CN113735974B - 针对Claudin18.2的抗体及其用途 - Google Patents
针对Claudin18.2的抗体及其用途 Download PDFInfo
- Publication number
- CN113735974B CN113735974B CN202110587892.XA CN202110587892A CN113735974B CN 113735974 B CN113735974 B CN 113735974B CN 202110587892 A CN202110587892 A CN 202110587892A CN 113735974 B CN113735974 B CN 113735974B
- Authority
- CN
- China
- Prior art keywords
- seq
- amino acid
- ser
- acid sequence
- antigen binding
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 210000004027 cell Anatomy 0.000 claims abstract description 161
- 102000025171 antigen binding proteins Human genes 0.000 claims abstract description 126
- 108091000831 antigen binding proteins Proteins 0.000 claims abstract description 126
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 79
- 230000027455 binding Effects 0.000 claims abstract description 49
- 210000004881 tumor cell Anatomy 0.000 claims abstract description 23
- 230000002401 inhibitory effect Effects 0.000 claims abstract description 15
- 230000012010 growth Effects 0.000 claims abstract description 7
- 239000013598 vector Substances 0.000 claims description 49
- 238000000034 method Methods 0.000 claims description 40
- 108020004707 nucleic acids Proteins 0.000 claims description 40
- 102000039446 nucleic acids Human genes 0.000 claims description 40
- 150000007523 nucleic acids Chemical class 0.000 claims description 40
- 239000000427 antigen Substances 0.000 claims description 38
- 108091007433 antigens Proteins 0.000 claims description 38
- 102000036639 antigens Human genes 0.000 claims description 38
- 239000012634 fragment Substances 0.000 claims description 29
- 239000008194 pharmaceutical composition Substances 0.000 claims description 23
- 239000003814 drug Substances 0.000 claims description 17
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims description 10
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims description 10
- 238000004519 manufacturing process Methods 0.000 claims description 10
- 201000002528 pancreatic cancer Diseases 0.000 claims description 10
- 208000008443 pancreatic carcinoma Diseases 0.000 claims description 10
- 208000005718 Stomach Neoplasms Diseases 0.000 claims description 9
- 206010017758 gastric cancer Diseases 0.000 claims description 9
- 201000011549 stomach cancer Diseases 0.000 claims description 9
- 210000004899 c-terminal region Anatomy 0.000 claims description 8
- 108010067060 Immunoglobulin Variable Region Proteins 0.000 claims description 5
- 102000017727 Immunoglobulin Variable Region Human genes 0.000 claims description 5
- 239000002671 adjuvant Substances 0.000 claims description 5
- 238000012258 culturing Methods 0.000 claims description 3
- 230000002147 killing effect Effects 0.000 claims description 3
- 101001055311 Equus asinus Immunoglobulin heavy constant alpha Proteins 0.000 claims description 2
- 230000008569 process Effects 0.000 claims description 2
- 125000003275 alpha amino acid group Chemical group 0.000 claims 18
- 230000000694 effects Effects 0.000 abstract description 41
- 230000010056 antibody-dependent cellular cytotoxicity Effects 0.000 abstract description 13
- 230000001939 inductive effect Effects 0.000 abstract description 5
- 230000001747 exhibiting effect Effects 0.000 abstract description 4
- 150000001413 amino acids Chemical group 0.000 description 205
- 108090000623 proteins and genes Proteins 0.000 description 50
- 235000018102 proteins Nutrition 0.000 description 35
- 102000004169 proteins and genes Human genes 0.000 description 35
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 29
- 108010047041 Complementarity Determining Regions Proteins 0.000 description 23
- 229940127121 immunoconjugate Drugs 0.000 description 20
- 201000011510 cancer Diseases 0.000 description 16
- 201000010099 disease Diseases 0.000 description 16
- 108090000765 processed proteins & peptides Proteins 0.000 description 16
- 229950007157 zolbetuximab Drugs 0.000 description 15
- 102000004196 processed proteins & peptides Human genes 0.000 description 14
- 208000035475 disorder Diseases 0.000 description 13
- 239000000203 mixture Substances 0.000 description 13
- 229920001184 polypeptide Polymers 0.000 description 13
- 102000002029 Claudin Human genes 0.000 description 12
- 108050009302 Claudin Proteins 0.000 description 12
- 239000000523 sample Substances 0.000 description 12
- 210000001519 tissue Anatomy 0.000 description 12
- 206010009944 Colon cancer Diseases 0.000 description 11
- 235000001014 amino acid Nutrition 0.000 description 11
- 201000007270 liver cancer Diseases 0.000 description 11
- 208000014018 liver neoplasm Diseases 0.000 description 11
- 108020004414 DNA Proteins 0.000 description 10
- 108060003951 Immunoglobulin Proteins 0.000 description 10
- 241000880493 Leptailurus serval Species 0.000 description 10
- 238000001943 fluorescence-activated cell sorting Methods 0.000 description 10
- 102000018358 immunoglobulin Human genes 0.000 description 10
- 238000012216 screening Methods 0.000 description 10
- 238000011282 treatment Methods 0.000 description 9
- 208000000461 Esophageal Neoplasms Diseases 0.000 description 8
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 8
- 206010030155 Oesophageal carcinoma Diseases 0.000 description 8
- 206010033128 Ovarian cancer Diseases 0.000 description 8
- 206010061535 Ovarian neoplasm Diseases 0.000 description 8
- 108010087924 alanylproline Proteins 0.000 description 8
- 208000029742 colonic neoplasm Diseases 0.000 description 8
- 238000001514 detection method Methods 0.000 description 8
- 239000012636 effector Substances 0.000 description 8
- 201000004101 esophageal cancer Diseases 0.000 description 8
- 108010015792 glycyllysine Proteins 0.000 description 8
- 238000011534 incubation Methods 0.000 description 8
- 208000024891 symptom Diseases 0.000 description 8
- 230000004614 tumor growth Effects 0.000 description 8
- 108010003137 tyrosyltyrosine Proteins 0.000 description 8
- QLSRIZIDQXDQHK-RCWTZXSCSA-N Arg-Val-Thr Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O QLSRIZIDQXDQHK-RCWTZXSCSA-N 0.000 description 7
- 206010005003 Bladder cancer Diseases 0.000 description 7
- 208000008839 Kidney Neoplasms Diseases 0.000 description 7
- 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 7
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 7
- 206010038389 Renal cancer Diseases 0.000 description 7
- 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 7
- 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 7
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 description 7
- 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 7
- 150000001875 compounds Chemical class 0.000 description 7
- 230000006870 function Effects 0.000 description 7
- 201000010982 kidney cancer Diseases 0.000 description 7
- 239000003446 ligand Substances 0.000 description 7
- 201000005202 lung cancer Diseases 0.000 description 7
- 208000020816 lung neoplasm Diseases 0.000 description 7
- 201000005112 urinary bladder cancer Diseases 0.000 description 7
- 108010073969 valyllysine Proteins 0.000 description 7
- 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
- LCNASHSOFMRYFO-WDCWCFNPSA-N Leu-Thr-Gln Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@H](C(O)=O)CCC(N)=O LCNASHSOFMRYFO-WDCWCFNPSA-N 0.000 description 6
- 239000012472 biological sample Substances 0.000 description 6
- XKUKSGPZAADMRA-UHFFFAOYSA-N glycyl-glycyl-glycine Natural products NCC(=O)NCC(=O)NCC(O)=O XKUKSGPZAADMRA-UHFFFAOYSA-N 0.000 description 6
- 108010070409 phenylalanyl-glycyl-glycine Proteins 0.000 description 6
- 229940124597 therapeutic agent Drugs 0.000 description 6
- 230000001225 therapeutic effect Effects 0.000 description 6
- 238000001890 transfection Methods 0.000 description 6
- 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 5
- 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 5
- 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 5
- 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 5
- 241000124008 Mammalia Species 0.000 description 5
- 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 5
- 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 5
- 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 5
- 210000004369 blood Anatomy 0.000 description 5
- 239000008280 blood Substances 0.000 description 5
- 239000003795 chemical substances by application Substances 0.000 description 5
- 238000003745 diagnosis Methods 0.000 description 5
- 238000000684 flow cytometry Methods 0.000 description 5
- 108010089804 glycyl-threonine Proteins 0.000 description 5
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 5
- 108010051242 phenylalanylserine Proteins 0.000 description 5
- 239000013612 plasmid Substances 0.000 description 5
- 210000002966 serum Anatomy 0.000 description 5
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 4
- ARHJJAAWNWOACN-FXQIFTODSA-N Ala-Ser-Val Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(O)=O ARHJJAAWNWOACN-FXQIFTODSA-N 0.000 description 4
- GCACQYDBDHRVGE-LKXGYXEUSA-N Asp-Thr-Ser Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H]([C@H](O)C)NC(=O)[C@@H](N)CC(O)=O GCACQYDBDHRVGE-LKXGYXEUSA-N 0.000 description 4
- 201000009030 Carcinoma Diseases 0.000 description 4
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 4
- 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 4
- 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 4
- FFJQHWKSGAWSTJ-BFHQHQDPSA-N Gly-Thr-Ala Chemical compound [H]NCC(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C)C(O)=O FFJQHWKSGAWSTJ-BFHQHQDPSA-N 0.000 description 4
- DNVDEMWIYLVIQU-RCOVLWMOSA-N Gly-Val-Asp Chemical compound NCC(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(O)=O)C(O)=O DNVDEMWIYLVIQU-RCOVLWMOSA-N 0.000 description 4
- YGHSQRJSHKYUJY-SCZZXKLOSA-N Gly-Val-Pro Chemical compound CC(C)[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)CN YGHSQRJSHKYUJY-SCZZXKLOSA-N 0.000 description 4
- PXKACEXYLPBMAD-JBDRJPRFSA-N Ile-Ser-Ser Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)O)N PXKACEXYLPBMAD-JBDRJPRFSA-N 0.000 description 4
- PMGDADKJMCOXHX-UHFFFAOYSA-N L-Arginyl-L-glutamin-acetat Natural products NC(=N)NCCCC(N)C(=O)NC(CCC(N)=O)C(O)=O PMGDADKJMCOXHX-UHFFFAOYSA-N 0.000 description 4
- 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 4
- 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 4
- 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 4
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 4
- 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 4
- 206010039491 Sarcoma Diseases 0.000 description 4
- 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 4
- YOOAQCZYZHGUAZ-KATARQTJSA-N Thr-Leu-Ser Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(O)=O YOOAQCZYZHGUAZ-KATARQTJSA-N 0.000 description 4
- PKZIWSHDJYIPRH-JBACZVJFSA-N Trp-Tyr-Gln Chemical compound [H]N[C@@H](CC1=CNC2=C1C=CC=C2)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CCC(N)=O)C(O)=O PKZIWSHDJYIPRH-JBACZVJFSA-N 0.000 description 4
- SSYBNWFXCFNRFN-GUBZILKMSA-N Val-Pro-Ser Chemical compound CC(C)[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CO)C(O)=O SSYBNWFXCFNRFN-GUBZILKMSA-N 0.000 description 4
- 108010008355 arginyl-glutamine Proteins 0.000 description 4
- 108010068265 aspartyltyrosine Proteins 0.000 description 4
- 238000003556 assay Methods 0.000 description 4
- 230000010261 cell growth Effects 0.000 description 4
- 239000002299 complementary DNA Substances 0.000 description 4
- 239000000306 component Substances 0.000 description 4
- 238000010494 dissociation reaction Methods 0.000 description 4
- 230000005593 dissociations Effects 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 239000013604 expression vector Substances 0.000 description 4
- 108020001507 fusion proteins Proteins 0.000 description 4
- 102000037865 fusion proteins Human genes 0.000 description 4
- 108010078144 glutaminyl-glycine Proteins 0.000 description 4
- 108010010147 glycylglutamine Proteins 0.000 description 4
- 108010037850 glycylvaline Proteins 0.000 description 4
- 238000000338 in vitro Methods 0.000 description 4
- 238000001727 in vivo Methods 0.000 description 4
- 238000001802 infusion Methods 0.000 description 4
- 239000002245 particle Substances 0.000 description 4
- 210000003819 peripheral blood mononuclear cell Anatomy 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 108010031719 prolyl-serine Proteins 0.000 description 4
- 108010070643 prolylglutamic acid Proteins 0.000 description 4
- 235000020183 skimmed milk Nutrition 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 241000894007 species Species 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 239000006228 supernatant Substances 0.000 description 4
- 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 3
- KQESEZXHYOUIIM-CQDKDKBSSA-N Ala-Lys-Tyr Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O KQESEZXHYOUIIM-CQDKDKBSSA-N 0.000 description 3
- MSWSRLGNLKHDEI-ACZMJKKPSA-N Ala-Ser-Glu Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(O)=O)C(O)=O MSWSRLGNLKHDEI-ACZMJKKPSA-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
- 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 3
- QXHVOUSPVAWEMX-ZLUOBGJFSA-N Asp-Asp-Ser Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(O)=O QXHVOUSPVAWEMX-ZLUOBGJFSA-N 0.000 description 3
- BFOYULZBKYOKAN-OLHMAJIHSA-N Asp-Asp-Thr Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O BFOYULZBKYOKAN-OLHMAJIHSA-N 0.000 description 3
- 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 3
- MNQMTYSEKZHIDF-GCJQMDKQSA-N Asp-Thr-Ala Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C)C(O)=O MNQMTYSEKZHIDF-GCJQMDKQSA-N 0.000 description 3
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
- 241000283690 Bos taurus Species 0.000 description 3
- 108010001857 Cell Surface Receptors Proteins 0.000 description 3
- 102000000844 Cell Surface Receptors Human genes 0.000 description 3
- 102000002038 Claudin-18 Human genes 0.000 description 3
- 108050009324 Claudin-18 Proteins 0.000 description 3
- 102000004190 Enzymes Human genes 0.000 description 3
- 108090000790 Enzymes Proteins 0.000 description 3
- 102000009109 Fc receptors Human genes 0.000 description 3
- 108010087819 Fc receptors Proteins 0.000 description 3
- WUAYFMZULZDSLB-ACZMJKKPSA-N Gln-Ala-Asn Chemical compound NC(=O)C[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CCC(N)=O WUAYFMZULZDSLB-ACZMJKKPSA-N 0.000 description 3
- 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 3
- JSYULGSPLTZDHM-NRPADANISA-N Gln-Ala-Val Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](C(C)C)C(O)=O JSYULGSPLTZDHM-NRPADANISA-N 0.000 description 3
- ZBKUIQNCRIYVGH-SDDRHHMPSA-N Gln-Leu-Pro Chemical compound CC(C)C[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](CCC(=O)N)N ZBKUIQNCRIYVGH-SDDRHHMPSA-N 0.000 description 3
- 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 3
- WZZSKAJIHTUUSG-ACZMJKKPSA-N Glu-Ala-Asp Chemical compound OC(=O)C[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CCC(O)=O WZZSKAJIHTUUSG-ACZMJKKPSA-N 0.000 description 3
- TWTPDFFBLQEBOE-IUCAKERBSA-N Gly-Leu-Gln Chemical compound [H]NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(O)=O TWTPDFFBLQEBOE-IUCAKERBSA-N 0.000 description 3
- MIIVFRCYJABHTQ-ONGXEEELSA-N Gly-Leu-Val Chemical compound [H]NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(O)=O MIIVFRCYJABHTQ-ONGXEEELSA-N 0.000 description 3
- TVTZEOHWHUVYCG-KYNKHSRBSA-N Gly-Thr-Thr Chemical compound [H]NCC(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O TVTZEOHWHUVYCG-KYNKHSRBSA-N 0.000 description 3
- GBYYQVBXFVDJPJ-WLTAIBSBSA-N Gly-Tyr-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CC1=CC=C(C=C1)O)NC(=O)CN)O GBYYQVBXFVDJPJ-WLTAIBSBSA-N 0.000 description 3
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 3
- 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 3
- 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 3
- HXIDVIFHRYRXLZ-NAKRPEOUSA-N Ile-Ser-Val Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(=O)O)N HXIDVIFHRYRXLZ-NAKRPEOUSA-N 0.000 description 3
- YJRSIJZUIUANHO-NAKRPEOUSA-N Ile-Val-Ala Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C)C(=O)O)N YJRSIJZUIUANHO-NAKRPEOUSA-N 0.000 description 3
- 102000003855 L-lactate dehydrogenase Human genes 0.000 description 3
- 108700023483 L-lactate dehydrogenases Proteins 0.000 description 3
- ZTLGVASZOIKNIX-DCAQKATOSA-N Leu-Gln-Glu Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H](CCC(=O)O)C(=O)O)N ZTLGVASZOIKNIX-DCAQKATOSA-N 0.000 description 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
- VCHVSKNMTXWIIP-SRVKXCTJSA-N Leu-Lys-Ser Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CO)C(O)=O VCHVSKNMTXWIIP-SRVKXCTJSA-N 0.000 description 3
- 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 3
- 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 3
- 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 3
- UWKNTTJNVSYXPC-CIUDSAMLSA-N Lys-Ala-Ser Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CCCCN UWKNTTJNVSYXPC-CIUDSAMLSA-N 0.000 description 3
- OIQSIMFSVLLWBX-VOAKCMCISA-N Lys-Leu-Thr Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O OIQSIMFSVLLWBX-VOAKCMCISA-N 0.000 description 3
- YTJFXEDRUOQGSP-DCAQKATOSA-N Lys-Pro-Ser Chemical compound [H]N[C@@H](CCCCN)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CO)C(O)=O YTJFXEDRUOQGSP-DCAQKATOSA-N 0.000 description 3
- 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 3
- UGCIQUYEJIEHKX-GVXVVHGQSA-N Lys-Val-Glu Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(O)=O)C(O)=O UGCIQUYEJIEHKX-GVXVVHGQSA-N 0.000 description 3
- 241000699666 Mus <mouse, genus> Species 0.000 description 3
- 241000699670 Mus sp. Species 0.000 description 3
- 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 3
- 108010079364 N-glycylalanine Proteins 0.000 description 3
- 239000002202 Polyethylene glycol Substances 0.000 description 3
- WOIFYRZPIORBRY-AVGNSLFASA-N Pro-Lys-Val Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C(C)C)C(O)=O WOIFYRZPIORBRY-AVGNSLFASA-N 0.000 description 3
- PRKWBYCXBBSLSK-GUBZILKMSA-N Pro-Ser-Val Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(O)=O PRKWBYCXBBSLSK-GUBZILKMSA-N 0.000 description 3
- 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 3
- 108010029485 Protein Isoforms Proteins 0.000 description 3
- 102000001708 Protein Isoforms Human genes 0.000 description 3
- YQHZVYJAGWMHES-ZLUOBGJFSA-N Ser-Ala-Ser Chemical compound OC[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](CO)C(O)=O YQHZVYJAGWMHES-ZLUOBGJFSA-N 0.000 description 3
- IDCKUIWEIZYVSO-WFBYXXMGSA-N Ser-Ala-Trp Chemical compound C1=CC=C2C(C[C@H](NC(=O)[C@@H](NC(=O)[C@@H](N)CO)C)C(O)=O)=CNC2=C1 IDCKUIWEIZYVSO-WFBYXXMGSA-N 0.000 description 3
- HJEBZBMOTCQYDN-ACZMJKKPSA-N Ser-Glu-Asp Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(O)=O HJEBZBMOTCQYDN-ACZMJKKPSA-N 0.000 description 3
- 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 3
- 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 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
- GJFYFGOEWLDQGW-GUBZILKMSA-N Ser-Leu-Gln Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)O)NC(=O)[C@H](CO)N GJFYFGOEWLDQGW-GUBZILKMSA-N 0.000 description 3
- 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 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
- 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 3
- WLJPJRGQRNCIQS-ZLUOBGJFSA-N Ser-Ser-Asn Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(O)=O WLJPJRGQRNCIQS-ZLUOBGJFSA-N 0.000 description 3
- 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 3
- JZRYFUGREMECBH-XPUUQOCRSA-N Ser-Val-Gly Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(=O)NCC(O)=O JZRYFUGREMECBH-XPUUQOCRSA-N 0.000 description 3
- 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 3
- JGUWRQWULDWNCM-FXQIFTODSA-N Ser-Val-Ser Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CO)C(O)=O JGUWRQWULDWNCM-FXQIFTODSA-N 0.000 description 3
- 108010087230 Sincalide Proteins 0.000 description 3
- 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 3
- 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 3
- 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 3
- 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 3
- OGOYMQWIWHGTGH-KZVJFYERSA-N Thr-Val-Ala Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C)C(O)=O OGOYMQWIWHGTGH-KZVJFYERSA-N 0.000 description 3
- 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 3
- VTFWAGGJDRSQFG-MELADBBJSA-N Tyr-Asn-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CC(=O)N)NC(=O)[C@H](CC2=CC=C(C=C2)O)N)C(=O)O VTFWAGGJDRSQFG-MELADBBJSA-N 0.000 description 3
- YMUQBRQQCPQEQN-CXTHYWKRSA-N Tyr-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](CC2=CC=C(C=C2)O)N YMUQBRQQCPQEQN-CXTHYWKRSA-N 0.000 description 3
- ZPFLBLFITJCBTP-QWRGUYRKSA-N Tyr-Ser-Gly Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CO)C(=O)NCC(O)=O ZPFLBLFITJCBTP-QWRGUYRKSA-N 0.000 description 3
- ANHVRCNNGJMJNG-BZSNNMDCSA-N Tyr-Tyr-Cys Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)N[C@@H](CC2=CC=C(C=C2)O)C(=O)N[C@@H](CS)C(=O)O)N)O ANHVRCNNGJMJNG-BZSNNMDCSA-N 0.000 description 3
- JQTYTBPCSOAZHI-FXQIFTODSA-N Val-Ser-Cys Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CS)C(=O)O)N JQTYTBPCSOAZHI-FXQIFTODSA-N 0.000 description 3
- DVLWZWNAQUBZBC-ZNSHCXBVSA-N Val-Thr-Pro Chemical compound C[C@H]([C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](C(C)C)N)O DVLWZWNAQUBZBC-ZNSHCXBVSA-N 0.000 description 3
- 108010069020 alanyl-prolyl-glycine Proteins 0.000 description 3
- 108010086434 alanyl-seryl-glycine Proteins 0.000 description 3
- 108010047857 aspartylglycine Proteins 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- 230000004071 biological effect Effects 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 238000010609 cell counting kit-8 assay Methods 0.000 description 3
- 238000004113 cell culture Methods 0.000 description 3
- 210000000170 cell membrane Anatomy 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 230000000295 complement effect Effects 0.000 description 3
- 238000011161 development Methods 0.000 description 3
- 230000018109 developmental process Effects 0.000 description 3
- 108010049041 glutamylalanine Proteins 0.000 description 3
- VPZXBVLAVMBEQI-UHFFFAOYSA-N glycyl-DL-alpha-alanine Natural products OC(=O)C(C)NC(=O)CN VPZXBVLAVMBEQI-UHFFFAOYSA-N 0.000 description 3
- 108010000434 glycyl-alanyl-leucine Proteins 0.000 description 3
- 108010078326 glycyl-glycyl-valine Proteins 0.000 description 3
- 108010050475 glycyl-leucyl-tyrosine Proteins 0.000 description 3
- 108010050848 glycylleucine Proteins 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 238000010253 intravenous injection Methods 0.000 description 3
- 108010073472 leucyl-prolyl-proline Proteins 0.000 description 3
- 108010064235 lysylglycine Proteins 0.000 description 3
- 108010017391 lysylvaline Proteins 0.000 description 3
- 238000002823 phage display Methods 0.000 description 3
- 229920001223 polyethylene glycol Polymers 0.000 description 3
- 230000002265 prevention Effects 0.000 description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 3
- 108010077112 prolyl-proline Proteins 0.000 description 3
- 108010048397 seryl-lysyl-leucine Proteins 0.000 description 3
- IZTQOLKUZKXIRV-YRVFCXMDSA-N sincalide Chemical compound C([C@@H](C(=O)N[C@@H](CCSC)C(=O)NCC(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@@H](N)CC(O)=O)C1=CC=C(OS(O)(=O)=O)C=C1 IZTQOLKUZKXIRV-YRVFCXMDSA-N 0.000 description 3
- 108010072986 threonyl-seryl-lysine Proteins 0.000 description 3
- 238000013519 translation Methods 0.000 description 3
- 108010052774 valyl-lysyl-glycyl-phenylalanyl-tyrosine Proteins 0.000 description 3
- YEJQWBFDKKTPNO-UHFFFAOYSA-N 2-[[2-[[1-(2-amino-3-methylbutanoyl)pyrrolidine-2-carbonyl]amino]acetyl]amino]-3-methylbutanoic acid Chemical compound CC(C)C(N)C(=O)N1CCCC1C(=O)NCC(=O)NC(C(C)C)C(O)=O YEJQWBFDKKTPNO-UHFFFAOYSA-N 0.000 description 2
- 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 2
- 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 2
- MNZHHDPWDWQJCQ-YUMQZZPRSA-N Ala-Leu-Gly Chemical compound C[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)NCC(O)=O MNZHHDPWDWQJCQ-YUMQZZPRSA-N 0.000 description 2
- DPNZTBKGAUAZQU-DLOVCJGASA-N Ala-Leu-His Chemical compound C[C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)N DPNZTBKGAUAZQU-DLOVCJGASA-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
- SUHLZMHFRALVSY-YUMQZZPRSA-N Ala-Lys-Gly Chemical compound NCCCC[C@H](NC(=O)[C@@H](N)C)C(=O)NCC(O)=O SUHLZMHFRALVSY-YUMQZZPRSA-N 0.000 description 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
- XWFWAXPOLRTDFZ-FXQIFTODSA-N Ala-Pro-Ser Chemical compound C[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CO)C(O)=O XWFWAXPOLRTDFZ-FXQIFTODSA-N 0.000 description 2
- 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 2
- 206010061424 Anal cancer Diseases 0.000 description 2
- 208000007860 Anus Neoplasms Diseases 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
- ATABBWFGOHKROJ-GUBZILKMSA-N Arg-Pro-Ser Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CO)C(O)=O ATABBWFGOHKROJ-GUBZILKMSA-N 0.000 description 2
- 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 2
- ZJBUILVYSXQNSW-YTWAJWBKSA-N Arg-Thr-Pro Chemical compound C[C@H]([C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](CCCN=C(N)N)N)O ZJBUILVYSXQNSW-YTWAJWBKSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- RCENDENBBJFJHZ-ACZMJKKPSA-N Asn-Asn-Gln Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(O)=O RCENDENBBJFJHZ-ACZMJKKPSA-N 0.000 description 2
- OOWSBIOUKIUWLO-RCOVLWMOSA-N Asn-Gly-Val Chemical compound [H]N[C@@H](CC(N)=O)C(=O)NCC(=O)N[C@@H](C(C)C)C(O)=O OOWSBIOUKIUWLO-RCOVLWMOSA-N 0.000 description 2
- WQLJRNRLHWJIRW-KKUMJFAQSA-N Asn-His-Tyr Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)O)NC(=O)[C@H](CC2=CN=CN2)NC(=O)[C@H](CC(=O)N)N)O WQLJRNRLHWJIRW-KKUMJFAQSA-N 0.000 description 2
- RCFGLXMZDYNRSC-CIUDSAMLSA-N Asn-Lys-Ala Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(O)=O RCFGLXMZDYNRSC-CIUDSAMLSA-N 0.000 description 2
- GMUOCGCDOYYWPD-FXQIFTODSA-N Asn-Pro-Ser Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CO)C(O)=O GMUOCGCDOYYWPD-FXQIFTODSA-N 0.000 description 2
- 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 2
- HNXWVVHIGTZTBO-LKXGYXEUSA-N Asn-Ser-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC(N)=O HNXWVVHIGTZTBO-LKXGYXEUSA-N 0.000 description 2
- 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 2
- 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 2
- 238000011729 BALB/c nude mouse Methods 0.000 description 2
- 206010004593 Bile duct cancer Diseases 0.000 description 2
- 206010006187 Breast cancer Diseases 0.000 description 2
- 208000026310 Breast neoplasm Diseases 0.000 description 2
- 241000282472 Canis lupus familiaris Species 0.000 description 2
- 241000283707 Capra Species 0.000 description 2
- 206010007275 Carcinoid tumour Diseases 0.000 description 2
- 206010008342 Cervix carcinoma Diseases 0.000 description 2
- AMRLSQGGERHDHJ-FXQIFTODSA-N Cys-Ala-Arg Chemical compound [H]N[C@@H](CS)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O AMRLSQGGERHDHJ-FXQIFTODSA-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
- YMBAVNPKBWHDAW-CIUDSAMLSA-N Cys-Asp-Lys Chemical compound C(CCN)C[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)O)NC(=O)[C@H](CS)N YMBAVNPKBWHDAW-CIUDSAMLSA-N 0.000 description 2
- 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 2
- 206010014733 Endometrial cancer Diseases 0.000 description 2
- 206010014759 Endometrial neoplasm Diseases 0.000 description 2
- 241000283086 Equidae Species 0.000 description 2
- 241000282326 Felis catus Species 0.000 description 2
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 2
- 241000287828 Gallus gallus Species 0.000 description 2
- 206010017993 Gastrointestinal neoplasms Diseases 0.000 description 2
- NVEASDQHBRZPSU-BQBZGAKWSA-N Gln-Gln-Gly Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)NCC(O)=O NVEASDQHBRZPSU-BQBZGAKWSA-N 0.000 description 2
- 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 2
- OSCLNNWLKKIQJM-WDSKDSINSA-N Gln-Ser-Gly Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CO)C(=O)NCC(O)=O OSCLNNWLKKIQJM-WDSKDSINSA-N 0.000 description 2
- 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
- HUFCEIHAFNVSNR-IHRRRGAJSA-N Glu-Gln-Tyr Chemical compound OC(=O)CC[C@H](N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 HUFCEIHAFNVSNR-IHRRRGAJSA-N 0.000 description 2
- 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 2
- BPCLDCNZBUYGOD-BPUTZDHNSA-N Glu-Trp-Glu Chemical compound C1=CC=C2C(C[C@H](NC(=O)[C@H](CCC(O)=O)N)C(=O)N[C@@H](CCC(O)=O)C(O)=O)=CNC2=C1 BPCLDCNZBUYGOD-BPUTZDHNSA-N 0.000 description 2
- WGYHAAXZWPEBDQ-IFFSRLJSSA-N Glu-Val-Thr Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O WGYHAAXZWPEBDQ-IFFSRLJSSA-N 0.000 description 2
- PABFFPWEJMEVEC-JGVFFNPUSA-N Gly-Gln-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CCC(=O)N)NC(=O)CN)C(=O)O PABFFPWEJMEVEC-JGVFFNPUSA-N 0.000 description 2
- 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 2
- AAHSHTLISQUZJL-QSFUFRPTSA-N Gly-Ile-Ile Chemical compound [H]NCC(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O AAHSHTLISQUZJL-QSFUFRPTSA-N 0.000 description 2
- 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 2
- POJJAZJHBGXEGM-YUMQZZPRSA-N Gly-Ser-Lys Chemical compound C(CCN)C[C@@H](C(=O)O)NC(=O)[C@H](CO)NC(=O)CN POJJAZJHBGXEGM-YUMQZZPRSA-N 0.000 description 2
- JSLVAHYTAJJEQH-QWRGUYRKSA-N Gly-Ser-Phe Chemical compound NCC(=O)N[C@@H](CO)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 JSLVAHYTAJJEQH-QWRGUYRKSA-N 0.000 description 2
- LCRDMSSAKLTKBU-ZDLURKLDSA-N Gly-Ser-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)[C@H](CO)NC(=O)CN LCRDMSSAKLTKBU-ZDLURKLDSA-N 0.000 description 2
- NVTPVQLIZCOJFK-FOHZUACHSA-N Gly-Thr-Asp Chemical compound [H]NCC(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(O)=O)C(O)=O NVTPVQLIZCOJFK-FOHZUACHSA-N 0.000 description 2
- 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 2
- 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 2
- 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 2
- SYOJVRNQCXYEOV-XVKPBYJWSA-N Gly-Val-Glu Chemical compound [H]NCC(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(O)=O)C(O)=O SYOJVRNQCXYEOV-XVKPBYJWSA-N 0.000 description 2
- 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 2
- QCBYAHHNOHBXIH-UWVGGRQHSA-N His-Pro-Gly Chemical compound C([C@H](N)C(=O)N1[C@@H](CCC1)C(=O)NCC(O)=O)C1=CN=CN1 QCBYAHHNOHBXIH-UWVGGRQHSA-N 0.000 description 2
- 241000282412 Homo Species 0.000 description 2
- MKWSZEHGHSLNPF-NAKRPEOUSA-N Ile-Ala-Val Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](C)C(=O)N[C@@H](C(C)C)C(=O)O)N MKWSZEHGHSLNPF-NAKRPEOUSA-N 0.000 description 2
- ASCFJMSGKUIRDU-ZPFDUUQYSA-N Ile-Arg-Gln Chemical compound CC[C@H](C)[C@H](N)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(N)=O)C(O)=O ASCFJMSGKUIRDU-ZPFDUUQYSA-N 0.000 description 2
- 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 2
- FGBRXCZYVRFNKQ-MXAVVETBSA-N Ile-Phe-Ser Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CO)C(=O)O)N FGBRXCZYVRFNKQ-MXAVVETBSA-N 0.000 description 2
- 108010054477 Immunoglobulin Fab Fragments Proteins 0.000 description 2
- 102000001706 Immunoglobulin Fab Fragments Human genes 0.000 description 2
- 108010021625 Immunoglobulin Fragments Proteins 0.000 description 2
- 102000008394 Immunoglobulin Fragments Human genes 0.000 description 2
- 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 2
- 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 2
- GPICTNQYKHHHTH-GUBZILKMSA-N Leu-Gln-Ser Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CO)C(O)=O GPICTNQYKHHHTH-GUBZILKMSA-N 0.000 description 2
- UHNQRAFSEBGZFZ-YESZJQIVSA-N Leu-Phe-Pro Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N2CCC[C@@H]2C(=O)O)N UHNQRAFSEBGZFZ-YESZJQIVSA-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
- 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 2
- 206010025323 Lymphomas Diseases 0.000 description 2
- 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 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
- 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 2
- GQFDWEDHOQRNLC-QWRGUYRKSA-N Lys-Gly-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)CNC(=O)[C@@H](N)CCCCN GQFDWEDHOQRNLC-QWRGUYRKSA-N 0.000 description 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
- GILLQRYAWOMHED-DCAQKATOSA-N Lys-Val-Ser Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](N)CCCCN GILLQRYAWOMHED-DCAQKATOSA-N 0.000 description 2
- 208000032271 Malignant tumor of penis Diseases 0.000 description 2
- 208000000172 Medulloblastoma Diseases 0.000 description 2
- 102000018697 Membrane Proteins Human genes 0.000 description 2
- 108010052285 Membrane Proteins Proteins 0.000 description 2
- 206010027406 Mesothelioma Diseases 0.000 description 2
- SJDQOYTYNGZZJX-SRVKXCTJSA-N Met-Glu-Leu Chemical compound CSCC[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(O)=O SJDQOYTYNGZZJX-SRVKXCTJSA-N 0.000 description 2
- RKIIYGUHIQJCBW-SRVKXCTJSA-N Met-His-Glu Chemical compound [H]N[C@@H](CCSC)C(=O)N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CCC(O)=O)C(O)=O RKIIYGUHIQJCBW-SRVKXCTJSA-N 0.000 description 2
- FWAHLGXNBLWIKB-NAKRPEOUSA-N Met-Ile-Ser Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H]([C@@H](C)CC)NC(=O)[C@@H](N)CCSC FWAHLGXNBLWIKB-NAKRPEOUSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 241000699660 Mus musculus Species 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- 206010052399 Neuroendocrine tumour Diseases 0.000 description 2
- 241001494479 Pecora Species 0.000 description 2
- 208000002471 Penile Neoplasms Diseases 0.000 description 2
- 206010034299 Penile cancer Diseases 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
- JDMKQHSHKJHAHR-UHFFFAOYSA-N Phe-Phe-Leu-Tyr Natural products C=1C=C(O)C=CC=1CC(C(O)=O)NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)CC1=CC=CC=C1 JDMKQHSHKJHAHR-UHFFFAOYSA-N 0.000 description 2
- 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 2
- 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 2
- 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 2
- SJRQWEDYTKYHHL-SLFFLAALSA-N Phe-Tyr-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CC2=CC=C(C=C2)O)NC(=O)[C@H](CC3=CC=CC=C3)N)C(=O)O SJRQWEDYTKYHHL-SLFFLAALSA-N 0.000 description 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
- VPEVBAUSTBWQHN-NHCYSSNCSA-N Pro-Glu-Val Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(O)=O VPEVBAUSTBWQHN-NHCYSSNCSA-N 0.000 description 2
- 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 2
- FDMKYQQYJKYCLV-GUBZILKMSA-N Pro-Pro-Ser Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@H]1NCCC1 FDMKYQQYJKYCLV-GUBZILKMSA-N 0.000 description 2
- GMJDSFYVTAMIBF-FXQIFTODSA-N Pro-Ser-Asp Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(O)=O)C(O)=O GMJDSFYVTAMIBF-FXQIFTODSA-N 0.000 description 2
- 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 2
- 206010060862 Prostate cancer Diseases 0.000 description 2
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 2
- 108020004511 Recombinant DNA Proteins 0.000 description 2
- 208000015634 Rectal Neoplasms Diseases 0.000 description 2
- 201000000582 Retinoblastoma Diseases 0.000 description 2
- 208000004337 Salivary Gland Neoplasms Diseases 0.000 description 2
- 206010061934 Salivary gland cancer Diseases 0.000 description 2
- 229920002684 Sepharose Polymers 0.000 description 2
- QEDMOZUJTGEIBF-FXQIFTODSA-N Ser-Arg-Asp Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(O)=O QEDMOZUJTGEIBF-FXQIFTODSA-N 0.000 description 2
- HZWAHWQZPSXNCB-BPUTZDHNSA-N Ser-Arg-Trp Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC1=CNC2=C1C=CC=C2)C(O)=O HZWAHWQZPSXNCB-BPUTZDHNSA-N 0.000 description 2
- VAUMZJHYZQXZBQ-WHFBIAKZSA-N Ser-Asn-Gly Chemical compound OC[C@H](N)C(=O)N[C@@H](CC(N)=O)C(=O)NCC(O)=O VAUMZJHYZQXZBQ-WHFBIAKZSA-N 0.000 description 2
- 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 2
- 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 2
- 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 2
- 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 2
- 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 2
- 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 2
- SRSPTFBENMJHMR-WHFBIAKZSA-N Ser-Ser-Gly Chemical compound OC[C@H](N)C(=O)N[C@@H](CO)C(=O)NCC(O)=O SRSPTFBENMJHMR-WHFBIAKZSA-N 0.000 description 2
- BDMWLJLPPUCLNV-XGEHTFHBSA-N Ser-Thr-Val Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(O)=O BDMWLJLPPUCLNV-XGEHTFHBSA-N 0.000 description 2
- UKKROEYWYIHWBD-ZKWXMUAHSA-N Ser-Val-Asp Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(O)=O)C(O)=O UKKROEYWYIHWBD-ZKWXMUAHSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 208000024313 Testicular Neoplasms Diseases 0.000 description 2
- 206010057644 Testis cancer Diseases 0.000 description 2
- GFDUZZACIWNMPE-KZVJFYERSA-N Thr-Ala-Met Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C)C(=O)N[C@@H](CCSC)C(O)=O GFDUZZACIWNMPE-KZVJFYERSA-N 0.000 description 2
- 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
- SXAGUVRFGJSFKC-ZEILLAHLSA-N Thr-His-Thr Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CNC=N1)C(=O)N[C@@H]([C@@H](C)O)C(O)=O SXAGUVRFGJSFKC-ZEILLAHLSA-N 0.000 description 2
- BIBYEFRASCNLAA-CDMKHQONSA-N Thr-Phe-Gly Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@H](C(=O)NCC(O)=O)CC1=CC=CC=C1 BIBYEFRASCNLAA-CDMKHQONSA-N 0.000 description 2
- SGAOHNPSEPVAFP-ZDLURKLDSA-N Thr-Ser-Gly Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(=O)NCC(O)=O SGAOHNPSEPVAFP-ZDLURKLDSA-N 0.000 description 2
- HUPLKEHTTQBXSC-YJRXYDGGSA-N Thr-Ser-Tyr Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 HUPLKEHTTQBXSC-YJRXYDGGSA-N 0.000 description 2
- BKIOKSLLAAZYTC-KKHAAJSZSA-N Thr-Val-Asn Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(N)=O)C(O)=O BKIOKSLLAAZYTC-KKHAAJSZSA-N 0.000 description 2
- 208000024770 Thyroid neoplasm Diseases 0.000 description 2
- SVGAWGVHFIYAEE-JSGCOSHPSA-N Trp-Gly-Gln Chemical compound C1=CC=C2C(C[C@H](N)C(=O)NCC(=O)N[C@@H](CCC(N)=O)C(O)=O)=CNC2=C1 SVGAWGVHFIYAEE-JSGCOSHPSA-N 0.000 description 2
- KIMOCKLJBXHFIN-YLVFBTJISA-N Trp-Ile-Gly Chemical compound C1=CC=C2C(C[C@H](N)C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(O)=O)=CNC2=C1 KIMOCKLJBXHFIN-YLVFBTJISA-N 0.000 description 2
- HWCBFXAWVTXXHZ-NYVOZVTQSA-N Trp-Ser-Trp Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CC3=CNC4=CC=CC=C43)C(=O)O)N HWCBFXAWVTXXHZ-NYVOZVTQSA-N 0.000 description 2
- 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 2
- QYSBJAUCUKHSLU-JYJNAYRXSA-N Tyr-Arg-Val Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C(C)C)C(O)=O QYSBJAUCUKHSLU-JYJNAYRXSA-N 0.000 description 2
- SMLCYZYQFRTLCO-UWJYBYFXSA-N Tyr-Cys-Ala 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(O)=O SMLCYZYQFRTLCO-UWJYBYFXSA-N 0.000 description 2
- QOIKZODVIPOPDD-AVGNSLFASA-N Tyr-Cys-Gln Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCC(N)=O)C(O)=O QOIKZODVIPOPDD-AVGNSLFASA-N 0.000 description 2
- QUILOGWWLXMSAT-IHRRRGAJSA-N Tyr-Gln-Gln Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(O)=O QUILOGWWLXMSAT-IHRRRGAJSA-N 0.000 description 2
- GZUIDWDVMWZSMI-KKUMJFAQSA-N Tyr-Lys-Cys Chemical compound NCCCC[C@@H](C(=O)N[C@@H](CS)C(O)=O)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 GZUIDWDVMWZSMI-KKUMJFAQSA-N 0.000 description 2
- XYNFFTNEQDWZNY-ULQDDVLXSA-N Tyr-Met-His Chemical compound CSCC[C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)NC(=O)[C@H](CC2=CC=C(C=C2)O)N XYNFFTNEQDWZNY-ULQDDVLXSA-N 0.000 description 2
- MQGGXGKQSVEQHR-KKUMJFAQSA-N Tyr-Ser-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 MQGGXGKQSVEQHR-KKUMJFAQSA-N 0.000 description 2
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 description 2
- 208000002495 Uterine Neoplasms Diseases 0.000 description 2
- ZLFHAAGHGQBQQN-GUBZILKMSA-N Val-Ala-Pro Natural products CC(C)[C@H](N)C(=O)N[C@@H](C)C(=O)N1CCC[C@H]1C(O)=O ZLFHAAGHGQBQQN-GUBZILKMSA-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
- OACSGBOREVRSME-NHCYSSNCSA-N Val-His-Asn Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](Cc1cnc[nH]1)C(=O)N[C@@H](CC(N)=O)C(O)=O OACSGBOREVRSME-NHCYSSNCSA-N 0.000 description 2
- 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 2
- CKTMJBPRVQWPHU-JSGCOSHPSA-N Val-Phe-Gly Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)NCC(=O)O)N CKTMJBPRVQWPHU-JSGCOSHPSA-N 0.000 description 2
- 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 2
- 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 2
- NZYNRRGJJVSSTJ-GUBZILKMSA-N Val-Ser-Val Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(O)=O NZYNRRGJJVSSTJ-GUBZILKMSA-N 0.000 description 2
- TVGWMCTYUFBXAP-QTKMDUPCSA-N Val-Thr-His Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)NC(=O)[C@H](C(C)C)N)O TVGWMCTYUFBXAP-QTKMDUPCSA-N 0.000 description 2
- USXYVSTVPHELAF-RCWTZXSCSA-N Val-Thr-Met Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCSC)C(=O)O)NC(=O)[C@H](C(C)C)N)O USXYVSTVPHELAF-RCWTZXSCSA-N 0.000 description 2
- QHSSPPHOHJSTML-HOCLYGCPSA-N Val-Trp-Gly Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC1=CNC2=CC=CC=C21)C(=O)NCC(=O)O)N QHSSPPHOHJSTML-HOCLYGCPSA-N 0.000 description 2
- 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 2
- 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 2
- 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 2
- 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 2
- 206010047741 Vulval cancer Diseases 0.000 description 2
- 208000009956 adenocarcinoma Diseases 0.000 description 2
- 201000011165 anus cancer Diseases 0.000 description 2
- 108010052670 arginyl-glutamyl-glutamic acid Proteins 0.000 description 2
- 108010009111 arginyl-glycyl-glutamic acid Proteins 0.000 description 2
- 108010069205 aspartyl-phenylalanine Proteins 0.000 description 2
- 108010038633 aspartylglutamate Proteins 0.000 description 2
- 108010092854 aspartyllysine Proteins 0.000 description 2
- 230000001580 bacterial effect Effects 0.000 description 2
- 208000026900 bile duct neoplasm Diseases 0.000 description 2
- 238000001574 biopsy Methods 0.000 description 2
- 201000000053 blastoma Diseases 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 208000002458 carcinoid tumor Diseases 0.000 description 2
- YCIMNLLNPGFGHC-UHFFFAOYSA-N catechol Chemical compound OC1=CC=CC=C1O YCIMNLLNPGFGHC-UHFFFAOYSA-N 0.000 description 2
- 230000024245 cell differentiation Effects 0.000 description 2
- 230000004663 cell proliferation Effects 0.000 description 2
- 201000010881 cervical cancer Diseases 0.000 description 2
- 235000013330 chicken meat Nutrition 0.000 description 2
- 230000004069 differentiation Effects 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- 231100000673 dose–response relationship Toxicity 0.000 description 2
- 239000000975 dye Substances 0.000 description 2
- 201000008184 embryoma Diseases 0.000 description 2
- 230000002357 endometrial effect Effects 0.000 description 2
- 210000002919 epithelial cell Anatomy 0.000 description 2
- 210000000981 epithelium Anatomy 0.000 description 2
- 239000013613 expression plasmid Substances 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 230000005714 functional activity Effects 0.000 description 2
- 108010063718 gamma-glutamylaspartic acid Proteins 0.000 description 2
- 208000015419 gastrin-producing neuroendocrine tumor Diseases 0.000 description 2
- 201000000052 gastrinoma Diseases 0.000 description 2
- 238000001502 gel electrophoresis Methods 0.000 description 2
- 238000010353 genetic engineering Methods 0.000 description 2
- 208000005017 glioblastoma Diseases 0.000 description 2
- 108010013768 glutamyl-aspartyl-proline Proteins 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
- 108010087823 glycyltyrosine Proteins 0.000 description 2
- 230000009422 growth inhibiting effect Effects 0.000 description 2
- 201000010536 head and neck cancer Diseases 0.000 description 2
- 208000014829 head and neck neoplasm Diseases 0.000 description 2
- 208000019691 hematopoietic and lymphoid cell neoplasm Diseases 0.000 description 2
- 230000002440 hepatic effect Effects 0.000 description 2
- 210000000987 immune system Anatomy 0.000 description 2
- 238000010166 immunofluorescence Methods 0.000 description 2
- 229940072221 immunoglobulins Drugs 0.000 description 2
- 238000003364 immunohistochemistry Methods 0.000 description 2
- 238000002513 implantation Methods 0.000 description 2
- 238000011081 inoculation Methods 0.000 description 2
- 230000003993 interaction Effects 0.000 description 2
- 239000007928 intraperitoneal injection Substances 0.000 description 2
- 108010044311 leucyl-glycyl-glycine Proteins 0.000 description 2
- 206010024627 liposarcoma Diseases 0.000 description 2
- 239000002502 liposome Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 108010025153 lysyl-alanyl-alanine Proteins 0.000 description 2
- 108010038320 lysylphenylalanine Proteins 0.000 description 2
- RLSSMJSEOOYNOY-UHFFFAOYSA-N m-cresol Chemical compound CC1=CC=CC(O)=C1 RLSSMJSEOOYNOY-UHFFFAOYSA-N 0.000 description 2
- 230000001404 mediated effect Effects 0.000 description 2
- 239000002609 medium Substances 0.000 description 2
- 201000001441 melanoma Diseases 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- 206010027191 meningioma Diseases 0.000 description 2
- 208000007538 neurilemmoma Diseases 0.000 description 2
- 208000016065 neuroendocrine neoplasm Diseases 0.000 description 2
- 201000011519 neuroendocrine tumor Diseases 0.000 description 2
- 238000011580 nude mouse model Methods 0.000 description 2
- 201000002530 pancreatic endocrine carcinoma Diseases 0.000 description 2
- AQIXEPGDORPWBJ-UHFFFAOYSA-N pentan-3-ol Chemical compound CCC(O)CC AQIXEPGDORPWBJ-UHFFFAOYSA-N 0.000 description 2
- 108010024654 phenylalanyl-prolyl-alanine Proteins 0.000 description 2
- 108010073101 phenylalanylleucine Proteins 0.000 description 2
- 210000002381 plasma Anatomy 0.000 description 2
- 238000003752 polymerase chain reaction Methods 0.000 description 2
- 108091033319 polynucleotide Proteins 0.000 description 2
- 102000040430 polynucleotide Human genes 0.000 description 2
- 239000002157 polynucleotide Substances 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 108010090894 prolylleucine Proteins 0.000 description 2
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 2
- 206010038038 rectal cancer Diseases 0.000 description 2
- 201000001275 rectum cancer Diseases 0.000 description 2
- 230000010076 replication Effects 0.000 description 2
- GHMLBKRAJCXXBS-UHFFFAOYSA-N resorcinol Chemical compound OC1=CC=CC(O)=C1 GHMLBKRAJCXXBS-UHFFFAOYSA-N 0.000 description 2
- 206010039667 schwannoma Diseases 0.000 description 2
- 108010069117 seryl-lysyl-aspartic acid Proteins 0.000 description 2
- 210000002784 stomach Anatomy 0.000 description 2
- 210000002437 synoviocyte Anatomy 0.000 description 2
- 201000003120 testicular cancer Diseases 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- 108010071097 threonyl-lysyl-proline Proteins 0.000 description 2
- 201000002510 thyroid cancer Diseases 0.000 description 2
- 238000013518 transcription Methods 0.000 description 2
- 108010080629 tryptophan-leucine Proteins 0.000 description 2
- 108010044292 tryptophyltyrosine Proteins 0.000 description 2
- 108010071635 tyrosyl-prolyl-arginine Proteins 0.000 description 2
- 206010046766 uterine cancer Diseases 0.000 description 2
- 210000003462 vein Anatomy 0.000 description 2
- 201000005102 vulva cancer Diseases 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- 108010027345 wheylin-1 peptide Proteins 0.000 description 2
- HDTRYLNUVZCQOY-UHFFFAOYSA-N α-D-glucopyranosyl-α-D-glucopyranoside Natural products OC1C(O)C(O)C(CO)OC1OC1C(O)C(O)C(O)C(CO)O1 HDTRYLNUVZCQOY-UHFFFAOYSA-N 0.000 description 1
- IESDGNYHXIOKRW-YXMSTPNBSA-N (2s)-2-[[(2s)-1-[(2s)-6-amino-2-[[(2s,3r)-2-amino-3-hydroxybutanoyl]amino]hexanoyl]pyrrolidine-2-carbonyl]amino]-5-(diaminomethylideneamino)pentanoic acid Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@@H](CCCCN)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCCNC(N)=N)C(O)=O IESDGNYHXIOKRW-YXMSTPNBSA-N 0.000 description 1
- DIBLBAURNYJYBF-XLXZRNDBSA-N (2s)-2-[[(2s)-2-[[2-[[(2s)-6-amino-2-[[(2s)-2-amino-3-methylbutanoyl]amino]hexanoyl]amino]acetyl]amino]-3-phenylpropanoyl]amino]-3-(4-hydroxyphenyl)propanoic acid Chemical compound C([C@H](NC(=O)CNC(=O)[C@H](CCCCN)NC(=O)[C@@H](N)C(C)C)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(O)=O)C1=CC=CC=C1 DIBLBAURNYJYBF-XLXZRNDBSA-N 0.000 description 1
- KPAGQPARRIJPFL-UHFFFAOYSA-N 2-(2-phenylethoxy)ethanamine;hydrochloride Chemical compound Cl.NCCOCCC1=CC=CC=C1 KPAGQPARRIJPFL-UHFFFAOYSA-N 0.000 description 1
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 1
- FVFVNNKYKYZTJU-UHFFFAOYSA-N 6-chloro-1,3,5-triazine-2,4-diamine Chemical group NC1=NC(N)=NC(Cl)=N1 FVFVNNKYKYZTJU-UHFFFAOYSA-N 0.000 description 1
- 241000251468 Actinopterygii Species 0.000 description 1
- CXRCVCURMBFFOL-FXQIFTODSA-N Ala-Ala-Pro Chemical compound C[C@H](N)C(=O)N[C@@H](C)C(=O)N1CCC[C@H]1C(O)=O CXRCVCURMBFFOL-FXQIFTODSA-N 0.000 description 1
- BUDNAJYVCUHLSV-ZLUOBGJFSA-N Ala-Asp-Ser Chemical compound C[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(O)=O BUDNAJYVCUHLSV-ZLUOBGJFSA-N 0.000 description 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
- WCBVQNZTOKJWJS-ACZMJKKPSA-N Ala-Cys-Glu Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCC(O)=O)C(O)=O WCBVQNZTOKJWJS-ACZMJKKPSA-N 0.000 description 1
- SMCGQGDVTPFXKB-XPUUQOCRSA-N Ala-Gly-Val Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)CNC(=O)[C@H](C)N SMCGQGDVTPFXKB-XPUUQOCRSA-N 0.000 description 1
- 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 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
- 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
- NCQMBSJGJMYKCK-ZLUOBGJFSA-N Ala-Ser-Ser Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(O)=O NCQMBSJGJMYKCK-ZLUOBGJFSA-N 0.000 description 1
- 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
- PHQXWZGXKAFWAZ-ZLIFDBKOSA-N Ala-Trp-Lys Chemical compound C1=CC=C2C(C[C@H](NC(=O)[C@@H](N)C)C(=O)N[C@@H](CCCCN)C(O)=O)=CNC2=C1 PHQXWZGXKAFWAZ-ZLIFDBKOSA-N 0.000 description 1
- ZDILXFDENZVOTL-BPNCWPANSA-N Ala-Val-Tyr Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O ZDILXFDENZVOTL-BPNCWPANSA-N 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- 235000002198 Annona diversifolia Nutrition 0.000 description 1
- GIVATXIGCXFQQA-FXQIFTODSA-N Arg-Ala-Ser Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CCCN=C(N)N GIVATXIGCXFQQA-FXQIFTODSA-N 0.000 description 1
- BECXEHHOZNFFFX-IHRRRGAJSA-N Arg-Ser-Tyr Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O BECXEHHOZNFFFX-IHRRRGAJSA-N 0.000 description 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
- 239000004475 Arginine Substances 0.000 description 1
- 206010003445 Ascites Diseases 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
- SLKLLQWZQHXYSV-CIUDSAMLSA-N Asn-Ala-Lys Chemical compound NC(=O)C[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCN)C(O)=O SLKLLQWZQHXYSV-CIUDSAMLSA-N 0.000 description 1
- 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
- APHUDFFMXFYRKP-CIUDSAMLSA-N Asn-Asn-Lys Chemical compound C(CCN)C[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)N)NC(=O)[C@H](CC(=O)N)N APHUDFFMXFYRKP-CIUDSAMLSA-N 0.000 description 1
- BVLIJXXSXBUGEC-SRVKXCTJSA-N Asn-Asn-Tyr Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O BVLIJXXSXBUGEC-SRVKXCTJSA-N 0.000 description 1
- SRUUBQBAVNQZGJ-LAEOZQHASA-N Asn-Gln-Val Chemical compound CC(C)[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)N)NC(=O)[C@H](CC(=O)N)N SRUUBQBAVNQZGJ-LAEOZQHASA-N 0.000 description 1
- RBOBTTLFPRSXKZ-BZSNNMDCSA-N Asn-Phe-Tyr Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O RBOBTTLFPRSXKZ-BZSNNMDCSA-N 0.000 description 1
- VLDRQOHCMKCXLY-SRVKXCTJSA-N Asn-Ser-Phe Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O VLDRQOHCMKCXLY-SRVKXCTJSA-N 0.000 description 1
- BCADFFUQHIMQAA-KKHAAJSZSA-N Asn-Thr-Val Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(O)=O BCADFFUQHIMQAA-KKHAAJSZSA-N 0.000 description 1
- LGCVSPFCFXWUEY-IHPCNDPISA-N Asn-Trp-Tyr Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)N[C@@H](CC3=CC=C(C=C3)O)C(=O)O)NC(=O)[C@H](CC(=O)N)N LGCVSPFCFXWUEY-IHPCNDPISA-N 0.000 description 1
- 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
- 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
- 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
- YNQIDCRRTWGHJD-ZLUOBGJFSA-N Asp-Asn-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](N)CC(O)=O YNQIDCRRTWGHJD-ZLUOBGJFSA-N 0.000 description 1
- HSWYMWGDMPLTTH-FXQIFTODSA-N Asp-Glu-Gln Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(N)=O)C(O)=O HSWYMWGDMPLTTH-FXQIFTODSA-N 0.000 description 1
- PDECQIHABNQRHN-GUBZILKMSA-N Asp-Glu-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](N)CC(O)=O PDECQIHABNQRHN-GUBZILKMSA-N 0.000 description 1
- SNDBKTFJWVEVPO-WHFBIAKZSA-N Asp-Gly-Ser Chemical compound [H]N[C@@H](CC(O)=O)C(=O)NCC(=O)N[C@@H](CO)C(O)=O SNDBKTFJWVEVPO-WHFBIAKZSA-N 0.000 description 1
- WSGVTKZFVJSJOG-RCOVLWMOSA-N Asp-Gly-Val Chemical compound [H]N[C@@H](CC(O)=O)C(=O)NCC(=O)N[C@@H](C(C)C)C(O)=O WSGVTKZFVJSJOG-RCOVLWMOSA-N 0.000 description 1
- NVFSJIXJZCDICF-SRVKXCTJSA-N Asp-Lys-Lys Chemical compound C(CCN)C[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CC(=O)O)N NVFSJIXJZCDICF-SRVKXCTJSA-N 0.000 description 1
- GYWQGGUCMDCUJE-DLOVCJGASA-N Asp-Phe-Ala Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](C)C(O)=O GYWQGGUCMDCUJE-DLOVCJGASA-N 0.000 description 1
- AHWRSSLYSGLBGD-CIUDSAMLSA-N Asp-Pro-Glu Chemical compound OC(=O)C[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCC(O)=O)C(O)=O AHWRSSLYSGLBGD-CIUDSAMLSA-N 0.000 description 1
- VNXQRBXEQXLERQ-CIUDSAMLSA-N Asp-Ser-Lys Chemical compound C(CCN)C[C@@H](C(=O)O)NC(=O)[C@H](CO)NC(=O)[C@H](CC(=O)O)N VNXQRBXEQXLERQ-CIUDSAMLSA-N 0.000 description 1
- MGSVBZIBCCKGCY-ZLUOBGJFSA-N Asp-Ser-Ser Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(O)=O MGSVBZIBCCKGCY-ZLUOBGJFSA-N 0.000 description 1
- YIDFBWRHIYOYAA-LKXGYXEUSA-N Asp-Ser-Thr Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(O)=O YIDFBWRHIYOYAA-LKXGYXEUSA-N 0.000 description 1
- JSNWZMFSLIWAHS-HJGDQZAQSA-N Asp-Thr-Leu Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)O)NC(=O)[C@H](CC(=O)O)N)O JSNWZMFSLIWAHS-HJGDQZAQSA-N 0.000 description 1
- YUELDQUPTAYEGM-XIRDDKMYSA-N Asp-Trp-Leu Chemical compound CC(C)C[C@@H](C(=O)O)NC(=O)[C@H](CC1=CNC2=CC=CC=C21)NC(=O)[C@H](CC(=O)O)N YUELDQUPTAYEGM-XIRDDKMYSA-N 0.000 description 1
- 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
- 102000004506 Blood Proteins Human genes 0.000 description 1
- 108010017384 Blood Proteins Proteins 0.000 description 1
- 241000282832 Camelidae Species 0.000 description 1
- 241000251730 Chondrichthyes Species 0.000 description 1
- 208000005443 Circulating Neoplastic Cells Diseases 0.000 description 1
- 102000004162 Claudin-1 Human genes 0.000 description 1
- 108090000600 Claudin-1 Proteins 0.000 description 1
- 108091026890 Coding region Proteins 0.000 description 1
- 108020004705 Codon Proteins 0.000 description 1
- 241000938605 Crocodylia Species 0.000 description 1
- NDUSUIGBMZCOIL-ZKWXMUAHSA-N Cys-Asn-Val Chemical compound CC(C)[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)N)NC(=O)[C@H](CS)N NDUSUIGBMZCOIL-ZKWXMUAHSA-N 0.000 description 1
- SFRQEQGPRTVDPO-NRPADANISA-N Cys-Gln-Val Chemical compound [H]N[C@@H](CS)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](C(C)C)C(O)=O SFRQEQGPRTVDPO-NRPADANISA-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
- VPQZSNQICFCCSO-BJDJZHNGSA-N Cys-Leu-Ile Chemical compound [H]N[C@@H](CS)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O VPQZSNQICFCCSO-BJDJZHNGSA-N 0.000 description 1
- ZXCAQANTQWBICD-DCAQKATOSA-N Cys-Lys-Val Chemical compound CC(C)[C@@H](C(=O)O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CS)N ZXCAQANTQWBICD-DCAQKATOSA-N 0.000 description 1
- SMEYEQDCCBHTEF-FXQIFTODSA-N Cys-Pro-Ala Chemical compound [H]N[C@@H](CS)C(=O)N1CCC[C@H]1C(=O)N[C@@H](C)C(O)=O SMEYEQDCCBHTEF-FXQIFTODSA-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
- ALTQTAKGRFLRLR-GUBZILKMSA-N Cys-Val-Val Chemical compound CC(C)[C@@H](C(=O)N[C@@H](C(C)C)C(=O)O)NC(=O)[C@H](CS)N ALTQTAKGRFLRLR-GUBZILKMSA-N 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- WQZGKKKJIJFFOK-QTVWNMPRSA-N D-mannopyranose Chemical compound OC[C@H]1OC(O)[C@@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-QTVWNMPRSA-N 0.000 description 1
- 102000053602 DNA Human genes 0.000 description 1
- 238000001712 DNA sequencing Methods 0.000 description 1
- 239000004375 Dextrin Substances 0.000 description 1
- 229920001353 Dextrin Polymers 0.000 description 1
- 206010061818 Disease progression Diseases 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 108700024394 Exon Proteins 0.000 description 1
- 239000012739 FreeStyle 293 Expression medium Substances 0.000 description 1
- 108700028146 Genetic Enhancer Elements Proteins 0.000 description 1
- 108700039691 Genetic Promoter Regions Proteins 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
- 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 1
- LPYPANUXJGFMGV-FXQIFTODSA-N Gln-Gln-Ala Chemical compound C[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)N)NC(=O)[C@H](CCC(=O)N)N LPYPANUXJGFMGV-FXQIFTODSA-N 0.000 description 1
- GNMQDOGFWYWPNM-LAEOZQHASA-N Gln-Gly-Ile Chemical compound CC[C@H](C)[C@H](NC(=O)CNC(=O)[C@@H](N)CCC(N)=O)C(O)=O GNMQDOGFWYWPNM-LAEOZQHASA-N 0.000 description 1
- FGYPOQPQTUNESW-IUCAKERBSA-N Gln-Gly-Leu Chemical compound CC(C)C[C@@H](C(=O)O)NC(=O)CNC(=O)[C@H](CCC(=O)N)N FGYPOQPQTUNESW-IUCAKERBSA-N 0.000 description 1
- SBHVGKBYOQKAEA-SDDRHHMPSA-N Gln-His-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CC2=CN=CN2)NC(=O)[C@H](CCC(=O)N)N)C(=O)O SBHVGKBYOQKAEA-SDDRHHMPSA-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
- 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
- XZLLTYBONVKGLO-SDDRHHMPSA-N Gln-Lys-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CCCCN)NC(=O)[C@H](CCC(=O)N)N)C(=O)O XZLLTYBONVKGLO-SDDRHHMPSA-N 0.000 description 1
- ZEEPYMXTJWIMSN-GUBZILKMSA-N Gln-Lys-Ser Chemical compound NCCCC[C@@H](C(=O)N[C@@H](CO)C(O)=O)NC(=O)[C@@H](N)CCC(N)=O ZEEPYMXTJWIMSN-GUBZILKMSA-N 0.000 description 1
- XUMFMAVDHQDATI-DCAQKATOSA-N Gln-Pro-Arg Chemical compound NC(=O)CC[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCCN=C(N)N)C(O)=O XUMFMAVDHQDATI-DCAQKATOSA-N 0.000 description 1
- OKARHJKJTKFQBM-ACZMJKKPSA-N Gln-Ser-Asn Chemical compound C(CC(=O)N)[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(=O)N)C(=O)O)N OKARHJKJTKFQBM-ACZMJKKPSA-N 0.000 description 1
- XKPACHRGOWQHFH-IRIUXVKKSA-N Gln-Thr-Tyr Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O XKPACHRGOWQHFH-IRIUXVKKSA-N 0.000 description 1
- FITIQFSXXBKFFM-NRPADANISA-N Gln-Val-Ser Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CO)C(O)=O FITIQFSXXBKFFM-NRPADANISA-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
- GLWXKFRTOHKGIT-ACZMJKKPSA-N Glu-Asn-Asn Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O GLWXKFRTOHKGIT-ACZMJKKPSA-N 0.000 description 1
- 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
- SBCYJMOOHUDWDA-NUMRIWBASA-N Glu-Asp-Thr Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O SBCYJMOOHUDWDA-NUMRIWBASA-N 0.000 description 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
- MIQCYAJSDGNCNK-BPUTZDHNSA-N Glu-Gln-Trp Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC1=CNC2=C1C=CC=C2)C(O)=O MIQCYAJSDGNCNK-BPUTZDHNSA-N 0.000 description 1
- HNVFSTLPVJWIDV-CIUDSAMLSA-N Glu-Glu-Gln Chemical compound OC(=O)CC[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(N)=O)C(O)=O HNVFSTLPVJWIDV-CIUDSAMLSA-N 0.000 description 1
- MUSGDMDGNGXULI-DCAQKATOSA-N Glu-Glu-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](N)CCC(O)=O MUSGDMDGNGXULI-DCAQKATOSA-N 0.000 description 1
- RAUDKMVXNOWDLS-WDSKDSINSA-N Glu-Gly-Ser Chemical compound OC(=O)CC[C@H](N)C(=O)NCC(=O)N[C@@H](CO)C(O)=O RAUDKMVXNOWDLS-WDSKDSINSA-N 0.000 description 1
- MWMJCGBSIORNCD-AVGNSLFASA-N Glu-Leu-Leu Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O MWMJCGBSIORNCD-AVGNSLFASA-N 0.000 description 1
- NJCALAAIGREHDR-WDCWCFNPSA-N Glu-Leu-Thr Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O NJCALAAIGREHDR-WDCWCFNPSA-N 0.000 description 1
- QDMVXRNLOPTPIE-WDCWCFNPSA-N Glu-Lys-Thr Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(O)=O QDMVXRNLOPTPIE-WDCWCFNPSA-N 0.000 description 1
- 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
- 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
- DMYACXMQUABZIQ-NRPADANISA-N Glu-Ser-Val Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(O)=O DMYACXMQUABZIQ-NRPADANISA-N 0.000 description 1
- CAQXJMUDOLSBPF-SUSMZKCASA-N Glu-Thr-Thr Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O CAQXJMUDOLSBPF-SUSMZKCASA-N 0.000 description 1
- MFYLRRCYBBJYPI-JYJNAYRXSA-N Glu-Tyr-Lys Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CCC(=O)O)N)O MFYLRRCYBBJYPI-JYJNAYRXSA-N 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- VSVZIEVNUYDAFR-YUMQZZPRSA-N Gly-Ala-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)CN VSVZIEVNUYDAFR-YUMQZZPRSA-N 0.000 description 1
- JRDYDYXZKFNNRQ-XPUUQOCRSA-N Gly-Ala-Val Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)CN JRDYDYXZKFNNRQ-XPUUQOCRSA-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
- GRIRDMVMJJDZKV-RCOVLWMOSA-N Gly-Asn-Val Chemical compound [H]NCC(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](C(C)C)C(O)=O GRIRDMVMJJDZKV-RCOVLWMOSA-N 0.000 description 1
- BIRKKBCSAIHDDF-WDSKDSINSA-N Gly-Glu-Cys Chemical compound NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CS)C(O)=O BIRKKBCSAIHDDF-WDSKDSINSA-N 0.000 description 1
- 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
- IKAIKUBBJHFNBZ-LURJTMIESA-N Gly-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)CN IKAIKUBBJHFNBZ-LURJTMIESA-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
- 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 1
- 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 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
- ZLCLYFGMKFCDCN-XPUUQOCRSA-N Gly-Ser-Val Chemical compound CC(C)[C@H](NC(=O)[C@H](CO)NC(=O)CN)C(O)=O ZLCLYFGMKFCDCN-XPUUQOCRSA-N 0.000 description 1
- ZZWUYQXMIFTIIY-WEDXCCLWSA-N Gly-Thr-Leu Chemical compound [H]NCC(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(O)=O ZZWUYQXMIFTIIY-WEDXCCLWSA-N 0.000 description 1
- 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 1
- 239000004471 Glycine Substances 0.000 description 1
- 102000003886 Glycoproteins Human genes 0.000 description 1
- 108090000288 Glycoproteins Proteins 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
- SDTPKSOWFXBACN-GUBZILKMSA-N His-Glu-Asp Chemical compound [H]N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(O)=O SDTPKSOWFXBACN-GUBZILKMSA-N 0.000 description 1
- TVMNTHXFRSXZGR-IHRRRGAJSA-N His-Lys-Val Chemical compound [H]N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C(C)C)C(O)=O TVMNTHXFRSXZGR-IHRRRGAJSA-N 0.000 description 1
- ALPXXNRQBMRCPZ-MEYUZBJRSA-N His-Thr-Phe Chemical compound [H]N[C@@H](CC1=CNC=N1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O ALPXXNRQBMRCPZ-MEYUZBJRSA-N 0.000 description 1
- 101001066129 Homo sapiens Glyceraldehyde-3-phosphate dehydrogenase Proteins 0.000 description 1
- 108010001336 Horseradish Peroxidase Proteins 0.000 description 1
- FADXGVVLSPPEQY-GHCJXIJMSA-N Ile-Cys-Asn Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(=O)N)C(=O)O)N FADXGVVLSPPEQY-GHCJXIJMSA-N 0.000 description 1
- SVBAHOMTJRFSIC-SXTJYALSSA-N Ile-Ile-Asn Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(=O)N)C(=O)O)N SVBAHOMTJRFSIC-SXTJYALSSA-N 0.000 description 1
- NZGTYCMLUGYMCV-XUXIUFHCSA-N Ile-Lys-Arg Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCN=C(N)N)C(=O)O)N NZGTYCMLUGYMCV-XUXIUFHCSA-N 0.000 description 1
- 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 1
- 108700005091 Immunoglobulin Genes Proteins 0.000 description 1
- 102100029567 Immunoglobulin kappa light chain Human genes 0.000 description 1
- 101710189008 Immunoglobulin kappa light chain Proteins 0.000 description 1
- 108010065920 Insulin Lispro Proteins 0.000 description 1
- 108091092195 Intron Proteins 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 1
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 description 1
- RCFDOSNHHZGBOY-UHFFFAOYSA-N L-isoleucyl-L-alanine Natural products CCC(C)C(N)C(=O)NC(C)C(O)=O RCFDOSNHHZGBOY-UHFFFAOYSA-N 0.000 description 1
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 1
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 1
- 241000282838 Lama Species 0.000 description 1
- UCOCBWDBHCUPQP-DCAQKATOSA-N Leu-Arg-Ser Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(O)=O UCOCBWDBHCUPQP-DCAQKATOSA-N 0.000 description 1
- 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 1
- PVMPDMIKUVNOBD-CIUDSAMLSA-N Leu-Asp-Ser Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(O)=O PVMPDMIKUVNOBD-CIUDSAMLSA-N 0.000 description 1
- 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
- QJUWBDPGGYVRHY-YUMQZZPRSA-N Leu-Gly-Cys Chemical compound CC(C)C[C@@H](C(=O)NCC(=O)N[C@@H](CS)C(=O)O)N QJUWBDPGGYVRHY-YUMQZZPRSA-N 0.000 description 1
- HYMLKESRWLZDBR-WEDXCCLWSA-N Leu-Gly-Thr Chemical compound CC(C)C[C@H](N)C(=O)NCC(=O)N[C@@H]([C@@H](C)O)C(O)=O HYMLKESRWLZDBR-WEDXCCLWSA-N 0.000 description 1
- BKTXKJMNTSMJDQ-AVGNSLFASA-N Leu-His-Gln Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)N[C@@H](CCC(=O)N)C(=O)O)N BKTXKJMNTSMJDQ-AVGNSLFASA-N 0.000 description 1
- QLDHBYRUNQZIJQ-DKIMLUQUSA-N Leu-Ile-Phe Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O QLDHBYRUNQZIJQ-DKIMLUQUSA-N 0.000 description 1
- HRTRLSRYZZKPCO-BJDJZHNGSA-N Leu-Ile-Ser Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(O)=O HRTRLSRYZZKPCO-BJDJZHNGSA-N 0.000 description 1
- NRFGTHFONZYFNY-MGHWNKPDSA-N Leu-Ile-Tyr Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 NRFGTHFONZYFNY-MGHWNKPDSA-N 0.000 description 1
- IAJFFZORSWOZPQ-SRVKXCTJSA-N Leu-Leu-Asn Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(O)=O IAJFFZORSWOZPQ-SRVKXCTJSA-N 0.000 description 1
- 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 1
- WMIOEVKKYIMVKI-DCAQKATOSA-N Leu-Pro-Ala Chemical compound [H]N[C@@H](CC(C)C)C(=O)N1CCC[C@H]1C(=O)N[C@@H](C)C(O)=O WMIOEVKKYIMVKI-DCAQKATOSA-N 0.000 description 1
- XOWMDXHFSBCAKQ-SRVKXCTJSA-N Leu-Ser-Leu Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@H](C(O)=O)CC(C)C XOWMDXHFSBCAKQ-SRVKXCTJSA-N 0.000 description 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
- LJBVRCDPWOJOEK-PPCPHDFISA-N Leu-Thr-Ile Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O LJBVRCDPWOJOEK-PPCPHDFISA-N 0.000 description 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
- KLSUAWUZBMAZCL-RHYQMDGZSA-N Leu-Thr-Pro Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1CCC[C@H]1C(O)=O KLSUAWUZBMAZCL-RHYQMDGZSA-N 0.000 description 1
- TUIOUEWKFFVNLH-DCAQKATOSA-N Leu-Val-Cys Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CS)C(O)=O TUIOUEWKFFVNLH-DCAQKATOSA-N 0.000 description 1
- YQFZRHYZLARWDY-IHRRRGAJSA-N Leu-Val-Lys Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@H](C(O)=O)CCCCN YQFZRHYZLARWDY-IHRRRGAJSA-N 0.000 description 1
- FZIJIFCXUCZHOL-CIUDSAMLSA-N Lys-Ala-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@@H](N)CCCCN FZIJIFCXUCZHOL-CIUDSAMLSA-N 0.000 description 1
- MPGHETGWWWUHPY-CIUDSAMLSA-N Lys-Ala-Asp Chemical compound OC(=O)C[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CCCCN MPGHETGWWWUHPY-CIUDSAMLSA-N 0.000 description 1
- KCXUCYYZNZFGLL-SRVKXCTJSA-N Lys-Ala-Leu Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(O)=O KCXUCYYZNZFGLL-SRVKXCTJSA-N 0.000 description 1
- KNKHAVVBVXKOGX-JXUBOQSCSA-N Lys-Ala-Thr Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O KNKHAVVBVXKOGX-JXUBOQSCSA-N 0.000 description 1
- KWUKZRFFKPLUPE-HJGDQZAQSA-N Lys-Asp-Thr Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O KWUKZRFFKPLUPE-HJGDQZAQSA-N 0.000 description 1
- NNCDAORZCMPZPX-GUBZILKMSA-N Lys-Gln-Ser Chemical compound C(CCN)C[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H](CO)C(=O)O)N NNCDAORZCMPZPX-GUBZILKMSA-N 0.000 description 1
- XNKDCYABMBBEKN-IUCAKERBSA-N Lys-Gly-Gln Chemical compound NCCCC[C@H](N)C(=O)NCC(=O)N[C@H](C(O)=O)CCC(N)=O XNKDCYABMBBEKN-IUCAKERBSA-N 0.000 description 1
- 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
- QQPSCXKFDSORFT-IHRRRGAJSA-N Lys-Lys-Val Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](N)CCCCN QQPSCXKFDSORFT-IHRRRGAJSA-N 0.000 description 1
- ODTZHNZPINULEU-KKUMJFAQSA-N Lys-Phe-Asn Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)O)NC(=O)[C@H](CCCCN)N ODTZHNZPINULEU-KKUMJFAQSA-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
- CTJUSALVKAWFFU-CIUDSAMLSA-N Lys-Ser-Cys Chemical compound C(CCN)C[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CS)C(=O)O)N CTJUSALVKAWFFU-CIUDSAMLSA-N 0.000 description 1
- SBQDRNOLGSYHQA-YUMQZZPRSA-N Lys-Ser-Gly Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CO)C(=O)NCC(O)=O SBQDRNOLGSYHQA-YUMQZZPRSA-N 0.000 description 1
- IOQWIOPSKJOEKI-SRVKXCTJSA-N Lys-Ser-Leu Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(O)=O IOQWIOPSKJOEKI-SRVKXCTJSA-N 0.000 description 1
- 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 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
- IEVXCWPVBYCJRZ-IXOXFDKPSA-N Lys-Thr-His Chemical compound NCCCC[C@H](N)C(=O)N[C@@H]([C@H](O)C)C(=O)N[C@H](C(O)=O)CC1=CN=CN1 IEVXCWPVBYCJRZ-IXOXFDKPSA-N 0.000 description 1
- DLCAXBGXGOVUCD-PPCPHDFISA-N Lys-Thr-Ile Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O DLCAXBGXGOVUCD-PPCPHDFISA-N 0.000 description 1
- CAVRAQIDHUPECU-UVOCVTCTSA-N Lys-Thr-Thr Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O CAVRAQIDHUPECU-UVOCVTCTSA-N 0.000 description 1
- 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
- XABXVVSWUVCZST-GVXVVHGQSA-N Lys-Val-Gln Chemical compound NC(=O)CC[C@@H](C(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](N)CCCCN XABXVVSWUVCZST-GVXVVHGQSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- KSIPKXNIQOWMIC-RCWTZXSCSA-N Met-Thr-Arg Chemical compound CSCC[C@H](N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@H](C(O)=O)CCCNC(N)=N KSIPKXNIQOWMIC-RCWTZXSCSA-N 0.000 description 1
- VYDLZDRMOFYOGV-TUAOUCFPSA-N Met-Val-Pro Chemical compound CC(C)[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](CCSC)N VYDLZDRMOFYOGV-TUAOUCFPSA-N 0.000 description 1
- 206010027476 Metastases Diseases 0.000 description 1
- WUGMRIBZSVSJNP-UHFFFAOYSA-N N-L-alanyl-L-tryptophan Natural products C1=CC=C2C(CC(NC(=O)C(N)C)C(O)=O)=CNC2=C1 WUGMRIBZSVSJNP-UHFFFAOYSA-N 0.000 description 1
- YBAFDPFAUTYYRW-UHFFFAOYSA-N N-L-alpha-glutamyl-L-leucine Natural products CC(C)CC(C(O)=O)NC(=O)C(N)CCC(O)=O YBAFDPFAUTYYRW-UHFFFAOYSA-N 0.000 description 1
- KZNQNBZMBZJQJO-UHFFFAOYSA-N N-glycyl-L-proline Natural products NCC(=O)N1CCCC1C(O)=O KZNQNBZMBZJQJO-UHFFFAOYSA-N 0.000 description 1
- 108091061960 Naked DNA Proteins 0.000 description 1
- 208000005890 Neuroma Diseases 0.000 description 1
- 108091034117 Oligonucleotide Proteins 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- HXSUFWQYLPKEHF-IHRRRGAJSA-N Phe-Asn-Arg Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CCCN=C(N)N)C(=O)O)N HXSUFWQYLPKEHF-IHRRRGAJSA-N 0.000 description 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
- BWTKUQPNOMMKMA-FIRPJDEBSA-N Phe-Ile-Phe Chemical compound C([C@H](N)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)C1=CC=CC=C1 BWTKUQPNOMMKMA-FIRPJDEBSA-N 0.000 description 1
- MSHZERMPZKCODG-ACRUOGEOSA-N Phe-Leu-Phe Chemical compound C([C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)C1=CC=CC=C1 MSHZERMPZKCODG-ACRUOGEOSA-N 0.000 description 1
- JLLJTMHNXQTMCK-UBHSHLNASA-N Phe-Pro-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@@H]1CCCN1C(=O)[C@@H](N)CC1=CC=CC=C1 JLLJTMHNXQTMCK-UBHSHLNASA-N 0.000 description 1
- WWPAHTZOWURIMR-ULQDDVLXSA-N Phe-Pro-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@@H](N)CC1=CC=CC=C1 WWPAHTZOWURIMR-ULQDDVLXSA-N 0.000 description 1
- 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
- IIEOLPMQYRBZCN-SRVKXCTJSA-N Phe-Ser-Cys Chemical compound N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CO)C(=O)N[C@@H](CS)C(=O)O IIEOLPMQYRBZCN-SRVKXCTJSA-N 0.000 description 1
- UNBFGVQVQGXXCK-KKUMJFAQSA-N Phe-Ser-Leu Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(O)=O UNBFGVQVQGXXCK-KKUMJFAQSA-N 0.000 description 1
- 108010039918 Polylysine Proteins 0.000 description 1
- TUYWCHPXKQTISF-LPEHRKFASA-N Pro-Cys-Pro Chemical compound C1C[C@H](NC1)C(=O)N[C@@H](CS)C(=O)N2CCC[C@@H]2C(=O)O TUYWCHPXKQTISF-LPEHRKFASA-N 0.000 description 1
- UAYHMOIGIQZLFR-NHCYSSNCSA-N Pro-Gln-Val Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](C(C)C)C(O)=O UAYHMOIGIQZLFR-NHCYSSNCSA-N 0.000 description 1
- VDGTVWFMRXVQCT-GUBZILKMSA-N Pro-Glu-Gln Chemical compound NC(=O)CC[C@@H](C(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H]1CCCN1 VDGTVWFMRXVQCT-GUBZILKMSA-N 0.000 description 1
- NXEYSLRNNPWCRN-SRVKXCTJSA-N Pro-Glu-Leu Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(O)=O NXEYSLRNNPWCRN-SRVKXCTJSA-N 0.000 description 1
- LGSANCBHSMDFDY-GARJFASQSA-N Pro-Glu-Pro Chemical compound C1C[C@H](NC1)C(=O)N[C@@H](CCC(=O)O)C(=O)N2CCC[C@@H]2C(=O)O LGSANCBHSMDFDY-GARJFASQSA-N 0.000 description 1
- CLNJSLSHKJECME-BQBZGAKWSA-N Pro-Gly-Ala Chemical compound OC(=O)[C@H](C)NC(=O)CNC(=O)[C@@H]1CCCN1 CLNJSLSHKJECME-BQBZGAKWSA-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
- OFGUOWQVEGTVNU-DCAQKATOSA-N Pro-Lys-Ala Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(O)=O OFGUOWQVEGTVNU-DCAQKATOSA-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
- RMODQFBNDDENCP-IHRRRGAJSA-N Pro-Lys-Leu Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(O)=O RMODQFBNDDENCP-IHRRRGAJSA-N 0.000 description 1
- ULWBBFKQBDNGOY-RWMBFGLXSA-N Pro-Lys-Pro Chemical compound C1C[C@H](NC1)C(=O)N[C@@H](CCCCN)C(=O)N2CCC[C@@H]2C(=O)O ULWBBFKQBDNGOY-RWMBFGLXSA-N 0.000 description 1
- MHHQQZIFLWFZGR-DCAQKATOSA-N Pro-Lys-Ser Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CO)C(O)=O MHHQQZIFLWFZGR-DCAQKATOSA-N 0.000 description 1
- PCWLNNZTBJTZRN-AVGNSLFASA-N Pro-Pro-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@H]1NCCC1 PCWLNNZTBJTZRN-AVGNSLFASA-N 0.000 description 1
- GOMUXSCOIWIJFP-GUBZILKMSA-N Pro-Ser-Arg Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O GOMUXSCOIWIJFP-GUBZILKMSA-N 0.000 description 1
- OWQXAJQZLWHPBH-FXQIFTODSA-N Pro-Ser-Asn Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(O)=O OWQXAJQZLWHPBH-FXQIFTODSA-N 0.000 description 1
- BGWKULMLUIUPKY-BQBZGAKWSA-N Pro-Ser-Gly Chemical compound OC(=O)CNC(=O)[C@H](CO)NC(=O)[C@@H]1CCCN1 BGWKULMLUIUPKY-BQBZGAKWSA-N 0.000 description 1
- SXJOPONICMGFCR-DCAQKATOSA-N Pro-Ser-Lys Chemical compound C1C[C@H](NC1)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCCN)C(=O)O SXJOPONICMGFCR-DCAQKATOSA-N 0.000 description 1
- IURWWZYKYPEANQ-HJGDQZAQSA-N Pro-Thr-Glu Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCC(O)=O)C(O)=O IURWWZYKYPEANQ-HJGDQZAQSA-N 0.000 description 1
- 239000012980 RPMI-1640 medium Substances 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
- QGMLKFGTGXWAHF-IHRRRGAJSA-N Ser-Arg-Phe Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O QGMLKFGTGXWAHF-IHRRRGAJSA-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
- OOKCGAYXSNJBGQ-ZLUOBGJFSA-N Ser-Asn-Asn Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O OOKCGAYXSNJBGQ-ZLUOBGJFSA-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
- 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
- QPFJSHSJFIYDJZ-GHCJXIJMSA-N Ser-Asp-Ile Chemical compound CC[C@H](C)[C@@H](C(O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@@H](N)CO QPFJSHSJFIYDJZ-GHCJXIJMSA-N 0.000 description 1
- OLIJLNWFEQEFDM-SRVKXCTJSA-N Ser-Asp-Phe Chemical compound OC[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 OLIJLNWFEQEFDM-SRVKXCTJSA-N 0.000 description 1
- TUYBIWUZWJUZDD-ACZMJKKPSA-N Ser-Cys-Gln Chemical compound OC[C@H](N)C(=O)N[C@@H](CS)C(=O)N[C@H](C(O)=O)CCC(N)=O TUYBIWUZWJUZDD-ACZMJKKPSA-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
- 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
- GZFAWAQTEYDKII-YUMQZZPRSA-N Ser-Gly-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)CNC(=O)[C@@H](N)CO GZFAWAQTEYDKII-YUMQZZPRSA-N 0.000 description 1
- XXXAXOWMBOKTRN-XPUUQOCRSA-N Ser-Gly-Val Chemical compound [H]N[C@@H](CO)C(=O)NCC(=O)N[C@@H](C(C)C)C(O)=O XXXAXOWMBOKTRN-XPUUQOCRSA-N 0.000 description 1
- QBUWQRKEHJXTOP-DCAQKATOSA-N Ser-His-Arg Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O QBUWQRKEHJXTOP-DCAQKATOSA-N 0.000 description 1
- GZSZPKSBVAOGIE-CIUDSAMLSA-N Ser-Lys-Ala Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(O)=O GZSZPKSBVAOGIE-CIUDSAMLSA-N 0.000 description 1
- 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 1
- XUDRHBPSPAPDJP-SRVKXCTJSA-N Ser-Lys-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](N)CO XUDRHBPSPAPDJP-SRVKXCTJSA-N 0.000 description 1
- FPCGZYMRFFIYIH-CIUDSAMLSA-N Ser-Lys-Ser Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CO)C(O)=O FPCGZYMRFFIYIH-CIUDSAMLSA-N 0.000 description 1
- CKDXFSPMIDSMGV-GUBZILKMSA-N Ser-Pro-Val Chemical compound [H]N[C@@H](CO)C(=O)N1CCC[C@H]1C(=O)N[C@@H](C(C)C)C(O)=O CKDXFSPMIDSMGV-GUBZILKMSA-N 0.000 description 1
- HHJFMHQYEAAOBM-ZLUOBGJFSA-N Ser-Ser-Ala Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H](C)C(O)=O HHJFMHQYEAAOBM-ZLUOBGJFSA-N 0.000 description 1
- 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
- CUXJENOFJXOSOZ-BIIVOSGPSA-N Ser-Ser-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CO)NC(=O)[C@H](CO)N)C(=O)O CUXJENOFJXOSOZ-BIIVOSGPSA-N 0.000 description 1
- XQJCEKXQUJQNNK-ZLUOBGJFSA-N Ser-Ser-Ser Chemical compound OC[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(O)=O XQJCEKXQUJQNNK-ZLUOBGJFSA-N 0.000 description 1
- DKGRNFUXVTYRAS-UBHSHLNASA-N Ser-Ser-Trp Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC1=CNC2=C1C=CC=C2)C(O)=O DKGRNFUXVTYRAS-UBHSHLNASA-N 0.000 description 1
- VGQVAVQWKJLIRM-FXQIFTODSA-N Ser-Ser-Val Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(O)=O VGQVAVQWKJLIRM-FXQIFTODSA-N 0.000 description 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
- 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 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
- PIQRHJQWEPWFJG-UWJYBYFXSA-N Ser-Tyr-Ala Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](C)C(O)=O PIQRHJQWEPWFJG-UWJYBYFXSA-N 0.000 description 1
- PLQWGQUNUPMNOD-KKUMJFAQSA-N Ser-Tyr-Leu Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC(C)C)C(O)=O PLQWGQUNUPMNOD-KKUMJFAQSA-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
- OSFZCEQJLWCIBG-BZSNNMDCSA-N Ser-Tyr-Tyr Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O OSFZCEQJLWCIBG-BZSNNMDCSA-N 0.000 description 1
- RCOUFINCYASMDN-GUBZILKMSA-N Ser-Val-Met Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCSC)C(O)=O RCOUFINCYASMDN-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
- 108010071390 Serum Albumin Proteins 0.000 description 1
- 102000007562 Serum Albumin Human genes 0.000 description 1
- 108010003723 Single-Domain Antibodies Proteins 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- DWYAUVCQDTZIJI-VZFHVOOUSA-N Thr-Ala-Ser Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](CO)C(O)=O DWYAUVCQDTZIJI-VZFHVOOUSA-N 0.000 description 1
- 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
- DSLHSTIUAPKERR-XGEHTFHBSA-N Thr-Cys-Val Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CS)C(=O)N[C@@H](C(C)C)C(O)=O DSLHSTIUAPKERR-XGEHTFHBSA-N 0.000 description 1
- 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
- VOHWDZNIESHTFW-XKBZYTNZSA-N Thr-Glu-Cys Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CS)C(=O)O)N)O VOHWDZNIESHTFW-XKBZYTNZSA-N 0.000 description 1
- GKWNLDNXMMLRMC-GLLZPBPUSA-N Thr-Glu-Gln Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CCC(=O)N)C(=O)O)N)O GKWNLDNXMMLRMC-GLLZPBPUSA-N 0.000 description 1
- 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
- WPSDXXQRIVKBAY-NKIYYHGXSA-N Thr-His-Glu Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)N[C@@H](CCC(=O)O)C(=O)O)N)O WPSDXXQRIVKBAY-NKIYYHGXSA-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
- PRNGXSILMXSWQQ-OEAJRASXSA-N Thr-Leu-Phe Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O PRNGXSILMXSWQQ-OEAJRASXSA-N 0.000 description 1
- NCXVJIQMWSGRHY-KXNHARMFSA-N Thr-Leu-Pro Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N1CCC[C@@H]1C(=O)O)N)O NCXVJIQMWSGRHY-KXNHARMFSA-N 0.000 description 1
- VRUFCJZQDACGLH-UVOCVTCTSA-N Thr-Leu-Thr Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O VRUFCJZQDACGLH-UVOCVTCTSA-N 0.000 description 1
- BDGBHYCAZJPLHX-HJGDQZAQSA-N Thr-Lys-Asn Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(O)=O BDGBHYCAZJPLHX-HJGDQZAQSA-N 0.000 description 1
- JLNMFGCJODTXDH-WEDXCCLWSA-N Thr-Lys-Gly Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCCN)C(=O)NCC(O)=O JLNMFGCJODTXDH-WEDXCCLWSA-N 0.000 description 1
- DXPURPNJDFCKKO-RHYQMDGZSA-N Thr-Lys-Val Chemical compound CC(C)[C@H](NC(=O)[C@H](CCCCN)NC(=O)[C@@H](N)[C@@H](C)O)C(O)=O DXPURPNJDFCKKO-RHYQMDGZSA-N 0.000 description 1
- 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 1
- MROIJTGJGIDEEJ-RCWTZXSCSA-N Thr-Pro-Pro Chemical compound C[C@@H](O)[C@H](N)C(=O)N1CCC[C@H]1C(=O)N1[C@H](C(O)=O)CCC1 MROIJTGJGIDEEJ-RCWTZXSCSA-N 0.000 description 1
- KERCOYANYUPLHJ-XGEHTFHBSA-N Thr-Pro-Ser Chemical compound C[C@@H](O)[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CO)C(O)=O KERCOYANYUPLHJ-XGEHTFHBSA-N 0.000 description 1
- 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 1
- ZESGVALRVJIVLZ-VFCFLDTKSA-N Thr-Thr-Pro Chemical compound C[C@H]([C@@H](C(=O)N[C@@H]([C@@H](C)O)C(=O)N1CCC[C@@H]1C(=O)O)N)O ZESGVALRVJIVLZ-VFCFLDTKSA-N 0.000 description 1
- COYHRQWNJDJCNA-NUJDXYNKSA-N Thr-Thr-Thr Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O COYHRQWNJDJCNA-NUJDXYNKSA-N 0.000 description 1
- BEZTUFWTPVOROW-KJEVXHAQSA-N Thr-Tyr-Arg Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC1=CC=C(C=C1)O)C(=O)N[C@@H](CCCN=C(N)N)C(=O)O)N)O BEZTUFWTPVOROW-KJEVXHAQSA-N 0.000 description 1
- RPECVQBNONKZAT-WZLNRYEVSA-N Thr-Tyr-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)[C@H](CC1=CC=C(C=C1)O)NC(=O)[C@H]([C@@H](C)O)N RPECVQBNONKZAT-WZLNRYEVSA-N 0.000 description 1
- CYCGARJWIQWPQM-YJRXYDGGSA-N Thr-Tyr-Ser Chemical compound C[C@@H](O)[C@H]([NH3+])C(=O)N[C@H](C(=O)N[C@@H](CO)C([O-])=O)CC1=CC=C(O)C=C1 CYCGARJWIQWPQM-YJRXYDGGSA-N 0.000 description 1
- 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 1
- KPMIQCXJDVKWKO-IFFSRLJSSA-N Thr-Val-Glu Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(O)=O)C(O)=O KPMIQCXJDVKWKO-IFFSRLJSSA-N 0.000 description 1
- HDTRYLNUVZCQOY-WSWWMNSNSA-N Trehalose Natural products O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-WSWWMNSNSA-N 0.000 description 1
- UKINEYBQXPMOJO-UBHSHLNASA-N Trp-Asn-Ser Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CO)C(=O)O)N UKINEYBQXPMOJO-UBHSHLNASA-N 0.000 description 1
- DQDXHYIEITXNJY-BPUTZDHNSA-N Trp-Gln-Gln Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H](CCC(=O)N)C(=O)O)N DQDXHYIEITXNJY-BPUTZDHNSA-N 0.000 description 1
- GQHAIUPYZPTADF-FDARSICLSA-N Trp-Ile-Arg Chemical compound C1=CC=C2C(C[C@H](N)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCCN=C(N)N)C(O)=O)=CNC2=C1 GQHAIUPYZPTADF-FDARSICLSA-N 0.000 description 1
- XGFGVFMXDXALEV-XIRDDKMYSA-N Trp-Leu-Asn Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)O)NC(=O)[C@H](CC1=CNC2=CC=CC=C21)N XGFGVFMXDXALEV-XIRDDKMYSA-N 0.000 description 1
- NLLARHRWSFNEMH-NUTKFTJISA-N Trp-Lys-Ala Chemical compound C[C@@H](C(=O)O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CC1=CNC2=CC=CC=C21)N NLLARHRWSFNEMH-NUTKFTJISA-N 0.000 description 1
- ULHASJWZGUEUNN-XIRDDKMYSA-N Trp-Lys-Ser Chemical compound [H]N[C@@H](CC1=CNC2=C1C=CC=C2)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CO)C(O)=O ULHASJWZGUEUNN-XIRDDKMYSA-N 0.000 description 1
- NLWCSMOXNKBRLC-WDSOQIARSA-N Trp-Lys-Val Chemical compound [H]N[C@@H](CC1=CNC2=C1C=CC=C2)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C(C)C)C(O)=O NLWCSMOXNKBRLC-WDSOQIARSA-N 0.000 description 1
- SSSDKJMQMZTMJP-BVSLBCMMSA-N Trp-Tyr-Val Chemical compound C([C@@H](C(=O)N[C@@H](C(C)C)C(O)=O)NC(=O)[C@@H](N)CC=1C2=CC=CC=C2NC=1)C1=CC=C(O)C=C1 SSSDKJMQMZTMJP-BVSLBCMMSA-N 0.000 description 1
- SCCKSNREWHMKOJ-SRVKXCTJSA-N Tyr-Asn-Ser Chemical compound N[C@@H](Cc1ccc(O)cc1)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CO)C(O)=O SCCKSNREWHMKOJ-SRVKXCTJSA-N 0.000 description 1
- SLCSPPCQWUHPPO-JYJNAYRXSA-N Tyr-Glu-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 SLCSPPCQWUHPPO-JYJNAYRXSA-N 0.000 description 1
- 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
- NSGZILIDHCIZAM-KKUMJFAQSA-N Tyr-Leu-Ser Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CO)C(=O)O)NC(=O)[C@H](CC1=CC=C(C=C1)O)N NSGZILIDHCIZAM-KKUMJFAQSA-N 0.000 description 1
- SINRIKQYQJRGDQ-MEYUZBJRSA-N Tyr-Lys-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 SINRIKQYQJRGDQ-MEYUZBJRSA-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
- 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
- RIVVDNTUSRVTQT-IRIUXVKKSA-N Tyr-Thr-Gln Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)O)NC(=O)[C@H](CC1=CC=C(C=C1)O)N)O RIVVDNTUSRVTQT-IRIUXVKKSA-N 0.000 description 1
- FZADUTOCSFDBRV-RNXOBYDBSA-N Tyr-Tyr-Trp Chemical compound C([C@H](N)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(O)=O)C1=CC=C(O)C=C1 FZADUTOCSFDBRV-RNXOBYDBSA-N 0.000 description 1
- SQUMHUZLJDUROQ-YDHLFZDLSA-N Tyr-Val-Asp Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(O)=O)C(O)=O SQUMHUZLJDUROQ-YDHLFZDLSA-N 0.000 description 1
- ZLFHAAGHGQBQQN-AEJSXWLSSA-N Val-Ala-Pro Chemical compound C[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](C(C)C)N ZLFHAAGHGQBQQN-AEJSXWLSSA-N 0.000 description 1
- GNWUWQAVVJQREM-NHCYSSNCSA-N Val-Asn-His Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)N GNWUWQAVVJQREM-NHCYSSNCSA-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
- SCBITHMBEJNRHC-LSJOCFKGSA-N Val-Asp-Val Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](C(C)C)C(=O)O)N SCBITHMBEJNRHC-LSJOCFKGSA-N 0.000 description 1
- 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
- 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
- VCAWFLIWYNMHQP-UKJIMTQDSA-N Val-Glu-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)O)NC(=O)[C@H](C(C)C)N VCAWFLIWYNMHQP-UKJIMTQDSA-N 0.000 description 1
- WDIGUPHXPBMODF-UMNHJUIQSA-N Val-Glu-Pro Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)N1CCC[C@@H]1C(=O)O)N WDIGUPHXPBMODF-UMNHJUIQSA-N 0.000 description 1
- 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 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
- UMPVMAYCLYMYGA-ONGXEEELSA-N Val-Leu-Gly Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)NCC(O)=O UMPVMAYCLYMYGA-ONGXEEELSA-N 0.000 description 1
- XTDDIVQWDXMRJL-IHRRRGAJSA-N Val-Leu-His Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)NC(=O)[C@H](C(C)C)N XTDDIVQWDXMRJL-IHRRRGAJSA-N 0.000 description 1
- SYSWVVCYSXBVJG-RHYQMDGZSA-N Val-Leu-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](C(C)C)N)O SYSWVVCYSXBVJG-RHYQMDGZSA-N 0.000 description 1
- RWOGENDAOGMHLX-DCAQKATOSA-N Val-Lys-Ala Chemical compound C[C@@H](C(=O)O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C(C)C)N RWOGENDAOGMHLX-DCAQKATOSA-N 0.000 description 1
- HPANGHISDXDUQY-ULQDDVLXSA-N Val-Lys-Phe Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)O)N HPANGHISDXDUQY-ULQDDVLXSA-N 0.000 description 1
- KISFXYYRKKNLOP-IHRRRGAJSA-N Val-Phe-Ser Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CO)C(=O)O)N KISFXYYRKKNLOP-IHRRRGAJSA-N 0.000 description 1
- 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 1
- GVNLOVJNNDZUHS-RHYQMDGZSA-N Val-Thr-Lys Chemical compound [H]N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCCN)C(O)=O GVNLOVJNNDZUHS-RHYQMDGZSA-N 0.000 description 1
- 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
- PDASTHRLDFOZMG-JYJNAYRXSA-N Val-Tyr-Met Chemical compound CSCC[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)C(C)C)CC1=CC=C(O)C=C1 PDASTHRLDFOZMG-JYJNAYRXSA-N 0.000 description 1
- ZHWZDZFWBXWPDW-GUBZILKMSA-N Val-Val-Cys Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CS)C(O)=O ZHWZDZFWBXWPDW-GUBZILKMSA-N 0.000 description 1
- LLJLBRRXKZTTRD-GUBZILKMSA-N Val-Val-Ser Chemical compound CC(C)[C@@H](C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CO)C(=O)O)N LLJLBRRXKZTTRD-GUBZILKMSA-N 0.000 description 1
- 241000251539 Vertebrata <Metazoa> Species 0.000 description 1
- 208000014070 Vestibular schwannoma Diseases 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- GKXVJHDEWHKBFH-UHFFFAOYSA-N [2-(aminomethyl)phenyl]methanamine Chemical compound NCC1=CC=CC=C1CN GKXVJHDEWHKBFH-UHFFFAOYSA-N 0.000 description 1
- JLCPHMBAVCMARE-UHFFFAOYSA-N [3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-hydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methyl [5-(6-aminopurin-9-yl)-2-(hydroxymethyl)oxolan-3-yl] hydrogen phosphate Polymers Cc1cn(C2CC(OP(O)(=O)OCC3OC(CC3OP(O)(=O)OCC3OC(CC3O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c3nc(N)[nH]c4=O)C(COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3CO)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cc(C)c(=O)[nH]c3=O)n3cc(C)c(=O)[nH]c3=O)n3ccc(N)nc3=O)n3cc(C)c(=O)[nH]c3=O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)O2)c(=O)[nH]c1=O JLCPHMBAVCMARE-UHFFFAOYSA-N 0.000 description 1
- 230000001594 aberrant effect Effects 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 108010081404 acein-2 Proteins 0.000 description 1
- 208000004064 acoustic neuroma Diseases 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000012190 activator Substances 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 238000001042 affinity chromatography Methods 0.000 description 1
- 108010044940 alanylglutamine Proteins 0.000 description 1
- 108010047495 alanylglycine Proteins 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- HDTRYLNUVZCQOY-LIZSDCNHSA-N alpha,alpha-trehalose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-LIZSDCNHSA-N 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
- 210000004381 amniotic fluid Anatomy 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 238000011319 anticancer therapy Methods 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 238000000149 argon plasma sintering Methods 0.000 description 1
- 210000003567 ascitic fluid Anatomy 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 108010077245 asparaginyl-proline Proteins 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- 230000001363 autoimmune Effects 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 229960000686 benzalkonium chloride Drugs 0.000 description 1
- 229960001950 benzethonium chloride Drugs 0.000 description 1
- UREZNYTWGJKWBI-UHFFFAOYSA-M benzethonium chloride Chemical compound [Cl-].C1=CC(C(C)(C)CC(C)(C)C)=CC=C1OCCOCC[N+](C)(C)CC1=CC=CC=C1 UREZNYTWGJKWBI-UHFFFAOYSA-M 0.000 description 1
- 235000019445 benzyl alcohol Nutrition 0.000 description 1
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- 230000001588 bifunctional effect Effects 0.000 description 1
- 238000010170 biological method Methods 0.000 description 1
- 239000000090 biomarker Substances 0.000 description 1
- 229960002685 biotin Drugs 0.000 description 1
- 239000011616 biotin Substances 0.000 description 1
- HUTDDBSSHVOYJR-UHFFFAOYSA-H bis[(2-oxo-1,3,2$l^{5},4$l^{2}-dioxaphosphaplumbetan-2-yl)oxy]lead Chemical compound [Pb+2].[Pb+2].[Pb+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O HUTDDBSSHVOYJR-UHFFFAOYSA-H 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 239000012503 blood component Substances 0.000 description 1
- 210000001124 body fluid Anatomy 0.000 description 1
- 239000010839 body fluid Substances 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 235000014633 carbohydrates Nutrition 0.000 description 1
- 230000003915 cell function Effects 0.000 description 1
- 230000006037 cell lysis Effects 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 210000001175 cerebrospinal fluid Anatomy 0.000 description 1
- 239000002738 chelating agent Substances 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 210000004978 chinese hamster ovary cell Anatomy 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 150000001860 citric acid derivatives Chemical class 0.000 description 1
- 102000004361 claudin 10 Human genes 0.000 description 1
- 108090000999 claudin 10 Proteins 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 238000002648 combination therapy Methods 0.000 description 1
- 230000024203 complement activation Effects 0.000 description 1
- 230000004154 complement system Effects 0.000 description 1
- 230000004540 complement-dependent cytotoxicity Effects 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- HPXRVTGHNJAIIH-UHFFFAOYSA-N cyclohexanol Chemical compound OC1CCCCC1 HPXRVTGHNJAIIH-UHFFFAOYSA-N 0.000 description 1
- 125000000151 cysteine group Chemical group N[C@@H](CS)C(=O)* 0.000 description 1
- 229940127089 cytotoxic agent Drugs 0.000 description 1
- 231100000599 cytotoxic agent Toxicity 0.000 description 1
- 239000002619 cytotoxin Substances 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 238000000432 density-gradient centrifugation Methods 0.000 description 1
- 235000019425 dextrin Nutrition 0.000 description 1
- UQLDLKMNUJERMK-UHFFFAOYSA-L di(octadecanoyloxy)lead Chemical compound [Pb+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O UQLDLKMNUJERMK-UHFFFAOYSA-L 0.000 description 1
- FSXRLASFHBWESK-UHFFFAOYSA-N dipeptide phenylalanyl-tyrosine Natural products C=1C=C(O)C=CC=1CC(C(O)=O)NC(=O)C(N)CC1=CC=CC=C1 FSXRLASFHBWESK-UHFFFAOYSA-N 0.000 description 1
- 150000002016 disaccharides Chemical class 0.000 description 1
- 230000005750 disease progression Effects 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 238000004520 electroporation Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 239000003623 enhancer Substances 0.000 description 1
- 210000003527 eukaryotic cell Anatomy 0.000 description 1
- 210000003722 extracellular fluid Anatomy 0.000 description 1
- 239000003889 eye drop Substances 0.000 description 1
- 238000005206 flow analysis Methods 0.000 description 1
- MHMNJMPURVTYEJ-UHFFFAOYSA-N fluorescein-5-isothiocyanate Chemical compound O1C(=O)C2=CC(N=C=S)=CC=C2C21C1=CC=C(O)C=C1OC1=CC(O)=CC=C21 MHMNJMPURVTYEJ-UHFFFAOYSA-N 0.000 description 1
- 239000007850 fluorescent dye Substances 0.000 description 1
- 230000002538 fungal effect Effects 0.000 description 1
- 230000004927 fusion Effects 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 210000004602 germ cell Anatomy 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 1
- 108010055341 glutamyl-glutamic acid Proteins 0.000 description 1
- 108020004445 glyceraldehyde-3-phosphate dehydrogenase Proteins 0.000 description 1
- 102000006602 glyceraldehyde-3-phosphate dehydrogenase Human genes 0.000 description 1
- 230000013595 glycosylation Effects 0.000 description 1
- 238000006206 glycosylation reaction Methods 0.000 description 1
- 108010027668 glycyl-alanyl-valine Proteins 0.000 description 1
- 108010051307 glycyl-glycyl-proline Proteins 0.000 description 1
- 108010010096 glycyl-glycyl-tyrosine Proteins 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
- 201000005787 hematologic cancer Diseases 0.000 description 1
- 208000024200 hematopoietic and lymphoid system neoplasm Diseases 0.000 description 1
- 231100000844 hepatocellular carcinoma Toxicity 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 1
- 102000047486 human GAPDH Human genes 0.000 description 1
- 229920001477 hydrophilic polymer Polymers 0.000 description 1
- 230000003463 hyperproliferative effect Effects 0.000 description 1
- 238000003384 imaging method Methods 0.000 description 1
- 210000002865 immune cell Anatomy 0.000 description 1
- 230000007124 immune defense Effects 0.000 description 1
- 230000028993 immune response Effects 0.000 description 1
- 208000026278 immune system disease Diseases 0.000 description 1
- 238000002649 immunization Methods 0.000 description 1
- 230000003053 immunization Effects 0.000 description 1
- 238000003018 immunoassay Methods 0.000 description 1
- 238000003119 immunoblot Methods 0.000 description 1
- 239000000568 immunological adjuvant Substances 0.000 description 1
- 239000002955 immunomodulating agent Substances 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000002458 infectious effect Effects 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000001361 intraarterial administration Methods 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 108010027338 isoleucylcysteine Proteins 0.000 description 1
- 238000005304 joining Methods 0.000 description 1
- 108010034529 leucyl-lysine Proteins 0.000 description 1
- 108010091871 leucylmethionine Proteins 0.000 description 1
- 108010057821 leucylproline Proteins 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 108010003700 lysyl aspartic acid Proteins 0.000 description 1
- 230000003211 malignant effect Effects 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 239000003550 marker Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 102000006240 membrane receptors Human genes 0.000 description 1
- 108020004084 membrane receptors Proteins 0.000 description 1
- 108020004999 messenger RNA Proteins 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 230000009401 metastasis Effects 0.000 description 1
- 208000037819 metastatic cancer Diseases 0.000 description 1
- 208000011575 metastatic malignant neoplasm Diseases 0.000 description 1
- 229930182817 methionine Natural products 0.000 description 1
- 108010056582 methionylglutamic acid Proteins 0.000 description 1
- 108010005942 methionylglycine Proteins 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 1
- 229960002216 methylparaben Drugs 0.000 description 1
- 239000004530 micro-emulsion Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 238000010369 molecular cloning Methods 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 150000002772 monosaccharides Chemical class 0.000 description 1
- 229940126619 mouse monoclonal antibody Drugs 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- 238000007857 nested PCR Methods 0.000 description 1
- 230000000626 neurodegenerative effect Effects 0.000 description 1
- 239000002736 nonionic surfactant Substances 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
- 210000000633 nuclear envelope Anatomy 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- LXCFILQKKLGQFO-UHFFFAOYSA-N p-hydroxybenzoic acid methyl ester Natural products COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 1
- 230000003725 paracellular diffusion Effects 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 108010073025 phenylalanylphenylalanine Proteins 0.000 description 1
- 235000021317 phosphate Nutrition 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 238000007747 plating Methods 0.000 description 1
- 229920001983 poloxamer Polymers 0.000 description 1
- 229920000656 polylysine Polymers 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 230000036515 potency Effects 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 238000004393 prognosis Methods 0.000 description 1
- 108010029020 prolylglycine Proteins 0.000 description 1
- 108010053725 prolylvaline Proteins 0.000 description 1
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 1
- 239000004405 propyl p-hydroxybenzoate Substances 0.000 description 1
- 229960003415 propylparaben Drugs 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000003259 recombinant expression Methods 0.000 description 1
- 238000005215 recombination Methods 0.000 description 1
- 230000006798 recombination Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 230000022532 regulation of transcription, DNA-dependent Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000003362 replicative effect Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 108010048818 seryl-histidine Proteins 0.000 description 1
- 108010026333 seryl-proline Proteins 0.000 description 1
- 238000011125 single therapy Methods 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 229910001415 sodium ion Inorganic materials 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 230000009870 specific binding Effects 0.000 description 1
- SFVFIFLLYFPGHH-UHFFFAOYSA-M stearalkonium chloride Chemical compound [Cl-].CCCCCCCCCCCCCCCCCC[N+](C)(C)CC1=CC=CC=C1 SFVFIFLLYFPGHH-UHFFFAOYSA-M 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 210000002536 stromal cell Anatomy 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000036964 tight binding Effects 0.000 description 1
- 230000001256 tonic effect Effects 0.000 description 1
- 239000003053 toxin Substances 0.000 description 1
- 231100000765 toxin Toxicity 0.000 description 1
- 108700012359 toxins Proteins 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- 230000005026 transcription initiation Effects 0.000 description 1
- 230000002103 transcriptional effect Effects 0.000 description 1
- 230000009261 transgenic effect Effects 0.000 description 1
- 230000014621 translational initiation Effects 0.000 description 1
- 108091005703 transmembrane proteins Proteins 0.000 description 1
- 102000035160 transmembrane proteins Human genes 0.000 description 1
- 230000005909 tumor killing Effects 0.000 description 1
- 108010079202 tyrosyl-alanyl-cysteine Proteins 0.000 description 1
- 108010051110 tyrosyl-lysine Proteins 0.000 description 1
- 238000011144 upstream manufacturing Methods 0.000 description 1
- 239000013603 viral vector Substances 0.000 description 1
- 210000002845 virion Anatomy 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- 238000001262 western blot Methods 0.000 description 1
- 210000005253 yeast cell Anatomy 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
- A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
- A61K39/3955—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against proteinaceous materials, e.g. enzymes, hormones, lymphokines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/30—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants from tumour cells
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
- C12N15/09—Recombinant DNA-technology
- C12N15/63—Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
- C07K2317/565—Complementarity determining region [CDR]
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
- C07K2317/567—Framework region [FR]
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Organic Chemistry (AREA)
- Medicinal Chemistry (AREA)
- Immunology (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Engineering & Computer Science (AREA)
- Biochemistry (AREA)
- Biophysics (AREA)
- Molecular Biology (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Microbiology (AREA)
- Biotechnology (AREA)
- Biomedical Technology (AREA)
- General Chemical & Material Sciences (AREA)
- Zoology (AREA)
- Mycology (AREA)
- Epidemiology (AREA)
- Wood Science & Technology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Engineering & Computer Science (AREA)
- Endocrinology (AREA)
- Physics & Mathematics (AREA)
- Plant Pathology (AREA)
- Cell Biology (AREA)
- Peptides Or Proteins (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
Abstract
本申请涉及一种分离的抗原结合蛋白,具有能够特异性结合细胞表面的Claudin18.2、对Claudin18.2阳性肿瘤细胞显示CDC效应、对Claudin18.2阳性肿瘤细胞诱导ADCC效应,并具有抑制Claudin18.2阳性肿瘤的生长的效果。
Description
技术领域
本申请涉及生物医药领域,具体涉及一种针对Claudin18.2的抗体及其用途。
背景技术
密蛋白(Claudin)是一类建立细胞旁屏障并控制细胞间分子流动的细胞表面蛋白家族。Claudin是紧密结合的必要成分,在保持上皮细胞极性、控制细胞旁扩散以及调控细胞生长分化方面起到重要作用。不同的Claudins在不同组织中表达,其改变的功能与各组织的癌症形成有关。Claudin-1表达已被证明在结肠癌,Claudin-18在胃癌,Claudin-10在肝细胞癌中具有预后价值。因此claudins也成为了一类有前景的治疗靶点。Claudin18有2个变体,其中Claudin18.1在正常肺和胃的上皮中选择性表达,Claudin18.2仅在正常胃上皮的分化短寿细胞中有微量表达,但在多种肿瘤中可发现Claudin18.2呈现强烈表达,如在胃癌患者中有75%呈高表达,胰腺癌患者中50%呈高表达,食管癌患者中30%呈高表达,肺癌患者中也有一定程度的高表达。
CN103509114A公开了用于治疗癌症的针对密蛋白-18的单克隆抗体,其中公开的175D10抗体,即为Astellas公司目前用于临床试验的IMAB362,该抗体表现出特异性结合CLD18.2并介导杀伤表达CLD18.2的细胞的活性。开发特异性针对Claudin18.2的抗体是对未被满足的医学需求的补充。并且还需要活性更好,包括结合活性、效应细胞活性、肿瘤杀伤活性、药效等方面性能更好的针对Claudin18.2的抗体,以满足本领域病人治疗,及治疗相关需求。
发明内容
本申请提供一种针对Claudin18.2的抗体及其用途,包括针对Claudin18.2特异性活性高的分离的抗原结合蛋白、核酸分子、载体、细胞,及其制备方法、药物组合物和用途。
本申请提供了一种分离的抗原结合蛋白,其具有下述性质中的一种或多种:
1)在FACS测定中,能够特异性结合细胞表面的Claudin18.2;
2)在FACS测定中,不结合细胞表面的Claudin18.1;
3)对Claudin18.2阳性肿瘤细胞显示CDC效应;
4)对Claudin18.1阳性肿瘤细胞不显示CDC效应;
5)对Claudin18.2阳性肿瘤细胞诱导ADCC效应;
6)抑制Claudin18.2阳性肿瘤的生长。
在某些实施方式中,所述分离的抗原结合蛋白选自抗体或其抗原结合片段。
在某些实施方式中,所述抗体选自嵌合抗体、人源化抗体或全人源抗体,优选为全人源抗体。
在某些实施方式中,所述抗原结合片段选自Fab、Fab’、F(ab)2、Fv片段、F(ab’)2、scFv、di-scFv或dAb。
在某些实施方式中,所述分离的抗原结合蛋白包含重链可变区VH,所述VH包含至少一个如下HCDR:
HCDR1,其氨基酸序列如SEQ ID NO:2或SEQ ID NO:12所示,或包含SEQ ID NO:2或SEQ ID NO:12所示氨基酸序列;
HCDR2,其氨基酸序列如SEQ ID NO:3或SEQ ID NO:13所示,或包含SEQ ID NO:3或SEQ ID NO:13所示氨基酸序列;
HCDR3,其氨基酸序列如SEQ ID NO:4或SEQ ID NO:14所示,或包含SEQ ID NO:4或SEQ ID NO:14所示氨基酸序列;
在某些实施方式中,所述分离的抗原结合蛋白的包含轻链可变区VL,所述VL包含至少一个如下LCDR:
LCDR1,其氨基酸序列如SEQ ID NO:7或SEQ ID NO:17所示,或包含SEQ ID NO:7或SEQ ID NO:17所示氨基酸序列;
LCDR2,其氨基酸序列如SEQ ID NO:8或SEQ ID NO:18所示,或包含SEQ ID NO:8或SEQ ID NO:18所示氨基酸序列;
LCDR3,其氨基酸序列如SEQ ID NO:9或SEQ ID NO:19所示,或包含SEQ ID NO:9或SEQ ID NO:19所示氨基酸序列。
在某些实施方式中,所述VH包含分别如SEQ ID NO:2、SEQ ID NO:3和SEQ ID NO:4所示的HCDR1、HCDR2和HCDR3。
在某些实施方式中,所述VH包含分别如SEQ ID NO:12、SEQ ID NO:13和SEQ IDNO:14所示的HCDR1、HCDR2和HCDR3。
在某些实施方式中,所述VL包含分别如SEQ ID NO:7、SEQ ID NO:8和SEQ ID NO:9所示的LCDR1、LCDR2和LCDR3。
在某些实施方式中,所述VL包含分别如SEQ ID NO:17、SEQ ID NO:18和SEQ IDNO:19所示的LCDR1、LCDR2和LCDR3。
在某些实施方式中,所述VH包含分别如SEQ ID NO:2、SEQ ID NO:3和SEQ ID NO:4所示的HCDR1、HCDR2和HCDR3,且所述VL包含分别如SEQ ID NO:7、SEQ ID NO:8和SEQ IDNO:9所示的LCDR1、LCDR2和LCDR3。
在某些实施方式中,所述VH包含分别如SEQ ID NO:12、SEQ ID NO:13和SEQ IDNO:14所示的HCDR1、HCDR2和HCDR3;且所述VL包含分别如SEQ ID NO:17、SEQ ID NO:18和SEQ ID NO:19所示的LCDR1、LCDR2和LCDR3。
在某些实施方式中,所述的分离的抗原结合蛋白的VH包括框架区H-FR1、H-FR2、H-FR3和H-FR4。
在某些实施方式中,所述H-FR1的C末端与所述HCDR1的N末端直接或间接相连,且所述H-FR1包含SEQ ID NO:21或29所示氨基酸序列。
在某些实施方式中,所述H-FR2位于所述HCDR1与所述HCDR2之间,且所述H-FR2包含SEQ ID NO:22或30所示氨基酸序列。
在某些实施方式中,所述H-FR3位于所述HCDR2与所述HCDR3之间,且所述H-FR3包含SEQ ID NO:23或31所示氨基酸序列。
在某些实施方式中,所述H-FR4的N末端与所述HCDR3的C末端直接或间接相连,且所述H-FR4包含SEQ ID NO:24或32所示氨基酸序列。
在某些实施方式中,所述的分离的抗原结合蛋白的VL包括框架区L-FR1、L-FR2、L-FR3和L-FR4。
在某些实施方式中,所述L-FR1的C末端与所述LCDR1的N末端直接或间接相连,且所述L-FR1包含SEQ ID NO:25或33所示氨基酸序列。
在某些实施方式中,所述L-FR2位于所述LCDR1与所述LCDR2之间,且所述L-FR2包含SEQ ID NO:26或34所示氨基酸序列。
在某些实施方式中,所述L-FR3位于所述LCDR2与所述LCDR3之间,且所述L-FR3包含SEQ ID NO:27或35所示氨基酸序列。
在某些实施方式中,所述L-FR4的N末端与所述LCDR3的C末端直接或间接相连,且所述L-FR4包含SEQ ID NO:28或36所示氨基酸序列。
在某些实施方式中,所述VH包含SEQ ID NO:1或11所示氨基酸序列。
在某些实施方式中,所述VL包含SEQ ID NO:6或16所示氨基酸序列。
在某些实施方式中,所述VH的氨基酸序列如SEQ ID NO:1所示,且所述VL的氨基酸序列如SEQ ID NO:6所示。
在某些实施方式中,所述VH的氨基酸序列如SEQ ID NO:11所示,且所述VL的氨基酸序列如SEQ ID NO:16所示。
在某些实施方式中,所述分离的抗原结合蛋白进一步包含抗体重链恒定区,所述抗体重链恒定区选自人IgG恒定区、IgA恒定区、IgM恒定区、IgD恒定区或IgE恒定区,所述人IgG恒定区进一步选自人IgG1恒定区、IgG2恒定区、IgG3恒定区或IgG4恒定区;
在某些实施方式中,所述抗体重链恒定区包含SEQ ID NO:37所示的氨基酸序列;
在某些实施方式中,所述分离的抗原结合蛋白包含抗体轻链恒定区,所述抗体轻链恒定区选自人Igκ恒定区或人Igλ恒定区。
在某些实施方式中,所述抗体轻链恒定区包含SEQ ID NO:38或39所示的氨基酸序列。
在某些实施方式中,所述分离的抗原结合蛋白包含抗体重链HC和抗体轻链LC。
在某些实施方式中,所述HC包含SEQ ID NO:5或15所示氨基酸序列。
在某些实施方式中,所述LC包含SEQ ID NO:10或20所示氨基酸序列。
在某些实施方式中,所述HC包含SEQ ID NO:5所示氨基酸序列,且所述LC包含SEQID NO:10所示氨基酸序列。
在某些实施方式中,所述HC包含SEQ ID NO:15所示的氨基酸序列,且所述LC包含SEQ ID NO:20所示的氨基酸序列。
另一方面,本申请提供了免疫缀合物,其包含本申请任一项所述的分离的抗原结合蛋白。
另一方面,本申请提供了分离的核酸分子,其编码本申请任一项所述的分离的抗原结合蛋白或所述的免疫缀合物。
另一方面,本申请提供了载体,其包含本申请所述的核酸分子。
另一方面,本申请提供了细胞,其包含本申请所述的核酸分子或所述的载体。
另一方面,本申请提供了制备所述分离的抗原结合蛋白方法,所述方法包括在使得本申请所述的分离的抗原结合蛋白表达的条件下,培养所述的细胞。
另一方面,本申请提供了药物组合物,其包含本申请所述的分离的抗原结合蛋白、所述的免疫缀合物、所述的核酸分子、所述的载体或所述的细胞,以及任选地药学上可接受的佐剂。
另一方面,本申请提供了所述的分离的抗原结合蛋白、所述的免疫缀合物、所述的核酸分子、所述的载体、所述的细胞或所述的药物组合物在制备药物中的用途,所述药物用于预防、诊断、缓解或治疗肿瘤。
另一方面,本申请提供了所述的分离的抗原结合蛋白、所述的免疫缀合物、所述的核酸分子、所述的载体、所述的细胞和/或所述的药物组合物在制备药物中的用途,所述肿瘤包括实体瘤和/或血液肿瘤。
另一方面,本申请提供了所述的分离的抗原结合蛋白、所述的免疫缀合物、所述的核酸分子、所述的载体、所述的细胞和/或所述的药物组合物在制备药物中的用途,所述实体瘤包括肺癌、结肠癌、肝癌、食管癌、卵巢癌、膀胱癌、胃癌、肾癌和/或胰腺癌。
另一方面,本申请提供了预防、诊断、缓解和/或治疗肿瘤的方法,其包括以有效治疗癌症的量向需要其的对象施用所述的分离的抗原结合蛋白、所述的免疫缀合物、所述的核酸分子、所述的载体、所述的细胞或所述的药物组合物。
另一方面,本申请提供了施用所述的分离的抗原结合蛋白、所述的免疫缀合物、所述的核酸分子、所述的载体、所述的细胞和/或所述的药物组合物用于预防、诊断、缓解和/或治疗肿瘤的方法,所述肿瘤包括实体瘤和/或血液肿瘤。
另一方面,本申请提供了施用所述的分离的抗原结合蛋白、所述的免疫缀合物、所述的核酸分子、所述的载体、所述的细胞或所述的药物组合物用于预防、诊断、缓解和/或治疗肿瘤的方法,所述实体瘤包括肺癌、结肠癌、肝癌、食管癌、卵巢癌、膀胱癌、胃癌、肾癌和/或胰腺癌。
另一方面,本申请提供了所述的分离的抗原结合蛋白、所述的免疫缀合物、所述的核酸分子、所述的载体、所述的细胞或所述的药物组合物,其用于预防、诊断、缓解和/或治疗肿瘤。
另一方面,本申请提供了所述的分离的抗原结合蛋白、所述的免疫缀合物、所述的核酸分子、所述的载体、所述的细胞或所述的药物组合物,其用于预防、诊断、缓解和/或治疗肿瘤,所述肿瘤包括实体瘤和/或血液肿瘤。
另一方面,本申请提供了所述的分离的抗原结合蛋白、所述的免疫缀合物、所述的核酸分子、所述的载体、所述的细胞或所述的药物组合物,其用于预防、诊断、缓解或治疗肿瘤,所述实体瘤包括肺癌、结肠癌、肝癌、食管癌、卵巢癌、膀胱癌、胃癌、肾癌和/或胰腺癌。
另一方面,本申请提供了抑制Claudin18.2阳性肿瘤细胞的生长和/或杀伤所述Claudin18.2阳性肿瘤细胞的方法,包括使所述Claudin18.2阳性肿瘤细胞接触所述的分离的抗原结合蛋白或所述的免疫缀合物。
本申请提供的分离的抗原结合蛋白具有的有益效果包括以下一种或多种:能够特异性结合细胞表面的Claudin18.2、不结合细胞表面的Claudin18.1、对Claudin18.2阳性肿瘤细胞显示CDC效应、对Claudin18.1阳性肿瘤细胞不显示CDC效应、对Claudin18.2阳性肿瘤细胞诱导ADCC效应和/或抑制Claudin18.2阳性肿瘤的生长。
本领域技术人员能够从下文的详细描述中容易地洞察到本申请的其它方面和优势。下文的详细描述中仅显示和描述了本申请的示例性实施方式。如本领域技术人员将认识到的,本申请的内容使得本领域技术人员能够对所公开的具体实施方式进行改动而不脱离本申请所涉及发明的精神和范围。相应地,本申请的附图和说明书中的描述仅仅是示例性的,而非为限制性的。
附图说明
图1显示的是本申请所述抗Claudin18.2抗体与Claudin18.2阳性HEK293细胞的亲和力。
图2显示的是本申请所述抗体HDR002C04与Claudin18.1阳性HEK293细胞或Claudin18.2阳性HEK293细胞的亲和力。
图3显示的是本申请所述抗体HDR002C06与Claudin18.1阳性HEK293细胞或Claudin18.2阳性HEK293细胞的亲和力。
图4显示的是本申请所述抗Claudin18.2抗体对Claudin18.2阳性HEK293细胞发挥CDC活性。
图5显示的是本申请所述抗Claudin18.2抗体对Claudin18.2阳性BxPC3细胞发挥CDC活性。
图6显示的是本申请所述抗Claudin18.2抗体对Claudin18.2阳性N87细胞发挥CDC活性。
图7显示的是本申请所述抗体HDR002C04的特异性CDC活性。
图8显示的是本申请所述抗体HDR002C06的特异性CDC活性。
图9显示的是本申请所述抗Claudin18.2抗体对Claudin18.2阳性BxPC3细胞发挥ADCC活性。
图10显示的是本申请所述抗Claudin18.2抗体对Claudin18.2阳性N87细胞发挥ADCC活性。
图11显示的是本申请所述抗体HDR002C04抑制肿瘤体积生长效果。
图12显示的是本申请所述抗体HDR002C04抑制肿瘤重量增加效果。
图13显示的是本申请所述抗体HDR002C06抑制肿瘤体积生长效果。
图14显示的是本申请所述抗体HDR002C06抑制肿瘤重量增加效果。
具体实施方式
以下由特定的具体实施例说明本申请发明的实施方式,熟悉此技术的人士可由本说明书所公开的内容容易地了解本申请发明的其他优点及效果。
术语定义
为了更容易理解本发明,以下具体定义了某些技术和科学术语。除显而易见在本文件中另有明确定义,否则本文使用的所有技术和科学术语都具有本发明所属领域的一般技术人员通常理解的含义。
本申请的术语“Claudin18.2蛋白”是位于细胞膜上的一个跨膜蛋,在正常的组织中仅表达在分化的胃粘膜上皮细胞上,在原发胃癌及转移癌症中大部分都表达。除此之外,肺癌、胰腺癌,卵巢癌中也能观察到Claudin18.2蛋白的激活表达。
在本申请中,术语“不结合”或“基本不结合”蛋白或细胞是指,不与蛋白或细胞结合,或者不以高亲和力与其结合,即结合蛋白或细胞的KD为1.0x10-6M以上,可以是1.0x10-5M以上,可以是1.0x10-4M以上、1.0x10-3M以上,可以是1.0x10-2M以上。
在本申请中,术语“参比抗体”通常是指与本申请中涉及的蛋白质、多肽和/或氨基酸序列具备相同或类似功能的变体或同源物,本申请所述抗原结合蛋白与参比抗体竞争结合抗原Claudin18.2蛋白。本申请的术语“分离的抗原结合蛋白”是指基本不含具有不同抗原特异性的其他抗原结合蛋白的抗原结合蛋白。例如,与Claudin18.2蛋白特异结合的分离抗原结合蛋白基本不含特异结合Claudin18.2蛋白之外抗原的抗原结合蛋白。但是,特异结合人Claudin18.2蛋白的分离抗原结合蛋白可能对其他抗原例如其他物种的Claudin18.2蛋白具有交叉结合性。
在本申请中,术语“恒定区”通常是指相对于该免疫球蛋白分子的其它部分或含有抗原结合位点的可变区,具有更保守的氨基酸序列的免疫球蛋白分子部分。恒定区含有重链的CH1、CH2和CH3结构域和轻链的CL结构域。
在本申请中,术语“诊断”包括,例如,诊断或检测与Claudin18.2表达有关或由其介导的病理学过度增生性形成肿瘤的障碍的存在,监测疾病的进展,和鉴别或检测指示与Claudin18.2表达有关的障碍的细胞或样品。术语“诊断”、“检测”、“鉴别”等在本文中互换使用。
在本申请中,术语“缓解”指减少、缩减或消除某病状、疾病、病症或表型,包括畸形或症状。
在本申请中,术语“抗体”、“Ig”或“免疫球蛋白”是指包括全长抗体及其任何抗原结合片段(即,抗原结合部分)或单链。此类抗体包括但不限于全人源抗体、灵长类化抗体、嵌合抗体、单克隆抗体、单特异性抗体、多克隆抗体、多特异性抗体、非特异性抗体、双特异性抗体、多特异性抗体、人源化抗体、合成抗体、重组抗体、杂合抗体、突变型抗体、嫁接偶联抗体(即偶联或融合至其它蛋白质、放射性标记物、细胞毒素的抗体)和体外生成的抗体。抗体可来自任何类的抗体,包括但不限于IgG、IgA、IgM、IgD、和IgE,及来自任何亚类(例如IgG1、IgG2、IgG3、和IgG4)的抗体。抗体可具有选自例如IgG1、IgG2、IgG3、或IgG4的重链恒定区。抗体还可具有选自例如卡帕(κ)或拉姆达(λ)的轻链。本发明的抗体可衍生自任何物种,包括但不限于小鼠、人、骆驼、美洲驼、鱼、鲨鱼、山羊、家兔、鸡、和牛。抗体的恒定区可进行改变,例如突变,以修饰抗体的特性(例如以提高或降低下述一项或多项:Fc受体结合、抗体糖基化、半胱氨酸残基的数目、效应器细胞功能、或补体功能)。通常,抗体特异性结合预定抗原,例如与病症有关的抗原,病症例如炎性的、免疫性的、自身免疫性的、神经变性性的、代谢的、和/或恶性的病症。全长抗体是包含至少两条重链(HC)和两条轻链(LC)的糖蛋白,重链和轻链由二硫键连接。各重链由重链可变区(简称VH或VH)和重链恒定区构成。重链恒定区由三个结构域构成,即CH1、CH2和CH3。各轻链由轻链可变区(简称VL或VL)和轻链恒定区构成。轻链恒定区由一个结构域CL构成。VH和VL区还可以划分为称作互补决定区(CDR)的高变区,其由较为保守的骨架区(FR)区分隔开。各VH和VL由三个CDR以及四个FR构成,从氨基端到羧基端以FR1、CDR1、FR2、CDR2、FR3、CDR3、FR4的顺序排布。重链和轻链的可变区包含与抗原相互作用的结合域。抗体的恒定区可以介导免疫球蛋白与宿主组织或因子的结合,包括多种免疫系统细胞(例如,效应细胞)和传统补体系统的第一组分(C1q)。
在本申请中,术语“嵌合抗体”通常是指其轻链和重链基因通过基因工程从属于不同物种的免疫球蛋白基因区段已被构建的抗体。例如,小鼠单克隆抗体基因的可变区(V)区段可能结合人恒定(C)区段如IgG1和IgG4。例如可以是人同种型IgG1。因此,典型的嵌合抗体是由小鼠抗体V或抗原结合结构域和人抗体的C或效应子结构域的杂种蛋白。
在本申请中,术语“人源化抗体”是指这样的抗体,与亲本免疫球蛋白的CDR相比较,其中构架或“互补决定区”(CDR)已经被修饰成包括不同特异性的免疫球蛋白CDR。在另一个实施方案中,将小鼠CDR移植到人抗体的构架区,以制备所述“人源化抗体”。参见,例如,Riechmann,L,等.,Nature332(1988)323-327;和Neuberger,M.S.,等.,Nature314(1985)268-270。另外,CDRs对应代表识别上文提及的抗原序列的那些,所述抗原针对嵌合的和双功能抗体。本发明包括的其它形式的“人源化抗体”是其中的恒定区已经从初始抗体的恒定区另外修饰或改变,以产生按照本发明的特性,特别是关于Clq结合和/或Fc受体(FcR)结合的特性的那些抗体。
在本申请中,术语“抗原结合蛋白”是指由识别并特异性地结合至靶标例如Claudin18.2的一种或多种多肽构成的分子,如抗Claudin18.2抗体或其抗原结合片段。
在本申请中,术语“抗原结合片段”(或简称为“抗体部分”)是指保持有抗体的特异结合抗原(例如,Claudin18.2蛋白)能力的一个或多个片段。已证实,抗体的抗原结合功能可以通过全长抗体的片段来实施。包含在抗体的“抗原结合部分”中的结合片段的例子包括Fab,Fab’,F(ab)2,Fv片段,F(ab’)2,scFv,di-scFv和/或dAb。以下列举了多个抗原结合片段:(i)Fab片段,由VL、VH、CL和CH1构成的单价片段;(ii)F(ab′)2片段,包含铰链区二硫桥连接的两个Fab片段的二价片段;(iii)由VH和CH1构成的Fd片段;(iv)由抗体单臂VL和VH构成的Fv片段;(v)由VH构成的dAb片段;(vi)分离的互补决定区(CDR);以及(vii)纳米抗体,一种包含单可变结构域和两个恒定结构域的重链可变区。此外,尽管Fv片段的两个结构域VL和VH由不同的基因编码,它们可以通过重组法经由使两者成为单蛋白链的合成接头而连接,其中VL和VH区配对形成单价分子(称为单链Fv(scFv))。这些单链抗体也已包括在术语涵义中。这些抗体片段可以通过本领域技术人员已知的常用技术而得到,且片段可以通过与完整抗体相同的方式进行功能筛选。
在本申请中,术语“可变区”或“可变结构域”可互换使用,通常是指抗体中轻链或重链的一部分,通常是指抗体的氨基末端。其可以包含重链中约100-130个氨基酸或轻链中约90至115个氨基酸,在抗体之间的序列差别很大,并且用于特定抗体对特定抗原的结合特异性。序列的可变性集中在称为互补决定区(CDR)的那些区域中,而可变结构域中更高度保守的区域称为框架区(FR)。轻链和重链的CDR主要负责抗体与抗原的相互作用和特异性。
在本申请中,术语“框架区”是指本领域识别的抗体可变区中存在于分歧性更高的(即高变)CDR之间的部分。此类框架区典型地称为框架1至4(FR1、FR2、FR3和FR4)且提供用于在三维空间中呈现六个CDR(三个来自重链且三个来自轻链)的骨架,以形成抗原结合表面。
在本申请中,术语“免疫缀合物”或“抗体缀合物”通常是指抗体或其抗体片段与其它活性剂的连接,诸如化疗剂,毒素,免疫治疗剂,成像探针,光谱探针,等等。所述连接可以是共价键,或例如通过静电力的非共价相互作用。可以使用本领域中已知的多种接头以形成免疫缀合物。此外,该免疫缀合物可以以融合蛋白的形式提供,所述融合蛋白可以从编码该免疫缀合物的多核苷酸表达。如本文所用的“融合蛋白”指的是通过连接两个或多个最初编码独立的蛋白(包括肽和多肽)的基因或基因片段产生的蛋白。融合基因的翻译产生具有来自各原始蛋白的功能特性的单一蛋白。
在本申请中,术语“轻链”通常是指具有足够的可变区序列以给予对特定抗原的特异性的任何多肽。全长轻链包括可变区结构域VL,和恒定区结构域CL。如同重链,轻链的可变区结构域位于多肽的氨基末端。轻链包括κ链和λ链。
在本申请中,术语“全人源抗体”指代仅包含人类免疫球蛋白蛋白质序列的抗体。可通过噬菌体展示或其它分子生物学方法,在人体内、在具有人类免疫球蛋白种系序列的转基因动物体内生成全人源抗体。噬菌体抗体表达技术允许在没有动物免疫的情况下产生特异性抗体,如美国专利No.6,946,546中所述,所述专利在此全文引入作为参考。这些技术在Marks(1992);Stemmer(1994);Gram等(1992);Barbas等(1994)和Schier等(1996)中进一步描述,在此将其全文引入作为参考。噬菌体展示方法(参见美国专利Nos.4,444,887和4,716,111;和国际公开Nos.WO98/46645,WO98/50433,WO98/24893,WO98/16654,WO96/34096,WO96/33735和WO91/10741)。其它技术,如使用文库,是本领域已知的。
在本申请中,术语“结合”可以是涉及特异性结合,“特异性结合”是指试剂(如抗体)与其特异性靶标(如表位)的结合强于与其它靶标的结合。如果试剂与第一种靶标结合的解离常数(KD)低于与第二种靶标的解离常数,则其与第一种靶标的结合强于与第二种靶标的结合。另外,试剂特异性结合的靶标的解离常数(KD)低于该试剂非特异性结合的靶标的解离常数(KD)的1/10以下,可以是1/20以下,可以是1/50以下,甚至可以是1/100、1/200、1/500或1/1000以下。
在本申请中,术语“细胞”、“细胞系”和“细胞培养物”可互换使用,并且所有这类名称都包括后代。还应当理解的是,由于故意或非有意的突变,所有后代在DNA含量方面不可能精确相同。包括具有与最初转化细胞中筛选的相同的功能或生物学活性的突变后代。在意指不同名称的情况下,其由上下文清楚可见。
在本申请中,术语“效靶比”是指效应细胞与靶细胞的数量之比。
在本申请中,术语“抑制生长”(例如涉及细胞)意指包括与未接触抗Claudin18.2抗体的相同细胞的生长相比,使与抗Claudin18.2抗体接触时细胞生长的任何可测量的降低,例如,细胞的生长被抑制至少约10%、20%、30%、40%、50%、60%、70%、80%、90%、99%或100%。
在本申请中,术语“药物”通常是指当将其正确给予患者时,能够诱导期望的治疗效果的化学化合物或组合物。
在本申请中,术语“药物组合物”表示含有一种或多种本申请所述化合物或其生理学上/可药用的盐或前体药物与其他化学组分的混合物,以及其他组分例如生理学/可药用的载体和赋形剂。药物组合物的目的是促进对生物体的给药,利于活性成分的吸收进而发挥生物活性。治疗性组合物一般应当是无菌的并且在制造和储存条件下稳定。可以将组合物配制为溶液、微乳液、分散剂、脂质体或适合高抗体浓度的其他有序结构。可以通过将活性化合物(即抗体或抗体部分)以要求的量连同上文所列举的一种成分或成分组合在适宜的溶剂中并入,根据需要,随后过滤消毒,制备无菌可注射溶液剂。
在本申请中,术语“载体”通常是指能够转运与它连接的另一核酸的核酸分子。一类载体是“质粒”,其指其他DNA区段可以连接入其中的环状双链DNA环。另一类载体是病毒载体,其中其他DNA区段可以连接入病毒基因组。某些载体能够在它们所引入的宿主细胞中自主复制(例如,具有细菌复制起点的细菌载体和附加型哺乳动物载体)。其他载体(例如非附加型哺乳动物载体)可以在引入宿主细胞时整合入宿主细胞的基因组,从而与宿主基因组一起复制,如不能自主复制的裸RNA多核苷酸、裸DNA多核苷酸、在同一链中由DNA和RNA构成的多核苷酸、聚-赖氨酸-偶联的DNA或RNA、肽-偶联的DNA或RNA、脂质体-偶联的DNA等。此外,某些载体能够指导与它们有效连接的基因的表达。这类载体在本文中称为“重组表达载体”(或简称“表达载体”)。一般而言,用于重组DNA技术中的表达载体通常是质粒的形式。在本说明书中,“质粒”和“载体”可互换使用,因为质粒是最常用的载体形式。
在本申请中,术语“直接或间接相连”指氨基酸的共价连接(直接或间接的)。例如,与编码配体的基因的内含子编码的至少一个氨基酸有效相连的配体(例如HGF)的至少一个结构域表示,来自配体的结构域的氨基酸共价连接到来自配体基因的内含子编码的氨基酸上。此类连接,典型地,通过肽键直接的,还可间接实现,例如通过接头或者通过非肽连接实现。因此,含有与编码细胞表面受体的基因的内含子编码的至少一个氨基酸有效相连的配体的至少一个结构域的多肽可以是内含子融合蛋白。当内含子序列被剪接,或者符合读框地共价连接到外显子序列(编码细胞表面受体的结构域)上时,可产生编码此类多肽的核酸。核酸分子的翻译产生了下述多肽,其中,氨基酸的内含子编码部分(至少含有内含子序列编码的终止密码子)与配体的结构域共价相连。还可通过将含有外显子的部分连到含有内含子的部分上,来对它们进行合成生产,包括嵌合内含子融合蛋白,其中外显子是由来自与内含子部分不同的同种型的基因编码的,所述同种型包括不同的配体同种型或细胞表面受体同种型,反之亦然。
在本申请中,术语“治疗”意指给予患者内用或外用治疗剂,诸如包含本申请的任一种结合化合物的组合物,所述患者具有一种或多种疾病症状,而已知所述治疗剂对这些症状具有治疗作用。通常,在受治疗患者或群体中以有效缓解一种或多种疾病症状的量给予治疗剂,无论是通过诱导这类症状退化还是抑制这类症状发展到任何临床可测量的程度。有效缓解任何具体疾病症状的治疗剂的量(也称作“治疗有效量”)可根据多种因素变化,例如患者的疾病状态、年龄和体重,以及药物在患者产生需要疗效的能力。治疗的治疗效果包括但不限于预防疾病的发生或复发、症状的缓解、疾病的任何直接或间接病理学后果的减少、预防转移、降低疾病进展的速度、减轻或缓和疾病状态、和缓解或改善的预后。
在本申请中,术语“肿瘤”或“肿瘤细胞”通常是指或描述哺乳动物中通常以不受调节的细胞生长为特征的生理状况。肿瘤的例子包括但不限于,癌瘤、淋巴瘤、母细胞瘤(包括髓母细胞瘤和视网膜母细胞瘤)、肉瘤(包括脂肪肉瘤和滑膜细胞肉瘤)、神经内分泌肿瘤(包括类癌肿瘤、胃泌素瘤和胰岛细胞癌)、间皮瘤、神经鞘瘤(schwannoma)(包括听神经瘤)、脑膜瘤、腺癌和黑素瘤。“肿瘤细胞”进一步包括“实体瘤”,其指的是选自下组的肿瘤:胃肠癌、胰腺癌、成胶质细胞瘤、宫颈癌、卵巢癌、肝癌(liver cancer)、膀胱癌、肝瘤(hepatoma)、乳腺癌、结肠癌、直肠癌、结肠直肠癌、子宫内膜或子宫癌、唾液腺癌、肾癌、前列腺癌、外阴癌、甲状腺癌、肝癌(hepatic carcinoma)、肛门癌、阴茎癌、睾丸癌、食管癌、胆管肿瘤、以及头和颈癌,可以是肺癌、结肠癌、肝癌、食管癌、卵巢癌、膀胱癌、胃癌、肾癌和/或胰腺癌。
在本申请中,术语“重链”通常是指全长重链及其具有足够可变区序列以赋予结合特异性的片段。哺乳动物全长重链抗体一般包括可变区结构域VH以及3个恒定区结构域CH1、CH2和CH3。VH结构域朝向多肽的氨基末端,并且CH结构域朝向羧基末端,其中CH3与多肽的羧基末端最接近。人重链一般可以是包括IgG(包括IgG1、IgG2、IgG3和IgG4亚型)、IgA(包括IgA1和IgA2亚型)、IgM和IgE的同种型。
在本申请中,术语“佐剂”通常是指辅助或调节药物作用的任何物质,包括但不仅限于免疫学佐剂,它使对抗原的免疫反应增强或免疫反应多样化。
在本申请中,术语“受试者”包括任何人或非人动物。术语“非人动物”包括所有脊椎动物,例如哺乳类和非哺乳类,例如非人灵长类、羊、狗、猫、牛、马、鸡、两栖类、和爬行类,可以是哺乳动物,例如非人灵长类、羊、狗、猫、牛和马。
在本申请中,术语“治疗有效量”是指足以防止或减缓与疾病或病症(例如癌症)相关的症状的本申请抗体量。治疗有效量与被治疗的疾病相关,其中本领域技术人员可以方便地判别出实际的有效量。
在本申请中,术语“ADCC效应”、“抗体依赖的细胞毒性”、“抗体依赖的细胞介导的细胞毒性”或“ADCC”是指细胞介导的免疫防御,其中免疫系统效应细胞主动地将细胞膜表面抗原与抗体,例如Claudin18.2抗体,结合的靶细胞例如癌细胞裂解。
在本申请中,术语“CDC效应”、“补体依赖的细胞毒性”或“CDC”是指IgG和IgM抗体的效应功能,当与表面抗原结合时引发典型的补体途径,包括形成膜攻击复合体以及靶细胞裂解。本申请的抗原结合蛋白,与Claudin18.2结合时,引发对癌细胞的CDC。
在本申请中,术语“CDR”和其复数形式“CDRs”通常是指互补决定区(CDR),其中三者构成轻链可变区的结合特性(LCDR1、LCDR2和LCDR3);三者构成重链可变区的结合特性(HCDR1、HCDR2和HCDR3)。CDR有助于抗体分子的功能活性并且通过包含骨架或构架区的氨基酸序列分离。
在本申请中,术语“Claudin18.1”、“claudin18.1”、“CLD18.1”或“密蛋白18.1”包括指1型Claudin18。该术语包括变体、同源物、直向同源物和平行同源物。
在本申请中,术语“Claudin18.1阳性肿瘤细胞”指在其表面上表达Claudin18.1的细胞。
在本申请中,术语“Claudin18.2”、“claudin18.2”、“CLD18.2”或“密蛋白18.2”包括指2型Claudin18。该术语包括变体、同源物、直向同源物和平行同源物。
在本申请中,术语“Claudin18.2阳性肿瘤”是指表达Claudin18.2蛋白的肿瘤。
在本申请中,术语“Claudin18.2阳性肿瘤细胞”指在其表面上表达Claudin18.2的肿瘤细胞。
在本申请中,术语“FACS”或“流式细胞术”指用于查询细胞表型和特征的工具。它通过经过传感区域的激光(通过辐射的受激发射的光放大)/光束,感测在液体流中移动时的细胞或颗粒。测量微观颗粒的相对光散射和颜色区分荧光。细胞的流动分析和区分基于大小、颗粒性以及细胞是否携带以抗体或染料形式的荧光分子。当细胞通过激光束时,光在所有方向上散射,并且在与轴的低角度(0.5-10°)处在前向方向上散射的光与球体半径的平方成比例,并且因此与细胞或颗粒的大小成比例。光可以进入细胞;因此,90°光(直角,侧面)散射可以用荧光染料连接的抗体标记,或者用荧光膜、细胞质或核染料染色。因此,可以促进细胞类型的区分、膜受体和抗原的存在、膜电位、pH、酶活性和DNA含量。流式细胞仪是多参数,对于每个细胞记录几次测量;因此,能够在异质群体内鉴定同质亚群。允许分离物理特征太过相似而无法通过大小或密度分开的不同细胞群体的荧光活化细胞分选(FACS),使用荧光标签来检测差异表达的表面蛋白,允许在物理上同质的细胞群体中进行细微区别。
在本申请中,术语“在……之间”通常是指某种氨基酸片段的C端与第一氨基酸片段的N端直接或间接连接,并且其N端与第二氨基酸片段的C端直接或间接连接。在轻链中,例如,所述L-FR2的N末端与所述LCDR1的C末端直接或间接相连,且所述L-FR2的C末端与所述LCDR2的N末端直接或间接相连。又例如,所述L-FR3的N末端与所述LCDR2的C末端直接或间接相连,且所述L-FR3的C末端与所述LCDR3的N末端直接或间接相连。在重链中,例如,所述H-FR2的N末端与所述HCDR1的C末端直接或间接相连,且所述H-FR2的C末端与所述HCDR2的N末端直接或间接相连。又例如,所述H-FR3的N末端与所述HCDR2的C末端直接或间接相连,且所述H-FR3的C末端与所述HCDR3的N末端直接或间接相连。在本申请中,“第一氨基酸片段”和“第二氨基酸片段”可以为相同或不同的任意一段氨基酸片段。
在本申请中,术语“轻链恒定区”是指包含轻链恒定结构域CL的区域。人免疫球蛋白的轻链通常分类为κ和λ轻链,并且这些链各自包含一个可变域和一个恒定域,术语“Igκ恒定区”或“Igλ恒定区”分别对应免疫球蛋白κ轻链恒定结构域CL的区域或免疫球蛋白λ轻链恒定结构域CL的区域。
在本申请中,术语“pfu”表示噬斑形成单位,其是感染性噬菌体颗粒(病毒体)或噬菌体滴度的数量的量度。
抗原结合蛋白
在一个方面,本申请提供了一种抗原结合蛋白,其包含抗体轻链可变区VL中的至少一个CDR。
在本申请中,所述抗原结合蛋白可包含LCDR1,且所述LCDR1可包含SEQ ID NO:7或17所示的氨基酸序列。
在本申请中,所述抗原结合蛋白可包含LCDR2,且所述LCDR2可包含SEQ ID NO:8或18所示的氨基酸序列。
在本申请中,所述抗原结合蛋白可包含LCDR3,且所述LCDR3可包含SEQ ID NO:9或19所示的氨基酸序列。
在本申请中,所述抗原结合蛋白可包含框架区L-FR1,所述L-FR1的C末端与所述LCDR1的N末端直接或间接相连,且所述的L-FR1可包含SEQ ID NO:25或33所示的氨基酸序列。
在本申请中,所述抗原结合蛋白可包含框架区L-FR2,所述的L-FR2位于所述LCDR1与所述LCDR2之间,且所述的L-FR2可包含SEQ ID NO:26或34所示的氨基酸序列。
在本申请中,所述抗原结合蛋白可包含框架区L-FR3,所述的L-FR3位于所述LCDR2与所述LCDR3之间,且所述的L-FR3可包含SEQ ID NO:27或35所示的氨基酸序列。
在本申请中,所述抗原结合蛋白可包含框架区L-FR4,所述的L-FR4的N末端与所述LCDR3的C末端直接或间接相连,且所述的L-FR4可包含SEQ ID NO:28或36所示的氨基酸序列。
在本申请中,所述抗原结合蛋白可包含轻链可变区VL,且所述VL可包含SEQ IDNO:6或16所示的氨基酸序列。
在本申请中,所述抗原结合蛋白可包含轻链恒定区CL,且所述抗体轻链恒定区包括人Igκ恒定区或人Igλ恒定区,例如所述CL可包含SEQ ID NO:38或39所示的氨基酸序列。
在本申请中,所述抗原结合蛋白可包含轻链LC,且所述LC可包含SEQ ID NO:10或20所示的氨基酸序列。
本申请所述的抗原结合蛋白所述的抗原结合蛋白可包含抗体重链可变区VH中的至少一个CDR。
在本申请中,所述抗原结合蛋白可包含HCDR1,且所述HCDR1可包含SEQ ID NO:2或12所示的氨基酸序列。
在本申请中,所述抗原结合蛋白可包含HCDR2,且所述HCDR2可包含SEQ ID NO:3或13所示的氨基酸序列。
在本申请中,所述抗原结合蛋白可包含HCDR3,且所述HCDR3可包含SEQ ID NO:4或14所示的氨基酸序列。
在本申请中,所述抗原结合蛋白可包含框架区H-FR1,所述H-FR1的C末端与所述HCDR1的N末端直接或间接相连,且所述的H-FR1可包含SEQ ID NO:21或29所示的氨基酸序列。
在本申请中,所述抗原结合蛋白可包含框架区H-FR2,所述的H-FR2位于所述HCDR1与所述HCDR2之间,且所述的H-FR2可包含SEQ ID NO:22或30所示的氨基酸序列。
在本申请中,所述抗原结合蛋白可包含框架区H-FR3,所述的H-FR3位于所述HCDR2与所述HCDR3之间,且所述的H-FR3可包含SEQ ID NO:23或31所示的氨基酸序列。
在本申请中,所述抗原结合蛋白可包含框架区H-FR4,所述的H-FR4的N末端与所述HCDR3的C末端直接或间接相连,且所述的H-FR4可包含SEQ ID NO:24或32所示的氨基酸序列。
在本申请中,所述抗原结合蛋白可包含重链可变区VH,且所述VH可包含SEQ IDNO:1或11所示的氨基酸序列。
在本申请中,所述抗原结合蛋白可包含重链恒定区CH,且所述抗体重链恒定区包括人IgG恒定区,优选地,本申请所述抗体重链恒定区包括人IgG1恒定区,例如所述CH可包含SEQ ID NO:37所示的氨基酸序列。
在本申请中,所述抗原结合蛋白可包含重链HC,且所述HC可包含SEQ ID NO:5或15所示的氨基酸序列。
在本申请中,所述分离的抗原结合蛋白可包含LCDR1-3,其中,所述LCDR1包含SEQID NO:7或17所示的氨基酸序列;所述LCDR2包含SEQ ID NO:8或18所示的氨基酸序列;且所述LCDR3包含SEQ ID NO:9或19所示的氨基酸序列。
例如,本申请所述的抗原结合蛋白可包含与HDR002C04相同的LCDR1-3,其中,所述LCDR1可包含SEQ ID NO:7所示的氨基酸序列;所述LCDR2可包含SEQ ID NO:8所示的氨基酸序列;且所述LCDR3可包含SEQ ID NO:9所示的氨基酸序列。
例如,本申请所述的抗原结合蛋白可包含与HDR002C06相同的LCDR1-3,其中,所述LCDR1可包含SEQ ID NO:17所示的氨基酸序列;所述LCDR2可包含SEQ ID NO:18所示的氨基酸序列;且所述LCDR3可包含SEQ ID NO:19所示的氨基酸序列。
在本申请中,所述分离的抗原结合蛋白可包含L-FR1-4,其中,所述L-FR1包含SEQID NO:25或33所示的氨基酸序列;所述L-FR2包含SEQ ID NO:26或34所示的氨基酸序列;所述L-FR3包含SEQ ID NO:27或35所示的氨基酸序列;且所述L-FR4包含SEQ ID NO:28或36所示的氨基酸序列。
例如,本申请所述的抗原结合蛋白可包含与HDR002C04相同的L-FR1-4,其中,所述L-FR1可包含SEQ ID NO:25所示的氨基酸序列,L-FR2可包含SEQ ID NO:26所示的氨基酸序列,L-FR3可包含SEQ ID NO:27所示的氨基酸序列,且L-FR4可包含SEQ ID NO:28所示的氨基酸序列。
例如,本申请所述的抗原结合蛋白可包含与HDR002C06相同的L-FR1-4,其中,所述L-FR1可包含SEQ ID NO:33所示的氨基酸序列,L-FR2可包含SEQ ID NO:34所示的氨基酸序列,L-FR3可包含SEQ ID NO:35所示的氨基酸序列,且L-FR4可包含SEQ ID NO:36所示的氨基酸序列。
在本申请中,所述分离的抗原结合蛋白可包含HCDR1-3,其中,所述HCDR1包含SEQID NO:2或12所示的氨基酸序列;所述HCDR2包含SEQ ID NO:3或13所示的氨基酸序列;且所述HCDR3包含SEQ ID NO:4或14所示的氨基酸序列。
例如,本申请所述的抗原结合蛋白可包含与HDR002C04相同的HCDR1-3,其中,所述HCDR1可包含SEQ ID NO:2所示的氨基酸序列;所述HCDR2可包含SEQ ID NO:3所示的氨基酸序列;且所述HCDR3可包含SEQ ID NO:4所示的氨基酸序列。
例如,本申请所述的抗原结合蛋白可包含与HDR002C06相同的HCDR1-3,其中,所述HCDR1可包含SEQ ID NO:12所示的氨基酸序列;所述HCDR2可包含SEQ ID NO:13所示的氨基酸序列;且所述HCDR3可包含SEQ ID NO:14所示的氨基酸序列。
在本申请中,所述分离的抗原结合蛋白可包含H-FR1-4,其中,所述H-FR1包含SEQID NO:21或29所示的氨基酸序列;所述H-FR2包含SEQ ID NO:22或30所示的氨基酸序列;所述H-FR3包含SEQ ID NO:23或31所示的氨基酸序列;且所述H-FR4包含SEQ ID NO:24或32所示的氨基酸序列。
例如,本申请所述的抗原结合蛋白可包含与HDR002C04相同的H-FR1-4,其中,所述H-FR1可包含SEQ ID NO:21所示的氨基酸序列,H-FR2可包含SEQ ID NO:22所示的氨基酸序列,H-FR3可包含SEQ ID NO:23所示的氨基酸序列,且H-FR4可包含SEQ ID NO:24所示的氨基酸序列。
例如,本申请所述的抗原结合蛋白可包含与HDR002C06相同的H-FR1-4,其中,所述H-FR1可包含SEQ ID NO:29所示的氨基酸序列,H-FR2可包含SEQ ID NO:30所示的氨基酸序列,H-FR3可包含SEQ ID NO:31所示的氨基酸序列,且H-FR4可包含SEQ ID NO:32所示的氨基酸序列。
在本申请中,所述分离的抗原结合蛋白可包含LCDR1-3和HCDR1-3,其中,所述LCDR1包含SEQ ID NO:7或17所示的氨基酸序列;所述LCDR2包含SEQ ID NO:8或18所示的氨基酸序列;所述LCDR3包含SEQ ID NO:9或19所示的氨基酸序列;所述HCDR1包含SEQ ID NO:2或12所示的氨基酸序列;所述HCDR2包含SEQ ID NO:3或13所示的氨基酸序列;且所述HCDR3包含SEQ ID NO:4或14所示的氨基酸序列。
例如,本申请所述的抗原结合蛋白可包含与HDR002C04相同的LCDR1-3和HCDR1-3,其中,所述LCDR1可包含SEQ ID NO:7所示的氨基酸序列;所述LCDR2可包含SEQ ID NO:8所示的氨基酸序列;所述LCDR3可包含SEQ ID NO:9所示的氨基酸序列;所述HCDR1可包含SEQID NO:2所示的氨基酸序列;所述HCDR2可包含SEQ ID NO:3所示的氨基酸序列;且所述HCDR3可包含SEQ ID NO:4所示的氨基酸序列。
例如,本申请所述的抗原结合蛋白可包含与HDR002C06相同的LCDR1-3和HCDR1-3,其中,所述LCDR1可包含SEQ ID NO:17所示的氨基酸序列;所述LCDR2可包含SEQ ID NO:18所示的氨基酸序列;所述LCDR3可包含SEQ ID NO:19所示的氨基酸序列;所述HCDR1可包含SEQ ID NO:12所示的氨基酸序列;所述HCDR2可包含SEQ ID NO:13所示的氨基酸序列;且所述HCDR3可包含SEQ ID NO:14所示的氨基酸序列。
在本申请中,所述抗原结合蛋白可包含轻链可变区VL和重链可变区VH,其中,所述VL可包含SEQ ID NO:6或16所示的氨基酸序列,且所述VH可包含SEQ ID NO:1或11所示的氨基酸序列。
例如,本申请所述的抗原结合蛋白可包含与HDR002C04相同的轻链可变区VL和重链可变区VH,其中,所述VL可包含SEQ ID NO:6所示的氨基酸序列,且所述VH可包含SEQ IDNO:1所示的氨基酸序列。
例如,本申请所述的抗原结合蛋白可包含与HDR002C06相同的轻链可变区VL和重链可变区VH,其中,所述VL可包含SEQ ID NO:16所示的氨基酸序列,且所述VH可包含SEQ IDNO:11所示的氨基酸序列。
在本申请中,所述抗原结合蛋白可包含轻链恒定区CL和重链恒定区CH,其中,所述CL可包含SEQ ID NO:38或39所示的氨基酸序列,且所述CH可包含SEQ ID NO:37所示的氨基酸序列。
例如,本申请所述的抗原结合蛋白可包含与HDR002C04相同的轻链恒定区CL和重链恒定区CH,其中,所述CL可包含SEQ ID NO:38所示的氨基酸序列,且所述CH可包含SEQ IDNO:37所示的氨基酸序列。
例如,本申请所述的抗原结合蛋白可包含与HDR002C06相同的轻链恒定区CL和重链恒定区CH,其中,所述CL可包含SEQ ID NO:39所示的氨基酸序列,且所述CH可包含SEQ IDNO:37所示的氨基酸序列。
本申请中,所述抗原结合蛋白可包含抗体轻链LC和抗体重链HC,其中,所述LC可包含SEQ ID NO:10或20所示的氨基酸序列,且所述HC可包含SEQ ID NO:5或15所示的氨基酸序列。
例如,本申请所述的抗原结合蛋白可包含与HDR002C04相同的抗体轻链LC和抗体重链HC,其中,所述LC可包含SEQ ID NO:10所示的氨基酸序列,且所述HC可包含SEQ ID NO:5所示的氨基酸序列。
例如,本申请所述的抗原结合蛋白可包含与HDR002C06相同的抗体轻链LC和抗体重链HC,其中,所述LC可包含SEQ ID NO:20所示的氨基酸序列,且所述HC可包含SEQ ID NO:15所示的氨基酸序列。
本申请所述的抗原结合蛋白可包含LCDR1-3和L-FR1-4,其中,所述LCDR1可包含SEQ ID NO:7所示的氨基酸序列;所述LCDR2可包含SEQ ID NO:8所示的氨基酸序列;且所述LCDR3可包含SEQ ID NO:9所示的氨基酸序列;所述L-FR1可包含SEQ ID NO:25所示的氨基酸序列,L-FR2可包含SEQ ID NO:26所示的氨基酸序列,L-FR3可包含SEQ ID NO:27所示的氨基酸序列,且L-FR4可包含SEQ ID NO:28所示的氨基酸序列。所述抗原结合蛋白可包含VL和CL,且所述VL可包含SEQ ID NO:6所示的氨基酸序列,所述CL可包含SEQ ID NO:38所示的氨基酸序列。所述抗原结合蛋白还可包含HCDR1-3和H-FR1-4,其中,所述HCDR1可包含SEQID NO:2所示的氨基酸序列;所述HCDR2可包含SEQ ID NO:3所示的氨基酸序列;且所述HCDR3可包含SEQ ID NO:4所示的氨基酸序列;所述H-FR1可包含SEQ ID NO:21所示的氨基酸序列,H-FR2可包含SEQ ID NO:22所示的氨基酸序列,H-FR3可包含SEQ ID NO:23所示的氨基酸序列,且H-FR4可包含SEQ ID NO:24所示的氨基酸序列。所述抗原结合蛋白可包含VH和CH,且所述VH可包含SEQ ID NO:1所示的氨基酸序列,所述CH可包含SEQ ID NO:37所示的氨基酸序列。且所述抗原结合蛋白可包含LC和HC,其中,所述LC可包含SEQ ID NO:10所示的氨基酸序列,且所述HC可包含SEQ ID NO:5所示的氨基酸序列。例如,所述抗原结合蛋白可包含与HDR002C04相同的抗体轻链和抗体重链。
本申请所述的抗原结合蛋白可包含LCDR1-3和L-FR1-4,其中,所述LCDR1可包含SEQ ID NO:17所示的氨基酸序列;所述LCDR2可包含SEQ ID NO:18所示的氨基酸序列;且所述LCDR3可包含SEQ ID NO:19所示的氨基酸序列;所述L-FR1可包含SEQ ID NO:33所示的氨基酸序列,L-FR2可包含SEQ ID NO:34所示的氨基酸序列,L-FR3可包含SEQ ID NO:35所示的氨基酸序列,且L-FR4可包含SEQ ID NO:36所示的氨基酸序列。所述抗原结合蛋白可包含VL和CL,且所述VL可包含SEQ ID NO:16所示的氨基酸序列,所述CL可包含SEQ ID NO:39所示的氨基酸序列。所述抗原结合蛋白还可包含HCDR1-3和H-FR1-4,其中,所述HCDR1可包含SEQ ID NO:12所示的氨基酸序列;所述HCDR2可包含SEQ ID NO:13所示的氨基酸序列;且所述HCDR3可包含SEQ ID NO:14所示的氨基酸序列;所述H-FR1可包含SEQ ID NO:29所示的氨基酸序列,H-FR2可包含SEQ ID NO:30所示的氨基酸序列,H-FR3可包含SEQ ID NO:31所示的氨基酸序列,且H-FR4可包含SEQ ID NO:32所示的氨基酸序列。所述抗原结合蛋白可包含VH和CH,且所述VH可包含SEQ ID NO:11所示的氨基酸序列,所述CH可包含SEQ ID NO:37所示的氨基酸序列。且所述抗原结合蛋白可包含LC和HC,其中,所述LC可包含SEQ ID NO:20所示的氨基酸序列,且所述HC可包含SEQ ID NO:15所示的氨基酸序列。例如,所述抗原结合蛋白可包含与HDR002C06相同的抗体轻链和抗体重链。
参比抗体
在本申请中涉及的蛋白质、多肽和/或氨基酸序列,还应理解为至少包含以下的范围:与该所述蛋白质或多肽具备相同或类似功能的变体或同源物,且包含在本申请的保护范围内,其被称为参比抗体。
本申请所述的分离的抗原结合蛋白,其可与参比抗体竞争结合所述Claudin18.2。在本申请中,所述参比抗体可包含LCDR1-3。其中,所述LCDR1包含SEQ ID NO:7或17所示的氨基酸序列;所述LCDR2包含SEQ ID NO:8或18所示的氨基酸序列;且所述LCDR3包含SEQ IDNO:9或19所示的氨基酸序列。
本申请中,所述参比抗体可包含HCDR1-3。其中,所述HCDR1包含SEQ ID NO:2或12所示的氨基酸序列;所述HCDR2包含SEQ ID NO:3或13所示的氨基酸序列;且所述HCDR3包含SEQ ID NO:4或14所示的氨基酸序列。
在本申请中,所述参比抗体可包含LCDR1-3和HCDR1-3。其中,所述LCDR1包含SEQID NO:7或17所示的氨基酸序列;所述LCDR2包含SEQ ID NO:8或18所示的氨基酸序列;所述LCDR3包含SEQ ID NO:9或19所示的氨基酸序列;所述HCDR1包含SEQ ID NO:2或12所示的氨基酸序列;所述HCDR2包含SEQ ID NO:3或13所示的氨基酸序列;且所述HCDR3包含SEQ IDNO:4或14所示的氨基酸序列。
在本申请中,所述参比抗体可包含轻链可变区VL和重链可变区VH。其中,所述VL可包含SEQ ID NO:6或16所示的氨基酸序列,且所述VH可包含SEQ ID NO:1或11所示的氨基酸序列。
检测方法
可通过本领域已知的各种测定鉴别、筛选或表征本申请所述的Claudin18.2抗原结合蛋白的物理/化学特性和/或生物活性。
核酸、载体、宿主细胞和制备方法
在另一个方面,本申请还提供了分离的一种或多种核酸分子。所述一种或多种核酸分子可编码本申请所述的抗原结合蛋白。例如,所述一种或多种核酸分子中的每一个核酸分子可以编码完整的所述抗原结合蛋白,也可以编码其中的一部分(例如,HCDR1-3、LCDR1-3、VL、VH、轻链或重链中的一种或多种)。
本申请所述的核酸分子可以为分离的。例如,其可以是通过以下方法产生或合成的:(i)在体外扩增的,例如通过聚合酶链式反应(PCR)扩增产生的,(ii)通过克隆重组产生的,(iii)纯化的,例如通过酶切和凝胶电泳分级分离,或者(iv)合成的,例如通过化学合成。在某些实施方式中,所述分离的核酸是通过重组DNA技术制备的核酸分子。
在本申请中,可以通过本领域已知的多种方法来制备编码所述抗体、其抗原结合片段的核酸,这些方法包括但不限于,采用限制性片段操作或采用合成性寡核苷酸的重叠延伸PCR,具体操作可参见Sambrook等人,Molecular Cloning,A Laboratory Manual,ColdSpring Harbor Laboratory Press,Cold Spring Harbor,N.Y.,1989;和Ausube等人Current Protocols in Molecular Biology,Greene Publishing and Wiley-Interscience,New York N.Y.,1993。
在另一个方面,本申请提供了一种或多种载体,其包含本申请所述的一种或多种核酸分子。每种载体中可包含一种或多种所述核酸分子。此外,所述载体中还可包含其他基因,例如允许在适当的宿主细胞中和在适当的条件下选择该载体的标记基因。此外,所述载体还可包含允许编码区在适当宿主中正确表达的表达控制元件。这样的控制元件为本领域技术人员所熟知的,例如,可包括启动子、核糖体结合位点、增强子和调节基因转录或mRNA翻译的其他控制元件等。在某些实施方式中,所述表达控制序列为可调的元件。所述表达控制序列的具体结构可根据物种或细胞类型的功能而变化,但通常包含分别参与转录和翻译起始的5’非转录序列和5’及3’非翻译序列,例如TATA盒、加帽序列、CAAT序列等。例如,5’非转录表达控制序列可包含启动子区,启动子区可包含用于转录控制功能性连接核酸的启动子序列。所述表达控制序列还可包括增强子序列或上游活化子序列。在本申请中,适当的启动子可包括,例如用于SP6、T3和T7聚合酶的启动子、人U6RNA启动子、CMV启动子及其人工杂合启动子(如CMV),其中启动子的某部分可与其他细胞蛋白(如人GAPDH,甘油醛-3-磷酸脱氢酶)基因启动子的某部分融合,其可包含或不包含另外的内含子。本申请所述的一种或多种核酸分子可以与所述表达控制元件可操作地连接。
所述载体可以包括,例如质粒、粘粒、病毒、噬菌体或者在例如遗传工程中通常使用的其他载体。例如,所述载体为表达载体。
在另一个方面,本申请提供了宿主细胞,所述宿主细胞可包含本申请所述的一种或多种核酸分子和/或本申请所述的一种或多种载体。在某些实施方式中,每种或每个宿主细胞可包含一个或一种本申请所述的核酸分子或载体。在某些实施方式中,每种或每个宿主细胞可包含多个(例如,2个或以上)或多种(例如,2种或以上)本申请所述的核酸分子或载体。例如,可将本申请所述的载体引入所述宿主细胞中,例如真核细胞,如来自植物的细胞、真菌或酵母细胞等。可通过本领域已知的方法将本申请所述的载体引入所述宿主细胞中,例如电穿孔、lipofectine转染、lipofectamin转染等。
在另一个方面,本申请提供了制备所述的抗体或其抗原结合片段的方法。所述方法可包括,在使得所述的抗体或其抗原结合片段表达的条件下,培养所述本申请所述的宿主细胞。例如,可通过使用适当的培养基、适当的温度和培养时间等,这些方法是本领域普通技术人员所了解的。
在某些情形中,所述方法还可包括分离和/或纯化所述抗体或其抗原结合片段的步骤。例如,可以采用蛋白G-琼脂糖或蛋白A-琼脂糖进行亲和层析,还可通过凝胶电泳和/或高效液相色谱等来纯化和分离本申请所述的抗体或其抗原结合片段。
药物组合物、方法、用途
在另一个方面,本申请提供了一种药物组合物,其可包含本申请所述的抗原结合蛋白和/或所述免疫缀合物,所述的核酸分子,所述的载体,所述的宿主细胞,以及任选地药学上可接受的佐剂。本申请所述的药物组合物可以包含预防和/或治疗有效量的所述抗体、其抗原结合片段。所述预防和/或治疗有效量是能够预防和/或治疗(至少部分治疗)患有或具有发展风险的受试者中的疾病或病症和/或其任何并发症而所需的剂量。所述药学上可接受的佐剂在所采用的剂量和浓度下对接受者无毒性,并且可包括缓冲剂,诸如磷酸盐、柠檬酸盐和其他有机酸;抗氧化剂,包括抗坏血酸和甲硫氨酸;防腐剂(诸如十八烷基二甲基苄基氯化铵、氯化六烃季铵(hexamethonium chloride)、氯化苯二甲羟铵(benzalkoniumchloride)、氯化苄甲乙氧铵(benzethonium chloride)、苯酚、丁醇或苄醇;对羟苯甲酸烷酯,诸如对羟苯甲酸甲酯或丙酯;儿茶酚;间苯二酚;环己醇;3-戊醇和间-甲酚);低分子量(小于约10个残基)多肽;蛋白质,诸如血清白蛋白、凝胶或免疫球蛋白;亲水性聚合物,诸如聚乙烯基吡咯烷酮;氨基酸,诸如甘氨酸、谷酰氨酸、天冬酰氨酸、组氨酸、精氨酸或赖氨酸;单糖、双糖以及其他碳水化合物,包括葡萄糖、甘露糖或糊精;螯合剂,诸如EDTA;糖,诸如蔗糖、甘露醇、海藻糖或山梨醇;成盐反离子,诸如钠离子;金属络合物(例如,Zn-蛋白质络合物);和/或非离子表面活性剂,诸如TWEENTM、PLURONICSTM或聚乙二醇(PEG)。本申请中的药物组合物还可含有多于一种活性化合物,通常为不会不利地影响彼此的具有互补活性的那些活性化合物。此类药物的类型和有效量取决于例如制剂中存在的拮抗剂的量和类型,以及受试者的临床参数。
本申请还提供了以下描述的检测生物样品中Claudin18.2表达的方法。在某些情形中,所述方法包括使生物样品与本申请所述的抗原结合蛋白在容许所述抗原结合蛋白结合Claudin18.2的条件下接触,和检测在所述抗原结合蛋白与Claudin18.2之间是否形成复合物。例如,所述肿瘤或癌症为与非肿瘤或癌症样品相比,Claudin18.2表达升高的肿瘤或癌症。此类方法可以是体外或体内方法。本申请所述抗原结合蛋白可用于例如免疫测定中,所述免疫测定包括例如免疫组织化学(IHC)、免疫荧光(IF)、免疫印迹(例如,蛋白质印迹)、流式细胞术(例如,FACS)和酶联免疫吸附测定(ELISA)。在某些情形中,例如当Claudin18.2为用于选择患者的生物标记时,所述抗原结合蛋白用来选择适于用本申请所述抗原结合蛋白进行的疗法的受试者。
所述药物组合物可以用于抑制肿瘤生长。例如,本申请的药物组合物可以抑制或延缓疾病的发展或进展,可以减小肿瘤大小(甚至基本消除肿瘤),和/或可以减轻和/或稳定疾病状态。肿瘤的例子包括但不限于,癌瘤、淋巴瘤、母细胞瘤(包括髓母细胞瘤和视网膜母细胞瘤)、肉瘤(包括脂肪肉瘤和滑膜细胞肉瘤)、神经内分泌肿瘤(包括类癌肿瘤、胃泌素瘤和胰岛细胞癌)、间皮瘤、神经鞘瘤(包括听神经瘤)、脑膜瘤、腺癌和黑素瘤。“肿瘤细胞”进一步包括“实体瘤”,其指的是选自下组的肿瘤:胃肠癌、胰腺癌、成胶质细胞瘤、宫颈癌、卵巢癌、肝癌(liver cancer)、膀胱癌、肝瘤(hepatoma)、乳腺癌、结肠癌、直肠癌、结肠直肠癌、子宫内膜或子宫癌、唾液腺癌、肾癌、前列腺癌、外阴癌、甲状腺癌、肝癌(hepaticcarcinoma)、肛门癌、阴茎癌、睾丸癌、食管癌、胆管肿瘤、以及头和颈癌,可以是肺癌、结肠癌、肝癌、食管癌、卵巢癌、膀胱癌、胃癌、肾癌和/或胰腺癌。
另一方面,本申请提供了治疗受试者中的癌症、抑制受试者中肿瘤生长和/或抑制肿瘤细胞增殖的方法,包括向有需要的受试者或所述肿瘤细胞施用本申请所述的抗原结合片段和/或所述免疫缀合物、所述的分子核酸、所述的载体、所述的宿主细胞和/或所述的药物组合物。可通过任何合适的方法来施用,所述合适的方法包括例如:以静脉内方式、以肌内方式、以皮下方式、以皮内方式、以经皮方式、以动脉内方式、以腹膜内方式、以损伤内方式、以颅内方式、以关节内方式、以前列腺内方式、以胸膜内方式、以气管内方式、以鞘内方式、以鼻内方式、以阴道内方式、以直肠内方式、以局部方式、以肿瘤内方式、以腹膜方式、以结膜下方式、以囊内方式、以粘膜方式、以心包内方式、以脐内方式、以眼内方式、以眶内方式、以口服方式、以局部方式、以透皮方式、以玻璃体内方式(例如,通过玻璃体内注射)、通过滴眼剂、通过吸入、通过注射、通过植入、通过输注、通过连续输注、通过直接沐浴靶细胞的局部灌注、通过导管、通过灌洗、以乳膏形式或以脂质组合物形式。用于本文描述的方法中的组合物还可以全身方式或以局部方式施用。施用方法可以根据各种因素(例如,所施用的化合物或组合物以及所治疗的病状、疾病或病症的严重性)而变化。在某些实施方案中,以静脉内方式、以肌内方式、以皮下方式、以局部方式、以口服方式、以透皮方式、以腹膜内方式、以眶内方式、通过植入、通过吸入、以鞘内方式、以心室内方式或以鼻内方式施用抗癌疗法(例如,抗Claudin18.2抗体)。部分地根据施用是否为短暂的或长期的,给药可通过任何适合的途径进行,例如通过注射,诸如静脉内或皮下注射。本文涵盖各种给药排程,包括但不限于单次施用或各种时间点内的多次施用、推注施用和脉冲输注。
另一方面,本申请提供了所述抗原结合蛋白在制备药物中的用途。所述药物用于诊断癌症、治疗癌症、抑制肿瘤生长和/或抑制肿瘤细胞增殖。在某些实施方式中,所述肿瘤或癌症包含结直肠肿瘤或癌症。在某些实施方式中,所述肿瘤或癌症为Claudin18.2表达异常的肿瘤或癌症。
本申请还提供了所述抗原结合蛋白在诊断患有病症(例如,癌症或免疫功能失调)的受试者的方法中的用途,所述方法包括:通过使样品与本发明的所述抗原结合蛋白接触并检测结合的所述抗原结合蛋白的存在来确定获自受试者的样品中Claudin18.2的存在或表达水平。在一些情况下,所述样品可选自由以下组成的组:组织样品、全血样品、血清样品和血浆样品。在一些情况下,所述组织样品可以为肿瘤样品。在一些情况下,所述肿瘤样品可包含肿瘤浸润性免疫细胞、肿瘤细胞、基质细胞及其任何组合。在一些情况下,生物样品包括组织或细胞样品。例如,生物样品可包括来自正常或癌症患者的细胞或组织。在某些情况下,组织或细胞样品的来源可为如来自新鲜、冷冻和/或防腐器官或组织样品或活检物或吸出物的固体组织;血液或任何血液成分;体液,诸如脑脊髓液、羊水、腹膜液或间质液;来自受试者妊娠或发育的任何时间的细胞。在另一些情形中,所述生物样品获自体外组织或细胞培养物。本申请中的生物样品的实例包括但不限于肿瘤活检、循环肿瘤细胞、血清或血浆、循环血浆蛋白、腹水、来源于肿瘤的或展现出肿瘤样特性的原代细胞培养物或细胞系,以及保存的肿瘤样品,诸如福尔马林固定石蜡包埋的肿瘤样品或冷冻的肿瘤样品。
本文所述的抗原结合蛋白或药物组合物可以符合良好医疗实践的方式配制、给药和施用。在此情形下的考虑因素包括所治疗的特定病症、所治疗的特定哺乳动物、单个患者的临床病状、病症的病因、药剂递送部位、施用方法、施用排程和医学从业者已知的其他因素。治疗剂(例如,抗Claudin18.2抗体)无需但任选地与一种或多种当前用来预防或治疗所考虑的病症的药剂一起配制和/或同时施用。此类其他药剂的有效量取决于制剂中存在的治疗剂(例如,抗Claudin18.2抗体)的量、病症或治疗的类型以及以上论述的其他因素。这些药剂通常可以凭经验/临床上确定为适当的任何剂量且通过凭经验/临床上确定为适当的任何途径加以使用。与单个治疗相比,可减少组合治疗中施用的抗体的剂量。通过常规技术易于监测此疗法的进展。
并且本申请中所述Claudin18.2蛋白,优选为人Claudin18.2蛋白,GenBank登记号NP_001002026;Claudin18.2阳性细胞指将含有编码人Claudin18.2的cDNA序列的载体转染至空白细胞株,以生成过表达人Claudin18.2的稳定细胞株,例如Claudin18.2阳性HEK293细胞是指将编码人Claudin18.2的cDNA序列的载体转染至空白HEK293细胞株,以生成过表达人Claudin18.2的HEK293细胞株;Claudin18.1阳性细胞指将含有编码人Claudin18.1(GenBank登记号NP_057453)的cDNA序列的载体转染至空白细胞株,以生成过表达人Claudin18.1的稳定细胞株,例如Claudin18.1阳性HEK293细胞是指编码人Claudin18.1的cDNA序列的载体转染至空白HEK293细胞株,以生成过表达人Claudin18.1的HEK293细胞株。以类似方法,制备得到表达人Claudin18.1或表达人Claudin18.2的CHO阳性细胞、BxPC3阳性细胞、N87阳性细胞。
熟不欲被任何理论所限,下文中的实施例仅仅是为了阐释本申请的抗原结合蛋白、制备方法和用途等,而不用于限制本申请发明的范围。悉此技术的人士可由本说明书所公开的内容容易地了解本申请发明的其他优点及效果。本发明实施例中未注明具体条件的实验方法,通常按照常规条件,或按照原料或商品制造厂商所建议的条件。未注明具体来源的试剂,为市场购买的常规试剂。
实施例
实施例1筛选特异性抗Claudin18.2抗体
采用标准的天然全人抗体文库噬菌体展示技术来筛选获得抗Claudin18.2的抗体。简单来说,用人Claudin18.2蛋白或Claudin18.2阳性细胞筛选出全人噬菌体文库中Claudin18.2阳性的抗体,用Claudin18.1阳性细胞排除对Claudin18.1非特异性结合的抗Claudin18.2抗体,获得全人源单克隆抗体。过程如下:全人噬菌体文库(GenScript:Kappa和Lambda)使用PEG/NaCl沉淀,PBS重悬后,采用以下2种方法筛选,方法1:2轮蛋白筛选加1轮细胞筛选;方法2:3-4轮细胞筛选。
蛋白筛选过程如下:人Claudin18.2蛋白包被ELISA板,2×1012pfu的噬菌体用溶于PBS的5%(w/v)脱脂奶粉稀释后,加入到3%脱脂奶粉包被的空白孔孵育去除非特异性结合噬菌体,再将噬菌体转移到人Claudin18.2蛋白包被孔中,室温孵育后,经0.05%PBST、PBS洗涤后收集抗原结合噬菌体。
细胞筛选过程如下:噬菌体用3%(w/v)脱脂奶粉封闭后,与Claudin18.1阳性HEK293细胞室温孵育45分钟。离心收集上清噬菌体,与3%(w/v)脱脂奶粉封闭后的2×107个Claudin18.2阳性CHO细胞或Claudin18.2阳性HEK293细胞室温孵育。使用1%BSA-PBS缓冲液洗涤后,用0.1M TEA洗脱细胞结合噬菌体,并用1M Tris-HCl(pH7.4)中和。洗脱的噬菌体感染感受态细胞TG1后,通过M13K07(NEB,Cat.No.:N0315S)辅助噬菌体释放。筛选得到的噬菌体通过感染感受态细胞TG1后挑选单克隆进行酶联免疫方法(ELISA)检测:重组Claudin18.2蛋白在4℃下包被过夜,洗涤封闭后加入噬菌体上清,之后用缀合辣根过氧化物酶的小鼠抗M13 IgG(Sino Biological)作为检测抗体,3,3'5,5"-四甲基联苯胺(TMB)显色,终止后使用酶标仪在450nm下读板。
ELISA检测的阳性单克隆进行流式细胞仪(FACS)检测,采用Claudin18.2阳性或Claudin18.1阳性的HEK293细胞检测上清液,抗fd噬菌体-生物素(Anti-fdBacteriophage-Biotin)(B2661,Sigma-Aldrich)孵育洗涤后用FACS读取信号,选择FACS阳性克隆进行DNA测序。将测序得到的表达Claudin18.2抗体的轻、重链DNA全长序列分别插入pCDNA3.4中,得到全长抗体的表达质粒。重链和轻链表达质粒共转染Expi293F细胞,培养6-7天后收获上清进行Protein A纯化。
表1a筛选得到的抗Claudin18.2抗体及其序列号
表1b筛选得到的抗Claudin18.2抗体及其序列号
IMAB362即专利申请CN103509114A1中的175D10,该抗体目前用于Astellas公司的3期临床试验,根据该专利申请公开的序列和方法制备得到抗Claudin18.2的对照抗体IMAB362。
实施例2抗Claudin18.2抗体与Claudin18.2阳性细胞系的亲和力检测
通过流式细胞仪检测本申请抗体对Claudin18.2阳性HEK293细胞结合能力。将Claudin18.2阳性HEK293细胞或Claudin18.1阳性HEK293细胞铺板在96孔板中,并向板中加入梯度稀释(0.1μg/mL、0.3μg/mL、1.0μg/mL、3.0μg/mL10μg/mL)的本申请抗体HDR002C04、HDR002C06或对照抗体IMAB362,空白组不加入任何抗体。于4℃孵育30分钟,PBS洗涤,加入FITC标记的山羊抗人IgG二抗(1:100,Jackson ImmunoResearch),在4℃孵育30分钟,PBS洗涤,之后使用FACS仪(Beckman)检测细胞荧光。
如图1所示,HDR002C04对Claudin18.2阳性HEK293细胞的亲和力相近于对照抗体IMAB362,HDR002C06的亲和力显著强于IMAB362。图2是HDR002C04针对Claudin18.1阳性HEK293细胞或Claudin18.2阳性HEK293细胞的结合情况,图3是HDR002C06针对Claudin18.1阳性HEK293细胞或Claudin18.2阳性HEK293细胞的结合情况,结果显示,HDR002C04和HDR002C06与空白组一样,对Claudin18.1阳性HEK293细胞没有结合;HDR002C04和HDR002C06对Claudin18.2阳性HEK293细胞具有较强的亲和力。
实施例3抗Claudin18.2抗体对Claudin18.2阳性细胞系的CDC效应
从健康志愿者抽血,全血静置离心制备正常人血清。使用CCK-8检测试剂盒(CK04,同仁化学),检测本申请抗体HDR002C04和HDR002C06以及对照抗体IMAB362针对人Claudin18.2阳性HEK293细胞,Claudin18.2阳性BxPC3细胞和Claudin18.2阳性N87细胞3种靶细胞引发的CDC效应的能力。
Claudin18.2阳性HEK293细胞,Claudin18.2阳性BxPC3或Claudin18.2阳性N87细胞于1000rpm离心5分钟,然后用完全培养基(Gibco)重悬。将靶细胞以20000个/孔的数量加入到在96孔板中,本申请抗体或对照抗体稀释至不同浓度加入检测孔。本申请抗体或对照抗体与靶细胞孵育1小时后,加入终浓度为20%的上述正常人血清,37℃孵育1-3小时,CCK-8试剂(同仁化学)以10μl/孔的浓度添加,之后继续置于37℃孵箱孵育。用酶标仪测定450nm处的吸光度。
检测结果如图4、图5和图6所示,本申请抗体HDR002C04、HDR002C06和对照抗体对Claudin18.2阳性HEK293细胞、Claudin18.2阳性BxPC3或Claudin18.2阳性N87细胞均能以剂量依赖方式诱导强CDC效应,并且本申请抗体HDR002C04和HDR002C06对Claudin18.2阳性细胞的CDC活性要强于对照抗体IMAB362。
实施例4抗Claudin18.2抗体对Claudin18.1阳性细胞系的CDC效应
为确定本申请抗体HDR002C04和HDR002C06对表达Claudin18.2的靶细胞特异性地表现出CDC效应,而对表达Claudin18.1的细胞不具有CDC效应,使用Claudin18.1阳性HEK293细胞或Claudin18.2阳性HEK293细胞作为靶细胞进行CDC活性检测。
首先将靶细胞1000rpm离心5分钟,然后用FreeStyle 293表达培养基(Gibco)重悬。将靶细胞以20000个/孔的数量加入到96孔板中,加入本申请抗体HDR002C04或HDR002C06的稀释液,终浓度10μg/mL,37℃孵育1小时,加入实施例3中所述正常人血清,37℃孵育后以CCK-8显色,酶标仪读板。
检测结果如图7和图8所示,实验结果显示,本申请抗体HDR002C04和HDR002C06均对Claudin18.1阳性HEK293细胞没有显示CDC活性,而对Claudin18.2阳性HEK293细胞显示较强的CDC活性,表明本申请抗体引起的CDC活性效应对Claudin18.2阳性细胞系是高度特异的。
实施例5抗Claudin18.2抗体对Claudin18.2阳性细胞系的ADCC效应
从健康志愿者抽血,密度梯度离心提取正常人外周血单核细胞(PBMC)。使用乳酸脱氢酶(LDH)检测试剂盒(Roche)检测本申请抗体HDR002C04、HDR002C06和对照抗体IMAB362针对Claudin18.2阳性BxPC3细胞或Claudin18.2阳性N87细胞引发的ADCC效应的能力。
将本申请抗体HDR002C04、HDR002C06和对照抗体IMAB362稀释至不同浓度加入96孔板中,靶细胞Claudin18.2阳性BxPC3细胞、Claudin18.2阳性N87细胞和效应细胞PBMC分别收集至洁净离心管中,于2500rpm离心5分钟,然后用无酚红RPMI 1640培养基(Gibco)重悬。将人PBMC细胞和靶细胞(Claudin18.2阳性BxPC3细胞或Claudin18.2阳性N87细胞之一)按照效靶比24:1混合均匀,铺板于检测孔,置于37℃孵育20-24小时,加入LDH显色液,常温避光放置10-20分钟,终止后用MD SpectrsMax 190酶标仪读板。
如图9和图10所示,所有本申请抗体和对照抗体对Claudin18.2阳性细胞系均能以剂量依赖方式诱导强ADCC效应,并且本申请抗体HDR002C04和HDR002C06对Claudin18.2阳性细胞的ADCC活性要强于对照抗体IMAB362。
实施例6抗体HDR002C04体内抑制肿瘤生长效果
将BALB/c裸鼠随机分组,在第0天,用5×106个Claudin18.2阳性N87细胞皮下接瘤于裸鼠腋下。接瘤数小时后当天尾静脉给药,实验组每只以10mg/kg剂量给予本申请抗体HDR002C04或对照抗体IMAB362(稀释于PBS溶液中);之后静脉注射与腹腔注射交替进行,一周给药2次,连续给药3周。空白组以同样方式注射PBS。随时间推移监测肿瘤生长,用游标卡尺测量肿瘤的长与宽,并通过公式:肿瘤体积=(长×宽2)/2,计算肿瘤体积;实验结束时,取出并测量肿瘤重量;计算每组小鼠肿瘤的平均体积和重量。
如图11和图12显示,10mg/kg剂量下,对照抗体IMAB362未发挥活性,实验结束时肿瘤重量和空白组没有显著差异,而本申请抗体HDR002C04显示较好的抗肿瘤活性。
实施例7抗体HDR002C06的体内抑制肿瘤生长效果
将BALB/c裸鼠随机分组,在第0天,用5×106个Claudin18.2阳性BxPC3细胞皮下接瘤于裸鼠腋下。接瘤后第3天尾静脉给药,实验组每只以10mg/kg剂量给与本申请抗体HDR002C06或对照抗体IMAB362(稀释于PBS溶液中);之后静脉注射与腹腔注射交替进行,一周给药2次,连续给药3周。空白组以同样方式注射PBS。随时间推移监测肿瘤生长,用游标卡尺测量肿瘤的长与宽,并通过公式:肿瘤体积=(长×宽2)/2,计算肿瘤体积;实验结束时,取出并测量肿瘤重量;计算每组小鼠肿瘤的平均体积和重量。
如图13和图14显示,10mg/kg剂量下,HDR002C06的体内抑制肿瘤生长效果优于阳性对照IMAB362。
序列表
<110> 杭州邦顺制药有限公司
<120> 针对Claudin18.2的抗体及其用途
<150> 202010474861.9
<151> 2020-05-29
<160> 39
<170> SIPOSequenceListing 1.0
<210> 1
<211> 122
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 1
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Ile Ile Asn Pro Ser Gly Gly Ser Thr Ser Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Gly Ser Val Asp Thr Ala Met Val Pro Gly Val Asp Tyr Trp
100 105 110
Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 2
<211> 5
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 2
Ser Tyr Tyr Met His
1 5
<210> 3
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 3
Ile Ile Asn Pro Ser Gly Gly Ser Thr Ser Tyr Ala Gln Lys Phe Gln
1 5 10 15
Gly
<210> 4
<211> 13
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 4
Gly Ser Val Asp Thr Ala Met Val Pro Gly Val Asp Tyr
1 5 10
<210> 5
<211> 452
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 5
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Ile Ile Asn Pro Ser Gly Gly Ser Thr Ser Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Gly Ser Val Asp Thr Ala Met Val Pro Gly Val Asp Tyr Trp
100 105 110
Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro
115 120 125
Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr
130 135 140
Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr
145 150 155 160
Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro
165 170 175
Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr
180 185 190
Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn
195 200 205
His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser
210 215 220
Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu
225 230 235 240
Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu
245 250 255
Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser
260 265 270
His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu
275 280 285
Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr
290 295 300
Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn
305 310 315 320
Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro
325 330 335
Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln
340 345 350
Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val
355 360 365
Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
370 375 380
Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
385 390 395 400
Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr
405 410 415
Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val
420 425 430
Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
435 440 445
Ser Pro Gly Lys
450
<210> 6
<211> 110
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 6
Gln Ala Val Leu Thr Gln Pro Ser Ser Ala Ser Glu Thr Pro Gly Gln
1 5 10 15
Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Ser Asn
20 25 30
Thr Val Asn Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Val Leu
35 40 45
Ile Phe Ser Asn Asn Gln Arg Pro Ser Gly Val Pro Asp Arg Phe Ser
50 55 60
Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Gln
65 70 75 80
Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ala Trp Asp Asp Ser Leu
85 90 95
Asn Gly Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
100 105 110
<210> 7
<211> 13
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 7
Ser Gly Ser Ser Ser Asn Ile Gly Ser Asn Thr Val Asn
1 5 10
<210> 8
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 8
Ser Asn Asn Gln Arg Pro Ser
1 5
<210> 9
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 9
Ser Ala Trp Asp Asp Ser Leu Asn Gly Val Val
1 5 10
<210> 10
<211> 216
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 10
Gln Ala Val Leu Thr Gln Pro Ser Ser Ala Ser Glu Thr Pro Gly Gln
1 5 10 15
Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Ser Asn
20 25 30
Thr Val Asn Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Val Leu
35 40 45
Ile Phe Ser Asn Asn Gln Arg Pro Ser Gly Val Pro Asp Arg Phe Ser
50 55 60
Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Gln
65 70 75 80
Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ala Trp Asp Asp Ser Leu
85 90 95
Asn Gly Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gln
100 105 110
Pro Lys Ala Ala Pro Ser Val Thr Leu Phe Pro Pro Ser Ser Glu Glu
115 120 125
Leu Gln Ala Asn Lys Ala Thr Leu Val Cys Leu Ile Ser Asp Phe Tyr
130 135 140
Pro Gly Ala Val Thr Val Ala Trp Lys Ala Asp Ser Ser Pro Val Lys
145 150 155 160
Ala Gly Val Glu Thr Thr Thr Pro Ser Lys Gln Ser Asn Asn Lys Tyr
165 170 175
Ala Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys Ser His
180 185 190
Arg Ser Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr Val Glu Lys
195 200 205
Thr Val Ala Pro Thr Glu Cys Ser
210 215
<210> 11
<211> 120
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 11
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Gly
20 25 30
Gly Tyr Tyr Trp Ser Trp Ile Arg Gln His Pro Gly Lys Gly Leu Glu
35 40 45
Trp Ile Gly Tyr Ile Tyr Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser
50 55 60
Leu Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe
65 70 75 80
Ser Leu Lys Leu Ser Ser Val Thr Pro Asp Asp Thr Ala Lys Tyr Tyr
85 90 95
Cys Ala Arg Ile Val Ala Ser Val Gly Gly Val Asp Val Trp Gly Gln
100 105 110
Gly Thr Thr Val Thr Val Ser Ser
115 120
<210> 12
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 12
Ser Gly Gly Tyr Tyr Trp Ser
1 5
<210> 13
<211> 16
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 13
Tyr Ile Tyr Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser Leu Lys Ser
1 5 10 15
<210> 14
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 14
Ile Val Ala Ser Val Gly Gly Val Asp Val
1 5 10
<210> 15
<211> 450
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 15
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Gly
20 25 30
Gly Tyr Tyr Trp Ser Trp Ile Arg Gln His Pro Gly Lys Gly Leu Glu
35 40 45
Trp Ile Gly Tyr Ile Tyr Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser
50 55 60
Leu Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe
65 70 75 80
Ser Leu Lys Leu Ser Ser Val Thr Pro Asp Asp Thr Ala Lys Tyr Tyr
85 90 95
Cys Ala Arg Ile Val Ala Ser Val Gly Gly Val Asp Val Trp Gly Gln
100 105 110
Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val
115 120 125
Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala
130 135 140
Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
145 150 155 160
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
165 170 175
Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
180 185 190
Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys
195 200 205
Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp
210 215 220
Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly
225 230 235 240
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
245 250 255
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
260 265 270
Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
275 280 285
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg
290 295 300
Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
305 310 315 320
Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu
325 330 335
Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
340 345 350
Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu
355 360 365
Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
370 375 380
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
385 390 395 400
Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp
405 410 415
Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His
420 425 430
Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
435 440 445
Gly Lys
450
<210> 16
<211> 107
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 16
Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser Trp
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr 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 Gln Gln Ala Asn Ser Phe Pro Leu
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 17
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 17
Arg Ala Ser Gln Gly Ile Ser Ser Trp Leu Ala
1 5 10
<210> 18
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 18
Ala Ala Ser Ser Leu Gln Ser
1 5
<210> 19
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 19
Gln Gln Ala Asn Ser Phe Pro Leu Thr
1 5
<210> 20
<211> 214
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 20
Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser Trp
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr 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 Gln Gln Ala Asn Ser Phe Pro Leu
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys
210
<210> 21
<211> 30
<212> PRT
<213> 人工序列(Artificial Sequence)
<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 Thr Phe Thr
20 25 30
<210> 22
<211> 14
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 22
Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met Gly
1 5 10
<210> 23
<211> 32
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 23
Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr Met Glu
1 5 10 15
Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Lys
20 25 30
<210> 24
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 24
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
1 5 10
<210> 25
<211> 22
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 25
Gln Ala Val Leu Thr Gln Pro Ser Ser Ala Ser Glu Thr Pro Gly Gln
1 5 10 15
Arg Val Thr Ile Ser Cys
20
<210> 26
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 26
Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Val Leu Ile Phe
1 5 10 15
<210> 27
<211> 32
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 27
Gly Val Pro Asp Arg Phe Ser Gly Ser Lys Ser Gly Thr Ser Ala Ser
1 5 10 15
Leu Ala Ile Ser Gly Leu Gln Ser Glu Asp Glu Ala Asp Tyr Tyr Cys
20 25 30
<210> 28
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 28
Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
1 5 10
<210> 29
<211> 30
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 29
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser
20 25 30
<210> 30
<211> 14
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 30
Trp Ile Arg Gln His Pro Gly Lys Gly Leu Glu Trp Ile Gly
1 5 10
<210> 31
<211> 32
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 31
Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu Lys
1 5 10 15
Leu Ser Ser Val Thr Pro Asp Asp Thr Ala Lys Tyr Tyr Cys Ala Arg
20 25 30
<210> 32
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 32
Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser
1 5 10
<210> 33
<211> 23
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 33
Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys
20
<210> 34
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 34
Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr
1 5 10 15
<210> 35
<211> 32
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 35
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
1 5 10 15
Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys
20 25 30
<210> 36
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 36
Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
1 5 10
<210> 37
<211> 330
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 37
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 Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
100 105 110
Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
115 120 125
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
130 135 140
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
145 150 155 160
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
165 170 175
Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
180 185 190
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
195 200 205
Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
210 215 220
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu
225 230 235 240
Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
245 250 255
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
260 265 270
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
275 280 285
Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
290 295 300
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
305 310 315 320
Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
325 330
<210> 38
<211> 106
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 38
Gly Gln Pro Lys Ala Ala Pro Ser Val Thr Leu Phe Pro Pro Ser Ser
1 5 10 15
Glu Glu Leu Gln Ala Asn Lys Ala Thr Leu Val Cys Leu Ile Ser Asp
20 25 30
Phe Tyr Pro Gly Ala Val Thr Val Ala Trp Lys Ala Asp Ser Ser Pro
35 40 45
Val Lys Ala Gly Val Glu Thr Thr Thr Pro Ser Lys Gln Ser Asn Asn
50 55 60
Lys Tyr Ala Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys
65 70 75 80
Ser His Arg Ser Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr Val
85 90 95
Glu Lys Thr Val Ala Pro Thr Glu Cys Ser
100 105
<210> 39
<211> 107
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 39
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
100 105
Claims (14)
1.一种分离的抗原结合蛋白,其包含重链可变区VH和轻链可变区VL,其中所述VH包含分别如SEQ ID NO:2、SEQ ID NO:3和SEQ ID NO:4所示的HCDR1、HCDR2和HCDR3,且所述VL包含分别如SEQ ID NO:7、SEQ ID NO:8和SEQ ID NO:9所示的LCDR1、LCDR2和LCDR3;
或者,
所述VH包含分别如SEQ ID NO:12、SEQ ID NO:13和SEQ ID NO:14所示的HCDR1、HCDR2和HCDR3,且所述VL包含分别如SEQ ID NO:17、SEQ ID NO:18和SEQ ID NO:19所示的LCDR1、LCDR2和LCDR3;
所述的分离的抗原结合蛋白能够特异性结合细胞表面的Claudin18.2。
2.如权利要求1所述的分离的抗原结合蛋白,其中,
所述VH包括框架区H-FR1、H-FR2、H-FR3和H-FR4,所述H-FR1的C末端与所述HCDR1的N末端直接或间接相连,且所述H-FR1包含SEQ ID NO:21或29所示氨基酸序列;所述H-FR2位于所述HCDR1与所述HCDR2之间,且所述H-FR2包含SEQ ID NO:22或30所示氨基酸序列;所述H-FR3位于所述HCDR2与所述HCDR3之间,且所述H-FR3包含SEQ ID NO:23或31所示氨基酸序列;所述H-FR4的N末端与所述HCDR3的C末端直接或间接相连,且所述H-FR4包含SEQ ID NO:24或32所示氨基酸序列;
和/或
所述VL包括框架区L-FR1、L-FR2、L-FR3和L-FR4,所述L-FR1的C末端与所述LCDR1的N末端直接或间接相连,且所述L-FR1包含SEQ ID NO:25或33所示氨基酸序列;所述L-FR2位于所述LCDR1与所述LCDR2之间,且所述L-FR2包含SEQ ID NO:26或34所示氨基酸序列;所述L-FR3位于所述LCDR2与所述LCDR3之间,且所述L-FR3包含SEQ ID NO:27或35所示氨基酸序列;所述L-FR4的N末端与所述LCDR3的C末端直接或间接相连,且所述L-FR4包含SEQ ID NO:28或36所示氨基酸序列。
3.如权利要求2所述的分离的抗原结合蛋白,所述VH的氨基酸序列如SEQ ID NO:1所示,且所述VL的氨基酸序列如SEQ ID NO:6所示;或者
所述VH的氨基酸序列如SEQ ID NO:11所示,且所述VL的氨基酸序列如SEQ ID NO:16所示。
4.如权利要求3所述的分离的抗原结合蛋白,其进一步包含:
抗体重链恒定区,所述抗体重链恒定区选自人IgG恒定区、IgA恒定区、IgM恒定区、IgD恒定区或IgE恒定区,所述人IgG恒定区选自人IgG1恒定区、IgG2恒定区、IgG3恒定区或IgG4恒定区;和/或
抗体轻链恒定区,所述抗体轻链恒定区选自人Igκ恒定区或人Igλ恒定区。
5.如权利要求4所述的分离的抗原结合蛋白,所述抗体重链恒定区包含SEQ ID NO:37所示的氨基酸序列;所述抗体轻链恒定区包含SEQ ID NO:38或39所示的氨基酸序列。
6.如权利要求5所述的分离的抗原结合蛋白,所述HC包含SEQ ID NO:5所示的氨基酸序列,且所述LC包含SEQ ID NO:10所示氨基酸序列;或者
所述HC包含SEQ ID NO:15所示的氨基酸序列,且所述LC包含SEQ ID NO:20所示氨基酸序列。
7.如权利要求1-6任一项所述的分离的抗原结合蛋白,其选自抗体或其抗原结合片段,所述抗体选自嵌合抗体、人源化抗体或全人源抗体,所述抗原结合片段选自Fab、Fab’、F(ab)2、Fv片段或F(ab’)2。
8.如权利要求7所述的分离的抗原结合蛋白,所述抗原结合片段选自scFv。
9.分离的核酸分子,其编码权利要求1-8中任一项所述的分离的抗原结合蛋白。
10.载体,其包含如权利要求9所述的核酸分子。
11.细胞,其包含如权利要求9所述的核酸分子或如权利要求10所述的载体。
12.制备权利要求1-8中任一项所述的分离的抗原结合蛋白的方法,所述方法包括在使得权利要求1-8中任一项所述的分离的抗原结合蛋白表达的条件下,培养如权利要求11所述的细胞。
13.药物组合物,其包含权利要求1-8中任一项所述的分离的抗原结合蛋白、权利要求9所述的核酸分子、权利要求10所述的载体或权利要求11所述的细胞,以及任选地药学上可接受的佐剂。
14.权利要求1-8中任一项所述的分离的抗原结合蛋白、权利要求9所述的核酸分子、权利要求10所述的载体、权利要求11所述的细胞或权利要求13所述的药物组合物在制备抑制Claudin18.2阳性肿瘤细胞的生长或杀伤Claudin18.2阳性肿瘤细胞的药物中的用途,所述药物用于预防、诊断、缓解或治疗肿瘤;所述肿瘤选自实体瘤;所述实体瘤选自胃癌或胰腺癌。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202010474861 | 2020-05-29 | ||
CN2020104748619 | 2020-05-29 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN113735974A CN113735974A (zh) | 2021-12-03 |
CN113735974B true CN113735974B (zh) | 2023-10-27 |
Family
ID=78728364
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202110587892.XA Active CN113735974B (zh) | 2020-05-29 | 2021-05-27 | 针对Claudin18.2的抗体及其用途 |
Country Status (2)
Country | Link |
---|---|
CN (1) | CN113735974B (zh) |
WO (1) | WO2021239026A1 (zh) |
Families Citing this family (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2023134657A1 (zh) * | 2022-01-11 | 2023-07-20 | 原启生物科技(上海)有限责任公司 | 抗cldn18.2和4-1bb的双特异性抗原结合蛋白及其用途 |
CN114428174B (zh) * | 2022-04-07 | 2022-07-08 | 北京肿瘤医院(北京大学肿瘤医院) | 一种胃癌预后生物标志物及其应用 |
CN114989304B (zh) * | 2022-06-30 | 2024-04-19 | 深圳市乐土生物医药有限公司 | 一种抗人Claudin18.2抗体及其应用 |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2014146672A1 (en) * | 2013-03-18 | 2014-09-25 | Ganymed Pharmaceuticals Ag | Therapy involving antibodies against claudin 18.2 for treatment of cancer |
KR20150008095A (ko) * | 2012-05-09 | 2015-01-21 | 가니메드 파마슈티칼스 아게 | 암 진단에 유용한 클로딘 18.2에 대한 항체 |
CN109762067A (zh) * | 2019-01-17 | 2019-05-17 | 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 |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1790664A1 (en) * | 2005-11-24 | 2007-05-30 | Ganymed Pharmaceuticals AG | Monoclonal antibodies against claudin-18 for treatment of cancer |
CN110606891B (zh) * | 2018-06-17 | 2022-12-06 | 上海健信生物医药科技有限公司 | 一种针对人cldn18.2的抗体分子,抗原结合片段及其医药用途 |
-
2021
- 2021-05-27 WO PCT/CN2021/096205 patent/WO2021239026A1/zh active Application Filing
- 2021-05-27 CN CN202110587892.XA patent/CN113735974B/zh active Active
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR20150008095A (ko) * | 2012-05-09 | 2015-01-21 | 가니메드 파마슈티칼스 아게 | 암 진단에 유용한 클로딘 18.2에 대한 항체 |
WO2014146672A1 (en) * | 2013-03-18 | 2014-09-25 | Ganymed Pharmaceuticals Ag | Therapy involving antibodies against claudin 18.2 for treatment of cancer |
CN109762067A (zh) * | 2019-01-17 | 2019-05-17 | 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 |
Non-Patent Citations (4)
Title |
---|
Anti-claudin18.2 antibody as new targeted therapy for advanced gastric cancer;Singh P et al;《Journal of Hematology and Oncology》;第10卷(第1期);全文 * |
claudin蛋白与消化系统肿瘤;徐胤;房殿春;;现代消化及介入诊疗(第06期);全文 * |
CLDN18.2蛋白在恶性肿瘤治疗中的研究进展;徐良额;何天阳;张丽;陆一丹;罗聪;;中国肿瘤临床(第06期);全文 * |
胃癌靶向治疗的现状和研究进展;刘瑾;高源;徐农;;肿瘤学杂志(第12期);全文 * |
Also Published As
Publication number | Publication date |
---|---|
WO2021239026A1 (zh) | 2021-12-02 |
CN113735974A (zh) | 2021-12-03 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
KR102136742B1 (ko) | 새로운 cd47 단일클론 항체 및 그 용도 | |
ES2927090T3 (es) | Anticuerpo anti-TROP-2 humano que muestra actividad antitumoral in vivo | |
KR101782487B1 (ko) | 신규 항-메소텔린 항체 및 이를 포함하는 조성물 | |
CN113735974B (zh) | 针对Claudin18.2的抗体及其用途 | |
JP5570218B2 (ja) | Fgfr4抗体 | |
EP2997042B1 (en) | Anti-cxcl1, cxcl7 and cxcl8 antibodies and their applications | |
KR20190105024A (ko) | 항-cd47 항체 및 그 용도 | |
AU2019310803A1 (en) | Anti-TIGIT antibody and uses thereof | |
KR101695056B1 (ko) | 카드헤린-11의 ec1 도메인을 표적으로 하는 인간화 항체 및 관련 조성물 및 방법 | |
KR20140101738A (ko) | 항 il-36r 항체 | |
US20090070890A1 (en) | Product | |
WO2020151761A1 (zh) | 结合pd-l1和ox40的双特异性抗体 | |
US11820831B2 (en) | Antibody binding to carbonic anhydrase and use thereof | |
AU2019215202A1 (en) | Antibodies to Galectin-3 and methods of use thereof | |
WO2021063350A1 (zh) | 一种融合蛋白及其应用 | |
CN109414489B (zh) | 网蛋白-1结合抗体及其用途 | |
EP4279507A1 (en) | Cd73-binding protein and use thereof | |
EP4169947A1 (en) | Anti-claudin18.2 antibody and use thereof | |
JP2024500512A (ja) | 抗b7-h3抗体およびその使用 | |
KR20230003067A (ko) | 미스폴딩된 tdp-43에 대한 단일쇄 항체 및 인트라바디 그리고 사용 방법 | |
WO2020156507A1 (zh) | 抗pd-l1的新型抗体及其用途 | |
RU2786434C2 (ru) | Антитело к tigit и его использование | |
WO2018142323A1 (en) | Anti-psma antibodies and uses thereof for diagnostic and therapeutic applications | |
CN113164601B (zh) | 一种分离的抗原结合蛋白及其用途 | |
CN113166264B (zh) | 一种分离的抗原结合蛋白及其用途 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
GR01 | Patent grant | ||
GR01 | Patent grant |