CN116940598A - 用于治疗表达cldn18.2的实体瘤的cldn18.2/cd3双特异性抗体 - Google Patents
用于治疗表达cldn18.2的实体瘤的cldn18.2/cd3双特异性抗体 Download PDFInfo
- Publication number
- CN116940598A CN116940598A CN202280011082.2A CN202280011082A CN116940598A CN 116940598 A CN116940598 A CN 116940598A CN 202280011082 A CN202280011082 A CN 202280011082A CN 116940598 A CN116940598 A CN 116940598A
- Authority
- CN
- China
- Prior art keywords
- amino acid
- acid sequence
- ser
- antibody
- seq
- 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
- 206010028980 Neoplasm Diseases 0.000 title claims abstract description 38
- 238000011282 treatment Methods 0.000 title description 11
- 230000027455 binding Effects 0.000 claims abstract description 209
- 102000036639 antigens Human genes 0.000 claims abstract description 127
- 108091007433 antigens Proteins 0.000 claims abstract description 127
- 239000000427 antigen Substances 0.000 claims abstract description 126
- 239000012634 fragment Substances 0.000 claims abstract description 80
- 201000011510 cancer Diseases 0.000 claims abstract description 22
- 150000007523 nucleic acids Chemical class 0.000 claims abstract description 20
- 238000000034 method Methods 0.000 claims abstract description 18
- 108020004707 nucleic acids Proteins 0.000 claims abstract description 18
- 102000039446 nucleic acids Human genes 0.000 claims abstract description 18
- 239000013598 vector Substances 0.000 claims abstract description 14
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 12
- 208000005718 Stomach Neoplasms Diseases 0.000 claims abstract description 9
- 206010017758 gastric cancer Diseases 0.000 claims abstract description 9
- 201000011549 stomach cancer Diseases 0.000 claims abstract description 9
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims abstract description 5
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims abstract description 5
- 201000002528 pancreatic cancer Diseases 0.000 claims abstract description 5
- 208000008443 pancreatic carcinoma Diseases 0.000 claims abstract description 5
- 230000000694 effects Effects 0.000 claims description 20
- 108010021625 Immunoglobulin Fragments Proteins 0.000 claims description 17
- 102000008394 Immunoglobulin Fragments Human genes 0.000 claims description 17
- 230000035772 mutation Effects 0.000 claims description 6
- 108010054477 Immunoglobulin Fab Fragments Proteins 0.000 claims description 5
- 102000001706 Immunoglobulin Fab Fragments Human genes 0.000 claims description 5
- 108091028043 Nucleic acid sequence Proteins 0.000 claims description 3
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 3
- 108010067060 Immunoglobulin Variable Region Proteins 0.000 claims description 2
- 102000017727 Immunoglobulin Variable Region Human genes 0.000 claims description 2
- 201000005787 hematologic cancer Diseases 0.000 claims description 2
- 239000007787 solid Substances 0.000 claims description 2
- 125000003275 alpha amino acid group Chemical group 0.000 claims 44
- 230000010056 antibody-dependent cellular cytotoxicity Effects 0.000 claims 1
- 239000003937 drug carrier Substances 0.000 abstract description 4
- 210000004027 cell Anatomy 0.000 description 124
- 150000001413 amino acids Chemical group 0.000 description 99
- 230000001404 mediated effect Effects 0.000 description 33
- 241001529936 Murinae Species 0.000 description 29
- 102000002029 Claudin Human genes 0.000 description 24
- 108050009302 Claudin Proteins 0.000 description 24
- 102000004127 Cytokines Human genes 0.000 description 20
- 108090000695 Cytokines Proteins 0.000 description 20
- 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 18
- 241000880493 Leptailurus serval Species 0.000 description 17
- 108090000623 proteins and genes Proteins 0.000 description 17
- 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 16
- 230000002147 killing effect Effects 0.000 description 16
- 235000018102 proteins Nutrition 0.000 description 15
- 102000004169 proteins and genes Human genes 0.000 description 15
- 238000013207 serial dilution Methods 0.000 description 15
- 210000004881 tumor cell Anatomy 0.000 description 15
- XKUKSGPZAADMRA-UHFFFAOYSA-N glycyl-glycyl-glycine Natural products NCC(=O)NCC(=O)NCC(O)=O XKUKSGPZAADMRA-UHFFFAOYSA-N 0.000 description 14
- 108090000765 processed proteins & peptides Proteins 0.000 description 14
- 108010003137 tyrosyltyrosine Proteins 0.000 description 14
- 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 13
- 210000001744 T-lymphocyte Anatomy 0.000 description 13
- 108010086434 alanyl-seryl-glycine Proteins 0.000 description 13
- 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 12
- 108010069020 alanyl-prolyl-glycine Proteins 0.000 description 12
- 108010047041 Complementarity Determining Regions Proteins 0.000 description 11
- 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 11
- 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 11
- 239000000872 buffer Substances 0.000 description 11
- 238000001943 fluorescence-activated cell sorting Methods 0.000 description 11
- 108010063718 gamma-glutamylaspartic acid Proteins 0.000 description 11
- 108010037850 glycylvaline Proteins 0.000 description 11
- 108010044292 tryptophyltyrosine Proteins 0.000 description 11
- 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 10
- UIGMAMGZOJVTDN-WHFBIAKZSA-N Ser-Gly-Ser Chemical compound OC[C@H](N)C(=O)NCC(=O)N[C@@H](CO)C(O)=O UIGMAMGZOJVTDN-WHFBIAKZSA-N 0.000 description 10
- 210000003819 peripheral blood mononuclear cell Anatomy 0.000 description 10
- 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 9
- 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 9
- 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 9
- 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 9
- 241000699666 Mus <mouse, genus> Species 0.000 description 9
- 108010079364 N-glycylalanine Proteins 0.000 description 9
- KLYYKKGCPOGDPE-OEAJRASXSA-N Phe-Thr-Leu Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(O)=O KLYYKKGCPOGDPE-OEAJRASXSA-N 0.000 description 9
- 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 9
- QUILOGWWLXMSAT-IHRRRGAJSA-N Tyr-Gln-Gln Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(O)=O QUILOGWWLXMSAT-IHRRRGAJSA-N 0.000 description 9
- 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 9
- 125000000539 amino acid group Chemical group 0.000 description 9
- 108010008355 arginyl-glutamine Proteins 0.000 description 9
- 210000004978 chinese hamster ovary cell Anatomy 0.000 description 9
- 238000011156 evaluation Methods 0.000 description 9
- VPZXBVLAVMBEQI-UHFFFAOYSA-N glycyl-DL-alpha-alanine Natural products OC(=O)C(C)NC(=O)CN VPZXBVLAVMBEQI-UHFFFAOYSA-N 0.000 description 9
- 108010050848 glycylleucine Proteins 0.000 description 9
- 108010038745 tryptophylglycine Proteins 0.000 description 9
- 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 8
- 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 8
- IAJFFZORSWOZPQ-SRVKXCTJSA-N Leu-Leu-Asn Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(O)=O IAJFFZORSWOZPQ-SRVKXCTJSA-N 0.000 description 8
- 239000005089 Luciferase Substances 0.000 description 8
- 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 8
- GQZMPWBZQALKJO-UWVGGRQHSA-N Lys-Gly-Arg Chemical compound [H]N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(O)=O GQZMPWBZQALKJO-UWVGGRQHSA-N 0.000 description 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
- 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 8
- 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 8
- 108010008685 alanyl-glutamyl-aspartic acid Proteins 0.000 description 8
- 108010069205 aspartyl-phenylalanine Proteins 0.000 description 8
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 8
- 239000012636 effector Substances 0.000 description 8
- 238000000684 flow cytometry Methods 0.000 description 8
- 108010010147 glycylglutamine Proteins 0.000 description 8
- 230000008685 targeting Effects 0.000 description 8
- 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
- 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 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
- 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 7
- 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 7
- UIQGJYUEQDOODF-KWQFWETISA-N Gly-Tyr-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)CN)CC1=CC=C(O)C=C1 UIQGJYUEQDOODF-KWQFWETISA-N 0.000 description 7
- 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 7
- YMIZSYUAZJSOFL-SRVKXCTJSA-N Phe-Ser-Asn Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(O)=O YMIZSYUAZJSOFL-SRVKXCTJSA-N 0.000 description 7
- PCWLNNZTBJTZRN-AVGNSLFASA-N Pro-Pro-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@H]1NCCC1 PCWLNNZTBJTZRN-AVGNSLFASA-N 0.000 description 7
- 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 7
- FQPDRTDDEZXCEC-SVSWQMSJSA-N Thr-Ile-Ser Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(O)=O FQPDRTDDEZXCEC-SVSWQMSJSA-N 0.000 description 7
- 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 7
- 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 7
- 239000011230 binding agent Substances 0.000 description 7
- 238000003501 co-culture Methods 0.000 description 7
- 201000010099 disease Diseases 0.000 description 7
- 108010067216 glycyl-glycyl-glycine Proteins 0.000 description 7
- 108010044374 isoleucyl-tyrosine Proteins 0.000 description 7
- 238000004020 luminiscence type Methods 0.000 description 7
- 230000011664 signaling Effects 0.000 description 7
- 239000006228 supernatant Substances 0.000 description 7
- HKZAAJSTFUZYTO-LURJTMIESA-N (2s)-2-[[2-[[2-[[2-[(2-aminoacetyl)amino]acetyl]amino]acetyl]amino]acetyl]amino]-3-hydroxypropanoic acid Chemical compound NCC(=O)NCC(=O)NCC(=O)NCC(=O)N[C@@H](CO)C(O)=O HKZAAJSTFUZYTO-LURJTMIESA-N 0.000 description 6
- 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 6
- WYPUMLRSQMKIJU-BPNCWPANSA-N Ala-Arg-Tyr Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O WYPUMLRSQMKIJU-BPNCWPANSA-N 0.000 description 6
- NVUIWHJLPSZZQC-CYDGBPFRSA-N Arg-Ile-Arg Chemical compound NC(N)=NCCC[C@H](N)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCCN=C(N)N)C(O)=O NVUIWHJLPSZZQC-CYDGBPFRSA-N 0.000 description 6
- 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 6
- FJIRXKVEDFLLOQ-SRVKXCTJSA-N Asn-Cys-Phe Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)O)NC(=O)[C@H](CS)NC(=O)[C@H](CC(=O)N)N FJIRXKVEDFLLOQ-SRVKXCTJSA-N 0.000 description 6
- DXVMJJNAOVECBA-WHFBIAKZSA-N Asn-Gly-Asn Chemical compound NC(=O)C[C@H](N)C(=O)NCC(=O)N[C@@H](CC(N)=O)C(O)=O DXVMJJNAOVECBA-WHFBIAKZSA-N 0.000 description 6
- IICZCLFBILYRCU-WHFBIAKZSA-N Asn-Gly-Asp Chemical compound [H]N[C@@H](CC(N)=O)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(O)=O IICZCLFBILYRCU-WHFBIAKZSA-N 0.000 description 6
- 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 6
- 238000002965 ELISA Methods 0.000 description 6
- 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 6
- 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 6
- WJZLEENECIOOSA-WDSKDSINSA-N Gly-Asn-Gln Chemical compound NCC(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)O WJZLEENECIOOSA-WDSKDSINSA-N 0.000 description 6
- BPQYBFAXRGMGGY-LAEOZQHASA-N Gly-Gln-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)N)NC(=O)CN BPQYBFAXRGMGGY-LAEOZQHASA-N 0.000 description 6
- WNZOCXUOGVYYBJ-CDMKHQONSA-N Gly-Phe-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CC1=CC=CC=C1)NC(=O)CN)O WNZOCXUOGVYYBJ-CDMKHQONSA-N 0.000 description 6
- 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
- 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 6
- PXHCFKXNSBJSTQ-KKUMJFAQSA-N Lys-Asn-Tyr Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)N)NC(=O)[C@H](CCCCN)N)O PXHCFKXNSBJSTQ-KKUMJFAQSA-N 0.000 description 6
- 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 6
- 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 6
- 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 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
- QJKPECIAWNNKIT-KKUMJFAQSA-N Ser-Lys-Tyr Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O QJKPECIAWNNKIT-KKUMJFAQSA-N 0.000 description 6
- 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 6
- 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 6
- KKPOGALELPLJTL-MEYUZBJRSA-N Thr-Lys-Tyr Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@@H](CCCCN)C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 KKPOGALELPLJTL-MEYUZBJRSA-N 0.000 description 6
- 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 6
- RCMHSGRBJCMFLR-BPUTZDHNSA-N Trp-Met-Asn Chemical compound C1=CC=C2C(C[C@H](N)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(N)=O)C(O)=O)=CNC2=C1 RCMHSGRBJCMFLR-BPUTZDHNSA-N 0.000 description 6
- BURPTJBFWIOHEY-UWJYBYFXSA-N Tyr-Ala-Asp Chemical compound OC(=O)C[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 BURPTJBFWIOHEY-UWJYBYFXSA-N 0.000 description 6
- AKXBNSZMYAOGLS-STQMWFEESA-N Tyr-Arg-Gly Chemical compound NC(N)=NCCC[C@@H](C(=O)NCC(O)=O)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 AKXBNSZMYAOGLS-STQMWFEESA-N 0.000 description 6
- 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 6
- 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 6
- 108010092854 aspartyllysine Proteins 0.000 description 6
- 230000022534 cell killing Effects 0.000 description 6
- 230000003013 cytotoxicity Effects 0.000 description 6
- 231100000135 cytotoxicity Toxicity 0.000 description 6
- 238000010494 dissociation reaction Methods 0.000 description 6
- 230000005593 dissociations Effects 0.000 description 6
- 230000006870 function Effects 0.000 description 6
- 108010015792 glycyllysine Proteins 0.000 description 6
- 108010017391 lysylvaline Proteins 0.000 description 6
- 108010070409 phenylalanyl-glycyl-glycine Proteins 0.000 description 6
- 229920001184 polypeptide Polymers 0.000 description 6
- 102000004196 processed proteins & peptides Human genes 0.000 description 6
- MZOFCQQQCNRIBI-VMXHOPILSA-N (3s)-4-[[(2s)-1-[[(2s)-1-[[(1s)-1-carboxy-2-hydroxyethyl]amino]-4-methyl-1-oxopentan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-3-[[2-[[(2s)-2,6-diaminohexanoyl]amino]acetyl]amino]-4-oxobutanoic acid Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@@H](N)CCCCN MZOFCQQQCNRIBI-VMXHOPILSA-N 0.000 description 5
- 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 5
- NIXHTNJAGGFBAW-CIUDSAMLSA-N Cys-Lys-Ser Chemical compound C(CCN)C[C@@H](C(=O)N[C@@H](CO)C(=O)O)NC(=O)[C@H](CS)N NIXHTNJAGGFBAW-CIUDSAMLSA-N 0.000 description 5
- 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 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
- 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 5
- 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 5
- 102000003814 Interleukin-10 Human genes 0.000 description 5
- 108090000174 Interleukin-10 Proteins 0.000 description 5
- 108010002350 Interleukin-2 Proteins 0.000 description 5
- 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 5
- 108060001084 Luciferase Proteins 0.000 description 5
- 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 5
- 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 5
- FWTFAZKJORVTIR-VZFHVOOUSA-N Thr-Ser-Ala Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(=O)N[C@@H](C)C(O)=O FWTFAZKJORVTIR-VZFHVOOUSA-N 0.000 description 5
- 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 5
- 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 description 5
- CFSSLXZJEMERJY-NRPADANISA-N Val-Gln-Ala Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](C)C(O)=O CFSSLXZJEMERJY-NRPADANISA-N 0.000 description 5
- 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 5
- 206010052015 cytokine release syndrome Diseases 0.000 description 5
- 230000004927 fusion Effects 0.000 description 5
- 238000004519 manufacturing process Methods 0.000 description 5
- 230000003389 potentiating effect Effects 0.000 description 5
- 108010020755 prolyl-glycyl-glycine Proteins 0.000 description 5
- 238000002198 surface plasmon resonance spectroscopy Methods 0.000 description 5
- 210000001519 tissue Anatomy 0.000 description 5
- 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
- JPOQZCHGOTWRTM-FQPOAREZSA-N Ala-Tyr-Thr Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H]([C@@H](C)O)C(O)=O JPOQZCHGOTWRTM-FQPOAREZSA-N 0.000 description 4
- DAYDURRBMDCCFL-AAEUAGOBSA-N Asn-Trp-Gly Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)NCC(=O)O)NC(=O)[C@H](CC(=O)N)N DAYDURRBMDCCFL-AAEUAGOBSA-N 0.000 description 4
- KGHLGJAXYSVNJP-WHFBIAKZSA-N Asp-Ser-Gly Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CO)C(=O)NCC(O)=O KGHLGJAXYSVNJP-WHFBIAKZSA-N 0.000 description 4
- 241000283707 Capra Species 0.000 description 4
- 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 4
- FQCILXROGNOZON-YUMQZZPRSA-N Gln-Pro-Gly Chemical compound NC(=O)CC[C@H](N)C(=O)N1CCC[C@H]1C(=O)NCC(O)=O FQCILXROGNOZON-YUMQZZPRSA-N 0.000 description 4
- 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 4
- RFTVTKBHDXCEEX-WDSKDSINSA-N Glu-Ser-Gly Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(=O)NCC(O)=O RFTVTKBHDXCEEX-WDSKDSINSA-N 0.000 description 4
- 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 4
- 101000935587 Homo sapiens Flavin reductase (NADPH) Proteins 0.000 description 4
- 102100037850 Interferon gamma Human genes 0.000 description 4
- 108010074328 Interferon-gamma Proteins 0.000 description 4
- FAELBUXXFQLUAX-AJNGGQMLSA-N Leu-Leu-Ile Chemical compound CC[C@H](C)[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CC(C)C FAELBUXXFQLUAX-AJNGGQMLSA-N 0.000 description 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
- 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 4
- YDTUEBLEAVANFH-RCWTZXSCSA-N Pro-Val-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H]1CCCN1 YDTUEBLEAVANFH-RCWTZXSCSA-N 0.000 description 4
- 239000012980 RPMI-1640 medium Substances 0.000 description 4
- 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 4
- 108010003723 Single-Domain Antibodies Proteins 0.000 description 4
- 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 4
- 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 4
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 4
- BIWVVOHTKDLRMP-ULQDDVLXSA-N Tyr-Pro-Leu Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CC(C)C)C(O)=O BIWVVOHTKDLRMP-ULQDDVLXSA-N 0.000 description 4
- 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 4
- LCHZBEUVGAVMKS-RHYQMDGZSA-N Val-Thr-Leu Chemical compound CC(C)C[C@H](NC(=O)[C@@H](NC(=O)[C@@H](N)C(C)C)[C@@H](C)O)C(O)=O LCHZBEUVGAVMKS-RHYQMDGZSA-N 0.000 description 4
- 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 4
- 108010081404 acein-2 Proteins 0.000 description 4
- 108010087924 alanylproline Proteins 0.000 description 4
- 108010013835 arginine glutamate Proteins 0.000 description 4
- 238000003556 assay Methods 0.000 description 4
- 230000004540 complement-dependent cytotoxicity Effects 0.000 description 4
- 238000011161 development Methods 0.000 description 4
- 230000018109 developmental process Effects 0.000 description 4
- 230000003993 interaction Effects 0.000 description 4
- 238000010186 staining Methods 0.000 description 4
- 230000001988 toxicity Effects 0.000 description 4
- 231100000419 toxicity Toxicity 0.000 description 4
- 108010020532 tyrosyl-proline Proteins 0.000 description 4
- 108010073969 valyllysine Proteins 0.000 description 4
- FWBHETKCLVMNFS-UHFFFAOYSA-N 4',6-Diamino-2-phenylindol Chemical compound C1=CC(C(=N)N)=CC=C1C1=CC2=CC=C(C(N)=N)C=C2N1 FWBHETKCLVMNFS-UHFFFAOYSA-N 0.000 description 3
- 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 3
- RAAWHFXHAACDFT-FXQIFTODSA-N Ala-Met-Asn Chemical compound CSCC[C@H](NC(=O)[C@H](C)N)C(=O)N[C@@H](CC(N)=O)C(O)=O RAAWHFXHAACDFT-FXQIFTODSA-N 0.000 description 3
- 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 3
- ZJLORAAXDAJLDC-CQDKDKBSSA-N Ala-Tyr-Leu Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC(C)C)C(O)=O ZJLORAAXDAJLDC-CQDKDKBSSA-N 0.000 description 3
- DEAGTWNKODHUIY-MRFFXTKBSA-N Ala-Tyr-Trp Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC1=CNC2=C1C=CC=C2)C(O)=O DEAGTWNKODHUIY-MRFFXTKBSA-N 0.000 description 3
- 101000642536 Apis mellifera Venom serine protease 34 Proteins 0.000 description 3
- NTAZNGWBXRVEDJ-FXQIFTODSA-N Arg-Asp-Asp Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(O)=O)C(O)=O NTAZNGWBXRVEDJ-FXQIFTODSA-N 0.000 description 3
- MSILNNHVVMMTHZ-UWVGGRQHSA-N Arg-His-Gly Chemical compound NC(N)=NCCC[C@H](N)C(=O)N[C@H](C(=O)NCC(O)=O)CC1=CN=CN1 MSILNNHVVMMTHZ-UWVGGRQHSA-N 0.000 description 3
- HPBNLFLSSQDFQW-WHFBIAKZSA-N Asn-Ser-Gly Chemical compound NC(=O)C[C@H](N)C(=O)N[C@@H](CO)C(=O)NCC(O)=O HPBNLFLSSQDFQW-WHFBIAKZSA-N 0.000 description 3
- MYTHOBCLNIOFBL-SRVKXCTJSA-N Asn-Ser-Tyr Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O MYTHOBCLNIOFBL-SRVKXCTJSA-N 0.000 description 3
- 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 3
- 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 3
- 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 3
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 3
- 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 3
- 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 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
- 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 3
- FULZDMOZUZKGQU-ONGXEEELSA-N Gly-Val-His Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)NC(=O)CN FULZDMOZUZKGQU-ONGXEEELSA-N 0.000 description 3
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 3
- QQFSKBMCAKWHLG-UHFFFAOYSA-N Ile-Phe-Pro-Pro Chemical compound C1CCC(C(=O)N2C(CCC2)C(O)=O)N1C(=O)C(NC(=O)C(N)C(C)CC)CC1=CC=CC=C1 QQFSKBMCAKWHLG-UHFFFAOYSA-N 0.000 description 3
- 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 3
- 108060003951 Immunoglobulin Proteins 0.000 description 3
- 102000000588 Interleukin-2 Human genes 0.000 description 3
- AXZGZMGRBDQTEY-SRVKXCTJSA-N Leu-Gln-Met Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCSC)C(O)=O AXZGZMGRBDQTEY-SRVKXCTJSA-N 0.000 description 3
- 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 3
- YOKVEHGYYQEQOP-QWRGUYRKSA-N Leu-Leu-Gly Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)NCC(O)=O YOKVEHGYYQEQOP-QWRGUYRKSA-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
- SQXZLVXQXWILKW-KKUMJFAQSA-N Lys-Ser-Phe Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O SQXZLVXQXWILKW-KKUMJFAQSA-N 0.000 description 3
- 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 3
- QARPMYDMYVLFMW-KKUMJFAQSA-N Phe-Pro-Glu Chemical compound C([C@H](N)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCC(O)=O)C(O)=O)C1=CC=CC=C1 QARPMYDMYVLFMW-KKUMJFAQSA-N 0.000 description 3
- 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 3
- FMLRRBDLBJLJIK-DCAQKATOSA-N Pro-Leu-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H]1CCCN1 FMLRRBDLBJLJIK-DCAQKATOSA-N 0.000 description 3
- QEDMOZUJTGEIBF-FXQIFTODSA-N Ser-Arg-Asp Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(O)=O QEDMOZUJTGEIBF-FXQIFTODSA-N 0.000 description 3
- 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 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
- 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 3
- 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 3
- 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 3
- HNDMFDBQXYZSRM-IHRRRGAJSA-N Ser-Val-Phe Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O HNDMFDBQXYZSRM-IHRRRGAJSA-N 0.000 description 3
- 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
- JMBRNXUOLJFURW-BEAPCOKYSA-N Thr-Phe-Pro Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N2CCC[C@@H]2C(=O)O)N)O JMBRNXUOLJFURW-BEAPCOKYSA-N 0.000 description 3
- LECUEEHKUFYOOV-ZJDVBMNYSA-N Thr-Thr-Val Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@@H](N)[C@@H](C)O LECUEEHKUFYOOV-ZJDVBMNYSA-N 0.000 description 3
- 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 3
- QOEZFICGUZTRFX-IHRRRGAJSA-N Tyr-Cys-Val Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CS)C(=O)N[C@@H](C(C)C)C(O)=O QOEZFICGUZTRFX-IHRRRGAJSA-N 0.000 description 3
- HGJRMXOWUWVUOA-GVXVVHGQSA-N Val-Leu-Gln Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)O)NC(=O)[C@H](C(C)C)N HGJRMXOWUWVUOA-GVXVVHGQSA-N 0.000 description 3
- KTEZUXISLQTDDQ-NHCYSSNCSA-N Val-Lys-Asp Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(=O)O)C(=O)O)N KTEZUXISLQTDDQ-NHCYSSNCSA-N 0.000 description 3
- DIOSYUIWOQCXNR-ONGXEEELSA-N Val-Lys-Gly Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](CCCCN)C(=O)NCC(O)=O DIOSYUIWOQCXNR-ONGXEEELSA-N 0.000 description 3
- 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 3
- 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 3
- BZDGLJPROOOUOZ-XGEHTFHBSA-N Val-Thr-Cys Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CS)C(=O)O)NC(=O)[C@H](C(C)C)N)O BZDGLJPROOOUOZ-XGEHTFHBSA-N 0.000 description 3
- WUFHZIRMAZZWRS-OSUNSFLBSA-N Val-Thr-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](C(C)C)N WUFHZIRMAZZWRS-OSUNSFLBSA-N 0.000 description 3
- 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 3
- ZLNYBMWGPOKSLW-LSJOCFKGSA-N Val-Val-Asp Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(O)=O)C(O)=O ZLNYBMWGPOKSLW-LSJOCFKGSA-N 0.000 description 3
- LLJLBRRXKZTTRD-GUBZILKMSA-N Val-Val-Ser Chemical compound CC(C)[C@@H](C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CO)C(=O)O)N LLJLBRRXKZTTRD-GUBZILKMSA-N 0.000 description 3
- 108010047495 alanylglycine Proteins 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 230000000259 anti-tumor effect Effects 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- 210000004899 c-terminal region Anatomy 0.000 description 3
- 238000012790 confirmation Methods 0.000 description 3
- 230000009260 cross reactivity Effects 0.000 description 3
- 108010016616 cysteinylglycine Proteins 0.000 description 3
- 230000001461 cytolytic effect Effects 0.000 description 3
- 230000002496 gastric effect Effects 0.000 description 3
- 108010078144 glutaminyl-glycine Proteins 0.000 description 3
- 102000018358 immunoglobulin Human genes 0.000 description 3
- 108010044311 leucyl-glycyl-glycine Proteins 0.000 description 3
- 108010073472 leucyl-prolyl-proline Proteins 0.000 description 3
- 108010003700 lysyl aspartic acid Proteins 0.000 description 3
- 108010038320 lysylphenylalanine Proteins 0.000 description 3
- 238000012423 maintenance Methods 0.000 description 3
- 108010024654 phenylalanyl-prolyl-alanine Proteins 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 108010048397 seryl-lysyl-leucine Proteins 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- ZQJHYRVSKHGGJY-YPKJBDGSSA-N (2s,3r)-2-[[(2s)-2-[[(2s)-1-[(2s)-2-amino-3-(4-hydroxyphenyl)propanoyl]pyrrolidine-2-carbonyl]amino]-3-phenylpropanoyl]amino]-3-hydroxybutanoic acid Chemical compound C([C@@H](C(=O)N[C@@H]([C@H](O)C)C(O)=O)NC(=O)[C@H]1N(CCC1)C(=O)[C@@H](N)CC=1C=CC(O)=CC=1)C1=CC=CC=C1 ZQJHYRVSKHGGJY-YPKJBDGSSA-N 0.000 description 2
- SVBXIUDNTRTKHE-CIUDSAMLSA-N Ala-Arg-Glu Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(O)=O SVBXIUDNTRTKHE-CIUDSAMLSA-N 0.000 description 2
- OYJCVIGKMXUVKB-GARJFASQSA-N Ala-Leu-Pro Chemical compound C[C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N1CCC[C@@H]1C(=O)O)N OYJCVIGKMXUVKB-GARJFASQSA-N 0.000 description 2
- MEFILNJXAVSUTO-JXUBOQSCSA-N Ala-Leu-Thr Chemical compound C[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O MEFILNJXAVSUTO-JXUBOQSCSA-N 0.000 description 2
- OINVDEKBKBCPLX-JXUBOQSCSA-N Ala-Lys-Thr Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(O)=O OINVDEKBKBCPLX-JXUBOQSCSA-N 0.000 description 2
- 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 2
- VNFSAYFQLXPHPY-CIQUZCHMSA-N Ala-Thr-Ile Chemical compound [H]N[C@@H](C)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O VNFSAYFQLXPHPY-CIQUZCHMSA-N 0.000 description 2
- KUFVXLQLDHJVOG-SHGPDSBTSA-N Ala-Thr-Thr Chemical compound C[C@H]([C@@H](C(=O)N[C@@H]([C@@H](C)O)C(=O)O)NC(=O)[C@H](C)N)O KUFVXLQLDHJVOG-SHGPDSBTSA-N 0.000 description 2
- 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
- OTUQSEPIIVBYEM-IHRRRGAJSA-N Arg-Asn-Tyr Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O OTUQSEPIIVBYEM-IHRRRGAJSA-N 0.000 description 2
- COXMUHNBYCVVRG-DCAQKATOSA-N Arg-Leu-Ser Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(O)=O COXMUHNBYCVVRG-DCAQKATOSA-N 0.000 description 2
- AOHKLEBWKMKITA-IHRRRGAJSA-N Arg-Phe-Ser Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)N[C@@H](CO)C(=O)O)NC(=O)[C@H](CCCN=C(N)N)N AOHKLEBWKMKITA-IHRRRGAJSA-N 0.000 description 2
- ZCSHHTFOZULVLN-SZMVWBNQSA-N Arg-Trp-Val Chemical compound C1=CC=C2C(C[C@@H](C(=O)N[C@@H](C(C)C)C(O)=O)NC(=O)[C@@H](N)CCCN=C(N)N)=CNC2=C1 ZCSHHTFOZULVLN-SZMVWBNQSA-N 0.000 description 2
- SLKLLQWZQHXYSV-CIUDSAMLSA-N Asn-Ala-Lys Chemical compound NC(=O)C[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCN)C(O)=O SLKLLQWZQHXYSV-CIUDSAMLSA-N 0.000 description 2
- NLRJGXZWTKXRHP-DCAQKATOSA-N Asn-Leu-Arg Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O NLRJGXZWTKXRHP-DCAQKATOSA-N 0.000 description 2
- 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 2
- 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 2
- 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 2
- LKIYSIYBKYLKPU-BIIVOSGPSA-N Asp-Asp-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CC(=O)O)NC(=O)[C@H](CC(=O)O)N)C(=O)O LKIYSIYBKYLKPU-BIIVOSGPSA-N 0.000 description 2
- SNDBKTFJWVEVPO-WHFBIAKZSA-N Asp-Gly-Ser Chemical compound [H]N[C@@H](CC(O)=O)C(=O)NCC(=O)N[C@@H](CO)C(O)=O SNDBKTFJWVEVPO-WHFBIAKZSA-N 0.000 description 2
- 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 2
- WMLFFCRUSPNENW-ZLUOBGJFSA-N Asp-Ser-Ala Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](C)C(O)=O WMLFFCRUSPNENW-ZLUOBGJFSA-N 0.000 description 2
- RSMZEHCMIOKNMW-GSSVUCPTSA-N Asp-Thr-Thr Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O RSMZEHCMIOKNMW-GSSVUCPTSA-N 0.000 description 2
- SZQCDCKIGWQAQN-FXQIFTODSA-N Cys-Arg-Ala Chemical compound [H]N[C@@H](CS)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(O)=O SZQCDCKIGWQAQN-FXQIFTODSA-N 0.000 description 2
- 238000012286 ELISA Assay Methods 0.000 description 2
- 238000012413 Fluorescence activated cell sorting analysis Methods 0.000 description 2
- DHNWZLGBTPUTQQ-QEJZJMRPSA-N Gln-Asp-Trp Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)O)NC(=O)[C@H](CCC(=O)N)N DHNWZLGBTPUTQQ-QEJZJMRPSA-N 0.000 description 2
- WPJDPEOQUIXXOY-AVGNSLFASA-N Gln-Tyr-Asn Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)O)NC(=O)[C@H](CCC(=O)N)N)O WPJDPEOQUIXXOY-AVGNSLFASA-N 0.000 description 2
- 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 2
- DUYYPIRFTLOAJQ-YUMQZZPRSA-N Gly-Asn-His Chemical compound C1=C(NC=N1)C[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)N)NC(=O)CN DUYYPIRFTLOAJQ-YUMQZZPRSA-N 0.000 description 2
- IXKRSKPKSLXIHN-YUMQZZPRSA-N Gly-Cys-Leu Chemical compound [H]NCC(=O)N[C@@H](CS)C(=O)N[C@@H](CC(C)C)C(O)=O IXKRSKPKSLXIHN-YUMQZZPRSA-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
- OMOZPGCHVWOXHN-BQBZGAKWSA-N Gly-Met-Ser Chemical compound CSCC[C@@H](C(=O)N[C@@H](CO)C(=O)O)NC(=O)CN OMOZPGCHVWOXHN-BQBZGAKWSA-N 0.000 description 2
- HAOUOFNNJJLVNS-BQBZGAKWSA-N Gly-Pro-Ser Chemical compound NCC(=O)N1CCC[C@H]1C(=O)N[C@@H](CO)C(O)=O HAOUOFNNJJLVNS-BQBZGAKWSA-N 0.000 description 2
- VBOFRJNDIOPNDO-YUMQZZPRSA-N His-Gly-Asn Chemical compound C1=C(NC=N1)C[C@@H](C(=O)NCC(=O)N[C@@H](CC(=O)N)C(=O)O)N VBOFRJNDIOPNDO-YUMQZZPRSA-N 0.000 description 2
- HDODQNPMSHDXJT-GHCJXIJMSA-N Ile-Asn-Ser Chemical compound CC[C@H](C)[C@H](N)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CO)C(O)=O HDODQNPMSHDXJT-GHCJXIJMSA-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
- 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 2
- PELCGFMHLZXWBQ-BJDJZHNGSA-N Ile-Ser-Leu Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)O)N PELCGFMHLZXWBQ-BJDJZHNGSA-N 0.000 description 2
- JDCQDJVYUXNCGF-SPOWBLRKSA-N Ile-Ser-Trp Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CC1=CNC2=CC=CC=C21)C(=O)O)N JDCQDJVYUXNCGF-SPOWBLRKSA-N 0.000 description 2
- NAFIFZNBSPWYOO-RWRJDSDZSA-N Ile-Thr-Gln Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCC(=O)N)C(=O)O)N NAFIFZNBSPWYOO-RWRJDSDZSA-N 0.000 description 2
- 108010065920 Insulin Lispro Proteins 0.000 description 2
- AYFVYJQAPQTCCC-GBXIJSLDSA-N L-threonine Chemical compound C[C@@H](O)[C@H](N)C(O)=O AYFVYJQAPQTCCC-GBXIJSLDSA-N 0.000 description 2
- DBVWMYGBVFCRBE-CIUDSAMLSA-N Leu-Asn-Asn Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O DBVWMYGBVFCRBE-CIUDSAMLSA-N 0.000 description 2
- PVMPDMIKUVNOBD-CIUDSAMLSA-N Leu-Asp-Ser Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(O)=O PVMPDMIKUVNOBD-CIUDSAMLSA-N 0.000 description 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
- 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
- PPQRKXHCLYCBSP-IHRRRGAJSA-N Leu-Leu-Met Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)O)N PPQRKXHCLYCBSP-IHRRRGAJSA-N 0.000 description 2
- DPURXCQCHSQPAN-AVGNSLFASA-N Leu-Pro-Pro Chemical compound CC(C)C[C@H](N)C(=O)N1CCC[C@H]1C(=O)N1[C@H](C(O)=O)CCC1 DPURXCQCHSQPAN-AVGNSLFASA-N 0.000 description 2
- BRTVHXHCUSXYRI-CIUDSAMLSA-N Leu-Ser-Ser Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(O)=O BRTVHXHCUSXYRI-CIUDSAMLSA-N 0.000 description 2
- LINKCQUOMUDLKN-KATARQTJSA-N Leu-Thr-Cys Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CS)C(=O)O)NC(=O)[C@H](CC(C)C)N)O LINKCQUOMUDLKN-KATARQTJSA-N 0.000 description 2
- AIQWYVFNBNNOLU-RHYQMDGZSA-N Leu-Thr-Val Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(O)=O AIQWYVFNBNNOLU-RHYQMDGZSA-N 0.000 description 2
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 2
- 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 2
- MWVUEPNEPWMFBD-SRVKXCTJSA-N Lys-Cys-Lys Chemical compound NCCCC[C@H](N)C(=O)N[C@@H](CS)C(=O)N[C@H](C(O)=O)CCCCN MWVUEPNEPWMFBD-SRVKXCTJSA-N 0.000 description 2
- NKKFVJRLCCUJNA-QWRGUYRKSA-N Lys-Gly-Lys Chemical compound NCCCC[C@H](N)C(=O)NCC(=O)N[C@H](C(O)=O)CCCCN NKKFVJRLCCUJNA-QWRGUYRKSA-N 0.000 description 2
- 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 2
- AIRZWUMAHCDDHR-KKUMJFAQSA-N Lys-Leu-Leu Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O AIRZWUMAHCDDHR-KKUMJFAQSA-N 0.000 description 2
- QLFAPXUXEBAWEK-NHCYSSNCSA-N Lys-Val-Asp Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(O)=O)C(O)=O QLFAPXUXEBAWEK-NHCYSSNCSA-N 0.000 description 2
- 241000124008 Mammalia Species 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
- 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 2
- XMBSYZWANAQXEV-UHFFFAOYSA-N N-alpha-L-glutamyl-L-phenylalanine Natural products OC(=O)CCC(N)C(=O)NC(C(O)=O)CC1=CC=CC=C1 XMBSYZWANAQXEV-UHFFFAOYSA-N 0.000 description 2
- 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 2
- 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 2
- KXUZHWXENMYOHC-QEJZJMRPSA-N Phe-Leu-Ala Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C)C(O)=O KXUZHWXENMYOHC-QEJZJMRPSA-N 0.000 description 2
- IAOZOFPONWDXNT-IXOXFDKPSA-N Phe-Ser-Thr Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(O)=O IAOZOFPONWDXNT-IXOXFDKPSA-N 0.000 description 2
- BSKMOCNNLNDIMU-CDMKHQONSA-N Phe-Thr-Gly Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(O)=O BSKMOCNNLNDIMU-CDMKHQONSA-N 0.000 description 2
- 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 2
- CGBYDGAJHSOGFQ-LPEHRKFASA-N Pro-Ala-Pro Chemical compound C[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@@H]2CCCN2 CGBYDGAJHSOGFQ-LPEHRKFASA-N 0.000 description 2
- XQLBWXHVZVBNJM-FXQIFTODSA-N Pro-Ala-Ser Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H]1CCCN1 XQLBWXHVZVBNJM-FXQIFTODSA-N 0.000 description 2
- 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 2
- 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 2
- STGVYUTZKGPRCI-GUBZILKMSA-N Pro-Val-Cys Chemical compound SC[C@@H](C(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H]1CCCN1 STGVYUTZKGPRCI-GUBZILKMSA-N 0.000 description 2
- BGOWRLSWJCVYAQ-CIUDSAMLSA-N Ser-Asp-Leu Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(O)=O BGOWRLSWJCVYAQ-CIUDSAMLSA-N 0.000 description 2
- 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 2
- 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 2
- PPNPDKGQRFSCAC-CIUDSAMLSA-N Ser-Lys-Asp Chemical compound NCCCC[C@H](NC(=O)[C@@H](N)CO)C(=O)N[C@@H](CC(O)=O)C(O)=O PPNPDKGQRFSCAC-CIUDSAMLSA-N 0.000 description 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
- GZGFSPWOMUKKCV-NAKRPEOUSA-N Ser-Pro-Ile Chemical compound CC[C@H](C)[C@@H](C(O)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@@H](N)CO GZGFSPWOMUKKCV-NAKRPEOUSA-N 0.000 description 2
- 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 2
- PCJLFYBAQZQOFE-KATARQTJSA-N Ser-Thr-Lys Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CO)N)O PCJLFYBAQZQOFE-KATARQTJSA-N 0.000 description 2
- UBTNVMGPMYDYIU-HJPIBITLSA-N Ser-Tyr-Ile Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O UBTNVMGPMYDYIU-HJPIBITLSA-N 0.000 description 2
- BIWBTRRBHIEVAH-IHPCNDPISA-N Ser-Tyr-Trp Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC1=CNC2=C1C=CC=C2)C(O)=O BIWBTRRBHIEVAH-IHPCNDPISA-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
- 208000000453 Skin Neoplasms Diseases 0.000 description 2
- LVHHEVGYAZGXDE-KDXUFGMBSA-N Thr-Ala-Pro Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](C)C(=O)N1CCC[C@@H]1C(=O)O)N)O LVHHEVGYAZGXDE-KDXUFGMBSA-N 0.000 description 2
- 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 2
- ODSAPYVQSLDRSR-LKXGYXEUSA-N Thr-Cys-Asn Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(N)=O)C(O)=O ODSAPYVQSLDRSR-LKXGYXEUSA-N 0.000 description 2
- SLUWOCTZVGMURC-BFHQHQDPSA-N Thr-Gly-Ala Chemical compound C[C@@H](O)[C@H](N)C(=O)NCC(=O)N[C@@H](C)C(O)=O SLUWOCTZVGMURC-BFHQHQDPSA-N 0.000 description 2
- 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 2
- GXUWHVZYDAHFSV-FLBSBUHZSA-N Thr-Ile-Thr Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(O)=O GXUWHVZYDAHFSV-FLBSBUHZSA-N 0.000 description 2
- YOOAQCZYZHGUAZ-KATARQTJSA-N Thr-Leu-Ser Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(O)=O YOOAQCZYZHGUAZ-KATARQTJSA-N 0.000 description 2
- 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 2
- PCMDGXKXVMBIFP-VEVYYDQMSA-N Thr-Met-Asn Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(N)=O)C(O)=O PCMDGXKXVMBIFP-VEVYYDQMSA-N 0.000 description 2
- WRUWXBBEFUTJOU-XGEHTFHBSA-N Thr-Met-Ser Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CO)C(=O)O)N)O WRUWXBBEFUTJOU-XGEHTFHBSA-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
- 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 2
- VGNKUXWYFFDWDH-BEMMVCDISA-N Thr-Trp-Pro Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC1=CNC2=CC=CC=C21)C(=O)N3CCC[C@@H]3C(=O)O)N)O VGNKUXWYFFDWDH-BEMMVCDISA-N 0.000 description 2
- CYCGARJWIQWPQM-YJRXYDGGSA-N Thr-Tyr-Ser Chemical compound C[C@@H](O)[C@H]([NH3+])C(=O)N[C@H](C(=O)N[C@@H](CO)C([O-])=O)CC1=CC=C(O)C=C1 CYCGARJWIQWPQM-YJRXYDGGSA-N 0.000 description 2
- FYBFTPLPAXZBOY-KKHAAJSZSA-N Thr-Val-Asp Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(O)=O)C(O)=O FYBFTPLPAXZBOY-KKHAAJSZSA-N 0.000 description 2
- CDHQEOXPWBDFPL-QWRGUYRKSA-N Tyr-Gly-Asn Chemical compound NC(=O)C[C@@H](C(O)=O)NC(=O)CNC(=O)[C@@H](N)CC1=CC=C(O)C=C1 CDHQEOXPWBDFPL-QWRGUYRKSA-N 0.000 description 2
- PWKMJDQXKCENMF-MEYUZBJRSA-N Tyr-Thr-Leu Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(O)=O PWKMJDQXKCENMF-MEYUZBJRSA-N 0.000 description 2
- 208000002495 Uterine Neoplasms Diseases 0.000 description 2
- REJBPZVUHYNMEN-LSJOCFKGSA-N Val-Ala-His Chemical compound C[C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)NC(=O)[C@H](C(C)C)N REJBPZVUHYNMEN-LSJOCFKGSA-N 0.000 description 2
- 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 2
- BMGOFDMKDVVGJG-NHCYSSNCSA-N Val-Asp-Lys Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](CCCCN)C(=O)O)N BMGOFDMKDVVGJG-NHCYSSNCSA-N 0.000 description 2
- UEHRGZCNLSWGHK-DLOVCJGASA-N Val-Glu-Val Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(O)=O UEHRGZCNLSWGHK-DLOVCJGASA-N 0.000 description 2
- BZOSBRIDWSSTFN-AVGNSLFASA-N Val-Leu-Met Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CCSC)C(=O)O)NC(=O)[C@H](C(C)C)N BZOSBRIDWSSTFN-AVGNSLFASA-N 0.000 description 2
- VIKZGAUAKQZDOF-NRPADANISA-N Val-Ser-Glu Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@H](C(O)=O)CCC(O)=O VIKZGAUAKQZDOF-NRPADANISA-N 0.000 description 2
- OFTXTCGQJXTNQS-XGEHTFHBSA-N Val-Thr-Ser Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CO)C(=O)O)NC(=O)[C@H](C(C)C)N)O OFTXTCGQJXTNQS-XGEHTFHBSA-N 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 210000004102 animal cell Anatomy 0.000 description 2
- 108010047857 aspartylglycine Proteins 0.000 description 2
- 210000003169 central nervous system Anatomy 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 125000000151 cysteine group Chemical class N[C@@H](CS)C(=O)* 0.000 description 2
- 108010081447 cytochrophin-4 Proteins 0.000 description 2
- 230000029087 digestion Effects 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 239000013604 expression vector Substances 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 238000010353 genetic engineering Methods 0.000 description 2
- 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 2
- 108010001064 glycyl-glycyl-glycyl-glycine Proteins 0.000 description 2
- 108010087823 glycyltyrosine Proteins 0.000 description 2
- 230000036541 health Effects 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- 201000005202 lung cancer Diseases 0.000 description 2
- 208000020816 lung neoplasm Diseases 0.000 description 2
- 108010054155 lysyllysine Proteins 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 238000007857 nested PCR Methods 0.000 description 2
- 108010051242 phenylalanylserine Proteins 0.000 description 2
- 108010031719 prolyl-serine Proteins 0.000 description 2
- 108010070643 prolylglutamic acid Proteins 0.000 description 2
- 238000000159 protein binding assay Methods 0.000 description 2
- 230000000717 retained effect Effects 0.000 description 2
- 108010069117 seryl-lysyl-aspartic acid Proteins 0.000 description 2
- 201000000849 skin cancer Diseases 0.000 description 2
- 210000000130 stem cell Anatomy 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 230000004083 survival effect Effects 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- 108010061238 threonyl-glycine Proteins 0.000 description 2
- 210000001578 tight junction Anatomy 0.000 description 2
- 108010080629 tryptophan-leucine Proteins 0.000 description 2
- 108010051110 tyrosyl-lysine Proteins 0.000 description 2
- 108010071635 tyrosyl-prolyl-arginine Proteins 0.000 description 2
- 206010046766 uterine cancer Diseases 0.000 description 2
- 239000011534 wash buffer Substances 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 description 1
- JNTMAZFVYNDPLB-PEDHHIEDSA-N (2S,3S)-2-[[[(2S)-1-[(2S,3S)-2-amino-3-methyl-1-oxopentyl]-2-pyrrolidinyl]-oxomethyl]amino]-3-methylpentanoic acid Chemical compound CC[C@H](C)[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H]([C@@H](C)CC)C(O)=O JNTMAZFVYNDPLB-PEDHHIEDSA-N 0.000 description 1
- 101150028074 2 gene Proteins 0.000 description 1
- ALYNCZNDIQEVRV-UHFFFAOYSA-N 4-aminobenzoic acid Chemical compound NC1=CC=C(C(O)=O)C=C1 ALYNCZNDIQEVRV-UHFFFAOYSA-N 0.000 description 1
- LMFAFFIRCNUJJO-UHFFFAOYSA-N 5-(4-azidophenyl)-8-iodo-3-methyl-1,2,4,5-tetrahydro-3-benzazepin-7-ol Chemical compound C1N(C)CCC2=CC(I)=C(O)C=C2C1C1=CC=C(N=[N+]=[N-])C=C1 LMFAFFIRCNUJJO-UHFFFAOYSA-N 0.000 description 1
- GOZMBJCYMQQACI-UHFFFAOYSA-N 6,7-dimethyl-3-[[methyl-[2-[methyl-[[1-[3-(trifluoromethyl)phenyl]indol-3-yl]methyl]amino]ethyl]amino]methyl]chromen-4-one;dihydrochloride Chemical compound Cl.Cl.C=1OC2=CC(C)=C(C)C=C2C(=O)C=1CN(C)CCN(C)CC(C1=CC=CC=C11)=CN1C1=CC=CC(C(F)(F)F)=C1 GOZMBJCYMQQACI-UHFFFAOYSA-N 0.000 description 1
- RLMISHABBKUNFO-WHFBIAKZSA-N Ala-Ala-Gly Chemical compound C[C@H](N)C(=O)N[C@@H](C)C(=O)NCC(O)=O RLMISHABBKUNFO-WHFBIAKZSA-N 0.000 description 1
- JBGSZRYCXBPWGX-BQBZGAKWSA-N Ala-Arg-Gly Chemical compound OC(=O)CNC(=O)[C@@H](NC(=O)[C@@H](N)C)CCCN=C(N)N JBGSZRYCXBPWGX-BQBZGAKWSA-N 0.000 description 1
- XQJAFSDFQZPYCU-UWJYBYFXSA-N Ala-Asn-Tyr Chemical compound C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CC1=CC=C(C=C1)O)C(=O)O)N XQJAFSDFQZPYCU-UWJYBYFXSA-N 0.000 description 1
- KUDREHRZRIVKHS-UWJYBYFXSA-N Ala-Asp-Tyr Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O KUDREHRZRIVKHS-UWJYBYFXSA-N 0.000 description 1
- AWAXZRDKUHOPBO-GUBZILKMSA-N Ala-Gln-Lys Chemical compound C[C@H](N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCCN)C(O)=O AWAXZRDKUHOPBO-GUBZILKMSA-N 0.000 description 1
- SFNFGFDRYJKZKN-XQXXSGGOSA-N Ala-Gln-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)N)NC(=O)[C@H](C)N)O SFNFGFDRYJKZKN-XQXXSGGOSA-N 0.000 description 1
- 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 1
- VNYMOTCMNHJGTG-JBDRJPRFSA-N Ala-Ile-Ser Chemical compound [H]N[C@@H](C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(O)=O VNYMOTCMNHJGTG-JBDRJPRFSA-N 0.000 description 1
- QQACQIHVWCVBBR-GVARAGBVSA-N Ala-Ile-Tyr Chemical compound [H]N[C@@H](C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O QQACQIHVWCVBBR-GVARAGBVSA-N 0.000 description 1
- MNZHHDPWDWQJCQ-YUMQZZPRSA-N Ala-Leu-Gly Chemical compound C[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)NCC(O)=O MNZHHDPWDWQJCQ-YUMQZZPRSA-N 0.000 description 1
- UWIQWPWWZUHBAO-ZLIFDBKOSA-N Ala-Leu-Trp Chemical compound C1=CC=C2C(C[C@H](NC(=O)[C@@H](NC(=O)[C@H](C)N)CC(C)C)C(O)=O)=CNC2=C1 UWIQWPWWZUHBAO-ZLIFDBKOSA-N 0.000 description 1
- MDNAVFBZPROEHO-UHFFFAOYSA-N Ala-Lys-Val Natural products CC(C)C(C(O)=O)NC(=O)C(NC(=O)C(C)N)CCCCN MDNAVFBZPROEHO-UHFFFAOYSA-N 0.000 description 1
- MAEQBGQTDWDSJQ-LSJOCFKGSA-N Ala-Met-His Chemical compound C[C@@H](C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)N MAEQBGQTDWDSJQ-LSJOCFKGSA-N 0.000 description 1
- VQAVBBCZFQAAED-FXQIFTODSA-N Ala-Pro-Asn Chemical compound C[C@@H](C(=O)N1CCC[C@H]1C(=O)N[C@@H](CC(=O)N)C(=O)O)N VQAVBBCZFQAAED-FXQIFTODSA-N 0.000 description 1
- FEGOCLZUJUFCHP-CIUDSAMLSA-N Ala-Pro-Gln Chemical compound [H]N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCC(N)=O)C(O)=O FEGOCLZUJUFCHP-CIUDSAMLSA-N 0.000 description 1
- IORKCNUBHNIMKY-CIUDSAMLSA-N Ala-Pro-Glu Chemical compound C[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCC(O)=O)C(O)=O IORKCNUBHNIMKY-CIUDSAMLSA-N 0.000 description 1
- WQLDNOCHHRISMS-NAKRPEOUSA-N Ala-Pro-Ile Chemical compound [H]N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)N[C@@H]([C@@H](C)CC)C(O)=O WQLDNOCHHRISMS-NAKRPEOUSA-N 0.000 description 1
- WQKAQKZRDIZYNV-VZFHVOOUSA-N Ala-Ser-Thr Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(O)=O WQKAQKZRDIZYNV-VZFHVOOUSA-N 0.000 description 1
- QRIYOHQJRDHFKF-UWJYBYFXSA-N Ala-Tyr-Ser Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)C)CC1=CC=C(O)C=C1 QRIYOHQJRDHFKF-UWJYBYFXSA-N 0.000 description 1
- MUGAESARFRGOTQ-IGNZVWTISA-N Ala-Tyr-Tyr Chemical compound 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 MUGAESARFRGOTQ-IGNZVWTISA-N 0.000 description 1
- 108700028369 Alleles Proteins 0.000 description 1
- 206010061424 Anal cancer Diseases 0.000 description 1
- 208000007860 Anus Neoplasms Diseases 0.000 description 1
- 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 1
- DBKNLHKEVPZVQC-LPEHRKFASA-N Arg-Ala-Pro Chemical compound NC(N)=NCCC[C@H](N)C(=O)N[C@@H](C)C(=O)N1CCC[C@@H]1C(O)=O DBKNLHKEVPZVQC-LPEHRKFASA-N 0.000 description 1
- IIABBYGHLYWVOS-FXQIFTODSA-N Arg-Asn-Ser Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CO)C(O)=O IIABBYGHLYWVOS-FXQIFTODSA-N 0.000 description 1
- 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 1
- ZATRYQNPUHGXCU-DTWKUNHWSA-N Arg-Gly-Pro Chemical compound C1C[C@@H](N(C1)C(=O)CNC(=O)[C@H](CCCN=C(N)N)N)C(=O)O ZATRYQNPUHGXCU-DTWKUNHWSA-N 0.000 description 1
- QEHMMRSQJMOYNO-DCAQKATOSA-N Arg-His-Asn Chemical compound C1=C(NC=N1)C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)O)NC(=O)[C@H](CCCN=C(N)N)N QEHMMRSQJMOYNO-DCAQKATOSA-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
- XRNXPIGJPQHCPC-RCWTZXSCSA-N Arg-Thr-Val Chemical compound CC(C)[C@H](NC(=O)[C@@H](NC(=O)[C@@H](N)CCCNC(N)=N)[C@@H](C)O)C(O)=O XRNXPIGJPQHCPC-RCWTZXSCSA-N 0.000 description 1
- 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
- ULBHWNVWSCJLCO-NHCYSSNCSA-N Arg-Val-Glu Chemical compound OC(=O)CC[C@@H](C(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](N)CCCN=C(N)N ULBHWNVWSCJLCO-NHCYSSNCSA-N 0.000 description 1
- XYOVHPDDWCEUDY-CIUDSAMLSA-N Asn-Ala-Leu Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(O)=O XYOVHPDDWCEUDY-CIUDSAMLSA-N 0.000 description 1
- XHFXZQHTLJVZBN-FXQIFTODSA-N Asn-Arg-Asn Chemical compound C(C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)O)NC(=O)[C@H](CC(=O)N)N)CN=C(N)N XHFXZQHTLJVZBN-FXQIFTODSA-N 0.000 description 1
- GXMSVVBIAMWMKO-BQBZGAKWSA-N Asn-Arg-Gly Chemical compound NC(=O)C[C@H](N)C(=O)N[C@H](C(=O)NCC(O)=O)CCCN=C(N)N GXMSVVBIAMWMKO-BQBZGAKWSA-N 0.000 description 1
- PCKRJVZAQZWNKM-WHFBIAKZSA-N Asn-Asn-Gly Chemical compound NC(=O)C[C@H](N)C(=O)N[C@@H](CC(N)=O)C(=O)NCC(O)=O PCKRJVZAQZWNKM-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
- ZTRJUKDEALVRMW-SRVKXCTJSA-N Asn-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](CC(=O)N)N ZTRJUKDEALVRMW-SRVKXCTJSA-N 0.000 description 1
- GLWFAWNYGWBMOC-SRVKXCTJSA-N Asn-Leu-Leu Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O GLWFAWNYGWBMOC-SRVKXCTJSA-N 0.000 description 1
- YVXRYLVELQYAEQ-SRVKXCTJSA-N Asn-Leu-Lys Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CC(=O)N)N YVXRYLVELQYAEQ-SRVKXCTJSA-N 0.000 description 1
- VOKWBBBXJONREA-DCAQKATOSA-N Asn-Met-His Chemical compound CSCC[C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)NC(=O)[C@H](CC(=O)N)N VOKWBBBXJONREA-DCAQKATOSA-N 0.000 description 1
- PPCORQFLAZWUNO-QWRGUYRKSA-N Asn-Phe-Gly Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)NCC(=O)O)NC(=O)[C@H](CC(=O)N)N PPCORQFLAZWUNO-QWRGUYRKSA-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
- HNXWVVHIGTZTBO-LKXGYXEUSA-N Asn-Ser-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC(N)=O HNXWVVHIGTZTBO-LKXGYXEUSA-N 0.000 description 1
- ZUFPUBYQYWCMDB-NUMRIWBASA-N Asn-Thr-Glu Chemical compound NC(=O)C[C@H](N)C(=O)N[C@@H]([C@H](O)C)C(=O)N[C@@H](CCC(O)=O)C(O)=O ZUFPUBYQYWCMDB-NUMRIWBASA-N 0.000 description 1
- YQPSDMUGFKJZHR-QRTARXTBSA-N Asn-Trp-Val Chemical compound CC(C)[C@@H](C(=O)O)NC(=O)[C@H](CC1=CNC2=CC=CC=C21)NC(=O)[C@H](CC(=O)N)N YQPSDMUGFKJZHR-QRTARXTBSA-N 0.000 description 1
- QNNBHTFDFFFHGC-KKUMJFAQSA-N Asn-Tyr-Lys Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CC(=O)N)N)O QNNBHTFDFFFHGC-KKUMJFAQSA-N 0.000 description 1
- DXHINQUXBZNUCF-MELADBBJSA-N Asn-Tyr-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CC2=CC=C(C=C2)O)NC(=O)[C@H](CC(=O)N)N)C(=O)O DXHINQUXBZNUCF-MELADBBJSA-N 0.000 description 1
- MJIJBEYEHBKTIM-BYULHYEWSA-N Asn-Val-Asn Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)O)NC(=O)[C@H](CC(=O)N)N MJIJBEYEHBKTIM-BYULHYEWSA-N 0.000 description 1
- MYRLSKYSMXNLLA-LAEOZQHASA-N Asn-Val-Glu Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(O)=O)C(O)=O MYRLSKYSMXNLLA-LAEOZQHASA-N 0.000 description 1
- KBQOUDLMWYWXNP-YDHLFZDLSA-N Asn-Val-Phe Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)O)NC(=O)[C@H](CC(=O)N)N KBQOUDLMWYWXNP-YDHLFZDLSA-N 0.000 description 1
- SVFOIXMRMLROHO-SRVKXCTJSA-N Asp-Asp-Phe Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 SVFOIXMRMLROHO-SRVKXCTJSA-N 0.000 description 1
- BKXPJCBEHWFSTF-ACZMJKKPSA-N Asp-Gln-Asp Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(O)=O)C(O)=O BKXPJCBEHWFSTF-ACZMJKKPSA-N 0.000 description 1
- VAWNQIGQPUOPQW-ACZMJKKPSA-N Asp-Glu-Ala Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(O)=O VAWNQIGQPUOPQW-ACZMJKKPSA-N 0.000 description 1
- RRKCPMGSRIDLNC-AVGNSLFASA-N Asp-Glu-Tyr Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O RRKCPMGSRIDLNC-AVGNSLFASA-N 0.000 description 1
- KTTCQQNRRLCIBC-GHCJXIJMSA-N Asp-Ile-Ala Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(O)=O KTTCQQNRRLCIBC-GHCJXIJMSA-N 0.000 description 1
- CYCKJEFVFNRWEZ-UGYAYLCHSA-N Asp-Ile-Asn Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(N)=O)C(O)=O CYCKJEFVFNRWEZ-UGYAYLCHSA-N 0.000 description 1
- IVPNEDNYYYFAGI-GARJFASQSA-N Asp-Leu-Pro Chemical compound CC(C)C[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](CC(=O)O)N IVPNEDNYYYFAGI-GARJFASQSA-N 0.000 description 1
- UZFHNLYQWMGUHU-DCAQKATOSA-N Asp-Lys-Arg Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O UZFHNLYQWMGUHU-DCAQKATOSA-N 0.000 description 1
- LIQNMKIBMPEOOP-IHRRRGAJSA-N Asp-Phe-Met Chemical compound CSCC[C@@H](C(=O)O)NC(=O)[C@H](CC1=CC=CC=C1)NC(=O)[C@H](CC(=O)O)N LIQNMKIBMPEOOP-IHRRRGAJSA-N 0.000 description 1
- XUVTWGPERWIERB-IHRRRGAJSA-N Asp-Pro-Phe Chemical compound N[C@@H](CC(O)=O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](Cc1ccccc1)C(O)=O XUVTWGPERWIERB-IHRRRGAJSA-N 0.000 description 1
- CUQDCPXNZPDYFQ-ZLUOBGJFSA-N Asp-Ser-Asp Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(O)=O)C(O)=O CUQDCPXNZPDYFQ-ZLUOBGJFSA-N 0.000 description 1
- JSHWXQIZOCVWIA-ZKWXMUAHSA-N Asp-Ser-Val Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(O)=O JSHWXQIZOCVWIA-ZKWXMUAHSA-N 0.000 description 1
- NJLLRXWFPQQPHV-SRVKXCTJSA-N Asp-Tyr-Asn 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](CC(N)=O)C(O)=O NJLLRXWFPQQPHV-SRVKXCTJSA-N 0.000 description 1
- SQIARYGNVQWOSB-BZSNNMDCSA-N Asp-Tyr-Phe Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O SQIARYGNVQWOSB-BZSNNMDCSA-N 0.000 description 1
- CZIVKMOEXPILDK-SRVKXCTJSA-N Asp-Tyr-Ser Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CO)C(O)=O CZIVKMOEXPILDK-SRVKXCTJSA-N 0.000 description 1
- GYNUXDMCDILYIQ-QRTARXTBSA-N Asp-Val-Trp Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC1=CNC2=CC=CC=C21)C(=O)O)NC(=O)[C@H](CC(=O)O)N GYNUXDMCDILYIQ-QRTARXTBSA-N 0.000 description 1
- 206010003571 Astrocytoma Diseases 0.000 description 1
- 206010005003 Bladder cancer Diseases 0.000 description 1
- 206010005949 Bone cancer Diseases 0.000 description 1
- 208000018084 Bone neoplasm Diseases 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 206010006143 Brain stem glioma Diseases 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- 201000009030 Carcinoma Diseases 0.000 description 1
- 241000282693 Cercopithecidae Species 0.000 description 1
- 206010008342 Cervix carcinoma Diseases 0.000 description 1
- 206010009944 Colon cancer Diseases 0.000 description 1
- 241000699800 Cricetinae Species 0.000 description 1
- NOCCABSVTRONIN-CIUDSAMLSA-N Cys-Ala-Leu Chemical compound C[C@@H](C(=O)N[C@@H](CC(C)C)C(=O)O)NC(=O)[C@H](CS)N NOCCABSVTRONIN-CIUDSAMLSA-N 0.000 description 1
- 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 1
- HHABWQIFXZPZCK-ACZMJKKPSA-N Cys-Gln-Ser Chemical compound C(CC(=O)N)[C@@H](C(=O)N[C@@H](CO)C(=O)O)NC(=O)[C@H](CS)N HHABWQIFXZPZCK-ACZMJKKPSA-N 0.000 description 1
- YUZPQIQWXLRFBW-ACZMJKKPSA-N Cys-Glu-Ala Chemical compound [H]N[C@@H](CS)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(O)=O YUZPQIQWXLRFBW-ACZMJKKPSA-N 0.000 description 1
- VIRYODQIWJNWNU-NRPADANISA-N Cys-Glu-Val Chemical compound CC(C)[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)O)NC(=O)[C@H](CS)N VIRYODQIWJNWNU-NRPADANISA-N 0.000 description 1
- OHLLDUNVMPPUMD-DCAQKATOSA-N Cys-Leu-Val Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](C(C)C)C(=O)O)NC(=O)[C@H](CS)N OHLLDUNVMPPUMD-DCAQKATOSA-N 0.000 description 1
- VDUPGIDTWNQAJD-CIUDSAMLSA-N Cys-Lys-Cys Chemical compound NCCCC[C@H](NC(=O)[C@@H](N)CS)C(=O)N[C@@H](CS)C(O)=O VDUPGIDTWNQAJD-CIUDSAMLSA-N 0.000 description 1
- RWVBNRYBHAGYSG-GUBZILKMSA-N Cys-Met-Val Chemical compound CC(C)[C@@H](C(=O)O)NC(=O)[C@H](CCSC)NC(=O)[C@H](CS)N RWVBNRYBHAGYSG-GUBZILKMSA-N 0.000 description 1
- KSMSFCBQBQPFAD-GUBZILKMSA-N Cys-Pro-Pro Chemical compound SC[C@H](N)C(=O)N1CCC[C@H]1C(=O)N1[C@H](C(O)=O)CCC1 KSMSFCBQBQPFAD-GUBZILKMSA-N 0.000 description 1
- NDNZRWUDUMTITL-FXQIFTODSA-N Cys-Ser-Val Chemical compound [H]N[C@@H](CS)C(=O)N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(O)=O NDNZRWUDUMTITL-FXQIFTODSA-N 0.000 description 1
- 206010061818 Disease progression Diseases 0.000 description 1
- 238000008157 ELISA kit Methods 0.000 description 1
- 206010014733 Endometrial cancer Diseases 0.000 description 1
- 206010014759 Endometrial neoplasm Diseases 0.000 description 1
- 206010014967 Ependymoma Diseases 0.000 description 1
- 241000283086 Equidae Species 0.000 description 1
- 241000588724 Escherichia coli Species 0.000 description 1
- 208000000461 Esophageal Neoplasms Diseases 0.000 description 1
- 201000001342 Fallopian tube cancer Diseases 0.000 description 1
- 208000013452 Fallopian tube neoplasm Diseases 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 241001653121 Glenoides Species 0.000 description 1
- 201000010915 Glioblastoma multiforme Diseases 0.000 description 1
- 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 1
- INFBPLSHYFALDE-ACZMJKKPSA-N Gln-Asn-Ala Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](C)C(O)=O INFBPLSHYFALDE-ACZMJKKPSA-N 0.000 description 1
- ZPDVKYLJTOFQJV-WDSKDSINSA-N Gln-Asn-Gly Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)NCC(O)=O ZPDVKYLJTOFQJV-WDSKDSINSA-N 0.000 description 1
- OFPWCBGRYAOLMU-AVGNSLFASA-N Gln-Asp-Tyr Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)O)NC(=O)[C@H](CCC(=O)N)N)O OFPWCBGRYAOLMU-AVGNSLFASA-N 0.000 description 1
- MADFVRSKEIEZHZ-DCAQKATOSA-N Gln-Gln-Lys Chemical compound C(CCN)C[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)N)NC(=O)[C@H](CCC(=O)N)N MADFVRSKEIEZHZ-DCAQKATOSA-N 0.000 description 1
- IKFZXRLDMYWNBU-YUMQZZPRSA-N Gln-Gly-Arg Chemical compound NC(=O)CC[C@H](N)C(=O)NCC(=O)N[C@H](C(O)=O)CCCN=C(N)N IKFZXRLDMYWNBU-YUMQZZPRSA-N 0.000 description 1
- JKGHMESJHRTHIC-SIUGBPQLSA-N Gln-Ile-Tyr Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC1=CC=C(C=C1)O)C(=O)O)NC(=O)[C@H](CCC(=O)N)N JKGHMESJHRTHIC-SIUGBPQLSA-N 0.000 description 1
- LGIKBBLQVSWUGK-DCAQKATOSA-N Gln-Leu-Gln Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(O)=O LGIKBBLQVSWUGK-DCAQKATOSA-N 0.000 description 1
- IULKWYSYZSURJK-AVGNSLFASA-N Gln-Leu-Lys Chemical compound NC(=O)CC[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(O)=O IULKWYSYZSURJK-AVGNSLFASA-N 0.000 description 1
- 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
- HMIXCETWRYDVMO-GUBZILKMSA-N Gln-Pro-Glu Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCC(O)=O)C(O)=O HMIXCETWRYDVMO-GUBZILKMSA-N 0.000 description 1
- 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 1
- KVQOVQVGVKDZNW-GUBZILKMSA-N Gln-Ser-His Chemical compound C1=C(NC=N1)C[C@@H](C(=O)O)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(=O)N)N KVQOVQVGVKDZNW-GUBZILKMSA-N 0.000 description 1
- 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 1
- YRHZWVKUFWCEPW-GLLZPBPUSA-N Gln-Thr-Gln Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)O)NC(=O)[C@H](CCC(=O)N)N)O YRHZWVKUFWCEPW-GLLZPBPUSA-N 0.000 description 1
- SYTFJIQPBRJSOK-NKIYYHGXSA-N Gln-Thr-His Chemical compound NC(=O)CC[C@H](N)C(=O)N[C@@H]([C@H](O)C)C(=O)N[C@H](C(O)=O)CC1=CN=CN1 SYTFJIQPBRJSOK-NKIYYHGXSA-N 0.000 description 1
- 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 1
- HLRLXVPRJJITSK-IFFSRLJSSA-N Gln-Thr-Val Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(O)=O HLRLXVPRJJITSK-IFFSRLJSSA-N 0.000 description 1
- 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 1
- CSMHMEATMDCQNY-DZKIICNBSA-N Gln-Val-Tyr Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O CSMHMEATMDCQNY-DZKIICNBSA-N 0.000 description 1
- ITYRYNUZHPNCIK-GUBZILKMSA-N Glu-Ala-Leu Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(O)=O ITYRYNUZHPNCIK-GUBZILKMSA-N 0.000 description 1
- JJKKWYQVHRUSDG-GUBZILKMSA-N Glu-Ala-Lys Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCN)C(O)=O JJKKWYQVHRUSDG-GUBZILKMSA-N 0.000 description 1
- SRZLHYPAOXBBSB-HJGDQZAQSA-N Glu-Arg-Thr Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(O)=O SRZLHYPAOXBBSB-HJGDQZAQSA-N 0.000 description 1
- IESFZVCAVACGPH-PEFMBERDSA-N Glu-Asp-Ile Chemical compound CC[C@H](C)[C@@H](C(O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@@H](N)CCC(O)=O IESFZVCAVACGPH-PEFMBERDSA-N 0.000 description 1
- CKOFNWCLWRYUHK-XHNCKOQMSA-N Glu-Asp-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CC(=O)O)NC(=O)[C@H](CCC(=O)O)N)C(=O)O CKOFNWCLWRYUHK-XHNCKOQMSA-N 0.000 description 1
- CYHBMLHCQXXCCT-AVGNSLFASA-N Glu-Asp-Tyr Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O CYHBMLHCQXXCCT-AVGNSLFASA-N 0.000 description 1
- UENPHLAAKDPZQY-XKBZYTNZSA-N Glu-Cys-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CS)NC(=O)[C@H](CCC(=O)O)N)O UENPHLAAKDPZQY-XKBZYTNZSA-N 0.000 description 1
- CLROYXHHUZELFX-FXQIFTODSA-N Glu-Gln-Asp Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(O)=O)C(O)=O CLROYXHHUZELFX-FXQIFTODSA-N 0.000 description 1
- KASDBWKLWJKTLJ-GUBZILKMSA-N Glu-Glu-Met Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCSC)C(O)=O KASDBWKLWJKTLJ-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
- GJBUAAAIZSRCDC-GVXVVHGQSA-N Glu-Leu-Val Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(O)=O GJBUAAAIZSRCDC-GVXVVHGQSA-N 0.000 description 1
- YHOJJFFTSMWVGR-HJGDQZAQSA-N Glu-Met-Thr Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCSC)C(=O)N[C@@H]([C@@H](C)O)C(O)=O YHOJJFFTSMWVGR-HJGDQZAQSA-N 0.000 description 1
- TWYFJOHWGCCRIR-DCAQKATOSA-N Glu-Pro-Arg Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCCNC(N)=N)C(O)=O TWYFJOHWGCCRIR-DCAQKATOSA-N 0.000 description 1
- AAJHGGDRKHYSDH-GUBZILKMSA-N Glu-Pro-Gln Chemical compound C1C[C@H](N(C1)C(=O)[C@H](CCC(=O)O)N)C(=O)N[C@@H](CCC(=O)N)C(=O)O AAJHGGDRKHYSDH-GUBZILKMSA-N 0.000 description 1
- BFEZQZKEPRKKHV-SRVKXCTJSA-N Glu-Pro-Lys Chemical compound C1C[C@H](N(C1)C(=O)[C@H](CCC(=O)O)N)C(=O)N[C@@H](CCCCN)C(=O)O BFEZQZKEPRKKHV-SRVKXCTJSA-N 0.000 description 1
- BIYNPVYAZOUVFQ-CIUDSAMLSA-N Glu-Pro-Ser Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CO)C(O)=O BIYNPVYAZOUVFQ-CIUDSAMLSA-N 0.000 description 1
- ALMBZBOCGSVSAI-ACZMJKKPSA-N Glu-Ser-Asn Chemical compound C(CC(=O)O)[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(=O)N)C(=O)O)N ALMBZBOCGSVSAI-ACZMJKKPSA-N 0.000 description 1
- SFKMXFWWDUGXRT-NWLDYVSISA-N Glu-Trp-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CC1=CNC2=CC=CC=C21)NC(=O)[C@H](CCC(=O)O)N)O SFKMXFWWDUGXRT-NWLDYVSISA-N 0.000 description 1
- LSYFGBRDBIQYAQ-FHWLQOOXSA-N Glu-Tyr-Tyr Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O LSYFGBRDBIQYAQ-FHWLQOOXSA-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
- DJTXYXZNNDDEOU-WHFBIAKZSA-N Gly-Asn-Cys Chemical compound C([C@@H](C(=O)N[C@@H](CS)C(=O)O)NC(=O)CN)C(=O)N DJTXYXZNNDDEOU-WHFBIAKZSA-N 0.000 description 1
- JVACNFOPSUPDTK-QWRGUYRKSA-N Gly-Asn-Phe Chemical compound NCC(=O)N[C@@H](CC(N)=O)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 JVACNFOPSUPDTK-QWRGUYRKSA-N 0.000 description 1
- XCLCVBYNGXEVDU-WHFBIAKZSA-N Gly-Asn-Ser Chemical compound NCC(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CO)C(O)=O XCLCVBYNGXEVDU-WHFBIAKZSA-N 0.000 description 1
- PMNHJLASAAWELO-FOHZUACHSA-N Gly-Asp-Thr Chemical compound [H]NCC(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O PMNHJLASAAWELO-FOHZUACHSA-N 0.000 description 1
- DTRUBYPMMVPQPD-YUMQZZPRSA-N Gly-Gln-Arg Chemical compound [H]NCC(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O DTRUBYPMMVPQPD-YUMQZZPRSA-N 0.000 description 1
- PABFFPWEJMEVEC-JGVFFNPUSA-N Gly-Gln-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CCC(=O)N)NC(=O)CN)C(=O)O PABFFPWEJMEVEC-JGVFFNPUSA-N 0.000 description 1
- 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
- SWQALSGKVLYKDT-UHFFFAOYSA-N Gly-Ile-Ala Natural products NCC(=O)NC(C(C)CC)C(=O)NC(C)C(O)=O SWQALSGKVLYKDT-UHFFFAOYSA-N 0.000 description 1
- LIXWIUAORXJNBH-QWRGUYRKSA-N Gly-Leu-His Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)NC(=O)CN LIXWIUAORXJNBH-QWRGUYRKSA-N 0.000 description 1
- NNCSJUBVFBDDLC-YUMQZZPRSA-N Gly-Leu-Ser Chemical compound NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(O)=O NNCSJUBVFBDDLC-YUMQZZPRSA-N 0.000 description 1
- 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
- GMTXWRIDLGTVFC-IUCAKERBSA-N Gly-Lys-Glu Chemical compound [H]NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(O)=O GMTXWRIDLGTVFC-IUCAKERBSA-N 0.000 description 1
- NTBOEZICHOSJEE-YUMQZZPRSA-N Gly-Lys-Ser Chemical compound [H]NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CO)C(O)=O NTBOEZICHOSJEE-YUMQZZPRSA-N 0.000 description 1
- GLACUWHUYFBSPJ-FJXKBIBVSA-N Gly-Pro-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)[C@@H]1CCCN1C(=O)CN GLACUWHUYFBSPJ-FJXKBIBVSA-N 0.000 description 1
- FGPLUIQCSKGLTI-WDSKDSINSA-N Gly-Ser-Glu Chemical compound NCC(=O)N[C@@H](CO)C(=O)N[C@H](C(O)=O)CCC(O)=O FGPLUIQCSKGLTI-WDSKDSINSA-N 0.000 description 1
- 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 1
- FKYQEVBRZSFAMJ-QWRGUYRKSA-N Gly-Ser-Tyr Chemical compound NCC(=O)N[C@@H](CO)C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 FKYQEVBRZSFAMJ-QWRGUYRKSA-N 0.000 description 1
- CQMFNTVQVLQRLT-JHEQGTHGSA-N Gly-Thr-Gln Chemical compound [H]NCC(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCC(N)=O)C(O)=O CQMFNTVQVLQRLT-JHEQGTHGSA-N 0.000 description 1
- DBUNZBWUWCIELX-JHEQGTHGSA-N Gly-Thr-Glu Chemical compound [H]NCC(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCC(O)=O)C(O)=O DBUNZBWUWCIELX-JHEQGTHGSA-N 0.000 description 1
- 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 1
- 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 1
- KSOBNUBCYHGUKH-UWVGGRQHSA-N Gly-Val-Val Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)[C@H](C(C)C)NC(=O)CN KSOBNUBCYHGUKH-UWVGGRQHSA-N 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 108090000288 Glycoproteins Proteins 0.000 description 1
- 102000003886 Glycoproteins Human genes 0.000 description 1
- 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 1
- 241000238631 Hexapoda Species 0.000 description 1
- MAABHGXCIBEYQR-XVYDVKMFSA-N His-Asn-Ala Chemical compound C[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)N)NC(=O)[C@H](CC1=CN=CN1)N MAABHGXCIBEYQR-XVYDVKMFSA-N 0.000 description 1
- WMKXFMUJRCEGRP-SRVKXCTJSA-N His-Asn-His Chemical compound C1=C(NC=N1)C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CC2=CN=CN2)C(=O)O)N WMKXFMUJRCEGRP-SRVKXCTJSA-N 0.000 description 1
- FYVHHKMHFPMBBG-GUBZILKMSA-N His-Gln-Asp Chemical compound C1=C(NC=N1)C[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H](CC(=O)O)C(=O)O)N FYVHHKMHFPMBBG-GUBZILKMSA-N 0.000 description 1
- AKEDPWJFQULLPE-IUCAKERBSA-N His-Glu-Gly Chemical compound N[C@@H](Cc1cnc[nH]1)C(=O)N[C@@H](CCC(O)=O)C(=O)NCC(O)=O AKEDPWJFQULLPE-IUCAKERBSA-N 0.000 description 1
- CNHSMSFYVARZLI-YJRXYDGGSA-N His-His-Thr Chemical compound [H]N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CC1=CNC=N1)C(=O)N[C@@H]([C@@H](C)O)C(O)=O CNHSMSFYVARZLI-YJRXYDGGSA-N 0.000 description 1
- TTYKEFZRLKQTHH-MELADBBJSA-N His-Lys-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CCCCN)NC(=O)[C@H](CC2=CN=CN2)N)C(=O)O TTYKEFZRLKQTHH-MELADBBJSA-N 0.000 description 1
- BRQKGRLDDDQWQJ-MBLNEYKQSA-N His-Thr-Ala Chemical compound [H]N[C@@H](CC1=CNC=N1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C)C(O)=O BRQKGRLDDDQWQJ-MBLNEYKQSA-N 0.000 description 1
- 208000017604 Hodgkin disease Diseases 0.000 description 1
- 208000010747 Hodgkins lymphoma Diseases 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 101100113665 Homo sapiens CLDN18 gene Proteins 0.000 description 1
- 101000599940 Homo sapiens Interferon gamma Proteins 0.000 description 1
- 101000611183 Homo sapiens Tumor necrosis factor Proteins 0.000 description 1
- 102000009490 IgG Receptors Human genes 0.000 description 1
- 108010073807 IgG Receptors Proteins 0.000 description 1
- BOTVMTSMOUSDRW-GMOBBJLQSA-N Ile-Arg-Asn Chemical compound CC[C@H](C)[C@H](N)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CC(N)=O)C(O)=O BOTVMTSMOUSDRW-GMOBBJLQSA-N 0.000 description 1
- ZGGWRNBSBOHIGH-HVTMNAMFSA-N Ile-Gln-His Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)N ZGGWRNBSBOHIGH-HVTMNAMFSA-N 0.000 description 1
- JDAWAWXGAUZPNJ-ZPFDUUQYSA-N Ile-Glu-Arg Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CCCN=C(N)N)C(=O)O)N JDAWAWXGAUZPNJ-ZPFDUUQYSA-N 0.000 description 1
- DFJJAVZIHDFOGQ-MNXVOIDGSA-N Ile-Glu-Lys Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CCCCN)C(=O)O)N DFJJAVZIHDFOGQ-MNXVOIDGSA-N 0.000 description 1
- XLCZWMJPVGRWHJ-KQXIARHKSA-N Ile-Glu-Pro Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)N1CCC[C@@H]1C(=O)O)N XLCZWMJPVGRWHJ-KQXIARHKSA-N 0.000 description 1
- LBRCLQMZAHRTLV-ZKWXMUAHSA-N Ile-Gly-Ser Chemical compound CC[C@H](C)[C@H](N)C(=O)NCC(=O)N[C@@H](CO)C(O)=O LBRCLQMZAHRTLV-ZKWXMUAHSA-N 0.000 description 1
- RMNMUUCYTMLWNA-ZPFDUUQYSA-N Ile-Lys-Asp Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(=O)O)C(=O)O)N RMNMUUCYTMLWNA-ZPFDUUQYSA-N 0.000 description 1
- GLYJPWIRLBAIJH-FQUUOJAGSA-N Ile-Lys-Pro Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCCCN)C(=O)N1CCC[C@@H]1C(=O)O)N GLYJPWIRLBAIJH-FQUUOJAGSA-N 0.000 description 1
- 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 1
- 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 1
- WKSHBPRUIRGWRZ-KCTSRDHCSA-N Ile-Trp-Gly Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC1=CNC2=CC=CC=C21)C(=O)NCC(=O)O)N WKSHBPRUIRGWRZ-KCTSRDHCSA-N 0.000 description 1
- WRDTXMBPHMBGIB-STECZYCISA-N Ile-Tyr-Val Chemical compound CC[C@H](C)[C@H](N)C(=O)N[C@H](C(=O)N[C@@H](C(C)C)C(O)=O)CC1=CC=C(O)C=C1 WRDTXMBPHMBGIB-STECZYCISA-N 0.000 description 1
- 102000018071 Immunoglobulin Fc Fragments Human genes 0.000 description 1
- 108010091135 Immunoglobulin Fc Fragments Proteins 0.000 description 1
- 206010061252 Intraocular melanoma Diseases 0.000 description 1
- 208000008839 Kidney Neoplasms Diseases 0.000 description 1
- FADYJNXDPBKVCA-UHFFFAOYSA-N L-Phenylalanyl-L-lysin Natural products NCCCCC(C(O)=O)NC(=O)C(N)CC1=CC=CC=C1 FADYJNXDPBKVCA-UHFFFAOYSA-N 0.000 description 1
- HXWALXSAVBLTPK-NUTKFTJISA-N Leu-Ala-Trp Chemical compound C[C@@H](C(=O)N[C@@H](CC1=CNC2=CC=CC=C21)C(=O)O)NC(=O)[C@H](CC(C)C)N HXWALXSAVBLTPK-NUTKFTJISA-N 0.000 description 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
- OIARJGNVARWKFP-YUMQZZPRSA-N Leu-Asn-Gly Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)NCC(O)=O OIARJGNVARWKFP-YUMQZZPRSA-N 0.000 description 1
- OGCQGUIWMSBHRZ-CIUDSAMLSA-N Leu-Asn-Ser Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CO)C(O)=O OGCQGUIWMSBHRZ-CIUDSAMLSA-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
- CQGSYZCULZMEDE-SRVKXCTJSA-N Leu-Gln-Pro Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CCC(N)=O)C(=O)N1CCC[C@H]1C(O)=O CQGSYZCULZMEDE-SRVKXCTJSA-N 0.000 description 1
- 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
- CCQLQKZTXZBXTN-NHCYSSNCSA-N Leu-Gly-Ile Chemical compound [H]N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H]([C@@H](C)CC)C(O)=O CCQLQKZTXZBXTN-NHCYSSNCSA-N 0.000 description 1
- JRJLGNFWYFSJHB-HOCLYGCPSA-N Leu-Gly-Trp Chemical compound [H]N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](CC1=CNC2=C1C=CC=C2)C(O)=O JRJLGNFWYFSJHB-HOCLYGCPSA-N 0.000 description 1
- BTNXKBVLWJBTNR-SRVKXCTJSA-N Leu-His-Asn Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CC(N)=O)C(O)=O BTNXKBVLWJBTNR-SRVKXCTJSA-N 0.000 description 1
- QJXHMYMRGDOHRU-NHCYSSNCSA-N Leu-Ile-Gly Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(O)=O QJXHMYMRGDOHRU-NHCYSSNCSA-N 0.000 description 1
- RGUXWMDNCPMQFB-YUMQZZPRSA-N Leu-Ser-Gly Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CO)C(=O)NCC(O)=O RGUXWMDNCPMQFB-YUMQZZPRSA-N 0.000 description 1
- AMSSKPUHBUQBOQ-SRVKXCTJSA-N Leu-Ser-Lys Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCCN)C(=O)O)N AMSSKPUHBUQBOQ-SRVKXCTJSA-N 0.000 description 1
- SBANPBVRHYIMRR-GARJFASQSA-N Leu-Ser-Pro Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CO)C(=O)N1CCC[C@@H]1C(=O)O)N SBANPBVRHYIMRR-GARJFASQSA-N 0.000 description 1
- LCNASHSOFMRYFO-WDCWCFNPSA-N Leu-Thr-Gln Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@H](C(O)=O)CCC(N)=O LCNASHSOFMRYFO-WDCWCFNPSA-N 0.000 description 1
- DAYQSYGBCUKVKT-VOAKCMCISA-N Leu-Thr-Lys Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCCN)C(O)=O DAYQSYGBCUKVKT-VOAKCMCISA-N 0.000 description 1
- VUBIPAHVHMZHCM-KKUMJFAQSA-N Leu-Tyr-Ser Chemical compound CC(C)C[C@H](N)C(=O)N[C@H](C(=O)N[C@@H](CO)C(O)=O)CC1=CC=C(O)C=C1 VUBIPAHVHMZHCM-KKUMJFAQSA-N 0.000 description 1
- 208000028018 Lymphocytic leukaemia Diseases 0.000 description 1
- 206010025323 Lymphomas Diseases 0.000 description 1
- WSXTWLJHTLRFLW-SRVKXCTJSA-N Lys-Ala-Lys Chemical compound NCCCC[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCN)C(O)=O WSXTWLJHTLRFLW-SRVKXCTJSA-N 0.000 description 1
- YKIRNDPUWONXQN-GUBZILKMSA-N Lys-Asn-Gln Chemical compound C(CCN)C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CCC(=O)N)C(=O)O)N YKIRNDPUWONXQN-GUBZILKMSA-N 0.000 description 1
- JBRWKVANRYPCAF-XIRDDKMYSA-N Lys-Asn-Trp Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)N)NC(=O)[C@H](CCCCN)N JBRWKVANRYPCAF-XIRDDKMYSA-N 0.000 description 1
- IWWMPCPLFXFBAF-SRVKXCTJSA-N Lys-Asp-Leu Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(O)=O IWWMPCPLFXFBAF-SRVKXCTJSA-N 0.000 description 1
- NTBFKPBULZGXQL-KKUMJFAQSA-N Lys-Asp-Tyr Chemical compound NCCCC[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 NTBFKPBULZGXQL-KKUMJFAQSA-N 0.000 description 1
- NDORZBUHCOJQDO-GVXVVHGQSA-N Lys-Gln-Val Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](C(C)C)C(O)=O NDORZBUHCOJQDO-GVXVVHGQSA-N 0.000 description 1
- DUTMKEAPLLUGNO-JYJNAYRXSA-N Lys-Glu-Phe Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O DUTMKEAPLLUGNO-JYJNAYRXSA-N 0.000 description 1
- ODUQLUADRKMHOZ-JYJNAYRXSA-N Lys-Glu-Tyr Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)O)NC(=O)[C@H](CCCCN)N)O ODUQLUADRKMHOZ-JYJNAYRXSA-N 0.000 description 1
- RFQATBGBLDAKGI-VHSXEESVSA-N Lys-Gly-Pro Chemical compound C1C[C@@H](N(C1)C(=O)CNC(=O)[C@H](CCCCN)N)C(=O)O RFQATBGBLDAKGI-VHSXEESVSA-N 0.000 description 1
- FGMHXLULNHTPID-KKUMJFAQSA-N Lys-His-Lys Chemical compound NCCCC[C@H](N)C(=O)N[C@H](C(=O)N[C@@H](CCCCN)C(O)=O)CC1=CN=CN1 FGMHXLULNHTPID-KKUMJFAQSA-N 0.000 description 1
- IUWMQCZOTYRXPL-ZPFDUUQYSA-N Lys-Ile-Asp Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(O)=O)C(O)=O IUWMQCZOTYRXPL-ZPFDUUQYSA-N 0.000 description 1
- QOJDBRUCOXQSSK-AJNGGQMLSA-N Lys-Ile-Lys Chemical compound NCCCC[C@H](N)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCCCN)C(O)=O QOJDBRUCOXQSSK-AJNGGQMLSA-N 0.000 description 1
- OVAOHZIOUBEQCJ-IHRRRGAJSA-N Lys-Leu-Arg Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O OVAOHZIOUBEQCJ-IHRRRGAJSA-N 0.000 description 1
- RIJCHEVHFWMDKD-SRVKXCTJSA-N Lys-Lys-Asn Chemical compound NCCCC[C@H](N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(O)=O RIJCHEVHFWMDKD-SRVKXCTJSA-N 0.000 description 1
- LUTDBHBIHHREDC-IHRRRGAJSA-N Lys-Pro-Lys Chemical compound NCCCC[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCCCN)C(O)=O LUTDBHBIHHREDC-IHRRRGAJSA-N 0.000 description 1
- WQDKIVRHTQYJSN-DCAQKATOSA-N Lys-Ser-Arg Chemical compound C(CCN)C[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCN=C(N)N)C(=O)O)N WQDKIVRHTQYJSN-DCAQKATOSA-N 0.000 description 1
- JMNRXRPBHFGXQX-GUBZILKMSA-N Lys-Ser-Glu Chemical compound NCCCC[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@H](C(O)=O)CCC(O)=O JMNRXRPBHFGXQX-GUBZILKMSA-N 0.000 description 1
- MIFFFXHMAHFACR-KATARQTJSA-N Lys-Ser-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CCCCN MIFFFXHMAHFACR-KATARQTJSA-N 0.000 description 1
- QVTDVTONTRSQMF-WDCWCFNPSA-N Lys-Thr-Glu Chemical compound OC(=O)CC[C@@H](C(O)=O)NC(=O)[C@H]([C@H](O)C)NC(=O)[C@@H](N)CCCCN QVTDVTONTRSQMF-WDCWCFNPSA-N 0.000 description 1
- IEVXCWPVBYCJRZ-IXOXFDKPSA-N Lys-Thr-His Chemical compound NCCCC[C@H](N)C(=O)N[C@@H]([C@H](O)C)C(=O)N[C@H](C(O)=O)CC1=CN=CN1 IEVXCWPVBYCJRZ-IXOXFDKPSA-N 0.000 description 1
- YKBSXQFZWFXFIB-VOAKCMCISA-N Lys-Thr-Lys Chemical compound NCCCC[C@H](N)C(=O)N[C@@H]([C@H](O)C)C(=O)N[C@@H](CCCCN)C(O)=O YKBSXQFZWFXFIB-VOAKCMCISA-N 0.000 description 1
- CAVRAQIDHUPECU-UVOCVTCTSA-N Lys-Thr-Thr Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O CAVRAQIDHUPECU-UVOCVTCTSA-N 0.000 description 1
- SUZVLFWOCKHWET-CQDKDKBSSA-N Lys-Tyr-Ala Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](C)C(O)=O SUZVLFWOCKHWET-CQDKDKBSSA-N 0.000 description 1
- PELXPRPDQRFBGQ-KKUMJFAQSA-N Lys-Tyr-Asn Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)O)NC(=O)[C@H](CCCCN)N)O PELXPRPDQRFBGQ-KKUMJFAQSA-N 0.000 description 1
- YQAIUOWPSUOINN-IUCAKERBSA-N Lys-Val Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)[C@@H](N)CCCCN YQAIUOWPSUOINN-IUCAKERBSA-N 0.000 description 1
- MDDUIRLQCYVRDO-NHCYSSNCSA-N Lys-Val-Asn Chemical compound NC(=O)C[C@@H](C(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](N)CCCCN MDDUIRLQCYVRDO-NHCYSSNCSA-N 0.000 description 1
- 206010064912 Malignant transformation Diseases 0.000 description 1
- 208000032271 Malignant tumor of penis Diseases 0.000 description 1
- 208000000172 Medulloblastoma Diseases 0.000 description 1
- 206010027406 Mesothelioma Diseases 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
- NHDMNXBBSGVYGP-PYJNHQTQSA-N Met-His-Ile Chemical compound CSCC[C@H](N)C(=O)N[C@H](C(=O)N[C@@H]([C@@H](C)CC)C(O)=O)CC1=CN=CN1 NHDMNXBBSGVYGP-PYJNHQTQSA-N 0.000 description 1
- LXCSZPUQKMTXNW-BQBZGAKWSA-N Met-Ser-Gly Chemical compound CSCC[C@H](N)C(=O)N[C@@H](CO)C(=O)NCC(O)=O LXCSZPUQKMTXNW-BQBZGAKWSA-N 0.000 description 1
- MIXPUVSPPOWTCR-FXQIFTODSA-N Met-Ser-Ser Chemical compound [H]N[C@@H](CCSC)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(O)=O MIXPUVSPPOWTCR-FXQIFTODSA-N 0.000 description 1
- IHRFZLQEQVHXFA-RHYQMDGZSA-N Met-Thr-Lys Chemical compound CSCC[C@H](N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@H](C(O)=O)CCCCN IHRFZLQEQVHXFA-RHYQMDGZSA-N 0.000 description 1
- PNHRPOWKRRJATF-IHRRRGAJSA-N Met-Tyr-Ser Chemical compound CSCC[C@H](N)C(=O)N[C@H](C(=O)N[C@@H](CO)C(O)=O)CC1=CC=C(O)C=C1 PNHRPOWKRRJATF-IHRRRGAJSA-N 0.000 description 1
- GHQFLTYXGUETFD-UFYCRDLUSA-N Met-Tyr-Tyr Chemical compound CSCC[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 GHQFLTYXGUETFD-UFYCRDLUSA-N 0.000 description 1
- IIHMNTBFPMRJCN-RCWTZXSCSA-N Met-Val-Thr Chemical compound CSCC[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O IIHMNTBFPMRJCN-RCWTZXSCSA-N 0.000 description 1
- 206010027476 Metastases Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 101000935589 Mus musculus Flavin reductase (NADPH) Proteins 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- WYBVBIHNJWOLCJ-UHFFFAOYSA-N N-L-arginyl-L-leucine Natural products CC(C)CC(C(O)=O)NC(=O)C(N)CCCN=C(N)N WYBVBIHNJWOLCJ-UHFFFAOYSA-N 0.000 description 1
- XZFYRXDAULDNFX-UHFFFAOYSA-N N-L-cysteinyl-L-phenylalanine Natural products SCC(N)C(=O)NC(C(O)=O)CC1=CC=CC=C1 XZFYRXDAULDNFX-UHFFFAOYSA-N 0.000 description 1
- 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 1
- 206010029260 Neuroblastoma Diseases 0.000 description 1
- 206010030155 Oesophageal carcinoma Diseases 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 206010033128 Ovarian cancer Diseases 0.000 description 1
- 206010061535 Ovarian neoplasm Diseases 0.000 description 1
- 108090000526 Papain Proteins 0.000 description 1
- 208000000821 Parathyroid Neoplasms Diseases 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- 208000002471 Penile Neoplasms Diseases 0.000 description 1
- 206010034299 Penile cancer Diseases 0.000 description 1
- 102000057297 Pepsin A Human genes 0.000 description 1
- 108090000284 Pepsin A Proteins 0.000 description 1
- FPTXMUIBLMGTQH-ONGXEEELSA-N Phe-Ala-Gly Chemical compound OC(=O)CNC(=O)[C@H](C)NC(=O)[C@@H](N)CC1=CC=CC=C1 FPTXMUIBLMGTQH-ONGXEEELSA-N 0.000 description 1
- KAHUBGWSIQNZQQ-KKUMJFAQSA-N Phe-Asn-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](N)CC1=CC=CC=C1 KAHUBGWSIQNZQQ-KKUMJFAQSA-N 0.000 description 1
- JOXIIFVCSATTDH-IHPCNDPISA-N Phe-Asn-Trp Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CC2=CNC3=CC=CC=C32)C(=O)O)N JOXIIFVCSATTDH-IHPCNDPISA-N 0.000 description 1
- QPQDWBAJWOGAMJ-IHPCNDPISA-N Phe-Asp-Trp Chemical compound C([C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(O)=O)C1=CC=CC=C1 QPQDWBAJWOGAMJ-IHPCNDPISA-N 0.000 description 1
- WPTYDQPGBMDUBI-QWRGUYRKSA-N Phe-Gly-Asn Chemical compound N[C@@H](Cc1ccccc1)C(=O)NCC(=O)N[C@@H](CC(N)=O)C(O)=O WPTYDQPGBMDUBI-QWRGUYRKSA-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
- KNYPNEYICHHLQL-ACRUOGEOSA-N Phe-Leu-Tyr Chemical compound C([C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(O)=O)C1=CC=CC=C1 KNYPNEYICHHLQL-ACRUOGEOSA-N 0.000 description 1
- CJAHQEZWDZNSJO-KKUMJFAQSA-N Phe-Lys-Cys Chemical compound NCCCC[C@@H](C(=O)N[C@@H](CS)C(O)=O)NC(=O)[C@@H](N)CC1=CC=CC=C1 CJAHQEZWDZNSJO-KKUMJFAQSA-N 0.000 description 1
- CKJACGQPCPMWIT-UFYCRDLUSA-N Phe-Pro-Phe Chemical compound C([C@H](N)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)C1=CC=CC=C1 CKJACGQPCPMWIT-UFYCRDLUSA-N 0.000 description 1
- ZJPGOXWRFNKIQL-JYJNAYRXSA-N Phe-Pro-Pro Chemical compound C([C@H](N)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(O)=O)C1=CC=CC=C1 ZJPGOXWRFNKIQL-JYJNAYRXSA-N 0.000 description 1
- 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 1
- 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 1
- GOUWCZRDTWTODO-YDHLFZDLSA-N Phe-Val-Asn Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(N)=O)C(O)=O GOUWCZRDTWTODO-YDHLFZDLSA-N 0.000 description 1
- 206010035226 Plasma cell myeloma Diseases 0.000 description 1
- 241000288906 Primates Species 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
- OLTFZQIYCNOBLI-DCAQKATOSA-N Pro-Cys-Lys Chemical compound C1C[C@H](NC1)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCCCN)C(=O)O OLTFZQIYCNOBLI-DCAQKATOSA-N 0.000 description 1
- MGDFPGCFVJFITQ-CIUDSAMLSA-N Pro-Glu-Asp Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(O)=O MGDFPGCFVJFITQ-CIUDSAMLSA-N 0.000 description 1
- 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
- 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
- JMVQDLDPDBXAAX-YUMQZZPRSA-N Pro-Gly-Gln Chemical compound NC(=O)CC[C@@H](C(O)=O)NC(=O)CNC(=O)[C@@H]1CCCN1 JMVQDLDPDBXAAX-YUMQZZPRSA-N 0.000 description 1
- 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
- AFXCXDQNRXTSBD-FJXKBIBVSA-N Pro-Gly-Thr Chemical compound [H]N1CCC[C@H]1C(=O)NCC(=O)N[C@@H]([C@@H](C)O)C(O)=O AFXCXDQNRXTSBD-FJXKBIBVSA-N 0.000 description 1
- AUQGUYPHJSMAKI-CYDGBPFRSA-N Pro-Ile-Val Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)[C@H]([C@@H](C)CC)NC(=O)[C@@H]1CCCN1 AUQGUYPHJSMAKI-CYDGBPFRSA-N 0.000 description 1
- VTFXTWDFPTWNJY-RHYQMDGZSA-N Pro-Leu-Thr Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O VTFXTWDFPTWNJY-RHYQMDGZSA-N 0.000 description 1
- ZLXKLMHAMDENIO-DCAQKATOSA-N Pro-Lys-Asp Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(O)=O)C(O)=O ZLXKLMHAMDENIO-DCAQKATOSA-N 0.000 description 1
- ABSSTGUCBCDKMU-UWVGGRQHSA-N Pro-Lys-Gly Chemical compound NCCCC[C@@H](C(=O)NCC(O)=O)NC(=O)[C@@H]1CCCN1 ABSSTGUCBCDKMU-UWVGGRQHSA-N 0.000 description 1
- RFWXYTJSVDUBBZ-DCAQKATOSA-N Pro-Pro-Glu Chemical compound OC(=O)CC[C@@H](C(O)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@H]1NCCC1 RFWXYTJSVDUBBZ-DCAQKATOSA-N 0.000 description 1
- KBUAPZAZPWNYSW-SRVKXCTJSA-N Pro-Pro-Val Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@H]1NCCC1 KBUAPZAZPWNYSW-SRVKXCTJSA-N 0.000 description 1
- MKGIILKDUGDRRO-FXQIFTODSA-N Pro-Ser-Ser Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H]1CCCN1 MKGIILKDUGDRRO-FXQIFTODSA-N 0.000 description 1
- KHRLUIPIMIQFGT-AVGNSLFASA-N Pro-Val-Leu Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O KHRLUIPIMIQFGT-AVGNSLFASA-N 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
- 239000004365 Protease Substances 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 208000015634 Rectal Neoplasms Diseases 0.000 description 1
- 206010038389 Renal cancer Diseases 0.000 description 1
- 208000006265 Renal cell carcinoma Diseases 0.000 description 1
- 208000007660 Residual Neoplasm Diseases 0.000 description 1
- UEJYSALTSUZXFV-SRVKXCTJSA-N Rigin Chemical compound NCC(=O)N[C@@H](CCC(N)=O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCCN=C(N)N)C(O)=O UEJYSALTSUZXFV-SRVKXCTJSA-N 0.000 description 1
- 241000283984 Rodentia Species 0.000 description 1
- 206010039491 Sarcoma Diseases 0.000 description 1
- IDQFQFVEWMWRQQ-DLOVCJGASA-N Ser-Ala-Phe Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](C)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O IDQFQFVEWMWRQQ-DLOVCJGASA-N 0.000 description 1
- YUSRGTQIPCJNHQ-CIUDSAMLSA-N Ser-Arg-Glu Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(O)=O YUSRGTQIPCJNHQ-CIUDSAMLSA-N 0.000 description 1
- OYEDZGNMSBZCIM-XGEHTFHBSA-N Ser-Arg-Thr Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(O)=O OYEDZGNMSBZCIM-XGEHTFHBSA-N 0.000 description 1
- VGNYHOBZJKWRGI-CIUDSAMLSA-N Ser-Asn-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](N)CO VGNYHOBZJKWRGI-CIUDSAMLSA-N 0.000 description 1
- UGJRQLURDVGULT-LKXGYXEUSA-N Ser-Asn-Thr Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O UGJRQLURDVGULT-LKXGYXEUSA-N 0.000 description 1
- FTVRVZNYIYWJGB-ACZMJKKPSA-N Ser-Asp-Glu Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(O)=O FTVRVZNYIYWJGB-ACZMJKKPSA-N 0.000 description 1
- KNCJWSPMTFFJII-ZLUOBGJFSA-N Ser-Cys-Asp Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(O)=O)C(O)=O KNCJWSPMTFFJII-ZLUOBGJFSA-N 0.000 description 1
- MOVJSUIKUNCVMG-ZLUOBGJFSA-N Ser-Cys-Ser Chemical compound C([C@@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CO)C(=O)O)N)O MOVJSUIKUNCVMG-ZLUOBGJFSA-N 0.000 description 1
- ZOHGLPQGEHSLPD-FXQIFTODSA-N Ser-Gln-Glu Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(O)=O ZOHGLPQGEHSLPD-FXQIFTODSA-N 0.000 description 1
- 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 1
- BPMRXBZYPGYPJN-WHFBIAKZSA-N Ser-Gly-Asn Chemical compound [H]N[C@@H](CO)C(=O)NCC(=O)N[C@@H](CC(N)=O)C(O)=O BPMRXBZYPGYPJN-WHFBIAKZSA-N 0.000 description 1
- 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 1
- XUDRHBPSPAPDJP-SRVKXCTJSA-N Ser-Lys-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](N)CO XUDRHBPSPAPDJP-SRVKXCTJSA-N 0.000 description 1
- RWDVVSKYZBNDCO-MELADBBJSA-N Ser-Phe-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CC2=CC=CC=C2)NC(=O)[C@H](CO)N)C(=O)O RWDVVSKYZBNDCO-MELADBBJSA-N 0.000 description 1
- RHAPJNVNWDBFQI-BQBZGAKWSA-N Ser-Pro-Gly Chemical compound OC[C@H](N)C(=O)N1CCC[C@H]1C(=O)NCC(O)=O RHAPJNVNWDBFQI-BQBZGAKWSA-N 0.000 description 1
- GYDFRTRSSXOZCR-ACZMJKKPSA-N Ser-Ser-Glu Chemical compound OC[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@H](C(O)=O)CCC(O)=O GYDFRTRSSXOZCR-ACZMJKKPSA-N 0.000 description 1
- SRSPTFBENMJHMR-WHFBIAKZSA-N Ser-Ser-Gly Chemical compound OC[C@H](N)C(=O)N[C@@H](CO)C(=O)NCC(O)=O SRSPTFBENMJHMR-WHFBIAKZSA-N 0.000 description 1
- 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
- SNXUIBACCONSOH-BWBBJGPYSA-N Ser-Thr-Ser Chemical compound OC[C@H](N)C(=O)N[C@@H]([C@H](O)C)C(=O)N[C@@H](CO)C(O)=O SNXUIBACCONSOH-BWBBJGPYSA-N 0.000 description 1
- 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
- NERYDXBVARJIQS-JYBASQMISA-N Ser-Trp-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CC1=CNC2=CC=CC=C21)NC(=O)[C@H](CO)N)O NERYDXBVARJIQS-JYBASQMISA-N 0.000 description 1
- VVKVHAOOUGNDPJ-SRVKXCTJSA-N Ser-Tyr-Ser Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CO)C(O)=O VVKVHAOOUGNDPJ-SRVKXCTJSA-N 0.000 description 1
- 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 1
- IAOHCSQDQDWRQU-GUBZILKMSA-N Ser-Val-Arg Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O IAOHCSQDQDWRQU-GUBZILKMSA-N 0.000 description 1
- 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 1
- HSWXBJCBYSWBPT-GUBZILKMSA-N Ser-Val-Val Chemical compound CC(C)[C@H](NC(=O)[C@@H](NC(=O)[C@@H](N)CO)C(C)C)C(O)=O HSWXBJCBYSWBPT-GUBZILKMSA-N 0.000 description 1
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 1
- 208000021712 Soft tissue sarcoma Diseases 0.000 description 1
- 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 1
- ASJDFGOPDCVXTG-KATARQTJSA-N Thr-Cys-Leu Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(C)C)C(O)=O ASJDFGOPDCVXTG-KATARQTJSA-N 0.000 description 1
- KWQBJOUOSNJDRR-XAVMHZPKSA-N Thr-Cys-Pro Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CS)C(=O)N1CCC[C@@H]1C(=O)O)N)O KWQBJOUOSNJDRR-XAVMHZPKSA-N 0.000 description 1
- LAFLAXHTDVNVEL-WDCWCFNPSA-N Thr-Gln-Lys Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H](CCCCN)C(=O)O)N)O LAFLAXHTDVNVEL-WDCWCFNPSA-N 0.000 description 1
- LHEZGZQRLDBSRR-WDCWCFNPSA-N Thr-Glu-Leu Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(O)=O LHEZGZQRLDBSRR-WDCWCFNPSA-N 0.000 description 1
- KBLYJPQSNGTDIU-LOKLDPHHSA-N Thr-Glu-Pro Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)N1CCC[C@@H]1C(=O)O)N)O KBLYJPQSNGTDIU-LOKLDPHHSA-N 0.000 description 1
- NQVDGKYAUHTCME-QTKMDUPCSA-N Thr-His-Arg Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)N[C@@H](CCCN=C(N)N)C(=O)O)N)O NQVDGKYAUHTCME-QTKMDUPCSA-N 0.000 description 1
- CYVQBKQYQGEELV-NKIYYHGXSA-N Thr-His-Gln Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)N[C@@H](CCC(=O)N)C(=O)O)N)O CYVQBKQYQGEELV-NKIYYHGXSA-N 0.000 description 1
- FKIGTIXHSRNKJU-IXOXFDKPSA-N Thr-His-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)[C@H](O)C)CC1=CN=CN1 FKIGTIXHSRNKJU-IXOXFDKPSA-N 0.000 description 1
- AHOLTQCAVBSUDP-PPCPHDFISA-N Thr-Ile-Lys Chemical compound CC[C@H](C)[C@H](NC(=O)[C@@H](N)[C@@H](C)O)C(=O)N[C@@H](CCCCN)C(O)=O AHOLTQCAVBSUDP-PPCPHDFISA-N 0.000 description 1
- FIFDDJFLNVAVMS-RHYQMDGZSA-N Thr-Leu-Met Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(O)=O FIFDDJFLNVAVMS-RHYQMDGZSA-N 0.000 description 1
- MGJLBZFUXUGMML-VOAKCMCISA-N Thr-Lys-Lys Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)O)N)O MGJLBZFUXUGMML-VOAKCMCISA-N 0.000 description 1
- XSEPSRUDSPHMPX-KATARQTJSA-N Thr-Lys-Ser Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CO)C(O)=O XSEPSRUDSPHMPX-KATARQTJSA-N 0.000 description 1
- XKWABWFMQXMUMT-HJGDQZAQSA-N Thr-Pro-Glu Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCC(O)=O)C(O)=O XKWABWFMQXMUMT-HJGDQZAQSA-N 0.000 description 1
- MXDOAJQRJBMGMO-FJXKBIBVSA-N Thr-Pro-Gly Chemical compound C[C@@H](O)[C@H](N)C(=O)N1CCC[C@H]1C(=O)NCC(O)=O MXDOAJQRJBMGMO-FJXKBIBVSA-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
- LXXCHJKHJYRMIY-FQPOAREZSA-N Thr-Tyr-Ala Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](C)C(O)=O LXXCHJKHJYRMIY-FQPOAREZSA-N 0.000 description 1
- AYFVYJQAPQTCCC-UHFFFAOYSA-N Threonine Natural products CC(O)C(N)C(O)=O AYFVYJQAPQTCCC-UHFFFAOYSA-N 0.000 description 1
- 239000004473 Threonine Substances 0.000 description 1
- 208000024770 Thyroid neoplasm Diseases 0.000 description 1
- AVYVKJMBNLPWRX-WFBYXXMGSA-N Trp-Ala-Ser Chemical compound C1=CC=C2C(C[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](CO)C(O)=O)=CNC2=C1 AVYVKJMBNLPWRX-WFBYXXMGSA-N 0.000 description 1
- WACMTVIJWRNVSO-CWRNSKLLSA-N Trp-Asp-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CC(=O)O)NC(=O)[C@H](CC2=CNC3=CC=CC=C32)N)C(=O)O WACMTVIJWRNVSO-CWRNSKLLSA-N 0.000 description 1
- DQDXHYIEITXNJY-BPUTZDHNSA-N Trp-Gln-Gln Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H](CCC(=O)N)C(=O)O)N DQDXHYIEITXNJY-BPUTZDHNSA-N 0.000 description 1
- FNOQJVHFVLVMOS-AAEUAGOBSA-N Trp-Gly-Asn Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)NCC(=O)N[C@@H](CC(=O)N)C(=O)O)N FNOQJVHFVLVMOS-AAEUAGOBSA-N 0.000 description 1
- 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 1
- HJWLQSFTGDQSRX-BPUTZDHNSA-N Trp-Met-Ser Chemical compound [H]N[C@@H](CC1=CNC2=C1C=CC=C2)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CO)C(O)=O HJWLQSFTGDQSRX-BPUTZDHNSA-N 0.000 description 1
- HHPSUFUXXBOFQY-AQZXSJQPSA-N Trp-Thr-Asn Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)O)NC(=O)[C@H](CC1=CNC2=CC=CC=C21)N)O HHPSUFUXXBOFQY-AQZXSJQPSA-N 0.000 description 1
- ZJPSMXCFEKMZFE-IHPCNDPISA-N Trp-Tyr-Ser 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](CO)C(O)=O ZJPSMXCFEKMZFE-IHPCNDPISA-N 0.000 description 1
- LNGFWVPNKLWATF-ZVZYQTTQSA-N Trp-Val-Glu Chemical compound [H]N[C@@H](CC1=CNC2=C1C=CC=C2)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(O)=O)C(O)=O LNGFWVPNKLWATF-ZVZYQTTQSA-N 0.000 description 1
- VCXWRWYFJLXITF-AUTRQRHGSA-N Tyr-Ala-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 VCXWRWYFJLXITF-AUTRQRHGSA-N 0.000 description 1
- JWHOIHCOHMZSAR-QWRGUYRKSA-N Tyr-Asp-Gly Chemical compound OC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 JWHOIHCOHMZSAR-QWRGUYRKSA-N 0.000 description 1
- YLRLHDFMMWDYTK-KKUMJFAQSA-N Tyr-Cys-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](CS)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 YLRLHDFMMWDYTK-KKUMJFAQSA-N 0.000 description 1
- JJNXZIPLIXIGBX-HJPIBITLSA-N Tyr-Ile-Cys Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CS)C(=O)O)NC(=O)[C@H](CC1=CC=C(C=C1)O)N JJNXZIPLIXIGBX-HJPIBITLSA-N 0.000 description 1
- JAGGEZACYAAMIL-CQDKDKBSSA-N Tyr-Lys-Ala Chemical compound C[C@@H](C(=O)O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CC1=CC=C(C=C1)O)N JAGGEZACYAAMIL-CQDKDKBSSA-N 0.000 description 1
- GITNQBVCEQBDQC-KKUMJFAQSA-N Tyr-Lys-Asn Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(O)=O GITNQBVCEQBDQC-KKUMJFAQSA-N 0.000 description 1
- WPRVVBVWIUWLOH-UFYCRDLUSA-N Tyr-Phe-Met Chemical compound CSCC[C@@H](C(=O)O)NC(=O)[C@H](CC1=CC=CC=C1)NC(=O)[C@H](CC2=CC=C(C=C2)O)N WPRVVBVWIUWLOH-UFYCRDLUSA-N 0.000 description 1
- AUZADXNWQMBZOO-JYJNAYRXSA-N Tyr-Pro-Arg Chemical compound C([C@H](N)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCN=C(N)N)C(O)=O)C1=CC=C(O)C=C1 AUZADXNWQMBZOO-JYJNAYRXSA-N 0.000 description 1
- MNWINJDPGBNOED-ULQDDVLXSA-N Tyr-Pro-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@@H](N)CC1=CC=C(O)C=C1 MNWINJDPGBNOED-ULQDDVLXSA-N 0.000 description 1
- YYLHVUCSTXXKBS-IHRRRGAJSA-N Tyr-Pro-Ser Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CO)C(O)=O YYLHVUCSTXXKBS-IHRRRGAJSA-N 0.000 description 1
- SOAUMCDLIUGXJJ-SRVKXCTJSA-N Tyr-Ser-Asn Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(O)=O SOAUMCDLIUGXJJ-SRVKXCTJSA-N 0.000 description 1
- KWKJGBHDYJOVCR-SRVKXCTJSA-N Tyr-Ser-Cys Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CS)C(=O)O)N)O KWKJGBHDYJOVCR-SRVKXCTJSA-N 0.000 description 1
- NHOVZGFNTGMYMI-KKUMJFAQSA-N Tyr-Ser-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 NHOVZGFNTGMYMI-KKUMJFAQSA-N 0.000 description 1
- GAKBTSMAPGLQFA-JNPHEJMOSA-N Tyr-Thr-Tyr Chemical compound C([C@H](N)C(=O)N[C@@H]([C@H](O)C)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(O)=O)C1=CC=C(O)C=C1 GAKBTSMAPGLQFA-JNPHEJMOSA-N 0.000 description 1
- YOTRXXBHTZHKLU-BVSLBCMMSA-N Tyr-Trp-Met Chemical compound C([C@H](N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCSC)C(O)=O)C1=CC=C(O)C=C1 YOTRXXBHTZHKLU-BVSLBCMMSA-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
- 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 1
- RMRFSFXLFWWAJZ-HJOGWXRNSA-N Tyr-Tyr-Tyr Chemical compound C([C@H](N)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(O)=O)C1=CC=C(O)C=C1 RMRFSFXLFWWAJZ-HJOGWXRNSA-N 0.000 description 1
- PQPWEALFTLKSEB-DZKIICNBSA-N Tyr-Val-Glu Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(O)=O)C(O)=O PQPWEALFTLKSEB-DZKIICNBSA-N 0.000 description 1
- 208000023915 Ureteral Neoplasms Diseases 0.000 description 1
- 206010046392 Ureteric cancer Diseases 0.000 description 1
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 description 1
- 208000006593 Urologic Neoplasms Diseases 0.000 description 1
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 description 1
- 201000005969 Uveal melanoma Diseases 0.000 description 1
- CVUDMNSZAIZFAE-UHFFFAOYSA-N Val-Arg-Pro Natural products NC(N)=NCCCC(NC(=O)C(N)C(C)C)C(=O)N1CCCC1C(O)=O CVUDMNSZAIZFAE-UHFFFAOYSA-N 0.000 description 1
- QHDXUYOYTPWCSK-RCOVLWMOSA-N Val-Asp-Gly Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)NCC(=O)O)N QHDXUYOYTPWCSK-RCOVLWMOSA-N 0.000 description 1
- LHADRQBREKTRLR-DCAQKATOSA-N Val-Cys-Leu Chemical compound CC(C)C[C@@H](C(=O)O)NC(=O)[C@H](CS)NC(=O)[C@H](C(C)C)N LHADRQBREKTRLR-DCAQKATOSA-N 0.000 description 1
- SRWWRLKBEJZFPW-IHRRRGAJSA-N Val-Cys-Phe Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)O)N SRWWRLKBEJZFPW-IHRRRGAJSA-N 0.000 description 1
- OXVPMZVGCAPFIG-BQFCYCMXSA-N Val-Gln-Trp Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H](CC1=CNC2=CC=CC=C21)C(=O)O)N OXVPMZVGCAPFIG-BQFCYCMXSA-N 0.000 description 1
- BRPKEERLGYNCNC-NHCYSSNCSA-N Val-Glu-Arg Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@H](C(O)=O)CCCN=C(N)N BRPKEERLGYNCNC-NHCYSSNCSA-N 0.000 description 1
- ZXAGTABZUOMUDO-GVXVVHGQSA-N Val-Glu-Lys Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CCCCN)C(=O)O)N ZXAGTABZUOMUDO-GVXVVHGQSA-N 0.000 description 1
- RKIGNDAHUOOIMJ-BQFCYCMXSA-N Val-Glu-Trp Chemical compound C1=CC=C2C(C[C@H](NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](N)C(C)C)C(O)=O)=CNC2=C1 RKIGNDAHUOOIMJ-BQFCYCMXSA-N 0.000 description 1
- RHYOAUJXSRWVJT-GVXVVHGQSA-N Val-His-Glu Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)N[C@@H](CCC(=O)O)C(=O)O)N RHYOAUJXSRWVJT-GVXVVHGQSA-N 0.000 description 1
- ZIGZPYJXIWLQFC-QTKMDUPCSA-N Val-His-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CC1=CN=CN1)NC(=O)[C@H](C(C)C)N)O ZIGZPYJXIWLQFC-QTKMDUPCSA-N 0.000 description 1
- 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 1
- FEXILLGKGGTLRI-NHCYSSNCSA-N Val-Leu-Asn Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)O)NC(=O)[C@H](C(C)C)N FEXILLGKGGTLRI-NHCYSSNCSA-N 0.000 description 1
- XTDDIVQWDXMRJL-IHRRRGAJSA-N Val-Leu-His Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)NC(=O)[C@H](C(C)C)N XTDDIVQWDXMRJL-IHRRRGAJSA-N 0.000 description 1
- ZHQWPWQNVRCXAX-XQQFMLRXSA-N Val-Leu-Pro Chemical compound CC(C)C[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](C(C)C)N ZHQWPWQNVRCXAX-XQQFMLRXSA-N 0.000 description 1
- SYSWVVCYSXBVJG-RHYQMDGZSA-N Val-Leu-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](C(C)C)N)O SYSWVVCYSXBVJG-RHYQMDGZSA-N 0.000 description 1
- PHZGFLFMGLXCFG-FHWLQOOXSA-N Val-Lys-Trp Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC1=CNC2=CC=CC=C21)C(=O)O)N PHZGFLFMGLXCFG-FHWLQOOXSA-N 0.000 description 1
- SBJCTAZFSZXWSR-AVGNSLFASA-N Val-Met-His Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)N SBJCTAZFSZXWSR-AVGNSLFASA-N 0.000 description 1
- FMQGYTMERWBMSI-HJWJTTGWSA-N Val-Phe-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)[C@H](CC1=CC=CC=C1)NC(=O)[C@H](C(C)C)N FMQGYTMERWBMSI-HJWJTTGWSA-N 0.000 description 1
- HJSLDXZAZGFPDK-ULQDDVLXSA-N Val-Phe-Leu Chemical compound CC(C)C[C@@H](C(=O)O)NC(=O)[C@H](CC1=CC=CC=C1)NC(=O)[C@H](C(C)C)N HJSLDXZAZGFPDK-ULQDDVLXSA-N 0.000 description 1
- KSFXWENSJABBFI-ZKWXMUAHSA-N Val-Ser-Asn Chemical compound [H]N[C@@H](C(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(O)=O KSFXWENSJABBFI-ZKWXMUAHSA-N 0.000 description 1
- KRAHMIJVUPUOTQ-DCAQKATOSA-N Val-Ser-His Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)N KRAHMIJVUPUOTQ-DCAQKATOSA-N 0.000 description 1
- GBIUHAYJGWVNLN-UHFFFAOYSA-N Val-Ser-Pro Natural products CC(C)C(N)C(=O)NC(CO)C(=O)N1CCCC1C(O)=O GBIUHAYJGWVNLN-UHFFFAOYSA-N 0.000 description 1
- SDHZOOIGIUEPDY-JYJNAYRXSA-N Val-Ser-Trp Chemical compound C1=CC=C2C(C[C@H](NC(=O)[C@H](CO)NC(=O)[C@@H](N)C(C)C)C(O)=O)=CNC2=C1 SDHZOOIGIUEPDY-JYJNAYRXSA-N 0.000 description 1
- 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
- QPJSIBAOZBVELU-BPNCWPANSA-N Val-Tyr-Ala Chemical compound C[C@@H](C(=O)O)NC(=O)[C@H](CC1=CC=C(C=C1)O)NC(=O)[C@H](C(C)C)N QPJSIBAOZBVELU-BPNCWPANSA-N 0.000 description 1
- 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
- ZNGPROMGGGFOAA-JYJNAYRXSA-N Val-Tyr-Val Chemical compound CC(C)[C@H](N)C(=O)N[C@H](C(=O)N[C@@H](C(C)C)C(O)=O)CC1=CC=C(O)C=C1 ZNGPROMGGGFOAA-JYJNAYRXSA-N 0.000 description 1
- JVGDAEKKZKKZFO-RCWTZXSCSA-N Val-Val-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](C(C)C)NC(=O)[C@H](C(C)C)N)O JVGDAEKKZKKZFO-RCWTZXSCSA-N 0.000 description 1
- 206010047741 Vulval cancer Diseases 0.000 description 1
- 241000269370 Xenopus <genus> Species 0.000 description 1
- 201000005188 adrenal gland cancer Diseases 0.000 description 1
- 208000024447 adrenal gland neoplasm Diseases 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 108010076324 alanyl-glycyl-glycine Proteins 0.000 description 1
- 108010024078 alanyl-glycyl-serine Proteins 0.000 description 1
- 108010041407 alanylaspartic acid Proteins 0.000 description 1
- 108010005233 alanylglutamic acid Proteins 0.000 description 1
- 108010044940 alanylglutamine Proteins 0.000 description 1
- KOSRFJWDECSPRO-UHFFFAOYSA-N alpha-L-glutamyl-L-glutamic acid Natural products OC(=O)CCC(N)C(=O)NC(CCC(O)=O)C(O)=O KOSRFJWDECSPRO-UHFFFAOYSA-N 0.000 description 1
- 108010050025 alpha-glutamyltryptophan Proteins 0.000 description 1
- 210000002821 alveolar epithelial cell Anatomy 0.000 description 1
- 235000001014 amino acid Nutrition 0.000 description 1
- 230000002494 anti-cea effect Effects 0.000 description 1
- 229940125644 antibody drug Drugs 0.000 description 1
- 102000025171 antigen binding proteins Human genes 0.000 description 1
- 108091000831 antigen binding proteins Proteins 0.000 description 1
- 230000000890 antigenic effect Effects 0.000 description 1
- 201000011165 anus cancer Diseases 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 108010001271 arginyl-glutamyl-arginine Proteins 0.000 description 1
- 108010052670 arginyl-glutamyl-glutamic acid Proteins 0.000 description 1
- 108010009111 arginyl-glycyl-glutamic acid Proteins 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 201000009036 biliary tract cancer Diseases 0.000 description 1
- 208000020790 biliary tract neoplasm Diseases 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 230000003915 cell function Effects 0.000 description 1
- 230000006037 cell lysis Effects 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 201000010881 cervical cancer Diseases 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 208000029742 colonic neoplasm Diseases 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000002596 correlated effect Effects 0.000 description 1
- 230000000875 corresponding effect Effects 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 235000018417 cysteine Nutrition 0.000 description 1
- 108010060199 cysteinylproline Proteins 0.000 description 1
- 230000009089 cytolysis Effects 0.000 description 1
- 230000001086 cytosolic effect Effects 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- 108010054812 diprotin A Proteins 0.000 description 1
- 230000005750 disease progression Effects 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 125000002228 disulfide group Chemical group 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 210000003162 effector t lymphocyte Anatomy 0.000 description 1
- 210000000750 endocrine system Anatomy 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 210000002919 epithelial cell Anatomy 0.000 description 1
- 210000000981 epithelium Anatomy 0.000 description 1
- 201000004101 esophageal cancer Diseases 0.000 description 1
- 210000003236 esophagogastric junction Anatomy 0.000 description 1
- 210000003527 eukaryotic cell Anatomy 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000002825 functional assay Methods 0.000 description 1
- 230000002538 fungal effect Effects 0.000 description 1
- 108020001507 fusion proteins Proteins 0.000 description 1
- 102000037865 fusion proteins Human genes 0.000 description 1
- 210000004211 gastric acid Anatomy 0.000 description 1
- 210000001156 gastric mucosa Anatomy 0.000 description 1
- 208000005017 glioblastoma Diseases 0.000 description 1
- 108010013768 glutamyl-aspartyl-proline Proteins 0.000 description 1
- 108010055341 glutamyl-glutamic acid Proteins 0.000 description 1
- 108010049041 glutamylalanine Proteins 0.000 description 1
- 108010000434 glycyl-alanyl-leucine Proteins 0.000 description 1
- 108010050475 glycyl-leucyl-tyrosine Proteins 0.000 description 1
- 108010079413 glycyl-prolyl-glutamic acid Proteins 0.000 description 1
- 108010089804 glycyl-threonine Proteins 0.000 description 1
- 108010048994 glycyl-tyrosyl-alanine Proteins 0.000 description 1
- 108010081551 glycylphenylalanine Proteins 0.000 description 1
- 201000010536 head and neck cancer Diseases 0.000 description 1
- 208000014829 head and neck neoplasm Diseases 0.000 description 1
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 1
- 231100000844 hepatocellular carcinoma Toxicity 0.000 description 1
- 210000004408 hybridoma Anatomy 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000005304 joining Methods 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 201000010982 kidney cancer Diseases 0.000 description 1
- 108010053037 kyotorphin Proteins 0.000 description 1
- 108010034529 leucyl-lysine Proteins 0.000 description 1
- 108010057821 leucylproline Proteins 0.000 description 1
- 238000003670 luciferase enzyme activity assay Methods 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 208000003747 lymphoid leukemia Diseases 0.000 description 1
- 108010025153 lysyl-alanyl-alanine Proteins 0.000 description 1
- 108010064235 lysylglycine Proteins 0.000 description 1
- 230000036212 malign transformation Effects 0.000 description 1
- 230000036210 malignancy Effects 0.000 description 1
- 208000026045 malignant tumor of parathyroid gland Diseases 0.000 description 1
- 210000004962 mammalian cell Anatomy 0.000 description 1
- 239000003550 marker Substances 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 230000009401 metastasis Effects 0.000 description 1
- 108010022588 methionyl-lysyl-proline Proteins 0.000 description 1
- 230000005012 migration Effects 0.000 description 1
- 238000013508 migration Methods 0.000 description 1
- 201000000050 myeloid neoplasm Diseases 0.000 description 1
- 230000009871 nonspecific binding Effects 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 201000002575 ocular melanoma Diseases 0.000 description 1
- 210000000287 oocyte Anatomy 0.000 description 1
- 210000000277 pancreatic duct Anatomy 0.000 description 1
- 229940055729 papain Drugs 0.000 description 1
- 235000019834 papain Nutrition 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 229940111202 pepsin Drugs 0.000 description 1
- 238000009520 phase I clinical trial Methods 0.000 description 1
- 108010073025 phenylalanylphenylalanine Proteins 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 238000004393 prognosis Methods 0.000 description 1
- 230000002062 proliferating effect Effects 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 108010004914 prolylarginine Proteins 0.000 description 1
- 108010090894 prolylleucine Proteins 0.000 description 1
- 108010053725 prolylvaline Proteins 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 230000002797 proteolythic effect Effects 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 206010038038 rectal cancer Diseases 0.000 description 1
- 201000001275 rectum cancer Diseases 0.000 description 1
- 230000008929 regeneration Effects 0.000 description 1
- 238000011069 regeneration method Methods 0.000 description 1
- 208000015347 renal cell adenocarcinoma Diseases 0.000 description 1
- 108010091078 rigin Proteins 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 108010071207 serylmethionine Proteins 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 201000002314 small intestine cancer Diseases 0.000 description 1
- 230000009870 specific binding Effects 0.000 description 1
- 208000037959 spinal tumor Diseases 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000011255 standard chemotherapy Methods 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 231100001274 therapeutic index Toxicity 0.000 description 1
- 125000003396 thiol group Chemical group [H]S* 0.000 description 1
- 108010071097 threonyl-lysyl-proline Proteins 0.000 description 1
- 201000002510 thyroid cancer Diseases 0.000 description 1
- 230000001131 transforming effect Effects 0.000 description 1
- 108091005703 transmembrane proteins Proteins 0.000 description 1
- 102000035160 transmembrane proteins Human genes 0.000 description 1
- 230000001960 triggered effect Effects 0.000 description 1
- 108010079202 tyrosyl-alanyl-cysteine Proteins 0.000 description 1
- 231100000402 unacceptable toxicity Toxicity 0.000 description 1
- 201000011294 ureter cancer Diseases 0.000 description 1
- 201000005112 urinary bladder cancer Diseases 0.000 description 1
- 206010046885 vaginal cancer Diseases 0.000 description 1
- 208000013139 vaginal neoplasm Diseases 0.000 description 1
- 201000005102 vulva cancer Diseases 0.000 description 1
- 229950007157 zolbetuximab Drugs 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- 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
- C07K16/2803—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 immunoglobulin superfamily
- C07K16/2809—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 immunoglobulin superfamily against the T-cell receptor (TcR)-CD3 complex
-
- 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
- C07K2317/31—Immunoglobulins specific features characterized by aspects of specificity or valency multispecific
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/52—Constant or Fc region; Isotype
- C07K2317/53—Hinge
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/60—Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments
- C07K2317/62—Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments comprising only variable region components
- C07K2317/622—Single chain antibody (scFv)
-
- 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
- C07K2317/71—Decreased effector function due to an Fc-modification
-
- 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
- C07K2317/73—Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
- C07K2317/92—Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Immunology (AREA)
- Organic Chemistry (AREA)
- Medicinal Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Biophysics (AREA)
- Biochemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Peptides Or Proteins (AREA)
Abstract
本申请涉及CLDN18.2抗体或其抗原结合片段和相关的CLDN18.2/CD3双特异性抗体,以及编码它们的对应核酸、包含所述核酸的载体和用所述核酸或载体转染的宿主细胞。本申请还涉及分离的CLDN18.2抗体或其抗原结合片段和相关的CLDN18.2/CD3双特异性抗体;包含所述抗体、抗原结合片段、双特异性抗体、核酸、载体或宿主细胞的药物组合物;任选的药学上可接受的载体;以及通过施用所述药物组合物治疗有需要的受试者的癌症的方法。根据本申请治疗的癌症包括CLDN18.2阳性癌症,尤其诸如胃癌和胰腺癌。
Description
本申请要求于2021年2月8日提交的名称为“CLDN18.2/CD3 bispecificantibodies for the therapy of CLDN18.2-expressing solid tumors”的美国临时专利申请第63/147,233号的权益,其内容通过引用的方式整体并入本文。
技术领域
本申请涉及CLDN18.2抗体或其抗原结合片段和相关的CLDN18.2/CD3双特异性抗体,以及编码它们的对应核酸、包含所述核酸的载体和用所述核酸或载体转染的宿主细胞。本申请还涉及分离的CLDN18.2抗体或其抗原结合片段和相关的CLDN18.2/CD3双特异性抗体;包含所述抗体、抗原结合片段、双特异性抗体、核酸、载体或宿主细胞的药物组合物;任选的药学上可接受的载体;以及通过施用所述药物组合物治疗有需要的受试者的癌症的方法。根据本申请治疗的癌症包括CLDN18.2阳性癌症,尤其诸如胃癌和胰腺癌。
背景技术
CLDN18.2蛋白质是跨膜蛋白,属于Claudin(CLDN)家族。整个蛋白质在细胞膜上表达,并且是细胞紧密连接的重要结构组分。Claudin具有4个跨膜区、2个胞外环和1个胞质内环,它们参与细胞之间紧密连接的形成。人CLDN18基因的第一外显子中存在两个等位基因,它们可表达两种不同的剪接突变体:CLDN18.1和CLDN18.2,由此在包含胞外环1的N-末端处产生69个氨基酸的序列。因此,该两种胞外表位之间存在差异。尽管大多数CLDN广泛表达,但单个成员通常在特定组织中高度选择性表达。
其中,CLDN18.1蛋白质是由肺泡上皮细胞选择性表达的特定抗原,该抗原仅在正常肺泡组织中高度表达,而在包括胰腺管在内的其他正常组织中没有发现;CLDN18.2蛋白质也是高度选择性标记蛋白,但其分布与CLDN18.1蛋白质完全不同。CLDN18.2蛋白质在正常健康组织中的表达受到高度限制。它在未分化的胃干细胞中不表达。它仅在分化的胃粘膜上皮细胞中表达,并且表达水平非常有限。这有利于维持胃粘膜,胃粘膜的屏障功能可以防止胃酸中的H+通过细胞旁途径泄漏。然而,CLDN18.2蛋白质在多种恶性肿瘤发展期间经常发生异常变化。例如,当胃上皮组织发生恶性转化时,所引起的细胞极性紊乱将导致细胞表面上的CLDN18.2蛋白质表位被暴露。同时,CLDN18.2基因也将被异常激活,并且在参与肿瘤细胞的增殖、分化和迁移的特定肿瘤组织中高度选择性地稳定表达。
近年来,CLDN18.2已经成为肿瘤治疗的有前景的靶标。迄今为止,近20家创新型制药公司已经展开了CLDN18.2靶向药物开发。这些研究项目大多数是单靶点抗体药物。其中,CLDN18.2特异性抗体Claudiximab(Zolebtuximab/IMAB362)在临床试验中已取得显著的成功。来自欧洲的II期研究显示,与单独的化疗相比,晚期胃癌患者在经过IMAB362和标准化疗治疗后的总生存期从8.4个月延长至13.2个月。在该研究中,claudin 18.2水平最高的患者具有更长的中位总生存期(16.7个月)。此外,CLDN18.2双抗体药物也迎来了实体瘤治疗中令人兴奋的新发展。最近,一种新的CLDN18.2/CD3双特异性抗体AMG 910已经被批准用于胃癌和胃食管结合部癌的I期临床试验。
总之,来自当前临床试验的证据已经证明CLDN18.2抗体作为用于CLDN18.2阳性晚期胃癌患者的靶向药物具有高安全性、耐受性和抗肿瘤活性。
发明内容
本申请提供了新型CLDN18.2抗体或其抗原结合片段,并且也提供了相关的双特异性抗体,这些相关的双特异性抗体具有特别有利的特性,诸如高可生产性、稳定性、结合亲和力、生物活性、CLDN18.2阳性细胞的特异性靶向、靶向效率、保持肿瘤细胞杀伤和/或降低的毒性。
在一方面,本申请提供了CLDN18.2抗体或其抗原结合片段,该抗体或其抗原结合片段包含重链可变区和轻链可变区,该重链可变区包含含有SEQ ID NO.11所示的氨基酸序列的HCDR1、含有SEQ ID NO.12所示的氨基酸序列的HCDR2和含有SEQ ID NO.13所示的氨基酸序列的HCDR3,和/或该轻链可变区包含含有SEQ ID NO.14所示的氨基酸序列的LCDR1、含有SEQ ID NO.15所示的氨基酸序列的LCDR2和含有SEQ ID NO.16所示的氨基酸序列的LCDR3。
在本申请的另一方面,抗原结合片段选自scFv片段、Fv片段、F(ab')2片段、Fab'-SH片段和Fab'片段。
在进一步的方面,CLDN18.2抗体或抗原结合片段与CLDN18.2结合,而不与CLDN18.1结合。
在进一步的方面,上述抗体是单克隆抗体或人源化抗体。
在进一步的方面,所述单克隆抗体或人源化抗体包括由杂交瘤或宿主细胞产生的抗体,这些宿主细胞用通过基因工程技术修饰为携带抗体基因的表达载体来转化。在进一步的实施方案中,单克隆抗体或人源化抗体可包括包含两条重链和两条轻链的IgG抗体;小鼠IgG抗体的重链根据其重链的恒定区分为五个亚类:IgG1、IgG2a、IgG2b、IgG2c和IgG3,其轻链可以是小鼠λ型或κ型;并且人IgG抗体的重链根据其重链的恒定区进一步分为四个亚类:IgG1、IgG2、IgG3和IgG4,其轻链可以是人λ型或κ型。
在进一步的方面,本申请还提供了包含轻链可变区和重链可变区的单克隆CLDN18.2抗体,其中重链可变区包含与SEQ ID NO.1的序列具有至少95%、96%、97%、98%、99%或100%序列同一性的氨基酸序列,和/或轻链可变区包含与SEQ ID NO.2的序列具有至少95%、96%、97%、98%、99%或100%序列同一性的氨基酸序列。
在进一步的方面,本申请还提供了包含轻链可变区和重链可变区的单克隆CLDN18.2抗体,其中重链可变区包含与SEQ ID No.3的序列具有至少95%、96%、97%、98%、99%或100%序列同一性的氨基酸序列,和/或轻链可变区包含与SEQ ID NO.4的序列具有至少95%、96%、97%、98%、99%或100%序列同一性的氨基酸序列。
在进一步的方面,本申请还提供了包含轻链可变区和重链可变区的单克隆CLDN18.2抗体,其中重链可变区包含与SEQ ID NO.5的序列具有至少95%、96%、97%、98%、99%或100%序列同一性的氨基酸序列,和/或轻链可变区包含与SEQ ID NO.6的序列具有至少95%、96%、97%、98%、99%或100%序列同一性的氨基酸序列。
在进一步的方面,本申请还提供了包含轻链可变区和重链可变区的单克隆CLDN18.2抗体,其中重链可变区包含与SEQ ID NO.7的序列具有至少95%、96%、97%、98%、99%或100%序列同一性的氨基酸序列,和/或轻链可变区包含与SEQ ID NO.8的序列具有至少95%、96%、97%、98%、99%或100%序列同一性的氨基酸序列。
在进一步的方面,本申请还提供了包含轻链可变区和重链可变区的单克隆CLDN18.2抗体,其中重链可变区包含与SEQ ID NO.9的序列具有至少95%、96%、97%、98%、99%或100%序列同一性的氨基酸序列,和/或轻链可变区包含与SEQ ID NO.10的序列具有至少95%、96%、97%、98%、99%或100%序列同一性的氨基酸序列。
在进一步的方面,抗体或其抗原结合片段是人源化抗体或其抗原结合片段,其中人源化CLDN18.2抗体包含轻链可变区和重链可变区,其中重链可变区包含与SEQ IDNO.17-21中任一个的序列具有至少95%、96%、97%、98%、99%或100%序列同一性的氨基酸序列,和/或轻链可变区包含与SEQ ID NO.22-24中任一个的序列具有至少95%、96%、97%、98%、99%或100%序列同一性的氨基酸序列。
在进一步的方面,抗体或其抗原结合片段是人源化抗体或其抗原结合片段,人源化CLDN18.2抗体包含轻链可变区和重链可变区,其中重链可变区包含与SEQ ID NO.17的序列具有至少95%、96%、97%、98%、99%或100%序列同一性的氨基酸序列,并且轻链可变区包含与SEQ ID NO.22的序列具有至少95%、96%、97%、98%、99%或100%序列同一性的氨基酸序列。
在进一步的实施方案中,抗体包含轻链恒定结构域和任选的重链恒定结构域。
任选地,重链恒定结构域为人IgG1重链恒定结构域,或者轻链恒定结构域为人κ轻链恒定结构域。在进一步的实施方案中,重链恒定结构域可含有一个或多个降低或消除ADCC效应和/或CDC效应的突变,例如,突变L234A、L235A和P329A。
在一个具体的方面,本申请提供了特异性结合CD3的CD3抗原结合结构域,其中抗原结合片段包含重链可变区和轻链可变区,其中
重链可变区包含含有SEQ ID NO.31所示的氨基酸序列的HCDR1、含有SEQ IDNO.32所示的氨基酸序列的HCDR2和含有SEQ ID NO.33所示的氨基酸序列的HCDR3,和/或轻链可变区包含含有SEQ ID NO.34所示的氨基酸序列的LCDR1、含有SEQ ID NO.35所示的氨基酸序列的LCDR2和含有SEQ ID NO.36所示的氨基酸序列的LCDR3;
重链可变区包含含有SEQ ID NO.37所示的氨基酸序列的HCDR1、含有SEQ IDNO.38所示的氨基酸序列的HCDR2和含有SEQ ID NO.39所示的氨基酸序列的HCDR3,和/或轻链可变区包含含有SEQ ID NO.34所示的氨基酸序列的LCDR1、含有SEQ ID NO.35所示的氨基酸序列的LCDR2和含有SEQ ID NO.36所示的氨基酸序列的LCDR3;或者
重链可变区包含含有SEQ ID NO.37所示的氨基酸序列的HCDR1、含有SEQ IDNO.40所示的氨基酸序列的HCDR2和含有SEQ ID NO.39所示的氨基酸序列的HCDR3,和/或轻链可变区包含含有SEQ ID NO.34所示的氨基酸序列的LCDR1、含有SEQ ID NO.35所示的氨基酸序列的LCDR2和含有SEQ ID NO.36所示的氨基酸序列的LCDR3。
在一个具体的方面,本申请提供了特异性结合CD3的CD3抗原结合结构域,其中抗原结合片段包含重链可变区(VH结构域)和轻链可变区(VL结构域),其中:
重链可变区包含与SEQ ID NO.25的序列具有至少95%、96%、97%、98%、99%或100%序列同一性的氨基酸序列,并且轻链可变区包含与SEQ ID NO.26的序列具有至少95%、96%、97%、98%、99%或100%序列同一性的氨基酸序列;或者
重链可变区包含与SEQ ID NO.27的序列具有至少95%、96%、97%、98%、99%或100%序列同一性的氨基酸序列,并且轻链可变区包含与SEQ ID NO.26的序列具有至少95%、96%、97%、98%、99%或100%序列同一性的氨基酸序列;或者
重链可变区包含与SEQ ID NO.28的序列具有至少95%、96%、97%、98%、99%或100%序列同一性的氨基酸序列,并且轻链可变区包含与SEQ ID NO.26的序列具有至少95%、96%、97%、98%、99%或100%序列同一性的氨基酸序列。
在进一步的方面,本申请提供了双特异性抗体,该双特异性抗体包含特异性结合CLDN18.2或它们的天然存在的变体的第一抗体或其抗原结合片段,以及特异性结合CD3或它们的天然存在的变体的第二抗原结合结构域。
在进一步的方面,在上述双特异性抗体中,第一抗体或其抗原结合片段为上述CLDN18.2抗体或其抗原结合片段,并且第二抗原结合结构域为上述CD3抗原结合结构域。
在进一步的方面,在上述双特异性抗体中,第一抗体或其抗原结合片段包含两条相同的重链和两条相同的轻链,并且第二抗原结合结构域包含两个相同的单链抗体片段(scFv)。
在进一步的方面,在上述双特异性抗体中,第一抗体或抗原结合片段的每条轻链与第二抗原结合结构域的每个所述单链抗体片段(scFv)融合。
在进一步的方面,在上述双特异性抗体中,第一抗体或抗原结合片段的每条所述轻链的恒定区的C-末端直接或通过肽接头与第二抗原结合结构域的每个所述单链抗体片段(scFv)的重链可变区的N-末端融合。
在进一步的方面,上述双特异性抗体包括单克隆抗体,该单克隆抗体为与CLDN18.2结合的免疫球蛋白,所述免疫球蛋白包含两条相同的重链和两条相同的轻链,其中所述轻链为第一轻链和第二轻链,其中第一轻链通过肽接头与第一单链可变片段(scFv)融合以产生第一轻链融合多肽,并且其中第二轻链通过肽接头与第二scFv融合以产生第二轻链融合多肽,其中第一scFv和第二scFv(i)是相同的,并且(ii)与CD3结合,并且其中第一轻链融合多肽和第二轻链融合多肽是相同的。
在一个具体的方面,在上述双特异性抗体中,第一轻链的恒定区的C-末端直接或通过肽接头与第一scFv的重链可变区的N-末端融合,并且第二轻链的恒定区的C-末端直接或通过肽接头与第二scFv的重链可变区的N-末端融合。
在一个具体的方面,在上述双特异性抗体中,第一scFv和第二scFv中的每一个都包含上述CD3抗原结合结构域。
在一个具体的方面,本文提供的上述双特异性抗体结合CLDN18.2和CD3两者。
在一个具体的方面,上述肽接头的序列示于SEQ ID NO.41或SEQ ID NO.42中。
在进一步的方面,本申请提供了双特异性抗体,该双特异性抗体包含特异性结合CLDN18.2或它们的天然存在的变体的第一抗体或其抗原结合片段,以及特异性结合CD3或它们的天然存在的变体的第二抗原结合结构域,其中第一抗体或其抗原结合片段包含轻链可变区和重链可变区,其中重链可变区包含含有SEQ ID NO.11所示的氨基酸序列的HCDR1、含有SEQ ID NO.12所示的氨基酸序列的HCDR2和含有SEQ ID NO.13所示的氨基酸序列的HCDR3,并且轻链可变区包含含有SEQ ID NO.14所示的氨基酸序列的LCDR1、含有SEQ IDNO.15所示的氨基酸序列的LCDR2和含有SEQ ID NO.16所示的氨基酸序列的LCDR3;并且第二抗原结合结构域包含重链可变区和轻链可变区,其中重链可变区包含含有SEQ ID NO.31所示的氨基酸序列的HCDR1、含有SEQ ID NO.32所示的氨基酸序列的HCDR2和含有SEQ IDNO.33所示的氨基酸序列的HCDR3,并且轻链可变区包含含有SEQ ID NO.34所示的氨基酸序列的LCDR1、含有SEQ ID NO.35所示的氨基酸序列的LCDR2和含有SEQ ID NO.36所示的氨基酸序列的LCDR3。
在进一步的方面,本申请提供了双特异性抗体,该双特异性抗体包含特异性结合CLDN18.2或它们的天然存在的变体的第一抗体或其抗原结合片段,以及特异性结合CD3或它们的天然存在的变体的第二抗原结合结构域,其中第一抗体或其抗原结合片段包含轻链可变区和重链可变区,其中重链可变区包含含有SEQ ID NO.11所示的氨基酸序列的HCDR1、含有SEQ ID NO.12所示的氨基酸序列的HCDR2和含有SEQ ID NO.13所示的氨基酸序列的HCDR3,并且轻链可变区包含含有SEQ ID NO.14所示的氨基酸序列的LCDR1、含有SEQ IDNO.15所示的氨基酸序列的LCDR2和含有SEQ ID NO.16所示的氨基酸序列的LCDR3;并且第二抗原结合结构域包含重链可变区和轻链可变区,其中重链可变区包含含有SEQ ID NO.37所示的氨基酸序列的HCDR1、含有SEQ ID NO.38所示的氨基酸序列的HCDR2和含有SEQ IDNO.39所示的氨基酸序列的HCDR3,并且轻链可变区包含含有SEQ ID NO.34所示的氨基酸序列的LCDR1、含有SEQ ID NO.35所示的氨基酸序列的LCDR2和含有SEQ ID NO.36所示的氨基酸序列的LCDR3。
在进一步的方面,本申请提供了双特异性抗体,该双特异性抗体包含特异性结合CLDN18.2或它们的天然存在的变体的第一抗体或其抗原结合片段,以及特异性结合CD3或它们的天然存在的变体的第二抗原结合结构域,其中第一抗体或其抗原结合片段包含轻链可变区和重链可变区,其中重链可变区包含含有SEQ ID NO.11所示的氨基酸序列的HCDR1、含有SEQ ID NO.12所示的氨基酸序列的HCDR2和含有SEQ ID NO.13所示的氨基酸序列的HCDR3,并且轻链可变区包含含有SEQ ID NO.14所示的氨基酸序列的LCDR1、含有SEQ IDNO.15所示的氨基酸序列的LCDR2和含有SEQ ID NO.16所示的氨基酸序列的LCDR3;并且第二抗原结合结构域包含重链可变区和轻链可变区,其中重链可变区包含含有SEQ ID NO.37所示的氨基酸序列的HCDR1、含有SEQ ID NO.40所示的氨基酸序列的HCDR2和含有SEQ IDNO.39所示的氨基酸序列的HCDR3,并且轻链可变区包含含有SEQ ID NO.34所示的氨基酸序列的LCDR1、含有SEQ ID NO.35所示的氨基酸序列的LCDR2和含有SEQ ID NO.36所示的氨基酸序列的LCDR3。
在进一步的方面,本申请提供了双特异性抗体,该双特异性抗体包含特异性结合CLDN18.2或它们的天然存在的变体的第一抗体或其抗原结合片段,以及特异性结合CD3或它们的天然存在的变体的第二抗原结合结构域,其中第一抗体或其抗原结合片段包含轻链可变区和重链可变区,其中重链可变区包含与SEQ ID NO.17的序列具有至少95%、96%、97%、98%、99%或100%序列同一性的氨基酸序列,并且轻链可变区包含与SEQ ID NO.22的序列具有至少95%、96%、97%、98%、99%或100%序列同一性的氨基酸序列;并且第二抗原结合结构域包含重链可变区和轻链可变区,其中重链可变区包含与SEQ ID NO.25的序列具有至少95%、96%、97%、98%、99%或100%序列同一性的氨基酸序列,并且轻链可变区包含与SEQ ID NO.26的序列具有至少95%、96%、97%、98%、99%或100%序列同一性的氨基酸序列。
在进一步的方面,本申请提供了双特异性抗体,该双特异性抗体包含特异性结合CLDN18.2或它们的天然存在的变体的第一抗体或其抗原结合片段,以及特异性结合CD3或它们的天然存在的变体的第二抗原结合结构域,其中第一抗体或其抗原结合片段包含轻链可变区和重链可变区,其中重链可变区包含与SEQ ID NO.17的序列具有至少95%、96%、97%、98%、99%或100%序列同一性的氨基酸序列,并且轻链可变区包含与SEQ ID NO.22的序列具有至少95%、96%、97%、98%、99%或100%序列同一性的氨基酸序列;并且第二抗原结合结构域包含重链可变区和轻链可变区,其中重链可变区包含与SEQ ID NO.27的序列具有至少95%、96%、97%、98%、99%或100%序列同一性的氨基酸序列,并且轻链可变区包含与SEQ ID NO.26的序列具有至少95%、96%、97%、98%、99%或100%序列同一性的氨基酸序列。
在进一步的方面,本申请提供了双特异性抗体,该双特异性抗体包含特异性结合CLDN18.2或它们的天然存在的变体的第一抗体或其抗原结合片段,以及特异性结合CD3或它们的天然存在的变体的第二抗原结合结构域,其中第一抗体或其抗原结合片段包含轻链可变区和重链可变区,其中重链可变区包含与SEQ ID NO.17的序列具有至少95%、96%、97%、98%、99%或100%序列同一性的氨基酸序列,并且轻链可变区包含与SEQ ID NO.22的序列具有至少95%、96%、97%、98%、99%或100%序列同一性的氨基酸序列;并且第二抗原结合结构域包含重链可变区和轻链可变区,其中重链可变区包含与SEQ ID NO.28的序列具有至少95%、96%、97%、98%、99%或100%序列同一性的氨基酸序列,并且轻链可变区包含与SEQ ID NO.26的序列具有至少95%、96%、97%、98%、99%或100%序列同一性的氨基酸序列。
在进一步的方面,本文提供的上述双特异性抗体具有有利的特性,诸如高可生产性、稳定性、结合亲和力、生物活性、某些T细胞的特异性靶向、靶向效率、保持肿瘤细胞杀伤和降低的毒性。
在进一步的方面,与野生型CD3结合物(CD3 binder)相比,本文提供的上述双特异性抗体显示与CD3的结合亲和力降低。
在进一步的方面,本文提供的上述双特异性抗体显示TCR信号传导强度降低。
在进一步的方面,本文提供的上述双特异性抗体显示由突变CD3结合物变体介导的细胞因子释放减少。
在进一步的方面,本申请还提供了分离的核酸,该分离的核酸包含编码上述CLDN18.2抗体或其抗原结合片段或上述双特异性抗体的核酸序列。
在进一步的方面,本申请还提供了载体,该载体包含编码上述CLDN18.2抗体或其抗原结合片段或上述双特异性抗体的核酸。
在进一步的方面,本申请还提供了分离的宿主细胞,该分离的宿主细胞包含上述载体或上述分离的核酸。
用上述载体转化合适的宿主细胞,获得表达上述CLDN18.2抗体或其抗原结合片段或上述双特异性抗体的上述宿主细胞。
在进一步的方面,本申请还提供了各种已知的宿主细胞/表达载体组合,这些宿主细胞/表达载体组合通过将分离的抗体基因引入合适的宿主中来制备抗体。用作宿主细胞的合适的真核细胞包括动物细胞、植物细胞和真菌细胞。具体地,动物细胞包括例如以下细胞:(1)哺乳动物细胞:CHO、COS、骨髓瘤、幼仓鼠肾(BHK)、HeLa、Vero等;(2)两栖动物细胞:爪蟾卵母细胞等;以及(3)昆虫细胞:sf9、sf21、Tn5等。
在进一步的方面,本申请还提供了产生上述抗体或其抗原结合片段或上述双特异性抗体的方法,该方法包括培养上述宿主细胞,使得产生抗体或其抗原结合片段或双特异性抗体。在进一步的方面,该方法还包括回收由宿主细胞产生的抗体或其抗原结合片段或双特异性抗体。
在进一步的方面,本申请还提供了通过上述方法产生的分离的抗体或其抗原结合片段或双特异性抗体。
在进一步的方面,本申请还提供了药物组合物,该药物组合物包含上述CLDN18.2抗体或其抗原结合片段或上述双特异性抗体、核酸、载体、宿主细胞和任选的药学上可接受的载体。
在进一步的方面,本申请还提供了治疗有需要的受试者的癌症的方法,该方法包括向受试者施用上述药物组合物,上述药物组合物包含上述CLDN18.2抗体或其抗原结合片段或上述双特异性抗体、核酸、载体、宿主细胞和任选的药学上可接受的载体。
在进一步的方面,上述癌症为CLDN18.2阳性癌症。
在进一步的方面,癌症是血液癌或实体癌。
在进一步的方面,CLDN18.2阳性癌症包括但不限于胃癌或胰腺癌。
本申请的技术方案具有以下优点中的一个或多个优点:
1.CLDN18.2抗体或抗原结合片段对CLDN18.2具有高度选择性和特异性;抗体具有特别有利的特性,诸如高可生产性、稳定性、结合亲和力、生物活性、CLDN18.2阳性细胞的特异性靶向、有效的TCR信号传导强度、靶向效率、保持肿瘤细胞杀伤和降低的细胞毒性。
2.本文提供的上述双特异性抗体具有有利的特性,例如高生产性、稳定性、结合亲和力、生物活性、某些T细胞的特异性靶向、靶向效率、剩余肿瘤细胞杀伤和降低的毒性。
3.与具有野生型CD3结合物的双特异性抗体相比,本文提供的具有突变CD3结合物的上述双特异性抗体显示与CD3的结合亲和力降低,以及由突变CD3结合物变体介导的细胞因子释放减少。
4.本申请实现了期望的癌症治疗,其不仅具有高水平的安全性,而且降低了身体上的负担,并且对于患者而言非常方便。
附图说明
本申请的新颖特征在所附权利要求中具体地阐述。在以下实施方案和实施例的详细描述中阐释了本申请的一些特征和优点。
图1示出了CLDN18.2/CD3双特异性抗体结构的图示。每个抗CD3单链可变片段(scFv)都与抗CLDN18.2轻链的C-末端连接。抗CD3序列包含关键点突变(L234A、L235A和P329A),这些突变消除Fcγ受体(FcγR)的结合,从而消除抗体定向细胞毒性(ADCC)和补体依赖细胞毒性(CDC)效应子功能。
图2A至图2C:CLDN18.2单克隆抗体m-13对hCLDN18.2蛋白质(图2A)、过表达CLDN18.2的HEK293细胞(图2B)和SNU601细胞(图2C)的结合亲和力的确认。
图3A至图3B:CLDN18.2/CD3双特异性抗体(h-808/CD3-p、h-841/CD3-p、m-13/CD3-p、m-6/CD3-p)的结合亲和力与Amgen CLDN18.2/CD3双特异性抗体(AMG-910)的结合亲和力的对比。用连续稀释浓度的CLDN18.2/CD3双特异性抗体对过表达CLDN18.2的HEK293细胞(图3A)和CD3阳性Jurkat细胞(图3B)进行染色。通过流式细胞术测定平均荧光强度(MFI)。
图4:NFAT-报告Jurkat细胞中由CLDN18.2/CD3双特异性抗体介导的TCR-NFAT活性。将NFAT报告Jurkat细胞与表达CLDN18.2的SNU620细胞(E/T:3/1)在CLDN18.2/CD3双特异性抗体的连续稀释液中共培养6小时。通过相对发光单位(RLU)测定NFAT活性。
图5A至图5F:由鼠CLDN18.2/CD3双特异性抗体介导的针对具有各种CLDN18.2表达水平的靶细胞的杀伤活性的对比。收集过表达CLDN18.2的HEK(即CLDN18.2+HEK或过表达CLDN18.2的HEK293)(图5A)、适中表达CLDN18.2的SNU620(图5B)和低表达CLDN18.2的KATOIII靶细胞(图5C),计数并且接种于96孔板中。将效应细胞PBMC以在RPMI 1640中20:1的比例加入每个孔中。在RPMI 1640培养基中进行所示抗体的连续稀释,并且将连续稀释液加入含有靶细胞/效应细胞的孔中。将板温育48小时并测定荧光素酶强度。图5D至图5F示出了鼠CLDN18.2/CD3双特异性抗体的杀伤效力的EC50。
图6:由鼠CLDN18.2/CD3双特异性抗体介导的细胞因子释放水平的对比。从健康供体分离新鲜分离的PMBC,并且与表达CLDN18.2的HEK(即CLDN18.2+HEK)、SNU620和KATO III靶细胞在CLDN18.2/CD3双特异性抗体的连续稀释液中共培养。在48小时收集上清。通过ELISA测定来确定IFN-γ和TNF-α。
图7:与Amgen CLDN18.2抗体(即AMG-910)一样,鼠CLDN18.2抗体(即m-6/CD3-p、m-12/CD3-p、m-13/CD3-p)和h841/CD3-p抗体不显示与CLDN18.1的交叉反应性。用h808/CD3、h841/CD3、三种鼠CLDN18.2/CD3或Amgen CLDN18.2/CD3双特异性抗体对过表达CLDN18.1的CHO细胞进行染色。上图示出了用DYKDDDK表位标签抗体、抗人IgG对照、h808/CD3和h841/CD3双特异性抗体对表达CLDN18.1-DYK标签的CHO细胞进行染色。下图示出了用m-6、m-12、m-13和Amgen CLDN18.2/CD3双特异性抗体对表达CLDN18.1-DYK标签的CHO细胞进行染色。
图8:将新鲜分离的T细胞(效应细胞)与表达CLDN18.2的SNU620 Luc靶细胞(T)以20/1的E/T比在CLDN18.2/CD3双特异性抗体(CLDN18.2-808/CD3和CLDN18.2-841/CD3双特异性抗体)的连续稀释液中共培养48小时。进行荧光素酶定量测定来确定针对靶细胞的细胞毒性活性。
图9:鼠CLDN18.2-12克隆与CLDN18.2阴性LoVo和LS-174T细胞非特异性结合。用m-6、m-12和m-13/CD3双特异性抗体对CLDN18.2阴性LoVo肿瘤细胞(上图)和CLDN18.2阴性LS-174T肿瘤细胞(下图)进行染色。
图10:人源化CLDN18.2-13亚克隆显示与细胞表面上的CLDN18.2相似的结合亲和力。使用CLDN18.2-13亚克隆VH1-5+VL1、亲本m-13和Amgen CLDN18.2/CD3双特异性抗体对过表达CLDN18.2的HEK细胞(左上图)进行染色;使用h-13亚克隆VH1-5+VL2、亲本m-13和Amgen CLDN18.2/CD3双特异性抗体对天然表达CLDN18.2的SNU620细胞(右上图)进行染色;使用h-13亚克隆VH1-5+VL3、m-13亲本和Amgen CLDN18.2/CD3双特异性抗体对过表达CLDN18.2的HEK细胞(左下图)进行染色;鼠CLDN18.2-13的人源化评分示于右下图。
图11:CLDN18.2-13/CD3双特异性抗体的高特异性。用h-13VH1-5+VL1(上图)、VH1-5+VL2(中图)和LV3+HV1-5(下图)亚克隆/CD3双特异性抗体对过表达CLDN18.1的CHO细胞进行染色。
图12:由人源化CLDN18.2-13/CD3-p双特异性抗体介导的NFAT活性与由亲本鼠CLDN18.2-13/CD3-p介导的NFAT活性相当。将NFAT报告Jurkat细胞与表达CLDN18.2的SNU620细胞(E/T:3/1)在hCLDNE18.2-13VL1+VH1-5(左图)、VL2+VH1-5(中图)和VL3+VH1-5(右图)亚克隆/CD3双特异性抗体的连续稀释液中共培养6小时。通过相对发光单位(RLU)测定NFAT活性。
图13:由人源化CLDN18.2/CD3介导的杀伤活性和由鼠CLDN18.2-13/CD3双特异性抗体介导的杀伤活性相当。收集表达CLDN18.2的SNU620和过表达CLDN18.2的HEK细胞,计数并接种于96孔板中。将效应细胞PBMC以在VL1+VH1-5(左上图)、VL1+VH1-5(右上图)、VL3+HV1-5(左下图)和VL3+VL1-5(右下图)双特异性抗体的连续稀释液中20:1的比例加入每个孔中。将板温育48小时并测定荧光素酶强度。
图14A至图14D:人源化CLDN18.2/CD3双特异性抗体的结合亲和力与鼠亲本CLDN18.2-13/CD3双特异性抗体的结合亲和力的对比。用h-13/CD3、m-13/CD3、AmgenCLDN18.2/CD3双特异性抗体或IgG对照对表达CLDN18.2的SNU620细胞(图14A)和Jurkat细胞(图14C)进行染色,随后用PE缀合的抗人IgG ab染色。通过流式细胞术测定平均荧光强度(MFI)。图14B和图14D示出了人源化CLDN18.2/CD3双特异性抗体的结合亲和力的EC50与鼠亲本CLDN18.2-13/CD3双特异性抗体的结合亲和力的EC50。
图15:由CLDN18.2-13/CD3双特异性抗体介导的TCR-NFAT信号传导的对比。将NFAT报告Jurkat细胞与表达CLDN18.2的SNU620细胞(E/T:3/1)在h-13/CD3、m-13/CD3和AMG-910的连续稀释液中共培养6小时。通过相对发光单位(RLU)测定NFAT活性。
图16:由h-13/CD3双特异性抗体介导的针对表达CLDN18.2的各种靶标的杀伤效力的对比。收集过表达CLDN18.2的HEK(即CLDN18.2+HEK)、天然表达CLDN18.2的SNU620和天然表达CLDN18.2的KATO III靶细胞,计数并接种于96孔板中。将效应细胞PBMC以在RPMI 1640中20:1的比例加入每个孔中。在RPMI 1640培养基中进行所示抗体的连续稀释,并且将连续稀释液加入含有靶细胞/效应细胞的孔中。将板温育48小时并测定荧光素酶强度。
图17:由CLDN18.2-13/CD3双特异性抗体介导的细胞因子释放的对比。从健康供体分离新鲜分离的PBMC,并且与表达CLDN18.2的SNU620靶细胞在具有各种CD3结合亲和力的所示CLDN18.2/CD3双特异性抗体的连续稀释液中共培养。在48小时收集上清。通过ELISA测定来确定IFN-γ、TNF-α、IL-2和IL-10浓度。
具体实施方式
除非另有定义,否则本文所用的技术和科学术语具有与本申请所属领域中通常使用的相同的含义。出于解释本说明书的目的,将应用以下定义,并且只要适当,以单数形式使用的术语也将包括复数形式,并且反之,以复数形式使用的术语也将包括单数形式。如本文和所附权利要求书中所用,除非上下文另有明确规定,否则单数形式“一个(a)”、“一种(an)”和“所述/该”也指复数形式,例如,提及“一种宿主细胞”时包括多种所述宿主细胞。
如本文所用,术语“抗原结合片段”或“抗原结合分子”在其最广泛的意义上指特异性结合抗原决定簇的分子。抗原结合分子的示例是抗体、抗体片段和支架抗原结合蛋白质。本文中的术语“抗体”以最广泛的含义使用,并且涵盖各种抗体结构,包括但不限于单克隆抗体、多克隆抗体、单特异性和多特异性抗体(例如双特异性抗体)和抗体片段,只要它们表现出期望的抗原结合活性即可。
本文所用的术语“抗体”指从基本上同质的抗体群体获得的抗体,即构成群体的各个抗体是相同的和/或结合相同的表位,不同的是可能的变体抗体,例如包含天然存在的突变或在单克隆抗体制剂的生产过程中产生的变体,所述变体通常以少量存在。与通常包含针对不同决定簇(表位)的不同抗体的多克隆抗体制剂相反,单克隆抗体制剂的每种单克隆抗体只针对抗原上的单个决定簇。
人源化抗体也被称为重构人抗体。具体地,通过将非人动物抗体诸如小鼠抗体的CDR移植到人抗体而制备的人源化抗体是本领域已知的。用于获得人源化抗体的常规基因工程技术也是已知的。具体地,例如,重叠延伸PCR是已知的用于将小鼠抗体CDR移植到人FR的方法。在重叠延伸PCR中,将编码待移植的小鼠抗体CDR的核苷酸序列加入用于合成人抗体FR的引物中。针对四个FR中的每个FR制备引物。通常认为,当将小鼠CDR移植到人FR时,选择与小鼠FR具有高同一性的人FR有利于保持CDR功能。即,通常优选使用人FR,该人FR包含与待移植的小鼠CDR相邻的FR的氨基酸序列具有高同一性的氨基酸序列。
术语“双特异性”是指抗体能够特异性结合至少两个不同的抗原决定簇,例如两个结合位点,每个位点均通过一对抗体重链可变结构域(VH)和抗体轻链可变结构域(VL)结合不同抗原或相同抗原上的不同表位形成。这样的双特异性抗体被称为1+1形式。其他双特异性抗体形式是2+1形式(包括两个用于第一抗原或表位的结合位点和一个用于第二抗原或表位的结合位点)或2+2形式(包括两个用于第一抗原或表位的结合位点和两个用于第二抗原或表位的结合位点)。通常,双特异性抗体包括两个抗原结合位点,每个抗原结合位点特异于不同的抗原决定簇。本申请中使用的术语“价”表示抗原结合分子中存在特定数量的结合结构域。因此,术语“二价”、“四价”和“六价”分别表示在抗原结合分子中存在两个结合结构域、四个结合结构域和六个结合结构域。根据本申请的双特异性抗体至少是“二价的”并且可以是“三价的”或“多价的”(例如,“四价的”或“六价的”)。在一个具体方面,本申请的抗体具有两个或多个结合位点并且是双特异性的。即,抗体可以是双特异性的,即使在存在多于两个结合位点的情况下(即抗体是三价或多价的)。术语“全长抗体”、“完整抗体”和“全抗体”在本文中可互换使用,指具有与天然抗体结构基本上相似的结构的抗体。“天然抗体”指具有不同结构的天然存在的免疫球蛋白分子。例如,天然IgG类抗体是由二硫键键合的两条轻链和两条重链组成的约150,000道尔顿的异四聚体糖蛋白。从N-末端到C-末端,每条重链具有可变区(VH,也称为可变重域或重链可变结构域),随后是三个恒定结构域(CH1、CH2和CH3,也称为重链恒定区)。类似地,从N-末端到C-末端,每条轻链具有可变区(VL,也称为可变轻域或轻链可变结构域),随后是轻链恒定结构域(CL,也称为轻链恒定区)。抗体的重链可归入五种类型(称为α(IgA)、δ(IgD)、ε(IgE)、γ(IgG)或μ(IgM))中的一种,它们中的一些类型可进一步划分成亚类,例如γ1(IgG1)、γ2(IgG2)、γ3(IgG3)、γ4(IgG4)、αl(IgA1)和α2(IgA2)。基于其恒定结构域的氨基酸序列,抗体轻链可归入两种类型中的一种,称作kappa(κ)和lambda(λ)。“抗体片段”指包含完整抗体的结合完整抗体所结合的抗原的一部分但不同于完整抗体的分子。抗体片段的示例包括但不限于Fv、Fab、Fab'、Fab'-SH、F(ab')2;双抗体、三抗体、四抗体、交叉Fab片段;线性抗体;单链抗体分子(例如scFv);由抗体片段和单结构域抗体形成的多特异性抗体。单结构域抗体是包含抗体的重链可变结构域的全部或一部分或轻链可变结构域的全部或一部分的抗体片段。在某些实施方案中,单结构域抗体为人单结构域抗体。此外,抗体片段包含单链多肽,这些单链多肽具有VH结构域的特征,即能够与VL结构域一起组装;或具有VL结构域的特征,即能够与VH结构域一起组装到功能性抗原结合位点,从而提供全长抗体的抗原结合特性。抗体片段可以通过各种技术制备,这些技术包括但不限于完整抗体的蛋白水解消化以及通过重组宿主细胞(例如,大肠杆菌或噬菌体)的产生,如本文所述。木瓜蛋白酶消化完整抗体产生两个相同的抗原结合片段,称为“Fab”片段,每个片段均包含重链可变结构域和轻链可变结构域,并且还包含轻链的恒定结构域和重链的第一恒定结构域(CH1)。如本文所用,术语“Fab片段”指包含轻链片段以及重链的VH结构域和第一恒定结构域(CH1)的抗体片段,该轻链片段包含轻链的VL结构域和恒定结构域(CL)。Fab'片段与Fab片段的区别在于在重链CH1结构域的羧基末端处加入几个残基,这些残基包括来自抗体铰链区的一个或多个半胱氨酸。Fab'-SH为其中恒定结构域的半胱氨酸残基带有游离巯基基团的Fab'片段。胃蛋白酶处理产生具有两个抗原结合位点(两个Fab片段)和Fc区的一部分的F(ab')2片段。
“单链可变片段(scFv)”为抗体的重链可变区(VH)和轻链可变区(VL)通过10个至约25个氨基酸的短接头肽连接的融合蛋白。该接头通常富含甘氨酸以提供柔性,以及富含丝氨酸或苏氨酸以提供溶解性,并且可以将VH的N-末端与VL的C-末端连接,或反之,可以将VL的C-末端与VH的N-末端连接。尽管去除了恒定区并引入了接头,但该蛋白质仍保留了原始抗体的特异性。此外,包含单链多肽的抗体片段具有VH结构域的特征,即能够与VL结构域一起组装;或具有VL结构域的特征,即能够与VH结构域一起组装到功能性抗原结合位点,从而提供全长抗体的抗原结合特性。
“特异性结合”指结合对抗原具有选择性,并且可与除抗原之外的底物的不需要的或非特异性的相互作用区分开。抗原结合分子结合特定抗原的能力可以通过酶联免疫吸附测定(ELISA)或本领域技术人员熟悉的其他技术和传统结合测定来测量。在本申请的一个实施方案中,如例如通过SPR所测量的,抗原结合分子与无关蛋白质的结合程度小于抗原结合分子与抗原的结合程度的约10%。在某些实施方案中,结合抗原的分子具有<1μM、<100nM、<10nM、<1nM、<0.1nM、<0.01nM或<0.001nM(例如10-7M或更小,例如10-7M至10-13M,例如10-9M至10-13M)的解离常数(Kd)。
“亲和力”或“结合亲和力”指分子(例如抗体)的单个结合位点与其结合配偶体(例如抗原)之间的非共价相互作用的总和的强度。除非另有说明,否则如本文所用,“结合亲和力”指反映结合对(例如,抗体与抗原)的成员之间1:1相互作用的内在结合亲和力。分子X对其配偶体Y的亲和力通常可以用解离常数(Kd)表示,Kd是解离速率常数和结合速率常数(分别为koff和kon)的比值。因此,等同亲和力可以包括不同的速率常数,只要速率常数的比值保持相同即可。亲和力可通过本领域已知的常规方法来测量,包括本文所述的方法。一种用于测量亲和力的具体方法为表面等离子体共振(SPR)。如本文所用,术语抗体的“高亲和力”指抗体对靶抗原的Kd为10-9M或更小,甚至更特别地为10-10M或更小。术语抗体的“低亲和力”指抗体的Kd为10-8或更大。
术语“可变区”或“可变结构域”指抗体重链或轻链的结构域,其参与抗原结合分子与抗原的结合。天然抗体的重链和轻链的可变结构域(分别为VH和VL)通常具有相似的结构,其中每个结构域包含四个保守框架区(FR)和三个高变区(HVR)。单个VH或VL结构域可足以赋予抗原结合特异性。
高变区(HVR)也称为互补决定区(CDR),并且这些术语在本文中可互换地用于指可变区的形成抗原结合区的部分。美国卫生与公众服务部的Kabat等人已描述了该特定区域,其中的定义包括当相互比较时氨基酸残基的重叠或子集。然而,涉及抗体或其变体的CDR的任一定义的应用均旨在处于如本文定义和使用的术语范围内。包含特定CDR的确切残基数目将根据CDR的序列和大小而变化。给定抗体的可变区氨基酸序列,本领域的技术人员可以常规地确定哪些残基包含特定CDR。
Kabat等人还定义了适用于任何抗体的可变区序列的编号系统。本领域的普通技术人员可以明确地将这种“Kabat编号”系统分配给任何可变区序列,而不依赖于序列本身之外的任何实验数据。如本文所用,“Kabat编号”指美国卫生与公众服务部的Kabat等人提出的编号系统。除非另有说明,否则本文中提及的抗体可变区中特定氨基酸残基位置的编号都是根据Kabat编号系统。除了VH中的CDR1外,CDR通常包含形成超变环的氨基酸残基。CDR还包含“特异性决定残基”或“SDR”(它们是接触抗原的残基)。SDR包含在称为缩写CDR或α-CDR的CDR区内。示例性a-CDR(a-CDR-L1、a-CDR-L2、a-CDR-L3、a-CDR-H1、a-CDR-H2和a-CDR-H3)存在于L1的氨基酸残基31-34、L2的氨基酸残基50-55、L3的氨基酸残基89-96、H1的氨基酸残基31-35B、H2的氨基酸残基50-58和H3的氨基酸残基95-102处。除非另有说明,否则HVR残基和可变结构域中的其他残基(例如FR残基)在本文中根据Kabat等人编号。
“融合”或“连接”指组分(例如抗原结合结构域和FC结构域)通过肽键直接连接,或通过一个或多个肽接头连接。
术语“宿主细胞”、“宿主细胞系”和“宿主细胞培养物”可以互换使用,指已引入外源核酸的细胞,包括所述细胞的子代。宿主细胞包括“转化体”和“转化细胞”,其包括原代转化细胞和由其衍生的子代,而不考虑传代次数。
药剂例如药物组合物的“治疗有效量”指在必要的剂量和时间段下,有效实现期望的治疗或预防结果的量。例如,药剂的治疗有效量可以消除、减少、延迟、最大程度地减少或预防疾病的副作用。
“个体”或“受试者”为哺乳动物。哺乳动物包括但不限于驯化动物(例如,奶牛、绵羊、猫、犬和马)、灵长类(例如,人和非人灵长类诸如猴)、兔和啮齿类(例如,小鼠和大鼠)。特别地,个体或受试者为人。术语“药物组合物”指这样的制剂,其处于使得包含在其中的活性成分的生物学活性有效的形式,并且不含对该配制品所施用的受试者具有不可接受的毒性的另外的组分。“药学上可接受的赋形剂”指药物组合物中除活性成分以外的对受试者无毒的成分。药学上可接受的赋形剂包括但不限于缓冲剂、稳定剂或防腐剂。
如本文所用,“治疗(treatment)”(及其语法变型诸如“treat”或“treating”)指试图改变被治疗个体的自然过程的临床干预,并且可以为了预防而进行或在临床病理学过程期间进行。期望的治疗效果包括但不限于防止疾病的发生或复发、减轻症状、减少疾病的任何直接或间接病理学后果、防止转移、降低疾病进展速率、改善或缓和疾病状态,以及缓解或改善预后。在一些实施方案中,本申请的分子用于延缓疾病的发展或减慢疾病的进展。
本文所用的术语“癌症”指增殖性疾病,诸如淋巴瘤、淋巴细胞性白血病、肺癌、非小细胞肺(NSCL)癌、细支气管肺泡细胞肺癌、骨癌、胰腺癌、皮肤癌、头颈癌、皮肤癌或眼内黑色素瘤、子宫癌、卵巢癌、直肠癌、肛门癌、胃癌(stomach cancer/gastric cancer)、结肠癌、乳腺癌、子宫癌、输卵管癌、子宫内膜癌、宫颈癌、阴道癌、外阴癌、霍奇金病、食道癌、小肠癌、内分泌系统癌、甲状腺癌、甲状旁腺癌、肾上腺癌、软组织肉瘤、尿道癌、阴茎癌、前列腺癌、膀胱癌、肾或输尿管癌、肾细胞癌、肾盂癌、间皮瘤、肝细胞癌、胆道癌、中枢神经系统(CNS)肿瘤、脊柱肿瘤、脑干胶质瘤、多形性成胶质细胞瘤、星形细胞瘤、神经鞘瘤、室管膜瘤、髓母细胞瘤、脑膜瘤、鳞状细胞癌、垂体腺瘤和尤因氏肉瘤,包括上述癌症中任何一种的难治性形式,或上述癌症中任何一种或多种的组合。
定义
为了解释在以下实施例中使用的抗体,提供以下定义。
1.在以下实施例中使用的抗CLDN18.2单克隆抗体的定义:
1)2种先导人源化CLDN18.2抗体:hCLDN18.2 841(即h841)、hCLDN18.2 808(即h808)及其序列如表1所示;
2)3种先导鼠抗人CLDN18.2抗体:m-抗人CLDN18.2-6(即m-6)、m-抗人CLDN18.2-12(即m-12)和m-抗人CLDN18.2-13(即m-13)及其序列如表1所示;
3)人源化m-13:h-13及其VH和VL如表2所示;
4)人源化m-6:h-6及其VH和VL如表2-1所示。
2.在以下实施例中使用的抗CD3抗体的定义:
1)人源化抗CD3抗体:SP34(即CD3-p或CD3亲本)、突变CD3抗体(CD3-v1、CD3-v2)及其序列如表3所示;
3.在以下实施例中使用的抗CLDN18.2/CD3 BsAb的定义:
1)CLDN18.2/CD3 bsAb:
①h808/CD3-p、h841/CD3-p、m-6/CD3-p、m-13/CD3-p;
②h841/CD3-v1、h841/CD3-v2;
2)使用人源化m-13的CLDN18.2/CD3 bsAb,即CLDN18.2-13/CD3双特异性抗体或h-13/CD3 bsAb:
①具有CD3-p(即CD3亲本)臂的CLDN18.2-13/CD3双特异性抗体(即h-13/CD3bsAb)(即15种人源化CLDN18.2-13/CD3双特异性抗体):
h-13VH1-VL1/CD3-p、h-13VH2-VL1/CD3-p、h-13VH3-VL1/CD3-p、h-13VH4-VL1/CD3-p、h-13VH5-VL1/CD3-p、
h-13VH1-VL2/CD3-p、h-13VH2-VL2/CD3-p、h-13VH3-VL2/CD3-p、h-13VH4-VL2/CD3-p、h-13VH5-VL2/CD3-p、
h-13VH1-VL3/CD3-p、h-13VH2-VL3/CD3-p、h-13VH3-VL3/CD3-p、h-13VH4-VL3/CD3-p、h-13VH5-VL3/CD3-p,
②具有突变CD3臂(CD3-v1或CD3-v2)的CLDN18.2-13/CD3双特异性抗体(即h-13/CD3bsAb):
h-13VH1-VL1/CD3-v1、h-13VH1-VL1/CD3-v2、h-13VH1-VL2/CD3-v2和hVH1-VL3/CD3-v2
3)基准双特异性抗体:AMG-910。
表1.抗CLDN18.2单克隆抗体的VH或VL序列(用下划线标出的序列代表CDR,分析系统为Kabat系统)
表2.人源化m-13(即h-13)及其VH和VL的序列(用下划线标出的序列代表CDR,分析系统为Kabat系统)
表2-1.人源化m-6(即h-6)及其VH和VL的序列
表3.CD3臂(CD3亲本和CD3-v1、CD3-v2)的VH序列和VL序列(用下划线标出的序列代表CDR,分析系统为Kabat系统)
表4.用于抗CLDN18.2克隆或CLDN18.2-13/CD3双特异性抗体的接头和恒定区
实施例
实施例1.抗CLDN18.2单克隆抗体以及抗CLDN18.2单克隆抗体对CLDN18.2蛋白质或表达CLDN18.2的细胞的结合能力和特异性的确认
1.先导鼠抗人CLDN18.2抗体和人源化抗CLDN18.2抗体
我们选择了三种先导鼠抗人CLDN18.2抗体(m-抗人CLDN18.2-6(也称为m-6)、m-抗人CLDN18.2-12(也称为m-12)和m-抗人CLDN18.2-13(也称为m-13))以及两种人源化CLDN18.2抗体hCLDN18.2 808和hCLDN18.2 841。其VH和VL序列列于表1中。
2.基于表面等离子体共振(SRP)技术,使用BIAcore 8K仪器来测量CLDN18.2单克隆抗体m-13与hCLDDN18.2蛋白质结合的动力学。
m-13的VH和VL序列如表1所示,m-13的重链恒定区是小鼠IgG2a重链的恒定区,并且m-13的轻链是小鼠κ轻链。其序列列于表4中。
对于动力学测量,将hCLDN18.2蛋白质(Genscript)用HBS-EP+1×(Cytiva,BR-1006-69)缓冲液连续稀释,从50nM开始2倍稀释出4个浓度梯度,并设置0浓度。启动3次。m-13抗体:2μg/mL,注射时间100s,流速10μL/min,用ProA芯片捕获(Cytiva,29127556);抗原蛋白质hCLDND18.2(Genscript):结合120s,流速30μL/min,解离600s;再生:用MgCl2缓冲液再生30秒,流速30μL/min。
使用1:1结合模型(BIAcore评价软件3.2版)计算结合常数(ka)和解离常数(kd),并以kd/ka的比值计算平衡解离常数(KD)。结果可见于图2A,并且m-13和hCLDN18.2之间的KD值为9.15E-09。
3.CLDN18.2单克隆抗体m-13对过表达CLDN18.2的HEK293细胞和SNU601细胞的结合亲和力的确认
3.1我们首先对比了CLDN18.2单克隆抗体对过表达人CLDN18.2的HEK293细胞的结合亲和力。
为了测定CLDN18.2单克隆抗体在细胞表面上的结合;将每孔五万个表达hCLDN18.2的HEK293细胞(KYinno)置于96孔V底板(Corning)中,并与测试单克隆抗体m-13在冰上一起温育30分钟。用FACS缓冲液(PBS、2% FBS和1mM EDTA)洗涤HEK293细胞,并在冰上用山羊抗人IgG-PE Fab(Jackson Immuno Research)染色30分钟。用FACS缓冲液将HEK293细胞洗涤两次,并且将DAPI加入最终的悬浮液中,通过流式细胞术评估表观结合活性,结果如图2B所示。IC50=0.701μg/mL,图2B中使用的同种型是针对另一靶标,但是具有与m-13相同的Fc的抗体。
3.2我们进一步对比了CLDN18.2单克隆抗体对人SNU601细胞的结合亲和力。
为了测定CLDN18.2单克隆抗体在细胞表面上的结合;将每孔五万个SNU601细胞(Cobioer)置于96孔V底板(Corning)中,并与测试单克隆抗体m-13在冰上一起温育30分钟。用FACS缓冲液(PBS、2% FBS和1mM EDTA)洗涤SNU601细胞,并在冰上用山羊抗人IgG-PEFab(Jackson Immuno Research)染色30分钟。用FACS缓冲液将SNU601细胞洗涤两次,并且将DAPI加入最终的悬浮液中,通过流式细胞术评估表观结合活性,结果如图2C所示。IC50=0.811μg/mL,图2C中使用的同种型是针对另一靶标,但是具有与m-13相同的Fc的抗体。
实施例2.CLDN18.2/CD3双特异性抗体的产生和这些双特异性抗体的评价
1.CLDN18.2/CD3双特异性抗体的产生、这些双特异性抗体的评价以及先导CLDN18.2/CD3双特异性抗体候选物选择
1.1.CLDN18.2/CD3双特异性抗体的产生
使用上述两种先导人源化CLDN18.2抗体(hCLDN18.2 808和hCLDN18.2 841)和三种先导鼠抗人CLDN18.2抗体(m-抗人CLDN18.2-6(也称为m-6)、m-抗人CLDN18.2-12(也称为m-12)和m-抗人CLDN18.2-13(也称为m-13))来开发新的CLDN18.2/CD3双特异性抗体(针对人CLDN18.2和CD3的双特异性抗体)以用于治疗CLDN18.2阳性肿瘤。人源化抗CD3抗体:SP34(即CD3-p或CD3亲本)、CD3-v1或CD3-v2用作一个臂以构建蝴蝶构型CLDN18.2/CD3双特异性抗体(图1)。
在这种蝴蝶构型中,抗CLDN18.2抗体的Fab用于结合在肿瘤细胞上表达的CLDN18.2,并且与抗CLDN18.2的轻链的C-末端融合的两个抗CD3 scFv臂用于结合T细胞上的CD3。这种形式对于CLDN18.2是二价的,而对于CD3是功能上单价的。具体地,对于双特异性抗体,抗CLDN18.2克隆可变区(VH和VL)分别与人IgG1重链的恒定区和人κ轻链的恒定区融合;恒定区的序列列于表4中。抗CD3单链可变片段(scFv)与抗CLDN18.2的轻链的C-末端融合。为了避免Ig Fc介导的相互作用,在人IgG1 Fc区中引入突变L234A、L235A和P329A,以消除效应子功能(例如ADCC功能/CDC功能)。具有常规Fc(例如IgG1、IgG2、IgG3或IgG4的Fc)的CLDN18.2/CD3双特异性抗体也可以介导杀伤作用。
1.2.CLDN18.2/CD3双特异性抗体(即CLDN18.2/CD3 bsAb)对过表达人CLDN18.2的HEK293细胞的结合亲和力的评价
我们首先对比了CLDN18.2/CD3 bsAb对过表达人CLDN18.2的HEK293细胞的结合亲和力。
为了测定CLND18.2/CD3双特异性抗体在细胞表面上的结合;将每孔二万个过表达hCLND18.2的HEK293细胞(ATCC,CRL-3216)置于96孔V底板(Corning)中,并与测试bsAb(h808/CD3-p、h841/CD3-p、m-6/CD3-p、m-13/CD3-p或AMG-910)在冰上一起温育30分钟。用FACS缓冲液(PBS、2% FBS和1mM EDTA)洗涤HEK293细胞,并在冰上用山羊抗人IgG-PE Fab(Jackson Immuno Research)染色30分钟。用FACS缓冲液将细胞洗涤两次,并且将DAPI加入最终的悬浮液中。通过流式细胞术评估表观结合活性,结果如图3A所示,hCLDN18.2808/CD3(也称为h-808/CD3-p)和两种鼠CLDN18.2/CD3-p(m-6/CD3-p和m-13/CD3-p)对CLDN18.2具有相当的结合亲和力,并且与hCLDN18.2 841/CD3-p(也称为h841/CD3-p)和基准双特异性抗体Amgen CLDN18.2/CD3(AMG-910)(US20200055932A1的SEQ ID NO:132中描述的氨基酸序列)相比,对CLDN18.2具有更高的结合亲和力。
1.3.CLDN18.2/CD3双特异性抗体对CD3+Jurkat细胞的结合亲和力的评价
为了对比Amgen CLDN18.2/CD3(AMG-910)bsAb的CD3结合亲和力与具有突变抗CD3臂的CLDN18.2/CD3 bsAb(h841/CD3-v1和h841/CD3-v2)或具有亲本抗CD3臂的CLDN18.2/CD3 bsAb(h841/CD3-p)的CD3结合亲和力,用h841/CD3-p、h841/CD3-v1以及h841/CD3-v2对CD3+Jurkat细胞(ATCC,克隆E6-1)进行染色,其中CD3-v1和CD3-v2两者都具有降低的CD3结合亲和力。如图3B所示,AMG-910bsAb显示出与具有亲本抗CD3臂(也称为CD3-p)的h841/CD3-p bsAb相似的对CD3的结合亲和力,但比我们的具有突变抗CD3臂(即CD3-v1和CD3-v2)的h841/CD3-v1和h841/CD3-v2高得多的结合亲和力(图3B)(CD3-p、CD3-v1和CD3-v2的VH序列和VL序列列于表3中)。
1.4.NFAT-报告Jurkat细胞中由CLDN18.2/CD3 bsAb介导的TCR-NFAT活性的评价
我们进一步证实了NFAT-报告Jurkat细胞(InvivoGen,jktl-nfat)中由CLDN18.2/CD3 bsAb介导的TCR-NFAT活性。由AMG-910bsAb和h841/CD3-p介导的NFAT活性显著低于由h808/CD3-p、m-6/CD3-p和m-13/CD3-p介导的NFAT活性(图4),即使h808/CD3-p、h841/CD3-p和AMG-910对CD3具有相似的结合亲和力。这一发现表明,由CLDN18.2/CD3 bsAb触发的TCR信号传导强度取决于CLDN18.2/CD3 bsAb对CD3以及靶分子CLDN18.2的结合亲和力。
1.5.具有不同hCLDN18.2表达水平的三种肿瘤细胞系中由CLDN18.2/CD3 bsAb介导的T细胞杀伤作用的评价
在选择先导候选抗体时,最重要的功能之一是其是否可以有效地介导T细胞杀伤靶标。为了评价这一点,我们选择了具有不同hCLDN18.2表达水平的三种肿瘤细胞系作为靶标。将新鲜分离的人PBMC(STEMCELL Technologies)与靶细胞以20:1的E/T比在所测试的CLDN18.2/CD3 bsAb的连续稀释液中共培养48小时。当用荧光素酶转染这些靶细胞时,通过发光单位测定对靶细胞的杀伤活性。如图5A至图5C所示,与h841/CD3-p和AMG-910BsAb相比,三种鼠CLDN18.2/CD3 bsAb(即mCLDN18.2/CD3 bsAb):m-6/CD3-p、m-12/CD3-p和m-13/CD3-p表现出针对高表达CLDN18.2的HEK(ATCC,CRL-3216)(即CLDN18.2+HEK)(图5A)、适中表达CLDN18.2的SNU620(韩国细胞系库,00620.1)(图5B)和低表达CLDN18.2的KATO III(ATCC,HTB-103)(图5C)靶细胞的更好的杀伤活性。mCLDN18.2/CD3 bsAb和AMG-910之间的针对适中表达CLDN18.2的细胞(SNU620)(图5B)和低表达CLDN18.2的细胞(KATO III)(图5C)的杀伤效力的差异甚至更大,这表明mCLDN18.2/CD3 bsAb的治疗指数比AMG-910更好,具有显著的潜在开发价值。图5D至图5F示出了鼠CLDN18.2/CD3双特异性抗体的杀伤效力的EC50。
1.6.由CLDN18.2/CD3 bsAb介导的细胞因子释放的评价
T细胞衔接器抗体可以介导CTL与靶细胞之间的直接细胞-细胞接触,这会导致杀伤靶细胞。在另一方面,只要TCR刺激因抗体接合而继续,活化的T细胞就可以同时分泌细胞因子,诸如IFN-α和TNF-γ。这些细胞因子影响靶细胞或效应T细胞远侧的细胞。TNF-α接合其在靶细胞上的受体并触发靶细胞凋亡,并且IFN-γ增加Fas介导的靶细胞裂解。然而,虽然细胞因子对于T细胞的功能是必需的,但是由T细胞衔接器抗体介导的高细胞因子释放水平会诱导潜在不利的细胞因子释放综合征(CRS)。因此,当评价先导候选物时,需要考虑由CLDN18.2/CD3双特异性抗体介导的细胞因子释放的适当水平。为此,设计了平行研究以研究在与杀伤测定相同的共培养条件下的细胞因子释放。将靶细胞和人PBMC以20:1的E:T比置于96孔微孔板中,并与各种浓度的抗CLDN18.2/CD3 bsAb(h841/CD3-p、AMG-910、m-6/CD3-p、m-12/CD3-p和m-13/CD3-p)共培养。温育48小时后,收集无细胞上清液,并通过ELISA测量PBMC与表达CLDN18.2的各种HEK(即CLDN18.2+HEK)、SNU620和KATO III靶细胞的共培养物的上清中INF-α、TNF-γ、IL-2和IL-10分泌的产量。与细胞溶解活性一致,m-6/CD3-p、m-12/CD3-p和m-13/CD3-p克隆诱导较高的INF-α(图6)、TNF-γ(图6)、IL-2和IL-10释放(数据未显示)。相比之下,从h841/CD3-p和AMG-910观察到较低水平的细胞因子释放。
1.7.抗CLDN18.2抗体的结合特异性的评价与先导CLDN18.2/CD3双特异性抗体候选物选择
由于CLDN18.1和CLDN18.2共享高度同源的序列,因此评估抗CLDN18.2抗体的结合特异性对于开发治疗性Claudin18.2双特异性抗体是关键的。从杀伤测定(图5A至图5C)中,我们发现三种鼠抗人CLDN18.2(m-6、m-12和m-13)CD3 bsAb针对表达CLDN18.2的各种靶标表现出比h841/CD3更有效的细胞毒性。因此,需要评估这些CLDN18.2抗体针对表达CLDN18.1的细胞系的结合特异性。
如上所述,我们测试了h808/CD-3-p、h841/CD3-p和三种鼠CLDN18.2/CD3-p BsAb对过表达人CLDN18.1的CHO细胞(Creative Biogene,SCS-R00629)的特异性。通常,在将细胞解离并在PBS中洗涤之后,将1×105个表达CLDN18.1的CHO细胞接种于96孔板中。将以25μg/mL的最终浓度制备的抗CLDN18.2/CD3抗体与细胞在4℃下一起温育1小时。在用FACS洗涤缓冲液洗涤后,将板与PE缀合的山羊抗人IgG、Fc片段特异性抗体(在FACS洗涤缓冲液中以1:200稀释)在4℃下一起温育20分钟。使用NovoCyte 2060测量平均荧光强度(MFI),并通过GraphPad软件分析结果。
如图7所示,m-6/CD3-p、m-12/CD3-p、m-13/CD3-p、h841/CD3-p和AMG-910表现出明显的结合特异性,并且与过表达人CLDN18.1的CHO没有交叉反应性。出乎意料的是,来自流式细胞术测定的数据显示h808/CD3-p与CLDN18.1具有高交叉反应性。因此,这种交叉反应性导致h808/CD3-p双特异性抗体作为用于进一步开发的先导候选物的价值降低,即使它表现出非常强效的细胞毒性(图8)。此外,h841/CD3-p没有显示与CLDN18.1结合;然而,对靶细胞的较低结合亲和力和弱杀伤效力是利用h841/CD3-p的劣势(图8)。
为了进一步证实鼠CLDN18.2克隆的结合特异性,使用流式细胞术测定来测试m-6/CD3-p、m-12/CD3-p和m-13/CD3-p对CLDN18.2阴性肿瘤细胞系LoVo(ACTT,CCL-229)和LS-174T(ATCC,LC-188)的结合特异性。如图9所示,没有发现m-6/CD3-p和m-13/CD3-p与所测试的CLDN18.2阴性肿瘤细胞结合,而m-12/CD3-p显示与LoVo和LS-174T细胞的弱结合和非特异性结合(图9)。
2.人源化CLDN18.2-13/CD3双特异性抗体的评价
2.1CLDN18.2-13/CD3双特异性抗体的结合亲和力
由于m-13和m-6克隆表现出高结合亲和力、高特异性和强效细胞毒性,因此最终选择m-13作为用于人源化的先导候选物,而m-6也被人源化为备用克隆。人源化m-6(即h-6)的VH序列和VL序列分别如表2-1中列出的SEQ ID No.29-30所示。对于m-13,获得了达到高人源化评分的前3条人源化可变轻链和前5条可变重链(VL1—90.1%、VL2—89.1%、VL3—88.1%、VH1—86.7%、VH2—82.7%、VH3—81.6%、VH4—80.6%和VH5—79.6%)(VH序列和VL序列列于表2中)。为了表征由那些人源化重链(即VH1-VH5)和轻链(即VL1-VL3)产生的CLDN18.2-13抗体(即CLDN18.2-h-13抗体),将每条人源化轻链与每条人源化CLDN18.2-13重链以CD3双特异性形式共转染。因此,产生15种人源化CLDN18.2-13/CD3双特异性抗体。为了测定它们的表观结合活性,将作为靶标的高表达CLDN18.2的HEK293和SNU620细胞系与作为二抗的抗人IgG-PE在不同浓度的人源化CLDN18.2/CD3双特异性抗体中一起温育。然后用FACS缓冲液将细胞洗涤两次。FACS分析在FACS流式细胞仪上进行。通过流式细胞术测定,我们表征了人源化CLDN18.2-13/CD3亚克隆在过表达hCLDN18.2的HEK293细胞(高表达CLDN18.2)和天然表达CLDN18.2的SNU-620细胞(适中表达CLDN18.2)上对CLDN18.2的结合亲和力。我们发现,根据对高度表达CLDN18.2的HEK细胞以及适中表达CLDN18.2的SNU620细胞两者的平均荧光强度(MFI)判断,所有15种人源化CLDN18.2-13/CD3候选物都具有与亲本m-13相当的结合亲和力(图10)。
2.2CLDN18.2-13/CD3双特异性抗体的高特异性
尽管所有人源化CLDN18.2-13/CD3 bsAb都保留了与亲本m-13相似的对CLDN18.2的高结合亲和力,但m-13克隆的人源化是否会改变结合特异性对于确定所得的人源化重链和轻链也是非常重要的。因此,我们通过对过表达人CLDN18.1的CHO细胞进行染色研究了人源化CLDN18.2-13/CD3亚克隆的结合特异性。如图11所示,所有15种人源化CLDN18.2-13亚克隆在转染的CHO细胞上都不与CLDN18.1结合,这表明人源化CLDN18.2重链和轻链保留了与其亲本m-13相似的对CLDN18.2的结合特异性。
2.3由具有CD3-p(即CD3亲本)臂的CLDN18.2-13/CD3双特异性抗体(即h-13/CD3bsAb)介导的TCR/CD3信号传导强度。
除了结合亲和力之外,还使用NFAT-荧光素酶Jurkat细胞与CLDN18.2+SNU620细胞的6小时共培养物验证了由人源化CLDN18.2-13/CD3亚克隆介导的TCR/CD3信号传导强度。为此,将1×105个Jurkat NFAT-荧光素酶报道细胞和1×105个表达CLDN18.2的NSU620肿瘤细胞接种于96孔板中,并在100μL培养基+10% FBS和抗CEA/CD3 bsAb的连续稀释液中在37℃下温育6小时。加入Bio-GloTm试剂(Promega),并使用BioMax Discover系统定量发光。使用GraphPad Prism 8软件将数据拟合成4PL曲线。
基于发光读数对比由15种人源化CLDN18.2-13/CD3-p亚克隆、m-13/CD3-p和AmgenCLDN18.2/CD3 bsAb(AMG-910)介导的NFAT活性。正如预期的那样,人源化CLDN18.2-13/CD3-p亚克隆诱导与它们的亲本m-13/CD3-p相似水平的NFAT活性(图12)。
2.4具有CD3-p(即CD3亲本)臂的CLDN18.2-13/CD3双特异性抗体(即h-13/CD3bsAb)的抗肿瘤作用
最后,我们对比了人源化CLDN18.2-13/CD3亚克隆(即h-13/CD3-p亚克隆)的抗肿瘤作用与m-13/CD3-p的抗肿瘤作用。过表达CLDN18.2的HEK/Luc细胞(即CLDN18.2+HEK)(ATCC,CRL-3216)和适中表达CLDN18.2的SNU620细胞与PBMC以20:1的最终E/T比在所测试抗体的连续稀释液中共培养。在共培养48小时后通过荧光素酶强度单位的定量来确定肿瘤细胞的特异性裂解。如图13所示,人源化CLDN18.2-13/CD3亚克隆诱导针对其靶标的强效T细胞重定向细胞毒性。正如预期的那样,由人源化CLDN18.2-13/CD3亚克隆和亲本m-13/CD3-p介导的杀伤效力是由AMG-910介导的杀伤效力的100倍(图13)。总之,这些功能性测定表明鼠CLDN18.2克隆13已经被成功人源化。
2.5具有突变CD3臂(CD3-V1或CD3-V2)的CLDN18.2-13/CD3双特异性抗体(即h-13/CD3bsAb)对CLDN18.2和CD3的结合亲和力
由于h-13/CD3-p携带对CD3具有高结合亲和力的SP34作为CD3臂,因此在临床上可能诱导潜在的细胞因子释放综合征(CRS)。为了产生安全且有效的CLDN18.2/CD3双特异性抗体并降低潜在的CRS相关毒性,我们使用我们优化后的CD3平台,其包括具有各种结合亲和力的若干CD3结合物。我们先前的项目已经证明,使用较低结合的CD3结合物作为用于构建CEA/CD3双特异性抗体的臂可以显著降低细胞因子释放,并且仍然保持强效的杀伤活性。
因此,使用人源化CLDN18.2-13重链1(VH1)和与CD3-P或突变CD3结合物(CD3-V1和CD3-V2)连接的h-13轻链(VL1)(序列列于表3中)来共转染CHO细胞。最后,产生了三种h-13/CD3变体双特异性抗体:h-13VH1-VL1/CD3-p、h-13VH1-VL1/CD3-v1和h-13VH1-VL1/CD3-v2。由于突变CD3 scFv与hCLDN18.2轻链连接,我们首先研究了h-13/CD3-v1和h-13/CD3-v2与细胞表面上的CLDN18.2的结合亲和力是否会受到影响。因此,通过FACS测定用h-13/CD3变体双特异性抗体对CLDN18.2阳性SNU620细胞进行染色。如图14A所示,所有h-13/CD3亚克隆均具有与其亲本m-13结合物(即m-13/CD3-p)相当的对CLDN18.2的结合亲和力。图14B示出了与鼠亲本CLDN18.2-13/CD3双特异性抗体相比,人源化CLDN18.2/CD3双特异性抗体的结合亲和力的EC50。
为了证实CD3变体与T细胞上的CD3的结合,我们进行了Jurkat结合测定。正如我们预期的那样,FACS分析显示,与具有亲本CD3结合物(即m-13/CD3-p)的h-13/CD3-p相比,h-13/CD3-v1和h-13/CD3-v2表现出显著降低的结合亲和力(图14C)。图14D示出了与鼠亲本CLDN18.2-13/CD3双特异性抗体相比,人源化CLDN18.2/CD3双特异性抗体的结合亲和力的EC50。
2.6由具有突变CD3臂(CD3-V1或CD3-V2)的CLDN18.2-13/CD3双特异性抗体(即h-13/CD3 bsAb)介导的TCR信号传导
然后我们通过NFAT报告测定进一步评估了由h-13/CD3 bsAb介导的TCR信号传导的强度。如第2.3节所述,将Jurkat NFAT-荧光素酶报告细胞和表达CLDN18.2的NSU620肿瘤细胞接种于96孔板中,并温育6小时。使用BioMax Discover系统定量发光。
与它们的结合亲和力一致(图14C),在Jurkat-NFAT报告细胞与SNU620靶细胞的共培养物中,与h-13/CD3-p相比,三种h-13/CD3-v2亚克隆和h-13/CD3-v1亚克隆诱导较低的NFAT活性(图15)。然而,与携带更高CD3结合亲和力结合臂的Amgen 18.2/CD3 bsAb(即AMG-910)相比,由h-13/CD3-v1和h-13/CD3-v2亚克隆介导的NFAT活性也更高,这再次表明对CLDN18.2的结合亲和力也在T细胞衔接器中起重要作用。
2.7由具有突变CD3臂(CD3-V1或CD3-V2)的CLDN18.2-13/CD3双特异性抗体(即h-13/CD3 bsAb)介导的细胞溶解效力
由于CLDN18.2-13/CD3-v2对CD3具有较低的结合亲和力,这将显著减少细胞因子释放,因此产生了具有VH1和不同的VL1-3链的三种CLDN18.2/CD3-v2双特异性抗体。因此,我们使用表达CLDN18.2的各种HEK(即CLDN18.2+HEK)、SNU620和KATO III细胞作为肿瘤靶标进一步对比了由3h-13/CD3亚克隆介导的细胞溶解效力(图16左图)。有趣的是,尽管与其他h-13/CD3-v2亚克隆具有相似的结合和NFAT活性(图15),h-13VH1-VL1/CD3-v2对m-13/CD3-v2克隆和人源化h-13/CD3-v2亚克隆中表达CLDN18.2的各种靶细胞显示出最高的效力(图16右图)。
2.8由具有突变CD3臂(CD3-V1或CD3-V2)的CLDN18.2-13/CD3双特异性抗体(即h-13/CD3 bsAb)介导的细胞因子释放水平
此外,由于细胞因子释放水平通常与杀伤效力相关,我们进一步对比了从SNU620和PBMC共培养系统的上清中释放的细胞因子。
如第1.6节所述,收集SNU620和PBMC共培养实验的上清液,以用于48小时后的细胞因子释放测量。使用BD optEIA人IFNγ和TNFαELISA试剂盒定量IFN-γ、TNF-α、IL-10和IL-2释放。简言之,用捕获抗体将ELISA板包被过夜。用ELISA缓冲液以1:20稀释上清液,并在温育2小时后加入检测抗体。加入ELISA底物,并在向每孔中加入HRP后,在SpectraMax读数器中读取450nM处板的读数。有趣的是,h-13VH1-VL1/CD3-v2诱导与其他两个h-13/CD3-v2亚克隆相当的IFN-γ、TNF-α、IL-10和IL-2释放(图17)。最重要的是,与h-13/CD3-p相比,h-13/CD3-v2亚克隆介导显著更低的细胞因子释放,这显然是由h-13/CD3-p的较高的CD3结合亲和力驱动的。总之,基于h-13VH1-VL1/CD3-v2与其他两种h-13/CD3-v2亚克隆相比更高的杀伤效力和相似的细胞因子释放,选择h-13VH1-VL1/CD3-v2作为先导候选抗体。
序列表
<110> 山东博安生物技术股份有限公司
<120> 用于治疗表达CLDN18.2的实体瘤的CLDN18.2/CD3双特异性抗体
<130> BA15
<150> US63/147,233
<151> 2021-02-08
<160> 52
<170> PatentIn version 3.5
<210> 1
<211> 125
<212> PRT
<213> 人工序列
<220>
<223> VH
<400> 1
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr
20 25 30
Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Ile Pro Ile Leu Gly Ile Ala Asn Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Val Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Glu Arg Asp Asn Trp Asp Pro Tyr Tyr Tyr Tyr Tyr Gly Met
100 105 110
Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser
115 120 125
<210> 2
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> VL
<400> 2
Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Asn Ser Trp
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Lys Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asn Ser Phe Pro Leu
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 3
<211> 124
<212> PRT
<213> 人工序列
<220>
<223> VH
<400> 3
Glu Val Gln Leu Val Gln 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 His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Glu Leu Arg Phe Phe Asp Trp Leu Leu Gly Ser Ala Phe Asp
100 105 110
Ile Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser
115 120
<210> 4
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> VL
<400> 4
Asp Ile Val 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 Ile Arg Asn Asp
20 25 30
Leu Gly Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ala Ala Ser Ser Leu Gln 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 Leu Gln Asp Tyr Asn Tyr Pro Arg
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 5
<211> 118
<212> PRT
<213> 人工序列
<220>
<223> VH
<400> 5
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Gly Met Ser Trp Val Arg Gln Thr Pro Asp Lys Arg Leu Glu Leu Val
35 40 45
Ala Thr Ile Asn Ser Asn Gly Gly Ser Thr Tyr Tyr Pro Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Ser Ser Leu Lys Ser Glu Asp Thr Ala Met Tyr Tyr Cys
85 90 95
Ala Arg Leu Ser Tyr Gly Asn Ser Phe Ala Asn Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser
115
<210> 6
<211> 113
<212> PRT
<213> 人工序列
<220>
<223> VL
<400> 6
Asp Ile Gln Ile Thr Gln Ser Pro Ser Ser Leu Thr Val Thr Ala Gly
1 5 10 15
Glu Lys Val Thr Met Ser Cys Gln Ser Ser Gln Ser Leu Leu Asn Ser
20 25 30
Gly Asn His Arg Asn Tyr Leu Thr Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Pro Pro Lys Leu Leu Met Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val
50 55 60
Pro Asp Arg Phe Ala Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Val Gln Ala Glu Asp Leu Ala Ile Tyr Tyr Cys Gln Asn
85 90 95
Thr Tyr Tyr Tyr Pro Phe Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile
100 105 110
Lys
<210> 7
<211> 119
<212> PRT
<213> 人工序列
<220>
<223> VH
<400> 7
Asp Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Met Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Ile Ser Cys Lys Ala Ser Asp Tyr Ser Phe Thr Ser Tyr
20 25 30
Asn Met His Trp Val Lys Gln Ser His Gly Lys Ser Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Asp Pro Phe Asn Gly Gly Thr Arg Tyr Asn Gln Lys Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met His Ile Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Ala Tyr Tyr Gly Asn Ser Phe Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 8
<211> 113
<212> PRT
<213> 人工序列
<220>
<223> VL
<400> 8
Asp Ile Val Met Thr Gln Ser Pro Ser Ser Leu Thr Val Thr Ala Gly
1 5 10 15
Glu Lys Val Thr Met Asn Cys Lys Ser Ser Gln Ser Leu Leu Asn Ser
20 25 30
Gly Asn Gln Lys Asn Tyr Leu Thr Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Pro Pro Lys Leu Leu Asn Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val
50 55 60
Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Gly Ser Val Gln Ala Glu Asp Leu Ala Val Tyr Tyr Cys Gln Asn
85 90 95
Ala Tyr Ser Phe Pro Phe Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile
100 105 110
Lys
<210> 9
<211> 118
<212> PRT
<213> 人工序列
<220>
<223> VH
<400> 9
Gln Leu Gln Leu Gln Gln Ser Gly Thr Glu Leu Val Arg Pro Gly Ser
1 5 10 15
Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ala Phe Ser Asn Tyr
20 25 30
Trp Met Asn Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Gln Ile Tyr Pro Gly Asn Gly Asp Thr Lys Tyr Asn Gly Asn Phe
50 55 60
Lys Gly 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 Asp Tyr Phe Cys
85 90 95
Ala Arg Tyr Tyr Arg Gly Asn Cys Phe Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Thr Leu Thr Val Ser Ser
115
<210> 10
<211> 113
<212> PRT
<213> 人工序列
<220>
<223> VL
<400> 10
Asp Ile Val Leu Thr Gln Ser Pro Ser Ser Leu Thr Val Thr Ala Gly
1 5 10 15
Glu Lys Val Thr Met Ser Cys Lys Ser Ser Gln Ser Leu Leu Asn Ser
20 25 30
Gly Asn Gln Lys Asn Tyr Leu Thr Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Asp Ser Gly Val
50 55 60
Pro Ala Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Asn Ser Val Gln Ala Glu Asp Leu Ala Val Tyr Tyr Cys Gln Asn
85 90 95
Ala Tyr Thr Tyr Pro Leu Thr Phe Gly Ala Gly Thr Lys Leu Glu Ile
100 105 110
Lys
<210> 11
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> CDR1
<400> 11
Gly Tyr Ala Phe Ser Asn Tyr Trp Met Asn
1 5 10
<210> 12
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> CDR2
<400> 12
Gln Ile Tyr Pro Gly Asn Gly Asp Thr Lys Tyr Asn Gly Asn Phe Lys
1 5 10 15
Gly
<210> 13
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> CDR3
<400> 13
Tyr Tyr Arg Gly Asn Cys Phe Asp Tyr
1 5
<210> 14
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> CDR1
<400> 14
Lys Ser Ser Gln Ser Leu Leu Asn Ser Gly Asn Gln Lys Asn Tyr Leu
1 5 10 15
Thr
<210> 15
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> CDR2
<400> 15
Trp Ala Ser Thr Arg Asp Ser
1 5
<210> 16
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> CDR3
<400> 16
Gln Asn Ala Tyr Thr Tyr Pro Leu Thr
1 5
<210> 17
<211> 118
<212> PRT
<213> 人工序列
<220>
<223> VH1
<400> 17
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 Ala Phe Ser Asn Tyr
20 25 30
Trp Met Asn Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
35 40 45
Gly Gln Ile Tyr Pro Gly Asn Gly Asp Thr Lys Tyr Asn Gly Asn Phe
50 55 60
Lys Gly Arg Val Thr Ile Thr Arg Asp Thr Ser Ala Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Tyr Tyr Arg Gly Asn Cys Phe Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser
115
<210> 18
<211> 118
<212> PRT
<213> 人工序列
<220>
<223> VH2
<400> 18
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ala Phe Ser Asn Tyr
20 25 30
Trp Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Gln Ile Tyr Pro Gly Asn Gly Asp Thr Lys Tyr Asn Gly Asn Phe
50 55 60
Lys Gly Arg Val Thr Ile Thr Ala Asp Thr Ser Ala Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Phe Cys
85 90 95
Ala Arg Tyr Tyr Arg Gly Asn Cys Phe Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser
115
<210> 19
<211> 118
<212> PRT
<213> 人工序列
<220>
<223> VH3
<400> 19
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 Ala Phe Ser Asn Tyr
20 25 30
Trp Met Asn Trp Val Lys Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Gln Ile Tyr Pro Gly Asn Gly Asp Thr Lys Tyr Asn Gly Asn Phe
50 55 60
Lys Gly Arg Val Thr Ile Thr Ala Asp Thr Ser Ala Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Phe Cys
85 90 95
Ala Arg Tyr Tyr Arg Gly Asn Cys Phe Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser
115
<210> 20
<211> 118
<212> PRT
<213> 人工序列
<220>
<223> VH4
<400> 20
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 Ala Phe Ser Asn Tyr
20 25 30
Trp Met Asn Trp Val Lys Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Gln Ile Tyr Pro Gly Asn Gly Asp Thr Lys Tyr Asn Gly Asn Phe
50 55 60
Lys Gly Arg Val Thr Leu Thr Ala Asp Thr Ser Ala Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Phe Cys
85 90 95
Ala Arg Tyr Tyr Arg Gly Asn Cys Phe Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser
115
<210> 21
<211> 118
<212> PRT
<213> 人工序列
<220>
<223> VH5
<400> 21
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 Ala Phe Ser Asn Tyr
20 25 30
Trp Met Asn Trp Val Lys Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Gln Ile Tyr Pro Gly Asn Gly Asp Thr Lys Tyr Asn Gly Asn Phe
50 55 60
Lys Gly Arg Ala Thr Leu Thr Ala Asp Thr Ser Ala Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Phe Cys
85 90 95
Ala Arg Tyr Tyr Arg Gly Asn Cys Phe Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser
115
<210> 22
<211> 113
<212> PRT
<213> 人工序列
<220>
<223> VL1
<400> 22
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 Ser Ser Gln Ser Leu Leu Asn Ser
20 25 30
Gly Asn Gln Lys Asn Tyr Leu Thr Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Asp Ser Gly Val
50 55 60
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Asn
85 90 95
Ala Tyr Thr Tyr Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile
100 105 110
Lys
<210> 23
<211> 113
<212> PRT
<213> 人工序列
<220>
<223> VL2
<400> 23
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 Ser Ser Gln Ser Leu Leu Asn Ser
20 25 30
Gly Asn Gln Lys Asn Tyr Leu Thr Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Asp Ser Gly Val
50 55 60
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Val Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Asn
85 90 95
Ala Tyr Thr Tyr Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile
100 105 110
Lys
<210> 24
<211> 113
<212> PRT
<213> 人工序列
<220>
<223> VL3
<400> 24
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Met Asn Cys Lys Ser Ser Gln Ser Leu Leu Asn Ser
20 25 30
Gly Asn Gln Lys Asn Tyr Leu Thr Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Asp Ser Gly Val
50 55 60
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Val Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Asn
85 90 95
Ala Tyr Thr Tyr Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile
100 105 110
Lys
<210> 25
<211> 125
<212> PRT
<213> 人工序列
<220>
<223> VH
<400> 25
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Lys Tyr
20 25 30
Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp
50 55 60
Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr
65 70 75 80
Ala Tyr Leu Gln Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Val Arg His Gly Asn Phe Gly Asn Ser Tyr Ile Ser Tyr Trp
100 105 110
Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120 125
<210> 26
<211> 109
<212> PRT
<213> 人工序列
<220>
<223> VL
<400> 26
Gln Thr Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly
1 5 10 15
Thr Val Thr Leu Thr Cys Gly Ser Ser Thr Gly Ala Val Thr Ser Gly
20 25 30
Tyr Tyr Pro Asn Trp Val Gln Gln Lys Pro Gly Gln Ala Pro Arg Gly
35 40 45
Leu Ile Gly Gly Thr Lys Phe Leu Ala Pro Gly Thr Pro Ala Arg Phe
50 55 60
Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Leu Ser Gly Val
65 70 75 80
Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Ala Leu Trp Tyr Ser Asn
85 90 95
Arg Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
100 105
<210> 27
<211> 125
<212> PRT
<213> 人工序列
<220>
<223> VH
<400> 27
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Thr Tyr
20 25 30
Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp
50 55 60
Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr
65 70 75 80
Ala Tyr Leu Gln Met Asn Asn Leu Arg Thr Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Val Arg His Gly Asn Trp Gly Asn Ser Tyr Ile Ser Tyr Trp
100 105 110
Ala Tyr Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser
115 120 125
<210> 28
<211> 125
<212> PRT
<213> 人工序列
<220>
<223> VH
<400> 28
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Thr Tyr
20 25 30
Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala Thr Thr Tyr Ala Asp
50 55 60
Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr
65 70 75 80
Ala Tyr Leu Gln Met Asn Asn Leu Arg Thr Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Val Arg His Gly Asn Trp Gly Asn Ser Tyr Ile Ser Tyr Trp
100 105 110
Ala Tyr Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser
115 120 125
<210> 29
<211> 118
<212> PRT
<213> 人工序列
<220>
<223> VH
<400> 29
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Thr Ile Asn Ser Asn Gly Gly Ser Thr Tyr Tyr Pro Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Leu Ser Tyr Gly Asn Ser Phe Ala Asn Trp Gly Gln Gly Thr
100 105 110
Thr Val Thr Val Ser Ser
115
<210> 30
<211> 113
<212> PRT
<213> 人工序列
<220>
<223> VL
<400> 30
Asp Ile Val Ile Thr Gln Ser Pro Ser Ser Leu Ser Val Thr Leu Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ser Ser Gln Ser Leu Leu Asn Ser
20 25 30
Gly Asn His Arg Asn Tyr Leu Thr Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Ala Pro Arg Leu Leu Met Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val
50 55 60
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Asn
85 90 95
Thr Tyr Tyr Tyr Pro Phe Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile
100 105 110
Lys
<210> 31
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> CDR1
<400> 31
Lys Tyr Ala Met Asn
1 5
<210> 32
<211> 19
<212> PRT
<213> 人工序列
<220>
<223> CDR2
<400> 32
Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser
1 5 10 15
Val Lys Asp
<210> 33
<211> 14
<212> PRT
<213> 人工序列
<220>
<223> CDR3
<400> 33
His Gly Asn Phe Gly Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr
1 5 10
<210> 34
<211> 14
<212> PRT
<213> 人工序列
<220>
<223> CDR1
<400> 34
Gly Ser Ser Thr Gly Ala Val Thr Ser Gly Tyr Tyr Pro Asn
1 5 10
<210> 35
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> CDR2
<400> 35
Gly Thr Lys Phe Leu Ala Pro
1 5
<210> 36
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> CDR3
<400> 36
Ala Leu Trp Tyr Ser Asn Arg Trp Val
1 5
<210> 37
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> CDR1
<400> 37
Thr Tyr Ala Met Asn
1 5
<210> 38
<211> 19
<212> PRT
<213> 人工序列
<220>
<223> CDR2
<400> 38
Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser
1 5 10 15
Val Lys Asp
<210> 39
<211> 14
<212> PRT
<213> 人工序列
<220>
<223> CDR3
<400> 39
His Gly Asn Trp Gly Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr
1 5 10
<210> 40
<211> 19
<212> PRT
<213> 人工序列
<220>
<223> CDR2
<400> 40
Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala Thr Thr Tyr Ala Asp Ser
1 5 10 15
Val Lys Asp
<210> 41
<211> 15
<212> PRT
<213> 人工序列
<220>
<223> 接头-1
<400> 41
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
1 5 10 15
<210> 42
<211> 30
<212> PRT
<213> 人工序列
<220>
<223> 接头-2
<400> 42
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
1 5 10 15
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
20 25 30
<210> 43
<211> 109
<212> PRT
<213> 人工序列
<220>
<223> CL (人 kappa 轻链的恒定区)
<400> 43
Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu
1 5 10 15
Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe
20 25 30
Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln
35 40 45
Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
50 55 60
Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu
65 70 75 80
Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser
85 90 95
Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys Thr Ser
100 105
<210> 44
<211> 98
<212> PRT
<213> 人工序列
<220>
<223> 人 IgG1重链的CH1
<400> 44
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys
1 5 10 15
Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr
65 70 75 80
Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Lys Val
<210> 45
<211> 15
<212> PRT
<213> 人工序列
<220>
<223> 铰链
<400> 45
Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro
1 5 10 15
<210> 46
<211> 110
<212> PRT
<213> 人工序列
<220>
<223> 人 IgG1重链的CH2
<400> 46
Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys
1 5 10 15
Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val
20 25 30
Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr
35 40 45
Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu
50 55 60
Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His
65 70 75 80
Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys
85 90 95
Ala Leu Ala Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys
100 105 110
<210> 47
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> 人 IgG1重链的CH3
<400> 47
Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu
1 5 10 15
Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
20 25 30
Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
35 40 45
Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
50 55 60
Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly
65 70 75 80
Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
85 90 95
Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
100 105
<210> 48
<211> 330
<212> PRT
<213> 人工序列
<220>
<223> 鼠 IgG2a重链的恒定区
<400> 48
Ala Lys Thr Thr Ala Pro Ser Val Tyr Pro Leu Ala Pro Val Cys Gly
1 5 10 15
Asp Thr Thr Gly Ser Ser Val Thr Leu Gly Cys Leu Val Lys Gly Tyr
20 25 30
Phe Pro Glu Pro Val Thr Leu Thr Trp Asn Ser Gly Ser Leu Ser Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Asp Leu Tyr Thr Leu
50 55 60
Ser Ser Ser Val Thr Val Thr Ser Ser Thr Trp Pro Ser Gln Ser Ile
65 70 75 80
Thr Cys Asn Val Ala His Pro Ala Ser Ser Thr Lys Val Asp Lys Lys
85 90 95
Ile Glu Pro Arg Gly Pro Thr Ile Lys Pro Cys Pro Pro Cys Lys Cys
100 105 110
Pro Ala Pro Asn Leu Leu Gly Gly Pro Ser Val Phe Ile Phe Pro Pro
115 120 125
Lys Ile Lys Asp Val Leu Met Ile Ser Leu Ser Pro Ile Val Thr Cys
130 135 140
Val Val Val Asp Val Ser Glu Asp Asp Pro Asp Val Gln Ile Ser Trp
145 150 155 160
Phe Val Asn Asn Val Glu Val His Thr Ala Gln Thr Gln Thr His Arg
165 170 175
Glu Asp Tyr Asn Ser Thr Leu Arg Val Val Ser Ala Leu Pro Ile Gln
180 185 190
His Gln Asp Trp Met Ser Gly Lys Glu Phe Lys Cys Lys Val Asn Asn
195 200 205
Lys Asp Leu Pro Ala Pro Ile Glu Arg Thr Ile Ser Lys Pro Lys Gly
210 215 220
Ser Val Arg Ala Pro Gln Val Tyr Val Leu Pro Pro Pro Glu Glu Glu
225 230 235 240
Met Thr Lys Lys Gln Val Thr Leu Thr Cys Met Val Thr Asp Phe Met
245 250 255
Pro Glu Asp Ile Tyr Val Glu Trp Thr Asn Asn Gly Lys Thr Glu Leu
260 265 270
Asn Tyr Lys Asn Thr Glu Pro Val Leu Asp Ser Asp Gly Ser Tyr Phe
275 280 285
Met Tyr Ser Lys Leu Arg Val Glu Lys Lys Asn Trp Val Glu Arg Asn
290 295 300
Ser Tyr Ser Cys Ser Val Val His Glu Gly Leu His Asn His His Thr
305 310 315 320
Thr Lys Ser Phe Ser Arg Thr Pro Gly Lys
325 330
<210> 49
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 鼠 IgG2a重链恒定区的铰链区
<400> 49
Glu Pro Arg Gly Pro Thr Ile Lys Pro Cys Pro Pro Cys Lys Cys Pro
1 5 10 15
<210> 50
<211> 97
<212> PRT
<213> 人工序列
<220>
<223> 鼠 IgG2a重链恒定区的CH1
<400> 50
Ala Lys Thr Thr Ala Pro Ser Val Tyr Pro Leu Ala Pro Val Cys Gly
1 5 10 15
Asp Thr Thr Gly Ser Ser Val Thr Leu Gly Cys Leu Val Lys Gly Tyr
20 25 30
Phe Pro Glu Pro Val Thr Leu Thr Trp Asn Ser Gly Ser Leu Ser Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Asp Leu Tyr Thr Leu
50 55 60
Ser Ser Ser Val Thr Val Thr Ser Ser Thr Trp Pro Ser Gln Ser Ile
65 70 75 80
Thr Cys Asn Val Ala His Pro Ala Ser Ser Thr Lys Val Asp Lys Lys
85 90 95
Ile
<210> 51
<211> 217
<212> PRT
<213> 人工序列
<220>
<223> 鼠 IgG2a重链恒定区的CH2+CH3
<400> 51
Ala Pro Asn Leu Leu Gly Gly Pro Ser Val Phe Ile Phe Pro Pro Lys
1 5 10 15
Ile Lys Asp Val Leu Met Ile Ser Leu Ser Pro Ile Val Thr Cys Val
20 25 30
Val Val Asp Val Ser Glu Asp Asp Pro Asp Val Gln Ile Ser Trp Phe
35 40 45
Val Asn Asn Val Glu Val His Thr Ala Gln Thr Gln Thr His Arg Glu
50 55 60
Asp Tyr Asn Ser Thr Leu Arg Val Val Ser Ala Leu Pro Ile Gln His
65 70 75 80
Gln Asp Trp Met Ser Gly Lys Glu Phe Lys Cys Lys Val Asn Asn Lys
85 90 95
Asp Leu Pro Ala Pro Ile Glu Arg Thr Ile Ser Lys Pro Lys Gly Ser
100 105 110
Val Arg Ala Pro Gln Val Tyr Val Leu Pro Pro Pro Glu Glu Glu Met
115 120 125
Thr Lys Lys Gln Val Thr Leu Thr Cys Met Val Thr Asp Phe Met Pro
130 135 140
Glu Asp Ile Tyr Val Glu Trp Thr Asn Asn Gly Lys Thr Glu Leu Asn
145 150 155 160
Tyr Lys Asn Thr Glu Pro Val Leu Asp Ser Asp Gly Ser Tyr Phe Met
165 170 175
Tyr Ser Lys Leu Arg Val Glu Lys Lys Asn Trp Val Glu Arg Asn Ser
180 185 190
Tyr Ser Cys Ser Val Val His Glu Gly Leu His Asn His His Thr Thr
195 200 205
Lys Ser Phe Ser Arg Thr Pro Gly Lys
210 215
<210> 52
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> CL (鼠 kappa 轻链的恒定区)
<400> 52
Arg Ala Asp Ala Ala Pro Thr Val Ser Ile Phe Pro Pro Ser Ser Glu
1 5 10 15
Gln Leu Thr Ser Gly Gly Ala Ser Val Val Cys Phe Leu Asn Asn Phe
20 25 30
Tyr Pro Lys Asp Ile Asn Val Lys Trp Lys Ile Asp Gly Ser Glu Arg
35 40 45
Gln Asn Gly Val Leu Asn Ser Trp Thr Asp Gln Asp Ser Lys Asp Ser
50 55 60
Thr Tyr Ser Met Ser Ser Thr Leu Thr Leu Thr Lys Asp Glu Tyr Glu
65 70 75 80
Arg His Asn Ser Tyr Thr Cys Glu Ala Thr His Lys Thr Ser Thr Ser
85 90 95
Pro Ile Val Lys Ser Phe Asn Arg Asn Glu Cys
100 105
Claims (15)
1.一种CLDN18.2抗体或抗原结合片段,所述抗体或抗原结合片段包含重链可变区和轻链可变区,其中所述重链可变区包含含有SEQ ID NO.11所示的氨基酸序列的HCDR1、含有SEQ ID NO.12所示的氨基酸序列的HCDR2和含有SEQ ID NO.13所示的氨基酸序列的HCDR3,和/或所述轻链可变区包含含有SEQ ID NO.14所示的氨基酸序列的LCDR1、含有SEQ IDNO.15所示的氨基酸序列的LCDR2和含有SEQ ID NO.16所示的氨基酸序列的LCDR3。
2.根据权利要求1所述的CLDN18.2抗体或抗原结合片段,其中所述抗原结合片段选自scFv片段、Fv片段、F(ab')2片段、Fab'-SH片段和Fab'片段。
3.根据权利要求1至2中任一项所述的CLDN18.2抗体或抗原结合片段,其中所述抗体是单克隆抗体和/或所述抗体是人源化抗体;
优选地,所述重链可变区包含与SEQ ID NO.9所示的氨基酸序列具有至少约95%、96%、97%、98%、99%或100%同一性的氨基酸序列,和/或所述轻链可变区包含与SEQ IDNO.10所示的氨基酸序列具有至少约95%、96%、97%、98%、99%或100%同一性的氨基酸序列;或者
所述抗体或其抗原结合片段是人源化抗体或其抗原结合片段,所述重链可变区包含与SEQ ID NO.17-21中任一个所示的氨基酸序列具有至少约95%、96%、97%、98%、99%或100%同一性的氨基酸序列,和/或所述轻链可变区包含与SEQ ID NO.22-24中任一个所示的氨基酸序列具有至少约95%、96%、97%、98%、99%或100%同一性的氨基酸序列。
4.根据权利要求1至3中任一项所述的CLDN18.2抗体或抗原结合片段,其中所述抗体或抗原结合片段包含轻链恒定结构域,优选地包含重链恒定结构域;并且
更优选地,所述抗体或抗原结合片段包含重链恒定结构域,并且所述重链恒定结构域含有一个或多个降低或消除ADCC效应和/或CDC效应的突变。
5.一种双特异性抗体,所述双特异性抗体包含与CLDN18.2或其变体结合的第一抗体或抗原结合片段以及与CD3或其变体结合的第二抗原结合结构域,其中所述第一抗体或抗原结合片段为根据权利要求1至4中任一项所述的CLDN18.2抗体或抗原结合片段。
6.根据权利要求5所述的双特异性抗体,其中所述第一抗体或抗原结合片段包含两条相同的重链和两条相同的轻链,并且其中所述第二抗原结合结构域包含两个相同的单链抗体片段(scFv)。
7.根据权利要求6所述的双特异性抗体,其中所述第一抗体或其抗原结合片段的每条所述轻链与所述第二抗原结合结构域的每个所述单链抗体片段(scFv)融合;优选地,所述第一抗体或抗原结合片段的每条所述轻链的恒定区的C-末端直接或通过接头与所述第二抗原结合结构域的每个所述单链抗体片段(scFv)的所述重链可变区的N-末端融合。
8.根据权利要求6至7中任一项所述的双特异性抗体,其中CD3的所述单链抗体片段(scFv)包含重链可变区和轻链可变区,其中
所述重链可变区包含含有SEQ ID NO.31所示的氨基酸序列的HCDR1、含有SEQ IDNO.32所示的氨基酸序列的HCDR2和含有SEQ ID NO.33所示的氨基酸序列的HCDR3,和/或所述轻链可变区包含含有SEQ ID NO.34所示的氨基酸序列的LCDR1、含有SEQ ID NO.35所示的氨基酸序列的LCDR2和含有SEQ ID NO.36所示的氨基酸序列的LCDR3;
所述重链可变区包含含有SEQ ID NO.37所示的氨基酸序列的HCDR1、含有SEQ IDNO.38所示的氨基酸序列的HCDR2和含有SEQ ID NO.39所示的氨基酸序列的HCDR3,和/或所述轻链可变区包含含有SEQ ID NO.34所示的氨基酸序列的LCDR1、含有SEQ ID NO.35所示的氨基酸序列的LCDR2和含有SEQ ID NO.36所示的氨基酸序列的LCDR3;或者
所述重链可变区包含含有SEQ ID NO.37所示的氨基酸序列的HCDR1、含有SEQ IDNO.40所示的氨基酸序列的HCDR2和含有SEQ ID NO.39所示的氨基酸序列的HCDR3,和/或所述轻链可变区包含含有SEQ ID NO.34所示的氨基酸序列的LCDR1、含有SEQ ID NO.35所示的氨基酸序列的LCDR2和含有SEQ ID NO.36所示的氨基酸序列的LCDR3。
9.根据权利要求8所述的双特异性抗体,其中
所述重链可变区包含与SEQ ID NO.25所示的氨基酸序列具有至少约95%、96%、97%、98%、99%或100%同一性的氨基酸序列,并且轻链可变区包含与SEQ ID NO.26所示的氨基酸序列具有至少约95%、96%、97%、98%、99%或100%同一性的氨基酸序列;
所述重链可变区包含与SEQ ID NO.27所示的氨基酸序列具有至少约95%、96%、97%、98%、99%或100%同一性的氨基酸序列,并且轻链可变区包含与SEQ ID NO.26所示的氨基酸序列具有至少约95%、96%、97%、98%、99%或100%同一性的氨基酸序列;或者
所述重链可变区包含与SEQ ID NO.28所示的氨基酸序列具有至少约95%、96%、97%、98%、99%或100%同一性的氨基酸序列,并且轻链可变区包含与SEQ ID NO.26所示的氨基酸序列具有至少约95%、96%、97%、98%、99%或100%同一性的氨基酸序列。
10.一种分离的核酸,所述分离的核酸包含编码根据权利要求1至4中任一项所述的CLDN18.2抗体或抗原结合片段或根据权利要求5至9中任一项所述的双特异性抗体的核酸序列。
11.一种载体,所述载体包含根据权利要求10所述的核酸。
12.一种分离的宿主细胞,所述分离的宿主细胞包含根据权利要求1至4中任一项所述的CLDN18.2抗体或其抗原结合片段或根据权利要求5至9中任一项所述的双特异性抗体或根据权利要求10所述的核酸或根据权利要求11所述的载体。
13.一种药物组合物,所述药物组合物包含根据权利要求1至4中任一项所述的CLDN18.2抗体或抗原结合片段或根据权利要求5至9中任一项所述的双特异性抗体或根据权利要求10所述的核酸或根据权利要求11所述的载体或根据权利要求12所述的宿主细胞;
优选地,所述药物组合物还包含一种或多种药学上可接受的赋形剂。
14.一种治疗有需要的受试者的癌症的方法,所述方法包括向所述受试者施用根据权利要求13所述的药物组合物。
15.根据权利要求14所述的方法,其中所述癌症是CLDN18.2阳性癌症;优选地,所述癌症是血液癌或实体癌;更优选地,所述CLDN18.2阳性癌症为胃癌或胰腺癌。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US202163147233P | 2021-02-08 | 2021-02-08 | |
US63/147,233 | 2021-02-08 | ||
PCT/CN2022/075326 WO2022166940A1 (en) | 2021-02-08 | 2022-02-07 | Cldn18.2/cd3 bispecific antibodies for the therapy of cldn18.2-expressing solid tumors |
Publications (1)
Publication Number | Publication Date |
---|---|
CN116940598A true CN116940598A (zh) | 2023-10-24 |
Family
ID=82740924
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202280011082.2A Pending CN116940598A (zh) | 2021-02-08 | 2022-02-07 | 用于治疗表达cldn18.2的实体瘤的cldn18.2/cd3双特异性抗体 |
Country Status (3)
Country | Link |
---|---|
US (1) | US20240117035A1 (zh) |
CN (1) | CN116940598A (zh) |
WO (1) | WO2022166940A1 (zh) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2024067759A1 (zh) * | 2022-09-29 | 2024-04-04 | 北京诺诚健华医药科技有限公司 | 一种能够结合cldn18.2的抗体或其抗原结合片段及其应用 |
Family Cites Families (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2013167153A1 (en) * | 2012-05-09 | 2013-11-14 | Ganymed Pharmaceuticals Ag | Antibodies useful in cancer diagnosis |
BR112021002032A2 (pt) * | 2018-08-03 | 2021-07-20 | Amgen Research (Munich) Gmbh | construtos de anticorpos para cldn18.2 e cd3 |
JP2022516505A (ja) * | 2018-12-28 | 2022-02-28 | スパークス・セラピューティクス・インコーポレイテッド | 癌および他の疾患の治療のための、クローディン18.2に特異的な結合分子、その組成物および方法 |
AU2019415848A1 (en) * | 2018-12-28 | 2021-08-19 | Nanjing GenScript Biotech Co., Ltd. | Claudin18.2 binding moieties and uses thereof |
CN109762067B (zh) * | 2019-01-17 | 2020-02-28 | 北京天广实生物技术股份有限公司 | 结合人Claudin 18.2的抗体及其用途 |
-
2022
- 2022-02-07 CN CN202280011082.2A patent/CN116940598A/zh active Pending
- 2022-02-07 WO PCT/CN2022/075326 patent/WO2022166940A1/en active Application Filing
- 2022-02-07 US US18/276,159 patent/US20240117035A1/en active Pending
Also Published As
Publication number | Publication date |
---|---|
US20240117035A1 (en) | 2024-04-11 |
WO2022166940A1 (en) | 2022-08-11 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN110305210B (zh) | 新型抗体分子、其制备方法及其用途 | |
WO2019184909A1 (zh) | 新型抗体分子、其制备方法及其用途 | |
US11319371B2 (en) | Anti-CD3 antibodies | |
KR20200055052A (ko) | 신규 항-cd3엡실론 항체 | |
CN114728065A (zh) | 针对cd3和bcma的抗体和自其制备的双特异性结合蛋白 | |
WO2021218684A1 (zh) | 四价双特异性抗体、其制备方法和用途 | |
WO2021227782A1 (zh) | 一种抗pd-1和pd-l1的四价双特异性抗体 | |
KR20220111308A (ko) | 인간화 cldn18.2 항체 | |
CN114206931A (zh) | 抗pd-1抗体及其用途 | |
CA3201064A1 (en) | Anti-human b7-h3 antibody and application thereof | |
CN114901365A (zh) | 肿瘤特异性密蛋白18.2抗体 | |
WO2019080909A1 (en) | TARGETING THERAPEUTIC ANTIBODY RANKL | |
WO2022135536A1 (zh) | Cd3人源化抗体及其应用 | |
CA3207791A1 (en) | Anti-cd112r antibody and use thereof | |
WO2021143914A1 (zh) | 一种激活型抗ox40抗体、生产方法及应用 | |
CN116940598A (zh) | 用于治疗表达cldn18.2的实体瘤的cldn18.2/cd3双特异性抗体 | |
US20210115146A1 (en) | Novel anti-egfr antibody polypeptide | |
KR20200063147A (ko) | Pdl1 표적화 항체 및 이의 사용 방법 | |
CN114667296B (zh) | 一种双特异性抗体及其用途 | |
US10584175B2 (en) | FN14-binding proteins and uses thereof | |
JP7392145B2 (ja) | 免疫療法のためのt細胞二重特異性抗体の作製における最適化された抗cd3アーム | |
WO2023193732A1 (zh) | 一种抗ccr8抗体或其抗原结合片段 | |
WO2023198019A1 (zh) | 一种抗ceacam5和ceacam6抗体及其应用 | |
US20220135686A1 (en) | Antibody that binds to human pd-l1 | |
CA3230246A1 (en) | Bispecific antibody and use thereof |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination |