAOYSA-N 0.000 description 2
- 206010061523 Lip and/or oral cavity cancer Diseases 0.000 description 2
- 239000012097 Lipofectamine 2000 Substances 0.000 description 2
- 206010025323 Lymphomas Diseases 0.000 description 2
- XFIHDSBIPWEYJJ-YUMQZZPRSA-N Lys-Ala-Gly Chemical compound OC(=O)CNC(=O)[C@H](C)NC(=O)[C@@H](N)CCCCN XFIHDSBIPWEYJJ-YUMQZZPRSA-N 0.000 description 2
- DIBZLYZXTSVGLN-CIUDSAMLSA-N Lys-Ser-Ser Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(O)=O DIBZLYZXTSVGLN-CIUDSAMLSA-N 0.000 description 2
- 101710179758 Mannose-specific lectin Proteins 0.000 description 2
- 101710150763 Mannose-specific lectin 1 Proteins 0.000 description 2
- 101710150745 Mannose-specific lectin 2 Proteins 0.000 description 2
- WRXOPYNEKGZWAZ-FXQIFTODSA-N Met-Ser-Cys Chemical compound CSCC[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CS)C(O)=O WRXOPYNEKGZWAZ-FXQIFTODSA-N 0.000 description 2
- IIHMNTBFPMRJCN-RCWTZXSCSA-N Met-Val-Thr Chemical compound CSCC[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O IIHMNTBFPMRJCN-RCWTZXSCSA-N 0.000 description 2
- 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 2
- 108091007491 NSP3 Papain-like protease domains Proteins 0.000 description 2
- 206010029260 Neuroblastoma Diseases 0.000 description 2
- 108091028043 Nucleic acid sequence Proteins 0.000 description 2
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 2
- 206010034277 Pemphigoid Diseases 0.000 description 2
- 108091005804 Peptidases Proteins 0.000 description 2
- HXSUFWQYLPKEHF-IHRRRGAJSA-N Phe-Asn-Arg Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CCCN=C(N)N)C(=O)O)N HXSUFWQYLPKEHF-IHRRRGAJSA-N 0.000 description 2
- SCKXGHWQPPURGT-KKUMJFAQSA-N Phe-Lys-Ser Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CO)C(O)=O SCKXGHWQPPURGT-KKUMJFAQSA-N 0.000 description 2
- CFVRJNZJQHDQPP-CYDGBPFRSA-N Pro-Ile-Met Chemical compound CSCC[C@@H](C(O)=O)NC(=O)[C@H]([C@@H](C)CC)NC(=O)[C@@H]1CCCN1 CFVRJNZJQHDQPP-CYDGBPFRSA-N 0.000 description 2
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 2
- 239000004365 Protease Substances 0.000 description 2
- 201000000582 Retinoblastoma Diseases 0.000 description 2
- 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 description 2
- 241000219061 Rheum Species 0.000 description 2
- 241000283984 Rodentia Species 0.000 description 2
- 229920002684 Sepharose Polymers 0.000 description 2
- 206010040047 Sepsis Diseases 0.000 description 2
- WDXYVIIVDIDOSX-DCAQKATOSA-N Ser-Arg-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)CO)CCCN=C(N)N WDXYVIIVDIDOSX-DCAQKATOSA-N 0.000 description 2
- KDGARKCAKHBEDB-NKWVEPMBSA-N Ser-Gly-Pro Chemical compound C1C[C@@H](N(C1)C(=O)CNC(=O)[C@H](CO)N)C(=O)O KDGARKCAKHBEDB-NKWVEPMBSA-N 0.000 description 2
- SFTZWNJFZYOLBD-ZDLURKLDSA-N Ser-Gly-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)CNC(=O)[C@@H](N)CO SFTZWNJFZYOLBD-ZDLURKLDSA-N 0.000 description 2
- CUXJENOFJXOSOZ-BIIVOSGPSA-N Ser-Ser-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CO)NC(=O)[C@H](CO)N)C(=O)O CUXJENOFJXOSOZ-BIIVOSGPSA-N 0.000 description 2
- NADLKBTYNKUJEP-KATARQTJSA-N Ser-Thr-Leu Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(O)=O NADLKBTYNKUJEP-KATARQTJSA-N 0.000 description 2
- BDMWLJLPPUCLNV-XGEHTFHBSA-N Ser-Thr-Val Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(O)=O BDMWLJLPPUCLNV-XGEHTFHBSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 206010041067 Small cell lung cancer Diseases 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 208000005718 Stomach Neoplasms Diseases 0.000 description 2
- 108090000054 Syndecan-2 Proteins 0.000 description 2
- 101000748795 Thermus thermophilus (strain ATCC 27634 / DSM 579 / HB8) Cytochrome c oxidase polypeptide I+III Proteins 0.000 description 2
- XHWCDRUPDNSDAZ-XKBZYTNZSA-N Thr-Ser-Glu Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(=O)O)C(=O)O)N)O XHWCDRUPDNSDAZ-XKBZYTNZSA-N 0.000 description 2
- NQQMWWVVGIXUOX-SVSWQMSJSA-N Thr-Ser-Ile Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O NQQMWWVVGIXUOX-SVSWQMSJSA-N 0.000 description 2
- RVMNUBQWPVOUKH-HEIBUPTGSA-N Thr-Ser-Thr Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(O)=O RVMNUBQWPVOUKH-HEIBUPTGSA-N 0.000 description 2
- UOXPLPBMEPLZBW-WDSOQIARSA-N Trp-Val-Lys Chemical compound C1=CC=C2C(C[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(O)=O)=CNC2=C1 UOXPLPBMEPLZBW-WDSOQIARSA-N 0.000 description 2
- 206010067584 Type 1 diabetes mellitus Diseases 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
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 description 2
- ZHWZDZFWBXWPDW-GUBZILKMSA-N Val-Val-Cys Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CS)C(O)=O ZHWZDZFWBXWPDW-GUBZILKMSA-N 0.000 description 2
- 238000002835 absorbance Methods 0.000 description 2
- 230000002411 adverse Effects 0.000 description 2
- 239000000910 agglutinin Substances 0.000 description 2
- 238000012867 alanine scanning Methods 0.000 description 2
- 229960000548 alemtuzumab Drugs 0.000 description 2
- 229910021529 ammonia Inorganic materials 0.000 description 2
- 239000002246 antineoplastic agent Substances 0.000 description 2
- 239000011616 biotin Substances 0.000 description 2
- 229960002685 biotin Drugs 0.000 description 2
- 235000020958 biotin Nutrition 0.000 description 2
- 201000001531 bladder carcinoma Diseases 0.000 description 2
- 210000001124 body fluid Anatomy 0.000 description 2
- 239000010839 body fluid Substances 0.000 description 2
- 238000004113 cell culture Methods 0.000 description 2
- 230000030833 cell death Effects 0.000 description 2
- 230000004663 cell proliferation Effects 0.000 description 2
- 210000003169 central nervous system Anatomy 0.000 description 2
- 238000005119 centrifugation Methods 0.000 description 2
- 201000010881 cervical cancer Diseases 0.000 description 2
- 238000002512 chemotherapy Methods 0.000 description 2
- 208000006990 cholangiocarcinoma Diseases 0.000 description 2
- 208000029742 colonic neoplasm Diseases 0.000 description 2
- 238000011284 combination treatment Methods 0.000 description 2
- 230000009827 complement-dependent cellular cytotoxicity Effects 0.000 description 2
- 238000010276 construction Methods 0.000 description 2
- 238000005314 correlation function Methods 0.000 description 2
- 238000005336 cracking Methods 0.000 description 2
- 235000018417 cysteine Nutrition 0.000 description 2
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 2
- 239000000824 cytostatic agent Substances 0.000 description 2
- 230000001085 cytostatic effect Effects 0.000 description 2
- 230000003013 cytotoxicity Effects 0.000 description 2
- 231100000135 cytotoxicity Toxicity 0.000 description 2
- 230000034994 death Effects 0.000 description 2
- 230000001419 dependent effect Effects 0.000 description 2
- 238000000151 deposition Methods 0.000 description 2
- 230000008021 deposition Effects 0.000 description 2
- 238000013461 design Methods 0.000 description 2
- UQLDLKMNUJERMK-UHFFFAOYSA-L di(octadecanoyloxy)lead Chemical compound [Pb+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O UQLDLKMNUJERMK-UHFFFAOYSA-L 0.000 description 2
- 206010012818 diffuse large B-cell lymphoma Diseases 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- OGPBJKLSAFTDLK-IGMARMGPSA-N europium-152 Chemical compound [152Eu] OGPBJKLSAFTDLK-IGMARMGPSA-N 0.000 description 2
- 206010017758 gastric cancer Diseases 0.000 description 2
- 108010079413 glycyl-prolyl-glutamic acid Proteins 0.000 description 2
- 210000003714 granulocyte Anatomy 0.000 description 2
- 208000006454 hepatitis Diseases 0.000 description 2
- 231100000283 hepatitis Toxicity 0.000 description 2
- 206010020718 hyperplasia Diseases 0.000 description 2
- 210000000987 immune system Anatomy 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- 230000006698 induction Effects 0.000 description 2
- 230000002757 inflammatory effect Effects 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 2
- 238000007912 intraperitoneal administration Methods 0.000 description 2
- 210000003734 kidney Anatomy 0.000 description 2
- 108010034529 leucyl-lysine Proteins 0.000 description 2
- 108010000761 leucylarginine Proteins 0.000 description 2
- 208000032839 leukemia Diseases 0.000 description 2
- 210000002751 lymph Anatomy 0.000 description 2
- 208000012804 lymphangiosarcoma Diseases 0.000 description 2
- 210000002540 macrophage Anatomy 0.000 description 2
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 2
- 238000013507 mapping Methods 0.000 description 2
- 201000001441 melanoma Diseases 0.000 description 2
- MYWUZJCMWCOHBA-VIFPVBQESA-N methamphetamine Chemical compound CN[C@@H](C)CC1=CC=CC=C1 MYWUZJCMWCOHBA-VIFPVBQESA-N 0.000 description 2
- 206010028417 myasthenia gravis Diseases 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- 239000002777 nucleoside Substances 0.000 description 2
- 125000003835 nucleoside group Chemical group 0.000 description 2
- 210000000056 organ Anatomy 0.000 description 2
- 201000008968 osteosarcoma Diseases 0.000 description 2
- 210000001322 periplasm Anatomy 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 230000005855 radiation Effects 0.000 description 2
- 230000002285 radioactive effect Effects 0.000 description 2
- 201000009410 rhabdomyosarcoma Diseases 0.000 description 2
- PYWVYCXTNDRMGF-UHFFFAOYSA-N rhodamine B Chemical compound [Cl-].C=12C=CC(=[N+](CC)CC)C=C2OC2=CC(N(CC)CC)=CC=C2C=1C1=CC=CC=C1C(O)=O PYWVYCXTNDRMGF-UHFFFAOYSA-N 0.000 description 2
- 210000003491 skin Anatomy 0.000 description 2
- 150000003384 small molecules Chemical class 0.000 description 2
- 238000002415 sodium dodecyl sulfate polyacrylamide gel electrophoresis Methods 0.000 description 2
- 201000011549 stomach cancer Diseases 0.000 description 2
- 238000005728 strengthening Methods 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- 230000001629 suppression Effects 0.000 description 2
- 210000001550 testis Anatomy 0.000 description 2
- 231100000167 toxic agent Toxicity 0.000 description 2
- 239000003440 toxic substance Substances 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 239000003053 toxin Substances 0.000 description 2
- 231100000765 toxin Toxicity 0.000 description 2
- 238000001890 transfection Methods 0.000 description 2
- 239000012096 transfection reagent Substances 0.000 description 2
- 235000002374 tyrosine Nutrition 0.000 description 2
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 2
- 108010003137 tyrosyltyrosine Proteins 0.000 description 2
- 238000000108 ultra-filtration Methods 0.000 description 2
- 208000010570 urinary bladder carcinoma Diseases 0.000 description 2
- ZQJHYRVSKHGGJY-YPKJBDGSSA-N (2s,3r)-2-[[(2s)-2-[[(2s)-1-[(2s)-2-amino-3-(4-hydroxyphenyl)propanoyl]pyrrolidine-2-carbonyl]amino]-3-phenylpropanoyl]amino]-3-hydroxybutanoic acid Chemical compound C([C@@H](C(=O)N[C@@H]([C@H](O)C)C(O)=O)NC(=O)[C@H]1N(CCC1)C(=O)[C@@H](N)CC=1C=CC(O)=CC=1)C1=CC=CC=C1 ZQJHYRVSKHGGJY-YPKJBDGSSA-N 0.000 description 1
- NFGXHKASABOEEW-UHFFFAOYSA-N 1-methylethyl 11-methoxy-3,7,11-trimethyl-2,4-dodecadienoate Chemical compound COC(C)(C)CCCC(C)CC=CC(C)=CC(=O)OC(C)C NFGXHKASABOEEW-UHFFFAOYSA-N 0.000 description 1
- PXFBZOLANLWPMH-UHFFFAOYSA-N 16-Epiaffinine Natural products C1C(C2=CC=CC=C2N2)=C2C(=O)CC2C(=CC)CN(C)C1C2CO PXFBZOLANLWPMH-UHFFFAOYSA-N 0.000 description 1
- IJJWOSAXNHWBPR-HUBLWGQQSA-N 5-[(3as,4s,6ar)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]-n-(6-hydrazinyl-6-oxohexyl)pentanamide Chemical compound N1C(=O)N[C@@H]2[C@H](CCCCC(=O)NCCCCCC(=O)NN)SC[C@@H]21 IJJWOSAXNHWBPR-HUBLWGQQSA-N 0.000 description 1
- CJIJXIFQYOPWTF-UHFFFAOYSA-N 7-hydroxycoumarin Natural products O1C(=O)C=CC2=CC(O)=CC=C21 CJIJXIFQYOPWTF-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 108010066676 Abrin Proteins 0.000 description 1
- 208000031261 Acute myeloid leukaemia Diseases 0.000 description 1
- 208000026872 Addison Disease Diseases 0.000 description 1
- 108010000239 Aequorin Proteins 0.000 description 1
- WRDANSJTFOHBPI-FXQIFTODSA-N Ala-Arg-Cys Chemical compound C[C@@H](C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CS)C(=O)O)N WRDANSJTFOHBPI-FXQIFTODSA-N 0.000 description 1
- NHCPCLJZRSIDHS-ZLUOBGJFSA-N Ala-Asp-Ala Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](C)C(O)=O NHCPCLJZRSIDHS-ZLUOBGJFSA-N 0.000 description 1
- WCBVQNZTOKJWJS-ACZMJKKPSA-N Ala-Cys-Glu Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCC(O)=O)C(O)=O WCBVQNZTOKJWJS-ACZMJKKPSA-N 0.000 description 1
- SFNFGFDRYJKZKN-XQXXSGGOSA-N Ala-Gln-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)N)NC(=O)[C@H](C)N)O SFNFGFDRYJKZKN-XQXXSGGOSA-N 0.000 description 1
- NHLAEBFGWPXFGI-WHFBIAKZSA-N Ala-Gly-Asn Chemical compound C[C@@H](C(=O)NCC(=O)N[C@@H](CC(=O)N)C(=O)O)N NHLAEBFGWPXFGI-WHFBIAKZSA-N 0.000 description 1
- CBCCCLMNOBLBSC-XVYDVKMFSA-N Ala-His-Ser Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CO)C(O)=O CBCCCLMNOBLBSC-XVYDVKMFSA-N 0.000 description 1
- OINVDEKBKBCPLX-JXUBOQSCSA-N Ala-Lys-Thr Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(O)=O OINVDEKBKBCPLX-JXUBOQSCSA-N 0.000 description 1
- OSRZOHXQCUFIQG-FPMFFAJLSA-N Ala-Phe-Pro Chemical compound C([C@H](NC(=O)[C@@H]([NH3+])C)C(=O)N1[C@H](CCC1)C([O-])=O)C1=CC=CC=C1 OSRZOHXQCUFIQG-FPMFFAJLSA-N 0.000 description 1
- FEGOCLZUJUFCHP-CIUDSAMLSA-N Ala-Pro-Gln Chemical compound [H]N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCC(N)=O)C(O)=O FEGOCLZUJUFCHP-CIUDSAMLSA-N 0.000 description 1
- WQLDNOCHHRISMS-NAKRPEOUSA-N Ala-Pro-Ile Chemical compound [H]N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)N[C@@H]([C@@H](C)CC)C(O)=O WQLDNOCHHRISMS-NAKRPEOUSA-N 0.000 description 1
- NCQMBSJGJMYKCK-ZLUOBGJFSA-N Ala-Ser-Ser Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(O)=O NCQMBSJGJMYKCK-ZLUOBGJFSA-N 0.000 description 1
- AAWLEICNDUHIJM-MBLNEYKQSA-N Ala-Thr-His Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)NC(=O)[C@H](C)N)O AAWLEICNDUHIJM-MBLNEYKQSA-N 0.000 description 1
- 206010027654 Allergic conditions Diseases 0.000 description 1
- 208000024827 Alzheimer disease Diseases 0.000 description 1
- 201000003076 Angiosarcoma Diseases 0.000 description 1
- RCAUJZASOAFTAJ-FXQIFTODSA-N Arg-Asp-Cys Chemical compound C(C[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](CS)C(=O)O)N)CN=C(N)N RCAUJZASOAFTAJ-FXQIFTODSA-N 0.000 description 1
- FVBZXNSRIDVYJS-AVGNSLFASA-N Arg-Pro-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@@H](N)CCCN=C(N)N FVBZXNSRIDVYJS-AVGNSLFASA-N 0.000 description 1
- ATABBWFGOHKROJ-GUBZILKMSA-N Arg-Pro-Ser Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CO)C(O)=O ATABBWFGOHKROJ-GUBZILKMSA-N 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- HOIFSHOLNKQCSA-FXQIFTODSA-N Asn-Arg-Asp Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(O)=O HOIFSHOLNKQCSA-FXQIFTODSA-N 0.000 description 1
- QCWJKJLNCFEVPQ-WHFBIAKZSA-N Asn-Gln Chemical compound NC(=O)C[C@H](N)C(=O)N[C@H](C(O)=O)CCC(N)=O QCWJKJLNCFEVPQ-WHFBIAKZSA-N 0.000 description 1
- MECFLTFREHAZLH-ACZMJKKPSA-N Asn-Glu-Cys Chemical compound C(CC(=O)O)[C@@H](C(=O)N[C@@H](CS)C(=O)O)NC(=O)[C@H](CC(=O)N)N MECFLTFREHAZLH-ACZMJKKPSA-N 0.000 description 1
- OOWSBIOUKIUWLO-RCOVLWMOSA-N Asn-Gly-Val Chemical compound [H]N[C@@H](CC(N)=O)C(=O)NCC(=O)N[C@@H](C(C)C)C(O)=O OOWSBIOUKIUWLO-RCOVLWMOSA-N 0.000 description 1
- UYRPHDGXHKBZHJ-CIUDSAMLSA-N Asn-Met-Gln Chemical compound CSCC[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)O)NC(=O)[C@H](CC(=O)N)N UYRPHDGXHKBZHJ-CIUDSAMLSA-N 0.000 description 1
- XHTUGJCAEYOZOR-UBHSHLNASA-N Asn-Ser-Trp Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC1=CNC2=C1C=CC=C2)C(O)=O XHTUGJCAEYOZOR-UBHSHLNASA-N 0.000 description 1
- QYRMBFWDSFGSFC-OLHMAJIHSA-N Asn-Thr-Asn Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)O)NC(=O)[C@H](CC(=O)N)N)O QYRMBFWDSFGSFC-OLHMAJIHSA-N 0.000 description 1
- QUMKPKWYDVMGNT-NUMRIWBASA-N Asn-Thr-Gln Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)O)NC(=O)[C@H](CC(=O)N)N)O QUMKPKWYDVMGNT-NUMRIWBASA-N 0.000 description 1
- LMIWYCWRJVMAIQ-NHCYSSNCSA-N Asn-Val-Lys Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CC(=O)N)N LMIWYCWRJVMAIQ-NHCYSSNCSA-N 0.000 description 1
- XPGVTUBABLRGHY-BIIVOSGPSA-N Asp-Ala-Pro Chemical compound C[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](CC(=O)O)N XPGVTUBABLRGHY-BIIVOSGPSA-N 0.000 description 1
- YNQIDCRRTWGHJD-ZLUOBGJFSA-N Asp-Asn-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](N)CC(O)=O YNQIDCRRTWGHJD-ZLUOBGJFSA-N 0.000 description 1
- LKIYSIYBKYLKPU-BIIVOSGPSA-N Asp-Asp-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CC(=O)O)NC(=O)[C@H](CC(=O)O)N)C(=O)O LKIYSIYBKYLKPU-BIIVOSGPSA-N 0.000 description 1
- HSWYMWGDMPLTTH-FXQIFTODSA-N Asp-Glu-Gln Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(N)=O)C(O)=O HSWYMWGDMPLTTH-FXQIFTODSA-N 0.000 description 1
- SNDBKTFJWVEVPO-WHFBIAKZSA-N Asp-Gly-Ser Chemical compound [H]N[C@@H](CC(O)=O)C(=O)NCC(=O)N[C@@H](CO)C(O)=O SNDBKTFJWVEVPO-WHFBIAKZSA-N 0.000 description 1
- HOBNTSHITVVNBN-ZPFDUUQYSA-N Asp-Ile-Leu Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC(C)C)C(=O)O)NC(=O)[C@H](CC(=O)O)N HOBNTSHITVVNBN-ZPFDUUQYSA-N 0.000 description 1
- NVFSJIXJZCDICF-SRVKXCTJSA-N Asp-Lys-Lys Chemical compound C(CCN)C[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CC(=O)O)N NVFSJIXJZCDICF-SRVKXCTJSA-N 0.000 description 1
- MYLZFUMPZCPJCJ-NHCYSSNCSA-N Asp-Lys-Val Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C(C)C)C(O)=O MYLZFUMPZCPJCJ-NHCYSSNCSA-N 0.000 description 1
- UCHSVZYJKJLPHF-BZSNNMDCSA-N Asp-Phe-Phe Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O UCHSVZYJKJLPHF-BZSNNMDCSA-N 0.000 description 1
- XMKXONRMGJXCJV-LAEOZQHASA-N Asp-Val-Glu Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(O)=O)C(O)=O XMKXONRMGJXCJV-LAEOZQHASA-N 0.000 description 1
- GIKOVDMXBAFXDF-NHCYSSNCSA-N Asp-Val-Leu Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O GIKOVDMXBAFXDF-NHCYSSNCSA-N 0.000 description 1
- DCXYFEDJOCDNAF-UHFFFAOYSA-N Asparagine Natural products OC(=O)C(N)CC(N)=O DCXYFEDJOCDNAF-UHFFFAOYSA-N 0.000 description 1
- 241000432824 Asparagus densiflorus Species 0.000 description 1
- 208000000659 Autoimmune lymphoproliferative syndrome Diseases 0.000 description 1
- 108090001008 Avidin Proteins 0.000 description 1
- 208000036170 B-Cell Marginal Zone Lymphoma Diseases 0.000 description 1
- 208000003950 B-cell lymphoma Diseases 0.000 description 1
- 206010004593 Bile duct cancer Diseases 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- 208000003170 Bronchiolo-Alveolar Adenocarcinoma Diseases 0.000 description 1
- 208000011691 Burkitt lymphomas Diseases 0.000 description 1
- 238000011740 C57BL/6 mouse Methods 0.000 description 1
- 102100025221 CD70 antigen Human genes 0.000 description 1
- 241000283707 Capra Species 0.000 description 1
- 206010007953 Central nervous system lymphoma Diseases 0.000 description 1
- 208000005243 Chondrosarcoma Diseases 0.000 description 1
- 201000009047 Chordoma Diseases 0.000 description 1
- 108091026890 Coding region Proteins 0.000 description 1
- 208000015943 Coeliac disease Diseases 0.000 description 1
- 208000009798 Craniopharyngioma Diseases 0.000 description 1
- 241000195493 Cryptophyta Species 0.000 description 1
- XGHYKIDVGYYHDC-JBDRJPRFSA-N Cys-Ile-Cys Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CS)C(=O)O)NC(=O)[C@H](CS)N XGHYKIDVGYYHDC-JBDRJPRFSA-N 0.000 description 1
- XMVZMBGFIOQONW-GARJFASQSA-N Cys-Lys-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CCCCN)NC(=O)[C@H](CS)N)C(=O)O XMVZMBGFIOQONW-GARJFASQSA-N 0.000 description 1
- PEZINYWZBQNTIX-NAKRPEOUSA-N Cys-Met-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)[C@H](CCSC)NC(=O)[C@H](CS)N PEZINYWZBQNTIX-NAKRPEOUSA-N 0.000 description 1
- IGXWBGJHJZYPQS-SSDOTTSWSA-N D-Luciferin Chemical compound OC(=O)[C@H]1CSC(C=2SC3=CC=C(O)C=C3N=2)=N1 IGXWBGJHJZYPQS-SSDOTTSWSA-N 0.000 description 1
- 238000001712 DNA sequencing Methods 0.000 description 1
- CYCGRDQQIOGCKX-UHFFFAOYSA-N Dehydro-luciferin Natural products OC(=O)C1=CSC(C=2SC3=CC(O)=CC=C3N=2)=N1 CYCGRDQQIOGCKX-UHFFFAOYSA-N 0.000 description 1
- 102000016607 Diphtheria Toxin Human genes 0.000 description 1
- 108010053187 Diphtheria Toxin Proteins 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 201000009051 Embryonal Carcinoma Diseases 0.000 description 1
- 206010014759 Endometrial neoplasm Diseases 0.000 description 1
- 102100031780 Endonuclease Human genes 0.000 description 1
- 108010042407 Endonucleases Proteins 0.000 description 1
- 208000004232 Enteritis Diseases 0.000 description 1
- 206010014967 Ependymoma Diseases 0.000 description 1
- 208000031637 Erythroblastic Acute Leukemia Diseases 0.000 description 1
- 208000036566 Erythroleukaemia Diseases 0.000 description 1
- 241000588724 Escherichia coli Species 0.000 description 1
- 208000006168 Ewing Sarcoma Diseases 0.000 description 1
- 201000008808 Fibrosarcoma Diseases 0.000 description 1
- BJGNCJDXODQBOB-UHFFFAOYSA-N Fivefly Luciferin Natural products OC(=O)C1CSC(C=2SC3=CC(O)=CC=C3N=2)=N1 BJGNCJDXODQBOB-UHFFFAOYSA-N 0.000 description 1
- 208000032612 Glial tumor Diseases 0.000 description 1
- 206010018338 Glioma Diseases 0.000 description 1
- LMPBBFWHCRURJD-LAEOZQHASA-N Gln-Asn-Val Chemical compound CC(C)[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)N)NC(=O)[C@H](CCC(=O)N)N LMPBBFWHCRURJD-LAEOZQHASA-N 0.000 description 1
- LOJYQMFIIJVETK-WDSKDSINSA-N Gln-Gln Chemical compound NC(=O)CC[C@H](N)C(=O)N[C@@H](CCC(N)=O)C(O)=O LOJYQMFIIJVETK-WDSKDSINSA-N 0.000 description 1
- FGYPOQPQTUNESW-IUCAKERBSA-N Gln-Gly-Leu Chemical compound CC(C)C[C@@H](C(=O)O)NC(=O)CNC(=O)[C@H](CCC(=O)N)N FGYPOQPQTUNESW-IUCAKERBSA-N 0.000 description 1
- RCCDHXSRMWCOOY-GUBZILKMSA-N Glu-Arg-Gln Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(N)=O)C(O)=O RCCDHXSRMWCOOY-GUBZILKMSA-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
- MFNUFCFRAZPJFW-JYJNAYRXSA-N Glu-Lys-Phe Chemical compound OC(=O)CC[C@H](N)C(=O)N[C@@H](CCCCN)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 MFNUFCFRAZPJFW-JYJNAYRXSA-N 0.000 description 1
- RBXSZQRSEGYDFG-GUBZILKMSA-N Glu-Lys-Ser Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CO)C(O)=O RBXSZQRSEGYDFG-GUBZILKMSA-N 0.000 description 1
- QDMVXRNLOPTPIE-WDCWCFNPSA-N Glu-Lys-Thr Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(O)=O QDMVXRNLOPTPIE-WDCWCFNPSA-N 0.000 description 1
- DMYACXMQUABZIQ-NRPADANISA-N Glu-Ser-Val Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(O)=O DMYACXMQUABZIQ-NRPADANISA-N 0.000 description 1
- DLISPGXMKZTWQG-IFFSRLJSSA-N Glu-Thr-Val Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(O)=O DLISPGXMKZTWQG-IFFSRLJSSA-N 0.000 description 1
- ZNOHKCPYDAYYDA-BPUTZDHNSA-N Glu-Trp-Gln Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC1=CNC2=C1C=CC=C2)C(=O)N[C@@H](CCC(N)=O)C(O)=O ZNOHKCPYDAYYDA-BPUTZDHNSA-N 0.000 description 1
- QXUPRMQJDWJDFR-NRPADANISA-N Glu-Val-Ser Chemical compound CC(C)[C@H](NC(=O)[C@@H](N)CCC(O)=O)C(=O)N[C@@H](CO)C(O)=O QXUPRMQJDWJDFR-NRPADANISA-N 0.000 description 1
- LJPIRKICOISLKN-WHFBIAKZSA-N Gly-Ala-Ser Chemical compound NCC(=O)N[C@@H](C)C(=O)N[C@@H](CO)C(O)=O LJPIRKICOISLKN-WHFBIAKZSA-N 0.000 description 1
- KKBWDNZXYLGJEY-UHFFFAOYSA-N Gly-Arg-Pro Natural products NCC(=O)NC(CCNC(=N)N)C(=O)N1CCCC1C(=O)O KKBWDNZXYLGJEY-UHFFFAOYSA-N 0.000 description 1
- CIMULJZTTOBOPN-WHFBIAKZSA-N Gly-Asn-Asn Chemical compound NCC(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O CIMULJZTTOBOPN-WHFBIAKZSA-N 0.000 description 1
- XCLCVBYNGXEVDU-WHFBIAKZSA-N Gly-Asn-Ser Chemical compound NCC(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CO)C(O)=O XCLCVBYNGXEVDU-WHFBIAKZSA-N 0.000 description 1
- BIRKKBCSAIHDDF-WDSKDSINSA-N Gly-Glu-Cys Chemical compound NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CS)C(O)=O BIRKKBCSAIHDDF-WDSKDSINSA-N 0.000 description 1
- 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 1
- CCBIBMKQNXHNIN-ZETCQYMHSA-N Gly-Leu-Gly Chemical compound NCC(=O)N[C@@H](CC(C)C)C(=O)NCC(O)=O CCBIBMKQNXHNIN-ZETCQYMHSA-N 0.000 description 1
- LIXWIUAORXJNBH-QWRGUYRKSA-N Gly-Leu-His Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)NC(=O)CN LIXWIUAORXJNBH-QWRGUYRKSA-N 0.000 description 1
- 208000024869 Goodpasture syndrome Diseases 0.000 description 1
- 206010018691 Granuloma Diseases 0.000 description 1
- 206010072579 Granulomatosis with polyangiitis Diseases 0.000 description 1
- 208000003807 Graves Disease Diseases 0.000 description 1
- 208000015023 Graves' disease Diseases 0.000 description 1
- 102100025594 Guided entry of tail-anchored proteins factor CAMLG Human genes 0.000 description 1
- 208000035895 Guillain-Barré syndrome Diseases 0.000 description 1
- RVKIPWVMZANZLI-UHFFFAOYSA-N H-Lys-Trp-OH Natural products C1=CC=C2C(CC(NC(=O)C(N)CCCCN)C(O)=O)=CNC2=C1 RVKIPWVMZANZLI-UHFFFAOYSA-N 0.000 description 1
- 208000001258 Hemangiosarcoma Diseases 0.000 description 1
- 208000035186 Hemolytic Autoimmune Anemia Diseases 0.000 description 1
- 201000004331 Henoch-Schoenlein purpura Diseases 0.000 description 1
- 206010019617 Henoch-Schonlein purpura Diseases 0.000 description 1
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 description 1
- HRGGKHFHRSFSDE-CIUDSAMLSA-N His-Asn-Ser Chemical compound C1=C(NC=N1)C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CO)C(=O)O)N HRGGKHFHRSFSDE-CIUDSAMLSA-N 0.000 description 1
- CNHSMSFYVARZLI-YJRXYDGGSA-N His-His-Thr Chemical compound [H]N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CC1=CNC=N1)C(=O)N[C@@H]([C@@H](C)O)C(O)=O CNHSMSFYVARZLI-YJRXYDGGSA-N 0.000 description 1
- TVMNTHXFRSXZGR-IHRRRGAJSA-N His-Lys-Val Chemical compound [H]N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C(C)C)C(O)=O TVMNTHXFRSXZGR-IHRRRGAJSA-N 0.000 description 1
- 101000934356 Homo sapiens CD70 antigen Proteins 0.000 description 1
- 101000932902 Homo sapiens Guided entry of tail-anchored proteins factor CAMLG Proteins 0.000 description 1
- 101001138126 Homo sapiens Immunoglobulin kappa variable 1-16 Proteins 0.000 description 1
- 108090000144 Human Proteins Proteins 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 208000031814 IgA Vasculitis Diseases 0.000 description 1
- 102100026120 IgG receptor FcRn large subunit p51 Human genes 0.000 description 1
- 101710177940 IgG receptor FcRn large subunit p51 Proteins 0.000 description 1
- FTUZWJVSNZMLPI-RVMXOQNASA-N Ile-Met-Pro Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCSC)C(=O)N1CCC[C@@H]1C(=O)O)N FTUZWJVSNZMLPI-RVMXOQNASA-N 0.000 description 1
- FQYQMFCIJNWDQZ-CYDGBPFRSA-N Ile-Pro-Pro Chemical compound CC[C@H](C)[C@H](N)C(=O)N1CCC[C@H]1C(=O)N1[C@H](C(O)=O)CCC1 FQYQMFCIJNWDQZ-CYDGBPFRSA-N 0.000 description 1
- QHUREMVLLMNUAX-OSUNSFLBSA-N Ile-Thr-Val Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(=O)O)N QHUREMVLLMNUAX-OSUNSFLBSA-N 0.000 description 1
- NJGXXYLPDMMFJB-XUXIUFHCSA-N Ile-Val-Lys Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)O)N NJGXXYLPDMMFJB-XUXIUFHCSA-N 0.000 description 1
- RQZFWBLDTBDEOF-RNJOBUHISA-N Ile-Val-Pro Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@@H]1C(=O)O)N RQZFWBLDTBDEOF-RNJOBUHISA-N 0.000 description 1
- 102100020946 Immunoglobulin kappa variable 1-16 Human genes 0.000 description 1
- 208000022559 Inflammatory bowel disease Diseases 0.000 description 1
- 108090001061 Insulin Proteins 0.000 description 1
- 102000004877 Insulin Human genes 0.000 description 1
- 208000036232 King Evil Diseases 0.000 description 1
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 description 1
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 1
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 description 1
- AGPKZVBTJJNPAG-WHFBIAKZSA-N L-isoleucine Chemical compound CC[C@H](C)[C@H](N)C(O)=O AGPKZVBTJJNPAG-WHFBIAKZSA-N 0.000 description 1
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 description 1
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 1
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 description 1
- KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical compound CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 description 1
- 239000002177 L01XE27 - Ibrutinib Substances 0.000 description 1
- 208000018142 Leiomyosarcoma Diseases 0.000 description 1
- GPICTNQYKHHHTH-GUBZILKMSA-N Leu-Gln-Ser Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CO)C(O)=O GPICTNQYKHHHTH-GUBZILKMSA-N 0.000 description 1
- KXODZBLFVFSLAI-AVGNSLFASA-N Leu-His-Glu Chemical compound OC(=O)CC[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)CC(C)C)CC1=CN=CN1 KXODZBLFVFSLAI-AVGNSLFASA-N 0.000 description 1
- IAJFFZORSWOZPQ-SRVKXCTJSA-N Leu-Leu-Asn Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(O)=O IAJFFZORSWOZPQ-SRVKXCTJSA-N 0.000 description 1
- VCHVSKNMTXWIIP-SRVKXCTJSA-N Leu-Lys-Ser Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CO)C(O)=O VCHVSKNMTXWIIP-SRVKXCTJSA-N 0.000 description 1
- ADJWHHZETYAAAX-SRVKXCTJSA-N Leu-Ser-His Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)N ADJWHHZETYAAAX-SRVKXCTJSA-N 0.000 description 1
- 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 1
- KLSUAWUZBMAZCL-RHYQMDGZSA-N Leu-Thr-Pro Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1CCC[C@H]1C(O)=O KLSUAWUZBMAZCL-RHYQMDGZSA-N 0.000 description 1
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 description 1
- 206010062038 Lip neoplasm Diseases 0.000 description 1
- 206010024612 Lipoma Diseases 0.000 description 1
- DDWFXDSYGUXRAY-UHFFFAOYSA-N Luciferin Natural products CCc1c(C)c(CC2NC(=O)C(=C2C=C)C)[nH]c1Cc3[nH]c4C(=C5/NC(CC(=O)O)C(C)C5CC(=O)O)CC(=O)c4c3C DDWFXDSYGUXRAY-UHFFFAOYSA-N 0.000 description 1
- 208000028018 Lymphocytic leukaemia Diseases 0.000 description 1
- 206010025280 Lymphocytosis Diseases 0.000 description 1
- MPGHETGWWWUHPY-CIUDSAMLSA-N Lys-Ala-Asp Chemical compound OC(=O)C[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CCCCN MPGHETGWWWUHPY-CIUDSAMLSA-N 0.000 description 1
- OVIVOCSURJYCTM-GUBZILKMSA-N Lys-Asp-Glu Chemical compound NCCCC[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@H](C(O)=O)CCC(O)=O OVIVOCSURJYCTM-GUBZILKMSA-N 0.000 description 1
- GRADYHMSAUIKPS-DCAQKATOSA-N Lys-Glu-Gln Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(N)=O)C(O)=O GRADYHMSAUIKPS-DCAQKATOSA-N 0.000 description 1
- NNKLKUUGESXCBS-KBPBESRZSA-N Lys-Gly-Tyr Chemical compound [H]N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O NNKLKUUGESXCBS-KBPBESRZSA-N 0.000 description 1
- NJNRBRKHOWSGMN-SRVKXCTJSA-N Lys-Leu-Asn Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(O)=O NJNRBRKHOWSGMN-SRVKXCTJSA-N 0.000 description 1
- MUXNCRWTWBMNHX-SRVKXCTJSA-N Lys-Leu-Asp Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(O)=O)C(O)=O MUXNCRWTWBMNHX-SRVKXCTJSA-N 0.000 description 1
- HKXSZKJMDBHOTG-CIUDSAMLSA-N Lys-Ser-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CCCCN HKXSZKJMDBHOTG-CIUDSAMLSA-N 0.000 description 1
- RMOKGALPSPOYKE-KATARQTJSA-N Lys-Thr-Ser Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(O)=O RMOKGALPSPOYKE-KATARQTJSA-N 0.000 description 1
- PELXPRPDQRFBGQ-KKUMJFAQSA-N Lys-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](CCCCN)N)O PELXPRPDQRFBGQ-KKUMJFAQSA-N 0.000 description 1
- XABXVVSWUVCZST-GVXVVHGQSA-N Lys-Val-Gln Chemical compound NC(=O)CC[C@@H](C(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](N)CCCCN XABXVVSWUVCZST-GVXVVHGQSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- 239000012515 MabSelect SuRe Substances 0.000 description 1
- 208000000172 Medulloblastoma Diseases 0.000 description 1
- QAHFGYLFLVGBNW-DCAQKATOSA-N Met-Ala-Lys Chemical compound CSCC[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@H](C(O)=O)CCCCN QAHFGYLFLVGBNW-DCAQKATOSA-N 0.000 description 1
- 206010049567 Miller Fisher syndrome Diseases 0.000 description 1
- 208000003250 Mixed connective tissue disease Diseases 0.000 description 1
- 208000003445 Mouth Neoplasms Diseases 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 208000014767 Myeloproliferative disease Diseases 0.000 description 1
- 201000007224 Myeloproliferative neoplasm Diseases 0.000 description 1
- XZFYRXDAULDNFX-UHFFFAOYSA-N N-L-cysteinyl-L-phenylalanine Natural products SCC(N)C(=O)NC(C(O)=O)CC1=CC=CC=C1 XZFYRXDAULDNFX-UHFFFAOYSA-N 0.000 description 1
- 208000002454 Nasopharyngeal Carcinoma Diseases 0.000 description 1
- 206010061306 Nasopharyngeal cancer Diseases 0.000 description 1
- 206010029164 Nephrotic syndrome Diseases 0.000 description 1
- 101710163270 Nuclease Proteins 0.000 description 1
- 108700020796 Oncogene Proteins 0.000 description 1
- 240000007594 Oryza sativa Species 0.000 description 1
- 235000007164 Oryza sativa Nutrition 0.000 description 1
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 1
- 241000721454 Pemphigus Species 0.000 description 1
- 208000031845 Pernicious anaemia Diseases 0.000 description 1
- 208000009565 Pharyngeal Neoplasms Diseases 0.000 description 1
- JEGFCFLCRSJCMA-IHRRRGAJSA-N Phe-Arg-Ser Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CO)C(=O)O)N JEGFCFLCRSJCMA-IHRRRGAJSA-N 0.000 description 1
- BWTKUQPNOMMKMA-FIRPJDEBSA-N Phe-Ile-Phe Chemical compound C([C@H](N)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)C1=CC=CC=C1 BWTKUQPNOMMKMA-FIRPJDEBSA-N 0.000 description 1
- KBVJZCVLQWCJQN-KKUMJFAQSA-N Phe-Leu-Asn Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(O)=O KBVJZCVLQWCJQN-KKUMJFAQSA-N 0.000 description 1
- CJAHQEZWDZNSJO-KKUMJFAQSA-N Phe-Lys-Cys Chemical compound NCCCC[C@@H](C(=O)N[C@@H](CS)C(O)=O)NC(=O)[C@@H](N)CC1=CC=CC=C1 CJAHQEZWDZNSJO-KKUMJFAQSA-N 0.000 description 1
- SRILZRSXIKRGBF-HRCADAONSA-N Phe-Met-Pro Chemical compound CSCC[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](CC2=CC=CC=C2)N SRILZRSXIKRGBF-HRCADAONSA-N 0.000 description 1
- FQUUYTNBMIBOHS-IHRRRGAJSA-N Phe-Met-Ser Chemical compound CSCC[C@@H](C(=O)N[C@@H](CO)C(=O)O)NC(=O)[C@H](CC1=CC=CC=C1)N FQUUYTNBMIBOHS-IHRRRGAJSA-N 0.000 description 1
- MMJJFXWMCMJMQA-STQMWFEESA-N Phe-Pro-Gly Chemical compound C([C@H](N)C(=O)N1[C@@H](CCC1)C(=O)NCC(O)=O)C1=CC=CC=C1 MMJJFXWMCMJMQA-STQMWFEESA-N 0.000 description 1
- MRWOVVNKSXXLRP-IHPCNDPISA-N Phe-Ser-Trp Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC1=CNC2=C1C=CC=C2)C(O)=O MRWOVVNKSXXLRP-IHPCNDPISA-N 0.000 description 1
- JSGWNFKWZNPDAV-YDHLFZDLSA-N Phe-Val-Asp Chemical compound OC(=O)C[C@@H](C(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](N)CC1=CC=CC=C1 JSGWNFKWZNPDAV-YDHLFZDLSA-N 0.000 description 1
- 208000007641 Pinealoma Diseases 0.000 description 1
- 235000008331 Pinus X rigitaeda Nutrition 0.000 description 1
- 235000011613 Pinus brutia Nutrition 0.000 description 1
- 241000018646 Pinus brutia Species 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- IWNOFCGBMSFTBC-CIUDSAMLSA-N Pro-Ala-Glu Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(O)=O IWNOFCGBMSFTBC-CIUDSAMLSA-N 0.000 description 1
- MGDFPGCFVJFITQ-CIUDSAMLSA-N Pro-Glu-Asp Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(O)=O MGDFPGCFVJFITQ-CIUDSAMLSA-N 0.000 description 1
- ZLXKLMHAMDENIO-DCAQKATOSA-N Pro-Lys-Asp Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(O)=O)C(O)=O ZLXKLMHAMDENIO-DCAQKATOSA-N 0.000 description 1
- PRKWBYCXBBSLSK-GUBZILKMSA-N Pro-Ser-Val Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(O)=O PRKWBYCXBBSLSK-GUBZILKMSA-N 0.000 description 1
- CXGLFEOYCJFKPR-RCWTZXSCSA-N Pro-Thr-Val Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(O)=O CXGLFEOYCJFKPR-RCWTZXSCSA-N 0.000 description 1
- QHSSUIHLAIWXEE-IHRRRGAJSA-N Pro-Tyr-Asn Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC(N)=O)C(O)=O QHSSUIHLAIWXEE-IHRRRGAJSA-N 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
- 108010076504 Protein Sorting Signals Proteins 0.000 description 1
- 201000004681 Psoriasis Diseases 0.000 description 1
- 206010037549 Purpura Diseases 0.000 description 1
- 241001672981 Purpura Species 0.000 description 1
- 108020004511 Recombinant DNA Proteins 0.000 description 1
- 208000033464 Reiter syndrome Diseases 0.000 description 1
- 208000025747 Rheumatic disease Diseases 0.000 description 1
- 108010039491 Ricin Proteins 0.000 description 1
- 108010084592 Saporins Proteins 0.000 description 1
- 208000034189 Sclerosis Diseases 0.000 description 1
- 108091058545 Secretory proteins Proteins 0.000 description 1
- 102000040739 Secretory proteins Human genes 0.000 description 1
- 201000010208 Seminoma Diseases 0.000 description 1
- YQHZVYJAGWMHES-ZLUOBGJFSA-N Ser-Ala-Ser Chemical compound OC[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](CO)C(O)=O YQHZVYJAGWMHES-ZLUOBGJFSA-N 0.000 description 1
- CTLVSHXLRVEILB-UBHSHLNASA-N Ser-Asn-Trp Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)N)NC(=O)[C@H](CO)N CTLVSHXLRVEILB-UBHSHLNASA-N 0.000 description 1
- BGOWRLSWJCVYAQ-CIUDSAMLSA-N Ser-Asp-Leu Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(O)=O BGOWRLSWJCVYAQ-CIUDSAMLSA-N 0.000 description 1
- YQQKYAZABFEYAF-FXQIFTODSA-N Ser-Glu-Gln Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(N)=O)C(O)=O YQQKYAZABFEYAF-FXQIFTODSA-N 0.000 description 1
- LWMQRHDTXHQQOV-MXAVVETBSA-N Ser-Ile-Phe Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O LWMQRHDTXHQQOV-MXAVVETBSA-N 0.000 description 1
- ZOPISOXXPQNOCO-SVSWQMSJSA-N Ser-Ile-Thr Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H]([C@@H](C)O)C(=O)O)NC(=O)[C@H](CO)N ZOPISOXXPQNOCO-SVSWQMSJSA-N 0.000 description 1
- RHAPJNVNWDBFQI-BQBZGAKWSA-N Ser-Pro-Gly Chemical compound OC[C@H](N)C(=O)N1CCC[C@H]1C(=O)NCC(O)=O RHAPJNVNWDBFQI-BQBZGAKWSA-N 0.000 description 1
- XQJCEKXQUJQNNK-ZLUOBGJFSA-N Ser-Ser-Ser Chemical compound OC[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(O)=O XQJCEKXQUJQNNK-ZLUOBGJFSA-N 0.000 description 1
- ZVBCMFDJIMUELU-BZSNNMDCSA-N Ser-Tyr-Phe Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)O)NC(=O)[C@H](CC2=CC=C(C=C2)O)NC(=O)[C@H](CO)N ZVBCMFDJIMUELU-BZSNNMDCSA-N 0.000 description 1
- HNDMFDBQXYZSRM-IHRRRGAJSA-N Ser-Val-Phe Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O HNDMFDBQXYZSRM-IHRRRGAJSA-N 0.000 description 1
- BQCADISMDOOEFD-UHFFFAOYSA-N Silver Chemical compound [Ag] BQCADISMDOOEFD-UHFFFAOYSA-N 0.000 description 1
- 208000000453 Skin Neoplasms Diseases 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- 235000018259 Solanum vestissimum Nutrition 0.000 description 1
- 240000002825 Solanum vestissimum Species 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 108700002718 TACI receptor-IgG Fc fragment fusion Proteins 0.000 description 1
- DWYAUVCQDTZIJI-VZFHVOOUSA-N Thr-Ala-Ser Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](CO)C(O)=O DWYAUVCQDTZIJI-VZFHVOOUSA-N 0.000 description 1
- DCCGCVLVVSAJFK-NUMRIWBASA-N Thr-Asp-Gln Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](CCC(=O)N)C(=O)O)N)O DCCGCVLVVSAJFK-NUMRIWBASA-N 0.000 description 1
- ODSAPYVQSLDRSR-LKXGYXEUSA-N Thr-Cys-Asn Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(N)=O)C(O)=O ODSAPYVQSLDRSR-LKXGYXEUSA-N 0.000 description 1
- DHPPWTOLRWYIDS-XKBZYTNZSA-N Thr-Cys-Glu Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCC(O)=O)C(O)=O DHPPWTOLRWYIDS-XKBZYTNZSA-N 0.000 description 1
- LIXBDERDAGNVAV-XKBZYTNZSA-N Thr-Gln-Ser Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CO)C(O)=O LIXBDERDAGNVAV-XKBZYTNZSA-N 0.000 description 1
- GKWNLDNXMMLRMC-GLLZPBPUSA-N Thr-Glu-Gln Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CCC(=O)N)C(=O)O)N)O GKWNLDNXMMLRMC-GLLZPBPUSA-N 0.000 description 1
- RFKVQLIXNVEOMB-WEDXCCLWSA-N Thr-Leu-Gly Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)O)N)O RFKVQLIXNVEOMB-WEDXCCLWSA-N 0.000 description 1
- VRUFCJZQDACGLH-UVOCVTCTSA-N Thr-Leu-Thr Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O VRUFCJZQDACGLH-UVOCVTCTSA-N 0.000 description 1
- JLNMFGCJODTXDH-WEDXCCLWSA-N Thr-Lys-Gly Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCCN)C(=O)NCC(O)=O JLNMFGCJODTXDH-WEDXCCLWSA-N 0.000 description 1
- DXPURPNJDFCKKO-RHYQMDGZSA-N Thr-Lys-Val Chemical compound CC(C)[C@H](NC(=O)[C@H](CCCCN)NC(=O)[C@@H](N)[C@@H](C)O)C(O)=O DXPURPNJDFCKKO-RHYQMDGZSA-N 0.000 description 1
- MXNAOGFNFNKUPD-JHYOHUSXSA-N Thr-Phe-Thr Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H]([C@@H](C)O)C(O)=O MXNAOGFNFNKUPD-JHYOHUSXSA-N 0.000 description 1
- MROIJTGJGIDEEJ-RCWTZXSCSA-N Thr-Pro-Pro Chemical compound C[C@@H](O)[C@H](N)C(=O)N1CCC[C@H]1C(=O)N1[C@H](C(O)=O)CCC1 MROIJTGJGIDEEJ-RCWTZXSCSA-N 0.000 description 1
- VUXIQSUQQYNLJP-XAVMHZPKSA-N Thr-Ser-Pro Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CO)C(=O)N1CCC[C@@H]1C(=O)O)N)O VUXIQSUQQYNLJP-XAVMHZPKSA-N 0.000 description 1
- BJJRNAVDQGREGC-HOUAVDHOSA-N Thr-Trp-Asn Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC1=CNC2=CC=CC=C21)C(=O)N[C@@H](CC(=O)N)C(=O)O)N)O BJJRNAVDQGREGC-HOUAVDHOSA-N 0.000 description 1
- OGOYMQWIWHGTGH-KZVJFYERSA-N Thr-Val-Ala Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C)C(O)=O OGOYMQWIWHGTGH-KZVJFYERSA-N 0.000 description 1
- QNXZCKMXHPULME-ZNSHCXBVSA-N Thr-Val-Pro Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@@H]1C(=O)O)N)O QNXZCKMXHPULME-ZNSHCXBVSA-N 0.000 description 1
- AYFVYJQAPQTCCC-UHFFFAOYSA-N Threonine Natural products CC(O)C(N)C(O)=O AYFVYJQAPQTCCC-UHFFFAOYSA-N 0.000 description 1
- 239000004473 Threonine Substances 0.000 description 1
- 208000031981 Thrombocytopenic Idiopathic Purpura Diseases 0.000 description 1
- 208000024770 Thyroid neoplasm Diseases 0.000 description 1
- 206010062129 Tongue neoplasm Diseases 0.000 description 1
- 101710120037 Toxin CcdB Proteins 0.000 description 1
- 108700019146 Transgenes Proteins 0.000 description 1
- 108700002109 Transmembrane Activator and CAML Interactor Proteins 0.000 description 1
- 102000050862 Transmembrane Activator and CAML Interactor Human genes 0.000 description 1
- MHNHRNHJMXAVHZ-AAEUAGOBSA-N Trp-Asn-Gly Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)NCC(=O)O)N MHNHRNHJMXAVHZ-AAEUAGOBSA-N 0.000 description 1
- OSYOKZZRVGUDMO-HSCHXYMDSA-N Trp-Lys-Ile Chemical compound [H]N[C@@H](CC1=CNC2=C1C=CC=C2)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O OSYOKZZRVGUDMO-HSCHXYMDSA-N 0.000 description 1
- NLWCSMOXNKBRLC-WDSOQIARSA-N Trp-Lys-Val Chemical compound [H]N[C@@H](CC1=CNC2=C1C=CC=C2)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C(C)C)C(O)=O NLWCSMOXNKBRLC-WDSOQIARSA-N 0.000 description 1
- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 description 1
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 1
- MTEQZJFSEMXXRK-CFMVVWHZSA-N Tyr-Asn-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)N)NC(=O)[C@H](CC1=CC=C(C=C1)O)N MTEQZJFSEMXXRK-CFMVVWHZSA-N 0.000 description 1
- XQYHLZNPOTXRMQ-KKUMJFAQSA-N Tyr-Glu-Arg 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](CCCNC(N)=N)C(O)=O XQYHLZNPOTXRMQ-KKUMJFAQSA-N 0.000 description 1
- SLCSPPCQWUHPPO-JYJNAYRXSA-N Tyr-Glu-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 SLCSPPCQWUHPPO-JYJNAYRXSA-N 0.000 description 1
- NXRGXTBPMOGFID-CFMVVWHZSA-N Tyr-Ile-Asn Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(N)=O)C(O)=O NXRGXTBPMOGFID-CFMVVWHZSA-N 0.000 description 1
- MQGGXGKQSVEQHR-KKUMJFAQSA-N Tyr-Ser-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 MQGGXGKQSVEQHR-KKUMJFAQSA-N 0.000 description 1
- XYBNMHRFAUKPAW-IHRRRGAJSA-N Tyr-Ser-Met Chemical compound CSCC[C@@H](C(=O)O)NC(=O)[C@H](CO)NC(=O)[C@H](CC1=CC=C(C=C1)O)N XYBNMHRFAUKPAW-IHRRRGAJSA-N 0.000 description 1
- 208000002495 Uterine Neoplasms Diseases 0.000 description 1
- 206010046851 Uveitis Diseases 0.000 description 1
- REJBPZVUHYNMEN-LSJOCFKGSA-N Val-Ala-His Chemical compound C[C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)NC(=O)[C@H](C(C)C)N REJBPZVUHYNMEN-LSJOCFKGSA-N 0.000 description 1
- JLFKWDAZBRYCGX-ZKWXMUAHSA-N Val-Asn-Ser Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CO)C(=O)O)N JLFKWDAZBRYCGX-ZKWXMUAHSA-N 0.000 description 1
- ZEVNVXYRZRIRCH-GVXVVHGQSA-N Val-Gln-Lys Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H](CCCCN)C(=O)O)N ZEVNVXYRZRIRCH-GVXVVHGQSA-N 0.000 description 1
- ZIGZPYJXIWLQFC-QTKMDUPCSA-N Val-His-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CC1=CN=CN1)NC(=O)[C@H](C(C)C)N)O ZIGZPYJXIWLQFC-QTKMDUPCSA-N 0.000 description 1
- LYERIXUFCYVFFX-GVXVVHGQSA-N Val-Leu-Glu Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)O)NC(=O)[C@H](C(C)C)N LYERIXUFCYVFFX-GVXVVHGQSA-N 0.000 description 1
- VIKZGAUAKQZDOF-NRPADANISA-N Val-Ser-Glu Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@H](C(O)=O)CCC(O)=O VIKZGAUAKQZDOF-NRPADANISA-N 0.000 description 1
- TVGWMCTYUFBXAP-QTKMDUPCSA-N Val-Thr-His Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)NC(=O)[C@H](C(C)C)N)O TVGWMCTYUFBXAP-QTKMDUPCSA-N 0.000 description 1
- GVNLOVJNNDZUHS-RHYQMDGZSA-N Val-Thr-Lys Chemical compound [H]N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCCN)C(O)=O GVNLOVJNNDZUHS-RHYQMDGZSA-N 0.000 description 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
- IECQJCJNPJVUSB-IHRRRGAJSA-N Val-Tyr-Ser Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)N[C@@H](CO)C(O)=O IECQJCJNPJVUSB-IHRRRGAJSA-N 0.000 description 1
- BGTDGENDNWGMDQ-KJEVXHAQSA-N Val-Tyr-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CC1=CC=C(C=C1)O)NC(=O)[C@H](C(C)C)N)O BGTDGENDNWGMDQ-KJEVXHAQSA-N 0.000 description 1
- KZSNJWFQEVHDMF-UHFFFAOYSA-N Valine Natural products CC(C)C(N)C(O)=O KZSNJWFQEVHDMF-UHFFFAOYSA-N 0.000 description 1
- 241000251539 Vertebrata <Metazoa> Species 0.000 description 1
- 208000014070 Vestibular schwannoma Diseases 0.000 description 1
- 229940122803 Vinca alkaloid Drugs 0.000 description 1
- 208000008383 Wilms tumor Diseases 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 208000004064 acoustic neuroma Diseases 0.000 description 1
- 208000017733 acquired polycythemia vera Diseases 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 238000001994 activation Methods 0.000 description 1
- 239000012190 activator Substances 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 238000001467 acupuncture Methods 0.000 description 1
- 208000021841 acute erythroid leukemia Diseases 0.000 description 1
- 208000009956 adenocarcinoma Diseases 0.000 description 1
- 238000001042 affinity chromatography Methods 0.000 description 1
- 238000001261 affinity purification Methods 0.000 description 1
- 235000004279 alanine Nutrition 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 230000007815 allergy Effects 0.000 description 1
- 108010004469 allophycocyanin Proteins 0.000 description 1
- KOSRFJWDECSPRO-UHFFFAOYSA-N alpha-L-glutamyl-L-glutamic acid Natural products OC(=O)CCC(N)C(=O)NC(CCC(O)=O)C(O)=O KOSRFJWDECSPRO-UHFFFAOYSA-N 0.000 description 1
- VREFGVBLTWBCJP-UHFFFAOYSA-N alprazolam Chemical compound C12=CC(Cl)=CC=C2N2C(C)=NN=C2CN=C1C1=CC=CC=C1 VREFGVBLTWBCJP-UHFFFAOYSA-N 0.000 description 1
- 238000012870 ammonium sulfate precipitation Methods 0.000 description 1
- 239000004037 angiogenesis inhibitor Substances 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 239000003957 anion exchange resin Substances 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 230000008485 antagonism Effects 0.000 description 1
- 230000003367 anti-collagen effect Effects 0.000 description 1
- 239000002256 antimetabolite Substances 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 108010009111 arginyl-glycyl-glutamic acid Proteins 0.000 description 1
- 210000001367 artery Anatomy 0.000 description 1
- 230000002917 arthritic effect Effects 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 235000009582 asparagine Nutrition 0.000 description 1
- 229960001230 asparagine Drugs 0.000 description 1
- 108010077245 asparaginyl-proline Proteins 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- 108010068265 aspartyltyrosine Proteins 0.000 description 1
- 210000001130 astrocyte Anatomy 0.000 description 1
- 229950009925 atacicept Drugs 0.000 description 1
- 201000000448 autoimmune hemolytic anemia Diseases 0.000 description 1
- 201000003710 autoimmune thrombocytopenic purpura Diseases 0.000 description 1
- XSCHRSMBECNVNS-UHFFFAOYSA-N benzopyrazine Natural products N1=CC=NC2=CC=CC=C21 XSCHRSMBECNVNS-UHFFFAOYSA-N 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- 208000026900 bile duct neoplasm Diseases 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 230000008827 biological function Effects 0.000 description 1
- 230000001851 biosynthetic effect Effects 0.000 description 1
- 238000001815 biotherapy Methods 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 210000002798 bone marrow cell Anatomy 0.000 description 1
- 210000000133 brain stem Anatomy 0.000 description 1
- 244000144987 brood Species 0.000 description 1
- 206010006514 bruxism Diseases 0.000 description 1
- 208000000594 bullous pemphigoid Diseases 0.000 description 1
- JQQZVABVKIDEFR-UHFFFAOYSA-J bumadizone calcium hemihydrate Chemical compound O.[Ca+2].[Ca+2].C=1C=CC=CC=1N(C(=O)C(C([O-])=O)CCCC)NC1=CC=CC=C1.C=1C=CC=CC=1N(C(=O)C(C([O-])=O)CCCC)NC1=CC=CC=C1.C=1C=CC=CC=1N(C(=O)C(C([O-])=O)CCCC)NC1=CC=CC=C1.C=1C=CC=CC=1N(C(=O)C(C([O-])=O)CCCC)NC1=CC=CC=C1 JQQZVABVKIDEFR-UHFFFAOYSA-J 0.000 description 1
- 102220367741 c.210G>A Human genes 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 239000003729 cation exchange resin Substances 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 230000007541 cellular toxicity Effects 0.000 description 1
- 239000013522 chelant Substances 0.000 description 1
- 230000000973 chemotherapeutic effect Effects 0.000 description 1
- 239000012829 chemotherapy agent Substances 0.000 description 1
- 238000011098 chromatofocusing Methods 0.000 description 1
- 210000000349 chromosome Anatomy 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 208000024207 chronic leukemia Diseases 0.000 description 1
- 208000025302 chronic primary adrenal insufficiency Diseases 0.000 description 1
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 1
- 229960004316 cisplatin Drugs 0.000 description 1
- 208000009060 clear cell adenocarcinoma Diseases 0.000 description 1
- 239000000084 colloidal system Substances 0.000 description 1
- 201000002660 colon sarcoma Diseases 0.000 description 1
- 201000010989 colorectal carcinoma Diseases 0.000 description 1
- 238000002742 combinatorial mutagenesis Methods 0.000 description 1
- 230000002301 combined effect Effects 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 238000012875 competitive assay Methods 0.000 description 1
- 230000002860 competitive effect Effects 0.000 description 1
- 239000002131 composite material Substances 0.000 description 1
- 238000007906 compression Methods 0.000 description 1
- 230000006835 compression Effects 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 230000003750 conditioning effect Effects 0.000 description 1
- 235000009508 confectionery Nutrition 0.000 description 1
- 239000000356 contaminant Substances 0.000 description 1
- 239000005289 controlled pore glass Substances 0.000 description 1
- 208000002445 cystadenocarcinoma Diseases 0.000 description 1
- 108010016616 cysteinylglycine Proteins 0.000 description 1
- 230000009089 cytolysis Effects 0.000 description 1
- 125000001295 dansyl group Chemical group [H]C1=C([H])C(N(C([H])([H])[H])C([H])([H])[H])=C2C([H])=C([H])C([H])=C(C2=C1[H])S(*)(=O)=O 0.000 description 1
- 229960002204 daratumumab Drugs 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 230000022811 deglycosylation Effects 0.000 description 1
- 238000011033 desalting Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 230000006866 deterioration Effects 0.000 description 1
- 238000000502 dialysis Methods 0.000 description 1
- 210000002249 digestive system Anatomy 0.000 description 1
- 238000006471 dimerization reaction Methods 0.000 description 1
- 229940042399 direct acting antivirals protease inhibitors Drugs 0.000 description 1
- 239000003596 drug target Substances 0.000 description 1
- 230000005611 electricity Effects 0.000 description 1
- 229960004137 elotuzumab Drugs 0.000 description 1
- 210000002257 embryonic structure Anatomy 0.000 description 1
- 201000002491 encephalomyelitis Diseases 0.000 description 1
- 201000003914 endometrial carcinoma Diseases 0.000 description 1
- 239000002158 endotoxin Substances 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 210000002919 epithelial cell Anatomy 0.000 description 1
- 238000012869 ethanol precipitation Methods 0.000 description 1
- 208000024519 eye neoplasm Diseases 0.000 description 1
- ZFKJVJIDPQDDFY-UHFFFAOYSA-N fluorescamine Chemical compound C12=CC=CC=C2C(=O)OC1(C1=O)OC=C1C1=CC=CC=C1 ZFKJVJIDPQDDFY-UHFFFAOYSA-N 0.000 description 1
- GNBHRKFJIUUOQI-UHFFFAOYSA-N fluorescein Chemical compound O1C(=O)C2=CC=CC=C2C21C1=CC=C(O)C=C1OC1=CC(O)=CC=C21 GNBHRKFJIUUOQI-UHFFFAOYSA-N 0.000 description 1
- 239000007850 fluorescent dye Substances 0.000 description 1
- 238000005194 fractionation Methods 0.000 description 1
- 238000001502 gel electrophoresis Methods 0.000 description 1
- 230000002068 genetic effect Effects 0.000 description 1
- 210000004907 gland Anatomy 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 1
- 235000004554 glutamine Nutrition 0.000 description 1
- 108010055341 glutamyl-glutamic acid Proteins 0.000 description 1
- 150000002334 glycols Chemical class 0.000 description 1
- XKUKSGPZAADMRA-UHFFFAOYSA-N glycyl-glycyl-glycine Natural products NCC(=O)NCC(=O)NCC(O)=O XKUKSGPZAADMRA-UHFFFAOYSA-N 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 201000010536 head and neck cancer Diseases 0.000 description 1
- 208000014829 head and neck neoplasm Diseases 0.000 description 1
- 230000035876 healing Effects 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 208000025750 heavy chain disease Diseases 0.000 description 1
- 201000002222 hemangioblastoma Diseases 0.000 description 1
- 230000002489 hematologic effect Effects 0.000 description 1
- 229920000669 heparin Polymers 0.000 description 1
- 229960002897 heparin Drugs 0.000 description 1
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 1
- 210000003630 histaminocyte Anatomy 0.000 description 1
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 230000008348 humoral response Effects 0.000 description 1
- 210000004408 hybridoma Anatomy 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 229910052588 hydroxylapatite Inorganic materials 0.000 description 1
- 230000002390 hyperplastic effect Effects 0.000 description 1
- XYFPWWZEPKGCCK-GOSISDBHSA-N ibrutinib Chemical compound C1=2C(N)=NC=NC=2N([C@H]2CN(CCC2)C(=O)C=C)N=C1C(C=C1)=CC=C1OC1=CC=CC=C1 XYFPWWZEPKGCCK-GOSISDBHSA-N 0.000 description 1
- 229960001507 ibrutinib Drugs 0.000 description 1
- YKLIKGKUANLGSB-HNNXBMFYSA-N idelalisib Chemical compound C1([C@@H](NC=2[C]3N=CN=C3N=CN=2)CC)=NC2=CC=CC(F)=C2C(=O)N1C1=CC=CC=C1 YKLIKGKUANLGSB-HNNXBMFYSA-N 0.000 description 1
- 229960003445 idelalisib Drugs 0.000 description 1
- 230000001900 immune effect Effects 0.000 description 1
- 230000036737 immune function Effects 0.000 description 1
- 230000002163 immunogen Effects 0.000 description 1
- 208000015446 immunoglobulin a vasculitis Diseases 0.000 description 1
- 229940072221 immunoglobulins Drugs 0.000 description 1
- 229960001438 immunostimulant agent Drugs 0.000 description 1
- 239000003022 immunostimulating agent Substances 0.000 description 1
- 230000003308 immunostimulating effect Effects 0.000 description 1
- 238000009169 immunotherapy Methods 0.000 description 1
- 238000002513 implantation Methods 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 208000021267 infertility disease Diseases 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 229940125396 insulin Drugs 0.000 description 1
- 238000001361 intraarterial administration Methods 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 238000007737 ion beam deposition Methods 0.000 description 1
- 238000005342 ion exchange Methods 0.000 description 1
- AGPKZVBTJJNPAG-UHFFFAOYSA-N isoleucine Natural products CCC(C)C(N)C(O)=O AGPKZVBTJJNPAG-UHFFFAOYSA-N 0.000 description 1
- 229960000310 isoleucine Drugs 0.000 description 1
- 108010031424 isoleucyl-prolyl-proline Proteins 0.000 description 1
- 108010044374 isoleucyl-tyrosine Proteins 0.000 description 1
- 150000002540 isothiocyanates Chemical class 0.000 description 1
- 208000018937 joint inflammation Diseases 0.000 description 1
- 210000003292 kidney cell Anatomy 0.000 description 1
- 230000002147 killing effect Effects 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 201000006721 lip cancer Diseases 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 201000007270 liver cancer Diseases 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- 201000007227 lymph node tuberculosis Diseases 0.000 description 1
- 210000004698 lymphocyte Anatomy 0.000 description 1
- 208000003747 lymphoid leukemia Diseases 0.000 description 1
- 201000000564 macroglobulinemia Diseases 0.000 description 1
- 208000016847 malignant urinary system neoplasm Diseases 0.000 description 1
- 201000007924 marginal zone B-cell lymphoma Diseases 0.000 description 1
- 208000021937 marginal zone lymphoma Diseases 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 238000002483 medication Methods 0.000 description 1
- 206010027191 meningioma Diseases 0.000 description 1
- 108020004999 messenger RNA Proteins 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000003607 modifier Substances 0.000 description 1
- 230000002969 morbid Effects 0.000 description 1
- 210000001167 myeloblast Anatomy 0.000 description 1
- 210000003887 myelocyte Anatomy 0.000 description 1
- 210000003643 myeloid progenitor cell Anatomy 0.000 description 1
- 201000011216 nasopharynx carcinoma Diseases 0.000 description 1
- 239000013642 negative control Substances 0.000 description 1
- 208000009928 nephrosis Diseases 0.000 description 1
- 231100001027 nephrosis Toxicity 0.000 description 1
- 210000000440 neutrophil Anatomy 0.000 description 1
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 1
- 201000008106 ocular cancer Diseases 0.000 description 1
- 229960002450 ofatumumab Drugs 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 208000020717 oral cavity carcinoma Diseases 0.000 description 1
- 201000008482 osteoarthritis Diseases 0.000 description 1
- 210000002997 osteoclast Anatomy 0.000 description 1
- 208000004019 papillary adenocarcinoma Diseases 0.000 description 1
- 201000010198 papillary carcinoma Diseases 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- XYJRXVWERLGGKC-UHFFFAOYSA-D pentacalcium;hydroxide;triphosphate Chemical compound [OH-].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O XYJRXVWERLGGKC-UHFFFAOYSA-D 0.000 description 1
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 1
- 230000000079 pharmacotherapeutic effect Effects 0.000 description 1
- 201000008006 pharynx cancer Diseases 0.000 description 1
- RXNXLAHQOVLMIE-UHFFFAOYSA-N phenyl 10-methylacridin-10-ium-9-carboxylate Chemical compound C12=CC=CC=C2[N+](C)=C2C=CC=CC2=C1C(=O)OC1=CC=CC=C1 RXNXLAHQOVLMIE-UHFFFAOYSA-N 0.000 description 1
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 1
- 108010070409 phenylalanyl-glycyl-glycine Proteins 0.000 description 1
- 108010084572 phenylalanyl-valine Proteins 0.000 description 1
- ZWLUXSQADUDCSB-UHFFFAOYSA-N phthalaldehyde Chemical compound O=CC1=CC=CC=C1C=O ZWLUXSQADUDCSB-UHFFFAOYSA-N 0.000 description 1
- 208000024724 pineal body neoplasm Diseases 0.000 description 1
- 201000004123 pineal gland cancer Diseases 0.000 description 1
- 231100000614 poison Toxicity 0.000 description 1
- 239000002574 poison Substances 0.000 description 1
- 108700028325 pokeweed antiviral Proteins 0.000 description 1
- 108010054442 polyalanine Proteins 0.000 description 1
- 208000037244 polycythemia vera Diseases 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 238000002600 positron emission tomography Methods 0.000 description 1
- 230000001323 posttranslational effect Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 208000016800 primary central nervous system lymphoma Diseases 0.000 description 1
- 208000029340 primitive neuroectodermal tumor Diseases 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000004393 prognosis Methods 0.000 description 1
- 108010004914 prolylarginine Proteins 0.000 description 1
- 108010070643 prolylglutamic acid Proteins 0.000 description 1
- 108020001580 protein domains Proteins 0.000 description 1
- 230000012846 protein folding Effects 0.000 description 1
- 238000001814 protein method Methods 0.000 description 1
- 238000001742 protein purification Methods 0.000 description 1
- 230000017854 proteolysis Effects 0.000 description 1
- 230000005180 public health Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 230000036647 reaction Effects 0.000 description 1
- 208000002574 reactive arthritis Diseases 0.000 description 1
- 238000010188 recombinant method Methods 0.000 description 1
- 201000001275 rectum cancer Diseases 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 201000007048 respiratory system cancer Diseases 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 238000004007 reversed phase HPLC Methods 0.000 description 1
- 235000009566 rice Nutrition 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 229950006348 sarilumab Drugs 0.000 description 1
- 201000008407 sebaceous adenocarcinoma Diseases 0.000 description 1
- 230000003248 secreting effect Effects 0.000 description 1
- 238000002864 sequence alignment Methods 0.000 description 1
- 108010048397 seryl-lysyl-leucine Proteins 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 229910052709 silver Inorganic materials 0.000 description 1
- 239000004332 silver Substances 0.000 description 1
- 201000000849 skin cancer Diseases 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 238000009987 spinning Methods 0.000 description 1
- 210000001543 spongioblast Anatomy 0.000 description 1
- 206010041823 squamous cell carcinoma Diseases 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 210000001179 synovial fluid Anatomy 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 229950010265 tabalumab Drugs 0.000 description 1
- 238000010257 thawing Methods 0.000 description 1
- 231100001274 therapeutic index Toxicity 0.000 description 1
- 235000008521 threonine Nutrition 0.000 description 1
- 201000002510 thyroid cancer Diseases 0.000 description 1
- 229960003989 tocilizumab Drugs 0.000 description 1
- 201000006134 tongue cancer Diseases 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- 230000010474 transient expression Effects 0.000 description 1
- 238000013519 translation Methods 0.000 description 1
- 102000035160 transmembrane proteins Human genes 0.000 description 1
- 108091005703 transmembrane proteins Proteins 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 1
- 108010020532 tyrosyl-proline Proteins 0.000 description 1
- 108010071635 tyrosyl-prolyl-arginine Proteins 0.000 description 1
- ORHBXUUXSCNDEV-UHFFFAOYSA-N umbelliferone Chemical compound C1=CC(=O)OC2=CC(O)=CC=C21 ORHBXUUXSCNDEV-UHFFFAOYSA-N 0.000 description 1
- HFTAFOQKODTIJY-UHFFFAOYSA-N umbelliferone Natural products Cc1cc2C=CC(=O)Oc2cc1OCC=CC(C)(C)O HFTAFOQKODTIJY-UHFFFAOYSA-N 0.000 description 1
- 201000004435 urinary system cancer Diseases 0.000 description 1
- 206010046766 uterine cancer Diseases 0.000 description 1
- 239000004474 valine Substances 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 230000010148 water-pollination Effects 0.000 description 1
- 230000003442 weekly effect Effects 0.000 description 1
- 108010027345 wheylin-1 peptide Proteins 0.000 description 1
- XRASPMIURGNCCH-UHFFFAOYSA-N zoledronic acid Chemical compound OP(=O)(O)C(P(O)(O)=O)(O)CN1C=CN=C1 XRASPMIURGNCCH-UHFFFAOYSA-N 0.000 description 1
- 229960004276 zoledronic acid Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/2875—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the NGF/TNF superfamily, e.g. CD70, CD95L, CD153, CD154
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
- A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
- A61K39/3955—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against proteinaceous materials, e.g. enzymes, hormones, lymphokines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- 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
- G01N33/564—Immunoassay; Biospecific binding assay; Materials therefor for pre-existing immune complex or autoimmune disease, i.e. systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, rheumatoid factors or complement components C1-C9
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
- G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
- G01N33/57484—Immunoassay; Biospecific binding assay; Materials therefor for cancer involving compounds serving as markers for tumor, cancer, neoplasia, e.g. cellular determinants, receptors, heat shock/stress proteins, A-protein, oligosaccharides, metabolites
- G01N33/57488—Immunoassay; Biospecific binding assay; Materials therefor for cancer involving compounds serving as markers for tumor, cancer, neoplasia, e.g. cellular determinants, receptors, heat shock/stress proteins, A-protein, oligosaccharides, metabolites involving compounds identifable in body fluids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
- C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
- C07K2317/33—Crossreactivity, e.g. for species or epitope, or lack of said crossreactivity
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—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
- C07K2317/50—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
- C07K2317/567—Framework region [FR]
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
- C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
- C07K2317/92—Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
- C07K2317/94—Stability, e.g. half-life, pH, temperature or enzyme-resistance
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2800/00—Detection or diagnosis of diseases
- G01N2800/24—Immunology or allergic disorders
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Immunology (AREA)
- Engineering & Computer Science (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Molecular Biology (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Hematology (AREA)
- Urology & Nephrology (AREA)
- Biomedical Technology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biochemistry (AREA)
- Cell Biology (AREA)
- Microbiology (AREA)
- Analytical Chemistry (AREA)
- Physics & Mathematics (AREA)
- Food Science & Technology (AREA)
- Biotechnology (AREA)
- General Physics & Mathematics (AREA)
- Pathology (AREA)
- Rheumatology (AREA)
- Epidemiology (AREA)
- Genetics & Genomics (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Biophysics (AREA)
- Oncology (AREA)
- Rehabilitation Therapy (AREA)
- Hospice & Palliative Care (AREA)
- Mycology (AREA)
- Endocrinology (AREA)
- Pain & Pain Management (AREA)
Abstract
本公开涉及APRIL结合抗体,所述抗体与具有hAPRIL.01A抗原结合位点的抗体结合相同的人类APRIL表位。相较于hAPRIL.01A,本公开的抗体包含特异性选择的VH和VL结构域框架序列并且具有意外的特征。本公开还涉及包含本发明抗体的组合物及所述抗体和组合物的医学和诊断用途。
Description
发明领域
本发明涉及结合人类APRIL的分离的抗体,包括其片段;编码此类抗体的多核苷酸;以及产生所述抗体的宿主细胞。所述抗体可以用于治疗癌症并抑制免疫细胞增殖和可能得益于此类免疫细胞增殖抑制的病症,如自身免疫性疾病、炎症性疾病或与免疫球蛋白过量产生有关的疾病。此外,所述抗体还可以用作诊断工具及用于抑制免疫细胞增殖和/或存活的体外试剂。
发明背景
APRIL是作为II型跨膜蛋白表达,但与大多数其它TNF家族成员不同,它主要作为分泌蛋白加工并在高尔基体中裂解,在高尔基体中,它被弗林转化酶裂解而释放可溶性活性形式(Lopez-Fraga等人,2001,EMBO Rep 2:945-51)。APRIL与多个其它TNF家族配体组装成在蛋白质折叠中具有类似结构同源性的非共价连接的同三聚体(Wallweber等人,2004,Mol Biol 343,283-90)。APRIL结合两种TNF受体:B细胞成熟抗原(BCMA)及跨膜活化物和钙调亲环素配体相互作用因子(TACI)(综述于Kimberley等人,2009,J Cell Physiol.218(1):1-8中)。此外,近期还显示APRIL结合硫酸类肝素蛋白聚糖(HSPG)(Hendriks等人,2005,Cell Death Differ 12,637-48)。已显示,APRIL在B细胞信号传导中起作用并且在体外驱动人类和鼠类B细胞增殖和存活(综述于Kimberley等人,2009,J Cell Physiol.218(1):1-8中)。
APRIL主要由免疫细胞亚群,如单核细胞、巨噬细胞、树突状细胞、嗜中性粒细胞、B细胞及T细胞表达,其中有许多还表达BAFF。此外,APRIL还可以由非免疫细胞,如破骨细胞、上皮细胞及多个肿瘤组织表达(综述于Kimberley等人,2009,J Cell Physiol.218(1):1-8中)。事实上,APRIL最初是基于其在癌细胞中的表达鉴别(Hahne等人,1998,JExp Med 188,1185-90)。在一组肿瘤细胞系以及如结肠癌和淋巴癌等人类原发肿瘤中发现较高的APRILmRNA表达水平。
基于95名慢性淋巴细胞性白血病(CLL)CLL患者的回顾性研究显示血清中APRIL含量增加,这与疾病进展和总体患者存活率相关,并且APRIL血清含量较高的患者预后较差(Planelles等人,2007,Haematologica 92,1284-5)。类似地,已显示在霍奇金氏淋巴瘤、非霍奇金氏淋巴瘤(NHL)及多发性骨髓瘤(MM)中表达(较高水平的)APRIL(综述于Kimberley等人,2009,J Cell Physiol.218(1):1-8中)。在DLBCL患者(NHL)中进行的回顾性研究显示,癌症病变中APRIL的表达与较差存活率相关(Schwaller等人,2007,Blood 109,331-8)。近来,已显示来自结肠直肠癌患者的血清中的APRIL血清含量具有积极的诊断价值(Ding等人,2013,Clin.Biochemistry,http://dx.doi.org/10.1016/ j.clinbiochem.2013.06.008)。
由于APRIL在B细胞生物学中的作用,它还在许多自身免疫性疾病中起到作用。在许多SLE患者中都报告APRIL血清含量增加(Koyama等人,2005,Ann Rheum Dis 64,1065-7)。回顾性分析披露,APRIL血清含量往往与抗dsDNA抗体滴度相关。另外,还检测到在患有炎症性关节炎患者的滑膜液中APRIL含量相较于患有如骨关节炎等非炎症性关节炎的患者的APRIL含量明显增加(Stohl等人,2006,Endocr Metab Immune Disord Drug Targets 6,351-8;Tan等人,2003,Arthritis Rheum 48,982-92)。
若干研究集中在患有多种全身免疫类风湿性疾病(斯耶格伦氏综合症(syndrome)、瑞特氏综合症(Reiter′s syndrome)、银屑病关节炎、多肌炎及强直性脊柱炎现也包括在内)的患者的血清中APRI L的存在,并且发现在这些患者中APRIL水平明显增加,表明APRI L在这些疾病中也具有重要作用(Jonsson等人,1986,Scand J Rheum atol增刊61,166-9;Roschke等人,2002,J Immunol 169,4314-21)。此外,还在特应性皮肤炎患者的血清中检测到APRIL血清含量增加(Matsushita等人,2007,Exp.Dermatology 17,197-202)。在败血病中血清APRIL含量也升高并且预示垂危患者的死亡(Roderburg等人,J.Critical Care,2013,http://dx.doi.org/10.1016/j.jcrc.2012.11.007)。另外发现,在IgA肾病患者中APRIL血清含量增加(McCarthy等人,2011,J.Clin.Invest.121(10):3991-4002)。
最后,APRIL表达增加也已经与多发性硬化(MS)相关联。在MS患者的星形细胞中发现APRIL表达相较于正常对照有所增加。这与所描述的在成胶质细胞瘤中以及成胶质细胞瘤患者的血清中APRIL的表达情况相符(Deshayes等人,2004,Oncogene 23,3005-12;Roth等人,2001,Cell Death Differ 8,403-10)。
APRIL在若干B细胞恶性疾病以及可能的一些实体肿瘤的存活和增殖能力方面起到重要作用。APRIL还在炎症性疾病或自身免疫性方面起到关键作用。因此,拮抗APRIL的策略是多种此类疾病的治疗目标。实际上,当前正在进行用TACI-Fc(Atacicept)靶向APRIL的临床研究,旨在治疗若干自身免疫性疾病。不过,TACI-Fc也靶向BAFF,该因子也涉及到正常B细胞维持。WO9614328、WO2001/60397、WO2002/94192、WO9912965、WO2001/196528、WO9900518及WO2010/100056中描述了针对APRIL的抗体。WO2010/100056描述了特异性靶向APRIL的抗体。WO2010/100056的抗体完全阻断APRIL与TACI的结合,并且至少部分阻断APRIL与BCMA的结合。抗体hAPRIL.01A完全阻断与BCMA和TACI两者的结合。hAPRIL.01A抗体在体外和体内抑制B细胞增殖、存活及抗原特异性免疫球蛋白分泌(Guadagnoli等人,2011,Blood 117(25):6856-65)。此外,hAPRIL.01A在体外和体内抑制人类CLL和MM疾病特有的恶性细胞的增殖和存活(Guadagnoli等人,2011,Blood 117(25):6856-65;Lascano等人,2013,Blood 122(24):3960-3;Tai等人,2014,ASH poster 2098)。最后,hAPRIL.01A抑制抗原特异性IgA的分泌(Guadagnoli等人,2011,Blood 117(25):6856-65)。鉴于这些独特的结合特征,这一鼠类抗体具有独特的药学效用。然而,由于这一抗体是鼠类来源的,故该抗体在人类医学中的药学效用还存在某些缺点。因此,本发明旨在提供更适用于人类医学的改良型hAPRIL.01A抗体。
发明概述
本发明提供了在VH和VL结构域框架区包含某些取代的hAPRIL.01A类似物。已意外地发现,当在hAPRIL.01A的抗原结合位点中,hAPRIL.01A的VH结构域框架区被选自SEQ IDNO 12、14、16或18的VH氨基酸序列框架区取代,并且hAPRIL.01A的VL结构域框架区被选自SEQ ID NO 30的VL氨基酸序列框架区取代时,获得功能性hAPRIL.01A类似物。这一意外发现归于以下事实:本发明的发明人研究显示,仅有限的替代性人类来源VH和VL框架序列的组合可以支持hAPRIL.01A CDR与人类APRIL的适当结合并由此可以产生功能性hAPRIL.01A类似物。此外,本发明的发明人还显示,通过引入某些特定氨基酸取代可以进一步改进hAPRIL.01类似物。具体地说,所选择的VH氨基酸序列中的氨基酸取代R72S和/或双取代R67K加V68A。
因此,根据第一方面,本发明涉及一种APRIL结合抗体,该抗体与具有hAPRIL.01A抗原结合位点的抗体,如WO2010/100056中公开的单克隆抗体hAPRIL.01A结合至相同的人类APRIL表位,所述人类APRIL接恶化抗体包括含VH和VL结构域的多个抗原结合位点,其中在抗原结合位点中,VH结构域的框架序列与选自SEQ ID NO:12、14、16或18,优选与SEQ IDNO:14或18,最优选与SEQ ID NO:18的VH氨基酸序列的框架序列具有至少70%序列相似性,并且VL结构域的框架序列与选自SEQ ID NO:30的VL氨基酸序列的框架序列具有至少70%序列相似性。
本发明另一方面涉及编码本发明抗体的重链和轻链可变区的呈分离形式的多核苷酸;包含多个所述多核苷酸的表达单元;以及包含所述表达单元和/或多个所述多核苷酸的宿主细胞。
本发明又另一方面涉及一种产生本发明抗体的方法,该方法包括:
a)在培养基中,在表达所述多个多核苷酸的条件下培养本发明的宿主细胞,由此产生包含轻链可变区和重链可变区的多肽;和
b)从所述宿主细胞或培养基回收所述多肽。
本发明另一方面的主题是一种组合物,该组合物包含本发明的抗体和药学上可接受的载剂或稀释剂,以及任选使用的多种其它活性化合物。
本发明又另一方面是本发明抗体的治疗和诊断用途。
序列简述
序列表中呈现的序列涉及VH和VL结构域以及重链和轻链的氨基酸序列和编码DNA序列,来自所述重链和轻链的框架序列可以用于根据本发明的抗体中。另外,还呈现了hAPRIL.01A中VH和VL结构域的CDR以及重链和轻链的氨基酸序列。根据本发明的某些实施方案,hAPRIL.01A的CDR被用于本发明的抗体中。下表1将序列ID与其对应序列相关联。
表1:序列表
SEQ ID NO:11-52涉及工程改造的所述免疫球蛋白VH、VL、重链或轻链序列。
附图简述
图1显示在针对不依赖T细胞的B细胞反应的体内测试中用hAPRIL.01A或类似物14_1G.15靶向APRIL的结果。用250μg NP-Ficoll(第0天)激发转基因小鼠(APRIL-Tg),并在第-1天和第3天用hAPRIL.01A或14_1G.15治疗。使用PBS和野生型小鼠(WT)作为阴性对照。利用ELISA测量免疫球蛋白滴度(IgA1(图A)和IgA2(图B)、IgG(图C)及IgM(图D)。14_1G.15抑制针对NP-Ficoll的不依赖T细胞的免疫反应的有效性高于其hAPRIL.01A类似物。
详述
因此,本发明涉及与具有hAPRIL.01A抗原结合位点的抗体,包括抗体类似物,如抗体片段结合至相同的人类APRIL表位的抗体。WO2010/100056中公开了抗体hAPRIL.01A以及VH和VL结构域及CDR的序列。本发明的发明人发现,不太可能用人类替代物取代hAPRIL.01A的VH和VL结构域的小鼠框架区。此外,所选择的替代性框架序列产生具有意外的特征的替代性抗人类APRIL抗体。据信,所选择的框架序列在结合至hAPRIL.01A的人类APRIL表位的情况下表现其特有特征,并因此在这一情况下具有广泛效用。因此,本发明旨在与hAPRIL.01A结合至相同表位并且在VH和VL结构域内包含所选择的框架序列的任何抗体(包括片段和/或衍生物和/或类似物)。在某些实施方案中,此类抗体将包含与hAPRIL.01A的CDR不同的替代性CDR。不过,根据其它实施方案,该抗体将包含与hAPRIL.01A的CDR类似或甚至相同的CDR。根据某些实施方案,包含hAPRIL.01A的VH结构域CDR1、CDR2及CDR3以及VL结构域CDR1、CDR2及CDR3,或者所述序列中任一个的变体的抗体被认为是与单克隆抗体hAPRIL.01A结合至相同人类APRIL表位的抗体。特别是当该抗体以约100nM或更低KD结合人类APRIL和/或以约100nM或更低IC50阻断热内APRIL与人类BCMA和TACI的结合时更是如此。在本发明内,优选抗体以约100nM或更低,如在选自100-0.001nM,例如100-0.010、100-0.050、100-0.100、100-0.150、100-0.200、100-0.250、100-0.300、100-0.350、100-0.400、100-0.450、90-0.500、80-0.550、70-0.600、60-0.650、50-0.700、40-0.750、30-0.800、20-0.850、10-0.900或1.0-0.950nM的区间内的KD值结合人类APRIL。技术人员应了解,优选较小的KD值,如低于50、20、10、1.00nM的值。KD值在此类区间内的抗体适于临床应用(参见例如,Presta等人,2001,Thromb.Haemost.85:379-389;Yang等人,2001,Crit.Rev.Oncol.Hematol.38:17-23;Carnahan等人,2003,Clin.Cancer Res.(增刊)9:3982s-3990s)。抗体亲和力可以使用技术人员已知的标准分析,例如实验部分中例示的分析法测定。
更优选本发明的抗体以约100nM或更低,如在选自100-0.001nM,例如100-0.010、100-0.050、100-0.100、100-0.150、100-0.200、100-0.250、100-0.300、100-0.350、100-0.400,100-0.450、90-0.500、80-0.550、70-0.600、60-0.650、50-0.700、40-0.750、30-0.800、20-0.850、10-0.900或1.0-0.950nM的区间内的IC50值阻断人类APRIL与人类BCMA和TACI的结合。技术人员应了解,优选较小的IC50值,如低于50、20、10、1.00nM的值。
抗体与hAPRIL.01A结合相同的表位可以根据WO2010/100056实施例2或5中呈现的方法,通过评估本发明抗体和具有hAPRIL.01A抗原结合位点的参考抗体竞争结合人类APRIL,或利用以下所论述的技术人员已知的其它交叉阻断或表位定位技术来评价。hAPRIL.01A的抗原结合位点是由SEQ ID NO:3和4中所呈现的VH和VL结构域界定。因此,包含SEQ ID NO:3和4中所呈现的VH和VL结构域的任何抗体,包括抗体类似物,如抗体片段,都可以用作参考抗体以评价与hAPRIL.01A结合至相同人类APRIL表位。WO2010/100056中公开的抗体hAPRIL.01A是具有hAPRIL.01A抗原结合位点的抗体的一个例子,并且在本发明的情况下是适合的参考抗体。不过,来源于hAPRIL.01A的抗体片段,如Fab、F(ab)2或Fv片段也可以用作参考抗体。基于SEQ ID NO:1和2的DNA序列以及SEQ ID NO:3和4的氨基酸序列,技术人员将能够构造并产生这些来源于hAPRIL.01A的抗体片段。基于所提供的序列,技术人员还能够通过将SEQ ID NO:3的重链可变区氨基酸序列(由SEQ ID NO:1编码)与IgG1恒定区(来自小鼠或来自不同物种,优选来自小鼠)接合并且将SEQ ID NO:4的轻链可变区氨基酸序列(由SEQ ID NO:2编码)与k恒定区(来自小鼠或来自不同物种,优选来自小鼠)结合而产生用作参考抗体的hAPRIL.01A类似物。
当用所述方法评价时,与hAPRIL.01A结合至相同的人类APRIL表位的抗体可以阻断具有hAPRIL.01A抗原结合位点的参考抗体与人类APRIL的结合,其IC50值是约100nM或更低,如在选自100-0.001nM,例如100-0.010、100-0.050、100-0.100、100-0.150、100-0.200、100-0.250、100-0.300、100-0.350、100-0.400、100-0.450、90-0.500、80-0.550、70-0.600、60-0.650、50-0.700、40-0.750、30-0.800、20-0.850、10-0.900或1.0-0.950nM的区间内。技术人员应了解,优选较小的IC50值,如低于50、20、10、1.00nM的值。
因此,本发明抗体具有以下特征中的一个或多个:
(i)以约100nM或更低KD结合人类APRIL;
(ii)以约100nM或更低IC50阻断人类APRIL与人类BCMA和人类TACI的结合;
(iii)以约100nM或更低IC50阻断hAPRIL.01A与人类APRIL的结合。
这些特征可以组合成以下组合:(i)或(ii)或(iii);(i)和(ii);(i)和(iii);(ii)和(iii);(i)和(ii)及(iii)。
根据本发明,选择该抗体的抗原结合位点中VH结构域框架序列使得其与选自SEQID NO.12、14、16或18的VH氨基酸序列的框架序列具有至少70%序列相似性。根据一个优选实施方案,选择该抗体的VH结构域框架序列使得其与选自SEQ ID NO.14或18,最优选SEQID NO:18的VH氨基酸序列的框架序列具有至少70%序列相似性。选择该抗体的抗原结合位点中VL结构域框架序列使得其与选自SEQ ID NO.30的VL氨基酸序列的框架序列具有至少70%序列相似性。
选自SEQ ID NO.12、14、16或18的VH氨基酸序列以及选自SEQ ID NO.30的VL氨基酸序列同时包含框架序列和CDR序列。并入这些VH和VL氨基酸序列中的CDR序列是hAPRIL.01A的那些序列,并且对应于SEQ ID NO.5(hAPRIL.01A VH CDR1)、6(hAPRIL.01A VH CDR2)、7(hAPRIL.01A VH CDR3)、8(hAPRIL.01A VL CDR1)、9(hAPRIL.01A VL CDR2)、10(hAPRIL.01AVL CDR3)。不过,如上文所述,使用如本发明内选择的VH和VL框架序列不局限于与hAPRIL.01A的特定CDR组合。因此,根据某些实施方案,至少70%的序列相似性应仅认为针对框架序列,而不是针对如选自SEQ ID NO.12、14、16或18的完整VH氨基酸序列或如选自SEQ ID NO.30的完整VL氨基酸序列。在SEQ ID NO.12、14、16或18中呈现的VH氨基酸序列的框架序列是这些序列中除VH CDR外的部分,即,除与SEQ ID NO.5(hAPRIL.01A VH CDR1)、6(hAPRIL.01A VH CDR2)、7(hAPRIL.01A VH CDR3)相同的序列部分外的部分。在SEQ IDNO.30中呈现的VL氨基酸序列的框架序列是这一序列中除VL CDR外的部分,即,除与SEQ IDNO.8(hAPRIL.01A VL CDR1)、9(hAPRIL.01A VL CDR2)、10(hAPRIL.01A VL CDR3)相同的序列部分外的部分。
根据替代性实施方案,至少70%的序列相似性应认为是针对选自SEQ ID NO.12、14、16或18的完整VH氨基酸序列及选自SEQ ID NO.30的完整VL氨基酸序列。
在本发明的说明中,至少70%序列相似性应理解为是指至少80%,如至少85%,优选至少90%,更优选至少95%,如至少99%序列相似性。
技术人员应了解,“序列相似性”是指个别核苷酸或肽序列相似的程度。两个序列之间的相似程度是基于一致性程度加上保守变化的程度。“序列相似性”百分比是相同或保守变化的氨基酸或核苷酸的百分比,即“序列相似性”=(%序列一致性)+(%保守变化)。
出于本发明的目的,“保守变化”和“一致性”被视为范围较宽的术语“相似性”的种类。因此,在使用术语序列“相似性”时,它包含序列“一致性”和“保守变化”。根据某些实施方案,不考虑保守变化并且%序列相似性是指%序列一致性。
术语“序列一致性”是技术人员所知的。为了测定两个氨基酸序列或两个核酸的序列一致性程度,出于最佳比较的目的,将这些序列对准(例如,可以在第一个氨基酸序列或核酸序列中引入空位,以便与第二个氨基酸或核酸序列达到最佳对准)。此类对准可以在所比较序列的全长内进行。或者,该对准可以在较短比较长度内进行,例如在约20、约50、约100或更多个核酸/碱基或氨基酸内进行。
接着比较在对应氨基酸位置或核苷酸位置处的氨基酸或核苷酸。当第一个序列中的某一位置被与第二个序列中对应位置相同的氨基酸残基或核苷酸占据时,则分子在该位置处一致。序列间共有的一致性程度典型地以两个序列之间的一致性百分比表示并且随着这些序列中一致残基所共有的一致位置的数量变化(即,%一致性=对应位置处一致残基的数量/位置总数×100)。优选的是,比较的两个序列具有相同或大体上相同的长度。
“保守变化”百分比可以按与序列一致性百分比类似的方式测定。不过,在这一情况下,在氨基酸或核苷酸序列的特定位置处可能保留原始残基的功能特性的变化根据是否未发生变化进行评分。
对于氨基酸序列,相关功能特性是氨基酸的物理-化学特性。本发明多肽中氨基酸的保守取代可以选自该氨基酸所属类别其它成员。举例来说,蛋白质生物化学领域中众所周知,属于具有特定大小或特征(如电荷、疏水性及亲水性)的一组氨基酸的氨基酸可以被另一氨基酸取代,而基本上不改变蛋白质特性,特别是在蛋白质与生物活性不直接相关的区域中(参见例如,Watson等人,Molecular Biology of the Gene,The Benjamin/Cummings Pub.Co.,第224页(第4版,1987))。举例来说,非极性(疏水性)氨基酸包括丙氨酸、亮氨酸、异亮氨酸、缬氨酸、脯氨酸、苯丙氨酸、色氨酸及酪氨酸。极性中性氨基酸包括甘氨酸、丝氨酸、苏氨酸、半胱氨酸、酪氨酸、天冬酰胺及谷氨酰胺。带正电(碱性)氨基酸包括精氨酸、赖氨酸及组氨酸。带负电(酸性)氨基酸包括天冬氨酸和谷氨酸。保守取代包括例如,Lys被Arg取代及Arg被Lys取代,由此保持正电荷;Glu被Asp取代及Asp被Glu取代,由此保持负电荷;Ser被Thr取代及Thr被Ser取代,由此保持游离-OH;以及Gln被Asn取代及Asn被Gln取代,由此保持游离-NH2。
本发明的CD70结合肽的氨基酸序列中的示例性保守取代可以根据以下陈述的那些进行:
表2:示例性保守氨基酸取代
对于核苷酸序列,相关功能特性主要是在与转录和/或翻译机器有关序列的开放阅读框内某一核苷酸所携带的生物信息。众所周知,遗传密码具有简并性(或冗余)并且多个密码子关于其编码的氨基酸可以携带相同的信息。举例来说,在某些物种中,氨基酸亮氨酸是由UUA、UUG、CUU、CUC、CUA、CUG密码子(或对于DNA是TTA、TTG、CTT、CTC、CTA、CTG)编码,并且氨基酸丝氨酸是由UCA、UCG、UCC、UCU、AGU、AGC(或对于DNA是TCA、TCG、TCC、TCT、AGT、AGC)指明。不改变翻译的信息的核苷酸变化被视为保守变化。
技术人员应意识到以下事实:使用不同的数学算法的若干不同计算机程序可用于测定两个序列之间的一致性。举例来说,可以使用采用了Needleman和Wunsch算法的计算机程序(Needleman等人(1970))。根据一个实施方案,计算机程序是Accelrys GCG软件包(Accelrys Inc.,San Diego U.S.A)中的GAP程序。可以使用的取代矩阵是例如BLOSUM 62矩阵或PAM250矩阵,其中空位权重是16、14、12、10、8、6或4并且长度权重是1、2、3、4、5或6。技术人员应理解,所有这些不同参数将得到略有不同的结果,而且当使用不同算法时,两个序列的总体一致性百分比无明显改变。
根据一个实施方案,使用Accelrys GCG软件包(Accelrys Inc.,San DiegoU.S.A)中的GAP程序测定两个核苷酸序列之间的一致性百分比。使用NWSgapdna CMP矩阵以及40、50、60、70或80的空位权重和1、2、3、4、5或6的长度权重。
在另一实施方案中,使用被合并于ALIGN程序(2.0版)(使用Ge nestream服务器IGH Montpellier France http://xylian.igh.cnrs.fr/bin/align-guess.cgi的序列数据,在ALIGN Query获得)中的E.Meyers和W.Miller(Meyers等人(1989))算法,使用PAM120残基权重表、12分的空位长度罚分及4分的空位罚分,测定两个氨基酸或核苷酸序列之间的一致性百分比。
对于本发明,最优选使用BLAST(基本局部比对工具)测定核苷酸或氨基酸序列之间的一致性和/或相似性百分比。
使用Altschul等人(1990)的BLASTn、BLASTp、BLASTx、tBLASTn及tBLASTx程序的查询可以登录http://www.ncbi.nlm.nih.gov,经由BLAST的线上版本发布。或者,可以使用经NCBI互联网站下载的单机版BLAST(例如2.2.29版(2014年1月3日发布))。优选用以下参数进行BLAST查询。为了测定氨基酸序列之间的一致性和/或相似性百分比:算法:blastp;字长:3;评分矩阵:BLOSUM62;空位罚分:存在:11;延伸:1;组成调整:条件性组成评分矩阵调整;过滤器:关;掩码:关。为了测定核苷酸序列之间的一致性和/或相似性百分比:算法:blastn;字长:11;查询范围内的最大匹配数:0;匹配/错配评分:2,-3;空位罚分:存在:5;延伸:2;过滤器:低复杂度区域;掩码:仅针对查询表的掩码。
“保守变化”百分比可以按与序列一致性百分比类似的方式,借助于指定算法和计算机程序测定。一些计算机程序,例如BLASTp,呈现正值(=相似性)的数量/百分比和一致性数量/百分比。保守变化的百分比可以通过用正值/相似性百分比减去一致性百分比得到(保守变化百分比=相似性百分比-一致性百分比)。
技术人员应了解,本发明的抗体将包含多个抗原结合位点。所选择的VH和VL结构域的氨基酸序列框架序列连同CDR序列组合于抗原结合位点中。来自本发明所设想的VH和VL结构域的框架序列的具体组合如下表3中所示,其中“X”存在于所设想的VH和VL结构域组合的位置处。
表3:VH和VL的框架序列组合.
来自这些VH和VL结构域的框架序列的组合产生能够结合至人类APRIL的抗体。应注意的是,如在实验部分中进一步呈现,在本发明的发明人所进行的测试中,当将本发明的VH序列与SEQ ID NO:30(VL15)的VL序列组合时,仅获得具有APRIL结合功能的抗体。在所测试的所选VH序列与其它VL序列(VL10-VL14)的组合中,所得抗体不具有功能性APRIL结合特性。如在实验部分中所呈现,根据本发明使用的VH与VL序列的组合的另一意外作用是,使(热)稳定性相较于具有hAPRIL.01A VH与VL序列的抗体有所改善。
优选将SEQ ID NO:30的VL框架序列与来自SEQ ID NO:18或其衍生序列,如SEQ IDNO 32、34、36、38、40的VH框架序列的VH框架序列组合。这些优选组合在表3中以加下划线的“X”呈现。来自SEQ ID NO:30的VL框架序列与来自SEQ ID NO:40的VH框架序列的最优选组合在表3中以粗体字(并加下划线)显示的“X”呈现。已经意外地发现,这些VH与VL框架序列组合产生的抗体具有额外的有益特征,包括有益的稳定性特征和/或改善的与人类APRIL靶的结合。
根据某些实施方案,在VH结构域中,CDR1、CDR2、CDR3中至少一个是选自分别由SEQNO 5、6、7或所述序列中任一个的变体组成的组。优选在VH结构域中,CDR1、CDR2及CDR3分别选自SEQ NO 5、6、7或所述序列中任一个的变体。这些VH结构域CDR序列对应于hAPRIL.01A的VH结构域CDR。
根据某些实施方案,在VL结构域中,CDR1、CDR2、CDR3中至少一个是选自分别由SEQNO 8、9、10或所述序列中任一个的变体组成的组。优选在VL结构域中,CDR1、CDR2及CDR3分别选自SEQ NO 8、9、10或所述序列中任一个的变体。这些VL结构域CDR序列对应于hAPRIL.01A的VL结构域CDR。
根据某些实施方案,在抗体的抗原结合位点中,VH结构域CDR1、CDR2及CDR3分别选自SEQ NO 5、6、7或所述序列中任一个的变体,并且VL结构域CDR1、CDR2及CDR3分别选自SEQNO 8、9、10或所述序列中任一个的变体。
本发明的发明人意外地发现,组合了本发明中所使用的VH和VL框架序列的抗体可以作进一步改善。具体地说,VH氨基酸序列中的取代R72S改善与人类APRIL的结合。
此外,VH氨基酸序列中的组合取代R67K-V68A也改善与人类APRIL的结合。因此,根据某些实施方案,本发明涉及VH氨基酸序列中的72位氨基酸是S的抗体。SEQ ID NO.32、34、36、38、40的VH氨基酸序列是此类在72位具有S残基的VH氨基酸序列的实例。根据其它实施方案,本发明涉及VH氨基酸序列中的67位氨基酸是K并且68位氨基酸是A的抗体。预计全部三个氨基酸取代R72S、R67K及V68A的组合也在本发明的范围内。因此,根据其它实施方案,本发明涉及VH氨基酸序列中的72位氨基酸是S,67位氨基酸是K并且68位氨基酸是A的抗体。
除VH和VL结构域外,该抗体还可以包含额外的结构域,如适量的CH结构域及适量的CL结构域。CH结构域和CL结构域可以是人类来源的。这些结构域还包括向抗体提供经过修饰(或阻断的)Fc区以提供改变的效应功能的结构域。参见例如,美国专利号5,624,821;WO2003/086310;WO2005/120571;WO2006/0057702;Presta,2006,Adv.Drug DeliveryRev.58:640-656;Vincent和Zurini,Biotechnol.J.,2012,7:1444-50;Kaneko和Niwa,Biodrugs,2011,25:1-11。此类修饰可以用于增强或抑制免疫系统的各种反应,而且可能在诊断和疗法中具有有益作用。Fc区的变化包括氨基酸变化(取代、缺失及插入)、糖基化或去糖基化,以及添加多个Fc。根据某些实施方案,优选使用展示较低Fc效应功能的Fc区。根据某些实施方案,本发明的抗体也可以具有源自于人类IgG4的Fc区和/或带有N297Q糖基化缺陷型突变的Fc区。CL结构域可以选自人类κ或λ恒定结构域。优选使用人类κCL结构域。
根据本发明的某些实施方案,提供了包含Fc和CL结构域的抗体,其中VH结构域氨基酸序列是在与选自SEQ ID NO:42、44、46、48、52,优选SEQ ID NO:48或52,最优选SEQ IDNO:52的氨基酸序列具有至少70%序列相似性的重链氨基酸序列中,并且VL结构域氨基酸序列是在与选自SEQ ID NO:50的氨基酸序列具有至少70%序列相似性的轻链氨基酸序列中。
本发明所设想的这些重链和轻链的特定组合的具体组合如下表4中所示,其中“X”存在于所设想的重链和轻链组合的位置处。
表4
优选的组合以带下划线的“X”指示。更优选的组合是以粗体(并且加下划线)“X”指示。
根据另一方面,本发明涉及分离的多核苷酸,该多核苷酸编码根据本发明的抗体的VH结构域和/或VL结构域。编码VH结构域的多核苷酸序列优选是与选自SEQ ID NO:11、13、15、17、31、39、41、43、45、47、51,优选地选自SEQ ID NO:17、31、39、47或51,更优选SEQ IDNO:51的多核苷酸序列具有至少70%序列相似性的多核苷酸序列。编码VL结构域的多核苷酸序列优选是与选自SEQ ID NO:29或49,优选SEQ ID NO:49的多核苷酸序列具有至少70%序列相似性的多核苷酸序列.
本发明还涉及一种包含多个表达载体的表达单元,这些表达载体包含处于适合调控序列控制下的多个根据本发明的多核苷酸,其中所述多个多核苷酸编码根据本发明的抗体的VH结构域和VL结构域。所述表达单元可以被设计成使得编码VH结构域的多核苷酸序列和编码VL结构域的多核苷酸序列能在同一表达载体上。因此,该表达单元可以包含单一载体。或者,编码VH结构域的多核苷酸序列和编码VL结构域的多核苷酸序列可以在不同表达载体上。在此类实施方案中,该表达单元将包含多个,如2个表达载体。
本发明另一方面涉及一种宿主细胞,该宿主细胞包含多个本发明的多核苷酸和/或本发明的表达单元。该表达单元优选是包括了同时包含编码VH结构域的多核苷酸序列和编码VL结构域的多核苷酸序列的表达载体的表达单元。
本发明的抗体可以是以下任一种:
-嵌合抗体或其片段;
-人源化抗体或其片段;或
-选自由Fab、Fab′、Fab′-SH、Fv、scFv、F(ab′)2、双特异性单克隆抗体及双抗体。优选包含多个基于hAPRIL.01A的CDR的抗原结合位点的人源化抗体。应注意,根据本发明选择的框架区是来自人类来源并因此适用于获得人源化抗体,特别是当与来自人类来源的恒定区组合时。
根据另一方面,本发明涉及一种产生本发明的抗体的方法,该方法包括:
a)在培养基中,在表达本发明的多核苷酸的条件下,培养包含多个所述多核苷酸的宿主细胞和/或本发明的表达单元,由此产生包含轻链和重链可变区的多肽;以及
b)从所述宿主细胞或培养基回收所述多肽。
本发明另外涉及一种组合物,该组合物包含本发明的抗体以及药学上可接受的载剂或稀释剂。在一个实施方案中,此类组合物可以包含超过一种抗体。在一个实施方案中,该组合物除包含一种或多种本发明的抗体外,还包含一种或多种其它活性化合物。此类组合性组合物可以用于组合疗法中,例如用于治疗癌症。在此情况下,所述抗体可以与一种或多种常用抗癌药组合。对于其它组合疗法,可以使用其它额外的活性化合物。对于组合疗法,不一定要在同一组合物中具有两种或更多种活性化合物。因此,所述抗体和其它活性化合物的组合或后续用途也是本发明的一部分,其中该抗体和该其它活性化合物是同时或依序施用。
从以上说明可知,本发明的抗体可以用于疗法和诊断中并且用于其它非治疗目的。因此,本发明另外涉及在疗法和诊断中以及其它非治疗目的中使用所述抗体的方法。
在一个实施方案中,该疗法包括抑制免疫细胞增殖和/或免疫细胞存活。在另一实施方案中,治疗旨在治疗癌症。在一个实施方案中,该疗法包括治疗自身免疫性疾病。在一个实施方案中,该疗法包括治疗炎症性疾病。在一个实施方案中,该疗法包括治疗Ig分泌介导的疾病,特别是IgA分泌介导的疾病。下文将更详细地论述本发明抗体的治疗应用。
本发明的抗体当用于非治疗性应用中时,可以例如在体外或离体技术中应用,如流式细胞术、蛋白质印迹、酶联免疫吸附测定(ELISA)及免疫组织化学分析。
疗法
鉴于本发明抗体与hAPRIL.01A类似,也结合至人类APRIL的事实,本发明的抗体适用于与hAPRIL.01A类似的疗法中,并且其改良之处在以上及实验部分中予以论述。因此,本发明的抗体适于治疗已知或预期通过阻断人类APRIL与BCMA和/或TACI的相互作用可以得到改善的病症。如本领域中所知,阻断人类APRIL与BCMA和/或TACI的相互作用可抑制免疫细胞增殖和/或存活,并因此可以用于治疗得益于此类免疫细胞增殖和/或存活阻断的病症,如炎症性疾病、由Ig分泌介导的疾病和/或自身免疫性疾病。阻断人类APRIL与BCMA和/或TACI的相互作用也有益于治疗癌症。
可能得益于本发明抗体的自身免疫性病症可以选自多发性硬化、类风湿性关节炎、1型糖尿病、银屑病、克罗恩氏病(Crohn′s disease),以及其它炎症性肠病如溃疡性结肠炎、全身性红斑狼疮(SLE)、自身免疫性脑脊髓炎、重症肌无力(MG)、桥本氏甲状腺炎(Hashimoto′s thyroiditis)、古帕斯捷氏综合征(Goodpasture′s syndrome)、天疱疮、格雷夫斯氏病(Graves disease)、自身免疫性溶血性贫血、自身免疫性血小板减少性紫癜、含抗胶原蛋白抗体的硬皮病、混合性结缔组织病、多肌炎、恶性贫血、特发性阿狄森病(idiopathic Addison′s disease)、自身免疫相关性不孕、肾小球性肾炎、新月体性肾小球肾炎、增生性肾小球肾炎、大疱性类天疱疮、斯耶格伦氏综合症、银屑病关节炎、胰岛素抵抗、自身免疫性糖尿病、自身免疫性肝炎、自身免疫性血友病、自身免疫性淋巴细胞增生综合症(ALPS)、自身免疫性肝炎、自身免疫性血友病、自身免疫性细胞增生综合症、自身免疫性葡萄膜炎、格林-巴利综合症(Guillain-Bare syndrome)、动脉硬化及阿尔茨海默氏病(Alzheimer′s disease)。
此外,本发明的抗体还可以有利地治疗得益于免疫反应降低的其它相关病症,如移植物(移植)排斥反应或过敏性病症。
另外,本发明的抗体可以有利地治疗得益于免疫球蛋白水平,如IgA(包括IgA1或IgA2)、IgG、IgM水平降低的其它病症,如与Ig分泌,特别是IgA分泌;Ig过量产生,如IgA(包括IgA1或IgA2)、IgG、IgM过量产生,特别是IgA过量产生;或Ig沉积,特别是IgA沉积有关的病症。此类病症的实例包括但不限于,IgA肾病及其它形式肾小球肾炎、脂泻病、类天疱疮疾病、亨诺-许兰二氏紫癜(Henloch-purpura),以及与Ig沉积有关的其它自身免疫疾病。
在本发明范围内,“病症”的治疗包括抗人类APRIL抗体的任何治疗用途,包括预防性和治疗性用途。因此,术语“病症”可以指疾病状态,而且在不使生理变化至有害状态的预防情况下还指生理状态。
在本发明范围内的癌症包括但不限于,白血病、急性淋巴细胞白血病、急性髓细胞白血病、成髓细胞早幼粒细胞、髓单核细胞性单核细胞红白血病、慢性白血病、慢性髓细胞(粒细胞)白血病、慢性淋巴细胞白血病、套细胞淋巴瘤、原发性中枢神经系统淋巴瘤、伯基特氏淋巴瘤(Burkitt′s lymphoma)及边缘区B细胞淋巴瘤、真性红细胞增多症淋巴瘤、霍奇金氏病(Hodgkin′s disease)、非霍奇金氏病、多发性骨髓瘤、瓦尔登斯特伦氏巨球蛋白血症(Waldenstrom′s macroglobulinemia)、重链疾病、实体肿瘤、肉瘤及癌瘤,纤维肉瘤、粘液肉瘤、脂肪肉瘤、软骨肉瘤、成骨肉瘤、骨肉瘤、脊索瘤、血管肉瘤、内皮肉瘤、淋巴管肉瘤、淋巴管内皮肉瘤、滑膜瘤、间皮瘤、尤因氏肿瘤(Ewing′s tumor)、平滑肌肉瘤、横纹肌肉瘤、结肠肉瘤、结肠直肠癌瘤、胰腺癌、乳癌、卵巢癌、前列腺癌、鳞状细胞癌、基底细胞癌、腺癌、汗腺癌、皮脂腺癌、乳头状癌、乳头状腺癌、囊腺癌、髓样癌、支气管癌、肾细胞癌、肝细胞瘤、胆管癌、绒毛膜癌、精原细胞瘤、胚胎性癌、维尔姆斯氏肿瘤(Wilm′s tumor)、子宫颈癌、子宫癌、睾丸癌、肺癌、小细胞肺癌、非小细胞肺癌、膀胱癌、上皮细胞癌、神经胶质瘤、星形细胞瘤、髓母细胞瘤、颅咽管瘤、室管膜瘤、松果体瘤、血管母细胞瘤、听神经瘤、寡树突胶质瘤、脑膜瘤、黑色素瘤、成神经细胞瘤、视网膜母细胞瘤、鼻咽癌、食管癌、基底细胞癌、胆管癌、膀胱癌、骨癌、脑和中枢神经系统(CNS)癌症、子宫颈癌、绒毛膜癌、结肠直肠癌、结缔组织癌、消化系统癌症、子宫内膜癌、食管癌、眼癌、头颈癌、胃癌、上皮内赘瘤、肾癌、喉癌、肝癌、肺癌(小细胞肺癌、大细胞肺癌)、黑色素瘤、成神经细胞瘤;口腔癌(例如唇癌、舌癌、口癌及咽癌)、卵巢癌、胰腺癌、视网膜母细胞瘤、横纹肌肉瘤、直肠癌;呼吸系统癌症、肉瘤、皮肤癌、胃癌、睾丸癌、甲状腺癌、子宫癌及泌尿系统癌症。特别值得关注的癌症是具有表达APRIL的细胞,如B细胞源性恶性疾病、淋巴癌或结肠癌或肺癌,或多发性骨髓瘤(MM),或慢性淋巴细胞白血病(CLL)B细胞的癌症。
为了治疗以上提到的任何病症,可以将本发明的抗体单独或与其它治疗剂组合直接给与受试者。因此,根据本发明某些实施方案,本发明的抗体可以与多种化学治疗剂组合于其应用中和/或组合物中,所述化学治疗剂被用于治疗多发性骨髓瘤(MM)、骨髓增生异常综合症(MDS)、Waldenstroms巨球蛋白血症、B-CLL、弥漫性大细胞B细胞淋巴瘤、非霍奇金氏淋巴瘤,以及韦格纳氏肉芽肿(wegenersgranulomatosis),如美法仑(melphalan)、长春新碱(vincristine)、氟达拉滨(fludarabine)、苯丁酸氮芥(chlorambucil)、苯达莫司汀(bendamustine)、依托泊苷(etoposide)、多柔比星(doxorubicin)、环磷酰胺、顺铂(cisplatin)。此外,本发明的抗体可以与多种免疫调节剂组合于其应用中和/或组合物中,如皮质类固醇(地塞米松(dexamethasone)、泼尼松龙(prednisolone))、沙利度胺类似物(thalidomide analog)(沙利度胺、来那度胺(lenalidomide)、泊马度胺(pomalidomide))。本发明的抗体还可以与多种靶向激酶抑制剂组合于其应用中和/或组合物中,例如依鲁替尼(ibrutinib)、艾达拉里斯(idelalisib)。另外,本发明的抗体还可以与多种靶向CD20的抗体疗法,如利妥昔单抗(rituximab)、奥法木单抗(ofatumumab)、奥奴珠单抗(obinotuzumab);或靶向CD52的抗体疗法,如阿仑珠单抗(alemtuzumab);靶向CD38的抗体疗法,如达雷木单抗(daratumumab);靶向IL-6或IL-6受体的抗体疗法(如萨利奴单抗(sarilumab)、托珠单抗(tocilizumab));靶向CS-1的抗体疗法(如埃罗妥珠单抗(elotuzumab);靶向BCMA的抗体疗法(如GSK2857916);或靶向BAFF或BLyss的抗体疗法(如他贝鲁单抗(tabalumab))组合于其应用中和/或组合物中。此外,本发明的抗体还可以与多种双膦酸盐(如帕米膦酸盐(pamidronate)、唑来膦酸(zolendronic acid))组合于其应用中和/或组合物中。先前已描述,APRIL保护MM细胞免受IL-6损失、地塞米松及硼替佐米(bortezomib)治疗影响(Moreaux等人,2004,Blood 103(8):3148-57;Li等人,2010,MedOncol.27:439-45)。经显示,hAPRIL.01A在来那度胺和地塞米松治疗中逆转APRIL介导的MM细胞存活(Tai等人,2014,ASH poster 2098)。鉴于本领域中的这些发现,本发明的抗体可以与选自以下的另外的治疗剂组合于其应用中和/或组合物中:皮质类固醇,例如地塞米松、泼尼松龙,优选地塞米松;或沙利度胺类似物,例如沙利度胺、来那度胺、泊马度胺,特别是来那度胺;或硼替佐米。
诊断
利用代表疾病,如但不限于自身免疫性疾病、炎症性疾病及恶性疾病的重要标记物的APRIL,检测人类受试者血清和/或组织中的APRIL极为重要。对于诊断应用,抗体典型地将用可检测部分标记(直接或间接地)。多种标记是可用的,这些标记一般可以归为以下类别:生物素、荧光染料、放射性核苷酸、酶、碘及生物合成标记。
经显示,众多不同患者的血清和其它体液和/或组织中存在的适合APRIL与患者疾病的严重程度相关。举例来说,患有慢性淋巴细胞白血病(CLL)、霍奇金氏淋巴瘤、非霍奇金氏淋巴瘤(NHL)及多发性骨髓瘤(MM)、DLBCL患者(NHL)、结肠直肠癌、SLE、多种全身免疫类风湿性疾病(斯耶格伦氏综合症、瑞特氏综合症、银屑病关节炎、多肌炎及强直性脊柱炎现也包括在内)及特应性皮肤炎的患者展示血清可溶性APRIL水平增加。另外,在IgA肾病患者中血清APRIL含量升高(McCarthy等人,2011,J.Clin.Invest.121(10):3991-4002)。在败血病中血清APRIL含量也升高并且预示垂危患者的死亡(Jonsson等人,1986,Scand JRheumatol增刊61,166-9;Roschke等人,2002,J Immunol 169,4314-21)。基于hAPRIL.01A所展示的结合特征,根据本发明的抗体可以用作诊断工具以检测体液和/或组织中的可溶性APRIL。
本发明的抗体可以用于任何已知的测定方法中,如竞争性结合测定、直接和间接夹心测定,以及免疫沉淀测定。Zola,Monoclonal Antibodies.A Manual of Techniques,第147-158页(CRC Press,Inc.1987)。
本发明的抗体还可以用于体内诊断测定中。一般说来,该抗体用放射性核素标记,由此可以使用免疫闪烁法或正电子发射计算机断层摄影定位抗原或表达该抗原的细胞。
非治疗性用途
根据本发明其它方面,所述抗体具有其它非治疗性用途。本发明抗体的非治疗性用途包括流式细胞术、蛋白质印迹、酶联免疫吸附测定(ELISA)及免疫组织化学分析。
本发明抗体可以例如经由固定至蛋白质A-琼脂糖凝胶柱而作为亲和纯化试剂使用。
通用定义
术语“抗体”是指展现所希望的生物活性,如抑制配体与其受体的结合,或抑制配体诱导的受体信号传导的任何形式的抗体。在本发明中,生物活性包含阻断APRIL与其受体BCMA和/或TACI的结合。因此,“抗体”是以其最广泛意义使用并且特别涵盖但不限于,单克隆抗体(包括全长单克隆抗体)和多特异性抗体(例如双特异性抗体),如基于技术(Genmab)或技术(Genmab),或抗体片段。
“抗体片段”和“抗体结合片段”意思指抗体的抗原结合片段和类似物,典型地包括亲本抗体的抗原结合或可变区(例如一个或多个CDR)的至少一部分。抗体片段保留亲本抗体的至少一部分结合特异性。典型地,当以摩尔浓度表示活性时,抗体片段保持至少10%的亲本结合活性。优选抗体片段保留至少20%、50%、70%、80%、90%、95%或100%或更高的亲本抗体对靶的结合亲和力。抗体片段的实例包括但不限于,Fab、Fab′、F(ab′)2及Fv片段;双抗体;线性抗体;单链抗体分子,例如sc-Fv;单抗体(来自Genmab的技术);纳米抗体(来自Ablynx的技术);结构域抗体(来自Domantis的抗体);以及由抗体片段形成的多特异性抗体。工程改造的抗体变体综述于Holliger和Hudson,2005,Nat.Biotechnol.23:1126-1136中。
“Fab片段”由一条轻链以及一条重链的CH1和可变区构成。Fab分子的重链无法与另一重链分子形成二硫键。
“Fc”区含有两个重链片段,包含抗体的CH1和CH2结构域。这两个重链片段通过两个或更多个二硫键及与CH3结构域的疏水相互作用保持在一起。
“Fab′片段”含有一条轻链以及一条重链的一部分,所述重链的一部分含有VH结构域和CH1结构域以及在CH1与CH2结构域之间的区域,由此可以在两个Fab′片段的两条重链之间形成链间二硫键,从而形成F(ab′)2分子。
“F(ab′)2片段”含有两条轻链以及两条重链,所述两条重链含有在CH1与CH2结构域之间的恒定区的一部分,由此在该两条重链之间形成链间二硫键。因此,F(ab′)2片段是由通过两条重链之间的二硫键保持在一起的两个Fab′片段构成。
“Fv区”包含来自重链和轻链的可变区,但缺乏恒定区。
“单链Fv抗体”(或“scFv抗体”)是指包含抗体的VH和VL结构域的抗体片段,其中这些结构域存在于单一多肽链中。一般来说,Fv多肽另外包含在VH与VL结构域之间的多肽连接子,所述连接子使scFv能够形成抗原结合所希望的结构。有关scFv的综述,参见Pluckthun,1994,The Pharmacology of Monoclonal Antibodies,第113卷,Rosenburg和Moore编,Springer-Verlag,New York,第269-315页。另参见国际专利申请公布号WO 88/01649以及美国专利号4,946,778和5,260,203。
“双抗体”是具有两个抗原结合位点的小抗体片段。这些片段包含在同一多肽链(VH-VL或VL-VH)中连接至轻链可变结构域(VL)的重链可变结构域(VH)。通过使用太短而无法使同一链中的两个结构域之间配对的连接子,迫使这些结构域与另一条链的互补结构域配对并产生两个抗原结合位点。双抗体更完整地描述于例如EP 404,097;WO 93/11161;以及Hollinger等人(1993)Proc.Natl.Acad.Sci.USA 90:6444-6448中。
“Duobody”是具有正常IgG结构的双特异性抗体(Labrijn等人,2013,Proc.Natl.Acad.Sci.USA 110(13):5145-5150)。
“Hexabody”是尽管保持常规结构和特异性但杀灭能力增加的抗体(Diebolder等人,2014,Science 343(6176):1260-3)。
“结构域抗体片段”是仅含有重链可变区或轻链可变区的具有免疫功能的免疫球蛋白片段。在一些情况下,两个或更多个VH区与肽连接子共价接合以产生二价结构域抗体片段。二价结构域抗体片段的两个VH区可以靶向相同或不同的抗原。
如本文所使用,抗体hAPRIL.01A是重链具有氨基酸序列SEQ ID NO:55并且轻链具有氨基酸序列SEQ ID NO:56的小鼠抗体。
本发明的抗体片段可以包含足够部分的恒定区以允许具有还原的二硫键性能,例如其中通常涉及重链间二硫键的至少一个铰链半胱氨酸如本文所描述而改变的重链二聚化(或多聚化)。在另一实施方案中,抗体片段,例如包含Fc区的抗体片段,保持通常至少一种与完整抗体中存在的Fc区有关的生物功能,如FcRn结合、抗体半衰期调节、抗体依赖性细胞毒性(ADCC)功能和/或补体结合(例如,其中抗体具有ADCC功能或补体结合所需的糖基化特征)。
术语“嵌合”抗体是指这样一类抗体,在这些抗体中,一部分重链及/或轻链与源自于特定物种或属于特定抗体种类或亚类的抗体中的相应序列一致或同源,而这些链的其余部分与源自于另一物种或属于另一抗体种类或亚类的抗体中的相应序列一致或同源;以及此类抗体的片段,只要其展现出所希望的生物活性(参见例如,美国专利号4,816,567;以及Morrison等人,1984,Proc.Natl.Acad.Sci.USA 81:6851-6855)。
如本文所使用,术语“人源化抗体”是指含有来自非人类(例如鼠类)抗体以及人类抗体的序列的抗体形式。此类抗体含有源自非人类免疫球蛋白的最小序列。一般来说,人源化抗体将包含至少一个且典型地两个可变结构域的基本上全部,其中所有或基本上所有高变环与非人类免疫球蛋白的高变环对应并且所有或基本上所有FR区都是人类免疫球蛋白序列的FR区。人源化抗体任选还将包含免疫球蛋白恒定区(Fc)的至少一部分,典型地是人类免疫球蛋白恒定区的至少一部分。啮齿动物抗体的人源化形式基本上包含与亲本啮齿动物抗体的相同CDR序列,不过可以包括某些氨基酸取代以增加人源化抗体的亲和力,增加稳定性或用于其它目的。
本发明的抗体还包括Fc区被修饰(或阻断)以提供改变的效应功能的抗体。参见例如,美国专利号5,624,821;WO2003/086310;WO2005/120571;WO2006/0057702;Presta,2006,Adv.Drug Delivery Rev.58:640-656。此类修饰可以用于增强或抑制免疫系统的各种反应,而且可能在诊断和疗法中具有有益作用。Fc区的变化包括氨基酸变化(取代、缺失及插入)、糖基化或去糖基化,以及添加多个Fc。使Fc变化还可以改变治疗性抗体的抗体半衰期,并且较长的半衰期将降低给药频率,同时增加便利性并减少材料的使用。参见Presta,2005,J.Allergy Clin.Immunol.116:731,第734-35页。
本发明的抗体还包括具有完整Fc区以提供完整效应功能的抗体,例如同种型IgG1抗体,这些抗体在靶细胞中诱导补体依赖性细胞毒性(CDC)或抗体依赖性细胞的细胞毒性(ADCC)。
这些抗体还可以与改善抗体在储存期间的稳定性或增加抗体的体内半衰期的分子偶联(例如共价连接)。增加半衰期的分子的实例有白蛋白(例如,人血清白蛋白)及聚乙二醇(PEG)。抗体的白蛋白连接衍生物及聚乙二醇化衍生物可以使用本领域众所周知的技术制备。参见例如,Chapman,2002,Adv.Drug Deliv.Rev.54:531-545;Anderson和Tomasi,1988,J.Immunol.Methods 109:37-42;Suzuki等人,1984,Biochim.Biophys.Acta 788:248-255;以及Brekke和Sandlie,2003,Nature Rev.2:52-62。
如本文所使用,术语“高变区”是指抗体中负责抗原结合的氨基酸残基。高变区包含通过序列比对确定的来自“互补决定区”或“CDR”的氨基酸残基,例如轻链可变结构域中的残基24-34(L1)、50-56(L2)及89-97(L3),以及重链可变结构域中的残基31-35(H1)、50-65(H2)及95-102(H3)(参见Rabat等人,1991,Sequences of proteins of ImmunologicalInterest,第5版,Public Health Service,National Institutes of Health,Bethesda,Md.),和/或通过结构确定的来自“高变环”(HVL)的氨基残基,例如轻链可变结构域中的残基26-32(L1)、50-52(L2)及91-96(L3),以及重链可变结构域中的残基26-32(H1)、53-55(H2)及96-101(H3)(参见Chothia和Leskl,1987,J.Mol.Biol.196:901-917)。
“框架”或“FR”残基是除如本文中所定义的CDR残基以外的那些可变结构域残基或序列。
根据某些实施方案,本发明的抗体可以是分离的抗体。“分离的”抗体是从其天然环境的组分鉴别并且分离和/或回收的抗体。其天然环境的污染组分是典型地干扰该多肽的诊断或治疗用途的物质,并且可以包括酶、激素及其它蛋白质或非蛋白质溶质。在一些实施方案中,抗体将纯化:(1)通过例如Lowry法测定达到以重量计超过95%,并且最优选达到以重量计超过99%的抗体;(2)达到利用转杯式测序仪足以获得N末端或内部氨基酸序列的至少15个残基的程度;或(3)使用考马斯蓝(Coomassie blue)或优选银染色,在非还原或还原条件下通过SDS-PAGE达到均质。分离的抗体包括在重组细胞内原位产生的抗体,因为该抗体天然环境中的至少一种组分将不存在。不过,分离的多肽通常是通过至少一个纯化步骤制备。
“分离的”核酸分子是经过鉴别且从在多肽核酸的天然来源中通常与其缔合的至少一种污染核酸分子分离的核酸分子。分离的核酸分子不处于其在自然界中所呈现的形式或环境中。因此,分离的核酸分子与核酸分子的区别之处在于,所述核酸分子存在于天然细胞中。然而,分离的核酸分子包括通常表达抗体的细胞中所含的核酸分子,其中例如,该核酸分子是在与天然细胞核酸分子不同的染色体位置中。
如本文所使用,术语“单克隆抗体”是指从基本上同源的抗体群获得的一种抗体,即,构成该群体的个别抗体除以微量存在的可能的天然存在的突变外是一致的。单克隆抗体针对单一抗原位点具有高度特异性。此外,与典型地包括针对不同决定基(表位)的不同抗体的常规(多克隆)抗体制剂相对,每一单克隆抗体是针对抗原上单个决定基。修饰语“单克隆”指示如从基本上同源的抗体群获得的抗体的特征,且不应理解为需要通过任何特定方法产生该抗体。举例来说,根据本发明使用的单克隆抗体可以通过Kohler等人,1975,Nature 256:495最先描述的杂交瘤法制备,或者可以通过重组DNA法制备(参见例如,美国专利号4,816,567)。“单克隆抗体”还可以使用例如Clackson等人,1991,Nature 352:624-628;以及Marks等人,1991,J.Mol.Biol.222:581-597中所描述的技术,从噬菌体抗体文库分离。本文中的单克隆抗体特别包括“嵌合”抗体。
如本文所使用,术语“免疫细胞”包括造血来源并且在免疫反应中起作用的细胞。免疫细胞包括淋巴细胞,如B细胞和T细胞;自然杀手细胞;骨髓细胞,如单核细胞、巨噬细胞、嗜酸性细胞、肥大细胞、嗜碱性细胞及粒细胞。
如本文所使用,“免疫偶联物”是指与治疗部分,如细菌毒素、细胞毒性药物或放射性毒素偶联的抗人类APRIL抗体,或其片段。毒素部分可以使用本领域中可用的方法与本发明抗体偶联。
如本文所使用,序列“变体”或“变体序列”是指与所公开的序列在一个或多个氨基酸残基处不同但保留亲本分子的生物活性的序列。本发明包括通过各种序列清楚地公开的抗体变体。对于VH结构域CDR1、CDR2及CDR3序列,根据一些实施方案,变体序列可以在CDR1、CDR2及CDR3序列中总计包含至多6个氨基酸取代,如1、2、3、4、5或6个氨基酸取代。类似地,对于VL结构域CDR1、CDR2及CDR3序列,根据一些实施方案,变体序列可以在CDR1、CDR2及CDR3序列中总计包含至多6个氨基酸取代,如1、2、3、4、5或6个氨基酸取代。
“保守修饰的变体”或“保守氨基酸取代”是指氨基酸取代是本领域技术人员已知的并且一般可以在不改变所得分子的生物活性情况下进行。本领域技术人员应认识到,一般说来,多肽非必需区中的单一氨基酸取代基本上不会改变生物活性(参见例如,Watson等人,Molecular Biology of the Gene,The Benjamin/Cummings Pub.Co.,第224页(第4版,1987))。此类示例性取代优选是根据以上表2中所陈述的那些进行。
如本文所使用,术语“约”是指一个值是在由本领域普通技术人员所测定的特定值的可接受的误差范围内,这将部分取决于该值的测量或测定方法,即,测量系统的限制。举例来说,“约”可以指根据本领域中的实践,在1或超过1个标准差范围内。或者,“约”或“基本上包含”可以指在至多20%范围内。另外,特别是就生物系统或方法来说,这些术语可以指一个值的至多一个数量级或至多5倍。当在申请和权利要求书中提供特定值时,除非另作陈述,否则“约”或“基本上包含”的含义应视为在该特定值的可接受的误差范围内。
术语“多个(种)”应理解为表示一个(种)或多个(种)。取决于其使用环境,“多个(种)”可以指选自1、2、3、4、5、6、7、8、9、10的任何适合数字。根据某些实施方案,“多个(种)”可以指“多数(a plurality)”。取决于其使用环境,“多数”可以指选自2、3、4、5、6、7 8、9、10的任何适合数字。
当提到配体/受体、抗体/抗原,或其它结合对时,“特异性”结合表示在蛋白质和/或其它生物异质群中决定蛋白质(例如APRIL)的存在的结合反应。因此,在指定条件下,指定配体/抗原结合至特定受体/抗体并且不会大量结合至样品中存在的其它蛋白质。
“施用”、“疗法”及“治疗”当用于动物、人类、实验受试者、细胞、组织、器官或生物流体时,是指外源药物、治疗剂、诊断剂或组合物与该动物、人类、受试者、细胞、组织、器官或生物流体的接触。“施用”、“疗法”及“治疗”可以指例如治疗方法、药物动力学方法、诊断方法、研究方法及实验方法。细胞的治疗包含一种试剂与该细胞接触,以及一种试剂与一种流体接触,其中该流体与该细胞接触。“施用”、“疗法”及“治疗”还指一种试剂、诊断剂、结合组合物和/或细胞对另一细胞的体外和离体治疗。在本发明的本说明内,术语“体外”和“离体”具有类似含义并且可以互换使用。
也可以例如通过用人类重链和轻链恒定结构域的编码序列取代同源鼠类序列(美国专利号4,816,567;Morrison等人,1984,Proc.Natl Acad.Sci.USA,81:6851),或通过将非免疫球蛋白物质(例如蛋白质结构域)的全部或一部分编码序列与免疫球蛋白编码序列共价接合来修饰抗体DNA。典型地,用所述非免疫球蛋白材料取代抗体的恒定结构域,或者用其取代抗体一个抗原组合位点的可变结构域,由此产生一个抗原组合位点对一种抗原具有特异性并且另一个抗原组合位点对不同抗原具有特异性的嵌合二价抗体。
本发明的抗人类APRIL抗体的氨基酸序列变体是通过将适当核苷酸变化引入编码DNA中或通过肽合成制备。此类变体包括例如所示抗APRIL抗体的氨基酸序列内残基的缺失,和/或插入,和/或取代。可进行缺失、插入及取代的任何组合以获得最终构建体,只要最终构建体具有所希望的特征。氨基酸变化也可以改变抗APRIL抗体的翻译后加工,如改变糖基化位点的数目或位置。
用于鉴别抗APRIL抗体中作为优选诱变位置的某些残基或区域的一种有用方法称为“丙氨酸扫描诱变”,如Cunningham及Wells,1989,Science 244:1081-1085所述。此处,鉴别一个残基或一组靶残基(例如,带电残基,如Arg、Asp、His、Lys及Glu)并用呈中性或带负电的氨基酸(最优选丙氨酸或聚丙氨酸)置换来影响抗体与APRIL抗原的相互作用。然后,通过将另外或其它变体引入取代位点处或用于取代位点来改进对取代展示功能性敏感性的氨基酸残基。因此,尽管引入氨基酸序列变异的位点是预定的,但突变本身的性质不必是预定的。举例来说,为了分析给定位点处突变的性能,在靶密码子或区域处进行Ala扫描或随机诱变并针对所希望的活性筛选所表达的抗APRIL抗体的变体。
通常,抗APRIL抗体的氨基酸序列变体将具有与初始抗体的重链或轻链氨基酸序列具有至少75%,更优选至少80%,更优选至少85%,更优选至少90%,并且最优选至少95%、98%或99%序列相似性的氨基酸序列。关于这一序列的相似性或同源性如上文所定义。
可以针对体外生物活性增加或适合结合亲和力筛选具有本文标识为合乎需要的特征的抗体。为了筛选与hAPRIL.01A结合至人类APRIL上相同表位的抗体,可以进行常规交叉阻断测定,如Antibodies,A Laboratory Manual,Cold Spring Harbor Laboratory,Harlow和David Lane编(1988)中所述的测定。结合至该相同表位的抗体可能在此类测定中交叉阻断,但并非所有交叉阻断抗体都必定精确地结合该相同表位,因为交叉阻断可能是由在重叠表位处或甚至是非重叠表位附近的抗体结合对抗体结合的空间阻碍引起。
或者,可以进行表位定位,例如Champe等人,1995,J.Biol.Chem.270:1388-1394中所描述,以确定抗体是否结合至所关注表位。还可以使用Cunningham和Wells,1989,Science 244:1081-1085所描述的“丙氨酸扫描诱变”,或针对人类APRIL中氨基酸残基的一些其它形式的点诱变确定本发明抗APRIL抗体的功能表位。
如Slootstra等人(Slootstra等人,1996,Mol.Diversity 1:87-96)和Timmerman等人(Timmerman等人,2007,J.Mol.Recognit.20:283-299)所描述,定位抗体表位的另一方法是研究抗体与合成线性CLIPS肽的结合,这些肽可以使用信用卡形式的小型PEPSCAN卡筛选。所述抗体与每种肽的结合是在基于PEPSCAN的酶联免疫测定(ELISA)中测定。
与hAPRIL.01A结合至相同表位的额外抗体可以例如通过关于与该表位的结合来筛选针对APRIL的抗体,或通过用包括含所述表位序列的人类APRIL片段的肽对动物进行免疫来获得。预期结合至该相同功能表位的抗体可能展现类似的生物活性,如类似的APRIL结合以及BCMA和TACI阻断活性,并且此类活性可以通过抗体功能测定来确定。
所述抗体可以选自任何种类的免疫球蛋白,包括IgM、IgG、IgD、IgA及IgE。优选该抗体是IgG抗体。可以使用任何IgG同种型,包括IgG1、IgG2、IgG3及IgG4。也涵盖IgG同种型的变体。该抗体可以包含来自超过一种类别或同种型的序列。通过在实施例中所描述的生物测定中筛选抗体,易于优化必要的恒定结构域序列以产生所希望的生物活性。
同样,在本文中的组合物和方法中可以使用任一类别的轻链。具体地说,κ、λ或其变体可用于本发明组合物和方法中。
本发明的抗体和抗体片段还可以与如细胞毒性剂等细胞毒性有效负载,或如99Tc、90Y、111In、32P、14C、125I、3H、131I、11C、15O、13N、18F、35S、51Cr、57To、226Ra、60Co、59Fe、57Se、152Eu、67Cu、217Ci、211At、212Pb、47Sc、109pd、234Th和40K、157Gd、55Mn、52Tr及56Fe等放射性核苷酸偶联。此类抗体偶联物可以用于免疫疗法中以选择性靶向并杀灭表达在表面上表达靶(该抗体的抗原)的细胞。示例性细胞毒性剂包括蓖麻毒素、长春生物碱、甲氨蝶呤(methotrexate)、假单胞菌内毒素、皂草素、白喉毒素、顺铂、多柔比星、相思豆毒素、白树毒苏及美洲商路抗病毒蛋白。
本发明的抗体和抗体片段还可以与荧光或化学发光标记偶联,包括荧光团,如稀土螯合物、荧光素和其衍生物、罗丹明(rhodamine)和其衍生物、异硫氰酸酯、藻红素、藻蓝蛋白、别藻蓝蛋白、邻苯二甲醛、荧光胺、152Eu、丹磺酰基、伞形酮、虫荧光素、鲁米那标记(1uminal label)、异鲁米那标记、芳香族吖啶酯标记、咪唑标记、吖啶盐标记、草酸酯标记、水母蛋白标记、2,3-二氢酞嗪二酮、生物素/抗生物素蛋白、自旋标记及稳定自由基。
本领域已知用于将本发明的抗体分子或蛋白质分子与各种部分偶联的任何方法都可以使用,包括Hunter等人,1962,Nature 144:945;David等人,1974,Biochemistry 13:1014;Pain等人,1981,J.Immunol.Meth.40:219;以及Nygren,J.,1982,Histochem.andCytochem.30:407众所描的那些方法。用于偶联抗体和蛋白质的方法是本领域中的常规方法并且是众所周知的。
抗体纯化
当使用重组技术时,可以在细胞内,在周质空间中产生抗体,或将抗体直接分泌至培养基中。如果是在细胞内产生抗体,那么作为第一个步骤,通过例如离心或超滤来去除宿主细胞或溶解的片段的颗粒状碎片。Carter等人,1992,Bio/Technology 10:163-167描述了用于分离抗体的程序,这些抗体被分泌至大肠杆菌的周质空间中。简而言之,在乙酸钠(pH 3.5)、EDTA及苯甲基磺酰氟(PMSF)存在下经约30分钟解冻细胞糊。细胞碎片可以通过离心去除。在将抗体分泌到培养基中的情况下,一般首先使用可商购的蛋白质浓缩过滤器,例如Amicon或Millipore Pellicon超滤单元,对来自这些表达系统的上清液进行浓缩。在任一前述步骤中可以包括蛋白酶抑制剂,如PMSF,以抑制蛋白水解,并且可以包括抗生素以防止外来污染物的生长。
由细胞制备的抗体组合物可以使用例如羟磷灰石色谱法、凝胶电泳、透析及亲和色谱法纯化,其中亲和色谱法是优选的纯化技术。蛋白质A作为亲和配体的适合性取决于抗体中存在的任何免疫球蛋白Fc区的物种和同种型。蛋白质A可以用于纯化基于人类Igγ1、Igγ2或Igγ4重链的抗体(Lindmark等人,1983,J.Immunol.Meth.62:1-13)。蛋白质G被推荐用于所有小鼠同种型和人类γ3(Guss等人,1986,EMBO J 5:1567-1575)。亲和配体所附接的基质最常见是琼脂糖,但其它基质也是可用的。
相较于用琼脂糖可以达到的速率和时间,机械稳定的基质,如可控孔度玻璃或聚(苯乙烯二乙烯基)苯允许较快的流动速率及较短的加工时间。在抗体包含CH3结构域的情况下,Bakerbond ABXTM树脂(J.T.Baker,Phillipsburg,N.J.)可用于纯化。取决于有待回收的抗体,用于蛋白质纯化的其它技术,如在离子交换柱上分级分离、乙醇沉淀、反相HPLC、在二氧化硅上进行的色谱法、在肝素上进行的色谱法、在阴离子或阳离子交换树脂(如聚天冬氨酸柱)上进行的SEPHAROSETM色谱法、色谱聚焦、SDS-PAGE及硫酸铵沉淀也可使用。
在一个实施方案中,可以通过吸附至凝集素基质(例如凝集素亲和柱)上以去除制剂中含果糖的糖蛋白并由此富集无果糖的糖蛋白,从而纯化得到糖蛋白。
药物配制物
本发明包含抗人类ARPIL抗体的药物配制物。为了制备药物组合物或无菌组合物,将抗体,特别是抗体或其片段与药学上可接受的载剂或赋形剂混合,参见例如,Remington′s Pharmaceutical Sciences and U.S.Pharmacopeia:National Formulary,MackPublishing Company,Easton,PA(1984)。的配制物可以通过将治疗剂和诊断剂与生理学上可接受的载剂、赋形剂或稳定剂混合来制备呈例如冻干粉、浆液、水溶液或悬浮液形式的配制物(参见例如,Hardman等人,2001,Goodman and Gilman′s The Pharmacological Basisof Therapeutics,McGraw-Hill,New York,NY;Gennaro,2000,Remington:The Scienceand Practice of Pharmacy,Lippincott,Williams,及Wilkins,New York,NY;Avis等人(编),1993,Pharmaceutical Dosage Forms:Parenteral Medications,Marcel Dekker,NY;Lieberman等人(编),1990,Pharmaceutical Dosage Forms:Tablets,Marcel Dekker,NY;Lieberman等人(编),1990,Pharmaceutical Dosage Forms:Disperse Systems,MarcelDekker,NY;Weiner及Kotkoskie,2000,Excipient Toxicity and Safety,Marcel Dekker,Inc.,New York,NY)。
单独或与另一药剂,如常用抗癌药组合施用的抗体组合物的毒性和治疗功效可以通过例如用于测定LD50(使群体的50%死亡的剂量)和ED50(在群体的50%中治疗有效的剂量)的标准药物程序,在细胞培养物或实验动物中测定。有毒作用与治疗作用之间的剂量比率是治疗指数并且其可以表示为LD50与ED50之间的比率。由这些细胞培养物测定和动物研究得到的数据可以用于配制用于人类的一系列剂量。此类化合物的剂量优选在包括ED50在内并具有极少或无毒性的一系列循环浓度范围内。取决于所用剂型和所用施用途径,该剂量可以在此范围内变化。
适合施用途径包括肠胃外施用,如肌肉内、静脉内或皮下施用;以及口服施用。施用本发明的药物组合物中使用的抗体或施用抗体以实践本发明的方法可以按多种常规方式进行,如口服摄取、吸入、外敷或皮肤、皮下、腹膜内、肠胃外、动脉内或静脉内注射。在一个实施方案中,本发明的抗体是静脉内施用的。在另一个实施方案中,本发明的抗体是皮下施用的。
或者,可以通过局部而非全身方式,例如经由将抗体直接注射至作用部位中来施用抗体,该抗体通常呈积存式或持续释放配制物形式。另外,可以通过靶向药物递送系统来施用抗体。
有关选择抗体、细胞因子及小分子的适合剂量的指导是易于得到的(参见例如,Wawrzynczak,1996,Antibody Therapy,Bios Scientific Pub.Ltd,Oxfordshire,UK;Kresina(编),1991,Monoclonal Antibodies,Cytokines and Arthritis,Marcel Dekker,New York,NY;Bach(编),1993,Monoclonal Antibodies and Peptide Therapy inAutoimmune Diseases,Marcel Dekker,New York,NY;Baert等人,2003,NewEngl.J.Med.348:601-608;Milgrom等人,1999,New Engl.J.Med.341:1966-1973;Slamon等人,2001,New Engl.J.Med.344:783-792;Beniaminovitz等人,2000,New Engl.J.Med.342:613-619;Ghosh等人,2003,New Engl.J.Med.348:24-32;Lipsky等人,2000,NewEngl.J.Med.343:1594-1602)。
适当剂量是由临床医师,例如使用本领域中已知或怀疑会影响治疗或预测会影响治疗的参数或因子来决定。一般来说,剂量是以略低于最佳剂量的量开始,并且随后以较小增量增加,直至相对于任何不良副作用,实现所希望的或最佳的作用。重要的诊断措施包括例如炎症的症状或所产生的炎性细胞因子的含量。
优选的剂量方案是涉及避免明显不希望的副作用的最大剂量或剂量频率的方案。总每周剂量一般是至少0.05μg/kg体重,更一般是至少0.2μg/kg,最一般是至少0.5μg/kg,典型地是至少1μg/kg,更典型是至少10μg/kg,最典型是至少100μg/kg,优选是至少0.2mg/kg,更优选是至少1.0mg/kg,最优选是至少2.0mg/kg,最佳是至少10mg/kg,更佳是至少25mg/kg,并且最佳是至少50mg/kg(参见例如,Yang等人,2003,New Engl.J.Med.349:427-434;Herold等人,2002,New Engl.J.Med.346:1692-1698;Liu等人,1999,J.Neurol.Neurosurg.Psych.67:451-456;Portielji等人,2003,Cancer.Immunol.Immunother.52:133-144)。以mol/kg计,小分子治疗剂,例如肽模拟物、天然产物或有机化学试剂的所需剂量与抗体或多肽大致相同。
如本文所使用,“抑制”或“治疗(treat/treatment)”包括疾病相关症状发生的延缓和/或将伴随所述疾病发生或预期会与所述疾病一起发生的此类症状的严重程度降低。这些术语另外包括改善现有症状、防止额外症状,以及改善或防止此类症状的潜在病因。因此,这些术语表示,使患有疾病的脊椎动物受试者获得有益结果。
用于治疗目的的本发明抗体是以治疗有效量施用。如本文所使用,术语“治疗有效量”或“有效量”是指当单独或与额外治疗剂组合施用至细胞、组织或受试者时有效防止或改善呆治疗疾病或病症的抗ARPIL抗体或其片段的量。治疗有效剂量还指足以引起症状改善,例如治疗、治愈、预防或改善相关医学病状,或使此类病症的治疗、治愈、预防或改善率增加的化合物的量。当应用于单独施用的个别活性成分时,治疗有效剂量仅指所述成分。当应用于组合时,治疗有效剂量是指引起治疗作用的各活性成分的组合量,不管是依序还是同时组合施用。有效量的治疗剂将使症状典型地减少至少10%;通常减少至少20%;优选减少至少约30%;更优选至少40%;并且最优选至少50%。
有关共施用第二治疗剂或用第二治疗剂治疗的方法是本领域中众所周知的,参见例如,Hardman等人,(编),2001,Goodman and Gilman′s The Pharmacological Basis ofTherapeutics,第10版,McGraw-Hill,New York,NY;Poole和Peterson(编),2001,Pharmacotherapeutics for Advanced Practice:A Practical Approach,Lippincott,Williams&Wilkins,Phila.,PA;Chabner and Longo(编),2001,Cancer Chemotherapy andBiotherapy,Lippincott,Williams&Wilkins,Phila.,PA。
本发明的药物组合物还可以含有其它药剂,包括但不限于,细胞毒性剂、化学治疗剂、细胞抑制剂、抗血管生成剂或抗代谢物剂、肿瘤靶向剂、免疫刺激剂或免疫调节剂,或与细胞毒性剂、细胞抑制剂或其它毒性剂偶联的抗体。该药物组合物也可以与其它治疗方法,如手术、化学疗法及放射一起使用。
现将参照以下非限制性实验进一步说明并支持本发明。
实验
实验1
抗ARPIL人源化抗体设计
CDR移植
先前已鉴别出结合人类APRIL的独特抗体hAPRIL.01A(WO2010/100056)。通过CDR移植技术使小鼠hAPRIL.01A抗体人源化(参见例如,美国专利号5,225,539;以及Williams,D.G.等人,2010,Antibody Engineering,第1卷,第21章)。在所设计的策略中,首先使用IgBLAST鉴别人类生殖系序列(Ye J.等人,2013,Nucleic Acids Res.41:W34-40)。对于hAPRIL.01A VH,鉴别人类生殖系序列IGHV1-3*01(70.4%一致性),并且对于hAPRIL.01AVL,鉴别人类生殖系序列IGKV1-16*01(65.3%一致性)。
接下来,构建含有IMGT数据库(发布201222-4:161905个条目,索引2012-6-04)中可得到的所有人类成熟序列的数据库(Lefranc,M.-P.等人,1999,Nucleic Acid Res.27:209-212),标识出90,401个独立序列。使用TBLASTN(2.2.26+)查询这些序列以鉴别与hAPRIL.01A VH和VL序列展示最高一致性的模板序列(分别是SEQ ID 3和4)。选择三个VH序列和七个VL序列,这些序列分别与hAPRIL.01A VH CDR1、CDR2、CDR3(SEQ ID.5-7)及VLCDR1、CDR2及CDR3(SEQ ID.8-10)显示80%或更高的相似性评分并且展示类似,优选一致的CDR长度。
对于重链,选择由GenBank(Benson,D.A.等人,2013,Nucleic Acids Res.41(D1):D36-42)登记号AF022000、AB363149及AB063827编码的框架用于直接移植hAPRIL.01A VHCDR,分别产生以下cDNA构建体:SEQ ID.11、13及15。对于轻链,选择由GenBank登记号AX375917、DD272023、AB363267、AJ241396、DI152527及DQ840975编码的框架用于直接移植hAPRIL.01A VL CDR,分别产生以下cDNA构建体:SEQ ID.19、21、23、25、27及29。
基于通过比对来自TBLASTN结果的25个最佳匹配序列(E值5e-46至9e-43)得到的共同序列,设计额外重链序列,得到以下cDNA构建体:SEQ ID 17。
为了确定框架残基人源化的结构影响,使用WHATIF制备hAPRIL.01A抗体同源物模型(Krieger E.等人,2003,Methods Biochem Anal.44:509-23)。使用蛋白质数据库(www.rcsb.org,2012年6月发布;Berman H.M.等人,2000,Nucleic Acids Res.28:235-242),通过BLASTP搜索(Altschul,S.F.等人,1990,J.Mol.Biol.215:403-410)分别鉴别出VH和VL链的模板2GKI(Kim Y.R.等人,2006,J.Biol.Chem.281:15287-15295)和2AEQ(Venkatramani L.等人,2006,J.Mol.Biol.356:651-663)。使用由2AEQ模板引导的MUSTANG比对(Konagurthu A.S.等人,2006,Proteins 64:559-574),将VH和VL链组合成Fab片段形式。使用所构建的hAPRIL.01A同源物模型选择受人源化影响并且能影响人源化构建体的功能的残基并评价是否置换所选残基:对于六个VL模板(VL15),决定用较小的S49和F87置换VL残基Y49和Y87。
信号肽鉴别
使用NCBI IgBlast(BLASTN)(Ye J.等人,2013,Nucleic Acids Res.41(WebServer issue):W34-40)鉴别,匹配小鼠hAPRIL.01A VH和VL的人类生殖系谱系并使用其选择VH和VL的分泌前导序列:VH,基于生殖系IGHV1-3*01(NCBI登记号X62107),以及VL,基于生殖系IGKV16*01(NCBI登记号X62109)。使用以下由SEQ ID NO:57编码的VH分泌前导序列“MDWTWRILFLVAAATGAHS”(SEQ ID NO:58)及由SEQ ID NO:59编码的VL分泌前导序列“MDMRVLAQLLGLLLLCFPGARC”(SEQ ID NO:60)表达所有人源化VH和VL构建体。
产生具有稳定Adair突变的IgG4形式人源化抗体(Angal S.等人,1993,MolImmunol.30:105-108),其中丝氨酸241(Kabat编号)转变成脯氨酸。
实验2
合成、亚克隆、表达、结合
合成
使用OptGene软件(2.0.6.0版)对编码人源化VH和VL构建体的cDNA,SEQ ID 11、13、15、17、21、23、25、27、29进行密码子优化,并由Baseclear进行化学合成。接着,使用5′-HindIII和3′-ApaI(VH)或3′-BsiWI(VL)限制性内切核酸酶裂解位点将序列克隆至pUC57载体(BaseClear)中。
亚克隆
使用以上提到的限制性内切核酸酶裂解位点,将人类VH构建体克隆至含有已经克隆至EcoRI和HindIII限制性内切核酸酶裂解位点中的人类IgG4恒定结构域(CH1-CH3,GenBank登记号K01316)的pcDNA3.1(+)载体(Invitrogen)中。使用以上提到的限制性内切核酸酶裂解位点,将人类VL构建体克隆至含有已经克隆至HindIII和EcoRI限制性内切核酸酶裂解位点中的人类CL(κ)结构域(GenBank登记号J00241)的pcDNA3.1(+)载体(Invitrogen)中。使用制造商的说明,在亚克隆有效DH5α感受态细胞(Invitrogen)中转化构建体。根据制造商的方案,使用Qiagen Plasmid Midi试剂盒(QIAGEN)分离质粒DNA。利用DNA测序(Macrogen)确定构建体的完整性。
表达和结合
以1∶3比率(总计4μg)混合编码VH和VL构建体的质粒,并通过遵循制造商的说明,使用Lipofectamine 2000转染试剂(Invitrogen)将这些质粒转染至HEK293T人类胚胎肾细胞(HEK293T/17,ATCC-CRL-11268)中来进行短暂表达。5天后收集细胞上清液并使用酶联免疫测定(ELISA)测试抗体的表达及与APRIL的结合。在这些ELISA中,所有培育步骤之后都是用PBST(含0.01%吐温20的PBS)洗涤的步骤。用0.5μg/ml抗FLAG(Sigma)或抗IgG4(Jacksonlaboratories)涂布Maxisorb 96孔板(Nunc)并在4℃下培育过夜。随后,将涂有抗FLAG的96孔板与FLAG标记的人类APRIL一起在室温下培育1小时。接下来,培育上清液及其稀释液1小时,随后将其与小鼠抗人类IgG HRP偶联物(Southern Biotechnology)一起培育1小时。
用100μl TMB稳定的生色团(Invitrogen)观测免疫反应性。用100μl的0.5M H2SO4停止反应并在450nm和620nm下测量吸光度。
实验3
纯化和稳定性
纯化
选择一小组以上描述的人源化抗体进行进一步分析。再次,以1∶3比率(32μg)混合编码VH和VL构建体的质粒,并通过遵循制造商的说明,使用Lipofectamine 2000转染试剂(Invitrogen)将这些质粒转染至(8*106个)HEK293T人类胚胎肾细胞(HEK293T)中来进行短暂表达。收集上清液(10ml)并根据制造商的说明,使用MabSelect Sure蛋白质A树脂(GEHealthcare)纯化抗体。使用Zeba脱盐柱(Thermo Scientific)将缓冲液交换成PBS。基于OD280(Nanodrop ND-1000)测定纯化抗体的浓度。使用以上描述的APRIL ELISA确定纯化抗体与APRIL的结合。在竞争ELISA中测试人源化抗体阻断与BCMA和TACI受体结合的能力。在这些ELISA中,所有培育步骤之后都是用PBST(含0.01%吐温20的PBS)洗涤的步骤。用0.5μg/ml Fc-BCMA(R&D Systems)或Fc-TACI(R&D Systems)涂布Maxisorb 96孔板(Nunc)并在4℃下培育过夜。随后,将与FLAG标记的APRIL预混合的人源化抗体及其稀释液培育1小时,接着与抗FLAG HRP偶联物(Sigma)一起培育1小时。用100μl TMB稳定的生色团(Invitrogen)观测免疫反应性。用100μl的0.5M H2SO4停止反应并在450nm和620nm下测量吸光度。代表使得观察到总结合信号的50%或阻断的浓度的EC50和IC50计算值呈现于表5中。
表5:EC50值,结合至ARPIL。IC50,阻断ARPIL与BCMA-Fc的结合。在每次ELISA中都使用C4-hAPRIL.01A作为实验参照物。
n.c.指示有抑制作用,但由于拟合不当而无法计算出IC50。
VH.VL组合 | EC50(nM) | IC50(nM) |
C4-hAPRIL.01A | 5.7 | 7.6 |
VH11.VL15 | 120.8 | 4.3 |
VH12.VL15 | 19.8 | n.c. |
VH13.VL15 | 223.4 | n.c. |
VH14.VL15 | 48.3 | n.c. |
对于阻断ARPIL与TACI-Fc的结合,观察到类似的阻断作用。
意外的是,VH11-VH14与VL10-VL14的组合不显示纳摩尔浓度或微摩尔浓度的EC50值,而且只有所选VH框架序列与VL15框架序列的组合才产生具有功能性ARPIL结合特性的抗体。
稳定性
为了测定人源化对抗体稳定性的影响,使人源化抗体暴露于一系列温度,保持10分钟。在PBS中将纯化的抗体稀释至3.16μg/ml并得到其稀释液。接着,使这些溶液暴露于65℃或70℃,并如先前所述,使用FLAG标记的APRIL ELISA测定法测量在热处理之后抗体的残基结合情况(参看表6)。
表6:利用ELISA测定的(人源化)抗体与FLAG-APRIL的残基结合情况。结合作用是以三种浓度测量:3.16μg/ml、1μg/ml及0.316μg/ml。在65℃或70℃下的结合%表示为在室温下(=100%)所观察的每种抗体的结合%。
实验4
通过回复突变和微调残基改善结合作用、阻断作用及稳定性
通过回复突变改善结合和阻断作用
对序列和结构水平进行分析以了解有关结合和阻断不同VH/VL组合的差异的分子基础。如先前所述,制备人源化抗体同源物模型。针对VH和VL选择的模板是3HC4(JordanJ.L.等人,2009,Proteins 77:832-841)。通过仔细地分析所建立的模型,本发明的发明人推断,所选VH链中的残基S72对于CDR2环取向至关重要。为了研究这一推断,在VH 14中引入突变R72S,产生由核苷酸序列SEQ ID 31编码的VH 14_1,即SEQ ID 32。如先前所述,测试抗体14_1.15的结合和阻断作用。如表7中所示,相对于表5中所示的抗体14.15的结合,抗体14_1.15的结合和阻断作用都有所改善。
表7:抗体14_1.15结合至APRIL并阻断APRIL与BCMA-Fc的结合。在每次ELISA中都使用hAPRIL.01A和C4-hAPRIL.01A作为实验参照物。
VH.VL组合 | EC50(nM) | IC50(nM) |
VH14_1.VL15 | 1.29±0.16 | 2.63±0.55 |
C4-hAPRIL.01A | 0.35±0.13 | 0.77±0.22 |
hAPRIL.01A | 0.16±0.14 | 0.46±0.35 |
对于阻断ARPIL与TACI-Fc的结合,获得类似的IC50值。
微调残基
对序列和结构水平进行分析以进一步改善抗体14_1.15的结合和阻断作用。如先前所述,制备此人hAPRIL.01A类似物的同源物模型。所选模板对于VH链是2GKI并且对于VL链是4GMT(Lee P.S.等人,2012,PNAS 109:17040-17045),在模板2AEQ引导下组合成Fab片段形式。
对接近于CDR的残基进行详细研究,因为这些残基可能影响环构象。在本分析中,发明人鉴别出多个潜在相关的微调残基(Vernier residue)(Foote J.等人,1992,J.Mol.Biol.224:487-499)。为了评价其相关性,用小鼠氨基酸对其进行取代。
引入突变M70I产生VH14_1C(SEQ ID 33、34),突变T74K存在于VH14_1D(SEQ ID35、36)中,并且突变Q1E产生VH14_1E(SEQ ID 37、38)。R67K和V68A的组合突变产生VH 14_1G,即SEQ ID 39、40。如先前所述,测试这些抗体的结合作用、阻断作用及稳定性。如表8中所示,意外的是,结合和阻断作用有2至3倍的改善。具体地说,在抗体VH14_1G.VL15中引入突变意外地呈现相当大的改善。
表8:抗体14_1.15和微调区突变体的结合和阻断作用。在每次ELISA中都使用hAPRIL.01A作为实验参照物。
此外,如使用实施例3中所描述的热稳定性研究所测定,被取代的人源化抗体的稳定性也有所改善(参见表9)。
表9:利用ELISA测定的(人源化)抗体与FLAG-APRIL的残基结合情况。结合作用是以三种浓度测量:3.16μg/ml、1μg/ml及0.316μg/ml。在65℃或70℃下的%结合表示为在室温下(=100%)所观察的每种抗体的%结合。
实验5
14 1G.15展示更有效的体内抑制作用.
为了展示APRIL类似物抗体对APRIL功能的体内阻断作用,对这些抗体阻断NP-Ficoll诱导的小鼠体液反应的能力进行检查。所用小鼠是8-10周龄的APRIL转基因(TG)小鼠及野生型(WT)同窝仔畜,都是基于C57BL/6背景。APRIL转基因小鼠中Lck远端启动子下表达人类APRIL,该启动子引导转基因表达成为成熟胸腺细胞和周围T淋巴细胞(Stein等人,2002,J Clin Invest 109,1587-98)。小鼠是在Academic Medical Center的动物设施中饲养并且实验得到研究机构伦理委员会的批准。将小鼠分成若干组并处理如下:WT小鼠用PBS(200μ1)处理并且3组APRIL转基因小鼠用以下分子处理:hAPRIL.01A或14_1G.15(在第-1天和第3天,含200μg/小鼠的200μl PBS)或PBS。第0天,用NP-Ficoll对小鼠进行免疫(第0天;100μl i.p.,含250μg免疫原)。在第-1天、第3天、第7天、第10天,经尾静脉收集血液。如先前所描述(Hardenberg等人,Immunol Cell Biol,86(6):530-4,(2008);Guadagnoli等人,2011,Blood 117(25):6856-65),使用稀释血清,通过ELISA测定抗(4-羟基-硝基苯乙酰基)(NP)特异性抗体(IgM、IgG及IgAa/2)。简而言之,在4℃下用含5μg/ml NP-BSA(BiosearchTechnologies)的碳酸钠缓冲液(pH9.6)涂布96孔ELISA板(Greiner)过夜。在37℃下用1%BSA阻断各孔1小时并将其与稀释血清在室温下培育2小时。使用HRP偶联的同种型特异性抗体(山羊抗小鼠IgG、IgA及IgM;来自Southern Biotech)作为揭示抗体(revealingantibody)。所有稀释液都在PBS/BSA 1%/吐温20 0.05%中制备。从图1可知,hAPRIL.01A和14_1G.15都在体内抑制不依赖T细胞的B细胞反应。hAPRIL.01A抑制此反应的有效性不如14_1G.15。PBS和作为同种型相配的对照的IgG1不影响IgA、IgM及IgG抗NP反应。
序列表
<110> Aduro Biotech Holdings, Europe B.V.
<120> 改良的APRIL结合抗体
<130> 0
<160> 60
<170> BiSSAP 1.2
<210> 1
<211> 363
<212> DNA
<213> 小家鼠
<220>
<221> 来源
<222> 1..363
<223> /分子类型="未指定的DNA"
/生物体="小家鼠"
<400> 1
gaggtccagt tgcagcagtc tggacctgag ctggtaaagc ctggggcttc agtgaagatg 60
tcctgcaagg cttctggata cacattcact agctatgtga tgcactgggt gaagcagaag 120
cctgggcagg gccttgagtg gattggatat attaatcctt ataatgatgc tcctaaatac 180
aatgagaagt tcaaaggcaa ggccacagtg acttcagaca agtcctccgg cacagcctac 240
atggagctca gcagcctgac ctctgaggac tctgcggtct attactgtgc aaggggcttg 300
ggttacgccc tttactatgc tatggactac tggggtcaag gaacctcagt caccgtctcc 360
tca 363
<210> 2
<211> 321
<212> DNA
<213> 小家鼠
<220>
<221> 来源
<222> 1..321
<223> /分子类型="未指定的DNA"
/生物体="小家鼠"
<400> 2
gacattgtga tgacccagtc tcaaaaattc aagtccacat cagtaggaga cagggtcagc 60
gtcacctgca aggccagtca gaatgtgggt aataatgtag cctggtatca acagaaagca 120
gggcaatctc ctaaagcact gatttcctcg gcatccaacc gtgacagtgg agtccctgat 180
cgcttcacag gcagtggatc tgggacagat ttcactctca ccatcagcaa tgtgcagtct 240
gaagacttgg cagactattt ctgtcagcaa tataacatct atccattcac gttcggctcg 300
gggacaaagt tggaaataaa a 321
<210> 3
<211> 121
<212> PRT
<213> 小家鼠
<400> 3
Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Val Met His Trp Val Lys Gln Lys Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Asn Pro Tyr Asn Asp Ala Pro Lys Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Lys Ala Thr Val Thr Ser Asp Lys Ser Ser Gly Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Leu Gly Tyr Ala Leu Tyr Tyr Ala Met Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Ser Val Thr Val Ser Ser
115 120
<210> 4
<211> 107
<212> PRT
<213> 小家鼠
<400> 4
Asp Ile Val Met Thr Gln Ser Gln Lys Phe Lys Ser Thr Ser Val Gly
1 5 10 15
Asp Arg Val Ser Val Thr Cys Lys Ala Ser Gln Asn Val Gly Asn Asn
20 25 30
Val Ala Trp Tyr Gln Gln Lys Ala Gly Gln Ser Pro Lys Ala Leu Ile
35 40 45
Ser Ser Ala Ser Asn Arg Asp Ser Gly Val Pro Asp Arg Phe Thr Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Asn Val Gln Ser
65 70 75 80
Glu Asp Leu Ala Asp Tyr Phe Cys Gln Gln Tyr Asn Ile Tyr Pro Phe
85 90 95
Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 5
<211> 8
<212> PRT
<213> 小家鼠
<400> 5
Gly Tyr Thr Phe Thr Ser Tyr Val
1 5
<210> 6
<211> 16
<212> PRT
<213> 小家鼠
<400> 6
Tyr Ile Asn Pro Tyr Asn Asp Ala Pro Lys Tyr Asn Glu Lys Phe Lys
1 5 10 15
<210> 7
<211> 12
<212> PRT
<213> 小家鼠
<400> 7
Gly Leu Gly Tyr Ala Leu Tyr Tyr Ala Met Asp Tyr
1 5 10
<210> 8
<211> 11
<212> PRT
<213> 小家鼠
<400> 8
Lys Ala Ser Gln Asn Val Gly Asn Asn Val Ala
1 5 10
<210> 9
<211> 7
<212> PRT
<213> 小家鼠
<400> 9
Ser Ala Ser Asn Arg Asp Ser
1 5
<210> 10
<211> 10
<212> PRT
<213> 小家鼠
<400> 10
Gln Gln Tyr Asn Ile Tyr Pro Phe Thr Phe
1 5 10
<210> 11
<211> 363
<212> DNA
<213> 人工序列
<220>
<221> 来源
<222> 1..363
<223> /分子类型="未指定的DNA"
/注释="工程改造的免疫球蛋白VH序列"
/生物体="人工序列"
<400> 11
caggtccagc ttgtgcagtc tggggctgag gtgaagaagc ctggggcctc agtgaaggtt 60
tcctgcaagg cttctggata cacattcact agctatgtga tgcattgggt gcgccaggcc 120
cccggacaaa ggcttgagtg gatgggatat attaatcctt ataatgatgc tcctaaatac 180
aatgagaagt tcaaaggcag agtcaccatt accagggaca catccgcgag cacagcctac 240
atggagctga gcagcctgag atctgaagac acggctgtgt attactgtgc gagaggcttg 300
ggttacgccc tttactatgc tatggactac tggggccaag ggaccacggt caccgtctcc 360
tca 363
<210> 12
<211> 121
<212> PRT
<213> 人工序列
<220>
<223> 工程改造的免疫球蛋白VH序列
<400> 12
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Val Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
35 40 45
Gly Tyr Ile Asn Pro Tyr Asn Asp Ala Pro Lys Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Arg Val Thr Ile Thr Arg Asp Thr Ser Ala Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Leu Gly Tyr Ala Leu Tyr Tyr Ala Met Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Thr Val Thr Val Ser Ser
115 120
<210> 13
<211> 363
<212> DNA
<213> 人工序列
<220>
<221> 来源
<222> 1..363
<223> /分子类型="未指定的DNA"
/注释="工程改造的免疫球蛋白VH序列"
/生物体="人工序列"
<400> 13
caggtccagc ttgtgcagtc tggggctgag gtgaagaagc ctggggcctc agtgaaggtc 60
tcctgcaagg cttctggata cacattcact agctatgtga tgcactgggt gcgacaggcc 120
cctggacaag ggcttgagtg gatgggatat attaatcctt ataatgatgc tcctaaatac 180
aatgagaagt tcaaaggcag ggtcaccatg accagggaca cgtccatcag cacagcctac 240
atggagctga gcaggctgag atctgacgac acggccgtgt attactgtgc gagaggcttg 300
ggttacgccc tttactatgc tatggactac tggggccaag ggaccacggt caccgtctcg 360
agc 363
<210> 14
<211> 121
<212> PRT
<213> 人工序列
<220>
<223> 工程改造的免疫球蛋白VH序列
<400> 14
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Val Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Tyr Ile Asn Pro Tyr Asn Asp Ala Pro Lys Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Leu Gly Tyr Ala Leu Tyr Tyr Ala Met Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Thr Val Thr Val Ser Ser
115 120
<210> 15
<211> 363
<212> DNA
<213> 人工序列
<220>
<221> 来源
<222> 1..363
<223> /分子类型="未指定的DNA"
/注释="工程改造的免疫球蛋白VH序列"
/生物体="人工序列"
<400> 15
caggtccagc ttgtgcagtc tggggctgag gtgaagaagc ctggggcctc agtgaaggtt 60
tcctgcaagg catctggata cacattcact agctatgtga tgcactgggt gcgacaggcc 120
cctggacaag ggcttgagtg gatgggatat attaatcctt ataatgatgc tcctaaatac 180
aatgagaagt tcaaaggcag agtcaccatg accagggaca cgtccacgag cacagtctac 240
atggagctga gcagcctgag atctgaggac acggccgtgt attactgtgc gagaggcttg 300
ggttacgccc tttactatgc tatggactac tggggccaag ggacaatggt caccgtctcg 360
agc 363
<210> 16
<211> 121
<212> PRT
<213> 人工序列
<220>
<223> 工程改造的免疫球蛋白VH序列
<400> 16
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Val Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Tyr Ile Asn Pro Tyr Asn Asp Ala Pro Lys Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Leu Gly Tyr Ala Leu Tyr Tyr Ala Met Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Met Val Thr Val Ser Ser
115 120
<210> 17
<211> 363
<212> DNA
<213> 人工序列
<220>
<221> 来源
<222> 1..363
<223> /分子类型="未指定的DNA"
/注释="工程改造的免疫球蛋白VH序列"
/生物体="人工序列"
<400> 17
caggtccagc ttgtgcagtc tggggctgag gtgaagaagc ccggcgccag cgtgaaggtg 60
agctgcaagg ccagcggata cacattcact agctatgtga tgcactgggt gagacaggcc 120
cccggccagg gcctggagtg gatgggctat attaatcctt ataatgatgc tcctaaatac 180
aatgagaagt tcaaaggcag agtgaccatg accagagaca ccagcgccag caccgcctac 240
atggagctga gcagcctgag aagcgacgac accgccgtgt actactgcgc cagaggcttg 300
ggttacgccc tttactatgc tatggactac tggggccagg gcaccaccgt gaccgtgagc 360
agc 363
<210> 18
<211> 121
<212> PRT
<213> 人工序列
<220>
<223> 工程改造的免疫球蛋白VH序列
<400> 18
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Val Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Tyr Ile Asn Pro Tyr Asn Asp Ala Pro Lys Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ala Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Leu Gly Tyr Ala Leu Tyr Tyr Ala Met Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Thr Val Thr Val Ser Ser
115 120
<210> 19
<211> 321
<212> DNA
<213> 人工序列
<220>
<221> 来源
<222> 1..321
<223> /分子类型="未指定的DNA"
/注释="工程改造的免疫球蛋白VL序列"
/生物体="人工序列"
<400> 19
gacattgtga tgacccagtc tcaaaaattc atgtccacat ccgtaggaga cagggtcagc 60
atcacctgca aggccagtca gaatgtgggt aataatgtag cctggtatca acagaaacca 120
ggacaatctc ctaaattgct gatttactcg gcatccaacc gtgacagtgg agtccctgat 180
cgcttctcag gcagtgggtc tgggacagat ttcactctca ccatcagcaa tatgcagtct 240
gaagacctgg cagattattt ctgccagcaa tataacatct atccattcac gttcggaggg 300
gggaccaagc tggaaatcaa a 321
<210> 20
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> 工程改造的免疫球蛋白VL序列
<400> 20
Asp Ile Val Met Thr Gln Ser Gln Lys Phe Met Ser Thr Ser Val Gly
1 5 10 15
Asp Arg Val Ser Ile Thr Cys Lys Ala Ser Gln Asn Val Gly Asn Asn
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Asn Arg Asp Ser Gly Val Pro Asp Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Asn Met Gln Ser
65 70 75 80
Glu Asp Leu Ala Asp Tyr Phe Cys Gln Gln Tyr Asn Ile Tyr Pro Phe
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 21
<211> 321
<212> DNA
<213> 人工序列
<220>
<221> 来源
<222> 1..321
<223> /分子类型="未指定的DNA"
/注释="工程改造的免疫球蛋白VL序列"
/生物体="人工序列"
<400> 21
gacattgtga tgacccagtc tcaaaaattc atgcccacat cagtaggaga cagggtcagc 60
gtcacctgca aggccagtca gaatgtgggt aataatgtag cctggtatca acagaaacca 120
gggcaatctc ctaaagcact gatttactcg gcatccaacc gtgacagtgg agtccctgat 180
cgcttcacag gcagtggatc tgggacagat ttcactctca ccatcaccaa tgtgcagtct 240
gaagacttgg cagagtattt ctgtcagcaa tataacatct atccattcac gttcggtgct 300
gggaccaagc tggagctgaa a 321
<210> 22
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> 工程改造的免疫球蛋白VL序列
<400> 22
Asp Ile Val Met Thr Gln Ser Gln Lys Phe Met Pro Thr Ser Val Gly
1 5 10 15
Asp Arg Val Ser Val Thr Cys Lys Ala Ser Gln Asn Val Gly Asn Asn
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Lys Ala Leu Ile
35 40 45
Tyr Ser Ala Ser Asn Arg Asp Ser Gly Val Pro Asp Arg Phe Thr Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Thr Asn Val Gln Ser
65 70 75 80
Glu Asp Leu Ala Glu Tyr Phe Cys Gln Gln Tyr Asn Ile Tyr Pro Phe
85 90 95
Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys
100 105
<210> 23
<211> 321
<212> DNA
<213> 人工序列
<220>
<221> 来源
<222> 1..321
<223> /分子类型="未指定的DNA"
/注释="工程改造的免疫球蛋白VL序列"
/生物体="人工序列"
<400> 23
gaaattgtgt tgacgcagtc tccttccacc cagtctgcat ctgtaggaga cagagtcacc 60
atcacttgca aggccagtca gaatgtgggt aataatgtag cctggtatca gcagaaacca 120
gggaaagccc ctaaactcct aatctattcg gcatccaacc gtgacagtgg ggtcccatca 180
aggttcagcg gcagtggatc tgggacagag ttcactctca ccatcagcag cctgcagcct 240
gatgattttg caacttatta ctgccagcaa tataacatct atccattcac gtttggccag 300
gggaccaagc tggagatcaa a 321
<210> 24
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> 工程改造的免疫球蛋白VL序列
<400> 24
Glu Ile Val Leu Thr Gln Ser Pro Ser Thr Gln Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asn Val Gly Asn Asn
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Asn Arg Asp 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 Ile Tyr Pro Phe
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 25
<211> 321
<212> DNA
<213> 人工序列
<220>
<221> 来源
<222> 1..321
<223> /分子类型="未指定的DNA"
/注释="工程改造的免疫球蛋白VL序列"
/生物体="人工序列"
<400> 25
gacatcgtga tgacccagtc tccttctacc ctgtctgcat ctgtgggaga cagagtcacc 60
atcacttgca aggccagtca gaatgtgggt aataatgtag cctggtatca gcagaaacca 120
gggaaagccc ctaagctcct gatctattcg gcatccaacc gtgacagtgg ggtcccatca 180
aggttcagcg gcagtggatc tgggacagag ttcactctca ccatcagcag cctgcagcct 240
gatgattttg caacttatta ctgccagcaa tataacatct atccattcac gtttggccag 300
gggaccaagc tggagatcaa a 321
<210> 26
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> 工程改造的免疫球蛋白VL序列
<400> 26
Asp Ile Val Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asn Val Gly Asn Asn
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Asn Arg Asp 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 Ile Tyr Pro Phe
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 27
<211> 321
<212> DNA
<213> 人工序列
<220>
<221> 来源
<222> 1..321
<223> /分子类型="未指定的DNA"
/注释="工程改造的免疫球蛋白VL序列"
/生物体="人工序列"
<400> 27
gatatcctga tgacccagtc tcaaaaaatc atgcccacat cagtgggaga cagggtcagc 60
gtcacctgca aggccagtca gaatgtgggt aataatgtag cctggtatca acagaaacca 120
ggacagtctc ctaaagcact gatttactcg gcatccaacc gtgacagtgg agtccctgat 180
cgcttcacag gcagtggatc tgggacagat ttcactctca ccatcaccaa tgtgcagtct 240
gaggacttgg cagagtattt ctgtcagcaa tataacatct atccattcac gttcggtgct 300
gggaccaagc tggacctgaa a 321
<210> 28
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> 工程改造的免疫球蛋白VL序列
<400> 28
Asp Ile Leu Met Thr Gln Ser Gln Lys Ile Met Pro Thr Ser Val Gly
1 5 10 15
Asp Arg Val Ser Val Thr Cys Lys Ala Ser Gln Asn Val Gly Asn Asn
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Lys Ala Leu Ile
35 40 45
Tyr Ser Ala Ser Asn Arg Asp Ser Gly Val Pro Asp Arg Phe Thr Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Thr Asn Val Gln Ser
65 70 75 80
Glu Asp Leu Ala Glu Tyr Phe Cys Gln Gln Tyr Asn Ile Tyr Pro Phe
85 90 95
Thr Phe Gly Ala Gly Thr Lys Leu Asp Leu Lys
100 105
<210> 29
<211> 321
<212> DNA
<213> 人工序列
<220>
<221> 来源
<222> 1..321
<223> /分子类型="未指定的DNA"
/注释="工程改造的免疫球蛋白VL序列"
/生物体="人工序列"
<400> 29
gacatcgtga tgacccagtc tccttccacc ctgtctgcat ctgtaggaga cagagtcacc 60
atcacttgca aggccagtca gaatgtgggt aataatgtag cctggtatca gcagaaacca 120
gggaaagccc ctaagctcct gatctcttcg gcatccaacc gtgacagtgg ggtcccatca 180
aggttcagcg gcagtggatc tgggacagag ttcactctca ccatcagcag cctgcagcct 240
gatgattttg caacttattt ctgccagcaa tataacatct atccattcac gtttggccag 300
gggaccaagc tggagatcaa a 321
<210> 30
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> 工程改造的免疫球蛋白VL序列
<400> 30
Asp Ile Val Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asn Val Gly Asn Asn
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Ser Ser Ala Ser Asn Arg Asp 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 Phe Cys Gln Gln Tyr Asn Ile Tyr Pro Phe
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 31
<211> 363
<212> DNA
<213> 人工序列
<220>
<221> 来源
<222> 1..363
<223> /分子类型="未指定的DNA"
/注释="工程改造的免疫球蛋白VH序列"
/生物体="人工序列"
<400> 31
caggtccagc ttgtgcagtc tggggctgag gtgaagaagc ccggcgccag cgtgaaggtg 60
agctgcaagg ccagcggata cacattcact agctatgtga tgcactgggt gagacaggcc 120
cccggccagg gcctggagtg gatgggctat attaatcctt ataatgatgc tcctaaatac 180
aatgagaagt tcaaaggcag agtgaccatg accagtgaca ccagcgccag caccgcctac 240
atggagctga gcagcctgag aagcgacgac accgccgtgt actactgcgc cagaggcttg 300
ggttacgccc tttactatgc tatggactac tggggccagg gcaccaccgt gaccgtgagc 360
agc 363
<210> 32
<211> 121
<212> PRT
<213> 人工序列
<220>
<223> 工程改造的免疫球蛋白VH序列
<400> 32
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Val Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Tyr Ile Asn Pro Tyr Asn Asp Ala Pro Lys Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Arg Val Thr Met Thr Ser Asp Thr Ser Ala Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Leu Gly Tyr Ala Leu Tyr Tyr Ala Met Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Thr Val Thr Val Ser Ser
115 120
<210> 33
<211> 363
<212> DNA
<213> 人工序列
<220>
<221> 来源
<222> 1..363
<223> /分子类型="未指定的DNA"
/注释="工程改造的免疫球蛋白VH序列"
/生物体="人工序列"
<400> 33
caggtccagc ttgtgcagtc tggggctgag gtgaagaagc ccggcgccag cgtgaaggtg 60
agctgcaagg ccagcggata cacattcact agctatgtga tgcactgggt gagacaggcc 120
cccggccagg gcctggagtg gatgggctat attaatcctt ataatgatgc tcctaaatac 180
aatgagaagt tcaaaggcag agtgaccatc accagtgaca ccagcgccag caccgcctac 240
atggagctga gcagcctgag aagcgacgac accgccgtgt actactgcgc cagaggcttg 300
ggttacgccc tttactatgc tatggactac tggggccagg gcaccaccgt gaccgtgagc 360
agc 363
<210> 34
<211> 121
<212> PRT
<213> 人工序列
<220>
<223> 工程改造的免疫球蛋白VH序列
<400> 34
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Val Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Tyr Ile Asn Pro Tyr Asn Asp Ala Pro Lys Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Arg Val Thr Ile Thr Ser Asp Thr Ser Ala Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Leu Gly Tyr Ala Leu Tyr Tyr Ala Met Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Thr Val Thr Val Ser Ser
115 120
<210> 35
<211> 363
<212> DNA
<213> 人工序列
<220>
<221> 来源
<222> 1..363
<223> /分子类型="未指定的DNA"
/注释="工程改造的免疫球蛋白VH序列"
/生物体="人工序列"
<400> 35
caggtccagc ttgtgcagtc tggggctgag gtgaagaagc ccggcgccag cgtgaaggtg 60
agctgcaagg ccagcggata cacattcact agctatgtga tgcactgggt gagacaggcc 120
cccggccagg gcctggagtg gatgggctat attaatcctt ataatgatgc tcctaaatac 180
aatgagaagt tcaaaggcag agtgaccatg accagtgaca agagcgccag caccgcctac 240
atggagctga gcagcctgag aagcgacgac accgccgtgt actactgcgc cagaggcttg 300
ggttacgccc tttactatgc tatggactac tggggccagg gcaccaccgt gaccgtgagc 360
agc 363
<210> 36
<211> 121
<212> PRT
<213> 人工序列
<220>
<223> 工程改造的免疫球蛋白VH序列
<400> 36
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Val Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Tyr Ile Asn Pro Tyr Asn Asp Ala Pro Lys Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Arg Val Thr Met Thr Ser Asp Lys Ser Ala Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Leu Gly Tyr Ala Leu Tyr Tyr Ala Met Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Thr Val Thr Val Ser Ser
115 120
<210> 37
<211> 363
<212> DNA
<213> 人工序列
<220>
<221> 来源
<222> 1..363
<223> /分子类型="未指定的DNA"
/注释="工程改造的免疫球蛋白VH序列"
/生物体="人工序列"
<400> 37
gaggtccagc ttgtgcagtc tggggctgag gtgaagaagc ccggcgccag cgtgaaggtg 60
agctgcaagg ccagcggata cacattcact agctatgtga tgcactgggt gagacaggcc 120
cccggccagg gcctggagtg gatgggctat attaatcctt ataatgatgc tcctaaatac 180
aatgagaagt tcaaaggcag agtgaccatg accagtgaca ccagcgccag caccgcctac 240
atggagctga gcagcctgag aagcgacgac accgccgtgt actactgcgc cagaggcttg 300
ggttacgccc tttactatgc tatggactac tggggccagg gcaccaccgt gaccgtgagc 360
agc 363
<210> 38
<211> 121
<212> PRT
<213> 人工序列
<220>
<223> 工程改造的免疫球蛋白VH序列
<400> 38
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Val Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Tyr Ile Asn Pro Tyr Asn Asp Ala Pro Lys Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Arg Val Thr Met Thr Ser Asp Thr Ser Ala Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Leu Gly Tyr Ala Leu Tyr Tyr Ala Met Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Thr Val Thr Val Ser Ser
115 120
<210> 39
<211> 363
<212> DNA
<213> 人工序列
<220>
<221> 来源
<222> 1..363
<223> /分子类型="未指定的DNA"
/注释="工程改造的免疫球蛋白VH序列"
/生物体="人工序列"
<400> 39
caggtccagc ttgtgcagtc tggggctgag gtgaagaagc ccggcgccag cgtgaaggtg 60
agctgcaagg ccagcggata cacattcact agctatgtga tgcactgggt gagacaggcc 120
cccggccagg gcctggagtg gatgggctat attaatcctt ataatgatgc tcctaaatac 180
aatgagaagt tcaaaggcaa agcgaccatg accagtgaca ccagcgccag caccgcctac 240
atggagctga gcagcctgag aagcgacgac accgccgtgt actactgcgc cagaggcttg 300
ggttacgccc tttactatgc tatggactac tggggccagg gcaccaccgt gaccgtgagc 360
agc 363
<210> 40
<211> 121
<212> PRT
<213> 人工序列
<220>
<223> 工程改造的免疫球蛋白VH序列
<400> 40
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Val Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Tyr Ile Asn Pro Tyr Asn Asp Ala Pro Lys Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Lys Ala Thr Met Thr Ser Asp Thr Ser Ala Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Leu Gly Tyr Ala Leu Tyr Tyr Ala Met Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Thr Val Thr Val Ser Ser
115 120
<210> 41
<211> 1344
<212> DNA
<213> 人工序列
<220>
<221> 来源
<222> 1..1344
<223> /分子类型="未指定的DNA"
/注释="工程改造的免疫球蛋白重链序列"
/生物体="人工序列"
<400> 41
caggtccagc ttgtgcagtc tggggctgag gtgaagaagc ctggggcctc agtgaaggtt 60
tcctgcaagg cttctggata cacattcact agctatgtga tgcattgggt gcgccaggcc 120
cccggacaaa ggcttgagtg gatgggatat attaatcctt ataatgatgc tcctaaatac 180
aatgagaagt tcaaaggcag agtcaccatt accagggaca catccgcgag cacagcctac 240
atggagctga gcagcctgag atctgaagac acggctgtgt attactgtgc gagaggcttg 300
ggttacgccc tttactatgc tatggactac tggggccaag ggaccacggt caccgtctcc 360
tcagcatcca ccaagggccc atccgtcttc cccctggcgc cctgctccag gagcacctcc 420
gagagcacag ccgccctggg ctgcctggtc aaggactact tccccgaacc ggtgacggtg 480
tcgtggaact caggcgccct gaccagcggc gtgcacacct tcccggctgt cctacagtcc 540
tcaggactct actccctcag cagcgtggtg accgtgccct ccagcagctt gggcacgaag 600
acctacacct gcaacgtaga tcacaagccc agcaacacca aggtggacaa gagagttgag 660
tccaaatatg gtcccccatg cccaccatgc ccagcacctg agttcctggg gggaccatca 720
gtcttcctgt tccccccaaa acccaaggac actctcatga tctcccggac ccctgaggtc 780
acgtgcgtgg tggtggacgt gagccaggaa gaccccgagg tccagttcaa ctggtacgtg 840
gatggcgtgg aggtgcataa tgccaagaca aagccgcggg aggagcagtt caacagcacg 900
taccgtgtgg tcagcgtcct caccgtcctg caccaggact ggctgaacgg caaggagtac 960
aagtgcaagg tctccaacaa aggcctcccg tcctccatcg agaaaaccat ctccaaagcc 1020
aaagggcagc cccgagagcc acaggtgtac accctgcccc catcccagga ggagatgacc 1080
aagaaccagg tcagcctgac ctgcctggtc aaaggcttct accccagcga catcgccgtg 1140
gagtgggaga gcaatgggca gccggagaac aactacaaga ccacgcctcc cgtgctggac 1200
tccgacggct ccttcttcct ctacagcagg ctaaccgtgg acaagagcag gtggcaggag 1260
gggaatgtct tctcatgctc cgtgatgcat gaggctctgc acaaccacta cacacagaag 1320
agcctctccc tgtctctggg taaa 1344
<210> 42
<211> 448
<212> PRT
<213> 人工序列
<220>
<223> 工程改造的免疫球蛋白重链序列
<400> 42
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Val Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
35 40 45
Gly Tyr Ile Asn Pro Tyr Asn Asp Ala Pro Lys Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Arg Val Thr Ile Thr Arg Asp Thr Ser Ala Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Leu Gly Tyr Ala Leu Tyr Tyr Ala Met Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
115 120 125
Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala
130 135 140
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
145 150 155 160
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
165 170 175
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
180 185 190
Pro Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His
195 200 205
Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly
210 215 220
Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser
225 230 235 240
Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
245 250 255
Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro
260 265 270
Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
275 280 285
Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val
290 295 300
Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
305 310 315 320
Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr
325 330 335
Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
340 345 350
Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys
355 360 365
Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
370 375 380
Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
385 390 395 400
Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser
405 410 415
Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
420 425 430
Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
435 440 445
<210> 43
<211> 1344
<212> DNA
<213> 人工序列
<220>
<221> 来源
<222> 1..1344
<223> /分子类型="未指定的DNA"
/注释="工程改造的免疫球蛋白重链序列"
/生物体="人工序列"
<400> 43
caggtccagc ttgtgcagtc tggggctgag gtgaagaagc ctggggcctc agtgaaggtc 60
tcctgcaagg cttctggata cacattcact agctatgtga tgcactgggt gcgacaggcc 120
cctggacaag ggcttgagtg gatgggatat attaatcctt ataatgatgc tcctaaatac 180
aatgagaagt tcaaaggcag ggtcaccatg accagggaca cgtccatcag cacagcctac 240
atggagctga gcaggctgag atctgacgac acggccgtgt attactgtgc gagaggcttg 300
ggttacgccc tttactatgc tatggactac tggggccaag ggaccacggt caccgtctcg 360
agcgcatcca ccaagggccc atccgtcttc cccctggcgc cctgctccag gagcacctcc 420
gagagcacag ccgccctggg ctgcctggtc aaggactact tccccgaacc ggtgacggtg 480
tcgtggaact caggcgccct gaccagcggc gtgcacacct tcccggctgt cctacagtcc 540
tcaggactct actccctcag cagcgtggtg accgtgccct ccagcagctt gggcacgaag 600
acctacacct gcaacgtaga tcacaagccc agcaacacca aggtggacaa gagagttgag 660
tccaaatatg gtcccccatg cccaccatgc ccagcacctg agttcctggg gggaccatca 720
gtcttcctgt tccccccaaa acccaaggac actctcatga tctcccggac ccctgaggtc 780
acgtgcgtgg tggtggacgt gagccaggaa gaccccgagg tccagttcaa ctggtacgtg 840
gatggcgtgg aggtgcataa tgccaagaca aagccgcggg aggagcagtt caacagcacg 900
taccgtgtgg tcagcgtcct caccgtcctg caccaggact ggctgaacgg caaggagtac 960
aagtgcaagg tctccaacaa aggcctcccg tcctccatcg agaaaaccat ctccaaagcc 1020
aaagggcagc cccgagagcc acaggtgtac accctgcccc catcccagga ggagatgacc 1080
aagaaccagg tcagcctgac ctgcctggtc aaaggcttct accccagcga catcgccgtg 1140
gagtgggaga gcaatgggca gccggagaac aactacaaga ccacgcctcc cgtgctggac 1200
tccgacggct ccttcttcct ctacagcagg ctaaccgtgg acaagagcag gtggcaggag 1260
gggaatgtct tctcatgctc cgtgatgcat gaggctctgc acaaccacta cacacagaag 1320
agcctctccc tgtctctggg taaa 1344
<210> 44
<211> 448
<212> PRT
<213> 人工序列
<220>
<223> 工程改造的免疫球蛋白重链序列
<400> 44
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Val Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Tyr Ile Asn Pro Tyr Asn Asp Ala Pro Lys Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Leu Gly Tyr Ala Leu Tyr Tyr Ala Met Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
115 120 125
Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala
130 135 140
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
145 150 155 160
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
165 170 175
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
180 185 190
Pro Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His
195 200 205
Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly
210 215 220
Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser
225 230 235 240
Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
245 250 255
Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro
260 265 270
Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
275 280 285
Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val
290 295 300
Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
305 310 315 320
Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr
325 330 335
Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
340 345 350
Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys
355 360 365
Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
370 375 380
Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
385 390 395 400
Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser
405 410 415
Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
420 425 430
Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
435 440 445
<210> 45
<211> 1344
<212> DNA
<213> 人工序列
<220>
<221> 来源
<222> 1..1344
<223> /分子类型="未指定的DNA"
/注释="工程改造的免疫球蛋白重链序列"
/生物体="人工序列"
<400> 45
caggtccagc ttgtgcagtc tggggctgag gtgaagaagc ctggggcctc agtgaaggtt 60
tcctgcaagg catctggata cacattcact agctatgtga tgcactgggt gcgacaggcc 120
cctggacaag ggcttgagtg gatgggatat attaatcctt ataatgatgc tcctaaatac 180
aatgagaagt tcaaaggcag agtcaccatg accagggaca cgtccacgag cacagtctac 240
atggagctga gcagcctgag atctgaggac acggccgtgt attactgtgc gagaggcttg 300
ggttacgccc tttactatgc tatggactac tggggccaag ggacaatggt caccgtctcg 360
agcgcatcca ccaagggccc atccgtcttc cccctggcgc cctgctccag gagcacctcc 420
gagagcacag ccgccctggg ctgcctggtc aaggactact tccccgaacc ggtgacggtg 480
tcgtggaact caggcgccct gaccagcggc gtgcacacct tcccggctgt cctacagtcc 540
tcaggactct actccctcag cagcgtggtg accgtgccct ccagcagctt gggcacgaag 600
acctacacct gcaacgtaga tcacaagccc agcaacacca aggtggacaa gagagttgag 660
tccaaatatg gtcccccatg cccaccatgc ccagcacctg agttcctggg gggaccatca 720
gtcttcctgt tccccccaaa acccaaggac actctcatga tctcccggac ccctgaggtc 780
acgtgcgtgg tggtggacgt gagccaggaa gaccccgagg tccagttcaa ctggtacgtg 840
gatggcgtgg aggtgcataa tgccaagaca aagccgcggg aggagcagtt caacagcacg 900
taccgtgtgg tcagcgtcct caccgtcctg caccaggact ggctgaacgg caaggagtac 960
aagtgcaagg tctccaacaa aggcctcccg tcctccatcg agaaaaccat ctccaaagcc 1020
aaagggcagc cccgagagcc acaggtgtac accctgcccc catcccagga ggagatgacc 1080
aagaaccagg tcagcctgac ctgcctggtc aaaggcttct accccagcga catcgccgtg 1140
gagtgggaga gcaatgggca gccggagaac aactacaaga ccacgcctcc cgtgctggac 1200
tccgacggct ccttcttcct ctacagcagg ctaaccgtgg acaagagcag gtggcaggag 1260
gggaatgtct tctcatgctc cgtgatgcat gaggctctgc acaaccacta cacacagaag 1320
agcctctccc tgtctctggg taaa 1344
<210> 46
<211> 448
<212> PRT
<213> 人工序列
<220>
<223> 工程改造的免疫球蛋白重链序列
<400> 46
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Val Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Tyr Ile Asn Pro Tyr Asn Asp Ala Pro Lys Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Leu Gly Tyr Ala Leu Tyr Tyr Ala Met Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
115 120 125
Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala
130 135 140
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
145 150 155 160
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
165 170 175
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
180 185 190
Pro Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His
195 200 205
Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly
210 215 220
Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser
225 230 235 240
Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
245 250 255
Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro
260 265 270
Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
275 280 285
Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val
290 295 300
Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
305 310 315 320
Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr
325 330 335
Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
340 345 350
Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys
355 360 365
Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
370 375 380
Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
385 390 395 400
Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser
405 410 415
Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
420 425 430
Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
435 440 445
<210> 47
<211> 1344
<212> DNA
<213> 人工序列
<220>
<221> 来源
<222> 1..1344
<223> /分子类型="未指定的DNA"
/注释="工程改造的免疫球蛋白重链序列"
/生物体="人工序列"
<400> 47
caggtccagc ttgtgcagtc tggggctgag gtgaagaagc ccggcgccag cgtgaaggtg 60
agctgcaagg ccagcggata cacattcact agctatgtga tgcactgggt gagacaggcc 120
cccggccagg gcctggagtg gatgggctat attaatcctt ataatgatgc tcctaaatac 180
aatgagaagt tcaaaggcag agtgaccatg accagagaca ccagcgccag caccgcctac 240
atggagctga gcagcctgag aagcgacgac accgccgtgt actactgcgc cagaggcttg 300
ggttacgccc tttactatgc tatggactac tggggccagg gcaccaccgt gaccgtgagc 360
agcgcatcca ccaagggccc atccgtcttc cccctggcgc cctgctccag gagcacctcc 420
gagagcacag ccgccctggg ctgcctggtc aaggactact tccccgaacc ggtgacggtg 480
tcgtggaact caggcgccct gaccagcggc gtgcacacct tcccggctgt cctacagtcc 540
tcaggactct actccctcag cagcgtggtg accgtgccct ccagcagctt gggcacgaag 600
acctacacct gcaacgtaga tcacaagccc agcaacacca aggtggacaa gagagttgag 660
tccaaatatg gtcccccatg cccaccatgc ccagcacctg agttcctggg gggaccatca 720
gtcttcctgt tccccccaaa acccaaggac actctcatga tctcccggac ccctgaggtc 780
acgtgcgtgg tggtggacgt gagccaggaa gaccccgagg tccagttcaa ctggtacgtg 840
gatggcgtgg aggtgcataa tgccaagaca aagccgcggg aggagcagtt caacagcacg 900
taccgtgtgg tcagcgtcct caccgtcctg caccaggact ggctgaacgg caaggagtac 960
aagtgcaagg tctccaacaa aggcctcccg tcctccatcg agaaaaccat ctccaaagcc 1020
aaagggcagc cccgagagcc acaggtgtac accctgcccc catcccagga ggagatgacc 1080
aagaaccagg tcagcctgac ctgcctggtc aaaggcttct accccagcga catcgccgtg 1140
gagtgggaga gcaatgggca gccggagaac aactacaaga ccacgcctcc cgtgctggac 1200
tccgacggct ccttcttcct ctacagcagg ctaaccgtgg acaagagcag gtggcaggag 1260
gggaatgtct tctcatgctc cgtgatgcat gaggctctgc acaaccacta cacacagaag 1320
agcctctccc tgtctctggg taaa 1344
<210> 48
<211> 448
<212> PRT
<213> 人工序列
<220>
<223> 工程改造的免疫球蛋白重链序列
<400> 48
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Val Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Tyr Ile Asn Pro Tyr Asn Asp Ala Pro Lys Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ala Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Leu Gly Tyr Ala Leu Tyr Tyr Ala Met Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
115 120 125
Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala
130 135 140
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
145 150 155 160
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
165 170 175
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
180 185 190
Pro Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His
195 200 205
Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly
210 215 220
Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser
225 230 235 240
Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
245 250 255
Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro
260 265 270
Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
275 280 285
Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val
290 295 300
Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
305 310 315 320
Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr
325 330 335
Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
340 345 350
Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys
355 360 365
Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
370 375 380
Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
385 390 395 400
Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser
405 410 415
Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
420 425 430
Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
435 440 445
<210> 49
<211> 642
<212> DNA
<213> 人工序列
<220>
<221> 来源
<222> 1..642
<223> /分子类型="未指定的DNA"
/注释="工程改造的免疫球蛋白轻链序列"
/生物体="人工序列"
<400> 49
gacattgtga tgacccagtc tccttccact ctctctgcat ctgtgggaga cagagtaacc 60
atcacttgca aggccagtca gaatgtgggt aataatgtag cctggtatca gcagaaacca 120
gggaaagccc ctaagctact gatctcttcc gcatccaacc gggacagtgg tgtgccctca 180
aggtttagcg gcagtggatc agggacagag ttcacattga ccatatccag cctgcagcct 240
gatgattttg ctacttattt ctgccaacaa tataacattt acccattcac gtttggccag 300
ggcaccaagc tagagatcaa acggacggtt gctgcaccct ctgtctttat cttcccgcca 360
tctgatgaac agttgaagtc cggaacagcc tctgttgtgt gcctgctgaa taacttttat 420
ccccgcgagg cgaaagttca gtggaaggtg gataacgccc tccaatcagg caattcccag 480
gagagtgtga cagagcaaga ttccaaggac tcaacctaca gcctcagcag tactttaact 540
ctgagcaaag cagactacga gaagcacaaa gtctacgctt gcgaagtcac ccatcagggc 600
cttagctcgc ccgtcacaaa gagctttaac aggggagaat gt 642
<210> 50
<211> 214
<212> PRT
<213> 人工序列
<220>
<223> 工程改造的免疫球蛋白轻链序列
<400> 50
Asp Ile Val Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asn Val Gly Asn Asn
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Ser Ser Ala Ser Asn Arg Asp 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 Phe Cys Gln Gln Tyr Asn Ile Tyr Pro Phe
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys
210
<210> 51
<211> 1344
<212> DNA
<213> 人工序列
<220>
<221> 来源
<222> 1..1344
<223> /分子类型="未指定的DNA"
/注释="工程改造的免疫球蛋白重链序列"
/生物体="人工序列"
<400> 51
caggtccaac ttgtgcagtc tggggctgaa gtgaagaagc ccggcgctag tgtgaaggtt 60
tcatgtaagg cttctggata cacatttact tcatatgtaa tgcactgggt gcgtcaagcc 120
cctggccagg gcctggagtg gatggggtat attaatcctt ataatgatgc tcctaaatac 180
aatgagaagt tcaaaggaaa agcaactatg accagtgata ctagcgcttc aaccgcctac 240
atggagctga gcagcttaag aagcgacgac accgccgtgt actattgtgc caggggcttg 300
ggttacgccc tttattatgc tatggactac tggggtcagg gcaccacagt gaccgttagc 360
tctgcatcta ctaagggacc atccgtcttc cccctggcgc catgctcccg cagtacaagt 420
gagagcacag cagccctggg ctgtttggta aaggactact tccccgaacc tgtgactgtg 480
tcttggaact caggcgccct gactagcggc gtgcacactt tccctgctgt cctacagtcc 540
tcaggactat actccctctc gtctgtggtg acagtgcctt cctcatcatt gggaacgaaa 600
acctatactt gcaacgttga tcacaagccc agcaacacca aggtggacaa gagagttgag 660
tccaaatatg gtcccccatg tccaccatgt ccagcacctg agtttcttgg cggaccaagt 720
gttttcctgt tccccccaaa acccaaggat actctcatga taagtcgcac ccctgaagtc 780
acttgcgtgg tggtggacgt tagccaggaa gatcccgaag tccaattcaa ctggtacgta 840
gatggcgtag aagtgcataa tgcgaagaca aagccgagag aggagcagtt taattcgacg 900
tatcgggtgg tcagcgtcct cacagtcctg caccaggact ggctgaacgg caaggagtat 960
aagtgcaagg tctccaacaa aggtctcccg tcctccattg agaaaacaat ctccaaagca 1020
aaagggcagc cccgagaacc acaagtgtac accctgcccc catctcagga ggagatgacc 1080
aagaaccagg tcagtcttac ctgcctggtc aaaggctttt atccctcaga tatcgccgtt 1140
gagtgggaaa gcaatgggca gccggagaac aactacaaga ccacgcctcc cgttctggat 1200
tctgacggat cgttcttttt atacagcagg ctaaccgtgg acaagtctcg gtggcaggaa 1260
gggaatgtat tttcttgcag tgtaatgcat gaggctctgc acaatcatta cacacagaag 1320
tctctctccc tgtctcttgg taaa 1344
<210> 52
<211> 448
<212> PRT
<213> 人工序列
<220>
<223> 工程改造的免疫球蛋白重链序列
<400> 52
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Val Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Tyr Ile Asn Pro Tyr Asn Asp Ala Pro Lys Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Lys Ala Thr Met Thr Ser Asp Thr Ser Ala Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Leu Gly Tyr Ala Leu Tyr Tyr Ala Met Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
115 120 125
Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala
130 135 140
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
145 150 155 160
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
165 170 175
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
180 185 190
Pro Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His
195 200 205
Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly
210 215 220
Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser
225 230 235 240
Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
245 250 255
Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro
260 265 270
Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
275 280 285
Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val
290 295 300
Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
305 310 315 320
Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr
325 330 335
Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
340 345 350
Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys
355 360 365
Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
370 375 380
Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
385 390 395 400
Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser
405 410 415
Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
420 425 430
Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
435 440 445
<210> 53
<211> 1335
<212> DNA
<213> 小家鼠
<220>
<221> 来源
<222> 1..1335
<223> /分子类型="未指定的DNA"
/生物体="小家鼠"
<400> 53
gaggtccagt tgcagcagtc tggacctgag ctggtaaagc ctggggcttc agtgaagatg 60
tcctgcaagg cttctggata cacattcact agctatgtga tgcactgggt gaagcagaag 120
cctgggcagg gccttgagtg gattggatat attaatcctt ataatgatgc tcctaaatac 180
aatgagaagt tcaaaggcaa ggccacagtg acttcagaca agtcctccgg cacagcctac 240
atggagctca gcagcctgac ctctgaggac tctgcggtct attactgtgc aaggggcttg 300
ggttacgccc tttactatgc tatggactac tggggtcaag gaacctcagt caccgtctcc 360
tcagccaaaa cgacaccccc atctgtctat ccactggccc ctggatctgc tgcccaaact 420
aactccatgg tgaccctggg atgcctggtc aagggctatt tccctgagcc agtgacagtg 480
acctggaact ctggatccct gtccagcggt gtgcacacct tcccagctgt cctggagtct 540
gacctctaca ctctgagcag ctcagtgact gtcccctcca gccctcggcc cagcgagacc 600
gtcacctgca acgttgccca cccggccagc agcaccaagg tggacaagaa aattgtgccc 660
agggattgtg gttgtaagcc ttgcatatgt acagtcccag aagtatcatc tgtcttcatc 720
ttccccccaa agcccaagga tgtgctcacc attactctga ctcctaaggt cacgtgtgtt 780
gtggtagaca tcagcaagga tgatcccgag gtccagttca gctggtttgt agatgatgtg 840
gaggtgcaca cagctcagac gcaaccccgg gaggagcagt tcaacagcac tttccgctca 900
gtcagtgaac ttcccatcat gcaccaggac tggctcaatg gcaaggagtt caaatgcagg 960
gtcaacagtg cagctttccc tgcccccatc gagaaaacca tctccaaaac caaaggcaga 1020
ccgaaggctc cacaggtgta caccattcca cctcccaagg agcagatggc caaggataaa 1080
gtcagtctga cctgcatgat aacagacttc ttccctgaag acattactgt ggagtggcag 1140
tggaatgggc agccagcgga gaactacaag aacactcagc ccatcatgaa cacgaatggc 1200
tcttacttcg tctacagcaa gctcaatgtg cagaagagca actgggaggc aggaaatact 1260
ttcacctgct ctgtgttaca tgagggcctg cacaaccacc atactgagaa gagcctctcc 1320
cactctcctg gtaaa 1335
<210> 54
<211> 642
<212> DNA
<213> 小家鼠
<220>
<221> 来源
<222> 1..642
<223> /分子类型="未指定的DNA"
/生物体="小家鼠"
<400> 54
gacattgtga tgacccagtc tcaaaaattc aagtccacat cagtaggaga cagggtcagc 60
gtcacctgca aggccagtca gaatgtgggt aataatgtag cctggtatca acagaaagca 120
gggcaatctc ctaaagcact gatttcctcg gcatccaacc gtgacagtgg agtccctgat 180
cgcttcacag gcagtggatc tgggacagat ttcactctca ccatcagcaa tgtgcagtct 240
gaagacttgg cagactattt ctgtcagcaa tataacatct atccattcac gttcggctcg 300
gggacaaagt tggaaataaa acgggctgat gctgcaccaa ctgtatccat cttcccacca 360
tccagtgagc agttaacatc tggaggtgcc tcagtcgtgt gcttcttgaa caacttctac 420
cccaaagaca tcaatgtcaa gtggaagatt gatggcagtg aacgacaaaa tggcgtcctg 480
aacagttgga ctgatcagga cagcaaagac agcacctaca gcatgagcag caccctcacg 540
ttgaccaagg acgagtatga acgacataac agctatacct gtgaggccac tcacaagaca 600
tcaacttcac ccattgtcaa gagcttcaac aggaatgagt gt 642
<210> 55
<211> 445
<212> PRT
<213> 小家鼠
<400> 55
Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Val Met His Trp Val Lys Gln Lys Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Asn Pro Tyr Asn Asp Ala Pro Lys Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Lys Ala Thr Val Thr Ser Asp Lys Ser Ser Gly Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Leu Gly Tyr Ala Leu Tyr Tyr Ala Met Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Ser Val Thr Val Ser Ser Ala Lys Thr Thr Pro Pro Ser
115 120 125
Val Tyr Pro Leu Ala Pro Gly Ser Ala Ala Gln Thr Asn Ser Met Val
130 135 140
Thr Leu Gly Cys Leu Val Lys Gly Tyr Phe Pro Glu Pro Val Thr Val
145 150 155 160
Thr Trp Asn Ser Gly Ser Leu Ser Ser Gly Val His Thr Phe Pro Ala
165 170 175
Val Leu Glu Ser Asp Leu Tyr Thr Leu Ser Ser Ser Val Thr Val Pro
180 185 190
Ser Ser Pro Arg Pro Ser Glu Thr Val Thr Cys Asn Val Ala His Pro
195 200 205
Ala Ser Ser Thr Lys Val Asp Lys Lys Ile Val Pro Arg Asp Cys Gly
210 215 220
Cys Lys Pro Cys Ile Cys Thr Val Pro Glu Val Ser Ser Val Phe Ile
225 230 235 240
Phe Pro Pro Lys Pro Lys Asp Val Leu Thr Ile Thr Leu Thr Pro Lys
245 250 255
Val Thr Cys Val Val Val Asp Ile Ser Lys Asp Asp Pro Glu Val Gln
260 265 270
Phe Ser Trp Phe Val Asp Asp Val Glu Val His Thr Ala Gln Thr Gln
275 280 285
Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Ser Val Ser Glu Leu
290 295 300
Pro Ile Met His Gln Asp Trp Leu Asn Gly Lys Glu Phe Lys Cys Arg
305 310 315 320
Val Asn Ser Ala Ala Phe Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys
325 330 335
Thr Lys Gly Arg Pro Lys Ala Pro Gln Val Tyr Thr Ile Pro Pro Pro
340 345 350
Lys Glu Gln Met Ala Lys Asp Lys Val Ser Leu Thr Cys Met Ile Thr
355 360 365
Asp Phe Phe Pro Glu Asp Ile Thr Val Glu Trp Gln Trp Asn Gly Gln
370 375 380
Pro Ala Glu Asn Tyr Lys Asn Thr Gln Pro Ile Met Asn Thr Asn Gly
385 390 395 400
Ser Tyr Phe Val Tyr Ser Lys Leu Asn Val Gln Lys Ser Asn Trp Glu
405 410 415
Ala Gly Asn Thr Phe Thr Cys Ser Val Leu His Glu Gly Leu His Asn
420 425 430
His His Thr Glu Lys Ser Leu Ser His Ser Pro Gly Lys
435 440 445
<210> 56
<211> 214
<212> PRT
<213> 小家鼠
<400> 56
Asp Ile Val Met Thr Gln Ser Gln Lys Phe Lys Ser Thr Ser Val Gly
1 5 10 15
Asp Arg Val Ser Val Thr Cys Lys Ala Ser Gln Asn Val Gly Asn Asn
20 25 30
Val Ala Trp Tyr Gln Gln Lys Ala Gly Gln Ser Pro Lys Ala Leu Ile
35 40 45
Ser Ser Ala Ser Asn Arg Asp Ser Gly Val Pro Asp Arg Phe Thr Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Asn Val Gln Ser
65 70 75 80
Glu Asp Leu Ala Asp Tyr Phe Cys Gln Gln Tyr Asn Ile Tyr Pro Phe
85 90 95
Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys Arg Ala Asp Ala Ala
100 105 110
Pro Thr Val Ser Ile Phe Pro Pro Ser Ser Glu Gln Leu Thr Ser Gly
115 120 125
Gly Ala Ser Val Val Cys Phe Leu Asn Asn Phe Tyr Pro Lys Asp Ile
130 135 140
Asn Val Lys Trp Lys Ile Asp Gly Ser Glu Arg Gln Asn Gly Val Leu
145 150 155 160
Asn Ser Trp Thr Asp Gln Asp Ser Lys Asp Ser Thr Tyr Ser Met Ser
165 170 175
Ser Thr Leu Thr Leu Thr Lys Asp Glu Tyr Glu Arg His Asn Ser Tyr
180 185 190
Thr Cys Glu Ala Thr His Lys Thr Ser Thr Ser Pro Ile Val Lys Ser
195 200 205
Phe Asn Arg Asn Glu Cys
210
<210> 57
<211> 57
<212> DNA
<213> 智人
<220>
<221> 来源
<222> 1..57
<223> /分子类型="未指定的DNA"
/生物体="智人"
<400> 57
atggactgga cctggaggat cctctttttg gtggcagcag ccacaggtgc ccactcc 57
<210> 58
<211> 19
<212> PRT
<213> 智人
<400> 58
Met Asp Trp Thr Trp Arg Ile Leu Phe Leu Val Ala Ala Ala Thr Gly
1 5 10 15
Ala His Ser
<210> 59
<211> 66
<212> DNA
<213> 智人
<220>
<221> 来源
<222> 1..66
<223> /分子类型="未指定的DNA"
/生物体="智人"
<400> 59
atggacatga gagtcctcgc tcagctcctg gggctcctgc tgctctgttt cccaggtgcc 60
agatgt 66
<210> 60
<211> 22
<212> PRT
<213> 智人
<400> 60
Met Asp Met Arg Val Leu Ala Gln Leu Leu Gly Leu Leu Leu Leu Cys
1 5 10 15
Phe Pro Gly Ala Arg Cys
20
Claims (22)
1.一种APRIL结合抗体,包括抗体类似物,如抗体片段,所述抗体与具有hAPRIL.01A抗原结合位点的抗体,包括抗体类似物,如抗体片段竞争结合至相同的人类APRIL表位,所述APRIL结合抗体包括含VH和VL结构域的多个抗原结合位点,其中在抗原结合位点中所述VH结构域的框架序列与选自SEQ ID NO:12、14、16、18,优选地SEQ ID NO:14或18的VH氨基酸序列的框架序列具有至少70%序列相似性,并且所述VL结构域的框架序列与SEQ ID NO:30的框架氨基酸序列具有至少70%序列相似性。
2.根据权利要求1所述的抗体,其中:
-在所述VH结构域中,CDR1、CDR2、CDR3中至少一个并且优选全部三个分别选自由SEQNO:5、6、7或所述序列中任一个的变体组成的组;和/或
-在所述VL结构域中,CDR1、CDR2、CDR3中至少一个并且优选全部三个分别选自由SEQNO:8、9及10,或所述序列中任一个的变体组成的组。
3.根据前述权利要求中任一项所述的抗体,其中所述VH结构域氨基酸序列是在与选自SEQ ID NO:42、44、46、48,优选SEQ ID NO:44或48的氨基酸序列具有至少70%序列相似性的重链氨基酸序列中,并且所述VL结构域氨基酸序列是在与SEQ ID NO:50的氨基酸序列具有至少70%序列相似性的轻链氨基酸序列中。
4.根据前述权利要求中任一项所述的抗体,其中在所述VH氨基酸序列中,72位的氨基酸是S,所述VH氨基酸序列优选是选自SEQ ID NO:32、34、36、38或40。
5.根据前述权利要求中任一项所述的抗体,其中至少70%序列相似性是至少85%序列相似性。
6.根据权利要求1至4中任一项所述的抗体,其中至少70%序列相似性是至少90%序列相似性。
7.根据权利要求1至4中任一项所述的抗体,其中至少70%序列相似性是至少95%序列相似性。
8.根据权利要求1至4中任一项所述的抗体,其中至少70%序列相似性是至少99%序列相似性。
9.根据前述权利要求中任一项所述的抗体,其中在所述VH氨基酸序列中67位的氨基酸是K并且68位的氨基酸是A,所述VH氨基酸序列优选是选自SEQ ID NO:40。
10.根据前述权利要求中任一项所述的抗体,其中所述抗体具有以下特征中的一个或多个:
-以约100nM或更低KD结合人类APRIL;
-以约100nM或更低IC50阻断人类APRIL与人类BCMA和人类TACI的结合;
-以约100nM或更低IC50阻断hAPRIL.01A与人类APRIL的结合。
11.一种分离的多核苷酸,所述多核苷酸编码根据权利要求1至10中任一项所述的抗体的VH结构域和/或VL结构域,其中编码所述VH结构域的多核苷酸优选是与选自SEQ ID NO:11、13、15、17,更优选SEQ ID NO:13或17的多核苷酸序列具有至少70%序列相似性的多核苷酸序列,并且编码所述VL结构域的多核苷酸优选是与选自SEQ ID NO:29的多核苷酸序列具有至少70%序列相似性的多核苷酸序列。
12.一种包含多个表达载体的表达单元,所述表达载体包含处于适合调控序列控制下的多个根据权利要求11所述的多核苷酸,其中所述多个多核苷酸编码根据权利要求1至10中任一项所述的抗体的VH结构域和VL结构域,并且其中编码所述VH结构域的多核苷酸序列可以与编码所述VL结构域的多核苷酸序列在相同或不同表达载体上。
13.一种宿主细胞,所述宿主细胞包含多个根据权利要求11所述的多核苷酸和/或根据权利要求12所述的表达单元,优选包括同时包含编码所述VH结构域的多核苷酸序列和编码所述VL结构域的多核苷酸序列的表达载体的表达单元。
14.一种产生根据权利要求1至10中任一项所述的抗体的方法,所述方法包括:
a)在培养基中在表达所述多个多核苷酸的条件下培养根据权利要求13所述的宿主细胞,由此产生包含轻链可变区和重链可变区的多肽;和
b)从所述宿主细胞或培养基回收所述多肽。
15.一种组合物,所述组合物包含根据权利要求1至10中任一项所述的抗体以及载剂或稀释剂,优选药学上可接受的载剂或稀释剂,以及任选的多种其它活性化合物,特别是多种治疗活性化合物,如选自美法仑;长春新碱;氟达拉滨;苯丁酸氮芥;苯达莫司汀;依托泊苷;多柔比星;环磷酰胺;顺铂;免疫调节剂,如皮质类固醇,例如地塞米松、泼尼松龙,沙利度胺类似物,例如沙利度胺、来那度胺、泊马度胺;激酶抑制剂,例如依鲁替尼、艾达拉里斯;靶向CD20的抗体疗法,如利妥昔单抗、奥法木单抗、奥奴珠单抗;靶向CD52的抗体疗法,如阿仑珠单抗;靶向CD38的抗体疗法,如达雷木单抗;靶向IL-6或IL-6受体的抗体疗法,如萨利奴单抗、托珠单抗;靶向CS-1的抗体疗法,如埃罗妥珠单抗;靶向BCMA的抗体疗法,如GSK2857916;靶向BAFF或BLyss的抗体疗法,如他贝鲁单抗;双膦酸盐,如帕米膦酸盐或唑来膦酸;或硼替佐米。
16.根据权利要求1至10中任一项所述的抗体,所述抗体用于疗法中,优选用于旨在选自以下一项或多项的疗法中:
a.抑制免疫细胞增殖和/或存活;
b.治疗癌症;
c.治疗自身免疫性疾病;
d.治疗炎症性疾病;或
e.治疗得益于免疫球蛋白水平降低的病症。
17.一种用于治疗受试者,优选人类受试者的方法,所述方法包括施用治疗有效量的根据权利要求1至10中任一项所述的抗体。
18.根据权利要求17所述的方法,其中所述治疗旨在选自以下一项或多项:
a.抑制免疫细胞增殖和/或存活;
b.治疗癌症;
c.治疗自身免疫性疾病;
d.治疗炎症性疾病;或
e.治疗得益于免疫球蛋白水平降低的病症。
19.根据权利要求1至10中任一项所述的抗体的用途,所述抗体用于诊断方法中,优选用于离体或体外诊断方法中,如选自流式细胞术、蛋白质印迹、酶联免疫吸附测定(ELISA)或免疫组织化学分析的诊断方法。
20.一种人源化抗体,所述抗体包含选自由以下组成的组的重链可变区.轻链可变区对:VH11.VL15、VH12.VL15、VH13.VL15、VH14.VL15、VH14_1.VL15、VH14_1C.VL15、VH14_1D.VL15、VH14_1E.VL15和VH14_1G.VL15。
21.一种编码根据权利要求20所述的人源化抗体的多核苷酸。
22.一种表达载体,所述表达载体包含编码根据权利要求20所述的人源化抗体的多核苷酸,所述多核苷酸可操作地连接至被配置用于提供所述人源化抗体的表达的调控序列。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
NL2014108 | 2015-01-09 | ||
NL2014108A NL2014108B1 (en) | 2015-01-09 | 2015-01-09 | Altered april binding antibodies. |
PCT/EP2016/050314 WO2016110587A1 (en) | 2015-01-09 | 2016-01-08 | Altered april binding antibodies |
Publications (2)
Publication Number | Publication Date |
---|---|
CN107207602A true CN107207602A (zh) | 2017-09-26 |
CN107207602B CN107207602B (zh) | 2021-05-25 |
Family
ID=53783809
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201680006375.6A Active CN107207602B (zh) | 2015-01-09 | 2016-01-08 | 改良的april结合抗体 |
Country Status (20)
Country | Link |
---|---|
US (4) | US9969808B2 (zh) |
EP (2) | EP3242892B1 (zh) |
JP (2) | JP6824190B2 (zh) |
KR (2) | KR20230170120A (zh) |
CN (1) | CN107207602B (zh) |
AU (1) | AU2016205977B2 (zh) |
BR (1) | BR112017014771A2 (zh) |
CA (1) | CA2973286A1 (zh) |
DK (1) | DK3242892T3 (zh) |
EA (1) | EA201791270A1 (zh) |
ES (1) | ES2902901T3 (zh) |
HK (1) | HK1243435A1 (zh) |
IL (1) | IL253306B (zh) |
MA (1) | MA41313A (zh) |
MX (2) | MX2017009052A (zh) |
NL (1) | NL2014108B1 (zh) |
PL (1) | PL3242892T3 (zh) |
SG (1) | SG11201705589UA (zh) |
WO (1) | WO2016110587A1 (zh) |
ZA (2) | ZA201704920B (zh) |
Families Citing this family (17)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
NL2011406C2 (en) | 2013-09-06 | 2015-03-10 | Bionovion Holding B V | Method for obtaining april-binding peptides, process for producing the peptides, april-binding peptides obtainable with said method/process and use of the april-binding peptides. |
NL2014108B1 (en) | 2015-01-09 | 2016-09-30 | Aduro Biotech Holdings Europe B V | Altered april binding antibodies. |
CN109089419B (zh) | 2015-11-25 | 2024-03-01 | 威特拉公司 | April的抗体分子及其应用 |
KR20180107102A (ko) | 2015-12-16 | 2018-10-01 | 그릿스톤 온콜로지, 인코포레이티드 | 신생항원 동정, 제조, 및 용도 |
CN110945030A (zh) * | 2017-06-20 | 2020-03-31 | 丹娜法伯癌症研究院 | 使用april-taci相互作用的调节剂调节调控性t细胞、调控性b细胞和免疫响应的方法 |
CN111465989A (zh) | 2017-10-10 | 2020-07-28 | 磨石肿瘤生物技术公司 | 使用热点进行的新抗原鉴别 |
EP3714275A4 (en) | 2017-11-22 | 2021-10-27 | Gritstone bio, Inc. | REDUCTION OF JUNCTION EPITOPIC PRESENTATION FOR NEOANTIGENS |
US20200190163A1 (en) * | 2018-10-26 | 2020-06-18 | Lijun Wu | Humanized bcma-car-t cells |
WO2020144535A1 (en) | 2019-01-08 | 2020-07-16 | Aduro Biotech Holdings, Europe B.V. | Methods and compositions for treatment of multiple myeloma |
US20240132598A1 (en) * | 2019-10-15 | 2024-04-25 | Dragonfly Therapeutics, Inc. | Antibodies targeting flt3 and use thereof |
TW202128759A (zh) * | 2019-10-15 | 2021-08-01 | 美商蜻蜓醫療公司 | 結合nkg2d、cd及flt3之蛋白質 |
AU2021279035A1 (en) * | 2020-05-29 | 2023-02-02 | Aduro Biotech Holding, Europe B.V. | Methods of treating IgA nephropathy with an APRIL binding antibody |
JP2024500847A (ja) | 2020-12-18 | 2024-01-10 | センチュリー セラピューティクス,インコーポレイテッド | 適合可能な受容体特異性を有するキメラ抗原受容体システム |
IL308336A (en) | 2021-05-07 | 2024-01-01 | Alpine Immune Sciences Inc | Methods of dosing and treatment with TACI-FC modulatory fusion protein |
WO2023212518A1 (en) | 2022-04-25 | 2023-11-02 | Visterra, Inc. | Antibody molecules to april and uses thereof |
WO2024077018A2 (en) | 2022-10-04 | 2024-04-11 | Alpine Immune Sciences, Inc. | Methods and uses of taci-fc fusion immunomodulatory protein |
WO2024092240A1 (en) | 2022-10-28 | 2024-05-02 | Chinook Therapeutics, Inc. | Treatment of iga nephropathy using an endothelin receptor antagonist and an april binding antibody |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2001060397A1 (en) * | 2000-02-16 | 2001-08-23 | Genentech, Inc. | Uses of agonists and antagonists to modulate activity of tnf-related molecules |
WO2010100056A2 (en) * | 2009-03-02 | 2010-09-10 | Stichting Top Institute Pharma | Antibodies against a proliferating inducing ligand (april) |
CN101928345A (zh) * | 2010-06-21 | 2010-12-29 | 中国科学技术大学 | 一种人源化抗体及其人源化改造方法 |
Family Cites Families (26)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US778A (en) | 1838-06-12 | Thomas wright | ||
US4946A (en) | 1847-01-26 | Improvement in carriage-wheels | ||
US4816567A (en) | 1983-04-08 | 1989-03-28 | Genentech, Inc. | Recombinant immunoglobin preparations |
DD272023A3 (de) | 1985-12-04 | 1989-09-27 | Ilmenau Tech Hochschule | Vorrichtung, insbesondere zur praezisionslichtstrahlablenkung |
US5225539A (en) | 1986-03-27 | 1993-07-06 | Medical Research Council | Recombinant altered antibodies and methods of making altered antibodies |
US4946778A (en) | 1987-09-21 | 1990-08-07 | Genex Corporation | Single polypeptide chain binding molecules |
US5260203A (en) | 1986-09-02 | 1993-11-09 | Enzon, Inc. | Single polypeptide chain binding molecules |
ATE87659T1 (de) | 1986-09-02 | 1993-04-15 | Enzon Lab Inc | Bindungsmolekuele mit einzelpolypeptidkette. |
WO1988007089A1 (en) | 1987-03-18 | 1988-09-22 | Medical Research Council | Altered antibodies |
US5530101A (en) * | 1988-12-28 | 1996-06-25 | Protein Design Labs, Inc. | Humanized immunoglobulins |
DE3920358A1 (de) | 1989-06-22 | 1991-01-17 | Behringwerke Ag | Bispezifische und oligospezifische, mono- und oligovalente antikoerperkonstrukte, ihre herstellung und verwendung |
ES2241710T3 (es) | 1991-11-25 | 2005-11-01 | Enzon, Inc. | Procedimiento para producir proteinas multivalentes de union a antigeno. |
EP0792278B1 (en) | 1994-11-07 | 2007-06-13 | Human Genome Sciences, Inc. | Tumor necrosis factor-gamma |
US6171787B1 (en) | 1997-06-26 | 2001-01-09 | Abbott Laboratories | Member of the TNF family useful for treatment and diagnosis of disease |
EP1027431A2 (en) | 1997-09-12 | 2000-08-16 | Apotech R&D S.A. | April- a novel protein with growth effects |
EP1294949A4 (en) | 2000-06-15 | 2004-08-25 | Human Genome Sciences Inc | HUMAN TUMORNESCROSE FACTOR DELTA AND EPSILON |
CA2446734A1 (en) | 2001-05-24 | 2002-11-28 | Human Genome Sciences, Inc. | Antibodies against tumor necrosis factor delta (april) |
AU2003226356A1 (en) | 2002-04-12 | 2003-10-27 | Ramot At Tel Aviv University Ltd. | Prevention of brain inflammation as a result of induced autoimmune response |
US7410483B2 (en) | 2003-05-23 | 2008-08-12 | Novare Surgical Systems, Inc. | Hand-actuated device for remote manipulation of a grasping tool |
DE602005022871D1 (de) | 2004-06-07 | 2010-09-23 | Univ Ramot | Verfahren zur passiven immunisierung gegen eine durch amyloidaggregation gekennzeichnete krankheit oder erkrankung mit vermindertem nervenentzündungsrisiko |
UY30776A1 (es) * | 2006-12-21 | 2008-07-03 | Medarex Inc | Anticuerpos cd44 |
KR20110044991A (ko) * | 2008-07-02 | 2011-05-03 | 이머전트 프로덕트 디벨롭먼트 시애틀, 엘엘씨 | TNF-α 길항제 다-표적 결합 단백질 |
MX2011001911A (es) * | 2008-08-18 | 2011-07-04 | Pfizer | Anticuerpos para ccr2. |
CA2734330A1 (en) * | 2008-09-19 | 2010-03-25 | Medimmune, Llc | Antibodies against sonic hedgehog homolog and uses thereof |
NL2014108B1 (en) | 2015-01-09 | 2016-09-30 | Aduro Biotech Holdings Europe B V | Altered april binding antibodies. |
CN109089419B (zh) * | 2015-11-25 | 2024-03-01 | 威特拉公司 | April的抗体分子及其应用 |
-
2015
- 2015-01-09 NL NL2014108A patent/NL2014108B1/en active
-
2016
- 2016-01-08 EP EP16700803.6A patent/EP3242892B1/en active Active
- 2016-01-08 SG SG11201705589UA patent/SG11201705589UA/en unknown
- 2016-01-08 MX MX2017009052A patent/MX2017009052A/es unknown
- 2016-01-08 ES ES16700803T patent/ES2902901T3/es active Active
- 2016-01-08 CN CN201680006375.6A patent/CN107207602B/zh active Active
- 2016-01-08 WO PCT/EP2016/050314 patent/WO2016110587A1/en active Application Filing
- 2016-01-08 CA CA2973286A patent/CA2973286A1/en active Pending
- 2016-01-08 KR KR1020237041391A patent/KR20230170120A/ko active Application Filing
- 2016-01-08 MA MA041313A patent/MA41313A/fr unknown
- 2016-01-08 EP EP21203559.6A patent/EP4029879A1/en active Pending
- 2016-01-08 PL PL16700803T patent/PL3242892T3/pl unknown
- 2016-01-08 DK DK16700803.6T patent/DK3242892T3/da active
- 2016-01-08 US US14/991,708 patent/US9969808B2/en active Active
- 2016-01-08 JP JP2017554648A patent/JP6824190B2/ja active Active
- 2016-01-08 AU AU2016205977A patent/AU2016205977B2/en active Active
- 2016-01-08 KR KR1020177020607A patent/KR102612373B1/ko active IP Right Grant
- 2016-01-08 EA EA201791270A patent/EA201791270A1/ru unknown
- 2016-01-08 BR BR112017014771-8A patent/BR112017014771A2/pt active Search and Examination
-
2017
- 2017-07-04 IL IL253306A patent/IL253306B/en active IP Right Grant
- 2017-07-07 MX MX2022007774A patent/MX2022007774A/es unknown
- 2017-07-19 ZA ZA2017/04920A patent/ZA201704920B/en unknown
-
2018
- 2018-02-28 HK HK18102920.1A patent/HK1243435A1/zh unknown
- 2018-05-14 US US15/978,699 patent/US10377830B2/en active Active
- 2018-06-27 ZA ZA2018/04317A patent/ZA201804317B/en unknown
-
2019
- 2019-08-12 US US16/538,526 patent/US10961316B2/en active Active
-
2021
- 2021-01-12 JP JP2021002780A patent/JP7060728B2/ja active Active
- 2021-03-29 US US17/301,201 patent/US20210221900A1/en active Pending
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2001060397A1 (en) * | 2000-02-16 | 2001-08-23 | Genentech, Inc. | Uses of agonists and antagonists to modulate activity of tnf-related molecules |
WO2010100056A2 (en) * | 2009-03-02 | 2010-09-10 | Stichting Top Institute Pharma | Antibodies against a proliferating inducing ligand (april) |
CN101928345A (zh) * | 2010-06-21 | 2010-12-29 | 中国科学技术大学 | 一种人源化抗体及其人源化改造方法 |
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN107207602A (zh) | 改良的april结合抗体 | |
WO2010071208A1 (ja) | 抗体の精製方法 | |
AU2014226093A1 (en) | Anti-TNF-anti-IL-17 bispecific antibodies | |
CN102325795A (zh) | 针对组织因子途径抑制剂的抗体 | |
KR20150063311A (ko) | Il-6 결합 분자 | |
AU2020210635A1 (en) | Antibodies against IL-7R alpha subunit and uses thereof | |
BR112020019647A2 (pt) | Anticorpo anti-cd27, fragmento de ligação ao antígeno do mesmo e uso médico do mesmo | |
CN113527482B (zh) | 抗人神经生长因子的抗体 | |
KR101943724B1 (ko) | Ang2 항체 | |
CN114057877A (zh) | 抗pd-l1抗体及其应用 | |
CN113527483B (zh) | 抗人神经生长因子的抗体 | |
KR20190052137A (ko) | 항-rankl 항체 및 그의 용도 | |
CN117715932A (zh) | 一种cdc平台抗体 |
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 | ||
REG | Reference to a national code |
Ref country code: HK Ref legal event code: DE Ref document number: 1243435 Country of ref document: HK |
|
GR01 | Patent grant | ||
GR01 | Patent grant |