CN102574924A - 抗-gitr抗体 - Google Patents
抗-gitr抗体 Download PDFInfo
- Publication number
- CN102574924A CN102574924A CN2010800497565A CN201080049756A CN102574924A CN 102574924 A CN102574924 A CN 102574924A CN 2010800497565 A CN2010800497565 A CN 2010800497565A CN 201080049756 A CN201080049756 A CN 201080049756A CN 102574924 A CN102574924 A CN 102574924A
- Authority
- CN
- China
- Prior art keywords
- ser
- antibody
- gly
- thr
- leu
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 101000801234 Homo sapiens Tumor necrosis factor receptor superfamily member 18 Proteins 0.000 claims abstract description 139
- 102100033728 Tumor necrosis factor receptor superfamily member 18 Human genes 0.000 claims description 139
- 238000000034 method Methods 0.000 claims description 83
- 210000004027 cell Anatomy 0.000 claims description 81
- 125000003275 alpha amino acid group Chemical group 0.000 claims description 51
- 230000027455 binding Effects 0.000 claims description 46
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 42
- 150000001875 compounds Chemical class 0.000 claims description 32
- 108020004707 nucleic acids Proteins 0.000 claims description 31
- 102000039446 nucleic acids Human genes 0.000 claims description 31
- 150000007523 nucleic acids Chemical class 0.000 claims description 31
- 239000012634 fragment Substances 0.000 claims description 27
- 229920001184 polypeptide Polymers 0.000 claims description 27
- 102000004196 processed proteins & peptides Human genes 0.000 claims description 27
- 235000001014 amino acid Nutrition 0.000 claims description 18
- 230000009385 viral infection Effects 0.000 claims description 15
- 108010021625 Immunoglobulin Fragments Proteins 0.000 claims description 13
- 102000008394 Immunoglobulin Fragments Human genes 0.000 claims description 13
- 230000004044 response Effects 0.000 claims description 13
- 238000012360 testing method Methods 0.000 claims description 12
- 210000004408 hybridoma Anatomy 0.000 claims description 10
- 238000006467 substitution reaction Methods 0.000 claims description 8
- 239000002773 nucleotide Substances 0.000 claims description 6
- 125000003729 nucleotide group Chemical group 0.000 claims description 6
- 230000000903 blocking effect Effects 0.000 claims description 4
- 201000001880 Sexual dysfunction Diseases 0.000 claims description 3
- 239000013604 expression vector Substances 0.000 claims description 3
- 206010020718 hyperplasia Diseases 0.000 claims description 3
- 230000036961 partial effect Effects 0.000 claims description 3
- 239000008194 pharmaceutical composition Substances 0.000 claims description 3
- 230000005855 radiation Effects 0.000 claims description 3
- 231100000872 sexual dysfunction Toxicity 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 2
- 238000001890 transfection Methods 0.000 claims description 2
- 102100035360 Cerebellar degeneration-related antigen 1 Human genes 0.000 claims 3
- 238000011282 treatment Methods 0.000 abstract description 40
- 208000026278 immune system disease Diseases 0.000 abstract description 3
- 230000002062 proliferating effect Effects 0.000 abstract description 3
- 102000047758 human TNFRSF18 Human genes 0.000 abstract 1
- 206010028980 Neoplasm Diseases 0.000 description 68
- 241000699660 Mus musculus Species 0.000 description 67
- 241000282414 Homo sapiens Species 0.000 description 57
- 108010047041 Complementarity Determining Regions Proteins 0.000 description 41
- 201000011510 cancer Diseases 0.000 description 38
- 208000015181 infectious disease Diseases 0.000 description 38
- 241000700605 Viruses Species 0.000 description 37
- 239000000427 antigen Substances 0.000 description 34
- 108091007433 antigens Proteins 0.000 description 33
- 102000036639 antigens Human genes 0.000 description 33
- 230000000694 effects Effects 0.000 description 32
- 230000008859 change Effects 0.000 description 29
- 206010022000 influenza Diseases 0.000 description 28
- 241000700157 Rattus norvegicus Species 0.000 description 26
- 108010003137 tyrosyltyrosine Proteins 0.000 description 26
- 108090000623 proteins and genes Proteins 0.000 description 25
- 241000699666 Mus <mouse, genus> Species 0.000 description 23
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 23
- 108010089804 glycyl-threonine Proteins 0.000 description 23
- 239000000203 mixture Substances 0.000 description 23
- 210000001519 tissue Anatomy 0.000 description 23
- 201000010099 disease Diseases 0.000 description 22
- 241001465754 Metazoa Species 0.000 description 21
- 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 20
- 108060003951 Immunoglobulin Proteins 0.000 description 20
- 239000003153 chemical reaction reagent Substances 0.000 description 20
- 102000018358 immunoglobulin Human genes 0.000 description 20
- 208000024891 symptom Diseases 0.000 description 20
- 239000003795 chemical substances by application Substances 0.000 description 19
- 241000880493 Leptailurus serval Species 0.000 description 18
- 210000001744 T-lymphocyte Anatomy 0.000 description 18
- 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 17
- 239000003814 drug Substances 0.000 description 17
- XKUKSGPZAADMRA-UHFFFAOYSA-N glycyl-glycyl-glycine Natural products NCC(=O)NCC(=O)NCC(O)=O XKUKSGPZAADMRA-UHFFFAOYSA-N 0.000 description 17
- 102000004169 proteins and genes Human genes 0.000 description 17
- 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 16
- 229940024606 amino acid Drugs 0.000 description 16
- 230000003053 immunization Effects 0.000 description 16
- 238000002649 immunization Methods 0.000 description 16
- 235000018102 proteins Nutrition 0.000 description 16
- 230000000875 corresponding effect Effects 0.000 description 15
- SOEGEPHNZOISMT-BYPYZUCNSA-N Gly-Ser-Gly Chemical compound NCC(=O)N[C@@H](CO)C(=O)NCC(O)=O SOEGEPHNZOISMT-BYPYZUCNSA-N 0.000 description 14
- 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 14
- 239000000556 agonist Substances 0.000 description 14
- 108010086434 alanyl-seryl-glycine 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
- 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 13
- 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 13
- 150000001413 amino acids Chemical class 0.000 description 13
- -1 cation lipid Chemical class 0.000 description 13
- 230000036541 health Effects 0.000 description 13
- 238000002360 preparation method Methods 0.000 description 13
- 108010073969 valyllysine Proteins 0.000 description 13
- 102000004127 Cytokines Human genes 0.000 description 12
- 108090000695 Cytokines Proteins 0.000 description 12
- 108020004414 DNA Proteins 0.000 description 12
- 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 12
- 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 12
- 230000001684 chronic effect Effects 0.000 description 12
- 230000013595 glycosylation Effects 0.000 description 12
- 238000006206 glycosylation reaction Methods 0.000 description 12
- 108010037850 glycylvaline Proteins 0.000 description 12
- 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 11
- LINKCQUOMUDLKN-KATARQTJSA-N Leu-Thr-Cys Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CS)C(=O)O)NC(=O)[C@H](CC(C)C)N)O LINKCQUOMUDLKN-KATARQTJSA-N 0.000 description 11
- 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 11
- MNYNCKZAEIAONY-XGEHTFHBSA-N Thr-Val-Ser Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CO)C(O)=O MNYNCKZAEIAONY-XGEHTFHBSA-N 0.000 description 11
- 108010050848 glycylleucine Proteins 0.000 description 11
- 108010051242 phenylalanylserine Proteins 0.000 description 11
- 238000011160 research Methods 0.000 description 11
- 239000000523 sample Substances 0.000 description 11
- 210000002966 serum Anatomy 0.000 description 11
- 230000001225 therapeutic effect Effects 0.000 description 11
- 108010072986 threonyl-seryl-lysine Proteins 0.000 description 11
- SZQCDCKIGWQAQN-FXQIFTODSA-N Cys-Arg-Ala Chemical compound [H]N[C@@H](CS)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(O)=O SZQCDCKIGWQAQN-FXQIFTODSA-N 0.000 description 10
- 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 10
- 241000711549 Hepacivirus C Species 0.000 description 10
- WCNWGAUZWWSYDG-SVSWQMSJSA-N Ile-Thr-Ser Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(=O)O)N WCNWGAUZWWSYDG-SVSWQMSJSA-N 0.000 description 10
- 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 10
- FEHQLKKBVJHSEC-SZMVWBNQSA-N Leu-Glu-Trp Chemical compound C1=CC=C2C(C[C@H](NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](N)CC(C)C)C(O)=O)=CNC2=C1 FEHQLKKBVJHSEC-SZMVWBNQSA-N 0.000 description 10
- 241000283984 Rodentia Species 0.000 description 10
- QYSFWUIXDFJUDW-DCAQKATOSA-N Ser-Leu-Arg Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O QYSFWUIXDFJUDW-DCAQKATOSA-N 0.000 description 10
- YUJLIIRMIAGMCQ-CIUDSAMLSA-N Ser-Leu-Ser Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(O)=O YUJLIIRMIAGMCQ-CIUDSAMLSA-N 0.000 description 10
- 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 10
- 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 10
- 230000004913 activation Effects 0.000 description 10
- 125000000539 amino acid group Chemical group 0.000 description 10
- 108010008355 arginyl-glutamine Proteins 0.000 description 10
- 230000006870 function Effects 0.000 description 10
- 208000006454 hepatitis Diseases 0.000 description 10
- 238000004519 manufacturing process Methods 0.000 description 10
- 238000002703 mutagenesis Methods 0.000 description 10
- 231100000350 mutagenesis Toxicity 0.000 description 10
- 238000012545 processing Methods 0.000 description 10
- 238000002560 therapeutic procedure Methods 0.000 description 10
- 108010044292 tryptophyltyrosine Proteins 0.000 description 10
- GCACQYDBDHRVGE-LKXGYXEUSA-N Asp-Thr-Ser Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H]([C@H](O)C)NC(=O)[C@@H](N)CC(O)=O GCACQYDBDHRVGE-LKXGYXEUSA-N 0.000 description 9
- XTZDZAXYPDISRR-MNXVOIDGSA-N Glu-Ile-Lys Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CCC(=O)O)N XTZDZAXYPDISRR-MNXVOIDGSA-N 0.000 description 9
- WNZOCXUOGVYYBJ-CDMKHQONSA-N Gly-Phe-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CC1=CC=CC=C1)NC(=O)CN)O WNZOCXUOGVYYBJ-CDMKHQONSA-N 0.000 description 9
- 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 9
- 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 9
- VEYXZZGMIBKXCN-UBHSHLNASA-N Trp-Asp-Asp Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](CC(=O)O)C(=O)O)N VEYXZZGMIBKXCN-UBHSHLNASA-N 0.000 description 9
- VTFWAGGJDRSQFG-MELADBBJSA-N Tyr-Asn-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CC(=O)N)NC(=O)[C@H](CC2=CC=C(C=C2)O)N)C(=O)O VTFWAGGJDRSQFG-MELADBBJSA-N 0.000 description 9
- ANHVRCNNGJMJNG-BZSNNMDCSA-N Tyr-Tyr-Cys Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)N[C@@H](CC2=CC=C(C=C2)O)C(=O)N[C@@H](CS)C(=O)O)N)O ANHVRCNNGJMJNG-BZSNNMDCSA-N 0.000 description 9
- 230000006907 apoptotic process Effects 0.000 description 9
- 108010068265 aspartyltyrosine Proteins 0.000 description 9
- 238000006073 displacement reaction Methods 0.000 description 9
- 238000005516 engineering process Methods 0.000 description 9
- 108010010147 glycylglutamine Proteins 0.000 description 9
- 102000005962 receptors Human genes 0.000 description 9
- 108020003175 receptors Proteins 0.000 description 9
- 238000012216 screening Methods 0.000 description 9
- 108010038745 tryptophylglycine Proteins 0.000 description 9
- 108010045269 tryptophyltryptophan Proteins 0.000 description 9
- 229960005486 vaccine Drugs 0.000 description 9
- 229910052727 yttrium Inorganic materials 0.000 description 9
- YYSWCHMLFJLLBJ-ZLUOBGJFSA-N Ala-Ala-Ser Chemical compound C[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](CO)C(O)=O YYSWCHMLFJLLBJ-ZLUOBGJFSA-N 0.000 description 8
- ZDILXFDENZVOTL-BPNCWPANSA-N Ala-Val-Tyr Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O ZDILXFDENZVOTL-BPNCWPANSA-N 0.000 description 8
- 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 8
- MIIVFRCYJABHTQ-ONGXEEELSA-N Gly-Leu-Val Chemical compound [H]NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(O)=O MIIVFRCYJABHTQ-ONGXEEELSA-N 0.000 description 8
- ZTLGVASZOIKNIX-DCAQKATOSA-N Leu-Gln-Glu Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H](CCC(=O)O)C(=O)O)N ZTLGVASZOIKNIX-DCAQKATOSA-N 0.000 description 8
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 8
- YMTLKLXDFCSCNX-BYPYZUCNSA-N Ser-Gly-Gly Chemical compound OC[C@H](N)C(=O)NCC(=O)NCC(O)=O YMTLKLXDFCSCNX-BYPYZUCNSA-N 0.000 description 8
- UIPXCLNLUUAMJU-JBDRJPRFSA-N Ser-Ile-Ser Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(O)=O UIPXCLNLUUAMJU-JBDRJPRFSA-N 0.000 description 8
- UBRMZSHOOIVJPW-SRVKXCTJSA-N Ser-Leu-Lys Chemical compound OC[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(O)=O UBRMZSHOOIVJPW-SRVKXCTJSA-N 0.000 description 8
- 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 8
- 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 8
- 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 8
- 108010081404 acein-2 Proteins 0.000 description 8
- 108010069205 aspartyl-phenylalanine Proteins 0.000 description 8
- 108010067216 glycyl-glycyl-glycine Proteins 0.000 description 8
- 230000005764 inhibitory process Effects 0.000 description 8
- 108010038320 lysylphenylalanine Proteins 0.000 description 8
- 239000000126 substance Substances 0.000 description 8
- 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 7
- 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 7
- 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 7
- QNFRBNZGVVKBNJ-PEFMBERDSA-N Asp-Ile-Gln Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)O)NC(=O)[C@H](CC(=O)O)N QNFRBNZGVVKBNJ-PEFMBERDSA-N 0.000 description 7
- 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
- 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 7
- 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 7
- RYAOJUMWLWUGNW-QMMMGPOBSA-N Gly-Val-Gly Chemical compound NCC(=O)N[C@@H](C(C)C)C(=O)NCC(O)=O RYAOJUMWLWUGNW-QMMMGPOBSA-N 0.000 description 7
- 241000700721 Hepatitis B virus Species 0.000 description 7
- 108010065920 Insulin Lispro Proteins 0.000 description 7
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 7
- AIMGJYMCTAABEN-GVXVVHGQSA-N Leu-Val-Glu Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(O)=O)C(O)=O AIMGJYMCTAABEN-GVXVVHGQSA-N 0.000 description 7
- 101100425749 Mus musculus Tnfrsf18 gene Proteins 0.000 description 7
- 108010079364 N-glycylalanine Proteins 0.000 description 7
- 241000700159 Rattus Species 0.000 description 7
- XXXAXOWMBOKTRN-XPUUQOCRSA-N Ser-Gly-Val Chemical compound [H]N[C@@H](CO)C(=O)NCC(=O)N[C@@H](C(C)C)C(O)=O XXXAXOWMBOKTRN-XPUUQOCRSA-N 0.000 description 7
- 238000013459 approach Methods 0.000 description 7
- 108010077245 asparaginyl-proline Proteins 0.000 description 7
- 238000006243 chemical reaction Methods 0.000 description 7
- 238000003745 diagnosis Methods 0.000 description 7
- VPZXBVLAVMBEQI-UHFFFAOYSA-N glycyl-DL-alpha-alanine Natural products OC(=O)C(C)NC(=O)CN VPZXBVLAVMBEQI-UHFFFAOYSA-N 0.000 description 7
- 108010018006 histidylserine Proteins 0.000 description 7
- 230000036039 immunity Effects 0.000 description 7
- 230000013011 mating Effects 0.000 description 7
- 230000001404 mediated effect Effects 0.000 description 7
- 210000000056 organ Anatomy 0.000 description 7
- 150000003384 small molecules Chemical class 0.000 description 7
- 241000894007 species Species 0.000 description 7
- 238000010561 standard procedure Methods 0.000 description 7
- ZRKFYGHZFMAOKI-QMGMOQQFSA-N tgfbeta Chemical compound C([C@H](NC(=O)[C@H](C(C)C)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CC(C)C)NC(=O)CNC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CCSC)C(C)C)[C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O)C1=CC=C(O)C=C1 ZRKFYGHZFMAOKI-QMGMOQQFSA-N 0.000 description 7
- 108010061238 threonyl-glycine Proteins 0.000 description 7
- 229910052720 vanadium Inorganic materials 0.000 description 7
- GOKCTAJWRPSCHP-VHWLVUOQSA-N Asn-Ile-Trp Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC1=CNC2=CC=CC=C21)C(=O)O)NC(=O)[C@H](CC(=O)N)N GOKCTAJWRPSCHP-VHWLVUOQSA-N 0.000 description 6
- JUWZKMBALYLZCK-WHFBIAKZSA-N Asp-Gly-Asn Chemical compound OC(=O)C[C@H](N)C(=O)NCC(=O)N[C@@H](CC(N)=O)C(O)=O JUWZKMBALYLZCK-WHFBIAKZSA-N 0.000 description 6
- RXBGWGRSWXOBGK-KKUMJFAQSA-N Asp-Lys-Tyr Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O RXBGWGRSWXOBGK-KKUMJFAQSA-N 0.000 description 6
- 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 6
- 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 6
- YUXIEONARHPUTK-JBACZVJFSA-N Glu-Phe-Trp Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)N[C@@H](CC2=CNC3=CC=CC=C32)C(=O)O)NC(=O)[C@H](CCC(=O)O)N YUXIEONARHPUTK-JBACZVJFSA-N 0.000 description 6
- LCNXZQROPKFGQK-WHFBIAKZSA-N Gly-Asp-Ser Chemical compound NCC(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(O)=O LCNXZQROPKFGQK-WHFBIAKZSA-N 0.000 description 6
- GGAPHLIUUTVYMX-QWRGUYRKSA-N Gly-Phe-Ser Chemical compound OC[C@@H](C([O-])=O)NC(=O)[C@@H](NC(=O)C[NH3+])CC1=CC=CC=C1 GGAPHLIUUTVYMX-QWRGUYRKSA-N 0.000 description 6
- ZZWUYQXMIFTIIY-WEDXCCLWSA-N Gly-Thr-Leu Chemical compound [H]NCC(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(O)=O ZZWUYQXMIFTIIY-WEDXCCLWSA-N 0.000 description 6
- XHVONGZZVUUORG-WEDXCCLWSA-N Gly-Thr-Lys Chemical compound NCC(=O)N[C@@H]([C@H](O)C)C(=O)N[C@H](C(O)=O)CCCCN XHVONGZZVUUORG-WEDXCCLWSA-N 0.000 description 6
- GBYYQVBXFVDJPJ-WLTAIBSBSA-N Gly-Tyr-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CC1=CC=C(C=C1)O)NC(=O)CN)O GBYYQVBXFVDJPJ-WLTAIBSBSA-N 0.000 description 6
- ADDYYRVQQZFIMW-MNXVOIDGSA-N Ile-Lys-Glu Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(=O)O)C(=O)O)N ADDYYRVQQZFIMW-MNXVOIDGSA-N 0.000 description 6
- AYFVYJQAPQTCCC-GBXIJSLDSA-N L-threonine Chemical compound C[C@@H](O)[C@H](N)C(O)=O AYFVYJQAPQTCCC-GBXIJSLDSA-N 0.000 description 6
- 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 6
- 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 6
- KIZIOFNVSOSKJI-CIUDSAMLSA-N Leu-Ser-Cys Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CS)C(=O)O)N KIZIOFNVSOSKJI-CIUDSAMLSA-N 0.000 description 6
- PPGBXYKMUMHFBF-KATARQTJSA-N Leu-Ser-Thr Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(O)=O PPGBXYKMUMHFBF-KATARQTJSA-N 0.000 description 6
- 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 6
- 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 6
- 201000005505 Measles Diseases 0.000 description 6
- 108091007491 NSP3 Papain-like protease domains Proteins 0.000 description 6
- 108091028043 Nucleic acid sequence Proteins 0.000 description 6
- 208000037581 Persistent Infection Diseases 0.000 description 6
- YOFKMVUAZGPFCF-IHRRRGAJSA-N Phe-Met-Asn Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(N)=O)C(O)=O YOFKMVUAZGPFCF-IHRRRGAJSA-N 0.000 description 6
- SSSFPISOZOLQNP-GUBZILKMSA-N Pro-Arg-Asp Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(O)=O SSSFPISOZOLQNP-GUBZILKMSA-N 0.000 description 6
- ULVMNZOKDBHKKI-ACZMJKKPSA-N Ser-Gln-Asp Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(O)=O)C(O)=O ULVMNZOKDBHKKI-ACZMJKKPSA-N 0.000 description 6
- 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 6
- 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 6
- VVKVHAOOUGNDPJ-SRVKXCTJSA-N Ser-Tyr-Ser Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CO)C(O)=O VVKVHAOOUGNDPJ-SRVKXCTJSA-N 0.000 description 6
- 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 6
- 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 6
- BOMYCJXTWRMKJA-RNXOBYDBSA-N Trp-Phe-Phe Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)N[C@@H](CC2=CC=CC=C2)C(=O)O)NC(=O)[C@H](CC3=CNC4=CC=CC=C43)N BOMYCJXTWRMKJA-RNXOBYDBSA-N 0.000 description 6
- YXSSXUIBUJGHJY-SFJXLCSZSA-N Trp-Thr-Phe Chemical compound C([C@H](NC(=O)[C@@H](NC(=O)[C@@H](N)CC=1C2=CC=CC=C2NC=1)[C@H](O)C)C(O)=O)C1=CC=CC=C1 YXSSXUIBUJGHJY-SFJXLCSZSA-N 0.000 description 6
- JVYIGCARISMLMV-HOCLYGCPSA-N Val-Gly-Trp Chemical compound CC(C)[C@@H](C(=O)NCC(=O)N[C@@H](CC1=CNC2=CC=CC=C21)C(=O)O)N JVYIGCARISMLMV-HOCLYGCPSA-N 0.000 description 6
- VHIZXDZMTDVFGX-DCAQKATOSA-N Val-Ser-Leu Chemical compound CC(C)C[C@@H](C(=O)O)NC(=O)[C@H](CO)NC(=O)[C@H](C(C)C)N VHIZXDZMTDVFGX-DCAQKATOSA-N 0.000 description 6
- 230000001154 acute effect Effects 0.000 description 6
- 108010069020 alanyl-prolyl-glycine Proteins 0.000 description 6
- 230000000890 antigenic effect Effects 0.000 description 6
- 230000005540 biological transmission Effects 0.000 description 6
- 229940079593 drug Drugs 0.000 description 6
- 239000012530 fluid Substances 0.000 description 6
- 108010045126 glycyl-tyrosyl-glycine Proteins 0.000 description 6
- 108010015792 glycyllysine Proteins 0.000 description 6
- 231100000283 hepatitis Toxicity 0.000 description 6
- 238000011081 inoculation Methods 0.000 description 6
- 125000001360 methionine group Chemical group N[C@@H](CCSC)C(=O)* 0.000 description 6
- 230000001717 pathogenic effect Effects 0.000 description 6
- 108010077112 prolyl-proline Proteins 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 239000002512 suppressor factor Substances 0.000 description 6
- 239000003981 vehicle Substances 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
- BTYTYHBSJKQBQA-GCJQMDKQSA-N Ala-Asp-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CC(=O)O)NC(=O)[C@H](C)N)O BTYTYHBSJKQBQA-GCJQMDKQSA-N 0.000 description 5
- GIVATXIGCXFQQA-FXQIFTODSA-N Arg-Ala-Ser Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CCCN=C(N)N GIVATXIGCXFQQA-FXQIFTODSA-N 0.000 description 5
- RYEWQKQXRJCHIO-SRVKXCTJSA-N Asp-Asn-Tyr Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 RYEWQKQXRJCHIO-SRVKXCTJSA-N 0.000 description 5
- FQCILXROGNOZON-YUMQZZPRSA-N Gln-Pro-Gly Chemical compound NC(=O)CC[C@H](N)C(=O)N1CCC[C@H]1C(=O)NCC(O)=O FQCILXROGNOZON-YUMQZZPRSA-N 0.000 description 5
- BJVBMSTUUWGZKX-JYJNAYRXSA-N Gln-Tyr-His Chemical compound N[C@@H](CCC(N)=O)C(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)N[C@@H](Cc1cnc[nH]1)C(O)=O BJVBMSTUUWGZKX-JYJNAYRXSA-N 0.000 description 5
- AVZHGSCDKIQZPQ-CIUDSAMLSA-N Glu-Arg-Ala Chemical compound C[C@H](NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@@H](N)CCC(O)=O)C(O)=O AVZHGSCDKIQZPQ-CIUDSAMLSA-N 0.000 description 5
- PAQUJCSYVIBPLC-AVGNSLFASA-N Glu-Asp-Phe Chemical compound OC(=O)CC[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 PAQUJCSYVIBPLC-AVGNSLFASA-N 0.000 description 5
- PDUHNKAFQXQNLH-ZETCQYMHSA-N Gly-Lys-Gly Chemical compound NCCCC[C@H](NC(=O)CN)C(=O)NCC(O)=O PDUHNKAFQXQNLH-ZETCQYMHSA-N 0.000 description 5
- 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 5
- ASCFJMSGKUIRDU-ZPFDUUQYSA-N Ile-Arg-Gln Chemical compound CC[C@H](C)[C@H](N)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(N)=O)C(O)=O ASCFJMSGKUIRDU-ZPFDUUQYSA-N 0.000 description 5
- QESXLSQLQHHTIX-RHYQMDGZSA-N Leu-Val-Thr Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O QESXLSQLQHHTIX-RHYQMDGZSA-N 0.000 description 5
- YKIRNDPUWONXQN-GUBZILKMSA-N Lys-Asn-Gln Chemical compound C(CCN)C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CCC(=O)N)C(=O)O)N YKIRNDPUWONXQN-GUBZILKMSA-N 0.000 description 5
- 241000283973 Oryctolagus cuniculus Species 0.000 description 5
- JMVQDLDPDBXAAX-YUMQZZPRSA-N Pro-Gly-Gln Chemical compound NC(=O)CC[C@@H](C(O)=O)NC(=O)CNC(=O)[C@@H]1CCCN1 JMVQDLDPDBXAAX-YUMQZZPRSA-N 0.000 description 5
- RCYUBVHMVUHEBM-RCWTZXSCSA-N Pro-Pro-Thr Chemical compound [H]N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)N[C@@H]([C@@H](C)O)C(O)=O RCYUBVHMVUHEBM-RCWTZXSCSA-N 0.000 description 5
- LNICFEXCAHIJOR-DCAQKATOSA-N Pro-Ser-Leu Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(O)=O LNICFEXCAHIJOR-DCAQKATOSA-N 0.000 description 5
- FMDHKPRACUXATF-ACZMJKKPSA-N Ser-Gln-Ser Chemical compound OC[C@H](N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CO)C(O)=O FMDHKPRACUXATF-ACZMJKKPSA-N 0.000 description 5
- RXUOAOOZIWABBW-XGEHTFHBSA-N Ser-Thr-Arg Chemical compound OC[C@H](N)C(=O)N[C@@H]([C@H](O)C)C(=O)N[C@H](C(O)=O)CCCN=C(N)N RXUOAOOZIWABBW-XGEHTFHBSA-N 0.000 description 5
- 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 5
- NKANXQFJJICGDU-QPLCGJKRSA-N Tamoxifen Chemical compound C=1C=CC=CC=1C(/CC)=C(C=1C=CC(OCCN(C)C)=CC=1)/C1=CC=CC=C1 NKANXQFJJICGDU-QPLCGJKRSA-N 0.000 description 5
- KRPKYGOFYUNIGM-XVSYOHENSA-N Thr-Asp-Phe Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)O)N)O KRPKYGOFYUNIGM-XVSYOHENSA-N 0.000 description 5
- 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 5
- YOPQYBJJNSIQGZ-JNPHEJMOSA-N Thr-Tyr-Tyr Chemical compound C([C@H](NC(=O)[C@@H](N)[C@H](O)C)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(O)=O)C1=CC=C(O)C=C1 YOPQYBJJNSIQGZ-JNPHEJMOSA-N 0.000 description 5
- 102000004887 Transforming Growth Factor beta Human genes 0.000 description 5
- 108090001012 Transforming Growth Factor beta Proteins 0.000 description 5
- SVGAWGVHFIYAEE-JSGCOSHPSA-N Trp-Gly-Gln Chemical compound C1=CC=C2C(C[C@H](N)C(=O)NCC(=O)N[C@@H](CCC(N)=O)C(O)=O)=CNC2=C1 SVGAWGVHFIYAEE-JSGCOSHPSA-N 0.000 description 5
- 108060008683 Tumor Necrosis Factor Receptor Proteins 0.000 description 5
- WQOHKVRQDLNDIL-YJRXYDGGSA-N Tyr-Thr-Ser 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](CO)C(O)=O WQOHKVRQDLNDIL-YJRXYDGGSA-N 0.000 description 5
- 239000002253 acid Substances 0.000 description 5
- 108010008685 alanyl-glutamyl-aspartic acid Proteins 0.000 description 5
- 108010087924 alanylproline Proteins 0.000 description 5
- 230000000840 anti-viral effect Effects 0.000 description 5
- 238000003556 assay Methods 0.000 description 5
- 230000008901 benefit Effects 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
- 239000008280 blood Substances 0.000 description 5
- 210000001124 body fluid Anatomy 0.000 description 5
- 239000010839 body fluid Substances 0.000 description 5
- 238000002648 combination therapy Methods 0.000 description 5
- 230000002950 deficient Effects 0.000 description 5
- 238000000684 flow cytometry Methods 0.000 description 5
- 108010063718 gamma-glutamylaspartic acid Proteins 0.000 description 5
- 230000002068 genetic effect Effects 0.000 description 5
- 108010078144 glutaminyl-glycine Proteins 0.000 description 5
- 230000001900 immune effect Effects 0.000 description 5
- 230000001939 inductive effect Effects 0.000 description 5
- 230000004054 inflammatory process Effects 0.000 description 5
- 239000002245 particle Substances 0.000 description 5
- 108010070409 phenylalanyl-glycyl-glycine Proteins 0.000 description 5
- 239000013612 plasmid Substances 0.000 description 5
- 230000008569 process Effects 0.000 description 5
- 108010087846 prolyl-prolyl-glycine Proteins 0.000 description 5
- 230000000638 stimulation Effects 0.000 description 5
- 102000003298 tumor necrosis factor receptor Human genes 0.000 description 5
- AWNAEZICPNGAJK-FXQIFTODSA-N Ala-Met-Ser Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CO)C(O)=O AWNAEZICPNGAJK-FXQIFTODSA-N 0.000 description 4
- DYXOFPBJBAHWFY-JBDRJPRFSA-N Ala-Ser-Ile Chemical compound CC[C@H](C)[C@@H](C(O)=O)NC(=O)[C@H](CO)NC(=O)[C@H](C)N DYXOFPBJBAHWFY-JBDRJPRFSA-N 0.000 description 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
- JGDGLDNAQJJGJI-AVGNSLFASA-N Arg-Arg-His Chemical compound C1=C(NC=N1)C[C@@H](C(=O)O)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CCCN=C(N)N)N JGDGLDNAQJJGJI-AVGNSLFASA-N 0.000 description 4
- PNHQRQTVBRDIEF-CIUDSAMLSA-N Asn-Leu-Ala Chemical compound C[C@@H](C(=O)O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(=O)N)N PNHQRQTVBRDIEF-CIUDSAMLSA-N 0.000 description 4
- HFPXZWPUVFVNLL-GUBZILKMSA-N Asn-Leu-Gln Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(O)=O HFPXZWPUVFVNLL-GUBZILKMSA-N 0.000 description 4
- MRQQMVZUHXUPEV-IHRRRGAJSA-N Asp-Arg-Phe Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O MRQQMVZUHXUPEV-IHRRRGAJSA-N 0.000 description 4
- OFYVKOXTTDCUIL-FXQIFTODSA-N Asp-Ser-Met Chemical compound CSCC[C@@H](C(=O)O)NC(=O)[C@H](CO)NC(=O)[C@H](CC(=O)O)N OFYVKOXTTDCUIL-FXQIFTODSA-N 0.000 description 4
- 208000023275 Autoimmune disease Diseases 0.000 description 4
- 201000009030 Carcinoma Diseases 0.000 description 4
- 206010011224 Cough Diseases 0.000 description 4
- GEEXORWTBTUOHC-FXQIFTODSA-N Cys-Arg-Ser Chemical compound C(C[C@@H](C(=O)N[C@@H](CO)C(=O)O)NC(=O)[C@H](CS)N)CN=C(N)N GEEXORWTBTUOHC-FXQIFTODSA-N 0.000 description 4
- 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 4
- 238000002965 ELISA Methods 0.000 description 4
- 102000004190 Enzymes Human genes 0.000 description 4
- 108090000790 Enzymes Proteins 0.000 description 4
- SMLDOQHTOAAFJQ-WDSKDSINSA-N Gln-Gly-Ser Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)NCC(=O)N[C@@H](CO)C(O)=O SMLDOQHTOAAFJQ-WDSKDSINSA-N 0.000 description 4
- ICDIMQAMJGDHSE-GUBZILKMSA-N Gln-His-Ser Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CO)C(O)=O ICDIMQAMJGDHSE-GUBZILKMSA-N 0.000 description 4
- WLRYGVYQFXRJDA-DCAQKATOSA-N Gln-Pro-Pro Chemical compound NC(=O)CC[C@H](N)C(=O)N1CCC[C@H]1C(=O)N1[C@H](C(O)=O)CCC1 WLRYGVYQFXRJDA-DCAQKATOSA-N 0.000 description 4
- IEGFSKKANYKBDU-QWHCGFSZSA-N Gly-Phe-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CC2=CC=CC=C2)NC(=O)CN)C(=O)O IEGFSKKANYKBDU-QWHCGFSZSA-N 0.000 description 4
- LCRDMSSAKLTKBU-ZDLURKLDSA-N Gly-Ser-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)[C@H](CO)NC(=O)CN LCRDMSSAKLTKBU-ZDLURKLDSA-N 0.000 description 4
- HQSKKSLNLSTONK-JTQLQIEISA-N Gly-Tyr-Gly Chemical compound OC(=O)CNC(=O)[C@@H](NC(=O)CN)CC1=CC=C(O)C=C1 HQSKKSLNLSTONK-JTQLQIEISA-N 0.000 description 4
- NGBGZCUWFVVJKC-IRXDYDNUSA-N Gly-Tyr-Tyr Chemical compound C([C@H](NC(=O)CN)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(O)=O)C1=CC=C(O)C=C1 NGBGZCUWFVVJKC-IRXDYDNUSA-N 0.000 description 4
- YGHSQRJSHKYUJY-SCZZXKLOSA-N Gly-Val-Pro Chemical compound CC(C)[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)CN YGHSQRJSHKYUJY-SCZZXKLOSA-N 0.000 description 4
- KSOBNUBCYHGUKH-UWVGGRQHSA-N Gly-Val-Val Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)[C@H](C(C)C)NC(=O)CN KSOBNUBCYHGUKH-UWVGGRQHSA-N 0.000 description 4
- WZBLRQQCDYYRTD-SIXJUCDHSA-N His-Ile-Trp Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC1=CNC2=CC=CC=C21)C(=O)O)NC(=O)[C@H](CC3=CN=CN3)N WZBLRQQCDYYRTD-SIXJUCDHSA-N 0.000 description 4
- MDOBWSFNSNPENN-PMVVWTBXSA-N His-Thr-Gly Chemical compound [H]N[C@@H](CC1=CNC=N1)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(O)=O MDOBWSFNSNPENN-PMVVWTBXSA-N 0.000 description 4
- PXKACEXYLPBMAD-JBDRJPRFSA-N Ile-Ser-Ser Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)O)N PXKACEXYLPBMAD-JBDRJPRFSA-N 0.000 description 4
- DTPGSUQHUMELQB-GVARAGBVSA-N Ile-Tyr-Ala Chemical compound CC[C@H](C)[C@H](N)C(=O)N[C@H](C(=O)N[C@@H](C)C(O)=O)CC1=CC=C(O)C=C1 DTPGSUQHUMELQB-GVARAGBVSA-N 0.000 description 4
- 206010061218 Inflammation Diseases 0.000 description 4
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 4
- 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 4
- BQSLGJHIAGOZCD-CIUDSAMLSA-N Leu-Ala-Ser Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](CO)C(O)=O BQSLGJHIAGOZCD-CIUDSAMLSA-N 0.000 description 4
- NRFGTHFONZYFNY-MGHWNKPDSA-N Leu-Ile-Tyr Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 NRFGTHFONZYFNY-MGHWNKPDSA-N 0.000 description 4
- RNYLNYTYMXACRI-VFAJRCTISA-N Leu-Thr-Trp Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CNC2=C1C=CC=C2)C(O)=O RNYLNYTYMXACRI-VFAJRCTISA-N 0.000 description 4
- SKRGVGLIRUGANF-AVGNSLFASA-N Lys-Leu-Glu Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(O)=O SKRGVGLIRUGANF-AVGNSLFASA-N 0.000 description 4
- LBSWWNKMVPAXOI-GUBZILKMSA-N Met-Val-Ser Chemical compound CSCC[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CO)C(O)=O LBSWWNKMVPAXOI-GUBZILKMSA-N 0.000 description 4
- PESQCPHRXOFIPX-UHFFFAOYSA-N N-L-methionyl-L-tyrosine Natural products CSCCC(N)C(=O)NC(C(O)=O)CC1=CC=C(O)C=C1 PESQCPHRXOFIPX-UHFFFAOYSA-N 0.000 description 4
- AJHCSUXXECOXOY-UHFFFAOYSA-N N-glycyl-L-tryptophan Natural products C1=CC=C2C(CC(NC(=O)CN)C(O)=O)=CNC2=C1 AJHCSUXXECOXOY-UHFFFAOYSA-N 0.000 description 4
- 108091034117 Oligonucleotide Proteins 0.000 description 4
- BPCLGWHVPVTTFM-QWRGUYRKSA-N Phe-Ser-Gly Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CO)C(=O)NCC(O)=O BPCLGWHVPVTTFM-QWRGUYRKSA-N 0.000 description 4
- 206010035226 Plasma cell myeloma Diseases 0.000 description 4
- HBOABDXGTMMDSE-GUBZILKMSA-N Ser-Arg-Val Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C(C)C)C(O)=O HBOABDXGTMMDSE-GUBZILKMSA-N 0.000 description 4
- XWCYBVBLJRWOFR-WDSKDSINSA-N Ser-Gln-Gly Chemical compound OC[C@H](N)C(=O)N[C@@H](CCC(N)=O)C(=O)NCC(O)=O XWCYBVBLJRWOFR-WDSKDSINSA-N 0.000 description 4
- VQBCMLMPEWPUTB-ACZMJKKPSA-N Ser-Glu-Ser Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(O)=O VQBCMLMPEWPUTB-ACZMJKKPSA-N 0.000 description 4
- HDBOEVPDIDDEPC-CIUDSAMLSA-N Ser-Lys-Asn Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(O)=O HDBOEVPDIDDEPC-CIUDSAMLSA-N 0.000 description 4
- ADJDNJCSPNFFPI-FXQIFTODSA-N Ser-Pro-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@@H]1CCCN1C(=O)[C@@H](N)CO ADJDNJCSPNFFPI-FXQIFTODSA-N 0.000 description 4
- 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
- 208000037065 Subacute sclerosing leukoencephalitis Diseases 0.000 description 4
- 206010042297 Subacute sclerosing panencephalitis Diseases 0.000 description 4
- PAXANSWUSVPFNK-IUKAMOBKSA-N Thr-Ile-Asn Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)O)NC(=O)[C@H]([C@@H](C)O)N PAXANSWUSVPFNK-IUKAMOBKSA-N 0.000 description 4
- 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 4
- MECLEFZMPPOEAC-VOAKCMCISA-N Thr-Leu-Lys Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)O)N)O MECLEFZMPPOEAC-VOAKCMCISA-N 0.000 description 4
- KZSYAEWQMJEGRZ-RHYQMDGZSA-N Thr-Leu-Val Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(O)=O KZSYAEWQMJEGRZ-RHYQMDGZSA-N 0.000 description 4
- SPVHQURZJCUDQC-VOAKCMCISA-N Thr-Lys-Leu Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(O)=O SPVHQURZJCUDQC-VOAKCMCISA-N 0.000 description 4
- 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 4
- GQHAIUPYZPTADF-FDARSICLSA-N Trp-Ile-Arg Chemical compound C1=CC=C2C(C[C@H](N)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCCN=C(N)N)C(O)=O)=CNC2=C1 GQHAIUPYZPTADF-FDARSICLSA-N 0.000 description 4
- BGWSLEYVITZIQP-DCPHZVHLSA-N Trp-Phe-Ala Chemical compound C[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N)Cc1c[nH]c2ccccc12)C(O)=O BGWSLEYVITZIQP-DCPHZVHLSA-N 0.000 description 4
- PKZIWSHDJYIPRH-JBACZVJFSA-N Trp-Tyr-Gln Chemical compound [H]N[C@@H](CC1=CNC2=C1C=CC=C2)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CCC(N)=O)C(O)=O PKZIWSHDJYIPRH-JBACZVJFSA-N 0.000 description 4
- 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 4
- AOIZTZRWMSPPAY-KAOXEZKKSA-N Tyr-Thr-Pro Chemical compound C[C@H]([C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](CC2=CC=C(C=C2)O)N)O AOIZTZRWMSPPAY-KAOXEZKKSA-N 0.000 description 4
- ZYVAAYAOTVJBSS-GMVOTWDCSA-N Tyr-Trp-Ala Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC1=CNC2=C1C=CC=C2)C(=O)N[C@@H](C)C(O)=O ZYVAAYAOTVJBSS-GMVOTWDCSA-N 0.000 description 4
- YMZYSCDRTXEOKD-IHPCNDPISA-N Tyr-Trp-Asn Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)O)NC(=O)[C@H](CC3=CC=C(C=C3)O)N YMZYSCDRTXEOKD-IHPCNDPISA-N 0.000 description 4
- NUQZCPSZHGIYTA-HKUYNNGSSA-N Tyr-Trp-Gly Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)NCC(=O)O)NC(=O)[C@H](CC3=CC=C(C=C3)O)N NUQZCPSZHGIYTA-HKUYNNGSSA-N 0.000 description 4
- GZWPQZDVTBZVEP-BZSNNMDCSA-N Tyr-Tyr-Asn Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC(N)=O)C(O)=O GZWPQZDVTBZVEP-BZSNNMDCSA-N 0.000 description 4
- 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 4
- BYOHPUZJVXWHAE-BYULHYEWSA-N Val-Asn-Asn Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CC(=O)N)C(=O)O)N BYOHPUZJVXWHAE-BYULHYEWSA-N 0.000 description 4
- 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 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
- 208000036142 Viral infection Diseases 0.000 description 4
- 108010050025 alpha-glutamyltryptophan Proteins 0.000 description 4
- 230000003321 amplification Effects 0.000 description 4
- 239000003443 antiviral agent Substances 0.000 description 4
- 230000001580 bacterial effect Effects 0.000 description 4
- 210000004369 blood Anatomy 0.000 description 4
- 230000000295 complement effect Effects 0.000 description 4
- 239000013078 crystal Substances 0.000 description 4
- OPTASPLRGRRNAP-UHFFFAOYSA-N cytosine Chemical compound NC=1C=CNC(=O)N=1 OPTASPLRGRRNAP-UHFFFAOYSA-N 0.000 description 4
- 230000009849 deactivation Effects 0.000 description 4
- 230000001419 dependent effect Effects 0.000 description 4
- 238000011161 development Methods 0.000 description 4
- 230000008034 disappearance Effects 0.000 description 4
- 238000010494 dissociation reaction Methods 0.000 description 4
- 230000005593 dissociations Effects 0.000 description 4
- 239000012636 effector Substances 0.000 description 4
- OVBPIULPVIDEAO-LBPRGKRZSA-N folic acid Chemical compound C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-LBPRGKRZSA-N 0.000 description 4
- 208000002672 hepatitis B Diseases 0.000 description 4
- 108010036413 histidylglycine Proteins 0.000 description 4
- 108010025306 histidylleucine Proteins 0.000 description 4
- 229910052739 hydrogen Inorganic materials 0.000 description 4
- 230000002998 immunogenetic effect Effects 0.000 description 4
- 208000027866 inflammatory disease Diseases 0.000 description 4
- 230000002757 inflammatory effect Effects 0.000 description 4
- 238000003780 insertion Methods 0.000 description 4
- 230000037431 insertion Effects 0.000 description 4
- 238000012004 kinetic exclusion assay Methods 0.000 description 4
- 201000007270 liver cancer Diseases 0.000 description 4
- 208000014018 liver neoplasm Diseases 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 238000005259 measurement Methods 0.000 description 4
- 229960000485 methotrexate Drugs 0.000 description 4
- 230000004048 modification Effects 0.000 description 4
- 238000012986 modification Methods 0.000 description 4
- 238000003199 nucleic acid amplification method Methods 0.000 description 4
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Substances [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 4
- 108010029020 prolylglycine Proteins 0.000 description 4
- 230000008521 reorganization Effects 0.000 description 4
- 150000003839 salts Chemical class 0.000 description 4
- 230000028327 secretion Effects 0.000 description 4
- 108010026333 seryl-proline Proteins 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 230000009466 transformation Effects 0.000 description 4
- 108010009962 valyltyrosine Proteins 0.000 description 4
- 230000003612 virological effect Effects 0.000 description 4
- 208000030507 AIDS Diseases 0.000 description 3
- 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 3
- KXEVYGKATAMXJJ-ACZMJKKPSA-N Ala-Glu-Asp Chemical compound C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(O)=O KXEVYGKATAMXJJ-ACZMJKKPSA-N 0.000 description 3
- KLALXKYLOMZDQT-ZLUOBGJFSA-N Ala-Ser-Asn Chemical compound C[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@H](C(O)=O)CC(N)=O KLALXKYLOMZDQT-ZLUOBGJFSA-N 0.000 description 3
- HOVPGJUNRLMIOZ-CIUDSAMLSA-N Ala-Ser-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](CO)NC(=O)[C@H](C)N HOVPGJUNRLMIOZ-CIUDSAMLSA-N 0.000 description 3
- MCYJBCKCAPERSE-FXQIFTODSA-N Arg-Ala-Asp Chemical compound OC(=O)C[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CCCN=C(N)N MCYJBCKCAPERSE-FXQIFTODSA-N 0.000 description 3
- HUZGPXBILPMCHM-IHRRRGAJSA-N Asn-Arg-Phe Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O HUZGPXBILPMCHM-IHRRRGAJSA-N 0.000 description 3
- JSHWXQIZOCVWIA-ZKWXMUAHSA-N Asp-Ser-Val Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(O)=O JSHWXQIZOCVWIA-ZKWXMUAHSA-N 0.000 description 3
- 241000894006 Bacteria Species 0.000 description 3
- MBABCNBNDNGODA-LTGLSHGVSA-N Bullatacin Natural products O=C1C(C[C@H](O)CCCCCCCCCC[C@@H](O)[C@@H]2O[C@@H]([C@@H]3O[C@H]([C@@H](O)CCCCCCCCCC)CC3)CC2)=C[C@H](C)O1 MBABCNBNDNGODA-LTGLSHGVSA-N 0.000 description 3
- 241000195493 Cryptophyta Species 0.000 description 3
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 3
- UHDGCWIWMRVCDJ-CCXZUQQUSA-N Cytarabine Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O1 UHDGCWIWMRVCDJ-CCXZUQQUSA-N 0.000 description 3
- 208000016192 Demyelinating disease Diseases 0.000 description 3
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 3
- RBWKVOSARCFSQQ-FXQIFTODSA-N Gln-Gln-Ser Chemical compound NC(=O)CC[C@H](N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CO)C(O)=O RBWKVOSARCFSQQ-FXQIFTODSA-N 0.000 description 3
- HNAUFGBKJLTWQE-IFFSRLJSSA-N Gln-Val-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](C(C)C)NC(=O)[C@H](CCC(=O)N)N)O HNAUFGBKJLTWQE-IFFSRLJSSA-N 0.000 description 3
- LKDIBBOKUAASNP-FXQIFTODSA-N Glu-Ala-Glu Chemical compound OC(=O)CC[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(O)=O LKDIBBOKUAASNP-FXQIFTODSA-N 0.000 description 3
- DYFJZDDQPNIPAB-NHCYSSNCSA-N Glu-Arg-Val Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C(C)C)C(O)=O DYFJZDDQPNIPAB-NHCYSSNCSA-N 0.000 description 3
- WATXSTJXNBOHKD-LAEOZQHASA-N Glu-Asp-Val Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](C(C)C)C(O)=O WATXSTJXNBOHKD-LAEOZQHASA-N 0.000 description 3
- 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 3
- YQPFCZVKMUVZIN-AUTRQRHGSA-N Glu-Val-Gln Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(N)=O)C(O)=O YQPFCZVKMUVZIN-AUTRQRHGSA-N 0.000 description 3
- 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 3
- OCDLPQDYTJPWNG-YUMQZZPRSA-N Gly-Asn-Lys Chemical compound C(CCN)C[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)N)NC(=O)CN OCDLPQDYTJPWNG-YUMQZZPRSA-N 0.000 description 3
- UESJMAMHDLEHGM-NHCYSSNCSA-N Gly-Ile-Leu Chemical compound NCC(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(C)C)C(O)=O UESJMAMHDLEHGM-NHCYSSNCSA-N 0.000 description 3
- HAXARWKYFIIHKD-ZKWXMUAHSA-N Gly-Ile-Ser Chemical compound NCC(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(O)=O HAXARWKYFIIHKD-ZKWXMUAHSA-N 0.000 description 3
- DNAZKGFYFRGZIH-QWRGUYRKSA-N Gly-Tyr-Ser Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)CN)CC1=CC=C(O)C=C1 DNAZKGFYFRGZIH-QWRGUYRKSA-N 0.000 description 3
- SBVMXEZQJVUARN-XPUUQOCRSA-N Gly-Val-Ser Chemical compound NCC(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CO)C(O)=O SBVMXEZQJVUARN-XPUUQOCRSA-N 0.000 description 3
- 241000701044 Human gammaherpesvirus 4 Species 0.000 description 3
- 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 3
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 3
- DCXYFEDJOCDNAF-REOHCLBHSA-N L-asparagine Chemical compound OC(=O)[C@@H](N)CC(N)=O DCXYFEDJOCDNAF-REOHCLBHSA-N 0.000 description 3
- FQZPTCNSNPWHLJ-AVGNSLFASA-N Leu-Gln-Lys Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCCN)C(O)=O FQZPTCNSNPWHLJ-AVGNSLFASA-N 0.000 description 3
- HYIFFZAQXPUEAU-QWRGUYRKSA-N Leu-Gly-Leu Chemical compound CC(C)C[C@H](N)C(=O)NCC(=O)N[C@H](C(O)=O)CC(C)C HYIFFZAQXPUEAU-QWRGUYRKSA-N 0.000 description 3
- HVHRPWQEQHIQJF-AVGNSLFASA-N Leu-Lys-Glu Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(O)=O HVHRPWQEQHIQJF-AVGNSLFASA-N 0.000 description 3
- SBANPBVRHYIMRR-UHFFFAOYSA-N Leu-Ser-Pro Natural products CC(C)CC(N)C(=O)NC(CO)C(=O)N1CCCC1C(O)=O SBANPBVRHYIMRR-UHFFFAOYSA-N 0.000 description 3
- SBANPBVRHYIMRR-GARJFASQSA-N Leu-Ser-Pro Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CO)C(=O)N1CCC[C@@H]1C(=O)O)N SBANPBVRHYIMRR-GARJFASQSA-N 0.000 description 3
- LJBVRCDPWOJOEK-PPCPHDFISA-N Leu-Thr-Ile Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O LJBVRCDPWOJOEK-PPCPHDFISA-N 0.000 description 3
- 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 3
- 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 3
- 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 3
- WALVCOOOKULCQM-ULQDDVLXSA-N Lys-Arg-Phe Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O WALVCOOOKULCQM-ULQDDVLXSA-N 0.000 description 3
- WGILOYIKJVQUPT-DCAQKATOSA-N Lys-Pro-Asp Chemical compound [H]N[C@@H](CCCCN)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CC(O)=O)C(O)=O WGILOYIKJVQUPT-DCAQKATOSA-N 0.000 description 3
- UGCIQUYEJIEHKX-GVXVVHGQSA-N Lys-Val-Glu Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(O)=O)C(O)=O UGCIQUYEJIEHKX-GVXVVHGQSA-N 0.000 description 3
- GILLQRYAWOMHED-DCAQKATOSA-N Lys-Val-Ser Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](N)CCCCN GILLQRYAWOMHED-DCAQKATOSA-N 0.000 description 3
- 241000124008 Mammalia Species 0.000 description 3
- 241000712079 Measles morbillivirus Species 0.000 description 3
- 102000018697 Membrane Proteins Human genes 0.000 description 3
- 108010052285 Membrane Proteins Proteins 0.000 description 3
- QPCDCPDFJACHGM-UHFFFAOYSA-N N,N-bis{2-[bis(carboxymethyl)amino]ethyl}glycine Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(=O)O)CCN(CC(O)=O)CC(O)=O QPCDCPDFJACHGM-UHFFFAOYSA-N 0.000 description 3
- WUGMRIBZSVSJNP-UHFFFAOYSA-N N-L-alanyl-L-tryptophan Natural products C1=CC=C2C(CC(NC(=O)C(N)C)C(O)=O)=CNC2=C1 WUGMRIBZSVSJNP-UHFFFAOYSA-N 0.000 description 3
- YYKZDTVQHTUKDW-RYUDHWBXSA-N Phe-Gly-Gln Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)NCC(=O)N[C@@H](CCC(=O)N)C(=O)O)N YYKZDTVQHTUKDW-RYUDHWBXSA-N 0.000 description 3
- LRBSWBVUCLLRLU-BZSNNMDCSA-N Phe-Leu-Lys Chemical compound CC(C)C[C@H](NC(=O)[C@@H](N)Cc1ccccc1)C(=O)N[C@@H](CCCCN)C(O)=O LRBSWBVUCLLRLU-BZSNNMDCSA-N 0.000 description 3
- WEDZFLRYSIDIRX-IHRRRGAJSA-N Phe-Ser-Arg Chemical compound NC(=N)NCCC[C@@H](C(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC1=CC=CC=C1 WEDZFLRYSIDIRX-IHRRRGAJSA-N 0.000 description 3
- XDMMOISUAHXXFD-SRVKXCTJSA-N Phe-Ser-Asp Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(O)=O)C(O)=O XDMMOISUAHXXFD-SRVKXCTJSA-N 0.000 description 3
- MCIXMYKSPQUMJG-SRVKXCTJSA-N Phe-Ser-Ser Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(O)=O MCIXMYKSPQUMJG-SRVKXCTJSA-N 0.000 description 3
- KLYYKKGCPOGDPE-OEAJRASXSA-N Phe-Thr-Leu Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(O)=O KLYYKKGCPOGDPE-OEAJRASXSA-N 0.000 description 3
- 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 3
- 206010035664 Pneumonia Diseases 0.000 description 3
- HJSCRFZVGXAGNG-SRVKXCTJSA-N Pro-Gln-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H]1CCCN1 HJSCRFZVGXAGNG-SRVKXCTJSA-N 0.000 description 3
- 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 3
- VTFXTWDFPTWNJY-RHYQMDGZSA-N Pro-Leu-Thr Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O VTFXTWDFPTWNJY-RHYQMDGZSA-N 0.000 description 3
- BGWKULMLUIUPKY-BQBZGAKWSA-N Pro-Ser-Gly Chemical compound OC(=O)CNC(=O)[C@H](CO)NC(=O)[C@@H]1CCCN1 BGWKULMLUIUPKY-BQBZGAKWSA-N 0.000 description 3
- HJEBZBMOTCQYDN-ACZMJKKPSA-N Ser-Glu-Asp Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(O)=O HJEBZBMOTCQYDN-ACZMJKKPSA-N 0.000 description 3
- JFWDJFULOLKQFY-QWRGUYRKSA-N Ser-Gly-Phe Chemical compound [H]N[C@@H](CO)C(=O)NCC(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O JFWDJFULOLKQFY-QWRGUYRKSA-N 0.000 description 3
- ZOPISOXXPQNOCO-SVSWQMSJSA-N Ser-Ile-Thr Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H]([C@@H](C)O)C(=O)O)NC(=O)[C@H](CO)N ZOPISOXXPQNOCO-SVSWQMSJSA-N 0.000 description 3
- FUMGHWDRRFCKEP-CIUDSAMLSA-N Ser-Leu-Ala Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C)C(O)=O FUMGHWDRRFCKEP-CIUDSAMLSA-N 0.000 description 3
- 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 3
- KCGIREHVWRXNDH-GARJFASQSA-N Ser-Leu-Pro Chemical compound CC(C)C[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](CO)N KCGIREHVWRXNDH-GARJFASQSA-N 0.000 description 3
- 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 3
- 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 3
- XQJCEKXQUJQNNK-ZLUOBGJFSA-N Ser-Ser-Ser Chemical compound OC[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(O)=O XQJCEKXQUJQNNK-ZLUOBGJFSA-N 0.000 description 3
- 108010003723 Single-Domain Antibodies Proteins 0.000 description 3
- XSLXHSYIVPGEER-KZVJFYERSA-N Thr-Ala-Val Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C)C(=O)N[C@@H](C(C)C)C(O)=O XSLXHSYIVPGEER-KZVJFYERSA-N 0.000 description 3
- LGNBRHZANHMZHK-NUMRIWBASA-N Thr-Glu-Asp Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CC(=O)O)C(=O)O)N)O LGNBRHZANHMZHK-NUMRIWBASA-N 0.000 description 3
- AYCQVUUPIJHJTA-IXOXFDKPSA-N Thr-His-Leu Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CC(C)C)C(O)=O AYCQVUUPIJHJTA-IXOXFDKPSA-N 0.000 description 3
- YUPVPKZBKCLFLT-QTKMDUPCSA-N Thr-His-Val Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)N[C@@H](C(C)C)C(=O)O)N)O YUPVPKZBKCLFLT-QTKMDUPCSA-N 0.000 description 3
- WNQJTLATMXYSEL-OEAJRASXSA-N Thr-Phe-Leu Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CC(C)C)C(O)=O WNQJTLATMXYSEL-OEAJRASXSA-N 0.000 description 3
- ABWNZPOIUJMNKT-IXOXFDKPSA-N Thr-Phe-Ser Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CO)C(O)=O ABWNZPOIUJMNKT-IXOXFDKPSA-N 0.000 description 3
- KERCOYANYUPLHJ-XGEHTFHBSA-N Thr-Pro-Ser Chemical compound C[C@@H](O)[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CO)C(O)=O KERCOYANYUPLHJ-XGEHTFHBSA-N 0.000 description 3
- JAWUQFCGNVEDRN-MEYUZBJRSA-N Thr-Tyr-Leu Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC1=CC=C(C=C1)O)C(=O)N[C@@H](CC(C)C)C(=O)O)N)O JAWUQFCGNVEDRN-MEYUZBJRSA-N 0.000 description 3
- CXPJPTFWKXNDKV-NUTKFTJISA-N Trp-Leu-Ala Chemical compound C1=CC=C2C(C[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C)C(O)=O)=CNC2=C1 CXPJPTFWKXNDKV-NUTKFTJISA-N 0.000 description 3
- ZMKDQRJLMRZHRI-ACRUOGEOSA-N Tyr-Phe-His Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)N[C@@H](CC2=CN=CN2)C(=O)O)NC(=O)[C@H](CC3=CC=C(C=C3)O)N ZMKDQRJLMRZHRI-ACRUOGEOSA-N 0.000 description 3
- ZPFLBLFITJCBTP-QWRGUYRKSA-N Tyr-Ser-Gly Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CO)C(=O)NCC(O)=O ZPFLBLFITJCBTP-QWRGUYRKSA-N 0.000 description 3
- SYFHQHYTNCQCCN-MELADBBJSA-N Tyr-Ser-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CO)NC(=O)[C@H](CC2=CC=C(C=C2)O)N)C(=O)O SYFHQHYTNCQCCN-MELADBBJSA-N 0.000 description 3
- UUYCNAXCCDNULB-QXEWZRGKSA-N Val-Arg-Asn Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CC(N)=O)C(O)=O UUYCNAXCCDNULB-QXEWZRGKSA-N 0.000 description 3
- CGGVNFJRZJUVAE-BYULHYEWSA-N Val-Asp-Asn Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](CC(=O)N)C(=O)O)N CGGVNFJRZJUVAE-BYULHYEWSA-N 0.000 description 3
- VCAWFLIWYNMHQP-UKJIMTQDSA-N Val-Glu-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)O)NC(=O)[C@H](C(C)C)N VCAWFLIWYNMHQP-UKJIMTQDSA-N 0.000 description 3
- 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 3
- DZBUGLKDJFMEHC-UHFFFAOYSA-N acridine Chemical class C1=CC=CC2=CC3=CC=CC=C3N=C21 DZBUGLKDJFMEHC-UHFFFAOYSA-N 0.000 description 3
- 108010070944 alanylhistidine Proteins 0.000 description 3
- 208000026935 allergic disease Diseases 0.000 description 3
- 239000005557 antagonist Substances 0.000 description 3
- 108010043240 arginyl-leucyl-glycine Proteins 0.000 description 3
- 108010047857 aspartylglycine Proteins 0.000 description 3
- 210000004204 blood vessel Anatomy 0.000 description 3
- 239000000872 buffer Substances 0.000 description 3
- 238000004113 cell culture Methods 0.000 description 3
- 230000001413 cellular effect Effects 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- 230000034994 death Effects 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 238000009792 diffusion process Methods 0.000 description 3
- 239000002552 dosage form Substances 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 238000013467 fragmentation Methods 0.000 description 3
- 238000006062 fragmentation reaction Methods 0.000 description 3
- 230000004927 fusion Effects 0.000 description 3
- 210000004907 gland Anatomy 0.000 description 3
- 239000003862 glucocorticoid Substances 0.000 description 3
- 108010010096 glycyl-glycyl-tyrosine Proteins 0.000 description 3
- 210000003783 haploid cell Anatomy 0.000 description 3
- 230000005847 immunogenicity Effects 0.000 description 3
- 230000006872 improvement Effects 0.000 description 3
- 238000011534 incubation Methods 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 238000007912 intraperitoneal administration Methods 0.000 description 3
- 108010044374 isoleucyl-tyrosine Proteins 0.000 description 3
- 210000003734 kidney Anatomy 0.000 description 3
- 108010073472 leucyl-prolyl-proline Proteins 0.000 description 3
- 239000003446 ligand Substances 0.000 description 3
- 210000004072 lung Anatomy 0.000 description 3
- 108010064235 lysylglycine Proteins 0.000 description 3
- 108010017391 lysylvaline Proteins 0.000 description 3
- 206010025482 malaise Diseases 0.000 description 3
- 238000013507 mapping Methods 0.000 description 3
- GLVAUDGFNGKCSF-UHFFFAOYSA-N mercaptopurine Chemical compound S=C1NC=NC2=C1NC=N2 GLVAUDGFNGKCSF-UHFFFAOYSA-N 0.000 description 3
- MYWUZJCMWCOHBA-VIFPVBQESA-N methamphetamine Chemical compound CN[C@@H](C)CC1=CC=CC=C1 MYWUZJCMWCOHBA-VIFPVBQESA-N 0.000 description 3
- KKZJGLLVHKMTCM-UHFFFAOYSA-N mitoxantrone Chemical compound O=C1C2=C(O)C=CC(O)=C2C(=O)C2=C1C(NCCNCCO)=CC=C2NCCNCCO KKZJGLLVHKMTCM-UHFFFAOYSA-N 0.000 description 3
- 210000004400 mucous membrane Anatomy 0.000 description 3
- 239000002777 nucleoside Substances 0.000 description 3
- 210000001672 ovary Anatomy 0.000 description 3
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 3
- 229910052697 platinum Inorganic materials 0.000 description 3
- 230000002265 prevention Effects 0.000 description 3
- 108010070643 prolylglutamic acid Proteins 0.000 description 3
- 210000003289 regulatory T cell Anatomy 0.000 description 3
- MBABCNBNDNGODA-WPZDJQSSSA-N rolliniastatin 1 Natural products O1[C@@H]([C@@H](O)CCCCCCCCCC)CC[C@H]1[C@H]1O[C@@H]([C@H](O)CCCCCCCCCC[C@@H](O)CC=2C(O[C@@H](C)C=2)=O)CC1 MBABCNBNDNGODA-WPZDJQSSSA-N 0.000 description 3
- HXCHCVDVKSCDHU-PJKCJEBCSA-N s-[(2r,3s,4s,6s)-6-[[(2r,3s,4s,5r,6r)-5-[(2s,4s,5s)-5-(ethylamino)-4-methoxyoxan-2-yl]oxy-4-hydroxy-6-[[(2s,5z,9r,13e)-9-hydroxy-12-(methoxycarbonylamino)-13-[2-(methyltrisulfanyl)ethylidene]-11-oxo-2-bicyclo[7.3.1]trideca-1(12),5-dien-3,7-diynyl]oxy]-2-m Chemical compound C1[C@H](OC)[C@@H](NCC)CO[C@H]1O[C@H]1[C@H](O[C@@H]2C\3=C(NC(=O)OC)C(=O)C[C@@](C/3=C/CSSSC)(O)C#C\C=C/C#C2)O[C@H](C)[C@@H](NO[C@@H]2O[C@H](C)[C@@H](SC(=O)C=3C(=C(OC)C(O[C@H]4[C@@H]([C@H](OC)[C@@H](O)[C@H](C)O4)O)=C(I)C=3C)OC)[C@@H](O)C2)[C@@H]1O HXCHCVDVKSCDHU-PJKCJEBCSA-N 0.000 description 3
- 108010069117 seryl-lysyl-aspartic acid Proteins 0.000 description 3
- 238000001228 spectrum Methods 0.000 description 3
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 3
- WYWHKKSPHMUBEB-UHFFFAOYSA-N tioguanine Chemical compound N1C(N)=NC(=S)C2=C1N=CN2 WYWHKKSPHMUBEB-UHFFFAOYSA-N 0.000 description 3
- 231100000331 toxic Toxicity 0.000 description 3
- 230000002588 toxic effect Effects 0.000 description 3
- 230000001988 toxicity Effects 0.000 description 3
- 231100000419 toxicity Toxicity 0.000 description 3
- 238000012546 transfer Methods 0.000 description 3
- 108010015385 valyl-prolyl-proline Proteins 0.000 description 3
- 230000029812 viral genome replication Effects 0.000 description 3
- 210000005253 yeast cell Anatomy 0.000 description 3
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 2
- TZCPCKNHXULUIY-RGULYWFUSA-N 1,2-distearoyl-sn-glycero-3-phosphoserine Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@H](COP(O)(=O)OC[C@H](N)C(O)=O)OC(=O)CCCCCCCCCCCCCCCCC TZCPCKNHXULUIY-RGULYWFUSA-N 0.000 description 2
- UBCHPRBFMUDMNC-UHFFFAOYSA-N 1-(1-adamantyl)ethanamine Chemical compound C1C(C2)CC3CC2CC1(C(N)C)C3 UBCHPRBFMUDMNC-UHFFFAOYSA-N 0.000 description 2
- WYXSYVWAUAUWLD-SHUUEZRQSA-N 6-azauridine Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C=N1 WYXSYVWAUAUWLD-SHUUEZRQSA-N 0.000 description 2
- STQGQHZAVUOBTE-UHFFFAOYSA-N 7-Cyan-hept-2t-en-4,6-diinsaeure Natural products C1=2C(O)=C3C(=O)C=4C(OC)=CC=CC=4C(=O)C3=C(O)C=2CC(O)(C(C)=O)CC1OC1CC(N)C(O)C(C)O1 STQGQHZAVUOBTE-UHFFFAOYSA-N 0.000 description 2
- QDRGPQWIVZNJQD-CIUDSAMLSA-N Ala-Arg-Gln Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(N)=O)C(O)=O QDRGPQWIVZNJQD-CIUDSAMLSA-N 0.000 description 2
- LWUWMHIOBPTZBA-DCAQKATOSA-N Ala-Arg-Lys Chemical compound NC(=N)NCCC[C@H](NC(=O)[C@@H](N)C)C(=O)N[C@@H](CCCCN)C(O)=O LWUWMHIOBPTZBA-DCAQKATOSA-N 0.000 description 2
- KUDREHRZRIVKHS-UWJYBYFXSA-N Ala-Asp-Tyr Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O KUDREHRZRIVKHS-UWJYBYFXSA-N 0.000 description 2
- XYTNPQNAZREREP-XQXXSGGOSA-N Ala-Glu-Thr Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O XYTNPQNAZREREP-XQXXSGGOSA-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
- 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 2
- FVNAUOZKIPAYNA-BPNCWPANSA-N Ala-Met-Tyr Chemical compound CSCC[C@H](NC(=O)[C@H](C)N)C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 FVNAUOZKIPAYNA-BPNCWPANSA-N 0.000 description 2
- WPWUFUBLGADILS-WDSKDSINSA-N Ala-Pro Chemical compound C[C@H](N)C(=O)N1CCC[C@H]1C(O)=O WPWUFUBLGADILS-WDSKDSINSA-N 0.000 description 2
- GCTANJIJJROSLH-GVARAGBVSA-N Ala-Tyr-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)[C@H](CC1=CC=C(C=C1)O)NC(=O)[C@H](C)N GCTANJIJJROSLH-GVARAGBVSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- VKKYFICVTYKFIO-CIUDSAMLSA-N Arg-Ala-Glu Chemical compound OC(=O)CC[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CCCN=C(N)N VKKYFICVTYKFIO-CIUDSAMLSA-N 0.000 description 2
- PQWTZSNVWSOFFK-FXQIFTODSA-N Arg-Asp-Asn Chemical compound C(C[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](CC(=O)N)C(=O)O)N)CN=C(N)N PQWTZSNVWSOFFK-FXQIFTODSA-N 0.000 description 2
- HKRXJBBCQBAGIM-FXQIFTODSA-N Arg-Asp-Ser Chemical compound C(C[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](CO)C(=O)O)N)CN=C(N)N HKRXJBBCQBAGIM-FXQIFTODSA-N 0.000 description 2
- YSUVMPICYVWRBX-VEVYYDQMSA-N Arg-Asp-Thr Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O YSUVMPICYVWRBX-VEVYYDQMSA-N 0.000 description 2
- HQIZDMIGUJOSNI-IUCAKERBSA-N Arg-Gly-Arg Chemical compound N[C@@H](CCCNC(N)=N)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(O)=O HQIZDMIGUJOSNI-IUCAKERBSA-N 0.000 description 2
- NVCIXQYNWYTLDO-IHRRRGAJSA-N Arg-His-Leu Chemical compound CC(C)C[C@@H](C(=O)O)NC(=O)[C@H](CC1=CN=CN1)NC(=O)[C@H](CCCN=C(N)N)N NVCIXQYNWYTLDO-IHRRRGAJSA-N 0.000 description 2
- YBZMTKUDWXZLIX-UWVGGRQHSA-N Arg-Leu-Gly Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)NCC(O)=O YBZMTKUDWXZLIX-UWVGGRQHSA-N 0.000 description 2
- 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 2
- MNBHKGYCLBUIBC-UFYCRDLUSA-N Arg-Phe-Phe Chemical compound C([C@H](NC(=O)[C@H](CCCNC(N)=N)N)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)C1=CC=CC=C1 MNBHKGYCLBUIBC-UFYCRDLUSA-N 0.000 description 2
- 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 2
- 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 2
- KMFPQTITXUKJOV-DCAQKATOSA-N Arg-Ser-Leu Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(O)=O KMFPQTITXUKJOV-DCAQKATOSA-N 0.000 description 2
- FRBAHXABMQXSJQ-FXQIFTODSA-N Arg-Ser-Ser Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(O)=O FRBAHXABMQXSJQ-FXQIFTODSA-N 0.000 description 2
- BECXEHHOZNFFFX-IHRRRGAJSA-N Arg-Ser-Tyr Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O BECXEHHOZNFFFX-IHRRRGAJSA-N 0.000 description 2
- MOGMYRUNTKYZFB-UNQGMJICSA-N Arg-Thr-Phe Chemical compound NC(N)=NCCC[C@H](N)C(=O)N[C@@H]([C@H](O)C)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 MOGMYRUNTKYZFB-UNQGMJICSA-N 0.000 description 2
- LFWOQHSQNCKXRU-UFYCRDLUSA-N Arg-Tyr-Phe Chemical compound C([C@H](NC(=O)[C@H](CCCN=C(N)N)N)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)C1=CC=C(O)C=C1 LFWOQHSQNCKXRU-UFYCRDLUSA-N 0.000 description 2
- VYZBPPBKFCHCIS-WPRPVWTQSA-N Arg-Val-Gly Chemical compound OC(=O)CNC(=O)[C@H](C(C)C)NC(=O)[C@@H](N)CCCN=C(N)N VYZBPPBKFCHCIS-WPRPVWTQSA-N 0.000 description 2
- BFYIZQONLCFLEV-DAELLWKTSA-N Aromasine Chemical compound O=C1C=C[C@]2(C)[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CC(=C)C2=C1 BFYIZQONLCFLEV-DAELLWKTSA-N 0.000 description 2
- RCENDENBBJFJHZ-ACZMJKKPSA-N Asn-Asn-Gln Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(O)=O RCENDENBBJFJHZ-ACZMJKKPSA-N 0.000 description 2
- NVGWESORMHFISY-SRVKXCTJSA-N Asn-Asn-Phe Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O NVGWESORMHFISY-SRVKXCTJSA-N 0.000 description 2
- VJTWLBMESLDOMK-WDSKDSINSA-N Asn-Gln-Gly Chemical compound NC(=O)C[C@H](N)C(=O)N[C@@H](CCC(N)=O)C(=O)NCC(O)=O VJTWLBMESLDOMK-WDSKDSINSA-N 0.000 description 2
- QNJIRRVTOXNGMH-GUBZILKMSA-N Asn-Gln-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](N)CC(N)=O QNJIRRVTOXNGMH-GUBZILKMSA-N 0.000 description 2
- 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 2
- QXOPPIDJKPEKCW-GUBZILKMSA-N Asn-Pro-Arg Chemical compound C1C[C@H](N(C1)C(=O)[C@H](CC(=O)N)N)C(=O)N[C@@H](CCCN=C(N)N)C(=O)O QXOPPIDJKPEKCW-GUBZILKMSA-N 0.000 description 2
- VCJCPARXDBEGNE-GUBZILKMSA-N Asn-Pro-Pro Chemical compound NC(=O)C[C@H](N)C(=O)N1CCC[C@H]1C(=O)N1[C@H](C(O)=O)CCC1 VCJCPARXDBEGNE-GUBZILKMSA-N 0.000 description 2
- 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 2
- UPAGTDJAORYMEC-VHWLVUOQSA-N Asn-Trp-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)[C@H](CC1=CNC2=CC=CC=C21)NC(=O)[C@H](CC(=O)N)N UPAGTDJAORYMEC-VHWLVUOQSA-N 0.000 description 2
- RTFXPCYMDYBZNQ-SRVKXCTJSA-N Asn-Tyr-Asn Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC(N)=O)C(O)=O RTFXPCYMDYBZNQ-SRVKXCTJSA-N 0.000 description 2
- FAEIQWHBRBWUBN-FXQIFTODSA-N Asp-Arg-Ser Chemical compound C(C[C@@H](C(=O)N[C@@H](CO)C(=O)O)NC(=O)[C@H](CC(=O)O)N)CN=C(N)N FAEIQWHBRBWUBN-FXQIFTODSA-N 0.000 description 2
- AYFVRYXNDHBECD-YUMQZZPRSA-N Asp-Leu-Gly Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)NCC(O)=O AYFVRYXNDHBECD-YUMQZZPRSA-N 0.000 description 2
- WOPJVEMFXYHZEE-SRVKXCTJSA-N Asp-Phe-Asp Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CC(O)=O)C(O)=O WOPJVEMFXYHZEE-SRVKXCTJSA-N 0.000 description 2
- RPUYTJJZXQBWDT-SRVKXCTJSA-N Asp-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](CC(=O)O)N RPUYTJJZXQBWDT-SRVKXCTJSA-N 0.000 description 2
- USNJAPJZSGTTPX-XVSYOHENSA-N Asp-Phe-Thr Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H]([C@@H](C)O)C(O)=O USNJAPJZSGTTPX-XVSYOHENSA-N 0.000 description 2
- KOWYNSKRPUWSFG-IHPCNDPISA-N Asp-Phe-Trp Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)N[C@@H](CC2=CNC3=CC=CC=C32)C(=O)O)NC(=O)[C@H](CC(=O)O)N KOWYNSKRPUWSFG-IHPCNDPISA-N 0.000 description 2
- UEFODXNXUAVPTC-VEVYYDQMSA-N Asp-Thr-Met Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCSC)C(=O)O)NC(=O)[C@H](CC(=O)O)N)O UEFODXNXUAVPTC-VEVYYDQMSA-N 0.000 description 2
- XWKPSMRPIKKDDU-RCOVLWMOSA-N Asp-Val-Gly Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)NCC(O)=O XWKPSMRPIKKDDU-RCOVLWMOSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 201000001178 Bacterial Pneumonia Diseases 0.000 description 2
- 208000019838 Blood disease Diseases 0.000 description 2
- GAGWJHPBXLXJQN-UORFTKCHSA-N Capecitabine Chemical compound C1=C(F)C(NC(=O)OCCCCC)=NC(=O)N1[C@H]1[C@H](O)[C@H](O)[C@@H](C)O1 GAGWJHPBXLXJQN-UORFTKCHSA-N 0.000 description 2
- 108090000565 Capsid Proteins Proteins 0.000 description 2
- 102100023321 Ceruloplasmin Human genes 0.000 description 2
- 206010008909 Chronic Hepatitis Diseases 0.000 description 2
- 108020004705 Codon Proteins 0.000 description 2
- 206010009944 Colon cancer Diseases 0.000 description 2
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 2
- 206010010741 Conjunctivitis Diseases 0.000 description 2
- 241000699802 Cricetulus griseus Species 0.000 description 2
- HAYVTMHUNMMXCV-IMJSIDKUSA-N Cys-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@@H](N)CS HAYVTMHUNMMXCV-IMJSIDKUSA-N 0.000 description 2
- XMTDCXXLDZKAGI-ACZMJKKPSA-N Cys-Ala-Gln Chemical compound C[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)O)NC(=O)[C@H](CS)N XMTDCXXLDZKAGI-ACZMJKKPSA-N 0.000 description 2
- BPHKULHWEIUDOB-FXQIFTODSA-N Cys-Gln-Gln Chemical compound SC[C@H](N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(O)=O BPHKULHWEIUDOB-FXQIFTODSA-N 0.000 description 2
- BBQIWFFTTQTNOC-AVGNSLFASA-N Cys-Phe-Gln Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)O)NC(=O)[C@H](CS)N BBQIWFFTTQTNOC-AVGNSLFASA-N 0.000 description 2
- CMYVIUWVYHOLRD-ZLUOBGJFSA-N Cys-Ser-Ala Chemical compound [H]N[C@@H](CS)C(=O)N[C@@H](CO)C(=O)N[C@@H](C)C(O)=O CMYVIUWVYHOLRD-ZLUOBGJFSA-N 0.000 description 2
- ZGERHCJBLPQPGV-ACZMJKKPSA-N Cys-Ser-Gln Chemical compound C(CC(=O)N)[C@@H](C(=O)O)NC(=O)[C@H](CO)NC(=O)[C@H](CS)N ZGERHCJBLPQPGV-ACZMJKKPSA-N 0.000 description 2
- NRVQLLDIJJEIIZ-VZFHVOOUSA-N Cys-Thr-Ala Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](C)C(=O)O)NC(=O)[C@H](CS)N)O NRVQLLDIJJEIIZ-VZFHVOOUSA-N 0.000 description 2
- 206010012305 Demyelination Diseases 0.000 description 2
- 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 description 2
- 238000012286 ELISA Assay Methods 0.000 description 2
- 206010015150 Erythema Diseases 0.000 description 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 2
- 241000272190 Falco peregrinus Species 0.000 description 2
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 2
- RGXXLQWXBFNXTG-CIUDSAMLSA-N Gln-Arg-Ala Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(O)=O RGXXLQWXBFNXTG-CIUDSAMLSA-N 0.000 description 2
- XOKGKOQWADCLFQ-GARJFASQSA-N Gln-Arg-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CCC(=O)N)N)C(=O)O XOKGKOQWADCLFQ-GARJFASQSA-N 0.000 description 2
- 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 2
- GPISLLFQNHELLK-DCAQKATOSA-N Gln-Gln-His Chemical compound C1=C(NC=N1)C[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)N)NC(=O)[C@H](CCC(=O)N)N GPISLLFQNHELLK-DCAQKATOSA-N 0.000 description 2
- MADFVRSKEIEZHZ-DCAQKATOSA-N Gln-Gln-Lys Chemical compound C(CCN)C[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)N)NC(=O)[C@H](CCC(=O)N)N MADFVRSKEIEZHZ-DCAQKATOSA-N 0.000 description 2
- NPTGGVQJYRSMCM-GLLZPBPUSA-N Gln-Gln-Thr Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O NPTGGVQJYRSMCM-GLLZPBPUSA-N 0.000 description 2
- LVSYIKGMLRHKME-IUCAKERBSA-N Gln-Gly-His Chemical compound C1=C(NC=N1)C[C@@H](C(=O)O)NC(=O)CNC(=O)[C@H](CCC(=O)N)N LVSYIKGMLRHKME-IUCAKERBSA-N 0.000 description 2
- ORYMMTRPKVTGSJ-XVKPBYJWSA-N Gln-Gly-Val Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)CNC(=O)[C@@H](N)CCC(N)=O ORYMMTRPKVTGSJ-XVKPBYJWSA-N 0.000 description 2
- FFVXLVGUJBCKRX-UKJIMTQDSA-N Gln-Ile-Val Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](C(C)C)C(=O)O)NC(=O)[C@H](CCC(=O)N)N FFVXLVGUJBCKRX-UKJIMTQDSA-N 0.000 description 2
- MSHXWFKYXJTLEZ-CIUDSAMLSA-N Gln-Met-Asn Chemical compound CSCC[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)O)NC(=O)[C@H](CCC(=O)N)N MSHXWFKYXJTLEZ-CIUDSAMLSA-N 0.000 description 2
- LHMWTCWZARHLPV-CIUDSAMLSA-N Gln-Met-Ser Chemical compound CSCC[C@@H](C(=O)N[C@@H](CO)C(=O)O)NC(=O)[C@H](CCC(=O)N)N LHMWTCWZARHLPV-CIUDSAMLSA-N 0.000 description 2
- VNTGPISAOMAXRK-CIUDSAMLSA-N Gln-Pro-Ser Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CO)C(O)=O VNTGPISAOMAXRK-CIUDSAMLSA-N 0.000 description 2
- OSCLNNWLKKIQJM-WDSKDSINSA-N Gln-Ser-Gly Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CO)C(=O)NCC(O)=O OSCLNNWLKKIQJM-WDSKDSINSA-N 0.000 description 2
- LPIKVBWNNVFHCQ-GUBZILKMSA-N Gln-Ser-Leu Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(O)=O LPIKVBWNNVFHCQ-GUBZILKMSA-N 0.000 description 2
- SYZZMPFLOLSMHL-XHNCKOQMSA-N Gln-Ser-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CO)NC(=O)[C@H](CCC(=O)N)N)C(=O)O SYZZMPFLOLSMHL-XHNCKOQMSA-N 0.000 description 2
- VLOLPWWCNKWRNB-LOKLDPHHSA-N Gln-Thr-Pro Chemical compound C[C@H]([C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](CCC(=O)N)N)O VLOLPWWCNKWRNB-LOKLDPHHSA-N 0.000 description 2
- JPHYJQHPILOKHC-ACZMJKKPSA-N Glu-Asp-Asp Chemical compound OC(=O)CC[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(O)=O)C(O)=O JPHYJQHPILOKHC-ACZMJKKPSA-N 0.000 description 2
- SJJHXJDSNQJMMW-SRVKXCTJSA-N Glu-Lys-Arg Chemical compound OC(=O)CC[C@H](N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCN=C(N)N)C(O)=O SJJHXJDSNQJMMW-SRVKXCTJSA-N 0.000 description 2
- QJVZSVUYZFYLFQ-CIUDSAMLSA-N Glu-Pro-Ala Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](C)C(O)=O QJVZSVUYZFYLFQ-CIUDSAMLSA-N 0.000 description 2
- 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 2
- RMWAOBGCZZSJHE-UMNHJUIQSA-N Glu-Val-Pro Chemical compound CC(C)[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](CCC(=O)O)N RMWAOBGCZZSJHE-UMNHJUIQSA-N 0.000 description 2
- WGYHAAXZWPEBDQ-IFFSRLJSSA-N Glu-Val-Thr Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O WGYHAAXZWPEBDQ-IFFSRLJSSA-N 0.000 description 2
- KRRMJKMGWWXWDW-STQMWFEESA-N Gly-Arg-Phe Chemical compound NC(=N)NCCC[C@H](NC(=O)CN)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 KRRMJKMGWWXWDW-STQMWFEESA-N 0.000 description 2
- FMNHBTKMRFVGRO-FOHZUACHSA-N Gly-Asn-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)[C@H](CC(N)=O)NC(=O)CN FMNHBTKMRFVGRO-FOHZUACHSA-N 0.000 description 2
- CQZDZKRHFWJXDF-WDSKDSINSA-N Gly-Gln-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@H](CCC(N)=O)NC(=O)CN CQZDZKRHFWJXDF-WDSKDSINSA-N 0.000 description 2
- PABFFPWEJMEVEC-JGVFFNPUSA-N Gly-Gln-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CCC(=O)N)NC(=O)CN)C(=O)O PABFFPWEJMEVEC-JGVFFNPUSA-N 0.000 description 2
- STVHDEHTKFXBJQ-LAEOZQHASA-N Gly-Glu-Ile Chemical compound [H]NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O STVHDEHTKFXBJQ-LAEOZQHASA-N 0.000 description 2
- YWAQATDNEKZFFK-BYPYZUCNSA-N Gly-Gly-Ser Chemical compound NCC(=O)NCC(=O)N[C@@H](CO)C(O)=O YWAQATDNEKZFFK-BYPYZUCNSA-N 0.000 description 2
- BHPQOIPBLYJNAW-NGZCFLSTSA-N Gly-Ile-Pro Chemical compound CC[C@H](C)[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)CN BHPQOIPBLYJNAW-NGZCFLSTSA-N 0.000 description 2
- HHRODZSXDXMUHS-LURJTMIESA-N Gly-Met-Gly Chemical compound CSCC[C@H](NC(=O)C[NH3+])C(=O)NCC([O-])=O HHRODZSXDXMUHS-LURJTMIESA-N 0.000 description 2
- IBYOLNARKHMLBG-WHOFXGATSA-N Gly-Phe-Ile Chemical compound CC[C@H](C)[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)CN)CC1=CC=CC=C1 IBYOLNARKHMLBG-WHOFXGATSA-N 0.000 description 2
- NSVOVKWEKGEOQB-LURJTMIESA-N Gly-Pro-Gly Chemical compound NCC(=O)N1CCC[C@H]1C(=O)NCC(O)=O NSVOVKWEKGEOQB-LURJTMIESA-N 0.000 description 2
- JSLVAHYTAJJEQH-QWRGUYRKSA-N Gly-Ser-Phe Chemical compound NCC(=O)N[C@@H](CO)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 JSLVAHYTAJJEQH-QWRGUYRKSA-N 0.000 description 2
- WCORRBXVISTKQL-WHFBIAKZSA-N Gly-Ser-Ser Chemical compound NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(O)=O WCORRBXVISTKQL-WHFBIAKZSA-N 0.000 description 2
- HUFUVTYGPOUCBN-MBLNEYKQSA-N Gly-Thr-Ile Chemical compound [H]NCC(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O HUFUVTYGPOUCBN-MBLNEYKQSA-N 0.000 description 2
- TVTZEOHWHUVYCG-KYNKHSRBSA-N Gly-Thr-Thr Chemical compound [H]NCC(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O TVTZEOHWHUVYCG-KYNKHSRBSA-N 0.000 description 2
- JYGYNWYVKXENNE-OALUTQOASA-N Gly-Tyr-Trp Chemical compound [H]NCC(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC1=CNC2=C1C=CC=C2)C(O)=O JYGYNWYVKXENNE-OALUTQOASA-N 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- ZWZWYGMENQVNFU-UHFFFAOYSA-N Glycerophosphorylserin Natural products OC(=O)C(N)COP(O)(=O)OCC(O)CO ZWZWYGMENQVNFU-UHFFFAOYSA-N 0.000 description 2
- 208000024869 Goodpasture syndrome Diseases 0.000 description 2
- JBCLFWXMTIKCCB-UHFFFAOYSA-N H-Gly-Phe-OH Natural products NCC(=O)NC(C(O)=O)CC1=CC=CC=C1 JBCLFWXMTIKCCB-UHFFFAOYSA-N 0.000 description 2
- 208000030836 Hashimoto thyroiditis Diseases 0.000 description 2
- 206010019233 Headaches Diseases 0.000 description 2
- 101710154606 Hemagglutinin Proteins 0.000 description 2
- 208000005176 Hepatitis C Diseases 0.000 description 2
- 206010060766 Heteroplasia Diseases 0.000 description 2
- MJNWEIMBXKKCSF-XVYDVKMFSA-N His-Ala-Asn Chemical compound C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)O)NC(=O)[C@H](CC1=CN=CN1)N MJNWEIMBXKKCSF-XVYDVKMFSA-N 0.000 description 2
- ZPVJJPAIUZLSNE-DCAQKATOSA-N His-Arg-Ser Chemical compound [H]N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(O)=O ZPVJJPAIUZLSNE-DCAQKATOSA-N 0.000 description 2
- FMRKUXFLLPKVPG-JYJNAYRXSA-N His-Gln-Tyr Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)N)NC(=O)[C@H](CC2=CN=CN2)N)O FMRKUXFLLPKVPG-JYJNAYRXSA-N 0.000 description 2
- ZHHLTWUOWXHVQJ-YUMQZZPRSA-N His-Ser-Gly Chemical compound C1=C(NC=N1)C[C@@H](C(=O)N[C@@H](CO)C(=O)NCC(=O)O)N ZHHLTWUOWXHVQJ-YUMQZZPRSA-N 0.000 description 2
- FOCSWPCHUDVNLP-PMVMPFDFSA-N His-Trp-Tyr Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)N[C@@H](CC3=CC=C(C=C3)O)C(=O)O)NC(=O)[C@H](CC4=CN=CN4)N FOCSWPCHUDVNLP-PMVMPFDFSA-N 0.000 description 2
- 108010001336 Horseradish Peroxidase Proteins 0.000 description 2
- 241000701806 Human papillomavirus Species 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 206010020751 Hypersensitivity Diseases 0.000 description 2
- QYZYJFXHXYUZMZ-UGYAYLCHSA-N Ile-Asn-Asn Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CC(=O)N)C(=O)O)N QYZYJFXHXYUZMZ-UGYAYLCHSA-N 0.000 description 2
- GLYJPWIRLBAIJH-UHFFFAOYSA-N Ile-Lys-Pro Natural products CCC(C)C(N)C(=O)NC(CCCCN)C(=O)N1CCCC1C(O)=O GLYJPWIRLBAIJH-UHFFFAOYSA-N 0.000 description 2
- JHNJNTMTZHEDLJ-NAKRPEOUSA-N Ile-Ser-Arg Chemical compound CC[C@H](C)[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCN=C(N)N)C(O)=O JHNJNTMTZHEDLJ-NAKRPEOUSA-N 0.000 description 2
- 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 2
- SAEWJTCJQVZQNZ-IUKAMOBKSA-N Ile-Thr-Asn Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(=O)N)C(=O)O)N SAEWJTCJQVZQNZ-IUKAMOBKSA-N 0.000 description 2
- ZGKVPOSSTGHJAF-HJPIBITLSA-N Ile-Tyr-Ser Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC1=CC=C(C=C1)O)C(=O)N[C@@H](CO)C(=O)O)N ZGKVPOSSTGHJAF-HJPIBITLSA-N 0.000 description 2
- 102100037850 Interferon gamma Human genes 0.000 description 2
- 108010074328 Interferon-gamma Proteins 0.000 description 2
- 241000235058 Komagataella pastoris Species 0.000 description 2
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 2
- OXKYZSRZKBTVEY-ZPFDUUQYSA-N Leu-Asn-Ile Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O OXKYZSRZKBTVEY-ZPFDUUQYSA-N 0.000 description 2
- USTCFDAQCLDPBD-XIRDDKMYSA-N Leu-Asn-Trp Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CC1=CNC2=CC=CC=C21)C(=O)O)N USTCFDAQCLDPBD-XIRDDKMYSA-N 0.000 description 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
- AXZGZMGRBDQTEY-SRVKXCTJSA-N Leu-Gln-Met Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCSC)C(O)=O AXZGZMGRBDQTEY-SRVKXCTJSA-N 0.000 description 2
- CQGSYZCULZMEDE-SRVKXCTJSA-N Leu-Gln-Pro Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CCC(N)=O)C(=O)N1CCC[C@H]1C(O)=O CQGSYZCULZMEDE-SRVKXCTJSA-N 0.000 description 2
- HPBCTWSUJOGJSH-MNXVOIDGSA-N Leu-Glu-Ile Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O HPBCTWSUJOGJSH-MNXVOIDGSA-N 0.000 description 2
- VGPCJSXPPOQPBK-YUMQZZPRSA-N Leu-Gly-Ser Chemical compound CC(C)C[C@H](N)C(=O)NCC(=O)N[C@@H](CO)C(O)=O VGPCJSXPPOQPBK-YUMQZZPRSA-N 0.000 description 2
- JFSGIJSCJFQGSZ-MXAVVETBSA-N Leu-Ile-His Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)NC(=O)[C@H](CC(C)C)N JFSGIJSCJFQGSZ-MXAVVETBSA-N 0.000 description 2
- HRTRLSRYZZKPCO-BJDJZHNGSA-N Leu-Ile-Ser Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(O)=O HRTRLSRYZZKPCO-BJDJZHNGSA-N 0.000 description 2
- KYIIALJHAOIAHF-KKUMJFAQSA-N Leu-Leu-His Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](C(O)=O)CC1=CN=CN1 KYIIALJHAOIAHF-KKUMJFAQSA-N 0.000 description 2
- JLWZLIQRYCTYBD-IHRRRGAJSA-N Leu-Lys-Arg Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O JLWZLIQRYCTYBD-IHRRRGAJSA-N 0.000 description 2
- WXUOJXIGOPMDJM-SRVKXCTJSA-N Leu-Lys-Asn Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(O)=O WXUOJXIGOPMDJM-SRVKXCTJSA-N 0.000 description 2
- 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 2
- UCBPDSYUVAAHCD-UWVGGRQHSA-N Leu-Pro-Gly Chemical compound CC(C)C[C@H](N)C(=O)N1CCC[C@H]1C(=O)NCC(O)=O UCBPDSYUVAAHCD-UWVGGRQHSA-N 0.000 description 2
- BRTVHXHCUSXYRI-CIUDSAMLSA-N Leu-Ser-Ser Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(O)=O BRTVHXHCUSXYRI-CIUDSAMLSA-N 0.000 description 2
- 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 2
- LMDVGHQPPPLYAR-IHRRRGAJSA-N Leu-Val-His Chemical compound N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC1=CNC=N1)C(=O)O LMDVGHQPPPLYAR-IHRRRGAJSA-N 0.000 description 2
- 206010025323 Lymphomas Diseases 0.000 description 2
- FLCMXEFCTLXBTL-DCAQKATOSA-N Lys-Asp-Arg Chemical compound C(CCN)C[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](CCCN=C(N)N)C(=O)O)N FLCMXEFCTLXBTL-DCAQKATOSA-N 0.000 description 2
- LMVOVCYVZBBWQB-SRVKXCTJSA-N Lys-Asp-Lys Chemical compound NCCCC[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@H](C(O)=O)CCCCN LMVOVCYVZBBWQB-SRVKXCTJSA-N 0.000 description 2
- ULUQBUKAPDUKOC-GVXVVHGQSA-N Lys-Glu-Val Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(O)=O ULUQBUKAPDUKOC-GVXVVHGQSA-N 0.000 description 2
- WRODMZBHNNPRLN-SRVKXCTJSA-N Lys-Leu-Ser Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(O)=O WRODMZBHNNPRLN-SRVKXCTJSA-N 0.000 description 2
- AEIIJFBQVGYVEV-YESZJQIVSA-N Lys-Phe-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CC2=CC=CC=C2)NC(=O)[C@H](CCCCN)N)C(=O)O AEIIJFBQVGYVEV-YESZJQIVSA-N 0.000 description 2
- HYSVGEAWTGPMOA-IHRRRGAJSA-N Lys-Pro-Leu Chemical compound [H]N[C@@H](CCCCN)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CC(C)C)C(O)=O HYSVGEAWTGPMOA-IHRRRGAJSA-N 0.000 description 2
- WQDKIVRHTQYJSN-DCAQKATOSA-N Lys-Ser-Arg Chemical compound C(CCN)C[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCN=C(N)N)C(=O)O)N WQDKIVRHTQYJSN-DCAQKATOSA-N 0.000 description 2
- 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 2
- HOTNHEUETJELDL-BPNCWPANSA-N Met-Tyr-Ala Chemical compound C[C@@H](C(=O)O)NC(=O)[C@H](CC1=CC=C(C=C1)O)NC(=O)[C@H](CCSC)N HOTNHEUETJELDL-BPNCWPANSA-N 0.000 description 2
- 208000034578 Multiple myelomas Diseases 0.000 description 2
- 208000000112 Myalgia Diseases 0.000 description 2
- 208000033214 Myopericarditis Diseases 0.000 description 2
- NWIBSHFKIJFRCO-WUDYKRTCSA-N Mytomycin Chemical compound C1N2C(C(C(C)=C(N)C3=O)=O)=C3[C@@H](COC(N)=O)[C@@]2(OC)[C@@H]2[C@H]1N2 NWIBSHFKIJFRCO-WUDYKRTCSA-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
- SITLTJHOQZFJGG-UHFFFAOYSA-N N-L-alpha-glutamyl-L-valine Natural products CC(C)C(C(O)=O)NC(=O)C(N)CCC(O)=O SITLTJHOQZFJGG-UHFFFAOYSA-N 0.000 description 2
- AUEJLPRZGVVDNU-UHFFFAOYSA-N N-L-tyrosyl-L-leucine Natural products CC(C)CC(C(O)=O)NC(=O)C(N)CC1=CC=C(O)C=C1 AUEJLPRZGVVDNU-UHFFFAOYSA-N 0.000 description 2
- BQVUABVGYYSDCJ-UHFFFAOYSA-N Nalpha-L-Leucyl-L-tryptophan Natural products C1=CC=C2C(CC(NC(=O)C(N)CC(C)C)C(O)=O)=CNC2=C1 BQVUABVGYYSDCJ-UHFFFAOYSA-N 0.000 description 2
- 208000012902 Nervous system disease Diseases 0.000 description 2
- 108010006232 Neuraminidase Proteins 0.000 description 2
- 102000005348 Neuraminidase Human genes 0.000 description 2
- 208000025966 Neurological disease Diseases 0.000 description 2
- 206010033078 Otitis media Diseases 0.000 description 2
- 101710093908 Outer capsid protein VP4 Proteins 0.000 description 2
- 101710135467 Outer capsid protein sigma-1 Proteins 0.000 description 2
- 229930012538 Paclitaxel Natural products 0.000 description 2
- NOFBJKKOPKJDCO-KKXDTOCCSA-N Phe-Ala-Tyr Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](C)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O NOFBJKKOPKJDCO-KKXDTOCCSA-N 0.000 description 2
- FQUUYTNBMIBOHS-IHRRRGAJSA-N Phe-Met-Ser Chemical compound CSCC[C@@H](C(=O)N[C@@H](CO)C(=O)O)NC(=O)[C@H](CC1=CC=CC=C1)N FQUUYTNBMIBOHS-IHRRRGAJSA-N 0.000 description 2
- RVEVENLSADZUMS-IHRRRGAJSA-N Phe-Pro-Asn Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CC(N)=O)C(O)=O RVEVENLSADZUMS-IHRRRGAJSA-N 0.000 description 2
- UNBFGVQVQGXXCK-KKUMJFAQSA-N Phe-Ser-Leu Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(O)=O UNBFGVQVQGXXCK-KKUMJFAQSA-N 0.000 description 2
- BPIMVBKDLSBKIJ-FCLVOEFKSA-N Phe-Thr-Phe Chemical compound C([C@H](N)C(=O)N[C@@H]([C@H](O)C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)C1=CC=CC=C1 BPIMVBKDLSBKIJ-FCLVOEFKSA-N 0.000 description 2
- ZVJGAXNBBKPYOE-HKUYNNGSSA-N Phe-Trp-Gly Chemical compound C([C@H](N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)NCC(O)=O)C1=CC=CC=C1 ZVJGAXNBBKPYOE-HKUYNNGSSA-N 0.000 description 2
- MHNBYYFXWDUGBW-RPTUDFQQSA-N Phe-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=CC=CC=C2)N)O MHNBYYFXWDUGBW-RPTUDFQQSA-N 0.000 description 2
- 241000276498 Pollachius virens Species 0.000 description 2
- 206010036105 Polyneuropathy Diseases 0.000 description 2
- 206010067268 Post procedural infection Diseases 0.000 description 2
- 241000288906 Primates Species 0.000 description 2
- CYQQWUPHIZVCNY-GUBZILKMSA-N Pro-Arg-Ser Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(O)=O CYQQWUPHIZVCNY-GUBZILKMSA-N 0.000 description 2
- AFXCXDQNRXTSBD-FJXKBIBVSA-N Pro-Gly-Thr Chemical compound [H]N1CCC[C@H]1C(=O)NCC(=O)N[C@@H]([C@@H](C)O)C(O)=O AFXCXDQNRXTSBD-FJXKBIBVSA-N 0.000 description 2
- RMODQFBNDDENCP-IHRRRGAJSA-N Pro-Lys-Leu Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(O)=O RMODQFBNDDENCP-IHRRRGAJSA-N 0.000 description 2
- XZBYTHCRAVAXQQ-DCAQKATOSA-N Pro-Met-Glu Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCC(O)=O)C(O)=O XZBYTHCRAVAXQQ-DCAQKATOSA-N 0.000 description 2
- LEIKGVHQTKHOLM-IUCAKERBSA-N Pro-Pro-Gly Chemical compound OC(=O)CNC(=O)[C@@H]1CCCN1C(=O)[C@H]1NCCC1 LEIKGVHQTKHOLM-IUCAKERBSA-N 0.000 description 2
- RTQKBZIRDWZLDF-BZSNNMDCSA-N Pro-Pro-Trp Chemical compound C([C@H]1C(=O)N[C@@H](CC=2C3=CC=CC=C3NC=2)C(=O)O)CCN1C(=O)[C@@H]1CCCN1 RTQKBZIRDWZLDF-BZSNNMDCSA-N 0.000 description 2
- GOMUXSCOIWIJFP-GUBZILKMSA-N Pro-Ser-Arg Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O GOMUXSCOIWIJFP-GUBZILKMSA-N 0.000 description 2
- 206010060862 Prostate cancer Diseases 0.000 description 2
- 101710176177 Protein A56 Proteins 0.000 description 2
- 206010037660 Pyrexia Diseases 0.000 description 2
- 108020004511 Recombinant DNA Proteins 0.000 description 2
- 201000007981 Reye syndrome Diseases 0.000 description 2
- IWUCXVSUMQZMFG-AFCXAGJDSA-N Ribavirin Chemical compound N1=C(C(=O)N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 IWUCXVSUMQZMFG-AFCXAGJDSA-N 0.000 description 2
- 206010039491 Sarcoma Diseases 0.000 description 2
- RZEQTVHJZCIUBT-WDSKDSINSA-N Ser-Arg Chemical compound OC[C@H](N)C(=O)N[C@H](C(O)=O)CCCNC(N)=N RZEQTVHJZCIUBT-WDSKDSINSA-N 0.000 description 2
- QEDMOZUJTGEIBF-FXQIFTODSA-N Ser-Arg-Asp Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(O)=O QEDMOZUJTGEIBF-FXQIFTODSA-N 0.000 description 2
- FIDMVVBUOCMMJG-CIUDSAMLSA-N Ser-Asn-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](N)CO FIDMVVBUOCMMJG-CIUDSAMLSA-N 0.000 description 2
- ICHZYBVODUVUKN-SRVKXCTJSA-N Ser-Asn-Tyr Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O ICHZYBVODUVUKN-SRVKXCTJSA-N 0.000 description 2
- CLKKNZQUQMZDGD-SRVKXCTJSA-N Ser-His-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)CO)CC1=CN=CN1 CLKKNZQUQMZDGD-SRVKXCTJSA-N 0.000 description 2
- ZIFYDQAFEMIZII-GUBZILKMSA-N Ser-Leu-Glu Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(O)=O ZIFYDQAFEMIZII-GUBZILKMSA-N 0.000 description 2
- 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 2
- IXZHZUGGKLRHJD-DCAQKATOSA-N Ser-Leu-Val Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(O)=O IXZHZUGGKLRHJD-DCAQKATOSA-N 0.000 description 2
- XUDRHBPSPAPDJP-SRVKXCTJSA-N Ser-Lys-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](N)CO XUDRHBPSPAPDJP-SRVKXCTJSA-N 0.000 description 2
- ZSLFCBHEINFXRS-LPEHRKFASA-N Ser-Met-Pro Chemical compound CSCC[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](CO)N ZSLFCBHEINFXRS-LPEHRKFASA-N 0.000 description 2
- NQZFFLBPNDLTPO-DLOVCJGASA-N Ser-Phe-Ala Chemical compound C[C@@H](C(=O)O)NC(=O)[C@H](CC1=CC=CC=C1)NC(=O)[C@H](CO)N NQZFFLBPNDLTPO-DLOVCJGASA-N 0.000 description 2
- FKYWFUYPVKLJLP-DCAQKATOSA-N Ser-Pro-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@@H](N)CO FKYWFUYPVKLJLP-DCAQKATOSA-N 0.000 description 2
- VGQVAVQWKJLIRM-FXQIFTODSA-N Ser-Ser-Val Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(O)=O VGQVAVQWKJLIRM-FXQIFTODSA-N 0.000 description 2
- PURRNJBBXDDWLX-ZDLURKLDSA-N Ser-Thr-Gly Chemical compound C[C@H]([C@@H](C(=O)NCC(=O)O)NC(=O)[C@H](CO)N)O PURRNJBBXDDWLX-ZDLURKLDSA-N 0.000 description 2
- 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 2
- RTXKJFWHEBTABY-IHPCNDPISA-N Ser-Trp-Tyr Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)N[C@@H](CC3=CC=C(C=C3)O)C(=O)O)NC(=O)[C@H](CO)N RTXKJFWHEBTABY-IHPCNDPISA-N 0.000 description 2
- OQSQCUWQOIHECT-YJRXYDGGSA-N Ser-Tyr-Thr Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H]([C@@H](C)O)C(O)=O OQSQCUWQOIHECT-YJRXYDGGSA-N 0.000 description 2
- OSFZCEQJLWCIBG-BZSNNMDCSA-N Ser-Tyr-Tyr Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O OSFZCEQJLWCIBG-BZSNNMDCSA-N 0.000 description 2
- LLSLRQOEAFCZLW-NRPADANISA-N Ser-Val-Gln Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(N)=O)C(O)=O LLSLRQOEAFCZLW-NRPADANISA-N 0.000 description 2
- ODRUTDLAONAVDV-IHRRRGAJSA-N Ser-Val-Tyr Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O ODRUTDLAONAVDV-IHRRRGAJSA-N 0.000 description 2
- 241000256251 Spodoptera frugiperda Species 0.000 description 2
- 206010042566 Superinfection Diseases 0.000 description 2
- NJEMRSFGDNECGF-GCJQMDKQSA-N Thr-Ala-Asp Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@H](C(O)=O)CC(O)=O NJEMRSFGDNECGF-GCJQMDKQSA-N 0.000 description 2
- GFDUZZACIWNMPE-KZVJFYERSA-N Thr-Ala-Met Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C)C(=O)N[C@@H](CCSC)C(O)=O GFDUZZACIWNMPE-KZVJFYERSA-N 0.000 description 2
- CAJFZCICSVBOJK-SHGPDSBTSA-N Thr-Ala-Thr Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O CAJFZCICSVBOJK-SHGPDSBTSA-N 0.000 description 2
- PKXHGEXFMIZSER-QTKMDUPCSA-N Thr-Arg-His Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)N)O PKXHGEXFMIZSER-QTKMDUPCSA-N 0.000 description 2
- JVTHIXKSVYEWNI-JRQIVUDYSA-N Thr-Asn-Tyr Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O JVTHIXKSVYEWNI-JRQIVUDYSA-N 0.000 description 2
- UYTYTDMCDBPDSC-URLPEUOOSA-N Thr-Ile-Phe Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)O)NC(=O)[C@H]([C@@H](C)O)N UYTYTDMCDBPDSC-URLPEUOOSA-N 0.000 description 2
- NCXVJIQMWSGRHY-KXNHARMFSA-N Thr-Leu-Pro Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N1CCC[C@@H]1C(=O)O)N)O NCXVJIQMWSGRHY-KXNHARMFSA-N 0.000 description 2
- IJVNLNRVDUTWDD-MEYUZBJRSA-N Thr-Leu-Tyr Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O IJVNLNRVDUTWDD-MEYUZBJRSA-N 0.000 description 2
- LHNNQVXITHUCAB-QTKMDUPCSA-N Thr-Met-His Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)N)O LHNNQVXITHUCAB-QTKMDUPCSA-N 0.000 description 2
- STUAPCLEDMKXKL-LKXGYXEUSA-N Thr-Ser-Asn Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(O)=O STUAPCLEDMKXKL-LKXGYXEUSA-N 0.000 description 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
- 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 2
- 239000004473 Threonine Substances 0.000 description 2
- 208000024770 Thyroid neoplasm Diseases 0.000 description 2
- 101710183280 Topoisomerase Proteins 0.000 description 2
- 102000009618 Transforming Growth Factors Human genes 0.000 description 2
- 108010009583 Transforming Growth Factors Proteins 0.000 description 2
- AVYVKJMBNLPWRX-WFBYXXMGSA-N Trp-Ala-Ser Chemical compound C1=CC=C2C(C[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](CO)C(O)=O)=CNC2=C1 AVYVKJMBNLPWRX-WFBYXXMGSA-N 0.000 description 2
- UKINEYBQXPMOJO-UBHSHLNASA-N Trp-Asn-Ser Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CO)C(=O)O)N UKINEYBQXPMOJO-UBHSHLNASA-N 0.000 description 2
- YTCNLMSUXPCFBW-SXNHZJKMSA-N Trp-Ile-Glu Chemical compound [H]N[C@@H](CC1=CNC2=C1C=CC=C2)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCC(O)=O)C(O)=O YTCNLMSUXPCFBW-SXNHZJKMSA-N 0.000 description 2
- ZHDQRPWESGUDST-JBACZVJFSA-N Trp-Phe-Gln Chemical compound C([C@H](NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)N)C(=O)N[C@@H](CCC(N)=O)C(O)=O)C1=CC=CC=C1 ZHDQRPWESGUDST-JBACZVJFSA-N 0.000 description 2
- 102100035283 Tumor necrosis factor ligand superfamily member 18 Human genes 0.000 description 2
- FBVGQXJIXFZKSQ-GMVOTWDCSA-N Tyr-Ala-Trp Chemical compound C[C@@H](C(=O)N[C@@H](CC1=CNC2=CC=CC=C21)C(=O)O)NC(=O)[C@H](CC3=CC=C(C=C3)O)N FBVGQXJIXFZKSQ-GMVOTWDCSA-N 0.000 description 2
- AZGZDDNKFFUDEH-QWRGUYRKSA-N Tyr-Gly-Ser Chemical compound OC[C@@H](C(O)=O)NC(=O)CNC(=O)[C@@H](N)CC1=CC=C(O)C=C1 AZGZDDNKFFUDEH-QWRGUYRKSA-N 0.000 description 2
- ULHJJQYGMWONTD-HKUYNNGSSA-N Tyr-Gly-Trp Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)NCC(=O)N[C@@H](CC1=CNC2=C1C=CC=C2)C(O)=O ULHJJQYGMWONTD-HKUYNNGSSA-N 0.000 description 2
- CTDPLKMBVALCGN-JSGCOSHPSA-N Tyr-Gly-Val Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)NCC(=O)N[C@@H](C(C)C)C(O)=O CTDPLKMBVALCGN-JSGCOSHPSA-N 0.000 description 2
- MVYRJYISVJWKSX-KBPBESRZSA-N Tyr-His-Gly Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)N[C@@H](CC2=CN=CN2)C(=O)NCC(=O)O)N)O MVYRJYISVJWKSX-KBPBESRZSA-N 0.000 description 2
- HFJJDMOFTCQGEI-STECZYCISA-N Tyr-Ile-Met Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCSC)C(=O)O)NC(=O)[C@H](CC1=CC=C(C=C1)O)N HFJJDMOFTCQGEI-STECZYCISA-N 0.000 description 2
- QARCDOCCDOLJSF-HJPIBITLSA-N Tyr-Ile-Ser Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CO)C(=O)O)NC(=O)[C@H](CC1=CC=C(C=C1)O)N QARCDOCCDOLJSF-HJPIBITLSA-N 0.000 description 2
- ARJASMXQBRNAGI-YESZJQIVSA-N Tyr-Leu-Pro Chemical compound CC(C)C[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](CC2=CC=C(C=C2)O)N ARJASMXQBRNAGI-YESZJQIVSA-N 0.000 description 2
- SBLZVFCEOCWRLS-BPNCWPANSA-N Tyr-Met-Ala Chemical compound C[C@@H](C(=O)O)NC(=O)[C@H](CCSC)NC(=O)[C@H](CC1=CC=C(C=C1)O)N SBLZVFCEOCWRLS-BPNCWPANSA-N 0.000 description 2
- UPODKYBYUBTWSV-BZSNNMDCSA-N Tyr-Phe-Cys Chemical compound C([C@H](N)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CS)C(O)=O)C1=CC=C(O)C=C1 UPODKYBYUBTWSV-BZSNNMDCSA-N 0.000 description 2
- 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 2
- RZAGEHHVNYESNR-RNXOBYDBSA-N Tyr-Trp-Tyr Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC1=CNC2=C1C=CC=C2)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O RZAGEHHVNYESNR-RNXOBYDBSA-N 0.000 description 2
- OJCISMMNNUNNJA-BZSNNMDCSA-N Tyr-Tyr-Asp Chemical compound C([C@H](N)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CC(O)=O)C(O)=O)C1=CC=C(O)C=C1 OJCISMMNNUNNJA-BZSNNMDCSA-N 0.000 description 2
- KHPLUFDSWGDRHD-SLFFLAALSA-N Tyr-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=C(C=C3)O)N)C(=O)O KHPLUFDSWGDRHD-SLFFLAALSA-N 0.000 description 2
- KSGKJSFPWSMJHK-JNPHEJMOSA-N Tyr-Tyr-Thr Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H]([C@@H](C)O)C(O)=O KSGKJSFPWSMJHK-JNPHEJMOSA-N 0.000 description 2
- 101150117115 V gene Proteins 0.000 description 2
- PVPAOIGJYHVWBT-KKHAAJSZSA-N Val-Asn-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CC(=O)N)NC(=O)[C@H](C(C)C)N)O PVPAOIGJYHVWBT-KKHAAJSZSA-N 0.000 description 2
- IQQYYFPCWKWUHW-YDHLFZDLSA-N Val-Asn-Tyr Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CC1=CC=C(C=C1)O)C(=O)O)N IQQYYFPCWKWUHW-YDHLFZDLSA-N 0.000 description 2
- OVLIFGQSBSNGHY-KKHAAJSZSA-N Val-Asp-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CC(=O)O)NC(=O)[C@H](C(C)C)N)O OVLIFGQSBSNGHY-KKHAAJSZSA-N 0.000 description 2
- OVBMCNDKCWAXMZ-NAKRPEOUSA-N Val-Ile-Ser Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CO)C(=O)O)NC(=O)[C@H](C(C)C)N OVBMCNDKCWAXMZ-NAKRPEOUSA-N 0.000 description 2
- CEKSLIVSNNGOKH-KZVJFYERSA-N Val-Thr-Ala Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](C)C(=O)O)NC(=O)[C@H](C(C)C)N)O CEKSLIVSNNGOKH-KZVJFYERSA-N 0.000 description 2
- DVLWZWNAQUBZBC-ZNSHCXBVSA-N Val-Thr-Pro Chemical compound C[C@H]([C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](C(C)C)N)O DVLWZWNAQUBZBC-ZNSHCXBVSA-N 0.000 description 2
- 241000251539 Vertebrata <Metazoa> Species 0.000 description 2
- 208000002552 acute disseminated encephalomyelitis Diseases 0.000 description 2
- 229960001997 adefovir Drugs 0.000 description 2
- WOZSCQDILHKSGG-UHFFFAOYSA-N adefovir depivoxil Chemical compound N1=CN=C2N(CCOCP(=O)(OCOC(=O)C(C)(C)C)OCOC(=O)C(C)(C)C)C=NC2=C1N WOZSCQDILHKSGG-UHFFFAOYSA-N 0.000 description 2
- 238000012867 alanine scanning Methods 0.000 description 2
- 230000007815 allergy Effects 0.000 description 2
- 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 2
- DKNWSYNQZKUICI-UHFFFAOYSA-N amantadine Chemical compound C1C(C2)CC3CC2CC1(N)C3 DKNWSYNQZKUICI-UHFFFAOYSA-N 0.000 description 2
- 229960003805 amantadine Drugs 0.000 description 2
- 229960003437 aminoglutethimide Drugs 0.000 description 2
- ROBVIMPUHSLWNV-UHFFFAOYSA-N aminoglutethimide Chemical compound C=1C=C(N)C=CC=1C1(CC)CCC(=O)NC1=O ROBVIMPUHSLWNV-UHFFFAOYSA-N 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- YBBLVLTVTVSKRW-UHFFFAOYSA-N anastrozole Chemical compound N#CC(C)(C)C1=CC(C(C)(C#N)C)=CC(CN2N=CN=C2)=C1 YBBLVLTVTVSKRW-UHFFFAOYSA-N 0.000 description 2
- 125000000129 anionic group Chemical group 0.000 description 2
- 230000000259 anti-tumor effect Effects 0.000 description 2
- 230000027645 antigenic variation Effects 0.000 description 2
- 108010059459 arginyl-threonyl-phenylalanine Proteins 0.000 description 2
- 108010062796 arginyllysine Proteins 0.000 description 2
- 230000002917 arthritic effect Effects 0.000 description 2
- 108010040443 aspartyl-aspartic acid Proteins 0.000 description 2
- 230000002238 attenuated effect Effects 0.000 description 2
- 210000003719 b-lymphocyte Anatomy 0.000 description 2
- IQFYYKKMVGJFEH-UHFFFAOYSA-N beta-L-thymidine Natural products O=C1NC(=O)C(C)=CN1C1OC(CO)C(O)C1 IQFYYKKMVGJFEH-UHFFFAOYSA-N 0.000 description 2
- VEZXCJBBBCKRPI-UHFFFAOYSA-N beta-propiolactone Chemical compound O=C1CCO1 VEZXCJBBBCKRPI-UHFFFAOYSA-N 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 239000013060 biological fluid Substances 0.000 description 2
- 210000004556 brain Anatomy 0.000 description 2
- MBABCNBNDNGODA-LUVUIASKSA-N bullatacin Chemical compound O1[C@@H]([C@@H](O)CCCCCCCCCC)CC[C@@H]1[C@@H]1O[C@@H]([C@H](O)CCCCCCCCCC[C@@H](O)CC=2C(O[C@@H](C)C=2)=O)CC1 MBABCNBNDNGODA-LUVUIASKSA-N 0.000 description 2
- 210000004899 c-terminal region Anatomy 0.000 description 2
- 229930195731 calicheamicin Natural products 0.000 description 2
- 150000001720 carbohydrates Chemical group 0.000 description 2
- XREUEWVEMYWFFA-CSKJXFQVSA-N carminomycin Chemical compound C1[C@H](N)[C@H](O)[C@H](C)O[C@H]1O[C@@H]1C2=C(O)C(C(=O)C3=C(O)C=CC=C3C3=O)=C3C(O)=C2C[C@@](O)(C(C)=O)C1 XREUEWVEMYWFFA-CSKJXFQVSA-N 0.000 description 2
- XREUEWVEMYWFFA-UHFFFAOYSA-N carminomycin I Natural products C1C(N)C(O)C(C)OC1OC1C2=C(O)C(C(=O)C3=C(O)C=CC=C3C3=O)=C3C(O)=C2CC(O)(C(C)=O)C1 XREUEWVEMYWFFA-UHFFFAOYSA-N 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 229950001725 carubicin Drugs 0.000 description 2
- 230000034303 cell budding Effects 0.000 description 2
- 230000004663 cell proliferation Effects 0.000 description 2
- 230000000973 chemotherapeutic effect Effects 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 208000019425 cirrhosis of liver Diseases 0.000 description 2
- 238000010367 cloning Methods 0.000 description 2
- 201000010989 colorectal carcinoma Diseases 0.000 description 2
- 239000002299 complementary DNA Substances 0.000 description 2
- 239000013068 control sample Substances 0.000 description 2
- 238000011443 conventional therapy Methods 0.000 description 2
- XLJMAIOERFSOGZ-UHFFFAOYSA-N cyanic acid Chemical compound OC#N XLJMAIOERFSOGZ-UHFFFAOYSA-N 0.000 description 2
- 230000001461 cytolytic effect Effects 0.000 description 2
- 231100000433 cytotoxic Toxicity 0.000 description 2
- 210000001151 cytotoxic T lymphocyte Anatomy 0.000 description 2
- 229940127089 cytotoxic agent Drugs 0.000 description 2
- 239000002254 cytotoxic agent Substances 0.000 description 2
- 231100000599 cytotoxic agent Toxicity 0.000 description 2
- 230000001472 cytotoxic effect Effects 0.000 description 2
- 230000003013 cytotoxicity Effects 0.000 description 2
- 231100000135 cytotoxicity Toxicity 0.000 description 2
- STQGQHZAVUOBTE-VGBVRHCVSA-N daunorubicin 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(C)=O)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 STQGQHZAVUOBTE-VGBVRHCVSA-N 0.000 description 2
- FSIRXIHZBIXHKT-MHTVFEQDSA-N edatrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CC(CC)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FSIRXIHZBIXHKT-MHTVFEQDSA-N 0.000 description 2
- 229950006700 edatrexate Drugs 0.000 description 2
- 206010014599 encephalitis Diseases 0.000 description 2
- 229950007432 endomycin Drugs 0.000 description 2
- 230000002708 enhancing effect Effects 0.000 description 2
- 229960000980 entecavir Drugs 0.000 description 2
- YXPVEXCTPGULBZ-WQYNNSOESA-N entecavir hydrate Chemical compound O.C1=NC=2C(=O)NC(N)=NC=2N1[C@H]1C[C@H](O)[C@@H](CO)C1=C YXPVEXCTPGULBZ-WQYNNSOESA-N 0.000 description 2
- 231100000321 erythema Toxicity 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000000284 extract Substances 0.000 description 2
- 229960004396 famciclovir Drugs 0.000 description 2
- GGXKWVWZWMLJEH-UHFFFAOYSA-N famcyclovir Chemical compound N1=C(N)N=C2N(CCC(COC(=O)C)COC(C)=O)C=NC2=C1 GGXKWVWZWMLJEH-UHFFFAOYSA-N 0.000 description 2
- 229960002949 fluorouracil Drugs 0.000 description 2
- 235000019152 folic acid Nutrition 0.000 description 2
- 239000011724 folic acid Substances 0.000 description 2
- CHPZKNULDCNCBW-UHFFFAOYSA-N gallium nitrate Chemical compound [Ga+3].[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O CHPZKNULDCNCBW-UHFFFAOYSA-N 0.000 description 2
- 229960002963 ganciclovir Drugs 0.000 description 2
- IRSCQMHQWWYFCW-UHFFFAOYSA-N ganciclovir Chemical compound O=C1NC(N)=NC2=C1N=CN2COC(CO)CO IRSCQMHQWWYFCW-UHFFFAOYSA-N 0.000 description 2
- SDUQYLNIPVEERB-QPPQHZFASA-N gemcitabine Chemical compound O=C1N=C(N)C=CN1[C@H]1C(F)(F)[C@H](O)[C@@H](CO)O1 SDUQYLNIPVEERB-QPPQHZFASA-N 0.000 description 2
- 108010057083 glutamyl-aspartyl-leucine Proteins 0.000 description 2
- 108010074027 glycyl-seryl-phenylalanine Proteins 0.000 description 2
- 231100000869 headache Toxicity 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 239000000185 hemagglutinin Substances 0.000 description 2
- 208000014951 hematologic disease Diseases 0.000 description 2
- 208000018706 hematopoietic system disease Diseases 0.000 description 2
- 208000010710 hepatitis C virus infection Diseases 0.000 description 2
- 210000003494 hepatocyte Anatomy 0.000 description 2
- 229940088597 hormone Drugs 0.000 description 2
- 239000005556 hormone Substances 0.000 description 2
- 102000011749 human hepatitis C immune globulin Human genes 0.000 description 2
- 108010062138 human hepatitis C immune globulin Proteins 0.000 description 2
- HOMGKSMUEGBAAB-UHFFFAOYSA-N ifosfamide Chemical compound ClCCNP1(=O)OCCCN1CCCl HOMGKSMUEGBAAB-UHFFFAOYSA-N 0.000 description 2
- 229960001101 ifosfamide Drugs 0.000 description 2
- 230000002163 immunogen Effects 0.000 description 2
- 230000002134 immunopathologic effect Effects 0.000 description 2
- 239000003018 immunosuppressive agent Substances 0.000 description 2
- 238000009169 immunotherapy Methods 0.000 description 2
- 230000001965 increasing effect Effects 0.000 description 2
- 230000002458 infectious effect Effects 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 230000003993 interaction Effects 0.000 description 2
- 210000001503 joint Anatomy 0.000 description 2
- 238000002372 labelling Methods 0.000 description 2
- 229960001627 lamivudine Drugs 0.000 description 2
- JTEGQNOMFQHVDC-NKWVEPMBSA-N lamivudine Chemical compound O=C1N=C(N)C=CN1[C@H]1O[C@@H](CO)SC1 JTEGQNOMFQHVDC-NKWVEPMBSA-N 0.000 description 2
- HPJKCIUCZWXJDR-UHFFFAOYSA-N letrozole Chemical compound C1=CC(C#N)=CC=C1C(N1N=CN=C1)C1=CC=C(C#N)C=C1 HPJKCIUCZWXJDR-UHFFFAOYSA-N 0.000 description 2
- 108010057821 leucylproline Proteins 0.000 description 2
- 239000002502 liposome Substances 0.000 description 2
- 210000004185 liver Anatomy 0.000 description 2
- 210000005229 liver cell Anatomy 0.000 description 2
- 230000005923 long-lasting effect Effects 0.000 description 2
- HWYHZTIRURJOHG-UHFFFAOYSA-N luminol Chemical compound O=C1NNC(=O)C2=C1C(N)=CC=C2 HWYHZTIRURJOHG-UHFFFAOYSA-N 0.000 description 2
- 108010057952 lysyl-phenylalanyl-lysine Proteins 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 201000001441 melanoma Diseases 0.000 description 2
- 229960001428 mercaptopurine Drugs 0.000 description 2
- 229930182817 methionine Natural products 0.000 description 2
- 229960001156 mitoxantrone Drugs 0.000 description 2
- 238000010369 molecular cloning Methods 0.000 description 2
- 239000003068 molecular probe Substances 0.000 description 2
- 201000000050 myeloid neoplasm Diseases 0.000 description 2
- 229930014626 natural product Natural products 0.000 description 2
- QZGIWPZCWHMVQL-UIYAJPBUSA-N neocarzinostatin chromophore Chemical compound O1[C@H](C)[C@H](O)[C@H](O)[C@@H](NC)[C@H]1O[C@@H]1C/2=C/C#C[C@H]3O[C@@]3([C@@H]3OC(=O)OC3)C#CC\2=C[C@H]1OC(=O)C1=C(O)C=CC2=C(C)C=C(OC)C=C12 QZGIWPZCWHMVQL-UIYAJPBUSA-N 0.000 description 2
- 229960003301 nivolumab Drugs 0.000 description 2
- 108091027963 non-coding RNA Proteins 0.000 description 2
- 102000042567 non-coding RNA Human genes 0.000 description 2
- 150000003833 nucleoside derivatives Chemical class 0.000 description 2
- 229960001592 paclitaxel Drugs 0.000 description 2
- 238000007911 parenteral administration Methods 0.000 description 2
- 230000006320 pegylation Effects 0.000 description 2
- FWZLYKYJQSQEPN-SKLAJPBESA-N peregrine Chemical compound OC1[C@H]2[C@@H]3C4([C@@H]5C6OC(C)=O)C(OC)CC[C@@]5(C)CN(CC)[C@H]4C6[C@@]2(OC)C[C@H](OC)[C@H]1C3 FWZLYKYJQSQEPN-SKLAJPBESA-N 0.000 description 2
- FWZLYKYJQSQEPN-UHFFFAOYSA-N peregrine Natural products OC1C2C3C4(C5C6OC(C)=O)C(OC)CCC5(C)CN(CC)C4C6C2(OC)CC(OC)C1C3 FWZLYKYJQSQEPN-UHFFFAOYSA-N 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 108010073025 phenylalanylphenylalanine Proteins 0.000 description 2
- 229920003229 poly(methyl methacrylate) Polymers 0.000 description 2
- 239000004926 polymethyl methacrylate Substances 0.000 description 2
- 230000007824 polyneuropathy Effects 0.000 description 2
- 208000037955 postinfectious encephalomyelitis Diseases 0.000 description 2
- 230000003449 preventive effect Effects 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 108010020755 prolyl-glycyl-glycine Proteins 0.000 description 2
- 229960000380 propiolactone Drugs 0.000 description 2
- 238000001742 protein purification Methods 0.000 description 2
- 230000002685 pulmonary effect Effects 0.000 description 2
- RXWNCPJZOCPEPQ-NVWDDTSBSA-N puromycin Chemical compound C1=CC(OC)=CC=C1C[C@H](N)C(=O)N[C@H]1[C@@H](O)[C@H](N2C3=NC=NC(=C3N=C2)N(C)C)O[C@@H]1CO RXWNCPJZOCPEPQ-NVWDDTSBSA-N 0.000 description 2
- 230000002285 radioactive effect Effects 0.000 description 2
- 229960004622 raloxifene Drugs 0.000 description 2
- GZUITABIAKMVPG-UHFFFAOYSA-N raloxifene Chemical compound C1=CC(O)=CC=C1C1=C(C(=O)C=2C=CC(OCCN3CCCCC3)=CC=2)C2=CC=C(O)C=C2S1 GZUITABIAKMVPG-UHFFFAOYSA-N 0.000 description 2
- 230000006798 recombination Effects 0.000 description 2
- 238000005215 recombination Methods 0.000 description 2
- 210000000664 rectum Anatomy 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 230000033458 reproduction Effects 0.000 description 2
- 210000002345 respiratory system Anatomy 0.000 description 2
- 238000012340 reverse transcriptase PCR Methods 0.000 description 2
- 206010039083 rhinitis Diseases 0.000 description 2
- 229960000329 ribavirin Drugs 0.000 description 2
- HZCAHMRRMINHDJ-DBRKOABJSA-N ribavirin Natural products O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1N=CN=C1 HZCAHMRRMINHDJ-DBRKOABJSA-N 0.000 description 2
- 229960000888 rimantadine Drugs 0.000 description 2
- 230000001932 seasonal effect Effects 0.000 description 2
- 229940095743 selective estrogen receptor modulator Drugs 0.000 description 2
- 239000000333 selective estrogen receptor modulator Substances 0.000 description 2
- 235000004400 serine Nutrition 0.000 description 2
- 210000003491 skin Anatomy 0.000 description 2
- 230000009870 specific binding Effects 0.000 description 2
- 238000011301 standard therapy Methods 0.000 description 2
- 238000011272 standard treatment Methods 0.000 description 2
- PVYJZLYGTZKPJE-UHFFFAOYSA-N streptonigrin Chemical compound C=1C=C2C(=O)C(OC)=C(N)C(=O)C2=NC=1C(C=1N)=NC(C(O)=O)=C(C)C=1C1=CC=C(OC)C(OC)=C1O PVYJZLYGTZKPJE-UHFFFAOYSA-N 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 230000002195 synergetic effect Effects 0.000 description 2
- 230000009885 systemic effect Effects 0.000 description 2
- 229960001603 tamoxifen Drugs 0.000 description 2
- 229960005311 telbivudine Drugs 0.000 description 2
- IQFYYKKMVGJFEH-CSMHCCOUSA-N telbivudine Chemical compound O=C1NC(=O)C(C)=CN1[C@H]1O[C@@H](CO)[C@H](O)C1 IQFYYKKMVGJFEH-CSMHCCOUSA-N 0.000 description 2
- 231100001274 therapeutic index Toxicity 0.000 description 2
- 201000002510 thyroid cancer Diseases 0.000 description 2
- 239000003053 toxin Substances 0.000 description 2
- 231100000765 toxin Toxicity 0.000 description 2
- 108700012359 toxins Proteins 0.000 description 2
- 238000013519 translation Methods 0.000 description 2
- 210000004881 tumor cell Anatomy 0.000 description 2
- 229910052721 tungsten Inorganic materials 0.000 description 2
- 241000701161 unidentified adenovirus Species 0.000 description 2
- 241000712461 unidentified influenza virus Species 0.000 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 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 description 2
- 239000011735 vitamin B7 Substances 0.000 description 2
- 230000003442 weekly effect Effects 0.000 description 2
- 229950009268 zinostatin Drugs 0.000 description 2
- 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 1
- NNJPGOLRFBJNIW-HNNXBMFYSA-N (-)-demecolcine Chemical compound C1=C(OC)C(=O)C=C2[C@@H](NC)CCC3=CC(OC)=C(OC)C(OC)=C3C2=C1 NNJPGOLRFBJNIW-HNNXBMFYSA-N 0.000 description 1
- FLWWDYNPWOSLEO-HQVZTVAUSA-N (2s)-2-[[4-[1-(2-amino-4-oxo-1h-pteridin-6-yl)ethyl-methylamino]benzoyl]amino]pentanedioic acid Chemical compound C=1N=C2NC(N)=NC(=O)C2=NC=1C(C)N(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FLWWDYNPWOSLEO-HQVZTVAUSA-N 0.000 description 1
- URLVCROWVOSNPT-XOTOMLERSA-N (2s)-4-[(13r)-13-hydroxy-13-[(2r,5r)-5-[(2r,5r)-5-[(1r)-1-hydroxyundecyl]oxolan-2-yl]oxolan-2-yl]tridecyl]-2-methyl-2h-furan-5-one Chemical compound O1[C@@H]([C@H](O)CCCCCCCCCC)CC[C@@H]1[C@@H]1O[C@@H]([C@H](O)CCCCCCCCCCCCC=2C(O[C@@H](C)C=2)=O)CC1 URLVCROWVOSNPT-XOTOMLERSA-N 0.000 description 1
- XRBSKUSTLXISAB-XVVDYKMHSA-N (5r,6r,7r,8r)-8-hydroxy-7-(hydroxymethyl)-5-(3,4,5-trimethoxyphenyl)-5,6,7,8-tetrahydrobenzo[f][1,3]benzodioxole-6-carboxylic acid Chemical compound COC1=C(OC)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@H](O)[C@@H](CO)[C@@H]2C(O)=O)=C1 XRBSKUSTLXISAB-XVVDYKMHSA-N 0.000 description 1
- XRBSKUSTLXISAB-UHFFFAOYSA-N (7R,7'R,8R,8'R)-form-Podophyllic acid Natural products COC1=C(OC)C(OC)=CC(C2C3=CC=4OCOC=4C=C3C(O)C(CO)C2C(O)=O)=C1 XRBSKUSTLXISAB-UHFFFAOYSA-N 0.000 description 1
- JXVAMODRWBNUSF-KZQKBALLSA-N (7s,9r,10r)-7-[(2r,4s,5s,6s)-5-[[(2s,4as,5as,7s,9s,9ar,10ar)-2,9-dimethyl-3-oxo-4,4a,5a,6,7,9,9a,10a-octahydrodipyrano[4,2-a:4',3'-e][1,4]dioxin-7-yl]oxy]-4-(dimethylamino)-6-methyloxan-2-yl]oxy-10-[(2s,4s,5s,6s)-4-(dimethylamino)-5-hydroxy-6-methyloxan-2 Chemical compound O([C@@H]1C2=C(O)C=3C(=O)C4=CC=CC(O)=C4C(=O)C=3C(O)=C2[C@@H](O[C@@H]2O[C@@H](C)[C@@H](O[C@@H]3O[C@@H](C)[C@H]4O[C@@H]5O[C@@H](C)C(=O)C[C@@H]5O[C@H]4C3)[C@H](C2)N(C)C)C[C@]1(O)CC)[C@H]1C[C@H](N(C)C)[C@H](O)[C@H](C)O1 JXVAMODRWBNUSF-KZQKBALLSA-N 0.000 description 1
- FPVKHBSQESCIEP-UHFFFAOYSA-N (8S)-3-(2-deoxy-beta-D-erythro-pentofuranosyl)-3,6,7,8-tetrahydroimidazo[4,5-d][1,3]diazepin-8-ol Natural products C1C(O)C(CO)OC1N1C(NC=NCC2O)=C2N=C1 FPVKHBSQESCIEP-UHFFFAOYSA-N 0.000 description 1
- IEXUMDBQLIVNHZ-YOUGDJEHSA-N (8s,11r,13r,14s,17s)-11-[4-(dimethylamino)phenyl]-17-hydroxy-17-(3-hydroxypropyl)-13-methyl-1,2,6,7,8,11,12,14,15,16-decahydrocyclopenta[a]phenanthren-3-one Chemical compound C1=CC(N(C)C)=CC=C1[C@@H]1C2=C3CCC(=O)C=C3CC[C@H]2[C@H](CC[C@]2(O)CCCO)[C@@]2(C)C1 IEXUMDBQLIVNHZ-YOUGDJEHSA-N 0.000 description 1
- FDKXTQMXEQVLRF-ZHACJKMWSA-N (E)-dacarbazine Chemical compound CN(C)\N=N\c1[nH]cnc1C(N)=O FDKXTQMXEQVLRF-ZHACJKMWSA-N 0.000 description 1
- LKJPYSCBVHEWIU-KRWDZBQOSA-N (R)-bicalutamide Chemical compound C([C@@](O)(C)C(=O)NC=1C=C(C(C#N)=CC=1)C(F)(F)F)S(=O)(=O)C1=CC=C(F)C=C1 LKJPYSCBVHEWIU-KRWDZBQOSA-N 0.000 description 1
- AGNGYMCLFWQVGX-AGFFZDDWSA-N (e)-1-[(2s)-2-amino-2-carboxyethoxy]-2-diazonioethenolate Chemical compound OC(=O)[C@@H](N)CO\C([O-])=C\[N+]#N AGNGYMCLFWQVGX-AGFFZDDWSA-N 0.000 description 1
- WNXJIVFYUVYPPR-UHFFFAOYSA-N 1,3-dioxolane Chemical compound C1COCO1 WNXJIVFYUVYPPR-UHFFFAOYSA-N 0.000 description 1
- BTOTXLJHDSNXMW-POYBYMJQSA-N 2,3-dideoxyuridine Chemical compound O1[C@H](CO)CC[C@@H]1N1C(=O)NC(=O)C=C1 BTOTXLJHDSNXMW-POYBYMJQSA-N 0.000 description 1
- BOMZMNZEXMAQQW-UHFFFAOYSA-N 2,5,11-trimethyl-6h-pyrido[4,3-b]carbazol-2-ium-9-ol;acetate Chemical compound CC([O-])=O.C[N+]1=CC=C2C(C)=C(NC=3C4=CC(O)=CC=3)C4=C(C)C2=C1 BOMZMNZEXMAQQW-UHFFFAOYSA-N 0.000 description 1
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 1
- ZBMRKNMTMPPMMK-UHFFFAOYSA-N 2-amino-4-[hydroxy(methyl)phosphoryl]butanoic acid;azane Chemical compound [NH4+].CP(O)(=O)CCC(N)C([O-])=O ZBMRKNMTMPPMMK-UHFFFAOYSA-N 0.000 description 1
- VNBAOSVONFJBKP-UHFFFAOYSA-N 2-chloro-n,n-bis(2-chloroethyl)propan-1-amine;hydrochloride Chemical compound Cl.CC(Cl)CN(CCCl)CCCl VNBAOSVONFJBKP-UHFFFAOYSA-N 0.000 description 1
- CTRPRMNBTVRDFH-UHFFFAOYSA-N 2-n-methyl-1,3,5-triazine-2,4,6-triamine Chemical class CNC1=NC(N)=NC(N)=N1 CTRPRMNBTVRDFH-UHFFFAOYSA-N 0.000 description 1
- RSEBUVRVKCANEP-UHFFFAOYSA-N 2-pyrroline Chemical compound C1CC=CN1 RSEBUVRVKCANEP-UHFFFAOYSA-N 0.000 description 1
- NDMPLJNOPCLANR-UHFFFAOYSA-N 3,4-dihydroxy-15-(4-hydroxy-18-methoxycarbonyl-5,18-seco-ibogamin-18-yl)-16-methoxy-1-methyl-6,7-didehydro-aspidospermidine-3-carboxylic acid methyl ester Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 NDMPLJNOPCLANR-UHFFFAOYSA-N 0.000 description 1
- PWMYMKOUNYTVQN-UHFFFAOYSA-N 3-(8,8-diethyl-2-aza-8-germaspiro[4.5]decan-2-yl)-n,n-dimethylpropan-1-amine Chemical compound C1C[Ge](CC)(CC)CCC11CN(CCCN(C)C)CC1 PWMYMKOUNYTVQN-UHFFFAOYSA-N 0.000 description 1
- FQWNGSKQHPNIQG-UHFFFAOYSA-N 3-[[bis(2-chloroethyl)amino-(2-chloroethoxy)phosphoryl]amino]propan-1-ol Chemical compound OCCCNP(=O)(OCCCl)N(CCCl)CCCl FQWNGSKQHPNIQG-UHFFFAOYSA-N 0.000 description 1
- AOJJSUZBOXZQNB-VTZDEGQISA-N 4'-epidoxorubicin 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-VTZDEGQISA-N 0.000 description 1
- CLPFFLWZZBQMAO-UHFFFAOYSA-N 4-(5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-5-yl)benzonitrile Chemical compound C1=CC(C#N)=CC=C1C1N2C=NC=C2CCC1 CLPFFLWZZBQMAO-UHFFFAOYSA-N 0.000 description 1
- TVZGACDUOSZQKY-LBPRGKRZSA-N 4-aminofolic acid Chemical compound C1=NC2=NC(N)=NC(N)=C2N=C1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 TVZGACDUOSZQKY-LBPRGKRZSA-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
- IDPUKCWIGUEADI-UHFFFAOYSA-N 5-[bis(2-chloroethyl)amino]uracil Chemical compound ClCCN(CCCl)C1=CNC(=O)NC1=O IDPUKCWIGUEADI-UHFFFAOYSA-N 0.000 description 1
- NMUSYJAQQFHJEW-KVTDHHQDSA-N 5-azacytidine Chemical compound O=C1N=C(N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 NMUSYJAQQFHJEW-KVTDHHQDSA-N 0.000 description 1
- KYBXNPIASYUWLN-UHFFFAOYSA-N 5-hydroxypyrrolidine-2-carboxylic acid Chemical compound OC1CCC(C(O)=O)N1 KYBXNPIASYUWLN-UHFFFAOYSA-N 0.000 description 1
- AOJJSUZBOXZQNB-UHFFFAOYSA-N 7-[(4-amino-5-hydroxy-6-methyl-2-oxanyl)oxy]-6,9,11-trihydroxy-9-(2-hydroxy-1-oxoethyl)-4-methoxy-8,10-dihydro-7H-tetracene-5,12-dione Chemical compound C1=2C(O)=C3C(=O)C=4C(OC)=CC=CC=4C(=O)C3=C(O)C=2CC(O)(C(=O)CO)CC1OC1CC(N)C(O)C(C)O1 AOJJSUZBOXZQNB-UHFFFAOYSA-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
- HDZZVAMISRMYHH-UHFFFAOYSA-N 9beta-Ribofuranosyl-7-deazaadenin Natural products C1=CC=2C(N)=NC=NC=2N1C1OC(CO)C(O)C1O HDZZVAMISRMYHH-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 101100230376 Acetivibrio thermocellus (strain ATCC 27405 / DSM 1237 / JCM 9322 / NBRC 103400 / NCIMB 10682 / NRRL B-4536 / VPI 7372) celI gene Proteins 0.000 description 1
- 206010001497 Agitation Diseases 0.000 description 1
- DKJPOZOEBONHFS-ZLUOBGJFSA-N Ala-Ala-Asp Chemical compound C[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@H](C(O)=O)CC(O)=O DKJPOZOEBONHFS-ZLUOBGJFSA-N 0.000 description 1
- CXRCVCURMBFFOL-FXQIFTODSA-N Ala-Ala-Pro Chemical compound C[C@H](N)C(=O)N[C@@H](C)C(=O)N1CCC[C@H]1C(O)=O CXRCVCURMBFFOL-FXQIFTODSA-N 0.000 description 1
- JBVSSSZFNTXJDX-YTLHQDLWSA-N Ala-Ala-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@H](C)N JBVSSSZFNTXJDX-YTLHQDLWSA-N 0.000 description 1
- TTXMOJWKNRJWQJ-FXQIFTODSA-N Ala-Arg-Ser Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)C)CCCN=C(N)N TTXMOJWKNRJWQJ-FXQIFTODSA-N 0.000 description 1
- CVGNCMIULZNYES-WHFBIAKZSA-N Ala-Asn-Gly Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CC(N)=O)C(=O)NCC(O)=O CVGNCMIULZNYES-WHFBIAKZSA-N 0.000 description 1
- HJCMDXDYPOUFDY-WHFBIAKZSA-N Ala-Gln Chemical compound C[C@H](N)C(=O)N[C@H](C(O)=O)CCC(N)=O HJCMDXDYPOUFDY-WHFBIAKZSA-N 0.000 description 1
- XZWXFWBHYRFLEF-FSPLSTOPSA-N Ala-His Chemical compound C[C@H](N)C(=O)N[C@H](C(O)=O)CC1=CN=CN1 XZWXFWBHYRFLEF-FSPLSTOPSA-N 0.000 description 1
- SOBIAADAMRHGKH-CIUDSAMLSA-N Ala-Leu-Ser Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(O)=O SOBIAADAMRHGKH-CIUDSAMLSA-N 0.000 description 1
- REAQAWSENITKJL-DDWPSWQVSA-N Ala-Met-Asp-Tyr Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O REAQAWSENITKJL-DDWPSWQVSA-N 0.000 description 1
- MAZZQZWCCYJQGZ-GUBZILKMSA-N Ala-Pro-Arg Chemical compound [H]N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCCNC(N)=N)C(O)=O MAZZQZWCCYJQGZ-GUBZILKMSA-N 0.000 description 1
- IPWKGIFRRBGCJO-IMJSIDKUSA-N Ala-Ser Chemical compound C[C@H]([NH3+])C(=O)N[C@@H](CO)C([O-])=O IPWKGIFRRBGCJO-IMJSIDKUSA-N 0.000 description 1
- RTZCUEHYUQZIDE-WHFBIAKZSA-N Ala-Ser-Gly Chemical compound C[C@H](N)C(=O)N[C@@H](CO)C(=O)NCC(O)=O RTZCUEHYUQZIDE-WHFBIAKZSA-N 0.000 description 1
- NZGRHTKZFSVPAN-BIIVOSGPSA-N Ala-Ser-Pro Chemical compound C[C@@H](C(=O)N[C@@H](CO)C(=O)N1CCC[C@@H]1C(=O)O)N NZGRHTKZFSVPAN-BIIVOSGPSA-N 0.000 description 1
- IOFVWPYSRSCWHI-JXUBOQSCSA-N Ala-Thr-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](C)N IOFVWPYSRSCWHI-JXUBOQSCSA-N 0.000 description 1
- JJHBEVZAZXZREW-LFSVMHDDSA-N Ala-Thr-Phe Chemical compound C[C@@H](O)[C@H](NC(=O)[C@H](C)N)C(=O)N[C@@H](Cc1ccccc1)C(O)=O JJHBEVZAZXZREW-LFSVMHDDSA-N 0.000 description 1
- BOKLLPVAQDSLHC-FXQIFTODSA-N Ala-Val-Cys Chemical compound C[C@@H](C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CS)C(=O)O)N BOKLLPVAQDSLHC-FXQIFTODSA-N 0.000 description 1
- REWSWYIDQIELBE-FXQIFTODSA-N Ala-Val-Ser Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CO)C(O)=O REWSWYIDQIELBE-FXQIFTODSA-N 0.000 description 1
- 108010012934 Albumin-Bound Paclitaxel Proteins 0.000 description 1
- 241000124001 Alcyonacea Species 0.000 description 1
- 108090000644 Angiozyme Proteins 0.000 description 1
- 208000031295 Animal disease Diseases 0.000 description 1
- 101710145634 Antigen 1 Proteins 0.000 description 1
- CPSHGRGUPZBMOK-CIUDSAMLSA-N Arg-Asn-Gln Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(O)=O CPSHGRGUPZBMOK-CIUDSAMLSA-N 0.000 description 1
- LLZXKVAAEWBUPB-KKUMJFAQSA-N Arg-Gln-Phe Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O LLZXKVAAEWBUPB-KKUMJFAQSA-N 0.000 description 1
- ZEAYJGRKRUBDOB-GARJFASQSA-N Arg-Gln-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CCC(=O)N)NC(=O)[C@H](CCCN=C(N)N)N)C(=O)O ZEAYJGRKRUBDOB-GARJFASQSA-N 0.000 description 1
- AUFHLLPVPSMEOG-YUMQZZPRSA-N Arg-Gly-Glu Chemical compound NC(N)=NCCC[C@H](N)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(O)=O AUFHLLPVPSMEOG-YUMQZZPRSA-N 0.000 description 1
- MMGCRPZQZWTZTA-IHRRRGAJSA-N Arg-His-His Chemical compound C1=C(NC=N1)C[C@@H](C(=O)N[C@@H](CC2=CN=CN2)C(=O)O)NC(=O)[C@H](CCCN=C(N)N)N MMGCRPZQZWTZTA-IHRRRGAJSA-N 0.000 description 1
- OTZMRMHZCMZOJZ-SRVKXCTJSA-N Arg-Leu-Glu Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(O)=O OTZMRMHZCMZOJZ-SRVKXCTJSA-N 0.000 description 1
- JEXPNDORFYHJTM-IHRRRGAJSA-N Arg-Leu-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CCCN=C(N)N JEXPNDORFYHJTM-IHRRRGAJSA-N 0.000 description 1
- HGKHPCFTRQDHCU-IUCAKERBSA-N Arg-Pro-Gly Chemical compound NC(N)=NCCC[C@H](N)C(=O)N1CCC[C@H]1C(=O)NCC(O)=O HGKHPCFTRQDHCU-IUCAKERBSA-N 0.000 description 1
- AWMAZIIEFPFHCP-RCWTZXSCSA-N Arg-Pro-Thr Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N1CCC[C@H]1C(=O)N[C@@H]([C@@H](C)O)C(O)=O AWMAZIIEFPFHCP-RCWTZXSCSA-N 0.000 description 1
- KXOPYFNQLVUOAQ-FXQIFTODSA-N Arg-Ser-Ala Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)N[C@@H](C)C(O)=O KXOPYFNQLVUOAQ-FXQIFTODSA-N 0.000 description 1
- VRTWYUYCJGNFES-CIUDSAMLSA-N Arg-Ser-Gln Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(O)=O VRTWYUYCJGNFES-CIUDSAMLSA-N 0.000 description 1
- 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 1
- ICRHGPYYXMWHIE-LPEHRKFASA-N Arg-Ser-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CO)NC(=O)[C@H](CCCN=C(N)N)N)C(=O)O ICRHGPYYXMWHIE-LPEHRKFASA-N 0.000 description 1
- BWMMKQPATDUYKB-IHRRRGAJSA-N Arg-Tyr-Asn Chemical compound NC(N)=NCCC[C@H](N)C(=O)N[C@H](C(=O)N[C@@H](CC(N)=O)C(O)=O)CC1=CC=C(O)C=C1 BWMMKQPATDUYKB-IHRRRGAJSA-N 0.000 description 1
- 102000014654 Aromatase Human genes 0.000 description 1
- 108010078554 Aromatase Proteins 0.000 description 1
- 229940122815 Aromatase inhibitor Drugs 0.000 description 1
- BVLIJXXSXBUGEC-SRVKXCTJSA-N Asn-Asn-Tyr Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O BVLIJXXSXBUGEC-SRVKXCTJSA-N 0.000 description 1
- TWXZVVXRRRRSLT-IMJSIDKUSA-N Asn-Cys Chemical compound NC(=O)C[C@H](N)C(=O)N[C@@H](CS)C(O)=O TWXZVVXRRRRSLT-IMJSIDKUSA-N 0.000 description 1
- FAEFJTCTNZTPHX-ACZMJKKPSA-N Asn-Gln-Ala Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](C)C(O)=O FAEFJTCTNZTPHX-ACZMJKKPSA-N 0.000 description 1
- QPTAGIPWARILES-AVGNSLFASA-N Asn-Gln-Phe Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O QPTAGIPWARILES-AVGNSLFASA-N 0.000 description 1
- IIFDPDVJAHQFSR-WHFBIAKZSA-N Asn-Glu Chemical compound NC(=O)C[C@H](N)C(=O)N[C@H](C(O)=O)CCC(O)=O IIFDPDVJAHQFSR-WHFBIAKZSA-N 0.000 description 1
- OLVIPTLKNSAYRJ-YUMQZZPRSA-N Asn-Gly-Lys Chemical compound C(CCN)C[C@@H](C(=O)O)NC(=O)CNC(=O)[C@H](CC(=O)N)N OLVIPTLKNSAYRJ-YUMQZZPRSA-N 0.000 description 1
- IBLAOXSULLECQZ-IUKAMOBKSA-N Asn-Ile-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)[C@H]([C@@H](C)CC)NC(=O)[C@@H](N)CC(N)=O IBLAOXSULLECQZ-IUKAMOBKSA-N 0.000 description 1
- BXUHCIXDSWRSBS-CIUDSAMLSA-N Asn-Leu-Asp Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(O)=O)C(O)=O BXUHCIXDSWRSBS-CIUDSAMLSA-N 0.000 description 1
- GMUOCGCDOYYWPD-FXQIFTODSA-N Asn-Pro-Ser Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CO)C(O)=O GMUOCGCDOYYWPD-FXQIFTODSA-N 0.000 description 1
- REQUGIWGOGSOEZ-ZLUOBGJFSA-N Asn-Ser-Asn Chemical compound C([C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(=O)N)C(=O)O)N)C(=O)N REQUGIWGOGSOEZ-ZLUOBGJFSA-N 0.000 description 1
- MKJBPDLENBUHQU-CIUDSAMLSA-N Asn-Ser-Leu Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(O)=O MKJBPDLENBUHQU-CIUDSAMLSA-N 0.000 description 1
- UGXYFDQFLVCDFC-CIUDSAMLSA-N Asn-Ser-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC(N)=O UGXYFDQFLVCDFC-CIUDSAMLSA-N 0.000 description 1
- NCXTYSVDWLAQGZ-ZKWXMUAHSA-N Asn-Ser-Val Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC(N)=O NCXTYSVDWLAQGZ-ZKWXMUAHSA-N 0.000 description 1
- WLVLIYYBPPONRJ-GCJQMDKQSA-N Asn-Thr-Ala Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C)C(O)=O WLVLIYYBPPONRJ-GCJQMDKQSA-N 0.000 description 1
- JBDLMLZNDRLDIX-HJGDQZAQSA-N Asn-Thr-Leu Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(O)=O JBDLMLZNDRLDIX-HJGDQZAQSA-N 0.000 description 1
- KZYSHAMXEBPJBD-JRQIVUDYSA-N Asn-Thr-Tyr Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O KZYSHAMXEBPJBD-JRQIVUDYSA-N 0.000 description 1
- NJPLPRFQLBZAMH-IHRRRGAJSA-N Asn-Tyr-Met Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CCSC)C(O)=O NJPLPRFQLBZAMH-IHRRRGAJSA-N 0.000 description 1
- KRXIWXCXOARFNT-ZLUOBGJFSA-N Asp-Ala-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC(O)=O KRXIWXCXOARFNT-ZLUOBGJFSA-N 0.000 description 1
- WXASLRQUSYWVNE-FXQIFTODSA-N Asp-Cys-Met Chemical compound CSCC[C@@H](C(=O)O)NC(=O)[C@H](CS)NC(=O)[C@H](CC(=O)O)N WXASLRQUSYWVNE-FXQIFTODSA-N 0.000 description 1
- NYQHSUGFEWDWPD-ACZMJKKPSA-N Asp-Gln-Ala Chemical compound C[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)N)NC(=O)[C@H](CC(=O)O)N NYQHSUGFEWDWPD-ACZMJKKPSA-N 0.000 description 1
- GYWQGGUCMDCUJE-DLOVCJGASA-N Asp-Phe-Ala Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](C)C(O)=O GYWQGGUCMDCUJE-DLOVCJGASA-N 0.000 description 1
- 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 1
- QSFHZPQUAAQHAQ-CIUDSAMLSA-N Asp-Ser-Leu Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(O)=O QSFHZPQUAAQHAQ-CIUDSAMLSA-N 0.000 description 1
- MGSVBZIBCCKGCY-ZLUOBGJFSA-N Asp-Ser-Ser Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(O)=O MGSVBZIBCCKGCY-ZLUOBGJFSA-N 0.000 description 1
- PLNJUJGNLDSFOP-UWJYBYFXSA-N Asp-Tyr-Ala 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](C)C(O)=O PLNJUJGNLDSFOP-UWJYBYFXSA-N 0.000 description 1
- MFDPBZAFCRKYEY-LAEOZQHASA-N Asp-Val-Gln Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(N)=O)C(O)=O MFDPBZAFCRKYEY-LAEOZQHASA-N 0.000 description 1
- ZUNMTUPRQMWMHX-LSJOCFKGSA-N Asp-Val-Val Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(O)=O ZUNMTUPRQMWMHX-LSJOCFKGSA-N 0.000 description 1
- BHELIUBJHYAEDK-OAIUPTLZSA-N Aspoxicillin Chemical compound C1([C@H](C(=O)N[C@@H]2C(N3[C@H](C(C)(C)S[C@@H]32)C(O)=O)=O)NC(=O)[C@H](N)CC(=O)NC)=CC=C(O)C=C1 BHELIUBJHYAEDK-OAIUPTLZSA-N 0.000 description 1
- 108090001008 Avidin Proteins 0.000 description 1
- NOWKCMXCCJGMRR-UHFFFAOYSA-N Aziridine Chemical compound C1CN1 NOWKCMXCCJGMRR-UHFFFAOYSA-N 0.000 description 1
- 208000023328 Basedow disease Diseases 0.000 description 1
- VGGGPCQERPFHOB-MCIONIFRSA-N Bestatin Chemical compound CC(C)C[C@H](C(O)=O)NC(=O)[C@@H](O)[C@H](N)CC1=CC=CC=C1 VGGGPCQERPFHOB-MCIONIFRSA-N 0.000 description 1
- 208000008439 Biliary Liver Cirrhosis Diseases 0.000 description 1
- 208000033222 Biliary cirrhosis primary Diseases 0.000 description 1
- 206010005003 Bladder cancer Diseases 0.000 description 1
- 108010006654 Bleomycin Proteins 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- KGGVWMAPBXIMEM-ZRTAFWODSA-N Bullatacinone Chemical compound O1[C@@H]([C@@H](O)CCCCCCCCCC)CC[C@@H]1[C@@H]1O[C@@H]([C@H](O)CCCCCCCCCC[C@H]2OC(=O)[C@H](CC(C)=O)C2)CC1 KGGVWMAPBXIMEM-ZRTAFWODSA-N 0.000 description 1
- KGGVWMAPBXIMEM-JQFCFGFHSA-N Bullatacinone Natural products O=C(C[C@H]1C(=O)O[C@H](CCCCCCCCCC[C@H](O)[C@@H]2O[C@@H]([C@@H]3O[C@@H]([C@@H](O)CCCCCCCCCC)CC3)CC2)C1)C KGGVWMAPBXIMEM-JQFCFGFHSA-N 0.000 description 1
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 1
- 241000282836 Camelus dromedarius Species 0.000 description 1
- GAGWJHPBXLXJQN-UHFFFAOYSA-N Capecitabine Natural products C1=C(F)C(NC(=O)OCCCCC)=NC(=O)N1C1C(O)C(O)C(C)O1 GAGWJHPBXLXJQN-UHFFFAOYSA-N 0.000 description 1
- SHHKQEUPHAENFK-UHFFFAOYSA-N Carboquone Chemical compound O=C1C(C)=C(N2CC2)C(=O)C(C(COC(N)=O)OC)=C1N1CC1 SHHKQEUPHAENFK-UHFFFAOYSA-N 0.000 description 1
- 208000009458 Carcinoma in Situ Diseases 0.000 description 1
- 208000017897 Carcinoma of esophagus Diseases 0.000 description 1
- AOCCBINRVIKJHY-UHFFFAOYSA-N Carmofur Chemical compound CCCCCCNC(=O)N1C=C(F)C(=O)NC1=O AOCCBINRVIKJHY-UHFFFAOYSA-N 0.000 description 1
- DLGOEMSEDOSKAD-UHFFFAOYSA-N Carmustine Chemical compound ClCCNC(=O)N(N=O)CCCl DLGOEMSEDOSKAD-UHFFFAOYSA-N 0.000 description 1
- 102000014914 Carrier Proteins Human genes 0.000 description 1
- 108010078791 Carrier Proteins Proteins 0.000 description 1
- 108090000994 Catalytic RNA Proteins 0.000 description 1
- 102000053642 Catalytic RNA Human genes 0.000 description 1
- 241000282693 Cercopithecidae Species 0.000 description 1
- 206010008342 Cervix carcinoma Diseases 0.000 description 1
- JWBOIMRXGHLCPP-UHFFFAOYSA-N Chloditan Chemical compound C=1C=CC=C(Cl)C=1C(C(Cl)Cl)C1=CC=C(Cl)C=C1 JWBOIMRXGHLCPP-UHFFFAOYSA-N 0.000 description 1
- 206010008609 Cholangitis sclerosing Diseases 0.000 description 1
- 208000015943 Coeliac disease Diseases 0.000 description 1
- 206010009900 Colitis ulcerative Diseases 0.000 description 1
- 208000035473 Communicable disease Diseases 0.000 description 1
- 206010010356 Congenital anomaly Diseases 0.000 description 1
- 241000699800 Cricetinae Species 0.000 description 1
- 208000011231 Crohn disease Diseases 0.000 description 1
- 229930188224 Cryptophycin Natural products 0.000 description 1
- GMXSSZUVDNPRMA-FXQIFTODSA-N Cys-Arg-Asp Chemical compound [H]N[C@@H](CS)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(O)=O GMXSSZUVDNPRMA-FXQIFTODSA-N 0.000 description 1
- LDIKUWLAMDFHPU-FXQIFTODSA-N Cys-Cys-Arg Chemical compound [H]N[C@@H](CS)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O LDIKUWLAMDFHPU-FXQIFTODSA-N 0.000 description 1
- SDWZYDDNSMPBRM-AVGNSLFASA-N Cys-Gln-Phe Chemical compound SC[C@H](N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 SDWZYDDNSMPBRM-AVGNSLFASA-N 0.000 description 1
- GUKYYUFHWYRMEU-WHFBIAKZSA-N Cys-Gly-Asp Chemical compound [H]N[C@@H](CS)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(O)=O GUKYYUFHWYRMEU-WHFBIAKZSA-N 0.000 description 1
- SDDJEOCJUFKAPV-BPUTZDHNSA-N Cys-Met-Trp Chemical compound C1=CC=C2C(C[C@H](NC(=O)[C@@H](NC(=O)[C@@H](N)CS)CCSC)C(O)=O)=CNC2=C1 SDDJEOCJUFKAPV-BPUTZDHNSA-N 0.000 description 1
- MHYHLWUGWUBUHF-GUBZILKMSA-N Cys-Val-Arg Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCCN=C(N)N)C(=O)O)NC(=O)[C@H](CS)N MHYHLWUGWUBUHF-GUBZILKMSA-N 0.000 description 1
- IOLWXFWVYYCVTJ-NRPADANISA-N Cys-Val-Gln Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)O)NC(=O)[C@H](CS)N IOLWXFWVYYCVTJ-NRPADANISA-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
- 101100372758 Danio rerio vegfaa gene Proteins 0.000 description 1
- WEAHRLBPCANXCN-UHFFFAOYSA-N Daunomycin Natural products CCC1(O)CC(OC2CC(N)C(O)C(C)O2)c3cc4C(=O)c5c(OC)cccc5C(=O)c4c(O)c3C1 WEAHRLBPCANXCN-UHFFFAOYSA-N 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
- 108010002156 Depsipeptides Proteins 0.000 description 1
- 206010012438 Dermatitis atopic Diseases 0.000 description 1
- 206010012442 Dermatitis contact Diseases 0.000 description 1
- 206010048768 Dermatosis Diseases 0.000 description 1
- AUGQEEXBDZWUJY-ZLJUKNTDSA-N Diacetoxyscirpenol Chemical compound C([C@]12[C@]3(C)[C@H](OC(C)=O)[C@@H](O)[C@H]1O[C@@H]1C=C(C)CC[C@@]13COC(=O)C)O2 AUGQEEXBDZWUJY-ZLJUKNTDSA-N 0.000 description 1
- AUGQEEXBDZWUJY-UHFFFAOYSA-N Diacetoxyscirpenol Natural products CC(=O)OCC12CCC(C)=CC1OC1C(O)C(OC(C)=O)C2(C)C11CO1 AUGQEEXBDZWUJY-UHFFFAOYSA-N 0.000 description 1
- 102000016607 Diphtheria Toxin Human genes 0.000 description 1
- 108010053187 Diphtheria Toxin Proteins 0.000 description 1
- 206010061818 Disease progression Diseases 0.000 description 1
- ZQZFYGIXNQKOAV-OCEACIFDSA-N Droloxifene Chemical compound C=1C=CC=CC=1C(/CC)=C(C=1C=C(O)C=CC=1)\C1=CC=C(OCCN(C)C)C=C1 ZQZFYGIXNQKOAV-OCEACIFDSA-N 0.000 description 1
- 206010014759 Endometrial neoplasm Diseases 0.000 description 1
- SAMRUMKYXPVKPA-VFKOLLTISA-N Enocitabine Chemical compound O=C1N=C(NC(=O)CCCCCCCCCCCCCCCCCCCCC)C=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O1 SAMRUMKYXPVKPA-VFKOLLTISA-N 0.000 description 1
- HTIJFSOGRVMCQR-UHFFFAOYSA-N Epirubicin Natural products COc1cccc2C(=O)c3c(O)c4CC(O)(CC(OC5CC(N)C(=O)C(C)O5)c4c(O)c3C(=O)c12)C(=O)CO HTIJFSOGRVMCQR-UHFFFAOYSA-N 0.000 description 1
- OBMLHUPNRURLOK-XGRAFVIBSA-N Epitiostanol Chemical compound C1[C@@H]2S[C@@H]2C[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CC[C@H]21 OBMLHUPNRURLOK-XGRAFVIBSA-N 0.000 description 1
- 206010015218 Erythema multiforme Diseases 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- JOYRKODLDBILNP-UHFFFAOYSA-N Ethyl urethane Chemical compound CCOC(N)=O JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 description 1
- 108010020195 FLAG peptide Proteins 0.000 description 1
- XZWYTXMRWQJBGX-VXBMVYAYSA-N FLAG peptide Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](NC(=O)[C@@H](N)CC(O)=O)CC1=CC=C(O)C=C1 XZWYTXMRWQJBGX-VXBMVYAYSA-N 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 206010016654 Fibrosis 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
- 238000012413 Fluorescence activated cell sorting analysis Methods 0.000 description 1
- 208000004262 Food Hypersensitivity Diseases 0.000 description 1
- 206010016946 Food allergy Diseases 0.000 description 1
- 241000233866 Fungi Species 0.000 description 1
- 206010017993 Gastrointestinal neoplasms Diseases 0.000 description 1
- 108700004714 Gelonium multiflorum GEL Proteins 0.000 description 1
- 108700028146 Genetic Enhancer Elements Proteins 0.000 description 1
- 201000010915 Glioblastoma multiforme Diseases 0.000 description 1
- CRRFJBGUGNNOCS-PEFMBERDSA-N Gln-Asp-Ile Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O CRRFJBGUGNNOCS-PEFMBERDSA-N 0.000 description 1
- NVEASDQHBRZPSU-BQBZGAKWSA-N Gln-Gln-Gly Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)NCC(O)=O NVEASDQHBRZPSU-BQBZGAKWSA-N 0.000 description 1
- QFJPFPCSXOXMKI-BPUTZDHNSA-N Gln-Gln-Trp Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)N)NC(=O)[C@H](CCC(=O)N)N QFJPFPCSXOXMKI-BPUTZDHNSA-N 0.000 description 1
- JEFZIKRIDLHOIF-BYPYZUCNSA-N Gln-Gly Chemical compound NC(=O)CC[C@H](N)C(=O)NCC(O)=O JEFZIKRIDLHOIF-BYPYZUCNSA-N 0.000 description 1
- XSBGUANSZDGULP-IUCAKERBSA-N Gln-Gly-Lys Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)NCC(=O)N[C@@H](CCCCN)C(O)=O XSBGUANSZDGULP-IUCAKERBSA-N 0.000 description 1
- XITLYYAIPBBHPX-ZKWXMUAHSA-N Gln-Ile Chemical compound CC[C@H](C)[C@@H](C(O)=O)NC(=O)[C@@H](N)CCC(N)=O XITLYYAIPBBHPX-ZKWXMUAHSA-N 0.000 description 1
- CAXXTYYGFYTBPV-IUCAKERBSA-N Gln-Leu-Gly Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)NCC(O)=O CAXXTYYGFYTBPV-IUCAKERBSA-N 0.000 description 1
- YPMDZWPZFOZYFG-GUBZILKMSA-N Gln-Leu-Ser Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(O)=O YPMDZWPZFOZYFG-GUBZILKMSA-N 0.000 description 1
- MLSKFHLRFVGNLL-WDCWCFNPSA-N Gln-Leu-Thr Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O MLSKFHLRFVGNLL-WDCWCFNPSA-N 0.000 description 1
- ILKYYKRAULNYMS-JYJNAYRXSA-N Gln-Lys-Phe Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O ILKYYKRAULNYMS-JYJNAYRXSA-N 0.000 description 1
- OUBUHIODTNUUTC-WDCWCFNPSA-N Gln-Thr-Lys Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CCC(=O)N)N)O OUBUHIODTNUUTC-WDCWCFNPSA-N 0.000 description 1
- QXQDADBVIBLBHN-FHWLQOOXSA-N Gln-Tyr-Phe Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O QXQDADBVIBLBHN-FHWLQOOXSA-N 0.000 description 1
- HPBKQFJXDUVNQV-FHWLQOOXSA-N Gln-Tyr-Tyr Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)N[C@@H](CC2=CC=C(C=C2)O)C(=O)O)NC(=O)[C@H](CCC(=O)N)N)O HPBKQFJXDUVNQV-FHWLQOOXSA-N 0.000 description 1
- 206010018364 Glomerulonephritis Diseases 0.000 description 1
- QPRZKNOOOBWXSU-CIUDSAMLSA-N Glu-Asp-Arg Chemical compound OC(=O)CC[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@H](C(O)=O)CCCN=C(N)N QPRZKNOOOBWXSU-CIUDSAMLSA-N 0.000 description 1
- 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 1
- MXPBQDFWIMBACQ-ACZMJKKPSA-N Glu-Cys-Cys Chemical compound OC(=O)CC[C@H](N)C(=O)N[C@@H](CS)C(=O)N[C@@H](CS)C(O)=O MXPBQDFWIMBACQ-ACZMJKKPSA-N 0.000 description 1
- LGYZYFFDELZWRS-DCAQKATOSA-N Glu-Glu-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](N)CCC(O)=O LGYZYFFDELZWRS-DCAQKATOSA-N 0.000 description 1
- CAVMESABQIKFKT-IUCAKERBSA-N Glu-Gly-His Chemical compound C1=C(NC=N1)C[C@@H](C(=O)O)NC(=O)CNC(=O)[C@H](CCC(=O)O)N CAVMESABQIKFKT-IUCAKERBSA-N 0.000 description 1
- QIQABBIDHGQXGA-ZPFDUUQYSA-N Glu-Ile-Arg Chemical compound OC(=O)CC[C@H](N)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCCN=C(N)N)C(O)=O QIQABBIDHGQXGA-ZPFDUUQYSA-N 0.000 description 1
- QXDXIXFSFHUYAX-MNXVOIDGSA-N Glu-Ile-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H]([C@@H](C)CC)NC(=O)[C@@H](N)CCC(O)=O QXDXIXFSFHUYAX-MNXVOIDGSA-N 0.000 description 1
- HVYWQYLBVXMXSV-GUBZILKMSA-N Glu-Leu-Ala Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C)C(O)=O HVYWQYLBVXMXSV-GUBZILKMSA-N 0.000 description 1
- DWBBKNPKDHXIAC-SRVKXCTJSA-N Glu-Leu-Met Chemical compound CSCC[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CCC(O)=O DWBBKNPKDHXIAC-SRVKXCTJSA-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
- SUIAHERNFYRBDZ-GVXVVHGQSA-N Glu-Lys-Val Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C(C)C)C(O)=O SUIAHERNFYRBDZ-GVXVVHGQSA-N 0.000 description 1
- DXVOKNVIKORTHQ-GUBZILKMSA-N Glu-Pro-Glu Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCC(O)=O)C(O)=O DXVOKNVIKORTHQ-GUBZILKMSA-N 0.000 description 1
- UZWUBBRJWFTHTD-LAEOZQHASA-N Glu-Val-Asn Chemical compound NC(=O)C[C@@H](C(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](N)CCC(O)=O UZWUBBRJWFTHTD-LAEOZQHASA-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
- OCQUNKSFDYDXBG-QXEWZRGKSA-N Gly-Arg-Ile Chemical compound CC[C@H](C)[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)CN)CCCN=C(N)N OCQUNKSFDYDXBG-QXEWZRGKSA-N 0.000 description 1
- OVSKVOOUFAKODB-UWVGGRQHSA-N Gly-Arg-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)CN)CCCN=C(N)N OVSKVOOUFAKODB-UWVGGRQHSA-N 0.000 description 1
- WKJKBELXHCTHIJ-WPRPVWTQSA-N Gly-Arg-Val Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)CN)CCCN=C(N)N WKJKBELXHCTHIJ-WPRPVWTQSA-N 0.000 description 1
- FZQLXNIMCPJVJE-YUMQZZPRSA-N Gly-Asp-Leu Chemical compound [H]NCC(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(O)=O FZQLXNIMCPJVJE-YUMQZZPRSA-N 0.000 description 1
- PDAWDNVHMUKWJR-ZETCQYMHSA-N Gly-Gly-His Chemical compound NCC(=O)NCC(=O)N[C@H](C(O)=O)CC1=CNC=N1 PDAWDNVHMUKWJR-ZETCQYMHSA-N 0.000 description 1
- BUEFQXUHTUZXHR-LURJTMIESA-N Gly-Gly-Pro zwitterion Chemical compound NCC(=O)NCC(=O)N1CCC[C@H]1C(O)=O BUEFQXUHTUZXHR-LURJTMIESA-N 0.000 description 1
- 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
- ADZGCWWDPFDHCY-ZETCQYMHSA-N Gly-His-Gly Chemical compound OC(=O)CNC(=O)[C@@H](NC(=O)CN)CC1=CN=CN1 ADZGCWWDPFDHCY-ZETCQYMHSA-N 0.000 description 1
- ULZCYBYDTUMHNF-IUCAKERBSA-N Gly-Leu-Glu Chemical compound NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(O)=O ULZCYBYDTUMHNF-IUCAKERBSA-N 0.000 description 1
- VBOBNHSVQKKTOT-YUMQZZPRSA-N Gly-Lys-Ala Chemical compound [H]NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(O)=O VBOBNHSVQKKTOT-YUMQZZPRSA-N 0.000 description 1
- YYXJFBMCOUSYSF-RYUDHWBXSA-N Gly-Phe-Gln Chemical compound [H]NCC(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CCC(N)=O)C(O)=O YYXJFBMCOUSYSF-RYUDHWBXSA-N 0.000 description 1
- JPVGHHQGKPQYIL-KBPBESRZSA-N Gly-Phe-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)CN)CC1=CC=CC=C1 JPVGHHQGKPQYIL-KBPBESRZSA-N 0.000 description 1
- VDCRBJACQKOSMS-JSGCOSHPSA-N Gly-Phe-Val Chemical compound [H]NCC(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](C(C)C)C(O)=O VDCRBJACQKOSMS-JSGCOSHPSA-N 0.000 description 1
- WNGHUXFWEWTKAO-YUMQZZPRSA-N Gly-Ser-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](CO)NC(=O)CN WNGHUXFWEWTKAO-YUMQZZPRSA-N 0.000 description 1
- BLCLNMBMMGCOAS-URPVMXJPSA-N Goserelin Chemical compound C([C@@H](C(=O)N[C@H](COC(C)(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N1[C@@H](CCC1)C(=O)NNC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H]1NC(=O)CC1)C1=CC=C(O)C=C1 BLCLNMBMMGCOAS-URPVMXJPSA-N 0.000 description 1
- 108010069236 Goserelin Proteins 0.000 description 1
- 208000009329 Graft vs Host Disease Diseases 0.000 description 1
- 208000015023 Graves' disease Diseases 0.000 description 1
- 239000007995 HEPES buffer Substances 0.000 description 1
- 208000031886 HIV Infections Diseases 0.000 description 1
- 208000037357 HIV infectious disease Diseases 0.000 description 1
- 208000001204 Hashimoto Disease Diseases 0.000 description 1
- 208000035186 Hemolytic Autoimmune Anemia Diseases 0.000 description 1
- 208000037319 Hepatitis infectious Diseases 0.000 description 1
- 241000709715 Hepatovirus Species 0.000 description 1
- 208000009889 Herpes Simplex Diseases 0.000 description 1
- 241000238631 Hexapoda Species 0.000 description 1
- WSDOHRLQDGAOGU-BQBZGAKWSA-N His-Asn Chemical compound NC(=O)C[C@@H](C(O)=O)NC(=O)[C@@H](N)CC1=CN=CN1 WSDOHRLQDGAOGU-BQBZGAKWSA-N 0.000 description 1
- MDCTVRUPVLZSPG-BQBZGAKWSA-N His-Asp Chemical compound OC(=O)C[C@@H](C(O)=O)NC(=O)[C@@H](N)CC1=CNC=N1 MDCTVRUPVLZSPG-BQBZGAKWSA-N 0.000 description 1
- JENKOCSDMSVWPY-SRVKXCTJSA-N His-Leu-Asn Chemical compound [H]N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(O)=O JENKOCSDMSVWPY-SRVKXCTJSA-N 0.000 description 1
- CCUSLCQWVMWTIS-IXOXFDKPSA-N His-Thr-Leu Chemical compound [H]N[C@@H](CC1=CNC=N1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(O)=O CCUSLCQWVMWTIS-IXOXFDKPSA-N 0.000 description 1
- 101000917826 Homo sapiens Low affinity immunoglobulin gamma Fc region receptor II-a Proteins 0.000 description 1
- 101000917824 Homo sapiens Low affinity immunoglobulin gamma Fc region receptor II-b Proteins 0.000 description 1
- 101001012157 Homo sapiens Receptor tyrosine-protein kinase erbB-2 Proteins 0.000 description 1
- 101000597779 Homo sapiens Tumor necrosis factor ligand superfamily member 18 Proteins 0.000 description 1
- VSNHCAURESNICA-UHFFFAOYSA-N Hydroxyurea Chemical compound NC(=O)NO VSNHCAURESNICA-UHFFFAOYSA-N 0.000 description 1
- MPBVHIBUJCELCL-UHFFFAOYSA-N Ibandronate Chemical compound CCCCCN(C)CCC(O)(P(O)(O)=O)P(O)(O)=O MPBVHIBUJCELCL-UHFFFAOYSA-N 0.000 description 1
- XDXDZDZNSLXDNA-TZNDIEGXSA-N Idarubicin Chemical compound C1[C@H](N)[C@H](O)[C@H](C)O[C@H]1O[C@@H]1C2=C(O)C(C(=O)C3=CC=CC=C3C3=O)=C3C(O)=C2C[C@@](O)(C(C)=O)C1 XDXDZDZNSLXDNA-TZNDIEGXSA-N 0.000 description 1
- XDXDZDZNSLXDNA-UHFFFAOYSA-N Idarubicin Natural products C1C(N)C(O)C(C)OC1OC1C2=C(O)C(C(=O)C3=CC=CC=C3C3=O)=C3C(O)=C2CC(O)(C(C)=O)C1 XDXDZDZNSLXDNA-UHFFFAOYSA-N 0.000 description 1
- 201000009794 Idiopathic Pulmonary Fibrosis Diseases 0.000 description 1
- 206010021245 Idiopathic thrombocytopenic purpura Diseases 0.000 description 1
- XLDYDEDTGMHUCZ-GHCJXIJMSA-N Ile-Asp-Cys Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](CS)C(=O)O)N XLDYDEDTGMHUCZ-GHCJXIJMSA-N 0.000 description 1
- NPAYJTAXWXJKLO-NAKRPEOUSA-N Ile-Met-Ser Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CO)C(=O)O)N NPAYJTAXWXJKLO-NAKRPEOUSA-N 0.000 description 1
- FBGXMKUWQFPHFB-JBDRJPRFSA-N Ile-Ser-Cys Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CS)C(=O)O)N FBGXMKUWQFPHFB-JBDRJPRFSA-N 0.000 description 1
- ZLFNNVATRMCAKN-ZKWXMUAHSA-N Ile-Ser-Gly Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CO)C(=O)NCC(=O)O)N ZLFNNVATRMCAKN-ZKWXMUAHSA-N 0.000 description 1
- AGGIYSLVUKVOPT-HTFCKZLJSA-N Ile-Ser-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)CC)C(=O)O)N AGGIYSLVUKVOPT-HTFCKZLJSA-N 0.000 description 1
- WLRJHVNFGAOYPS-HJPIBITLSA-N Ile-Ser-Tyr Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CC1=CC=C(C=C1)O)C(=O)O)N WLRJHVNFGAOYPS-HJPIBITLSA-N 0.000 description 1
- MUFXDFWAJSPHIQ-XDTLVQLUSA-N Ile-Tyr Chemical compound CC[C@H](C)[C@H]([NH3+])C(=O)N[C@H](C([O-])=O)CC1=CC=C(O)C=C1 MUFXDFWAJSPHIQ-XDTLVQLUSA-N 0.000 description 1
- ZSESFIFAYQEKRD-CYDGBPFRSA-N Ile-Val-Met Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCSC)C(=O)O)N ZSESFIFAYQEKRD-CYDGBPFRSA-N 0.000 description 1
- 108010067060 Immunoglobulin Variable Region Proteins 0.000 description 1
- 102000017727 Immunoglobulin Variable Region Human genes 0.000 description 1
- 206010061217 Infestation Diseases 0.000 description 1
- 108010050904 Interferons Proteins 0.000 description 1
- 102000014150 Interferons Human genes 0.000 description 1
- 208000003456 Juvenile Arthritis Diseases 0.000 description 1
- SITWEMZOJNKJCH-UHFFFAOYSA-N L-alanine-L-arginine Natural products CC(N)C(=O)NC(C(O)=O)CCCNC(N)=N SITWEMZOJNKJCH-UHFFFAOYSA-N 0.000 description 1
- UGTHTQWIQKEDEH-BQBZGAKWSA-N L-alanyl-L-prolylglycine zwitterion Chemical compound C[C@H](N)C(=O)N1CCC[C@H]1C(=O)NCC(O)=O UGTHTQWIQKEDEH-BQBZGAKWSA-N 0.000 description 1
- 125000000010 L-asparaginyl group Chemical group O=C([*])[C@](N([H])[H])([H])C([H])([H])C(=O)N([H])[H] 0.000 description 1
- JLERVPBPJHKRBJ-UHFFFAOYSA-N LY 117018 Chemical compound C1=CC(O)=CC=C1C1=C(C(=O)C=2C=CC(OCCN3CCCC3)=CC=2)C2=CC=C(O)C=C2S1 JLERVPBPJHKRBJ-UHFFFAOYSA-N 0.000 description 1
- 241000283953 Lagomorpha Species 0.000 description 1
- 229920001491 Lentinan Polymers 0.000 description 1
- VKOAHIRLIUESLU-ULQDDVLXSA-N Leu-Arg-Phe Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O VKOAHIRLIUESLU-ULQDDVLXSA-N 0.000 description 1
- CLVUXCBGKUECIT-HJGDQZAQSA-N Leu-Asp-Thr Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O CLVUXCBGKUECIT-HJGDQZAQSA-N 0.000 description 1
- VQPPIMUZCZCOIL-GUBZILKMSA-N Leu-Gln-Ala Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](C)C(O)=O VQPPIMUZCZCOIL-GUBZILKMSA-N 0.000 description 1
- LOLUPZNNADDTAA-AVGNSLFASA-N Leu-Gln-Leu Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(C)C)C(O)=O LOLUPZNNADDTAA-AVGNSLFASA-N 0.000 description 1
- QVFGXCVIXXBFHO-AVGNSLFASA-N Leu-Glu-Leu Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(O)=O QVFGXCVIXXBFHO-AVGNSLFASA-N 0.000 description 1
- OGUUKPXUTHOIAV-SDDRHHMPSA-N Leu-Glu-Pro Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)N1CCC[C@@H]1C(=O)O)N OGUUKPXUTHOIAV-SDDRHHMPSA-N 0.000 description 1
- LLBQJYDYOLIQAI-JYJNAYRXSA-N Leu-Glu-Tyr Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O LLBQJYDYOLIQAI-JYJNAYRXSA-N 0.000 description 1
- FIYMBBHGYNQFOP-IUCAKERBSA-N Leu-Gly-Gln Chemical compound CC(C)C[C@@H](C(=O)NCC(=O)N[C@@H](CCC(=O)N)C(=O)O)N FIYMBBHGYNQFOP-IUCAKERBSA-N 0.000 description 1
- VWHGTYCRDRBSFI-ZETCQYMHSA-N Leu-Gly-Gly Chemical compound CC(C)C[C@H](N)C(=O)NCC(=O)NCC(O)=O VWHGTYCRDRBSFI-ZETCQYMHSA-N 0.000 description 1
- OYQUOLRTJHWVSQ-SRVKXCTJSA-N Leu-His-Ser Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CO)C(O)=O OYQUOLRTJHWVSQ-SRVKXCTJSA-N 0.000 description 1
- IFMPDNRWZZEZSL-SRVKXCTJSA-N Leu-Leu-Cys Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CS)C(O)=O IFMPDNRWZZEZSL-SRVKXCTJSA-N 0.000 description 1
- QNBVTHNJGCOVFA-AVGNSLFASA-N Leu-Leu-Glu Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](C(O)=O)CCC(O)=O QNBVTHNJGCOVFA-AVGNSLFASA-N 0.000 description 1
- IEWBEPKLKUXQBU-VOAKCMCISA-N Leu-Leu-Thr Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O IEWBEPKLKUXQBU-VOAKCMCISA-N 0.000 description 1
- BGZCJDGBBUUBHA-KKUMJFAQSA-N Leu-Lys-Leu Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(O)=O BGZCJDGBBUUBHA-KKUMJFAQSA-N 0.000 description 1
- HDHQQEDVWQGBEE-DCAQKATOSA-N Leu-Met-Ser Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CO)C(O)=O HDHQQEDVWQGBEE-DCAQKATOSA-N 0.000 description 1
- VTJUNIYRYIAIHF-IUCAKERBSA-N Leu-Pro Chemical compound CC(C)C[C@H](N)C(=O)N1CCC[C@H]1C(O)=O VTJUNIYRYIAIHF-IUCAKERBSA-N 0.000 description 1
- BMVFXOQHDQZAQU-DCAQKATOSA-N Leu-Pro-Asp Chemical compound CC(C)C[C@@H](C(=O)N1CCC[C@H]1C(=O)N[C@@H](CC(=O)O)C(=O)O)N BMVFXOQHDQZAQU-DCAQKATOSA-N 0.000 description 1
- 108010000817 Leuprolide Proteins 0.000 description 1
- GQYIWUVLTXOXAJ-UHFFFAOYSA-N Lomustine Chemical compound ClCCN(N=O)C(=O)NC1CCCCC1 GQYIWUVLTXOXAJ-UHFFFAOYSA-N 0.000 description 1
- 102100029204 Low affinity immunoglobulin gamma Fc region receptor II-a Human genes 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
- 208000019693 Lung disease Diseases 0.000 description 1
- KNKHAVVBVXKOGX-JXUBOQSCSA-N Lys-Ala-Thr Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O KNKHAVVBVXKOGX-JXUBOQSCSA-N 0.000 description 1
- QKXZCUCBFPEXNK-KKUMJFAQSA-N Lys-Leu-His Chemical compound NCCCC[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](C(O)=O)CC1=CN=CN1 QKXZCUCBFPEXNK-KKUMJFAQSA-N 0.000 description 1
- XFANQCRHTMOEAP-WDSOQIARSA-N Lys-Pro-Trp Chemical compound [H]N[C@@H](CCCCN)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CC1=CNC2=C1C=CC=C2)C(O)=O XFANQCRHTMOEAP-WDSOQIARSA-N 0.000 description 1
- 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 1
- HMZPYMSEAALNAE-ULQDDVLXSA-N Lys-Val-Tyr Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O HMZPYMSEAALNAE-ULQDDVLXSA-N 0.000 description 1
- 239000007987 MES buffer Substances 0.000 description 1
- VJRAUFKOOPNFIQ-UHFFFAOYSA-N Marcellomycin Natural products C12=C(O)C=3C(=O)C4=C(O)C=CC(O)=C4C(=O)C=3C=C2C(C(=O)OC)C(CC)(O)CC1OC(OC1C)CC(N(C)C)C1OC(OC1C)CC(O)C1OC1CC(O)C(O)C(C)O1 VJRAUFKOOPNFIQ-UHFFFAOYSA-N 0.000 description 1
- 229930126263 Maytansine Natural products 0.000 description 1
- IVDYZAAPOLNZKG-KWHRADDSSA-N Mepitiostane Chemical compound O([C@@H]1[C@]2(CC[C@@H]3[C@@]4(C)C[C@H]5S[C@H]5C[C@@H]4CC[C@H]3[C@@H]2CC1)C)C1(OC)CCCC1 IVDYZAAPOLNZKG-KWHRADDSSA-N 0.000 description 1
- FWCDNVNUSIIDNP-UHFFFAOYSA-N Met Gln Phe Ser Chemical compound CSCCC(N)C(=O)NC(CCC(N)=O)C(=O)NC(C(=O)NC(CO)C(O)=O)CC1=CC=CC=C1 FWCDNVNUSIIDNP-UHFFFAOYSA-N 0.000 description 1
- CAODKDAPYGUMLK-FXQIFTODSA-N Met-Asn-Ser Chemical compound CSCC[C@H](N)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CO)C(O)=O CAODKDAPYGUMLK-FXQIFTODSA-N 0.000 description 1
- UZVWDRPUTHXQAM-FXQIFTODSA-N Met-Asp-Ala Chemical compound CSCC[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](C)C(O)=O UZVWDRPUTHXQAM-FXQIFTODSA-N 0.000 description 1
- XOMXAVJBLRROMC-IHRRRGAJSA-N Met-Asp-Phe Chemical compound CSCC[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 XOMXAVJBLRROMC-IHRRRGAJSA-N 0.000 description 1
- VOOINLQYUZOREH-SRVKXCTJSA-N Met-Gln-Leu Chemical compound CC(C)C[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)N)NC(=O)[C@H](CCSC)N VOOINLQYUZOREH-SRVKXCTJSA-N 0.000 description 1
- UYAKZHGIPRCGPF-CIUDSAMLSA-N Met-Glu-Ala Chemical compound C[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)O)NC(=O)[C@H](CCSC)N UYAKZHGIPRCGPF-CIUDSAMLSA-N 0.000 description 1
- BCRQJDMZQUHQSV-STQMWFEESA-N Met-Gly-Tyr Chemical compound [H]N[C@@H](CCSC)C(=O)NCC(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O BCRQJDMZQUHQSV-STQMWFEESA-N 0.000 description 1
- 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 1
- VFKZTMPDYBFSTM-KVTDHHQDSA-N Mitobronitol Chemical compound BrC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CBr VFKZTMPDYBFSTM-KVTDHHQDSA-N 0.000 description 1
- 229930192392 Mitomycin Natural products 0.000 description 1
- HRHKSTOGXBBQCB-UHFFFAOYSA-N Mitomycin E Natural products O=C1C(N)=C(C)C(=O)C2=C1C(COC(N)=O)C1(OC)C3N(C)C3CN12 HRHKSTOGXBBQCB-UHFFFAOYSA-N 0.000 description 1
- 101000597780 Mus musculus Tumor necrosis factor ligand superfamily member 18 Proteins 0.000 description 1
- 201000002481 Myositis Diseases 0.000 description 1
- OVBPIULPVIDEAO-UHFFFAOYSA-N N-Pteroyl-L-glutaminsaeure Natural products C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)NC(CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-UHFFFAOYSA-N 0.000 description 1
- ZDZOTLJHXYCWBA-VCVYQWHSSA-N N-debenzoyl-N-(tert-butoxycarbonyl)-10-deacetyltaxol Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=4C=CC=CC=4)C[C@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 ZDZOTLJHXYCWBA-VCVYQWHSSA-N 0.000 description 1
- 101710204212 Neocarzinostatin Proteins 0.000 description 1
- SNIOPGDIGTZGOP-UHFFFAOYSA-N Nitroglycerin Chemical compound [O-][N+](=O)OCC(O[N+]([O-])=O)CO[N+]([O-])=O SNIOPGDIGTZGOP-UHFFFAOYSA-N 0.000 description 1
- KGTDRFCXGRULNK-UHFFFAOYSA-N Nogalamycin Natural products COC1C(OC)(C)C(OC)C(C)OC1OC1C2=C(O)C(C(=O)C3=C(O)C=C4C5(C)OC(C(C(C5O)N(C)C)O)OC4=C3C3=O)=C3C=C2C(C(=O)OC)C(C)(O)C1 KGTDRFCXGRULNK-UHFFFAOYSA-N 0.000 description 1
- 208000015914 Non-Hodgkin lymphomas Diseases 0.000 description 1
- 206010030155 Oesophageal carcinoma Diseases 0.000 description 1
- 108020005187 Oligonucleotide Probes Proteins 0.000 description 1
- 108700020796 Oncogene Proteins 0.000 description 1
- 241000233855 Orchidaceae Species 0.000 description 1
- 206010033128 Ovarian cancer Diseases 0.000 description 1
- 206010061535 Ovarian neoplasm Diseases 0.000 description 1
- 208000002193 Pain Diseases 0.000 description 1
- VREZDOWOLGNDPW-MYVCAWNPSA-N Pancratistatin Natural products O=C1N[C@H]2[C@H](O)[C@H](O)[C@H](O)[C@H](O)[C@@H]2c2c1c(O)c1OCOc1c2 VREZDOWOLGNDPW-MYVCAWNPSA-N 0.000 description 1
- VREZDOWOLGNDPW-ALTGWBOUSA-N Pancratistatin Chemical compound C1=C2[C@H]3[C@@H](O)[C@H](O)[C@@H](O)[C@@H](O)[C@@H]3NC(=O)C2=C(O)C2=C1OCO2 VREZDOWOLGNDPW-ALTGWBOUSA-N 0.000 description 1
- 208000030852 Parasitic disease Diseases 0.000 description 1
- 208000000733 Paroxysmal Hemoglobinuria Diseases 0.000 description 1
- 108010057150 Peplomycin Proteins 0.000 description 1
- 102000035195 Peptidases Human genes 0.000 description 1
- 108091005804 Peptidases Proteins 0.000 description 1
- 102000007079 Peptide Fragments Human genes 0.000 description 1
- 108010033276 Peptide Fragments Proteins 0.000 description 1
- 241000009328 Perro Species 0.000 description 1
- LBSARGIQACMGDF-WBAXXEDZSA-N Phe-Ala-Phe Chemical compound C([C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)C1=CC=CC=C1 LBSARGIQACMGDF-WBAXXEDZSA-N 0.000 description 1
- BKWJQWJPZMUWEG-LFSVMHDDSA-N Phe-Ala-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC1=CC=CC=C1 BKWJQWJPZMUWEG-LFSVMHDDSA-N 0.000 description 1
- OJUMUUXGSXUZJZ-SRVKXCTJSA-N Phe-Asp-Ser Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(O)=O OJUMUUXGSXUZJZ-SRVKXCTJSA-N 0.000 description 1
- CUMXHKAOHNWRFQ-BZSNNMDCSA-N Phe-Asp-Tyr Chemical compound C([C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(O)=O)C1=CC=CC=C1 CUMXHKAOHNWRFQ-BZSNNMDCSA-N 0.000 description 1
- 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 1
- CTNODEMQIKCZGQ-JYJNAYRXSA-N Phe-Gln-His Chemical compound C([C@H](N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC=1NC=NC=1)C(O)=O)C1=CC=CC=C1 CTNODEMQIKCZGQ-JYJNAYRXSA-N 0.000 description 1
- WYPVCIACUMJRIB-JYJNAYRXSA-N Phe-Gln-Lys Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H](CCCCN)C(=O)O)N WYPVCIACUMJRIB-JYJNAYRXSA-N 0.000 description 1
- UAMFZRNCIFFMLE-FHWLQOOXSA-N Phe-Glu-Tyr Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CC2=CC=C(C=C2)O)C(=O)O)N UAMFZRNCIFFMLE-FHWLQOOXSA-N 0.000 description 1
- JJHVFCUWLSKADD-ONGXEEELSA-N Phe-Gly-Ala Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)NCC(=O)N[C@@H](C)C(O)=O JJHVFCUWLSKADD-ONGXEEELSA-N 0.000 description 1
- NAXPHWZXEXNDIW-JTQLQIEISA-N Phe-Gly-Gly Chemical compound OC(=O)CNC(=O)CNC(=O)[C@@H](N)CC1=CC=CC=C1 NAXPHWZXEXNDIW-JTQLQIEISA-N 0.000 description 1
- BIYWZVCPZIFGPY-QWRGUYRKSA-N Phe-Gly-Ser Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)NCC(=O)N[C@@H](CO)C(O)=O BIYWZVCPZIFGPY-QWRGUYRKSA-N 0.000 description 1
- CWFGECHCRMGPPT-MXAVVETBSA-N Phe-Ile-Ser Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(O)=O CWFGECHCRMGPPT-MXAVVETBSA-N 0.000 description 1
- JXQVYPWVGUOIDV-MXAVVETBSA-N Phe-Ser-Ile Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O JXQVYPWVGUOIDV-MXAVVETBSA-N 0.000 description 1
- GLJZDMZJHFXJQG-BZSNNMDCSA-N Phe-Ser-Phe Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O GLJZDMZJHFXJQG-BZSNNMDCSA-N 0.000 description 1
- FGWUALWGCZJQDJ-URLPEUOOSA-N Phe-Thr-Ile Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O FGWUALWGCZJQDJ-URLPEUOOSA-N 0.000 description 1
- FSXRLASFHBWESK-HOTGVXAUSA-N Phe-Tyr Chemical compound C([C@H](N)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(O)=O)C1=CC=CC=C1 FSXRLASFHBWESK-HOTGVXAUSA-N 0.000 description 1
- 102100036050 Phosphatidylinositol N-acetylglucosaminyltransferase subunit A Human genes 0.000 description 1
- 108010004729 Phycoerythrin Proteins 0.000 description 1
- KMSKQZKKOZQFFG-HSUXVGOQSA-N Pirarubicin Chemical compound O([C@H]1[C@@H](N)C[C@@H](O[C@H]1C)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]1CCCCO1 KMSKQZKKOZQFFG-HSUXVGOQSA-N 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 239000004698 Polyethylene Substances 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 208000012654 Primary biliary cholangitis Diseases 0.000 description 1
- VXCHGLYSIOOZIS-GUBZILKMSA-N Pro-Ala-Arg Chemical compound NC(N)=NCCC[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H]1CCCN1 VXCHGLYSIOOZIS-GUBZILKMSA-N 0.000 description 1
- 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 1
- VCYJKOLZYPYGJV-AVGNSLFASA-N Pro-Arg-Leu Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(O)=O VCYJKOLZYPYGJV-AVGNSLFASA-N 0.000 description 1
- ZSKJPKFTPQCPIH-RCWTZXSCSA-N Pro-Arg-Thr Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(O)=O ZSKJPKFTPQCPIH-RCWTZXSCSA-N 0.000 description 1
- JARJPEMLQAWNBR-GUBZILKMSA-N Pro-Asp-Arg Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O JARJPEMLQAWNBR-GUBZILKMSA-N 0.000 description 1
- ZCXQTRXYZOSGJR-FXQIFTODSA-N Pro-Asp-Ser Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(O)=O ZCXQTRXYZOSGJR-FXQIFTODSA-N 0.000 description 1
- WFLWKEUBTSOFMP-FXQIFTODSA-N Pro-Cys-Cys Chemical compound OC(=O)[C@H](CS)NC(=O)[C@H](CS)NC(=O)[C@@H]1CCCN1 WFLWKEUBTSOFMP-FXQIFTODSA-N 0.000 description 1
- GQLOZEMWEBDEAY-NAKRPEOUSA-N Pro-Cys-Ile Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CS)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O GQLOZEMWEBDEAY-NAKRPEOUSA-N 0.000 description 1
- TUYWCHPXKQTISF-LPEHRKFASA-N Pro-Cys-Pro Chemical compound C1C[C@H](NC1)C(=O)N[C@@H](CS)C(=O)N2CCC[C@@H]2C(=O)O TUYWCHPXKQTISF-LPEHRKFASA-N 0.000 description 1
- FRKBNXCFJBPJOL-GUBZILKMSA-N Pro-Glu-Glu Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(O)=O FRKBNXCFJBPJOL-GUBZILKMSA-N 0.000 description 1
- WFHYFCWBLSKEMS-KKUMJFAQSA-N Pro-Glu-Phe Chemical compound N([C@@H](CCC(=O)O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)C(=O)[C@@H]1CCCN1 WFHYFCWBLSKEMS-KKUMJFAQSA-N 0.000 description 1
- UUHXBJHVTVGSKM-BQBZGAKWSA-N Pro-Gly-Asn Chemical compound [H]N1CCC[C@H]1C(=O)NCC(=O)N[C@@H](CC(N)=O)C(O)=O UUHXBJHVTVGSKM-BQBZGAKWSA-N 0.000 description 1
- UIMCLYYSUCIUJM-UWVGGRQHSA-N Pro-Gly-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)CNC(=O)[C@@H]1CCCN1 UIMCLYYSUCIUJM-UWVGGRQHSA-N 0.000 description 1
- DXTOOBDIIAJZBJ-BQBZGAKWSA-N Pro-Gly-Ser Chemical compound [H]N1CCC[C@H]1C(=O)NCC(=O)N[C@@H](CO)C(O)=O DXTOOBDIIAJZBJ-BQBZGAKWSA-N 0.000 description 1
- SPLBRAKYXGOFSO-UNQGMJICSA-N Pro-Phe-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CC1=CC=CC=C1)NC(=O)[C@@H]2CCCN2)O SPLBRAKYXGOFSO-UNQGMJICSA-N 0.000 description 1
- FDMKYQQYJKYCLV-GUBZILKMSA-N Pro-Pro-Ser Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@H]1NCCC1 FDMKYQQYJKYCLV-GUBZILKMSA-N 0.000 description 1
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
- 108010076504 Protein Sorting Signals Proteins 0.000 description 1
- 102100024924 Protein kinase C alpha type Human genes 0.000 description 1
- 101710109947 Protein kinase C alpha type Proteins 0.000 description 1
- 206010037075 Protozoal infections Diseases 0.000 description 1
- 102100030086 Receptor tyrosine-protein kinase erbB-2 Human genes 0.000 description 1
- 208000006265 Renal cell carcinoma Diseases 0.000 description 1
- 206010057190 Respiratory tract infections Diseases 0.000 description 1
- 108010039491 Ricin Proteins 0.000 description 1
- 240000000111 Saccharum officinarum Species 0.000 description 1
- 235000007201 Saccharum officinarum Nutrition 0.000 description 1
- 206010039361 Sacroiliitis Diseases 0.000 description 1
- 206010061934 Salivary gland cancer Diseases 0.000 description 1
- 108010084592 Saporins Proteins 0.000 description 1
- 206010039710 Scleroderma Diseases 0.000 description 1
- 241000242583 Scyphozoa Species 0.000 description 1
- CWHJIJJSDGEHNS-MYLFLSLOSA-N Senegenin Chemical compound C1[C@H](O)[C@H](O)[C@@](C)(C(O)=O)[C@@H]2CC[C@@]3(C)C(CC[C@]4(CCC(C[C@H]44)(C)C)C(O)=O)=C4[C@@H](CCl)C[C@@H]3[C@]21C CWHJIJJSDGEHNS-MYLFLSLOSA-N 0.000 description 1
- MWMKFWJYRRGXOR-ZLUOBGJFSA-N Ser-Ala-Asn Chemical compound N[C@H](C(=O)N[C@H](C(=O)N[C@H](C(=O)O)CC(N)=O)C)CO MWMKFWJYRRGXOR-ZLUOBGJFSA-N 0.000 description 1
- MMGJPDWSIOAGTH-ACZMJKKPSA-N Ser-Ala-Gln Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(N)=O)C(O)=O MMGJPDWSIOAGTH-ACZMJKKPSA-N 0.000 description 1
- HBZBPFLJNDXRAY-FXQIFTODSA-N Ser-Ala-Val Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](C)C(=O)N[C@@H](C(C)C)C(O)=O HBZBPFLJNDXRAY-FXQIFTODSA-N 0.000 description 1
- KYKKKSWGEPFUMR-NAKRPEOUSA-N Ser-Arg-Ile Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O KYKKKSWGEPFUMR-NAKRPEOUSA-N 0.000 description 1
- BRIZMMZEYSAKJX-QEJZJMRPSA-N Ser-Glu-Trp Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)O)NC(=O)[C@H](CO)N BRIZMMZEYSAKJX-QEJZJMRPSA-N 0.000 description 1
- IOVHBRCQOGWAQH-ZKWXMUAHSA-N Ser-Gly-Ile Chemical compound [H]N[C@@H](CO)C(=O)NCC(=O)N[C@@H]([C@@H](C)CC)C(O)=O IOVHBRCQOGWAQH-ZKWXMUAHSA-N 0.000 description 1
- UAJAYRMZGNQILN-BQBZGAKWSA-N Ser-Gly-Met Chemical compound [H]N[C@@H](CO)C(=O)NCC(=O)N[C@@H](CCSC)C(O)=O UAJAYRMZGNQILN-BQBZGAKWSA-N 0.000 description 1
- NFDYGNFETJVMSE-BQBZGAKWSA-N Ser-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@@H](N)CO NFDYGNFETJVMSE-BQBZGAKWSA-N 0.000 description 1
- HEUVHBXOVZONPU-BJDJZHNGSA-N Ser-Leu-Ile Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O HEUVHBXOVZONPU-BJDJZHNGSA-N 0.000 description 1
- FPCGZYMRFFIYIH-CIUDSAMLSA-N Ser-Lys-Ser Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CO)C(O)=O FPCGZYMRFFIYIH-CIUDSAMLSA-N 0.000 description 1
- KJKQUQXDEKMPDK-FXQIFTODSA-N Ser-Met-Asp Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(O)=O KJKQUQXDEKMPDK-FXQIFTODSA-N 0.000 description 1
- IFLVBVIYADZIQO-DCAQKATOSA-N Ser-Met-Lys Chemical compound CSCC[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CO)N IFLVBVIYADZIQO-DCAQKATOSA-N 0.000 description 1
- TVPQRPNBYCRRLL-IHRRRGAJSA-N Ser-Phe-Met Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CCSC)C(O)=O TVPQRPNBYCRRLL-IHRRRGAJSA-N 0.000 description 1
- MQUZANJDFOQOBX-SRVKXCTJSA-N Ser-Phe-Ser Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CO)C(O)=O MQUZANJDFOQOBX-SRVKXCTJSA-N 0.000 description 1
- PJIQEIFXZPCWOJ-FXQIFTODSA-N Ser-Pro-Asp Chemical compound [H]N[C@@H](CO)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CC(O)=O)C(O)=O PJIQEIFXZPCWOJ-FXQIFTODSA-N 0.000 description 1
- NMZXJDSKEGFDLJ-DCAQKATOSA-N Ser-Pro-Lys Chemical compound C1C[C@H](N(C1)C(=O)[C@H](CO)N)C(=O)N[C@@H](CCCCN)C(=O)O NMZXJDSKEGFDLJ-DCAQKATOSA-N 0.000 description 1
- DINQYZRMXGWWTG-GUBZILKMSA-N Ser-Pro-Pro Chemical compound OC[C@H](N)C(=O)N1CCC[C@H]1C(=O)N1[C@H](C(O)=O)CCC1 DINQYZRMXGWWTG-GUBZILKMSA-N 0.000 description 1
- BMKNXTJLHFIAAH-CIUDSAMLSA-N Ser-Ser-Leu Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(O)=O BMKNXTJLHFIAAH-CIUDSAMLSA-N 0.000 description 1
- XJDMUQCLVSCRSJ-VZFHVOOUSA-N Ser-Thr-Ala Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C)C(O)=O XJDMUQCLVSCRSJ-VZFHVOOUSA-N 0.000 description 1
- 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 1
- UYLKOSODXYSWMQ-XGEHTFHBSA-N Ser-Thr-Met Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCSC)C(=O)O)NC(=O)[C@H](CO)N)O UYLKOSODXYSWMQ-XGEHTFHBSA-N 0.000 description 1
- ZKOKTQPHFMRSJP-YJRXYDGGSA-N Ser-Thr-Tyr Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O ZKOKTQPHFMRSJP-YJRXYDGGSA-N 0.000 description 1
- 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 1
- LZLREEUGSYITMX-JQWIXIFHSA-N Ser-Trp Chemical compound C1=CC=C2C(C[C@H](NC(=O)[C@H](CO)N)C(O)=O)=CNC2=C1 LZLREEUGSYITMX-JQWIXIFHSA-N 0.000 description 1
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 1
- 241000700584 Simplexvirus Species 0.000 description 1
- 208000021386 Sjogren Syndrome Diseases 0.000 description 1
- 206010041067 Small cell lung cancer Diseases 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- 240000002825 Solanum vestissimum Species 0.000 description 1
- 235000018259 Solanum vestissimum Nutrition 0.000 description 1
- 208000006045 Spondylarthropathies Diseases 0.000 description 1
- RAHZWNYVWXNFOC-UHFFFAOYSA-N Sulphur dioxide Chemical group O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 description 1
- 201000009594 Systemic Scleroderma Diseases 0.000 description 1
- 208000004732 Systemic Vasculitis Diseases 0.000 description 1
- 206010042953 Systemic sclerosis Diseases 0.000 description 1
- 230000006044 T cell activation Effects 0.000 description 1
- 230000006052 T cell proliferation Effects 0.000 description 1
- BXFOFFBJRFZBQZ-QYWOHJEZSA-N T-2 toxin Chemical compound C([C@@]12[C@]3(C)[C@H](OC(C)=O)[C@@H](O)[C@H]1O[C@H]1[C@]3(COC(C)=O)C[C@@H](C(=C1)C)OC(=O)CC(C)C)O2 BXFOFFBJRFZBQZ-QYWOHJEZSA-N 0.000 description 1
- 229940123237 Taxane Drugs 0.000 description 1
- IGROJMCBGRFRGI-YTLHQDLWSA-N Thr-Ala-Ala Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](C)C(O)=O IGROJMCBGRFRGI-YTLHQDLWSA-N 0.000 description 1
- PXQUBKWZENPDGE-CIQUZCHMSA-N Thr-Ala-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)[C@H](C)NC(=O)[C@H]([C@@H](C)O)N PXQUBKWZENPDGE-CIQUZCHMSA-N 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
- DGDCHPCRMWEOJR-FQPOAREZSA-N Thr-Ala-Tyr Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 DGDCHPCRMWEOJR-FQPOAREZSA-N 0.000 description 1
- 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 1
- JMQUAZXYFAEOIH-XGEHTFHBSA-N Thr-Arg-Cys Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CS)C(=O)O)N)O JMQUAZXYFAEOIH-XGEHTFHBSA-N 0.000 description 1
- UNURFMVMXLENAZ-KJEVXHAQSA-N Thr-Arg-Tyr Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O UNURFMVMXLENAZ-KJEVXHAQSA-N 0.000 description 1
- SKHPKKYKDYULDH-HJGDQZAQSA-N Thr-Asn-Leu Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(O)=O SKHPKKYKDYULDH-HJGDQZAQSA-N 0.000 description 1
- NLJKZUGAIIRWJN-LKXGYXEUSA-N Thr-Asp-Cys Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](CS)C(=O)O)N)O NLJKZUGAIIRWJN-LKXGYXEUSA-N 0.000 description 1
- RKDFEMGVMMYYNG-WDCWCFNPSA-N Thr-Gln-Leu Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(C)C)C(O)=O RKDFEMGVMMYYNG-WDCWCFNPSA-N 0.000 description 1
- XXNLGZRRSKPSGF-HTUGSXCWSA-N Thr-Gln-Phe Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)O)N)O XXNLGZRRSKPSGF-HTUGSXCWSA-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
- NIEWSKWFURSECR-FOHZUACHSA-N Thr-Gly-Asp Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(O)=O NIEWSKWFURSECR-FOHZUACHSA-N 0.000 description 1
- VUSAEKOXGNEYNE-PBCZWWQYSA-N Thr-His-Asn Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)N[C@@H](CC(=O)N)C(=O)O)N)O VUSAEKOXGNEYNE-PBCZWWQYSA-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
- YJVJPJPHHFOVMG-VEVYYDQMSA-N Thr-Met-Asp Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(=O)O)C(=O)O)N)O YJVJPJPHHFOVMG-VEVYYDQMSA-N 0.000 description 1
- KPNSNVTUVKSBFL-ZJDVBMNYSA-N Thr-Met-Thr Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCSC)C(=O)N[C@@H]([C@@H](C)O)C(=O)O)N)O KPNSNVTUVKSBFL-ZJDVBMNYSA-N 0.000 description 1
- DEGCBBCMYWNJNA-RHYQMDGZSA-N Thr-Pro-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@@H](N)[C@@H](C)O DEGCBBCMYWNJNA-RHYQMDGZSA-N 0.000 description 1
- YGCDFAJJCRVQKU-RCWTZXSCSA-N Thr-Pro-Val Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@@H](N)[C@@H](C)O YGCDFAJJCRVQKU-RCWTZXSCSA-N 0.000 description 1
- 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 1
- IQPWNQRRAJHOKV-KATARQTJSA-N Thr-Ser-Lys Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@H](C(O)=O)CCCCN IQPWNQRRAJHOKV-KATARQTJSA-N 0.000 description 1
- WPSKTVVMQCXPRO-BWBBJGPYSA-N Thr-Ser-Ser Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(O)=O WPSKTVVMQCXPRO-BWBBJGPYSA-N 0.000 description 1
- 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 1
- HUPLKEHTTQBXSC-YJRXYDGGSA-N Thr-Ser-Tyr Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 HUPLKEHTTQBXSC-YJRXYDGGSA-N 0.000 description 1
- DSGIVWSDDRDJIO-ZXXMMSQZSA-N Thr-Thr Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@@H]([C@@H](C)O)C(O)=O DSGIVWSDDRDJIO-ZXXMMSQZSA-N 0.000 description 1
- TZQWJCGVCIJDMU-HEIBUPTGSA-N Thr-Thr-Cys Chemical compound C[C@H]([C@@H](C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CS)C(=O)O)N)O TZQWJCGVCIJDMU-HEIBUPTGSA-N 0.000 description 1
- UQCNIMDPYICBTR-KYNKHSRBSA-N Thr-Thr-Gly Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(O)=O UQCNIMDPYICBTR-KYNKHSRBSA-N 0.000 description 1
- GRIUMVXCJDKVPI-IZPVPAKOSA-N Thr-Thr-Tyr Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O GRIUMVXCJDKVPI-IZPVPAKOSA-N 0.000 description 1
- ZEJBJDHSQPOVJV-UAXMHLISSA-N Thr-Trp-Thr Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CNC2=C1C=CC=C2)C(=O)N[C@@H]([C@@H](C)O)C(O)=O ZEJBJDHSQPOVJV-UAXMHLISSA-N 0.000 description 1
- SPIFGZFZMVLPHN-UNQGMJICSA-N Thr-Val-Phe Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O SPIFGZFZMVLPHN-UNQGMJICSA-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
- 208000031981 Thrombocytopenic Idiopathic Purpura Diseases 0.000 description 1
- 208000033781 Thyroid carcinoma Diseases 0.000 description 1
- IWEQQRMGNVVKQW-OQKDUQJOSA-N Toremifene citrate Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O.C1=CC(OCCN(C)C)=CC=C1C(\C=1C=CC=CC=1)=C(\CCCl)C1=CC=CC=C1 IWEQQRMGNVVKQW-OQKDUQJOSA-N 0.000 description 1
- 206010052779 Transplant rejections Diseases 0.000 description 1
- UMILHIMHKXVDGH-UHFFFAOYSA-N Triethylene glycol diglycidyl ether Chemical compound C1OC1COCCOCCOCCOCC1CO1 UMILHIMHKXVDGH-UHFFFAOYSA-N 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- FYAMXEPQQLNQDM-UHFFFAOYSA-N Tris(1-aziridinyl)phosphine oxide Chemical compound C1CN1P(N1CC1)(=O)N1CC1 FYAMXEPQQLNQDM-UHFFFAOYSA-N 0.000 description 1
- 241001504505 Troglodytes troglodytes Species 0.000 description 1
- ILDJYIDXESUBOE-HSCHXYMDSA-N Trp-Ile-Lys Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CC1=CNC2=CC=CC=C21)N ILDJYIDXESUBOE-HSCHXYMDSA-N 0.000 description 1
- UGFOSENEZHEQKX-PJODQICGSA-N Trp-Val-Ala Chemical compound CC(C)[C@H](NC(=O)[C@@H](N)Cc1c[nH]c2ccccc12)C(=O)N[C@@H](C)C(O)=O UGFOSENEZHEQKX-PJODQICGSA-N 0.000 description 1
- 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 1
- 102100040247 Tumor necrosis factor Human genes 0.000 description 1
- 101710187882 Tumor necrosis factor receptor superfamily member 18 Proteins 0.000 description 1
- TVOGEPLDNYTAHD-CQDKDKBSSA-N Tyr-Ala-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 TVOGEPLDNYTAHD-CQDKDKBSSA-N 0.000 description 1
- BVOCLAPFOBSJHR-KKUMJFAQSA-N Tyr-Cys-His Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CC2=CN=CN2)C(=O)O)N)O BVOCLAPFOBSJHR-KKUMJFAQSA-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
- DZKFGCNKEVMXFA-JUKXBJQTSA-N Tyr-Ile-His Chemical compound CC[C@H](C)[C@H](NC(=O)[C@@H](N)Cc1ccc(O)cc1)C(=O)N[C@@H](Cc1cnc[nH]1)C(O)=O DZKFGCNKEVMXFA-JUKXBJQTSA-N 0.000 description 1
- NKUGCYDFQKFVOJ-JYJNAYRXSA-N Tyr-Leu-Gln Chemical compound NC(=O)CC[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 NKUGCYDFQKFVOJ-JYJNAYRXSA-N 0.000 description 1
- CGWAPUBOXJWXMS-HOTGVXAUSA-N Tyr-Phe Chemical compound C([C@H](N)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)C1=CC=C(O)C=C1 CGWAPUBOXJWXMS-HOTGVXAUSA-N 0.000 description 1
- LMKKMCGTDANZTR-BZSNNMDCSA-N Tyr-Phe-Asp Chemical compound C([C@H](N)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC(O)=O)C(O)=O)C1=CC=C(O)C=C1 LMKKMCGTDANZTR-BZSNNMDCSA-N 0.000 description 1
- XJPXTYLVMUZGNW-IHRRRGAJSA-N Tyr-Pro-Asp Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CC(O)=O)C(O)=O XJPXTYLVMUZGNW-IHRRRGAJSA-N 0.000 description 1
- SZEIFUXUTBBQFQ-STQMWFEESA-N Tyr-Pro-Gly Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N1CCC[C@H]1C(=O)NCC(O)=O SZEIFUXUTBBQFQ-STQMWFEESA-N 0.000 description 1
- XFEMMSGONWQACR-KJEVXHAQSA-N Tyr-Thr-Met Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCSC)C(=O)O)NC(=O)[C@H](CC1=CC=C(C=C1)O)N)O XFEMMSGONWQACR-KJEVXHAQSA-N 0.000 description 1
- KUXCBJFJURINGF-PXDAIIFMSA-N Tyr-Trp-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)[C@H](CC1=CNC2=CC=CC=C21)NC(=O)[C@H](CC3=CC=C(C=C3)O)N KUXCBJFJURINGF-PXDAIIFMSA-N 0.000 description 1
- MWUYSCVVPVITMW-IGNZVWTISA-N Tyr-Tyr-Ala Chemical compound C([C@@H](C(=O)N[C@@H](C)C(O)=O)NC(=O)[C@@H](N)CC=1C=CC(O)=CC=1)C1=CC=C(O)C=C1 MWUYSCVVPVITMW-IGNZVWTISA-N 0.000 description 1
- GPLTZEMVOCZVAV-UFYCRDLUSA-N Tyr-Tyr-Arg Chemical compound C([C@H](N)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CCCN=C(N)N)C(O)=O)C1=CC=C(O)C=C1 GPLTZEMVOCZVAV-UFYCRDLUSA-N 0.000 description 1
- WYOBRXPIZVKNMF-IRXDYDNUSA-N Tyr-Tyr-Gly Chemical compound C([C@H](N)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)NCC(O)=O)C1=CC=C(O)C=C1 WYOBRXPIZVKNMF-IRXDYDNUSA-N 0.000 description 1
- KRXFXDCNKLANCP-CXTHYWKRSA-N Tyr-Tyr-Ile Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(O)=O)NC(=O)[C@@H](N)CC=1C=CC(O)=CC=1)C1=CC=C(O)C=C1 KRXFXDCNKLANCP-CXTHYWKRSA-N 0.000 description 1
- BUPRFDPUIJNOLS-UFYCRDLUSA-N Tyr-Tyr-Met Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CCSC)C(O)=O BUPRFDPUIJNOLS-UFYCRDLUSA-N 0.000 description 1
- VGQOVCHZGQWAOI-UHFFFAOYSA-N UNPD55612 Natural products N1C(O)C2CC(C=CC(N)=O)=CN2C(=O)C2=CC=C(C)C(O)=C12 VGQOVCHZGQWAOI-UHFFFAOYSA-N 0.000 description 1
- 201000006704 Ulcerative Colitis Diseases 0.000 description 1
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 description 1
- 208000024780 Urticaria Diseases 0.000 description 1
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 description 1
- JIODCDXKCJRMEH-NHCYSSNCSA-N Val-Arg-Gln Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CCC(=O)N)C(=O)O)N JIODCDXKCJRMEH-NHCYSSNCSA-N 0.000 description 1
- PWRITNSESKQTPW-NRPADANISA-N Val-Gln-Ser Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H](CO)C(=O)O)N PWRITNSESKQTPW-NRPADANISA-N 0.000 description 1
- PIFJAFRUVWZRKR-QMMMGPOBSA-N Val-Gly-Gly Chemical compound CC(C)[C@H]([NH3+])C(=O)NCC(=O)NCC([O-])=O PIFJAFRUVWZRKR-QMMMGPOBSA-N 0.000 description 1
- HQYVQDRYODWONX-DCAQKATOSA-N Val-His-Ser Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)N[C@@H](CO)C(=O)O)N HQYVQDRYODWONX-DCAQKATOSA-N 0.000 description 1
- 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
- DJQIUOKSNRBTSV-CYDGBPFRSA-N Val-Ile-Val Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](C(C)C)C(=O)O)NC(=O)[C@H](C(C)C)N DJQIUOKSNRBTSV-CYDGBPFRSA-N 0.000 description 1
- JKHXYJKMNSSFFL-IUCAKERBSA-N Val-Lys Chemical compound CC(C)[C@H](N)C(=O)N[C@H](C(O)=O)CCCCN JKHXYJKMNSSFFL-IUCAKERBSA-N 0.000 description 1
- GVJUTBOZZBTBIG-AVGNSLFASA-N Val-Lys-Arg Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCN=C(N)N)C(=O)O)N GVJUTBOZZBTBIG-AVGNSLFASA-N 0.000 description 1
- SJRUJQFQVLMZFW-WPRPVWTQSA-N Val-Pro-Gly Chemical compound CC(C)[C@H](N)C(=O)N1CCC[C@H]1C(=O)NCC(O)=O SJRUJQFQVLMZFW-WPRPVWTQSA-N 0.000 description 1
- QTPQHINADBYBNA-DCAQKATOSA-N Val-Ser-Lys Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@H](C(O)=O)CCCCN QTPQHINADBYBNA-DCAQKATOSA-N 0.000 description 1
- UQMPYVLTQCGRSK-IFFSRLJSSA-N Val-Thr-Gln Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)O)NC(=O)[C@H](C(C)C)N)O UQMPYVLTQCGRSK-IFFSRLJSSA-N 0.000 description 1
- PGBMPFKFKXYROZ-UFYCRDLUSA-N Val-Tyr-Phe Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC1=CC=C(C=C1)O)C(=O)N[C@@H](CC2=CC=CC=C2)C(=O)O)N PGBMPFKFKXYROZ-UFYCRDLUSA-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
- 206010047115 Vasculitis Diseases 0.000 description 1
- 101150030763 Vegfa gene Proteins 0.000 description 1
- 229940122803 Vinca alkaloid Drugs 0.000 description 1
- 229930003756 Vitamin B7 Natural products 0.000 description 1
- 208000008383 Wilms tumor Diseases 0.000 description 1
- 238000002441 X-ray diffraction Methods 0.000 description 1
- PVNFMCBFDPTNQI-UIBOPQHZSA-N [(1S,2R,5S,6S,16E,18E,20R,21S)-11-chloro-21-hydroxy-12,20-dimethoxy-2,5,9,16-tetramethyl-8,23-dioxo-4,24-dioxa-9,22-diazatetracyclo[19.3.1.110,14.03,5]hexacosa-10,12,14(26),16,18-pentaen-6-yl] acetate [(1S,2R,5S,6S,16E,18E,20R,21S)-11-chloro-21-hydroxy-12,20-dimethoxy-2,5,9,16-tetramethyl-8,23-dioxo-4,24-dioxa-9,22-diazatetracyclo[19.3.1.110,14.03,5]hexacosa-10,12,14(26),16,18-pentaen-6-yl] 3-methylbutanoate [(1S,2R,5S,6S,16E,18E,20R,21S)-11-chloro-21-hydroxy-12,20-dimethoxy-2,5,9,16-tetramethyl-8,23-dioxo-4,24-dioxa-9,22-diazatetracyclo[19.3.1.110,14.03,5]hexacosa-10,12,14(26),16,18-pentaen-6-yl] 2-methylpropanoate [(1S,2R,5S,6S,16E,18E,20R,21S)-11-chloro-21-hydroxy-12,20-dimethoxy-2,5,9,16-tetramethyl-8,23-dioxo-4,24-dioxa-9,22-diazatetracyclo[19.3.1.110,14.03,5]hexacosa-10,12,14(26),16,18-pentaen-6-yl] propanoate Chemical compound CO[C@@H]1\C=C\C=C(C)\Cc2cc(OC)c(Cl)c(c2)N(C)C(=O)C[C@H](OC(C)=O)[C@]2(C)OC2[C@H](C)[C@@H]2C[C@@]1(O)NC(=O)O2.CCC(=O)O[C@H]1CC(=O)N(C)c2cc(C\C(C)=C\C=C\[C@@H](OC)[C@@]3(O)C[C@H](OC(=O)N3)[C@@H](C)C3O[C@@]13C)cc(OC)c2Cl.CO[C@@H]1\C=C\C=C(C)\Cc2cc(OC)c(Cl)c(c2)N(C)C(=O)C[C@H](OC(=O)C(C)C)[C@]2(C)OC2[C@H](C)[C@@H]2C[C@@]1(O)NC(=O)O2.CO[C@@H]1\C=C\C=C(C)\Cc2cc(OC)c(Cl)c(c2)N(C)C(=O)C[C@H](OC(=O)CC(C)C)[C@]2(C)OC2[C@H](C)[C@@H]2C[C@@]1(O)NC(=O)O2 PVNFMCBFDPTNQI-UIBOPQHZSA-N 0.000 description 1
- IFJUINDAXYAPTO-UUBSBJJBSA-N [(8r,9s,13s,14s,17s)-17-[2-[4-[4-[bis(2-chloroethyl)amino]phenyl]butanoyloxy]acetyl]oxy-13-methyl-6,7,8,9,11,12,14,15,16,17-decahydrocyclopenta[a]phenanthren-3-yl] benzoate Chemical compound C([C@@H]1[C@@H](C2=CC=3)CC[C@]4([C@H]1CC[C@@H]4OC(=O)COC(=O)CCCC=1C=CC(=CC=1)N(CCCl)CCCl)C)CC2=CC=3OC(=O)C1=CC=CC=C1 IFJUINDAXYAPTO-UUBSBJJBSA-N 0.000 description 1
- IHGLINDYFMDHJG-UHFFFAOYSA-N [2-(4-methoxyphenyl)-3,4-dihydronaphthalen-1-yl]-[4-(2-pyrrolidin-1-ylethoxy)phenyl]methanone Chemical compound C1=CC(OC)=CC=C1C(CCC1=CC=CC=C11)=C1C(=O)C(C=C1)=CC=C1OCCN1CCCC1 IHGLINDYFMDHJG-UHFFFAOYSA-N 0.000 description 1
- JLCPHMBAVCMARE-UHFFFAOYSA-N [3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-hydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methyl [5-(6-aminopurin-9-yl)-2-(hydroxymethyl)oxolan-3-yl] hydrogen phosphate Polymers Cc1cn(C2CC(OP(O)(=O)OCC3OC(CC3OP(O)(=O)OCC3OC(CC3O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c3nc(N)[nH]c4=O)C(COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3CO)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cc(C)c(=O)[nH]c3=O)n3cc(C)c(=O)[nH]c3=O)n3ccc(N)nc3=O)n3cc(C)c(=O)[nH]c3=O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)O2)c(=O)[nH]c1=O JLCPHMBAVCMARE-UHFFFAOYSA-N 0.000 description 1
- USDJGQLNFPZEON-UHFFFAOYSA-N [[4,6-bis(hydroxymethylamino)-1,3,5-triazin-2-yl]amino]methanol Chemical compound OCNC1=NC(NCO)=NC(NCO)=N1 USDJGQLNFPZEON-UHFFFAOYSA-N 0.000 description 1
- 108010023617 abarelix Proteins 0.000 description 1
- AIWRTTMUVOZGPW-HSPKUQOVSA-N abarelix Chemical compound C([C@@H](C(=O)N[C@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCNC(C)C)C(=O)N1[C@@H](CCC1)C(=O)N[C@H](C)C(N)=O)N(C)C(=O)[C@H](CO)NC(=O)[C@@H](CC=1C=NC=CC=1)NC(=O)[C@@H](CC=1C=CC(Cl)=CC=1)NC(=O)[C@@H](CC=1C=C2C=CC=CC2=CC=1)NC(C)=O)C1=CC=C(O)C=C1 AIWRTTMUVOZGPW-HSPKUQOVSA-N 0.000 description 1
- 229960002184 abarelix Drugs 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 229940028652 abraxane Drugs 0.000 description 1
- ZOZKYEHVNDEUCO-XUTVFYLZSA-N aceglatone Chemical compound O1C(=O)[C@H](OC(C)=O)[C@@H]2OC(=O)[C@@H](OC(=O)C)[C@@H]21 ZOZKYEHVNDEUCO-XUTVFYLZSA-N 0.000 description 1
- 229950002684 aceglatone Drugs 0.000 description 1
- QUHYUSAHBDACNG-UHFFFAOYSA-N acerogenin 3 Natural products C1=CC(O)=CC=C1CCCCC(=O)CCC1=CC=C(O)C=C1 QUHYUSAHBDACNG-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- USZYSDMBJDPRIF-SVEJIMAYSA-N aclacinomycin A Chemical compound O([C@H]1[C@@H](O)C[C@@H](O[C@H]1C)O[C@H]1[C@H](C[C@@H](O[C@H]1C)O[C@H]1C[C@]([C@@H](C2=CC=3C(=O)C4=CC=CC(O)=C4C(=O)C=3C(O)=C21)C(=O)OC)(O)CC)N(C)C)[C@H]1CCC(=O)[C@H](C)O1 USZYSDMBJDPRIF-SVEJIMAYSA-N 0.000 description 1
- RJURFGZVJUQBHK-IIXSONLDSA-N actinomycin D Chemical compound C[C@H]1OC(=O)[C@H](C(C)C)N(C)C(=O)CN(C)C(=O)[C@@H]2CCCN2C(=O)[C@@H](C(C)C)NC(=O)[C@H]1NC(=O)C1=C(N)C(=O)C(C)=C2OC(C(C)=CC=C3C(=O)N[C@@H]4C(=O)N[C@@H](C(N5CCC[C@H]5C(=O)N(C)CC(=O)N(C)[C@@H](C(C)C)C(=O)O[C@@H]4C)=O)C(C)C)=C3N=C21 RJURFGZVJUQBHK-IIXSONLDSA-N 0.000 description 1
- 239000012042 active reagent Substances 0.000 description 1
- 210000005006 adaptive immune system Anatomy 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 229940009456 adriamycin Drugs 0.000 description 1
- 108010005233 alanylglutamic acid Proteins 0.000 description 1
- 108010044940 alanylglutamine Proteins 0.000 description 1
- 108700025316 aldesleukin Proteins 0.000 description 1
- 229940045714 alkyl sulfonate alkylating agent Drugs 0.000 description 1
- 150000008052 alkyl sulfonates Chemical class 0.000 description 1
- 229940100198 alkylating agent Drugs 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- SHGAZHPCJJPHSC-YCNIQYBTSA-N all-trans-retinoic acid Chemical compound OC(=O)\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C SHGAZHPCJJPHSC-YCNIQYBTSA-N 0.000 description 1
- 108010004469 allophycocyanin Proteins 0.000 description 1
- SRBFZHDQGSBBOR-LECHCGJUSA-N alpha-D-xylose Chemical compound O[C@@H]1CO[C@H](O)[C@H](O)[C@H]1O SRBFZHDQGSBBOR-LECHCGJUSA-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
- 229960000473 altretamine Drugs 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 239000003194 amino acid receptor blocking agent Substances 0.000 description 1
- 229960003896 aminopterin Drugs 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 229960001220 amsacrine Drugs 0.000 description 1
- XCPGHVQEEXUHNC-UHFFFAOYSA-N amsacrine Chemical compound COC1=CC(NS(C)(=O)=O)=CC=C1NC1=C(C=CC=C2)C2=NC2=CC=CC=C12 XCPGHVQEEXUHNC-UHFFFAOYSA-N 0.000 description 1
- 239000012491 analyte Substances 0.000 description 1
- 229960002932 anastrozole Drugs 0.000 description 1
- 239000003098 androgen Substances 0.000 description 1
- 229940030486 androgens Drugs 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- VGQOVCHZGQWAOI-HYUHUPJXSA-N anthramycin Chemical compound N1[C@@H](O)[C@@H]2CC(\C=C\C(N)=O)=CN2C(=O)C2=CC=C(C)C(O)=C12 VGQOVCHZGQWAOI-HYUHUPJXSA-N 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000001466 anti-adreneric effect Effects 0.000 description 1
- 230000002280 anti-androgenic effect Effects 0.000 description 1
- 229940046836 anti-estrogen Drugs 0.000 description 1
- 230000001833 anti-estrogenic effect Effects 0.000 description 1
- 230000003388 anti-hormonal effect Effects 0.000 description 1
- 230000002924 anti-infective effect Effects 0.000 description 1
- 239000000051 antiandrogen Substances 0.000 description 1
- 229940030495 antiandrogen sex hormone and modulator of the genital system Drugs 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 238000009175 antibody therapy Methods 0.000 description 1
- 239000000074 antisense oligonucleotide Substances 0.000 description 1
- 238000012230 antisense oligonucleotides Methods 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- 108010009111 arginyl-glycyl-glutamic acid Proteins 0.000 description 1
- 229940078010 arimidex Drugs 0.000 description 1
- 229940087620 aromasin Drugs 0.000 description 1
- 239000003886 aromatase inhibitor Substances 0.000 description 1
- 206010003246 arthritis Diseases 0.000 description 1
- 125000000613 asparagine group Chemical group N[C@@H](CC(N)=O)C(=O)* 0.000 description 1
- 229940009098 aspartate Drugs 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-L aspartate group Chemical group N[C@@H](CC(=O)[O-])C(=O)[O-] CKLJMWTZIZZHCS-REOHCLBHSA-L 0.000 description 1
- 108010093581 aspartyl-proline Proteins 0.000 description 1
- 108010092854 aspartyllysine Proteins 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 201000008937 atopic dermatitis Diseases 0.000 description 1
- 208000010927 atrophic thyroiditis Diseases 0.000 description 1
- 230000001363 autoimmune Effects 0.000 description 1
- 201000000448 autoimmune hemolytic anemia Diseases 0.000 description 1
- 201000003710 autoimmune thrombocytopenic purpura Diseases 0.000 description 1
- 230000005784 autoimmunity Effects 0.000 description 1
- 229960002756 azacitidine Drugs 0.000 description 1
- VSRXQHXAPYXROS-UHFFFAOYSA-N azanide;cyclobutane-1,1-dicarboxylic acid;platinum(2+) Chemical compound [NH2-].[NH2-].[Pt+2].OC(=O)C1(C(O)=O)CCC1 VSRXQHXAPYXROS-UHFFFAOYSA-N 0.000 description 1
- 229950011321 azaserine Drugs 0.000 description 1
- 150000001541 aziridines Chemical class 0.000 description 1
- 229950005567 benzodepa Drugs 0.000 description 1
- VFIUCBTYGKMLCM-UHFFFAOYSA-N benzyl n-[bis(aziridin-1-yl)phosphoryl]carbamate Chemical compound C=1C=CC=CC=1COC(=O)NP(=O)(N1CC1)N1CC1 VFIUCBTYGKMLCM-UHFFFAOYSA-N 0.000 description 1
- 229960000997 bicalutamide Drugs 0.000 description 1
- 238000004166 bioassay Methods 0.000 description 1
- 230000031018 biological processes and functions Effects 0.000 description 1
- 229960000074 biopharmaceutical Drugs 0.000 description 1
- 238000001815 biotherapy Methods 0.000 description 1
- 230000006287 biotinylation Effects 0.000 description 1
- 238000007413 biotinylation Methods 0.000 description 1
- 229950008548 bisantrene Drugs 0.000 description 1
- 208000029162 bladder disease Diseases 0.000 description 1
- 201000000053 blastoma Diseases 0.000 description 1
- 229960001561 bleomycin Drugs 0.000 description 1
- OYVAGSVQBOHSSS-UAPAGMARSA-O bleomycin A2 Chemical compound N([C@H](C(=O)N[C@H](C)[C@@H](O)[C@H](C)C(=O)N[C@@H]([C@H](O)C)C(=O)NCCC=1SC=C(N=1)C=1SC=C(N=1)C(=O)NCCC[S+](C)C)[C@@H](O[C@H]1[C@H]([C@@H](O)[C@H](O)[C@H](CO)O1)O[C@@H]1[C@H]([C@@H](OC(N)=O)[C@H](O)[C@@H](CO)O1)O)C=1N=CNC=1)C(=O)C1=NC([C@H](CC(N)=O)NC[C@H](N)C(N)=O)=NC(N)=C1C OYVAGSVQBOHSSS-UAPAGMARSA-O 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 229940098773 bovine serum albumin Drugs 0.000 description 1
- 238000009395 breeding Methods 0.000 description 1
- 230000001488 breeding effect Effects 0.000 description 1
- 238000005537 brownian motion Methods 0.000 description 1
- 229960005520 bryostatin Drugs 0.000 description 1
- MJQUEDHRCUIRLF-TVIXENOKSA-N bryostatin 1 Chemical compound C([C@@H]1CC(/[C@@H]([C@@](C(C)(C)/C=C/2)(O)O1)OC(=O)/C=C/C=C/CCC)=C\C(=O)OC)[C@H]([C@@H](C)O)OC(=O)C[C@H](O)C[C@@H](O1)C[C@H](OC(C)=O)C(C)(C)[C@]1(O)C[C@@H]1C\C(=C\C(=O)OC)C[C@H]\2O1 MJQUEDHRCUIRLF-TVIXENOKSA-N 0.000 description 1
- MUIWQCKLQMOUAT-AKUNNTHJSA-N bryostatin 20 Natural products COC(=O)C=C1C[C@@]2(C)C[C@]3(O)O[C@](C)(C[C@@H](O)CC(=O)O[C@](C)(C[C@@]4(C)O[C@](O)(CC5=CC(=O)O[C@]45C)C(C)(C)C=C[C@@](C)(C1)O2)[C@@H](C)O)C[C@H](OC(=O)C(C)(C)C)C3(C)C MUIWQCKLQMOUAT-AKUNNTHJSA-N 0.000 description 1
- 229960002092 busulfan Drugs 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- IVFYLRMMHVYGJH-PVPPCFLZSA-N calusterone Chemical compound C1C[C@]2(C)[C@](O)(C)CC[C@H]2[C@@H]2[C@@H](C)CC3=CC(=O)CC[C@]3(C)[C@H]21 IVFYLRMMHVYGJH-PVPPCFLZSA-N 0.000 description 1
- 229950009823 calusterone Drugs 0.000 description 1
- VSJKWCGYPAHWDS-FQEVSTJZSA-N camptothecin Chemical compound C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-FQEVSTJZSA-N 0.000 description 1
- 229960004117 capecitabine Drugs 0.000 description 1
- 235000014633 carbohydrates Nutrition 0.000 description 1
- 229960004562 carboplatin Drugs 0.000 description 1
- 229960002115 carboquone Drugs 0.000 description 1
- 229930188550 carminomycin Natural products 0.000 description 1
- 229960003261 carmofur Drugs 0.000 description 1
- 229960005243 carmustine Drugs 0.000 description 1
- 238000012219 cassette mutagenesis Methods 0.000 description 1
- 125000002091 cationic group Chemical group 0.000 description 1
- 230000021164 cell adhesion Effects 0.000 description 1
- 230000022131 cell cycle Effects 0.000 description 1
- 230000032823 cell division Effects 0.000 description 1
- 230000003915 cell function Effects 0.000 description 1
- 230000012292 cell migration Effects 0.000 description 1
- 230000010307 cell transformation Effects 0.000 description 1
- 230000007541 cellular toxicity Effects 0.000 description 1
- 201000010881 cervical cancer Diseases 0.000 description 1
- 238000001311 chemical methods and process Methods 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- ZYVSOIYQKUDENJ-WKSBCEQHSA-N chromomycin A3 Chemical compound O([C@@H]1C[C@@H](O[C@H](C)[C@@H]1OC(C)=O)OC=1C=C2C=C3C[C@H]([C@@H](C(=O)C3=C(O)C2=C(O)C=1C)O[C@@H]1O[C@H](C)[C@@H](O)[C@H](O[C@@H]2O[C@H](C)[C@@H](O)[C@H](O[C@@H]3O[C@@H](C)[C@H](OC(C)=O)[C@@](C)(O)C3)C2)C1)[C@H](OC)C(=O)[C@@H](O)[C@@H](C)O)[C@@H]1C[C@@H](O)[C@@H](OC)[C@@H](C)O1 ZYVSOIYQKUDENJ-WKSBCEQHSA-N 0.000 description 1
- 210000000349 chromosome Anatomy 0.000 description 1
- 230000004087 circulation Effects 0.000 description 1
- 238000005352 clarification Methods 0.000 description 1
- ACSIXWWBWUQEHA-UHFFFAOYSA-N clodronic acid Chemical compound OP(O)(=O)C(Cl)(Cl)P(O)(O)=O ACSIXWWBWUQEHA-UHFFFAOYSA-N 0.000 description 1
- 229960002286 clodronic acid Drugs 0.000 description 1
- 238000003501 co-culture Methods 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 210000001072 colon Anatomy 0.000 description 1
- 238000004737 colorimetric analysis Methods 0.000 description 1
- 238000012875 competitive assay Methods 0.000 description 1
- 230000002860 competitive effect Effects 0.000 description 1
- 230000024203 complement activation Effects 0.000 description 1
- 238000013329 compounding Methods 0.000 description 1
- 230000001143 conditioned effect Effects 0.000 description 1
- 235000009508 confectionery Nutrition 0.000 description 1
- 230000021615 conjugation Effects 0.000 description 1
- 208000010247 contact dermatitis Diseases 0.000 description 1
- 230000002596 correlated effect Effects 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- DMSZORWOGDLWGN-UHFFFAOYSA-N ctk1a3526 Chemical compound NP(N)(N)=O DMSZORWOGDLWGN-UHFFFAOYSA-N 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 108010004073 cysteinylcysteine Proteins 0.000 description 1
- 229940104302 cytosine Drugs 0.000 description 1
- 238000013016 damping Methods 0.000 description 1
- 229960000975 daunorubicin Drugs 0.000 description 1
- 230000005860 defense response to virus Effects 0.000 description 1
- 229950004239 defosfamide Drugs 0.000 description 1
- 201000001981 dermatomyositis Diseases 0.000 description 1
- URLVCROWVOSNPT-QTTMQESMSA-N desacetyluvaricin Natural products O=C1C(CCCCCCCCCCCC[C@@H](O)[C@H]2O[C@@H]([C@@H]3O[C@@H]([C@@H](O)CCCCCCCCCC)CC3)CC2)=C[C@H](C)O1 URLVCROWVOSNPT-QTTMQESMSA-N 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000000502 dialysis Methods 0.000 description 1
- WVYXNIXAMZOZFK-UHFFFAOYSA-N diaziquone Chemical compound O=C1C(NC(=O)OCC)=C(N2CC2)C(=O)C(NC(=O)OCC)=C1N1CC1 WVYXNIXAMZOZFK-UHFFFAOYSA-N 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- 108010009297 diglycyl-histidine Proteins 0.000 description 1
- FSXRLASFHBWESK-UHFFFAOYSA-N dipeptide phenylalanyl-tyrosine Natural products C=1C=C(O)C=CC=1CC(C(O)=O)NC(=O)C(N)CC1=CC=CC=C1 FSXRLASFHBWESK-UHFFFAOYSA-N 0.000 description 1
- 230000005750 disease progression Effects 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 229960003668 docetaxel Drugs 0.000 description 1
- AMRJKAQTDDKMCE-UHFFFAOYSA-N dolastatin Chemical compound CC(C)C(N(C)C)C(=O)NC(C(C)C)C(=O)N(C)C(C(C)C)C(OC)CC(=O)N1CCCC1C(OC)C(C)C(=O)NC(C=1SC=CN=1)CC1=CC=CC=C1 AMRJKAQTDDKMCE-UHFFFAOYSA-N 0.000 description 1
- 229930188854 dolastatin Natural products 0.000 description 1
- ZWAOHEXOSAUJHY-ZIYNGMLESA-N doxifluridine Chemical compound O[C@@H]1[C@H](O)[C@@H](C)O[C@H]1N1C(=O)NC(=O)C(F)=C1 ZWAOHEXOSAUJHY-ZIYNGMLESA-N 0.000 description 1
- 229950005454 doxifluridine Drugs 0.000 description 1
- 229950004203 droloxifene Drugs 0.000 description 1
- NOTIQUSPUUHHEH-UXOVVSIBSA-N dromostanolone propionate Chemical compound C([C@@H]1CC2)C(=O)[C@H](C)C[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H](OC(=O)CC)[C@@]2(C)CC1 NOTIQUSPUUHHEH-UXOVVSIBSA-N 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 239000003596 drug target Substances 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- VLCYCQAOQCDTCN-UHFFFAOYSA-N eflornithine Chemical compound NCCCC(N)(C(F)F)C(O)=O VLCYCQAOQCDTCN-UHFFFAOYSA-N 0.000 description 1
- 238000001962 electrophoresis Methods 0.000 description 1
- 229950000549 elliptinium acetate Drugs 0.000 description 1
- 201000008184 embryoma Diseases 0.000 description 1
- 201000003914 endometrial carcinoma Diseases 0.000 description 1
- JOZGNYDSEBIJDH-UHFFFAOYSA-N eniluracil Chemical compound O=C1NC=C(C#C)C(=O)N1 JOZGNYDSEBIJDH-UHFFFAOYSA-N 0.000 description 1
- 229950010213 eniluracil Drugs 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 239000002532 enzyme inhibitor Substances 0.000 description 1
- 229940125532 enzyme inhibitor Drugs 0.000 description 1
- 210000000222 eosinocyte Anatomy 0.000 description 1
- 229960001904 epirubicin Drugs 0.000 description 1
- 210000002919 epithelial cell Anatomy 0.000 description 1
- 229950002973 epitiostanol Drugs 0.000 description 1
- 201000005619 esophageal carcinoma Diseases 0.000 description 1
- ITSGNOIFAJAQHJ-BMFNZSJVSA-N esorubicin 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[C@H](C)O1 ITSGNOIFAJAQHJ-BMFNZSJVSA-N 0.000 description 1
- 229950002017 esorubicin Drugs 0.000 description 1
- 229960001842 estramustine Drugs 0.000 description 1
- FRPJXPJMRWBBIH-RBRWEJTLSA-N estramustine Chemical compound ClCCN(CCCl)C(=O)OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 FRPJXPJMRWBBIH-RBRWEJTLSA-N 0.000 description 1
- 239000000328 estrogen antagonist Substances 0.000 description 1
- 230000001076 estrogenic effect Effects 0.000 description 1
- QSRLNKCNOLVZIR-KRWDZBQOSA-N ethyl (2s)-2-[[2-[4-[bis(2-chloroethyl)amino]phenyl]acetyl]amino]-4-methylsulfanylbutanoate Chemical compound CCOC(=O)[C@H](CCSC)NC(=O)CC1=CC=C(N(CCCl)CCCl)C=C1 QSRLNKCNOLVZIR-KRWDZBQOSA-N 0.000 description 1
- 229960005237 etoglucid Drugs 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 229960000255 exemestane Drugs 0.000 description 1
- 208000021045 exocrine pancreatic carcinoma Diseases 0.000 description 1
- 238000013265 extended release Methods 0.000 description 1
- 201000001155 extrinsic allergic alveolitis Diseases 0.000 description 1
- 229950011548 fadrozole Drugs 0.000 description 1
- 229940043168 fareston Drugs 0.000 description 1
- 229940087476 femara Drugs 0.000 description 1
- 230000004761 fibrosis Effects 0.000 description 1
- 229960000390 fludarabine Drugs 0.000 description 1
- 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 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
- 229960002074 flutamide Drugs 0.000 description 1
- MKXKFYHWDHIYRV-UHFFFAOYSA-N flutamide Chemical compound CC(C)C(=O)NC1=CC=C([N+]([O-])=O)C(C(F)(F)F)=C1 MKXKFYHWDHIYRV-UHFFFAOYSA-N 0.000 description 1
- 229940064302 folacin Drugs 0.000 description 1
- 229960000304 folic acid Drugs 0.000 description 1
- 229960004421 formestane Drugs 0.000 description 1
- OSVMTWJCGUFAOD-KZQROQTASA-N formestane Chemical compound O=C1CC[C@]2(C)[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CCC2=C1O OSVMTWJCGUFAOD-KZQROQTASA-N 0.000 description 1
- 229960004783 fotemustine Drugs 0.000 description 1
- YAKWPXVTIGTRJH-UHFFFAOYSA-N fotemustine Chemical compound CCOP(=O)(OCC)C(C)NC(=O)N(CCCl)N=O YAKWPXVTIGTRJH-UHFFFAOYSA-N 0.000 description 1
- 229940044658 gallium nitrate Drugs 0.000 description 1
- 229960005277 gemcitabine Drugs 0.000 description 1
- 229940020967 gemzar Drugs 0.000 description 1
- 238000012239 gene modification Methods 0.000 description 1
- 238000001415 gene therapy Methods 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- 230000005017 genetic modification Effects 0.000 description 1
- 235000013617 genetically modified food Nutrition 0.000 description 1
- 208000005017 glioblastoma Diseases 0.000 description 1
- 229930182478 glucoside Natural products 0.000 description 1
- 108010080575 glutamyl-aspartyl-alanine Proteins 0.000 description 1
- 108010055341 glutamyl-glutamic acid Proteins 0.000 description 1
- 150000004676 glycans Chemical class 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- XBGGUPMXALFZOT-UHFFFAOYSA-N glycyl-L-tyrosine hemihydrate Natural products NCC(=O)NC(C(O)=O)CC1=CC=C(O)C=C1 XBGGUPMXALFZOT-UHFFFAOYSA-N 0.000 description 1
- 108010033719 glycyl-histidyl-glycine Proteins 0.000 description 1
- 229960002913 goserelin Drugs 0.000 description 1
- 208000024908 graft versus host disease Diseases 0.000 description 1
- 201000007192 granulomatous hepatitis Diseases 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
- 208000005252 hepatitis A Diseases 0.000 description 1
- 201000010284 hepatitis E Diseases 0.000 description 1
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 1
- UUVWYPNAQBNQJQ-UHFFFAOYSA-N hexamethylmelamine Chemical compound CN(C)C1=NC(N(C)C)=NC(N(C)C)=N1 UUVWYPNAQBNQJQ-UHFFFAOYSA-N 0.000 description 1
- 108010040030 histidinoalanine Proteins 0.000 description 1
- 108010092114 histidylphenylalanine Proteins 0.000 description 1
- 230000013632 homeostatic process Effects 0.000 description 1
- 208000033519 human immunodeficiency virus infectious disease Diseases 0.000 description 1
- 229940088013 hycamtin Drugs 0.000 description 1
- 229940042795 hydrazides for tuberculosis treatment Drugs 0.000 description 1
- 229960000443 hydrochloric acid Drugs 0.000 description 1
- 239000001257 hydrogen Substances 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
- 125000002349 hydroxyamino group Chemical group [H]ON([H])[*] 0.000 description 1
- 229960001330 hydroxycarbamide Drugs 0.000 description 1
- 229910052588 hydroxylapatite Inorganic materials 0.000 description 1
- 208000022098 hypersensitivity pneumonitis Diseases 0.000 description 1
- 229940015872 ibandronate Drugs 0.000 description 1
- 229960000908 idarubicin Drugs 0.000 description 1
- 150000002460 imidazoles Chemical class 0.000 description 1
- 230000036737 immune function Effects 0.000 description 1
- 210000000987 immune system Anatomy 0.000 description 1
- 229940127121 immunoconjugate Drugs 0.000 description 1
- 238000003364 immunohistochemistry Methods 0.000 description 1
- 238000001114 immunoprecipitation Methods 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
- 229960003444 immunosuppressant agent Drugs 0.000 description 1
- 230000001861 immunosuppressant effect Effects 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 230000008676 import Effects 0.000 description 1
- DBIGHPPNXATHOF-UHFFFAOYSA-N improsulfan Chemical compound CS(=O)(=O)OCCCNCCCOS(C)(=O)=O DBIGHPPNXATHOF-UHFFFAOYSA-N 0.000 description 1
- 229950008097 improsulfan Drugs 0.000 description 1
- 201000004933 in situ carcinoma Diseases 0.000 description 1
- 238000012296 in situ hybridization assay Methods 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000004968 inflammatory condition Effects 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 229940079322 interferon Drugs 0.000 description 1
- 208000036971 interstitial lung disease 2 Diseases 0.000 description 1
- 201000006334 interstitial nephritis Diseases 0.000 description 1
- 210000000936 intestine Anatomy 0.000 description 1
- 238000001361 intraarterial administration Methods 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- UWKQSNNFCGGAFS-XIFFEERXSA-N irinotecan Chemical compound C1=C2C(CC)=C3CN(C(C4=C([C@@](C(=O)OC4)(O)CC)C=4)=O)C=4C3=NC2=CC=C1OC(=O)N(CC1)CCC1N1CCCCC1 UWKQSNNFCGGAFS-XIFFEERXSA-N 0.000 description 1
- 238000005304 joining Methods 0.000 description 1
- 230000000366 juvenile effect Effects 0.000 description 1
- 230000002147 killing effect Effects 0.000 description 1
- 229940115286 lentinan Drugs 0.000 description 1
- 231100000636 lethal dose Toxicity 0.000 description 1
- 229960003881 letrozole Drugs 0.000 description 1
- 108010044311 leucyl-glycyl-glycine Proteins 0.000 description 1
- 108010034529 leucyl-lysine Proteins 0.000 description 1
- 108010090333 leucyl-lysyl-proline Proteins 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- GFIJNRVAKGFPGQ-LIJARHBVSA-N leuprolide Chemical compound CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CC(C)C)NC(=O)[C@@H](NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H]1NC(=O)CC1)CC1=CC=C(O)C=C1 GFIJNRVAKGFPGQ-LIJARHBVSA-N 0.000 description 1
- 229960004338 leuprorelin Drugs 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- WTFCBWXBJBYVOS-UHFFFAOYSA-L lithium;sodium;dichloride Chemical compound [Li+].[Na+].[Cl-].[Cl-] WTFCBWXBJBYVOS-UHFFFAOYSA-L 0.000 description 1
- 208000019423 liver disease Diseases 0.000 description 1
- 229960002247 lomustine Drugs 0.000 description 1
- 229960003538 lonidamine Drugs 0.000 description 1
- WDRYRZXSPDWGEB-UHFFFAOYSA-N lonidamine Chemical compound C12=CC=CC=C2C(C(=O)O)=NN1CC1=CC=C(Cl)C=C1Cl WDRYRZXSPDWGEB-UHFFFAOYSA-N 0.000 description 1
- YROQEQPFUCPDCP-UHFFFAOYSA-N losoxantrone Chemical compound OCCNCCN1N=C2C3=CC=CC(O)=C3C(=O)C3=C2C1=CC=C3NCCNCCO YROQEQPFUCPDCP-UHFFFAOYSA-N 0.000 description 1
- 229950008745 losoxantrone Drugs 0.000 description 1
- 206010025135 lupus erythematosus Diseases 0.000 description 1
- RVFGKBWWUQOIOU-NDEPHWFRSA-N lurtotecan Chemical compound O=C([C@]1(O)CC)OCC(C(N2CC3=4)=O)=C1C=C2C3=NC1=CC=2OCCOC=2C=C1C=4CN1CCN(C)CC1 RVFGKBWWUQOIOU-NDEPHWFRSA-N 0.000 description 1
- 229950002654 lurtotecan Drugs 0.000 description 1
- 239000008176 lyophilized powder Substances 0.000 description 1
- 239000006249 magnetic particle Substances 0.000 description 1
- 229950001474 maitansine Drugs 0.000 description 1
- 210000004962 mammalian cell Anatomy 0.000 description 1
- 210000001161 mammalian embryo Anatomy 0.000 description 1
- 210000005075 mammary gland Anatomy 0.000 description 1
- MQXVYODZCMMZEM-ZYUZMQFOSA-N mannomustine Chemical compound ClCCNC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CNCCCl MQXVYODZCMMZEM-ZYUZMQFOSA-N 0.000 description 1
- 229950008612 mannomustine Drugs 0.000 description 1
- 239000003550 marker Substances 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- WKPWGQKGSOKKOO-RSFHAFMBSA-N maytansine Chemical compound CO[C@@H]([C@@]1(O)C[C@](OC(=O)N1)([C@H]([C@@H]1O[C@@]1(C)[C@@H](OC(=O)[C@H](C)N(C)C(C)=O)CC(=O)N1C)C)[H])\C=C\C=C(C)\CC2=CC(OC)=C(Cl)C1=C2 WKPWGQKGSOKKOO-RSFHAFMBSA-N 0.000 description 1
- HAWPXGHAZFHHAD-UHFFFAOYSA-N mechlorethamine Chemical compound ClCCN(C)CCCl HAWPXGHAZFHHAD-UHFFFAOYSA-N 0.000 description 1
- 238000002483 medication Methods 0.000 description 1
- 229960001924 melphalan Drugs 0.000 description 1
- SGDBTWWWUNNDEQ-LBPRGKRZSA-N melphalan Chemical compound OC(=O)[C@@H](N)CC1=CC=C(N(CCCl)CCCl)C=C1 SGDBTWWWUNNDEQ-LBPRGKRZSA-N 0.000 description 1
- 229950009246 mepitiostane Drugs 0.000 description 1
- 108020004999 messenger RNA Proteins 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 230000001394 metastastic effect Effects 0.000 description 1
- 208000037819 metastatic cancer Diseases 0.000 description 1
- 208000011575 metastatic malignant neoplasm Diseases 0.000 description 1
- 206010061289 metastatic neoplasm Diseases 0.000 description 1
- 108010022588 methionyl-lysyl-proline Proteins 0.000 description 1
- 108010056582 methionylglutamic acid Proteins 0.000 description 1
- 108010005942 methionylglycine Proteins 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- VJRAUFKOOPNFIQ-TVEKBUMESA-N methyl (1r,2r,4s)-4-[(2r,4s,5s,6s)-5-[(2s,4s,5s,6s)-5-[(2s,4s,5s,6s)-4,5-dihydroxy-6-methyloxan-2-yl]oxy-4-hydroxy-6-methyloxan-2-yl]oxy-4-(dimethylamino)-6-methyloxan-2-yl]oxy-2-ethyl-2,5,7,10-tetrahydroxy-6,11-dioxo-3,4-dihydro-1h-tetracene-1-carboxylat Chemical compound O([C@H]1[C@@H](O)C[C@@H](O[C@H]1C)O[C@H]1[C@H](C[C@@H](O[C@H]1C)O[C@H]1C[C@]([C@@H](C2=CC=3C(=O)C4=C(O)C=CC(O)=C4C(=O)C=3C(O)=C21)C(=O)OC)(O)CC)N(C)C)[C@H]1C[C@H](O)[C@H](O)[C@H](C)O1 VJRAUFKOOPNFIQ-TVEKBUMESA-N 0.000 description 1
- HRHKSTOGXBBQCB-VFWICMBZSA-N methylmitomycin Chemical compound O=C1C(N)=C(C)C(=O)C2=C1[C@@H](COC(N)=O)[C@@]1(OC)[C@H]3N(C)[C@H]3CN12 HRHKSTOGXBBQCB-VFWICMBZSA-N 0.000 description 1
- HPNSFSBZBAHARI-UHFFFAOYSA-N micophenolic acid Natural products OC1=C(CC=C(C)CCC(O)=O)C(OC)=C(C)C2=C1C(=O)OC2 HPNSFSBZBAHARI-UHFFFAOYSA-N 0.000 description 1
- 230000000813 microbial effect Effects 0.000 description 1
- 229960005485 mitobronitol Drugs 0.000 description 1
- 229960003539 mitoguazone Drugs 0.000 description 1
- MXWHMTNPTTVWDM-NXOFHUPFSA-N mitoguazone Chemical compound NC(N)=N\N=C(/C)\C=N\N=C(N)N MXWHMTNPTTVWDM-NXOFHUPFSA-N 0.000 description 1
- VFKZTMPDYBFSTM-GUCUJZIJSA-N mitolactol Chemical compound BrC[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)CBr VFKZTMPDYBFSTM-GUCUJZIJSA-N 0.000 description 1
- 229950010913 mitolactol Drugs 0.000 description 1
- 229960004857 mitomycin Drugs 0.000 description 1
- 229960000350 mitotane Drugs 0.000 description 1
- 238000012900 molecular simulation Methods 0.000 description 1
- FOYWNSCCNCUEPU-UHFFFAOYSA-N mopidamol Chemical compound C12=NC(N(CCO)CCO)=NC=C2N=C(N(CCO)CCO)N=C1N1CCCCC1 FOYWNSCCNCUEPU-UHFFFAOYSA-N 0.000 description 1
- 229950010718 mopidamol Drugs 0.000 description 1
- 238000010172 mouse model Methods 0.000 description 1
- 201000006417 multiple sclerosis Diseases 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 229940087004 mustargen Drugs 0.000 description 1
- 229960000951 mycophenolic acid Drugs 0.000 description 1
- HPNSFSBZBAHARI-RUDMXATFSA-N mycophenolic acid Chemical compound OC1=C(C\C=C(/C)CCC(O)=O)C(OC)=C(C)C2=C1C(=O)OC2 HPNSFSBZBAHARI-RUDMXATFSA-N 0.000 description 1
- NJSMWLQOCQIOPE-OCHFTUDZSA-N n-[(e)-[10-[(e)-(4,5-dihydro-1h-imidazol-2-ylhydrazinylidene)methyl]anthracen-9-yl]methylideneamino]-4,5-dihydro-1h-imidazol-2-amine Chemical compound N1CCN=C1N\N=C\C(C1=CC=CC=C11)=C(C=CC=C2)C2=C1\C=N\NC1=NCCN1 NJSMWLQOCQIOPE-OCHFTUDZSA-N 0.000 description 1
- 239000002105 nanoparticle Substances 0.000 description 1
- 229940086322 navelbine Drugs 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- XWXYUMMDTVBTOU-UHFFFAOYSA-N nilutamide Chemical compound O=C1C(C)(C)NC(=O)N1C1=CC=C([N+]([O-])=O)C(C(F)(F)F)=C1 XWXYUMMDTVBTOU-UHFFFAOYSA-N 0.000 description 1
- 229960001420 nimustine Drugs 0.000 description 1
- VFEDRRNHLBGPNN-UHFFFAOYSA-N nimustine Chemical compound CC1=NC=C(CNC(=O)N(CCCl)N=O)C(N)=N1 VFEDRRNHLBGPNN-UHFFFAOYSA-N 0.000 description 1
- YMVWGSQGCWCDGW-UHFFFAOYSA-N nitracrine Chemical compound C1=CC([N+]([O-])=O)=C2C(NCCCN(C)C)=C(C=CC=C3)C3=NC2=C1 YMVWGSQGCWCDGW-UHFFFAOYSA-N 0.000 description 1
- 229950008607 nitracrine Drugs 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- OSTGTTZJOCZWJG-UHFFFAOYSA-N nitrosourea Chemical compound NC(=O)N=NO OSTGTTZJOCZWJG-UHFFFAOYSA-N 0.000 description 1
- KGTDRFCXGRULNK-JYOBTZKQSA-N nogalamycin Chemical compound CO[C@@H]1[C@@](OC)(C)[C@@H](OC)[C@H](C)O[C@H]1O[C@@H]1C2=C(O)C(C(=O)C3=C(O)C=C4[C@@]5(C)O[C@H]([C@H]([C@@H]([C@H]5O)N(C)C)O)OC4=C3C3=O)=C3C=C2[C@@H](C(=O)OC)[C@@](C)(O)C1 KGTDRFCXGRULNK-JYOBTZKQSA-N 0.000 description 1
- 229950009266 nogalamycin Drugs 0.000 description 1
- 229940085033 nolvadex Drugs 0.000 description 1
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 1
- 238000010899 nucleation Methods 0.000 description 1
- 125000003835 nucleoside group Chemical group 0.000 description 1
- 210000004940 nucleus Anatomy 0.000 description 1
- 239000002751 oligonucleotide probe Substances 0.000 description 1
- CZDBNBLGZNWKMC-MWQNXGTOSA-N olivomycin Chemical compound O([C@@H]1C[C@@H](O[C@H](C)[C@@H]1O)OC=1C=C2C=C3C[C@H]([C@@H](C(=O)C3=C(O)C2=C(O)C=1)O[C@H]1O[C@@H](C)[C@H](O)[C@@H](OC2O[C@@H](C)[C@H](O)[C@@H](O)C2)C1)[C@H](OC)C(=O)[C@@H](O)[C@@H](C)O)[C@H]1C[C@H](O)[C@H](OC)[C@H](C)O1 CZDBNBLGZNWKMC-MWQNXGTOSA-N 0.000 description 1
- 229950011093 onapristone Drugs 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000005022 packaging material Substances 0.000 description 1
- VREZDOWOLGNDPW-UHFFFAOYSA-N pancratistatine Natural products C1=C2C3C(O)C(O)C(O)C(O)C3NC(=O)C2=C(O)C2=C1OCO2 VREZDOWOLGNDPW-UHFFFAOYSA-N 0.000 description 1
- 201000003045 paroxysmal nocturnal hemoglobinuria Diseases 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 230000007170 pathology Effects 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
- 229960003330 pentetic acid Drugs 0.000 description 1
- 229960002340 pentostatin Drugs 0.000 description 1
- FPVKHBSQESCIEP-JQCXWYLXSA-N pentostatin Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(N=CNC[C@H]2O)=C2N=C1 FPVKHBSQESCIEP-JQCXWYLXSA-N 0.000 description 1
- QIMGFXOHTOXMQP-GFAGFCTOSA-N peplomycin Chemical compound N([C@H](C(=O)N[C@H](C)[C@@H](O)[C@H](C)C(=O)N[C@@H]([C@H](O)C)C(=O)NCCC=1SC=C(N=1)C=1SC=C(N=1)C(=O)NCCCN[C@@H](C)C=1C=CC=CC=1)[C@@H](O[C@H]1[C@H]([C@@H](O)[C@H](O)[C@H](CO)O1)O[C@@H]1[C@H]([C@@H](OC(N)=O)[C@H](O)[C@@H](CO)O1)O)C=1NC=NC=1)C(=O)C1=NC([C@H](CC(N)=O)NC[C@H](N)C(N)=O)=NC(N)=C1C QIMGFXOHTOXMQP-GFAGFCTOSA-N 0.000 description 1
- 229950003180 peplomycin Drugs 0.000 description 1
- 210000003819 peripheral blood mononuclear cell Anatomy 0.000 description 1
- 210000001428 peripheral nervous system Anatomy 0.000 description 1
- 102000013415 peroxidase activity proteins Human genes 0.000 description 1
- 108040007629 peroxidase activity proteins Proteins 0.000 description 1
- 230000002085 persistent effect Effects 0.000 description 1
- 238000002823 phage display Methods 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 230000000079 pharmacotherapeutic effect Effects 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
- 108010083476 phenylalanyltryptophan Proteins 0.000 description 1
- 230000026731 phosphorylation Effects 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- 230000035479 physiological effects, processes and functions Effects 0.000 description 1
- 108010025488 pinealon Proteins 0.000 description 1
- 229960000952 pipobroman Drugs 0.000 description 1
- NJBFOOCLYDNZJN-UHFFFAOYSA-N pipobroman Chemical compound BrCCC(=O)N1CCN(C(=O)CCBr)CC1 NJBFOOCLYDNZJN-UHFFFAOYSA-N 0.000 description 1
- NUKCGLDCWQXYOQ-UHFFFAOYSA-N piposulfan Chemical compound CS(=O)(=O)OCCC(=O)N1CCN(C(=O)CCOS(C)(=O)=O)CC1 NUKCGLDCWQXYOQ-UHFFFAOYSA-N 0.000 description 1
- 229950001100 piposulfan Drugs 0.000 description 1
- 229960001221 pirarubicin Drugs 0.000 description 1
- 210000002381 plasma Anatomy 0.000 description 1
- 150000003057 platinum Chemical class 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
- 230000008488 polyadenylation Effects 0.000 description 1
- 239000008389 polyethoxylated castor oil Substances 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 238000003752 polymerase chain reaction Methods 0.000 description 1
- 208000005987 polymyositis Diseases 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 229950004406 porfiromycin Drugs 0.000 description 1
- 230000004481 post-translational protein modification Effects 0.000 description 1
- FGIUAXJPYTZDNR-UHFFFAOYSA-N potassium nitrate Chemical compound [K+].[O-][N+]([O-])=O FGIUAXJPYTZDNR-UHFFFAOYSA-N 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- XOFYZVNMUHMLCC-ZPOLXVRWSA-N prednisone Chemical compound O=C1C=C[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 XOFYZVNMUHMLCC-ZPOLXVRWSA-N 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- CPTBDICYNRMXFX-UHFFFAOYSA-N procarbazine Chemical compound CNNCC1=CC=C(C(=O)NC(C)C)C=C1 CPTBDICYNRMXFX-UHFFFAOYSA-N 0.000 description 1
- 229960000624 procarbazine Drugs 0.000 description 1
- 229940087463 proleukin Drugs 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 108010031719 prolyl-serine Proteins 0.000 description 1
- 210000002307 prostate Anatomy 0.000 description 1
- 230000012846 protein folding Effects 0.000 description 1
- 230000001185 psoriatic effect Effects 0.000 description 1
- WOLQREOUPKZMEX-UHFFFAOYSA-N pteroyltriglutamic acid Chemical compound C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)NC(CCC(=O)NC(CCC(=O)NC(CCC(O)=O)C(O)=O)C(O)=O)C(O)=O)C=C1 WOLQREOUPKZMEX-UHFFFAOYSA-N 0.000 description 1
- 230000005180 public health Effects 0.000 description 1
- 150000003212 purines Chemical class 0.000 description 1
- 229950010131 puromycin Drugs 0.000 description 1
- 150000003230 pyrimidines Chemical class 0.000 description 1
- 239000002516 radical scavenger Substances 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 238000003127 radioimmunoassay Methods 0.000 description 1
- 238000002708 random mutagenesis Methods 0.000 description 1
- 229910052761 rare earth metal Inorganic materials 0.000 description 1
- 150000002910 rare earth metals Chemical class 0.000 description 1
- BMKDZUISNHGIBY-UHFFFAOYSA-N razoxane Chemical compound C1C(=O)NC(=O)CN1C(C)CN1CC(=O)NC(=O)C1 BMKDZUISNHGIBY-UHFFFAOYSA-N 0.000 description 1
- 229960000460 razoxane Drugs 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 238000003753 real-time PCR Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000010076 replication Effects 0.000 description 1
- 230000004043 responsiveness Effects 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 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 1
- 108091092562 ribozyme Proteins 0.000 description 1
- 229950004892 rodorubicin Drugs 0.000 description 1
- NSFWWJIQIKBZMJ-PAGWOCKZSA-N roridin a Chemical compound C([C@@]12[C@]3(C)[C@H]4C[C@H]1O[C@@H]1C=C(C)CC[C@@]13COC(=O)[C@@H](O)[C@H](C)CCO[C@H](\C=C\C=C/C(=O)O4)[C@H](O)C)O2 NSFWWJIQIKBZMJ-PAGWOCKZSA-N 0.000 description 1
- VHXNKPBCCMUMSW-FQEVSTJZSA-N rubitecan Chemical compound C1=CC([N+]([O-])=O)=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VHXNKPBCCMUMSW-FQEVSTJZSA-N 0.000 description 1
- 210000003296 saliva Anatomy 0.000 description 1
- 201000003804 salivary gland carcinoma Diseases 0.000 description 1
- 229930182947 sarcodictyin Natural products 0.000 description 1
- 201000000306 sarcoidosis Diseases 0.000 description 1
- 208000010157 sclerosing cholangitis Diseases 0.000 description 1
- 230000003248 secreting effect Effects 0.000 description 1
- 238000005204 segregation Methods 0.000 description 1
- 238000002864 sequence alignment Methods 0.000 description 1
- 239000003352 sequestering agent Substances 0.000 description 1
- 150000003355 serines Chemical class 0.000 description 1
- 108010071207 serylmethionine Proteins 0.000 description 1
- 230000008054 signal transmission Effects 0.000 description 1
- 238000002741 site-directed mutagenesis Methods 0.000 description 1
- 208000017520 skin disease Diseases 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 208000000587 small cell lung carcinoma Diseases 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- 239000007790 solid phase Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 229950006315 spirogermanium Drugs 0.000 description 1
- 210000000952 spleen Anatomy 0.000 description 1
- 210000004988 splenocyte Anatomy 0.000 description 1
- 201000005671 spondyloarthropathy Diseases 0.000 description 1
- 206010041823 squamous cell carcinoma Diseases 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 210000000130 stem cell Anatomy 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 238000005728 strengthening Methods 0.000 description 1
- 229960001052 streptozocin Drugs 0.000 description 1
- ZSJLQEPLLKMAKR-GKHCUFPYSA-N streptozocin Chemical compound O=NN(C)C(=O)N[C@H]1[C@@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O ZSJLQEPLLKMAKR-GKHCUFPYSA-N 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- NRUKOCRGYNPUPR-QBPJDGROSA-N teniposide 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](OC[C@H]4O3)C=3SC=CC=3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 NRUKOCRGYNPUPR-QBPJDGROSA-N 0.000 description 1
- 229960001278 teniposide Drugs 0.000 description 1
- 239000009871 tenuigenin Substances 0.000 description 1
- 210000001550 testis Anatomy 0.000 description 1
- 229960005353 testolactone Drugs 0.000 description 1
- BPEWUONYVDABNZ-DZBHQSCQSA-N testolactone Chemical compound O=C1C=C[C@]2(C)[C@H]3CC[C@](C)(OC(=O)CC4)[C@@H]4[C@@H]3CCC2=C1 BPEWUONYVDABNZ-DZBHQSCQSA-N 0.000 description 1
- 125000000341 threoninyl group Chemical group [H]OC([H])(C([H])([H])[H])C([H])(N([H])[H])C(*)=O 0.000 description 1
- 108010031491 threonyl-lysyl-glutamic acid Proteins 0.000 description 1
- 206010043554 thrombocytopenia Diseases 0.000 description 1
- 210000001541 thymus gland Anatomy 0.000 description 1
- 208000013077 thyroid gland carcinoma Diseases 0.000 description 1
- 206010043778 thyroiditis Diseases 0.000 description 1
- YFTWHEBLORWGNI-UHFFFAOYSA-N tiamiprine Chemical compound CN1C=NC([N+]([O-])=O)=C1SC1=NC(N)=NC2=C1NC=N2 YFTWHEBLORWGNI-UHFFFAOYSA-N 0.000 description 1
- 229960003087 tioguanine Drugs 0.000 description 1
- 230000008467 tissue growth Effects 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- UCFGDBYHRUNTLO-QHCPKHFHSA-N topotecan Chemical compound C1=C(O)C(CN(C)C)=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 UCFGDBYHRUNTLO-QHCPKHFHSA-N 0.000 description 1
- 229960005026 toremifene Drugs 0.000 description 1
- XFCLJVABOIYOMF-QPLCGJKRSA-N toremifene Chemical compound C1=CC(OCCN(C)C)=CC=C1C(\C=1C=CC=CC=1)=C(\CCCl)C1=CC=CC=C1 XFCLJVABOIYOMF-QPLCGJKRSA-N 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- 230000005030 transcription termination Effects 0.000 description 1
- 230000009261 transgenic effect Effects 0.000 description 1
- 238000011830 transgenic mouse model Methods 0.000 description 1
- 229950001353 tretamine Drugs 0.000 description 1
- IUCJMVBFZDHPDX-UHFFFAOYSA-N tretamine Chemical compound C1CN1C1=NC(N2CC2)=NC(N2CC2)=N1 IUCJMVBFZDHPDX-UHFFFAOYSA-N 0.000 description 1
- 229960001727 tretinoin Drugs 0.000 description 1
- PXSOHRWMIRDKMP-UHFFFAOYSA-N triaziquone Chemical compound O=C1C(N2CC2)=C(N2CC2)C(=O)C=C1N1CC1 PXSOHRWMIRDKMP-UHFFFAOYSA-N 0.000 description 1
- 229960004560 triaziquone Drugs 0.000 description 1
- 125000000210 trichothecene group Chemical class [H][C@]12O[C@]3([H])[C@H]([*])[C@@H]([*])[C@@](C)(C33CO3)C1(C[*])C([*])C([*])C(C)=C2 0.000 description 1
- KVJXBPDAXMEYOA-CXANFOAXSA-N trilostane Chemical compound OC1=C(C#N)C[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CC[C@@]32O[C@@H]31 KVJXBPDAXMEYOA-CXANFOAXSA-N 0.000 description 1
- NOYPYLRCIDNJJB-UHFFFAOYSA-N trimetrexate Chemical compound COC1=C(OC)C(OC)=CC(NCC=2C(=C3C(N)=NC(N)=NC3=CC=2)C)=C1 NOYPYLRCIDNJJB-UHFFFAOYSA-N 0.000 description 1
- 229960001099 trimetrexate Drugs 0.000 description 1
- 229950000212 trioxifene Drugs 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- HRXKRNGNAMMEHJ-UHFFFAOYSA-K trisodium citrate Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O HRXKRNGNAMMEHJ-UHFFFAOYSA-K 0.000 description 1
- 229940038773 trisodium citrate Drugs 0.000 description 1
- 229960000875 trofosfamide Drugs 0.000 description 1
- UMKFEPPTGMDVMI-UHFFFAOYSA-N trofosfamide Chemical compound ClCCN(CCCl)P1(=O)OCCCN1CCCl UMKFEPPTGMDVMI-UHFFFAOYSA-N 0.000 description 1
- 229950010147 troxacitabine Drugs 0.000 description 1
- RXRGZNYSEHTMHC-BQBZGAKWSA-N troxacitabine Chemical compound O=C1N=C(N)C=CN1[C@H]1O[C@@H](CO)OC1 RXRGZNYSEHTMHC-BQBZGAKWSA-N 0.000 description 1
- HDZZVAMISRMYHH-LITAXDCLSA-N tubercidin Chemical compound C1=CC=2C(N)=NC=NC=2N1[C@@H]1O[C@@H](CO)[C@H](O)[C@H]1O HDZZVAMISRMYHH-LITAXDCLSA-N 0.000 description 1
- 201000008827 tuberculosis Diseases 0.000 description 1
- 210000005239 tubule Anatomy 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 1
- 230000007306 turnover Effects 0.000 description 1
- 229950009811 ubenimex Drugs 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
- 241001430294 unidentified retrovirus Species 0.000 description 1
- 229960001055 uracil mustard Drugs 0.000 description 1
- SPDZFJLQFWSJGA-UHFFFAOYSA-N uredepa Chemical compound C1CN1P(=O)(NC(=O)OCC)N1CC1 SPDZFJLQFWSJGA-UHFFFAOYSA-N 0.000 description 1
- 229950006929 uredepa Drugs 0.000 description 1
- 201000005112 urinary bladder cancer Diseases 0.000 description 1
- 208000026533 urinary bladder disease Diseases 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 238000002255 vaccination Methods 0.000 description 1
- 230000004862 vasculogenesis Effects 0.000 description 1
- 239000013598 vector Substances 0.000 description 1
- 229960004528 vincristine Drugs 0.000 description 1
- UGGWPQSBPIFKDZ-KOTLKJBCSA-N vindesine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(N)=O)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1N=C1[C]2C=CC=C1 UGGWPQSBPIFKDZ-KOTLKJBCSA-N 0.000 description 1
- 229960004355 vindesine Drugs 0.000 description 1
- GBABOYUKABKIAF-IELIFDKJSA-N vinorelbine Chemical compound C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC GBABOYUKABKIAF-IELIFDKJSA-N 0.000 description 1
- 229960002066 vinorelbine Drugs 0.000 description 1
- CILBMBUYJCWATM-PYGJLNRPSA-N vinorelbine ditartrate Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O.OC(=O)[C@H](O)[C@@H](O)C(O)=O.C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC CILBMBUYJCWATM-PYGJLNRPSA-N 0.000 description 1
- 235000011912 vitamin B7 Nutrition 0.000 description 1
- 229960001771 vorozole Drugs 0.000 description 1
- XLMPPFTZALNBFS-INIZCTEOSA-N vorozole Chemical compound C1([C@@H](C2=CC=C3N=NN(C3=C2)C)N2N=CN=C2)=CC=C(Cl)C=C1 XLMPPFTZALNBFS-INIZCTEOSA-N 0.000 description 1
- 238000001262 western blot Methods 0.000 description 1
- 108010027345 wheylin-1 peptide Proteins 0.000 description 1
- 230000029663 wound healing Effects 0.000 description 1
- 229940053867 xeloda Drugs 0.000 description 1
- 229960003487 xylose Drugs 0.000 description 1
- 229960000641 zorubicin Drugs 0.000 description 1
- FBTUMDXHSRTGRV-ALTNURHMSA-N zorubicin 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(\C)=N\NC(=O)C=1C=CC=CC=1)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 FBTUMDXHSRTGRV-ALTNURHMSA-N 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- 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
- C07K16/2866—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against receptors for cytokines, lymphokines, interferons
-
- 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
- C07K16/2863—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against receptors for growth factors, growth regulators
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/18—Growth factors; Growth regulators
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/42—Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
- A61K49/08—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by the carrier
- A61K49/10—Organic compounds
- A61K49/14—Peptides, e.g. proteins
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
- A61K49/08—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by the carrier
- A61K49/10—Organic compounds
- A61K49/14—Peptides, e.g. proteins
- A61K49/16—Antibodies; Immunoglobulins; Fragments thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/18—Antivirals for RNA viruses for HIV
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/20—Antivirals for DNA viruses
-
- 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
- A61P37/04—Immunostimulants
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
-
- 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
-
- 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
-
- 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
- C07K16/2878—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-receptor/TNF-receptor superfamily, e.g. CD27, CD30, CD40, CD95
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/30—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants from tumour cells
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K19/00—Hybrid peptides, i.e. peptides covalently bound to nucleic acids, or non-covalently bound protein-protein complexes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
- A61K2039/507—Comprising a combination of two or more separate antibodies
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/10—Immunoglobulins specific features characterized by their source of isolation or production
- C07K2317/14—Specific host cells or culture conditions, e.g. components, pH or temperature
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
- C07K2317/21—Immunoglobulins specific features characterized by taxonomic origin from primates, e.g. man
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
- C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
- C07K2317/34—Identification of a linear epitope shorter than 20 amino acid residues or of a conformational epitope defined by amino acid residues
-
- 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
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
- C12N15/09—Recombinant DNA-technology
- C12N15/63—Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Organic Chemistry (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Immunology (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Molecular Biology (AREA)
- Pharmacology & Pharmacy (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Biochemistry (AREA)
- Genetics & Genomics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Biophysics (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Virology (AREA)
- Engineering & Computer Science (AREA)
- Epidemiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Oncology (AREA)
- Communicable Diseases (AREA)
- Zoology (AREA)
- Gastroenterology & Hepatology (AREA)
- Biotechnology (AREA)
- Radiology & Medical Imaging (AREA)
- Toxicology (AREA)
- Cell Biology (AREA)
- Inorganic Chemistry (AREA)
- Microbiology (AREA)
- Mycology (AREA)
- Pulmonology (AREA)
- Tropical Medicine & Parasitology (AREA)
- AIDS & HIV (AREA)
- Peptides Or Proteins (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
Abstract
提供了针对人GITR的抗体及其应用,例如,用于治疗增生性障碍和免疫障碍。
Description
技术领域
本发明概括地涉及对糖皮质激素诱导的TNF受体(GITR)特异性的抗体及其应用。更具体地,本发明涉及识别人GITR并调节其活性的人源化抗体,所述活性尤其为在免疫障碍和增生性障碍中的活性。
背景技术
糖皮质激素诱导的TNFR相关蛋白(GITR,TNFR超家族的一个成员)在先天性和适应性免疫系统的许多组分中表达(参见,例如,Hanabuchi等人(2006) Blood 107:3617-3623;和Nocentini和Riccardi (2005) Eur. J. Immunol. 2005. 35:1016-1022)。在T细胞活化后,它的膜表达增加(Hanabuchi, 同上;和Nocentini和Riccardi, 同上);它的触发会共活化效应性T淋巴细胞,并调节调节性T细胞(Treg)活性(参见,例如,McHugh, 等人(2002) Immunity 2002. 16:311-323; Shimizu, 等人(2002) Nat. Immunol.. 3:135-142; Ronchetti, 等人(2004) Eur. J. Immunol. 34:613-622;和Tone, 等人(2003) Proc. Natl. Acad. Sci. USA 100:15059-15064)。
GITR会被GITR配体(GITRL)活化,所述配体主要在APC上表达,且已经提出,其通过它的细胞质结构域来递送信号,尽管需要进一步研究来确定生化信号传递(Nocentini, 同上; Ronchetti, 同上; Suvas, 等人(2005) J. Virol. 79:11935-11942;和Shin, 等人(2002) Cytokine 19:187-192)。
GITR活化会增加对肿瘤和病毒感染的抗性,参与自身免疫过程/炎症性过程,并调节白细胞外渗(Nocentini同上; Cuzzocrea, 等人(2004) J. Leukoc. Biol. 76:933-940; Shevach等人(2006) Nat. Rev. Immunol. 6:613-618; Cuzzocrea, 等人(2006) J. Immunol. 177:631-641;和Cuzzocrea等人(2007) FASEB J. 21:117-129)。
需要改进的用于治疗免疫障碍和增生性障碍(例如,肿瘤和癌症)的方法和组合物,其中使用调节GITR活性的试剂。优选地,这样的激动剂对它的靶分子具有高亲和力,且能够在相对低剂量时刺激GITR信号传递。优选地,这样的方法和组合物对GITR是高度特异性的,且不会干扰其它受体的活性。优选地,这样的方法和组合物采用这样的激动剂:所述激动剂适用于修饰细胞毒性的有效负载向靶细胞的递送,而且也适用于非细胞毒性的应用。优选地,这样的方法和组合物采用这样的抗体:所述抗体被修饰成,当施用给有此需要的受试者时,会限制它们的抗原性。
附图简述
图1显示了DTA-1(对mGITR特异性的;参见,例如,Shimizu, 等人(2002) Nature Immunol. 3:135-142)和局部辐照的联合治疗的协同效应。“CR”是指完全消退。
图2显示了通过Naismith和Sprang (1998) Trends Biochem. Sci. 23:74-79所述的方法测得的GITR的模块。粗体残基指示如下测定的构象DTA-1-样表位。
发明内容
通过提供GITR的激动剂,例如人源化的抗-GITR抗体,本发明满足了本领域的这些需要和其它需要。
在一个方面,本发明提供了结合人GITR的结合化合物,诸如抗体或其片段,包括人源化的或嵌合的重组抗体,其包含:抗体轻链可变结构域或其抗原结合片段,其具有至少一个或多个选自SEQ ID NO: 56-88的CDR;和重链可变结构域,其具有至少一个或多个选自SEQ ID NO: 23-55的CDR。
在其它实施方案中,本发明的结合化合物包含前述2个段落中描述的轻链可变结构域和重链可变结构域或其抗原结合片段。
在有些实施方案中,结合化合物包含框架区,其中所述框架区的氨基酸序列是所有的或基本上所有的人免疫球蛋白氨基酸序列。
在有些实施方案中,所述轻链可变结构域包含选自SEQ ID NO: 12-22的序列或其变体。在有些实施方案中,所述重链可变结构域包含选自SEQ ID NO: 1-11的序列。在另一个实施方案中,结合化合物包含在本段中描述的轻链可变结构域和重链可变结构域或其抗原结合片段。
在其它实施方案中,本发明的结合化合物包含:基本上由选自SEQ ID NO: 91、93、95、97、99、101、103、105、107、109、111的序列组成的轻链可变结构域或其抗原结合片段,和/或基本上由选自SEQ ID NO: 90、92、94、96、98、100、102、104、106、108、110的序列组成的重链可变结构域或其抗原结合片段。
在一个实施方案中,本发明涉及抗体,所述抗体能够在交叉阻断试验中阻断本发明的结合化合物与人GITR的结合。在不同的实施方案中,所述抗体能够阻断人GITR与包含本文公开的抗体36E5、3D6、61G6、6H6、61F6、1D8、17F10、35D8、49A1、9E5或31H6的CDR序列的抗体的结合。在另一个实施方案中,本发明涉及结合化合物,其能够阻断GITR-介导的活性,这样的活性包括、但不限于:原初CD4+ T细胞增殖试验的共刺激。
在有些实施方案中,本发明的结合化合物另外包含重链恒定区,其中所述重链恒定区包括γ1、γ2、γ3或γ4人重链恒定区或其变体。在不同的实施方案中,所述轻链恒定区包括λ或κ人轻链恒定区。
在不同的实施方案中,本发明的结合化合物是多克隆的、单克隆的、嵌合的、人源化的或全人抗体或其片段。本发明也预见到,所述抗原结合片段是选自Fab、Fab’、Fab’-SH、Fv、scFv、F(ab’)2和双体的抗体片段。
本发明包括一种增强人受试者的免疫应答的方法,所述方法包括:给有此需要的受试者施用有效地刺激GITR信号传递的量的对GITR特异性的抗体(或其抗原结合片段)。在有些实施方案中,对GITR特异性的抗体是人源化的或嵌合的抗体。在其它实施方案中,所述免疫应答是抗感染应答或抗病毒应答。在某些实施方案中,所述GITR抗体或其抗原结合片段与TGFβ抗体或局部辐射共同施用。
本发明包括一种分离的核酸,其编码本发明的结合化合物的抗体实施方案的多肽序列。所述核酸可以是在表达载体中,其可操作地连接至所述载体转染的宿主细胞识别的控制序列上。也包括包含所述载体的宿主细胞和生产多肽的方法,所述方法包括:在表达所述核酸序列的条件下培养宿主细胞,从而生产多肽,并从宿主细胞或培养基回收多肽。
本发明提供了由保藏在美国典型培养物保藏中心(ATCC)的杂交瘤生产的抗体或其抗原结合片段,其中所述杂交瘤选自:PTA-9889、PTA-9890、PTA-9891、PTA-9892、PTA-9893、PTA-10286、PTA-10287、PTA-10288、PTA-10289、PTA-10290和PTA-10291。
本发明包括结合人GITR蛋白的抗体或抗原结合片段,其中所述抗体或抗原结合片段会识别跨人GITR蛋白(SEQ ID NO: 89)的模块3和模块4的表位。在某些实施方案中,所述表位包含Gly57、Arg65、His67、Lys80、Phe81、Ser82和Gln86。在还其它实施方案中,所述抗体会交叉阻断由选自下述的杂交瘤生产的抗体或抗体片段中的至少一种:PTA-9889、PTA-9890、PTA-9891、PTA-9892、PTA-9893、PTA-10286、PTA-10287、PTA-10288、PTA-10289、PTA-10290和PTA-10291。
详细描述
如本文(包括附加权利要求)所使用的,单词的单数形式如“一个”、“一种”和“该”包括其相应的复数含义,除非上下文另有明确说明。下面的表15提供了在本申请中使用的序列标识符的列表。本文引用的所有参考文献都通过引用并入,其程度如同每个单独的出版物、数据库登录项(例如Genbank序列或GeneID登录项)、专利申请或专利明确地且单独地被指出通过引用并入。在本文中对参考文献的引用并不意味着承认前述中的任一种是有关的现有技术,也不意味着它构成关于这些出版物或文件的内容或日期的任何承认。
I. 定义
术语“GITR”、“糖皮质激素诱导的TNFR相关蛋白”、“活化可诱导的TNFR家族受体”、“AITR”、“肿瘤坏死因子受体超家族成员18”和“TNFSF18”是本领域众所周知的。在WO 98/06842中公开了人和小鼠GITR核苷酸和多肽序列。人GITR氨基序列(Q9Y5U5)和小鼠GITR核酸和氨基酸序列(AF109216)的GenBank?保藏品也是可得到的。
“增殖活性”包括对于例如正常细胞分裂以及癌症、肿瘤、发育异常、细胞转化、转移或血管发生可促进、必需或特异性相关的活性。
“施用”和“处理”当应用于动物、人、实验受试者、细胞、组织、器官或生物流体时,是指外源性药物、治疗剂、诊断剂或组合物与动物、人、受试者、细胞、组织、器官或生物流体的接触。“施用”和“处理”可以指例如治疗、药物代谢动力学、诊断、研究和实验方法。细胞的处理包括试剂与细胞的接触,以及试剂与流体的接触,其中所述流体与细胞接触。“施用”和“处理”还意指通过试剂、诊断、结合组合物或通过另一种细胞体外和离体处理例如细胞。“处理”当应用于人、兽医学或研究受试者时,是指治疗处理、预防或预防性措施,研究和诊断应用。“处理”在应用于人、兽医学或研究受试者或者细胞、组织或器官时,包括试剂与动物受试者、细胞、组织、生理区室或生理流体的接触。“细胞的处理”还包括其中试剂接触GITR(例如在流体相或胶体相中)的情况,而且包括其中激动剂或拮抗剂不接触细胞或受体的情况。
本文使用的术语“抗体”是指表现出所需生物学活性的任何形式的抗体。因此,它以最广义使用,具体地涵盖:单克隆抗体(包括全长单克隆抗体)、多克隆抗体、多特异性抗体(例如双特异性抗体)、嵌合抗体、人源化抗体、全人抗体等。只要它们表现出所需生物学活性。
本文使用的术语“GITR结合片段”、“其结合片段”或“其抗原结合片段”包括抗体的片段或衍生物,其仍然基本上保留它的诱导GITR信号传递的生物学活性,在本文中称作“GITR诱导活性”。术语“抗体片段”或GITR结合片段是指全长抗体的一部分,通常是其抗原区或可变区。抗体片段的实例包括:Fab、Fab'、F(ab')2和Fv片段;双体;线性抗体;单链抗体分子,例如sc-Fv;和由抗体片段形成的多特异性抗体。通常,结合片段或衍生物保留它的GITR激动剂活性的至少10%。优选地,结合片段或衍生物保留它的GITR激动剂活性的至少25%、50%、60%、70%、80%、90%、95%、99%或100%(或更多),尽管具有足以产生所需生物学效应的亲和力的任意结合片段都是有用的。还预期,GITR结合片段可以包括这样的变体,其具有基本上不改变其生物学活性的保守氨基酸置换。
本文使用的术语“单克隆抗体”是指得自基本上均质抗体群体的抗体,即,除了可以以小量存在的可能天然发生的突变以外,构成群体的个体抗体是相同的。单克隆抗体是高度特异性的,针对单个抗原表位。相比之下,常规(多克隆)抗体制剂一般包括针对不同表位(或对其特异性)的许多抗体。修饰词“单克隆”指得自基本上均质的抗体群体的抗体特征,并且不应被解释为需要通过任何具体方法生产抗体。例如,依照本发明使用的单克隆抗体可以通过首先由Kohler等(1975)Nature 256: 495描述的杂交瘤方法制备,或可以通过重组DNA法(参见,例如,美国专利号4,816,567)制备。“单克隆抗体”还可以使用例如Clackson等(1991)Nature 352: 624-628和Marks等(1991)J. Mol. Biol. 222: 581-597中描述的技术从噬菌体抗体文库中分离。
本文的单克隆抗体具体包括“嵌合”抗体(免疫球蛋白),其中重链和/或轻链的部分与源于特定物种或属于特定抗体类或亚类的抗体的相应序列相同或同源,而一条或多条链的其余部分与源于另一物种或属于另一抗体类或亚类的抗体的相应序列相同或同源,以及此种类抗体的片段,只要它们具有所需生物学活性。美国专利号4,816,567; Morrison等人(1984)Proc. Natl. Acad. Sci. USA 81: 6851-6855。
“结构域抗体”为仅含有重链可变区或轻链可变区的免疫功能性免疫球蛋白片段。在某些情况下,两个或更多个VH区与肽接头共价连接,产生二价结构域抗体。二价结构域抗体的两个VH区可靶向相同的或不同的抗原。
“二价抗体”包含2个抗原结合位点。在某些情况下,2个结合部位具有相同抗原特异性。然而,二价抗体可以是双特异性的(参见下文)。
本文使用的术语“单链Fv”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条多肽链上。通常,Fv多肽另外包含在VH和VL结构域之间的多肽接头,其使scFv能够形成抗原结合所需的结构。关于scFv的综述,参见Pluckthun(1994)The Pharmacology of Monoclonal Antibodies,第113卷, Rosenburg和Moore编辑,Springer-Verlag, New York, 第269-315页。
本文的单克隆抗体还包括骆驼源化单结构域抗体。参见,例如,Muyldermans等(2001)Trends Biochem. Sci. 26:230;Reichmann等(1999)J. Immunol. Methods 231:25;WO 94/04678;WO 94/25591;美国专利号6,005,079。在一个实施方案中,本发明提供了包含修饰的2个VH结构域以致于形成单结构域抗体的单结构域抗体。
本文使用的术语“双体(diabody)”是指具有2个抗原结合位点的小抗体片段,所述片段在相同多肽链中包含与轻链可变结构域(VL)连接的重链可变结构域(VH)(VH-VL或VL-VH)。通过使用太短而不允许相同链上的2个结构域之间配对的接头,迫使结构域与另一条链的互补结构域配对,并产生2个抗原结合位点。在例如EP 404,097;WO 93/11161;和Holliger等(1993)Proc. Natl. Acad. Sci. USA 90: 6444-6448中更充分地描述了双体。关于工程改造的抗体变体的综述,一般参见Holliger和Hudson(2005)Nat. Biotechnol. 23:1126-1136。
本文使用的术语“人源化抗体”是指包含来自非人(例如,鼠)抗体以及人抗体的序列的抗体形式。这样的抗体含有源自非人免疫球蛋白的微小序列。一般而言,人源化抗体将包含基本上所有的至少1个且通常是2个可变结构域,其中所有的或基本上所有的高变环均对应于非人免疫球蛋白的那些,所有的或基本上所有的FR区都是人免疫球蛋白序列的那些。人源化抗体任选地还包含免疫球蛋白恒定区(Fc)的至少一部分,所述恒定区通常是人免疫球蛋白的恒定区。当需要将人源化抗体与母体啮齿动物抗体区分开时,将前缀“hum”、“hu”或“h”添加在抗体克隆名称上。啮齿动物抗体的人源化形式通常包含母体啮齿动物抗体的相同CDR序列,尽管可能包括某些氨基酸置换来增加亲和力、增加人源化抗体的稳定性或为了其它原因。
本发明的抗体还包括具有修饰的(或阻断的)Fc区以提供改变的效应子功能的抗体。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。此种修饰可用于增强或抑制免疫系统的各种反应,在诊断和治疗中具有可能有益的作用。Fc区的改变包括氨基酸变化(置换、缺失和插入)、糖基化或去糖基化和添加多个Fc。Fc的变化还可以改变治疗抗体的抗体半衰期,更长的半衰期会导致更低频率的给药,并增加方便性和减少材料使用。参见Presta(2005)J. Allergy Clin. Immunol. 116:731在734-35。
本发明的抗体也包括具有提供完全效应子功能的完整Fc区的抗体,例如同种型IgG1的抗体,其在靶向的细胞中诱导补体依赖性的细胞毒性(CDC)或抗体依赖性的细胞的细胞毒性(ADCC)。
本发明的抗体也包括与细胞毒性的有效负载(诸如细胞毒性剂或放射性核素)缀合的抗体。这样的抗体缀合物可以与抗-GITR治疗联合地用于免疫疗法中,以选择性地靶向和杀死在它们的表面上表达某些抗原的细胞。示例性的细胞毒性剂包括:蓖麻蛋白、长春花生物碱、甲氨蝶呤、假单胞菌外毒素、皂草素、白喉毒素、顺铂、多柔比星、相思豆毒蛋白毒素、白树毒素和美洲商陆抗病毒蛋白。与本发明的抗体一起用于免疫疗法中的示例性的放射性核素包括:125I、131I、90Y、67Cu、211At、177Lu、143Pr和213Bi。参见,例如,美国专利申请公开号2006/0014225。
术语“全人抗体”是指只包含人免疫球蛋白序列的抗体。如果全人抗体在小鼠、小鼠细胞或衍生自小鼠细胞的杂交瘤中生产,那么全人抗体可以包含小鼠碳水化合物链。类似地,“小鼠抗体”或“大鼠抗体”是指分别只包含小鼠或大鼠免疫球蛋白序列的抗体。全人抗体可以在人类中、在具有人免疫球蛋白种系序列的转基因动物中制备,通过噬菌体展示或其它分子生物学方法来制备。
本文使用的术语“高变区”是指负责抗原结合的抗体氨基酸残基。高变区包含来自“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(CDRL1)、50-56(CDRL2)和89-97(CDRL3),和重链可变结构域中的残基31-35(CDRH1)、50-65(CDRH2)和95-102(CDRH3);Kabat等(1991)Sequences of Proteins of Immunological Interest, 第5版,Public Health Service, National Institutes of Health, Bethesda, Md.)和/或来自“高变环”的那些残基(例如,轻链可变结构域中的残基26-32(L1)、50-52(L2)和91-96(L3),和重链可变结构域中的残基26-32(H1)、53-55(H2)和96-101(H3);Chothia和Lesk(1987)J. Mol. Biol. 196: 901-917)。本文使用的术语“框架”或“FR”残基是指除本文定义为CDR残基的高变区残基外的那些可变结构域残基。上面的残基编号遵循Kabat编号系统,且不一定详细地对应附随的序列表中的序列编号。
“结合化合物”是指能够与靶标结合的分子、小分子、大分子、多肽、抗体或其片段或类似物、或可溶性受体。“结合化合物”还可以指能够与靶标结合的分子复合物(例如非共价复合物)、电离分子以及共价或非共价修饰的分子(例如通过磷酸化、酰化、交联、环化或有限分裂修饰的分子)。当关于抗体使用时,术语“结合化合物”是指抗体和其抗原结合片段。“结合”是指结合组合物与靶标的结合,其中在结合组合物可以溶解或悬浮于溶液中的情况下,所述结合导致结合组合物的正常布朗运动减少。“结合组合物”是指与稳定剂、赋形剂、盐、缓冲剂、溶剂或添加剂相组合的、能够结合靶标的分子,例如结合化合物。
“保守修饰的变体”或“保守置换”是指本领域技术人员已知的氨基酸置换,且经常甚至在多肽的必需区域中进行,而不改变得到的分子的生物学活性。此种示例性置换优选依照如下表1中所示的那些来进行:
表1示例性的保守氨基酸置换
原始残基 | 保守置换 |
Ala(A) | Gly; Ser |
Arg(R) | Lys, His |
Asn(N) | Gln; His |
Asp(D) | Glu; Asn |
Cys(C) | Ser; Ala |
Gln(Q) | Asn |
Glu(E) | Asp; Gln |
Gly(G) | Ala |
His(H) | Asn; Gln |
Ile(I) | Leu; Val |
Leu(L) | Ile; Val |
Lys(K) | Arg; His |
Met(M) | Leu; Ile; Tyr |
Phe(F) | Tyr; Met; Leu |
Pro(P) | Ala |
Ser(S) | Thr |
Thr(T) | Ser |
Trp(W) | Tyr; Phe |
Tyr(Y) | Trp; Phe |
Val(V) | Ile; Leu |
本领域技术人员知晓,一般而言,多肽的非必需区域中的单个氨基酸置换基本上不改变生物学活性。参见,例如,Watson等(1987) Molecular Biology of the Gene, The Benjamin/Cummings Pub. Co., 第224页,(第4版)。
整个说明书和权利要求书中使用的短语“基本上由……组成”或其变形表示包括所有所述元件或元件组,并且任选包括与所述元件类似或不同性质的其它元件,所述其它元件非显著改变指定给药方案、方法或组合物的基本性质或新性质。作为非限制性实例,基本上由所提及的氨基酸序列组成的结合化合物还可以包括一种或多种氨基酸(包括一种或多种氨基酸残基的置换),其不显著影响结合化合物的性质。
“有效量”包含足以改善或预防医学病症的征状或病征的量。有效量还意指足以允许或促进诊断的量。用于特定患者或兽医学受试者的有效量可依据以下因素而变化:如待治疗的病症、患者的总体健康情况、给药的方法途径和剂量以及副作用严重性。参见,例如,美国专利号5,888,530。有效量可以是避免显著副作用或毒性作用的最大剂量或给药方案。效果将导致诊断测量或参数改善至少5%、通常至少10%、更通常至少20%、最通常至少30%、优选至少40%、更优选至少50%、最优选至少60%、理想地至少70%、更理想地至少80%和最理想地至少90%,其中100%被定义为由正常受试者显示的诊断参数。参见,例如,Maynard等(1996)A Handbook of SOPs for Good Clinical Practice, Interpharm Press, Boca Raton, FL;Dent(2001)Good Laboratory and Good Clinical Practice, Urch Publ., London, UK。
“免疫病症”或“免疫障碍”包括例如病理性炎症、炎性病症和自身免疫性病症或疾病。“免疫病症”还指感染、持续感染和增生性病症,例如癌症、肿瘤和血管发生,包括抗免疫系统根除的感染、肿瘤和癌症。“癌性病症”包括例如癌症、癌细胞、肿瘤、血管发生和癌变前病症,例如发育异常。
术语“免疫障碍”指哺乳动物中由哺乳动物免疫系统成分引起、介导、或以其它方式促成发病的疾病。还包括刺激或干预免疫应答对疾病发展具有改善作用的疾病。该术语包括自身免疫病、免疫介导的炎性疾病、非免疫介导的炎性疾病、传染病和免疫缺陷病。可依照本发明治疗的免疫相关疾病和炎性疾病的实例(其中有些是免疫或T细胞介导的)包括:系统性红斑狼疮、类风湿性关节炎、幼年型慢性关节炎、脊椎关节病、系统性硬化病(硬皮病)、特发性炎性肌病(皮肌炎、多肌炎)、干燥综合征、系统性血管炎、结节病、自身免疫性溶血性贫血(免疫性全血细胞减少症、阵发性夜间血红蛋白尿)、自身免疫性血小板减少症(特发性血小板减少性紫癜、免疫介导的血小板减少症)、甲状腺炎(格雷夫斯氏病、桥本甲状腺炎、幼年型淋巴细胞性甲状腺炎、萎缩性甲状腺炎)、糖尿病、免疫介导的肾病(肾小球肾炎、肾小管间质性肾炎)、中枢和周围神经系统的脱髓鞘病诸如多发性硬化病、特发性脱髓鞘多神经病或格-巴二氏(Guillain-Barre)综合征、和慢性炎性脱髓鞘多神经病、肝胆病诸如传染性肝炎(甲型、乙型、丙型、丁型、戊型和其它非嗜肝病毒肝炎)、自身免疫性慢性活动性肝炎、原发性胆汁性肝硬化、肉芽肿性肝炎、和硬化性胆管炎、炎性和纤维化肺病诸如炎性肠病(溃疡性结肠炎:克罗恩病)、麸胶敏感性肠病、和惠普尔氏(Whipple)病、自身免疫性或免疫介导的皮肤病包括大疱性皮肤病、多形红斑和接触性皮炎、银屑病、变应性疾病诸如哮喘、变应性鼻炎、特应性皮炎、食物超敏反应和荨麻疹、肺的免疫学疾病诸如嗜曙红细胞性肺炎、特发性肺纤维化和超敏感性肺炎、移植相关疾病包括移植物排斥和移植物抗宿主疾病。传染病包括AIDS(HIV感染)、甲型、乙型、丙型、丁型和戊型肝炎、细菌感染、真菌感染、原生动物感染和寄生虫感染。
术语“癌症”、“肿瘤”、“癌性的”和“恶性的”是指或描述哺乳动物中特征通常为细胞生长不受调节的生理状况。癌症的实例包括、但不限于:癌,包括腺癌、淋巴瘤、母细胞瘤、黑素瘤、肉瘤和白血病。此类癌症的更具体实例包括:鳞状细胞癌、小细胞肺癌、非小细胞肺癌、胃肠癌、何杰金氏和非何杰金氏淋巴瘤、胰腺癌、胶质母细胞瘤、神经胶质瘤、宫颈癌、卵巢癌、肝癌诸如肝的癌和肝细胞瘤、膀胱癌、乳癌、结肠癌、结肠直肠癌、子宫内膜癌、骨髓瘤(诸如多发性骨髓瘤)、唾液腺癌、肾癌诸如肾细胞癌和威尔曼瘤、基底细胞癌、黑素瘤、前列腺癌、外阴癌、甲状腺癌、睾丸癌、食管癌、及各种类型的头颈癌。
随着癌性细胞生长和倍增,它们形成癌性组织块,这就是肿瘤,其侵入和破坏正常的邻近组织。恶性肿瘤是癌症。恶性肿瘤经常可以切除,但是它们可能再生。来自恶性肿瘤的细胞可以侵入和破坏附近的组织和器官。另外,癌细胞可以脱离恶性肿瘤,并进入血流或淋巴系统,这是癌细胞从原发肿瘤(即,最初的癌)扩散以在其它器官中形成新肿瘤的途径。癌症在体内的扩散被称作转移(What You Need to Know About Cancer- an Overview, NIH公开号00-1566;2000年9月26日公布,2002年9月16日更新(2002))。
本文使用的术语“实体瘤”是指异常的组织生长或块,其通常不含有囊肿或液体区。实体瘤可以是良性的(非癌性的)或恶性的(癌性的)。不同类型的实体瘤根据形成它们的细胞的类型来命名。实体瘤的实例是:肉瘤、癌和淋巴瘤。白血病(血癌)通常不形成实体瘤(National Cancer Institute, Dictionary of Cancer Terms)。
本文使用的术语“原发癌”是指最初的肿瘤或首个肿瘤。癌症可以开始于身体的任何器官或组织。它通常根据它起源的身体部分或细胞类型而命名(Metastatic Cancer: Questions and Answers, Cancer Facts 6.20, National Cancer Institute,2004年9月1日综述(2004))。
本文使用的术语“原位癌”是指这样的癌性细胞:其仍然被包含在它们开始生长的组织内,且尚未变成侵入性的,或尚未扩散至身体的其它部分。
本文使用的术语“癌”是指上皮细胞的癌症,所述上皮细胞是覆盖身体的表面、产生激素和构成腺体的细胞。癌的实例是皮肤、肺、结肠、胃、乳腺、前列腺和甲状腺的癌症。
本文使用的术语“分离的核酸分子”是指这样的核酸分子:其从所述抗体核酸的天然来源中通常伴随的至少一种污染核酸分子中鉴别和分离出来。分离的核酸分子不同于它在自然界中发现的形式或场所。分离的核酸分子因此不同于在天然细胞中存在的核酸分子。但是,分离的核酸分子包括在通常表达抗体的细胞中含有的核酸分子,例如,其中所述核酸分子是在不同于天然细胞的染色体位置中。
表述“控制序列”是指在特定宿主生物中表达可操作地连接的编码序列所必需的DNA序列。适合于原核生物的控制序列例如包括启动子、任选的操纵子序列和核糖体结合位点。已知真核细胞利用启动子、多腺苷酸化信号和增强子。
当将核酸置于与另一个核酸序列的功能性关系之中时,它是“可操作地连接的”。例如,如果前序列或分泌前导序列的DNA被表达为参与多肽分泌的前蛋白,则该DNA与多肽的DNA可操作地连接;如果启动子或增强子影响序列的转录,则其与编码序列可操作地连接;或者如果核糖体结合位点的位置使得利于翻译,则其与编码序列可操作地连接。一般地,“可操作地连接的”意指被连接的DNA序列是邻接的,并且对分泌前导序列而言,是邻接的并在读码框中。然而,增强子不必是邻接的。通过在方便的限制位点上连接来实现相连。如果此种位点不存在,那么依照常规实践使用合成寡核苷酸连接物或接头。
本文使用的表述“细胞”、“细胞系”和“细胞培养物”可互换使用,并且所有这类名称都包括后代。因此,单词“转化体”和“转化细胞”包括原代受试细胞和由其衍生的培养物,而不考虑转移数目。还应当理解的是,由于故意或非有意的突变,所有后代在DNA含量方面不可能精确相同。包括具有与最初转化细胞中筛选的相同的功能或生物学活性的突变后代。在意指不同名称的情况下,其由上下文清楚可见。
本文使用的“聚合酶链式反应”或“PCR”是指其中微量的特定部分的核酸、RNA和/或DNA如在例如美国专利号4,683,195中所述扩增的程序或技术。一般来说,需要获得来自目标区域末端或之外的序列信息,使得可以设计寡核苷酸引物;这些引物在序列方面与待扩增模板的对应链相同或相似。2个引物的5’末端核苷酸可以与扩增材料的末端一致。PCR可用于扩增特定的RNA序列、来自总基因组DNA的特定DNA序列和由总细胞RNA转录的cDNA、噬菌体或质粒序列等。一般参见Mullis等(1987)Cold Spring Harbor Symp. Quant. Biol. 51:263;Erlich编辑, (1989)PCR Technology(Stockton Press, N.Y.)。本文使用的PCR被视为用于扩增核酸测试样品的核酸聚合酶反应法的一个实例,但不是唯一的实例,所述方法包括使用作为引物的已知核酸和核酸聚合酶,以扩增或产生核酸的特定部分。
本文使用的术语“种系序列”是指未重新排列的免疫球蛋白DNA序列的一个序列,包括啮齿动物(例如小鼠)和人种系序列。可以使用未重新排列的免疫球蛋白DNA的任意合适的来源。例如,可以从JOINSOLVER?种系数据库(在美国国立卫生研究院的国家关节炎和肌肉骨骼及皮肤病研究所网站上),得到人种系序列。例如,可以如在Giudicelli等人(2005)Nucleic Acids Res. 33:D256-D261中所述,得到小鼠种系序列。
为了检查GITR活性的增强程度,例如,用潜在的活化剂或抑制剂处理包含给定的例如蛋白、基因、细胞或生物体的样品或试验,并且与不使用所述试剂的对照样品比较。对照样品,即不用所述试剂处理的样品,被指定100%的相对活性值。当相对于对照的活性值为约90%以下、典型地85%以下、更典型地80%以下、最典型地75%以下、一般地70%以下、更一般地65%以下、最一般地60%以下、典型地55%以下、通常50%以下、更通常45%以下、最通常40%以下、优选35%以下、更优选30%以下、再更优选25%以下和最优选小于20%时,实现抑制。当相对于对照的活性值为约110%、一般至少120%、更一般至少140%、更一般至少160%、通常至少180%、更通常至少2倍、最通常至少2.5倍、经常至少5倍、更经常至少10倍、优选至少20倍、更优选至少40倍和最优选高于40倍时,实现活化。
活化或抑制的终点可以如下进行监测。例如细胞、生理学流体、组织、器官和动物或人受试者的活化、抑制和对处理的应答可以通过终点进行监测。终点可以包括预定量或百分比的例如炎症、致癌性或细胞脱粒或分泌的标记,例如细胞因子、有毒氧或蛋白酶的释放。终点可以包括例如预定量的离子流或运输;细胞迁移;细胞粘附;细胞增殖;转移潜力;细胞分化;和表型变化,例如,涉及炎症、凋亡、转化、细胞周期或转移的基因表达的变化(参见,例如,Knight(2000)Ann. Clin. Lab. Sci. 30:145-158;Hood和Cheresh(2002)Nature Rev. Cancer 2:91-100;Timme等, (2003)Curr. Drug Targets 4:251-261;Robbins和Itzkowitz(2002)Med. Clin. North Am. 86:1467-1495;Grady和Markowitz(2002)Annu. Rev. Genomics Hum. Genet. 3:101-128;Bauer等, (2001)Glia 36:235-243;Stanimirovic和Satoh(2000)Brain Pathol. 10:113-126)。
抑制终点一般是对照的75%以下、优选对照的50%以下、更优选对照的25%以下和最优选对照的10%以下。一般地,活化终点为对照的至少150%、优选对照的至少2倍、更优选对照的至少4倍和最优选对照的至少10倍。
“小分子”被定义为分子量小于10 kD、通常小于2 kD、优选小于1 kD的分子。小分子包括、但不限于:无机分子、有机分子、含无机组分的有机分子、含放射性原子的分子、合成分子、肽模拟物和抗体模拟物。作为治疗剂,小分子可以比大分子更能透过细胞、对降解更不易感和更不易于引发免疫应答。已描述了小分子,例如抗体和细胞因子的肽模拟物,以及小分子毒素。参见,例如,Casset等人(2003)Biochem. Biophys. Res. Commun. 307:198-205; Muyldermans(2001)J. Biotechnol. 74:277-302; Li(2000)Nat. Biotechnol. 18:1251-1256; Apostolopoulos等人(2002)Curr. Med. Chem. 9:411-420; Monfardini等人(2002)Curr. Pharm. Des. 8:2185-2199; Domingues等人(1999)Nat. Struct. Biol. 6:652-656; Sato和Sone(2003)Biochem. J. 371:603-608;美国专利号6,326,482。
“特异性地”或“选择性地”结合在指配体/受体、抗体/抗原或其它结合对时,指决定蛋白和其它生物产品的异质群体中的蛋白存在情况的结合反应。因此,在指定条件下,指定配体与特定受体结合,并且不以显著量与样品中存在的其它蛋白结合。如果本文使用的抗体结合包含GITR序列的多肽、但是不结合缺少GITR序列的蛋白,则称作它特异性地结合包含给定序列的多肽(在该情况下,GITR)。例如,特异性地结合包含GITR的多肽的抗体,可能结合FLAG?-标记形式的GITR,但是不会结合其它FLAG?-标记的蛋白。
预期方法的抗体或衍生自抗体的抗原结合位点的结合组合物与其抗原结合的亲和力,是与无关抗原的亲和力的至少2倍、优选至少10倍、更优选至少20倍和最优选至少100倍。在一个优选的实施方案中,所述抗体将具有大于约109升/mol的亲和力,例如通过Scatchard分析测定。Munsen等人(1980) Analyt. Biochem. 107:220-239。
本文使用的“慢性病毒感染”或“持续的病毒感染”是指人或其它动物的病毒感染,其能够感染宿主,并在宿主细胞内长时间繁殖——通常数周、数月或数年,而不致死。根据本发明可以治疗的、会造成慢性感染的病毒包括:人乳头瘤病毒(HPV)、单纯疱疹和其它疱疹病毒、乙型肝炎病毒和丙型肝炎病毒(HBV和HCV)以及其它肝炎病毒、麻疹病毒(它们都会产生重大临床疾病)和HIV。长期感染最终可能导致对患者致命的疾病的诱发,例如,在丙型肝炎病毒的情况下,所述疾病可能是肝癌。根据本发明可以治疗的其它慢性病毒感染包括:EB病毒(EBV)以及其它病毒,诸如可能与肿瘤有关的那些,或在动物的情况下,各种兽病毒疾病,例如家养宠物或在农业上重要的农用动物的那些。
术语“抗病毒活性”是指:抑制病毒向未感染的细胞传递,抑制病毒的复制,预防病毒在宿主中确立自身地位,或改善或减轻由病毒感染造成的疾病的征状。这些效果可以由病毒载量的减少或死亡率和/或发病率的降低来证实,它们的测定如下文所述。抗病毒剂或药物具有抗病毒活性,且可单独地或作为多药物联合治疗的一部分用于治疗持久的或慢性的病毒感染。
II. 概述
本发明提供了工程化的抗-GITR抗体,及其用于治疗免疫障碍、尤其是受损的对感染性疾病(包括病毒感染)和癌症的应答的应用。
GITR(也称作TNFRSF18)是属于TNR-R超家族的一种受体。迄今为止,不可得到人或小鼠GITR的晶体结构,但是,基于例如在Naismith和Sprang(1998)Trends Biochem. Sci. 23:74-79中所述的研究,可以建立所述分子的分子结构。图2表明,人GITR可以分成6个模块。从下面的研究可知,某些具有激动剂活性的抗体可能具有跨模块3和4的构象表位。
III. GITR特异性抗体的制备
可以使用任何适于产生单克隆抗体的方法。例如,可以用GITR或其片段免疫受体。可以使用任何合适的免疫接种方法。这类方法可以包括佐剂、其它免疫刺激剂、重复的加强免疫接种以及使用一种或多种免疫接种途径。GITR的任意合适的来源可以用作免疫原,用于制备本文公开的组合物和方法中的非人抗体。这样的形式包括、但不限于:通过本领域已知的重组方法、合成方法、化学方法或酶降解方法制备的完整蛋白、肽和表位。在优选的实施方案中,所述免疫原包含GITR的胞外部分。
任意形式的抗原可以用于制备足以产生生物活性抗体的抗体。因而,引发抗原可以是单个表位、多个表位或整个蛋白,它们是单独的或与本领域已知的一种或多种免疫原性增强剂相组合。引发抗原可以是分离的全长蛋白、细胞表面蛋白(例如,用被所述抗原的至少一部分转染的细胞免疫接种)或可溶性蛋白(例如,仅用所述蛋白的胞外结构域部分免疫接种)。可以在遗传修饰的细胞中生产所述抗原。编码所述抗原的DNA可以是基因组的或非基因组的(例如,cDNA),且编码胞外结构域的至少一部分。本文使用的术语“一部分”是指,适当地构成目标抗原的免疫原性表位的最小数目的氨基酸或核酸。可以采用适合转化目标细胞的任何遗传载体,包括、但不限于腺病毒载体、质粒和非病毒载体,诸如阳离子脂质。
任何合适的方法都可以用于激发具有所需生物学性质的抗体,以增强GITR信号传递。希望从不同的哺乳动物宿主(例如小鼠、大鼠、其它啮齿动物、人类、其它灵长类动物等)中制备单克隆抗体(mAb)。用于制备这样的单克隆抗体的技术的描述,可以参见,例如,Stites等人(编) Basic and Clinical Immunology (第4版) Lange Medical Publications, Los Altos, CA, 以及其中引用的参考文献; Harlow和Lane (1988) Antibodies: A Laboratory Manual CSH Press; Goding (1986) Monoclonal Antibodies: Principles and Practice (第2版) Academic Press, New York, NY。因此,单克隆抗体可以通过本领域研究人员熟悉的多种技术获得。通常,来自用所需抗原免疫的动物的脾细胞通常通过与骨髓瘤细胞融合而永生化。参见Kohler和Milstein(1976)Eur. J. Immunol. 6:511-519。永生化的替代方法包括用EB病毒、癌基因或逆转录酶病毒或本领域已知的其它方法转化。参见,例如,Doyle等(编辑)(1994和周期增刊)Cell and Tissue Culture: Laboratory Procedures, John Wiley and Sons, New York, NY。关于对抗原具有所需特异性和亲和力的抗体的生产,筛选产生于单一永生化细胞的集落,这类细胞生产的单克隆抗体的得率可以通过各种技术得到提高,包括注射入脊椎动物宿主的腹腔内。或者,通过根据例如Huse等人(1989)Science 246:1275-1281所述的一般方案,筛选来自人B细胞的DNA文库,可以分离出编码单克隆抗体或其抗原结合片段的DNA序列。
其它合适的技术涉及在噬菌体或相似载体中选择抗体文库。参见,例如,Huse等人同上;和Ward等人(1989)Nature 341:544-546。本发明的多肽和抗体可以经修饰或不经修饰使用,包括嵌合的或人源化的抗体。经常,通过共价地或非共价地连接提供可检测信号的物质来标记多肽和抗体。多种多样的标记和缀合技术是已知的,并且在科学文献和专利文献中广泛报道。合适的标记包括放射性核素、酶、底物、辅因子、抑制剂、荧光部分、化学发光部分、磁性颗粒等。教导此类标记使用的专利包括:美国专利号3,817,837; 3,850,752; 3,939,350; 3,996,345; 4,277,437; 4,275,149;和4,366,241。另外,可以生产重组免疫球蛋白,参见Cabilly的美国专利号4,816,567;和Queen等(1989)Proc. Nat'l Acad. Sci. USA 86:10029-10033;或可以在转基因小鼠中制备,参见Mendez等人(1997)Nature Genetics 15:146-156。还参见Abgenix和Medarex的技术。
或者,通过富集从用人GITR免疫接种的动物(例如,小鼠、大鼠、兔等)的脾分离出的B细胞的克隆群体,可以生产单克隆抗体(参见,例如,WO2008045140、US5627052和US20030186327)。
通过用多肽、片段、肽或表位与载体蛋白的缀合物免疫接种动物,可以产生针对预先确定的GITR片段的抗体或结合组合物。单克隆抗体从分泌所需抗体的细胞制备。可筛选这些抗体与正常或缺陷型GITR的结合。这些单克隆抗体通常将以至少约1 μM、更通常至少约300 nM、30 nM、10 nM、3 nM、1 nM、300 pM、100 pM、30 pM或更好的Kd结合,所述Kd通常通过ELISA或Biacore来测定。还可以使用下文实施例5和6中描述的生物学测定,鉴定合适的非人抗体。
在布达佩斯条约要求下,在2009年3月25日,将与克隆36E5、3D6、61G6、6H6和61F6相对应的杂交瘤保藏在美国典型培养物保藏中心(“ATCC”),分别作为PTA-9890、PTA-9889、PTA-9891、PTA-9892和PTA-9893。
根据布达佩斯条约要求,在2009年8月21日,将与克隆1D8、17F10、35D8、49A1、9E5和31H6相对应的杂交瘤保藏在ATCC,作为PTA-10286、PTA-10287、PTA-10288、PTA-10289、PTA-10290和PTA-10291。
IV. GITR特异性抗体的人源化
任何合适的非人抗体都可以用作高变区的来源。非人抗体的来源包括、但不限于:鼠(例如小家鼠(Mus musculus))、大鼠(例如褐家鼠(Rattus norvegicus))、兔类动物(包括兔)、牛和灵长类动物。在极大程度上,人源化抗体是这样的人免疫球蛋白(受体抗体):其中受体的高变区残基被来自具有所需特异性、亲和力和能力的非人物种(供体抗体)的高变区残基替换,所述非人物种例如为小鼠、大鼠、兔或非人灵长类动物。在某些情况下,人免疫球蛋白的Fv框架区(FR)残基被对应的非人残基替换。而且,人源化抗体可以包含在受体抗体或供体抗体中不存在的残基。进行这些修饰,以进一步精修所需生物学活性的抗体性能。关于进一步的细节,参见Jones等人(1986)Nature 321:522-525; Reichmann等人(1988)Nature 332:323-329;和Presta(1992)Curr. Op. Struct. Biol. 2:593-596。
已经描述了用于重组改造和生产抗体的方法,例如,Boss等人(美国专利号4,816,397), Cabilly等人(美国专利号4,816,567), Law等人(欧洲专利申请公开号438310)和Winter(欧洲专利申请公开号239400)。
通过将合适的核苷酸变化引入人源化的抗-GITR抗体DNA内,或通过肽合成,制备人源化的抗-GITR抗体的氨基酸序列变体。这样的变体包括,例如,在人源化的抗-GITR抗体的所示氨基酸序列内的残基的缺失和/或插入和/或置换。可造成缺失、插入和置换的任何组合,以获得最终构建体,前提是,最终构建体具有所需特征。氨基酸变化还可以改变人源化的抗-GITR抗体的翻译后加工,例如改变糖基化位点的数目或位置。
用于鉴定为诱变优选位置的人源化的抗-GITR抗体多肽的某些残基或区域的一种有用方法,被称为“丙氨酸扫描诱变”,其描述在Cunningham和Wells(1989)Science 244: 1081-1085。在这里,鉴定一个残基或一组靶残基(例如带电残基,如Arg、Asp、His、Lys和Glu),并被中性或带负电的氨基酸(最优选丙氨酸或聚丙氨酸)替换,以影响氨基酸与GITR抗原的相互作用。随后通过在置换部位处导入另外的或其它的变体,改进显示出对置换的功能敏感性的氨基酸残基。因而,尽管预先确定了用于导入氨基酸序列变化的部位,突变的性质本身不需要预先确定。例如,为了分析在给定部位处的突变的性能,在靶密码子或区域处进行Ala扫描或随机诱变,并筛选表达的人源化的抗-GITR抗体变体的所需活性。
氨基酸序列插入包括长度为1个残基至包含100个以上残基的多肽的氨基和/或羧基末端融合体,以及单个或多个氨基酸残基的序列内插入。末端插入的实例包括:具有N-末端甲硫氨酰残基的人源化的抗-GITR抗体或与表位标签融合的抗体。人源化的抗-GITR抗体分子的其它插入变体包括:增加抗体的血清半衰期的酶或多肽与人源化的抗-GITR抗体的N-末端或C-末端的融合体。
另一类变体是氨基酸置换变体。这些变体在人源化的抗-GITR抗体分子中去除了至少一个氨基酸残基,并在其位置中插入不同残基。最令人感兴趣的置换诱变位点包括高变环,但也预见到FR改变。
抗体的另一类氨基酸变体会改变抗体的最初糖基化模式。改变是指,消除抗体中的一个或多个碳水化合物部分,和/或添加一个或多个在抗体中不存在的糖基化位点。抗体的糖基化一般是N-连接的或O-连接的。N-连接的是指碳水化合物部分与天冬酰胺残基侧链相连。三肽序列天冬酰胺-X-丝氨酸和天冬酰胺-X-苏氨酸(其中X是除脯氨酸外的任何氨基酸)是碳水化合物部分与天冬酰胺侧链的酶促连接的识别序列。因而,这些三肽序列中的任一个在多肽中的存在,会产生潜在的糖基化位点。O-连接的糖基化是指糖类N-乙酰基半乳糖胺、半乳糖或木糖与羟氨基酸、最通常为丝氨酸或苏氨酸的连接,尽管还可以使用5-羟脯氨酸或5-羟赖氨酸。
通过改变氨基酸序列,使得它含有一个或多个上述的三肽序列,可以方便地向抗体添加糖基化位点(对于N-连接的糖基化位点)。通过向原始抗体的序列添加或置换一个或多个丝氨酸或苏氨酸残基,也可以做出改变(对于O-连接的糖基化位点)。
另一类氨基酸变体是残基的置换,以提供最终人源化抗体的更大化学稳定性。例如,可以改变天冬酰胺(N)残基,以减小在啮齿动物CDR内的任意NG序列处形成异天冬氨酸酯的可能性。类似的问题可能出现在DG序列处。Reissner和Aswad(2003)Cell. Mol. Life Sci. 60:1281。异天冬氨酸酯形成可能弱化或完全消除抗体与它的靶抗原的结合。Presta(2005)J. Allergy Clin. Immunol. 116:731在734。在一个实施方案中,将天冬酰胺改成谷氨酰胺(Q)。另外,可以改变啮齿动物CDR中的甲硫氨酸残基,以减小甲硫氨酸硫氧化的可能性,所述氧化会减小抗原结合亲和力,并且还促进最终的抗体制品中的分子异质性。同上。在一个实施方案中,将甲硫氨酸改成丙氨酸(A)。随后筛选具有这类置换的抗体,以确保所述置换没有降低GITR结合亲和力至不可接受的水平。
通过本领域已知的多种方法,制备编码人源化的GITR特异性抗体的氨基酸序列变体的核酸分子。这些方法包括、但不限于:从天然来源中分离(在天然存在的氨基酸序列变体的情况下),或通过人源化的抗-GITR抗体的早前制备的变体或非变体形式的寡核苷酸介导的(或定点)诱变、PCR诱变和盒式诱变来制备。
通常,人源化的抗-GITR抗体的氨基酸序列变体所具有的氨基酸序列与重链或轻链的原始人源化抗体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%和最优选至少95%、98%或99%氨基酸序列同一性。相对于该序列的同一性或同源性在本文中被定义为:在比对序列(在必要时引入空位,以达到最大序列同一性百分比,并且不将任何保守置换视为序列同一性的组成部分)后,候选序列中与人源化的抗-GITR残基相同的氨基酸残基的百分比。抗体序列的N末端、C末端或内部延伸、缺失或插入,都不被认为会影响序列同一性或同源性。
人源化抗体可以选自任何种类的免疫球蛋白,包括IgM、IgG、IgD、IgA和IgE。优选地,抗体是IgG抗体。可以使用IgG的任何同种型,包括IgG1、IgG2、IgG3和IgG4。还预见到IgG同种型的变体。人源化抗体可以包含来自一个以上的种类或同种型的序列。通过用实施例中描述的生物学测定筛选抗体易于实现必需恒定结构域序列的最优化,以产生所需生物学活性。
同样,任一类轻链都可以在本文的组合物和方法中使用。具体地说,κ、λ或其变体在本发明的组合物和方法中是有用的。
可以使用来自非人抗体的CDR序列的任何适宜部分。通过置换、插入或缺失至少一个残基,使得CDR序列不同于采用的人和非人抗体序列,可以诱变CDR序列。预见到,这类突变是最小的。典型地,至少75%的人源化抗体残基将对应于非人CDR残基的那些残基,更通常90%,最优选大于95%。
可以使用来自人抗体的FR序列的任何适宜部分。通过置换、插入或缺失至少一个残基,使得FR序列不同于采用的人和非人抗体序列,可以诱变FR序列。预见到,这类突变是最小的。典型地,至少75%的人源化抗体残基将对应于人FR残基的那些残基,更通常90%,最优选大于95%、98%或99%。
根据Kabat的标准序列定义,确定CDR和FR残基。Kabat等人(1987) Sequences of Proteins of Immunological Interest, National Institutes of Health, Bethesda Md。SEQ ID NO: 1-11显示了不同啮齿动物抗-人GITR抗体的重链可变结构域序列,SEQ ID NO: 12-22描绘了轻链可变结构域序列。
表2重链序列和结构域
表3轻链序列和结构域
在一个实施方案中,CDR包括本文公开的任意单个序列CDR(SEQ ID NO: 23-88)的变体,其中所述变体相对于公开的序列包含1、2、3、4、5、6、7、8、9、10或更多个保守氨基酸置换,如使用表1的数据所确定的。
也预见到嵌合抗体。如上面所指出的,典型的嵌合抗体包含重链和/或轻链的一部分,所述部分与源自特定物种或属于特定抗体类别或子类的抗体中的对应序列相同或同源,同时所述链的剩余部分与源自另一个物种或属于另一个抗体类别或子类的抗体中的对应序列相同或同源,以及这样的抗体的片段,只要它们表现出所需生物学活性。参见美国专利号4,816,567;和Morrison等人(1984)Proc. Natl. Acad. Sci. USA 81: 6851-6855。
双特异性抗体也可用于本发明的方法和组合物中。本文使用的术语“双特异性抗体”是指对至少2种不同抗原表位具有结合特异性的抗体。在一个实施方案中,表位来自相同抗原。在又一个实施方案中,表位来自2种不同抗原。用于制备双特异性抗体的方法是本领域已知的。例如,双特异性抗体可以使用2个免疫球蛋白重链/轻链对的共表达来重组生产。参见,例如,Milstein等(1983)Nature 305: 537-39。或者,双特异性抗体可以使用化学连接来制备。参见,例如,Brennan等人(1985)Science 229:81。双特异性抗体包括双特异性抗体片段。参见,例如,Holliger等人(1993)Proc. Natl. Acad. Sci. U.S.A. 90:6444-48, Gruber等人(1994)J. Immunol. 152:5368。
在其它的实施方案中,可以给源自本文提供的CDR的人源化的VL和VH区附加不同的恒定结构域。例如,如果本发明的抗体(或片段)的特定预期用途要求改变的效应子功能,那么可以使用除IgG1外的重链恒定结构域。尽管IgG1抗体提供长半衰期和效应子功能,例如补体活化和抗体依赖性细胞毒性,但此种活性可能不是抗体的所有用途所需要的。在此类情况下可以使用例如IgG4或IgG2恒定结构域。
本发明的抗体的母体形式和工程化形式也可以与化学部分缀合。除了别的以外,所述化学部分可以是聚合物、放射性核素或细胞毒性因子。优选地,所述化学部分是增加抗体分子在受试者体内的半衰期的聚合物。合适的聚合物包括、但不限于:聚乙二醇(PEG)(例如,分子量为2kDa、5 kDa、10 kDa、12kDa、20 kDa、30kDa或40kDa的PEG)、葡聚糖和单甲氧基聚乙二醇(mPEG)。Lee等人, (1999)(Bioconj. Chem. 10:973-981)公开了PEG缀合的单链抗体。Wen等人, (2001)(Bioconj. Chem. 12:545-553)公开了含有PEG的缀合抗体,所述PEG连接在放射性金属螯合剂(二亚乙基三胺五乙酸(DTPA))上。
也可以用标记缀合本发明的抗体和抗体片段或GITR可溶性蛋白或其片段,所述标记例如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和56Fe。
也可以用荧光标记或化学发光标记缀合本发明的抗体和抗体片段或GITR可溶性蛋白或其片段,所述标记包括:荧光团,诸如稀土螯合物、荧光素和它的衍生物、罗丹明和它的衍生物、异硫氰酸酯、藻红蛋白、藻蓝蛋白、别藻蓝蛋白、邻苯二甲醛、荧光胺、152Eu、丹磺酰、伞形酮、萤光素、鲁米诺标记、异鲁米诺标记、芳族吖啶酯标记、咪唑标记、吖啶盐标记、草酸酯标记、水母荧光素标记、2,3-二氢酞嗪二酮、生物素/抗生物素蛋白、旋转标记和稳定自由基。
可以采用本领域已知的将本发明的抗体分子或蛋白分子缀合到不同部分上的任意方法,包括在下述文献中描述的那些方法:Hunter等人, (1962)Nature 144:945; David等人, (1974)Biochemistry 13:1014; Pain等人, (1981)J. Immunol. Meth. 40:219;和Nygren, J., (1982)Histochem. and Cytochem. 30:407。用于缀合抗体和蛋白的方法是本领域常规的且众所周知的。
V. 人源化的抗-GITR抗体的生物学活性
可以关于体外抑制性生物活性或合适的结合亲和力,筛选具有在本文中鉴别为人源化的抗-GITR抗体所希望的特征的抗体。使用在实施例5中提供的生物学试验,可以将激动剂抗体与拮抗剂抗体区分开。表现出激动剂活性的抗体不会阻断GITR的活性,但是相反会刺激通常由GITR信号传递介导的应答。
为了筛选与在人GITR(其被目标抗体结合,所述目标抗体例如阻断GITR的结合的那些)上的表位结合的抗体,可以进行常规的交叉阻断试验,诸如在下述文献中描述的试验:Antibodies, A Laboratory Manual, Cold Spring Harbor Laboratory, Harlow和David Lane编(1988)。结合相同表位的抗体可能在这样的试验中交叉阻断,但是并非所有交叉阻断抗体必然地精确地结合相同表位,因为交叉阻断可能源自结合在重叠表位或甚至附近的非重叠表位处的抗体的抗体结合位阻。
或者,可以进行表位作图,例如,在Champe等人(1995)J. Biol. Chem. 270:1388-1394中所述的表位作图,以确定所述抗体是否结合目标表位。也可以使用由Cunningham和Wells(1989)Science 244: 1081-1085描述的“丙氨酸扫描诱变”或人GITR中的氨基酸残基的一些其它形式的点诱变,以确定本发明的抗-GITR抗体的功能表位。但是,诱变研究也可能揭示这样的氨基酸残基:所述残基对于GITR的总体三维结构而言是重要的,但是不直接参与抗体-抗原接触,因而可能需要其它方法来证实使用该方法确定的功能表位。
通过评估抗体与包含人GITR的片段(SEQ ID NO: 41)的肽的结合,也可以确定被特定抗体结合的表位。可以合成一系列包括GITR序列的重叠肽,并筛选其结合,例如在直接ELISA、竞争性ELISA(其中评估所述肽的阻止抗体与结合在微孔滴定板的孔上的GITR相结合的能力)中或在芯片上。这样的肽筛选方法可能不能够检测一些不连续的功能表位,即涉及沿着GITR多肽链的基本序列不连续的氨基酸残基的功能表位。
通过结构方法,诸如X-射线晶体结构测定(例如,WO2005/044853)、分子建模和核磁共振(NMR)波谱学,包括GITR(当游离时,和当结合在与目标抗体的复合物中时)中的不稳定酰胺氢的H-D交换率的NMR测定,也可以测定本发明的抗体所结合的表位(Zinn-Justin等人(1992)Biochemistry 31:11335-11347; Zinn-Justin等人(1993)Biochemistry 32:6884-6891)。
关于X-射线晶体学,使用本领域已知方法中的任一种(例如Giege等人(1994)Acta Crystallogr. D50:339-350; McPherson(1990)Eur. J. Biochem. 189:1-23),包括微批(microbatch)(例如Chayen(1997)Structure 5:1269-1274)、悬滴蒸汽扩散(例如McPherson(1976)J. Biol. Chem. 251:6300-6303)、引晶和透析,可以实现结晶。理想地,使用浓度为至少约1 mg/mL、优选约10 mg/mL至约20 mg/mL的蛋白制品。在沉淀剂溶液中可以最好地实现结晶,所述沉淀剂溶液含有聚乙二醇1000-20,000(PEG;平均分子量范围为约1000至约20,000 Da)、优选约5000至约7000 Da、更优选约6000 Da,浓度范围为约10%至约30% (w/v)。也可能希望包括蛋白稳定剂,例如浓度范围为约0.5%至约20%的甘油。也可能希望在沉淀剂溶液中含有合适的盐,诸如氯化钠、氯化锂或柠檬酸钠,优选地其浓度范围为约1 mM至约1000 mM。优选地将沉淀剂缓冲至约3.0至约5.0、优选约4.0的pH。可用于沉淀剂溶液中的具体缓冲剂可以变化,且是本领域众所周知的。Scopes, Protein Purification: Principles and Practice, 第3版, (1994) Springer-Verlag, New York。有用的缓冲剂的实例包括、但不限于:HEPES、Tris、MES和乙酸盐。晶体可以在宽温度范围生长,包括2 ℃、4 ℃、8 ℃和26 ℃。
使用众所周知的X-射线衍射技术,可以研究抗体:抗原晶体,且可以使用计算机软件诸如X-PLOR(Yale University, 1992, 由Molecular Simulations, Inc.发布;参见,例如,Blundell & Johnson(1985)Meth. Enzymol. 114 & 115, H. W. Wyckoff等人编, Academic Press;美国专利申请公开号2004/0014194)和BUSTER(Bricogne(1993)Acta Cryst. D49:37-60; Bricogne(1997)Meth. Enzymol. 276A:361-423, Carter & Sweet, 编; Roversi等人(2000)Acta Cryst. D56:1313-1323)来精化。
可以得到结合与本发明的抗体相同的表位的其它抗体,例如,通过筛选针对GITR产生的抗体与所述表位的结合,或通过用包含人GITR片段(其包含所述表位序列)的肽免疫接种动物。可能预期,结合相同功能表位的抗体会表现出类似的生物学活性,诸如阻断受体结合,且这样的活性可以通过所述抗体的功能试验来证实。
使用标准分析,可以测定抗体亲和力。优选的人源化抗体是以下述Kd值结合人GITR的那些:不超过约1x10-7;优选地不超过约1x10-8;更优选地不超过约1x10-9;最优选地不超过约1x10-10或甚至1x10-11 M。
可用于本发明的组合物和方法中的抗体和其片段是生物学上有活性的抗体和片段。本文使用的术语“生物学上有活性的”是指这样的抗体或抗体片段:其能够结合所需抗原表位,并且直接或间接发挥生物学作用。本文使用的术语“特异性”是指抗体与靶抗原表位的选择性结合。通过在一组给定条件下比较与GITR的结合和与无关抗原或抗原混合物的结合,可以测试抗体的结合特异性。如果抗体与GITR结合的亲和力是其对无关抗原或抗原混合物的亲和力的至少10倍、优选50倍,那么该抗体被视为特异性的。“特异性地结合”GITR的抗体不结合不含GITR衍生序列的蛋白,即,本文使用的“特异性”涉及GITR特异性,而不涉及可能存在于所研究的蛋白中的任何其它序列。例如,本文使用的“特异性地结合”包含GITR的多肽的抗体通常会结合FLAG?-GITR(它是包含GITR和FLAG?肽标签的融合蛋白),但是它不会结合FLAG?肽标签(单独的,或当它与非GITR的蛋白融合时)。
本发明的GITR-特异性的结合化合物,诸如激动性的GITR特异性抗体,可以以任意方式增强它的生物学活性,所述方式包括、但不限于增加对微生物感染的免疫应答。
VI. 药物组合物
为了制备药用的或无菌的包含GITR抗体的组合物,将细胞因子类似物或突变蛋白、针对它们的抗体或它们的核酸与药学上可接受的载体或赋形剂相混合。参见,例如,Remington'sPharmaceutical Sciences和U.S. Pharmacopeia: National Formulary, Mack Publishing Company, Easton, PA(1984)。
治疗剂和诊断剂的制剂可以通过与例如冻干粉末、淤浆、水溶液或混悬液形式的生理学上可接受的载体、赋形剂或稳定剂混合来制备。参见,例如,Hardman等, (2001)Goodman and Gilman’s The Pharmacological Basis of Therapeutics, McGraw-Hill, New York, NY;Gennaro(2000)Remington: The Science and Practice of Pharmacy, Lippincott, Williams和Wilkins, New York, NY;Avis等, (编辑)(1993)Pharmaceutical Dosage Forms: Parenteral Medications, Marcel Dekker, NY;Lieberman等, (编辑)(1990)Pharmaceutical Dosage Forms: Tablets, Marcel Dekker, NY;Lieberman等, (编辑)(1990)Pharmaceutical Dosage Forms: Disperse Systems, Marcel Dekker, NY;Weiner和Kotkoskie(2000)Excipient Toxicity and Safety, Marcel Dekker, Inc., New York, NY。
单独或与免疫抑制剂组合施用的抗体组合物的毒性和疗效可以通过细胞培养或实验动物的标准药学程序来测定,例如用于测定LD50(对50%的群体致死的剂量)和ED50(在50%的群体中治疗上有效的剂量)的标准药学程序。毒性和疗效之间的剂量比是治疗指数,它可以表示为LD50与ED50之比。优选显示高治疗指数的抗体。由这些细胞培养测定和动物研究获得的数据可以用于配制用于人使用的一系列剂量。这类组合物的剂量优选处于包括基本没有或没有毒性的ED50的循环浓度范围内。剂量可根据使用的剂型和给药途径在此范围内变化。
给药方式不是特别重要的。合适的给药途径可以包括例如,经口、直肠、透粘膜或肠内给药;肠胃外递送,包括肌内、皮下、髓内注射,以及鞘内、直接心室内、静脉内、腹膜内、鼻内或眼内注射。在药物组合物中使用的或用于实践本发明方法的抗体的给药,可以以多种常规方式进行,例如经口摄食、吸入、局部应用或皮肤、皮下、腹膜内、胃肠外、动脉内或静脉内注射。
或者,人们可以以局部而不是全身方式施用抗体,例如,将抗体直接注射到关节炎的关节或特征在于免疫病理学的病原体诱导的病灶内,通常以贮存或持续释放制剂。而且,人们可以施用在靶向药物递送系统中的抗体,例如,在用组织特异性抗体包被的脂质体中,靶向例如关节炎的关节或特征在于免疫病理学的病原体诱导的病灶。脂质体将被靶向受害组织并被受害组织选择性吸收。
为治疗剂选择给药方案取决于几种因素,包括实体的血清或组织周转率、征状水平、实体的免疫原性和生物基质中靶细胞的可接近性。优选地,给药方案会使递送给患者的治疗剂的量最大化,并与可接受的副作用水平相一致。因此,递送的生物制剂的量部分地取决于特定实体和待治疗病症的严重性。选择合适剂量的抗体、细胞因子和小分子的指引是可获得的。参见,例如,Wawrzynczak(1996)Antibody Therapy, Bios Scientific Pub. Ltd, Oxfordshire, UK; Kresina(ed.)(1991)Monoclonal Antibodies, Cytokines and Arthritis, Marcel Dekker, New York, NY; Bach(ed.)(1993)Monoclonal Antibodies and Peptide Therapy in Autoimmune Diseases, Marcel Dekker, New York, NY; Baert等人(2003)New Engl. 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)New Engl. J. Med. 343:1594-1602。
合适剂量的确定由临床医生进行,例如,使用本领域已知或怀疑影响治疗预测会影响治疗的参数或因素。一般地,剂量以略微小于最佳剂量的量开始,其后通过小增量增加,直至相对于任何负面副作用达到所需或最佳作用。重要的诊断测量包括例如产生的那些炎症征状或产生的炎性细胞因子水平。优选地,将要使用的生物制剂基本上源自与治疗靶向的动物相同的物种(例如用于治疗人受试者的人源化抗体),从而使针对试剂的任何免疫应答最小化。
抗体、抗体片段和细胞因子可以通过连续输注或通过间隔给药来提供,所述间隔给药例如1天1次、1-7次/周、1周1次、2周1次、1月1次、2月1次等。可以静脉内地、皮下地、局部地、经口地、鼻地、直肠地、肌内地、大脑内地、椎管内地或通过吸入,提供剂量。一个优选的剂量方案是,包括最大剂量或给药频率的方案,其避免显著的不希望的副作用。每周总剂量通常为至少0.05 μg/kg、0.2 μg/kg、0.5 μg/kg、1 μg/kg、10 μg/kg、100 μg/kg、0.2 mg/kg、1.0 mg/kg、2.0 mg/kg、10 mg/kg、25 mg/kg、50 mg/kg体重或更高。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(20003)Cancer Immunol. Immunother. 52:133-144。小分子治疗剂(例如,肽模仿物、天然产物或有机化学试剂)的所需剂量与抗体或多肽的剂量大致相同(以摩尔/kg为基础)。
本文使用的“抑制”或“治疗”或“处理”包括:与自身免疫病或病原体诱发的免疫病理学相关的征状发展的延缓,和/或将会或预期会发展的此种征状的严重性的降低。该术语进一步包括:改善现有的不受控的或不希望的自身免疫相关的或病原体诱发的免疫病理学征状,预防另外的征状,和改善或预防这类征状的潜在原因。因此,该术语指已赋予脊椎动物受试者的有益结果,所述受试者具有自身免疫或病原体诱发的免疫病理学疾病或征状,或可能发生此种疾病或征状。
本文使用的术语“治疗有效量”或“有效量”是指GITR-特异性的结合化合物(例如和抗体)的量,其在单独或与另外的治疗剂组合施用给细胞、组织或受试者时,可有效预防或改善自身免疫病或病原体诱发的免疫病理学相关的疾病或病症或疾病的进程。治疗有效剂量进一步指这样的化合物的量:其足以使征状改善,例如治疗、治愈、预防或改善相关医学病症,或治疗、治愈、预防或改善这类病症的比率增加。当应用于单独施用的单个活性成分时,治疗有效剂量是指单独的该成分。当应用于组合时,治疗有效剂量是指产生疗效的活性成分的组合量,无论是组合、顺次还是同时施用。治疗剂的有效量会使征状减少通常至少10%、通常至少20%、优选至少约30%、更优选至少40%、最优选至少50%。
与第二种治疗剂(例如,细胞因子、抗体、类固醇、化学治疗剂、抗生素、抗病毒剂或辐射)共同施用或治疗的方法,是本领域众所周知的,参见,例如,Hardman等人(编)(2001)Goodman和Gilman的The Pharmacological Basis of Therapeutics, 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和Longo(编)(2001)Cancer Chemotherapy and Biotherapy, Lippincott, Williams & Wilkins, Phila., PA。
化学治疗剂包括:烷化剂类,诸如塞替派和CYTOXAN?环磷酰胺;烷基磺酸酯类,诸如白消安、英丙舒凡和哌泊舒凡;氮丙啶类,诸如苯佐替派、卡波醌、美妥替派和乌瑞替派;乙烯亚胺类和甲基蜜胺类(methylamelamines),包括六甲蜜胺、曲他胺、三亚乙基磷酰胺、三亚乙基硫代磷酰胺和三羟甲蜜胺(trimethylolomelamine);番荔枝内酯类(acetogenin)(尤其是布拉他辛(bullatacin)和布拉他辛酮(bullatacinone));喜树碱(包括合成类似物托泊替康);苔藓抑素;callystatin;CC-1065(包括它的阿多来新、卡折来新和比折来新合成类似物);隐藻素类(cryptophycins)(特别是隐藻素1和隐藻素8);多拉司他汀;多卡米星(包括合成类似物,KW-2189和CB1-TM1);软珊瑚醇;pancratistatin;sarcodictyin;海绵抑素;氮芥类,诸如苯丁酸氮芥、萘氮芥、胆磷酰胺(cholophosphamide)、雌莫司汀、异环磷酰胺、氮芥、盐酸氧化氮芥、美法仑、新氮芥、泼尼氮芥、曲磷胺、乌拉莫司汀;亚硝脲类,诸如卡莫司汀、氯脲菌素、福莫司汀、洛莫司汀、尼莫司汀和雷莫司汀;抗生素类,诸如烯二炔类抗生素(例如,加利车霉素,尤其是加利车霉素γ1I和加利车霉素ωI1(参见,例如,Agnew, Chem. Intl. Ed. Engl., 33: 183-186(1994));达内霉素,包括达内霉素A;二膦酸盐类,诸如氯膦酸盐;埃斯波霉素;以及新制癌素发色团和相关色蛋白烯二炔类抗生素发色团)、阿克拉霉素、放线菌素、氨茴霉素、偶氮丝氨酸、博来霉素、放线菌素C、卡柔比星、洋红霉素、嗜癌霉素、色霉素、更生霉素、柔红霉素、地托比星、6-二氮杂-5-氧代-L-正亮氨酸、ADRIAMYCIN?多柔比星(包括吗啉代-多柔比星、氰基吗啉代-多柔比星、2-吡咯啉代-多柔比星和脱氧多柔比星)、表柔比星、依索比星、伊达比星、麻西罗霉素、丝裂霉素类诸如丝裂霉素C、麦考酚酸、诺拉霉素、橄榄霉素、培洛霉素、泊非霉素, 嘌罗霉素, 三铁阿霉素, 罗多比星, 链黑霉素, 链佐星, 杀结核菌素, 乌苯美司, 净司他丁, 佐柔比星;抗代谢物诸如甲氨蝶呤和5-氟尿嘧啶(5-FU);叶酸类似物诸如二甲叶酸, 甲氨蝶呤, 蝶罗呤, 三甲曲沙;嘌呤类似物诸如氟达拉滨, 6-巯嘌呤, 硫咪嘌呤, 硫鸟嘌呤;嘧啶类似物诸如安西他滨, 阿扎胞苷, 6-氮杂尿苷, 卡莫氟, 阿糖胞苷, 二脱氧尿苷, 去氧氟尿苷, 依诺他滨, 氮尿苷;雄激素类诸如卡普睾酮, 丙酸屈他雄酮, 环硫雄醇, 美雄烷, 睾内酪;抗肾上腺药诸如氨鲁米特, 米托坦, 曲洛司坦;叶酸补充剂,诸如亚叶酸(frolinic acid);醋葡醛内酯;醛磷酰胺糖苷;氨基乙酰丙酸;恩尿嘧啶;安吖啶;bestrabucil;比生群;依达曲沙(edatraxate);地磷酰胺(defofamine);秋水仙胺;地吖醌;elfomithine;依利醋铵;埃博霉素;依托格鲁;硝酸镓;羟基脲;香菇多糖;氯尼达明(lonidainine);美登木素生物碱类(maytansinoids),诸如美坦辛和安丝菌素;米托胍腙;米托蒽醌;莫哌达醇(mopidanmol);硝氨丙吖啶(nitracrine);喷司他丁;蛋氨氮芥;吡柔比星;洛索蒽醌;鬼臼酸;2-乙基酰肼;丙卡巴肼;PSK?多糖复合物(JHS Natural Products,Eugene,OR);雷佐生;根霉素;西左非兰;锗螺胺;替奴佐酸;三亚胺醌; 2,2′,2″-三氯三乙胺;单端孢霉烯类(尤其是T-2毒素、疣孢菌素A、杆孢菌素A和蛇行菌素(anguidine));乌拉坦;长春地辛;达卡巴嗪;甘露莫司汀;二溴甘露醇;二溴卫矛醇;哌泊溴烷; gacytosine;阿糖胞苷(“Ara-C”);环磷酰胺;塞替派;紫杉烷类,例如,泰素?紫杉醇(Bristol-Myers Squibb Oncology, Princeton, N.J.)、ABRAXANE?(不含克列莫佛)、白蛋白改造的紫杉醇纳米颗粒制剂(American Pharmaceutical Partners,Schaumberg, Ill.)和泰索帝?多西紫杉醇(Rh?ne-Poulenc Rorer, Antony, France);苯丁酸氮芥(chloranbucil);GEMZAR?吉西他滨; 6-硫鸟嘌呤;巯嘌呤;甲氨蝶呤;铂类似物,诸如顺铂和卡铂;长春碱;铂;依托泊苷(VP-16);异环磷酰胺;米托蒽醌;长春新碱;NAVELBINE?长春瑞滨;能灭瘤;替尼泊苷;依达曲沙;道诺霉素;氨基蝶呤;希罗达?卡培他滨;伊班膦酸盐;CPT-11;拓扑异构酶抑制剂RFS 2000;二氟甲基鸟氨酸(DMFO);维生素A酸类,诸如维A酸;及任何上述物质的药学上可接受的盐、酸或衍生物。
还包括作用为调节或抑制激素对肿瘤的作用的抗激素剂,诸如抗雌激素类和选择性雌激素受体调节剂(SERM),他莫昔芬(包括NOLVADEX?他莫昔芬)、雷洛昔芬、屈洛昔芬、4-羟基他莫昔芬、曲沃昔芬、那洛昔芬(keoxifene)、LY117018、奥那司酮和FARESTON?托瑞米芬;抑制调节肾上腺中的雌激素生成的芳香酶的芳香酶抑制剂,例如, 4(5)-咪唑、氨鲁米特, MEGASE?醋酸甲地孕酮、AROMASIN?依西美坦、福美坦(formestanie)、法倔唑、RIVISOR?伏氯唑、FEMARA?来曲唑和ARIMIDEX?阿那曲唑;抗雄激素类,诸如氟他胺、尼鲁米特、比卡鲁胺、亮丙瑞林和戈舍瑞林;以及曲沙他滨(1,3-二氧戊环核苷胞嘧啶类似物);反义寡核苷酸,特别是抑制涉入异常细胞增殖中的信号传递途径的基因表达的那些,例如PKC-α、Ralf和H-Ras;核酶,诸如VEGF表达抑制剂(例如,ANGIOZYME?核酶)和HER2表达抑制剂;疫苗,诸如基因疗法疫苗,例如ALLOVECTIN?疫苗、LEUVECTIN?疫苗和VAXID?疫苗;PROLEUKIN?rIL-2;LURTOTECAN?拓扑异构酶1抑制剂; ABARELIX?rmRH;及上述任一种的药学上可接受的盐、酸或衍生物。
具体地,转化生长因子(TGF)-?在细胞功能方面(诸如增殖、体内稳态、血管生成和伤口愈合)显示出一系列的多效作用。TGF-β功能的异常调节会促进癌症进展。大多数癌症的特征在于,肿瘤过量生产转化生长因子-β,后者可以促进肿瘤生长并介导上皮-至-间质转变。TGF-?也在免疫系统中起关键作用,其通过调节淋巴细胞增殖、分化和存活来维持耐受性。已经证实,TGF-?是增强Treg功能和降低肿瘤免疫的重要抑制元件。预见到TGF-β抑制剂与GITR激动剂(例如,抗体)的联合施用。
也预见到与抗病毒治疗剂的共同施用。抗病毒剂包括破坏病毒的任何药物。抗病毒剂可以包括起抑制病毒复制功能的干扰素、蛋白酶抑制剂和逆转录酶抑制剂或在HIV的高效抗逆转录病毒治疗(HAART)组合中包含的试剂。
典型的医用动物的(veterinary)、实验性的或研究性的受试者包括:猴、狗、猫、大鼠、小鼠、兔、豚鼠、马和人。
VII. 抗体生产
在一个实施方案中,为了重组生产本发明的抗体,分离出编码2条链的核酸,并插入一个或多个可复制的载体中,用于进一步克隆(DNA扩增)或用于表达。使用常规程序(例如通过使用能够与编码抗体的重链和轻链的基因特异性结合的寡核苷酸探针)易于分离并测序编码单克隆抗体的DNA。许多载体是可用的。载体组分一般包括、但不限于以下的一种或多种:信号序列、复制起点、一个或多个标记基因、增强子元件、启动子和转录终止序列。在一个实施方案中,本发明的人源化的抗-GITR抗体的轻链和重链这两者由相同载体例如质粒或腺病毒载体表达。
本发明的抗体可以通过本领域已知的任何方法生产。在一个实施方案中,抗体在培养的哺乳动物或昆虫细胞中表达,例如中国仓鼠卵巢(CHO)细胞、人胚肾(HEK)293细胞、小鼠骨髓瘤NSO细胞、幼仓鼠肾(BHK)细胞、草地夜蛾(Spodoptera frugiperda)卵巢(Sf9)细胞。在一个实施方案中,由CHO细胞分泌的抗体被回收并通过标准层析法进行纯化,例如A蛋白、阳离子交换、阴离子交换、疏水作用和羟磷灰石层析。所获抗体被浓缩并贮存于20 mM乙酸钠pH 5.5中。
在又一个实施方案中,本发明的抗体根据WO2005/040395中所述方法在酵母中进行生产。简言之,将编码目标抗体的单独轻链或重链的载体引入不同的酵母单倍体细胞内,例如不同交配型的酵母巴斯德毕赤氏酵母(Pichia pastoris),所述酵母单倍体细胞任选地为互补营养缺陷体。转化的单倍体酵母细胞随后可以进行交配或融合,以产生能够生产重链和轻链这两者的二倍体酵母细胞。二倍体菌株随后能够分泌完全装配的和生物学活性的抗体。2条链的相对表达水平例如可如下优化:使用具有不同拷贝数的载体、使用不同强度的转录启动子或由驱动编码1条或2条链的基因转录的诱导型启动子诱导表达。
在一个实施方案中,将多种不同的抗-GITR抗体(“原始”抗体)各自的重链和轻链引入酵母单倍体细胞内,以产生表达多条轻链的一种交配型的单倍体酵母菌株文库,和表达多条重链的不同交配型的单倍体酵母菌株文库。这些单倍体菌株文库可以进行交配(或融合为原生质球),以生产表达包含轻链和重链的各种可能排列的抗体组合文库的一系列二倍体酵母细胞。随后可以筛选抗体组合文库,以确定任一个抗体是否具有优于(例如对GITR的更高亲和力)原始抗体的性质。参见,例如,WO2005/040395。
在又一个实施方案中,本发明的抗体是其中抗体可变结构域的部分以分子量约13 kDa的多肽连接的人结构结构域抗体。参见,例如,美国专利公开号2004/0110941。就合成的容易性、稳定性和给药途径而言,这样的单结构域、低分子量物质提供了众多优点。
VIII. 应用
本发明提供了使用抗-GITR抗体和其片段治疗和诊断增生性或炎性障碍和病症的方法。
本发明提供了用于诊断微生物感染或癌症的存在的方法,其中分析实验细胞、组织或体液中的GITR的表达水平,并与来自对照的细胞、组织或体液(优选相同类型)中的GITR水平相对比。如本文所证实的,例如,与对照相比患者中GITR表达水平的增加与癌症的存在有关。
通常,对于定量诊断试验,指示受测患者具有癌症或传染性疾病的阳性结果是这样的:其中所述细胞、组织或体液的GITR表达水平升高了至少2倍、5倍、10倍、15倍、20倍、25倍。
可以用于测定本发明的基因和蛋白(诸如GITR)在源自宿主的样品中的表达水平的测定技术是本领域技术人员众所周知的。这样的测定方法包括:放射免疫测定法、逆转录酶PCR(RT-PCR)测定法、定量实时PCR测定法、免疫组织化学测定法、原位杂交测定法、竞争性结合测定法、蛋白印迹测定法、ELISA测定法和流式细胞计测定法,例如,肿瘤相关的巨噬细胞的M2表型相对于M1表型的双色FACS分析(Mantovani等人, (2002)TRENDS in Immunology 23:549-555)。
ELISA测定法最初包括制备对GITR特异性的本发明的抗体,优选36E5、3D6、61G6、6H6、61F6、1D8、17F10、35D8、49A1、9E5和31H6(统一称作“GITR抗体”)。另外,通常制备报告抗体,其特异性地结合GITR。将所述报告抗体连接到可检测的试剂诸如放射性试剂、荧光试剂或酶试剂(例如辣根过氧化物酶或碱性磷酸酶)上。
为了进行ELISA,在固体支持物(例如,结合抗体的聚苯乙烯盘子)上温育至少一种上述的GITR抗体。然后通过用非特异性的蛋白(诸如牛血清白蛋白)温育,覆盖盘子上的任何游离的蛋白结合位点。接着,在盘子中温育要分析的样品,在这期间,GITR会结合连接在聚苯乙烯盘子上的特异性GITR抗体。用缓冲液洗掉未结合的样品。将特异性地针对GITR并连接到辣根过氧化物酶上的报告抗体放入盘子中,导致所述报告抗体与GITR所结合的任何单克隆抗体的结合。然后洗掉未结合的报告抗体。然后将用于测定过氧化物酶活性的试剂(包括比色法底物)加入盘子中。固定化的过氧化物酶(与GITR抗体相连)产生有色的反应产物。在给定的时间段中形成的颜色的量与样品中存在的GITR蛋白的量成比例。通常通过参照标准曲线,得到定量结果。
可以采用竞争测定法,其中将对GITR特异性的抗体连接到固体支持物上,并使标记的GITR和源自宿主的样品在固体支持物上面经过,检测到的与固体支持物连接的标记的量可以与样品中GITR的量相关联。
可以在从患者得到的多种细胞、体液和/或组织提取物(诸如匀浆物或溶解组织)所衍生出的样品上,进行上述实验。常规地,从组织活组织检查和尸体剖检材料得到组织提取物。可用于本发明中的体液包括:血液、尿、唾液或任意其它身体排泄物或它们的衍生物。术语“血液”意在包括全血、血浆、血清或血液的任意衍生物。
本发明的抗体可以用于治疗病毒感染。HIV感染的特征在于,中枢记忆细胞的产生和维持的缺陷。与对照相比,在HIV-感染的个体中,CD8+ 中枢记忆细胞具有更短的半衰期和更低的丰度。另外,在开始高效抗逆转录病毒治疗(HAART)以后,CD4+和CD8+ HIV-特异性的T细胞的频率快速降低。抗-GITR对CD4+的共刺激,可以提供增加记忆性CD8+应答并促进病毒的清除的机制。已经证实,用抗-GITR抗体治疗Friend病毒持久感染的小鼠(以改善Tregs的抑制),会显著提高CD8+ T细胞的IFN-γ生产,并会显著减少病毒载量(Dittmer等人, (2004)Immunity 20: 293-303)。
HIV感染的另一个特征是,从HIV感染早期开始的CD4+ T细胞的大量细胞凋亡。CD4 T细胞的渐进性细胞凋亡性去除,会促进减弱的HIV-特异性的细胞免疫应答和AIDS的发展。已经证实,GITR共刺激会通过保护T细胞免于细胞凋亡而增加鼠抗原-特异性的细胞因子分泌。Lahey等人(2007)J Infect Dis. 196: 43-49)证实,HIV-特异性的CD4+ T细胞的抗-GITR治疗会增加它们的细胞因子表达,并保护它们免于细胞凋亡。
对于由病毒原因导致的感染,可以在施用治疗病毒感染的标准疗法的同时、之前或之后,联合施用本发明的抗体。这类标准疗法随病毒的类型而变化,尽管在几乎所有情况下,施用含有对所述病毒特异性的抗体(例如,IgA、IgG)的人血清可能是有效的。
流感感染会导致发烧、咳嗽、肌痛、头痛及全身乏力,其常见于季节性流行病中。流感也与许多传染后障碍有关,所述障碍例如:脑炎、心肌心包炎、肺出血肾炎综合征和瑞氏综合征。流感感染也会抑制正常的肺抗细菌防御,使得流感康复的患者具有增加的发展细菌性肺炎的风险。
流感病毒表面蛋白表现出显著的抗原性变异,所述变异源自突变和重组。因而,溶细胞性的T淋巴细胞是宿主在感染后消除病毒的主要媒介物。流感被分类为3大类:A、B和C。A型流感的独特之处在于,它感染人类和许多其它动物(例如,猪、马、禽类和海豹),且是大流行流感的主要原因。另外,当细胞被2种不同的A型流感株感染时,2个亲本病毒类型的片段化的RNA基因组在复制过程中混合以建立杂种复制子(replicant),产生新的传染株。B型流感不在动物中复制,因而具有更少的遗传变异,C型流感仅具有单个血清型。
最常规的疗法是由感染引起的征状的姑息剂,同时宿主的免疫应答实际上清除该疾病。但是,某些株(例如,A型流感)可以造成更严重的疾病和死亡。通过施用环胺类抑制剂金刚烷胺和金刚乙胺(它们抑制病毒复制),可以在临床上和预防性地治疗A型流感。但是,这些药物的临床实用性受到限制,这是由于不良反应的相对高发率、它们的狭窄抗病毒谱(仅A型流感)和病毒变得抗性的倾向。施用针对主要流感表面蛋白、血凝素和神经氨酸酶的血清IgG抗体,可以预防肺感染,而需要用粘膜IgA来预防上呼吸道和气管的感染。流感的目前最有效的治疗是,通过使用用福尔马林或β-丙内酯灭活的病毒进行疫苗接种。
在9-11天的潜伏期以后,被麻疹病毒感染的宿主会形成发热、咳嗽、鼻炎和结膜炎。在1-2天内,出现红斑性的斑丘疹,其迅速地扩散至全身。因为感染也会抑制细胞免疫,所述宿主处于更大的形成细菌重叠感染(包括中耳炎、肺炎和感染后脑脊髓炎)的风险中。急性感染伴有高发病率和死亡率,特别是在营养不良的青少年中。
麻疹的治疗包括:被动性施用混合的人IgG,其可以预防无免疫性的受试者的感染,即使在暴露后多达1周施用。
但是,用活的减毒病毒事先免疫接种,是最有效的治疗,且会在超过95%的免疫接种人群中预防疾病。由于该病毒存在一种血清型,单次免疫或感染通常会导致免于以后感染的终生保护。
在低比例的受感染宿主中,麻疹可以发展成SSPE,这是由中枢神经系统的持续性感染导致的一种慢性渐进性神经学障碍。SSPE由麻疹病毒的克隆变异体造成,所述变异体具有干扰病毒粒子装配和芽殖的缺陷。对于这些患者,希望用本发明的抗体重新活化T-细胞,从而促进病毒清除。
乙型肝炎病毒(HB-V)是最有传染性的已知的血液传染的病原体。它是急性和慢性肝炎和肝癌以及终生慢性感染的主要原因。在感染后,所述病毒在肝细胞中复制,它们随后也脱落表面抗原HBsAg。血清中过度的HBsAg水平的检测,被用作诊断乙型肝炎感染的标准方法。急性感染可以消退,或它可以发展成慢性持续性感染。
慢性HBV的现有治疗包括:α-干扰素,其会增加I类人白细胞抗原(HLA)在肝细胞表面上的表达,从而促进细胞毒性的T淋巴细胞对它们的识别。另外,核苷类似物更昔洛韦、泛昔洛韦和拉米夫定也已经在临床试验中在HBV感染的治疗方面表现出某些效力。HBV的其它治疗包括:聚乙二醇化的α-干扰素、阿德福韦(adenfovir)、恩替卡韦和替比夫定。尽管通过抗-HBsAg血清抗体的肠胃外施用可以赋予被动免疫,用灭活的或重组的HBsAg进行疫苗接种,也会赋予对感染的抗性。本发明的抗体可以与乙型肝炎感染的常规治疗相组合,实现治疗益处。
丙型肝炎病毒(HC-V)感染可能导致慢性形式的肝炎,导致肝硬化。尽管征状与乙型肝炎引起的感染类似,与HB-V明显不同的是,被感染的宿主可以不出现征状达10-20年。HC-V感染的治疗包括:施用α-干扰素和利巴韦林的组合。HC-V感染的一种有前途的潜在治疗是,蛋白酶抑制剂特拉匹韦(VX-960)。其它治疗包括:抗-PD-1抗体(MDX-1106, Medarex)、巴维昔单抗(一种以B2-糖蛋白I依赖性的方式结合阴离子性磷脂磷脂酰丝氨酸的抗体,Peregrine Pharmaceuticals)、抗-HPV病毒外壳蛋白E2抗体(例如,ATL 6865-Ab68+Ab65, XTL Pharmaceuticals)和Civacir?(多克隆抗-HCV人免疫球蛋白)。本发明的抗体可以与丙型肝炎感染的这些治疗中的一种或多种相组合,实现治疗益处。
参考下面的实施例,会最好地理解本发明的宽广范围,所述实施例无意将本发明限制为具体实施方案。本文描述的具体实施方案仅为了举例而提供,本发明由随附权利要求的条款连同此权利要求授权的等同方案的全部范围限定。
实施例
实施例1
一般方法
分子生物学的标准方法已有描述。Maniatis等, (1982)Molecular Cloning, A Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY;Sambrook和Russell(2001)Molecular Cloning, 第3版,Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY;Wu(1993)Recombinant DNA, 第217卷, Academic Press, San Diego, CA。标准方法还见于Ausbel等, (2001)Current Protocols in Molecular Biology, 第1-4卷, John Wiley and Sons, Inc. New York, NY, 其描述了在细菌细胞中克隆和DNA诱变(第1卷)、在哺乳动物细胞和酵母中克隆(第2卷)、复合糖和蛋白表达(第3卷),以及生物信息学(第4卷)。
蛋白纯化的方法,包括免疫沉淀、层析、电泳、离心和结晶,已有描述(Coligan等, (2000)Current Protocols in Protein Science, 第1卷, John Wiley and Sons, Inc., New York)。描述了化学分析、化学修饰、翻译后修饰、融合蛋白的生产、蛋白糖基化。参见,例如,Coligan等, (2000)Current Protocols in Protein Science, 第2卷, John Wiley and Sons, Inc., New York;Ausubel等, (2001)Current Protocols in Molecular Biology, 第3卷, John Wiley and Sons, Inc., NY, NY, 第16.0.5-16.22.17页;Sigma-Aldrich, Co. (2001)Products for Life Science Research, St. Louis, MO;第45-89页;Amersham Pharmacia Biotech(2001)BioDirectory, Piscataway, N.J., 第384-391页。多克隆抗体和单克隆抗体的生产、纯化和片段化已有描述。Coligan等, (2001)Current Protcols in Immunology, 第1卷, John Wiley and Sons, Inc., New York;Harlow和Lane(1999)Using Antibodies, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY;Harlow和Lane, 出处同上。用于表征配体/受体相互作用的标准技术是可用的。参见,例如,Coligan等, (2001)Current Protcols in Immunology, 第4卷, John Wiley, Inc., New York。
用于流式细胞术的方法,包括荧光活化细胞分选检测系统(FACS?),是可用的。参见,例如,Owens等, (1994)Flow Cytometry Principles for Clinical Laboratory Practice, John Wiley and Sons, Hoboken, NJ;Givan(2001)Flow Cytometry, 第2版;Wiley-Liss, Hoboken, NJ;Shapiro(2003)Practical Flow Cytometry, John Wiley and Sons, Hoboken, NJ。适于修饰核酸(包括核酸引物和探针)、多肽和抗体以及适合用作例如诊断试剂的荧光试剂是可用的。Molecular Probes(2003)Catalogue, Molecular Probes, Inc., Eugene, OR;Sigma-Aldrich(2003)Catalogue, St. Louis, MO。
描述了免疫系统组织学的标准方法。参见,例如,Muller-Harmelink(编辑)(1986)Human Thymus: Histopathology and Pathology, Springer Verlag, New York, NY;Hiatt等, (2000)Color Atlas of Histology, Lippincott, Williams和Wilkins, Phila, PA;Louis等, (2002)Basic Histology: Text and Atlas, McGraw-Hill, New York, NY。
用于测定例如抗原片段、前导序列、蛋白折叠、功能结构域、糖基化位点和序列比对的软件包和数据库是可用的。参见,例如,GenBank, Vector NTI?Suite(Informax, Inc, Bethesda, MD);GCG Wisconsin Package(Accelrys, Inc., San Diego, CA);DeCypher?(TimeLogic Corp., Crystal Bay, Nevada);Menne等, (2000)Bioinformatics 16: 741-742;Menne等, (2000)Bioinformatics Applications Note 16:741-742;Wren等, (2002)Comput. Methods Programs Biomed. 68:177-181;von Heijne(1983)Eur. J. Biochem. 133:17-21;von Heijne(1986)Nucleic Acids Res. 14:4683-4690。
实施例2
抗-人GITR抗体的人源化
抗体的人源化通常描述在,例如,PCT专利申请公开WO 2005/047324和WO 2005/047326。
简而言之,将非人VH结构域的氨基酸序列(例如SEQ ID NO: 1-11)与一组5条人VH种系氨基酸序列相对比:1条代表亚组IGHV1,1条代表IGHV4,3条代表亚组IGHV3。VH亚组列于:M.-P. Lefranc(2001)“Nomenclature of the human Immunoglobulin Heavy(IGH)Genes”, Experimental and Clinical Immunogenetics, 18:100-116。使用具有最接近匹配的人种系序列的框架序列,构建人源化的VH结构域。
在本文中公开的啮齿动物抗-huGITR抗体都属于VL的κ亚类。将非人VL结构域的氨基酸序列(例如SEQ ID NO: 12-22)与一组4条人VLκ种系氨基酸序列相对比。该组4条由来自4个确定的人VL亚组中的每一个的一个代表组成,所述人VL亚组列于:V. Barbie & M.-P. Lefranc (1998)“The Human Immunoglobulin Kappa Variable (IGKV) Genes and Joining (IGKJ) Segments”, Experimental and Clinical Immunogenetics 15:171-183和M.-P. Lefranc (2001)“Nomenclature of the Human Immunoglobulin Kappa (IGK) Genes”, Experimental and Clinical Immunogenetics 18:161-174。所述4个亚组也对应于在下述文献中列出的4个亚组:Kabat等人(1991–第5版)“Sequences of Proteins of Immunological Interest”, U. S. Department of Health and Human Services, NIH Pub. 91-3242, 第103-130页。使用具有最接近匹配的人种系序列的框架序列,构建人源化的VL结构域。
一旦确定可变重链和轻链的靶氨基酸序列,可以制备编码全长人源化抗体的质粒。使用Kunkel诱变(参见,例如,Kunkel T A. (1985)Proc. Natl. Acad. Sci. U.S.A 82:488-492),可以改变质粒序列,以将DNA序列改变成靶人源化抗体序列。同时,可以进行密码子优化,以提供可能最佳的表达。
使用鉴别人源化抗体的受体种系序列的方法,可以将本发明的抗体人源化,所述方法包括下述步骤:a)鉴别具有所需生物学活性的非人抗体;b)测定非人抗体VH和VL结构域的氨基酸序列;和c)将非人抗体序列与一组人种系序列相对比,其中所述对比包括下述子步骤:1)根据Kabat(同上),指定非人V序列残基编号;2)根据Kabat(同上),描绘序列中的CDR和FR区;3)在非人和人抗体种系序列的相同的特定残基位置处,指定预定数字记分;和4)累加所有残基记分,以建立每个人种系序列的总记分;和d)将具有最高总残基记分的人种系序列鉴别为受体种系序列。在一个实施方案中,所述方法另外包括下述子步骤:5)对于在子步骤(3)中没有记分的、非人和人抗体种系序列的相同的每个FR残基位置,指定1的数字记分,以得到在子步骤(4)以后具有相同总残基记分的种系序列;6)累加所有残基记分,以建立每个人种系序列的总记分。在一个具体的实施方案中,所述非人抗体对GITR是特异性的,并增强GITR的生物学活性。本文也提供了通过上述方法制备的抗体。
在一个实施方案中,使用下述方法,将GITR抗体人源化。首先,克隆GITR抗体的非人VL和VH结构域,测序,并测定氨基酸序列。然后,将非人VH序列与一组3条人VH种系氨基酸序列相对比。该组含有来自亚组IGHV1、IGHV3和IGHV4中的每一个的一个代表。VH亚组列于:M.-P. Lefranc, Exp. Clin. Immunogenetics, 18:100-116(2001)。具体地,所述3个种系序列的对比,从根据Kabat编号系统给非人VH序列指定残基编号开始。参见Kabat, 等人, 美国卫生和人类服务部(U. S. Department of Health and Human Services), NIH Pub. 91-3242(第5版, 1991)。然后将非人VH序列与3个人种系序列中的每一个相比对。由于V基因仅包含VH残基1-94,在比对中仅考虑这些残基。接着,描绘序列中的互补性决定区(CDR)和框架区(FR)。根据在Kabat, 等人, 美国卫生和人类服务部, NIH Pub. 91-3242(第5版, 1991),和C. Chothia & A.M. Lesk, J. Mol. Biol., 196:901-917(1987)中提供的定义的组合,描绘CDR和FR。因此,使用的CDR定义是:残基26-35(对于VH结构域的CDR1)、残基50-65(对于VH结构域的CDR2)、残基95-102(对于VH结构域的CDR3)。下一步包括,在鉴别出的非人和人序列的相同的残基位置处,指定数字记分。该记分的一个实例如下表4所示。
* 表示影响CDR构象,见C. Chothia等人, Nature 342:877-883(1989)。
在给残基位置指定数字记分以后,累加所有残基记分。受体种系序列是具有最高总记分的序列。对于两个或更多个种系序列具有相同记分的情况,则对于下述FR残基中非人和人序列相同的每个位置,向总记分增加1:1-23、25、36、38-47、66、68、70、72、74、75、77和79-93(最大60)。再次累加残基记分,受体种系序列是具有最高总记分的序列。如果两个或更多个种系序列仍具有相同记分,则任一个都可用作受体种系序列。
如果VL序列是VL的κ亚类的成员,则将来自GITR特异性抗体的非人VL序列与一组4条人VLκ种系氨基酸序列相对比。4条序列包括来自4个已确定的人VL亚组中的每一个的一个代表,所述人VL亚组列于:V. Barbie & M.-P. Lefranc, Exp. Clin. Immunogenetics 15:171-183 (1998)和M.-P. Lefranc, Exp. Clin. Immunogenetics 18:161-174 (2001)。4个序列还对应于在Kabat等人, 美国卫生和人类服务部, NIH Pub. 91-3242,第103-130页(第5版, 1991)中列出的4个亚组。所述非人序列与4个种系序列的对比,从根据Kabat等人, 美国卫生和人类服务部, NIH Pub. 91-3242(第5版, 1991)给非人VL序列残基指定残基编号开始。然后将非人VL序列与4个人种系序列中的每一个相比对。由于V基因仅包含VL残基1-95,在比对中仅考虑这些残基。接着,描绘序列中的互补性决定区(CDR)和框架区(FR)。根据在Kabat等人, 美国卫生和人类服务部, NIH Pub. 91-3242(第5版1991),和C. Chothia & A.M. Lesk, J. Mol. Biol., 196:901-917(1987)中提供的定义的组合,描绘CDR和FR。因此,使用的CDR定义是:残基24-34(对于VL结构域的CDR1)、残基50-56(对于VL结构域的CDR2)、残基89-97(对于VL结构域的CDR3)。下一步包括,在鉴别出的非人和人序列的相同的残基位置处,指定数字记分。该记分的一个实例如下表5所示。
* 表示影响CDR构象,见C. Chothia等人, Nature 342:877-883(1989)。
在给残基位置指定数字记分以后,累加所有残基记分。受体种系序列是具有最高总记分的序列。对于两个或更多个种系序列具有相同记分的情况,则对于下述FR残基中非人和人序列相同的每个位置,向总记分增加1:1-3、5-23、35-42、44-49、57、59-88(最大67)。再次累加残基记分,受体种系序列是具有最高总记分的序列。如果两个或更多个种系序列仍具有相同记分,则任一个都可用作受体种系序列。
使用该方法,将上述亲本单克隆抗体人源化。SEQ ID NO: 90、92、94、96、98、100、102、104、106、108和110是可变重链多肽的序列,SEQ ID NO: 91、93、95、97、99、101、103、105、107、109和111是可变轻链的序列。
实施例3
使用KinExA技术测定抗-人GITR抗体的平衡解离常数(Kd)
使用KinExA 3000仪器(Sapidyne Instruments Inc., Boise Idaho, USA),测定抗人GITR抗体的平衡解离常数(Kd)。KinExA使用动态排除测定法(Kinetic Exclusion Assay method)的原理,其基于测量抗体、抗原和抗体-抗原复合物的混合物中未复合抗体的浓度。通过使混合物接触固相固定化的抗原非常短暂的时间段,测量游离抗体的浓度。在实践中,这通过使溶液相抗原-抗体混合物流经流动池中捕获的抗原包被的颗粒来完成。由该仪器产生的数据使用定制软件进行分析。使用数学理论基于下述假定计算平衡常数:
1. 结合遵循关于平衡的可逆结合等式:
kon [Ab] [Ag] = koff[AbAg]
2. 抗体和抗原1:1结合,且总抗体等于抗原-抗体复合物加游离抗体
3. 仪器信号与游离抗体浓度线性相关。
按照Sapidyne“Protocol for coating PMMA particles with biotinylated ligands having short or nonexistent linker arms.”,用生物素化的GITR(或其片段,诸如胞外结构域)包被PMMA颗粒(Sapidyne, 目录号440198)。按照生产商的推荐(Pierce bulletin 0874),使用EZ-link TFP PEO-生物素(Pierce, 目录号21219)进行GITR的生物素化。
实施例4
使用BIAcore技术测定人源化的抗-人GITR抗体的平衡解离常数(Kd)
基本上如共同未决的、共同转让的美国专利申请号11/511,635(2006年8月29日提交)的实施例4所述,进行BIAcore测定。简而言之,使用标准的胺偶联规程,将结合配偶体固定化在BIAcore CM5传感器芯片上。使用BIAevaluation软件3.1,确定不同相互作用的动力学常数。使用计算的解离速率常数和结合速率常数,确定Kd。
GITR抗体36E5、3D6、61G6、6H6、61F6、1D8、17F10、35D8、49A1、9E5和31H6具有下述Kd值:
表6: GITR抗体的亲和力测量
实施例5
用于评估抗-GITR抗体的活化的生物测定法
通过对原初T细胞的增殖的影响(参见,例如,Ito等人, (2006)PNAS 103(35):13138-43),评估了单克隆抗体在生物学上增强GITR活性的能力。通过蔗聚糖离心,随后使用原初CD4 T细胞分离试剂盒(购自STEMCELL Technologies),从外周血单核细胞(PBMC)中分离出原初CD4+ T细胞。
在平底96-孔组织培养板(其已经用抗-CD3预包被)中,在有抗-hGITR抗体或同种型对照存在下,与辐照过的表达CD32的L细胞共培养共2x104个新鲜纯化的原初CD4 T细胞。
表7A和7B显示了不同剂量的抗-GITR抗体对原初CD4+ T细胞的增殖的影响(KM4-R63是同种型对照抗体)。
实施例5
用TGF-β和GITR抗体治疗肿瘤
以前的研究揭示,4T1肿瘤的基因表达已经增加了TGF-βmRNA的水平。据假设,与免疫抑制的去除(通过抑制TGF-β信号传递)相组合的抗-GITR激动剂的免疫共刺激,会诱导协同的抗肿瘤效力。
为了验证该假设,将1.5 x 105 4T1肿瘤细胞皮下地植入在Balb/C小鼠的右胁腹。在肿瘤植入后4或7天,以100 μg/200 μL,将针对鼠TGF-β的中和抗体(1D11; Bioexpress)皮下地注射在颈部,每3天重复1次,共7剂。在第7、14和21天,以500 μg/200 μL,注射抗-小鼠GITR激动剂抗体DTA-1。每3天测量肿瘤体积。如下面表8所示,单独的DTA-1或抗-TGF-?本身几乎不具有效果。在抗-TGF-β治疗开始(肿瘤植入后第4天或第7天)后任一天,联合治疗会诱导协同效应。值是肿瘤体积(mm3)。
实施例6
CT26肿瘤的抗体-辐射联合治疗
将CT26肿瘤细胞(3 x 105)皮下地植入在Balb/c小鼠的左胁腹。在观察到单独的DTA-1不具有杀死肿瘤效力以后,将局部辐照(10 Gy)施用于生长至300 mm3的肿瘤。在辐照后1天,将DTA-1(500ug)皮下地注射在颈部,每周重复1次,共3剂。每2-5天测量肿瘤体积。在接受局部辐照和DTA-1联合治疗的10只小鼠组中,5只小鼠完全排斥肿瘤,并存活了多达3个月。单独的DTA-1或辐照没有表现出肿瘤排斥(参见,例如,图1)。
实施例7
GITR抗体的表位作图
如上面所指出的,DTA-1是针对小鼠GITR产生的激动剂抗体(参见,例如,Shimizu, 等人同上)。已经证实,DTA-1在癌症的小鼠模型中具有有效的抗肿瘤活性(参见,例如,Cohen, 等人(2006) Cancer Res. 66:4904-4912; Ramirez-Montagut, 等人(2006) J. Immunol. 176:6434-6442; Zhou, 等人(2007) J. Immunol. 179:7365-7375;和Ko, 等人(2005) J. Exp. Med. 202:885-891)。
为了确定上述抗体是否结合在人GITR蛋白上的DTA-1-样表位,首先在小鼠GITR蛋白上绘制DTA-1表位的图谱。由于不可得到人或小鼠GITR的晶体结构,使用标准的定位诱变技术(参见,例如,Kunkel(1985)Proc. Natl. Acad. Sci. 82:488-492)和TNF-受体家族的模块性的一般原理(参见,例如,Naismith和Sprang, 同上),测定DTA-1表位。
一旦确定被DTA-1识别的小鼠GITR表位,将在人GITR上的对应残基改变成小鼠残基,从而将DTA-1结合性赋予人GITR。由此可以确定,在人GITR上的DTA-1-样表位跨模块3和4(参见图2),被上面鉴别出的抗体中的2种识别的人GITR(SEQ ID NO: 89)表位包含Gly57、Arg65、His67、Lys80、Phe81、Ser82和Gln86。
实施例8
用抗-GITR抗体治疗病毒感染
HIV感染的特征在于,中枢记忆细胞的产生和维持的缺陷。与对照相比,在HIV-感染的个体中,CD8+ 中枢记忆细胞具有更短的半衰期和更低的丰度。另外,在开始高效抗逆转录病毒治疗(HAART)以后,CD4+和CD8+ HIV-特异性的T细胞的频率快速降低。抗-GITR对CD4+的共刺激,可以提供增加记忆性CD8+应答并促进病毒的清除的机制。已经证实,用抗-GITR抗体治疗Friend病毒持久感染的小鼠(以改善Tregs的抑制),会显著提高CD8+ T细胞的IFN-γ生产,并会显著减少病毒载量(Dittmer等人, (2004)Immunity 20: 293-303)。
HIV感染的另一个特征是,从HIV感染早期开始的CD4+ T细胞的大量细胞凋亡。CD4 T细胞的渐进性细胞凋亡性去除,会促进减弱的HIV-特异性的细胞免疫应答和AIDS的发展。已经证实,GITR共刺激会通过保护T细胞免于细胞凋亡而增加鼠抗原-特异性的细胞因子分泌。Lahey等人(2007)J Infect Dis. 196: 43-49)证实,HIV-特异性的CD4+ T细胞的抗-GITR治疗会增加它们的细胞因子表达,并保护它们免于细胞凋亡。
对于由病毒原因导致的感染,可以在施用治疗病毒感染的标准疗法的同时、之前或之后,联合施用本发明的抗体。这类标准疗法随病毒的类型而变化,尽管在几乎所有情况下,施用含有对所述病毒特异性的抗体(例如,IgA、IgG)的人血清可能是有效的。
流感感染会导致发烧、咳嗽、肌痛、头痛及全身乏力,其常见于季节性流行病中。流感也与许多传染后障碍有关,所述障碍例如:脑炎、心肌心包炎、肺出血肾炎综合征和瑞氏综合征。流感感染也会抑制正常的肺抗细菌防御,使得流感康复的患者具有增加的发展细菌性肺炎的风险。
流感病毒表面蛋白表现出显著的抗原性变异,所述变异源自突变和重组。因而,溶细胞性的T淋巴细胞是宿主在感染后消除病毒的主要媒介物。流感被分类为3大类:A、B和C。A型流感的独特之处在于,它感染人类和许多其它动物(例如,猪、马、禽类和海豹),且是大流行流感的主要原因。另外,当细胞被2种不同的A型流感株感染时,2个亲本病毒类型的片段化的RNA基因组在复制过程中混合以建立杂种复制子(replicant),产生新的传染株。B型流感不在动物中复制,因而具有更少的遗传变异,C型流感仅具有单个血清型。
最常规的疗法是由感染引起的征状的姑息剂,同时宿主的免疫应答实际上清除该疾病。但是,某些株(例如,A型流感)可以造成更严重的疾病和死亡。通过施用环胺类抑制剂金刚烷胺和金刚乙胺(它们抑制病毒复制),可以在临床上和预防性地治疗A型流感。但是,这些药物的临床实用性受到限制,这是由于不良反应的相对高发率、它们的狭窄抗病毒谱(仅A型流感)和病毒变得抗性的倾向。施用针对主要流感表面蛋白、血凝素和神经氨酸酶的血清IgG抗体,可以预防肺感染,而需要用粘膜IgA来预防上呼吸道和气管的感染。流感的目前最有效的治疗是,通过使用用福尔马林或β-丙内酯灭活的病毒进行疫苗接种。
在9-11天的潜伏期以后,被麻疹病毒感染的宿主会形成发热、咳嗽、鼻炎和结膜炎。在1-2天内,出现红斑性的斑丘疹,其迅速地扩散至全身。因为感染也会抑制细胞免疫,所述宿主处于更大的形成细菌重叠感染(包括中耳炎、肺炎和感染后脑脊髓炎)的风险中。急性感染伴有高发病率和死亡率,特别是在营养不良的青少年中。
麻疹的治疗包括:被动性施用混合的人IgG,其可以预防无免疫性的受试者的感染,即使在暴露后多达1周施用。
但是,用活的减毒病毒事先免疫接种,是最有效的治疗,且会在超过95%的免疫接种人群中预防疾病。由于该病毒存在一种血清型,单次免疫或感染通常会导致免于以后感染的终生保护。
在低比例的受感染宿主中,麻疹可以发展成SSPE,这是由中枢神经系统的持续性感染导致的一种慢性渐进性神经学障碍。SSPE由麻疹病毒的克隆变异体造成,所述变异体具有干扰病毒粒子装配和芽殖的缺陷。对于这些患者,希望用本发明的抗体重新活化T-细胞,从而促进病毒清除。
乙型肝炎病毒(HB-V)是最有传染性的已知的血液传染的病原体。它是急性和慢性肝炎和肝癌以及终生慢性感染的主要原因。在感染后,所述病毒在肝细胞中复制,它们随后也脱落表面抗原HBsAg。血清中过度的HBsAg水平的检测,被用作诊断乙型肝炎感染的标准方法。急性感染可以消退,或它可以发展成慢性持续性感染。
慢性HBV的现有治疗包括:α-干扰素,其会增加I类人白细胞抗原(HLA)在肝细胞表面上的表达,从而促进细胞毒性的T淋巴细胞对它们的识别。另外,核苷类似物更昔洛韦、泛昔洛韦和拉米夫定也已经在临床试验中在HBV感染的治疗方面表现出某些效力。HBV的其它治疗包括:聚乙二醇化的α-干扰素、阿德福韦(adenfovir)、恩替卡韦和替比夫定。尽管通过抗-HBsAg血清抗体的肠胃外施用可以赋予被动免疫,用灭活的或重组的HBsAg进行疫苗接种,也会赋予对感染的抗性。本发明的抗-GITR抗体可以与乙型肝炎感染的常规治疗相组合,实现治疗益处。
丙型肝炎病毒(HC-V)感染可能导致慢性形式的肝炎,导致肝硬化。尽管征状与乙型肝炎引起的感染类似,与HB-V明显不同的是,被感染的宿主可以不出现征状达10-20年。HC-V感染的治疗包括:施用α-干扰素和利巴韦林的组合。HC-V感染的一种有前途的潜在治疗是,蛋白酶抑制剂特拉匹韦(VX-960)。其它治疗包括:抗-PD-1抗体(MDX-1106, Medarex)、巴维昔单抗(一种以B2-糖蛋白I依赖性的方式结合阴离子性磷脂磷脂酰丝氨酸的抗体,Peregrine Pharmaceuticals)、抗-HPV病毒外壳蛋白E2抗体(例如,ATL 6865-Ab68+Ab65, XTL Pharmaceuticals)和Civacir?(多克隆抗-HCV人免疫球蛋白)。本发明的抗-GITR抗体可以与丙型肝炎感染的这些治疗中的一种或多种相组合,实现治疗益处。
表9提供了序列表中的序列的简单描述。
SEQ ID NO.: | 描述 |
1 | 36E5重链可变区 |
2 | 3D6重链可变区 |
3 | 61G6重链可变区 |
4 | 6H6重链可变区 |
5 | 61F6重链可变区 |
6 | 1D8重链可变区 |
7 | 17F10重链可变区 |
8 | 35D8重链可变区 |
9 | 49A1重链可变区 |
10 | 9E5重链可变区 |
11 | 31H6重链可变区 |
12 | 36E5轻链可变区 |
13 | 3D6轻链可变区 |
14 | 61G6轻链可变区 |
15 | 6H6轻链可变区 |
16 | 61F6轻链可变区 |
17 | 1D8轻链可变区 |
18 | 17F10轻链可变区 |
19 | 35D8轻链可变区 |
20 | 49A1轻链可变区 |
21 | 9E5轻链可变区 |
22 | 31H6轻链可变区 |
23 | 36E5 CDRH1 |
24 | 3D6 CDRH1 |
25 | 61G6 CDRH1 |
26 | 6H6 CDRH1 |
27 | 61F6 CDRH1 |
28 | 1D8 CDRH1 |
29 | 17F10 CDRH1 |
30 | 35D8 CDRH1 |
31 | 49A1 CDRH1 |
32 | 9E5 CDRH1 |
33 | 31H6 CDRH1 |
34 | 36E5 CDRH2 |
35 | 3D6 CDRH2 |
36 | 61G6 CDRH2 |
37 | 6H6 CDRH2 |
38 | 61F6 CDRH2 |
39 | 1D8 CDRH2 |
40 | 17F10 CDRH2 |
41 | 35D8 CDRH2 |
42 | 49A1 CDRH2 |
43 | 9E5 CDRH2 |
44 | 31H6 CDRH2 |
45 | 36E5 CDRH3 |
46 | 3D6 CDRH3 |
47 | 61G6 CDRH3 |
48 | 6H6 CDRH3 |
49 | 61F6 CDRH3 |
50 | 1D8 CDRH3 |
51 | 17F10 CDRH3 |
52 | 35D8 CDRH3 |
53 | 49A1 CDRH3 |
54 | 9E5 CDRH3 |
55 | 31H6 CDRH3 |
56 | 36E5 CDRL1 |
57 | 3D6 CDRL1 |
58 | 61G6 CDRL1 |
59 | 6H6 CDRL1 |
60 | 61F6 CDRL1 |
61 | 1D8 CDRL1 |
62 | 17F10 CDR L1 |
63 | 35D8 CDR L1 |
64 | 49A1 CDR L1 |
65 | 9E5 CDR L1 |
66 | 31H6 CDR L1 |
67 | 36E5 CDRL2 |
68 | 3D6 CDRL2 |
69 | 61G6 CDRL2 |
70 | 6H6 CDRL2 |
71 | 61F6 CDRL2 |
72 | 1D8 CDRL2 |
73 | 17F10 CDR L2 |
74 | 35D8 CDR L2 |
75 | 49A1 CDR L2 |
76 | 9E5 CDR L2 |
77 | 31H6 CDR L2 |
78 | 36E5 CDRL3 |
79 | 3D6 CDRL3 |
80 | 61G6 CDRL3 |
81 | 6H6 CDRL3 |
82 | 61F6 CDRL3 |
83 | 1D8 CDRL3 |
84 | 17F10 CDR L3 |
85 | 35D8 CDR L3 |
86 | 49A1 CDR L3 |
87 | 9E5 CDR L3 |
88 | 31H6 CDR L3 |
89 | 人GITR |
90 | 人源化的1D8 VH |
91 | 人源化的1D8 VL |
92 | 人源化的3D6 VH |
93 | 人源化的3D6 VL |
94 | 人源化的6H6 VH |
95 | 人源化的6H6 VL |
96 | 人源化的9E5 VH |
97 | 人源化的9E5 VL |
98 | 人源化的31H6 VH |
99 | 人源化的31H6 VL |
100 | 人源化的17F10 VH |
101 | 人源化的17F10 VL |
102 | 人源化的35D8 VH |
103 | 人源化的35D8 VL |
104 | 人源化的36E5 VH |
105 | 人源化的36E5 VL |
106 | 人源化的49A1 VH |
107 | 人源化的49A1 VL |
108 | 人源化的61F6 VH |
109 | 人源化的61F6 VL |
110 | 人源化的61G6 VH |
111 | 人源化的61G6 VL |
序列表
<110> Schebye, Xiao-Min
Ermakov, Grigori
Hodges, Douglas J.
Presta, Leonard G.
<120> 抗-GITR抗体
<130> BP2009.6860WO
<150> 61/239,667
<151> 2009-09-03
<150> 61/307,767
<151> 2010-02-24
<150> 61/313,955
<151> 2010-03-15
<160> 111
<170> PatentIn version 3.5
<210> 1
<211> 118
<212> PRT
<213> 小家鼠
<400> 1
Glu Val Asn Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Lys Val Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Thr Pro Glu Lys Arg Leu Glu Trp Val
35 40 45
Ala Ser Ile Ser Ser Gly Gly Thr Thr Tyr Tyr Pro Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Arg Asn Ile Leu Tyr Leu
65 70 75 80
Gln Met Ser Ser Leu Arg Ser Glu Asp Thr Ala Met Tyr Tyr Cys Ala
85 90 95
Arg Val Gly Gly Tyr Tyr Asp Ser Met Asp Tyr Trp Gly Gln Gly Ile
100 105 110
Ser Val Thr Asp Ser Ser
115
<210> 2
<211> 123
<212> PRT
<213> 褐家鼠
<400> 2
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr
20 25 30
Tyr Met Ala Trp Val Arg Gln Ala Pro Thr Lys Gly Leu Glu Trp Val
35 40 45
Ala Tyr Ile His Ala Asn Gly Gly Ser Thr Tyr Tyr Arg Asp Ser Val
50 55 60
Arg Gly Arg Phe Ser Ile Ser Arg Asp Asn Gly Lys Ser Thr Leu Tyr
65 70 75 80
Leu Gln Met Asp Ser Leu Arg Ser Glu Asp Thr Ala Thr Tyr Tyr Cys
85 90 95
Thr Thr Gly Ser Phe Met Tyr Ala Ala Asp Tyr Tyr Ile Met Asp Ala
100 105 110
Trp Gly Gln Gly Ala Ser Val Thr Val Ser Ser
115 120
<210> 3
<211> 118
<212> PRT
<213> 小家鼠
<400> 3
Asp Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln
1 5 10 15
Ser Leu Ser Leu Thr Cys Thr Val Thr Gly Tyr Ser Ile Thr Ser Asp
20 25 30
Tyr Ala Trp Asn Trp Ile Arg Gln Phe Pro Gly Asn Lys Leu Glu Trp
35 40 45
Met Gly Tyr Ile Ser Tyr Ser Gly Ser Thr Arg Tyr Asn Pro Ser Leu
50 55 60
Lys Ser Arg Ile Ser Ile Thr Arg Asp Thr Ser Lys Asn Gln Phe Phe
65 70 75 80
Leu Gln Leu Asn Ser Val Thr Ser Glu Asp Thr Ala Thr Tyr Tyr Cys
85 90 95
Ala Arg Gln Leu Gly Leu Arg Phe Phe Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Thr Leu Thr Val Ser Ser
115
<210> 4
<211> 118
<212> PRT
<213> 小家鼠
<400> 4
Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Met Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Ile Ser Cys Lys Ala Thr Gly Tyr Thr Phe Ser Arg Tyr
20 25 30
Trp Ile Glu Trp Ile Lys Gln Arg Pro Gly His Gly Leu Glu Trp Ile
35 40 45
Gly Glu Ile Leu Pro Gly Ser Gly Ser Ser Asn Tyr Asn Glu Lys Phe
50 55 60
Lys Asp Lys Ala Thr Phe Thr Ala Asp Thr Ser Ser Asn Thr Ala Tyr
65 70 75 80
Met Gln Phe Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Lys Val Tyr Tyr Tyr Ala Met Asp Phe Trp Gly Gln Gly Thr
100 105 110
Ser Val Thr Val Ser Ser
115
<210> 5
<211> 119
<212> PRT
<213> 小家鼠
<400> 5
Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Ala Arg 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
Thr Met His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Asn Pro Arg Ser Val Tyr Thr Asn Tyr Asn Gln Lys Phe
50 55 60
Lys Asp Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Leu Gly Gly Tyr Tyr Asp Thr Met Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Ser Val Thr Val Ser Ser
115
<210> 6
<211> 122
<212> PRT
<213> 小家鼠
<400> 6
Gln Val Thr Leu Lys Glu Ser Gly Pro Gly Ile Leu Lys Pro Ser Gln
1 5 10 15
Thr Leu Ser Leu Thr Cys Ser Phe Ser Gly Phe Ser Leu Ser Thr Ser
20 25 30
Gly Met Gly Val Gly Trp Ile Arg Gln Pro Ser Gly Lys Gly Leu Glu
35 40 45
Trp Leu Ala His Ile Trp Trp Asp Asp Asp Lys Tyr Tyr Ser Pro Ser
50 55 60
Leu Lys Ser Gln Leu Thr Ile Ser Lys Asp Thr Ser Arg Asn Gln Val
65 70 75 80
Phe Leu Lys Ile Thr Ser Leu Asp Thr Ala Asp Thr Ala Thr Tyr Tyr
85 90 95
Cys Val Arg Ser Tyr Tyr Tyr Gly Ser Ser Gly Ala Met Asp Tyr Trp
100 105 110
Gly Gln Gly Thr Ser Val Thr Val Ser Ser
115 120
<210> 7
<211> 117
<212> PRT
<213> 小家鼠
<400> 7
Glu Val Lys Leu Val Glu Ser Gly Gly Gly Phe Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Val Arg Asn Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Thr Pro Glu Lys Arg Leu Glu Trp Val
35 40 45
Ala Ser Ile Ser Thr Gly Asp Arg Ser Tyr Leu Pro Asp Ser Met Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Arg Asn Ile Leu Tyr Leu
65 70 75 80
Gln Met Ser Ser Leu Arg Ser Glu Asp Thr Ala Ile Tyr Tyr Cys Gln
85 90 95
Arg Tyr Phe Asp Phe Asp Ser Phe Ala Phe Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ala
115
<210> 8
<211> 120
<212> PRT
<213> 小家鼠
<400> 8
Glu Val Gln Leu Gln Glu Ser Gly Pro Ser Leu Val Lys Pro Ser Gln
1 5 10 15
Thr Leu Ser Leu Thr Cys Ser Val Thr Gly Asp Ser Ile Thr Ser Gly
20 25 30
Tyr Trp Asn Trp Ile Arg Lys Phe Pro Gly Asn Lys Leu Glu Tyr Met
35 40 45
Gly Tyr Ile Ser Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser Leu Arg
50 55 60
Gly Arg Ile Ser Ile Thr Arg Asp Thr Ser Lys Ser Gln Tyr Tyr Leu
65 70 75 80
Gln Leu Ser Ser Val Thr Thr Glu Asp Thr Ala Thr Tyr Tyr Cys Ser
85 90 95
Arg Arg His Leu Gly Ser Gly Tyr Gly Trp Phe Ala Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ala
115 120
<210> 9
<211> 120
<212> PRT
<213> 小家鼠
<400> 9
Glu Val Gln Leu Gln Glu Ser Gly Pro Ser Leu Val Lys Pro Ser Gln
1 5 10 15
Thr Leu Ser Leu Thr Cys Ser Val Thr Gly Asp Ser Ile Thr Ser Gly
20 25 30
Tyr Trp Asn Trp Ile Arg Lys Phe Pro Gly Asn Lys Phe Glu Tyr Met
35 40 45
Gly Phe Ile Ser Tyr Ser Gly Asn Thr Tyr Tyr Asn Pro Ser Leu Arg
50 55 60
Ser Arg Ile Ser Ile Thr Arg Asp Thr Ser Lys Asn Gln Tyr Phe Leu
65 70 75 80
His Leu Asn Ser Val Thr Thr Glu Asp Thr Ala Thr Tyr Tyr Cys Ser
85 90 95
Arg Arg His Leu Ile Ser Gly Tyr Gly Trp Phe Ala Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ala
115 120
<210> 10
<211> 121
<212> PRT
<213> 褐家鼠
<400> 10
Gln Val Thr Leu Lys Glu Ser Gly Pro Gly Ile Leu Gln Pro Ser Gln
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Phe Ser Gly Phe Ser Leu Ser Thr Tyr
20 25 30
Gly Val Gly Val Gly Trp Ile Arg Gln Pro Ser Gly Lys Gly Leu Glu
35 40 45
Trp Leu Ala Asn Ile Trp Trp Asp Asp Asp Asn Tyr Tyr Asn Pro Ser
50 55 60
Leu Ile His Arg Leu Thr Val Ser Lys Asp Thr Ser Asn Asn Gln Ala
65 70 75 80
Phe Leu Lys Ile Thr Asn Val Asp Thr Ala Glu Thr Ala Thr Tyr Tyr
85 90 95
Cys Ala Gln Ile Lys Glu Pro Arg Asp Trp Phe Phe Glu Phe Trp Gly
100 105 110
Pro Gly Thr Met Val Ser Val Ser Ser
115 120
<210> 11
<211> 121
<212> PRT
<213> 褐家鼠
<400> 11
Gln Val Thr Leu Lys Glu Ser Gly Pro Gly Ile Leu Gln Pro Ser Gln
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Phe Ser Gly Phe Ser Leu Ser Thr Tyr
20 25 30
Gly Val Gly Val Gly Trp Ile Arg Gln Pro Ser Gly Lys Gly Leu Glu
35 40 45
Trp Leu Ala Asn Ile Trp Trp Asp Asp Asp Lys Tyr Tyr Asn Pro Ser
50 55 60
Leu Lys Asn Arg Leu Thr Ile Ser Lys Asp Thr Ser Asn Asn Gln Ala
65 70 75 80
Phe Leu Lys Ile Thr Asn Val Asp Thr Ala Glu Thr Ala Thr Tyr Tyr
85 90 95
Cys Ala Gln Ile Lys Glu Pro Arg Asp Trp Phe Phe Glu Phe Trp Gly
100 105 110
Pro Gly Thr Met Val Ser Val Ser Ser
115 120
<210> 12
<211> 113
<212> PRT
<213> 小家鼠
<400> 12
Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Gln Arg Ala Thr Ile Ser Cys Arg Ala Ser Glu Ser Val Asp Asn Tyr
20 25 30
Gly Val Ser Phe Met Asn Trp Phe Gln Gln Lys Pro Gly Gln Pro Pro
35 40 45
Lys Leu Leu Ile Tyr Ala Ala Ser Asn Gln Gly Ser Gly Val Pro Ala
50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Ser Leu Asn Ile His
65 70 75 80
Pro Met Glu Glu Asp Asp Thr Ala Met Tyr Phe Cys Gln Gln Thr Lys
85 90 95
Glu Val Thr Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg
100 105 110
Ala
<210> 13
<211> 113
<212> PRT
<213> 褐家鼠
<400> 13
Asp Val Val Met Thr Gln Thr Pro Val Ser Leu Ser Val Ser Leu Gly
1 5 10 15
Asn Gln Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Leu His Ser
20 25 30
Asp Gly Asn Thr Phe Leu Ser Trp Tyr Phe Gln Lys Pro Gly Gln Ser
35 40 45
Pro Gln Leu Leu Ile Tyr Leu Ala Ser Asn Arg Phe Ser Gly Val Ser
50 55 60
Asn Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Pro Glu Asp Leu Gly Val Tyr Tyr Cys Phe Gln His
85 90 95
Thr His Leu Pro Leu Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys
100 105 110
Arg
<210> 14
<211> 108
<212> PRT
<213> 小家鼠
<400> 14
Gln Ile Val Leu Thr Gln Ser Pro Ala Leu Met Ser Ala Ser Pro Gly
1 5 10 15
Glu Lys Val Thr Met Thr Cys Ser Ala Asn Ser Thr Val Asn Tyr Met
20 25 30
Tyr Trp Tyr Gln Gln Lys Pro Arg Ser Ser Pro Lys Pro Cys Ile Tyr
35 40 45
Leu Thr Ser Asn Leu Ala Ser Gly Val Pro Ala Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Ser Met Glu Ala Glu
65 70 75 80
Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Asn Ser Asn Pro Pro Thr
85 90 95
Phe Gly Ala Gly Thr Lys Leu Glu Leu Arg Arg Ala
100 105
<210> 15
<211> 110
<212> PRT
<213> 小家鼠
<400> 15
Gln Ile Val Leu Thr Gln Ser Pro Ala Ile Met Ser Val Ser Leu Gly
1 5 10 15
Glu Arg Val Thr Val Thr Cys Thr Ala Ser Ser Ser Val Ser Ser Ser
20 25 30
Tyr Phe His Trp Tyr Gln Gln Lys Pro Gly Ser Ser Pro Lys Leu Trp
35 40 45
Ile Tyr Ser Thr Ser Asn Leu Ala Ser Gly Val Pro Ala Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Thr Met Glu
65 70 75 80
Ala Glu Asp Ala Ala Thr Tyr Tyr Cys His Gln Tyr His Arg Ser Pro
85 90 95
Arg Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg Ala
100 105 110
<210> 16
<211> 113
<212> PRT
<213> 小家鼠
<400> 16
Asp Ile Val Val Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Gln Arg Ala Thr Ile Ser Cys Arg Ala Ser Glu Ser Val Asp Asn Tyr
20 25 30
Gly Ile Ser Phe Met Asn Trp Phe Gln Gln Lys Pro Gly Gln Pro Pro
35 40 45
Lys Leu Leu Ile Tyr Ala Ala Ser Asn Gln Gly Ser Gly Val Pro Ala
50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Ser Leu Asn Ile His
65 70 75 80
Pro Met Glu Glu Asp Asp Thr Ala Val Tyr Phe Cys Gln Gln Ser Lys
85 90 95
Glu Val Pro Phe Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys Arg
100 105 110
Ala
<210> 17
<211> 118
<212> PRT
<213> 小家鼠
<400> 17
Asp Ile Val Met Thr Gln Thr Pro Leu Ser Leu Pro Val Ser Leu Gly
1 5 10 15
Asp Gln Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Val His Ser
20 25 30
Asp Gly Asn Thr Tyr Leu His Trp Tyr Leu Gln Lys Pro Gly Gln Ser
35 40 45
Pro Lys Leu Leu Ile Tyr Lys Val Ser Lys Arg Phe Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Phe Cys Ser Gln Ser
85 90 95
Thr His Val Pro Pro Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105 110
Arg Ala Asp Ala Ala Pro
115
<210> 18
<211> 113
<212> PRT
<213> 小家鼠
<400> 18
Asp Ile Gln Met Thr Gln Thr Pro Ser Ser Leu Ser Ala Ser Leu Gly
1 5 10 15
Asp Arg Val Thr Ile Ser Cys Arg Ala Ser Gln Asp Ile Asn Asn Phe
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Asp Gly Ser Leu Lys Leu Leu Ile
35 40 45
Tyr Tyr Thr Ser Lys Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Ser Leu Thr Ile Ser Asn Leu Asp Gln
65 70 75 80
Glu Asp Val Ala Thr Tyr Phe Cys Gln Gln Gly His Thr Leu Pro Pro
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Val Lys Arg Ala Asp Ala Ala
100 105 110
Pro
<210> 19
<211> 114
<212> PRT
<213> 小家鼠
<400> 19
Asp Ile Val Met Thr Gln Ser His Lys Phe Met Ser Thr Ser Val Gly
1 5 10 15
Asp Arg Val Ser Ile Thr Cys Lys Ala Ser Gln Asp Val Asn Thr Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile
35 40 45
Tyr Trp Ala Ser Thr Arg His Thr Gly Val Pro Asp Arg Phe Thr Gly
50 55 60
Ser Gly Ser Gly Thr Asp Tyr Ala Leu Thr Ile Asn Ser Val Gln Ala
65 70 75 80
Glu Asp Leu Ala Leu Tyr Tyr Cys Gln Gln His Ser Tyr Thr Pro Pro
85 90 95
Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Arg Arg Ala Asp Ala
100 105 110
Ala Pro
<210> 20
<211> 114
<212> PRT
<213> 小家鼠
<400> 20
Val Ile Val Met Thr Gln Ser His Lys Phe Met Ser Thr Ser Ile Gly
1 5 10 15
Asp Arg Val Asn Ile Thr Cys Lys Ala Ser Gln Asp Val Ile Ser Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile
35 40 45
Tyr Trp Ala Ser Thr Arg His Thr Gly Val Pro Asp Arg Phe Thr Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Asn Ser Val Gln Ala
65 70 75 80
Glu Asp Arg Ala Leu Tyr Tyr Cys Gln Gln His Ser Tyr Thr Pro Pro
85 90 95
Trp Thr Phe Gly Gly Gly Thr Asn Leu Glu Ile Lys Arg Ala Asp Ala
100 105 110
Ala Pro
<210> 21
<211> 113
<212> PRT
<213> 褐家鼠
<400> 21
Asp Ile Gln Met Thr Gln Thr Pro Ser Ser Met Pro Ala Ser Leu Gly
1 5 10 15
Glu Arg Val Thr Ile Phe Cys Arg Ala Ser Gln Gly Val Asn Asn Phe
20 25 30
Leu Thr Trp Tyr Gln Gln Lys Pro Asp Gly Thr Ile Lys Pro Leu Ile
35 40 45
Phe Tyr Thr Ser Asn Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Tyr Ser Leu Ser Ile Ser Ser Leu Glu Pro
65 70 75 80
Glu Asp Phe Ala Met Tyr Tyr Cys Gln Gln Tyr His Gly Phe Pro Asn
85 90 95
Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg Ala Asp Ala Ala
100 105 110
Pro
<210> 22
<211> 113
<212> PRT
<213> 褐家鼠
<400> 22
Asp Ile Gln Met Thr Gln Thr Pro Ser Ser Met Pro Ala Ser Leu Gly
1 5 10 15
Glu Arg Val Thr Ile Phe Cys Arg Ala Ser Gln Gly Val Asn Asn Tyr
20 25 30
Leu Thr Trp Tyr Gln Gln Lys Pro Asp Gly Thr Ile Lys Pro Leu Ile
35 40 45
Phe Tyr Thr Ser Asn Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Tyr Ser Leu Ser Ile Ser Ser Leu Glu Pro
65 70 75 80
Glu Asp Phe Ala Met Tyr Tyr Cys Gln Gln Tyr His Gly Phe Pro Asn
85 90 95
Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg Ala Asp Ala Ala
100 105 110
Pro
<210> 23
<211> 10
<212> PRT
<213> 小家鼠
<400> 23
Gly Phe Thr Phe Ser Ser Tyr Ala Met Ser
1 5 10
<210> 24
<211> 10
<212> PRT
<213> 褐家鼠
<400> 24
Gly Phe Thr Phe Ser Asp Tyr Tyr Met Ala
1 5 10
<210> 25
<211> 11
<212> PRT
<213> 小家鼠
<400> 25
Gly Tyr Ser Ile Thr Ser Asp Tyr Ala Trp Asn
1 5 10
<210> 26
<211> 10
<212> PRT
<213> 小家鼠
<400> 26
Gly Tyr Thr Phe Ser Arg Tyr Trp Ile Glu
1 5 10
<210> 27
<211> 10
<212> PRT
<213> 小家鼠
<400> 27
Gly Tyr Thr Phe Thr Ser Tyr Thr Met His
1 5 10
<210> 28
<211> 12
<212> PRT
<213> 小家鼠
<400> 28
Gly Phe Ser Leu Ser Thr Ser Gly Met Gly Val Gly
1 5 10
<210> 29
<211> 10
<212> PRT
<213> 小家鼠
<400> 29
Gly Phe Thr Val Arg Asn Tyr Ala Met Ser
1 5 10
<210> 30
<211> 10
<212> PRT
<213> 小家鼠
<400> 30
Gly Asp Ser Ile Thr Ser Gly Tyr Trp Asn
1 5 10
<210> 31
<211> 10
<212> PRT
<213> 小家鼠
<400> 31
Gly Asp Ser Ile Thr Ser Gly Tyr Trp Asn
1 5 10
<210> 32
<211> 12
<212> PRT
<213> 褐家鼠
<400> 32
Gly Phe Ser Leu Ser Thr Tyr Gly Val Gly Val Gly
1 5 10
<210> 33
<211> 12
<212> PRT
<213> 褐家鼠
<400> 33
Gly Phe Ser Leu Ser Thr Tyr Gly Val Gly Val Gly
1 5 10
<210> 34
<211> 16
<212> PRT
<213> 小家鼠
<400> 34
Ser Ile Ser Ser Gly Gly Thr Thr Tyr Tyr Pro Asp Ser Val Lys Gly
1 5 10 15
<210> 35
<211> 17
<212> PRT
<213> 褐家鼠
<400> 35
Tyr Ile His Ala Asn Gly Gly Ser Thr Tyr Tyr Arg Asp Ser Val Arg
1 5 10 15
Gly
<210> 36
<211> 16
<212> PRT
<213> 小家鼠
<400> 36
Tyr Ile Ser Tyr Ser Gly Ser Thr Arg Tyr Asn Pro Ser Leu Lys Ser
1 5 10 15
<210> 37
<211> 17
<212> PRT
<213> 小家鼠
<400> 37
Glu Ile Leu Pro Gly Ser Gly Ser Ser Asn Tyr Asn Glu Lys Phe Lys
1 5 10 15
Asp
<210> 38
<211> 17
<212> PRT
<213> 小家鼠
<400> 38
Tyr Ile Asn Pro Arg Ser Val Tyr Thr Asn Tyr Asn Gln Lys Phe Lys
1 5 10 15
Asp
<210> 39
<211> 16
<212> PRT
<213> 小家鼠
<400> 39
His Ile Trp Trp Asp Asp Asp Lys Tyr Tyr Ser Pro Ser Leu Lys Ser
1 5 10 15
<210> 40
<211> 16
<212> PRT
<213> 小家鼠
<400> 40
Ser Ile Ser Thr Gly Asp Arg Ser Tyr Leu Pro Asp Ser Met Lys Gly
1 5 10 15
<210> 41
<211> 16
<212> PRT
<213> 小家鼠
<400> 41
Tyr Ile Ser Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser Leu Arg Gly
1 5 10 15
<210> 42
<211> 16
<212> PRT
<213> 小家鼠
<400> 42
Phe Ile Ser Tyr Ser Gly Asn Thr Tyr Tyr Asn Pro Ser Leu Arg Ser
1 5 10 15
<210> 43
<211> 16
<212> PRT
<213> 褐家鼠
<400> 43
Asn Ile Trp Trp Asp Asp Asp Asn Tyr Tyr Asn Pro Ser Leu Ile His
1 5 10 15
<210> 44
<211> 16
<212> PRT
<213> 褐家鼠
<400> 44
Asn Ile Trp Trp Asp Asp Asp Lys Tyr Tyr Asn Pro Ser Leu Lys Asn
1 5 10 15
<210> 45
<211> 10
<212> PRT
<213> 小家鼠
<400> 45
Val Gly Gly Tyr Tyr Asp Ser Met Asp Tyr
1 5 10
<210> 46
<211> 14
<212> PRT
<213> 褐家鼠
<400> 46
Gly Ser Phe Met Tyr Ala Ala Asp Tyr Tyr Ile Met Asp Ala
1 5 10
<210> 47
<211> 9
<212> PRT
<213> 小家鼠
<400> 47
Gln Leu Gly Leu Arg Phe Phe Asp Tyr
1 5
<210> 48
<211> 9
<212> PRT
<213> 小家鼠
<400> 48
Lys Val Tyr Tyr Tyr Ala Met Asp Phe
1 5
<210> 49
<211> 10
<212> PRT
<213> 小家鼠
<400> 49
Leu Gly Gly Tyr Tyr Asp Thr Met Asp Tyr
1 5 10
<210> 50
<211> 23
<212> PRT
<213> 小家鼠
<400> 50
Ser Tyr Tyr Tyr Gly Ser Ser Gly Ala Met Asp Tyr Trp Gly Gln Gly
1 5 10 15
Thr Ser Val Thr Val Ser Ser
20
<210> 51
<211> 20
<212> PRT
<213> 小家鼠
<400> 51
Tyr Phe Asp Phe Asp Ser Phe Ala Phe Trp Gly Gln Gly Thr Leu Val
1 5 10 15
Thr Val Ser Ala
20
<210> 52
<211> 23
<212> PRT
<213> 小家鼠
<400> 52
Arg His Leu Gly Ser Gly Tyr Gly Trp Phe Ala Tyr Trp Gly Gln Gly
1 5 10 15
Thr Leu Val Thr Val Ser Ala
20
<210> 53
<211> 23
<212> PRT
<213> 小家鼠
<400> 53
Arg His Leu Ile Ser Gly Tyr Gly Trp Phe Ala Tyr Trp Gly Gln Gly
1 5 10 15
Thr Leu Val Thr Val Ser Ala
20
<210> 54
<211> 22
<212> PRT
<213> 褐家鼠
<400> 54
Ile Lys Glu Pro Arg Asp Trp Phe Phe Glu Phe Trp Gly Pro Gly Thr
1 5 10 15
Met Val Ser Val Ser Ser
20
<210> 55
<211> 22
<212> PRT
<213> 褐家鼠
<400> 55
Ile Lys Glu Pro Arg Asp Trp Phe Phe Glu Phe Trp Gly Pro Gly Thr
1 5 10 15
Met Val Ser Val Ser Ser
20
<210> 56
<211> 15
<212> PRT
<213> 小家鼠
<400> 56
Arg Ala Ser Glu Ser Val Asp Asn Tyr Gly Val Ser Phe Met Asn
1 5 10 15
<210> 57
<211> 16
<212> PRT
<213> 褐家鼠
<400> 57
Arg Ser Ser Gln Ser Leu Leu His Ser Asp Gly Asn Thr Phe Leu Ser
1 5 10 15
<210> 58
<211> 10
<212> PRT
<213> 小家鼠
<400> 58
Ser Ala Asn Ser Thr Val Asn Tyr Met Tyr
1 5 10
<210> 59
<211> 12
<212> PRT
<213> 小家鼠
<400> 59
Thr Ala Ser Ser Ser Val Ser Ser Ser Tyr Phe His
1 5 10
<210> 60
<211> 15
<212> PRT
<213> 小家鼠
<400> 60
Arg Ala Ser Glu Ser Val Asp Asn Tyr Gly Ile Ser Phe Met Asn
1 5 10 15
<210> 61
<211> 16
<212> PRT
<213> 小家鼠
<400> 61
Arg Ser Ser Gln Ser Leu Val His Ser Asp Gly Asn Thr Tyr Leu His
1 5 10 15
<210> 62
<211> 11
<212> PRT
<213> 小家鼠
<400> 62
Arg Ala Ser Gln Asp Ile Asn Asn Phe Leu Asn
1 5 10
<210> 63
<211> 11
<212> PRT
<213> 小家鼠
<400> 63
Lys Ala Ser Gln Asp Val Asn Thr Ala Val Ala
1 5 10
<210> 64
<211> 11
<212> PRT
<213> 小家鼠
<400> 64
Lys Ala Ser Gln Asp Val Ile Ser Ala Val Ala
1 5 10
<210> 65
<211> 11
<212> PRT
<213> 褐家鼠
<400> 65
Arg Ala Ser Gln Gly Val Asn Asn Phe Leu Thr
1 5 10
<210> 66
<211> 11
<212> PRT
<213> 褐家鼠
<400> 66
Arg Ala Ser Gln Gly Val Asn Asn Tyr Leu Thr
1 5 10
<210> 67
<211> 7
<212> PRT
<213> 小家鼠
<400> 67
Ala Ala Ser Asn Gln Gly Ser
1 5
<210> 68
<211> 7
<212> PRT
<213> 褐家鼠
<400> 68
Leu Ala Ser Asn Arg Phe Ser
1 5
<210> 69
<211> 7
<212> PRT
<213> 小家鼠
<400> 69
Leu Thr Ser Asn Leu Ala Ser
1 5
<210> 70
<211> 7
<212> PRT
<213> 小家鼠
<400> 70
Ser Thr Ser Asn Leu Ala Ser
1 5
<210> 71
<211> 7
<212> PRT
<213> 小家鼠
<400> 71
Ala Ala Ser Asn Gln Gly Ser
1 5
<210> 72
<211> 7
<212> PRT
<213> 小家鼠
<400> 72
Lys Val Ser Lys Arg Phe Ser
1 5
<210> 73
<211> 7
<212> PRT
<213> 小家鼠
<400> 73
Tyr Thr Ser Lys Leu His Ser
1 5
<210> 74
<211> 7
<212> PRT
<213> 小家鼠
<400> 74
Trp Ala Ser Thr Arg His Thr
1 5
<210> 75
<211> 7
<212> PRT
<213> 小家鼠
<400> 75
Trp Ala Ser Thr Arg His Thr
1 5
<210> 76
<211> 7
<212> PRT
<213> 褐家鼠
<400> 76
Tyr Thr Ser Asn Leu Gln Ser
1 5
<210> 77
<211> 7
<212> PRT
<213> 褐家鼠
<400> 77
Tyr Thr Ser Asn Leu Gln Ser
1 5
<210> 78
<211> 9
<212> PRT
<213> 小家鼠
<400> 78
Gln Gln Thr Lys Glu Val Thr Trp Thr
1 5
<210> 79
<211> 9
<212> PRT
<213> 褐家鼠
<400> 79
Phe Gln His Thr His Leu Pro Leu Thr
1 5
<210> 80
<211> 9
<212> PRT
<213> 小家鼠
<400> 80
Gln Gln Trp Asn Ser Asn Pro Pro Thr
1 5
<210> 81
<211> 9
<212> PRT
<213> 小家鼠
<400> 81
His Gln Tyr His Arg Ser Pro Arg Thr
1 5
<210> 82
<211> 9
<212> PRT
<213> 小家鼠
<400> 82
Gln Gln Ser Lys Glu Val Pro Phe Thr
1 5
<210> 83
<211> 9
<212> PRT
<213> 小家鼠
<400> 83
Ser Gln Ser Thr His Val Pro Pro Thr
1 5
<210> 84
<211> 9
<212> PRT
<213> 小家鼠
<400> 84
Gln Gln Gly His Thr Leu Pro Pro Thr
1 5
<210> 85
<211> 10
<212> PRT
<213> 小家鼠
<400> 85
Gln Gln His Ser Tyr Thr Pro Pro Trp Thr
1 5 10
<210> 86
<211> 10
<212> PRT
<213> 小家鼠
<400> 86
Gln Gln His Ser Tyr Thr Pro Pro Trp Thr
1 5 10
<210> 87
<211> 9
<212> PRT
<213> 褐家鼠
<400> 87
Gln Gln Tyr His Gly Phe Pro Asn Thr
1 5
<210> 88
<211> 9
<212> PRT
<213> 褐家鼠
<400> 88
Gln Gln Tyr His Gly Phe Pro Asn Thr
1 5
<210> 89
<211> 241
<212> PRT
<213> 智人
<220>
<221> 信号
<222> (1)..(25)
<400> 89
Met Ala Gln His Gly Ala Met Gly Ala Phe Arg Ala Leu Cys Gly Leu
1 5 10 15
Ala Leu Leu Cys Ala Leu Ser Leu Gly Gln Arg Pro Thr Gly Gly Pro
20 25 30
Gly Cys Gly Pro Gly Arg Leu Leu Leu Gly Thr Gly Thr Asp Ala Arg
35 40 45
Cys Cys Arg Val His Thr Thr Arg Cys Cys Arg Asp Tyr Pro Gly Glu
50 55 60
Glu Cys Cys Ser Glu Trp Asp Cys Met Cys Val Gln Pro Glu Phe His
65 70 75 80
Cys Gly Asp Pro Cys Cys Thr Thr Cys Arg His His Pro Cys Pro Pro
85 90 95
Gly Gln Gly Val Gln Ser Gln Gly Lys Phe Ser Phe Gly Phe Gln Cys
100 105 110
Ile Asp Cys Ala Ser Gly Thr Phe Ser Gly Gly His Glu Gly His Cys
115 120 125
Lys Pro Trp Thr Asp Cys Thr Gln Phe Gly Phe Leu Thr Val Phe Pro
130 135 140
Gly Asn Lys Thr His Asn Ala Val Cys Val Pro Gly Ser Pro Pro Ala
145 150 155 160
Glu Pro Leu Gly Trp Leu Thr Val Val Leu Leu Ala Val Ala Ala Cys
165 170 175
Val Leu Leu Leu Thr Ser Ala Gln Leu Gly Leu His Ile Trp Gln Leu
180 185 190
Arg Ser Gln Cys Met Trp Pro Arg Glu Thr Gln Leu Leu Leu Glu Val
195 200 205
Pro Pro Ser Thr Glu Asp Ala Arg Ser Cys Gln Phe Pro Glu Glu Glu
210 215 220
Arg Gly Glu Arg Ser Ala Glu Glu Lys Gly Arg Leu Gly Asp Leu Trp
225 230 235 240
Val
<210> 90
<211> 122
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体序列
<220>
<221> 变体
<222> (24)..(24)
<223> 可以是A或F
<220>
<221> 变体
<222> (69)..(69)
<223> 可以是F或L
<220>
<221> 变体
<222> (73)..(73)
<223> 可以是R或K
<220>
<221> 变体
<222> (75)..(75)
<223> 可以是N或T
<220>
<221> 变体
<222> (80)..(80)
<223> 可以是L或V
<220>
<221> 变体
<222> (98)..(98)
<223> 可以是A或V
<400> 90
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Xaa Ser Gly Phe Ser Leu Ser Thr Ser
20 25 30
Gly Met Gly Val Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu
35 40 45
Trp Val Ala His Ile Trp Trp Asp Asp Asp Lys Tyr Tyr Ser Pro Ser
50 55 60
Leu Lys Ser Arg Xaa Thr Ile Ser Xaa Asp Xaa Ser Lys Asn Thr Xaa
65 70 75 80
Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr
85 90 95
Cys Xaa Arg Ser Tyr Tyr Tyr Gly Ser Ser Gly Ala Met Asp Tyr Trp
100 105 110
Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 91
<211> 113
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体序列
<400> 91
Asp Ile Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Pro Gly
1 5 10 15
Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Val His Ser
20 25 30
Asp Gly Asn Thr Tyr Leu His Trp Tyr Leu Gln Lys Pro Gly Gln Ser
35 40 45
Pro Gln Leu Leu Ile Tyr Lys Val Ser Lys Arg Phe Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Ser Gln Ser
85 90 95
Thr His Val Pro Pro Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105 110
Arg
<210> 92
<211> 123
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体序列
<220>
<221> 变体
<222> (97)..(97)
<223> 可以是A或T
<220>
<221> 变体
<222> (98)..(98)
<223> 可以是R或T
<400> 92
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr
20 25 30
Tyr Met Ala Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Tyr Ile His Ala Asn Gly Gly Ser Thr Tyr Tyr Arg Asp Ser Val
50 55 60
Arg Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Xaa Xaa Gly Ser Phe Met Tyr Ala Ala Asp Tyr Tyr Ile Met Asp Ala
100 105 110
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 93
<211> 113
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体序列
<400> 93
Asp Ile Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Pro Gly
1 5 10 15
Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Leu His Ser
20 25 30
Asp Gly Asn Thr Phe Leu Ser Trp Tyr Leu Gln Lys Pro Gly Gln Ser
35 40 45
Pro Gln Leu Leu Ile Tyr Leu Ala Ser Asn Arg Phe Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Phe Gln His
85 90 95
Thr His Leu Pro Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105 110
Arg
<210> 94
<211> 118
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体序列
<220>
<221> 变体
<222> (48)..(48)
<223> 可以是M或I
<220>
<221> 变体
<222> (68)..(68)
<223> 可以是V或A
<220>
<221> 变体
<222> (70)..(70)
<223> 可以是M或F
<220>
<221> 变体
<222> (72)..(72)
<223> 可以是T或A
<400> 94
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 Ser Arg Tyr
20 25 30
Trp Ile Glu Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Xaa
35 40 45
Gly Glu Ile Leu Pro Gly Ser Gly Ser Ser Asn Tyr Asn Glu Lys Phe
50 55 60
Lys Asp Arg Xaa Thr Xaa Thr Xaa Asp Thr Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Lys Val Tyr Tyr Tyr Ala Met Asp Phe Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser
115
<210> 95
<211> 109
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体序列
<220>
<221> 变体
<222> (48)..(48)
<223> 可以是L或W
<220>
<221> 变体
<222> (72)..(72)
<223> 可以是F或Y
<400> 95
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Thr Ala Ser Ser Ser Val Ser Ser Ser
20 25 30
Tyr Phe His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Xaa
35 40 45
Ile Tyr Ser Thr Ser Asn Leu Ala Ser Gly Ile Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Xaa Thr Leu Thr Ile Ser Arg Leu Glu
65 70 75 80
Pro Glu Asp Phe Ala Val Tyr Tyr Cys His Gln Tyr His Arg Ser Pro
85 90 95
Arg Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg
100 105
<210> 96
<211> 121
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体序列
<220>
<221> 变体
<222> (24)..(24)
<223> 可以是V或F
<220>
<221> 变体
<222> (50)..(50)
<223> 可以是I或L
<220>
<221> 变体
<222> (51)..(51)
<223> 可以是G或A
<220>
<221> 变体
<222> (69)..(69)
<223> 可以是V或L
<220>
<221> 变体
<222> (71)..(71)
<223> 可以是I或V
<220>
<221> 变体
<222> (73)..(73)
<223> 可以是V或K
<220>
<221> 变体
<222> (80)..(80)
<223> 可以是F或A
<220>
<221> 变体
<222> (99)..(99)
<223> 可以是R或Q
<400> 96
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Xaa Ser Gly Phe Ser Leu Ser Thr Tyr
20 25 30
Gly Val Gly Val Gly Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu
35 40 45
Trp Xaa Xaa Asn Ile Trp Trp Asp Asp Asp Asn Tyr Tyr Asn Pro Ser
50 55 60
Leu Ile His Arg Xaa Thr Xaa Ser Xaa Asp Thr Ser Lys Asn Gln Xaa
65 70 75 80
Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr
85 90 95
Cys Ala Xaa Ile Lys Glu Pro Arg Asp Trp Phe Phe Glu Phe Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 97
<211> 108
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体序列
<220>
<221> 变体
<222> (46)..(46)
<223> 可以是L或P
<220>
<221> 变体
<222> (49)..(49)
<223> 可以是Y或F
<220>
<221> 变体
<222> (71)..(71)
<223> 可以是F或Y
<400> 97
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Val Asn Asn Phe
20 25 30
Leu Thr Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Xaa Leu Ile
35 40 45
Xaa Tyr Thr Ser Asn Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Xaa Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr His Gly Phe Pro Asn
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg
100 105
<210> 98
<211> 121
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体序列
<220>
<221> 变体
<222> (24)..(24)
<223> 可以是V或F
<220>
<221> 变体
<222> (50)..(50)
<223> 可以是I或L
<220>
<221> 变体
<222> (51)..(51)
<223> 可以是G或A
<220>
<221> 变体
<222> (69)..(69)
<223> 可以是V或L
<220>
<221> 变体
<222> (73)..(73)
<223> 可以是V或K
<220>
<221> 变体
<222> (80)..(80)
<223> 可以是F或A
<220>
<221> 变体
<222> (99)..(99)
<223> 可以是R或Q
<400> 98
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Xaa Ser Gly Phe Ser Leu Ser Thr Tyr
20 25 30
Gly Val Gly Val Gly Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu
35 40 45
Trp Xaa Xaa Asn Ile Trp Trp Asp Asp Asp Lys Tyr Tyr Asn Pro Ser
50 55 60
Leu Lys Asn Arg Xaa Thr Ile Ser Xaa Asp Thr Ser Lys Asn Gln Xaa
65 70 75 80
Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr
85 90 95
Cys Ala Xaa Ile Lys Glu Pro Arg Asp Trp Phe Phe Glu Phe Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 99
<211> 108
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体序列
<220>
<221> 变体
<222> (46)..(46)
<223> 可以是L或P
<220>
<221> 变体
<222> (49)..(49)
<223> 可以是Y或F
<220>
<221> 变体
<222> (71)..(71)
<223> 可以是F或Y
<400> 99
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Val Asn Asn Tyr
20 25 30
Leu Thr Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Xaa Leu Ile
35 40 45
Xaa Tyr Thr Ser Asn Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Xaa Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr His Gly Phe Pro Asn
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg
100 105
<210> 100
<211> 117
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体序列
<220>
<221> 变体
<222> (96)..(96)
<223> 可以是A或Q
<400> 100
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Val Arg Asn Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Ser Ile Ser Thr Gly Asp Arg Ser Tyr Leu Pro Asp Ser Met Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Xaa
85 90 95
Arg Tyr Phe Asp Phe Asp Ser Phe Ala Phe Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 101
<211> 108
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体序列
<400> 101
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Asn Asn Phe
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Tyr Thr Ser Lys Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Gly His Thr Leu Pro Pro
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg
100 105
<210> 102
<211> 120
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体序列
<220>
<221> 变体
<222> (47)..(47)
<223> 可以是W或Y
<220>
<221> 变体
<222> (48)..(48)
<223> 可以是I或M
<220>
<221> 变体
<222> (71)..(71)
<223> 可以是V或R
<220>
<221> 变体
<222> (96)..(96)
<223> 可以是A或S
<400> 102
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Asp Ser Ile Thr Ser Gly
20 25 30
Tyr Trp Asn Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Xaa Xaa
35 40 45
Gly Tyr Ile Ser Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser Leu Arg
50 55 60
Gly Arg Val Thr Ile Ser Xaa Asp Thr Ser Lys Asn Gln Phe Ser Leu
65 70 75 80
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Xaa
85 90 95
Arg Arg His Leu Gly Ser Gly Tyr Gly Trp Phe Ala Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 103
<211> 109
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体序列
<220>
<221> 变体
<222> (71)..(71)
<223> 可以是F或Y
<400> 103
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Asn Cys Lys Ala Ser Gln Asp Val Asn Thr Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile
35 40 45
Tyr Trp Ala Ser Thr Arg His Thr Gly Val Pro Asp Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Xaa Thr Leu Thr Ile Ser Ser Leu Gln Ala
65 70 75 80
Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln His Ser Tyr Thr Pro Pro
85 90 95
Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg
100 105
<210> 104
<211> 118
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体序列
<400> 104
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Ser Ile Ser Ser Gly Gly Thr Thr Tyr Tyr Pro Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Val Gly Gly Tyr Tyr Asp Ser Met Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser
115
<210> 105
<211> 112
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体序列
<220>
<221> 变体
<222> (31)..(31)
<223> 可以是N或Q
<220>
<221> 变体
<222> (57)..(57)
<223> 可以是N或Q
<400> 105
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Glu Ser Val Asp Xaa Tyr
20 25 30
Gly Val Ser Phe Met Asn Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro
35 40 45
Arg Leu Leu Ile Tyr Ala Ala Ser Xaa Gln Gly Ser Gly Ile Pro Asp
50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser
65 70 75 80
Arg Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Thr Lys
85 90 95
Glu Val Thr Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg
100 105 110
<210> 106
<211> 120
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体序列
<220>
<221> 变体
<222> (47)..(47)
<223> 可以是W或Y
<220>
<221> 变体
<222> (48)..(48)
<223> 可以是I或M
<220>
<221> 变体
<222> (67)..(67)
<223> 可以是V或I
<220>
<221> 变体
<222> (71)..(71)
<223> 可以是V或R
<220>
<221> 变体
<222> (78)..(78)
<223> 可以是F或Y
<220>
<221> 变体
<222> (96)..(96)
<223> 可以是A或S
<400> 106
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Asp Ser Ile Thr Ser Gly
20 25 30
Tyr Trp Asn Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Xaa Xaa
35 40 45
Gly Phe Ile Ser Tyr Ser Gly Asn Thr Tyr Tyr Asn Pro Ser Leu Arg
50 55 60
Ser Arg Xaa Thr Ile Ser Xaa Asp Thr Ser Lys Asn Gln Xaa Ser Leu
65 70 75 80
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Xaa
85 90 95
Arg Arg His Leu Ile Ser Gly Tyr Gly Trp Phe Ala Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 107
<211> 109
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体序列
<220>
<221> 变体
<222> (1)..(1)
<223> 可以是D或V
<400> 107
Xaa Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Asn Cys Lys Ala Ser Gln Asp Val Ile Ser Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile
35 40 45
Tyr Trp Ala Ser Thr Arg His Thr Gly Val Pro Asp Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Ala
65 70 75 80
Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln His Ser Tyr Thr Pro Pro
85 90 95
Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg
100 105
<210> 108
<211> 119
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体序列
<220>
<221> 变体
<222> (48)..(48)
<223> 可以是M或I
<220>
<221> 变体
<222> (68)..(68)
<223> 可以是V或A
<220>
<221> 变体
<222> (70)..(70)
<223> 可以是M或L
<220>
<221> 变体
<222> (72)..(72)
<223> 可以是T或A
<220>
<221> 变体
<222> (74)..(74)
<223> 可以是T或K
<400> 108
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
Thr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Xaa
35 40 45
Gly Tyr Ile Asn Pro Arg Ser Val Tyr Thr Asn Tyr Asn Gln Lys Phe
50 55 60
Lys Asp Arg Xaa Thr Xaa Thr Xaa Asp Xaa Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Leu Gly Gly Tyr Tyr Asp Thr Met Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 109
<211> 112
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体序列
<400> 109
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Glu Ser Val Asp Asn Tyr
20 25 30
Gly Ile Ser Phe Met Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro
35 40 45
Lys Leu Leu Ile Tyr Ala Ala Ser Asn Gln Gly Ser Gly Val Pro Ser
50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser
65 70 75 80
Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Lys
85 90 95
Glu Val Pro Phe Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg
100 105 110
<210> 110
<211> 118
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体序列
<220>
<221> 变体
<222> (49)..(49)
<223> 可以是I或M
<220>
<221> 变体
<222> (68)..(68)
<223> 可以是V或I
<220>
<221> 变体
<222> (72)..(72)
<223> 可以是V或R
<400> 110
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Tyr Ser Ile Thr Ser Asp
20 25 30
Tyr Ala Trp Asn Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp
35 40 45
Xaa Gly Tyr Ile Ser Tyr Ser Gly Ser Thr Arg Tyr Asn Pro Ser Leu
50 55 60
Lys Ser Arg Xaa Thr Ile Ser Xaa Asp Thr Ser Lys Asn Gln Phe Ser
65 70 75 80
Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gln Leu Gly Leu Arg Phe Phe Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser
115
<210> 111
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体序列
<220>
<221> 变体
<222> (45)..(45)
<223> 可以是L或P
<220>
<221> 变体
<222> (46)..(46)
<223> 可以是L或C
<400> 111
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Ser Ala Asn Ser Thr Val Asn Tyr Met
20 25 30
Tyr Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Xaa Xaa Ile Tyr
35 40 45
Leu Thr Ser Asn Leu Ala Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu Pro Glu
65 70 75 80
Asp Phe Ala Val Tyr Tyr Cys Gln Gln Trp Asn Ser Asn Pro Pro Thr
85 90 95
Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg
100 105
Claims (22)
1.一种结合人GITR的结合化合物,其包含:
a)抗体轻链可变结构域或其抗原结合片段,其具有3个选自SEQ ID NO: 59-88的CDR序列;和
b)抗体重链可变结构域或其抗原结合片段,其具有3个选自SEQ ID NO: 23-55的CDR序列。
2.如权利要求1所述的结合化合物,其中所述CDR包含:
a)至少一个来自SEQ ID NO: 56-66的CDRL1;至少一个来自SEQ ID NO: 67-77的CDRL2;和至少一个来自SEQ ID NO: 78-88的CDRL3;和
b)至少一个来自SEQ ID NO: 23-33的CDRH1;至少一个来自SEQ ID NO: 34-44的CDRH2;和至少一个来自SEQ ID NO: 45-55的CDRH3。
3.如权利要求1所述的结合化合物,其中:
a)所述重链可变结构域的氨基酸序列选自SEQ ID NO: 90、92、94、96、98、100、102、104、106、108和110;且
b)所述轻链可变结构域的氨基酸序列选自SEQ ID NO:91、93、95、97、99、101、103、105、107、109和111。
4.如权利要求3所述的结合化合物,其中:
a)所述重链可变结构域的氨基酸序列是SEQ ID NO: 90,且所述轻链可变结构域的序列是SEQ ID NO: 91;
b)所述重链可变结构域的氨基酸序列是SEQ ID NO: 92,且所述重链可变结构域的氨基酸序列是SEQ ID NO: 93;
c)所述重链可变结构域的氨基酸序列是SEQ ID NO: 94,且所述重链可变结构域的氨基酸序列是SEQ ID NO: 95;
d)所述重链可变结构域的氨基酸序列是SEQ ID NO: 96,且所述重链可变结构域的氨基酸序列是SEQ ID NO: 97;
e)所述重链可变结构域的氨基酸序列是SEQ ID NO: 98,且所述重链可变结构域的氨基酸序列是SEQ ID NO: 99;
f)所述重链可变结构域的氨基酸序列是SEQ ID NO: 100,且所述重链可变结构域的氨基酸序列是SEQ ID NO: 101;
g)所述重链可变结构域的氨基酸序列是SEQ ID NO: 102,且所述重链可变结构域的氨基酸序列是SEQ ID NO: 103;
h)所述重链可变结构域的氨基酸序列是SEQ ID NO: 104,且所述重链可变结构域的氨基酸序列是SEQ ID NO: 105;
i)所述重链可变结构域的氨基酸序列是SEQ ID NO: 106,且所述重链可变结构域的氨基酸序列是SEQ ID NO: 107;
j)所述重链可变结构域的氨基酸序列是SEQ ID NO: 108,且所述重链可变结构域的氨基酸序列是SEQ ID NO: 109;或
k)所述重链可变结构域的氨基酸序列是SEQ ID NO: 110,且所述重链可变结构域的氨基酸序列是SEQ ID NO: 111。
5.一种抗体,其能够在交叉阻断试验中阻断如权利要求4所述的结合化合物与人GITR的结合。
6.一种分离的核酸,其编码如权利要求4所述的结合化合物的轻链可变结构域或重链可变结构域中的至少一个。
7.一种表达载体,其包含如权利要求6所述的核酸,所述核酸可操作地连接到当用所述载体转染宿主细胞时所述宿主细胞会识别的控制序列上。
8.一种宿主细胞,其包含如权利要求7所述的表达载体。
9.一种生产多肽的方法,所述方法包括:
在表达所述核酸序列的条件下,在培养基中培养如权利要求8所述的宿主细胞,从而生产包含轻链和重链可变结构域的多肽;和
从宿主细胞或培养基回收多肽。
10.如权利要求4所述的结合化合物,其另外包含重链恒定区,所述重链恒定区包含γ1人重链恒定区或其变体,其中所述恒定区变体包含最多20个保守修饰的氨基酸置换。
11.如权利要求4所述的结合化合物,其另外包含重链恒定区,所述重链恒定区包含γ4人重链恒定区或其变体,其中所述恒定区变体包含最多20个保守修饰的氨基酸置换。
12.如权利要求4所述的结合化合物,其中所述结合化合物是选自Fab、Fab’、Fab’-SH、Fv、scFv、F(ab’)2和双体的抗体片段。
13.一种增强人受试者的免疫应答的方法,所述方法包括:以有效地增加GITR的生物学活性的量,给有此需要的受试者施用对GITR特异性的抗体或其抗原结合片段,其中所述抗体是如权利要求5所述的抗体。
14.如权利要求13所述的方法,其中所述GITR抗体或其抗原结合片段与抗-TGFβ抗体共同施用。
15.如权利要求13所述的方法,其中所述GITR抗体或其抗原结合片段与局部辐射共同施用。
16.如权利要求13所述的方法,其中所述免疫应答是针对增生性障碍。
17.如权利要求13所述的方法,其中所述免疫应答是针对病毒感染。
18.一种药物组合物,其包含如权利要求4所述的抗体和药学上可接受的载体。
19.一种由保藏在美国典型培养物保藏中心(ATCC)的杂交瘤生产的抗体或其抗原结合片段,其中所述杂交瘤选自PTA-9889、PTA-9890、PTA-9891、PTA-9892、PTA-9893、PTA-10286、PTA-10287、PTA-10288、PTA-10289、PTA-10290和PTA-10291。
20.一种结合人GITR蛋白的抗体或抗原结合片段,其中所述抗体或抗原结合片段会识别跨人GITR蛋白(SEQ ID NO: 89)的模块3和模块4的表位。
21.如权利要求20所述的抗体或抗原结合片段,其中所述表位包含Gly57、Arg65、His67、Lys80、Phe81、Ser82和Gln86。
22.如权利要求20所述的抗体,其会交叉阻断由选自下述的杂交瘤生产的抗体或抗体片段中的至少一种:PTA-9889、PTA-9890、PTA-9891、PTA-9892、PTA-9893、PTA-10286、PTA-10287、PTA-10288、PTA-10289、PTA-10290和PTA-10291。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201410047532.0A CN103951753B (zh) | 2009-09-03 | 2010-08-31 | 抗‑gitr抗体 |
Applications Claiming Priority (7)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US23966709P | 2009-09-03 | 2009-09-03 | |
US61/239,667 | 2009-09-03 | ||
US30776710P | 2010-02-24 | 2010-02-24 | |
US61/307767 | 2010-02-24 | ||
US31395510P | 2010-03-15 | 2010-03-15 | |
US61/313955 | 2010-03-15 | ||
PCT/US2010/047248 WO2011028683A1 (en) | 2009-09-03 | 2010-08-31 | Anti-gitr antibodies |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201410047532.0A Division CN103951753B (zh) | 2009-09-03 | 2010-08-31 | 抗‑gitr抗体 |
Publications (1)
Publication Number | Publication Date |
---|---|
CN102574924A true CN102574924A (zh) | 2012-07-11 |
Family
ID=43649600
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN2010800497565A Pending CN102574924A (zh) | 2009-09-03 | 2010-08-31 | 抗-gitr抗体 |
CN201410047532.0A Active CN103951753B (zh) | 2009-09-03 | 2010-08-31 | 抗‑gitr抗体 |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201410047532.0A Active CN103951753B (zh) | 2009-09-03 | 2010-08-31 | 抗‑gitr抗体 |
Country Status (22)
Country | Link |
---|---|
US (3) | US8709424B2 (zh) |
EP (2) | EP2473531A4 (zh) |
JP (3) | JP6294585B2 (zh) |
KR (2) | KR20170119746A (zh) |
CN (2) | CN102574924A (zh) |
AU (1) | AU2010289677B2 (zh) |
BR (1) | BR112012004823B1 (zh) |
CA (2) | CA3067609A1 (zh) |
CY (1) | CY1123404T1 (zh) |
DK (1) | DK3023438T3 (zh) |
ES (1) | ES2788869T3 (zh) |
HR (1) | HRP20200720T1 (zh) |
HU (1) | HUE049825T2 (zh) |
IN (2) | IN2012DN01920A (zh) |
LT (1) | LT3023438T (zh) |
MX (1) | MX340953B (zh) |
PL (1) | PL3023438T3 (zh) |
PT (1) | PT3023438T (zh) |
RU (2) | RU2646139C1 (zh) |
SG (1) | SG178991A1 (zh) |
SI (1) | SI3023438T1 (zh) |
WO (1) | WO2011028683A1 (zh) |
Cited By (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN105829343A (zh) * | 2013-08-30 | 2016-08-03 | 美国安进公司 | Gitr抗原结合蛋白 |
CN106459203A (zh) * | 2014-06-06 | 2017-02-22 | 百时美施贵宝公司 | 抗糖皮质激素诱导肿瘤坏死因子受体(gitr)的抗体及其用途 |
CN107001476A (zh) * | 2014-10-08 | 2017-08-01 | 诺华股份有限公司 | 用于增强的免疫应答和癌症治疗的组合物和方法 |
CN107249624A (zh) * | 2015-02-27 | 2017-10-13 | 默沙东公司 | 抗人类pd‑1单克隆抗体的晶体 |
CN108473579A (zh) * | 2015-10-22 | 2018-08-31 | 埃博灵克斯股份有限公司 | Gitr激动剂 |
CN108650886A (zh) * | 2015-07-23 | 2018-10-12 | 伊布里克斯公司 | 多价和多特异性gitr-结合融合蛋白 |
WO2019201301A1 (zh) * | 2018-04-20 | 2019-10-24 | 信达生物制药(苏州)有限公司 | 抗gitr抗体及其用途 |
CN110461874A (zh) * | 2017-06-30 | 2019-11-15 | 江苏恒瑞医药股份有限公司 | 抗gitr抗体、其抗原结合片段及其医药用途 |
Families Citing this family (486)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US11046784B2 (en) | 2006-03-31 | 2021-06-29 | Chugai Seiyaku Kabushiki Kaisha | Methods for controlling blood pharmacokinetics of antibodies |
US8158757B2 (en) | 2007-07-02 | 2012-04-17 | Oncomed Pharmaceuticals, Inc. | Compositions and methods for treating and diagnosing cancer |
MX369784B (es) | 2007-09-26 | 2019-11-21 | Chugai Pharmaceutical Co Ltd | Metodo de modificacion del punto isoelectrico de anticuerpos mediante la sustitucion de aminoacidos en region de determinacion de complementariedad (cdr). |
DK2708559T3 (en) | 2008-04-11 | 2018-06-14 | Chugai Pharmaceutical Co Ltd | Antigen-binding molecule capable of repeatedly binding two or more antigen molecules |
LT3023438T (lt) | 2009-09-03 | 2020-05-11 | Merck Sharp & Dohme Corp. | Anti-gitr antikūnai |
CN108715614A (zh) | 2010-11-30 | 2018-10-30 | 中外制药株式会社 | 与多分子的抗原重复结合的抗原结合分子 |
CN107936121B (zh) | 2011-05-16 | 2022-01-14 | 埃泰美德(香港)有限公司 | 多特异性fab融合蛋白及其使用方法 |
CN106167526A (zh) | 2011-07-15 | 2016-11-30 | 昂考梅德药品有限公司 | Rspo结合剂和其应用 |
WO2013039954A1 (en) * | 2011-09-14 | 2013-03-21 | Sanofi | Anti-gitr antibodies |
KR101566539B1 (ko) | 2012-06-08 | 2015-11-05 | 국립암센터 | 신규한 Th2 세포 전환용 에피토프 및 이의 용도 |
MX2015000565A (es) | 2012-07-13 | 2015-04-10 | Oncomed Pharm Inc | Agentes de union de proteina de r-espondina humana (rspo3) y usos de los mismos. |
EP3597747B1 (en) | 2012-08-24 | 2023-03-15 | Chugai Seiyaku Kabushiki Kaisha | Mouse fcgammarii-specific fc antibody |
CA2882272C (en) | 2012-08-24 | 2023-08-29 | Chugai Seiyaku Kabushiki Kaisha | Fc.gamma.riib-specific fc region variant |
US10548957B2 (en) | 2012-09-28 | 2020-02-04 | Dana-Farber Cancer Institute, Inc. | Targeted expansion of Qa-1-peptide-specific regulatory CD8 T cells to ameliorate arthritis |
RS58528B1 (sr) | 2012-12-03 | 2019-04-30 | Bristol Myers Squibb Co | Poboljšanje anti-kancerske aktivnosti imunomodulatornih fc fuzionih proteina |
US9834610B2 (en) | 2013-01-31 | 2017-12-05 | Thomas Jefferson University | Fusion proteins for modulating regulatory and effector T cells |
WO2015116178A1 (en) * | 2014-01-31 | 2015-08-06 | Thomas Jefferson University | Fusion proteins for modulating regulatory and effector t cells |
TWI654206B (zh) | 2013-03-16 | 2019-03-21 | 諾華公司 | 使用人類化抗-cd19嵌合抗原受體治療癌症 |
AU2014250434B2 (en) | 2013-04-02 | 2019-08-08 | Chugai Seiyaku Kabushiki Kaisha | Fc region variant |
EP3030575B1 (en) | 2013-08-08 | 2018-07-11 | Cytune Pharma | Il-15 and il-15r-alpha sushi domain based modulokines |
AR097306A1 (es) * | 2013-08-20 | 2016-03-02 | Merck Sharp & Dohme | Modulación de la inmunidad tumoral |
KR102332302B1 (ko) * | 2013-09-13 | 2021-12-01 | 제넨테크, 인크. | 세포주에서 숙주 세포 단백질 및 재조합 폴리펩티드 생성물을 검출 및 정량화하기 위한 조성물 및 방법 |
EP3683232A1 (en) | 2013-09-13 | 2020-07-22 | F. Hoffmann-La Roche AG | Methods and compositions comprising purified recombinant polypeptides |
WO2015066413A1 (en) | 2013-11-01 | 2015-05-07 | Novartis Ag | Oxazolidinone hydroxamic acid compounds for the treatment of bacterial infections |
BR112016010716A8 (pt) | 2013-11-13 | 2020-04-22 | Novartis Ag | dose de reforço imunológico, baixa, de um inibidor de mtor, seu uso, e adjuvante de vacina |
CA3225453A1 (en) | 2013-12-19 | 2015-06-25 | Novartis Ag | Human mesothelin chimeric antigen receptors and uses thereof |
DK3466949T3 (da) | 2013-12-24 | 2021-03-15 | Bristol Myers Squibb Co | Tricyklisk forbindelse som anticancermidler |
JO3517B1 (ar) | 2014-01-17 | 2020-07-05 | Novartis Ag | ان-ازاسبيرو الكان حلقي كبديل مركبات اريل-ان مغايرة وتركيبات لتثبيط نشاط shp2 |
JOP20200094A1 (ar) | 2014-01-24 | 2017-06-16 | Dana Farber Cancer Inst Inc | جزيئات جسم مضاد لـ pd-1 واستخداماتها |
JOP20200096A1 (ar) | 2014-01-31 | 2017-06-16 | Children’S Medical Center Corp | جزيئات جسم مضاد لـ tim-3 واستخداماتها |
EP3116909B1 (en) | 2014-03-14 | 2019-11-13 | Novartis Ag | Antibody molecules to lag-3 and uses thereof |
EP3593812A3 (en) | 2014-03-15 | 2020-05-27 | Novartis AG | Treatment of cancer using chimeric antigen receptor |
ES2719136T3 (es) | 2014-03-24 | 2019-07-08 | Novartis Ag | Compuestos orgánicos de monobactam para el tratamiento de infecciones bacterianas |
HUE054588T2 (hu) | 2014-04-07 | 2021-09-28 | Novartis Ag | Rák kezelése CD19 elleni, kiméra antigénreceptor alkalmazásával |
KR102433464B1 (ko) | 2014-05-28 | 2022-08-17 | 아게누스 인코포레이티드 | 항-gitr 항체 및 이의 사용 방법 |
BR112016028255A2 (pt) | 2014-06-06 | 2017-08-22 | Flexus Biosciences Inc | agentes imunorreguladores |
TWI750110B (zh) | 2014-07-21 | 2021-12-21 | 瑞士商諾華公司 | 使用人類化抗-bcma嵌合抗原受體治療癌症 |
CN112481283A (zh) | 2014-07-21 | 2021-03-12 | 诺华股份有限公司 | 使用cd33嵌合抗原受体治疗癌症 |
US11542488B2 (en) | 2014-07-21 | 2023-01-03 | Novartis Ag | Sortase synthesized chimeric antigen receptors |
JP2017528433A (ja) | 2014-07-21 | 2017-09-28 | ノバルティス アーゲー | 低い免疫増強用量のmTOR阻害剤とCARの組み合わせ |
EP3174546B1 (en) | 2014-07-31 | 2019-10-30 | Novartis AG | Subset-optimized chimeric antigen receptor-containing t-cells |
WO2016020836A1 (en) | 2014-08-06 | 2016-02-11 | Novartis Ag | Quinolone derivatives as antibacterials |
JP6919118B2 (ja) | 2014-08-14 | 2021-08-18 | ノバルティス アーゲー | GFRα−4キメラ抗原受容体を用いる癌の治療 |
JP2017526356A (ja) * | 2014-08-15 | 2017-09-14 | オンコメッド ファーマシューティカルズ インコーポレイテッド | Rspo1結合剤およびその使用 |
MY189028A (en) | 2014-08-19 | 2022-01-20 | Novartis Ag | Anti-cd123 chimeric antigen receptor (car) for use in cancer treatment |
US20170269076A1 (en) | 2014-08-27 | 2017-09-21 | Dana-Farber Cancer Institute, Inc. | Intracellular osteopontin regulates the lineage commitment of lymphoid subsets |
EP3925622A1 (en) | 2014-09-13 | 2021-12-22 | Novartis AG | Combination therapies |
CA2961374A1 (en) | 2014-09-16 | 2016-03-24 | Oncomed Pharmaceuticals, Inc. | Treatment of fibrotic diseases |
AU2015317608B2 (en) | 2014-09-17 | 2021-03-11 | Novartis Ag | Targeting cytotoxic cells with chimeric receptors for adoptive immunotherapy |
CN107250159A (zh) * | 2014-10-03 | 2017-10-13 | 达纳-法伯癌症研究所公司 | 糖皮质激素诱导的肿瘤坏死因子受体(gitr)抗体及其使用方法 |
CA2963281A1 (en) | 2014-10-03 | 2016-04-07 | Novartis Ag | Combination therapies |
CA2963935A1 (en) | 2014-10-08 | 2016-04-14 | Novartis Ag | Biomarkers predictive of therapeutic responsiveness to chimeric antigen receptor therapy and uses thereof |
EP4245376A3 (en) | 2014-10-14 | 2023-12-13 | Novartis AG | Antibody molecules to pd-l1 and uses thereof |
JP2017538678A (ja) | 2014-11-05 | 2017-12-28 | フレクサス・バイオサイエンシーズ・インコーポレイテッドFlexus Biosciences, Inc. | 免疫調節剤 |
UY36390A (es) | 2014-11-05 | 2016-06-01 | Flexus Biosciences Inc | Compuestos moduladores de la enzima indolamina 2,3-dioxigenasa (ido), sus métodos de síntesis y composiciones farmacéuticas que los contienen |
UY36391A (es) | 2014-11-05 | 2016-06-01 | Flexus Biosciences Inc | Compuestos moduladores de la enzima indolamina 2,3-dioxigenasa (ido1), sus métodos de síntesis y composiciones farmacèuticas que las contienen |
PL3221346T3 (pl) | 2014-11-21 | 2021-03-08 | Bristol-Myers Squibb Company | Przeciwciała ze zmodyfikowanym regionem stałym łańcucha ciężkiego |
NZ731633A (en) | 2014-11-21 | 2022-01-28 | Bristol Myers Squibb Co | Antibodies against cd73 and uses thereof |
WO2016090034A2 (en) | 2014-12-03 | 2016-06-09 | Novartis Ag | Methods for b cell preconditioning in car therapy |
US9549916B2 (en) | 2014-12-16 | 2017-01-24 | Novartis Ag | Isoxazole hydroxamic acid compounds as LpxC inhibitors |
EP3233918A1 (en) | 2014-12-19 | 2017-10-25 | Novartis AG | Combination therapies |
JP6227191B1 (ja) | 2014-12-19 | 2017-11-08 | 中外製薬株式会社 | 抗ミオスタチン抗体、変異Fc領域を含むポリペプチド、および使用方法 |
AR103232A1 (es) | 2014-12-22 | 2017-04-26 | Bristol Myers Squibb Co | ANTAGONISTAS DE TGFbR |
SG10202006538TA (en) | 2014-12-23 | 2020-08-28 | Bristol Myers Squibb Co | Antibodies to tigit |
TW201631152A (zh) | 2014-12-29 | 2016-09-01 | 諾華公司 | 製造嵌合抗原受體-表現細胞之方法 |
US11161907B2 (en) | 2015-02-02 | 2021-11-02 | Novartis Ag | Car-expressing cells against multiple tumor antigens and uses thereof |
MA41460A (fr) | 2015-02-03 | 2017-12-12 | Oncomed Pharm Inc | Agents de liaison à la tnfrsf et leurs utilisations |
US10983128B2 (en) | 2015-02-05 | 2021-04-20 | Bristol-Myers Squibb Company | CXCL11 and SMICA as predictive biomarkers for efficacy of anti-CTLA4 immunotherapy |
KR102605798B1 (ko) | 2015-02-05 | 2023-11-23 | 추가이 세이야쿠 가부시키가이샤 | 이온 농도 의존적 항원 결합 도메인을 포함하는 항체, Fc 영역 개변체, IL-8에 결합하는 항체, 및 그들의 사용 |
KR20170122799A (ko) | 2015-03-02 | 2017-11-06 | 리겔 파마슈티칼스, 인크. | TGF-β 억제제 |
JO3746B1 (ar) | 2015-03-10 | 2021-01-31 | Aduro Biotech Inc | تركيبات وطرق لتنشيط الإشارات المعتمدة على "منبه أو تحفيز جين انترفيرون" |
PE20180117A1 (es) | 2015-04-03 | 2018-01-18 | Bristol Myers Squibb Co | Inhibidores de indolamina-2,3-dioxigenasa para el tratamiento de cancer |
EP3280795B1 (en) | 2015-04-07 | 2021-03-24 | Novartis AG | Combination of chimeric antigen receptor therapy and amino pyrimidine derivatives |
SI3280729T1 (sl) | 2015-04-08 | 2022-09-30 | Novartis Ag | Terapije CD20, terapije CD22 in kombinacija terapij s celico, ki izraža himerni antigenski receptor CD19 (CAR) |
WO2016162505A1 (en) | 2015-04-08 | 2016-10-13 | F-Star Biotechnology Limited | Her2 binding agent therapies |
CN114681608A (zh) | 2015-04-13 | 2022-07-01 | 戊瑞治疗有限公司 | 癌症组合疗法 |
GB201506411D0 (en) | 2015-04-15 | 2015-05-27 | Bergenbio As | Humanized anti-axl antibodies |
KR20170138477A (ko) | 2015-04-17 | 2017-12-15 | 브리스톨-마이어스 스큅 컴퍼니 | 항-pd-1 항체 및 또 다른 항체의 조합물을 포함하는 조성물 |
ES2948133T3 (es) | 2015-04-17 | 2023-08-31 | Novartis Ag | Métodos para mejorar la eficacia y expansión de células que expresan un receptor de antígeno quimérico |
WO2016172583A1 (en) | 2015-04-23 | 2016-10-27 | Novartis Ag | Treatment of cancer using chimeric antigen receptor and protein kinase a blocker |
US10683290B2 (en) | 2015-05-11 | 2020-06-16 | Bristol-Myers Squibb Company | Tricyclic compounds as anticancer agents |
US9725449B2 (en) | 2015-05-12 | 2017-08-08 | Bristol-Myers Squibb Company | Tricyclic compounds as anticancer agents |
EA201792497A1 (ru) | 2015-06-03 | 2018-05-31 | Бристол-Майерс Сквибб Компани | Антитела к gitr для диагностики злокачественной опухоли |
EP3302548A4 (en) * | 2015-06-03 | 2019-01-02 | Dana Farber Cancer Institute, Inc. | Methods to induce conversion of regulatory t cells into effector t cells for cancer immunotherapy |
JP2018526977A (ja) | 2015-06-29 | 2018-09-20 | ザ ロックフェラー ユニヴァーシティ | アゴニスト活性が増強されたcd40に対する抗体 |
WO2017009842A2 (en) | 2015-07-16 | 2017-01-19 | Biokine Therapeutics Ltd. | Compositions and methods for treating cancer |
EP3325504A1 (en) | 2015-07-21 | 2018-05-30 | Novartis AG | Methods for improving the efficacy and expansion of immune cells |
KR20180034548A (ko) | 2015-07-28 | 2018-04-04 | 브리스톨-마이어스 스큅 컴퍼니 | Tgf 베타 수용체 길항제 |
US20180207273A1 (en) | 2015-07-29 | 2018-07-26 | Novartis Ag | Combination therapies comprising antibody molecules to tim-3 |
LT3317301T (lt) | 2015-07-29 | 2021-07-26 | Novartis Ag | Kombinuotos terapijos, apimančios antikūno molekules prieš lag-3 |
EP3328418A1 (en) | 2015-07-29 | 2018-06-06 | Novartis AG | Combination therapies comprising antibody molecules to pd-1 |
CN108349976A (zh) | 2015-08-25 | 2018-07-31 | 百时美施贵宝公司 | TGFβ受体拮抗剂 |
CN108780084B (zh) | 2015-09-03 | 2022-07-22 | 诺华股份有限公司 | 预测细胞因子释放综合征的生物标志物 |
WO2017046746A1 (en) | 2015-09-15 | 2017-03-23 | Acerta Pharma B.V. | Therapeutic combinations of a btk inhibitor and a gitr binding molecule, a 4-1bb agonist, or an ox40 agonist |
JP6936221B2 (ja) | 2015-11-02 | 2021-09-15 | ファイブ プライム セラピューティクス, インコーポレイテッド | Cd80細胞外ドメインポリペプチドと、がん治療でのそれらの使用 |
MA43186B1 (fr) | 2015-11-03 | 2022-03-31 | Janssen Biotech Inc | Anticorps se liant spécifiquement à pd-1 et leurs utilisations |
WO2017087678A2 (en) | 2015-11-19 | 2017-05-26 | Bristol-Myers Squibb Company | Antibodies against glucocorticoid-induced tumor necrosis factor receptor (gitr) and uses thereof |
RU2021107536A (ru) | 2015-11-23 | 2021-07-02 | Файв Прайм Терапьютикс, Инк. | Ингибиторы fgfr2 отдельно или в комбинации с иммуностимулирующими агентами в лечении рака |
CN116063542A (zh) | 2015-12-02 | 2023-05-05 | 阿吉纳斯公司 | 抗体和其使用方法 |
JP6856648B2 (ja) | 2015-12-15 | 2021-04-07 | ブリストル−マイヤーズ スクイブ カンパニーBristol−Myers Squibb Company | Cxcr4受容体アンタゴニスト |
MX2018007423A (es) | 2015-12-17 | 2018-11-09 | Novartis Ag | Moleculas de anticuerpo que se unen a pd-1 y usos de las mismas. |
UY37030A (es) | 2015-12-18 | 2017-07-31 | Novartis Ag | Anticuerpos dirigidos a cd32b y métodos de uso de los mismos |
EP3393504A1 (en) | 2015-12-22 | 2018-10-31 | Novartis AG | Mesothelin chimeric antigen receptor (car) and antibody against pd-l1 inhibitor for combined use in anticancer therapy |
JP7141336B2 (ja) | 2015-12-25 | 2022-09-22 | 中外製薬株式会社 | 抗ミオスタチン抗体および使用方法 |
CN109153975A (zh) | 2015-12-28 | 2019-01-04 | 诺华股份有限公司 | 制备嵌合抗原受体表达细胞的方法 |
IL260218B2 (en) | 2016-01-11 | 2023-04-01 | Novartis Ag | Humanized monoclonal antibodies that elicit an immune response against interleukin-2, and their fusion proteins |
CA3014369A1 (en) | 2016-02-19 | 2017-08-24 | Novartis Ag | Tetracyclic pyridone compounds as antivirals |
WO2017149515A1 (en) | 2016-03-04 | 2017-09-08 | Novartis Ag | Cells expressing multiple chimeric antigen receptor (car) molecules and uses therefore |
EA201891983A8 (ru) | 2016-03-04 | 2020-05-28 | Бристол-Майерс Сквибб Компани | Комбинированная терапия антителами к cd73 |
EP3426297A4 (en) * | 2016-03-08 | 2019-08-14 | Janssen Biotech, Inc. | GITR ANTIBODIES, METHODS AND USES |
WO2017157305A1 (en) | 2016-03-15 | 2017-09-21 | Generon (Shanghai) Corporation Ltd. | Multispecific fab fusion proteins and use thereof |
JP7005508B2 (ja) | 2016-03-24 | 2022-01-21 | ノバルティス アーゲー | ヒトライノウイルスの阻害剤としてのアルキニルヌクレオシド類似体 |
US10894823B2 (en) | 2016-03-24 | 2021-01-19 | Gensun Biopharma Inc. | Trispecific inhibitors for cancer treatment |
CN109414421A (zh) | 2016-05-04 | 2019-03-01 | 百时美施贵宝公司 | 吲哚胺2,3-双加氧酶的抑制剂及其使用方法 |
WO2017192813A1 (en) | 2016-05-04 | 2017-11-09 | Bristol-Myers Squibb Company | Inhibitors of indoleamine 2,3-dioxygenase and methods of their use |
EP3452029A4 (en) | 2016-05-04 | 2019-10-30 | Bristol-Myers Squibb Company | INDOLEAMINE 2,3-DIOXYGENASE INHIBITORS AND METHODS OF USE |
WO2017192815A1 (en) | 2016-05-04 | 2017-11-09 | Bristol-Myers Squibb Company | Inhibitors of indoleamine 2,3-dioxygenase and methods of their use |
CN109348714A (zh) | 2016-05-04 | 2019-02-15 | 百时美施贵宝公司 | 吲哚胺2,3-双加氧酶的抑制剂及其使用方法 |
TWI786044B (zh) | 2016-05-13 | 2022-12-11 | 美商再生元醫藥公司 | 藉由投予pd-1抑制劑治療皮膚癌之方法 |
JP7169195B2 (ja) | 2016-05-20 | 2022-11-10 | バイオヘイブン・ファーマシューティカル・ホールディング・カンパニー・リミテッド | 癌を処置するためのリルゾール、リルゾールプロドラッグまたはリルゾール類似体と免疫療法との併用 |
US11623958B2 (en) | 2016-05-20 | 2023-04-11 | Harpoon Therapeutics, Inc. | Single chain variable fragment CD3 binding proteins |
MA45233A (fr) | 2016-06-10 | 2019-04-17 | Regeneron Pharma | Anticorps anti-gitr et leurs utilisations |
SI3468957T1 (sl) | 2016-06-14 | 2020-11-30 | Novartis Ag | Kristalna oblika (R)-4-(5-(ciklopropiletinil) izoksazol-3-IL)-N- hidroksi-2-metil-2-(metilsul fonil) butanamida kot antibakterijsko sredstvo |
WO2017216686A1 (en) | 2016-06-16 | 2017-12-21 | Novartis Ag | 8,9-fused 2-oxo-6,7-dihydropyrido-isoquinoline compounds as antivirals |
WO2017216685A1 (en) | 2016-06-16 | 2017-12-21 | Novartis Ag | Pentacyclic pyridone compounds as antivirals |
EP3471754A1 (en) | 2016-06-20 | 2019-04-24 | Kymab Limited | Anti-pd-l1 antibodies |
SG11201811237WA (en) | 2016-06-24 | 2019-01-30 | Infinity Pharmaceuticals Inc | Combination therapies |
EP3478721A1 (en) | 2016-07-01 | 2019-05-08 | Five Prime Therapeutics, Inc. | Combined anti tumor therapy with a gitr agonist and cpg |
EP3507367A4 (en) | 2016-07-05 | 2020-03-25 | Aduro BioTech, Inc. | CYCLIC DINUCLEOTID COMPOUNDS WITH INCLUDED NUCLEIC ACIDS AND USES THEREOF |
SG11201900026TA (en) | 2016-07-14 | 2019-01-30 | Bristol Myers Squibb Co | Antibodies against tim3 and uses thereof |
CN109641947B (zh) | 2016-07-20 | 2023-04-14 | 犹他大学研究基金会 | Cd229 car t细胞及其使用方法 |
WO2018017633A1 (en) | 2016-07-21 | 2018-01-25 | Bristol-Myers Squibb Company | TGF Beta RECEPTOR ANTAGONISTS |
CN109689689B (zh) * | 2016-07-22 | 2022-12-06 | 丹娜法伯癌症研究所公司 | 糖皮质激素诱导肿瘤坏死因子受体(gitr)抗体及其使用方法 |
JP6527643B2 (ja) | 2016-08-05 | 2019-06-05 | 中外製薬株式会社 | Il−8関連疾患の治療用又は予防用組成物 |
JP7178342B2 (ja) | 2016-08-12 | 2022-11-25 | ヤンセン バイオテツク,インコーポレーテツド | アゴニズム及びエフェクター機能が増強した改変抗体、及び他のFcドメイン含有分子 |
CA3033665A1 (en) | 2016-08-12 | 2018-02-15 | Janssen Biotech, Inc. | Fc engineered anti-tnfr superfamily member antibodies having enhanced agonistic activity and methods of using them |
US11351164B2 (en) | 2016-08-26 | 2022-06-07 | Bristol-Myers Squibb Company | Inhibitors of indoleamine 2,3-dioxygenase and methods of their use |
WO2018047109A1 (en) | 2016-09-09 | 2018-03-15 | Novartis Ag | Polycyclic pyridone compounds as antivirals |
US11077178B2 (en) | 2016-09-21 | 2021-08-03 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Chimeric antigen receptor (CAR) that targets chemokine receptor CCR4 and its use |
JOP20190061A1 (ar) | 2016-09-28 | 2019-03-26 | Novartis Ag | مثبطات بيتا-لاكتاماز |
TW202340473A (zh) | 2016-10-07 | 2023-10-16 | 瑞士商諾華公司 | 利用嵌合抗原受體之癌症治療 |
EA037973B1 (ru) * | 2016-10-12 | 2021-06-18 | Янссен Байотек, Инк. | Антитела к gitr, способы и применение |
TW201819380A (zh) | 2016-10-18 | 2018-06-01 | 瑞士商諾華公司 | 作為抗病毒劑之稠合四環吡啶酮化合物 |
TWI788307B (zh) | 2016-10-31 | 2023-01-01 | 美商艾歐凡斯生物治療公司 | 用於擴增腫瘤浸潤性淋巴細胞之工程化人造抗原呈現細胞 |
CA3041340A1 (en) | 2016-11-09 | 2018-05-17 | Agenus Inc. | Anti-ox40 antibodies, anti-gitr antibodies, and methods of use thereof |
US10660909B2 (en) | 2016-11-17 | 2020-05-26 | Syntrix Biosystems Inc. | Method for treating cancer using chemokine antagonists |
JOP20190100A1 (ar) | 2016-11-19 | 2019-05-01 | Potenza Therapeutics Inc | بروتينات ربط مولد ضد مضاد لـ gitr وطرق استخدامها |
MX2019006286A (es) | 2016-12-03 | 2020-02-07 | Juno Therapeutics Inc | Metodos para determinar la dosificacion en la terapia celular. |
LT3558955T (lt) | 2016-12-22 | 2021-11-10 | Amgen Inc. | Benzizotiazolo, izotiazolo[3,4-b]piridazino ir ftalazino, pirido[2,3-d] piridazino ir pirido[2,3-d]pirimidino dariniai, kaip kras g12c inhibitoriai, skirti plaučių, kasos arba storosios žarnos vėžio gydymui |
MX2019007019A (es) | 2016-12-22 | 2019-08-16 | Univ Degli Studi Magna Graecia Catanzaro | Anticuerpo monoclonal dirigido a un epitope de cd43 sialoglicosilado especifico asociado al cancer. |
US10537637B2 (en) | 2017-01-05 | 2020-01-21 | Gensun Biopharma Inc. | Checkpoint regulator antagonists |
US10961239B2 (en) | 2017-01-05 | 2021-03-30 | Bristol-Myers Squibb Company | TGF beta receptor antagonists |
US20200121719A1 (en) | 2017-01-06 | 2020-04-23 | Iovance Biotherapeutics, Inc. | Expansion of tumor infiltrating lymphocytes (tils) with tumor necrosis factor receptor superfamily (tnfrsf) agonists and therapeutic combinations of tils and tnfrsf agonists |
EP3570844B1 (en) | 2017-01-20 | 2023-09-06 | Arcus Biosciences, Inc. | Azolopyrimidine for the treatment of cancer-related disorders |
AU2018213124A1 (en) * | 2017-01-27 | 2019-09-12 | Ultrahuman One Limited | Binding agents |
EP3882271A3 (en) | 2017-02-10 | 2022-01-05 | Eutilex Co., Ltd. | Ifn-gamma-inducible regulatory t cell convertible anti-cancer (irtca) antibody and uses thereof |
KR20240011262A (ko) | 2017-02-21 | 2024-01-25 | 리제너론 파아마슈티컬스, 인크. | 폐암의 치료를 위한 항-pd-1 항체 |
AU2018226646A1 (en) * | 2017-03-03 | 2019-09-19 | Rinat Neuroscience Corp. | Anti-GITR antibodies and methods of use thereof |
WO2018183928A1 (en) | 2017-03-31 | 2018-10-04 | Bristol-Myers Squibb Company | Methods of treating tumor |
WO2018185618A1 (en) | 2017-04-03 | 2018-10-11 | Novartis Ag | Anti-cdh6 antibody drug conjugates and anti-gitr antibody combinations and methods of treatment |
WO2018187227A1 (en) | 2017-04-03 | 2018-10-11 | Concologie, Inc. | Methods for treating cancer using ps-targeting antibodies with immuno-oncology agents |
TWI788340B (zh) | 2017-04-07 | 2023-01-01 | 美商必治妥美雅史谷比公司 | 抗icos促效劑抗體及其用途 |
BR112019021680A2 (pt) | 2017-04-20 | 2020-05-12 | Adc Therapeutics Sa | Terapia de combinação com conjugado anticorpo-fármaco anti-cd25?? |
EP3612234B1 (en) | 2017-04-20 | 2024-03-13 | ADC Therapeutics SA | Combination therapy with an anti-axl antibody-drug conjugate |
MX2019012431A (es) | 2017-04-21 | 2020-08-03 | Ikena Oncology Inc | Inhibidores del receptor de hidrocarburos de arilo (ahr) de indol y usos de los mismos. |
KR20190141223A (ko) | 2017-04-26 | 2019-12-23 | 브리스톨-마이어스 스큅 컴퍼니 | 디술피드 결합 환원을 최소화하는 항체 생산 방법 |
AR111419A1 (es) | 2017-04-27 | 2019-07-10 | Novartis Ag | Compuestos fusionados de indazol piridona como antivirales |
WO2018201056A1 (en) | 2017-04-28 | 2018-11-01 | Novartis Ag | Cells expressing a bcma-targeting chimeric antigen receptor, and combination therapy with a gamma secretase inhibitor |
EP3628070B1 (en) | 2017-04-28 | 2021-09-08 | Five Prime Therapeutics, Inc. | Cd80 extracellular domain polypeptides for use in increasing central memory t cells |
AR111651A1 (es) | 2017-04-28 | 2019-08-07 | Novartis Ag | Conjugados de anticuerpos que comprenden agonistas del receptor de tipo toll y terapias de combinación |
UY37695A (es) | 2017-04-28 | 2018-11-30 | Novartis Ag | Compuesto dinucleótido cíclico bis 2’-5’-rr-(3’f-a)(3’f-a) y usos del mismo |
WO2018201051A1 (en) | 2017-04-28 | 2018-11-01 | Novartis Ag | Bcma-targeting agent, and combination therapy with a gamma secretase inhibitor |
JOP20190260A1 (ar) | 2017-05-02 | 2019-10-31 | Merck Sharp & Dohme | صيغ ثابتة لأجسام مضادة لمستقبل الموت المبرمج 1 (pd-1) وطرق استخدامها |
EA039583B1 (ru) * | 2017-05-02 | 2022-02-14 | Регенерон Фармасьютикалз, Инк. | Антитела против gitr и их применения |
US11845798B2 (en) | 2017-05-02 | 2023-12-19 | Merck Sharp & Dohme Llc | Formulations of anti-LAG3 antibodies and co-formulations of anti-LAG3 antibodies and anti-PD-1 antibodies |
AR111658A1 (es) | 2017-05-05 | 2019-08-07 | Novartis Ag | 2-quinolinonas tricíclicas como agentes antibacteriales |
US10543271B2 (en) | 2017-05-12 | 2020-01-28 | Harpoon Therapeutics, Inc. | Mesothelin binding proteins |
US11066392B2 (en) | 2017-05-12 | 2021-07-20 | Bristol-Myers Squibb Company | Inhibitors of indoleamine 2,3-dioxygenase and methods of their use |
KR20200006115A (ko) | 2017-05-16 | 2020-01-17 | 브리스톨-마이어스 스큅 컴퍼니 | 항-gitr 효능제 항체에 의한 암의 치료 |
JP7189155B2 (ja) | 2017-05-17 | 2022-12-13 | アーカス バイオサイエンシズ インコーポレイティド | 癌関連障害の治療のためのキナゾリン-ピラゾール誘導体 |
JOP20190272A1 (ar) | 2017-05-22 | 2019-11-21 | Amgen Inc | مثبطات kras g12c وطرق لاستخدامها |
KR20200013241A (ko) | 2017-05-25 | 2020-02-06 | 브리스톨-마이어스 스큅 컴퍼니 | 변형된 중쇄 불변 영역을 포함하는 항체 |
WO2018223004A1 (en) | 2017-06-01 | 2018-12-06 | Xencor, Inc. | Bispecific antibodies that bind cd20 and cd3 |
CN111344303A (zh) | 2017-06-01 | 2020-06-26 | Xencor股份有限公司 | 结合cd123和cd3的双特异性抗体 |
WO2018223101A1 (en) | 2017-06-02 | 2018-12-06 | Juno Therapeutics, Inc. | Articles of manufacture and methods for treatment using adoptive cell therapy |
JP2020523018A (ja) | 2017-06-09 | 2020-08-06 | プロビデンス ヘルス アンド サービシーズ−オレゴン | がんの処置のための腫瘍反応性ヒトt細胞の同定のためのcd39およびcd103の使用 |
MX2019015042A (es) | 2017-06-14 | 2020-08-06 | Adc Therapeutics Sa | Regimen de dosificacion. |
WO2018229715A1 (en) | 2017-06-16 | 2018-12-20 | Novartis Ag | Compositions comprising anti-cd32b antibodies and methods of use thereof |
CN109136275B (zh) | 2017-06-19 | 2021-03-16 | 百奥赛图(北京)医药科技股份有限公司 | 人源化gitr基因改造动物模型的制备方法及应用 |
EP3642240A1 (en) | 2017-06-22 | 2020-04-29 | Novartis AG | Antibody molecules to cd73 and uses thereof |
WO2018235056A1 (en) | 2017-06-22 | 2018-12-27 | Novartis Ag | IL-1BETA BINDING ANTIBODIES FOR USE IN THE TREATMENT OF CANCER |
PE20200717A1 (es) | 2017-06-22 | 2020-07-21 | Novartis Ag | Moleculas de anticuerpo que se unen a cd73 y usos de las mismas |
JP2020524694A (ja) | 2017-06-22 | 2020-08-20 | ノバルティス アーゲー | がんの処置における使用のためのIL−1β結合性抗体 |
EP3645037A1 (en) | 2017-06-27 | 2020-05-06 | Novartis AG | Dosage regimens for anti-tim-3 antibodies and uses thereof |
EP3644721A1 (en) | 2017-06-29 | 2020-05-06 | Juno Therapeutics, Inc. | Mouse model for assessing toxicities associated with immunotherapies |
IL271601B2 (en) | 2017-06-30 | 2024-05-01 | Bristol Myers Squibb Co | Amorphous and crystalline forms of IDO inhibitors |
US20200172617A1 (en) | 2017-07-20 | 2020-06-04 | Novartis Ag | Dosage regimens of anti-lag-3 antibodies and uses thereof |
KR20200032180A (ko) | 2017-07-28 | 2020-03-25 | 브리스톨-마이어스 스큅 컴퍼니 | 항암제로서의 시클릭 디뉴클레오티드 |
KR20200051646A (ko) | 2017-08-17 | 2020-05-13 | 이케나 온콜로지, 인코포레이티드 | Ahr 억제제 및 이의 용도 |
WO2019040780A1 (en) | 2017-08-25 | 2019-02-28 | Five Prime Therapeutics Inc. | ANTI-B7-H4 ANTIBODIES AND METHODS OF USE |
JP7316263B2 (ja) | 2017-08-31 | 2023-07-27 | ブリストル-マイヤーズ スクイブ カンパニー | 抗癌剤としての環状ジヌクレオチド |
US10947263B2 (en) | 2017-08-31 | 2021-03-16 | Bristol-Myers Squibb Company | Cyclic dinucleotides as anticancer agents |
US10953032B2 (en) | 2017-08-31 | 2021-03-23 | Bristol-Myers Squibb Company | Cyclic dinucleotides as anticancer agents |
TWI731264B (zh) | 2017-09-08 | 2021-06-21 | 美商安進公司 | Kras g12c抑制劑以及其使用方法 |
MX2020003190A (es) | 2017-09-22 | 2020-11-11 | Kymera Therapeutics Inc | Degradadores de proteinas y usos de los mismos. |
US11358948B2 (en) | 2017-09-22 | 2022-06-14 | Kymera Therapeutics, Inc. | CRBN ligands and uses thereof |
WO2019074822A1 (en) | 2017-10-09 | 2019-04-18 | Bristol-Myers Squibb Company | INDOLEAMINE 2,3-DIOXYGENASE INHIBITORS AND METHODS OF USE |
US11203592B2 (en) | 2017-10-09 | 2021-12-21 | Bristol-Myers Squibb Company | Inhibitors of indoleamine 2,3-dioxygenase and methods of their use |
CN111344297B (zh) | 2017-10-10 | 2023-10-20 | 百时美施贵宝公司 | 作为抗癌剂的环二核苷酸 |
US10927180B2 (en) | 2017-10-13 | 2021-02-23 | Harpoon Therapeutics, Inc. | B cell maturation antigen binding proteins |
US20200239577A1 (en) | 2017-10-15 | 2020-07-30 | Bristol-Myers Squibb Company | Methods of treating tumor |
KR20200065065A (ko) | 2017-10-16 | 2020-06-08 | 브리스톨-마이어스 스큅 컴퍼니 | 항암제로서의 시클릭 디뉴클레오티드 |
WO2019081983A1 (en) | 2017-10-25 | 2019-05-02 | Novartis Ag | CD32B TARGETING ANTIBODIES AND METHODS OF USE |
SG11202003177RA (en) | 2017-10-25 | 2020-05-28 | Novartis Ag | Methods of making chimeric antigen receptor-expressing cells |
BR112020008323A2 (pt) | 2017-11-01 | 2020-11-03 | Juno Therapeutics Inc | anticorpos e receptores de antígenos quiméricos específicos para antígeno de maturação de células b |
CA3082010A1 (en) | 2017-11-01 | 2019-05-09 | Juno Therapeutics, Inc. | Chimeric antigen receptors specific for b-cell maturation antigen (bcma) |
WO2019089858A2 (en) | 2017-11-01 | 2019-05-09 | Juno Therapeutics, Inc. | Methods of assessing or monitoring a response to a cell therapy |
JP7167146B2 (ja) | 2017-11-06 | 2022-11-08 | ブリストル-マイヤーズ スクイブ カンパニー | Hpk1阻害剤として有用なイソフラノン化合物 |
MX2020004756A (es) | 2017-11-16 | 2020-08-20 | Novartis Ag | Terapias de combinacion. |
CN111315749A (zh) | 2017-11-17 | 2020-06-19 | 诺华股份有限公司 | 新颖的二氢异噁唑化合物及其在治疗乙型肝炎中的用途 |
MA51210A (fr) | 2017-12-01 | 2020-10-07 | Juno Therapeutics Inc | Procédés de dosage et de modulation de cellules génétiquement modifiées |
US12006356B2 (en) | 2017-12-15 | 2024-06-11 | Juno Therapeutics, Inc. | Anti-CCT5 binding molecules and chimeric antigen receptors comprising the same |
JP2021507906A (ja) | 2017-12-20 | 2021-02-25 | ノバルティス アーゲー | 抗ウイルス剤としての融合三環式ピラゾロ−ジヒドロピラジニル−ピリドン化合物 |
JP2021508703A (ja) | 2017-12-26 | 2021-03-11 | カイメラ セラピューティクス, インコーポレイテッド | Irak分解剤およびそれらの使用 |
EP3732198A1 (en) | 2017-12-27 | 2020-11-04 | Bristol-Myers Squibb Company | Anti-cd40 antibodies and uses thereof |
WO2019136112A1 (en) | 2018-01-05 | 2019-07-11 | Bristol-Myers Squibb Company | Inhibitors of indoleamine 2,3-dioxygenase and methods of their use |
CN111886255A (zh) | 2018-01-12 | 2020-11-03 | 百时美施贵宝公司 | 抗tim3抗体及其用途 |
US11512080B2 (en) | 2018-01-12 | 2022-11-29 | Kymera Therapeutics, Inc. | CRBN ligands and uses thereof |
US11485743B2 (en) | 2018-01-12 | 2022-11-01 | Kymera Therapeutics, Inc. | Protein degraders and uses thereof |
US10988477B2 (en) | 2018-01-29 | 2021-04-27 | Merck Patent Gmbh | GCN2 inhibitors and uses thereof |
TW201940481A (zh) | 2018-01-29 | 2019-10-16 | 美商維泰克斯製藥公司 | Gcn2抑制劑及其用途 |
WO2019160829A1 (en) | 2018-02-13 | 2019-08-22 | Iovance Biotherapeutics, Inc. | Expansion of tumor infiltrating lymphocytes (tils) with adenosine a2a receptor antagonists and therapeutic combinations of tils and adenosine a2a receptor antagonists |
US10519187B2 (en) | 2018-02-13 | 2019-12-31 | Bristol-Myers Squibb Company | Cyclic dinucleotides as anticancer agents |
WO2019165315A1 (en) | 2018-02-23 | 2019-08-29 | Syntrix Biosystems Inc. | Method for treating cancer using chemokine antagonists alone or in combination |
US20200407365A1 (en) | 2018-02-28 | 2020-12-31 | Novartis Ag | Indole-2-carbonyl compounds and their use for the treatment of hepatitis b |
AU2019228600A1 (en) | 2018-03-02 | 2020-09-24 | Five Prime Therapeutics, Inc. | B7-H4 antibodies and methods of use thereof |
JP7250808B2 (ja) | 2018-03-08 | 2023-04-03 | ブリストル-マイヤーズ スクイブ カンパニー | 抗がん剤としての環状ジヌクレオチド |
CN111971304A (zh) | 2018-03-21 | 2020-11-20 | 戊瑞治疗有限公司 | 在酸性pH结合至VISTA的抗体 |
TW202003565A (zh) | 2018-03-23 | 2020-01-16 | 美商必治妥美雅史谷比公司 | 抗mica及/或micb抗體及其用途 |
CN110357958A (zh) | 2018-03-26 | 2019-10-22 | 信达生物制药(苏州)有限公司 | 抗糖皮质激素诱导的肿瘤坏死因子受体(gitr)的小型化抗体、其聚合物及应用 |
CN111918873A (zh) | 2018-03-27 | 2020-11-10 | 百时美施贵宝公司 | 使用紫外线信号实时监测滴度 |
WO2019184909A1 (zh) | 2018-03-27 | 2019-10-03 | 信达生物制药(苏州)有限公司 | 新型抗体分子、其制备方法及其用途 |
CN110305210B (zh) | 2018-03-27 | 2023-02-28 | 信达生物制药(苏州)有限公司 | 新型抗体分子、其制备方法及其用途 |
CN111971306A (zh) | 2018-03-30 | 2020-11-20 | 百时美施贵宝公司 | 治疗肿瘤的方法 |
US20210147547A1 (en) | 2018-04-13 | 2021-05-20 | Novartis Ag | Dosage Regimens For Anti-Pd-L1 Antibodies And Uses Thereof |
CN112292128A (zh) | 2018-04-16 | 2021-01-29 | 阿瑞斯医疗有限公司 | Ep4抑制剂和其用途 |
EP3784351A1 (en) | 2018-04-27 | 2021-03-03 | Novartis AG | Car t cell therapies with enhanced efficacy |
EP3788369A1 (en) | 2018-05-01 | 2021-03-10 | Novartis Ag | Biomarkers for evaluating car-t cells to predict clinical outcome |
WO2019213340A1 (en) | 2018-05-03 | 2019-11-07 | Bristol-Myers Squibb Company | Uracil derivatives as mer-axl inhibitors |
JP7266043B2 (ja) | 2018-05-04 | 2023-04-27 | アムジエン・インコーポレーテツド | KRas G12C阻害剤及びそれを使用する方法 |
MX2020011582A (es) | 2018-05-04 | 2020-11-24 | Amgen Inc | Inhibidores de kras g12c y metodos para su uso. |
JP7361720B2 (ja) | 2018-05-10 | 2023-10-16 | アムジエン・インコーポレーテツド | がんの治療のためのkras g12c阻害剤 |
US20220111065A1 (en) | 2018-05-23 | 2022-04-14 | Adc Therapeutics Sa | Molecular adjuvant |
US20210213063A1 (en) | 2018-05-25 | 2021-07-15 | Novartis Ag | Combination therapy with chimeric antigen receptor (car) therapies |
TW202015726A (zh) | 2018-05-30 | 2020-05-01 | 瑞士商諾華公司 | Entpd2抗體、組合療法、及使用該等抗體和組合療法之方法 |
US20210214459A1 (en) | 2018-05-31 | 2021-07-15 | Novartis Ag | Antibody molecules to cd73 and uses thereof |
EP3801617A1 (en) | 2018-06-01 | 2021-04-14 | Novartis Ag | Dosing of a bispecific antibody that bind cd123 and cd3 |
EP3802535B1 (en) | 2018-06-01 | 2022-12-14 | Amgen, Inc | Kras g12c inhibitors and methods of using the same |
AU2019284472B2 (en) | 2018-06-11 | 2024-05-30 | Amgen Inc. | KRAS G12C inhibitors for treating cancer |
AU2019336588B2 (en) | 2018-06-12 | 2022-07-28 | Amgen Inc. | KRAS G12C inhibitors encompassing a piperazine ring and use thereof in the treatment of cancer |
KR20210020932A (ko) | 2018-06-13 | 2021-02-24 | 노파르티스 아게 | Bcma 키메라 항원 수용체 및 이의 용도 |
US20210251994A1 (en) | 2018-06-15 | 2021-08-19 | Flagship Pioneering Innovations V, Inc. | Increasing immune activity through modulation of postcellular signaling factors |
US11180531B2 (en) | 2018-06-22 | 2021-11-23 | Bicycletx Limited | Bicyclic peptide ligands specific for Nectin-4 |
FI3814348T3 (fi) | 2018-06-27 | 2023-09-22 | Bristol Myers Squibb Co | Substituoituja naftyridinoniyhdisteitä, jotka ovat käyttökelpoisia t-solun aktivoijina |
EP3814347B1 (en) | 2018-06-27 | 2023-05-03 | Bristol-Myers Squibb Company | Naphthyridinone compounds useful as t cell activators |
EP3813880A4 (en) | 2018-06-29 | 2022-07-13 | Gensun Biopharma Inc. | ANTITUMORS IMMUNOTEST POINT REGULATOR ANTAGONISTS |
WO2020010177A1 (en) | 2018-07-06 | 2020-01-09 | Kymera Therapeutics, Inc. | Tricyclic crbn ligands and uses thereof |
EP3820904A2 (en) | 2018-07-09 | 2021-05-19 | Five Prime Therapeutics, Inc. | Antibodies binding to ilt4 |
AR116109A1 (es) | 2018-07-10 | 2021-03-31 | Novartis Ag | Derivados de 3-(5-amino-1-oxoisoindolin-2-il)piperidina-2,6-diona y usos de los mismos |
CR20210001A (es) | 2018-07-10 | 2021-04-19 | Novartis Ag | Derivados de 3-(5-hidroxi-1-oxoisoindolin-2-il)piperidina-2,6-diona y su uso en el tratamiento de trastornos dependientes de la proteina con dedos de zinc 2 de la familia ikaros (1kzf2) |
JP2022513421A (ja) | 2018-07-11 | 2022-02-08 | ファイブ プライム セラピューティクス, インコーポレイテッド | 酸性pHでVISTAと結合する抗体 |
US20210355113A1 (en) | 2018-07-23 | 2021-11-18 | Bristol-Myers Squibb Company | Inhibitors of indoleamine 2,3-dioxygenase and methods of their use |
US20210299126A1 (en) | 2018-07-23 | 2021-09-30 | Bristol-Myers Squibb Company | Inhibitors of indoleamine 2,3-dioxygenase and methods of their use |
WO2020021465A1 (en) | 2018-07-25 | 2020-01-30 | Advanced Accelerator Applications (Italy) S.R.L. | Method of treatment of neuroendocrine tumors |
WO2020023846A1 (en) | 2018-07-27 | 2020-01-30 | Arcus Biosciences, Inc. | Pyridone a2r antagonists |
US11253525B2 (en) | 2018-08-29 | 2022-02-22 | Bristol-Myers Squibb Company | Inhibitors of indoleamine 2,3-dioxygenase and methods of their use |
US10959986B2 (en) | 2018-08-29 | 2021-03-30 | Bristol-Myers Squibb Company | Inhibitors of indoleamine 2,3-dioxygenase and methods of their use |
TW202030323A (zh) | 2018-08-31 | 2020-08-16 | 瑞士商諾華公司 | 製備表現嵌合抗原受體的細胞之方法 |
EP3844265A2 (en) | 2018-08-31 | 2021-07-07 | Novartis AG | Methods of making chimeric antigen receptor-expressing cells |
CN113164419A (zh) | 2018-09-07 | 2021-07-23 | 皮克医疗公司 | Eif4e抑制剂和其用途 |
EP3847194A1 (en) | 2018-09-07 | 2021-07-14 | Pfizer Inc. | Anti-avb8 antibodies and compositions and uses thereof |
CN112996789A (zh) | 2018-09-12 | 2021-06-18 | 诺华股份有限公司 | 抗病毒吡啶并吡嗪二酮化合物 |
IL297931A (en) | 2018-09-25 | 2023-01-01 | Harpoon Therapeutics Inc | dll3 binding proteins and methods of use |
US20220047633A1 (en) | 2018-09-28 | 2022-02-17 | Novartis Ag | Cd22 chimeric antigen receptor (car) therapies |
US20210347851A1 (en) | 2018-09-28 | 2021-11-11 | Novartis Ag | Cd19 chimeric antigen receptor (car) and cd22 car combination therapies |
KR20210068473A (ko) | 2018-09-29 | 2021-06-09 | 노파르티스 아게 | Shp2 활성 억제용 화합물의 제조 방법 |
JP7453219B2 (ja) | 2018-10-11 | 2024-03-19 | インヒブリックス, インコーポレイテッド | Pd-1単一ドメイン抗体およびその治療用組成物 |
WO2020089811A1 (en) | 2018-10-31 | 2020-05-07 | Novartis Ag | Dc-sign antibody drug conjugates |
CN113646335A (zh) | 2018-11-01 | 2021-11-12 | 朱诺治疗学股份有限公司 | 使用对b细胞成熟抗原具有特异性的嵌合抗原受体的治疗的方法 |
AU2019374103A1 (en) | 2018-11-01 | 2021-05-20 | Juno Therapeutics, Inc. | Chimeric antigen receptors specific for G Protein-Coupled Receptor Class C Group 5 Member D (GPRC5D) |
JP2020090482A (ja) | 2018-11-16 | 2020-06-11 | アムジエン・インコーポレーテツド | Kras g12c阻害剤化合物の重要な中間体の改良合成法 |
US11274150B2 (en) | 2018-11-16 | 2022-03-15 | Bristol-Myers Squibb Company | Anti-human natural killer cell inhibitory receptor group 2A protein (NKG2A) antibodies |
US20220008465A1 (en) | 2018-11-16 | 2022-01-13 | Juno Therapeutics, Inc. | Methods of dosing engineered t cells for the treatment of b cell malignancies |
JP7377679B2 (ja) | 2018-11-19 | 2023-11-10 | アムジエン・インコーポレーテツド | がん治療のためのkrasg12c阻害剤及び1種以上の薬学的に活性な追加の薬剤を含む併用療法 |
EP3883565A1 (en) | 2018-11-19 | 2021-09-29 | Amgen Inc. | Kras g12c inhibitors and methods of using the same |
CN113348177A (zh) | 2018-11-28 | 2021-09-03 | 百时美施贵宝公司 | 包含经修饰的重链恒定区的抗体 |
CA3119773A1 (en) | 2018-11-30 | 2020-06-04 | Kymera Therapeutics, Inc. | Irak degraders and uses thereof |
SG11202105502RA (en) | 2018-11-30 | 2021-06-29 | Juno Therapeutics Inc | Methods for treatment using adoptive cell therapy |
WO2020132653A1 (en) | 2018-12-20 | 2020-06-25 | Amgen Inc. | Heteroaryl amides useful as kif18a inhibitors |
US11236069B2 (en) | 2018-12-20 | 2022-02-01 | Amgen Inc. | KIF18A inhibitors |
ES2953821T3 (es) | 2018-12-20 | 2023-11-16 | Amgen Inc | Inhibidores de KIF18A |
EP3670659A1 (en) | 2018-12-20 | 2020-06-24 | Abivax | Biomarkers, and uses in treatment of viral infections, inflammations, or cancer |
US20220056015A1 (en) | 2018-12-20 | 2022-02-24 | Amgen Inc. | Kif18a inhibitors |
KR20210106437A (ko) | 2018-12-20 | 2021-08-30 | 노파르티스 아게 | 3-(1-옥소이소인돌린-2-일)피페리딘-2,6-디온 유도체를 포함하는 투약 요법 및 약학적 조합물 |
AU2019409139A1 (en) | 2018-12-21 | 2021-06-03 | Novartis Ag | Use of IL-1β binding antibodies |
WO2020128613A1 (en) | 2018-12-21 | 2020-06-25 | Novartis Ag | Use of il-1beta binding antibodies |
WO2020128637A1 (en) | 2018-12-21 | 2020-06-25 | Novartis Ag | Use of il-1 binding antibodies in the treatment of a msi-h cancer |
JP2022516850A (ja) | 2018-12-21 | 2022-03-03 | ノバルティス アーゲー | 骨髄異形成症候群の治療又は予防におけるIL-1β抗体の使用 |
PE20212198A1 (es) | 2019-01-29 | 2021-11-16 | Juno Therapeutics Inc | Anticuerpos y receptores quimericos de antigenos especificos para receptor 1 huerfano tipo receptor tirosina-cinasa (ror1) |
US20220144807A1 (en) | 2019-02-15 | 2022-05-12 | Novartis Ag | 3-(1-oxo-5-(piperidin-4-yl)isoindolin-2-yl)piperidine-2,6-dione derivatives and uses thereof |
EP3924055B1 (en) | 2019-02-15 | 2024-04-03 | Novartis AG | Substituted 3-(1-oxoisoindolin-2-yl)piperidine-2,6-dione derivatives and uses thereof |
WO2020172658A1 (en) | 2019-02-24 | 2020-08-27 | Bristol-Myers Squibb Company | Methods of isolating a protein |
EP3931195A1 (en) | 2019-03-01 | 2022-01-05 | Revolution Medicines, Inc. | Bicyclic heteroaryl compounds and uses thereof |
AU2020232616A1 (en) | 2019-03-01 | 2021-09-09 | Revolution Medicines, Inc. | Bicyclic heterocyclyl compounds and uses thereof |
WO2020187998A1 (en) | 2019-03-19 | 2020-09-24 | Fundació Privada Institut D'investigació Oncològica De Vall Hebron | Combination therapy with omomyc and an antibody binding pd-1 or ctla-4 for the treatment of cancer |
MX2021011608A (es) | 2019-03-29 | 2021-12-10 | Myst Therapeutics Llc | Metodos ex vivo para producir celulas t terapeuticas y composiciones y metodos afines. |
AU2020253990A1 (en) | 2019-04-02 | 2021-10-28 | Bicycletx Limited | Bicycle toxin conjugates and uses thereof |
TW202106676A (zh) | 2019-04-05 | 2021-02-16 | 美商凱麥拉醫療公司 | Stat降解劑及其用途 |
EP3953455A1 (en) | 2019-04-12 | 2022-02-16 | Novartis AG | Methods of making chimeric antigen receptor-expressing cells |
RU2734432C1 (ru) * | 2019-04-23 | 2020-10-16 | Закрытое Акционерное Общество "Биокад" | Моноклональное антитело, которое специфически связывается с GITR |
WO2020219742A1 (en) | 2019-04-24 | 2020-10-29 | Novartis Ag | Compositions and methods for selective protein degradation |
EP3962493A2 (en) | 2019-05-03 | 2022-03-09 | Flagship Pioneering Innovations V, Inc. | Methods of modulating immune activity/level of irf or sting or of treating cancer, comprising the administration of a sting modulator and/or purinergic receptor modulator or postcellular signaling factor |
WO2020231766A1 (en) | 2019-05-13 | 2020-11-19 | Bristol-Myers Squibb Company | AGONISTS OF ROR GAMMAt |
US12012374B2 (en) | 2019-05-13 | 2024-06-18 | Bristol-Myers Squibb Company | Agonists of ROR GAMMAt |
EP3738593A1 (en) | 2019-05-14 | 2020-11-18 | Amgen, Inc | Dosing of kras inhibitor for treatment of cancers |
US11236091B2 (en) | 2019-05-21 | 2022-02-01 | Amgen Inc. | Solid state forms |
WO2020237221A1 (en) | 2019-05-23 | 2020-11-26 | Bristol-Myers Squibb Company | Methods of monitoring cell culture media |
WO2020243568A1 (en) | 2019-05-30 | 2020-12-03 | Bristol-Myers Squibb Company | Methods of identifying a subject suitable for an immuno-oncology (i-o) therapy |
KR20220016157A (ko) | 2019-05-30 | 2022-02-08 | 브리스톨-마이어스 스큅 컴퍼니 | 세포 국재화 시그너쳐 및 조합 요법 |
CN114174538A (zh) | 2019-05-30 | 2022-03-11 | 百时美施贵宝公司 | 适合于免疫肿瘤学疗法的多肿瘤基因特征 |
CN114502540A (zh) | 2019-05-31 | 2022-05-13 | 医肯纳肿瘤学公司 | Tead抑制剂和其用途 |
US10851157B2 (en) | 2019-07-01 | 2020-12-01 | Gensun Biopharma, Inc. | Antagonists targeting the TGF-β pathway |
JP2022542394A (ja) | 2019-08-02 | 2022-10-03 | アムジエン・インコーポレーテツド | Kif18a阻害剤として有用なヘテロアリールアミド |
CN114391012A (zh) | 2019-08-02 | 2022-04-22 | 美国安进公司 | 作为kif18a抑制剂的吡啶衍生物 |
CA3146693A1 (en) | 2019-08-02 | 2021-02-11 | Amgen Inc. | Kif18a inhibitors |
WO2021026099A1 (en) | 2019-08-02 | 2021-02-11 | Amgen Inc. | Kif18a inhibitors |
US20220306630A1 (en) | 2019-08-06 | 2022-09-29 | Bristol-Myers Squibb Company | AGONISTS OF ROR GAMMAt |
AR119821A1 (es) | 2019-08-28 | 2022-01-12 | Bristol Myers Squibb Co | Compuestos de piridopirimidinonilo sustituidos útiles como activadores de células t |
WO2021050964A1 (en) | 2019-09-13 | 2021-03-18 | Nimbus Saturn, Inc. | Hpk1 antagonists and uses thereof |
CN114502590A (zh) | 2019-09-18 | 2022-05-13 | 诺华股份有限公司 | Entpd2抗体、组合疗法、以及使用这些抗体和组合疗法的方法 |
JP2022548292A (ja) | 2019-09-19 | 2022-11-17 | ブリストル-マイヤーズ スクイブ カンパニー | 酸性pHでVISTAと結合する抗体 |
AU2020353055B2 (en) | 2019-09-26 | 2024-03-07 | Gilead Sciences, Inc. | Antiviral pyrazolopyridinone compounds |
BR112022007376A2 (pt) | 2019-10-21 | 2022-07-05 | Novartis Ag | Terapias de combinação com venetoclax e inibidores de tim-3 |
WO2021079195A1 (en) | 2019-10-21 | 2021-04-29 | Novartis Ag | Tim-3 inhibitors and uses thereof |
WO2021081212A1 (en) | 2019-10-24 | 2021-04-29 | Amgen Inc. | Pyridopyrimidine derivatives useful as kras g12c and kras g12d inhibitors in the treatment of cancer |
CN114867735A (zh) | 2019-11-04 | 2022-08-05 | 锐新医药公司 | Ras抑制剂 |
EP4054719A1 (en) | 2019-11-04 | 2022-09-14 | Revolution Medicines, Inc. | Ras inhibitors |
CN115873020A (zh) | 2019-11-04 | 2023-03-31 | 锐新医药公司 | Ras抑制剂 |
KR20220100903A (ko) | 2019-11-08 | 2022-07-18 | 레볼루션 메디슨즈, 인크. | 이환식 헤테로아릴 화합물 및 이의 용도 |
IL292315A (en) | 2019-11-14 | 2022-06-01 | Amgen Inc | Improved synthesis of a kras g12c inhibitory compound |
AU2020383535A1 (en) | 2019-11-14 | 2022-05-05 | Amgen Inc. | Improved synthesis of KRAS G12C inhibitor compound |
JP2023503052A (ja) | 2019-11-19 | 2023-01-26 | ブリストル-マイヤーズ スクイブ カンパニー | Heliosタンパク質の阻害剤として有用な化合物 |
IL292924A (en) | 2019-11-26 | 2022-07-01 | Novartis Ag | Chimeric antigen receptors cd19 and cd22 and their uses |
EP4065582A1 (en) | 2019-11-26 | 2022-10-05 | Ikena Oncology, Inc. | Polymorphic carbazole derivatives and uses thereof |
EP4065158A2 (en) | 2019-11-26 | 2022-10-05 | Novartis AG | Chimeric antigen receptors binding bcma and cd19 and uses thereof |
IL293357A (en) | 2019-11-26 | 2022-07-01 | Bristol Myers Squibb Co | Salts/crystals of (r)-n-(4-chlorophenyl)-2-((1s,4s)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide |
CN115023270A (zh) | 2019-11-27 | 2022-09-06 | 迈斯特治疗公司 | 使用调节剂产生肿瘤反应性t细胞组合物的方法 |
GB201917254D0 (en) | 2019-11-27 | 2020-01-08 | Adc Therapeutics Sa | Combination therapy |
EP4065231A1 (en) | 2019-11-27 | 2022-10-05 | Revolution Medicines, Inc. | Covalent ras inhibitors and uses thereof |
US20230114107A1 (en) | 2019-12-17 | 2023-04-13 | Flagship Pioneering Innovations V, Inc. | Combination anti-cancer therapies with inducers of iron-dependent cellular disassembly |
WO2021127283A2 (en) | 2019-12-17 | 2021-06-24 | Kymera Therapeutics, Inc. | Irak degraders and uses thereof |
US11779578B2 (en) | 2019-12-17 | 2023-10-10 | Kymera Therapeutics, Inc. | IRAK degraders and uses thereof |
WO2021123996A1 (en) | 2019-12-20 | 2021-06-24 | Novartis Ag | Uses of anti-tgf-beta antibodies and checkpoint inhibitors for the treatment of proliferative diseases |
AR120823A1 (es) | 2019-12-23 | 2022-03-23 | Bristol Myers Squibb Co | Compuestos bicíclicos sustituidos útiles como activadores de células t |
IL294269A (en) | 2019-12-23 | 2022-08-01 | Bristol Myers Squibb Co | Substitute quinolinyl piperazine compounds are useful as t-cell activators |
KR20220120624A (ko) | 2019-12-23 | 2022-08-30 | 브리스톨-마이어스 스큅 컴퍼니 | T 세포 활성화제로서 유용한 치환된 피페라진 유도체 |
CA3162502A1 (en) | 2019-12-23 | 2021-07-01 | Yi Zhang | Smarca degraders and uses thereof |
BR112022012179A2 (pt) | 2019-12-23 | 2022-09-06 | Bristol Myers Squibb Co | Compostos de quinazolina substituída úteis como ativadores de célula t |
CN114846015A (zh) | 2019-12-23 | 2022-08-02 | 百时美施贵宝公司 | 用作t细胞激活剂的经取代的杂芳基化合物 |
EP4087874A1 (en) | 2020-01-06 | 2022-11-16 | HiFiBiO (HK) Limited | Anti-tnfr2 antibody and uses thereof |
TW202140011A (zh) | 2020-01-07 | 2021-11-01 | 美商銳新醫藥公司 | Shp2抑制劑給藥和治療癌症的方法 |
MX2022008421A (es) | 2020-01-07 | 2022-09-23 | Hifibio Hk Ltd | Anticuerpo anti-galectina-9 y usos del mismo. |
JP2023510393A (ja) | 2020-01-17 | 2023-03-13 | ノバルティス アーゲー | 骨髄異形成症候群または慢性骨髄単球性白血病の処置に使用するためのtim-3阻害剤と低メチル化剤とを含む組合せ |
US20230111593A1 (en) | 2020-02-14 | 2023-04-13 | Novartis Ag | Method of predicting response to chimeric antigen receptor therapy |
EP4110377A2 (en) | 2020-02-27 | 2023-01-04 | Novartis AG | Methods of making chimeric antigen receptor-expressing cells |
CN115427438A (zh) | 2020-02-27 | 2022-12-02 | 迈斯特治疗公司 | 肿瘤反应性t细胞的离体富集和扩增的方法及其相关组合物 |
TW202146452A (zh) | 2020-02-28 | 2021-12-16 | 瑞士商諾華公司 | 結合cd123和cd3之雙特異性抗體的給藥 |
KR20220164706A (ko) | 2020-03-03 | 2022-12-13 | 피아이씨 테라퓨틱스 인코포레이티드 | Eif4e 억제제 및 이의 용도 |
CN115244084A (zh) | 2020-03-06 | 2022-10-25 | 瑞泽恩制药公司 | 抗gitr抗体及其用途 |
EP4118118A1 (en) | 2020-03-09 | 2023-01-18 | Bristol-Myers Squibb Company | Antibodies to cd40 with enhanced agonist activity |
MX2022011534A (es) | 2020-03-19 | 2022-10-13 | Arcus Biosciences Inc | Compuestos de tetralina y tetrahidroquinolina como inhibidores de hif-2alfa. |
JP2023518423A (ja) | 2020-03-19 | 2023-05-01 | カイメラ セラピューティクス, インコーポレイテッド | Mdm2分解剤およびそれらの使用 |
TW202140441A (zh) | 2020-03-23 | 2021-11-01 | 美商必治妥美雅史谷比公司 | 經取代之側氧基異吲哚啉化合物 |
KR20230009386A (ko) | 2020-04-10 | 2023-01-17 | 주노 쎄러퓨티크스 인코퍼레이티드 | B-세포 성숙 항원을 표적화하는 키메라 항원 수용체로 조작된 세포 요법 관련 방법 및 용도 |
US20230192867A1 (en) | 2020-05-15 | 2023-06-22 | Bristol-Myers Squibb Company | Antibodies to garp |
JP2023528036A (ja) | 2020-06-02 | 2023-07-03 | アーカス バイオサイエンシズ インコーポレイティド | Tigitに対する抗体 |
TW202210483A (zh) | 2020-06-03 | 2022-03-16 | 美商凱麥拉醫療公司 | Irak降解劑之結晶型 |
AU2021288224A1 (en) | 2020-06-11 | 2023-01-05 | Novartis Ag | ZBTB32 inhibitors and uses thereof |
IL299131A (en) | 2020-06-18 | 2023-02-01 | Revolution Medicines Inc | Methods for delaying, preventing and treating acquired resistance to RAS inhibitors |
WO2021258010A1 (en) | 2020-06-19 | 2021-12-23 | Gossamer Bio Services, Inc. | Oxime compounds useful as t cell activators |
CN115916199A (zh) | 2020-06-23 | 2023-04-04 | 诺华股份有限公司 | 包含3-(1-氧代异吲哚啉-2-基)哌啶-2,6-二酮衍生物的给药方案 |
EP4172323A1 (en) | 2020-06-29 | 2023-05-03 | Flagship Pioneering Innovations V, Inc. | Viruses engineered to promote thanotransmission and their use in treating cancer |
US11857535B2 (en) | 2020-07-30 | 2024-01-02 | Kymera Therapeutics, Inc. | Methods of treating mutant lymphomas |
US20230271940A1 (en) | 2020-08-03 | 2023-08-31 | Novartis Ag | Heteroaryl substituted 3-(1-oxoisoindolin-2-yl)piperidine-2,6-dione derivatives and uses thereof |
WO2022033419A2 (en) | 2020-08-10 | 2022-02-17 | Shanghai Xbh Biotechnology Co., Ltd. | Compositions and methods for treating autoimmune diseases and cancers by targeting igsf8 |
EP4196792A1 (en) | 2020-08-17 | 2023-06-21 | BicycleTX Limited | Bicycle conjugates specific for nectin-4 and uses thereof |
WO2022043557A1 (en) | 2020-08-31 | 2022-03-03 | Advanced Accelerator Applications International Sa | Method of treating psma-expressing cancers |
US20230303700A1 (en) | 2020-08-31 | 2023-09-28 | Bristol-Myers Squibb Company | Cell localization signature and immunotherapy |
US20230338587A1 (en) | 2020-08-31 | 2023-10-26 | Advanced Accelerator Applications International Sa | Method of treating psma-expressing cancers |
MX2023002248A (es) | 2020-09-03 | 2023-05-16 | Revolution Medicines Inc | Uso de inhibidores de sos1 para tratar neoplasias malignas con mutaciones de shp2. |
PE20231207A1 (es) | 2020-09-15 | 2023-08-17 | Revolution Medicines Inc | Derivados indolicos como inhibidores de ras en el tratamiento del cancer |
JP2023544410A (ja) | 2020-10-05 | 2023-10-23 | ブリストル-マイヤーズ スクイブ カンパニー | タンパク質を濃縮するための方法 |
CA3198447A1 (en) | 2020-11-13 | 2022-05-19 | Novartis Ag | Combination therapies with chimeric antigen receptor (car)-expressing cells |
EP4253530A1 (en) | 2020-11-25 | 2023-10-04 | Shanghai Juncell Therapeutics Co., Ltd. | Tumor infiltration lymphocyte culture medium and application thereof |
EP4252754A1 (en) | 2020-11-25 | 2023-10-04 | Shanghai Juncell Therapeutics Co., Ltd. | Pharmaceutical composition for enhancing cell killing, and use thereof |
WO2022120353A1 (en) | 2020-12-02 | 2022-06-09 | Ikena Oncology, Inc. | Tead inhibitors and uses thereof |
KR20230131189A (ko) | 2020-12-02 | 2023-09-12 | 이케나 온콜로지, 인코포레이티드 | Tead 억제제 및 이의 용도 |
WO2022120179A1 (en) | 2020-12-03 | 2022-06-09 | Bristol-Myers Squibb Company | Multi-tumor gene signatures and uses thereof |
EP4259149A1 (en) | 2020-12-08 | 2023-10-18 | Infinity Pharmaceuticals, Inc. | Eganelisib for use in the treatment of pd-l1 negative cancer |
CN117396472A (zh) | 2020-12-22 | 2024-01-12 | 上海齐鲁锐格医药研发有限公司 | Sos1抑制剂及其用途 |
EP4267105A1 (en) | 2020-12-28 | 2023-11-01 | Bristol-Myers Squibb Company | Antibody compositions and methods of use thereof |
EP4267172A1 (en) | 2020-12-28 | 2023-11-01 | Bristol-Myers Squibb Company | Subcutaneous administration of pd1/pd-l1 antibodies |
CN116761622A (zh) * | 2021-01-08 | 2023-09-15 | 苏州丁孚靶点生物技术有限公司 | 药物产品及其用途 |
EP4274597A1 (en) | 2021-01-11 | 2023-11-15 | BicycleTX Limited | Methods for treating cancer |
TW202246334A (zh) | 2021-02-02 | 2022-12-01 | 美商美國禮來大藥廠 | Gitr拮抗劑及其使用方法 |
US20230091528A1 (en) | 2021-02-02 | 2023-03-23 | Liminal Biosciences Limited | Gpr84 antagonists and uses thereof |
AU2022216810A1 (en) | 2021-02-02 | 2023-08-24 | Liminal Biosciences Limited | Gpr84 antagonists and uses thereof |
WO2022169921A1 (en) | 2021-02-04 | 2022-08-11 | Bristol-Myers Squibb Company | Benzofuran compounds as sting agonists |
CR20230382A (es) | 2021-02-12 | 2023-09-06 | Hoffmann La Roche | Derivados de tetrahidroazepina bicíclicos para el tratamiento del cáncer |
AU2022220869A1 (en) | 2021-02-15 | 2023-08-24 | Kymera Therapeutics, Inc. | Irak4 degraders and uses thereof |
GB202102396D0 (en) | 2021-02-19 | 2021-04-07 | Adc Therapeutics Sa | Molecular adjuvant |
WO2022187856A1 (en) | 2021-03-05 | 2022-09-09 | Nimbus Saturn, Inc. | Hpk1 antagonists and uses thereof |
WO2022192145A1 (en) | 2021-03-08 | 2022-09-15 | Blueprint Medicines Corporation | Map4k1 inhibitors |
US11918582B2 (en) | 2021-03-15 | 2024-03-05 | Rapt Therapeutics, Inc. | Pyrazole pyrimidine compounds and uses thereof |
US20220325287A1 (en) | 2021-03-31 | 2022-10-13 | Flagship Pioneering Innovations V, Inc. | Thanotransmission polypeptides and their use in treating cancer |
EP4314068A1 (en) | 2021-04-02 | 2024-02-07 | The Regents Of The University Of California | Antibodies against cleaved cdcp1 and uses thereof |
IL307338A (en) | 2021-04-05 | 2023-11-01 | Bristol Myers Squibb Co | Pyridinyl substituted oxisoisoindoline compounds for cancer therapy |
US11718601B2 (en) | 2021-04-06 | 2023-08-08 | Bristol-Myers Squibb Company | Pyridinyl substituted oxoisoindoline compounds |
TW202304979A (zh) | 2021-04-07 | 2023-02-01 | 瑞士商諾華公司 | 抗TGFβ抗體及其他治療劑用於治療增殖性疾病之用途 |
JP2024514879A (ja) | 2021-04-16 | 2024-04-03 | イケナ オンコロジー, インコーポレイテッド | Mek阻害剤及びその使用 |
EP4334324A1 (en) | 2021-05-05 | 2024-03-13 | Revolution Medicines, Inc. | Covalent ras inhibitors and uses thereof |
AU2022268962A1 (en) | 2021-05-05 | 2023-12-14 | Revolution Medicines, Inc. | Ras inhibitors for the treatment of cancer |
AR125782A1 (es) | 2021-05-05 | 2023-08-16 | Revolution Medicines Inc | Inhibidores de ras |
CN117813327A (zh) * | 2021-05-10 | 2024-04-02 | 美帝马布生物公司 | 抗gitr抗体及其用途 |
AR125874A1 (es) | 2021-05-18 | 2023-08-23 | Novartis Ag | Terapias de combinación |
TW202313602A (zh) | 2021-05-21 | 2023-04-01 | 美商阿克思生物科學有限公司 | Axl化合物 |
CN117337288A (zh) | 2021-05-21 | 2024-01-02 | 艾库斯生物科学有限公司 | Axl抑制剂化合物 |
TW202307210A (zh) | 2021-06-01 | 2023-02-16 | 瑞士商諾華公司 | Cd19和cd22嵌合抗原受體及其用途 |
CA3218590A1 (en) | 2021-06-07 | 2022-12-15 | Providence Health & Services - Oregon | Cxcr5, pd-1, and icos expressing tumor reactive cd4 t cells and their use |
AU2022303363A1 (en) | 2021-06-29 | 2024-01-18 | Flagship Pioneering Innovations V, Inc. | Immune cells engineered to promote thanotransmission and uses thereof |
US20230134932A1 (en) | 2021-08-25 | 2023-05-04 | PIC Therapeutics, Inc. | Eif4e inhibitors and uses thereof |
WO2023028235A1 (en) | 2021-08-25 | 2023-03-02 | PIC Therapeutics, Inc. | Eif4e inhibitors and uses thereof |
CA3231180A1 (en) | 2021-09-08 | 2023-03-16 | Redona Therapeutics, Inc. | Papd5 and/or papd7 inhibiting 4-oxo-1,4-dihydroquinoline-3-carboxylic acid derivatives |
AR127308A1 (es) | 2021-10-08 | 2024-01-10 | Revolution Medicines Inc | Inhibidores ras |
US20230159466A1 (en) | 2021-10-29 | 2023-05-25 | Arcus Biosciences, Inc. | Inhibitors of hif-2alpha and methods of use thereof |
WO2023114984A1 (en) | 2021-12-17 | 2023-06-22 | Ikena Oncology, Inc. | Tead inhibitors and uses thereof |
WO2023114954A1 (en) | 2021-12-17 | 2023-06-22 | Genzyme Corporation | Pyrazolopyrazine compounds as shp2 inhibitors |
WO2023122772A1 (en) | 2021-12-22 | 2023-06-29 | Gossamer Bio Services, Inc. | Oxime derivatives useful as t cell activators |
WO2023122778A1 (en) | 2021-12-22 | 2023-06-29 | Gossamer Bio Services, Inc. | Pyridazinone derivatives useful as t cell activators |
WO2023122777A1 (en) | 2021-12-22 | 2023-06-29 | Gossamer Bio Services, Inc. | Oxime derivatives useful as t cell activators |
WO2023150186A1 (en) | 2022-02-01 | 2023-08-10 | Arvinas Operations, Inc. | Dgk targeting compounds and uses thereof |
EP4227307A1 (en) | 2022-02-11 | 2023-08-16 | Genzyme Corporation | Pyrazolopyrazine compounds as shp2 inhibitors |
WO2023154905A1 (en) | 2022-02-14 | 2023-08-17 | Gilead Sciences, Inc. | Antiviral pyrazolopyridinone compounds |
WO2023172940A1 (en) | 2022-03-08 | 2023-09-14 | Revolution Medicines, Inc. | Methods for treating immune refractory lung cancer |
WO2023173011A1 (en) | 2022-03-09 | 2023-09-14 | Bristol-Myers Squibb Company | Transient expression of therapeutic proteins |
WO2023173053A1 (en) | 2022-03-10 | 2023-09-14 | Ikena Oncology, Inc. | Mek inhibitors and uses thereof |
WO2023173057A1 (en) | 2022-03-10 | 2023-09-14 | Ikena Oncology, Inc. | Mek inhibitors and uses thereof |
WO2023178192A1 (en) | 2022-03-15 | 2023-09-21 | Compugen Ltd. | Il-18bp antagonist antibodies and their use in monotherapy and combination therapy in the treatment of cancer |
WO2023175614A1 (en) | 2022-03-15 | 2023-09-21 | Yeda Research And Development Co. Ltd. | Anti glucocorticoid-induced tnfr-related (gitr) protein antibodies and uses thereof |
WO2023178329A1 (en) | 2022-03-18 | 2023-09-21 | Bristol-Myers Squibb Company | Methods of isolating polypeptides |
WO2023211889A1 (en) | 2022-04-25 | 2023-11-02 | Ikena Oncology, Inc. | Polymorphic compounds and uses thereof |
WO2023215719A1 (en) | 2022-05-02 | 2023-11-09 | Arcus Biosciences, Inc. | Anti-tigit antibodies and uses of the same |
WO2023215560A1 (en) | 2022-05-05 | 2023-11-09 | Atoosa Corporation | Tumor cell/immune cell multivalent receptor engager – bio-nanoparticle (timre-bnp) |
TW202404581A (zh) | 2022-05-25 | 2024-02-01 | 美商醫肯納腫瘤學公司 | Mek抑制劑及其用途 |
WO2023235847A1 (en) | 2022-06-02 | 2023-12-07 | Bristol-Myers Squibb Company | Antibody compositions and methods of use thereof |
WO2023240263A1 (en) | 2022-06-10 | 2023-12-14 | Revolution Medicines, Inc. | Macrocyclic ras inhibitors |
WO2023250400A1 (en) | 2022-06-22 | 2023-12-28 | Juno Therapeutics, Inc. | Treatment methods for second line therapy of cd19-targeted car t cells |
US20240124490A1 (en) | 2022-07-15 | 2024-04-18 | Arcus Biosciences, Inc. | Inhibitors of hpk1 and methods of use thereof |
WO2024020034A1 (en) | 2022-07-20 | 2024-01-25 | Arcus Biosciences, Inc. | Cbl-b inhibitors and methods of use thereof |
WO2024028365A1 (en) | 2022-08-02 | 2024-02-08 | Liminal Biosciences Limited | Substituted pyridone gpr84 antagonists and uses thereof |
WO2024028364A1 (en) | 2022-08-02 | 2024-02-08 | Liminal Biosciences Limited | Aryl-triazolyl and related gpr84 antagonists and uses thereof |
WO2024028363A1 (en) | 2022-08-02 | 2024-02-08 | Liminal Biosciences Limited | Heteroaryl carboxamide and related gpr84 antagonists and uses thereof |
WO2024031091A2 (en) | 2022-08-05 | 2024-02-08 | Juno Therapeutics, Inc. | Chimeric antigen receptors specific for gprc5d and bcma |
WO2024036100A1 (en) | 2022-08-08 | 2024-02-15 | Bristol-Myers Squibb Company | Substituted tetrazolyl compounds useful as t cell activators |
WO2024036101A1 (en) | 2022-08-09 | 2024-02-15 | Bristol-Myers Squibb Company | Tertiary amine substituted bicyclic compounds useful as t cell activators |
WO2024033388A1 (en) | 2022-08-11 | 2024-02-15 | F. Hoffmann-La Roche Ag | Bicyclic tetrahydrothiazepine derivatives |
WO2024033457A1 (en) | 2022-08-11 | 2024-02-15 | F. Hoffmann-La Roche Ag | Bicyclic tetrahydrothiazepine derivatives |
WO2024033389A1 (en) | 2022-08-11 | 2024-02-15 | F. Hoffmann-La Roche Ag | Bicyclic tetrahydrothiazepine derivatives |
WO2024033458A1 (en) | 2022-08-11 | 2024-02-15 | F. Hoffmann-La Roche Ag | Bicyclic tetrahydroazepine derivatives |
WO2024059142A1 (en) | 2022-09-14 | 2024-03-21 | Arcus Biosciences, Inc. | Dispersions of etrumadenant |
US20240174732A1 (en) | 2022-10-05 | 2024-05-30 | Flagship Pioneering Innovations V, Inc. | Nucleic acid molecules encoding trif and additional polypeptides and their use in treating cancer |
WO2024081916A1 (en) | 2022-10-14 | 2024-04-18 | Black Diamond Therapeutics, Inc. | Methods of treating cancers using isoquinoline or 6-aza-quinoline derivatives |
WO2024081385A1 (en) | 2022-10-14 | 2024-04-18 | Arcus Biosciences, Inc. | Hpk1 inhibitors and methods of use thereof |
WO2024086718A1 (en) | 2022-10-20 | 2024-04-25 | Arcus Biosciences, Inc. | Lyophilized formulations of cd73 compounds |
US20240208961A1 (en) | 2022-11-22 | 2024-06-27 | PIC Therapeutics, Inc. | Eif4e inhibitors and uses thereof |
WO2024129778A2 (en) | 2022-12-13 | 2024-06-20 | Juno Therapeutics, Inc. | Chimeric antigen receptors specific for baff-r and cd19 and methods and uses thereof |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20020150993A1 (en) * | 1998-02-09 | 2002-10-17 | Genentech, Inc. | Novel tumor necrosis factor receptor homolog and nucleic acids encoding the same |
US20040110930A1 (en) * | 2002-10-03 | 2004-06-10 | Reinl Stephen J. | Multimeric protein engineering |
CN1809589A (zh) * | 2003-05-23 | 2006-07-26 | Wyeth公司 | Gitr配体和gitr配体相关分子和抗体及其应用 |
US20070098719A1 (en) * | 2005-03-25 | 2007-05-03 | Tolerrx, Inc. | GITR binding molecules and uses therefor |
Family Cites Families (104)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
NL154598B (nl) | 1970-11-10 | 1977-09-15 | Organon Nv | Werkwijze voor het aantonen en bepalen van laagmoleculire verbindingen en van eiwitten die deze verbindingen specifiek kunnen binden, alsmede testverpakking. |
US3817837A (en) | 1971-05-14 | 1974-06-18 | Syva Corp | Enzyme amplification assay |
US3939350A (en) | 1974-04-29 | 1976-02-17 | Board Of Trustees Of The Leland Stanford Junior University | Fluorescent immunoassay employing total reflection for activation |
US3996345A (en) | 1974-08-12 | 1976-12-07 | Syva Company | Fluorescence quenching with immunological pairs in immunoassays |
US4275149A (en) | 1978-11-24 | 1981-06-23 | Syva Company | Macromolecular environment control in specific receptor assays |
US4277437A (en) | 1978-04-05 | 1981-07-07 | Syva Company | Kit for carrying out chemically induced fluorescence immunoassay |
US4366241A (en) | 1980-08-07 | 1982-12-28 | Syva Company | Concentrating zone method in heterogeneous immunoassays |
GB8308235D0 (en) | 1983-03-25 | 1983-05-05 | Celltech Ltd | Polypeptides |
US4816567A (en) | 1983-04-08 | 1989-03-28 | Genentech, Inc. | Recombinant immunoglobin preparations |
US4683195A (en) | 1986-01-30 | 1987-07-28 | Cetus Corporation | Process for amplifying, detecting, and/or-cloning nucleic acid sequences |
GB8607679D0 (en) | 1986-03-27 | 1986-04-30 | Winter G P | Recombinant dna product |
EP0307434B2 (en) | 1987-03-18 | 1998-07-29 | Scotgen Biopharmaceuticals, Inc. | Altered antibodies |
ES2052027T5 (es) | 1988-11-11 | 2005-04-16 | Medical Research Council | Clonacion de secuencias de dominio variable de inmunoglobulina. |
DE3920358A1 (de) | 1989-06-22 | 1991-01-17 | Behringwerke Ag | Bispezifische und oligospezifische, mono- und oligovalente antikoerperkonstrukte, ihre herstellung und verwendung |
EP0438310A1 (en) | 1990-01-19 | 1991-07-24 | Merck & Co. Inc. | Method for producing recombinant immunoglobuline |
US6916605B1 (en) * | 1990-07-10 | 2005-07-12 | Medical Research Council | Methods for producing members of specific binding pairs |
EP0542810A1 (en) | 1990-08-02 | 1993-05-26 | B.R. Centre Limited | Methods for the production of proteins with a desired function |
DK1136556T3 (da) | 1991-11-25 | 2005-10-03 | Enzon Inc | Fremgangsmåde til fremstilling af multivalente antigen-bindende proteiner |
US7381803B1 (en) | 1992-03-27 | 2008-06-03 | Pdl Biopharma, Inc. | Humanized antibodies against CD3 |
US6005079A (en) | 1992-08-21 | 1999-12-21 | Vrije Universiteit Brussels | Immunoglobulins devoid of light chains |
DK0656946T4 (da) | 1992-08-21 | 2010-07-26 | Univ Bruxelles | Immunoglobuliner uden lette kæder |
AU6796094A (en) | 1993-04-29 | 1994-11-21 | Raymond Hamers | Production of antibodies or (functionalized) fragments thereof derived from heavy chain immunoglobulins of (camelidae) |
US6309636B1 (en) | 1995-09-14 | 2001-10-30 | Cancer Research Institute Of Contra Costa | Recombinant peptides derived from the Mc3 anti-BA46 antibody, methods of use thereof, and methods of humanizing antibody peptides |
WO1997003715A1 (en) | 1995-07-21 | 1997-02-06 | The General Hospital Corporation | Method and apparatus of enhancing the delivery of a pharmaceutical formulation |
DE69738749D1 (de) | 1996-08-16 | 2008-07-17 | Schering Corp | Zelloberflächen-antigen aus säugetieren und verwandte reagenzien |
UA76934C2 (en) | 1996-10-04 | 2006-10-16 | Chugai Pharmaceutical Co Ltd | Reconstructed human anti-hm 1.24 antibody, coding dna, vector, host cell, method for production of reconstructed human antibody, pharmaceutical composition and drug for treating myeloma containing reconstructed human anti-hm 1.24 antibody |
US6800744B1 (en) | 1997-07-02 | 2004-10-05 | Genome Therapeutics Corporation | Nucleic acid and amino acid sequences relating to Streptococcus pneumoniae for diagnostics and therapeutics |
US6689607B2 (en) | 1997-10-21 | 2004-02-10 | Human Genome Sciences, Inc. | Human tumor, necrosis factor receptor-like proteins TR11, TR11SV1 and TR11SV2 |
US6503184B1 (en) | 1997-10-21 | 2003-01-07 | Human Genome Sciences, Inc. | Human tumor necrosis factor receptor-like proteins TR11, TR11SV1 and TR11SV2 |
JP2001520039A (ja) | 1997-10-21 | 2001-10-30 | ヒューマン ジノーム サイエンシーズ, インコーポレイテッド | ヒト腫瘍壊死因子レセプター様タンパク質、tr11,tr11sv1およびtr11sv2 |
US6326482B1 (en) | 1999-04-23 | 2001-12-04 | Genentech, Inc. | SH2 domain-containing peptides |
WO2000050459A1 (en) | 1999-02-24 | 2000-08-31 | Human Genome Sciences, Inc. | Human tumor necrosis factor receptor-like proteins tr11, tr11sv1, and tr11sv2 |
US20020010320A1 (en) | 1999-04-05 | 2002-01-24 | James W. Fett | Chemeric and humanized antibodies to angiogenin |
GB9908533D0 (en) | 1999-04-14 | 1999-06-09 | Novartis Ag | Organic compounds |
IL147442A0 (en) | 1999-07-12 | 2002-08-14 | Genentech Inc | Promotion or inhibition of angiogenesis and cardiovscularization by tumor necrosis factor ligand/receptor homologs |
US7279160B2 (en) * | 2000-05-02 | 2007-10-09 | The Uab Research Foundation | Combinations of DR5 antibodies and other therapeutic agents |
JP2004511430A (ja) * | 2000-05-24 | 2004-04-15 | イムクローン システムズ インコーポレイティド | 二重特異性免疫グロブリン様抗原結合蛋白および製造方法 |
AU2001268855A1 (en) | 2000-05-26 | 2001-12-03 | National Research Council Of Canada | Single-domain antigen-binding antibody fragments derived from llama antibodies |
US7329745B2 (en) | 2000-06-13 | 2008-02-12 | City Of Hope | Single-chain antibodies against human insulin-like growth factor I receptor: expression, purification, and effect on tumor growth |
KR100823764B1 (ko) * | 2000-06-22 | 2008-04-21 | 제넨테크, 인크. | 아고니스트 안티-티알케이-씨 모노클로날 항체 |
EP1392359B2 (en) | 2001-05-11 | 2013-03-13 | Ludwig Institute for Cancer Research Ltd. | Specific binding proteins and uses thereof |
US20030133936A1 (en) * | 2001-07-12 | 2003-07-17 | Byrne Michael Chapman | CD25markers and uses thereof |
US6701566B2 (en) * | 2001-07-26 | 2004-03-09 | Craig T. Rooke | Trailer electrical connector cleaning system |
US7658924B2 (en) | 2001-10-11 | 2010-02-09 | Amgen Inc. | Angiopoietin-2 specific binding agents |
US7365167B2 (en) * | 2001-11-26 | 2008-04-29 | Cell Matrix, Inc. | Humanized collagen antibodies and related methods |
EP1449851A4 (en) | 2001-11-27 | 2005-11-16 | Mochida Pharm Co Ltd | NEUTRALIZING ANTIBODIES OF IL13 ALPHA RECEPTOR 1 |
EP1554576B9 (en) | 2001-12-03 | 2008-08-20 | Amgen Fremont Inc. | Identification of high affinity molecules by limited dilution screening |
US20040014194A1 (en) | 2002-03-27 | 2004-01-22 | Schering Corporation | Beta-secretase crystals and methods for preparing and using the same |
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 |
AU2003231554A1 (en) | 2002-04-30 | 2003-11-17 | Kyowa Hakko Kogyo Co., Ltd. | Antibody to human insulin-like growth factor |
US7396913B2 (en) * | 2002-10-14 | 2008-07-08 | Abbott Laboratories | Erythropoietin receptor binding antibodies |
EA010570B1 (ru) * | 2002-11-07 | 2008-10-30 | Иммьюноджен, Инк. | Антитело к cd33 и способы его применения |
EP1565491B1 (en) | 2002-11-20 | 2010-03-31 | Cancer Research Technology Limited | Antibodies binding to human magic roundabout (mr), polypeptides and uses thereof for inhibition of angiogenesis |
US7670604B2 (en) | 2002-12-13 | 2010-03-02 | Aurelium Biopharma, Inc. | Vimentin directed diagnostics and therapeutics for multidrug resistant neoplastic disease |
US20060167230A1 (en) | 2003-01-20 | 2006-07-27 | Takaki Koga | Anti-pci neutralizing antibody |
WO2004067568A2 (en) | 2003-01-24 | 2004-08-12 | Applied Molecular Evolution, Inc | Human il-1 beta antagonists |
EP1462114A1 (en) | 2003-03-28 | 2004-09-29 | Universiteit Utrecht Holding B.V. | Methods and means to suppress symptons of an allergic disease by inhibiting the glucocorticoid-induced tumor necrosis factor receptor (GRIT or TNFRSF18) |
US7410483B2 (en) | 2003-05-23 | 2008-08-12 | Novare Surgical Systems, Inc. | Hand-actuated device for remote manipulation of a grasping tool |
EP1631588A2 (en) * | 2003-05-23 | 2006-03-08 | Wyeth | Gitr ligand and gitr ligand-related molecules and antibodies and uses thereof |
EP2267006A1 (en) | 2003-05-30 | 2010-12-29 | Intercell AG | Enterococcus antigens |
WO2005007190A1 (en) | 2003-07-11 | 2005-01-27 | Schering Corporation | Agonists or antagonists of the clucocorticoid-induced tumour necrosis factor receptor (gitr) or its ligand for the treatment of immune disorders, infections and cancer |
WO2005044853A2 (en) | 2003-11-01 | 2005-05-19 | Genentech, Inc. | Anti-vegf antibodies |
EP1670827A2 (en) | 2003-09-05 | 2006-06-21 | Eli Lilly And Company | Anti-ghrelin antibodies |
AU2003271174A1 (en) | 2003-10-10 | 2005-04-27 | Chugai Seiyaku Kabushiki Kaisha | Double specific antibodies substituting for functional protein |
DK1678314T3 (da) | 2003-10-22 | 2012-12-03 | Keck Graduate Inst | Fremgangsmåde til syntetisering af heteromultimere polypeptider i gær ved anvendelse af en haploid parringsstrategi |
PL1692516T3 (pl) | 2003-10-24 | 2011-05-31 | Immunaid Pty Ltd | Sposób terapii |
JP2007534307A (ja) | 2003-11-07 | 2007-11-29 | キュラジェン コーポレイション | 分泌性白血球プロテアーゼインヒビターに対する抗体 |
PE20090046A1 (es) | 2003-11-10 | 2009-01-26 | Schering Corp | Anticuerpo recombinante humanizado anti-interleuquina 10 |
US7312320B2 (en) * | 2003-12-10 | 2007-12-25 | Novimmune Sa | Neutralizing antibodies and methods of use thereof |
US20080025913A1 (en) | 2003-12-15 | 2008-01-31 | Bowdish Katherine S | Novel Anti-Dc-Sign Antibodies |
US20050153872A1 (en) | 2004-01-12 | 2005-07-14 | Xiao-Qing Qiu | Methods and compositions for the treatment of infection |
UY28886A1 (es) | 2004-05-10 | 2005-12-30 | Boehringer Ingelheim Int | Anticuerpos que consisten en polipéptidos y derivados conprendiendo tres secuencias conteniendo respectivamente los siguientes números de seq. id: 1-3 y 4-6; 7-9 y 10-12 y 13-15 ó 16-18 |
WO2006083289A2 (en) * | 2004-06-04 | 2006-08-10 | Duke University | Methods and compositions for enhancement of immunity by in vivo depletion of immunosuppressive cell activity |
WO2005120571A2 (en) | 2004-06-07 | 2005-12-22 | Ramot At Tel Aviv University Ltd. | Method of passive immunization against disease or disorder characterized by amyloid aggregation with diminished risk of neuroinflammation |
EP1805510B1 (en) | 2004-09-08 | 2012-02-22 | Immunaid Pty Ltd | Therapeutic strategy for treating autoimmune and degenerative diseases |
AU2005291486A1 (en) * | 2004-10-01 | 2006-04-13 | Max-Planck-Gesellschaft Zur Forderung Der Wissenschaften E.V. | Novel antibodies directed to the mammalian EAG1 ion channel protein |
AU2005306997B2 (en) * | 2004-10-25 | 2012-07-05 | Merck Sharp & Dohme Corp. | Anti-ADDL antibodies and uses thereof |
US20090061485A1 (en) | 2004-12-22 | 2009-03-05 | Chugai Seiyaku Kabushiki Kaisha | Method of Producing an Antibody Using a Cell in Which the Function of Fucose Transporter Is Inhibited |
JP2008527998A (ja) | 2005-01-19 | 2008-07-31 | ジェンザイム・コーポレイション | Nsclcの診断のためのgitr抗体 |
CN101115771B (zh) * | 2005-02-03 | 2013-06-05 | 安迪拓普有限公司 | 人类抗体和蛋白质 |
JP2008532559A (ja) | 2005-03-19 | 2008-08-21 | メディカル リサーチ カウンシル | ウイルス感染の治療及び予防又は治療及び予防の改善 |
JP2006278814A (ja) | 2005-03-30 | 2006-10-12 | Konica Minolta Opto Inc | 回路接続構造および回路接続方法 |
CA2603414C (en) | 2005-03-31 | 2012-09-18 | Biomedics Inc. | Anti-cd20 monoclonal antibody |
WO2006117910A1 (ja) | 2005-04-28 | 2006-11-09 | Mochida Pharmaceutical Co., Ltd. | 抗血小板膜糖蛋白質ⅵモノクローナル抗体 |
CA2609262A1 (en) | 2005-06-03 | 2006-12-07 | Mochida Pharmaceutical Co., Ltd. | Anti-cd14 antibody fusion protein |
WO2006132272A1 (ja) | 2005-06-07 | 2006-12-14 | The University Of Tokyo | 抗体の作製方法 |
US7741448B2 (en) | 2005-06-21 | 2010-06-22 | Medical & Biological Laboratories Co., Ltd. | Antibody having inhibitory effect on amyloid fibril formation |
GB0514319D0 (en) | 2005-07-13 | 2006-06-14 | Secr Defence | Antibodies for anthrax |
US20110212086A1 (en) | 2006-01-19 | 2011-09-01 | Genzyme Corporation | GITR Antibodies For The Treatment of Cancer |
CN101600793B (zh) | 2006-05-19 | 2013-06-26 | 奥尔德生物制药公司 | 用于获得抗原特异性b细胞的克隆群体的培养方法 |
US20080241069A1 (en) * | 2006-08-04 | 2008-10-02 | Yvonne Paterson | Methods and compositions for treating IgE-mediated diseases |
PT2059535E (pt) * | 2006-08-18 | 2014-01-29 | Novartis Ag | Anticorpos específicos do prlr e suas utulizações |
EP2066349B1 (en) * | 2006-09-08 | 2012-03-28 | MedImmune, LLC | Humanized anti-cd19 antibodies and their use in treatment of tumors, transplantation and autoimmune diseases |
JP2008278814A (ja) * | 2007-05-11 | 2008-11-20 | Igaku Seibutsugaku Kenkyusho:Kk | アゴニスティック抗ヒトgitr抗体による免疫制御の解除とその応用 |
EP2175884B8 (en) | 2007-07-12 | 2017-02-22 | GITR, Inc. | Combination therapies employing gitr binding molecules |
US7867497B2 (en) * | 2007-09-24 | 2011-01-11 | Vanderbilt University | Monoclonal antibodies to respiratory syncytial virus and uses therefor |
LT3023438T (lt) | 2009-09-03 | 2020-05-11 | Merck Sharp & Dohme Corp. | Anti-gitr antikūnai |
SG10201501784YA (en) | 2009-12-07 | 2015-05-28 | Univ Leland Stanford Junior | Methods for enhancing anti-tumor antibody therapy |
DK2542590T4 (da) | 2010-03-05 | 2020-07-13 | Univ Johns Hopkins | Sammensætninger og fremgangsmåde til målrettede immunomodulatoriske antistof-fer og fusionproteiner |
WO2013039954A1 (en) | 2011-09-14 | 2013-03-21 | Sanofi | Anti-gitr antibodies |
CA2853341A1 (en) | 2011-10-28 | 2013-05-02 | Merck Sharp & Dohme Corp. | Engineered lower eukaryotic host strains for recombinant protein expression |
KR101566539B1 (ko) | 2012-06-08 | 2015-11-05 | 국립암센터 | 신규한 Th2 세포 전환용 에피토프 및 이의 용도 |
AR097306A1 (es) | 2013-08-20 | 2016-03-02 | Merck Sharp & Dohme | Modulación de la inmunidad tumoral |
TW201605896A (zh) | 2013-08-30 | 2016-02-16 | 安美基股份有限公司 | Gitr抗原結合蛋白 |
-
2010
- 2010-08-31 LT LTEP15196341.0T patent/LT3023438T/lt unknown
- 2010-08-31 EP EP10814345.4A patent/EP2473531A4/en not_active Withdrawn
- 2010-08-31 PL PL15196341T patent/PL3023438T3/pl unknown
- 2010-08-31 RU RU2016128037A patent/RU2646139C1/ru active
- 2010-08-31 US US13/388,270 patent/US8709424B2/en active Active
- 2010-08-31 BR BR112012004823-6A patent/BR112012004823B1/pt not_active IP Right Cessation
- 2010-08-31 CA CA3067609A patent/CA3067609A1/en not_active Abandoned
- 2010-08-31 IN IN1920DEN2012 patent/IN2012DN01920A/en unknown
- 2010-08-31 MX MX2012002697A patent/MX340953B/es active IP Right Grant
- 2010-08-31 RU RU2012112829/10A patent/RU2595409C2/ru active
- 2010-08-31 CN CN2010800497565A patent/CN102574924A/zh active Pending
- 2010-08-31 IN IN2826DEN2015 patent/IN2015DN02826A/en unknown
- 2010-08-31 AU AU2010289677A patent/AU2010289677B2/en not_active Ceased
- 2010-08-31 ES ES15196341T patent/ES2788869T3/es active Active
- 2010-08-31 DK DK15196341.0T patent/DK3023438T3/da active
- 2010-08-31 SG SG2012015418A patent/SG178991A1/en unknown
- 2010-08-31 WO PCT/US2010/047248 patent/WO2011028683A1/en active Application Filing
- 2010-08-31 CN CN201410047532.0A patent/CN103951753B/zh active Active
- 2010-08-31 KR KR1020177030051A patent/KR20170119746A/ko not_active Application Discontinuation
- 2010-08-31 PT PT151963410T patent/PT3023438T/pt unknown
- 2010-08-31 EP EP15196341.0A patent/EP3023438B1/en active Active
- 2010-08-31 KR KR1020127008518A patent/KR101790802B1/ko active IP Right Grant
- 2010-08-31 SI SI201032004T patent/SI3023438T1/sl unknown
- 2010-08-31 JP JP2012527963A patent/JP6294585B2/ja not_active Expired - Fee Related
- 2010-08-31 CA CA2772613A patent/CA2772613C/en active Active
- 2010-08-31 HU HUE15196341A patent/HUE049825T2/hu unknown
-
2014
- 2014-04-24 US US14/261,152 patent/US9701751B2/en active Active
-
2016
- 2016-02-22 JP JP2016030770A patent/JP2016146834A/ja not_active Withdrawn
-
2017
- 2017-06-16 JP JP2017118446A patent/JP2017195893A/ja not_active Withdrawn
- 2017-06-16 US US15/625,307 patent/US10400040B2/en active Active
-
2020
- 2020-05-05 HR HRP20200720TT patent/HRP20200720T1/hr unknown
- 2020-05-13 CY CY20201100445T patent/CY1123404T1/el unknown
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20020150993A1 (en) * | 1998-02-09 | 2002-10-17 | Genentech, Inc. | Novel tumor necrosis factor receptor homolog and nucleic acids encoding the same |
US20040110930A1 (en) * | 2002-10-03 | 2004-06-10 | Reinl Stephen J. | Multimeric protein engineering |
CN1809589A (zh) * | 2003-05-23 | 2006-07-26 | Wyeth公司 | Gitr配体和gitr配体相关分子和抗体及其应用 |
US20070098719A1 (en) * | 2005-03-25 | 2007-05-03 | Tolerrx, Inc. | GITR binding molecules and uses therefor |
Non-Patent Citations (1)
Title |
---|
ADAM D. COHEN等: "Agonist Anti-GITR Antibody Enhances Vaccine-Induced CD8+ T-Cell Responses and Tumor Immunity", 《CANCER RES》, vol. 66, no. 9, 1 May 2006 (2006-05-01), pages 4904 - 4912, XP055049643, DOI: doi:10.1158/0008-5472.CAN-05-2813 * |
Cited By (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN105829343A (zh) * | 2013-08-30 | 2016-08-03 | 美国安进公司 | Gitr抗原结合蛋白 |
CN106459203A (zh) * | 2014-06-06 | 2017-02-22 | 百时美施贵宝公司 | 抗糖皮质激素诱导肿瘤坏死因子受体(gitr)的抗体及其用途 |
CN107001476A (zh) * | 2014-10-08 | 2017-08-01 | 诺华股份有限公司 | 用于增强的免疫应答和癌症治疗的组合物和方法 |
CN107249624A (zh) * | 2015-02-27 | 2017-10-13 | 默沙东公司 | 抗人类pd‑1单克隆抗体的晶体 |
CN107249624B (zh) * | 2015-02-27 | 2023-01-31 | 默沙东有限责任公司 | 抗人类pd-1单克隆抗体的晶体 |
CN108650886A (zh) * | 2015-07-23 | 2018-10-12 | 伊布里克斯公司 | 多价和多特异性gitr-结合融合蛋白 |
CN108473579A (zh) * | 2015-10-22 | 2018-08-31 | 埃博灵克斯股份有限公司 | Gitr激动剂 |
CN108473579B (zh) * | 2015-10-22 | 2022-03-01 | 埃博灵克斯股份有限公司 | Gitr激动剂 |
CN110461874A (zh) * | 2017-06-30 | 2019-11-15 | 江苏恒瑞医药股份有限公司 | 抗gitr抗体、其抗原结合片段及其医药用途 |
WO2019201301A1 (zh) * | 2018-04-20 | 2019-10-24 | 信达生物制药(苏州)有限公司 | 抗gitr抗体及其用途 |
CN111918878A (zh) * | 2018-04-20 | 2020-11-10 | 信达生物制药(苏州)有限公司 | 抗gitr抗体及其用途 |
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN102574924A (zh) | 抗-gitr抗体 | |
US20230044739A1 (en) | Anti il-36r antibodies combination therapy | |
ES2755732T3 (es) | Anticuerpos anti IL-36R | |
CN101326196B (zh) | 神经纤毛蛋白拮抗剂 | |
CN102131828B (zh) | 针对人程序性死亡受体pd-1的抗体 | |
CN102782149B (zh) | 经工程改造的抗-tslp抗体 | |
CN105934253A (zh) | 使用pd-1轴结合拮抗剂和抗her2抗体治疗her2阳性癌症的方法 | |
CN106102774A (zh) | 包含ox40结合激动剂和pd‑1轴结合拮抗剂的组合疗法 | |
CN101986784A (zh) | 基因工程tslpr抗体 | |
CN103282495A (zh) | 新的抗dr5抗体 | |
CN110407941A (zh) | Cd39的高亲和力抗体及其用途 | |
CN101679519A (zh) | Cd200r的抗体 | |
EP2882456A1 (en) | Use of il-20 antagonists for treating liver diseases | |
KR20200092976A (ko) | 항-cd137 항체 및 이의 용도 | |
CN101370832B (zh) | 结合多肽及其用途 | |
US20110117080A1 (en) | Anti-REG4 Antibodies |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C53 | Correction of patent of invention or patent application | ||
CB02 | Change of applicant information |
Address after: new jersey Applicant after: Schering Corporation Address before: new jersey Applicant before: SCHERING CORP (US) |
|
COR | Change of bibliographic data |
Free format text: CORRECT: APPLICANT; FROM: SCHERING CORP (US) TO: MSD CORP. |
|
C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20120711 |