KR20220107257A - 이중특이성 융합 단백질 및 그의 응용 - Google Patents
이중특이성 융합 단백질 및 그의 응용 Download PDFInfo
- Publication number
- KR20220107257A KR20220107257A KR1020227022059A KR20227022059A KR20220107257A KR 20220107257 A KR20220107257 A KR 20220107257A KR 1020227022059 A KR1020227022059 A KR 1020227022059A KR 20227022059 A KR20227022059 A KR 20227022059A KR 20220107257 A KR20220107257 A KR 20220107257A
- Authority
- KR
- South Korea
- Prior art keywords
- ser
- seq
- amino acid
- val
- thr
- Prior art date
Links
- 108020001507 fusion proteins Proteins 0.000 title claims abstract description 139
- 102000037865 fusion proteins Human genes 0.000 title claims abstract description 138
- 230000027455 binding Effects 0.000 claims abstract description 168
- 108090000765 processed proteins & peptides Proteins 0.000 claims abstract description 56
- 239000012634 fragment Substances 0.000 claims abstract description 37
- 230000014509 gene expression Effects 0.000 claims abstract description 25
- 238000004519 manufacturing process Methods 0.000 claims abstract description 14
- 125000003275 alpha amino acid group Chemical group 0.000 claims description 263
- 102100035360 Cerebellar degeneration-related antigen 1 Human genes 0.000 claims description 111
- 238000006467 substitution reaction Methods 0.000 claims description 74
- 101000914484 Homo sapiens T-lymphocyte activation antigen CD80 Proteins 0.000 claims description 65
- GOJUJUVQIVIZAV-UHFFFAOYSA-N 2-amino-4,6-dichloropyrimidine-5-carbaldehyde Chemical group NC1=NC(Cl)=C(C=O)C(Cl)=N1 GOJUJUVQIVIZAV-UHFFFAOYSA-N 0.000 claims description 63
- 206010028980 Neoplasm Diseases 0.000 claims description 63
- 210000004027 cell Anatomy 0.000 claims description 61
- 229940027941 immunoglobulin g Drugs 0.000 claims description 59
- 239000003446 ligand Substances 0.000 claims description 55
- 102100027222 T-lymphocyte activation antigen CD80 Human genes 0.000 claims description 48
- 102000005962 receptors Human genes 0.000 claims description 47
- 108020003175 receptors Proteins 0.000 claims description 47
- 102000004169 proteins and genes Human genes 0.000 claims description 45
- 108090000623 proteins and genes Proteins 0.000 claims description 45
- -1 A33 Proteins 0.000 claims description 37
- 108091008605 VEGF receptors Proteins 0.000 claims description 37
- 102100033177 Vascular endothelial growth factor receptor 2 Human genes 0.000 claims description 36
- 238000000034 method Methods 0.000 claims description 31
- 150000007523 nucleic acids Chemical class 0.000 claims description 31
- 150000001413 amino acids Chemical class 0.000 claims description 27
- 102100038664 Fibrinogen-like protein 1 Human genes 0.000 claims description 26
- 102000005789 Vascular Endothelial Growth Factors Human genes 0.000 claims description 25
- 108010019530 Vascular Endothelial Growth Factors Proteins 0.000 claims description 25
- 239000000427 antigen Substances 0.000 claims description 22
- 102000036639 antigens Human genes 0.000 claims description 22
- 108091007433 antigens Proteins 0.000 claims description 22
- 102000017578 LAG3 Human genes 0.000 claims description 21
- 101000914514 Homo sapiens T-cell-specific surface glycoprotein CD28 Proteins 0.000 claims description 20
- 102100024216 Programmed cell death 1 ligand 1 Human genes 0.000 claims description 20
- 102100027213 T-cell-specific surface glycoprotein CD28 Human genes 0.000 claims description 20
- 102100040678 Programmed cell death protein 1 Human genes 0.000 claims description 19
- 101710089372 Programmed cell death protein 1 Proteins 0.000 claims description 19
- 108010074708 B7-H1 Antigen Proteins 0.000 claims description 18
- 102100024834 T-cell immunoreceptor with Ig and ITIM domains Human genes 0.000 claims description 18
- 102000054189 human CD80 Human genes 0.000 claims description 18
- 230000008685 targeting Effects 0.000 claims description 18
- 102000008203 CTLA-4 Antigen Human genes 0.000 claims description 17
- 108010021064 CTLA-4 Antigen Proteins 0.000 claims description 17
- 101000831007 Homo sapiens T-cell immunoreceptor with Ig and ITIM domains Proteins 0.000 claims description 17
- 102100029740 Poliovirus receptor Human genes 0.000 claims description 17
- 108010048507 poliovirus receptor Proteins 0.000 claims description 17
- 102100027207 CD27 antigen Human genes 0.000 claims description 14
- 101000914511 Homo sapiens CD27 antigen Proteins 0.000 claims description 14
- 101000868279 Homo sapiens Leukocyte surface antigen CD47 Proteins 0.000 claims description 14
- 101000851370 Homo sapiens Tumor necrosis factor receptor superfamily member 9 Proteins 0.000 claims description 14
- 101000863873 Homo sapiens Tyrosine-protein phosphatase non-receptor type substrate 1 Proteins 0.000 claims description 14
- 101000851018 Homo sapiens Vascular endothelial growth factor receptor 1 Proteins 0.000 claims description 14
- 102100032913 Leukocyte surface antigen CD47 Human genes 0.000 claims description 14
- 102100022153 Tumor necrosis factor receptor superfamily member 4 Human genes 0.000 claims description 14
- 101710165473 Tumor necrosis factor receptor superfamily member 4 Proteins 0.000 claims description 14
- 102100036856 Tumor necrosis factor receptor superfamily member 9 Human genes 0.000 claims description 14
- 102100029948 Tyrosine-protein phosphatase non-receptor type substrate 1 Human genes 0.000 claims description 14
- 102100033178 Vascular endothelial growth factor receptor 1 Human genes 0.000 claims description 14
- 230000035772 mutation Effects 0.000 claims description 14
- 102100025221 CD70 antigen Human genes 0.000 claims description 13
- 101000934356 Homo sapiens CD70 antigen Proteins 0.000 claims description 13
- 108020004707 nucleic acids Proteins 0.000 claims description 13
- 102000039446 nucleic acids Human genes 0.000 claims description 13
- 101001137987 Homo sapiens Lymphocyte activation gene 3 protein Proteins 0.000 claims description 12
- 108010082808 4-1BB Ligand Proteins 0.000 claims description 11
- 101000916644 Homo sapiens Macrophage colony-stimulating factor 1 receptor Proteins 0.000 claims description 11
- 108010018951 Interleukin-8B Receptors Proteins 0.000 claims description 11
- 102100028123 Macrophage colony-stimulating factor 1 Human genes 0.000 claims description 11
- 102100028198 Macrophage colony-stimulating factor 1 receptor Human genes 0.000 claims description 11
- 108010042215 OX40 Ligand Proteins 0.000 claims description 11
- 102000004473 OX40 Ligand Human genes 0.000 claims description 11
- 230000019491 signal transduction Effects 0.000 claims description 10
- 102000002029 Claudin Human genes 0.000 claims description 9
- 108050009302 Claudin Proteins 0.000 claims description 9
- 101001012157 Homo sapiens Receptor tyrosine-protein kinase erbB-2 Proteins 0.000 claims description 9
- 101150030213 Lag3 gene Proteins 0.000 claims description 9
- 102100030086 Receptor tyrosine-protein kinase erbB-2 Human genes 0.000 claims description 9
- 239000003814 drug Substances 0.000 claims description 9
- 108091033319 polynucleotide Proteins 0.000 claims description 9
- 102000040430 polynucleotide Human genes 0.000 claims description 9
- 239000002157 polynucleotide Substances 0.000 claims description 9
- 102000006942 B-Cell Maturation Antigen Human genes 0.000 claims description 8
- 108010008014 B-Cell Maturation Antigen Proteins 0.000 claims description 8
- 102100036466 Delta-like protein 3 Human genes 0.000 claims description 8
- 108091008794 FGF receptors Proteins 0.000 claims description 8
- 102100031507 Fc receptor-like protein 5 Human genes 0.000 claims description 8
- 102100021197 G-protein coupled receptor family C group 5 member D Human genes 0.000 claims description 8
- 102100041003 Glutamate carboxypeptidase 2 Human genes 0.000 claims description 8
- 101000892862 Homo sapiens Glutamate carboxypeptidase 2 Proteins 0.000 claims description 8
- 101000617130 Homo sapiens Stromal cell-derived factor 1 Proteins 0.000 claims description 8
- 102100021669 Stromal cell-derived factor 1 Human genes 0.000 claims description 8
- 201000011510 cancer Diseases 0.000 claims description 8
- 229960005386 ipilimumab Drugs 0.000 claims description 8
- 238000011282 treatment Methods 0.000 claims description 8
- 102100022005 B-lymphocyte antigen CD20 Human genes 0.000 claims description 7
- 102100031351 Galectin-9 Human genes 0.000 claims description 7
- 101710121810 Galectin-9 Proteins 0.000 claims description 7
- 101000897405 Homo sapiens B-lymphocyte antigen CD20 Proteins 0.000 claims description 7
- 101000998120 Homo sapiens Interleukin-3 receptor subunit alpha Proteins 0.000 claims description 7
- 101000934338 Homo sapiens Myeloid cell surface antigen CD33 Proteins 0.000 claims description 7
- 102000037982 Immune checkpoint proteins Human genes 0.000 claims description 7
- 108091008036 Immune checkpoint proteins Proteins 0.000 claims description 7
- 108060003951 Immunoglobulin Proteins 0.000 claims description 7
- 102100033493 Interleukin-3 receptor subunit alpha Human genes 0.000 claims description 7
- 102000003735 Mesothelin Human genes 0.000 claims description 7
- 108090000015 Mesothelin Proteins 0.000 claims description 7
- 102100025243 Myeloid cell surface antigen CD33 Human genes 0.000 claims description 7
- 102000018358 immunoglobulin Human genes 0.000 claims description 7
- 238000003780 insertion Methods 0.000 claims description 7
- 229960003301 nivolumab Drugs 0.000 claims description 7
- 101000889276 Homo sapiens Cytotoxic T-lymphocyte protein 4 Proteins 0.000 claims description 6
- 101000846908 Homo sapiens Fc receptor-like protein 5 Proteins 0.000 claims description 6
- 102100035486 Nectin-4 Human genes 0.000 claims description 6
- 101710043865 Nectin-4 Proteins 0.000 claims description 6
- 108091005735 TGF-beta receptors Proteins 0.000 claims description 6
- 102000016715 Transforming Growth Factor beta Receptors Human genes 0.000 claims description 6
- 230000004927 fusion Effects 0.000 claims description 6
- 102000043321 human CTLA4 Human genes 0.000 claims description 6
- 230000037431 insertion Effects 0.000 claims description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims description 6
- FWMNVWWHGCHHJJ-SKKKGAJSSA-N 4-amino-1-[(2r)-6-amino-2-[[(2r)-2-[[(2r)-2-[[(2r)-2-amino-3-phenylpropanoyl]amino]-3-phenylpropanoyl]amino]-4-methylpentanoyl]amino]hexanoyl]piperidine-4-carboxylic acid Chemical compound C([C@H](C(=O)N[C@H](CC(C)C)C(=O)N[C@H](CCCCN)C(=O)N1CCC(N)(CC1)C(O)=O)NC(=O)[C@H](N)CC=1C=CC=CC=1)C1=CC=CC=C1 FWMNVWWHGCHHJJ-SKKKGAJSSA-N 0.000 claims description 5
- 229960003852 atezolizumab Drugs 0.000 claims description 5
- 229950002916 avelumab Drugs 0.000 claims description 5
- 238000012217 deletion Methods 0.000 claims description 5
- 230000037430 deletion Effects 0.000 claims description 5
- 229950009791 durvalumab Drugs 0.000 claims description 5
- 229960002621 pembrolizumab Drugs 0.000 claims description 5
- 102100034458 Hepatitis A virus cellular receptor 2 Human genes 0.000 claims description 4
- 101100166600 Homo sapiens CD28 gene Proteins 0.000 claims description 4
- 102000009524 Vascular Endothelial Growth Factor A Human genes 0.000 claims description 4
- 108010073929 Vascular Endothelial Growth Factor A Proteins 0.000 claims description 4
- 238000006471 dimerization reaction Methods 0.000 claims description 4
- 229940126546 immune checkpoint molecule Drugs 0.000 claims description 4
- 102100038078 CD276 antigen Human genes 0.000 claims description 3
- 102100032990 Trem-like transcript 2 protein Human genes 0.000 claims description 3
- 108010081667 aflibercept Proteins 0.000 claims description 3
- 210000004962 mammalian cell Anatomy 0.000 claims description 3
- 230000002829 reductive effect Effects 0.000 claims description 3
- 101710185679 CD276 antigen Proteins 0.000 claims description 2
- 238000009007 Diagnostic Kit Methods 0.000 claims description 2
- 241000588724 Escherichia coli Species 0.000 claims description 2
- 101000808011 Homo sapiens Vascular endothelial growth factor A Proteins 0.000 claims description 2
- 241000124008 Mammalia Species 0.000 claims description 2
- 241000283973 Oryctolagus cuniculus Species 0.000 claims description 2
- 210000004978 chinese hamster ovary cell Anatomy 0.000 claims description 2
- 238000012258 culturing Methods 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 210000003527 eukaryotic cell Anatomy 0.000 claims description 2
- 230000033581 fucosylation Effects 0.000 claims description 2
- 102000058223 human VEGFA Human genes 0.000 claims description 2
- 210000001236 prokaryotic cell Anatomy 0.000 claims description 2
- 238000011321 prophylaxis Methods 0.000 claims description 2
- 210000005253 yeast cell Anatomy 0.000 claims description 2
- 102000052116 epidermal growth factor receptor activity proteins Human genes 0.000 claims 15
- 108700015053 epidermal growth factor receptor activity proteins Proteins 0.000 claims 15
- YOHYSYJDKVYCJI-UHFFFAOYSA-N n-[3-[[6-[3-(trifluoromethyl)anilino]pyrimidin-4-yl]amino]phenyl]cyclopropanecarboxamide Chemical compound FC(F)(F)C1=CC=CC(NC=2N=CN=C(NC=3C=C(NC(=O)C4CC4)C=CC=3)C=2)=C1 YOHYSYJDKVYCJI-UHFFFAOYSA-N 0.000 claims 15
- 102000009024 Epidermal Growth Factor Human genes 0.000 claims 11
- 102100021866 Hepatocyte growth factor Human genes 0.000 claims 11
- 101001031635 Homo sapiens Fibrinogen-like protein 1 Proteins 0.000 claims 11
- 101000898034 Homo sapiens Hepatocyte growth factor Proteins 0.000 claims 11
- 101001076408 Homo sapiens Interleukin-6 Proteins 0.000 claims 11
- 101000868152 Homo sapiens Son of sevenless homolog 1 Proteins 0.000 claims 11
- 101710098940 Pro-epidermal growth factor Proteins 0.000 claims 11
- 101000851007 Homo sapiens Vascular endothelial growth factor receptor 2 Proteins 0.000 claims 8
- 102000004887 Transforming Growth Factor beta Human genes 0.000 claims 7
- 108090001012 Transforming Growth Factor beta Proteins 0.000 claims 7
- ZRKFYGHZFMAOKI-QMGMOQQFSA-N tgfbeta Chemical compound C([C@H](NC(=O)[C@H](C(C)C)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CC(C)C)NC(=O)CNC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CCSC)C(C)C)[C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O)C1=CC=C(O)C=C1 ZRKFYGHZFMAOKI-QMGMOQQFSA-N 0.000 claims 7
- 102100028989 C-X-C chemokine receptor type 2 Human genes 0.000 claims 5
- 102100028990 C-X-C chemokine receptor type 3 Human genes 0.000 claims 5
- 102100031650 C-X-C chemokine receptor type 4 Human genes 0.000 claims 5
- 102100025248 C-X-C motif chemokine 10 Human genes 0.000 claims 5
- 102100039398 C-X-C motif chemokine 2 Human genes 0.000 claims 5
- 102100036189 C-X-C motif chemokine 3 Human genes 0.000 claims 5
- 102100036150 C-X-C motif chemokine 5 Human genes 0.000 claims 5
- 102100036153 C-X-C motif chemokine 6 Human genes 0.000 claims 5
- 102100036170 C-X-C motif chemokine 9 Human genes 0.000 claims 5
- 108091011896 CSF1 Proteins 0.000 claims 5
- 229940045513 CTLA4 antagonist Drugs 0.000 claims 5
- 102100034221 Growth-regulated alpha protein Human genes 0.000 claims 5
- 101000916050 Homo sapiens C-X-C chemokine receptor type 3 Proteins 0.000 claims 5
- 101000922348 Homo sapiens C-X-C chemokine receptor type 4 Proteins 0.000 claims 5
- 101000858088 Homo sapiens C-X-C motif chemokine 10 Proteins 0.000 claims 5
- 101000889128 Homo sapiens C-X-C motif chemokine 2 Proteins 0.000 claims 5
- 101000947193 Homo sapiens C-X-C motif chemokine 3 Proteins 0.000 claims 5
- 101000947186 Homo sapiens C-X-C motif chemokine 5 Proteins 0.000 claims 5
- 101000947177 Homo sapiens C-X-C motif chemokine 6 Proteins 0.000 claims 5
- 101000947172 Homo sapiens C-X-C motif chemokine 9 Proteins 0.000 claims 5
- 101001069921 Homo sapiens Growth-regulated alpha protein Proteins 0.000 claims 5
- 101001019455 Homo sapiens ICOS ligand Proteins 0.000 claims 5
- 101001055222 Homo sapiens Interleukin-8 Proteins 0.000 claims 5
- 101000947178 Homo sapiens Platelet basic protein Proteins 0.000 claims 5
- 102100034980 ICOS ligand Human genes 0.000 claims 5
- 102100026236 Interleukin-8 Human genes 0.000 claims 5
- 102100036154 Platelet basic protein Human genes 0.000 claims 5
- 102100032101 Tumor necrosis factor ligand superfamily member 9 Human genes 0.000 claims 5
- BGFTWECWAICPDG-UHFFFAOYSA-N 2-[bis(4-chlorophenyl)methyl]-4-n-[3-[bis(4-chlorophenyl)methyl]-4-(dimethylamino)phenyl]-1-n,1-n-dimethylbenzene-1,4-diamine Chemical compound C1=C(C(C=2C=CC(Cl)=CC=2)C=2C=CC(Cl)=CC=2)C(N(C)C)=CC=C1NC(C=1)=CC=C(N(C)C)C=1C(C=1C=CC(Cl)=CC=1)C1=CC=C(Cl)C=C1 BGFTWECWAICPDG-UHFFFAOYSA-N 0.000 claims 3
- 101710083479 Hepatitis A virus cellular receptor 2 homolog Proteins 0.000 claims 3
- 101000914324 Homo sapiens Carcinoembryonic antigen-related cell adhesion molecule 5 Proteins 0.000 claims 3
- 101000914321 Homo sapiens Carcinoembryonic antigen-related cell adhesion molecule 7 Proteins 0.000 claims 3
- 101000928513 Homo sapiens Delta-like protein 3 Proteins 0.000 claims 3
- 101001040713 Homo sapiens G-protein coupled receptor family C group 5 member D Proteins 0.000 claims 3
- 101000692455 Homo sapiens Platelet-derived growth factor receptor beta Proteins 0.000 claims 3
- 101000617725 Homo sapiens Pregnancy-specific beta-1-glycoprotein 2 Proteins 0.000 claims 3
- 101000829127 Homo sapiens Somatostatin receptor type 2 Proteins 0.000 claims 3
- 102000001393 Platelet-Derived Growth Factor alpha Receptor Human genes 0.000 claims 3
- 108010068588 Platelet-Derived Growth Factor alpha Receptor Proteins 0.000 claims 3
- 102100026547 Platelet-derived growth factor receptor beta Human genes 0.000 claims 3
- 102100022019 Pregnancy-specific beta-1-glycoprotein 2 Human genes 0.000 claims 3
- 102000014128 RANK Ligand Human genes 0.000 claims 3
- 108010025832 RANK Ligand Proteins 0.000 claims 3
- 102100023802 Somatostatin receptor type 2 Human genes 0.000 claims 3
- 229940126547 T-cell immunoglobulin mucin-3 Drugs 0.000 claims 3
- 229940127276 delta-like ligand 3 Drugs 0.000 claims 3
- 102000052178 fibroblast growth factor receptor activity proteins Human genes 0.000 claims 3
- 229920001481 poly(stearyl methacrylate) Polymers 0.000 claims 3
- 102100033553 Delta-like protein 4 Human genes 0.000 claims 2
- 101000872077 Homo sapiens Delta-like protein 4 Proteins 0.000 claims 2
- 101000801234 Homo sapiens Tumor necrosis factor receptor superfamily member 18 Proteins 0.000 claims 1
- 101000597780 Mus musculus Tumor necrosis factor ligand superfamily member 18 Proteins 0.000 claims 1
- 102000002356 Nectin Human genes 0.000 claims 1
- 108060005251 Nectin Proteins 0.000 claims 1
- 101710149051 Trem-like transcript 2 protein Proteins 0.000 claims 1
- 102100035283 Tumor necrosis factor ligand superfamily member 18 Human genes 0.000 claims 1
- 102100033728 Tumor necrosis factor receptor superfamily member 18 Human genes 0.000 claims 1
- 230000002159 abnormal effect Effects 0.000 claims 1
- 238000006664 bond formation reaction Methods 0.000 claims 1
- 239000000178 monomer Substances 0.000 abstract description 13
- 230000001976 improved effect Effects 0.000 abstract description 7
- 230000008901 benefit Effects 0.000 abstract description 4
- 241000880493 Leptailurus serval Species 0.000 description 63
- 235000018102 proteins Nutrition 0.000 description 43
- 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 36
- 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 35
- XKUKSGPZAADMRA-UHFFFAOYSA-N glycyl-glycyl-glycine Natural products NCC(=O)NCC(=O)NCC(O)=O XKUKSGPZAADMRA-UHFFFAOYSA-N 0.000 description 34
- 108010031719 prolyl-serine Proteins 0.000 description 33
- 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 25
- 102000009484 Vascular Endothelial Growth Factor Receptors Human genes 0.000 description 23
- 108010044292 tryptophyltyrosine Proteins 0.000 description 23
- 108010017391 lysylvaline Proteins 0.000 description 22
- 108010067216 glycyl-glycyl-glycine Proteins 0.000 description 21
- 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 20
- 108010049041 glutamylalanine Proteins 0.000 description 20
- 229940124676 vascular endothelial growth factor receptor Drugs 0.000 description 20
- 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 19
- 238000011161 development Methods 0.000 description 19
- 230000018109 developmental process Effects 0.000 description 19
- 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 18
- 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 18
- 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 18
- 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 18
- 108010038745 tryptophylglycine Proteins 0.000 description 18
- 102000001301 EGF receptor Human genes 0.000 description 17
- 108060006698 EGF receptor Proteins 0.000 description 17
- 108010065920 Insulin Lispro Proteins 0.000 description 17
- 108010052670 arginyl-glutamyl-glutamic acid Proteins 0.000 description 17
- 108010069205 aspartyl-phenylalanine Proteins 0.000 description 17
- 101100505161 Caenorhabditis elegans mel-32 gene Proteins 0.000 description 16
- 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 16
- TYYLDKGBCJGJGW-UHFFFAOYSA-N L-tryptophan-L-tyrosine Natural products C=1NC2=CC=CC=C2C=1CC(N)C(=O)NC(C(O)=O)CC1=CC=C(O)C=C1 TYYLDKGBCJGJGW-UHFFFAOYSA-N 0.000 description 16
- 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 16
- 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 16
- 108010070643 prolylglutamic acid Proteins 0.000 description 16
- 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 15
- 206010009944 Colon cancer Diseases 0.000 description 15
- 101710197507 Fibrinogen-like protein 1 Proteins 0.000 description 15
- 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 15
- 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 15
- 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 15
- PZTZYZUTCPZWJH-FXQIFTODSA-N Val-Ser-Ser Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)O)N PZTZYZUTCPZWJH-FXQIFTODSA-N 0.000 description 15
- 108010008355 arginyl-glutamine Proteins 0.000 description 15
- 230000000875 corresponding effect Effects 0.000 description 15
- 108010069117 seryl-lysyl-aspartic acid Proteins 0.000 description 15
- 108010073969 valyllysine Proteins 0.000 description 15
- 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 14
- 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 14
- 241000699666 Mus <mouse, genus> Species 0.000 description 14
- 210000001744 T-lymphocyte Anatomy 0.000 description 14
- 108010053099 Vascular Endothelial Growth Factor Receptor-2 Proteins 0.000 description 14
- UQLDLKMNUJERMK-UHFFFAOYSA-L di(octadecanoyloxy)lead Chemical compound [Pb+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O UQLDLKMNUJERMK-UHFFFAOYSA-L 0.000 description 14
- 108010010147 glycylglutamine Proteins 0.000 description 14
- 108010044311 leucyl-glycyl-glycine Proteins 0.000 description 14
- HKZAAJSTFUZYTO-LURJTMIESA-N (2s)-2-[[2-[[2-[[2-[(2-aminoacetyl)amino]acetyl]amino]acetyl]amino]acetyl]amino]-3-hydroxypropanoic acid Chemical compound NCC(=O)NCC(=O)NCC(=O)NCC(=O)N[C@@H](CO)C(O)=O HKZAAJSTFUZYTO-LURJTMIESA-N 0.000 description 13
- JXFLPKSDLDEOQK-JHEQGTHGSA-N Gln-Gly-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)CNC(=O)[C@@H](N)CCC(N)=O JXFLPKSDLDEOQK-JHEQGTHGSA-N 0.000 description 13
- 108091028043 Nucleic acid sequence Proteins 0.000 description 13
- 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 13
- 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 13
- 208000029742 colonic neoplasm Diseases 0.000 description 13
- 108010060199 cysteinylproline Proteins 0.000 description 13
- 108010000434 glycyl-alanyl-leucine Proteins 0.000 description 13
- 108010001064 glycyl-glycyl-glycyl-glycine Proteins 0.000 description 13
- 108010050475 glycyl-leucyl-tyrosine Proteins 0.000 description 13
- 108010024654 phenylalanyl-prolyl-alanine Proteins 0.000 description 13
- 238000005406 washing Methods 0.000 description 13
- 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 12
- MKJBPDLENBUHQU-CIUDSAMLSA-N Asn-Ser-Leu Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(O)=O MKJBPDLENBUHQU-CIUDSAMLSA-N 0.000 description 12
- 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 12
- 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 12
- 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 12
- 102000003745 Hepatocyte Growth Factor Human genes 0.000 description 12
- 108090000100 Hepatocyte Growth Factor Proteins 0.000 description 12
- 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 12
- 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 12
- PDIDTSZKKFEDMB-UWVGGRQHSA-N Lys-Pro-Gly Chemical compound [H]N[C@@H](CCCCN)C(=O)N1CCC[C@H]1C(=O)NCC(O)=O PDIDTSZKKFEDMB-UWVGGRQHSA-N 0.000 description 12
- 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 12
- 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 12
- 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 12
- 108010069020 alanyl-prolyl-glycine Proteins 0.000 description 12
- 108010086434 alanyl-seryl-glycine Proteins 0.000 description 12
- 108010009111 arginyl-glycyl-glutamic acid Proteins 0.000 description 12
- 239000003480 eluent Substances 0.000 description 12
- 108010013768 glutamyl-aspartyl-proline Proteins 0.000 description 12
- 108010057821 leucylproline Proteins 0.000 description 12
- 108010077112 prolyl-proline Proteins 0.000 description 12
- 238000010079 rubber tapping Methods 0.000 description 12
- GJLXVWOMRRWCIB-MERZOTPQSA-N (2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-acetamido-5-(diaminomethylideneamino)pentanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-5-(diaminomethylideneamino)pentanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-6-aminohexanoyl]amino]-6-aminohexanoyl]amino]-6-aminohexanoyl]amino]-6-aminohexanoyl]amino]-6-aminohexanoyl]amino]-6-aminohexanoyl]amino]-6-aminohexanamide Chemical compound C([C@H](NC(=O)[C@H](CCCN=C(N)N)NC(=O)C)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(N)=O)C1=CC=C(O)C=C1 GJLXVWOMRRWCIB-MERZOTPQSA-N 0.000 description 11
- 101800003838 Epidermal growth factor Proteins 0.000 description 11
- 102400001368 Epidermal growth factor Human genes 0.000 description 11
- 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 11
- AXZGZMGRBDQTEY-SRVKXCTJSA-N Leu-Gln-Met Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCSC)C(O)=O AXZGZMGRBDQTEY-SRVKXCTJSA-N 0.000 description 11
- SBANPBVRHYIMRR-GARJFASQSA-N Leu-Ser-Pro Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CO)C(=O)N1CCC[C@@H]1C(=O)O)N SBANPBVRHYIMRR-GARJFASQSA-N 0.000 description 11
- GQZMPWBZQALKJO-UWVGGRQHSA-N Lys-Gly-Arg Chemical compound [H]N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(O)=O GQZMPWBZQALKJO-UWVGGRQHSA-N 0.000 description 11
- 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 11
- KZNQNBZMBZJQJO-UHFFFAOYSA-N N-glycyl-L-proline Natural products NCC(=O)N1CCCC1C(O)=O KZNQNBZMBZJQJO-UHFFFAOYSA-N 0.000 description 11
- FGWUALWGCZJQDJ-URLPEUOOSA-N Phe-Thr-Ile Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O FGWUALWGCZJQDJ-URLPEUOOSA-N 0.000 description 11
- 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 11
- QYSFWUIXDFJUDW-DCAQKATOSA-N Ser-Leu-Arg Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O QYSFWUIXDFJUDW-DCAQKATOSA-N 0.000 description 11
- 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 11
- 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 11
- MNYNCKZAEIAONY-XGEHTFHBSA-N Thr-Val-Ser Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CO)C(O)=O MNYNCKZAEIAONY-XGEHTFHBSA-N 0.000 description 11
- 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 11
- 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 11
- 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 11
- 229940116977 epidermal growth factor Drugs 0.000 description 11
- 108010089804 glycyl-threonine Proteins 0.000 description 11
- 108010015792 glycyllysine Proteins 0.000 description 11
- VBEQCZHXXJYVRD-GACYYNSASA-N uroanthelone Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CS)C(=O)N[C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCC(N)=O)C(=O)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)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)C(C)C)[C@@H](C)O)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CCSC)NC(=O)[C@H](CS)NC(=O)[C@@H](NC(=O)CNC(=O)CNC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CS)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CS)NC(=O)CNC(=O)[C@H]1N(CCC1)C(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC(N)=O)C(C)C)[C@@H](C)CC)C1=CC=C(O)C=C1 VBEQCZHXXJYVRD-GACYYNSASA-N 0.000 description 11
- 108010052774 valyl-lysyl-glycyl-phenylalanyl-tyrosine Proteins 0.000 description 11
- 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 10
- VKKYFICVTYKFIO-CIUDSAMLSA-N Arg-Ala-Glu Chemical compound OC(=O)CC[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CCCN=C(N)N VKKYFICVTYKFIO-CIUDSAMLSA-N 0.000 description 10
- 108050006947 CXC Chemokine Proteins 0.000 description 10
- 102000019388 CXC chemokine Human genes 0.000 description 10
- 101100315624 Caenorhabditis elegans tyr-1 gene Proteins 0.000 description 10
- FQCILXROGNOZON-YUMQZZPRSA-N Gln-Pro-Gly Chemical compound NC(=O)CC[C@H](N)C(=O)N1CCC[C@H]1C(=O)NCC(O)=O FQCILXROGNOZON-YUMQZZPRSA-N 0.000 description 10
- 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 10
- 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 10
- 108010067060 Immunoglobulin Variable Region Proteins 0.000 description 10
- 102000017727 Immunoglobulin Variable Region Human genes 0.000 description 10
- 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 10
- 241000699670 Mus sp. Species 0.000 description 10
- YMIZSYUAZJSOFL-SRVKXCTJSA-N Phe-Ser-Asn Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(O)=O YMIZSYUAZJSOFL-SRVKXCTJSA-N 0.000 description 10
- 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 10
- 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 10
- UIGMAMGZOJVTDN-WHFBIAKZSA-N Ser-Gly-Ser Chemical compound OC[C@H](N)C(=O)NCC(=O)N[C@@H](CO)C(O)=O UIGMAMGZOJVTDN-WHFBIAKZSA-N 0.000 description 10
- 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 10
- 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 10
- ADJDNJCSPNFFPI-FXQIFTODSA-N Ser-Pro-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@@H]1CCCN1C(=O)[C@@H](N)CO ADJDNJCSPNFFPI-FXQIFTODSA-N 0.000 description 10
- 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 10
- HSWXBJCBYSWBPT-GUBZILKMSA-N Ser-Val-Val Chemical compound CC(C)[C@H](NC(=O)[C@@H](NC(=O)[C@@H](N)CO)C(C)C)C(O)=O HSWXBJCBYSWBPT-GUBZILKMSA-N 0.000 description 10
- BMGOFDMKDVVGJG-NHCYSSNCSA-N Val-Asp-Lys Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](CCCCN)C(=O)O)N BMGOFDMKDVVGJG-NHCYSSNCSA-N 0.000 description 10
- 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 10
- 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 10
- 108010008685 alanyl-glutamyl-aspartic acid Proteins 0.000 description 10
- 108010041407 alanylaspartic acid Proteins 0.000 description 10
- 108010087924 alanylproline Proteins 0.000 description 10
- 230000005764 inhibitory process Effects 0.000 description 10
- 108010064235 lysylglycine Proteins 0.000 description 10
- 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 9
- 108010047041 Complementarity Determining Regions Proteins 0.000 description 9
- AVZHGSCDKIQZPQ-CIUDSAMLSA-N Glu-Arg-Ala Chemical compound C[C@H](NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@@H](N)CCC(O)=O)C(O)=O AVZHGSCDKIQZPQ-CIUDSAMLSA-N 0.000 description 9
- INGJLBQKTRJLFO-UKJIMTQDSA-N Glu-Ile-Val Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)[C@H]([C@@H](C)CC)NC(=O)[C@@H](N)CCC(O)=O INGJLBQKTRJLFO-UKJIMTQDSA-N 0.000 description 9
- SCWYHUQOOFRVHP-MBLNEYKQSA-N Gly-Ile-Thr Chemical compound NCC(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(O)=O SCWYHUQOOFRVHP-MBLNEYKQSA-N 0.000 description 9
- 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 9
- 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 9
- 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 9
- 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 9
- AIMGJYMCTAABEN-GVXVVHGQSA-N Leu-Val-Glu Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(O)=O)C(O)=O AIMGJYMCTAABEN-GVXVVHGQSA-N 0.000 description 9
- 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 9
- NNFMANHDYSVNIO-DCAQKATOSA-N Ser-Lys-Arg Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O NNFMANHDYSVNIO-DCAQKATOSA-N 0.000 description 9
- 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 9
- JWHOIHCOHMZSAR-QWRGUYRKSA-N Tyr-Asp-Gly Chemical compound OC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 JWHOIHCOHMZSAR-QWRGUYRKSA-N 0.000 description 9
- MYLNLEIZWHVENT-VKOGCVSHSA-N Val-Ile-Trp Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC1=CNC2=CC=CC=C21)C(=O)O)NC(=O)[C@H](C(C)C)N MYLNLEIZWHVENT-VKOGCVSHSA-N 0.000 description 9
- 108010047857 aspartylglycine Proteins 0.000 description 9
- 108010034529 leucyl-lysine Proteins 0.000 description 9
- 108010048397 seryl-lysyl-leucine Proteins 0.000 description 9
- 108010071097 threonyl-lysyl-proline Proteins 0.000 description 9
- 108010051110 tyrosyl-lysine Proteins 0.000 description 9
- 108010071635 tyrosyl-prolyl-arginine Proteins 0.000 description 9
- 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 8
- 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 8
- XQNRANMFRPCFFW-GCJQMDKQSA-N Ala-Thr-Asn Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)O)NC(=O)[C@H](C)N)O XQNRANMFRPCFFW-GCJQMDKQSA-N 0.000 description 8
- UGXYFDQFLVCDFC-CIUDSAMLSA-N Asn-Ser-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC(N)=O UGXYFDQFLVCDFC-CIUDSAMLSA-N 0.000 description 8
- JBDLMLZNDRLDIX-HJGDQZAQSA-N Asn-Thr-Leu Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(O)=O JBDLMLZNDRLDIX-HJGDQZAQSA-N 0.000 description 8
- ICDIMQAMJGDHSE-GUBZILKMSA-N Gln-His-Ser Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CO)C(O)=O ICDIMQAMJGDHSE-GUBZILKMSA-N 0.000 description 8
- 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 8
- 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 8
- 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 8
- 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 8
- 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 8
- 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 8
- 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 8
- NVTPVQLIZCOJFK-FOHZUACHSA-N Gly-Thr-Asp Chemical compound [H]NCC(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(O)=O)C(O)=O NVTPVQLIZCOJFK-FOHZUACHSA-N 0.000 description 8
- DNAZKGFYFRGZIH-QWRGUYRKSA-N Gly-Tyr-Ser Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)CN)CC1=CC=C(O)C=C1 DNAZKGFYFRGZIH-QWRGUYRKSA-N 0.000 description 8
- 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 8
- 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 8
- 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 8
- IHRFZLQEQVHXFA-RHYQMDGZSA-N Met-Thr-Lys Chemical compound CSCC[C@H](N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@H](C(O)=O)CCCCN IHRFZLQEQVHXFA-RHYQMDGZSA-N 0.000 description 8
- 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 8
- 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 8
- 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 8
- HWLKHNDRXWTFTN-GUBZILKMSA-N Pro-Pro-Cys Chemical compound C1C[C@H](NC1)C(=O)N2CCC[C@H]2C(=O)N[C@@H](CS)C(=O)O HWLKHNDRXWTFTN-GUBZILKMSA-N 0.000 description 8
- WDXYVIIVDIDOSX-DCAQKATOSA-N Ser-Arg-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)CO)CCCN=C(N)N WDXYVIIVDIDOSX-DCAQKATOSA-N 0.000 description 8
- OBXVZEAMXFSGPU-FXQIFTODSA-N Ser-Asn-Arg Chemical compound C(C[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)N)NC(=O)[C@H](CO)N)CN=C(N)N OBXVZEAMXFSGPU-FXQIFTODSA-N 0.000 description 8
- 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 8
- 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 8
- PWKMJDQXKCENMF-MEYUZBJRSA-N Tyr-Thr-Leu Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(O)=O PWKMJDQXKCENMF-MEYUZBJRSA-N 0.000 description 8
- 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 8
- 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 8
- 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 8
- 238000013461 design Methods 0.000 description 8
- 108010073472 leucyl-prolyl-proline Proteins 0.000 description 8
- 108010003700 lysyl aspartic acid Proteins 0.000 description 8
- 108010054155 lysyllysine Proteins 0.000 description 8
- 108010051242 phenylalanylserine Proteins 0.000 description 8
- 108010026333 seryl-proline Proteins 0.000 description 8
- 238000001890 transfection Methods 0.000 description 8
- 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 7
- DYJJJCHDHLEFDW-FXQIFTODSA-N Ala-Pro-Cys Chemical compound C[C@@H](C(=O)N1CCC[C@H]1C(=O)N[C@@H](CS)C(=O)O)N DYJJJCHDHLEFDW-FXQIFTODSA-N 0.000 description 7
- 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 7
- YJHKTAMKPGFJCT-NRPADANISA-N Ala-Val-Glu Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(O)=O)C(O)=O YJHKTAMKPGFJCT-NRPADANISA-N 0.000 description 7
- ZUVMUOOHJYNJPP-XIRDDKMYSA-N Arg-Trp-Gln Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC1=CNC2=C1C=CC=C2)C(=O)N[C@@H](CCC(N)=O)C(O)=O ZUVMUOOHJYNJPP-XIRDDKMYSA-N 0.000 description 7
- UVTGNSWSRSCPLP-UHFFFAOYSA-N Arg-Tyr Natural products NC(CCNC(=N)N)C(=O)NC(Cc1ccc(O)cc1)C(=O)O UVTGNSWSRSCPLP-UHFFFAOYSA-N 0.000 description 7
- WONGRTVAMHFGBE-WDSKDSINSA-N Asn-Gly-Gln Chemical compound C(CC(=O)N)[C@@H](C(=O)O)NC(=O)CNC(=O)[C@H](CC(=O)N)N WONGRTVAMHFGBE-WDSKDSINSA-N 0.000 description 7
- 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 7
- HNXWVVHIGTZTBO-LKXGYXEUSA-N Asn-Ser-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC(N)=O HNXWVVHIGTZTBO-LKXGYXEUSA-N 0.000 description 7
- 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 7
- 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 7
- VZNOVQKGJQJOCS-SRVKXCTJSA-N Asp-Asp-Tyr Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O VZNOVQKGJQJOCS-SRVKXCTJSA-N 0.000 description 7
- 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 7
- 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 7
- JSHWXQIZOCVWIA-ZKWXMUAHSA-N Asp-Ser-Val Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(O)=O JSHWXQIZOCVWIA-ZKWXMUAHSA-N 0.000 description 7
- JILRMFFFCHUUTJ-ACZMJKKPSA-N Gln-Ser-Ser Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(O)=O JILRMFFFCHUUTJ-ACZMJKKPSA-N 0.000 description 7
- 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 7
- YQPFCZVKMUVZIN-AUTRQRHGSA-N Glu-Val-Gln Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(N)=O)C(O)=O YQPFCZVKMUVZIN-AUTRQRHGSA-N 0.000 description 7
- ZYRXTRTUCAVNBQ-GVXVVHGQSA-N Glu-Val-Lys Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CCC(=O)O)N ZYRXTRTUCAVNBQ-GVXVVHGQSA-N 0.000 description 7
- 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 7
- 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 7
- RVGMVLVBDRQVKB-UWVGGRQHSA-N Gly-Met-His Chemical compound CSCC[C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)NC(=O)CN RVGMVLVBDRQVKB-UWVGGRQHSA-N 0.000 description 7
- 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 7
- 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 7
- KSOBNUBCYHGUKH-UWVGGRQHSA-N Gly-Val-Val Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)[C@H](C(C)C)NC(=O)CN KSOBNUBCYHGUKH-UWVGGRQHSA-N 0.000 description 7
- JBCLFWXMTIKCCB-UHFFFAOYSA-N H-Gly-Phe-OH Natural products NCC(=O)NC(C(O)=O)CC1=CC=CC=C1 JBCLFWXMTIKCCB-UHFFFAOYSA-N 0.000 description 7
- VGSPNSSCMOHRRR-BJDJZHNGSA-N Ile-Ser-Lys Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCCN)C(=O)O)N VGSPNSSCMOHRRR-BJDJZHNGSA-N 0.000 description 7
- 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 7
- 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 7
- 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 7
- BTNXKBVLWJBTNR-SRVKXCTJSA-N Leu-His-Asn Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CC(N)=O)C(O)=O BTNXKBVLWJBTNR-SRVKXCTJSA-N 0.000 description 7
- 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 7
- 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 7
- MWVUEPNEPWMFBD-SRVKXCTJSA-N Lys-Cys-Lys Chemical compound NCCCC[C@H](N)C(=O)N[C@@H](CS)C(=O)N[C@H](C(O)=O)CCCCN MWVUEPNEPWMFBD-SRVKXCTJSA-N 0.000 description 7
- 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 7
- 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 7
- MEQLGHAMAUPOSJ-DCAQKATOSA-N Lys-Ser-Val Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(O)=O MEQLGHAMAUPOSJ-DCAQKATOSA-N 0.000 description 7
- YKBSXQFZWFXFIB-VOAKCMCISA-N Lys-Thr-Lys Chemical compound NCCCC[C@H](N)C(=O)N[C@@H]([C@H](O)C)C(=O)N[C@@H](CCCCN)C(O)=O YKBSXQFZWFXFIB-VOAKCMCISA-N 0.000 description 7
- 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 7
- 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 7
- 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 7
- 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 7
- 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 7
- PCWLNNZTBJTZRN-AVGNSLFASA-N Pro-Pro-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@H]1NCCC1 PCWLNNZTBJTZRN-AVGNSLFASA-N 0.000 description 7
- 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 7
- 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 7
- 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 7
- FMDHKPRACUXATF-ACZMJKKPSA-N Ser-Gln-Ser Chemical compound OC[C@H](N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CO)C(O)=O FMDHKPRACUXATF-ACZMJKKPSA-N 0.000 description 7
- ZIFYDQAFEMIZII-GUBZILKMSA-N Ser-Leu-Glu Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(O)=O ZIFYDQAFEMIZII-GUBZILKMSA-N 0.000 description 7
- 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 7
- 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 7
- 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 7
- 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 7
- 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 7
- 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 7
- XSEPSRUDSPHMPX-KATARQTJSA-N Thr-Lys-Ser Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CO)C(O)=O XSEPSRUDSPHMPX-KATARQTJSA-N 0.000 description 7
- XKWABWFMQXMUMT-HJGDQZAQSA-N Thr-Pro-Glu Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCC(O)=O)C(O)=O XKWABWFMQXMUMT-HJGDQZAQSA-N 0.000 description 7
- 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 7
- UDCHKDYNMRJYMI-QEJZJMRPSA-N Trp-Glu-Ser Chemical compound [H]N[C@@H](CC1=CNC2=C1C=CC=C2)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(O)=O UDCHKDYNMRJYMI-QEJZJMRPSA-N 0.000 description 7
- 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 7
- GAYLGYUVTDMLKC-UWJYBYFXSA-N Tyr-Asp-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 GAYLGYUVTDMLKC-UWJYBYFXSA-N 0.000 description 7
- 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 7
- 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 7
- MWUYSCVVPVITMW-IGNZVWTISA-N Tyr-Tyr-Ala Chemical compound C([C@@H](C(=O)N[C@@H](C)C(O)=O)NC(=O)[C@@H](N)CC=1C=CC(O)=CC=1)C1=CC=C(O)C=C1 MWUYSCVVPVITMW-IGNZVWTISA-N 0.000 description 7
- HJSLDXZAZGFPDK-ULQDDVLXSA-N Val-Phe-Leu Chemical compound CC(C)C[C@@H](C(=O)O)NC(=O)[C@H](CC1=CC=CC=C1)NC(=O)[C@H](C(C)C)N HJSLDXZAZGFPDK-ULQDDVLXSA-N 0.000 description 7
- 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 7
- 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 7
- 108010050025 alpha-glutamyltryptophan Proteins 0.000 description 7
- 108010038633 aspartylglutamate Proteins 0.000 description 7
- 229960003008 blinatumomab Drugs 0.000 description 7
- 230000000694 effects Effects 0.000 description 7
- 108010050848 glycylleucine Proteins 0.000 description 7
- 108010047926 leucyl-lysyl-tyrosine Proteins 0.000 description 7
- 238000005259 measurement Methods 0.000 description 7
- 239000006228 supernatant Substances 0.000 description 7
- 108010031491 threonyl-lysyl-glutamic acid Proteins 0.000 description 7
- 108010080629 tryptophan-leucine Proteins 0.000 description 7
- 108010084932 tryptophyl-proline Proteins 0.000 description 7
- 102000002627 4-1BB Ligand Human genes 0.000 description 6
- 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 6
- WNHNMKOFKCHKKD-BFHQHQDPSA-N Ala-Thr-Gly Chemical compound [H]N[C@@H](C)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(O)=O WNHNMKOFKCHKKD-BFHQHQDPSA-N 0.000 description 6
- 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 6
- 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 6
- ANRZCQXIXGDXLR-CWRNSKLLSA-N Asn-Trp-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CC2=CNC3=CC=CC=C32)NC(=O)[C@H](CC(=O)N)N)C(=O)O ANRZCQXIXGDXLR-CWRNSKLLSA-N 0.000 description 6
- 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 6
- USNJAPJZSGTTPX-XVSYOHENSA-N Asp-Phe-Thr Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H]([C@@H](C)O)C(O)=O USNJAPJZSGTTPX-XVSYOHENSA-N 0.000 description 6
- 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 6
- 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 6
- 102000010919 CXC chemokine receptor 3 Human genes 0.000 description 6
- 108010061300 CXCR3 Receptors Proteins 0.000 description 6
- 102000012000 CXCR4 Receptors Human genes 0.000 description 6
- 108010061299 CXCR4 Receptors Proteins 0.000 description 6
- OHLLDUNVMPPUMD-DCAQKATOSA-N Cys-Leu-Val Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](C(C)C)C(=O)O)NC(=O)[C@H](CS)N OHLLDUNVMPPUMD-DCAQKATOSA-N 0.000 description 6
- NDNZRWUDUMTITL-FXQIFTODSA-N Cys-Ser-Val Chemical compound [H]N[C@@H](CS)C(=O)N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(O)=O NDNZRWUDUMTITL-FXQIFTODSA-N 0.000 description 6
- 108020004414 DNA Proteins 0.000 description 6
- XZLLTYBONVKGLO-SDDRHHMPSA-N Gln-Lys-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CCCCN)NC(=O)[C@H](CCC(=O)N)N)C(=O)O XZLLTYBONVKGLO-SDDRHHMPSA-N 0.000 description 6
- KASDBWKLWJKTLJ-GUBZILKMSA-N Glu-Glu-Met Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCSC)C(O)=O KASDBWKLWJKTLJ-GUBZILKMSA-N 0.000 description 6
- 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 6
- 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 6
- 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 6
- GGAPHLIUUTVYMX-QWRGUYRKSA-N Gly-Phe-Ser Chemical compound OC[C@@H](C([O-])=O)NC(=O)[C@@H](NC(=O)C[NH3+])CC1=CC=CC=C1 GGAPHLIUUTVYMX-QWRGUYRKSA-N 0.000 description 6
- 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 6
- 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 6
- IITVUURPOYGCTD-NAKRPEOUSA-N Ile-Pro-Ala Chemical compound CC[C@H](C)[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](C)C(O)=O IITVUURPOYGCTD-NAKRPEOUSA-N 0.000 description 6
- 102000002791 Interleukin-8B Receptors Human genes 0.000 description 6
- IBMVEYRWAWIOTN-UHFFFAOYSA-N L-Leucyl-L-Arginyl-L-Proline Natural products CC(C)CC(N)C(=O)NC(CCCN=C(N)N)C(=O)N1CCCC1C(O)=O IBMVEYRWAWIOTN-UHFFFAOYSA-N 0.000 description 6
- WSGXUIQTEZDVHJ-GARJFASQSA-N Leu-Ala-Pro Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](C)C(=O)N1CCC[C@@H]1C(O)=O WSGXUIQTEZDVHJ-GARJFASQSA-N 0.000 description 6
- FGNQZXKVAZIMCI-CIUDSAMLSA-N Leu-Asp-Cys Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](CS)C(=O)O)N FGNQZXKVAZIMCI-CIUDSAMLSA-N 0.000 description 6
- IDGZVZJLYFTXSL-DCAQKATOSA-N Leu-Ser-Arg Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@H](C(O)=O)CCCN=C(N)N IDGZVZJLYFTXSL-DCAQKATOSA-N 0.000 description 6
- 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 6
- 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 6
- LUTDBHBIHHREDC-IHRRRGAJSA-N Lys-Pro-Lys Chemical compound NCCCC[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCCCN)C(O)=O LUTDBHBIHHREDC-IHRRRGAJSA-N 0.000 description 6
- 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 6
- 108010046938 Macrophage Colony-Stimulating Factor Proteins 0.000 description 6
- 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 6
- 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 6
- 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 6
- SFTZWNJFZYOLBD-ZDLURKLDSA-N Ser-Gly-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)CNC(=O)[C@@H](N)CO SFTZWNJFZYOLBD-ZDLURKLDSA-N 0.000 description 6
- XNCUYZKGQOCOQH-YUMQZZPRSA-N Ser-Leu-Gly Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)NCC(O)=O XNCUYZKGQOCOQH-YUMQZZPRSA-N 0.000 description 6
- 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 6
- 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 6
- OZPDGESCTGGNAD-CIUDSAMLSA-N Ser-Ser-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CO OZPDGESCTGGNAD-CIUDSAMLSA-N 0.000 description 6
- PYTKULIABVRXSC-BWBBJGPYSA-N Ser-Ser-Thr Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(O)=O PYTKULIABVRXSC-BWBBJGPYSA-N 0.000 description 6
- 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 6
- 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 6
- 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 6
- 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 6
- 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 6
- 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 6
- FMQGYTMERWBMSI-HJWJTTGWSA-N Val-Phe-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)[C@H](CC1=CC=CC=C1)NC(=O)[C@H](C(C)C)N FMQGYTMERWBMSI-HJWJTTGWSA-N 0.000 description 6
- 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 6
- RYHUIHUOYRNNIE-NRPADANISA-N Val-Ser-Gln Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(=O)N)C(=O)O)N RYHUIHUOYRNNIE-NRPADANISA-N 0.000 description 6
- 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 6
- 238000002835 absorbance Methods 0.000 description 6
- 108010081404 acein-2 Proteins 0.000 description 6
- 230000003213 activating effect Effects 0.000 description 6
- 108010068265 aspartyltyrosine Proteins 0.000 description 6
- 239000011248 coating agent Substances 0.000 description 6
- 238000000576 coating method Methods 0.000 description 6
- 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 6
- 229940079593 drug Drugs 0.000 description 6
- 108010080575 glutamyl-aspartyl-alanine Proteins 0.000 description 6
- 108010079547 glutamylmethionine Proteins 0.000 description 6
- 108010081551 glycylphenylalanine Proteins 0.000 description 6
- 210000004698 lymphocyte Anatomy 0.000 description 6
- 108010073025 phenylalanylphenylalanine Proteins 0.000 description 6
- 230000004614 tumor growth Effects 0.000 description 6
- 108010035534 tyrosyl-leucyl-alanine Proteins 0.000 description 6
- 230000035899 viability Effects 0.000 description 6
- 108010027345 wheylin-1 peptide Proteins 0.000 description 6
- 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 5
- 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 5
- SUMYEVXWCAYLLJ-GUBZILKMSA-N Ala-Leu-Gln Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(O)=O SUMYEVXWCAYLLJ-GUBZILKMSA-N 0.000 description 5
- MNZHHDPWDWQJCQ-YUMQZZPRSA-N Ala-Leu-Gly Chemical compound C[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)NCC(O)=O MNZHHDPWDWQJCQ-YUMQZZPRSA-N 0.000 description 5
- SUHLZMHFRALVSY-YUMQZZPRSA-N Ala-Lys-Gly Chemical compound NCCCC[C@H](NC(=O)[C@@H](N)C)C(=O)NCC(O)=O SUHLZMHFRALVSY-YUMQZZPRSA-N 0.000 description 5
- MDNAVFBZPROEHO-DCAQKATOSA-N Ala-Lys-Val Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C(C)C)C(O)=O MDNAVFBZPROEHO-DCAQKATOSA-N 0.000 description 5
- PNQWAUXQDBIJDY-GUBZILKMSA-N Arg-Glu-Glu Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(O)=O PNQWAUXQDBIJDY-GUBZILKMSA-N 0.000 description 5
- AUFHLLPVPSMEOG-YUMQZZPRSA-N Arg-Gly-Glu Chemical compound NC(N)=NCCC[C@H](N)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(O)=O AUFHLLPVPSMEOG-YUMQZZPRSA-N 0.000 description 5
- FFEUXEAKYRCACT-PEDHHIEDSA-N Arg-Ile-Ile Chemical compound CC[C@H](C)[C@H](NC(=O)[C@@H](NC(=O)[C@@H](N)CCCNC(N)=N)[C@@H](C)CC)C(O)=O FFEUXEAKYRCACT-PEDHHIEDSA-N 0.000 description 5
- LRPZJPMQGKGHSG-XGEHTFHBSA-N Arg-Ser-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CO)NC(=O)[C@H](CCCN=C(N)N)N)O LRPZJPMQGKGHSG-XGEHTFHBSA-N 0.000 description 5
- 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 5
- NVGWESORMHFISY-SRVKXCTJSA-N Asn-Asn-Phe Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O NVGWESORMHFISY-SRVKXCTJSA-N 0.000 description 5
- PUUPMDXIHCOPJU-HJGDQZAQSA-N Asn-Thr-Lys Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CC(=O)N)N)O PUUPMDXIHCOPJU-HJGDQZAQSA-N 0.000 description 5
- 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 5
- 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 5
- ODNWIBOCFGMRTP-SRVKXCTJSA-N Asp-His-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)CC(O)=O)CC1=CN=CN1 ODNWIBOCFGMRTP-SRVKXCTJSA-N 0.000 description 5
- KNDCWFXCFKSEBM-AVGNSLFASA-N Asp-Tyr-Glu 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](CCC(O)=O)C(O)=O KNDCWFXCFKSEBM-AVGNSLFASA-N 0.000 description 5
- 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 5
- 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 5
- WVLZTXGTNGHPBO-SRVKXCTJSA-N Cys-Leu-Leu Chemical compound [H]N[C@@H](CS)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O WVLZTXGTNGHPBO-SRVKXCTJSA-N 0.000 description 5
- 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 5
- 101710112748 Delta-like protein 3 Proteins 0.000 description 5
- 102000044168 Fibroblast Growth Factor Receptor Human genes 0.000 description 5
- 101710174800 G-protein coupled receptor family C group 5 member D Proteins 0.000 description 5
- WLODHVXYKYHLJD-ACZMJKKPSA-N Gln-Asp-Ser Chemical compound C(CC(=O)N)[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](CO)C(=O)O)N WLODHVXYKYHLJD-ACZMJKKPSA-N 0.000 description 5
- 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 5
- RBWKVOSARCFSQQ-FXQIFTODSA-N Gln-Gln-Ser Chemical compound NC(=O)CC[C@H](N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CO)C(O)=O RBWKVOSARCFSQQ-FXQIFTODSA-N 0.000 description 5
- ZNZPKVQURDQFFS-FXQIFTODSA-N Gln-Glu-Ser Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(O)=O ZNZPKVQURDQFFS-FXQIFTODSA-N 0.000 description 5
- BETSEXMYBWCDAE-SZMVWBNQSA-N Gln-Trp-Lys Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CCC(=O)N)N BETSEXMYBWCDAE-SZMVWBNQSA-N 0.000 description 5
- 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 5
- 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 5
- GXMXPCXXKVWOSM-KQXIARHKSA-N Glu-Ile-Pro Chemical compound CC[C@H](C)[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](CCC(=O)O)N GXMXPCXXKVWOSM-KQXIARHKSA-N 0.000 description 5
- HRBYTAIBKPNZKQ-AVGNSLFASA-N Glu-Lys-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](N)CCC(O)=O HRBYTAIBKPNZKQ-AVGNSLFASA-N 0.000 description 5
- NNQDRRUXFJYCCJ-NHCYSSNCSA-N Glu-Pro-Val Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](C(C)C)C(O)=O NNQDRRUXFJYCCJ-NHCYSSNCSA-N 0.000 description 5
- 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
- YYPFZVIXAVDHIK-IUCAKERBSA-N Gly-Glu-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)CN YYPFZVIXAVDHIK-IUCAKERBSA-N 0.000 description 5
- BUEFQXUHTUZXHR-LURJTMIESA-N Gly-Gly-Pro zwitterion Chemical compound NCC(=O)NCC(=O)N1CCC[C@H]1C(O)=O BUEFQXUHTUZXHR-LURJTMIESA-N 0.000 description 5
- 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 5
- WNZOCXUOGVYYBJ-CDMKHQONSA-N Gly-Phe-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CC1=CC=CC=C1)NC(=O)CN)O WNZOCXUOGVYYBJ-CDMKHQONSA-N 0.000 description 5
- FGPLUIQCSKGLTI-WDSKDSINSA-N Gly-Ser-Glu Chemical compound NCC(=O)N[C@@H](CO)C(=O)N[C@H](C(O)=O)CCC(O)=O FGPLUIQCSKGLTI-WDSKDSINSA-N 0.000 description 5
- 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 5
- 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 5
- HZWWOGWOBQBETJ-CUJWVEQBSA-N His-Thr-Cys Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CS)C(=O)O)NC(=O)[C@H](CC1=CN=CN1)N)O HZWWOGWOBQBETJ-CUJWVEQBSA-N 0.000 description 5
- 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 5
- UWSMZKRTOZEGDD-CUJWVEQBSA-N His-Thr-Ser Chemical compound [H]N[C@@H](CC1=CNC=N1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(O)=O UWSMZKRTOZEGDD-CUJWVEQBSA-N 0.000 description 5
- CSTDQOOBZBAJKE-BWAGICSOSA-N His-Tyr-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CC1=CC=C(C=C1)O)NC(=O)[C@H](CC2=CN=CN2)N)O CSTDQOOBZBAJKE-BWAGICSOSA-N 0.000 description 5
- DFJJAVZIHDFOGQ-MNXVOIDGSA-N Ile-Glu-Lys Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CCCCN)C(=O)O)N DFJJAVZIHDFOGQ-MNXVOIDGSA-N 0.000 description 5
- BQSLGJHIAGOZCD-CIUDSAMLSA-N Leu-Ala-Ser Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](CO)C(O)=O BQSLGJHIAGOZCD-CIUDSAMLSA-N 0.000 description 5
- 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 5
- KIZIOFNVSOSKJI-CIUDSAMLSA-N Leu-Ser-Cys Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CS)C(=O)O)N KIZIOFNVSOSKJI-CIUDSAMLSA-N 0.000 description 5
- 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 5
- QWWPYKKLXWOITQ-VOAKCMCISA-N Leu-Thr-Leu 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)CC(C)C QWWPYKKLXWOITQ-VOAKCMCISA-N 0.000 description 5
- ILDSIMPXNFWKLH-KATARQTJSA-N Leu-Thr-Ser Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(O)=O ILDSIMPXNFWKLH-KATARQTJSA-N 0.000 description 5
- NTSPQIONFJUMJV-AVGNSLFASA-N Lys-Arg-Val Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C(C)C)C(O)=O NTSPQIONFJUMJV-AVGNSLFASA-N 0.000 description 5
- NRQRKMYZONPCTM-CIUDSAMLSA-N Lys-Asp-Ser Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(O)=O NRQRKMYZONPCTM-CIUDSAMLSA-N 0.000 description 5
- NTBFKPBULZGXQL-KKUMJFAQSA-N Lys-Asp-Tyr Chemical compound NCCCC[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 NTBFKPBULZGXQL-KKUMJFAQSA-N 0.000 description 5
- 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 5
- RKIIYGUHIQJCBW-SRVKXCTJSA-N Met-His-Glu Chemical compound [H]N[C@@H](CCSC)C(=O)N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CCC(O)=O)C(O)=O RKIIYGUHIQJCBW-SRVKXCTJSA-N 0.000 description 5
- FWAHLGXNBLWIKB-NAKRPEOUSA-N Met-Ile-Ser Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H]([C@@H](C)CC)NC(=O)[C@@H](N)CCSC FWAHLGXNBLWIKB-NAKRPEOUSA-N 0.000 description 5
- 108010002311 N-glycylglutamic acid Proteins 0.000 description 5
- 108091008606 PDGF receptors Proteins 0.000 description 5
- JOXIIFVCSATTDH-IHPCNDPISA-N Phe-Asn-Trp Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CC2=CNC3=CC=CC=C32)C(=O)O)N JOXIIFVCSATTDH-IHPCNDPISA-N 0.000 description 5
- 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 5
- 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 5
- 108010038512 Platelet-Derived Growth Factor Proteins 0.000 description 5
- 102000010780 Platelet-Derived Growth Factor Human genes 0.000 description 5
- 102000011653 Platelet-Derived Growth Factor Receptors Human genes 0.000 description 5
- 102100030485 Platelet-derived growth factor receptor alpha Human genes 0.000 description 5
- 101710148465 Platelet-derived growth factor receptor alpha Proteins 0.000 description 5
- OOLOTUZJUBOMAX-GUBZILKMSA-N Pro-Ala-Val Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](C)C(=O)N[C@@H](C(C)C)C(O)=O OOLOTUZJUBOMAX-GUBZILKMSA-N 0.000 description 5
- KIPIKSXPPLABPN-CIUDSAMLSA-N Pro-Glu-Asn Chemical compound NC(=O)C[C@@H](C(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H]1CCCN1 KIPIKSXPPLABPN-CIUDSAMLSA-N 0.000 description 5
- 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 5
- KHRLUIPIMIQFGT-AVGNSLFASA-N Pro-Val-Leu Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O KHRLUIPIMIQFGT-AVGNSLFASA-N 0.000 description 5
- 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 5
- 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 5
- CTLVSHXLRVEILB-UBHSHLNASA-N Ser-Asn-Trp Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)N)NC(=O)[C@H](CO)N CTLVSHXLRVEILB-UBHSHLNASA-N 0.000 description 5
- 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 5
- VQBCMLMPEWPUTB-ACZMJKKPSA-N Ser-Glu-Ser Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(O)=O VQBCMLMPEWPUTB-ACZMJKKPSA-N 0.000 description 5
- 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 5
- GDUZTEQRAOXYJS-SRVKXCTJSA-N Ser-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](CO)N GDUZTEQRAOXYJS-SRVKXCTJSA-N 0.000 description 5
- 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 5
- OLKICIBQRVSQMA-SRVKXCTJSA-N Ser-Ser-Tyr Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O OLKICIBQRVSQMA-SRVKXCTJSA-N 0.000 description 5
- IGROJMCBGRFRGI-YTLHQDLWSA-N Thr-Ala-Ala Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](C)C(O)=O IGROJMCBGRFRGI-YTLHQDLWSA-N 0.000 description 5
- KGKWKSSSQGGYAU-SUSMZKCASA-N Thr-Gln-Thr Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H]([C@@H](C)O)C(=O)O)N)O KGKWKSSSQGGYAU-SUSMZKCASA-N 0.000 description 5
- LHEZGZQRLDBSRR-WDCWCFNPSA-N Thr-Glu-Leu Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(O)=O LHEZGZQRLDBSRR-WDCWCFNPSA-N 0.000 description 5
- 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 5
- 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 5
- 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 5
- 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 5
- 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 5
- LVRFMARKDGGZMX-IZPVPAKOSA-N Thr-Tyr-Thr Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@H](C(=O)N[C@@H]([C@@H](C)O)C(O)=O)CC1=CC=C(O)C=C1 LVRFMARKDGGZMX-IZPVPAKOSA-N 0.000 description 5
- QNXZCKMXHPULME-ZNSHCXBVSA-N Thr-Val-Pro Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@@H]1C(=O)O)N)O QNXZCKMXHPULME-ZNSHCXBVSA-N 0.000 description 5
- KZTLZZQTJMCGIP-ZJDVBMNYSA-N Thr-Val-Thr Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O KZTLZZQTJMCGIP-ZJDVBMNYSA-N 0.000 description 5
- 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 5
- QJBWZNTWJSZUOY-UWJYBYFXSA-N Tyr-Ala-Cys Chemical compound C[C@@H](C(=O)N[C@@H](CS)C(=O)O)NC(=O)[C@H](CC1=CC=C(C=C1)O)N QJBWZNTWJSZUOY-UWJYBYFXSA-N 0.000 description 5
- QYSBJAUCUKHSLU-JYJNAYRXSA-N Tyr-Arg-Val Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C(C)C)C(O)=O QYSBJAUCUKHSLU-JYJNAYRXSA-N 0.000 description 5
- 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 5
- WURLIFOWSMBUAR-SLFFLAALSA-N Tyr-Phe-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CC2=CC=CC=C2)NC(=O)[C@H](CC3=CC=C(C=C3)O)N)C(=O)O WURLIFOWSMBUAR-SLFFLAALSA-N 0.000 description 5
- SQUMHUZLJDUROQ-YDHLFZDLSA-N Tyr-Val-Asp Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(O)=O)C(O)=O SQUMHUZLJDUROQ-YDHLFZDLSA-N 0.000 description 5
- CGGVNFJRZJUVAE-BYULHYEWSA-N Val-Asp-Asn Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](CC(=O)N)C(=O)O)N CGGVNFJRZJUVAE-BYULHYEWSA-N 0.000 description 5
- OACSGBOREVRSME-NHCYSSNCSA-N Val-His-Asn Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](Cc1cnc[nH]1)C(=O)N[C@@H](CC(N)=O)C(O)=O OACSGBOREVRSME-NHCYSSNCSA-N 0.000 description 5
- KISFXYYRKKNLOP-IHRRRGAJSA-N Val-Phe-Ser Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CO)C(=O)O)N KISFXYYRKKNLOP-IHRRRGAJSA-N 0.000 description 5
- KSFXWENSJABBFI-ZKWXMUAHSA-N Val-Ser-Asn Chemical compound [H]N[C@@H](C(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(O)=O KSFXWENSJABBFI-ZKWXMUAHSA-N 0.000 description 5
- 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 5
- BZDGLJPROOOUOZ-XGEHTFHBSA-N Val-Thr-Cys Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CS)C(=O)O)NC(=O)[C@H](C(C)C)N)O BZDGLJPROOOUOZ-XGEHTFHBSA-N 0.000 description 5
- UVHFONIHVHLDDQ-IFFSRLJSSA-N Val-Thr-Glu Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)O)NC(=O)[C@H](C(C)C)N)O UVHFONIHVHLDDQ-IFFSRLJSSA-N 0.000 description 5
- 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 5
- JVGDAEKKZKKZFO-RCWTZXSCSA-N Val-Val-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](C(C)C)NC(=O)[C@H](C(C)C)N)O JVGDAEKKZKKZFO-RCWTZXSCSA-N 0.000 description 5
- 201000010099 disease Diseases 0.000 description 5
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 5
- 108010055341 glutamyl-glutamic acid Proteins 0.000 description 5
- 108010027668 glycyl-alanyl-valine Proteins 0.000 description 5
- 108010037850 glycylvaline Proteins 0.000 description 5
- 230000001965 increasing effect Effects 0.000 description 5
- 108010027338 isoleucylcysteine Proteins 0.000 description 5
- 108010091871 leucylmethionine Proteins 0.000 description 5
- 108010020755 prolyl-glycyl-glycine Proteins 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 102000004052 somatostatin receptor 2 Human genes 0.000 description 5
- 108090000586 somatostatin receptor 2 Proteins 0.000 description 5
- 230000001225 therapeutic effect Effects 0.000 description 5
- 108010079202 tyrosyl-alanyl-cysteine Proteins 0.000 description 5
- 239000003981 vehicle Substances 0.000 description 5
- COEXAQSTZUWMRI-STQMWFEESA-N (2s)-1-[2-[[(2s)-2-amino-3-(4-hydroxyphenyl)propanoyl]amino]acetyl]pyrrolidine-2-carboxylic acid Chemical compound C([C@H](N)C(=O)NCC(=O)N1[C@@H](CCC1)C(O)=O)C1=CC=C(O)C=C1 COEXAQSTZUWMRI-STQMWFEESA-N 0.000 description 4
- 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 4
- BTYTYHBSJKQBQA-GCJQMDKQSA-N Ala-Asp-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CC(=O)O)NC(=O)[C@H](C)N)O BTYTYHBSJKQBQA-GCJQMDKQSA-N 0.000 description 4
- YHKANGMVQWRMAP-DCAQKATOSA-N Ala-Leu-Arg Chemical compound C[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](C(O)=O)CCCN=C(N)N YHKANGMVQWRMAP-DCAQKATOSA-N 0.000 description 4
- 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 4
- MCYJBCKCAPERSE-FXQIFTODSA-N Arg-Ala-Asp Chemical compound OC(=O)C[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CCCN=C(N)N MCYJBCKCAPERSE-FXQIFTODSA-N 0.000 description 4
- YHQGEARSFILVHL-HJGDQZAQSA-N Arg-Gln-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)N)NC(=O)[C@H](CCCN=C(N)N)N)O YHQGEARSFILVHL-HJGDQZAQSA-N 0.000 description 4
- FNXCAFKDGBROCU-STECZYCISA-N Arg-Ile-Tyr Chemical compound NC(N)=NCCC[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 FNXCAFKDGBROCU-STECZYCISA-N 0.000 description 4
- IBLAOXSULLECQZ-IUKAMOBKSA-N Asn-Ile-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)[C@H]([C@@H](C)CC)NC(=O)[C@@H](N)CC(N)=O IBLAOXSULLECQZ-IUKAMOBKSA-N 0.000 description 4
- KRXIWXCXOARFNT-ZLUOBGJFSA-N Asp-Ala-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC(O)=O KRXIWXCXOARFNT-ZLUOBGJFSA-N 0.000 description 4
- NECWUSYTYSIFNC-DLOVCJGASA-N Asp-Ala-Phe Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 NECWUSYTYSIFNC-DLOVCJGASA-N 0.000 description 4
- NJIKKGUVGUBICV-ZLUOBGJFSA-N Asp-Ala-Ser Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC(O)=O NJIKKGUVGUBICV-ZLUOBGJFSA-N 0.000 description 4
- DPNWSMBUYCLEDG-CIUDSAMLSA-N Asp-Lys-Ser Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CO)C(O)=O DPNWSMBUYCLEDG-CIUDSAMLSA-N 0.000 description 4
- 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 4
- 102100021277 Beta-secretase 2 Human genes 0.000 description 4
- 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 4
- 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 4
- 241000282326 Felis catus Species 0.000 description 4
- XKBASPWPBXNVLQ-WDSKDSINSA-N Gln-Gly-Asn Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)NCC(=O)N[C@@H](CC(N)=O)C(O)=O XKBASPWPBXNVLQ-WDSKDSINSA-N 0.000 description 4
- OTQSTOXRUBVWAP-NRPADANISA-N Gln-Ser-Val Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(O)=O OTQSTOXRUBVWAP-NRPADANISA-N 0.000 description 4
- 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 4
- 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 4
- FYBSCGZLICNOBA-XQXXSGGOSA-N Glu-Ala-Thr Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O FYBSCGZLICNOBA-XQXXSGGOSA-N 0.000 description 4
- 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 4
- HPJLZFTUUJKWAJ-JHEQGTHGSA-N Glu-Gly-Thr Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)NCC(=O)N[C@@H]([C@@H](C)O)C(O)=O HPJLZFTUUJKWAJ-JHEQGTHGSA-N 0.000 description 4
- ZCOJVESMNGBGLF-GRLWGSQLSA-N Glu-Ile-Ile Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O ZCOJVESMNGBGLF-GRLWGSQLSA-N 0.000 description 4
- 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 4
- 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 4
- 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 4
- KKBWDNZXYLGJEY-UHFFFAOYSA-N Gly-Arg-Pro Natural products NCC(=O)NC(CCNC(=N)N)C(=O)N1CCCC1C(=O)O KKBWDNZXYLGJEY-UHFFFAOYSA-N 0.000 description 4
- ZRZILYKEJBMFHY-BQBZGAKWSA-N Gly-Asp-Met Chemical compound CSCC[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)O)NC(=O)CN ZRZILYKEJBMFHY-BQBZGAKWSA-N 0.000 description 4
- 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 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
- MAABHGXCIBEYQR-XVYDVKMFSA-N His-Asn-Ala Chemical compound C[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)N)NC(=O)[C@H](CC1=CN=CN1)N MAABHGXCIBEYQR-XVYDVKMFSA-N 0.000 description 4
- 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 4
- HIAHVKLTHNOENC-HGNGGELXSA-N His-Glu-Ala Chemical compound [H]N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(O)=O HIAHVKLTHNOENC-HGNGGELXSA-N 0.000 description 4
- 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 4
- LPXHYGGZJOCAFR-MNXVOIDGSA-N Ile-Glu-Leu Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CC(C)C)C(=O)O)N LPXHYGGZJOCAFR-MNXVOIDGSA-N 0.000 description 4
- APDIECQNNDGFPD-PYJNHQTQSA-N Ile-His-Val Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)N[C@@H](C(C)C)C(=O)O)N APDIECQNNDGFPD-PYJNHQTQSA-N 0.000 description 4
- JHNJNTMTZHEDLJ-NAKRPEOUSA-N Ile-Ser-Arg Chemical compound CC[C@H](C)[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCN=C(N)N)C(O)=O JHNJNTMTZHEDLJ-NAKRPEOUSA-N 0.000 description 4
- SAEWJTCJQVZQNZ-IUKAMOBKSA-N Ile-Thr-Asn Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(=O)N)C(=O)O)N SAEWJTCJQVZQNZ-IUKAMOBKSA-N 0.000 description 4
- GVEODXUBBFDBPW-MGHWNKPDSA-N Ile-Tyr-Leu Chemical compound CC[C@H](C)[C@H](N)C(=O)N[C@H](C(=O)N[C@@H](CC(C)C)C(O)=O)CC1=CC=C(O)C=C1 GVEODXUBBFDBPW-MGHWNKPDSA-N 0.000 description 4
- 102000018071 Immunoglobulin Fc Fragments Human genes 0.000 description 4
- 108010091135 Immunoglobulin Fc Fragments Proteins 0.000 description 4
- 108010074328 Interferon-gamma Proteins 0.000 description 4
- WQWSMEOYXJTFRU-GUBZILKMSA-N Leu-Glu-Ser Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(O)=O WQWSMEOYXJTFRU-GUBZILKMSA-N 0.000 description 4
- VWHGTYCRDRBSFI-ZETCQYMHSA-N Leu-Gly-Gly Chemical compound CC(C)C[C@H](N)C(=O)NCC(=O)NCC(O)=O VWHGTYCRDRBSFI-ZETCQYMHSA-N 0.000 description 4
- CHJKEDSZNSONPS-DCAQKATOSA-N Leu-Pro-Ser Chemical compound [H]N[C@@H](CC(C)C)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CO)C(O)=O CHJKEDSZNSONPS-DCAQKATOSA-N 0.000 description 4
- KCXUCYYZNZFGLL-SRVKXCTJSA-N Lys-Ala-Leu Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(O)=O KCXUCYYZNZFGLL-SRVKXCTJSA-N 0.000 description 4
- JGAMUXDWYSXYLM-SRVKXCTJSA-N Lys-Arg-Glu Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(O)=O JGAMUXDWYSXYLM-SRVKXCTJSA-N 0.000 description 4
- IMAKMJCBYCSMHM-AVGNSLFASA-N Lys-Glu-Lys Chemical compound NCCCC[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@H](C(O)=O)CCCCN IMAKMJCBYCSMHM-AVGNSLFASA-N 0.000 description 4
- ODUQLUADRKMHOZ-JYJNAYRXSA-N Lys-Glu-Tyr Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)O)NC(=O)[C@H](CCCCN)N)O ODUQLUADRKMHOZ-JYJNAYRXSA-N 0.000 description 4
- GTAXSKOXPIISBW-AVGNSLFASA-N Lys-His-Gln Chemical compound C1=C(NC=N1)C[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)O)NC(=O)[C@H](CCCCN)N GTAXSKOXPIISBW-AVGNSLFASA-N 0.000 description 4
- 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 4
- 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 4
- ATNKHRAIZCMCCN-BZSNNMDCSA-N Lys-Lys-Phe Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CCCCN)N ATNKHRAIZCMCCN-BZSNNMDCSA-N 0.000 description 4
- 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 4
- 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 4
- XMBSYZWANAQXEV-UHFFFAOYSA-N N-alpha-L-glutamyl-L-phenylalanine Natural products OC(=O)CCC(N)C(=O)NC(C(O)=O)CC1=CC=CC=C1 XMBSYZWANAQXEV-UHFFFAOYSA-N 0.000 description 4
- CDNPIRSCAFMMBE-SRVKXCTJSA-N Phe-Asn-Ser Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CO)C(O)=O CDNPIRSCAFMMBE-SRVKXCTJSA-N 0.000 description 4
- GXDPQJUBLBZKDY-IAVJCBSLSA-N Phe-Ile-Ile Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O GXDPQJUBLBZKDY-IAVJCBSLSA-N 0.000 description 4
- VHDNDCPMHQMXIR-IHRRRGAJSA-N Phe-Met-Cys Chemical compound SC[C@@H](C(O)=O)NC(=O)[C@H](CCSC)NC(=O)[C@@H](N)CC1=CC=CC=C1 VHDNDCPMHQMXIR-IHRRRGAJSA-N 0.000 description 4
- 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 4
- ZSKJPKFTPQCPIH-RCWTZXSCSA-N Pro-Arg-Thr Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(O)=O ZSKJPKFTPQCPIH-RCWTZXSCSA-N 0.000 description 4
- 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 4
- 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 4
- SEZGGSHLMROBFX-CIUDSAMLSA-N Pro-Ser-Gln Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(O)=O SEZGGSHLMROBFX-CIUDSAMLSA-N 0.000 description 4
- AIOWVDNPESPXRB-YTWAJWBKSA-N Pro-Thr-Pro Chemical compound C[C@H]([C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@@H]2CCCN2)O AIOWVDNPESPXRB-YTWAJWBKSA-N 0.000 description 4
- QKWYXRPICJEQAJ-KJEVXHAQSA-N Pro-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]2CCCN2)O QKWYXRPICJEQAJ-KJEVXHAQSA-N 0.000 description 4
- 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 4
- 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 4
- BNFVPSRLHHPQKS-WHFBIAKZSA-N Ser-Asp-Gly Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC(O)=O)C(=O)NCC(O)=O BNFVPSRLHHPQKS-WHFBIAKZSA-N 0.000 description 4
- 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 4
- RRVFEDGUXSYWOW-BZSNNMDCSA-N Ser-Phe-Phe Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O RRVFEDGUXSYWOW-BZSNNMDCSA-N 0.000 description 4
- JCLAFVNDBJMLBC-JBDRJPRFSA-N Ser-Ser-Ile Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O JCLAFVNDBJMLBC-JBDRJPRFSA-N 0.000 description 4
- SYCFMSYTIFXWAJ-DCAQKATOSA-N Ser-Val-His Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)NC(=O)[C@H](CO)N SYCFMSYTIFXWAJ-DCAQKATOSA-N 0.000 description 4
- YEDSOSIKVUMIJE-DCAQKATOSA-N Ser-Val-Leu Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O YEDSOSIKVUMIJE-DCAQKATOSA-N 0.000 description 4
- 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 4
- 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 4
- 230000006044 T cell activation Effects 0.000 description 4
- CEXFELBFVHLYDZ-XGEHTFHBSA-N Thr-Arg-Ser Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(O)=O CEXFELBFVHLYDZ-XGEHTFHBSA-N 0.000 description 4
- 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 4
- FLPZMPOZGYPBEN-PPCPHDFISA-N Thr-Leu-Ile 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)CC)C(O)=O FLPZMPOZGYPBEN-PPCPHDFISA-N 0.000 description 4
- 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 4
- 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 4
- 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 4
- SCSVNSNWUTYSFO-WDCWCFNPSA-N Thr-Lys-Glu Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(O)=O SCSVNSNWUTYSFO-WDCWCFNPSA-N 0.000 description 4
- STUAPCLEDMKXKL-LKXGYXEUSA-N Thr-Ser-Asn Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(O)=O STUAPCLEDMKXKL-LKXGYXEUSA-N 0.000 description 4
- YRJOLUDFVAUXLI-GSSVUCPTSA-N Thr-Thr-Asp Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@H](C(O)=O)CC(O)=O YRJOLUDFVAUXLI-GSSVUCPTSA-N 0.000 description 4
- BKVICMPZWRNWOC-RHYQMDGZSA-N Thr-Val-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](N)[C@@H](C)O BKVICMPZWRNWOC-RHYQMDGZSA-N 0.000 description 4
- VTHNLRXALGUDBS-BPUTZDHNSA-N Trp-Gln-Glu 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)O)C(=O)O)N VTHNLRXALGUDBS-BPUTZDHNSA-N 0.000 description 4
- WSGPBCAGEGHKQJ-BBRMVZONSA-N Trp-Gly-Val Chemical compound CC(C)[C@@H](C(=O)O)NC(=O)CNC(=O)[C@H](CC1=CNC2=CC=CC=C21)N WSGPBCAGEGHKQJ-BBRMVZONSA-N 0.000 description 4
- 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 4
- LMKKMCGTDANZTR-BZSNNMDCSA-N Tyr-Phe-Asp Chemical compound C([C@H](N)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC(O)=O)C(O)=O)C1=CC=C(O)C=C1 LMKKMCGTDANZTR-BZSNNMDCSA-N 0.000 description 4
- 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 4
- JXGWQYWDUOWQHA-DZKIICNBSA-N Val-Gln-Phe Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)O)N JXGWQYWDUOWQHA-DZKIICNBSA-N 0.000 description 4
- 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 4
- AEMPCGRFEZTWIF-IHRRRGAJSA-N Val-Leu-Lys Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(O)=O AEMPCGRFEZTWIF-IHRRRGAJSA-N 0.000 description 4
- 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 4
- 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 4
- 230000010056 antibody-dependent cellular cytotoxicity Effects 0.000 description 4
- 108010038850 arginyl-isoleucyl-tyrosine Proteins 0.000 description 4
- 230000000903 blocking effect Effects 0.000 description 4
- 239000006285 cell suspension Substances 0.000 description 4
- 230000004540 complement-dependent cytotoxicity Effects 0.000 description 4
- 238000010276 construction Methods 0.000 description 4
- 108700041286 delta Proteins 0.000 description 4
- 238000005516 engineering process Methods 0.000 description 4
- 108010009298 lysylglutamic acid Proteins 0.000 description 4
- 108010038320 lysylphenylalanine Proteins 0.000 description 4
- 108010070409 phenylalanyl-glycyl-glycine Proteins 0.000 description 4
- 108010053725 prolylvaline Proteins 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- 238000011160 research Methods 0.000 description 4
- 238000012552 review Methods 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- 108010033670 threonyl-aspartyl-tyrosine Proteins 0.000 description 4
- 108010072986 threonyl-seryl-lysine Proteins 0.000 description 4
- 230000002100 tumorsuppressive effect Effects 0.000 description 4
- 108010020532 tyrosyl-proline Proteins 0.000 description 4
- GFBLJMHGHAXGNY-ZLUOBGJFSA-N Ala-Asn-Asp Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(O)=O)C(O)=O GFBLJMHGHAXGNY-ZLUOBGJFSA-N 0.000 description 3
- MKZCBYZBCINNJN-DLOVCJGASA-N Ala-Asp-Phe Chemical compound C[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 MKZCBYZBCINNJN-DLOVCJGASA-N 0.000 description 3
- 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 3
- SFNFGFDRYJKZKN-XQXXSGGOSA-N Ala-Gln-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)N)NC(=O)[C@H](C)N)O SFNFGFDRYJKZKN-XQXXSGGOSA-N 0.000 description 3
- OMMDTNGURYRDAC-NRPADANISA-N Ala-Glu-Val Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(O)=O OMMDTNGURYRDAC-NRPADANISA-N 0.000 description 3
- WEZNQZHACPSMEF-QEJZJMRPSA-N Ala-Phe-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)C)CC1=CC=CC=C1 WEZNQZHACPSMEF-QEJZJMRPSA-N 0.000 description 3
- KLALXKYLOMZDQT-ZLUOBGJFSA-N Ala-Ser-Asn Chemical compound C[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@H](C(O)=O)CC(N)=O KLALXKYLOMZDQT-ZLUOBGJFSA-N 0.000 description 3
- 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 3
- OCOZPTHLDVSFCZ-BPUTZDHNSA-N Arg-Asn-Trp Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)N)NC(=O)[C@H](CCCN=C(N)N)N OCOZPTHLDVSFCZ-BPUTZDHNSA-N 0.000 description 3
- HPSVTWMFWCHKFN-GARJFASQSA-N Arg-Glu-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CCC(=O)O)NC(=O)[C@H](CCCN=C(N)N)N)C(=O)O HPSVTWMFWCHKFN-GARJFASQSA-N 0.000 description 3
- NGTYEHIRESTSRX-UWVGGRQHSA-N Arg-Lys-Gly Chemical compound NCCCC[C@@H](C(=O)NCC(O)=O)NC(=O)[C@@H](N)CCCN=C(N)N NGTYEHIRESTSRX-UWVGGRQHSA-N 0.000 description 3
- YNSUUAOAFCVINY-OSUNSFLBSA-N Arg-Thr-Ile Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O YNSUUAOAFCVINY-OSUNSFLBSA-N 0.000 description 3
- PSUXEQYPYZLNER-QXEWZRGKSA-N Arg-Val-Asn Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(N)=O)C(O)=O PSUXEQYPYZLNER-QXEWZRGKSA-N 0.000 description 3
- VDCIPFYVCICPEC-FXQIFTODSA-N Asn-Arg-Ala Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(O)=O VDCIPFYVCICPEC-FXQIFTODSA-N 0.000 description 3
- KSBHCUSPLWRVEK-ZLUOBGJFSA-N Asn-Asn-Asp Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(O)=O)C(O)=O KSBHCUSPLWRVEK-ZLUOBGJFSA-N 0.000 description 3
- DAPLJWATMAXPPZ-CIUDSAMLSA-N Asn-Asn-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](N)CC(N)=O DAPLJWATMAXPPZ-CIUDSAMLSA-N 0.000 description 3
- PIWWUBYJNONVTJ-ZLUOBGJFSA-N Asn-Asp-Asn Chemical compound C([C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](CC(=O)N)C(=O)O)N)C(=O)N PIWWUBYJNONVTJ-ZLUOBGJFSA-N 0.000 description 3
- XVVOVPFMILMHPX-ZLUOBGJFSA-N Asn-Asp-Asp Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(O)=O)C(O)=O XVVOVPFMILMHPX-ZLUOBGJFSA-N 0.000 description 3
- OLVIPTLKNSAYRJ-YUMQZZPRSA-N Asn-Gly-Lys Chemical compound C(CCN)C[C@@H](C(=O)O)NC(=O)CNC(=O)[C@H](CC(=O)N)N OLVIPTLKNSAYRJ-YUMQZZPRSA-N 0.000 description 3
- AITGTTNYKAWKDR-CIUDSAMLSA-N Asn-His-Ser Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CO)C(O)=O AITGTTNYKAWKDR-CIUDSAMLSA-N 0.000 description 3
- HDHZCEDPLTVHFZ-GUBZILKMSA-N Asn-Leu-Glu Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(O)=O HDHZCEDPLTVHFZ-GUBZILKMSA-N 0.000 description 3
- MPXTVIOEYISUQC-DHATWTDPSA-N Asn-Met-Thr-Thr Chemical compound CSCC[C@H](NC(=O)[C@@H](N)CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O MPXTVIOEYISUQC-DHATWTDPSA-N 0.000 description 3
- YRTOMUMWSTUQAX-FXQIFTODSA-N Asn-Pro-Asp Chemical compound NC(=O)C[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CC(O)=O)C(O)=O YRTOMUMWSTUQAX-FXQIFTODSA-N 0.000 description 3
- QTKYFZCMSQLYHI-UBHSHLNASA-N Asn-Trp-Asn Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CC1=CNC2=C1C=CC=C2)C(=O)N[C@@H](CC(N)=O)C(O)=O QTKYFZCMSQLYHI-UBHSHLNASA-N 0.000 description 3
- DAYDURRBMDCCFL-AAEUAGOBSA-N Asn-Trp-Gly Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)NCC(=O)O)NC(=O)[C@H](CC(=O)N)N DAYDURRBMDCCFL-AAEUAGOBSA-N 0.000 description 3
- RATOMFTUDRYMKX-ACZMJKKPSA-N Asp-Glu-Cys Chemical compound C(CC(=O)O)[C@@H](C(=O)N[C@@H](CS)C(=O)O)NC(=O)[C@H](CC(=O)O)N RATOMFTUDRYMKX-ACZMJKKPSA-N 0.000 description 3
- KTTCQQNRRLCIBC-GHCJXIJMSA-N Asp-Ile-Ala Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(O)=O KTTCQQNRRLCIBC-GHCJXIJMSA-N 0.000 description 3
- KYQNAIMCTRZLNP-QSFUFRPTSA-N Asp-Ile-Val Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C(C)C)C(O)=O KYQNAIMCTRZLNP-QSFUFRPTSA-N 0.000 description 3
- UAXIKORUDGGIGA-DCAQKATOSA-N Asp-Pro-Lys Chemical compound C1C[C@H](N(C1)C(=O)[C@H](CC(=O)O)N)C(=O)N[C@@H](CCCCN)C(=O)O UAXIKORUDGGIGA-DCAQKATOSA-N 0.000 description 3
- 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 3
- NJLLRXWFPQQPHV-SRVKXCTJSA-N Asp-Tyr-Asn Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC(N)=O)C(O)=O NJLLRXWFPQQPHV-SRVKXCTJSA-N 0.000 description 3
- GFYOIYJJMSHLSN-QXEWZRGKSA-N Asp-Val-Arg Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCN=C(N)N)C(O)=O GFYOIYJJMSHLSN-QXEWZRGKSA-N 0.000 description 3
- 101710150190 Beta-secretase 2 Proteins 0.000 description 3
- UWXFFVQPAMBETM-ZLUOBGJFSA-N Cys-Asp-Asn Chemical compound [H]N[C@@H](CS)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O UWXFFVQPAMBETM-ZLUOBGJFSA-N 0.000 description 3
- MUZAUPFGPMMZSS-GUBZILKMSA-N Cys-Glu-Lys Chemical compound C(CCN)C[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)O)NC(=O)[C@H](CS)N MUZAUPFGPMMZSS-GUBZILKMSA-N 0.000 description 3
- NLDWTJBJFVWBDQ-KKUMJFAQSA-N Cys-Lys-Phe Chemical compound NCCCC[C@H](NC(=O)[C@@H](N)CS)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 NLDWTJBJFVWBDQ-KKUMJFAQSA-N 0.000 description 3
- HJGUQJJJXQGXGJ-FXQIFTODSA-N Cys-Met-Ser Chemical compound CSCC[C@@H](C(=O)N[C@@H](CO)C(=O)O)NC(=O)[C@H](CS)N HJGUQJJJXQGXGJ-FXQIFTODSA-N 0.000 description 3
- SRZZZTMJARUVPI-JBDRJPRFSA-N Cys-Ser-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)[C@H](CO)NC(=O)[C@H](CS)N SRZZZTMJARUVPI-JBDRJPRFSA-N 0.000 description 3
- YNJBLTDKTMKEET-ZLUOBGJFSA-N Cys-Ser-Ser Chemical compound SC[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(O)=O YNJBLTDKTMKEET-ZLUOBGJFSA-N 0.000 description 3
- 238000008157 ELISA kit Methods 0.000 description 3
- 102000018651 Epithelial Cell Adhesion Molecule Human genes 0.000 description 3
- 108010066687 Epithelial Cell Adhesion Molecule Proteins 0.000 description 3
- RGXXLQWXBFNXTG-CIUDSAMLSA-N Gln-Arg-Ala Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(O)=O RGXXLQWXBFNXTG-CIUDSAMLSA-N 0.000 description 3
- JFSNBQJNDMXMQF-XHNCKOQMSA-N Gln-Asp-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CC(=O)O)NC(=O)[C@H](CCC(=O)N)N)C(=O)O JFSNBQJNDMXMQF-XHNCKOQMSA-N 0.000 description 3
- UESYBOXFJWJVSB-AVGNSLFASA-N Gln-Phe-Ser Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CO)C(O)=O UESYBOXFJWJVSB-AVGNSLFASA-N 0.000 description 3
- WLRYGVYQFXRJDA-DCAQKATOSA-N Gln-Pro-Pro Chemical compound NC(=O)CC[C@H](N)C(=O)N1CCC[C@H]1C(=O)N1[C@H](C(O)=O)CCC1 WLRYGVYQFXRJDA-DCAQKATOSA-N 0.000 description 3
- DYVMTEWCGAVKSE-HJGDQZAQSA-N Gln-Thr-Arg Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCCN=C(N)N)C(=O)O)NC(=O)[C@H](CCC(=O)N)N)O DYVMTEWCGAVKSE-HJGDQZAQSA-N 0.000 description 3
- RONJIBWTGKVKFY-HTUGSXCWSA-N Gln-Thr-Phe Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)O)NC(=O)[C@H](CCC(=O)N)N)O RONJIBWTGKVKFY-HTUGSXCWSA-N 0.000 description 3
- CSMHMEATMDCQNY-DZKIICNBSA-N Gln-Val-Tyr Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O CSMHMEATMDCQNY-DZKIICNBSA-N 0.000 description 3
- AFODTOLGSZQDSL-PEFMBERDSA-N Glu-Asn-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)N)NC(=O)[C@H](CCC(=O)O)N AFODTOLGSZQDSL-PEFMBERDSA-N 0.000 description 3
- BUAKRRKDHSSIKK-IHRRRGAJSA-N Glu-Glu-Tyr Chemical compound OC(=O)CC[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 BUAKRRKDHSSIKK-IHRRRGAJSA-N 0.000 description 3
- DVLZZEPUNFEUBW-AVGNSLFASA-N Glu-His-Leu Chemical compound CC(C)C[C@@H](C(=O)O)NC(=O)[C@H](CC1=CN=CN1)NC(=O)[C@H](CCC(=O)O)N DVLZZEPUNFEUBW-AVGNSLFASA-N 0.000 description 3
- XTZDZAXYPDISRR-MNXVOIDGSA-N Glu-Ile-Lys Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CCC(=O)O)N XTZDZAXYPDISRR-MNXVOIDGSA-N 0.000 description 3
- HVYWQYLBVXMXSV-GUBZILKMSA-N Glu-Leu-Ala Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C)C(O)=O HVYWQYLBVXMXSV-GUBZILKMSA-N 0.000 description 3
- UGSVSNXPJJDJKL-SDDRHHMPSA-N Glu-Leu-Pro Chemical compound CC(C)C[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](CCC(=O)O)N UGSVSNXPJJDJKL-SDDRHHMPSA-N 0.000 description 3
- CUPSDFQZTVVTSK-GUBZILKMSA-N Glu-Lys-Asp Chemical compound OC(=O)C[C@@H](C(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](N)CCC(O)=O CUPSDFQZTVVTSK-GUBZILKMSA-N 0.000 description 3
- QOXDAWODGSIDDI-GUBZILKMSA-N Glu-Ser-Lys Chemical compound C(CCN)C[C@@H](C(=O)O)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(=O)O)N QOXDAWODGSIDDI-GUBZILKMSA-N 0.000 description 3
- CQGBSALYGOXQPE-HTUGSXCWSA-N Glu-Thr-Phe Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)O)NC(=O)[C@H](CCC(=O)O)N)O CQGBSALYGOXQPE-HTUGSXCWSA-N 0.000 description 3
- KIEICAOUSNYOLM-NRPADANISA-N Glu-Val-Ala Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C)C(O)=O KIEICAOUSNYOLM-NRPADANISA-N 0.000 description 3
- ZALGPUWUVHOGAE-GVXVVHGQSA-N Glu-Val-His Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)NC(=O)[C@H](CCC(=O)O)N ZALGPUWUVHOGAE-GVXVVHGQSA-N 0.000 description 3
- CQZDZKRHFWJXDF-WDSKDSINSA-N Gly-Gln-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@H](CCC(N)=O)NC(=O)CN CQZDZKRHFWJXDF-WDSKDSINSA-N 0.000 description 3
- UUYBFNKHOCJCHT-VHSXEESVSA-N Gly-Leu-Pro Chemical compound CC(C)C[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)CN UUYBFNKHOCJCHT-VHSXEESVSA-N 0.000 description 3
- LPHQAFLNEHWKFF-QXEWZRGKSA-N Gly-Met-Ile Chemical compound [H]NCC(=O)N[C@@H](CCSC)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O LPHQAFLNEHWKFF-QXEWZRGKSA-N 0.000 description 3
- RYAOJUMWLWUGNW-QMMMGPOBSA-N Gly-Val-Gly Chemical compound NCC(=O)N[C@@H](C(C)C)C(=O)NCC(O)=O RYAOJUMWLWUGNW-QMMMGPOBSA-N 0.000 description 3
- MDBYBTWRMOAJAY-NHCYSSNCSA-N His-Asn-Val Chemical compound CC(C)[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)N)NC(=O)[C@H](CC1=CN=CN1)N MDBYBTWRMOAJAY-NHCYSSNCSA-N 0.000 description 3
- WGVPDSNCHDEDBP-KKUMJFAQSA-N His-Asp-Phe Chemical compound [H]N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O WGVPDSNCHDEDBP-KKUMJFAQSA-N 0.000 description 3
- WSXNWASHQNSMRX-GVXVVHGQSA-N His-Val-Gln Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)O)NC(=O)[C@H](CC1=CN=CN1)N WSXNWASHQNSMRX-GVXVVHGQSA-N 0.000 description 3
- 101001117317 Homo sapiens Programmed cell death 1 ligand 1 Proteins 0.000 description 3
- 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 3
- DMSVBUWGDLYNLC-IAVJCBSLSA-N Ile-Ile-Phe Chemical compound CC[C@H](C)[C@H](N)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 DMSVBUWGDLYNLC-IAVJCBSLSA-N 0.000 description 3
- KLBVGHCGHUNHEA-BJDJZHNGSA-N Ile-Leu-Ala Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C)C(=O)O)N KLBVGHCGHUNHEA-BJDJZHNGSA-N 0.000 description 3
- HUORUFRRJHELPD-MNXVOIDGSA-N Ile-Leu-Glu Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(=O)O)C(=O)O)N HUORUFRRJHELPD-MNXVOIDGSA-N 0.000 description 3
- IIWQTXMUALXGOV-PCBIJLKTSA-N Ile-Phe-Asp Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CC(=O)O)C(=O)O)N IIWQTXMUALXGOV-PCBIJLKTSA-N 0.000 description 3
- 102100037850 Interferon gamma Human genes 0.000 description 3
- FADYJNXDPBKVCA-UHFFFAOYSA-N L-Phenylalanyl-L-lysin Natural products NCCCCC(C(O)=O)NC(=O)C(N)CC1=CC=CC=C1 FADYJNXDPBKVCA-UHFFFAOYSA-N 0.000 description 3
- WNGVUZWBXZKQES-YUMQZZPRSA-N Leu-Ala-Gly Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](C)C(=O)NCC(O)=O WNGVUZWBXZKQES-YUMQZZPRSA-N 0.000 description 3
- IBMVEYRWAWIOTN-RWMBFGLXSA-N Leu-Arg-Pro Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N1CCC[C@@H]1C(O)=O IBMVEYRWAWIOTN-RWMBFGLXSA-N 0.000 description 3
- MDVZJYGNAGLPGJ-KKUMJFAQSA-N Leu-Asn-Phe Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 MDVZJYGNAGLPGJ-KKUMJFAQSA-N 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
- APFJUBGRZGMQFF-QWRGUYRKSA-N Leu-Gly-Lys Chemical compound CC(C)C[C@H](N)C(=O)NCC(=O)N[C@H](C(O)=O)CCCCN APFJUBGRZGMQFF-QWRGUYRKSA-N 0.000 description 3
- HNDWYLYAYNBWMP-AJNGGQMLSA-N Leu-Ile-Lys Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CC(C)C)N HNDWYLYAYNBWMP-AJNGGQMLSA-N 0.000 description 3
- ONPJGOIVICHWBW-BZSNNMDCSA-N Leu-Lys-Tyr Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CCCCN)C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 ONPJGOIVICHWBW-BZSNNMDCSA-N 0.000 description 3
- AUNMOHYWTAPQLA-XUXIUFHCSA-N Leu-Met-Ile Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O AUNMOHYWTAPQLA-XUXIUFHCSA-N 0.000 description 3
- ADJWHHZETYAAAX-SRVKXCTJSA-N Leu-Ser-His Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)N ADJWHHZETYAAAX-SRVKXCTJSA-N 0.000 description 3
- FGZVGOAAROXFAB-IXOXFDKPSA-N Leu-Thr-His Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)NC(=O)[C@H](CC(C)C)N)O FGZVGOAAROXFAB-IXOXFDKPSA-N 0.000 description 3
- URHJPNHRQMQGOZ-RHYQMDGZSA-N Leu-Thr-Met Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCSC)C(O)=O URHJPNHRQMQGOZ-RHYQMDGZSA-N 0.000 description 3
- QESXLSQLQHHTIX-RHYQMDGZSA-N Leu-Val-Thr Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O QESXLSQLQHHTIX-RHYQMDGZSA-N 0.000 description 3
- DNEJSAIMVANNPA-DCAQKATOSA-N Lys-Asn-Arg Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O DNEJSAIMVANNPA-DCAQKATOSA-N 0.000 description 3
- 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 3
- KSFQPRLZAUXXPT-GARJFASQSA-N Lys-Cys-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CS)NC(=O)[C@H](CCCCN)N)C(=O)O KSFQPRLZAUXXPT-GARJFASQSA-N 0.000 description 3
- MUXNCRWTWBMNHX-SRVKXCTJSA-N Lys-Leu-Asp Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(O)=O)C(O)=O MUXNCRWTWBMNHX-SRVKXCTJSA-N 0.000 description 3
- WRODMZBHNNPRLN-SRVKXCTJSA-N Lys-Leu-Ser Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(O)=O WRODMZBHNNPRLN-SRVKXCTJSA-N 0.000 description 3
- KFSALEZVQJYHCE-AVGNSLFASA-N Lys-Met-Val Chemical compound CC(C)[C@@H](C(=O)O)NC(=O)[C@H](CCSC)NC(=O)[C@H](CCCCN)N KFSALEZVQJYHCE-AVGNSLFASA-N 0.000 description 3
- 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 3
- RQILLQOQXLZTCK-KBPBESRZSA-N Lys-Tyr-Gly Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)NCC(O)=O RQILLQOQXLZTCK-KBPBESRZSA-N 0.000 description 3
- QXEVZBXTDTVPCP-GMOBBJLQSA-N Met-Asn-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)N)NC(=O)[C@H](CCSC)N QXEVZBXTDTVPCP-GMOBBJLQSA-N 0.000 description 3
- RMHHNLKYPOOKQN-FXQIFTODSA-N Met-Cys-Ser Chemical compound [H]N[C@@H](CCSC)C(=O)N[C@@H](CS)C(=O)N[C@@H](CO)C(O)=O RMHHNLKYPOOKQN-FXQIFTODSA-N 0.000 description 3
- XKJUFUPCHARJKX-UWVGGRQHSA-N Met-Gly-His Chemical compound CSCC[C@H](N)C(=O)NCC(=O)N[C@H](C(O)=O)CC1=CNC=N1 XKJUFUPCHARJKX-UWVGGRQHSA-N 0.000 description 3
- PPHLBTXVBJNKOB-FDARSICLSA-N Met-Ile-Trp Chemical compound [H]N[C@@H](CCSC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC1=CNC2=C1C=CC=C2)C(O)=O PPHLBTXVBJNKOB-FDARSICLSA-N 0.000 description 3
- ODFBIJXEWPWSAN-CYDGBPFRSA-N Met-Ile-Val Chemical compound [H]N[C@@H](CCSC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C(C)C)C(O)=O ODFBIJXEWPWSAN-CYDGBPFRSA-N 0.000 description 3
- XOFDBXYPKZUAAM-GUBZILKMSA-N Met-Met-Ser Chemical compound CSCC[C@@H](C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CO)C(=O)O)N XOFDBXYPKZUAAM-GUBZILKMSA-N 0.000 description 3
- LXCSZPUQKMTXNW-BQBZGAKWSA-N Met-Ser-Gly Chemical compound CSCC[C@H](N)C(=O)N[C@@H](CO)C(=O)NCC(O)=O LXCSZPUQKMTXNW-BQBZGAKWSA-N 0.000 description 3
- IUVYJBMTHARMIP-PCBIJLKTSA-N Phe-Asp-Ile Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O IUVYJBMTHARMIP-PCBIJLKTSA-N 0.000 description 3
- KAGCQPSEVAETCA-JYJNAYRXSA-N Phe-Gln-Leu Chemical compound CC(C)C[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)N)NC(=O)[C@H](CC1=CC=CC=C1)N KAGCQPSEVAETCA-JYJNAYRXSA-N 0.000 description 3
- SMFGCTXUBWEPKM-KBPBESRZSA-N Phe-Leu-Gly Chemical compound OC(=O)CNC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CC1=CC=CC=C1 SMFGCTXUBWEPKM-KBPBESRZSA-N 0.000 description 3
- 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 3
- UPJGUQPLYWTISV-GUBZILKMSA-N Pro-Gln-Glu Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(O)=O UPJGUQPLYWTISV-GUBZILKMSA-N 0.000 description 3
- HJSCRFZVGXAGNG-SRVKXCTJSA-N Pro-Gln-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H]1CCCN1 HJSCRFZVGXAGNG-SRVKXCTJSA-N 0.000 description 3
- MGDFPGCFVJFITQ-CIUDSAMLSA-N Pro-Glu-Asp Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(O)=O MGDFPGCFVJFITQ-CIUDSAMLSA-N 0.000 description 3
- WFHYFCWBLSKEMS-KKUMJFAQSA-N Pro-Glu-Phe Chemical compound N([C@@H](CCC(=O)O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)C(=O)[C@@H]1CCCN1 WFHYFCWBLSKEMS-KKUMJFAQSA-N 0.000 description 3
- CLJLVCYFABNTHP-DCAQKATOSA-N Pro-Leu-Asp Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(O)=O)C(O)=O CLJLVCYFABNTHP-DCAQKATOSA-N 0.000 description 3
- YAZNFQUKPUASKB-DCAQKATOSA-N Pro-Lys-Cys Chemical compound C1C[C@H](NC1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CS)C(=O)O YAZNFQUKPUASKB-DCAQKATOSA-N 0.000 description 3
- KBUAPZAZPWNYSW-SRVKXCTJSA-N Pro-Pro-Val Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@H]1NCCC1 KBUAPZAZPWNYSW-SRVKXCTJSA-N 0.000 description 3
- IMNVAOPEMFDAQD-NHCYSSNCSA-N Pro-Val-Glu Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(O)=O)C(O)=O IMNVAOPEMFDAQD-NHCYSSNCSA-N 0.000 description 3
- HRNQLKCLPVKZNE-CIUDSAMLSA-N Ser-Ala-Leu Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(O)=O HRNQLKCLPVKZNE-CIUDSAMLSA-N 0.000 description 3
- WTUJZHKANPDPIN-CIUDSAMLSA-N Ser-Ala-Lys Chemical compound C[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CO)N WTUJZHKANPDPIN-CIUDSAMLSA-N 0.000 description 3
- 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 3
- RNFKSBPHLTZHLU-WHFBIAKZSA-N Ser-Cys-Gly Chemical compound C([C@@H](C(=O)N[C@@H](CS)C(=O)NCC(=O)O)N)O RNFKSBPHLTZHLU-WHFBIAKZSA-N 0.000 description 3
- 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 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
- QGAHMVHBORDHDC-YUMQZZPRSA-N Ser-His-Gly Chemical compound OC[C@H](N)C(=O)N[C@H](C(=O)NCC(O)=O)CC1=CN=CN1 QGAHMVHBORDHDC-YUMQZZPRSA-N 0.000 description 3
- DJACUBDEDBZKLQ-KBIXCLLPSA-N Ser-Ile-Glu Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCC(O)=O)C(O)=O DJACUBDEDBZKLQ-KBIXCLLPSA-N 0.000 description 3
- DOSZISJPMCYEHT-NAKRPEOUSA-N Ser-Ile-Val Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C(C)C)C(O)=O DOSZISJPMCYEHT-NAKRPEOUSA-N 0.000 description 3
- FUMGHWDRRFCKEP-CIUDSAMLSA-N Ser-Leu-Ala Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C)C(O)=O FUMGHWDRRFCKEP-CIUDSAMLSA-N 0.000 description 3
- HDBOEVPDIDDEPC-CIUDSAMLSA-N Ser-Lys-Asn Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(O)=O HDBOEVPDIDDEPC-CIUDSAMLSA-N 0.000 description 3
- 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 3
- PPCZVWHJWJFTFN-ZLUOBGJFSA-N Ser-Ser-Asp Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(O)=O)C(O)=O PPCZVWHJWJFTFN-ZLUOBGJFSA-N 0.000 description 3
- 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 3
- 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 3
- BEBVVQPDSHHWQL-NRPADANISA-N Ser-Val-Glu Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(O)=O)C(O)=O BEBVVQPDSHHWQL-NRPADANISA-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
- MQCPGOZXFSYJPS-KZVJFYERSA-N Thr-Ala-Arg Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O MQCPGOZXFSYJPS-KZVJFYERSA-N 0.000 description 3
- DFTCYYILCSQGIZ-GCJQMDKQSA-N Thr-Ala-Asn Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(N)=O)C(O)=O DFTCYYILCSQGIZ-GCJQMDKQSA-N 0.000 description 3
- NJEMRSFGDNECGF-GCJQMDKQSA-N Thr-Ala-Asp Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@H](C(O)=O)CC(O)=O NJEMRSFGDNECGF-GCJQMDKQSA-N 0.000 description 3
- XYEXCEPTALHNEV-RCWTZXSCSA-N Thr-Arg-Arg Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O XYEXCEPTALHNEV-RCWTZXSCSA-N 0.000 description 3
- LIXBDERDAGNVAV-XKBZYTNZSA-N Thr-Gln-Ser Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CO)C(O)=O LIXBDERDAGNVAV-XKBZYTNZSA-N 0.000 description 3
- VTVVYQOXJCZVEB-WDCWCFNPSA-N Thr-Leu-Glu Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(O)=O VTVVYQOXJCZVEB-WDCWCFNPSA-N 0.000 description 3
- GFRIEEKFXOVPIR-RHYQMDGZSA-N Thr-Pro-Lys Chemical compound C[C@@H](O)[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCCCN)C(O)=O GFRIEEKFXOVPIR-RHYQMDGZSA-N 0.000 description 3
- REJRKTOJTCPDPO-IRIUXVKKSA-N Thr-Tyr-Glu Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CCC(O)=O)C(O)=O REJRKTOJTCPDPO-IRIUXVKKSA-N 0.000 description 3
- FYBFTPLPAXZBOY-KKHAAJSZSA-N Thr-Val-Asp Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(O)=O)C(O)=O FYBFTPLPAXZBOY-KKHAAJSZSA-N 0.000 description 3
- AXEJRUGTOJPZKG-XGEHTFHBSA-N Thr-Val-Cys Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CS)C(=O)O)N)O AXEJRUGTOJPZKG-XGEHTFHBSA-N 0.000 description 3
- 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 3
- VPRHDRKAPYZMHL-SZMVWBNQSA-N Trp-Leu-Glu Chemical compound C1=CC=C2C(C[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(O)=O)=CNC2=C1 VPRHDRKAPYZMHL-SZMVWBNQSA-N 0.000 description 3
- IVBJBFSWJDNQFW-XIRDDKMYSA-N Trp-Pro-Glu Chemical compound [H]N[C@@H](CC1=CNC2=C1C=CC=C2)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCC(O)=O)C(O)=O IVBJBFSWJDNQFW-XIRDDKMYSA-N 0.000 description 3
- 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 3
- IJUTXXAXQODRMW-KBPBESRZSA-N Tyr-Gly-His Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)NCC(=O)N[C@@H](CC2=CN=CN2)C(=O)O)N)O IJUTXXAXQODRMW-KBPBESRZSA-N 0.000 description 3
- GULIUBBXCYPDJU-CQDKDKBSSA-N Tyr-Leu-Ala Chemical compound [O-]C(=O)[C@H](C)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H]([NH3+])CC1=CC=C(O)C=C1 GULIUBBXCYPDJU-CQDKDKBSSA-N 0.000 description 3
- GITNQBVCEQBDQC-KKUMJFAQSA-N Tyr-Lys-Asn Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(O)=O GITNQBVCEQBDQC-KKUMJFAQSA-N 0.000 description 3
- RWOKVQUCENPXGE-IHRRRGAJSA-N Tyr-Ser-Arg Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O RWOKVQUCENPXGE-IHRRRGAJSA-N 0.000 description 3
- LDKDSFQSEUOCOO-RPTUDFQQSA-N Tyr-Thr-Phe Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O LDKDSFQSEUOCOO-RPTUDFQQSA-N 0.000 description 3
- HMPMGPISLMLHSI-JBACZVJFSA-N Tyr-Trp-Gln Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)O)NC(=O)[C@H](CC3=CC=C(C=C3)O)N HMPMGPISLMLHSI-JBACZVJFSA-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
- SLLKXDSRVAOREO-KZVJFYERSA-N Val-Ala-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](C)NC(=O)[C@H](C(C)C)N)O SLLKXDSRVAOREO-KZVJFYERSA-N 0.000 description 3
- 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 3
- XJFXZQKJQGYFMM-GUBZILKMSA-N Val-Cys-Val Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](C(C)C)C(=O)O)N XJFXZQKJQGYFMM-GUBZILKMSA-N 0.000 description 3
- VCAWFLIWYNMHQP-UKJIMTQDSA-N Val-Glu-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)O)NC(=O)[C@H](C(C)C)N VCAWFLIWYNMHQP-UKJIMTQDSA-N 0.000 description 3
- RKIGNDAHUOOIMJ-BQFCYCMXSA-N Val-Glu-Trp Chemical compound C1=CC=C2C(C[C@H](NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](N)C(C)C)C(O)=O)=CNC2=C1 RKIGNDAHUOOIMJ-BQFCYCMXSA-N 0.000 description 3
- IJGPOONOTBNTFS-GVXVVHGQSA-N Val-Lys-Glu Chemical compound [H]N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(O)=O IJGPOONOTBNTFS-GVXVVHGQSA-N 0.000 description 3
- SBJCTAZFSZXWSR-AVGNSLFASA-N Val-Met-His Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)N SBJCTAZFSZXWSR-AVGNSLFASA-N 0.000 description 3
- VHIZXDZMTDVFGX-DCAQKATOSA-N Val-Ser-Leu Chemical compound CC(C)C[C@@H](C(=O)O)NC(=O)[C@H](CO)NC(=O)[C@H](C(C)C)N VHIZXDZMTDVFGX-DCAQKATOSA-N 0.000 description 3
- GBIUHAYJGWVNLN-AEJSXWLSSA-N Val-Ser-Pro Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CO)C(=O)N1CCC[C@@H]1C(=O)O)N GBIUHAYJGWVNLN-AEJSXWLSSA-N 0.000 description 3
- GBIUHAYJGWVNLN-UHFFFAOYSA-N Val-Ser-Pro Natural products CC(C)C(N)C(=O)NC(CO)C(=O)N1CCCC1C(O)=O GBIUHAYJGWVNLN-UHFFFAOYSA-N 0.000 description 3
- 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 3
- HVRRJRMULCPNRO-BZSNNMDCSA-N Val-Trp-Arg Chemical compound C1=CC=C2C(C[C@H](NC(=O)[C@@H](N)C(C)C)C(=O)N[C@@H](CCCN=C(N)N)C(O)=O)=CNC2=C1 HVRRJRMULCPNRO-BZSNNMDCSA-N 0.000 description 3
- 230000004913 activation Effects 0.000 description 3
- 108010044940 alanylglutamine Proteins 0.000 description 3
- 108010013835 arginine glutamate Proteins 0.000 description 3
- 108010062796 arginyllysine Proteins 0.000 description 3
- 108010092854 aspartyllysine Proteins 0.000 description 3
- 238000004113 cell culture Methods 0.000 description 3
- 230000009977 dual effect Effects 0.000 description 3
- 229950006925 emicizumab Drugs 0.000 description 3
- 230000006870 function Effects 0.000 description 3
- 108010077515 glycylproline Proteins 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 230000003834 intracellular effect Effects 0.000 description 3
- 230000000670 limiting effect Effects 0.000 description 3
- 230000001404 mediated effect Effects 0.000 description 3
- 108010085203 methionylmethionine Proteins 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- MXHCPCSDRGLRER-UHFFFAOYSA-N pentaglycine Chemical compound NCC(=O)NCC(=O)NCC(=O)NCC(=O)NCC(O)=O MXHCPCSDRGLRER-UHFFFAOYSA-N 0.000 description 3
- 238000003359 percent control normalization Methods 0.000 description 3
- 102000004196 processed proteins & peptides Human genes 0.000 description 3
- 108010087846 prolyl-prolyl-glycine Proteins 0.000 description 3
- 108010090894 prolylleucine Proteins 0.000 description 3
- 230000004044 response Effects 0.000 description 3
- 239000012089 stop solution Substances 0.000 description 3
- 108010061238 threonyl-glycine Proteins 0.000 description 3
- 230000009261 transgenic effect Effects 0.000 description 3
- 108010015666 tryptophyl-leucyl-glutamic acid Proteins 0.000 description 3
- 210000004881 tumor cell Anatomy 0.000 description 3
- 108010044087 AS-I toxin Proteins 0.000 description 2
- DVWVZSJAYIJZFI-FXQIFTODSA-N Ala-Arg-Asn Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(N)=O)C(O)=O DVWVZSJAYIJZFI-FXQIFTODSA-N 0.000 description 2
- KUDREHRZRIVKHS-UWJYBYFXSA-N Ala-Asp-Tyr Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O KUDREHRZRIVKHS-UWJYBYFXSA-N 0.000 description 2
- IFKQPMZRDQZSHI-GHCJXIJMSA-N Ala-Ile-Asn Chemical compound [H]N[C@@H](C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(N)=O)C(O)=O IFKQPMZRDQZSHI-GHCJXIJMSA-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
- REWSWYIDQIELBE-FXQIFTODSA-N Ala-Val-Ser Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CO)C(O)=O REWSWYIDQIELBE-FXQIFTODSA-N 0.000 description 2
- SSQHYGLFYWZWDV-UVBJJODRSA-N Ala-Val-Trp Chemical compound CC(C)[C@H](NC(=O)[C@H](C)N)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(O)=O SSQHYGLFYWZWDV-UVBJJODRSA-N 0.000 description 2
- 108010088751 Albumins Proteins 0.000 description 2
- 102000009027 Albumins Human genes 0.000 description 2
- OTOXOKCIIQLMFH-KZVJFYERSA-N Arg-Ala-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CCCN=C(N)N OTOXOKCIIQLMFH-KZVJFYERSA-N 0.000 description 2
- RVDVDRUZWZIBJQ-CIUDSAMLSA-N Arg-Asn-Glu Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(O)=O RVDVDRUZWZIBJQ-CIUDSAMLSA-N 0.000 description 2
- OTCJMMRQBVDQRK-DCAQKATOSA-N Arg-Asp-Leu Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(O)=O OTCJMMRQBVDQRK-DCAQKATOSA-N 0.000 description 2
- UFBURHXMKFQVLM-CIUDSAMLSA-N Arg-Glu-Ser Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(O)=O UFBURHXMKFQVLM-CIUDSAMLSA-N 0.000 description 2
- LVMUGODRNHFGRA-AVGNSLFASA-N Arg-Leu-Arg Chemical compound NC(N)=NCCC[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCN=C(N)N)C(O)=O LVMUGODRNHFGRA-AVGNSLFASA-N 0.000 description 2
- SSZGOKWBHLOCHK-DCAQKATOSA-N Arg-Lys-Asn Chemical compound NC(=O)C[C@@H](C(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](N)CCCN=C(N)N SSZGOKWBHLOCHK-DCAQKATOSA-N 0.000 description 2
- ULBHWNVWSCJLCO-NHCYSSNCSA-N Arg-Val-Glu Chemical compound OC(=O)CC[C@@H](C(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](N)CCCN=C(N)N ULBHWNVWSCJLCO-NHCYSSNCSA-N 0.000 description 2
- XEOXPCNONWHHSW-AVGNSLFASA-N Arg-Val-His Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)NC(=O)[C@H](CCCN=C(N)N)N XEOXPCNONWHHSW-AVGNSLFASA-N 0.000 description 2
- CMLGVVWQQHUXOZ-GHCJXIJMSA-N Asn-Ala-Ile Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](C)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O CMLGVVWQQHUXOZ-GHCJXIJMSA-N 0.000 description 2
- IARGXWMWRFOQPG-GCJQMDKQSA-N Asn-Ala-Thr Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O IARGXWMWRFOQPG-GCJQMDKQSA-N 0.000 description 2
- GOVUDFOGXOONFT-VEVYYDQMSA-N Asn-Arg-Thr Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(O)=O GOVUDFOGXOONFT-VEVYYDQMSA-N 0.000 description 2
- BHQQRVARKXWXPP-ACZMJKKPSA-N Asn-Asp-Glu Chemical compound C(CC(=O)O)[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)O)NC(=O)[C@H](CC(=O)N)N BHQQRVARKXWXPP-ACZMJKKPSA-N 0.000 description 2
- QNJIRRVTOXNGMH-GUBZILKMSA-N Asn-Gln-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](N)CC(N)=O QNJIRRVTOXNGMH-GUBZILKMSA-N 0.000 description 2
- CTQIOCMSIJATNX-WHFBIAKZSA-N Asn-Gly-Ala Chemical compound [H]N[C@@H](CC(N)=O)C(=O)NCC(=O)N[C@@H](C)C(O)=O CTQIOCMSIJATNX-WHFBIAKZSA-N 0.000 description 2
- OPEPUCYIGFEGSW-WDSKDSINSA-N Asn-Gly-Glu Chemical compound [H]N[C@@H](CC(N)=O)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(O)=O OPEPUCYIGFEGSW-WDSKDSINSA-N 0.000 description 2
- GWNMUVANAWDZTI-YUMQZZPRSA-N Asn-Gly-His Chemical compound C1=C(NC=N1)C[C@@H](C(=O)O)NC(=O)CNC(=O)[C@H](CC(=O)N)N GWNMUVANAWDZTI-YUMQZZPRSA-N 0.000 description 2
- OLISTMZJGQUOGS-GMOBBJLQSA-N Asn-Ile-Arg Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCCN=C(N)N)C(=O)O)NC(=O)[C@H](CC(=O)N)N OLISTMZJGQUOGS-GMOBBJLQSA-N 0.000 description 2
- GOKCTAJWRPSCHP-VHWLVUOQSA-N Asn-Ile-Trp Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC1=CNC2=CC=CC=C21)C(=O)O)NC(=O)[C@H](CC(=O)N)N GOKCTAJWRPSCHP-VHWLVUOQSA-N 0.000 description 2
- DJIMLSXHXKWADV-CIUDSAMLSA-N Asn-Leu-Ser Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CC(N)=O DJIMLSXHXKWADV-CIUDSAMLSA-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
- WLVLIYYBPPONRJ-GCJQMDKQSA-N Asn-Thr-Ala Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C)C(O)=O WLVLIYYBPPONRJ-GCJQMDKQSA-N 0.000 description 2
- HCZQKHSRYHCPSD-IUKAMOBKSA-N Asn-Thr-Ile Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O HCZQKHSRYHCPSD-IUKAMOBKSA-N 0.000 description 2
- AMGQTNHANMRPOE-LKXGYXEUSA-N Asn-Thr-Ser Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(O)=O AMGQTNHANMRPOE-LKXGYXEUSA-N 0.000 description 2
- UXHYOWXTJLBEPG-GSSVUCPTSA-N Asn-Thr-Thr Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O UXHYOWXTJLBEPG-GSSVUCPTSA-N 0.000 description 2
- FHCRKXCTKSHNOE-QEJZJMRPSA-N Asn-Trp-Glu Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)O)NC(=O)[C@H](CC(=O)N)N FHCRKXCTKSHNOE-QEJZJMRPSA-N 0.000 description 2
- ZAESWDKAMDVHLL-RCOVLWMOSA-N Asn-Val-Gly Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](C(C)C)C(=O)NCC(O)=O ZAESWDKAMDVHLL-RCOVLWMOSA-N 0.000 description 2
- PQKSVQSMTHPRIB-ZKWXMUAHSA-N Asn-Val-Ser Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CO)C(O)=O PQKSVQSMTHPRIB-ZKWXMUAHSA-N 0.000 description 2
- 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 2
- BUVNWKQBMZLCDW-UGYAYLCHSA-N Asp-Asn-Ile Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O BUVNWKQBMZLCDW-UGYAYLCHSA-N 0.000 description 2
- VHQOCWWKXIOAQI-WDSKDSINSA-N Asp-Gln-Gly Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)NCC(O)=O VHQOCWWKXIOAQI-WDSKDSINSA-N 0.000 description 2
- PZXPWHFYZXTFBI-YUMQZZPRSA-N Asp-Gly-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)CNC(=O)[C@@H](N)CC(O)=O PZXPWHFYZXTFBI-YUMQZZPRSA-N 0.000 description 2
- QNFRBNZGVVKBNJ-PEFMBERDSA-N Asp-Ile-Gln Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)O)NC(=O)[C@H](CC(=O)O)N QNFRBNZGVVKBNJ-PEFMBERDSA-N 0.000 description 2
- CJUKAWUWBZCTDQ-SRVKXCTJSA-N Asp-Leu-Lys Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(O)=O CJUKAWUWBZCTDQ-SRVKXCTJSA-N 0.000 description 2
- UZFHNLYQWMGUHU-DCAQKATOSA-N Asp-Lys-Arg Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O UZFHNLYQWMGUHU-DCAQKATOSA-N 0.000 description 2
- IDDMGSKZQDEDGA-SRVKXCTJSA-N Asp-Phe-Asn Chemical compound OC(=O)C[C@H](N)C(=O)N[C@H](C(=O)N[C@@H](CC(N)=O)C(O)=O)CC1=CC=CC=C1 IDDMGSKZQDEDGA-SRVKXCTJSA-N 0.000 description 2
- GWIJZUVQVDJHDI-AVGNSLFASA-N Asp-Phe-Glu Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CCC(O)=O)C(O)=O GWIJZUVQVDJHDI-AVGNSLFASA-N 0.000 description 2
- PCJOFZYFFMBZKC-PCBIJLKTSA-N Asp-Phe-Ile Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O PCJOFZYFFMBZKC-PCBIJLKTSA-N 0.000 description 2
- PWAIZUBWHRHYKS-MELADBBJSA-N Asp-Phe-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CC2=CC=CC=C2)NC(=O)[C@H](CC(=O)O)N)C(=O)O PWAIZUBWHRHYKS-MELADBBJSA-N 0.000 description 2
- QOJJMJKTMKNFEF-ZKWXMUAHSA-N Asp-Val-Ser Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](N)CC(O)=O QOJJMJKTMKNFEF-ZKWXMUAHSA-N 0.000 description 2
- ZUNMTUPRQMWMHX-LSJOCFKGSA-N Asp-Val-Val Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(O)=O ZUNMTUPRQMWMHX-LSJOCFKGSA-N 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- TVYMKYUSZSVOAG-ZLUOBGJFSA-N Cys-Ala-Ala Chemical compound [H]N[C@@H](CS)C(=O)N[C@@H](C)C(=O)N[C@@H](C)C(O)=O TVYMKYUSZSVOAG-ZLUOBGJFSA-N 0.000 description 2
- XGIAHEUULGOZHH-GUBZILKMSA-N Cys-Arg-Val Chemical compound CC(C)[C@@H](C(=O)O)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CS)N XGIAHEUULGOZHH-GUBZILKMSA-N 0.000 description 2
- RWAZRMXTVSIVJR-YUMQZZPRSA-N Cys-Gly-His Chemical compound [H]N[C@@H](CS)C(=O)NCC(=O)N[C@@H](CC1=CNC=N1)C(O)=O RWAZRMXTVSIVJR-YUMQZZPRSA-N 0.000 description 2
- QCUJUETWTSWPNZ-NAKRPEOUSA-N Cys-Ile-Met Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCSC)C(=O)O)NC(=O)[C@H](CS)N QCUJUETWTSWPNZ-NAKRPEOUSA-N 0.000 description 2
- DQGIAOGALAQBGK-BWBBJGPYSA-N Cys-Ser-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CO)NC(=O)[C@H](CS)N)O DQGIAOGALAQBGK-BWBBJGPYSA-N 0.000 description 2
- FCXJJTRGVAZDER-FXQIFTODSA-N Cys-Val-Ala Chemical compound [H]N[C@@H](CS)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C)C(O)=O FCXJJTRGVAZDER-FXQIFTODSA-N 0.000 description 2
- 238000002965 ELISA Methods 0.000 description 2
- 101710120217 Fc receptor-like protein 5 Proteins 0.000 description 2
- XJKAKYXMFHUIHT-AUTRQRHGSA-N Gln-Glu-Val Chemical compound CC(C)[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)O)NC(=O)[C@H](CCC(=O)N)N XJKAKYXMFHUIHT-AUTRQRHGSA-N 0.000 description 2
- 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 2
- HHQCBFGKQDMWSP-GUBZILKMSA-N Gln-Leu-Cys Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CS)C(=O)O)NC(=O)[C@H](CCC(=O)N)N HHQCBFGKQDMWSP-GUBZILKMSA-N 0.000 description 2
- HPCOBEHVEHWREJ-DCAQKATOSA-N Gln-Lys-Glu Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(O)=O HPCOBEHVEHWREJ-DCAQKATOSA-N 0.000 description 2
- AQPZYBSRDRZBAG-AVGNSLFASA-N Gln-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](CCC(=O)N)N AQPZYBSRDRZBAG-AVGNSLFASA-N 0.000 description 2
- MFORDNZDKAVNSR-SRVKXCTJSA-N Gln-Pro-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@@H](N)CCC(N)=O MFORDNZDKAVNSR-SRVKXCTJSA-N 0.000 description 2
- SGVGIVDZLSHSEN-RYUDHWBXSA-N Gln-Tyr-Gly Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)NCC(O)=O SGVGIVDZLSHSEN-RYUDHWBXSA-N 0.000 description 2
- WOMUDRVDJMHTCV-DCAQKATOSA-N Glu-Arg-Arg Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O WOMUDRVDJMHTCV-DCAQKATOSA-N 0.000 description 2
- CKRUHITYRFNUKW-WDSKDSINSA-N Glu-Asn-Gly Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)NCC(O)=O CKRUHITYRFNUKW-WDSKDSINSA-N 0.000 description 2
- KLJMRPIBBLTDGE-ACZMJKKPSA-N Glu-Cys-Asn Chemical compound OC(=O)CC[C@H](N)C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(N)=O)C(O)=O KLJMRPIBBLTDGE-ACZMJKKPSA-N 0.000 description 2
- FKGNJUCQKXQNRA-NRPADANISA-N Glu-Cys-Val Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)[C@H](CS)NC(=O)[C@@H](N)CCC(O)=O FKGNJUCQKXQNRA-NRPADANISA-N 0.000 description 2
- PXXGVUVQWQGGIG-YUMQZZPRSA-N Glu-Gly-Arg Chemical compound OC(=O)CC[C@H](N)C(=O)NCC(=O)N[C@H](C(O)=O)CCCN=C(N)N PXXGVUVQWQGGIG-YUMQZZPRSA-N 0.000 description 2
- ITBHUUMCJJQUSC-LAEOZQHASA-N Glu-Ile-Gly Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(O)=O ITBHUUMCJJQUSC-LAEOZQHASA-N 0.000 description 2
- VMKCPNBBPGGQBJ-GUBZILKMSA-N Glu-Leu-Asn Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)O)NC(=O)[C@H](CCC(=O)O)N VMKCPNBBPGGQBJ-GUBZILKMSA-N 0.000 description 2
- IOUQWHIEQYQVFD-JYJNAYRXSA-N Glu-Leu-Tyr Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O IOUQWHIEQYQVFD-JYJNAYRXSA-N 0.000 description 2
- GJBUAAAIZSRCDC-GVXVVHGQSA-N Glu-Leu-Val Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(O)=O GJBUAAAIZSRCDC-GVXVVHGQSA-N 0.000 description 2
- ILWHFUZZCFYSKT-AVGNSLFASA-N Glu-Lys-Leu Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(O)=O ILWHFUZZCFYSKT-AVGNSLFASA-N 0.000 description 2
- FMBWLLMUPXTXFC-SDDRHHMPSA-N Glu-Lys-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CCCCN)NC(=O)[C@H](CCC(=O)O)N)C(=O)O FMBWLLMUPXTXFC-SDDRHHMPSA-N 0.000 description 2
- PAZQYODKOZHXGA-SRVKXCTJSA-N Glu-Pro-His Chemical compound N[C@@H](CCC(O)=O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](Cc1cnc[nH]1)C(O)=O PAZQYODKOZHXGA-SRVKXCTJSA-N 0.000 description 2
- RFTVTKBHDXCEEX-WDSKDSINSA-N Glu-Ser-Gly Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(=O)NCC(O)=O RFTVTKBHDXCEEX-WDSKDSINSA-N 0.000 description 2
- QCMVGXDELYMZET-GLLZPBPUSA-N Glu-Thr-Glu Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCC(O)=O)C(O)=O QCMVGXDELYMZET-GLLZPBPUSA-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
- 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 2
- OGCIHJPYKVSMTE-YUMQZZPRSA-N Gly-Arg-Glu Chemical compound [H]NCC(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(O)=O OGCIHJPYKVSMTE-YUMQZZPRSA-N 0.000 description 2
- VXKCPBPQEKKERH-IUCAKERBSA-N Gly-Arg-Pro Chemical compound NC(N)=NCCC[C@H](NC(=O)CN)C(=O)N1CCC[C@H]1C(O)=O VXKCPBPQEKKERH-IUCAKERBSA-N 0.000 description 2
- LHRXAHLCRMQBGJ-RYUDHWBXSA-N Gly-Glu-Phe Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)O)NC(=O)CN LHRXAHLCRMQBGJ-RYUDHWBXSA-N 0.000 description 2
- XMPXVJIDADUOQB-RCOVLWMOSA-N Gly-Gly-Ile Chemical compound CC[C@H](C)[C@@H](C([O-])=O)NC(=O)CNC(=O)C[NH3+] XMPXVJIDADUOQB-RCOVLWMOSA-N 0.000 description 2
- YWAQATDNEKZFFK-BYPYZUCNSA-N Gly-Gly-Ser Chemical compound NCC(=O)NCC(=O)N[C@@H](CO)C(O)=O YWAQATDNEKZFFK-BYPYZUCNSA-N 0.000 description 2
- AYBKPDHHVADEDA-YUMQZZPRSA-N Gly-His-Asn Chemical compound [H]NCC(=O)N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CC(N)=O)C(O)=O AYBKPDHHVADEDA-YUMQZZPRSA-N 0.000 description 2
- FSPVILZGHUJOHS-QWRGUYRKSA-N Gly-His-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)CN)CC1=CNC=N1 FSPVILZGHUJOHS-QWRGUYRKSA-N 0.000 description 2
- BHPQOIPBLYJNAW-NGZCFLSTSA-N Gly-Ile-Pro Chemical compound CC[C@H](C)[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)CN BHPQOIPBLYJNAW-NGZCFLSTSA-N 0.000 description 2
- IEGFSKKANYKBDU-QWHCGFSZSA-N Gly-Phe-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CC2=CC=CC=C2)NC(=O)CN)C(=O)O IEGFSKKANYKBDU-QWHCGFSZSA-N 0.000 description 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
- 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
- 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
- VYUXYMRNGALHEA-DLOVCJGASA-N His-Leu-Ala Chemical compound [H]N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C)C(O)=O VYUXYMRNGALHEA-DLOVCJGASA-N 0.000 description 2
- LVXFNTIIGOQBMD-SRVKXCTJSA-N His-Leu-Ser Chemical compound [H]N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(O)=O LVXFNTIIGOQBMD-SRVKXCTJSA-N 0.000 description 2
- KHUFDBQXGLEIHC-BZSNNMDCSA-N His-Leu-Tyr Chemical compound C([C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(O)=O)C1=CN=CN1 KHUFDBQXGLEIHC-BZSNNMDCSA-N 0.000 description 2
- UMBKDWGQESDCTO-KKUMJFAQSA-N His-Lys-Lys Chemical compound [H]N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(O)=O UMBKDWGQESDCTO-KKUMJFAQSA-N 0.000 description 2
- WSEITRHJRVDTRX-QTKMDUPCSA-N His-Met-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CCSC)NC(=O)[C@H](CC1=CN=CN1)N)O WSEITRHJRVDTRX-QTKMDUPCSA-N 0.000 description 2
- IAYPZSHNZQHQNO-KKUMJFAQSA-N His-Ser-Phe Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)O)NC(=O)[C@H](CO)NC(=O)[C@H](CC2=CN=CN2)N IAYPZSHNZQHQNO-KKUMJFAQSA-N 0.000 description 2
- 101000797332 Homo sapiens Trem-like transcript 2 protein Proteins 0.000 description 2
- 102100026120 IgG receptor FcRn large subunit p51 Human genes 0.000 description 2
- HLYBGMZJVDHJEO-CYDGBPFRSA-N Ile-Arg-Arg Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CCCN=C(N)N)C(=O)O)N HLYBGMZJVDHJEO-CYDGBPFRSA-N 0.000 description 2
- NCSIQAFSIPHVAN-IUKAMOBKSA-N Ile-Asn-Thr Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H]([C@@H](C)O)C(=O)O)N NCSIQAFSIPHVAN-IUKAMOBKSA-N 0.000 description 2
- HGNUKGZQASSBKQ-PCBIJLKTSA-N Ile-Asp-Phe Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)O)N HGNUKGZQASSBKQ-PCBIJLKTSA-N 0.000 description 2
- LLZLRXBTOOFODM-QSFUFRPTSA-N Ile-Asp-Val Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](C(C)C)C(=O)O)N LLZLRXBTOOFODM-QSFUFRPTSA-N 0.000 description 2
- DURWCDDDAWVPOP-JBDRJPRFSA-N Ile-Cys-Ser Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CO)C(=O)O)N DURWCDDDAWVPOP-JBDRJPRFSA-N 0.000 description 2
- NYEYYMLUABXDMC-NHCYSSNCSA-N Ile-Gly-Leu Chemical compound CC[C@H](C)[C@@H](C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)O)N NYEYYMLUABXDMC-NHCYSSNCSA-N 0.000 description 2
- FFJQAEYLAQMGDL-MGHWNKPDSA-N Ile-Lys-Tyr Chemical compound CC[C@H](C)[C@H](N)C(=O)N[C@@H](CCCCN)C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 FFJQAEYLAQMGDL-MGHWNKPDSA-N 0.000 description 2
- ZUPJCJINYQISSN-XUXIUFHCSA-N Ile-Met-Lys Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCCCN)C(=O)O)N ZUPJCJINYQISSN-XUXIUFHCSA-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
- KTNGVMMGIQWIDV-OSUNSFLBSA-N Ile-Pro-Thr Chemical compound CC[C@H](C)[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H]([C@@H](C)O)C(O)=O KTNGVMMGIQWIDV-OSUNSFLBSA-N 0.000 description 2
- KBDIBHQICWDGDL-PPCPHDFISA-N Ile-Thr-Leu Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(=O)O)N KBDIBHQICWDGDL-PPCPHDFISA-N 0.000 description 2
- WCNWGAUZWWSYDG-SVSWQMSJSA-N Ile-Thr-Ser Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(=O)O)N WCNWGAUZWWSYDG-SVSWQMSJSA-N 0.000 description 2
- HZVRQFKRALAMQS-SLBDDTMCSA-N Ile-Trp-Asp Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC1=CNC2=CC=CC=C21)C(=O)N[C@@H](CC(=O)O)C(=O)O)N HZVRQFKRALAMQS-SLBDDTMCSA-N 0.000 description 2
- BQIIHAGJIYOQBP-YFYLHZKVSA-N Ile-Trp-Pro Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC1=CNC2=CC=CC=C21)C(=O)N3CCC[C@@H]3C(=O)O)N BQIIHAGJIYOQBP-YFYLHZKVSA-N 0.000 description 2
- DLEBSGAVWRPTIX-PEDHHIEDSA-N Ile-Val-Ile Chemical compound CC[C@H](C)[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@H](C(O)=O)[C@@H](C)CC DLEBSGAVWRPTIX-PEDHHIEDSA-N 0.000 description 2
- 102000008394 Immunoglobulin Fragments Human genes 0.000 description 2
- 108010021625 Immunoglobulin Fragments Proteins 0.000 description 2
- CQQGCWPXDHTTNF-GUBZILKMSA-N Leu-Ala-Glu Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@H](C(O)=O)CCC(O)=O CQQGCWPXDHTTNF-GUBZILKMSA-N 0.000 description 2
- BAJIJEGGUYXZGC-CIUDSAMLSA-N Leu-Asn-Cys Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CS)C(=O)O)N BAJIJEGGUYXZGC-CIUDSAMLSA-N 0.000 description 2
- JQSXWJXBASFONF-KKUMJFAQSA-N Leu-Asp-Phe Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O JQSXWJXBASFONF-KKUMJFAQSA-N 0.000 description 2
- CQGSYZCULZMEDE-UHFFFAOYSA-N Leu-Gln-Pro Natural products CC(C)CC(N)C(=O)NC(CCC(N)=O)C(=O)N1CCCC1C(O)=O CQGSYZCULZMEDE-UHFFFAOYSA-N 0.000 description 2
- HFBCHNRFRYLZNV-GUBZILKMSA-N Leu-Glu-Asp Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(O)=O HFBCHNRFRYLZNV-GUBZILKMSA-N 0.000 description 2
- WIDZHJTYKYBLSR-DCAQKATOSA-N Leu-Glu-Glu Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(O)=O WIDZHJTYKYBLSR-DCAQKATOSA-N 0.000 description 2
- ZFNLIDNJUWNIJL-WDCWCFNPSA-N Leu-Glu-Thr Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O ZFNLIDNJUWNIJL-WDCWCFNPSA-N 0.000 description 2
- QNBVTHNJGCOVFA-AVGNSLFASA-N Leu-Leu-Glu Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](C(O)=O)CCC(O)=O QNBVTHNJGCOVFA-AVGNSLFASA-N 0.000 description 2
- FAELBUXXFQLUAX-AJNGGQMLSA-N Leu-Leu-Ile Chemical compound CC[C@H](C)[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CC(C)C FAELBUXXFQLUAX-AJNGGQMLSA-N 0.000 description 2
- KPYAOIVPJKPIOU-KKUMJFAQSA-N Leu-Lys-Lys Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(O)=O KPYAOIVPJKPIOU-KKUMJFAQSA-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
- UCXQIIIFOOGYEM-ULQDDVLXSA-N Leu-Pro-Tyr Chemical compound CC(C)C[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 UCXQIIIFOOGYEM-ULQDDVLXSA-N 0.000 description 2
- MVHXGBZUJLWZOH-BJDJZHNGSA-N Leu-Ser-Ile Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O MVHXGBZUJLWZOH-BJDJZHNGSA-N 0.000 description 2
- PPGBXYKMUMHFBF-KATARQTJSA-N Leu-Ser-Thr Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(O)=O PPGBXYKMUMHFBF-KATARQTJSA-N 0.000 description 2
- HWMQRQIFVGEAPH-XIRDDKMYSA-N Leu-Ser-Trp Chemical compound C1=CC=C2C(C[C@H](NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC(C)C)C(O)=O)=CNC2=C1 HWMQRQIFVGEAPH-XIRDDKMYSA-N 0.000 description 2
- SVBJIZVVYJYGLA-DCAQKATOSA-N Leu-Ser-Val Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(O)=O SVBJIZVVYJYGLA-DCAQKATOSA-N 0.000 description 2
- RIHIGSWBLHSGLV-CQDKDKBSSA-N Leu-Tyr-Ala Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](C)C(O)=O RIHIGSWBLHSGLV-CQDKDKBSSA-N 0.000 description 2
- BTEMNFBEAAOGBR-BZSNNMDCSA-N Leu-Tyr-Lys Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CC1=CC=C(C=C1)O)C(=O)N[C@@H](CCCCN)C(=O)O)N BTEMNFBEAAOGBR-BZSNNMDCSA-N 0.000 description 2
- BGGTYDNTOYRTTR-MEYUZBJRSA-N Leu-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](CC(C)C)N)O BGGTYDNTOYRTTR-MEYUZBJRSA-N 0.000 description 2
- XZNJZXJZBMBGGS-NHCYSSNCSA-N Leu-Val-Asn Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(N)=O)C(O)=O XZNJZXJZBMBGGS-NHCYSSNCSA-N 0.000 description 2
- MVJRBCJCRYGCKV-GVXVVHGQSA-N Leu-Val-Gln Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(N)=O)C(O)=O MVJRBCJCRYGCKV-GVXVVHGQSA-N 0.000 description 2
- 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
- VHNOAIFVYUQOOY-XUXIUFHCSA-N Lys-Arg-Ile Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O VHNOAIFVYUQOOY-XUXIUFHCSA-N 0.000 description 2
- SWWCDAGDQHTKIE-RHYQMDGZSA-N Lys-Arg-Thr Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(O)=O SWWCDAGDQHTKIE-RHYQMDGZSA-N 0.000 description 2
- BYPMOIFBQPEWOH-CIUDSAMLSA-N Lys-Asn-Asp Chemical compound C(CCN)C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CC(=O)O)C(=O)O)N BYPMOIFBQPEWOH-CIUDSAMLSA-N 0.000 description 2
- DGWXCIORNLWGGG-CIUDSAMLSA-N Lys-Asn-Ser Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CO)C(O)=O DGWXCIORNLWGGG-CIUDSAMLSA-N 0.000 description 2
- ULUQBUKAPDUKOC-GVXVVHGQSA-N Lys-Glu-Val Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(O)=O ULUQBUKAPDUKOC-GVXVVHGQSA-N 0.000 description 2
- 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 2
- YPLVCBKEPJPBDQ-MELADBBJSA-N Lys-Leu-Pro Chemical compound CC(C)C[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](CCCCN)N YPLVCBKEPJPBDQ-MELADBBJSA-N 0.000 description 2
- LJADEBULDNKJNK-IHRRRGAJSA-N Lys-Leu-Val Chemical compound CC(C)C[C@H](NC(=O)[C@@H](N)CCCCN)C(=O)N[C@@H](C(C)C)C(O)=O LJADEBULDNKJNK-IHRRRGAJSA-N 0.000 description 2
- HVAUKHLDSDDROB-KKUMJFAQSA-N Lys-Lys-Leu Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(O)=O HVAUKHLDSDDROB-KKUMJFAQSA-N 0.000 description 2
- WBSCNDJQPKSPII-KKUMJFAQSA-N Lys-Lys-Lys Chemical compound NCCCC[C@H](N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(O)=O WBSCNDJQPKSPII-KKUMJFAQSA-N 0.000 description 2
- KJIXWRWPOCKYLD-IHRRRGAJSA-N Lys-Lys-Met Chemical compound CSCC[C@@H](C(=O)O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CCCCN)N KJIXWRWPOCKYLD-IHRRRGAJSA-N 0.000 description 2
- JPYPRVHMKRFTAT-KKUMJFAQSA-N Lys-Phe-Cys Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)N[C@@H](CS)C(=O)O)NC(=O)[C@H](CCCCN)N JPYPRVHMKRFTAT-KKUMJFAQSA-N 0.000 description 2
- AEIIJFBQVGYVEV-YESZJQIVSA-N Lys-Phe-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CC2=CC=CC=C2)NC(=O)[C@H](CCCCN)N)C(=O)O AEIIJFBQVGYVEV-YESZJQIVSA-N 0.000 description 2
- 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 2
- CUHGAUZONORRIC-HJGDQZAQSA-N Lys-Thr-Asn Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)O)NC(=O)[C@H](CCCCN)N)O CUHGAUZONORRIC-HJGDQZAQSA-N 0.000 description 2
- YFQSSOAGMZGXFT-MEYUZBJRSA-N Lys-Thr-Tyr Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O YFQSSOAGMZGXFT-MEYUZBJRSA-N 0.000 description 2
- FPQMQEOVSKMVMA-ACRUOGEOSA-N Lys-Tyr-Tyr Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)N[C@@H](CC2=CC=C(C=C2)O)C(=O)O)NC(=O)[C@H](CCCCN)N)O FPQMQEOVSKMVMA-ACRUOGEOSA-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
- PTYVBBNIAQWUFV-DCAQKATOSA-N Met-Cys-Leu Chemical compound CC(C)C[C@@H](C(=O)O)NC(=O)[C@H](CS)NC(=O)[C@H](CCSC)N PTYVBBNIAQWUFV-DCAQKATOSA-N 0.000 description 2
- WPTHAGXMYDRPFD-SRVKXCTJSA-N Met-Lys-Glu Chemical compound CSCC[C@H](N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(O)=O WPTHAGXMYDRPFD-SRVKXCTJSA-N 0.000 description 2
- HAQLBBVZAGMESV-IHRRRGAJSA-N Met-Lys-Lys Chemical compound CSCC[C@H](N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(O)=O HAQLBBVZAGMESV-IHRRRGAJSA-N 0.000 description 2
- SPSSJSICDYYTQN-HJGDQZAQSA-N Met-Thr-Gln Chemical compound CSCC[C@H](N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@H](C(O)=O)CCC(N)=O SPSSJSICDYYTQN-HJGDQZAQSA-N 0.000 description 2
- FXBKQTOGURNXSL-HJGDQZAQSA-N Met-Thr-Glu Chemical compound CSCC[C@H](N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@H](C(O)=O)CCC(O)=O FXBKQTOGURNXSL-HJGDQZAQSA-N 0.000 description 2
- PNHRPOWKRRJATF-IHRRRGAJSA-N Met-Tyr-Ser Chemical compound CSCC[C@H](N)C(=O)N[C@H](C(=O)N[C@@H](CO)C(O)=O)CC1=CC=C(O)C=C1 PNHRPOWKRRJATF-IHRRRGAJSA-N 0.000 description 2
- QAVZUKIPOMBLMC-AVGNSLFASA-N Met-Val-Leu Chemical compound CSCC[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@H](C(O)=O)CC(C)C QAVZUKIPOMBLMC-AVGNSLFASA-N 0.000 description 2
- 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 2
- LNIIRLODKOWQIY-IHRRRGAJSA-N Phe-Asn-Met Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCSC)C(O)=O LNIIRLODKOWQIY-IHRRRGAJSA-N 0.000 description 2
- CUMXHKAOHNWRFQ-BZSNNMDCSA-N Phe-Asp-Tyr Chemical compound C([C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(O)=O)C1=CC=CC=C1 CUMXHKAOHNWRFQ-BZSNNMDCSA-N 0.000 description 2
- YCCUXNNKXDGMAM-KKUMJFAQSA-N Phe-Leu-Ser Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(O)=O YCCUXNNKXDGMAM-KKUMJFAQSA-N 0.000 description 2
- BONHGTUEEPIMPM-AVGNSLFASA-N Phe-Ser-Glu Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(O)=O)C(O)=O BONHGTUEEPIMPM-AVGNSLFASA-N 0.000 description 2
- MCIXMYKSPQUMJG-SRVKXCTJSA-N Phe-Ser-Ser Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(O)=O MCIXMYKSPQUMJG-SRVKXCTJSA-N 0.000 description 2
- IAOZOFPONWDXNT-IXOXFDKPSA-N Phe-Ser-Thr Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(O)=O IAOZOFPONWDXNT-IXOXFDKPSA-N 0.000 description 2
- GLUYKHMBGKQBHE-JYJNAYRXSA-N Phe-Val-Arg Chemical compound NC(=N)NCCC[C@@H](C(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](N)CC1=CC=CC=C1 GLUYKHMBGKQBHE-JYJNAYRXSA-N 0.000 description 2
- YUPRIZTWANWWHK-DZKIICNBSA-N Phe-Val-Glu Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)O)NC(=O)[C@H](CC1=CC=CC=C1)N YUPRIZTWANWWHK-DZKIICNBSA-N 0.000 description 2
- XQLBWXHVZVBNJM-FXQIFTODSA-N Pro-Ala-Ser Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H]1CCCN1 XQLBWXHVZVBNJM-FXQIFTODSA-N 0.000 description 2
- OLHDPZMYUSBGDE-GUBZILKMSA-N Pro-Arg-Cys Chemical compound C1C[C@H](NC1)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CS)C(=O)O OLHDPZMYUSBGDE-GUBZILKMSA-N 0.000 description 2
- VCYJKOLZYPYGJV-AVGNSLFASA-N Pro-Arg-Leu Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(O)=O VCYJKOLZYPYGJV-AVGNSLFASA-N 0.000 description 2
- XWYXZPHPYKRYPA-GMOBBJLQSA-N Pro-Asn-Ile Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O XWYXZPHPYKRYPA-GMOBBJLQSA-N 0.000 description 2
- SGCZFWSQERRKBD-BQBZGAKWSA-N Pro-Asp-Gly Chemical compound OC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@@H]1CCCN1 SGCZFWSQERRKBD-BQBZGAKWSA-N 0.000 description 2
- UEHYFUCOGHWASA-HJGDQZAQSA-N Pro-Glu-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H]1CCCN1 UEHYFUCOGHWASA-HJGDQZAQSA-N 0.000 description 2
- QGOZJLYCGRYYRW-KKUMJFAQSA-N Pro-Glu-Tyr Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O QGOZJLYCGRYYRW-KKUMJFAQSA-N 0.000 description 2
- VYWNORHENYEQDW-YUMQZZPRSA-N Pro-Gly-Glu Chemical compound OC(=O)CC[C@@H](C(O)=O)NC(=O)CNC(=O)[C@@H]1CCCN1 VYWNORHENYEQDW-YUMQZZPRSA-N 0.000 description 2
- UIMCLYYSUCIUJM-UWVGGRQHSA-N Pro-Gly-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)CNC(=O)[C@@H]1CCCN1 UIMCLYYSUCIUJM-UWVGGRQHSA-N 0.000 description 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
- ITUDDXVFGFEKPD-NAKRPEOUSA-N Pro-Ser-Ile Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O ITUDDXVFGFEKPD-NAKRPEOUSA-N 0.000 description 2
- SHTKRJHDMNSKRM-ULQDDVLXSA-N Pro-Tyr-His Chemical compound C1C[C@H](NC1)C(=O)N[C@@H](CC2=CC=C(C=C2)O)C(=O)N[C@@H](CC3=CN=CN3)C(=O)O SHTKRJHDMNSKRM-ULQDDVLXSA-N 0.000 description 2
- 102000001708 Protein Isoforms Human genes 0.000 description 2
- 108010029485 Protein Isoforms Proteins 0.000 description 2
- QVOGDCQNGLBNCR-FXQIFTODSA-N Ser-Arg-Ser Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(O)=O QVOGDCQNGLBNCR-FXQIFTODSA-N 0.000 description 2
- WXUBSIDKNMFAGS-IHRRRGAJSA-N Ser-Arg-Tyr Chemical compound NC(N)=NCCC[C@H](NC(=O)[C@H](CO)N)C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 WXUBSIDKNMFAGS-IHRRRGAJSA-N 0.000 description 2
- XVAUJOAYHWWNQF-ZLUOBGJFSA-N Ser-Asn-Ala Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](C)C(O)=O XVAUJOAYHWWNQF-ZLUOBGJFSA-N 0.000 description 2
- UCXDHBORXLVBNC-ZLUOBGJFSA-N Ser-Asn-Cys Chemical compound OC[C@H](N)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CS)C(O)=O UCXDHBORXLVBNC-ZLUOBGJFSA-N 0.000 description 2
- UCOYFSCEIWQYNL-FXQIFTODSA-N Ser-Cys-Met Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCSC)C(O)=O UCOYFSCEIWQYNL-FXQIFTODSA-N 0.000 description 2
- SMIDBHKWSYUBRZ-ACZMJKKPSA-N Ser-Glu-Ala Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(O)=O SMIDBHKWSYUBRZ-ACZMJKKPSA-N 0.000 description 2
- UOLGINIHBRIECN-FXQIFTODSA-N Ser-Glu-Glu Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(O)=O UOLGINIHBRIECN-FXQIFTODSA-N 0.000 description 2
- 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 2
- DLPXTCTVNDTYGJ-JBDRJPRFSA-N Ser-Ile-Cys Chemical compound OC[C@H](N)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CS)C(O)=O DLPXTCTVNDTYGJ-JBDRJPRFSA-N 0.000 description 2
- UIPXCLNLUUAMJU-JBDRJPRFSA-N Ser-Ile-Ser Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(O)=O UIPXCLNLUUAMJU-JBDRJPRFSA-N 0.000 description 2
- ZOPISOXXPQNOCO-SVSWQMSJSA-N Ser-Ile-Thr Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H]([C@@H](C)O)C(=O)O)NC(=O)[C@H](CO)N ZOPISOXXPQNOCO-SVSWQMSJSA-N 0.000 description 2
- XJDMUQCLVSCRSJ-VZFHVOOUSA-N Ser-Thr-Ala Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C)C(O)=O XJDMUQCLVSCRSJ-VZFHVOOUSA-N 0.000 description 2
- 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 2
- AXKJPUBALUNJEO-UBHSHLNASA-N Ser-Trp-Asn Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC1=CNC2=C1C=CC=C2)C(=O)N[C@@H](CC(N)=O)C(O)=O AXKJPUBALUNJEO-UBHSHLNASA-N 0.000 description 2
- 108010003723 Single-Domain Antibodies Proteins 0.000 description 2
- 108700011201 Streptococcus IgG Fc-binding Proteins 0.000 description 2
- LVHHEVGYAZGXDE-KDXUFGMBSA-N Thr-Ala-Pro Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](C)C(=O)N1CCC[C@@H]1C(=O)O)N)O LVHHEVGYAZGXDE-KDXUFGMBSA-N 0.000 description 2
- JVTHIXKSVYEWNI-JRQIVUDYSA-N Thr-Asn-Tyr Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O JVTHIXKSVYEWNI-JRQIVUDYSA-N 0.000 description 2
- MFEBUIFJVPNZLO-OLHMAJIHSA-N Thr-Asp-Asn Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O MFEBUIFJVPNZLO-OLHMAJIHSA-N 0.000 description 2
- ODSAPYVQSLDRSR-LKXGYXEUSA-N Thr-Cys-Asn Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(N)=O)C(O)=O ODSAPYVQSLDRSR-LKXGYXEUSA-N 0.000 description 2
- KZUJCMPVNXOBAF-LKXGYXEUSA-N Thr-Cys-Asp Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(O)=O)C(O)=O KZUJCMPVNXOBAF-LKXGYXEUSA-N 0.000 description 2
- KBBRNEDOYWMIJP-KYNKHSRBSA-N Thr-Gly-Thr Chemical compound C[C@H]([C@@H](C(=O)NCC(=O)N[C@@H]([C@@H](C)O)C(=O)O)N)O KBBRNEDOYWMIJP-KYNKHSRBSA-N 0.000 description 2
- GMXIJHCBTZDAPD-QPHKQPEJSA-N Thr-Ile-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)O)NC(=O)[C@H]([C@@H](C)O)N GMXIJHCBTZDAPD-QPHKQPEJSA-N 0.000 description 2
- YJCVECXVYHZOBK-KNZXXDILSA-N Thr-Ile-Pro Chemical compound CC[C@H](C)[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H]([C@@H](C)O)N YJCVECXVYHZOBK-KNZXXDILSA-N 0.000 description 2
- 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 2
- KZURUCDWKDEAFZ-XVSYOHENSA-N Thr-Phe-Asn Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CC(=O)N)C(=O)O)N)O KZURUCDWKDEAFZ-XVSYOHENSA-N 0.000 description 2
- VEIKMWOMUYMMMK-FCLVOEFKSA-N Thr-Phe-Phe Chemical compound C([C@H](NC(=O)[C@@H](N)[C@H](O)C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)C1=CC=CC=C1 VEIKMWOMUYMMMK-FCLVOEFKSA-N 0.000 description 2
- NWECYMJLJGCBOD-UNQGMJICSA-N Thr-Phe-Val Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](C(C)C)C(O)=O NWECYMJLJGCBOD-UNQGMJICSA-N 0.000 description 2
- XHWCDRUPDNSDAZ-XKBZYTNZSA-N Thr-Ser-Glu Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(=O)O)C(=O)O)N)O XHWCDRUPDNSDAZ-XKBZYTNZSA-N 0.000 description 2
- NQQMWWVVGIXUOX-SVSWQMSJSA-N Thr-Ser-Ile Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O NQQMWWVVGIXUOX-SVSWQMSJSA-N 0.000 description 2
- VUXIQSUQQYNLJP-XAVMHZPKSA-N Thr-Ser-Pro Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CO)C(=O)N1CCC[C@@H]1C(=O)O)N)O VUXIQSUQQYNLJP-XAVMHZPKSA-N 0.000 description 2
- AAZOYLQUEQRUMZ-GSSVUCPTSA-N Thr-Thr-Asn Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@H](C(O)=O)CC(N)=O AAZOYLQUEQRUMZ-GSSVUCPTSA-N 0.000 description 2
- CJEHCEOXPLASCK-MEYUZBJRSA-N Thr-Tyr-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)[C@H](O)C)CC1=CC=C(O)C=C1 CJEHCEOXPLASCK-MEYUZBJRSA-N 0.000 description 2
- CYCGARJWIQWPQM-YJRXYDGGSA-N Thr-Tyr-Ser Chemical compound C[C@@H](O)[C@H]([NH3+])C(=O)N[C@H](C(=O)N[C@@H](CO)C([O-])=O)CC1=CC=C(O)C=C1 CYCGARJWIQWPQM-YJRXYDGGSA-N 0.000 description 2
- BXKWZPXTTSCOMX-AQZXSJQPSA-N Trp-Asn-Thr Chemical compound [H]N[C@@H](CC1=CNC2=C1C=CC=C2)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O BXKWZPXTTSCOMX-AQZXSJQPSA-N 0.000 description 2
- LTLBNCDNXQCOLB-UBHSHLNASA-N Trp-Asp-Ser Chemical compound C1=CC=C2C(C[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(O)=O)=CNC2=C1 LTLBNCDNXQCOLB-UBHSHLNASA-N 0.000 description 2
- PTAWAMWPRFTACW-SZMVWBNQSA-N Trp-Gln-Lys Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H](CCCCN)C(=O)O)N PTAWAMWPRFTACW-SZMVWBNQSA-N 0.000 description 2
- HXNVJPQADLRHGR-JBACZVJFSA-N Trp-Glu-Tyr Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CC3=CC=C(C=C3)O)C(=O)O)N HXNVJPQADLRHGR-JBACZVJFSA-N 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
- OGXQLUCMJZSJPW-LYSGOOTNSA-N Trp-Gly-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)CNC(=O)[C@H](CC1=CNC2=CC=CC=C21)N)O OGXQLUCMJZSJPW-LYSGOOTNSA-N 0.000 description 2
- YXSSXUIBUJGHJY-SFJXLCSZSA-N Trp-Thr-Phe Chemical compound C([C@H](NC(=O)[C@@H](NC(=O)[C@@H](N)CC=1C2=CC=CC=C2NC=1)[C@H](O)C)C(O)=O)C1=CC=CC=C1 YXSSXUIBUJGHJY-SFJXLCSZSA-N 0.000 description 2
- 108060008683 Tumor Necrosis Factor Receptor Proteins 0.000 description 2
- 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 2
- ZNFPUOSTMUMUDR-JRQIVUDYSA-N Tyr-Asn-Thr Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O ZNFPUOSTMUMUDR-JRQIVUDYSA-N 0.000 description 2
- IWRMTNJCCMEBEX-AVGNSLFASA-N Tyr-Glu-Cys Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CS)C(=O)O)N)O IWRMTNJCCMEBEX-AVGNSLFASA-N 0.000 description 2
- JLKVWTICWVWGSK-JYJNAYRXSA-N Tyr-Lys-Glu Chemical compound OC(=O)CC[C@@H](C(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 JLKVWTICWVWGSK-JYJNAYRXSA-N 0.000 description 2
- 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 2
- YYLHVUCSTXXKBS-IHRRRGAJSA-N Tyr-Pro-Ser Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CO)C(O)=O YYLHVUCSTXXKBS-IHRRRGAJSA-N 0.000 description 2
- 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 2
- QFHRUCJIRVILCK-YJRXYDGGSA-N Tyr-Thr-Cys Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CS)C(=O)O)NC(=O)[C@H](CC1=CC=C(C=C1)O)N)O QFHRUCJIRVILCK-YJRXYDGGSA-N 0.000 description 2
- NUQZCPSZHGIYTA-HKUYNNGSSA-N Tyr-Trp-Gly Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)NCC(=O)O)NC(=O)[C@H](CC3=CC=C(C=C3)O)N NUQZCPSZHGIYTA-HKUYNNGSSA-N 0.000 description 2
- CVUDMNSZAIZFAE-TUAOUCFPSA-N Val-Arg-Pro Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCCN=C(N)N)C(=O)N1CCC[C@@H]1C(=O)O)N CVUDMNSZAIZFAE-TUAOUCFPSA-N 0.000 description 2
- CVUDMNSZAIZFAE-UHFFFAOYSA-N Val-Arg-Pro Natural products NC(N)=NCCCC(NC(=O)C(N)C(C)C)C(=O)N1CCCC1C(O)=O CVUDMNSZAIZFAE-UHFFFAOYSA-N 0.000 description 2
- UDLYXGYWTVOIKU-QXEWZRGKSA-N Val-Asn-Arg Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CCCN=C(N)N)C(=O)O)N UDLYXGYWTVOIKU-QXEWZRGKSA-N 0.000 description 2
- GXAZTLJYINLMJL-LAEOZQHASA-N Val-Asn-Gln Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CCC(=O)N)C(=O)O)N GXAZTLJYINLMJL-LAEOZQHASA-N 0.000 description 2
- UDNYEPLJTRDMEJ-RCOVLWMOSA-N Val-Asn-Gly Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)NCC(=O)O)N UDNYEPLJTRDMEJ-RCOVLWMOSA-N 0.000 description 2
- ZQGPWORGSNRQLN-NHCYSSNCSA-N Val-Asp-His Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)N ZQGPWORGSNRQLN-NHCYSSNCSA-N 0.000 description 2
- YLHLNFUXDBOAGX-DCAQKATOSA-N Val-Cys-His Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)N YLHLNFUXDBOAGX-DCAQKATOSA-N 0.000 description 2
- SZTTYWIUCGSURQ-AUTRQRHGSA-N Val-Glu-Glu Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(O)=O SZTTYWIUCGSURQ-AUTRQRHGSA-N 0.000 description 2
- OQWNEUXPKHIEJO-NRPADANISA-N Val-Glu-Ser Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CO)C(=O)O)N OQWNEUXPKHIEJO-NRPADANISA-N 0.000 description 2
- WFENBJPLZMPVAX-XVKPBYJWSA-N Val-Gly-Glu Chemical compound CC(C)[C@H](N)C(=O)NCC(=O)N[C@H](C(O)=O)CCC(O)=O WFENBJPLZMPVAX-XVKPBYJWSA-N 0.000 description 2
- PMDOQZFYGWZSTK-LSJOCFKGSA-N Val-Gly-Ile Chemical compound CC[C@H](C)[C@@H](C(O)=O)NC(=O)CNC(=O)[C@@H](N)C(C)C PMDOQZFYGWZSTK-LSJOCFKGSA-N 0.000 description 2
- RHYOAUJXSRWVJT-GVXVVHGQSA-N Val-His-Glu Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)N[C@@H](CCC(=O)O)C(=O)O)N RHYOAUJXSRWVJT-GVXVVHGQSA-N 0.000 description 2
- KNYHAWKHFQRYOX-PYJNHQTQSA-N Val-Ile-His Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)NC(=O)[C@H](C(C)C)N KNYHAWKHFQRYOX-PYJNHQTQSA-N 0.000 description 2
- FTKXYXACXYOHND-XUXIUFHCSA-N Val-Ile-Leu Chemical compound CC(C)[C@H](N)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(C)C)C(O)=O FTKXYXACXYOHND-XUXIUFHCSA-N 0.000 description 2
- JZWZACGUZVCQPS-RNJOBUHISA-N Val-Ile-Pro Chemical compound CC[C@H](C)[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](C(C)C)N JZWZACGUZVCQPS-RNJOBUHISA-N 0.000 description 2
- FEXILLGKGGTLRI-NHCYSSNCSA-N Val-Leu-Asn Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)O)NC(=O)[C@H](C(C)C)N FEXILLGKGGTLRI-NHCYSSNCSA-N 0.000 description 2
- BTWMICVCQLKKNR-DCAQKATOSA-N Val-Leu-Ser Chemical compound CC(C)[C@H]([NH3+])C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C([O-])=O BTWMICVCQLKKNR-DCAQKATOSA-N 0.000 description 2
- 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 2
- VCIYTVOBLZHFSC-XHSDSOJGSA-N Val-Phe-Pro Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N2CCC[C@@H]2C(=O)O)N VCIYTVOBLZHFSC-XHSDSOJGSA-N 0.000 description 2
- UJMCYJKPDFQLHX-XGEHTFHBSA-N Val-Ser-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CO)NC(=O)[C@H](C(C)C)N)O UJMCYJKPDFQLHX-XGEHTFHBSA-N 0.000 description 2
- OFTXTCGQJXTNQS-XGEHTFHBSA-N Val-Thr-Ser Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CO)C(=O)O)NC(=O)[C@H](C(C)C)N)O OFTXTCGQJXTNQS-XGEHTFHBSA-N 0.000 description 2
- 239000012190 activator Substances 0.000 description 2
- 108010005233 alanylglutamic acid Proteins 0.000 description 2
- 230000000735 allogeneic effect Effects 0.000 description 2
- 108010077245 asparaginyl-proline Proteins 0.000 description 2
- 108010040443 aspartyl-aspartic acid Proteins 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 238000004364 calculation method Methods 0.000 description 2
- 229960000419 catumaxomab Drugs 0.000 description 2
- 230000003833 cell viability Effects 0.000 description 2
- 229940121420 cemiplimab Drugs 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 230000000139 costimulatory effect Effects 0.000 description 2
- 210000004443 dendritic cell Anatomy 0.000 description 2
- CEJLBZWIKQJOAT-UHFFFAOYSA-N dichloroisocyanuric acid Chemical compound ClN1C(=O)NC(=O)N(Cl)C1=O CEJLBZWIKQJOAT-UHFFFAOYSA-N 0.000 description 2
- 238000007876 drug discovery Methods 0.000 description 2
- 238000011156 evaluation Methods 0.000 description 2
- 239000003862 glucocorticoid Substances 0.000 description 2
- 108010020688 glycylhistidine Proteins 0.000 description 2
- 108010025306 histidylleucine Proteins 0.000 description 2
- 230000001900 immune effect Effects 0.000 description 2
- 208000026278 immune system disease Diseases 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 230000001939 inductive effect Effects 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 108010044374 isoleucyl-tyrosine Proteins 0.000 description 2
- 108010053037 kyotorphin Proteins 0.000 description 2
- 108010025153 lysyl-alanyl-alanine Proteins 0.000 description 2
- 230000003211 malignant effect Effects 0.000 description 2
- 238000000691 measurement method Methods 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 201000001441 melanoma Diseases 0.000 description 2
- 239000013642 negative control Substances 0.000 description 2
- 239000002773 nucleotide Substances 0.000 description 2
- 125000003729 nucleotide group Chemical group 0.000 description 2
- 238000005457 optimization Methods 0.000 description 2
- 239000013641 positive control Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 230000001737 promoting effect Effects 0.000 description 2
- 230000028327 secretion Effects 0.000 description 2
- 108010048818 seryl-histidine Proteins 0.000 description 2
- 230000011664 signaling Effects 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 230000004083 survival effect Effects 0.000 description 2
- 230000002195 synergetic effect Effects 0.000 description 2
- 238000010257 thawing Methods 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- 102000003298 tumor necrosis factor receptor Human genes 0.000 description 2
- 230000005760 tumorsuppression Effects 0.000 description 2
- 108010003137 tyrosyltyrosine Proteins 0.000 description 2
- NFGXHKASABOEEW-UHFFFAOYSA-N 1-methylethyl 11-methoxy-3,7,11-trimethyl-2,4-dodecadienoate Chemical compound COC(C)(C)CCCC(C)CC=CC(C)=CC(=O)OC(C)C NFGXHKASABOEEW-UHFFFAOYSA-N 0.000 description 1
- BWRRWBIBNBVHQF-UHFFFAOYSA-N 4-(3-pyridin-2-yl-1,2,4-oxadiazol-5-yl)butanoic acid Chemical compound O1C(CCCC(=O)O)=NC(C=2N=CC=CC=2)=N1 BWRRWBIBNBVHQF-UHFFFAOYSA-N 0.000 description 1
- ROMPPAWVATWIKR-UHFFFAOYSA-N 4-[3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl]butanoic acid Chemical compound O1C(CCCC(=O)O)=NC(C=2C=CC(Cl)=CC=2)=N1 ROMPPAWVATWIKR-UHFFFAOYSA-N 0.000 description 1
- RLMISHABBKUNFO-WHFBIAKZSA-N Ala-Ala-Gly Chemical compound C[C@H](N)C(=O)N[C@@H](C)C(=O)NCC(O)=O RLMISHABBKUNFO-WHFBIAKZSA-N 0.000 description 1
- SVBXIUDNTRTKHE-CIUDSAMLSA-N Ala-Arg-Glu Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(O)=O SVBXIUDNTRTKHE-CIUDSAMLSA-N 0.000 description 1
- JAMAWBXXKFGFGX-KZVJFYERSA-N Ala-Arg-Thr Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(O)=O JAMAWBXXKFGFGX-KZVJFYERSA-N 0.000 description 1
- STACJSVFHSEZJV-GHCJXIJMSA-N Ala-Asn-Ile Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O STACJSVFHSEZJV-GHCJXIJMSA-N 0.000 description 1
- NHCPCLJZRSIDHS-ZLUOBGJFSA-N Ala-Asp-Ala Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](C)C(O)=O NHCPCLJZRSIDHS-ZLUOBGJFSA-N 0.000 description 1
- KIUYPHAMDKDICO-WHFBIAKZSA-N Ala-Asp-Gly Chemical compound C[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)NCC(O)=O KIUYPHAMDKDICO-WHFBIAKZSA-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
- 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 1
- AWZKCUCQJNTBAD-SRVKXCTJSA-N Ala-Leu-Lys Chemical compound C[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](C(O)=O)CCCCN AWZKCUCQJNTBAD-SRVKXCTJSA-N 0.000 description 1
- OPZJWMJPCNNZNT-DCAQKATOSA-N Ala-Leu-Met Chemical compound C[C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)O)N OPZJWMJPCNNZNT-DCAQKATOSA-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
- SOBIAADAMRHGKH-CIUDSAMLSA-N Ala-Leu-Ser Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(O)=O SOBIAADAMRHGKH-CIUDSAMLSA-N 0.000 description 1
- YCRAFFCYWOUEOF-DLOVCJGASA-N Ala-Phe-Ser Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)C)CC1=CC=CC=C1 YCRAFFCYWOUEOF-DLOVCJGASA-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
- BTRULDJUUVGRNE-DCAQKATOSA-N Ala-Pro-Lys Chemical compound C[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCCCN)C(O)=O BTRULDJUUVGRNE-DCAQKATOSA-N 0.000 description 1
- NZGRHTKZFSVPAN-BIIVOSGPSA-N Ala-Ser-Pro Chemical compound C[C@@H](C(=O)N[C@@H](CO)C(=O)N1CCC[C@@H]1C(=O)O)N NZGRHTKZFSVPAN-BIIVOSGPSA-N 0.000 description 1
- 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
- SYIFFFHSXBNPMC-UWJYBYFXSA-N Ala-Ser-Tyr Chemical compound C[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CC1=CC=C(C=C1)O)C(=O)O)N SYIFFFHSXBNPMC-UWJYBYFXSA-N 0.000 description 1
- WZGZDOXCDLLTHE-SYWGBEHUSA-N Ala-Trp-Ile Chemical compound C1=CC=C2C(C[C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(O)=O)NC(=O)[C@H](C)N)=CNC2=C1 WZGZDOXCDLLTHE-SYWGBEHUSA-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
- XCIGOVDXZULBBV-DCAQKATOSA-N Ala-Val-Lys Chemical compound CC(C)[C@H](NC(=O)[C@H](C)N)C(=O)N[C@@H](CCCCN)C(O)=O XCIGOVDXZULBBV-DCAQKATOSA-N 0.000 description 1
- 102100034608 Angiopoietin-2 Human genes 0.000 description 1
- 108010048036 Angiopoietin-2 Proteins 0.000 description 1
- XPSGESXVBSQZPL-SRVKXCTJSA-N Arg-Arg-Arg Chemical compound NC(N)=NCCC[C@H](N)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CCCN=C(N)N)C(O)=O XPSGESXVBSQZPL-SRVKXCTJSA-N 0.000 description 1
- BIOCIVSVEDFKDJ-GUBZILKMSA-N Arg-Arg-Asp Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(O)=O BIOCIVSVEDFKDJ-GUBZILKMSA-N 0.000 description 1
- JGDGLDNAQJJGJI-AVGNSLFASA-N Arg-Arg-His Chemical compound C1=C(NC=N1)C[C@@H](C(=O)O)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CCCN=C(N)N)N JGDGLDNAQJJGJI-AVGNSLFASA-N 0.000 description 1
- NABSCJGZKWSNHX-RCWTZXSCSA-N Arg-Arg-Thr Chemical compound NC(N)=NCCC[C@@H](C(=O)N[C@@H]([C@H](O)C)C(O)=O)NC(=O)[C@@H](N)CCCN=C(N)N NABSCJGZKWSNHX-RCWTZXSCSA-N 0.000 description 1
- OZNSCVPYWZRQPY-CIUDSAMLSA-N Arg-Asp-Glu Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(O)=O OZNSCVPYWZRQPY-CIUDSAMLSA-N 0.000 description 1
- LKDHUGLXOHYINY-XUXIUFHCSA-N Arg-Ile-Lys Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CCCN=C(N)N)N LKDHUGLXOHYINY-XUXIUFHCSA-N 0.000 description 1
- JEXPNDORFYHJTM-IHRRRGAJSA-N Arg-Leu-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CCCN=C(N)N JEXPNDORFYHJTM-IHRRRGAJSA-N 0.000 description 1
- JEOCWTUOMKEEMF-RHYQMDGZSA-N Arg-Leu-Thr Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O JEOCWTUOMKEEMF-RHYQMDGZSA-N 0.000 description 1
- YFHATWYGAAXQCF-JYJNAYRXSA-N Arg-Pro-Phe Chemical compound NC(N)=NCCC[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 YFHATWYGAAXQCF-JYJNAYRXSA-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
- 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 1
- QHUOOCKNNURZSL-IHRRRGAJSA-N Arg-Tyr-Ser Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CO)C(O)=O QHUOOCKNNURZSL-IHRRRGAJSA-N 0.000 description 1
- JJGRJMKUOYXZRA-LPEHRKFASA-N Asn-Arg-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC(=O)N)N)C(=O)O JJGRJMKUOYXZRA-LPEHRKFASA-N 0.000 description 1
- PCKRJVZAQZWNKM-WHFBIAKZSA-N Asn-Asn-Gly Chemical compound NC(=O)C[C@H](N)C(=O)N[C@@H](CC(N)=O)C(=O)NCC(O)=O PCKRJVZAQZWNKM-WHFBIAKZSA-N 0.000 description 1
- 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
- BGINHSZTXRJIPP-FXQIFTODSA-N Asn-Asp-Met Chemical compound CSCC[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)O)NC(=O)[C@H](CC(=O)N)N BGINHSZTXRJIPP-FXQIFTODSA-N 0.000 description 1
- SPIPSJXLZVTXJL-ZLUOBGJFSA-N Asn-Cys-Ser Chemical compound NC(=O)C[C@H](N)C(=O)N[C@@H](CS)C(=O)N[C@@H](CO)C(O)=O SPIPSJXLZVTXJL-ZLUOBGJFSA-N 0.000 description 1
- PPMTUXJSQDNUDE-CIUDSAMLSA-N Asn-Glu-Arg Chemical compound NC(=O)C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@H](C(O)=O)CCCN=C(N)N PPMTUXJSQDNUDE-CIUDSAMLSA-N 0.000 description 1
- 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 1
- YYSYDIYQTUPNQQ-SXTJYALSSA-N Asn-Ile-Ile Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O YYSYDIYQTUPNQQ-SXTJYALSSA-N 0.000 description 1
- GLWFAWNYGWBMOC-SRVKXCTJSA-N Asn-Leu-Leu Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O GLWFAWNYGWBMOC-SRVKXCTJSA-N 0.000 description 1
- RTFWCVDISAMGEQ-SRVKXCTJSA-N Asn-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](CC(=O)N)N RTFWCVDISAMGEQ-SRVKXCTJSA-N 0.000 description 1
- GMUOCGCDOYYWPD-FXQIFTODSA-N Asn-Pro-Ser Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CO)C(O)=O GMUOCGCDOYYWPD-FXQIFTODSA-N 0.000 description 1
- IDUUACUJKUXKKD-VEVYYDQMSA-N Asn-Pro-Thr Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N1CCC[C@H]1C(=O)N[C@@H]([C@@H](C)O)C(O)=O IDUUACUJKUXKKD-VEVYYDQMSA-N 0.000 description 1
- 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 1
- WUQXMTITJLFXAU-JIOCBJNQSA-N Asn-Thr-Pro Chemical compound C[C@H]([C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](CC(=O)N)N)O WUQXMTITJLFXAU-JIOCBJNQSA-N 0.000 description 1
- DPSUVAPLRQDWAO-YDHLFZDLSA-N Asn-Tyr-Val Chemical compound CC(C)[C@@H](C(=O)O)NC(=O)[C@H](CC1=CC=C(C=C1)O)NC(=O)[C@H](CC(=O)N)N DPSUVAPLRQDWAO-YDHLFZDLSA-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
- XYBJLTKSGFBLCS-QXEWZRGKSA-N Asp-Arg-Val Chemical compound NC(N)=NCCC[C@@H](C(=O)N[C@@H](C(C)C)C(O)=O)NC(=O)[C@@H](N)CC(O)=O XYBJLTKSGFBLCS-QXEWZRGKSA-N 0.000 description 1
- UQBGYPFHWFZMCD-ZLUOBGJFSA-N Asp-Asn-Asn Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O UQBGYPFHWFZMCD-ZLUOBGJFSA-N 0.000 description 1
- ATYWBXGNXZYZGI-ACZMJKKPSA-N Asp-Asn-Gln Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(O)=O ATYWBXGNXZYZGI-ACZMJKKPSA-N 0.000 description 1
- UGKZHCBLMLSANF-CIUDSAMLSA-N Asp-Asn-Leu Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(O)=O UGKZHCBLMLSANF-CIUDSAMLSA-N 0.000 description 1
- VAWNQIGQPUOPQW-ACZMJKKPSA-N Asp-Glu-Ala Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(O)=O VAWNQIGQPUOPQW-ACZMJKKPSA-N 0.000 description 1
- XJQRWGXKUSDEFI-ACZMJKKPSA-N Asp-Glu-Asn Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O XJQRWGXKUSDEFI-ACZMJKKPSA-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
- OMMIEVATLAGRCK-BYPYZUCNSA-N Asp-Gly-Gly Chemical compound OC(=O)C[C@H](N)C(=O)NCC(=O)NCC(O)=O OMMIEVATLAGRCK-BYPYZUCNSA-N 0.000 description 1
- IVPNEDNYYYFAGI-GARJFASQSA-N Asp-Leu-Pro Chemical compound CC(C)C[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](CC(=O)O)N IVPNEDNYYYFAGI-GARJFASQSA-N 0.000 description 1
- 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
- DONWIPDSZZJHHK-HJGDQZAQSA-N Asp-Lys-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CC(=O)O)N)O DONWIPDSZZJHHK-HJGDQZAQSA-N 0.000 description 1
- SAKCBXNPWDRWPE-BQBZGAKWSA-N Asp-Met-Gly Chemical compound CSCC[C@@H](C(=O)NCC(=O)O)NC(=O)[C@H](CC(=O)O)N SAKCBXNPWDRWPE-BQBZGAKWSA-N 0.000 description 1
- CUQDCPXNZPDYFQ-ZLUOBGJFSA-N Asp-Ser-Asp Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(O)=O)C(O)=O CUQDCPXNZPDYFQ-ZLUOBGJFSA-N 0.000 description 1
- DRCOAZZDQRCGGP-GHCJXIJMSA-N Asp-Ser-Ile Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O DRCOAZZDQRCGGP-GHCJXIJMSA-N 0.000 description 1
- ALMIMUZAWTUNIO-BZSNNMDCSA-N Asp-Tyr-Tyr Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O ALMIMUZAWTUNIO-BZSNNMDCSA-N 0.000 description 1
- 101100512078 Caenorhabditis elegans lys-1 gene Proteins 0.000 description 1
- 101100510617 Caenorhabditis elegans sel-8 gene Proteins 0.000 description 1
- 101100314454 Caenorhabditis elegans tra-1 gene Proteins 0.000 description 1
- 102000014914 Carrier Proteins Human genes 0.000 description 1
- 108010078791 Carrier Proteins Proteins 0.000 description 1
- 102100026735 Coagulation factor VIII Human genes 0.000 description 1
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 1
- CLDCTNHPILWQCW-CIUDSAMLSA-N Cys-Arg-Glu Chemical compound C(C[C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)O)NC(=O)[C@H](CS)N)CN=C(N)N CLDCTNHPILWQCW-CIUDSAMLSA-N 0.000 description 1
- DEVDFMRWZASYOF-ZLUOBGJFSA-N Cys-Asn-Asp Chemical compound [H]N[C@@H](CS)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(O)=O)C(O)=O DEVDFMRWZASYOF-ZLUOBGJFSA-N 0.000 description 1
- WXKWQSDHEXKKNC-ZKWXMUAHSA-N Cys-Asp-Val Chemical compound CC(C)[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)O)NC(=O)[C@H](CS)N WXKWQSDHEXKKNC-ZKWXMUAHSA-N 0.000 description 1
- ANRWXLYGJRSQEQ-CIUDSAMLSA-N Cys-His-Asp Chemical compound [H]N[C@@H](CS)C(=O)N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CC(O)=O)C(O)=O ANRWXLYGJRSQEQ-CIUDSAMLSA-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
- UIKLEGZPIOXFHJ-DLOVCJGASA-N Cys-Phe-Ala Chemical compound [H]N[C@@H](CS)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](C)C(O)=O UIKLEGZPIOXFHJ-DLOVCJGASA-N 0.000 description 1
- BCWIFCLVCRAIQK-ZLUOBGJFSA-N Cys-Ser-Cys Chemical compound C([C@@H](C(=O)N[C@@H](CS)C(=O)O)NC(=O)[C@H](CS)N)O BCWIFCLVCRAIQK-ZLUOBGJFSA-N 0.000 description 1
- NRVQLLDIJJEIIZ-VZFHVOOUSA-N Cys-Thr-Ala Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](C)C(=O)O)NC(=O)[C@H](CS)N)O NRVQLLDIJJEIIZ-VZFHVOOUSA-N 0.000 description 1
- 206010050685 Cytokine storm Diseases 0.000 description 1
- 102000004127 Cytokines Human genes 0.000 description 1
- 108090000695 Cytokines Proteins 0.000 description 1
- 229920002307 Dextran Polymers 0.000 description 1
- 206010061818 Disease progression Diseases 0.000 description 1
- 108010048049 Factor IXa Proteins 0.000 description 1
- 108010054218 Factor VIII Proteins 0.000 description 1
- 102000001690 Factor VIII Human genes 0.000 description 1
- 201000003542 Factor VIII deficiency Diseases 0.000 description 1
- 108010014173 Factor X Proteins 0.000 description 1
- RZSLYUUFFVHFRQ-FXQIFTODSA-N Gln-Ala-Glu Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(O)=O RZSLYUUFFVHFRQ-FXQIFTODSA-N 0.000 description 1
- NVEASDQHBRZPSU-BQBZGAKWSA-N Gln-Gln-Gly Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)NCC(O)=O NVEASDQHBRZPSU-BQBZGAKWSA-N 0.000 description 1
- GPISLLFQNHELLK-DCAQKATOSA-N Gln-Gln-His Chemical compound C1=C(NC=N1)C[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)N)NC(=O)[C@H](CCC(=O)N)N GPISLLFQNHELLK-DCAQKATOSA-N 0.000 description 1
- SNLOOPZHAQDMJG-CIUDSAMLSA-N Gln-Glu-Glu Chemical compound NC(=O)CC[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(O)=O SNLOOPZHAQDMJG-CIUDSAMLSA-N 0.000 description 1
- SWDSRANUCKNBLA-AVGNSLFASA-N Gln-Phe-Asp Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)O)NC(=O)[C@H](CCC(=O)N)N SWDSRANUCKNBLA-AVGNSLFASA-N 0.000 description 1
- HMIXCETWRYDVMO-GUBZILKMSA-N Gln-Pro-Glu Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCC(O)=O)C(O)=O HMIXCETWRYDVMO-GUBZILKMSA-N 0.000 description 1
- KUBFPYIMAGXGBT-ACZMJKKPSA-N Gln-Ser-Ala Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](C)C(O)=O KUBFPYIMAGXGBT-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
- JKDBRTNMYXYLHO-JYJNAYRXSA-N Gln-Tyr-Leu Chemical compound NC(=O)CC[C@H](N)C(=O)N[C@H](C(=O)N[C@@H](CC(C)C)C(O)=O)CC1=CC=C(O)C=C1 JKDBRTNMYXYLHO-JYJNAYRXSA-N 0.000 description 1
- RDPOETHPAQEGDP-ACZMJKKPSA-N Glu-Asp-Ala Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](C)C(O)=O RDPOETHPAQEGDP-ACZMJKKPSA-N 0.000 description 1
- RFDHKPSHTXZKLL-IHRRRGAJSA-N Glu-Gln-Phe Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)N)NC(=O)[C@H](CCC(=O)O)N RFDHKPSHTXZKLL-IHRRRGAJSA-N 0.000 description 1
- UHVIQGKBMXEVGN-WDSKDSINSA-N Glu-Gly-Asn Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)NCC(=O)N[C@@H](CC(N)=O)C(O)=O UHVIQGKBMXEVGN-WDSKDSINSA-N 0.000 description 1
- OGNJZUXUTPQVBR-BQBZGAKWSA-N Glu-Gly-Glu Chemical compound OC(=O)CC[C@H](N)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(O)=O OGNJZUXUTPQVBR-BQBZGAKWSA-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
- BIHMNDPWRUROFZ-JYJNAYRXSA-N Glu-His-Phe Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O BIHMNDPWRUROFZ-JYJNAYRXSA-N 0.000 description 1
- MFNUFCFRAZPJFW-JYJNAYRXSA-N Glu-Lys-Phe Chemical compound OC(=O)CC[C@H](N)C(=O)N[C@@H](CCCCN)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 MFNUFCFRAZPJFW-JYJNAYRXSA-N 0.000 description 1
- YHOJJFFTSMWVGR-HJGDQZAQSA-N Glu-Met-Thr Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCSC)C(=O)N[C@@H]([C@@H](C)O)C(O)=O YHOJJFFTSMWVGR-HJGDQZAQSA-N 0.000 description 1
- ZTVGZOIBLRPQNR-KKUMJFAQSA-N Glu-Met-Tyr Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O ZTVGZOIBLRPQNR-KKUMJFAQSA-N 0.000 description 1
- JDUKCSSHWNIQQZ-IHRRRGAJSA-N Glu-Phe-Glu Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CCC(O)=O)C(O)=O JDUKCSSHWNIQQZ-IHRRRGAJSA-N 0.000 description 1
- QNJNPKSWAHPYGI-JYJNAYRXSA-N Glu-Phe-Leu Chemical compound OC(=O)CC[C@H](N)C(=O)N[C@H](C(=O)N[C@@H](CC(C)C)C(O)=O)CC1=CC=CC=C1 QNJNPKSWAHPYGI-JYJNAYRXSA-N 0.000 description 1
- AAJHGGDRKHYSDH-GUBZILKMSA-N Glu-Pro-Gln Chemical compound C1C[C@H](N(C1)C(=O)[C@H](CCC(=O)O)N)C(=O)N[C@@H](CCC(=O)N)C(=O)O AAJHGGDRKHYSDH-GUBZILKMSA-N 0.000 description 1
- CQAHWYDHKUWYIX-YUMQZZPRSA-N Glu-Pro-Gly Chemical compound OC(=O)CC[C@H](N)C(=O)N1CCC[C@H]1C(=O)NCC(O)=O CQAHWYDHKUWYIX-YUMQZZPRSA-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
- DLISPGXMKZTWQG-IFFSRLJSSA-N Glu-Thr-Val Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(O)=O DLISPGXMKZTWQG-IFFSRLJSSA-N 0.000 description 1
- UCZXXMREFIETQW-AVGNSLFASA-N Glu-Tyr-Asn Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC(N)=O)C(O)=O UCZXXMREFIETQW-AVGNSLFASA-N 0.000 description 1
- KCCNSVHJSMMGFS-NRPADANISA-N Glu-Val-Cys Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CS)C(=O)O)NC(=O)[C@H](CCC(=O)O)N KCCNSVHJSMMGFS-NRPADANISA-N 0.000 description 1
- CLODWIOAKCSBAN-BQBZGAKWSA-N Gly-Arg-Asp Chemical compound NC(N)=NCCC[C@H](NC(=O)CN)C(=O)N[C@@H](CC(O)=O)C(O)=O CLODWIOAKCSBAN-BQBZGAKWSA-N 0.000 description 1
- CIMULJZTTOBOPN-WHFBIAKZSA-N Gly-Asn-Asn Chemical compound NCC(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O CIMULJZTTOBOPN-WHFBIAKZSA-N 0.000 description 1
- BGVYNAQWHSTTSP-BYULHYEWSA-N Gly-Asn-Ile Chemical compound [H]NCC(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O BGVYNAQWHSTTSP-BYULHYEWSA-N 0.000 description 1
- HDNXXTBKOJKWNN-WDSKDSINSA-N Gly-Glu-Asn Chemical compound NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O HDNXXTBKOJKWNN-WDSKDSINSA-N 0.000 description 1
- SOEATRRYCIPEHA-BQBZGAKWSA-N Gly-Glu-Glu Chemical compound [H]NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(O)=O SOEATRRYCIPEHA-BQBZGAKWSA-N 0.000 description 1
- MBOAPAXLTUSMQI-JHEQGTHGSA-N Gly-Glu-Thr Chemical compound [H]NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O MBOAPAXLTUSMQI-JHEQGTHGSA-N 0.000 description 1
- KAJAOGBVWCYGHZ-JTQLQIEISA-N Gly-Gly-Phe Chemical compound [NH3+]CC(=O)NCC(=O)N[C@H](C([O-])=O)CC1=CC=CC=C1 KAJAOGBVWCYGHZ-JTQLQIEISA-N 0.000 description 1
- UPADCCSMVOQAGF-LBPRGKRZSA-N Gly-Gly-Trp Chemical compound C1=CC=C2C(C[C@H](NC(=O)CNC(=O)CN)C(O)=O)=CNC2=C1 UPADCCSMVOQAGF-LBPRGKRZSA-N 0.000 description 1
- ORXZVPZCPMKHNR-IUCAKERBSA-N Gly-His-Glu Chemical compound OC(=O)CC[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)CN)CC1=CNC=N1 ORXZVPZCPMKHNR-IUCAKERBSA-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
- UWQDKRIZSROAKS-FJXKBIBVSA-N Gly-Met-Thr Chemical compound [H]NCC(=O)N[C@@H](CCSC)C(=O)N[C@@H]([C@@H](C)O)C(O)=O UWQDKRIZSROAKS-FJXKBIBVSA-N 0.000 description 1
- GAFKBWKVXNERFA-QWRGUYRKSA-N Gly-Phe-Asp Chemical compound OC(=O)C[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)CN)CC1=CC=CC=C1 GAFKBWKVXNERFA-QWRGUYRKSA-N 0.000 description 1
- GGLIDLCEPDHEJO-BQBZGAKWSA-N Gly-Pro-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@@H]1CCCN1C(=O)CN GGLIDLCEPDHEJO-BQBZGAKWSA-N 0.000 description 1
- NSVOVKWEKGEOQB-LURJTMIESA-N Gly-Pro-Gly Chemical compound NCC(=O)N1CCC[C@H]1C(=O)NCC(O)=O NSVOVKWEKGEOQB-LURJTMIESA-N 0.000 description 1
- IXHQLZIWBCQBLQ-STQMWFEESA-N Gly-Pro-Phe Chemical compound NCC(=O)N1CCC[C@H]1C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 IXHQLZIWBCQBLQ-STQMWFEESA-N 0.000 description 1
- IRJWAYCXIYUHQE-WHFBIAKZSA-N Gly-Ser-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)CN IRJWAYCXIYUHQE-WHFBIAKZSA-N 0.000 description 1
- 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 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
- SFOXOSKVTLDEDM-HOTGVXAUSA-N Gly-Trp-Leu Chemical compound C1=CC=C2C(C[C@@H](C(=O)N[C@@H](CC(C)C)C(O)=O)NC(=O)CN)=CNC2=C1 SFOXOSKVTLDEDM-HOTGVXAUSA-N 0.000 description 1
- 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 1
- 208000009292 Hemophilia A Diseases 0.000 description 1
- LMMPTUVWHCFTOT-GARJFASQSA-N His-Asp-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CC(=O)O)NC(=O)[C@H](CC2=CN=CN2)N)C(=O)O LMMPTUVWHCFTOT-GARJFASQSA-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
- FDQYIRHBVVUTJF-ZETCQYMHSA-N His-Gly-Gly Chemical compound [O-]C(=O)CNC(=O)CNC(=O)[C@@H]([NH3+])CC1=CN=CN1 FDQYIRHBVVUTJF-ZETCQYMHSA-N 0.000 description 1
- FHKZHRMERJUXRJ-DCAQKATOSA-N His-Ser-Arg Chemical compound NC(N)=NCCC[C@@H](C(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC1=CN=CN1 FHKZHRMERJUXRJ-DCAQKATOSA-N 0.000 description 1
- GBMSSORHVHAYLU-QTKMDUPCSA-N His-Val-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC1=CN=CN1)N)O GBMSSORHVHAYLU-QTKMDUPCSA-N 0.000 description 1
- 101100005713 Homo sapiens CD4 gene Proteins 0.000 description 1
- 101000911390 Homo sapiens Coagulation factor VIII Proteins 0.000 description 1
- 101001068133 Homo sapiens Hepatitis A virus cellular receptor 2 Proteins 0.000 description 1
- 101000599940 Homo sapiens Interferon gamma Proteins 0.000 description 1
- 101001002657 Homo sapiens Interleukin-2 Proteins 0.000 description 1
- 101000611936 Homo sapiens Programmed cell death protein 1 Proteins 0.000 description 1
- 101000946850 Homo sapiens T-lymphocyte activation antigen CD86 Proteins 0.000 description 1
- 101710177940 IgG receptor FcRn large subunit p51 Proteins 0.000 description 1
- NKRJALPCDNXULF-BYULHYEWSA-N Ile-Asp-Gly Chemical compound [H]N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(O)=O)C(=O)NCC(O)=O NKRJALPCDNXULF-BYULHYEWSA-N 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
- KBHYLOIVRVBBEB-JBDRJPRFSA-N Ile-Cys-Cys Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CS)C(=O)O)N KBHYLOIVRVBBEB-JBDRJPRFSA-N 0.000 description 1
- LDRALPZEVHVXEK-KBIXCLLPSA-N Ile-Cys-Glu Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CCC(=O)O)C(=O)O)N LDRALPZEVHVXEK-KBIXCLLPSA-N 0.000 description 1
- AYLAAGNJNVZDPY-CYDGBPFRSA-N Ile-Met-Met Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCSC)C(=O)O)N AYLAAGNJNVZDPY-CYDGBPFRSA-N 0.000 description 1
- XQLGNKLSPYCRMZ-HJWJTTGWSA-N Ile-Phe-Val Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](C(C)C)C(=O)O)N XQLGNKLSPYCRMZ-HJWJTTGWSA-N 0.000 description 1
- VISRCHQHQCLODA-NAKRPEOUSA-N Ile-Pro-Cys Chemical compound CC[C@H](C)[C@@H](C(=O)N1CCC[C@H]1C(=O)N[C@@H](CS)C(=O)O)N VISRCHQHQCLODA-NAKRPEOUSA-N 0.000 description 1
- FQYQMFCIJNWDQZ-CYDGBPFRSA-N Ile-Pro-Pro Chemical compound CC[C@H](C)[C@H](N)C(=O)N1CCC[C@H]1C(=O)N1[C@H](C(O)=O)CCC1 FQYQMFCIJNWDQZ-CYDGBPFRSA-N 0.000 description 1
- JZNVOBUNTWNZPW-GHCJXIJMSA-N Ile-Ser-Asp Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(=O)O)C(=O)O)N JZNVOBUNTWNZPW-GHCJXIJMSA-N 0.000 description 1
- FBGXMKUWQFPHFB-JBDRJPRFSA-N Ile-Ser-Cys Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CS)C(=O)O)N FBGXMKUWQFPHFB-JBDRJPRFSA-N 0.000 description 1
- ZLFNNVATRMCAKN-ZKWXMUAHSA-N Ile-Ser-Gly Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CO)C(=O)NCC(=O)O)N ZLFNNVATRMCAKN-ZKWXMUAHSA-N 0.000 description 1
- 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 1
- WKSHBPRUIRGWRZ-KCTSRDHCSA-N Ile-Trp-Gly Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC1=CNC2=CC=CC=C21)C(=O)NCC(=O)O)N WKSHBPRUIRGWRZ-KCTSRDHCSA-N 0.000 description 1
- MITYXXNZSZLHGG-OBAATPRFSA-N Ile-Trp-Tyr Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC1=CNC2=CC=CC=C21)C(=O)N[C@@H](CC3=CC=C(C=C3)O)C(=O)O)N MITYXXNZSZLHGG-OBAATPRFSA-N 0.000 description 1
- OMDWJWGZGMCQND-CFMVVWHZSA-N Ile-Tyr-Asp Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC1=CC=C(C=C1)O)C(=O)N[C@@H](CC(=O)O)C(=O)O)N OMDWJWGZGMCQND-CFMVVWHZSA-N 0.000 description 1
- PRTZQMBYUZFSFA-XEGUGMAKSA-N Ile-Tyr-Gly Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC1=CC=C(C=C1)O)C(=O)NCC(=O)O)N PRTZQMBYUZFSFA-XEGUGMAKSA-N 0.000 description 1
- NXRNRBOKDBIVKQ-CXTHYWKRSA-N Ile-Tyr-Tyr Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC1=CC=C(C=C1)O)C(=O)N[C@@H](CC2=CC=C(C=C2)O)C(=O)O)N NXRNRBOKDBIVKQ-CXTHYWKRSA-N 0.000 description 1
- APQYGMBHIVXFML-OSUNSFLBSA-N Ile-Val-Thr Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)O)C(=O)O)N APQYGMBHIVXFML-OSUNSFLBSA-N 0.000 description 1
- MJOZZTKJZQFKDK-GUBZILKMSA-N Leu-Ala-Gln Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@H](C(O)=O)CCC(N)=O MJOZZTKJZQFKDK-GUBZILKMSA-N 0.000 description 1
- XIRYQRLFHWWWTC-QEJZJMRPSA-N Leu-Ala-Phe Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 XIRYQRLFHWWWTC-QEJZJMRPSA-N 0.000 description 1
- NTRAGDHVSGKUSF-AVGNSLFASA-N Leu-Arg-Arg Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CCCN=C(N)N)C(O)=O NTRAGDHVSGKUSF-AVGNSLFASA-N 0.000 description 1
- WUFYAPWIHCUMLL-CIUDSAMLSA-N Leu-Asn-Ala Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](C)C(O)=O WUFYAPWIHCUMLL-CIUDSAMLSA-N 0.000 description 1
- USTCFDAQCLDPBD-XIRDDKMYSA-N Leu-Asn-Trp Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CC1=CNC2=CC=CC=C21)C(=O)O)N USTCFDAQCLDPBD-XIRDDKMYSA-N 0.000 description 1
- NHHKSOGJYNQENP-SRVKXCTJSA-N Leu-Cys-Lys Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CCCCN)C(=O)O)N NHHKSOGJYNQENP-SRVKXCTJSA-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
- 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
- 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
- XVZCXCTYGHPNEM-UHFFFAOYSA-N Leu-Leu-Pro Natural products CC(C)CC(N)C(=O)NC(CC(C)C)C(=O)N1CCCC1C(O)=O XVZCXCTYGHPNEM-UHFFFAOYSA-N 0.000 description 1
- IEWBEPKLKUXQBU-VOAKCMCISA-N Leu-Leu-Thr Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O IEWBEPKLKUXQBU-VOAKCMCISA-N 0.000 description 1
- 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 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
- ODRREERHVHMIPT-OEAJRASXSA-N Leu-Thr-Phe Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 ODRREERHVHMIPT-OEAJRASXSA-N 0.000 description 1
- HGLKOTPFWOMPOB-MEYUZBJRSA-N Leu-Thr-Tyr Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 HGLKOTPFWOMPOB-MEYUZBJRSA-N 0.000 description 1
- WSXTWLJHTLRFLW-SRVKXCTJSA-N Lys-Ala-Lys Chemical compound NCCCC[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCN)C(O)=O WSXTWLJHTLRFLW-SRVKXCTJSA-N 0.000 description 1
- QUCDKEKDPYISNX-HJGDQZAQSA-N Lys-Asn-Thr Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O QUCDKEKDPYISNX-HJGDQZAQSA-N 0.000 description 1
- SFQPJNQDUUYCLA-BJDJZHNGSA-N Lys-Cys-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)[C@H](CS)NC(=O)[C@H](CCCCN)N SFQPJNQDUUYCLA-BJDJZHNGSA-N 0.000 description 1
- GGNOBVSOZPHLCE-GUBZILKMSA-N Lys-Gln-Asp Chemical compound NCCCC[C@H](N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(O)=O)C(O)=O GGNOBVSOZPHLCE-GUBZILKMSA-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
- GJJQCBVRWDGLMQ-GUBZILKMSA-N Lys-Glu-Ala Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(O)=O GJJQCBVRWDGLMQ-GUBZILKMSA-N 0.000 description 1
- DCRWPTBMWMGADO-AVGNSLFASA-N Lys-Glu-Leu Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(O)=O DCRWPTBMWMGADO-AVGNSLFASA-N 0.000 description 1
- LCMWVZLBCUVDAZ-IUCAKERBSA-N Lys-Gly-Glu Chemical compound [NH3+]CCCC[C@H]([NH3+])C(=O)NCC(=O)N[C@H](C([O-])=O)CCC([O-])=O LCMWVZLBCUVDAZ-IUCAKERBSA-N 0.000 description 1
- 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 1
- SKRGVGLIRUGANF-AVGNSLFASA-N Lys-Leu-Glu Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(O)=O SKRGVGLIRUGANF-AVGNSLFASA-N 0.000 description 1
- VMTYLUGCXIEDMV-QWRGUYRKSA-N Lys-Leu-Gly Chemical compound OC(=O)CNC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CCCCN VMTYLUGCXIEDMV-QWRGUYRKSA-N 0.000 description 1
- YXPJCVNIDDKGOE-MELADBBJSA-N Lys-Lys-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CCCCN)NC(=O)[C@H](CCCCN)N)C(=O)O YXPJCVNIDDKGOE-MELADBBJSA-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
- SVSQSPICRKBMSZ-SRVKXCTJSA-N Lys-Pro-Gln Chemical compound [H]N[C@@H](CCCCN)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCC(N)=O)C(O)=O SVSQSPICRKBMSZ-SRVKXCTJSA-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
- UWHCKWNPWKTMBM-WDCWCFNPSA-N Lys-Thr-Gln Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCC(N)=O)C(O)=O UWHCKWNPWKTMBM-WDCWCFNPSA-N 0.000 description 1
- IEVXCWPVBYCJRZ-IXOXFDKPSA-N Lys-Thr-His Chemical compound NCCCC[C@H](N)C(=O)N[C@@H]([C@H](O)C)C(=O)N[C@H](C(O)=O)CC1=CN=CN1 IEVXCWPVBYCJRZ-IXOXFDKPSA-N 0.000 description 1
- RIPJMCFGQHGHNP-RHYQMDGZSA-N Lys-Val-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](C(C)C)NC(=O)[C@H](CCCCN)N)O RIPJMCFGQHGHNP-RHYQMDGZSA-N 0.000 description 1
- 206010025538 Malignant ascites Diseases 0.000 description 1
- 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 1
- AFVOKRHYSSFPHC-STECZYCISA-N Met-Ile-Tyr Chemical compound CSCC[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 AFVOKRHYSSFPHC-STECZYCISA-N 0.000 description 1
- PCTFVQATEGYHJU-FXQIFTODSA-N Met-Ser-Asn Chemical compound [H]N[C@@H](CCSC)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(O)=O PCTFVQATEGYHJU-FXQIFTODSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 241000699660 Mus musculus Species 0.000 description 1
- PESQCPHRXOFIPX-UHFFFAOYSA-N N-L-methionyl-L-tyrosine Natural products CSCCC(N)C(=O)NC(C(O)=O)CC1=CC=C(O)C=C1 PESQCPHRXOFIPX-UHFFFAOYSA-N 0.000 description 1
- 108010079364 N-glycylalanine Proteins 0.000 description 1
- 102000007399 Nuclear hormone receptor Human genes 0.000 description 1
- 108020005497 Nuclear hormone receptor Proteins 0.000 description 1
- QMMRHASQEVCJGR-UBHSHLNASA-N Phe-Ala-Pro Chemical compound C([C@H](N)C(=O)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(O)=O)C1=CC=CC=C1 QMMRHASQEVCJGR-UBHSHLNASA-N 0.000 description 1
- ZBYHVSHBZYHQBW-SRVKXCTJSA-N Phe-Cys-Asp Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(=O)O)C(=O)O)N ZBYHVSHBZYHQBW-SRVKXCTJSA-N 0.000 description 1
- MGECUMGTSHYHEJ-QEWYBTABSA-N Phe-Glu-Ile Chemical compound CC[C@H](C)[C@@H](C(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](N)CC1=CC=CC=C1 MGECUMGTSHYHEJ-QEWYBTABSA-N 0.000 description 1
- ZLGQEBCCANLYRA-RYUDHWBXSA-N Phe-Gly-Glu Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(O)=O ZLGQEBCCANLYRA-RYUDHWBXSA-N 0.000 description 1
- DVOCGBNHAUHKHJ-DKIMLUQUSA-N Phe-Ile-Leu Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(C)C)C(O)=O DVOCGBNHAUHKHJ-DKIMLUQUSA-N 0.000 description 1
- DEZCWWXTRAKZKJ-UFYCRDLUSA-N Phe-Phe-Met Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CCSC)C(O)=O DEZCWWXTRAKZKJ-UFYCRDLUSA-N 0.000 description 1
- CZQZSMJXFGGBHM-KKUMJFAQSA-N Phe-Pro-Gln Chemical compound C1C[C@H](N(C1)C(=O)[C@H](CC2=CC=CC=C2)N)C(=O)N[C@@H](CCC(=O)N)C(=O)O CZQZSMJXFGGBHM-KKUMJFAQSA-N 0.000 description 1
- NJJBATPLUQHRBM-IHRRRGAJSA-N Phe-Pro-Ser Chemical compound C1C[C@H](N(C1)C(=O)[C@H](CC2=CC=CC=C2)N)C(=O)N[C@@H](CO)C(=O)O NJJBATPLUQHRBM-IHRRRGAJSA-N 0.000 description 1
- XDMMOISUAHXXFD-SRVKXCTJSA-N Phe-Ser-Asp Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(O)=O)C(O)=O XDMMOISUAHXXFD-SRVKXCTJSA-N 0.000 description 1
- JHSRGEODDALISP-XVSYOHENSA-N Phe-Thr-Asn 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(N)=O)C(O)=O JHSRGEODDALISP-XVSYOHENSA-N 0.000 description 1
- AIZVVCMAFRREQS-GUBZILKMSA-N Pro-Cys-Arg Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CS)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O AIZVVCMAFRREQS-GUBZILKMSA-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
- 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
- JMVQDLDPDBXAAX-YUMQZZPRSA-N Pro-Gly-Gln Chemical compound NC(=O)CC[C@@H](C(O)=O)NC(=O)CNC(=O)[C@@H]1CCCN1 JMVQDLDPDBXAAX-YUMQZZPRSA-N 0.000 description 1
- HAAQQNHQZBOWFO-LURJTMIESA-N Pro-Gly-Gly Chemical compound OC(=O)CNC(=O)CNC(=O)[C@@H]1CCCN1 HAAQQNHQZBOWFO-LURJTMIESA-N 0.000 description 1
- AFXCXDQNRXTSBD-FJXKBIBVSA-N Pro-Gly-Thr Chemical compound [H]N1CCC[C@H]1C(=O)NCC(=O)N[C@@H]([C@@H](C)O)C(O)=O AFXCXDQNRXTSBD-FJXKBIBVSA-N 0.000 description 1
- STASJMBVVHNWCG-IHRRRGAJSA-N Pro-His-Leu Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C([O-])=O)NC(=O)[C@H]1[NH2+]CCC1)C1=CN=CN1 STASJMBVVHNWCG-IHRRRGAJSA-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
- 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
- XYAFCOJKICBRDU-JYJNAYRXSA-N Pro-Phe-Val Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](C(C)C)C(O)=O XYAFCOJKICBRDU-JYJNAYRXSA-N 0.000 description 1
- SVXXJYJCRNKDDE-AVGNSLFASA-N Pro-Pro-His Chemical compound C([C@@H](C(=O)O)NC(=O)[C@H]1N(CCC1)C(=O)[C@H]1NCCC1)C1=CN=CN1 SVXXJYJCRNKDDE-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
- RNEFESSBTOQSAC-DCAQKATOSA-N Pro-Ser-His Chemical compound C1C[C@H](NC1)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC2=CN=CN2)C(=O)O RNEFESSBTOQSAC-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
- RMJZWERKFFNNNS-XGEHTFHBSA-N Pro-Thr-Ser Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(O)=O RMJZWERKFFNNNS-XGEHTFHBSA-N 0.000 description 1
- CXGLFEOYCJFKPR-RCWTZXSCSA-N Pro-Thr-Val Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(O)=O CXGLFEOYCJFKPR-RCWTZXSCSA-N 0.000 description 1
- AWJGUZSYVIVZGP-YUMQZZPRSA-N Pro-Val Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)[C@@H]1CCCN1 AWJGUZSYVIVZGP-YUMQZZPRSA-N 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 108020004511 Recombinant DNA Proteins 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
- LVVBAKCGXXUHFO-ZLUOBGJFSA-N Ser-Ala-Asp Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(O)=O)C(O)=O LVVBAKCGXXUHFO-ZLUOBGJFSA-N 0.000 description 1
- YUSRGTQIPCJNHQ-CIUDSAMLSA-N Ser-Arg-Glu Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(O)=O YUSRGTQIPCJNHQ-CIUDSAMLSA-N 0.000 description 1
- QFBNNYNWKYKVJO-DCAQKATOSA-N Ser-Arg-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)CO)CCCN=C(N)N QFBNNYNWKYKVJO-DCAQKATOSA-N 0.000 description 1
- 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 1
- 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 1
- YMEXHZTVKDAKIY-GHCJXIJMSA-N Ser-Asn-Ile Chemical compound CC[C@H](C)[C@H](NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](N)CO)C(O)=O YMEXHZTVKDAKIY-GHCJXIJMSA-N 0.000 description 1
- FIDMVVBUOCMMJG-CIUDSAMLSA-N Ser-Asn-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](N)CO FIDMVVBUOCMMJG-CIUDSAMLSA-N 0.000 description 1
- DKKGAAJTDKHWOD-BIIVOSGPSA-N Ser-Asn-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CC(=O)N)NC(=O)[C@H](CO)N)C(=O)O DKKGAAJTDKHWOD-BIIVOSGPSA-N 0.000 description 1
- RDFQNDHEHVSONI-ZLUOBGJFSA-N Ser-Asn-Ser Chemical compound OC[C@H](N)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CO)C(O)=O RDFQNDHEHVSONI-ZLUOBGJFSA-N 0.000 description 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
- RNMRYWZYFHHOEV-CIUDSAMLSA-N Ser-Gln-Arg Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O RNMRYWZYFHHOEV-CIUDSAMLSA-N 0.000 description 1
- ULVMNZOKDBHKKI-ACZMJKKPSA-N Ser-Gln-Asp Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(O)=O)C(O)=O ULVMNZOKDBHKKI-ACZMJKKPSA-N 0.000 description 1
- BRGQQXQKPUCUJQ-KBIXCLLPSA-N Ser-Glu-Ile Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O BRGQQXQKPUCUJQ-KBIXCLLPSA-N 0.000 description 1
- AEGUWTFAQQWVLC-BQBZGAKWSA-N Ser-Gly-Arg Chemical compound [H]N[C@@H](CO)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(O)=O AEGUWTFAQQWVLC-BQBZGAKWSA-N 0.000 description 1
- IOVHBRCQOGWAQH-ZKWXMUAHSA-N Ser-Gly-Ile Chemical compound [H]N[C@@H](CO)C(=O)NCC(=O)N[C@@H]([C@@H](C)CC)C(O)=O IOVHBRCQOGWAQH-ZKWXMUAHSA-N 0.000 description 1
- UAJAYRMZGNQILN-BQBZGAKWSA-N Ser-Gly-Met Chemical compound [H]N[C@@H](CO)C(=O)NCC(=O)N[C@@H](CCSC)C(O)=O UAJAYRMZGNQILN-BQBZGAKWSA-N 0.000 description 1
- LWMQRHDTXHQQOV-MXAVVETBSA-N Ser-Ile-Phe Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O LWMQRHDTXHQQOV-MXAVVETBSA-N 0.000 description 1
- GJFYFGOEWLDQGW-GUBZILKMSA-N Ser-Leu-Gln Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)O)NC(=O)[C@H](CO)N GJFYFGOEWLDQGW-GUBZILKMSA-N 0.000 description 1
- KCGIREHVWRXNDH-GARJFASQSA-N Ser-Leu-Pro Chemical compound CC(C)C[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](CO)N KCGIREHVWRXNDH-GARJFASQSA-N 0.000 description 1
- OWCVUSJMEBGMOK-YUMQZZPRSA-N Ser-Lys-Gly Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCCCN)C(=O)NCC(O)=O OWCVUSJMEBGMOK-YUMQZZPRSA-N 0.000 description 1
- NQZFFLBPNDLTPO-DLOVCJGASA-N Ser-Phe-Ala Chemical compound C[C@@H](C(=O)O)NC(=O)[C@H](CC1=CC=CC=C1)NC(=O)[C@H](CO)N NQZFFLBPNDLTPO-DLOVCJGASA-N 0.000 description 1
- UPLYXVPQLJVWMM-KKUMJFAQSA-N Ser-Phe-Leu Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CC(C)C)C(O)=O UPLYXVPQLJVWMM-KKUMJFAQSA-N 0.000 description 1
- NMZXJDSKEGFDLJ-DCAQKATOSA-N Ser-Pro-Lys Chemical compound C1C[C@H](N(C1)C(=O)[C@H](CO)N)C(=O)N[C@@H](CCCCN)C(=O)O NMZXJDSKEGFDLJ-DCAQKATOSA-N 0.000 description 1
- XGQKSRGHEZNWIS-IHRRRGAJSA-N Ser-Pro-Tyr Chemical compound N[C@@H](CO)C(=O)N1CCC[C@H]1C(=O)N[C@@H](Cc1ccc(O)cc1)C(O)=O XGQKSRGHEZNWIS-IHRRRGAJSA-N 0.000 description 1
- BMKNXTJLHFIAAH-CIUDSAMLSA-N Ser-Ser-Leu Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(O)=O BMKNXTJLHFIAAH-CIUDSAMLSA-N 0.000 description 1
- 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
- RXUOAOOZIWABBW-XGEHTFHBSA-N Ser-Thr-Arg Chemical compound OC[C@H](N)C(=O)N[C@@H]([C@H](O)C)C(=O)N[C@H](C(O)=O)CCCN=C(N)N RXUOAOOZIWABBW-XGEHTFHBSA-N 0.000 description 1
- SOACHCFYJMCMHC-BWBBJGPYSA-N Ser-Thr-Cys Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CS)C(=O)O)NC(=O)[C@H](CO)N)O SOACHCFYJMCMHC-BWBBJGPYSA-N 0.000 description 1
- RTXKJFWHEBTABY-IHPCNDPISA-N Ser-Trp-Tyr Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)N[C@@H](CC3=CC=C(C=C3)O)C(=O)O)NC(=O)[C@H](CO)N RTXKJFWHEBTABY-IHPCNDPISA-N 0.000 description 1
- GSCVDSBEYVGMJQ-SRVKXCTJSA-N Ser-Tyr-Asp Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)O)NC(=O)[C@H](CO)N)O GSCVDSBEYVGMJQ-SRVKXCTJSA-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
- PCMZJFMUYWIERL-ZKWXMUAHSA-N Ser-Val-Asn Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(N)=O)C(O)=O PCMZJFMUYWIERL-ZKWXMUAHSA-N 0.000 description 1
- MFQMZDPAZRZAPV-NAKRPEOUSA-N Ser-Val-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)[C@H](C(C)C)NC(=O)[C@H](CO)N MFQMZDPAZRZAPV-NAKRPEOUSA-N 0.000 description 1
- ODRUTDLAONAVDV-IHRRRGAJSA-N Ser-Val-Tyr Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O ODRUTDLAONAVDV-IHRRRGAJSA-N 0.000 description 1
- NHUHCSRWZMLRLA-UHFFFAOYSA-N Sulfisoxazole Chemical compound CC1=NOC(NS(=O)(=O)C=2C=CC(N)=CC=2)=C1C NHUHCSRWZMLRLA-UHFFFAOYSA-N 0.000 description 1
- 230000006052 T cell proliferation Effects 0.000 description 1
- 101710090983 T-cell immunoreceptor with Ig and ITIM domains Proteins 0.000 description 1
- 101710180188 T-lymphocyte activation antigen CD80 Proteins 0.000 description 1
- 102100034924 T-lymphocyte activation antigen CD86 Human genes 0.000 description 1
- KWQBJOUOSNJDRR-XAVMHZPKSA-N Thr-Cys-Pro Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CS)C(=O)N1CCC[C@@H]1C(=O)O)N)O KWQBJOUOSNJDRR-XAVMHZPKSA-N 0.000 description 1
- LAFLAXHTDVNVEL-WDCWCFNPSA-N Thr-Gln-Lys Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H](CCCCN)C(=O)O)N)O LAFLAXHTDVNVEL-WDCWCFNPSA-N 0.000 description 1
- DIPIPFHFLPTCLK-LOKLDPHHSA-N Thr-Gln-Pro Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)N1CCC[C@@H]1C(=O)O)N)O DIPIPFHFLPTCLK-LOKLDPHHSA-N 0.000 description 1
- WPAKPLPGQNUXGN-OSUNSFLBSA-N Thr-Ile-Arg Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O WPAKPLPGQNUXGN-OSUNSFLBSA-N 0.000 description 1
- UYTYTDMCDBPDSC-URLPEUOOSA-N Thr-Ile-Phe Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)O)NC(=O)[C@H]([C@@H](C)O)N UYTYTDMCDBPDSC-URLPEUOOSA-N 0.000 description 1
- HOVLHEKTGVIKAP-WDCWCFNPSA-N Thr-Leu-Gln Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(O)=O HOVLHEKTGVIKAP-WDCWCFNPSA-N 0.000 description 1
- KZSYAEWQMJEGRZ-RHYQMDGZSA-N Thr-Leu-Val Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(O)=O KZSYAEWQMJEGRZ-RHYQMDGZSA-N 0.000 description 1
- CJXURNZYNHCYFD-WDCWCFNPSA-N Thr-Lys-Gln Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(=O)N)C(=O)O)N)O CJXURNZYNHCYFD-WDCWCFNPSA-N 0.000 description 1
- LHNNQVXITHUCAB-QTKMDUPCSA-N Thr-Met-His Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)N)O LHNNQVXITHUCAB-QTKMDUPCSA-N 0.000 description 1
- UXUAZXWKIGPUCH-RCWTZXSCSA-N Thr-Met-Met Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCSC)C(O)=O UXUAZXWKIGPUCH-RCWTZXSCSA-N 0.000 description 1
- HSQXHRIRJSFDOH-URLPEUOOSA-N Thr-Phe-Ile Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O HSQXHRIRJSFDOH-URLPEUOOSA-N 0.000 description 1
- MEBDIIKMUUNBSB-RPTUDFQQSA-N Thr-Phe-Tyr Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O MEBDIIKMUUNBSB-RPTUDFQQSA-N 0.000 description 1
- DEGCBBCMYWNJNA-RHYQMDGZSA-N Thr-Pro-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@@H](N)[C@@H](C)O DEGCBBCMYWNJNA-RHYQMDGZSA-N 0.000 description 1
- 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
- IQPWNQRRAJHOKV-KATARQTJSA-N Thr-Ser-Lys Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@H](C(O)=O)CCCCN IQPWNQRRAJHOKV-KATARQTJSA-N 0.000 description 1
- NDZYTIMDOZMECO-SHGPDSBTSA-N Thr-Thr-Ala Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C)C(O)=O NDZYTIMDOZMECO-SHGPDSBTSA-N 0.000 description 1
- LECUEEHKUFYOOV-ZJDVBMNYSA-N Thr-Thr-Val Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@@H](N)[C@@H](C)O LECUEEHKUFYOOV-ZJDVBMNYSA-N 0.000 description 1
- XVHAUVJXBFGUPC-RPTUDFQQSA-N Thr-Tyr-Phe Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O XVHAUVJXBFGUPC-RPTUDFQQSA-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
- 102000046299 Transforming Growth Factor beta1 Human genes 0.000 description 1
- 101800002279 Transforming growth factor beta-1 Proteins 0.000 description 1
- 102100023935 Transmembrane glycoprotein NMB Human genes 0.000 description 1
- MVHHTXAUJCIOMZ-WDSOQIARSA-N Trp-Arg-Lys Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CCCCN)C(=O)O)N MVHHTXAUJCIOMZ-WDSOQIARSA-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
- MKDXQPMIQPTTAW-SIXJUCDHSA-N Trp-Ile-His Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)NC(=O)[C@H](CC2=CNC3=CC=CC=C32)N MKDXQPMIQPTTAW-SIXJUCDHSA-N 0.000 description 1
- UJRIVCPPPMYCNA-HOCLYGCPSA-N Trp-Leu-Gly Chemical compound CC(C)C[C@@H](C(=O)NCC(=O)O)NC(=O)[C@H](CC1=CNC2=CC=CC=C21)N UJRIVCPPPMYCNA-HOCLYGCPSA-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
- HJWLQSFTGDQSRX-BPUTZDHNSA-N Trp-Met-Ser Chemical compound [H]N[C@@H](CC1=CNC2=C1C=CC=C2)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CO)C(O)=O HJWLQSFTGDQSRX-BPUTZDHNSA-N 0.000 description 1
- WMIUTJPFHMMUGY-ZFWWWQNUSA-N Trp-Pro-Gly Chemical compound C1C[C@H](N(C1)C(=O)[C@H](CC2=CNC3=CC=CC=C32)N)C(=O)NCC(=O)O WMIUTJPFHMMUGY-ZFWWWQNUSA-N 0.000 description 1
- FHHYVSCGOMPLLO-IHPCNDPISA-N Trp-Tyr-Asp Chemical compound C([C@H](NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)N)C(=O)N[C@@H](CC(O)=O)C(O)=O)C1=CC=C(O)C=C1 FHHYVSCGOMPLLO-IHPCNDPISA-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
- UGFOSENEZHEQKX-PJODQICGSA-N Trp-Val-Ala Chemical compound CC(C)[C@H](NC(=O)[C@@H](N)Cc1c[nH]c2ccccc12)C(=O)N[C@@H](C)C(O)=O UGFOSENEZHEQKX-PJODQICGSA-N 0.000 description 1
- VCXWRWYFJLXITF-AUTRQRHGSA-N Tyr-Ala-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 VCXWRWYFJLXITF-AUTRQRHGSA-N 0.000 description 1
- OOEUVMFKKZYSRX-LEWSCRJBSA-N Tyr-Ala-Pro Chemical compound C[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](CC2=CC=C(C=C2)O)N OOEUVMFKKZYSRX-LEWSCRJBSA-N 0.000 description 1
- DXYWRYQRKPIGGU-BPNCWPANSA-N Tyr-Ala-Val Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 DXYWRYQRKPIGGU-BPNCWPANSA-N 0.000 description 1
- XHALUUQSNXSPLP-UFYCRDLUSA-N Tyr-Arg-Phe Chemical compound C([C@H](N)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)C1=CC=C(O)C=C1 XHALUUQSNXSPLP-UFYCRDLUSA-N 0.000 description 1
- FIRUOPRJKCBLST-KKUMJFAQSA-N Tyr-His-Asp Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)N[C@@H](CC2=CN=CN2)C(=O)N[C@@H](CC(=O)O)C(=O)O)N)O FIRUOPRJKCBLST-KKUMJFAQSA-N 0.000 description 1
- STTVVMWQKDOKAM-YESZJQIVSA-N Tyr-His-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CC2=CN=CN2)NC(=O)[C@H](CC3=CC=C(C=C3)O)N)C(=O)O STTVVMWQKDOKAM-YESZJQIVSA-N 0.000 description 1
- YKCXQOBTISTQJD-BZSNNMDCSA-N Tyr-Leu-His Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)NC(=O)[C@H](CC2=CC=C(C=C2)O)N YKCXQOBTISTQJD-BZSNNMDCSA-N 0.000 description 1
- DMWNPLOERDAHSY-MEYUZBJRSA-N Tyr-Leu-Thr Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O DMWNPLOERDAHSY-MEYUZBJRSA-N 0.000 description 1
- 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 1
- KZOZXAYPVKKDIO-UFYCRDLUSA-N Tyr-Met-Tyr Chemical compound C([C@H](N)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(O)=O)C1=CC=C(O)C=C1 KZOZXAYPVKKDIO-UFYCRDLUSA-N 0.000 description 1
- VYQQQIRHIFALGE-UWJYBYFXSA-N Tyr-Ser-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 VYQQQIRHIFALGE-UWJYBYFXSA-N 0.000 description 1
- 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 1
- TYFLVOUZHQUBGM-IHRRRGAJSA-N Tyr-Ser-Val Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 TYFLVOUZHQUBGM-IHRRRGAJSA-N 0.000 description 1
- WQOHKVRQDLNDIL-YJRXYDGGSA-N Tyr-Thr-Ser Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(O)=O WQOHKVRQDLNDIL-YJRXYDGGSA-N 0.000 description 1
- 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 1
- VJOWWOGRNXRQMF-UVBJJODRSA-N Val-Ala-Trp Chemical compound C1=CC=C2C(C[C@H](NC(=O)[C@H](C)NC(=O)[C@@H](N)C(C)C)C(O)=O)=CNC2=C1 VJOWWOGRNXRQMF-UVBJJODRSA-N 0.000 description 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
- YODDULVCGFQRFZ-ZKWXMUAHSA-N Val-Asp-Ser Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(O)=O YODDULVCGFQRFZ-ZKWXMUAHSA-N 0.000 description 1
- COSLEEOIYRPTHD-YDHLFZDLSA-N Val-Asp-Tyr Chemical compound CC(C)[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 COSLEEOIYRPTHD-YDHLFZDLSA-N 0.000 description 1
- ZEVNVXYRZRIRCH-GVXVVHGQSA-N Val-Gln-Lys Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H](CCCCN)C(=O)O)N ZEVNVXYRZRIRCH-GVXVVHGQSA-N 0.000 description 1
- AAOPYWQQBXHINJ-DZKIICNBSA-N Val-Gln-Tyr Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H](CC1=CC=C(C=C1)O)C(=O)O)N AAOPYWQQBXHINJ-DZKIICNBSA-N 0.000 description 1
- MHAHQDBEIDPFQS-NHCYSSNCSA-N Val-Glu-Met Chemical compound CSCC[C@@H](C(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](N)C(C)C MHAHQDBEIDPFQS-NHCYSSNCSA-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
- PIFJAFRUVWZRKR-QMMMGPOBSA-N Val-Gly-Gly Chemical compound CC(C)[C@H]([NH3+])C(=O)NCC(=O)NCC([O-])=O PIFJAFRUVWZRKR-QMMMGPOBSA-N 0.000 description 1
- LAYSXAOGWHKNED-XPUUQOCRSA-N Val-Gly-Ser Chemical compound CC(C)[C@H](N)C(=O)NCC(=O)N[C@@H](CO)C(O)=O LAYSXAOGWHKNED-XPUUQOCRSA-N 0.000 description 1
- KZKMBGXCNLPYKD-YEPSODPASA-N Val-Gly-Thr Chemical compound CC(C)[C@H](N)C(=O)NCC(=O)N[C@@H]([C@@H](C)O)C(O)=O KZKMBGXCNLPYKD-YEPSODPASA-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
- DIOSYUIWOQCXNR-ONGXEEELSA-N Val-Lys-Gly Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](CCCCN)C(=O)NCC(O)=O DIOSYUIWOQCXNR-ONGXEEELSA-N 0.000 description 1
- PHZGFLFMGLXCFG-FHWLQOOXSA-N Val-Lys-Trp Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC1=CNC2=CC=CC=C21)C(=O)O)N PHZGFLFMGLXCFG-FHWLQOOXSA-N 0.000 description 1
- OFQGGTGZTOTLGH-NHCYSSNCSA-N Val-Met-Gln Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCC(=O)N)C(=O)O)N OFQGGTGZTOTLGH-NHCYSSNCSA-N 0.000 description 1
- 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 1
- 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 1
- 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 1
- JAIZPWVHPQRYOU-ZJDVBMNYSA-N Val-Thr-Thr Chemical compound C[C@H]([C@@H](C(=O)N[C@@H]([C@@H](C)O)C(=O)O)NC(=O)[C@H](C(C)C)N)O JAIZPWVHPQRYOU-ZJDVBMNYSA-N 0.000 description 1
- BGTDGENDNWGMDQ-KJEVXHAQSA-N Val-Tyr-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CC1=CC=C(C=C1)O)NC(=O)[C@H](C(C)C)N)O BGTDGENDNWGMDQ-KJEVXHAQSA-N 0.000 description 1
- 238000001261 affinity purification Methods 0.000 description 1
- 230000001270 agonistic effect Effects 0.000 description 1
- 108010076324 alanyl-glycyl-glycine Proteins 0.000 description 1
- 125000000539 amino acid group Chemical group 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 235000021120 animal protein Nutrition 0.000 description 1
- 229940125644 antibody drug Drugs 0.000 description 1
- 229940124691 antibody therapeutics Drugs 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 108010001271 arginyl-glutamyl-arginine Proteins 0.000 description 1
- 108010093581 aspartyl-proline Proteins 0.000 description 1
- 230000001363 autoimmune Effects 0.000 description 1
- 210000003719 b-lymphocyte Anatomy 0.000 description 1
- 239000011324 bead Substances 0.000 description 1
- 230000001588 bifunctional effect Effects 0.000 description 1
- 238000005842 biochemical reaction Methods 0.000 description 1
- 229940088623 biologically active substance Drugs 0.000 description 1
- 229940101815 blincyto Drugs 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 230000000711 cancerogenic effect Effects 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 231100000315 carcinogenic Toxicity 0.000 description 1
- 230000020411 cell activation Effects 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 230000022534 cell killing Effects 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 230000019522 cellular metabolic process Effects 0.000 description 1
- 230000036755 cellular response Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 229940000425 combination drug Drugs 0.000 description 1
- 230000000295 complement effect Effects 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 238000012136 culture method Methods 0.000 description 1
- 206010052015 cytokine release syndrome Diseases 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 125000001295 dansyl group Chemical group [H]C1=C([H])C(N(C([H])([H])[H])C([H])([H])[H])=C2C([H])=C([H])C([H])=C(C2=C1[H])S(*)(=O)=O 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 230000005750 disease progression Effects 0.000 description 1
- 230000002222 downregulating effect Effects 0.000 description 1
- 235000013399 edible fruits Nutrition 0.000 description 1
- 230000012202 endocytosis Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 229960000301 factor viii Drugs 0.000 description 1
- 210000003194 forelimb Anatomy 0.000 description 1
- 108010078144 glutaminyl-glycine Proteins 0.000 description 1
- VPZXBVLAVMBEQI-UHFFFAOYSA-N glycyl-DL-alpha-alanine Natural products OC(=O)C(C)NC(=O)CN VPZXBVLAVMBEQI-UHFFFAOYSA-N 0.000 description 1
- XBGGUPMXALFZOT-UHFFFAOYSA-N glycyl-L-tyrosine hemihydrate Natural products NCC(=O)NC(C(O)=O)CC1=CC=C(O)C=C1 XBGGUPMXALFZOT-UHFFFAOYSA-N 0.000 description 1
- 108010075431 glycyl-alanyl-phenylalanine Proteins 0.000 description 1
- 108010010096 glycyl-glycyl-tyrosine Proteins 0.000 description 1
- 108010078326 glycyl-glycyl-valine Proteins 0.000 description 1
- 108010087823 glycyltyrosine Proteins 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 238000005734 heterodimerization reaction Methods 0.000 description 1
- 108010085325 histidylproline Proteins 0.000 description 1
- 102000048776 human CD274 Human genes 0.000 description 1
- 102000048362 human PDCD1 Human genes 0.000 description 1
- 230000028996 humoral immune response Effects 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 239000012642 immune effector Substances 0.000 description 1
- 230000028993 immune response Effects 0.000 description 1
- 210000000987 immune system Anatomy 0.000 description 1
- 230000005847 immunogenicity Effects 0.000 description 1
- 230000016784 immunoglobulin production Effects 0.000 description 1
- 229940072221 immunoglobulins Drugs 0.000 description 1
- 229940121354 immunomodulator Drugs 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 230000005732 intercellular adhesion Effects 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 108010031424 isoleucyl-prolyl-proline Proteins 0.000 description 1
- 108010076756 leucyl-alanyl-phenylalanine Proteins 0.000 description 1
- 108010012058 leucyltyrosine Proteins 0.000 description 1
- 230000004001 molecular interaction Effects 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 230000008450 motivation Effects 0.000 description 1
- 108010068617 neonatal Fc receptor Proteins 0.000 description 1
- 108020004017 nuclear receptors Proteins 0.000 description 1
- 238000001543 one-way ANOVA Methods 0.000 description 1
- 230000002018 overexpression Effects 0.000 description 1
- 230000008506 pathogenesis Effects 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 108010024607 phenylalanylalanine Proteins 0.000 description 1
- 108010073101 phenylalanylleucine Proteins 0.000 description 1
- 239000013612 plasmid Substances 0.000 description 1
- 238000006116 polymerization reaction Methods 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 208000017426 precursor B-cell acute lymphoblastic leukemia Diseases 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000033998 protein modification process Effects 0.000 description 1
- 230000005180 public health Effects 0.000 description 1
- 230000035802 rapid maturation Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000018448 secretion by cell Effects 0.000 description 1
- 238000011272 standard treatment Methods 0.000 description 1
- 210000000130 stem cell Anatomy 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 239000000021 stimulant Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 229940126622 therapeutic monoclonal antibody Drugs 0.000 description 1
- 239000012096 transfection reagent Substances 0.000 description 1
- 238000011830 transgenic mouse model Methods 0.000 description 1
- 108091007466 transmembrane glycoproteins Proteins 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- 108700004896 tripeptide FEG Proteins 0.000 description 1
- 108010017949 tyrosyl-glycyl-glycine Proteins 0.000 description 1
- 230000003827 upregulation Effects 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
- C07K16/2818—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against CD28 or CD152
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
- C07K16/2827—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against B7 molecules, e.g. CD80, CD86
-
- 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
- C07K16/2851—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the lectin superfamily, e.g. CD23, CD72
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/2863—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against receptors for growth factors, growth regulators
-
- 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
- C07K16/2896—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against molecules with a "CD"-designation, not provided for elsewhere
-
- 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
- C07K16/32—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against translation products of oncogenes
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K19/00—Hybrid peptides, i.e. peptides covalently bound to nucleic acids, or non-covalently bound protein-protein complexes
-
- 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
- C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
- C12N15/62—DNA sequences coding for fusion proteins
-
- 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
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
- G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/545—Medicinal preparations containing antigens or antibodies characterised by the dose, timing or administration schedule
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
- C07K2317/31—Immunoglobulins specific features characterized by aspects of specificity or valency multispecific
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/40—Immunoglobulins specific features characterized by post-translational modification
- C07K2317/41—Glycosylation, sialylation, or fucosylation
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/52—Constant or Fc region; Isotype
- C07K2317/53—Hinge
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/55—Fab or Fab'
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
- C07K2317/92—Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2319/00—Fusion polypeptide
- C07K2319/32—Fusion polypeptide fusions with soluble part of a cell surface receptor, "decoy receptors"
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2319/00—Fusion polypeptide
- C07K2319/70—Fusion polypeptide containing domain for protein-protein interaction
- C07K2319/74—Fusion polypeptide containing domain for protein-protein interaction containing a fusion for binding to a cell surface receptor
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
- G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
- G01N2333/705—Assays involving receptors, cell surface antigens or cell surface determinants
- G01N2333/70503—Immunoglobulin superfamily, e.g. VCAMs, PECAM, LFA-3
- G01N2333/70532—B7 molecules, e.g. CD80, CD86
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Immunology (AREA)
- Organic Chemistry (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- General Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Biochemistry (AREA)
- Medicinal Chemistry (AREA)
- Biophysics (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Biomedical Technology (AREA)
- Biotechnology (AREA)
- Zoology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Engineering & Computer Science (AREA)
- Urology & Nephrology (AREA)
- Wood Science & Technology (AREA)
- Physics & Mathematics (AREA)
- Hematology (AREA)
- Microbiology (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- Plant Pathology (AREA)
- Cell Biology (AREA)
- General Chemical & Material Sciences (AREA)
- Pathology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Physics & Mathematics (AREA)
- Oncology (AREA)
- Analytical Chemistry (AREA)
- Food Science & Technology (AREA)
- Hospice & Palliative Care (AREA)
- Gastroenterology & Hepatology (AREA)
- Epidemiology (AREA)
Abstract
신규한 구조를 갖는 이중특이성 융합 단백질을 제공한다. 제2결합 구조 도메인은 임의의 펩타이드 조인트에 의해 전체 길이(full length)로 IgG 힌지 영역에 삽입된다. 상기 융합 단백질은 IgG와 동일한 발현 및 생산 이점을 가지며, 융합 단백질의 Fab 영역의 결합 활성에 영향을 미치지 않아 안정성을 더욱 향상시키고 더 높은 반감기를 얻을 수 있다. 또한, 제2 결합 구조 도메인의 표적 결합 부위에 대한 결합 활성은, 가용성 천연 결합 단편에 상응하는 표적에 대한 단량체의 결합 활성에 비해 현저히 개선되었다.
Description
본 발명은 신규한 구조를 갖는 이중특이성 융합 단백질 및 이의 응용에 관한 것이다. 본 발명은 또한 폴리뉴클레오티드, 핵산 구조체 및 상기 융합 단백질을 코딩하거나 제조하는 숙주 세포에 관한 것이다.
생명공학의 발달로 항체는 성숙한 치료제로서 종양 및 면역질환의 치료에 중요한 역할을 하고 있다. 현재 시중에 나와 있는 대부분의 항체 약물은 단일 항원을 표적으로 하며 하나의 표적 분자에만 작용할 수 있다. 그러나, 자연에서의 복잡한 질병들은 종종 다양한 인자에 의하며, 질병 매개체의 과발현이나 시너지 효과, 또는 신호 전달 네트워크의 분자 상호 작용을 포함한 다양한 수용체의 상향 조절이 수반된다. 따라서 다중 신호 경로를 조절하면 치료 항체의 효능이 향상될 수 있다. 이중 표적화 전략을 사용한 이중특이성 항체(BsAb) 요법은 종양 및 면역 질환에 대한 효과적인 치료법 중 하나가 되었다 (Kontermann R. Dual targeting strategies with bispecific antibodies [C]//MAbs. Taylor & Francis, 2012, 4(2): 182-197.).
이중특이성 항체는 2개의 상이한 항원 또는 에피토프에 특이적으로 결합할 수 있다 (Carter P. Bispecific human IgG by design [J]. Journal of immunological methods, 2001, 248(1-2): 7-15). 1980년대에 Morrison 등은 융합 발현을 위한 유연한 펩타이드를 사용하여 다른 특이성을 가진 단일 사슬 항체를 연결하여 dextran 및 dansyl 그룹에 대한 최초의 진정한 4가 이중특이성 항체를 제조했다 (Coloma M J, Morrison S L. Design and production of novel tetravalent bispecific antibodies [J]. Nature biotechnology, 1997, 15(2): 159.). 그러나 항체 제조 기술의 병목 현상과 신호 경로에 대한 기초 연구 부족으로 이중특이성 항체의 개발에 차질을 빚고 있다. 질병의 발병기전에 대한 깊은 이해와 치료적 단일클론항체(McAbs) 관련 기술의 급속한 발전으로, 항체의 구성, 발현 및 정제 기술이 크게 향상되어, 이중특이성 항체의 개발에서 제한 요소들을 극복할 수 있는 기술과 동기를 갖도록 하고 있다. 현재 이중특이성 또는 다중특이성 항체의 기작은 주로 다음과 같다: (1) 가교 세포(in trans); (2) 수용체 억제(in-cis) 또는 수용체 활성화(in-cis); (3) 보조 인자 모방체; (4) PIgGyback 접근법 (Aran F. Labrijn, et al. Bispecific antibodies: a mechanistic review of the pipeline, Nature Reviews Drug Discovery volume 18, pages 585-608(2019)).
이중특이성 항체의 개발에 있어서 분자구조의 선택은 매우 중요하다. 이중특이성 항체 설계는 각기 장단점이 있지만 임상 치료 목적을 위한 이중특이성 항체 설계는 다음과 같은 문제를 해결해야 한다. 첫째, 서로 다른 경쇄와 중쇄의 두 쌍(또는 그 이상)의 올바른 커플링 또는 짝지음이 보장되어야 한다. 둘째, 각 단일클론항체의 각 결합도메인의 독립성을 유지하며, 서로 다른 에피토프를 동시에 결합할 경우 입체간섭이 일어나지 않아야 한다. 셋째, 항체 분자는 복잡한 단백질 변형 과정 없이 포유동물 세포에서 발현하기 쉬워야 한다. 넷째, 높은 열 안정성, 높은 화학적 안정성, 높은 용해도, 중합의 비 용이성, 낮은 점도, 높은 발현성, 적절한 반감기 등과 같은 우수한 약물성 등이 요구된다 (Spiess C, Zhai Q, Carter P J. Alternative molecular formats and therapeutic applications for bispecific antibodies [J]. Molecular immunology, 2015, 67(2): 95-106.).
상이한 분자 구조 형태(즉, 성분 및 구성 방법)에 따라, 이중특이성 항체는 많은 유형으로 나눌 수 있다. 예를 들어, 구조의 좌우 대칭에 따라 대칭 구조와 비대칭 구조로 나뉘고, Fc영역(Fc region)의 유무에 따라 Fc영역을 포함하는 이중특이성 항체와 Fc영역이 없는 이중특이성 항체로 나눌 수 있고, 항원 결합 영역의 수에 따라 2가, 3가, 4가 또는 다가 배열로 나뉘는 등과 같이 분류된다. 현재, 이중특이성 항체는 수십 개의 구조가 개발되었으며 (Spiess C, Zhai Q, Carter P J. Alternative molecule functions and therapy for bispecific antibody [J]. Molecular immunology, 2015, 67(2): 95-106.), 이러한 이중특이성 항체는 다양한 구조를 가지며 대략 5가지 범주로 나뉜다: IgG-유사 이중특이성 항체, 추가 기능 영역을 갖는 IgG-유사 이중특이성 항체, 직렬로 연결된 상이한 항원-결합 단편을 갖는 이중특이성 항체, 융합 단백질-유형 이중특이성 항체 및 화학적으로 결합된 이중특이성 항체. 그 중 IgG-유사 이중특이성 항체의 구성은 주로 구조적 변형을 위한 재조합 DNA 기술을 사용한다. 제조된 IgG 유사 이중특이성 항체는 완전 결정화 가능한 단편(즉, Fc 단편)을 가지므로 Fc 단편 매개 ADCC(항체 의존성 세포 매개 세포독성) 및 CDC(보체 매개 세포독성, 보체 의존성 세포독성) 등을 유지하면서 다른 항원에 결합할 수 있다. 동시에, 이러한 유형의 항체는 또한 신생아 Fc 수용체(FcRn)에 결합하여 항체의 생체내 반감기를 연장하는 특징을 유지한다 (Ridgway J B B, Presta L G, Carter P. 'Knobs-into-holes' engineering of antibody CH3 domains for heavy chain heterodimerization [J]. Protein Engineering, Design and Selection, 1996, 9(7): 617-621.); 추가 기능 영역이 있는 IgG 유사 이중특이성 항체는 일반적으로 기존의 IgG 항체를 기반으로 하며 융합 단백질을 통해 중쇄 및/또는 경쇄에 다른 특정 항원 결합 단편(즉, 단일 도메인 항체, 단일 사슬 항체 등과 같은 추가 기능 영역)을 추가하여 생성된다(LaFleur D, Abramyan D, Kanakaraj P, et al. Monoclonal antibody therapeutics with up to five specificities: functional enhancement through fusion of target-specific peptides [C]//MAbs. Taylor & Francis, 2013, 5(2): 208-218.); 서로 다른 항원 결합 단편이 직렬로 연결된 이중특이성 항체는 특정 서열의 서로 다른 Fab, 단일 사슬 항체, 단일 도메인 항체 또는 항원 결합 단편을 연결 펩타이드를 통해 연결하여 얻는다 (Stork R, Muller D, Kontermann R E. A novel tri-functional antibody fusion protein with improved pharmacokinetic properties generated by fusing a bispecific single-chain diabody with an albumin-binding domain from streptococcal protein G [J]. Protein Engineering, Design & Selection, 2007, 20(11): 569-576.); 융합 단백질형 이중특이성 항체는 2개 이상의 항원에 동시에 결합할 수 있는 단백질 분자로, 폴리펩타이드 단편과 같은 링커를 통해 특이성이 다른 항체/항체 단편(IgG, Fab, scFv, 등)을 연결함으로써 형성되고; 그리고 화학적으로 결합된 이중특이성 항체는 융합 단백질형 이중특이성 항체와 유사하지만, 화학적으로 결합된 이중특이성 항체의 경우 먼저 두 개의 항체/항체 단편을 별도로 준비해야 하며, 그 다음 이 두 항체는 화학 결합을 통해 결합되거나 두 항체 모두 운반체 단백질에 결합된다.
또한, 신호경로에 대한 기초연구의 발달과 이중항체 기전의 확장으로 이중특이성 항체 선택을 위한 표적 및 조합이 점점 더 많아지고 있으며, PD-1, PD-L1, CTLA-4, LAG-3, FGL1, TIM-3, 갈렉틴-9, TIGIT, CD155 및 TGF-β 수용체(TGF-βR), CD80, CD86, VEGFR, VEGF-트랩, FGL1, CD70, 4-1BBL, OX40L 및 SIRPα; 및 Claudin 18.2, HER-2, 메소테린(Mesothelin), BCMA, SSTR2, GPRC5D, PSMA, FCRH5, CD33, CD123, CD20, A33, CEA, CD28, DLL3, EGFR, VEGFR, VEGFR2, VEGF-A, Nectin-4, FGFR, C-met, RANKL, PDGF, PDGFR, PDGFRα, DLL4, Ang-1 및 Ang-2 등을 포함한 종양 항원 등이 있다. 면역 관문 표적 또는 종양 표적을 암세포의 발달 저항 또는 T-세포 활성화와 관련된 다른 표적과 조합하거나, 또는 다중 면역 관문 표적의 조합은, 종양과 같은 악성 질환의 치료 가능성을 크게 향상시킨다. 초기 단계에서는 두 개의 개별 체크포인트 항체의 조합을 임상적으로 사용하여 효능을 개선했다. 예를 들어, 이필리무맙 단독 치료와 비교하여 이필리무맙(항-CTLA4)과 니볼루맙(항-PD1)의 병용 치료는 흑색종 환자의 생존율을 향상시킬 수 있다. 현재 4개의 PD-1xCTLA4 bsAbs의 안전성과 초기 효능은 초기 임상 시험에서 평가되고 있다. 두 개의 면역 관문을 차단하는 억제제의 개념은 PD-1 x LAG 3, PD-1 x TIM3 및 PD-L1 x CTLA 4와 같은 다른 표적 조합에도 임상적으로 사용된다 (Wolchok, J. D. et al. Overall Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma, N.Engl. J. Med. 377(14): 1345-1356, (2017); Dovedi, S. J. et al. MEDI5752: A novel bispecific antibody that preferentially targets CTLA-4 on PD-1 expressing T-cells. Cancer Res.78(13), Supplement.Abstract 2776: (2018). Hedvat, M. et al. Simultaneous checkpoint ―checkpoint or checkpoint ― costimulatory receptortargeting with bispecific antibodies promotes enhanced human T cell activation [abstract P664]. Presented at the 2018 Society for Immunotherapyof Cancer (SITC) (2018); Aran F. Labrijn, et al. Bispecific antibodies: a mechanistic review of the pipeline, Nature Reviews Drug Discovery volume 18, pages 585-608(2019).
현재 이중특이성 항체의 대부분은 아직 임상 또는 전임상 연구 단계에 있으며, 현재 시판 허가를 받은 이중특이성 항체는 3개에 불과하다. 이들은 Trion Pharma의 카투막소맙 (Catumaxomab)(2017년 상업적 요인으로 인해 판매중지), Amgen의 블리나투모맙(Blinatumomab) 및 Roche의 에미시주맙(Emicizumab)이다. 카투막소맙은 Triomab 형태의 IgG 유사 이중특이성 항체이다. 이는 상피 세포 부착 분자(EpCAM)가 과발현되는 T 세포 및 종양 세포를 표적으로 하고, T 세포 활성화, 항체 의존성 세포 매개 세포독성(ADCC) 및 보체 의존성 세포독성(CDC)을 통해 종양 세포를 억제한다. 이는 2009년 EMA로부터 표준 치료에 효과가 없거나 실행 불가능한 EpCAM 양성 종양으로 인한 악성 복수(ascites)의 치료제로 승인되었으며, 시판 승인을 받은 최초의 이중특이성 항체이기도 하다. 블리나투모맙은 Fc 영역이 없는 이중특이성 항체로 BiTE(이중특이성 T 세포 인게이저)의 구조 형태를 채택한다. 블리나투모맙은 항-CD3 부분을 통해 T 세포에 결합하고, 항-CD19 부분을 통해 악성 및 정상 B 세포에 결합하여 T 세포 매개 종양 세포 사멸 효과를 유도한다. 2014년에는 블리나투모맙이 필라델피아 염색체 음성 전구체 B 세포 급성 림프모구성 백혈병 치료제로 FDA 승인을 받았다. 에미시주맙은 인자 IXa 및 인자 X에 결합할 수 있는 변형된 인간화 이중특이성 IgG4 단일클론 항체다. 이 항체는 Fc 디자인을 위한 "Knobs-into-Holes(KiH)", LC 디자인을 위한 "Common Light Chain-IgG(CLC-IgG)", 가변 영역 최적화를 위한 "Multidimensional Optimization"을 채택하여, 인자 VIII 억제제의 존재하 혈우병 A의 일상 예방을 위해 2017년 FDA 승인을 받았다.
이중특이성 항체 | 상표명 | 연구 기관 | 최초 승인 연도 |
카투막소맙 | Removab | Trion Pharma | 2009 (EMA) (2017년 판매중지(delisted)) |
블리나투모맙 | Blincyto | Amgen | 2014 (FDA) |
에미시주맙 | Hemlibra | Roche | 2017 (FDA) |
현재 수십 개의 이중특이성 항체/플랫폼과 3개의 시판 의약품에 대한 연구개발 경험이 있지만, 이중특이성 항체의 개발은 복잡한 구조와 다양한 기능적 특성으로 인해 일반 항체에 비해 더 많은 문제점과 과제가 있다. 예를 들어, IgG 유사 이중특이성 항체는 제조 과정에서 중쇄-중쇄 또는 중쇄-경쇄의 불일치 문제에 직면하며, 그 중 가장 대표적인 것이 카투막소맙이다. 카투막소맙은 시판 허가를 받은 최초의 이중특이성 항체이지만, 트리오맙 항체의 복잡한 생산 과정과 이종 항체가 상대적으로 출현하기 쉽다는 면역원성 문제에 주로 반영되는 몇 가지 매우 명백한 한계가 있으며, 2017년에 출시되었으나 상업적 요인으로 인해 판매 중지되었다; 다른 예를 들어, 직렬로 연결된 상이한 항원 결합 단편을 갖는 이중특이성 항체는 불변 영역의 결여, 특히 Fc 단편의 결여로 인해 짧은 반감기를 가지며, 발현 수준 및 발현 후 세포 내 안정성은 일반적으로 종래의 IgG보다 낮다 (Stork R, Mller D, Kontermann R E. A novel tri-functional antibody fusion protein with improved pharmacokinetic properties generated by fusing a bispecific single-chain diabody with an albumin-binding domain from streptococcal protein G [J]. Protein Engineering, Design & Selection, 2007, 20(11): 569-576.). 또한, 이러한 유형의 항체는 대부분 정제 과정에서 친화성 정제 수단(affinity purification means)을 채택하기 어렵기 때문에 정제 과정 및 완제품 내 불순물 분석도 기존의 IgG에 비해 복잡하며(Tan P H, Sandmaier B M, Stayton P S. Contributions of a highly conserved VH/VL hydrogen bonding interaction to scFv folding stability and refolding efficiency [J]. Biophysical journal, 1998, 75(3): 1473-1482.), 그 중 가장 대표적인 것이 블리나투모맙이다. 블리나투모맙은 Fc 단편이 없기 때문에 분자량이 작고, 혈액 내 반감기가 1.25±0.63h에 불과하여 온전한 항체의 반감기보다 훨씬 짧으므로, 유효량에 도달하기 위해서는 4주간의 지속적인 정맥 주사가 필요하며, 시약 사용 시에는 추가로 지속적인 주입 장치를 갖추어야 한다. 또한, 안정성이 좋지 않고 생산 중 응집체를 쉽게 형성하여 제품의 품질에 영향을 미치고 생산 비용을 증가시킨다. 현재 이중특이성 항체는 단일클론항체에 비해 낮은 발현, 낮은 안정성, 복잡한 생산공정, 현저히 높은 연구개발비 등 많은 문제점을 가지고 있어 이중특이성 항체의 개발을 제한하고 있다. 따라서 더 많은 임상 옵션을 제공할 수 있는 새로운 구조의 이중특이성 항체 개발이 시급하다.
상기와 같은 문제점을 해결하기 위해, 본 발명은 부가적인 기능 영역을 갖는 IgG 유사 이중특이성 융합 단백질에 속하는 신규한 구조의 이중특이성 융합 단백질을 제공한다.
상기와 같은 문제점을 해결하기 위해, 본 발명은 부가적인 기능 영역을 갖는 IgG 유사 이중특이성 융합 단백질에 속하는 신규한 구조의 이중특이성 융합 단백질을 제공한다. 구체적으로, 상기 융합 단백질은 전체 길이(전장)(full-length) 면역글로불린 G(IgG)의 힌지 영역에 임의의 펩타이드 링커를 통해 제2 결합 도메인(second binding domain)이 삽입된 구조를 갖고, IgG의 Fab 영역은 융합 단백질의 제1 결합 도메인(first binding domain)이며; 제2 결합 도메인을 삽입한 후, IgG의 중쇄는 융합 단백질의 중쇄이고, IgG의 경쇄는 융합 단백질의 경쇄이고; 제2 결합 도메인은 인간 수용체 또는 리간드(receptor or ligand), 수용체 또는 리간드의 세포외 영역 단편, 결합 도메인 단편, 및 수용체 또는 리간드의 단편 조합으로부터 선택되고; 여기서 수용체 또는 리간드는 자연 신호전달 경로에서 이량체화 또는 다량체화 구조를 형성하여 신호전달 경로를 활성화 또는 억제하고, 제2 결합 도메인 및 제1 결합 도메인은 상이한 표적을 표적화한다. 위와 같은 구조의 이중특이성 융합단백질을 하이바디(Hibody)(Hinge-insertion bispecific antibody) 구조의 융합단백질로 명명하였다 (이하 하이바디 구조 융합 단백질 또는 하이바디라 함).
또한, 제1 결합 도메인은 면역 관문 분자 또는 종양 항원을 표적으로 하여 결합한다.
또한, 면역 관문 분자는 PD-1(프로그램된 세포 사멸 단백질 1), PD-L1(프로그램된 세포 사멸 1 리간드 1), CTLA-4(세포독성 T 림프구 관련 항원-4), LAG-3 (림프구 활성화 유전자-3), FGL1(피브리노겐 유사 단백질 1), TIM-3(T 세포 면역글로불린-3), 갈렉틴-9, TIGIT(Ig 및 ITIM 도메인을 갖는 T 세포 면역수용체), CD155, CD47; Claudin 18.2, Her-2(인간 표피 성장 인자 수용체-2), Mesothelin, BCMA(B 세포 성숙 항원), SSTR2(소마토스타틴 수용체 2), GPRC5D(G-단백질 결합 수용체 패밀리 C 그룹 5 구성원 D), PSMA(전립선 특이적 막 항원), FcRH5(Fc 수용체 유사 단백질 5), CD33, CD123, CD20, A33, CEA(암배아 항원), CD28, DLL3(델타 유사 단백질 3), EGFR(표피 성장 인자 수용체), VEGFR(혈관 내피 성장 인자 수용체), VEGFR2(혈관 내피 성장 인자 수용체 2), VEGF-A(혈관 내피 성장 인자-A), Nectin-4, FGFR(섬유아세포 성장 인자 수용체), C-met , RANKL(핵인자 카파-B 리간드의 수용체 활성제), PDGF(혈소판 유래 성장 인자), PDGFR(혈소판 유래 성장 인자 수용체), PDGFRα(혈소판 유래 성장 인자 수용체 α), DLL4(델타 유사 리간드 4), Ang-1(안지오포이에틴-1) 및 Ang-2(안지오포이에틴-2)을 포함하는 종양 항원을 포함한다.
또한, 제2 결합 도메인은 인간 TGF-β(변형 성장 인자-β), CTLA-4, VEGF, LAG3, CD27, 4-1BB(CD137), OX40(CD134), CD47, FGL1(피브리노겐 유사 단백질 1), TLT-2(Trem-유사 전사체 2), CD28, HGF(간세포 성장 인자), CSF1(집락 자극 인자 1), CXCL1(CXC 케모카인 리간드 1), CXCL2(CXC 케모카인 리간드 2), CXCL3(CXC 케모카인 리간드 3), CXCL5(CXC 케모카인 리간드 5), CXCL6(CXC 케모카인 리간드 6), CXCL7(CXC 케모카인 리간드 7), CXCL8(CXC 케모카인 리간드 8), CXCL9(CXC 케모카인 리간드 9), CXCL10(CXC 케모카인 리간드 10), CXCCL12 (CXC 케모카인 리간드 12), GITR(글루코코르티코이드 유발 종양 괴사 인자 수용체), EGF(표피 성장 인자) 및 ICOSL(유도성 공동 자극제 리간드)를 표적으로 하여 결합한다.
또한, 상기 수용체 또는 리간드는 인간 TGF-β 수용체(TGF-βR), CD80, CD86, VEGFR, VEGF-트랩, FGL1, CD70, 4-1BBL, OX40L, SIRPα(신호 조절 단백질 α), B7-H3(CD276), C-met, CSF1R(집락 자극 인자 1 수용체), CXCR2(CXC 케모카인 수용체 2), CXCR3(CXC 케모카인 수용체 3), CXCR4(CXC 케모카인 수용체 4), GITRL(글루코코르티코이드 유도 TNF 수용체 리간드), EGFR 및 ICOS(유도성 공동 자극제)이다.
이 중 CD80 및 CD86은 면역글로불린 슈퍼패밀리(IgSF)의 구성원인 막관통 당단백질이다. 성숙한 CD80 분자는 세포외 도메인(ECD)의 208개 아미노산, 막횡단 도메인의 25개 아미노산, 세포내 도메인의 21개 아미노산을 포함하여 254개 아미노산으로 구성된다. 유사하게, 성숙한 CD86 분자는 세포외 도메인의 222개 아미노산, 막횡단 도메인의 20개 아미노산, 세포내 도메인의 61개 아미노산을 포함하여 303개의 아미노산으로 구성된다. CD80 및 CD86의 세포외 도메인은 면역글로불린 V(IgV) 및 면역글로불린 C(IgC) 영역을 포함한다. CD80 및 CD86은 면역글로불린 V(IgV) 영역을 통해 리간드 CD28 및 CTLA-4에 결합한다.. CD28에 결합하는 CD80 및 CD86의 경우, CD80 및 CD86은 항원 유도 T 세포 활성화, 증식 및 조절자 기능 생성에 중요한 조절 효과를 가지며 양성 조절자로서 작용하고, 반면 CD80 및 CD86이 CTLA-4에 결합하는 경우 CD80 및 CD86은 면역 반응을 하향 조절하여 음성 조절자 역할을 한다. 따라서 CD80과 CD86은 T림프구가 활성화될 때 공동자극인자로서 자가면역 모니터링, 체액성 면역반응 및 이식반응에 중요한 역할을 한다. 작용성(agonistic) 항-CD28 항체를 사용하여 T 세포를 활성화하는 것과 달리 CD28의 리간드 CD80을 활성화 인자로 사용하여 T 세포를 활성화하면 심각한 사이토카인 폭풍을 일으키지 않아 환자의 생명을 위험에 빠뜨릴 가능성이 크게 줄어든다.
일부 실시양태에서, CD80 ECD는 인간 CD80(예: 서열번호 134의 인간 CD80) 또는 CD80 이소형 2 또는 이소형 3(서열번호 135 및 136)으로부터 유래된 인간 CD80 ECD로부터 선택된다. CD80 ECD는 CD80 면역글로불린 V(IgV) 영역(CD80-IgV, 서열번호 133)을 포함한다. 한 실시양태에서, CD80 ECD는 인간 CD80 면역글로불린 V 영역 및 C 영역(CD80-IgVIgC, 서열번호 32)을 포함한다. 한 실시양태에서, CD80 ECD는 인간 CD80 ECD이다. 한 실시양태에서, CD80 ECD는 인간 CD80 IgV를 포함한다.
CD80-IgV (서열번호 133):
VIHVTKEVKE VATLSCGHNV SVEELAQTRI YWQKEKKMVL TMMSGDMNIW PEYKNRTIFD 60
ITNNLSIVIL ALRPSDEGTY ECVVLKYEKD AFKREHLAEV TLSVKADFPT PS 112
CD80-IgVIgC (서열번호 32):
VIHVTKEVKE VATLSCGHNV SVEELAQTRI YWQKEKKMVL TMMSGDMNIW PEYKNRTIFD 60
ITNNLSIVIL ALRPSDEGTY ECVVLKYEKD AFKREHLAEV TLSVKADFPT PSISDFEIPT 120
SNIRRIICST SGGFPEPHLS WLENGEELNA INTTVSQDPE TELYAVSSKL DFNMTTNHSF 180
MCLIKYGHLR VNQTFNWN 198
CD80 isotype 1 (서열번호 134):
MGHTRRQGTS PSKCPYLNFF QLLVLAGLSH FCSGVIHVTK EVKEVATLSC GHNVSVEELA 60
QTRIYWQKEK KMVLTMMSGD MNIWPEYKNR TIFDITNNLS IVILALRPSD EGTYECVVLK 120
YEKDAFKREH LAEVTLSVKA DFPTPSISDF EIPTSNIRRI ICSTSGGFPE PHLSWLENGE 180
ELNAINTTVS QDPETELYAV SSKLDFNMTT NHSFMCLIKY GHLRVNQTFN WNTTKQEHFP 240
DNLLPSWAIT LISVNGIFVI CCLTYCFAPR CRERRRNERL RRESVRPV 288
CD80 isotype 2 (서열번호 135):
MGHTRRQGTS PSKCPYLNFF QLLVLAGLSH FCSGVIHVTK EVKEVATLSC GHNVSVEELA 60
QTRIYWQKEK KMVLTMMSGD MNIWPEYKNR TIFDITNNLS IVILALRPSD EGTYECVVLK 120
YEKDAFKREH LAEVTLSVKA DFPTPSISDF EIPTSNIRRI ICSTSGGFPE PHLSWLENGE 180
ELNAINTTVS QDPETELYAV SSKLDFNMTT NHSFMCLIKY GHLRVNQTFN WNTSFAPRCR 240
ERRRNERLRR ESVRPV 256
CD80 isotype 3 (서열번호 136):
MGHTRRQGTS PSKCPYLNFF QLLVLAGLSH FCSGVIHVTK EVKEVATLSC GHNVSVEELA 60
QTRIYWQKEK KMVLTMMSGD MNIWPEYKNR TIFDITNNLS IVILALRPSD EGTYECVVLK 120
YEKDAFKREH LAEVTLSVKG FAPRCRERRR NERLRRESVR PV 162
또한, 제1 결합 도메인 및 제2 결합 도메인은 하기 조합으로부터 선택된다:
(1) 제1 결합 도메인은 PD-L1을 표적으로 하여 결합하고, 제2 결합 도메인은 인간 TGF-β, VEGF, FGL1, CD47, CD155, HGF, CSF1, CXCL1, CXCL2, CXCL3, CXCL5, CXCL6, CXCL7, CXCL8, CXCL9, CXCL10, CXCL12, EGF 또는 ICOSL을 표적으로 하여 이에 결합하거나; 또는
(2) 제1결합 도메인은 PD-1을 표적으로 하여 결합하고, 제2결합 도메인은 인간 CTLA-4, VEGF, HGF, EGF, CD28, LAG3, CD27, 4-1BB 또는 OX40을 표적으로 하여 결합하거나; 또는
(3) 제1 결합 도메인은 CTLA-4를 표적으로 하여 결합하고, 제2 결합 도메인은 인간 CD28, VEGF, HGF, EGF, LAG3, CD27, 4-1BB 또는 OX40을 표적으로 하여 결합하거나; 또는
(4) 제1 결합 도메인은 LAG-3을 표적으로 하여 결합하고, 제2 결합 도메인은 인간 CD28, VEGF, HGF, EGF, CTLA-4, CD27, 4-1BB 또는 OX40을 표적으로 하여 결합하거나; 또는
(5) 제1 결합 도메인은 FGL1을 표적으로 하여 결합하고, 제2 결합 도메인은 인간 TGF-β, VEGF, CD47, CD155, HGF, CSF1, CXCL1, CXCL2, CXCL3, CXCL5, CXCL6, CXCL7, CXCL8, CXCL9, CXCL10, CXCL12, EGF 또는 ICOSL을 표적으로 하여 결합하거나; 또는
(6) 제1 결합 도메인은 TIM-3을 표적으로 하여 결합하고, 제2 결합 도메인은 인간 VEGF, HGF, EGF, LAG3, CD27, 4-1BB 또는 OX40을 표적으로 하여 결합하거나; 또는
(7) 제1 결합 도메인은 갈렉틴-9를 표적으로 하여 결합하고, 제2 결합 도메인은 인간 TGF-β, VEGF, CD47, CD155, HGF, CSF1, CXCL1, CXCL2, CXCL3, CXCL5, CXCL6, CXCL7, CXCL8, CXCL9, CXCL10, CXCL12, EGF 또는 ICOSL을 표적으로 하여 결합하거나; 또는
(8) 제1 결합 도메인은 TIGIT를 표적으로 하여 결합하고, 제2 결합 도메인은 인간 TGF-β, HGF, EGF 또는 VEGF를 표적으로 하여 결합하거나; 또는
(9) 제1결합 도메인은 CD155를 표적으로 하여 결합하고, 제2결합 도메인은 인간 TGF-β, VEGF, HGF, EGF, CD47 또는 CD155를 표적으로 하여 결합하거나; 또는
(10) 제1 결합 도메인은 클라우딘 18.2, HER-2, 메조텔린, BCMA, SSTR2, GPRC5D, PSMA, FCRH5, CD33, CD123, CD20, A33, CEA, CD28, DLL3, EGFR, VEGFR, VEGFR2, VEGF-A, Nectin-4, FGFR, C-met, RANKL, PDGF, PDGFR, PDGFRα, DLL-4, Ang-1 또는 Ang-2를 표적으로 하고 결합하며, 제2 결합 도메인은 인간 CTLA-4, TGF-β, VEGF, FGL1, LAG3, 4-1BB, OX40, CD27, CD28, CD47, CD155, HGF, CSF1, CXCL1, CXCL2, CXCL3, CXCL5, CXCL6, CXCL7, CXCL8, CXCL9, CXCL10 또는 ICOSL 를 표적으로 하여 결합한다.
또한, 제1 결합 도메인 및 수용체 또는 리간드는 하기 조합으로부터 선택된다:
(1) 제1 결합 도메인은 PD-L1을 표적으로 하여 결합하고, 수용체 또는 리간드는 TGF-βRII, VEGFR, LAG-3, SIRPα, TIGIT, C-MET, CSF1R, CXCR2, CXCR3, CXCR4, EGFR 또는 ICOS에서 선택되거나; 또는
(2) 제1 결합 도메인은 PD-1을 표적으로 하여 결합하고, 수용체 또는 리간드는 인간 CD80, CD86, VEGFR, c-MET, EGFR, FGL1, CD70, 4-1BBL 또는 OX40L로부터 선택되거나; 또는
(3) 제1 결합 도메인은 CTLA-4를 표적으로 하여 결합하고, 수용체 또는 리간드는 인간 CD80, CD86, VEGFR, c-MET, EGFR, FGL1, CD70, 4-1BBL 또는 OX40L로부터 선택되거나; 또는
(4) 제1 결합 도메인은 LAG-3을 표적으로 하여 결합하고, 수용체 또는 리간드는 인간 VEGFR, c-MET, EGFR, CD80, CD86, CD70, 4-1BBL 또는 OX40L로부터 선택되거나; 또는
(5) 제1 결합 도메인은 FGL1을 표적으로 하여 결합하고, 수용체 또는 리간드는 인간 TGF-βRII, VEGFR, SIRPα, TIGIT, c-MET, CSF1R, CXCR2, CXCR3, CXCR4, EGFR 또는 ICOS로부터 선택되거나 ; 또는
(6) 제1 결합 도메인은 TIM-3을 표적으로 하여 결합하고, 수용체 또는 리간드는 인간 VEGFR, c-MET, EGFR, FGL1, CD70, 4-1BBL 또는 OX40L로부터 선택되거나; 또는
(7) 제1 결합 도메인은 갈렉틴-9를 표적으로 하여 결합하고, 수용체 또는 리간드는 인간 TGF-βRII, VEGFR, SIRPα, TIGIT, c-MET, CSF1R, CXCR2, CXCR3, CXCR4, EGFR 또는 ICOS로부터 선택되거나; 또는
(8) 제1 결합 도메인은 TIGIT를 표적으로 하여 결합하고, 수용체 또는 리간드는 인간 TGF-βRII, c-MET, EGFR 또는 VEGFR로부터 선택되거나; 또는
(9) 제1 결합 도메인은 CD155를 표적으로 하여 결합하고, 수용체 또는 리간드는 인간 TGF-βRII, VEGFR, c-MET, EGFR, SIRPα 또는 TIGIT로부터 선택되거나; 또는
(10) 제1 결합 도메인은 클라우딘 18.2, HER-2, 메조텔린, BCMA, SSTR2, GPRC5D, PSMA, FCRH5, CD33, CD123, CD20, A33, CEA, CD28, DLL3, EGFR, VEGFR, VEGFR2, Nectin-4, FGFR, c-MET, RANKL, PDGF, PDGFR, PDGFRα, DLL4, Ang-1 또는 Ang-2 을 표적으로 하여 결합하고, 수용체 또는 리간드는 인간 CTLA-4, CD80, CD86, TGF-βRII, VEGFR, FGL1, LAG3, 4-1BB, OX40, CD27, CD28, CD70, c-MET, SIRPα, TIGIT, CSF1R, CXCR2, CXCR3, CXCR4, EGFR 또는 ICOS에서 선택된다.
또한, 상기 수용체 또는 리간드의 단편은 세포외 영역의 단편 및 수용체 또는 리간드의 결합 도메인의 단편을 포함한다.
또한, 제1 결합 도메인은 PD-L1을 표적으로 하여 결합하고; 제2결합 도메인은 인간 TGF-βRII의 단편이거나; 또는 제1 결합 도메인은 PD-1을 표적으로 하여 결합하고, 제2 결합 도메인은 인간 CD80 ECD, CD80 IgV 영역, 인간 CD80 IgVIgC, VEGFR1 ECD, VEGFR2 ECD 또는 VEGFR1의 제2 세포외 영역과 VEGFR2의 제3 세포외 영역의 조합을 포함하거나; 또는 제1 결합 도메인은 클라우딘 18.2, HER-2 또는 EGFR을 표적으로 하여 결합하고, 제2 결합 도메인은 인간 CD80 ECD, CD80 IgV 영역, 인간 CD80 IgVIgC, VEGFR1 ECD, VEGFR2 ECD 또는 VEGFR1의 제2 세포외 영역 및 VEGFR2의 제3세포외 영역의 조합으로부터 선택된다.
또한, 제2 결합 도메인은 하기로부터 선택된다:
(1) 서열번호 31, 131 또는 132에 나타낸 서열, 또는 서열번호 31, 131 또는 132에 나타낸 서열과 비교하여 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% 이상의 상동성을 갖는 서열, 또는 서열번호 31, 131 또는 132에 나타낸 서열 상의 1, 2, 3, 4, 5, 6, 7, 8, 9 또는 10개의 아미노산 치환 또는 결실된 아미노산 서열을 포함하는, 인간 TGF-βRII; 또는
(2) 서열번호 32 또는 133에 나타낸 서열, 또는 서열번호 32 또는 133에 나타낸 서열과 비교하여 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% 이상의 상동성을 갖는 서열, 또는 서열번호 32 또는 133에 나타낸 서열에서 1, 2, 3, 4, 5, 6, 7, 8, 9, 또는 10개의 아미노산 치환 또는 결실을 갖는 아미노산 서열을 포함하는 CD80 ECD; 또는
(3) VEGFR1의 제2 세포외 영역 및 VEGFR2의 제3 세포외 영역의 조합으로서, 서열번호 33에 나타낸 서열, 또는 서열번호 33에 나타낸 서열과 비교하여 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% 이상의 상동성을 갖는 서열, 또는 서열번호 33에 나타낸 서열 상의 1, 2, 3, 4, 5, 6, 7, 8, 9, 또는 10개의 아미노산 치환 또는 결실을 포함한다.
또한, 제2 결합 도메인의 C-말단 또는/및 N-말단에는 펩타이드 링커가 있고, 펩타이드 링커는 2-30개의 아미노산으로 이루어진다.
추가로, 펩타이드 링커는 다음과 같을 수 있다:
(1) (GGGGS)n; 또는
(2) AKTTPKLEEEGEFSEAR(서열번호 80); 또는
(3) AKTTPKLEEEGEFSEARV(서열번호 81); 또는
(4) AKTTPKLGG(서열번호 82); 또는
(5) SAKTTPKLGG(서열번호 83); 또는
(6) SAKTTP(서열번호 84); 또는
(7) RADAAP(서열번호 85); 또는
(8) RADAAPTVS(서열번호 86); 또는
(9) RADAAAAGGPGS(서열번호 87); 또는
(10) RADAAAA(서열번호 88); 또는
(11) SAKTTPKLEEEGEFSEARV(서열번호 89); 또는
(12) ADAAP(서열번호 90); 또는
(13) DAAPTVSIFPP(서열번호 91); 또는
(14) TVAAP(서열번호 92); 또는
(15) TVAAPSVFIFFP(서열번호 93); 또는
(16) QPKAAP(서열번호 94); 또는
(17) QPKAAPSVTLFPP(서열번호 95); 또는
(18) AKTTPP(서열번호 96); 또는
(19) AKTTPPSVTPLAP(서열번호 97); 또는
(20) AKTTAP(서열번호 98); 또는
(21) AKTTAPSVYPLAP(서열번호 99); 또는
(22) ASTKGP(서열번호 100); 또는
(23) ASTKGPSVFPLAP(서열번호 101); 또는
(24) GENKVEYAPALMALS(서열번호 102); 또는
(25) GPAKELTPLKEAKVS(서열번호 103); 또는
(26) GHEAAAVMQVQYPAS(서열번호 104); 또는
(27) GGGGSGGGGSGGGGSA(서열번호 105),
여기서 n은 1, 2, 3 또는 4이고;
n=1일 때, (GGGGS)n은 GGGGS(서열번호 120)이고;
n=2일 때, (GGGGS)n은 GGGGSGGGGS(서열번호 121) 또는 (GGGGS)2이고;
n=3일 때, (GGGGS)n은 GGGGSGGGGSGGGGS(서열번호 122) 또는 (GGGGS)3이고;
n=4일 때, (GGGGS)n은 GGGGSGGGGSGGGGSGGGGS(서열번호 123) 또는 (GGGGS)4이다.
또한, 삽입된 제2 결합 도메인의 크기는 235, 240, 250, 260, 270, 280, 290 또는 300개의 아미노산을 초과하지 않는다.
또한, 상기 제2 결합 도메인의 삽입 부위는 상기 힌지 영역의 전면 중앙부에 위치하며, 상기 삽입 부위는 면역글로불린의 이황화 결합 형성에 영향을 미치지 않고, 상기 힌지 영역의 전면 중앙부는 일반적으로 231A 이전 부분을 나타낸다. 또한, 삽입 부위 전후의 힌지 영역의 아미노산의 일부가 치환 또는 결실되어 있다. 예를 들어, 힌지 영역은 D221G 및/또는 C220V 돌연변이를 포함한다.
또한, IgG는 포유동물 IgG, 인간화 IgG 및 인간 IgG로부터 선택되고, 포유동물에는 마우스, 래트 및 토끼가 포함되고; 바람직하게는, IgG는 IgG1, IgG2, IgG3 또는 IgG4이다.
또한, 융합 단백질의 Fc 영역은 비글리코실화 또는 탈글리코실화되거나, 푸코실화가 감소되거나 또는 비푸코실화된다.
또한, IgG는 아테졸리주맙, 아벨루맙, 더발루맙, 니볼루맙, 펨브롤리주맙, 세미플리맙 또는 이필리무맙이다. 바람직하게는, IgG는 아테졸리주맙이고, IgG의 중쇄의 아미노산 서열은 서열번호 106에 표시되고, IgG의 경쇄의 아미노산 서열은 서열번호 107에 표시되거나; 또는 IgG가 아벨루맙이고, IgG의 중쇄의 아미노산 서열이 서열번호 108에 제시되고, IgG의 경쇄의 아미노산 서열이 서열번호 109에 제시되거나; 또는 IgG가 더발루맙이고, IgG의 중쇄의 아미노산 서열이 서열번호 110에 제시되고, IgG의 경쇄의 아미노산 서열이 서열번호 111에 제시되거나; 또는 IgG가 니볼루맙이고, IgG의 중쇄의 아미노산 서열이 서열번호 112에 제시되고, IgG의 경쇄의 아미노산 서열이 서열번호 113에 제시되거나; 또는 IgG가 펨브롤리주맙이고, IgG의 중쇄의 아미노산 서열이 서열번호 114에 제시되고, IgG의 경쇄의 아미노산 서열이 서열번호 115에 제시되거나; 또는 IgG가 이필리무맙이고, IgG의 중쇄의 아미노산 서열이 서열번호 116에 제시되고, IgG의 경쇄의 아미노산 서열이 서열번호 117에 제시되거나; 또는 IgG는 세미플리맙이고, IgG의 중쇄의 아미노산 서열은 서열번호 118에 제시되고, IgG의 경쇄의 아미노산 서열은 서열번호 119에 제시된다.
구체적으로, 본 발명은 인간 PD-L1을 표적화하는 제1 결합 도메인을 갖는 하이바디 구조 융합 단백질을 제공하며, IgG의 Fab 내의 중쇄 가변 영역의 CDR 및/또는 경쇄 가변 영역의 CDR은 하기 서열로 정의된 항체와 동일한 CDR 서열을 가지거나, 하기 서열로 정의된 항체의 CDR에 1-2개의 아미노산 치환을 가지며, 상기 항체는 하기와 같이 정의된다:
(1) 서열번호 66의 중쇄 가변영역의 아미노산 서열; 및/또는
(2) 서열번호 67의 경쇄 가변영역의 아미노산 서열.
또한, IgG의 Fab에서 중쇄 가변 영역의 CDR 및/또는 경쇄 가변 영역의 CDR은 다음과 같다:
(1) 중쇄 가변 영역의 경우, CDR1의 아미노산 서열은 서열번호 1-5 및 서열번호 1-5에 1 또는 2개의 아미노산 치환을 갖는 아미노산 서열로부터 선택되고; CDR2의 아미노산 서열은 서열번호 6-10 및 서열번호 6-10에서 1 또는 2개의 아미노산 치환을 갖는 아미노산 서열로부터 선택되고; CDR3의 아미노산 서열은 서열번호 11-15 및 서열번호 11-15에서 1 또는 2개의 아미노산 치환을 갖는 아미노산 서열로부터 선택되고; 및/또는
(2) 경쇄 가변 영역의 경우, CDR1의 아미노산 서열은 서열번호 16-20 및 서열번호 16-20에 1 또는 2개의 아미노산 치환을 갖는 아미노산 서열로부터 선택되고; CDR2의 아미노산 서열은 서열번호 21-25 및 서열번호 21-25에서 1 또는 2개의 아미노산 치환을 갖는 아미노산 서열로부터 선택되고; CDR3의 아미노산 서열은 서열번호 26-30 및 서열번호 26-30에서 1 또는 2개의 아미노산 치환을 갖는 아미노산 서열로부터 선택된다.
특정 실시양태에서, 사용된 상이한 측정 방법 또는 시스템 식별에 따라, 상응하는 중쇄 및 경쇄 가변 영역의 상보성 결정 영역 CDR 1-3을 표 2에 제시한다.
카테고리 | 시스템 | CDR1 | CDR2 | CDR3 |
중쇄 | Chothia | 서열번호1 GFSLSRY |
서열번호 6 WGVGT |
서열번호 11 NWGTADYFDY |
AbM | 서열번호 2 GFSLSRYSVH |
서열번호 7 MIWGVGTTD |
서열번호 12 NWGTADYFDY |
|
Kabat | 서열번호 3RYSVH | 서열번호 8 MIWGVGTTDYNSALKS |
서열번호 13 NWGTADYFDY |
|
Contact | 서열번호 4SRYSVH | 서열번호 9 WLGMIWGVGTTD |
서열번호 14 ARNWGTADYFD |
|
IMGT | 서열번호 5GFSLSRYS | 서열번호 10 IWGVGTT |
서열번호 15 ARNWGTADYFDY |
|
경쇄 | Chothia | 서열번호 16 RASKSVHTSGYSYMH |
서열번호 21 LASNLES |
서열번호 26 QHSGELPYT |
AbM | 서열번호 17 RASKSVHTSGYSYMH |
서열번호 22 LASNLES |
서열번호 27 QHSGELPYT |
|
Kabat | 서열번호 18RASKSVHTSGYSYMH | 서열번호 23 LASNLES |
서열번호 28 QHSGELPYT |
|
Contact | 서열번호 19HTSGYSYMHWY | 서열번호 24 LLIYLASNLE |
서열번호 29 QHSGELPY |
|
IMGT | 서열번호 20KSVHTSGYSY | 서열번호 25 LAS |
서열번호 30 QHSGELPYT |
또한, 상기 융합 단백질은 하기 CDR 서열을 포함한다,
(1) 중쇄 가변영역의 CDR 1-3의 아미노산 서열은 서열번호 1, 6, 11, 또는 서열번호 1, 6, 11에 1 또는 2개의 아미노산 치환을 갖는 아미노산 서열이고; 및/또는 경쇄 가변 영역의 CDR 1-3의 아미노산 서열은 서열번호 16, 21, 26, 또는 서열번호 16, 21, 26에 1 또는 2개의 아미노산 치환을 갖는 아미노산 서열이거나; 또는
(2) 중쇄 가변영역의 CDR 1-3의 아미노산 서열은 서열번호 2, 7, 12, 또는 서열번호 2, 7, 12에 1 또는 2개의 아미노산 치환을 갖는 아미노산 서열이고; 및/또는 경쇄 가변 영역의 CDR 1-3의 아미노산 서열은 서열번호 17, 22, 27, 또는 서열번호: 17, 22, 27에서 1 또는 2개의 아미노산 치환을 갖는 아미노산 서열이거나; 또는
(3) 중쇄 가변영역의 CDR 1-3의 아미노산 서열은 서열번호 3, 8, 13 또는 서열번호 3, 8, 13에 1 또는 2개의 아미노산 치환을 갖는 아미노산 서열이고; 및/또는 경쇄 가변 영역의 CDR 1-3의 아미노산 서열은 서열번호 18, 23, 28, 또는 서열번호 18, 23, 28에 1 또는 2개의 아미노산 치환을 갖는 아미노산 서열이거나; 또는
(4) 중쇄 가변영역의 CDR 1-3의 아미노산 서열은 서열번호 4, 9, 14, 또는 서열번호 4, 9, 14에 1 또는 2개의 아미노산 치환을 갖는 아미노산 서열이고; 및/또는 경쇄 가변 영역의 CDR 1-3의 아미노산 서열은 서열번호 19, 24, 29, 또는 서열번호: 19, 24, 29에 1 또는 2개의 아미노산 치환을 갖는 아미노산 서열이거나; 또는
(5) 중쇄 가변영역의 CDR 1-3의 아미노산 서열은 서열번호 5, 10, 15 또는 서열번호 5, 10, 15에 1 또는 2개의 아미노산 치환을 갖는 아미노산 서열이고; 및/또는 경쇄 가변 영역의 CDR 1-3의 아미노산 서열은 서열번호 20, 25, 30, 또는 서열번호 20, 25, 30에서 1 또는 2개의 아미노산 치환을 갖는 아미노산 서열이다.
또한, 융합 단백질의 중쇄에서 중쇄 가변영역의 CDR 1-3의 아미노산 서열은 서열번호 3, 8, 13이고; 및/또는 경쇄 가변 영역의 CDR 1-3의 아미노산 서열은 서열 18, 23, 28이다.
또한, 융합 단백질의 중쇄 가변영역 및 경쇄 가변영역의 서열은 다음과 같다.
(1) 상기 중쇄 가변영역은 서열번호 66 에 나타낸 서열, 또는 서열번호 66과 동일한 CDR 1-3을 갖고, 서열번호 66과 비교하여 상동성이 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% 이상인 서열을 갖고; 및/또는
(2) 경쇄 가변영역은 서열번호 67에 나타낸 서열, 또는 서열번호 67과 동일한 CDR 1-3을 갖고, 서열번호 67과 비교하여 상동성이80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% 이상인 서열을 갖는다.
보다 구체적으로, 융합 단백질의 중쇄 및 경쇄의 아미노산 서열은 다음과 같다:
(1) 융합 단백질의 중쇄는 서열번호 72 에 나타낸 아미노산 서열, 또는 서열번호 72와 비교하여 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% 이상의 상동성을 갖는 서열을 가지고;
(2) 융합 단백질의 경쇄는 서열번호 73 에 나타낸 아미노산 서열, 또는 서열번호 73과 비교하여 상동성이80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% 이상인 서열을 갖는다.
또한, 융합 단백질의 중쇄 및 경쇄의 아미노산 서열은 다음과 같다.
(1) 융합 단백질의 중쇄의 아미노산 서열은 서열번호 72와 비교하여 1-15개의 아미노산 부위 돌연변이를 가지거나 대체 펩타이드 링커를 갖고;
(2) 융합 단백질의 경쇄의 아미노산 서열은 서열번호 73과 비교하여 1-10개의 아미노산 부위 돌연변이를 갖는다.
구체적으로, 본 발명은 인간 PD-1을 표적화하는 제1 결합 도메인을 갖는 하이바디 구조 융합 단백질을 제공하며, 여기서 Fab 내의 중쇄 가변 영역의 CDR 및/또는 경쇄 가변 영역의 CDR은 하기 서열로 정의된 항체와 동일한 CDR 서열, 또는 하기 서열로 정의된 항체의 CDR에 1-2개의 아미노산 치환을 가지며, 상기 항체는 하기와 같이 정의된다:
(1) 중쇄 가변영역의 아미노산 서열은 서열번호 64로 표시되며; 및/또는
(2) 경쇄 가변영역의 아미노산 서열은 서열번호 65로 표시된다.
또한, 융합 단백질에서 Fab의 중쇄 가변 영역의 CDR 및/또는 경쇄 가변 영역의 CDR은 다음과 같다:
(1) 중쇄 가변 영역의 경우, CDR1의 아미노산 서열은 서열번호 34-38 및 서열번호 34-38에서 1 또는 2개의 아미노산 치환을 갖는 아미노산 서열로부터 선택되고; CDR2의 아미노산 서열은 서열번호 39-43 및 서열번호 39-43에서 1 또는 2개의 아미노산 치환을 갖는 아미노산 서열로부터 선택되고; CDR3의 아미노산 서열은 서열번호 44-48 및 서열번호 44-48에서 1 또는 2개의 아미노산 치환을 갖는 아미노산 서열로부터 선택되고; 및/또는
(2) 경쇄 가변 영역의 경우, CDR1의 아미노산 서열은 서열번호 49-53 및 서열번호 49-53에서 1 또는 2개의 아미노산 치환을 갖는 아미노산 서열로부터 선택되고; CDR2의 아미노산 서열은 서열번호 54-58 및 서열번호 54-58에서 1 또는 2개의 아미노산 치환을 갖는 아미노산 서열로부터 선택되고; CDR3의 아미노산 서열은 서열번호 59-63 및 서열번호 59-63에서 1 또는 2개의 아미노산 치환을 갖는 아미노산 서열로부터 선택된다.
특정 실시양태에서, 사용된 상이한 측정 방법 또는 시스템 식별에 따라, 상응하는 중쇄 및 경쇄 가변 영역의 상보성 결정 영역 CDR 1-3을 표 3에 제시한다.
카테고리 | 시스템 | CDR1 | CDR2 | CDR3 |
중쇄 | Chothia | 서열번호 34 GITFSNS |
서열번호 39 WYDGSK |
서열번호 44 NDDY |
AbM | 서열번호 35 GITFSNSGMH |
서열번호 40 VIWYDGSKRY |
서열번호 45 NDDY |
|
Kabat | 서열번호 36NSGMH | 서열번호 41 VIWYDGSKRYYADSVKG |
서열번호 46 NDDY |
|
Contact | 서열번호 37SNSGMH | 서열번호 42 WVAVIWYDGSKRY |
서열번호 47 ATNDD |
|
IMGT | 서열번호 38GITFSNSG | 서열번호 43 IWYDGSKR |
서열번호 48 ATNDDY |
|
경쇄 | Chothia | 서열번호 49 RASQSVSSYLA |
서열번호 54 DASNRAT |
서열번호 59 QQSSNWPRT |
AbM | 서열번호 50 RASQSVSSYLA |
서열번호 55 DASNRAT |
서열번호 60 QQSSNWPRT |
|
Kabat | 서열번호 51RASQSVSSYLA | 서열번호 56 DASNRAT |
서열번호 61 QQSSNWPRT |
|
Contact | 서열번호 52SSYLAWY | 서열번호 57 LLIYDASNRA |
서열번호 62 QQSSNWPR |
|
IMGT | 서열번호 53QSVSSY | 서열번호 58 DAS |
서열번호 63 QQSSNWPRT |
또한, 융합 단백질의 가변 영역의 CDR 1-3은 다음과 같이 정의된다:
(1) 중쇄 가변영역의 CDR 1-3의 아미노산 서열은 서열번호 34, 39, 44 또는 서열번호 34, 39, 44에 1 또는 2개의 아미노산 치환을 갖는 아미노산 서열이고; 및/또는 경쇄 가변 영역의 CDR 1-3의 아미노산 서열은 서열번호 49, 54, 59, 또는 서열번호 49, 54, 59에서 1 또는 2개의 아미노산 치환을 갖는 아미노산 서열이거나; 또는
(2) 중쇄 가변영역의 CDR 1-3의 아미노산 서열은 서열번호 35, 40, 45, 또는 서열번호 35, 40, 45에 1 또는 2개의 아미노산 치환을 갖는 아미노산 서열이고; 및/또는 경쇄 가변 영역의 CDR 1-3의 아미노산 서열은 서열번호 50, 55, 60, 또는 서열번호 50, 55, 60에서 1 또는 2개의 아미노산 치환을 갖는 아미노산 서열이거나; 또는
(3) 중쇄 가변영역의 CDR 1-3의 아미노산 서열은 서열번호 36, 41, 46 또는 서열번호 36, 41, 46에 1 또는 2개의 아미노산 치환을 갖는 아미노산 서열이고; 및/또는 경쇄 가변 영역의 CDR 1-3의 아미노산 서열은 서열번호 51, 56, 61, 또는 서열번호 51, 56, 61에서 1 또는 2개의 아미노산 치환을 갖는 아미노산 서열이거나; 또는
(4) 중쇄 가변영역의 CDR 1-3의 아미노산 서열은 서열번호 37, 42, 47, 또는 서열번호 37, 42, 47에 1 또는 2개의 아미노산 치환을 갖는 아미노산 서열이고; 및/또는 경쇄 가변 영역의 CDR 1-3의 아미노산 서열은 서열번호 52, 57, 62, 또는 서열번호 52, 57, 62에 1 또는 2개의 아미노산 치환을 갖는 아미노산 서열이거나; 또는
(5) 중쇄 가변영역의 CDR 1-3의 아미노산 서열은 서열번호 38, 43, 48 또는 서열번호 38, 43, 48에 1 또는 2개의 아미노산 치환을 갖는 아미노산 서열이고; 및/또는 경쇄 가변 영역의 CDR 1-3의 아미노산 서열은 서열번호 53, 58, 63, 또는 서열번호 53, 58, 63에서 1 또는 2개의 아미노산 치환을 갖는 아미노산 서열이다.
또한, 융합 단백질의 가변 영역의 CDR 1-3은 다음과 같이 정의된다: 중쇄 가변 영역의 CDR 1-3의 아미노산 서열은 서열번호 36, 41, 46이고; 및/또는 경쇄 가변 영역의 CDR 1-3의 아미노산 서열은 서열번호 51, 56, 61이다.
또한, 융합 단백질의 중쇄 가변영역 및 경쇄 가변영역의 아미노산 서열은 다음과 같다.
(1) 중쇄 가변영역은 서열번호 64 에 나타낸 서열, 또는 서열번호 64와 동일한 CDR 1-3을 갖고, 서열번호 64와 비교하여 상동성이 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% 이상인 서열이고; 및/또는
(2) 경쇄 가변영역은 서열번호 65 에 나타낸 서열, 또는 서열번호 65와 동일한 CDR 1-3을 갖고 서열번호 65와 비교하여 상동성이 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% 이상인 서열이다.
보다 구체적으로, 융합 단백질의 중쇄 및 경쇄의 아미노산 서열은 다음과 같이 정의된다:
(1) 융합 단백질의 중쇄는 서열번호 68 에 나타낸 아미노산 서열, 또는 서열번호 68와 비교하여 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% 이상의 상동성을 갖는 서열을 가지고;
(2) 융합 단백질의 경쇄는 서열번호 69 에 나타낸 아미노산 서열, 또는 서열번호 69와 비교하여 상동성이 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% 이상인 서열을 갖는다.
또한, 융합 단백질의 중쇄 및 경쇄의 아미노산 서열은 다음과 같이 정의된다:
(1) 융합 단백질의 중쇄의 아미노산 서열은 서열번호 68과 비교하여 1-15개의 아미노산 부위 돌연변이를 갖거나 대체 펩타이드 링커를 갖고;
(2) 융합 단백질의 경쇄의 아미노산 서열은 서열번호 69와 비교하여 1-10개의 아미노산 부위 돌연변이를 갖는다.
보다 구체적으로, 융합 단백질의 중쇄 및 경쇄의 아미노산 서열은 다음과 같이 정의된다:
(1) 융합 단백질의 중쇄는 서열번호 70에 나타낸 아미노산 서열, 또는 서열번호 70과 비교하여 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% 이상의 상동성을 갖는 서열을 가지고;
(2) 융합 단백질의 경쇄는 서열번호 71에 나타낸 아미노산 서열, 또는 서열번호 71과 비교하여 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% 이상의 상동성을 갖는 서열을 갖는다.
또한, 융합 단백질의 중쇄 및 경쇄의 아미노산 서열은 다음과 같이 정의된다:
(1) 융합 단백질의 중쇄의 아미노산 서열은 서열번호 70과 비교하여 1-15개의 아미노산 부위 돌연변이를 가지거나 대체 펩타이드 링커를 갖고;
(2) 융합 단백질의 경쇄의 아미노산 서열은 서열번호 71과 비교하여 1-10개의 아미노산 부위 돌연변이를 갖는다.
본 발명은 또한 상기 융합 단백질을 코딩하는 단리된 폴리뉴클레오티드를 제공한다.
본 발명은 또한 상기 폴리뉴클레오티드를 포함하는 핵산 구조체를 제공하며, 바람직하게는 핵산 구조체는 벡터이다.
본 발명은 또한 상기 폴리뉴클레오티드 또는 상기 핵산 구조체 또는 벡터를 포함하는 숙주 세포를 제공하며, 바람직하게 상기 세포는 원핵 세포, 진핵 세포, 효모 세포, 포유동물 세포, 대장균 세포 또는 CHO 세포, NS0 세포, Sp2/0 세포 또는 BHK 세포이다.
본 발명은 또한 상기 융합 단백질 및 약학적으로 허용되는 담체를 포함하는 약학 조성물을 제공한다.
본 발명은 또한 치료 또는 완화를 필요로 하는 대상체에게 상기 융합 단백질 또는 제약 조성물을 투여하는 단계를 포함하는, 종양 또는 암을 치료하는 방법을 제공한다.
본 발명은 또한 종양 또는 암의 치료 또는 예방을 위한 의약의 제조에서의 상기 융합 단백질, 폴리뉴클레오티드, 핵산 구조체 또는 벡터, 또는 제약 조성물의 용도를 제공한다. 종양 또는 암은 고형 종양 또는 비-고형 종양을 포함한다.
본 발명은 또한 상기 융합 단백질을 포함하는 진단 키트를 제공한다.
본 발명은 또한 상기 핵산 구조체의 발현이 가능한 조건 하에 숙주 세포를 배양하고, 배양물로부터 생산된 융합 단백질을 회수하는 것을 포함하는, 융합 단백질의 제조 방법을 제공한다.
본 발명에서 제공되는 하이바디 구조 융합 단백질은 힌지 영역에 제2 결합 도메인이 삽입되어 있기 때문에 IgG와 동일한 발현 및 생산 이점을 가지며, 기존의 IgG 발현 플랫폼 및 정제 플랫폼에 원활하게 적용할 수 있고 이는 후속 개발 비용을 크게 줄인다. 구체적으로, 기존의 이중특이성 항체 플랫폼으로 구축한 이중특이성 항체에 비해 하이바디 플랫폼으로 구축한 이중특이성 항체는 발현량이 높고 경쇄와 중쇄의 미스매치 문제가 없어 항체 생산비용을 크게 절감할 수 있다. 또한, 두 개의 힌지 영역에 일정 크기의 제2 결합 도메인을 삽입하여, 융합 단백질의 Fab 영역의 결합 활성 및 단백질의 안정성에 영향을 미치지 않을 뿐만 아니라, 안정성과 더 긴 반감기를 얻는다. 특히, 표적 결합 부위에 대한 제2 결합 도메인의 결합 활성은 대응하는 표적에 대한 상응하는 가용성 천연 결합 단편 단량체의 결합 활성과 비교하여 상당히 개선되며, 이는 선택된 제2 결합 도메인의 수용체 또는 리간드가 신호 전달 경로를 활성화하거나 억제하기 위해 자연 신호경로에서 이량체화 또는 다량체화 구조를 형성한다. 또한 제2 결합 도메인이 힌지 영역에 삽입될 때, 힌지 영역에서 공간적 위치 관계는 상응하는 수용체 또는 리간드 또는 그의 단편의 이량체화 형성을 촉진하고, 이를 통해 천연 신호 경로를 모방함으로써 보다 현저하게 개선된 결합 활성이 생성되어 융합 단백질이 가용성 수용체 또는 리간드 또는 그의 단편에 비해 크게 증가된 활성화 또는 억제 능력을 갖도록 한다. 또한, 2개의 결합 도메인의 합리적인 조합을 통해 수용체 억제 또는 수용체 활성화의 표적을 유연하게 선택하여 효과적인 시너지 효과를 달성할 수 있다. 본 발명에서 제공되는 이중특이성 융합 단백질은 두 개의 표적 약물 또는 종래 기술의 이중특이성 항체를 별도로 투여하는 경우에 비해, 특히 다양한 종양 및 암에서 질병의 진행을 효과적으로 치료하거나 조절하는데 보다 유의한 질병 치료 효과를 갖는다.
본 발명의 융합 단백질은 IgG와 동일한 발현 및 생산 이점을 가지며, 융합 단백질의 Fab 영역의 결합 활성에 영향을 미치지 않아 안정성을 더욱 향상시키고 더 높은 반감기를 얻을 수 있다. 또한, 제2 결합 구조 도메인의 표적 결합 부위에 대한 결합 활성은, 가용성 천연 결합 단편에 상응하는 표적에 대한 단량체의 결합 활성에 비해 현저히 개선되었다.
도 1 은 하이바디 구조 융합 단백질의 개략도이다.
도 2는 마우스 결장암 모델 종양에 대한 Hib-PDV 및 그 대조군의 억제 곡선을 나타낸다.
도 3은 마우스 결장암 종양에 대한 Hib-PDC 및 그 대조군의 억제 곡선을 나타낸다.
도 4는 10-100 nM 수준에서 IFN-γ 인자의 세포 분비 촉진에 대한 Hib-PLT와 그 대조군의 비교 차트이다.
도 2는 마우스 결장암 모델 종양에 대한 Hib-PDV 및 그 대조군의 억제 곡선을 나타낸다.
도 3은 마우스 결장암 종양에 대한 Hib-PDC 및 그 대조군의 억제 곡선을 나타낸다.
도 4는 10-100 nM 수준에서 IFN-γ 인자의 세포 분비 촉진에 대한 Hib-PLT와 그 대조군의 비교 차트이다.
정의
달리 정의되지 않는 한, 여기에서 사용되는 모든 기술 및 과학 용어는 본 발명과 관련된 기술 분야에서 통상의 지식을 가진 자에 의해 일반적으로 이해되는 것과 동일한 의미를 갖는다. 당업자는 Dictionary of Cell and Molecular Biology, third edition, 1999, Academic Press; the Concise Dictionary of Biomedicine and Molecular Biology, Juo, Pei-Show, second edition, 2002, CRC Press; and the Oxford Dictionary of Biochemistry and Molecular Biology, revised edition, 2000 , Oxford University Press을 참고할 수 있다.
본 발명과 관련된 아미노산은 IUPAC-IUB 생화학적 명명 위원회에서 권장하는 일반적으로 알려진 3문자 기호 또는 단일 문자 기호로 나타낼 수 있다. 마찬가지로, 뉴클레오티드는 일반적으로 인식되는 한 글자 코드로 나타낼 수 있다.
본 발명에서, 항체 가변 도메인의 상보성 결정 영역(CDR)의 결정 또는 넘버링 방법은 IMGT, Kabat(Kabat et al., Sequences of Proteins of Immunological Interest, 5th edition, Public Health Service, National Institutes of Health, Bethesda MD. (1991)에 기재된 것과 같이), Chothia, AbM 및 콘택트법을 포함한다.
본 발명의 목적과 관련하여, 2개의 핵산 또는 아미노산 서열 사이의 "상동성", "동일성" 또는 "유사성"은 동일한 뉴클레오티드 또는 아미노산 잔기의 최적의 정렬 후 얻은 두 시퀀스 간의 비교 백분율을 지칭한다.
백분율은 오로지 통계적이며 두 시퀀스 간의 차이는 무작위로 분포되고, 전체 길이를 포함한다. 두 개의 핵산 또는 아미노산 서열 간의 비교는 일반적으로 최적의 방식으로 정렬한 후 이들 서열을 비교함으로써 수행되며, 세그먼트 또는 "비교 창"을 통해 수행될 수 있다. 수동 구현 외에도 Smith와 Waterman(1981)의 로컬 상동성 알고리즘을 이용하거나 [Ad. App. Math. 2: 482], Neddleman 및 Wunsch(1970)의 로컬 상동성 알고리즘을 이용하거나 [J. MoI. Biol. 48: 443], Pearson과 Lipman(1988)의 유사성 탐색 방법을 이용하거나 [Proc. Natl. Acad. Sci. USA 85: 2444), 및 이러한 알고리즘을 사용하는 컴퓨터 소프트웨어를 이용하여(GAP, BESTFIT, FASTA and TFASTA in the Wisconsin Genetics Software Package, Genetics Computer Group, 575 Science Dr., Madison, WI, 또는BLAST N or BLAST P comparison software을 통해) 서열 비교를 위한 최적의 정렬을 수행할 수 있다.
폭넓게 정의된 바와 같이, 본 발명에 관련된 면역글로불린은 2개의 동일한 경쇄 및 2개의 동일한 중쇄로 이루어진 항체 활성을 갖는 동물성 단백질을 지칭한다. 이는 면역 효과 분자의 중요한 부류이며 고등 동물 면역계의 림프구에 의해 생성되는 단백질이고, 항원의 유도에 의해 항체로 변형될 수 있다. 구조가 다르기 때문에 IgG, IgA, IgM, IgD 및 IgE의 5가지 유형으로 나눌 수 있다. 바람직하게는, 본 발명에 관련된 면역글로불린은 IgG이다.
폭넓게 정의된 바와 같이, 본 발명에 관련된 수용체는 세포막 또는 세포 내에 존재하고 세포 외부의 특정 신호 분자에 결합하여 세포 내에서 일련의 생화학적 반응을 활성화할 수 있는 일종의 특이 단백질이며, 세포가 외부 자극 하에서 상응하는 효과를 일으키도록 한다. 수용체에 결합하는 생물학적 활성 물질을 종합적으로 리간드라고 한다. 수용체와 리간드의 결합은 분자 형태 변화를 초래하고, 이는 세포간 신호 전달, 세포간 접착, 내포 작용(endocytosis) 등을 매개하는 것과 같은 세포 반응을 유발한다.
본 발명에 관련된 이중특이성 융합 단백질은 힌지 영역에 삽입된 제2 결합 도메인을 갖는 면역글로불린의 구조에 기초한다. 따라서, 본 발명에 관련된 이중특이성 융합 단백질은 2개의 결합 도메인을 갖는다.
실시예
본 발명은 하기 실시예에 의해 추가로 예시될 것이다. 하기 실시예는 본 발명의 추가적인 정교화 및 설명을 위한 것이며, 본 발명을 제한하는 것으로 간주되어서는 안된다는 점에 유의해야 한다.
실시예 1. 단백질의 구축
이 실시예에서, 하기 단백질 분자는 당업계의 통상적인 방법을 사용하여 제조되었고, 당업계의 통상적인 방법에 따라 일시적으로 또는 안정적으로 발현되었다:
(1) 3개의 하이바디 이중특이성 융합 단백질: Hib-PLT, Hib-PDC 및 Hib-PDV;
(2) 대조군 단백질 1-3: WO2015/118175의 이관능성(bifunctional) 분자 구조에 따라 구축됨;
(3) 기타 대조군 단백질: TGF-β-R-His, VEGF-R-His, CD80-His, PD-L1 대조군 항체.
융합단백질 코드 | 제1결합 도메인의 표적 | 제2결합 도메인의 표적 | 제2결합 도메인 단편 삽입 | 펩타이드 링커 |
Hib-PLT | PD-L1 | TGF-β | TGF-βRII 세포외 영역 단편 | (GGGGS)3 |
Hib-PDC | PD-1 | CD28 | CD80 | (GGGGS)3 |
Hib-PDV | PD-1 | VEGF | VEGFR1의 제2 세포외 영역과 VEGFR2의 제3 세포외 영역의 조합 | (GGGGS)3 |
대조군 단백질 1 | PD-L1 | TGF-β | TGF-βRII 세포외 영역 단편 | (GGGGS)3 |
대조군 단백질 2 | PD-1 | CD28 | CD80 | (GGGGS)3 |
대조군 단백질 3 | PD-1 | VEGF | VEGFR1의 제2 세포외 영역과 VEGFR2의 제3 세포외 영역의 조합 | (GGGGS)3 |
융합 단백질 Hib-PLT의 중쇄 및 경쇄의 핵산 서열 및 아미노산 서열은 다음과 같다:
융합 단백질 Hib-PLT 중쇄의 핵산 서열(서열번호 78):
CAGGTGCAGCTGCAGGAGTCCGGACCAGGACTGGTGAAGCCATCCGAGACCCTGAGCCTGACCTGTACAGTGTCCGGCTTCAGCCTGTCTAGGTACAGCGTGCACTGGATCAGACAGCCACCTGGCAAGGGACTGGAGTGGCTGGGCATGATCTGGGGCGTGGGCACCACAGACTACAACTCTGCTCTGAAGTCCAGACTGACCATCAGCAAGGATACATCTAAGAATCAGTTCAGCCTGAAGCTGTCCAGCGTGACCGCCGCTGACACAGCCGTGTACTATTGCGCTCGCAACTGGGGCACCGCCGACTACTTCGACTATTGGGGCCAGGGCACCACAGTGACAGTGTCTTCCGCTAGCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTGAGCCCAAATCTTGTGACAAAGGCGGGGGAGGCAGCGGCGGCGGAGGAAGCGGGGGCGGAGGTAGC ACCATCCCTCCACACGTGCAGAAGAGCGTGAACAATGACATGATCGTCACCGACAACAACGGCGCCGTCAAGTTCCCCCAGCTGTGCAAATTCTGCGACGTGAGGTTCTCCACGTGCGACAACCAGAAGAGCTGTATGAGCAACTGCAGCATCACATCCATCTGCGAAAAACCCCAGGAAGTGTGCGTCGCCGTCTGGCGGAAGAACGACGAGAACATCACACTGGAGACCGTGTGCCACGACCCCAAACTGCCCTACCACGACTTCATCCTGGAGGACGCCGCCAGCCCAAAGTGCATCATGAAAGAGAAGAAGAAGCCGGGCGAGACTTTCTTCATGTGCTCCTGCAGCTCCGACGAGTGCAACGATAATATCATCTTCAGCGAAGAATACAACACATCTAACCCAGAC GGAGGGGGCGGATCCGGGGGCGGCGGAAGCGGCGGGGGGGGCAGCACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAATGA
참고: 밑줄 친 굵은 서열은 TGF-βRII 핵산 서열이다.
융합 단백질 Hib-PLT 중쇄의 아미노산 서열(서열번호 72):
QVQLQESGPG LVKPSETLSL TCTVSGFSLS RYSVHWIRQP PGKGLEWLGM IWGVGTTDYN 60
SALKSRLTIS KDTSKNQFSL KLSSVTAADT AVYYCARNWG TADYFDYWGQ GTTVTVSSAS 120
TKGPSVFPLA PSSKSTSGGT AALGCLVKDY FPEPVTVSWN SGALTSGVHT FPAVLQSSGL 180
YSLSSVVTVP SSSLGTQTYI CNVNHKPSNT KVDKKV EPKS CDK GGGGSGG GGSGGGGS TI 240
PPHVQKSVNN DMIVTDNNGA VKFPQLCKFC DVRFSTCDNQ KSCMSNCSIT SICEKPQEVC 300
VAVWRKNDEN ITLETVCHDP KLPYHDFILE DAASPKCIMK EKKKPGETFF MCSCSSDECN 360
DNIIFSEEYN TSNPD GGGGS GGGGSGGGGS THTCPPCPAP ELLGGP SVFL FPPKPKDTLM 420
ISRTPEVTCV VVDVSHEDPE VKFNWYVDGV EVHNAKTKPR EEQYNSTYRV VSVLTVLHQD 480
WLNGKEYKCK VSNKALPAPI EKTISKAKGQ PREPQVYTLP PSREEMTKNQ VSLTCLVKGF 540
YPSDIAVEWE SNGQPENNYK TTPPVLDSDG SFFLYSKLTV DKSRWQQGNV FSCSVMHEAL 600
HNHYTQKSLS LSPGK 615
참고: 볼드체 및 밑줄친 단편은 힌지 영역 서열이고, 펩타이드 링커는 이탤릭체이며, 밑줄과 볼드체 서열은 TGF-βRII 아미노산 서열이다.
융합 단백질 Hib-PLT 경쇄의 핵산 서열(서열번호 79):
GATATCGTGCTGACCCAGTCTCCAGCTTCCCTGGCCGTGTCCCCAGGACAGAGGGCCACCATCACATGTCGGGCTTCCAAGAGCGTGCACACAAGCGGCTACTCTTATATGCATTGGTACCAGCAGAAGCCCGGCCAGCCCCCTAAGCTGCTGATCTATCTGGCTTCCAACCTGGAGAGCGGAGTGCCAGCTAGGTTCTCTGGCTCCGGCAGCGGCACCGACTTTACCCTGACAATCAATCCTGTGGAGGCCAACGATACAGCTAATTACTATTGCCAGCACTCCGGAGAGCTGCCATACACCTTCGGCGGAGGCACAAAGGTGGAGATCAAGCGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGTTAG
융합 단백질 Hib-PLT 경쇄의 아미노산 서열(서열번호 73):
DIVLTQSPAS LAVSPGQRAT ITCRASKSVH TSGYSYMHWY QQKPGQPPKL LIYLASNLES 60
GVPARFSGSG SGTDFTLTIN PVEANDTANY YCQHSGELPY TFGGGTKVEI KRTVAAPSVF 120
IFPPSDEQLK SGTASVVCLL NNFYPREAKV QWKVDNALQS GNSQESVTEQ DSKDSTYSLS 180
STLTLSKADY EKHKVYACEV THQGLSSPVT KSFNRGEC 218
융합 단백질 Hib-PDC의 중쇄 및 경쇄의 핵산 서열 및 아미노산 서열은 다음과 같다:
융합 단백질 Hib-PDC 중쇄의 핵산 서열(서열번호 74):
CAGGTGCAGCTCGTGGAGAGCGGGGGAGGCGTCGTCCAGCCTGGCCGTAGCCTGCGGCTGGACTGTAAGGCTAGCGGAATCACGTTCAGCAACAGCGGAATGCACTGGGTCAGACAGGCTCCTGGCAAAGGCCTCGAATGGGTCGCCGTGATCTGGTACGACGGGAGCAAGAGATACTACGCAGATTCAGTGAAGGGCCGTTTCACAATCAGCCGTGACAACTCGAAGAACACACTGTTCCTGCAGATGAACAGCCTGAGGGCAGAAGACACAGCAGTCTACTACTGCGCTACAAATGACGACTACTGGGGCCAGGGAACACTGGTCACCGTGAGCTCAGCTTCCACCAAGGGCCCATCCGTCTTCCCCCTGGCGCCCTGCTCCAGGAGCACCTCCGAGAGCACAGCCGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACGAAGACCTACACCTGCAACGTAGATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGTCCGGTGGCGGCGGAAGCGGCGGCGGAGGCAGCGGCGGAGGCGGCAGC GTGATCCATGTCACGAAGGAGGTCAAAGAAGTGGCCACCCTCAGCTGCGGTCACAACGTCAGCGTGGAAGAGTTGGCCCAGACCAGAATCTACTGGCAGAAGGAGAAGAAGATGGTCTTGACCATGATGAGCGGCGACATGAACATCTGGCCAGAGTACAAGAATAGAACTATCTTCGACATCACCAATAACCTGAGCATCGTGATCCTCGCTTTGCGTCCGAGCGACGAAGGCACCTACGAGTGCGTAGTGCTAAAGTACGAGAAAGACGCCTTCAAGCGGGAGCACCTGGCAGAAGTAACCCTGAGCGTGAAGGCAGACTTCCCAACGCCTAGCATCTCCGACTTCGAGATCCCCACAAGCAACATCCGGCGGATCATCTGTAGCACCTCCGGGGGTTTCCCCGAGCCTCACCTGTCCTGGCTCGAGAACGGCGAGGAGCTGAACGCCATCAACACCACCGTGAGCCAGGACCCCGAGACAGAACTGTACGCCGTGAGCTCCAAGCTCGACTTCAACATGACCACAAATCACAGCTTCATGTGCCTCATCAAGTACGGACACCTGCGGGTGAATCAGACGTTCAACTGGAAC GGCGGGGGGGGTAGCGGCGGCGGGGGCTCAGGTGGGGGGGGCTCAAAATATGGTCCCCCATGCCCACCATGCCCAGCACCTGAGTTCCTGGGGGGACCATCAGTCTTCCTGTTCCCCCCAAAACCCAAGGACACTCTCATGATCTCCCGGACCCCTGAGGTCACGTGCGTGGTGGTGGACGTGAGCCAGGAAGACCCCGAGGTCCAGTTCAACTGGTACGTGGATGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTTCAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAACGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGGCCTCCCGTCCTCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAGCCACAGGTGTACACCCTGCCCCCATCCCAGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTACCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAGGCTAACCGTGGACAAGAGCAGGTGGCAGGAGGGGAATGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACACAGAAGAGCCTCTCCCTGTCTCTGGGTAAATAG
참고: 밑줄과 볼드체 서열은 CD80 핵산 서열이다.
융합 단백질 Hib-PDC 중쇄의 아미노산 서열(서열번호 68):
QVQLVESGGG VVQPGRSLRL DCKASGITFS NSGMHWVRQA PGKGLEWVAV IWYDGSKRYY 60
ADSVKGRFTI SRDNSKNTLF LQMNSLRAED TAVYYCATND DYWGQGTLVT VSSASTKGPS 120
VFPLAPCSRS TSESTAALGC LVKDYFPEPV TVSWNSGALT SGVHTFPAVL QSSGLYSLSS 180
VVTVPSSSLG TKTYTCNVDH KPSNTKVDKR VESGGGGSGG GGSGGGGS VI HVTKEVKEVA 240
TLSCGHNVSV EELAQTRIYW QKEKKMVLTM MSGDMNIWPE YKNRTIFDIT NNLSIVILAL 300
RPSDEGTYEC VVLKYEKDAF KREHLAEVTL SVKADFPTPS ISDFEIPTSN IRRIICSTSG 360
GFPEPHLSWL ENGEELNAIN TTVSQDPETE LYAVSSKLDF NMTTNHSFMC LIKYGHLRVN 420
QTFNWN GGGG SGGGGSGGGG SKYGPPCPPC PAPEFLGGPS VFLFPPKPKD TLMISRTPEV 480
TCVVVDVSQE DPEVQFNWYV DGVEVHNAKT KPREEQFNST YRVVSVLTVL HQDWLNGKEY 540
KCKVSNKGLP SSIEKTISKA KGQPREPQVY TLPPSQEEMT KNQVSLTCLV KGFYPSDIAV 600
EWESNGQPEN NYKTTPPVLD SDGSFFLYSR LTVDKSRWQE GNVFSCSVMH EALHNHYTQK 660
SLSLSLGK 668
참고: 펩타이드 링커는 이탤릭체이며 밑줄과 굵은 글씨체는 CD80 아미노산 서열이다.
융합 단백질 Hib-PDC 경쇄의 핵산 서열(서열번호 75):
GAGATCGTGCTGACACAGAGCCCAGCCACTCTGTCACTGTCCCCAGGAGAAAGGGCTACTCTGTCTTGCCGGGCAAGCCAGTCTGTCTCCAGCTACCTGGCCTGGTATCAGCAGAAGCCCGGACAGGCTCCTAGACTGCTGATCTACGACGCAAGTAACAGAGCCACCGGCATCCCCGCACGCTTCAGTGGCTCAGGCTCCGGAACAGACTTTACTCTGACCATCTCTAGTCTGGAGCCTGAAGATTTCGCCGTGTACTATTGTCAGCAGAGCTCTAATTGGCCTAGAACCTTCGGCCAGGGCACCAAAGTCGAGATCAAGCGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGTTAG
융합 단백질 Hib-PDC 경쇄의 아미노산 서열(서열번호 69):
EIVLTQSPAT LSLSPGERAT LSCRASQSVS SYLAWYQQKP GQAPRLLIYD ASNRATGIPA 60
RFSGSGSGTD FTLTISSLEP EDFAVYYCQQ SSNWPRTFGQ GTKVEIKRTV AAPSVFIFPP 120
SDEQLKSGTA SVVCLLNNFY PREAKVQWKV DNALQSGNSQ ESVTEQDSKD STYSLSSTLT 180
LSKADYEKHK VYACEVTHQG LSSPVTKSFN RGEC 214
융합 단백질 Hib-PDV의 중쇄 및 경쇄의 핵산 서열 및 아미노산 서열은 다음과 같다:
융합 단백질 Hib-PDV 중쇄의 핵산 서열(서열번호 76):
CAGGTGCAGCTCGTGGAGAGCGGGGGAGGCGTCGTCCAGCCTGGCCGTAGCCTGCGGCTGGACTGTAAGGCTAGCGGAATCACGTTCAGCAACAGCGGAATGCACTGGGTCAGACAGGCTCCTGGCAAAGGCCTCGAATGGGTCGCCGTGATCTGGTACGACGGGAGCAAGAGATACTACGCAGATTCAGTGAAGGGCCGTTTCACAATCAGCCGTGACAACTCGAAGAACACACTGTTCCTGCAGATGAACAGCCTGAGGGCAGAAGACACAGCAGTCTACTACTGCGCTACAAATGACGACTACTGGGGCCAGGGAACACTGGTCACCGTGAGCTCAGCTTCCACCAAGGGCCCATCCGTCTTCCCCCTGGCGCCCTGCTCCAGGAGCACCTCCGAGAGCACAGCCGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACGAAGACCTACACCTGCAACGTAGATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGTCCGGTGGCGGCGGAAGCGGCGGCGGAGGCAGCGGCGGAGGCGGCAGC GGTAGACCATTCGTAGAGATGTACAGCGAAATCCCCGAAATCATCCACATGACTGAAGGAAGGGAGCTCGTCATCCCCTGCCGGGTTACGTCACCTAACATCACTGTTACTCTGAAGAAGTTCCCACTCGACACTTTGATCCCTGATGGAAAACGCATCATCTGGGACAGCAGAAAGGGCTTCATCATCTCAAATGCAACGTACAAAGAAATCGGACTCCTGACCTGTGAAGCAACAGTCAATGGACATTTGTATAAGACAAACTATCTCACACATCGACAGACCAATACAATCATCGATGTGGTTCTGAGCCCGTCTCATGGAATCGAACTATCTGTTGGAGAAAAGCTCGTCCTGAATTGTACAGCAAGAACTGAACTGAATGTGGGAATCGACTTCAACTGGGAATACCCTTCTTCGAAGCATCAGCATAAGAAACTCGTAAACCGAGACCTAAAGACCCAGTCTGGGAGCGAGATGAAGAAATTCTTGAGCACCCTGACTATCGATGGTGTAACCCGGAGCGACCAGGGATTGTACACCTGTGCAGCATCCAGCGGGCTGATGACCAAGAAGAACAGCACATTCGTCAGGGTCCATGAACCC GGCGGGGGGGGTAGCGGCGGCGGGGGCTCAGGTGGGGGGGGCTCAAAATATGGTCCCCCATGCCCACCATGCCCAGCACCTGAGTTCCTGGGGGGACCATCAGTCTTCCTGTTCCCCCCAAAACCCAAGGACACTCTCATGATCTCCCGGACCCCTGAGGTCACGTGCGTGGTGGTGGACGTGAGCCAGGAAGACCCCGAGGTCCAGTTCAACTGGTACGTGGATGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTTCAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAACGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGGCCTCCCGTCCTCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAGCCACAGGTGTACACCCTGCCCCCATCCCAGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTACCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAGGCTAACCGTGGACAAGAGCAGGTGGCAGGAGGGGAATGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACACAGAAGAGCCTCTCCCTGTCTCTGGGTAAATAG
참고: 밑줄과 굵은 글씨체는 VEGFR 핵산 서열이다.
융합 단백질 Hib-PDV 중쇄의 아미노산 서열(서열번호 70):
QVQLVESGGG VVQPGRSLRL DCKASGITFS NSGMHWVRQA PGKGLEWVAV IWYDGSKRYY 60
ADSVKGRFTI SRDNSKNTLF LQMNSLRAED TAVYYCATND DYWGQGTLVT VSSASTKGPS 120
VFPLAPCSRS TSESTAALGC LVKDYFPEPV TVSWNSGALT SGVHTFPAVL QSSGLYSLSS 180
VVTVPSSSLG TKTYTCNVDH KPSNTKVDKR VESGGGGSGG GGSGGGGS GR PFVEMYSEIP 240
EIIHMTEGRE LVIPCRVTSP NITVTLKKFP LDTLIPDGKR IIWDSRKGFI ISNATYKEIG 300
LLTCEATVNG HLYKTNYLTH RQTNTIIDVV LSPSHGIELS VGEKLVLNCT ARTELNVGID 360
FNWEYPSSKH QHKKLVNRDL KTQSGSEMKK FLSTLTIDGV TRSDQGLYTC AASSGLMTKK 420
NSTFVRVHEP GGGGSGGGGS GGGGSKYGPP CPPCPAPEFL GGPSVFLFPP KPKDTLMISR 480
TPEVTCVVVD VSQEDPEVQF NWYVDGVEVH NAKTKPREEQ FNSTYRVVSV LTVLHQDWLN 540
GKEYKCKVSN KGLPSSIEKT ISKAKGQPRE PQVYTLPPSQ EEMTKNQVSL TCLVKGFYPS 600
DIAVEWESNG QPENNYKTTP PVLDSDGSFF LYSRLTVDKS RWQEGNVFSC SVMHEALHNH 660
YTQKSLSLSL GK 672
참고: 펩타이드 링커는 이탤릭체이며 밑줄과 굵은 글씨체는 VEGF 아미노산 서열이다.
융합 단백질 Hib-PDV 경쇄의 핵산 서열(서열번호 77):
GAGATCGTGCTGACACAGAGCCCAGCCACTCTGTCACTGTCCCCAGGAGAAAGGGCTACTCTGTCTTGCCGGGCAAGCCAGTCTGTCTCCAGCTACCTGGCCTGGTATCAGCAGAAGCCCGGACAGGCTCCTAGACTGCTGATCTACGACGCAAGTAACAGAGCCACCGGCATCCCCGCACGCTTCAGTGGCTCAGGCTCCGGAACAGACTTTACTCTGACCATCTCTAGTCTGGAGCCTGAAGATTTCGCCGTGTACTATTGTCAGCAGAGCTCTAATTGGCCTAGAACCTTCGGCCAGGGCACCAAAGTCGAGATCAAGCGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGTTAG
융합 단백질 Hib-PDV 경쇄의 아미노산 서열(서열번호 71):
EIVLTQSPAT LSLSPGERAT LSCRASQSVS SYLAWYQQKP GQAPRLLIYD ASNRATGIPA 60
RFSGSGSGTD FTLTISSLEP EDFAVYYCQQ SSNWPRTFGQ GTKVEIKRTV AAPSVFIFPP 120
SDEQLKSGTA SVVCLLNNFY PREAKVQWKV DNALQSGNSQ ESVTEQDSKD STYSLSSTLT 180
LSKADYEKHK VYACEVTHQG LSSPVTKSFN RGEC 214
대조군 단백질 1의 중쇄 및 경쇄의 아미노산 서열
대조군 단백질 1 중쇄의 아미노산 서열(서열번호 124):
QVQLQESGPG LVKPSETLSL TCTVSGFSLS RYSVHWIRQP PGKGLEWLGM IWGVGTTDYN 60
SALKSRLTIS KDTSKNQFSL KLSSVTAADT AVYYCARNWG TADYFDYWGQ GTTVTVSSAS 120
TKGPSVFPLA PSSKSTSGGT AALGCLVKDY FPEPVTVSWN SGALTSGVHT FPAVLQSSGL 180
YSLSSVVTVP SSSLGTQTYI CNVNHKPSNT KVDKKVEPKS CDKTHTCPPC PAPELLGGPS 240
VFLFPPKPKD TLMISRTPEV TCVVVDVSHE DPEVKFNWYV DGVEVHNAKT KPREEQYNST 300
YRVVSVLTVL HQDWLNGKEY KCKVSNKALP APIEKTISKA KGQPREPQVY TLPPSREEMT 360
KNQVSLTCLV KGFYPSDIAV EWESNGQPEN NYKTTPPVLD SDGSFFLYSK LTVDKSRWQQ 420
GNVFSCSVMH EALHNHYTQK SLSLSPGKGG GGSGGGGSGG GGS TIPPHVQ KSVNNDMIVT 480
DNNGAVKFPQ LCKFCDVRFS TCDNQKSCMS NCSITSICEK PQEVCVAVWR KNDENITLET 540
VCHDPKLPYH DFILEDAASP KCIMKEKKKP GETFFMCSCS SDECNDNIIF SEEYNTSNPD 600
참고: 펩타이드 링커는 이탤릭체이며 밑줄과 굵은 글씨체는 TGF-βRII 아미노산 서열이다.
대조군 단백질 1 경쇄의 아미노산 서열(서열번호 125):
DIVLTQSPAS LAVSPGQRAT ITCRASKSVH TSGYSYMHWY QQKPGQPPKL LIYLASNLES 60
GVPARFSGSG SGTDFTLTIN PVEANDTANY YCQHSGELPY TFGGGTKVEI KRTVAAPSVF 120
IFPPSDEQLK SGTASVVCLL NNFYPREAKV QWKVDNALQS GNSQESVTEQ DSKDSTYSLS 180
STLTLSKADY EKHKVYACEV THQGLSSPVT KSFNRGEC 218
대조군 단백질 2의 중쇄 및 경쇄의 아미노산 서열
대조군 단백질 2 중쇄의 아미노산 서열(서열번호 126):
QVQLVESGGG VVQPGRSLRL DCKASGITFS NSGMHWVRQA PGKGLEWVAV IWYDGSKRYY 60
ADSVKGRFTI SRDNSKNTLF LQMNSLRAED TAVYYCATND DYWGQGTLVT VSSASTKGPS 120
VFPLAPCSRS TSESTAALGC LVKDYFPEPV TVSWNSGALT SGVHTFPAVL QSSGLYSLSS 180
VVTVPSSSLG TKTYTCNVDH KPSNTKVDKR VESKYGPPCP PCPAPEFLGG PSVFLFPPKP 240
KDTLMISRTP EVTCVVVDVS QEDPEVQFNW YVDGVEVHNA KTKPREEQFN STYRVVSVLT 300
VLHQDWLNGK EYKCKVSNKG LPSSIEKTIS KAKGQPREPQ VYTLPPSQEE MTKNQVSLTC 360
LVKGFYPSDI AVEWESNGQP ENNYKTTPPV LDSDGSFFLY SRLTVDKSRW QEGNVFSCSV 420
MHEALHNHYT QKSLSLSLGK GGGGSGGGGS GGGGS VIHVT KEVKEVATLS CGHNVSVEEL 480
AQTRIYWQKE KKMVLTMMSG DMNIWPEYKN RTIFDITNNL SIVILALRPS DEGTYECVVL 540
KYEKDAFKRE HLAEVTLSVK ADFPTPSISD FEIPTSNIRR IICSTSGGFP EPHLSWLENG 600
EELNAINTTV SQDPETELYA VSSKLDFNMT TNHSFMCLIK YGHLRVNQTF NWN 653
참고: 펩타이드 링커는 이탤릭체이며 밑줄과 굵은 글씨체는 CD80 아미노산 서열이다.
대조군 단백질 2 경쇄의 아미노산 서열(서열번호 127):
EIVLTQSPAT LSLSPGERAT LSCRASQSVS SYLAWYQQKP GQAPRLLIYD ASNRATGIPA 60
RFSGSGSGTD FTLTISSLEP EDFAVYYCQQ SSNWPRTFGQ GTKVEIKRTV AAPSVFIFPP 120
SDEQLKSGTA SVVCLLNNFY PREAKVQWKV DNALQSGNSQ ESVTEQDSKD STYSLSSTLT 180
LSKADYEKHK VYACEVTHQG LSSPVTKSFN RGEC 214
대조군 단백질 3의 중쇄 및 경쇄의 아미노산 서열
대조군 단백질 3 중쇄의 아미노산 서열(서열번호 128):
QVQLVESGGG VVQPGRSLRL DCKASGITFS NSGMHWVRQA PGKGLEWVAV IWYDGSKRYY 60
ADSVKGRFTI SRDNSKNTLF LQMNSLRAED TAVYYCATND DYWGQGTLVT VSSASTKGPS 120
VFPLAPCSRS TSESTAALGC LVKDYFPEPV TVSWNSGALT SGVHTFPAVL QSSGLYSLSS 180
VVTVPSSSLG TKTYTCNVDH KPSNTKVDKR VESKYGPPCP PCPAPEFLGG PSVFLFPPKP 240
KDTLMISRTP EVTCVVVDVS QEDPEVQFNW YVDGVEVHNA KTKPREEQFN STYRVVSVLT 300
VLHQDWLNGK EYKCKVSNKG LPSSIEKTIS KAKGQPREPQ VYTLPPSQEE MTKNQVSLTC 360
LVKGFYPSDI AVEWESNGQP ENNYKTTPPV LDSDGSFFLY SRLTVDKSRW QEGNVFSCSV 420
MHEALHNHYT QKSLSLSLGK GGGGSGGGGS GGGGS GRPFV EMYSEIPEII HMTEGRELVI 480
PCRVTSPNIT VTLKKFPLDT LIPDGKRIIW DSRKGFIISN ATYKEIGLLT CEATVNGHLY 540
KTNYLTHRQT NTIIDVVLSP SHGIELSVGE KLVLNCTART ELNVGIDFNW EYPSSKHQHK 600
KLVNRDLKTQ SGSEMKKFLS TLTIDGVTRS DQGLYTCAAS SGLMTKKNST FVRVHEP 657
참고: 펩타이드 링커는 이탤릭체이며 밑줄과 굵은 글씨체는 VEGFR 아미노산 서열이다.
대조군 단백질 3 경쇄의 아미노산 서열(서열번호 129):
EIVLTQSPAT LSLSPGERAT LSCRASQSVS SYLAWYQQKP GQAPRLLIYD ASNRATGIPA 60
RFSGSGSGTD FTLTISSLEP EDFAVYYCQQ SSNWPRTFGQ GTKVEIKRTV AAPSVFIFPP 120
SDEQLKSGTA SVVCLLNNFY PREAKVQWKV DNALQSGNSQ ESVTEQDSKD STYSLSSTLT 180
LSKADYEKHK VYACEVTHQG LSSPVTKSFN RGEC 214
TGF-β-R-His
TGF-β-R-His는 His-태깅된 TGF-βRII 세포외 영역 단편이고, 여기서 TGF-βRII 세포외 영역 단편(서열번호 137)의 아미노산 서열은 다음과 같다:
TIPPHVQKSV NNDMIVTDNN GAVKFPQLCK FCDVRFSTCD NQKSCMSNCS ITSICEKPQE 60
VCVAVWRKND ENITLETVCH DPKLPYHDFI LEDAASPKCI MKEKKKPGET FFMCSCSSDE 120
CNDNIIFSEE YNTSNPD 137
VEGF-R-His 아미노산 서열
VEGF-R-His는 VEGFR1의 제2 세포외 영역 및 VEGFR2의 제3 세포외 영역의 His-태그된 조합 단편이고, 여기서 VEGFR1의 제2 세포외 영역 및 VEGFR2의 제3 세포외 영역의 조합 단편의 아미노산 서열(서열번호 130)은 다음과 같다:
GRPFVEMYSE IPEIIHMTEG RELVIPCRVT SPNITVTLKK FPLDTLIPDG KRIIWDSRKG 60
FIISNATYKE IGLLTCEATV NGHLYKTNYL THRQTNTIID VVLSPSHGIE LSVGEKLVLN 120
CTARTELNVG IDFNWEYPSS KHQHKKLVNR DLKTQSGSEM KKFLSTLTID GVTRSDQGLY 180
TCAASSGLMT KKNSTFVRVH EP 202
CD80-His 아미노산 서열
CD80-His는 His-태깅된 CD80 단편이며, 여기서 CD80 단편(서열번호 32)의 아미노산 서열은 다음과 같다:
VIHVTKEVKE VATLSCGHNV SVEELAQTRI YWQKEKKMVL TMMSGDMNIW PEYKNRTIFD 60
ITNNLSIVIL ALRPSDEGTY ECVVLKYEKD AFKREHLAEV TLSVKADFPT PSISDFEIPT 120
SNIRRIICST SGGFPEPHLS WLENGEELNA INTTVSQDPE TELYAVSSKL DFNMTTNHSF 180
MCLIKYGHLR VNQTFNWN 198
실시예 2. CHO 발현
A. 세포 해동 및 확장:
CHO 숙주 세포를 10mL의 배양 부피 및 37.0℃, 200rpm, 8% CO2및 80% 습도의 배양 조건으로 해동시켰다. 해동 후 세포 밀도는 2.82 x 105 cells/mL이었고 생존율은 95.41%였다.
72시간의 세포 확장 및 배양 후, 생존 세포의 밀도는 2.22 x 106개 세포/mL이었고, 생존율은 98.32%였다.
세포 재주입 작업을 위해 세포를 5 x 105개 세포/mL로 재주입했다. 48시간 연속 배양 후 생존 세포의 밀도는 2Х106 cells/mL이었고 생존율은 98.68%였다.
세포를 5 x 105개 세포/웰로 6웰 플레이트에 2mL/웰의 배양 부피로 시딩하고, 이산화탄소 인큐베이터(배양 조건: 37℃, 8% CO2)에 넣어, 다음 날의 착생 및 형질감염을 위해 밤새도록 유지하였다.
B. 형질감염
형질감염 시약은 LTX 및 Plus 시약을 포함하는 Lipofectamine® LTX 시약(Invitrogen, 카탈로그 번호 15338-100)을 사용했다.
형질감염 절차: 6-웰 플레이트에서 배지 교체 및 형질감염 복합체 제조: LTX: 9㎕/웰 + 플라스미드: 2.5㎍/웰 + 플러스: 2.5㎕/웰. 형질감염 복합체를 6웰 플레이트에 250㎕/웰로 첨가하였다. 6-웰 플레이트의 각 웰의 배지는 세포 형질감염 5시간 후에 교체하였다. 형질감염 48시간 후, 상청액을 취하여 이중 항원 ELISA 방법으로 상청액의 항체 함량을 검출하였다.
C. 회분식 배양 및 유가식 배양
형질감염 48시간 후, 6-웰 플레이트의 세포를 소화시켜 세포 배양 튜브에 수집하고, 3 x 105개 세포/mL의 세포 밀도에서 현탁액에서 성장하도록 적응시켰다. 세포 생존율이 약 90%로 회복되면 Hib-PLT 발현 세포 풀과 대조군 단백질 1 발현 세포 풀을 회분식 배양으로 배양하고, Hib-PDC, 대조군 단백질 2, Hib-PDV 및 대조군 단백질 3을 유가 배양하였다.
배치 배양: 세포는 3 x 105개 세포/mL의 세포 밀도, 30mL의 부피 및 37.0°C, 200rpm, 8% CO2 및 80% 습도 배양 조건에서 TPP 세포 배양 튜브에서 배양되었고, 세포 생존력과 대사를 매일 모니터링했다. 생존율이 <60%가 될 때 배양을 종료하고, 배양 완료 후 세포 상층액을 채취하여 농도를 검출하였다.
유가식(Fed-batch) 배양: 세포는 3 x 105개 세포/mL의 세포 밀도, 30mL의 부피 및 37.0°C, 200rpm, 8% CO2 및 80% 습도의 배양 조건에서 TPP 세포 배양 튜브에서 배양되었다. 세포 농축 배지는 Glc가 2-6g/L로 조절되는 동안 특정 유가식 계획(표 5 참조)에 따라 제공되었다. 생존율이 <60%가 될 때까지 배양을 종료하고, 배양 완료 후 세포 상층액을 채취하여 농도를 검출하였다.
0일 | 3Х105/ml, 배양 부피30 ml |
4、6、8、10、12일 | 900 μL CellBoost7A、90 μL CellBoost7B |
16일 | VCD 및 생존력 검출, 샘플 비축 및 실험 종료 |
표 6은 하이바디 이중특이성 융합 단백질 Hib-PLT, Hib-PDC 및 Hib-PDV 및 이들의 상응하는 대조군 단백질의 발현 수준 결과를 나타낸다. 이러한 결과는 Hib-PLT 발현 수준 증가의 상대 값이 상응하는 대조군 단백질과 비교하여 52.85% 증가했음을 보여주며; Hib-PDC 발현 수준 증가의 상대값은 상응하는 대조군 단백질과 비교하여 33.43% 증가하였고; Hib-PDV 발현 수준 증가의 상대값은 상응하는 대조군 단백질과 비교하여 25.6% 증가하여, 본 발명에서 제공되는 하이바디 이중특이성 융합 단백질의 발현 수준이 상응하는 대조군 단백질의 발현 수준보다 현저히 우수함을 나타내고, 본 발명에서 제공되는 이중특이성 항체는 예상치 못한 기술적 효과를 가짐을 알 수 있다.
카테고리 | 배양 방법 | 발현 레벨 | 증가 상대값 |
Hib-PLT | 배치 배양 | 188 mg/L | 52.85% |
대조군 단백질1 | 배치 배양 | 123 mg/L | |
Hib-PDC | 유가식 배양 | 349.59 mg/L | 33.43% |
대조군 단백질 2 | 유가식 배양 | 262 mg/L | |
Hib-PDV | 유가식 배양 | 243.95 mg/L | 25.6% |
대조군 단백질 3 | 유가식 배양 | 194.22 mg/L |
참고: 증가의 상대값 = (본 발명에서 제공되는 이중특이성 융합 단백질의 발현 수준 - 해당 대조군 단백질의 발현 수준) / 해당 대조군 단백질의 발현 수준.
실시예 3. 결합 활성의 측정
1. Hib-PLT 결합 활성의 측정:
(1) 코팅 항원: TGF-β1을 코팅 완충액으로 2㎍/ml로 희석하고, 96-웰 플레이트에 100㎕/웰로 첨가하고, 2-8℃에서 밤새 방치하였다;
(2) 플레이트 세척: 플레이트를 용리액으로 사용된 PBST로 350 ㎕/웰로 3회 자동 세척하고 세척 후 가볍게 두드려 건조시켰다.
(3) 플레이트 차단: 플레이트를 차단 용액으로 사용하는 3% BSA-PBST로 300μl/웰로 차단하고 37°C에서 2시간 동안 인큐베이션했다.
(4) 플레이트 세척: 플레이트를 용리액으로 사용된 PBST로 350 ㎕/웰로 3회 자동 세척하고 세척 후 가볍게 두드려 건조시켰다.
(5) 시료의 첨가 : 시료의 각 농도점은 다음과 같다. 각 농도 지점의 샘플을 100μl/well로 96-웰 플레이트에 순차적으로 첨가하고, 각 농도 지점은 2개의 복제 웰과 평행하게 하고 플레이트를 37°C에서 2시간 동안 인큐베이션했다.
실험군 | S01 | S02 | S03 | S04 | S05 | S06 | S07 | S08 | S09 | S10 | S11 |
Hib-PLT | 555.556 | 55.556 | 5.556 | 1.852 | 0.617 | 0.206 | 0.069 | 0.023 | 0.008 | 0.001 | 0.000 |
TGF-β-R-His | 64516.000 | 6451.600 | 645.160 | 215.053 | 71.684 | 23.895 | 7.965 | 2.655 | 0.885 | 0.088 | 0.009 |
(단위: nM) |
(6) 플레이트 세척: 플레이트를 용리액으로 사용된 PBST로 350㎕/웰로 3회 자동 세척하고 세척 후 가볍게 두드려 건조시켰다.
(7) 2차 항체의 첨가:
Hib-PLT 샘플 웰: 염소-항-인간-Fc-HRP를 1:5000으로 희석하고 100 μl/웰로 첨가하였다. 그 다음 플레이트를 37°C에서 2시간 동안 인큐베이션했다.
TGF-β-R-His 웰: Anti-His-HRP를 1:5000으로 희석하고 100㎕/웰로 첨가하였다. 그 다음 플레이트를 37°C에서 2시간 동안 인큐베이션했다.
(8) 플레이트 세척: 플레이트를 용리액으로 사용된 PBST로 350 ㎕/웰로 5회 자동 세척하고 세척 후 가볍게 두드려 건조시켰다.
(9) 발색: 플레이트는 발색 용액으로 사용된 TMB를 사용하여 100μl/웰에서 2분 동안 발색되었다.
(10) 발색 종료: 플레이트는 정지 용액으로 사용된 2M H2SO4를 사용하여 50 μl/웰에서 발색을 위해 종료되었다.
(11) 판독: 흡광도 값은 MD 마이크로플레이트 판독기를 사용하여 각각 450/655 nm에서 판독되었다. 시험 샘플의 농도를 가로축으로, 흡광도 값을 세로축으로 하여 4-PL 곡선을 그리는 플롯을 만들고 소프트웨어에서 자동으로 EC50 값을 제공했다.
2. Hib-PDV 결합 활성의 측정:
(1) 코팅 항원: VEGF를 코팅 완충액으로 1㎍/ml로 희석하고, 96-웰 플레이트에 100㎕/웰로 첨가하고, 2-8℃에서 밤새 방치하였다;
(2) 플레이트 세척: 플레이트를 용리액으로 사용된 PBST로 350 ㎕/웰로 3회 자동 세척하고 세척 후 가볍게 두드려 건조시켰다.
(3) 플레이트 차단: 플레이트를 차단 용액으로 사용하는 3% BSA-PBST로 300μl/웰로 차단하고 37°C에서 2시간 동안 인큐베이션했다.
(4) 플레이트 세척: 플레이트를 용리액으로 사용된 PBST로 350 ㎕/웰로 3회 자동 세척하고 세척 후 가볍게 두드려 건조시켰다.
(5) 시료의 첨가 : 시료의 각 농도점은 다음과 같다. 각 농도 지점의 샘플을 100μl/well로 96-웰 플레이트에 순차적으로 첨가하고, 각 농도 지점은 2개의 복제 웰과 평행하게 하고 플레이트를 37°C에서 2시간 동안 인큐베이션했다.
실험군 | S01 | S02 | S03 | S04 | S05 | S06 | S07 | S08 | S09 | S10 | S11 |
Hib-PDV | 555.556 | 55.556 | 5.556 | 1.852 | 0.617 | 0.206 | 0.069 | 0.023 | 0.005 | 0.001 | 0.000 |
VEGFR-His | 43478.300 | 4347.830 | 434.783 | 144.928 | 48.309 | 16.103 | 5.368 | 1.789 | 0.358 | 0.036 | 0.004 |
(단위: nM) |
(6) 플레이트 세척: 플레이트를 용리액으로 사용된 PBST로 350㎕/웰로 3회 자동 세척하고 세척 후 가볍게 두드려 건조시켰다.
(7) 2차 항체의 첨가:
Hib-PDV 샘플 웰: 염소-항-인간-Fc-HRP를 1:5000으로 희석하고 100 μl/웰로 첨가하였다. 그 다음 플레이트를 37°C에서 2시간 동안 인큐베이션했다.
VEGFR-His 웰: Anti-His-HRP를 1:5000으로 희석하여 100㎕/well로 첨가하였다. 그 다음 플레이트를 37°C에서 2시간 동안 인큐베이션했다.
(8) 플레이트 세척: 플레이트를 용리액으로 사용된 PBST로 350 ㎕/웰로 5회 자동 세척하고 세척 후 가볍게 두드려 건조시켰다.
(9) 발색: 플레이트는 발색 용액으로 사용된 TMB를 사용하여 100μl/웰에서 2분 동안 발색되었다.
(10) 발색 종료: 플레이트는 정지 용액으로 사용된 2M H2SO4를 사용하여 50 μl/웰에서 발색을 위해 종료되었다.
(11) 판독: 흡광도 값은 MD 마이크로플레이트 판독기를 사용하여 각각 450/655 nm에서 판독되었다. 시험 샘플의 농도를 가로축으로, 흡광도 값을 세로축으로 하여 4-PL 곡선을 그리는 플롯을 만들고 소프트웨어에서 자동으로 EC50 값을 제공했다.
3. Hib-PDC 결합 활성의 측정:
(1) 코팅 항원: CTLA-4 단백질을 200μg/mL 농도의 멸균수 1mL로 재용해하고, 코팅 완충액으로 20μg/ml로 희석하고, 96-웰 플레이트에 100μl/웰로 첨가한 후 2-8℃에서 밤새 방치하였다;
(2) 플레이트 세척: 플레이트를 용리액으로 사용된 PBST로 350 ㎕/웰로 3회 자동 세척하고 세척 후 가볍게 두드려 건조시켰다.
(3) 플레이트 차단: 플레이트를 차단 용액으로 사용하는 3% BSA-PBST로 300μl/웰로 차단하고 37°C에서 2시간 ± 20분 동안 인큐베이션했다.
(4) 플레이트 세척: 플레이트를 용리액으로 사용된 PBST로 350 ㎕/웰로 3회 자동 세척하고 세척 후 가볍게 두드려 건조시켰다.
(5) 샘플 첨가: 비오틴화된 샘플을 PBST로 희석하였다. 시료의 각 농도점은 다음과 같다. 각 농도 지점의 샘플을 100μl/well로 96-웰 플레이트에 순차적으로 첨가하고, 각 농도 지점은 2개의 복제 웰과 평행했으며, 블랭크 웰은 PBST였고, 플레이트를 37°C에서 2시간 ± 20분 동안 인큐베이션했다.
실험군 | S01 | S02 | S03 | S04 | S05 | S06 | S07 | S08 | S09 | S10 |
Hib-PDC | 1000000 | 100000 | 10000 | 3333.333 | 1111.111 | 370.370 | 123.457 | 41.152 | 13.717 | 1.372 |
CD80-His | 1000000 | 100000 | 10000 | 3333.333 | 1111.111 | 370.370 | 123.457 | 41.152 | 13.717 | 1.372 |
(단위: nM) |
(6) 플레이트 세척: 플레이트를 용리액으로 사용된 PBST로 350㎕/웰로 3회 자동 세척하고 세척 후 가볍게 두드려 건조시켰다.
(7) 2차 항체의 첨가:
Hib-PDC 샘플 웰 및 CD80-His 웰: Streptavidin-HRP를 1:2000으로 희석하여 100μl/well로 첨가하였다. 그 다음 플레이트를 37°C에서 1시간 ± 10분 동안 인큐베이션했다.
(8) 플레이트 세척: 플레이트를 용리액으로 사용된 PBST로 350 ㎕/웰로 5회 자동 세척하고 세척 후 가볍게 두드려 건조시켰다.
(9) 발색: TMB Double Slow 기판을 100㎕/웰로 첨가하고 플레이트를 차광된 실온에서 6분 동안 발색시켰다.
(10) 발색 종료: 플레이트는 정지 용액으로 사용된 2M H2SO4를 사용하여 50 μl/웰에서 발색을 위해 종료되었다.
(11) 판독: 흡광도 값은 MD 마이크로플레이트 판독기를 사용하여 각각 450/655 nm에서 판독되었다. 시험 샘플의 농도를 가로축으로, 흡광도 값을 세로축으로 하여 4-PL 곡선을 그리는 플롯을 만들고 소프트웨어에서 자동으로 EC50 값을 제공했다. (표 10 참조).
실험군 | EC50 값 |
Hib-PLT | 0.164 nM |
TGF-β-R-His | 11.60 nM |
Hib-PDV | 0.061 nM |
VEGFR-His | 2154 nM |
Hib-PDC | 24.36 nM |
CD80-His | 50.69 nM |
결합 활성의 측정 결과는, Hib-PLT와 TGF-β 수용체 단량체의 비교 결과, Hib-PLT의 EC50 값은 0.164 nM이고, TGF-β 수용체 단량체의 EC50 값은 11.60 nM이며, Hib-PLT의 결합 활성은 TGF-β 수용체 단량체의 결합 활성보다 약 70배 더 우수하였다. Hib-PDV와 VEGF 수용체 단량체 간의 비교 결과, Hib-PDV는 0.061nM의 EC50 값을 갖고, VEGF 수용체 단량체는 2154nM의 EC50 값을 가지며, Hib-PDV 결합 활성은 VEGF 수용체 단량체의 결합 활성보다 약 35,311배 더 우수하였다. Hib-PDC와 CD80 단량체 간의 비교 결과, Hib-PDC의 EC50 값은 24.36nM이고, CD80 단량체의 EC50 값은 50.69 nM이며 Hib-PDC의 결합 활성은 CD80 단량체보다 약 2배 더 우수하였다. 즉, 본 발명에서 제공하는 이중항체 모델로 구축된 Hib-PLT, Hib-PDV, Hib-PDC의 결합 활성은 상응하는 단량체보다 훨씬 우수하였다.
실시예 4. C57BL/6J-hPD-1 마우스에서 결장암 MC38 세포의 피하 이식된 종양에 대한 Hib-PDV의 효능
32마리의 7주령, C57BL/6J 인간화 PD-1 형질전환 마우스(Shanghai Model Organisms Center, Inc.)를 수집하였다. 0.1 mL의 결장암 MC38 세포 현탁액(1 x 106 세포/마우스)을 마우스의 오른쪽 옆구리에 피하 접종하였다. 종양이 약 100 mm3로 성장했을 때, 마우스를 종양 크기에 따라 무작위로 비히클(PBS) 그룹, Hib-PDV(1.25 mg/kg) 그룹, Hib-PDV(2.5 mg/kg) 그룹 및 Hib-PDV(5 mg/kg) 그룹으로 각각 총 4개 그룹으로 나누었으며, 각 그룹은 8마리의 종양 보유 마우스를 갖는다. 주 1회 복강 내 투여하여 총 3회 투여하였으며, 투여 기간 동안 종양의 장경 및 단경 및 체중을 주 2회 측정하였다. 투여 후 21일째에 약효 평가를 위해 종양 성장 억제율(TGIRTV)을 표 11과 같이 계산하였다.
그룹 | 투여군 |
용량
(mg/kg) |
투여 경로 | 투여 주기 | 투여량 |
1 | 비히클 | -- | i.p. | QWХ3 | 10 mL/kg |
2 | Hib-PDV | 5 | i.p. | QWХ3 | 10 mL/kg |
3 | Hib-PDV | 2.5 | i.p. | QWХ3 | 10 mL/kg |
4 | Hib-PDV | 1.25 | i.p. | QWХ3 | 10 mL/kg |
계산 공식:
종양 부피: TV = D1ХD2 2/2, 여기서 D1 및 D2는 각각 종양의 장직경 및 단직경을 나타냄;
상대적 종양 부피: RTV = TVT/TV1, 여기서 TV1은 투여 전 종양 부피이고, TVT는 각 측정에서의 종양 부피임;
상대적 종양 억제율: TGIRTV(%) = (1-TRTV/CRTV) x 100%, 여기서 TRTV는 투여군 또는 양성 대조군의 RTV를 나타내고, CRTV는 음성 대조군의 RTV를 나타낸다.
결과 및 결론: 마우스 결장암 모델에 대한 Hib-PDV의 종양 억제 효과를 표 12 및 도 2에 나타내었고, 표 12는 마우스 결장암 모델에 대한 Hib-PDV의 종양 부피 및 종양 성장 억제율을 나타내고, 도 2는 투여 후 종양 성장의 그래프이다. 실험 결과는 Hib-PDV가 마우스 결장암 모델 종양에 상당한 억제 효과가 있음을 보여준다.
투여군 | 종양 부피(TV, mm 3 ) | TGIRTV (%) | |
D0 | D21 | ||
비히클 | 86+10 | 1299+174 | -- |
Hib-PDV (5 mg/kg) | 86+10 | 675+218 | 46 |
Hib-PDV (2.5 mg/kg) | 86+8 | 755+305 | 47 |
Hib-PDV (1.25 mg/kg) | 85+8 | 1088+259 | 14 |
실시예 5. C57BL/6J-hPD-1 마우스에서 형질전환 hPD-L1 MC38 세포의 피하 이식된 종양에 대한 Hib-PDC의 효능
32마리의 7-9주령 인간화 C57BL/6J 인간화 PD-1 트랜스제닉 암컷 마우스(Shanghai Model Organisms Center, Inc.)를 수집하였다. 0.1 mL의 형질전환 hPD-L1 MC38 세포 현탁액(1 x 106 세포/마우스)을 마우스의 오른쪽 앞다리 뒤쪽에 피하 이식하였다. 종양이 약 100 mm3로 성장했을 때, 마우스를 종양 크기에 따라 무작위로 비히클(PBS) 그룹, Hib-PDC(1.25 mg/kg) 그룹, Hib-PDC(2.5 mg/kg) 그룹 및 Hib-PDC(5 mg/kg) 그룹으로 각각 총 4개 그룹으로 나누었으며, 각 그룹은 8마리의 종양 보유 마우스를 갖는다. 주 1회 복강 내 투여하여 총 3회 투여하였으며, 투여 기간 동안 종양의 장경 및 단경 및 체중을 주 2회 측정하였다. 투여 후 21일째에 약효 평가를 위해 종양 성장 억제율(TGIRTV)을 표 13과 같이 계산하였다.
그룹 | 투여군 | Dosage (mg/kg) | 투여 경로 | 투여량 | 투여 주기 |
1 | 비히클(PBS) | -- | i.p. | 10 ml/kg | QWХ3 |
2 | Hib-PDC | 1.25 | i.p. | 10 ml/kg | QWХ3 |
3 | Hib-PDC | 2.5 | i.p. | 10 ml/kg | QWХ3 |
4 | Hib-PDC | 5 | i.p. | 10 ml/kg | QWХ3 |
계산 공식:
종양 부피: TV = D1ХD2 2/2, 여기서 D1 및 D2는 각각 종양의 장직경 및 단직경을 나타냄;
상대적 종양 부피: RTV = TVT/TV1, 여기서 TV1은 투여 전 종양 부피이고, TVT는 각 측정에서의 종양 부피임;
상대적 종양 억제율: TGIRTV(%) = (1-TRTV/CRTV) x 100%, 여기서 TRTV는 투여군 또는 양성 대조군의 RTV를 나타내고, CRTV는 음성 대조군의 RTV를 나타낸다.
결과 및 결론: 마우스 결장암 모델에 대한 Hib- PDC 의 종양 억제 효과를 표 14 및 도 3에 나타내었고, 표 14는 마우스 결장암 모델에 대한 Hib- PDC 의 종양 부피 및 종양 성장 억제율을 나타내고, 도 3은 투여 후 종양 성장의 그래프이다. 실험 결과는 Hib-PDC가 쥐의 피하 이식된 대장암 종양에 상당한 억제 효과가 있음을 보여준다.
군 |
용량
(mg/kg) |
종양 부피 (TV, mm 3 ) | TGIRTV (%) | |
D0 | D21 | |||
PBS | -- | 101±10 | 2319±517 | -- |
Hib-PDC | 1.25 | 101±8 | 1577±211 | 31 |
Hib-PDC | 2.5 | 101±9 | 813±74 | 63 |
Hib-PDC | 5 | 101±9 | 541±179 | 77 |
실시예 6. 동종 림프구의 혼합 반응에서 사이토카인 분비에 대한 Hib-PLT의 효과
CD4+ T 세포를 활성화하는데 Hib-PLT의 역할을 평가하기 위해, 세포 상청액에서 사이토카인 IFN-γ의 농도를 검출하고자 ELISA 방법을 사용하였다. 공여자 1의 단핵 림프구를 시험관 내 DC 세포 급속 성숙 시험관 키트(cat: CT-004, StemEry)로 성숙한 수지상 세포로 유도하고, 세포를 48시간 후에 수집하고 2 x 105 cells/mL로 희석하였다. 공여자2의 CD4+ T 세포를 마그네틱 비드(EasySep?? Human CD4+ T Cell Enrichment Kit, StemCell, cat: 19052)로 강화하고 1 x 106 cells/mL로 희석했다. 성숙한 수지상 세포와 CD4+ T 세포를 1:1의 부피비로 혼합하고, 혼합된 세포 현탁액을 100 μL/well의 부피로 96-웰 플레이트에 첨가하였다. Hib-PLT, PD-L1 대조군 항체 + TGF-β Trap(병용 약물), PD-L1 대조군 항체, TGF-β Trap 및 인간 IgG1(Biolegend)을 혼합 세포 현탁액이 포함된 96-웰 플레이트에 0.01-100nM의 최종 농도로 첨가하였다. 그 다음 플레이트를 37°C, 5% CO2 인큐베이터에 120시간 동안 놓고 2000rpm에서 5분 동안 원심분리하고 150-200μL의 세포 상청액을 수집했다. ELISA 키트(Human IL-2 Quantikine ELISA Kit, R&D, cat: S2050; Human IFN-gamma Quantikine ELISA Kit, R&D, cat: SIF50C)를 사용하여 동종 림프구의 혼합 반응 상청액에서 IFN-γ 인자를 검출했다. 그룹 간의 차이를 분석하는 데에 One-way ANOVA를 사용하였다.
결과 및 결론: 도 4에 도시된 바와 같이, IFN-γ 인자의 세포 분비를 촉진하는 10-100 nM 농도에서 Hib-PLT의 수준은 PD-L1 대조군 항체와 TGF-β 트랩의 병용 투여 군보다 유의하게 높았다(p<0.05). 이러한 결과는 10-100nM의 농도 수준에서 Hib-PLT가 혼합 림프구 반응에서 CD4+ T 세포의 활성화를 촉진하는 데 있어 복합 약물 그룹보다 더 우수함을 보여준다.
본 발명은 다양한 특정 실시예에 의해 예시되었다. 다만, 본 기술분야에서 통상의 지식을 가진 자라면 본 발명이 각각의 특정한 실시예에 한정되는 것은 아니며, 통상의 기술자는 본 발명의 범위 내에서 다양한 변경 또는 수정을 할 수 있고, 본 명세서의 여러 곳에서 언급된 각각의 기술적 특징은 본 발명의 본질 및 범위를 벗어나지 않고 서로 결합될 수 있다. 이러한 변경 및 수정은 본 발명의 범위 내에 있다.
<110> RemeGen Co., Ltd.
<120> BISPECIFIC FUSION PROTEIN AND APPLICATION THEREOF
<130> PI220009
<150> CN 202010199036.2
<151> 2020-03-20
<160> 137
<170> KoPatentIn 3.0
<210> 1
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> Heavy chain variable region CDR1
<400> 1
Gly Phe Ser Leu Ser Arg Tyr
1 5
<210> 2
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> Heavy chain variable region CDR1
<400> 2
Gly Phe Ser Leu Ser Arg Tyr Ser Val His
1 5 10
<210> 3
<211> 5
<212> PRT
<213> Artificial Sequence
<220>
<223> Heavy chain variable region CDR1
<400> 3
Arg Tyr Ser Val His
1 5
<210> 4
<211> 6
<212> PRT
<213> Artificial Sequence
<220>
<223> Heavy chain variable region CDR1
<400> 4
Ser Arg Tyr Ser Val His
1 5
<210> 5
<211> 8
<212> PRT
<213> Artificial Sequence
<220>
<223> Heavy chain variable region CDR1
<400> 5
Gly Phe Ser Leu Ser Arg Tyr Ser
1 5
<210> 6
<211> 5
<212> PRT
<213> Artificial Sequence
<220>
<223> Heavy chain variable region CDR2
<400> 6
Trp Gly Val Gly Thr
1 5
<210> 7
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> Heavy chain variable region CDR2
<400> 7
Met Ile Trp Gly Val Gly Thr Thr Asp
1 5
<210> 8
<211> 16
<212> PRT
<213> Artificial Sequence
<220>
<223> Heavy chain variable region CDR2
<400> 8
Met Ile Trp Gly Val Gly Thr Thr Asp Tyr Asn Ser Ala Leu Lys Ser
1 5 10 15
<210> 9
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Heavy chain variable region CDR2
<400> 9
Trp Leu Gly Met Ile Trp Gly Val Gly Thr Thr Asp
1 5 10
<210> 10
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> Heavy chain variable region CDR2
<400> 10
Ile Trp Gly Val Gly Thr Thr
1 5
<210> 11
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> Heavy chain variable region CDR3
<400> 11
Asn Trp Gly Thr Ala Asp Tyr Phe Asp Tyr
1 5 10
<210> 12
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> Heavy chain variable region CDR3
<400> 12
Asn Trp Gly Thr Ala Asp Tyr Phe Asp Tyr
1 5 10
<210> 13
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> Heavy chain variable region CDR3
<400> 13
Asn Trp Gly Thr Ala Asp Tyr Phe Asp Tyr
1 5 10
<210> 14
<211> 11
<212> PRT
<213> Artificial Sequence
<220>
<223> Heavy chain variable region CDR3
<400> 14
Ala Arg Asn Trp Gly Thr Ala Asp Tyr Phe Asp
1 5 10
<210> 15
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Heavy chain variable region CDR3
<400> 15
Ala Arg Asn Trp Gly Thr Ala Asp Tyr Phe Asp Tyr
1 5 10
<210> 16
<211> 15
<212> PRT
<213> Artificial Sequence
<220>
<223> Light chain variable region CDR1
<400> 16
Arg Ala Ser Lys Ser Val His Thr Ser Gly Tyr Ser Tyr Met His
1 5 10 15
<210> 17
<211> 15
<212> PRT
<213> Artificial Sequence
<220>
<223> Light chain variable region CDR1
<400> 17
Arg Ala Ser Lys Ser Val His Thr Ser Gly Tyr Ser Tyr Met His
1 5 10 15
<210> 18
<211> 15
<212> PRT
<213> Artificial Sequence
<220>
<223> Light chain variable region CDR1
<400> 18
Arg Ala Ser Lys Ser Val His Thr Ser Gly Tyr Ser Tyr Met His
1 5 10 15
<210> 19
<211> 11
<212> PRT
<213> Artificial Sequence
<220>
<223> Light chain variable region CDR1
<400> 19
His Thr Ser Gly Tyr Ser Tyr Met His Trp Tyr
1 5 10
<210> 20
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> Light chain variable region CDR1
<400> 20
Lys Ser Val His Thr Ser Gly Tyr Ser Tyr
1 5 10
<210> 21
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> Light chain variable region CDR2
<400> 21
Leu Ala Ser Asn Leu Glu Ser
1 5
<210> 22
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> Light chain variable region CDR2
<400> 22
Leu Ala Ser Asn Leu Glu Ser
1 5
<210> 23
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> Light chain variable region CDR2
<400> 23
Leu Ala Ser Asn Leu Glu Ser
1 5
<210> 24
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> Light chain variable region CDR2
<400> 24
Leu Leu Ile Tyr Leu Ala Ser Asn Leu Glu
1 5 10
<210> 25
<211> 3
<212> PRT
<213> Artificial Sequence
<220>
<223> Light chain variable region CDR2
<400> 25
Leu Ala Ser
1
<210> 26
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> Light chain variable region CDR3
<400> 26
Gln His Ser Gly Glu Leu Pro Tyr Thr
1 5
<210> 27
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> Light chain variable region CDR3
<400> 27
Gln His Ser Gly Glu Leu Pro Tyr Thr
1 5
<210> 28
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> Light chain variable region CDR3
<400> 28
Gln His Ser Gly Glu Leu Pro Tyr Thr
1 5
<210> 29
<211> 8
<212> PRT
<213> Artificial Sequence
<220>
<223> Light chain variable region CDR3
<400> 29
Gln His Ser Gly Glu Leu Pro Tyr
1 5
<210> 30
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> Light chain variable region CDR3
<400> 30
Gln His Ser Gly Glu Leu Pro Tyr Thr
1 5
<210> 31
<211> 137
<212> PRT
<213> Artificial Sequence
<220>
<223> Human TGF-betaRII
<400> 31
Thr Ile Pro Pro His Val Gln Lys Ser Val Asn Asn Asp Met Ile Val
1 5 10 15
Thr Asp Asn Asn Gly Ala Val Lys Phe Pro Gln Leu Cys Lys Phe Cys
20 25 30
Asp Val Arg Phe Ser Thr Cys Asp Asn Gln Lys Ser Cys Met Ser Asn
35 40 45
Cys Ser Ile Thr Ser Ile Cys Glu Lys Pro Gln Glu Val Cys Val Ala
50 55 60
Val Trp Arg Lys Asn Asp Glu Asn Ile Thr Leu Glu Thr Val Cys His
65 70 75 80
Asp Pro Lys Leu Pro Tyr His Asp Phe Ile Leu Glu Asp Ala Ala Ser
85 90 95
Pro Lys Cys Ile Met Lys Glu Lys Lys Lys Pro Gly Glu Thr Phe Phe
100 105 110
Met Cys Ser Cys Ser Ser Asp Glu Cys Asn Asp Asn Ile Ile Phe Ser
115 120 125
Glu Glu Tyr Asn Thr Ser Asn Pro Asp
130 135
<210> 32
<211> 198
<212> PRT
<213> Artificial Sequence
<220>
<223> CD80 ECD
<400> 32
Val Ile His Val Thr Lys Glu Val Lys Glu Val Ala Thr Leu Ser Cys
1 5 10 15
Gly His Asn Val Ser Val Glu Glu Leu Ala Gln Thr Arg Ile Tyr Trp
20 25 30
Gln Lys Glu Lys Lys Met Val Leu Thr Met Met Ser Gly Asp Met Asn
35 40 45
Ile Trp Pro Glu Tyr Lys Asn Arg Thr Ile Phe Asp Ile Thr Asn Asn
50 55 60
Leu Ser Ile Val Ile Leu Ala Leu Arg Pro Ser Asp Glu Gly Thr Tyr
65 70 75 80
Glu Cys Val Val Leu Lys Tyr Glu Lys Asp Ala Phe Lys Arg Glu His
85 90 95
Leu Ala Glu Val Thr Leu Ser Val Lys Ala Asp Phe Pro Thr Pro Ser
100 105 110
Ile Ser Asp Phe Glu Ile Pro Thr Ser Asn Ile Arg Arg Ile Ile Cys
115 120 125
Ser Thr Ser Gly Gly Phe Pro Glu Pro His Leu Ser Trp Leu Glu Asn
130 135 140
Gly Glu Glu Leu Asn Ala Ile Asn Thr Thr Val Ser Gln Asp Pro Glu
145 150 155 160
Thr Glu Leu Tyr Ala Val Ser Ser Lys Leu Asp Phe Asn Met Thr Thr
165 170 175
Asn His Ser Phe Met Cys Leu Ile Lys Tyr Gly His Leu Arg Val Asn
180 185 190
Gln Thr Phe Asn Trp Asn
195
<210> 33
<211> 202
<212> PRT
<213> Artificial Sequence
<220>
<223> VEGFR
<400> 33
Gly Arg Pro Phe Val Glu Met Tyr Ser Glu Ile Pro Glu Ile Ile His
1 5 10 15
Met Thr Glu Gly Arg Glu Leu Val Ile Pro Cys Arg Val Thr Ser Pro
20 25 30
Asn Ile Thr Val Thr Leu Lys Lys Phe Pro Leu Asp Thr Leu Ile Pro
35 40 45
Asp Gly Lys Arg Ile Ile Trp Asp Ser Arg Lys Gly Phe Ile Ile Ser
50 55 60
Asn Ala Thr Tyr Lys Glu Ile Gly Leu Leu Thr Cys Glu Ala Thr Val
65 70 75 80
Asn Gly His Leu Tyr Lys Thr Asn Tyr Leu Thr His Arg Gln Thr Asn
85 90 95
Thr Ile Ile Asp Val Val Leu Ser Pro Ser His Gly Ile Glu Leu Ser
100 105 110
Val Gly Glu Lys Leu Val Leu Asn Cys Thr Ala Arg Thr Glu Leu Asn
115 120 125
Val Gly Ile Asp Phe Asn Trp Glu Tyr Pro Ser Ser Lys His Gln His
130 135 140
Lys Lys Leu Val Asn Arg Asp Leu Lys Thr Gln Ser Gly Ser Glu Met
145 150 155 160
Lys Lys Phe Leu Ser Thr Leu Thr Ile Asp Gly Val Thr Arg Ser Asp
165 170 175
Gln Gly Leu Tyr Thr Cys Ala Ala Ser Ser Gly Leu Met Thr Lys Lys
180 185 190
Asn Ser Thr Phe Val Arg Val His Glu Pro
195 200
<210> 34
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> Heavy chain variable region CDR1
<400> 34
Gly Ile Thr Phe Ser Asn Ser
1 5
<210> 35
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> Heavy chain variable region CDR1
<400> 35
Gly Ile Thr Phe Ser Asn Ser Gly Met His
1 5 10
<210> 36
<211> 5
<212> PRT
<213> Artificial Sequence
<220>
<223> Heavy chain variable region CDR1
<400> 36
Asn Ser Gly Met His
1 5
<210> 37
<211> 6
<212> PRT
<213> Artificial Sequence
<220>
<223> Heavy chain variable region CDR1
<400> 37
Ser Asn Ser Gly Met His
1 5
<210> 38
<211> 8
<212> PRT
<213> Artificial Sequence
<220>
<223> Heavy chain variable region CDR1
<400> 38
Gly Ile Thr Phe Ser Asn Ser Gly
1 5
<210> 39
<211> 6
<212> PRT
<213> Artificial Sequence
<220>
<223> Heavy chain variable region CDR2
<400> 39
Trp Tyr Asp Gly Ser Lys
1 5
<210> 40
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> Heavy chain variable region CDR2
<400> 40
Val Ile Trp Tyr Asp Gly Ser Lys Arg Tyr
1 5 10
<210> 41
<211> 17
<212> PRT
<213> Artificial Sequence
<220>
<223> Heavy chain variable region CDR2
<400> 41
Val Ile Trp Tyr Asp Gly Ser Lys Arg Tyr Tyr Ala Asp Ser Val Lys
1 5 10 15
Gly
<210> 42
<211> 13
<212> PRT
<213> Artificial Sequence
<220>
<223> Heavy chain variable region CDR2
<400> 42
Trp Val Ala Val Ile Trp Tyr Asp Gly Ser Lys Arg Tyr
1 5 10
<210> 43
<211> 8
<212> PRT
<213> Artificial Sequence
<220>
<223> Heavy chain variable region CDR2
<400> 43
Ile Trp Tyr Asp Gly Ser Lys Arg
1 5
<210> 44
<211> 4
<212> PRT
<213> Artificial Sequence
<220>
<223> Heavy chain variable region CDR3
<400> 44
Asn Asp Asp Tyr
1
<210> 45
<211> 4
<212> PRT
<213> Artificial Sequence
<220>
<223> Heavy chain variable region CDR3
<400> 45
Asn Asp Asp Tyr
1
<210> 46
<211> 4
<212> PRT
<213> Artificial Sequence
<220>
<223> Heavy chain variable region CDR3
<400> 46
Asn Asp Asp Tyr
1
<210> 47
<211> 5
<212> PRT
<213> Artificial Sequence
<220>
<223> Heavy chain variable region CDR3
<400> 47
Ala Thr Asn Asp Asp
1 5
<210> 48
<211> 6
<212> PRT
<213> Artificial Sequence
<220>
<223> Heavy chain variable region CDR3
<400> 48
Ala Thr Asn Asp Asp Tyr
1 5
<210> 49
<211> 11
<212> PRT
<213> Artificial Sequence
<220>
<223> Light chain variable region CDR1
<400> 49
Arg Ala Ser Gln Ser Val Ser Ser Tyr Leu Ala
1 5 10
<210> 50
<211> 11
<212> PRT
<213> Artificial Sequence
<220>
<223> Light chain variable region CDR1
<400> 50
Arg Ala Ser Gln Ser Val Ser Ser Tyr Leu Ala
1 5 10
<210> 51
<211> 11
<212> PRT
<213> Artificial Sequence
<220>
<223> Light chain variable region CDR1
<400> 51
Arg Ala Ser Gln Ser Val Ser Ser Tyr Leu Ala
1 5 10
<210> 52
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> Light chain variable region CDR1
<400> 52
Ser Ser Tyr Leu Ala Trp Tyr
1 5
<210> 53
<211> 6
<212> PRT
<213> Artificial Sequence
<220>
<223> Light chain variable region CDR1
<400> 53
Gln Ser Val Ser Ser Tyr
1 5
<210> 54
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> Light chain variable region CDR2
<400> 54
Asp Ala Ser Asn Arg Ala Thr
1 5
<210> 55
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> Light chain variable region CDR2
<400> 55
Asp Ala Ser Asn Arg Ala Thr
1 5
<210> 56
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> Light chain variable region CDR2
<400> 56
Asp Ala Ser Asn Arg Ala Thr
1 5
<210> 57
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> Light chain variable region CDR2
<400> 57
Leu Leu Ile Tyr Asp Ala Ser Asn Arg Ala
1 5 10
<210> 58
<211> 3
<212> PRT
<213> Artificial Sequence
<220>
<223> Light chain variable region CDR2
<400> 58
Asp Ala Ser
1
<210> 59
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> Light chain variable region CDR3
<400> 59
Gln Gln Ser Ser Asn Trp Pro Arg Thr
1 5
<210> 60
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> Light chain variable region CDR3
<400> 60
Gln Gln Ser Ser Asn Trp Pro Arg Thr
1 5
<210> 61
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> Light chain variable region CDR3
<400> 61
Gln Gln Ser Ser Asn Trp Pro Arg Thr
1 5
<210> 62
<211> 8
<212> PRT
<213> Artificial Sequence
<220>
<223> Light chain variable region CDR3
<400> 62
Gln Gln Ser Ser Asn Trp Pro Arg
1 5
<210> 63
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> Light chain variable region CDR3
<400> 63
Gln Gln Ser Ser Asn Trp Pro Arg Thr
1 5
<210> 64
<211> 113
<212> PRT
<213> Artificial Sequence
<220>
<223> Heavy chain variable region amino acid sequence
<400> 64
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Asp Cys Lys Ala Ser Gly Ile Thr Phe Ser Asn Ser
20 25 30
Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Val Ile Trp Tyr Asp Gly Ser Lys Arg Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Phe
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Thr Asn Asp Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser
100 105 110
Ser
<210> 65
<211> 107
<212> PRT
<213> Artificial Sequence
<220>
<223> Light chain variable region amino acid sequence
<400> 65
Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Tyr
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Tyr Asp Ala Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro
65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Ser Ser Asn Trp Pro Arg
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 66
<211> 120
<212> PRT
<213> Artificial Sequence
<220>
<223> Heavy chain variable region amino acid sequence
<400> 66
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Ser Arg Tyr
20 25 30
Ser Val His Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Leu
35 40 45
Gly Met Ile Trp Gly Val Gly Thr Thr Asp Tyr Asn Ser Ala Leu Lys
50 55 60
Ser Arg Leu Thr Ile Ser Lys Asp Thr Ser Lys Asn Gln Phe Ser Leu
65 70 75 80
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Asn Trp Gly Thr Ala Asp Tyr Phe Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Thr Val Thr Val Ser Ser Ala Ser
115 120
<210> 67
<211> 113
<212> PRT
<213> Artificial Sequence
<220>
<223> Light chain variable region amino acid sequence
<400> 67
Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Pro Gly
1 5 10 15
Gln Arg Ala Thr Ile Thr Cys Arg Ala Ser Lys Ser Val His Thr Ser
20 25 30
Gly Tyr Ser Tyr Met His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro
35 40 45
Lys Leu Leu Ile Tyr Leu Ala Ser Asn Leu Glu Ser Gly Val Pro Ala
50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Asn
65 70 75 80
Pro Val Glu Ala Asn Asp Thr Ala Asn Tyr Tyr Cys Gln His Ser Gly
85 90 95
Glu Leu Pro Tyr Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg
100 105 110
Thr
<210> 68
<211> 668
<212> PRT
<213> Artificial Sequence
<220>
<223> Hib-PDC heavy chain amino acid sequence
<400> 68
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Asp Cys Lys Ala Ser Gly Ile Thr Phe Ser Asn Ser
20 25 30
Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Val Ile Trp Tyr Asp Gly Ser Lys Arg Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Phe
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Thr Asn Asp Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser
100 105 110
Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser
115 120 125
Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp
130 135 140
Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr
145 150 155 160
Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr
165 170 175
Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys
180 185 190
Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp
195 200 205
Lys Arg Val Glu Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
210 215 220
Gly Gly Gly Ser Val Ile His Val Thr Lys Glu Val Lys Glu Val Ala
225 230 235 240
Thr Leu Ser Cys Gly His Asn Val Ser Val Glu Glu Leu Ala Gln Thr
245 250 255
Arg Ile Tyr Trp Gln Lys Glu Lys Lys Met Val Leu Thr Met Met Ser
260 265 270
Gly Asp Met Asn Ile Trp Pro Glu Tyr Lys Asn Arg Thr Ile Phe Asp
275 280 285
Ile Thr Asn Asn Leu Ser Ile Val Ile Leu Ala Leu Arg Pro Ser Asp
290 295 300
Glu Gly Thr Tyr Glu Cys Val Val Leu Lys Tyr Glu Lys Asp Ala Phe
305 310 315 320
Lys Arg Glu His Leu Ala Glu Val Thr Leu Ser Val Lys Ala Asp Phe
325 330 335
Pro Thr Pro Ser Ile Ser Asp Phe Glu Ile Pro Thr Ser Asn Ile Arg
340 345 350
Arg Ile Ile Cys Ser Thr Ser Gly Gly Phe Pro Glu Pro His Leu Ser
355 360 365
Trp Leu Glu Asn Gly Glu Glu Leu Asn Ala Ile Asn Thr Thr Val Ser
370 375 380
Gln Asp Pro Glu Thr Glu Leu Tyr Ala Val Ser Ser Lys Leu Asp Phe
385 390 395 400
Asn Met Thr Thr Asn His Ser Phe Met Cys Leu Ile Lys Tyr Gly His
405 410 415
Leu Arg Val Asn Gln Thr Phe Asn Trp Asn Gly Gly Gly Gly Ser Gly
420 425 430
Gly Gly Gly Ser Gly Gly Gly Gly Ser Lys Tyr Gly Pro Pro Cys Pro
435 440 445
Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe
450 455 460
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
465 470 475 480
Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe
485 490 495
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
500 505 510
Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
515 520 525
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
530 535 540
Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala
545 550 555 560
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln
565 570 575
Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
580 585 590
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
595 600 605
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
610 615 620
Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu
625 630 635 640
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
645 650 655
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
660 665
<210> 69
<211> 214
<212> PRT
<213> Artificial Sequence
<220>
<223> Hib-PDC light chain amino acid sequence
<400> 69
Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Tyr
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Tyr Asp Ala Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro
65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Ser Ser Asn Trp Pro Arg
85 90 95
Thr Phe Gly Gln 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> 70
<211> 672
<212> PRT
<213> Artificial Sequence
<220>
<223> Hib-PDV heavy chain amino acid sequence
<400> 70
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Asp Cys Lys Ala Ser Gly Ile Thr Phe Ser Asn Ser
20 25 30
Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Val Ile Trp Tyr Asp Gly Ser Lys Arg Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Phe
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Thr Asn Asp Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser
100 105 110
Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser
115 120 125
Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp
130 135 140
Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr
145 150 155 160
Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr
165 170 175
Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys
180 185 190
Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp
195 200 205
Lys Arg Val Glu Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
210 215 220
Gly Gly Gly Ser Gly Arg Pro Phe Val Glu Met Tyr Ser Glu Ile Pro
225 230 235 240
Glu Ile Ile His Met Thr Glu Gly Arg Glu Leu Val Ile Pro Cys Arg
245 250 255
Val Thr Ser Pro Asn Ile Thr Val Thr Leu Lys Lys Phe Pro Leu Asp
260 265 270
Thr Leu Ile Pro Asp Gly Lys Arg Ile Ile Trp Asp Ser Arg Lys Gly
275 280 285
Phe Ile Ile Ser Asn Ala Thr Tyr Lys Glu Ile Gly Leu Leu Thr Cys
290 295 300
Glu Ala Thr Val Asn Gly His Leu Tyr Lys Thr Asn Tyr Leu Thr His
305 310 315 320
Arg Gln Thr Asn Thr Ile Ile Asp Val Val Leu Ser Pro Ser His Gly
325 330 335
Ile Glu Leu Ser Val Gly Glu Lys Leu Val Leu Asn Cys Thr Ala Arg
340 345 350
Thr Glu Leu Asn Val Gly Ile Asp Phe Asn Trp Glu Tyr Pro Ser Ser
355 360 365
Lys His Gln His Lys Lys Leu Val Asn Arg Asp Leu Lys Thr Gln Ser
370 375 380
Gly Ser Glu Met Lys Lys Phe Leu Ser Thr Leu Thr Ile Asp Gly Val
385 390 395 400
Thr Arg Ser Asp Gln Gly Leu Tyr Thr Cys Ala Ala Ser Ser Gly Leu
405 410 415
Met Thr Lys Lys Asn Ser Thr Phe Val Arg Val His Glu Pro Gly Gly
420 425 430
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Lys Tyr Gly
435 440 445
Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser
450 455 460
Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
465 470 475 480
Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro
485 490 495
Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
500 505 510
Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val
515 520 525
Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
530 535 540
Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr
545 550 555 560
Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
565 570 575
Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys
580 585 590
Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
595 600 605
Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
610 615 620
Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser
625 630 635 640
Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
645 650 655
Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
660 665 670
<210> 71
<211> 214
<212> PRT
<213> Artificial Sequence
<220>
<223> Hib-PDV light chain amino acid sequence
<400> 71
Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Tyr
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Tyr Asp Ala Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro
65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Ser Ser Asn Trp Pro Arg
85 90 95
Thr Phe Gly Gln 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> 72
<211> 615
<212> PRT
<213> Artificial Sequence
<220>
<223> Hib-PLT heavy chain amino acid sequence
<400> 72
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Ser Arg Tyr
20 25 30
Ser Val His Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Leu
35 40 45
Gly Met Ile Trp Gly Val Gly Thr Thr Asp Tyr Asn Ser Ala Leu Lys
50 55 60
Ser Arg Leu Thr Ile Ser Lys Asp Thr Ser Lys Asn Gln Phe Ser Leu
65 70 75 80
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Asn Trp Gly Thr Ala Asp Tyr Phe Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro
115 120 125
Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly
130 135 140
Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn
145 150 155 160
Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln
165 170 175
Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser
180 185 190
Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser
195 200 205
Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Gly
210 215 220
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Thr Ile
225 230 235 240
Pro Pro His Val Gln Lys Ser Val Asn Asn Asp Met Ile Val Thr Asp
245 250 255
Asn Asn Gly Ala Val Lys Phe Pro Gln Leu Cys Lys Phe Cys Asp Val
260 265 270
Arg Phe Ser Thr Cys Asp Asn Gln Lys Ser Cys Met Ser Asn Cys Ser
275 280 285
Ile Thr Ser Ile Cys Glu Lys Pro Gln Glu Val Cys Val Ala Val Trp
290 295 300
Arg Lys Asn Asp Glu Asn Ile Thr Leu Glu Thr Val Cys His Asp Pro
305 310 315 320
Lys Leu Pro Tyr His Asp Phe Ile Leu Glu Asp Ala Ala Ser Pro Lys
325 330 335
Cys Ile Met Lys Glu Lys Lys Lys Pro Gly Glu Thr Phe Phe Met Cys
340 345 350
Ser Cys Ser Ser Asp Glu Cys Asn Asp Asn Ile Ile Phe Ser Glu Glu
355 360 365
Tyr Asn Thr Ser Asn Pro Asp Gly Gly Gly Gly Ser Gly Gly Gly Gly
370 375 380
Ser Gly Gly Gly Gly Ser Thr His Thr Cys Pro Pro Cys Pro Ala Pro
385 390 395 400
Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
405 410 415
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
420 425 430
Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp
435 440 445
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr
450 455 460
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
465 470 475 480
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu
485 490 495
Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
500 505 510
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys
515 520 525
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
530 535 540
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
545 550 555 560
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
565 570 575
Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser
580 585 590
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
595 600 605
Leu Ser Leu Ser Pro Gly Lys
610 615
<210> 73
<211> 218
<212> PRT
<213> Artificial Sequence
<220>
<223> Hib-PLT light chain amino acid sequence
<400> 73
Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Pro Gly
1 5 10 15
Gln Arg Ala Thr Ile Thr Cys Arg Ala Ser Lys Ser Val His Thr Ser
20 25 30
Gly Tyr Ser Tyr Met His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro
35 40 45
Lys Leu Leu Ile Tyr Leu Ala Ser Asn Leu Glu Ser Gly Val Pro Ala
50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Asn
65 70 75 80
Pro Val Glu Ala Asn Asp Thr Ala Asn Tyr Tyr Cys Gln His Ser Gly
85 90 95
Glu Leu Pro Tyr Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg
100 105 110
Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln
115 120 125
Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr
130 135 140
Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser
145 150 155 160
Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr
165 170 175
Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys
180 185 190
His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro
195 200 205
Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 74
<211> 2007
<212> DNA
<213> Artificial Sequence
<220>
<223> Hib-PDC heavy chain nucleic acid sequence
<400> 74
caggtgcagc tcgtggagag cgggggaggc gtcgtccagc ctggccgtag cctgcggctg 60
gactgtaagg ctagcggaat cacgttcagc aacagcggaa tgcactgggt cagacaggct 120
cctggcaaag gcctcgaatg ggtcgccgtg atctggtacg acgggagcaa gagatactac 180
gcagattcag tgaagggccg tttcacaatc agccgtgaca actcgaagaa cacactgttc 240
ctgcagatga acagcctgag ggcagaagac acagcagtct actactgcgc tacaaatgac 300
gactactggg gccagggaac actggtcacc gtgagctcag cttccaccaa gggcccatcc 360
gtcttccccc tggcgccctg ctccaggagc acctccgaga gcacagccgc cctgggctgc 420
ctggtcaagg actacttccc cgaaccggtg acggtgtcgt ggaactcagg cgccctgacc 480
agcggcgtgc acaccttccc ggctgtccta cagtcctcag gactctactc cctcagcagc 540
gtggtgaccg tgccctccag cagcttgggc acgaagacct acacctgcaa cgtagatcac 600
aagcccagca acaccaaggt ggacaagaga gttgagtccg gtggcggcgg aagcggcggc 660
ggaggcagcg gcggaggcgg cagcgtgatc catgtcacga aggaggtcaa agaagtggcc 720
accctcagct gcggtcacaa cgtcagcgtg gaagagttgg cccagaccag aatctactgg 780
cagaaggaga agaagatggt cttgaccatg atgagcggcg acatgaacat ctggccagag 840
tacaagaata gaactatctt cgacatcacc aataacctga gcatcgtgat cctcgctttg 900
cgtccgagcg acgaaggcac ctacgagtgc gtagtgctaa agtacgagaa agacgccttc 960
aagcgggagc acctggcaga agtaaccctg agcgtgaagg cagacttccc aacgcctagc 1020
atctccgact tcgagatccc cacaagcaac atccggcgga tcatctgtag cacctccggg 1080
ggtttccccg agcctcacct gtcctggctc gagaacggcg aggagctgaa cgccatcaac 1140
accaccgtga gccaggaccc cgagacagaa ctgtacgccg tgagctccaa gctcgacttc 1200
aacatgacca caaatcacag cttcatgtgc ctcatcaagt acggacacct gcgggtgaat 1260
cagacgttca actggaacgg cggggggggt agcggcggcg ggggctcagg tggggggggc 1320
tcaaaatatg gtcccccatg cccaccatgc ccagcacctg agttcctggg gggaccatca 1380
gtcttcctgt tccccccaaa acccaaggac actctcatga tctcccggac ccctgaggtc 1440
acgtgcgtgg tggtggacgt gagccaggaa gaccccgagg tccagttcaa ctggtacgtg 1500
gatggcgtgg aggtgcataa tgccaagaca aagccgcggg aggagcagtt caacagcacg 1560
taccgtgtgg tcagcgtcct caccgtcctg caccaggact ggctgaacgg caaggagtac 1620
aagtgcaagg tctccaacaa aggcctcccg tcctccatcg agaaaaccat ctccaaagcc 1680
aaagggcagc cccgagagcc acaggtgtac accctgcccc catcccagga ggagatgacc 1740
aagaaccagg tcagcctgac ctgcctggtc aaaggcttct accccagcga catcgccgtg 1800
gagtgggaga gcaatgggca gccggagaac aactacaaga ccacgcctcc cgtgctggac 1860
tccgacggct ccttcttcct ctacagcagg ctaaccgtgg acaagagcag gtggcaggag 1920
gggaatgtct tctcatgctc cgtgatgcat gaggctctgc acaaccacta cacacagaag 1980
agcctctccc tgtctctggg taaatag 2007
<210> 75
<211> 645
<212> DNA
<213> Artificial Sequence
<220>
<223> Hib-PDC light chain nucleic acid sequence
<400> 75
gagatcgtgc tgacacagag cccagccact ctgtcactgt ccccaggaga aagggctact 60
ctgtcttgcc gggcaagcca gtctgtctcc agctacctgg cctggtatca gcagaagccc 120
ggacaggctc ctagactgct gatctacgac gcaagtaaca gagccaccgg catccccgca 180
cgcttcagtg gctcaggctc cggaacagac tttactctga ccatctctag tctggagcct 240
gaagatttcg ccgtgtacta ttgtcagcag agctctaatt ggcctagaac cttcggccag 300
ggcaccaaag tcgagatcaa gcgtacggtg gctgcaccat ctgtcttcat cttcccgcca 360
tctgatgagc agttgaaatc tggaactgcc tctgttgtgt gcctgctgaa taacttctat 420
cccagagagg ccaaagtaca gtggaaggtg gataacgccc tccaatcggg taactcccag 480
gagagtgtca cagagcagga cagcaaggac agcacctaca gcctcagcag caccctgacg 540
ctgagcaaag cagactacga gaaacacaaa gtctacgcct gcgaagtcac ccatcagggc 600
ctgagctcgc ccgtcacaaa gagcttcaac aggggagagt gttag 645
<210> 76
<211> 2019
<212> DNA
<213> Artificial Sequence
<220>
<223> Hib-PDV heavy chain nucleic acid sequence
<400> 76
caggtgcagc tcgtggagag cgggggaggc gtcgtccagc ctggccgtag cctgcggctg 60
gactgtaagg ctagcggaat cacgttcagc aacagcggaa tgcactgggt cagacaggct 120
cctggcaaag gcctcgaatg ggtcgccgtg atctggtacg acgggagcaa gagatactac 180
gcagattcag tgaagggccg tttcacaatc agccgtgaca actcgaagaa cacactgttc 240
ctgcagatga acagcctgag ggcagaagac acagcagtct actactgcgc tacaaatgac 300
gactactggg gccagggaac actggtcacc gtgagctcag cttccaccaa gggcccatcc 360
gtcttccccc tggcgccctg ctccaggagc acctccgaga gcacagccgc cctgggctgc 420
ctggtcaagg actacttccc cgaaccggtg acggtgtcgt ggaactcagg cgccctgacc 480
agcggcgtgc acaccttccc ggctgtccta cagtcctcag gactctactc cctcagcagc 540
gtggtgaccg tgccctccag cagcttgggc acgaagacct acacctgcaa cgtagatcac 600
aagcccagca acaccaaggt ggacaagaga gttgagtccg gtggcggcgg aagcggcggc 660
ggaggcagcg gcggaggcgg cagcggtaga ccattcgtag agatgtacag cgaaatcccc 720
gaaatcatcc acatgactga aggaagggag ctcgtcatcc cctgccgggt tacgtcacct 780
aacatcactg ttactctgaa gaagttccca ctcgacactt tgatccctga tggaaaacgc 840
atcatctggg acagcagaaa gggcttcatc atctcaaatg caacgtacaa agaaatcgga 900
ctcctgacct gtgaagcaac agtcaatgga catttgtata agacaaacta tctcacacat 960
cgacagacca atacaatcat cgatgtggtt ctgagcccgt ctcatggaat cgaactatct 1020
gttggagaaa agctcgtcct gaattgtaca gcaagaactg aactgaatgt gggaatcgac 1080
ttcaactggg aatacccttc ttcgaagcat cagcataaga aactcgtaaa ccgagaccta 1140
aagacccagt ctgggagcga gatgaagaaa ttcttgagca ccctgactat cgatggtgta 1200
acccggagcg accagggatt gtacacctgt gcagcatcca gcgggctgat gaccaagaag 1260
aacagcacat tcgtcagggt ccatgaaccc ggcggggggg gtagcggcgg cgggggctca 1320
ggtggggggg gctcaaaata tggtccccca tgcccaccat gcccagcacc tgagttcctg 1380
gggggaccat cagtcttcct gttcccccca aaacccaagg acactctcat gatctcccgg 1440
acccctgagg tcacgtgcgt ggtggtggac gtgagccagg aagaccccga ggtccagttc 1500
aactggtacg tggatggcgt ggaggtgcat aatgccaaga caaagccgcg ggaggagcag 1560
ttcaacagca cgtaccgtgt ggtcagcgtc ctcaccgtcc tgcaccagga ctggctgaac 1620
ggcaaggagt acaagtgcaa ggtctccaac aaaggcctcc cgtcctccat cgagaaaacc 1680
atctccaaag ccaaagggca gccccgagag ccacaggtgt acaccctgcc cccatcccag 1740
gaggagatga ccaagaacca ggtcagcctg acctgcctgg tcaaaggctt ctaccccagc 1800
gacatcgccg tggagtggga gagcaatggg cagccggaga acaactacaa gaccacgcct 1860
cccgtgctgg actccgacgg ctccttcttc ctctacagca ggctaaccgt ggacaagagc 1920
aggtggcagg aggggaatgt cttctcatgc tccgtgatgc atgaggctct gcacaaccac 1980
tacacacaga agagcctctc cctgtctctg ggtaaatag 2019
<210> 77
<211> 645
<212> DNA
<213> Artificial Sequence
<220>
<223> Hib-PDV light chain nucleic acid sequence
<400> 77
gagatcgtgc tgacacagag cccagccact ctgtcactgt ccccaggaga aagggctact 60
ctgtcttgcc gggcaagcca gtctgtctcc agctacctgg cctggtatca gcagaagccc 120
ggacaggctc ctagactgct gatctacgac gcaagtaaca gagccaccgg catccccgca 180
cgcttcagtg gctcaggctc cggaacagac tttactctga ccatctctag tctggagcct 240
gaagatttcg ccgtgtacta ttgtcagcag agctctaatt ggcctagaac cttcggccag 300
ggcaccaaag tcgagatcaa gcgtacggtg gctgcaccat ctgtcttcat cttcccgcca 360
tctgatgagc agttgaaatc tggaactgcc tctgttgtgt gcctgctgaa taacttctat 420
cccagagagg ccaaagtaca gtggaaggtg gataacgccc tccaatcggg taactcccag 480
gagagtgtca cagagcagga cagcaaggac agcacctaca gcctcagcag caccctgacg 540
ctgagcaaag cagactacga gaaacacaaa gtctacgcct gcgaagtcac ccatcagggc 600
ctgagctcgc ccgtcacaaa gagcttcaac aggggagagt gttag 645
<210> 78
<211> 1848
<212> DNA
<213> Artificial Sequence
<220>
<223> Hib-PLT light chain nucleic acid sequence
<400> 78
caggtgcagc tgcaggagtc cggaccagga ctggtgaagc catccgagac cctgagcctg 60
acctgtacag tgtccggctt cagcctgtct aggtacagcg tgcactggat cagacagcca 120
cctggcaagg gactggagtg gctgggcatg atctggggcg tgggcaccac agactacaac 180
tctgctctga agtccagact gaccatcagc aaggatacat ctaagaatca gttcagcctg 240
aagctgtcca gcgtgaccgc cgctgacaca gccgtgtact attgcgctcg caactggggc 300
accgccgact acttcgacta ttggggccag ggcaccacag tgacagtgtc ttccgctagc 360
accaagggcc catcggtctt ccccctggca ccctcctcca agagcacctc tgggggcaca 420
gcggccctgg gctgcctggt caaggactac ttccccgaac cggtgacggt gtcgtggaac 480
tcaggcgccc tgaccagcgg cgtgcacacc ttcccggctg tcctacagtc ctcaggactc 540
tactccctca gcagcgtggt gaccgtgccc tccagcagct tgggcaccca gacctacatc 600
tgcaacgtga atcacaagcc cagcaacacc aaggtggaca agaaagttga gcccaaatct 660
tgtgacaaag gcgggggagg cagcggcggc ggaggaagcg ggggcggagg tagcaccatc 720
cctccacacg tgcagaagag cgtgaacaat gacatgatcg tcaccgacaa caacggcgcc 780
gtcaagttcc cccagctgtg caaattctgc gacgtgaggt tctccacgtg cgacaaccag 840
aagagctgta tgagcaactg cagcatcaca tccatctgcg aaaaacccca ggaagtgtgc 900
gtcgccgtct ggcggaagaa cgacgagaac atcacactgg agaccgtgtg ccacgacccc 960
aaactgccct accacgactt catcctggag gacgccgcca gcccaaagtg catcatgaaa 1020
gagaagaaga agccgggcga gactttcttc atgtgctcct gcagctccga cgagtgcaac 1080
gataatatca tcttcagcga agaatacaac acatctaacc cagacggagg gggcggatcc 1140
gggggcggcg gaagcggcgg ggggggcagc actcacacat gcccaccgtg cccagcacct 1200
gaactcctgg ggggaccgtc agtcttcctc ttccccccaa aacccaagga caccctcatg 1260
atctcccgga cccctgaggt cacatgcgtg gtggtggacg tgagccacga agaccctgag 1320
gtcaagttca actggtacgt ggacggcgtg gaggtgcata atgccaagac aaagccgcgg 1380
gaggagcagt acaacagcac gtaccgtgtg gtcagcgtcc tcaccgtcct gcaccaggac 1440
tggctgaatg gcaaggagta caagtgcaag gtctccaaca aagccctccc agcccccatc 1500
gagaaaacca tctccaaagc caaagggcag ccccgagaac cacaggtgta caccctgccc 1560
ccatcccggg aggagatgac caagaaccag gtcagcctga cctgcctggt caaaggcttc 1620
tatcccagcg acatcgccgt ggagtgggag agcaatgggc agccggagaa caactacaag 1680
accacgcctc ccgtgctgga ctccgacggc tccttcttcc tctacagcaa gctcaccgtg 1740
gacaagagca ggtggcagca ggggaacgtc ttctcatgct ccgtgatgca tgaggctctg 1800
cacaaccact acacgcagaa gagcctctcc ctgtctccgg gtaaatga 1848
<210> 79
<211> 657
<212> DNA
<213> Artificial Sequence
<220>
<223> Hib-PLT light chain nucleic acid sequence
<400> 79
gatatcgtgc tgacccagtc tccagcttcc ctggccgtgt ccccaggaca gagggccacc 60
atcacatgtc gggcttccaa gagcgtgcac acaagcggct actcttatat gcattggtac 120
cagcagaagc ccggccagcc ccctaagctg ctgatctatc tggcttccaa cctggagagc 180
ggagtgccag ctaggttctc tggctccggc agcggcaccg actttaccct gacaatcaat 240
cctgtggagg ccaacgatac agctaattac tattgccagc actccggaga gctgccatac 300
accttcggcg gaggcacaaa ggtggagatc aagcgtacgg tggctgcacc atctgtcttc 360
atcttcccgc catctgatga gcagttgaaa tctggaactg cctctgttgt gtgcctgctg 420
aataacttct atcccagaga ggccaaagta cagtggaagg tggataacgc cctccaatcg 480
ggtaactccc aggagagtgt cacagagcag gacagcaagg acagcaccta cagcctcagc 540
agcaccctga cgctgagcaa agcagactac gagaaacaca aagtctacgc ctgcgaagtc 600
acccatcagg gcctgagctc gcccgtcaca aagagcttca acaggggaga gtgttag 657
<210> 80
<211> 16
<212> PRT
<213> Artificial Sequence
<220>
<223> Peptide linker
<400> 80
Ala Lys Thr Thr Pro Lys Leu Glu Glu Gly Glu Phe Ser Glu Ala Arg
1 5 10 15
<210> 81
<211> 17
<212> PRT
<213> Artificial Sequence
<220>
<223> Peptide linker
<400> 81
Ala Lys Thr Thr Pro Lys Leu Glu Glu Gly Glu Phe Ser Glu Ala Arg
1 5 10 15
Val
<210> 82
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> Peptide linker
<400> 82
Ala Lys Thr Thr Pro Lys Leu Gly Gly
1 5
<210> 83
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> Peptide linker
<400> 83
Ser Ala Lys Thr Thr Pro Lys Leu Gly Gly
1 5 10
<210> 84
<211> 6
<212> PRT
<213> Artificial Sequence
<220>
<223> Peptide linker
<400> 84
Ser Ala Lys Thr Thr Pro
1 5
<210> 85
<211> 6
<212> PRT
<213> Artificial Sequence
<220>
<223> Peptide linker
<400> 85
Arg Ala Asp Ala Ala Pro
1 5
<210> 86
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> Peptide linker
<400> 86
Arg Ala Asp Ala Ala Pro Thr Val Ser
1 5
<210> 87
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Peptide linker
<400> 87
Arg Ala Asp Ala Ala Ala Ala Gly Gly Pro Gly Ser
1 5 10
<210> 88
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> Peptide linker
<400> 88
Arg Ala Asp Ala Ala Ala Ala
1 5
<210> 89
<211> 18
<212> PRT
<213> Artificial Sequence
<220>
<223> Peptide linker
<400> 89
Ser Ala Lys Thr Thr Pro Lys Leu Glu Glu Gly Glu Phe Ser Glu Ala
1 5 10 15
Arg Val
<210> 90
<211> 5
<212> PRT
<213> Artificial Sequence
<220>
<223> Peptide linker
<400> 90
Ala Asp Ala Ala Pro
1 5
<210> 91
<211> 11
<212> PRT
<213> Artificial Sequence
<220>
<223> Peptide linker
<400> 91
Asp Ala Ala Pro Thr Val Ser Ile Phe Pro Pro
1 5 10
<210> 92
<211> 5
<212> PRT
<213> Artificial Sequence
<220>
<223> Peptide linker
<400> 92
Thr Val Ala Ala Pro
1 5
<210> 93
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Peptide linker
<400> 93
Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro
1 5 10
<210> 94
<211> 6
<212> PRT
<213> Artificial Sequence
<220>
<223> Peptide linker
<400> 94
Gln Pro Lys Ala Ala Pro
1 5
<210> 95
<211> 13
<212> PRT
<213> Artificial Sequence
<220>
<223> Peptide linker
<400> 95
Gln Pro Lys Ala Ala Pro Ser Val Thr Leu Phe Pro Pro
1 5 10
<210> 96
<211> 6
<212> PRT
<213> Artificial Sequence
<220>
<223> Peptide linker
<400> 96
Ala Lys Thr Thr Pro Pro
1 5
<210> 97
<211> 13
<212> PRT
<213> Artificial Sequence
<220>
<223> Peptide linker
<400> 97
Ala Lys Thr Thr Pro Pro Ser Val Thr Pro Leu Ala Pro
1 5 10
<210> 98
<211> 6
<212> PRT
<213> Artificial Sequence
<220>
<223> Peptide linker
<400> 98
Ala Lys Thr Thr Ala Pro
1 5
<210> 99
<211> 13
<212> PRT
<213> Artificial Sequence
<220>
<223> Peptide linker
<400> 99
Ala Lys Thr Thr Ala Pro Ser Val Tyr Pro Leu Ala Pro
1 5 10
<210> 100
<211> 6
<212> PRT
<213> Artificial Sequence
<220>
<223> Peptide linker
<400> 100
Ala Ser Thr Lys Gly Pro
1 5
<210> 101
<211> 13
<212> PRT
<213> Artificial Sequence
<220>
<223> Peptide linker
<400> 101
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro
1 5 10
<210> 102
<211> 15
<212> PRT
<213> Artificial Sequence
<220>
<223> Peptide linker
<400> 102
Gly Glu Asn Lys Val Glu Tyr Ala Pro Ala Leu Met Ala Leu Ser
1 5 10 15
<210> 103
<211> 15
<212> PRT
<213> Artificial Sequence
<220>
<223> Peptide linker
<400> 103
Gly Pro Ala Lys Glu Leu Thr Pro Leu Lys Glu Ala Lys Val Ser
1 5 10 15
<210> 104
<211> 15
<212> PRT
<213> Artificial Sequence
<220>
<223> Peptide linker
<400> 104
Gly His Glu Ala Ala Ala Val Met Gln Val Gln Tyr Pro Ala Ser
1 5 10 15
<210> 105
<211> 16
<212> PRT
<213> Artificial Sequence
<220>
<223> Peptide linker
<400> 105
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala
1 5 10 15
<210> 106
<211> 448
<212> PRT
<213> Artificial Sequence
<220>
<223> Heavy chain amino acid sequence of Atezolizumab
<400> 106
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Ser
20 25 30
Trp Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Trp Ile Ser Pro Tyr Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Arg His Trp Pro Gly Gly Phe Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro
115 120 125
Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly
130 135 140
Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn
145 150 155 160
Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln
165 170 175
Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser
180 185 190
Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser
195 200 205
Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr
210 215 220
His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser
225 230 235 240
Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
245 250 255
Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro
260 265 270
Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
275 280 285
Lys Thr Lys Pro Arg Glu Glu Gln Tyr Ala Ser Thr Tyr Arg Val Val
290 295 300
Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
305 310 315 320
Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr
325 330 335
Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
340 345 350
Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys
355 360 365
Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
370 375 380
Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
385 390 395 400
Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser
405 410 415
Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
420 425 430
Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
435 440 445
<210> 107
<211> 214
<212> PRT
<213> Artificial Sequence
<220>
<223> Light chain amino acid sequence of Atezolizumab
<400> 107
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Val Ser Thr Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Phe Leu Tyr 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 Tyr Leu Tyr His Pro Ala
85 90 95
Thr Phe Gly Gln 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> 108
<211> 450
<212> PRT
<213> Artificial Sequence
<220>
<223> Heavy chain amino acid sequence of Avelumab
<400> 108
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Ile Met Met Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ser Ile Tyr Pro Ser Gly Gly Ile Thr Phe Tyr Ala Asp Thr Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ile Lys Leu Gly Thr Val Thr Thr Val Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Leu 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> 109
<211> 216
<212> PRT
<213> Artificial Sequence
<220>
<223> Light chain amino acid sequence of Avelumab
<400> 109
Gln Ser Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln
1 5 10 15
Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Gly Tyr
20 25 30
Asn Tyr Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu
35 40 45
Met Ile Tyr Asp Val Ser Asn Arg Pro Ser Gly Val Ser Asn Arg Phe
50 55 60
Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu
65 70 75 80
Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Tyr Thr Ser Ser
85 90 95
Ser Thr Arg Val Phe Gly Thr Gly Thr Lys Val Thr Val Leu Gly Gln
100 105 110
Pro Lys Ala Asn Pro Thr 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 Gly Ser Pro Val Lys
145 150 155 160
Ala Gly Val Glu Thr Thr Lys 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> 110
<211> 451
<212> PRT
<213> Artificial Sequence
<220>
<223> Heavy chain amino acid sequence of Durvalumab
<400> 110
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Arg Tyr
20 25 30
Trp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Asn Ile Lys Gln Asp Gly Ser Glu Lys Tyr Tyr Val Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Glu Gly Gly Trp Phe Gly Glu Leu Ala Phe Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
115 120 125
Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
130 135 140
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
145 150 155 160
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
165 170 175
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
180 185 190
Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
195 200 205
Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys
210 215 220
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Phe Glu Gly
225 230 235 240
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
245 250 255
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
260 265 270
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
275 280 285
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
290 295 300
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
305 310 315 320
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Ser Ile
325 330 335
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
340 345 350
Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser
355 360 365
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
370 375 380
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
385 390 395 400
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
405 410 415
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
420 425 430
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
435 440 445
Pro Gly Lys
450
<210> 111
<211> 215
<212> PRT
<213> Artificial Sequence
<220>
<223> Light chain amino acid sequence of Durvalumab
<400> 111
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Arg Val Ser Ser Ser
20 25 30
Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
Ile Tyr Asp Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
65 70 75 80
Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Leu Pro
85 90 95
Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala
100 105 110
Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser
115 120 125
Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu
130 135 140
Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser
145 150 155 160
Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu
165 170 175
Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val
180 185 190
Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys
195 200 205
Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 112
<211> 440
<212> PRT
<213> Artificial Sequence
<220>
<223> Heavy chain amino acid sequence of Nivolumab
<400> 112
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Asp Cys Lys Ala Ser Gly Ile Thr Phe Ser Asn Ser
20 25 30
Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Val Ile Trp Tyr Asp Gly Ser Lys Arg Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Phe
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Thr Asn Asp Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser
100 105 110
Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser
115 120 125
Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp
130 135 140
Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr
145 150 155 160
Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr
165 170 175
Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys
180 185 190
Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp
195 200 205
Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala
210 215 220
Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
225 230 235 240
Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
245 250 255
Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val
260 265 270
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln
275 280 285
Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln
290 295 300
Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly
305 310 315 320
Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
325 330 335
Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr
340 345 350
Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser
355 360 365
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
370 375 380
Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr
385 390 395 400
Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe
405 410 415
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
420 425 430
Ser Leu Ser Leu Ser Leu Gly Lys
435 440
<210> 113
<211> 214
<212> PRT
<213> Artificial Sequence
<220>
<223> Light chain amino acid sequence of Nivolumab
<400> 113
Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Tyr
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Tyr Asp Ala Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro
65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Ser Ser Asn Trp Pro Arg
85 90 95
Thr Phe Gly Gln 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> 114
<211> 447
<212> PRT
<213> Artificial Sequence
<220>
<223> Pembrolizumab heavy chain amino acid sequence
<400> 114
Gln Val Gln Leu Val Gln Ser Gly Val 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 Asn Tyr
20 25 30
Tyr Met Tyr Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Gly Ile Asn Pro Ser Asn Gly Gly Thr Asn Phe Asn Glu Lys Phe
50 55 60
Lys Asn Arg Val Thr Leu Thr Thr Asp Ser Ser Thr Thr Thr Ala Tyr
65 70 75 80
Met Glu Leu Lys Ser Leu Gln Phe Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Arg Asp Tyr Arg Phe Asp Met Gly Phe Asp Tyr 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 Cys Ser Arg Ser Thr Ser Glu Ser 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 Lys Thr Tyr Thr Cys Asn Val Asp His Lys
195 200 205
Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro
210 215 220
Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val
225 230 235 240
Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr
245 250 255
Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu
260 265 270
Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
275 280 285
Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser
290 295 300
Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
305 310 315 320
Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile
325 330 335
Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro
340 345 350
Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu
355 360 365
Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn
370 375 380
Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser
385 390 395 400
Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg
405 410 415
Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu
420 425 430
His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
435 440 445
<210> 115
<211> 218
<212> PRT
<213> Artificial Sequence
<220>
<223> Pembrolizumab light chain amino acid sequence
<400> 115
Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Lys Gly Val Ser Thr Ser
20 25 30
Gly Tyr Ser Tyr Leu His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro
35 40 45
Arg Leu Leu Ile Tyr Leu Ala Ser Tyr Leu Glu Ser Gly Val Pro Ala
50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser
65 70 75 80
Ser Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln His Ser Arg
85 90 95
Asp Leu Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg
100 105 110
Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln
115 120 125
Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr
130 135 140
Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser
145 150 155 160
Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr
165 170 175
Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys
180 185 190
His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro
195 200 205
Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 116
<211> 448
<212> PRT
<213> Artificial Sequence
<220>
<223> Ipilimumab heavy chain amino acid sequence
<400> 116
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Thr Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Thr Phe Ile Ser Tyr Asp Gly Asn Asn Lys Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Ile Tyr Tyr Cys
85 90 95
Ala Arg Thr Gly Trp Leu Gly Pro Phe Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro
115 120 125
Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly
130 135 140
Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn
145 150 155 160
Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln
165 170 175
Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser
180 185 190
Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser
195 200 205
Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr
210 215 220
His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser
225 230 235 240
Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
245 250 255
Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro
260 265 270
Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
275 280 285
Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val
290 295 300
Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
305 310 315 320
Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr
325 330 335
Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
340 345 350
Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys
355 360 365
Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
370 375 380
Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
385 390 395 400
Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser
405 410 415
Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
420 425 430
Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
435 440 445
<210> 117
<211> 215
<212> PRT
<213> Artificial Sequence
<220>
<223> Ipilimumab light chain amino acid sequence
<400> 117
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Gly Ser Ser
20 25 30
Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
Ile Tyr Gly Ala Phe Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
65 70 75 80
Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser Pro
85 90 95
Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala
100 105 110
Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser
115 120 125
Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu
130 135 140
Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser
145 150 155 160
Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu
165 170 175
Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val
180 185 190
Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys
195 200 205
Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 118
<211> 444
<212> PRT
<213> Artificial Sequence
<220>
<223> Cemiplimab heavy chain amino acid sequence
<400> 118
Glu Val Gln Leu Leu Glu Ser Gly Gly Val Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Phe
20 25 30
Gly Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Gly Ile Ser Gly Gly Gly Arg Asp Thr Tyr Phe Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Lys Gly Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Val Lys Trp Gly Asn Ile Tyr Phe Asp Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu
115 120 125
Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys
130 135 140
Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser
145 150 155 160
Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser
165 170 175
Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser
180 185 190
Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn
195 200 205
Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro
210 215 220
Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe
225 230 235 240
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
245 250 255
Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe
260 265 270
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
275 280 285
Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
290 295 300
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
305 310 315 320
Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala
325 330 335
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln
340 345 350
Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
355 360 365
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
370 375 380
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
385 390 395 400
Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu
405 410 415
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
420 425 430
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
435 440
<210> 119
<211> 214
<212> PRT
<213> Artificial Sequence
<220>
<223> Cemiplimab light chain amino acid sequence
<400> 119
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Ser Ile Thr Ile Thr Cys Arg Ala Ser Leu Ser Ile Asn Thr Phe
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Asn Leu Leu Ile
35 40 45
Tyr Ala Ala Ser Ser Leu His Gly Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Arg Thr Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Ser Asn Thr Pro Phe
85 90 95
Thr Phe Gly Pro Gly Thr Val Val Asp Phe Arg 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> 120
<211> 5
<212> PRT
<213> Artificial Sequence
<220>
<223> Peptide linker
<400> 120
Gly Gly Gly Gly Ser
1 5
<210> 121
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> Peptide linker
<400> 121
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
1 5 10
<210> 122
<211> 15
<212> PRT
<213> Artificial Sequence
<220>
<223> Peptide linker
<400> 122
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
1 5 10 15
<210> 123
<211> 20
<212> PRT
<213> Artificial Sequence
<220>
<223> Peptide linker
<400> 123
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
1 5 10 15
Gly Gly Gly Ser
20
<210> 124
<211> 600
<212> PRT
<213> Artificial Sequence
<220>
<223> Heavy chain amino acid sequence of Control protein 1
<400> 124
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Ser Arg Tyr
20 25 30
Ser Val His Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Leu
35 40 45
Gly Met Ile Trp Gly Val Gly Thr Thr Asp Tyr Asn Ser Ala Leu Lys
50 55 60
Ser Arg Leu Thr Ile Ser Lys Asp Thr Ser Lys Asn Gln Phe Ser Leu
65 70 75 80
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Asn Trp Gly Thr Ala Asp Tyr Phe Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro
115 120 125
Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly
130 135 140
Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn
145 150 155 160
Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln
165 170 175
Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser
180 185 190
Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser
195 200 205
Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr
210 215 220
His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser
225 230 235 240
Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
245 250 255
Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro
260 265 270
Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
275 280 285
Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val
290 295 300
Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
305 310 315 320
Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr
325 330 335
Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
340 345 350
Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys
355 360 365
Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
370 375 380
Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
385 390 395 400
Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser
405 410 415
Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
420 425 430
Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
435 440 445
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Thr
450 455 460
Ile Pro Pro His Val Gln Lys Ser Val Asn Asn Asp Met Ile Val Thr
465 470 475 480
Asp Asn Asn Gly Ala Val Lys Phe Pro Gln Leu Cys Lys Phe Cys Asp
485 490 495
Val Arg Phe Ser Thr Cys Asp Asn Gln Lys Ser Cys Met Ser Asn Cys
500 505 510
Ser Ile Thr Ser Ile Cys Glu Lys Pro Gln Glu Val Cys Val Ala Val
515 520 525
Trp Arg Lys Asn Asp Glu Asn Ile Thr Leu Glu Thr Val Cys His Asp
530 535 540
Pro Lys Leu Pro Tyr His Asp Phe Ile Leu Glu Asp Ala Ala Ser Pro
545 550 555 560
Lys Cys Ile Met Lys Glu Lys Lys Lys Pro Gly Glu Thr Phe Phe Met
565 570 575
Cys Ser Cys Ser Ser Asp Glu Cys Asn Asp Asn Ile Ile Phe Ser Glu
580 585 590
Glu Tyr Asn Thr Ser Asn Pro Asp
595 600
<210> 125
<211> 218
<212> PRT
<213> Artificial Sequence
<220>
<223> Light chain amino acid sequence of Control protein 1
<400> 125
Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Pro Gly
1 5 10 15
Gln Arg Ala Thr Ile Thr Cys Arg Ala Ser Lys Ser Val His Thr Ser
20 25 30
Gly Tyr Ser Tyr Met His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro
35 40 45
Lys Leu Leu Ile Tyr Leu Ala Ser Asn Leu Glu Ser Gly Val Pro Ala
50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Asn
65 70 75 80
Pro Val Glu Ala Asn Asp Thr Ala Asn Tyr Tyr Cys Gln His Ser Gly
85 90 95
Glu Leu Pro Tyr Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg
100 105 110
Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln
115 120 125
Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr
130 135 140
Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser
145 150 155 160
Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr
165 170 175
Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys
180 185 190
His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro
195 200 205
Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 126
<211> 653
<212> PRT
<213> Artificial Sequence
<220>
<223> Heavy chain amino acid sequence of Control protein 2
<400> 126
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Asp Cys Lys Ala Ser Gly Ile Thr Phe Ser Asn Ser
20 25 30
Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Val Ile Trp Tyr Asp Gly Ser Lys Arg Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Phe
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Thr Asn Asp Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser
100 105 110
Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser
115 120 125
Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp
130 135 140
Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr
145 150 155 160
Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr
165 170 175
Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys
180 185 190
Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp
195 200 205
Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala
210 215 220
Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
225 230 235 240
Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
245 250 255
Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val
260 265 270
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln
275 280 285
Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln
290 295 300
Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly
305 310 315 320
Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
325 330 335
Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr
340 345 350
Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser
355 360 365
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
370 375 380
Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr
385 390 395 400
Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe
405 410 415
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
420 425 430
Ser Leu Ser Leu Ser Leu Gly Lys Gly Gly Gly Gly Ser Gly Gly Gly
435 440 445
Gly Ser Gly Gly Gly Gly Ser Val Ile His Val Thr Lys Glu Val Lys
450 455 460
Glu Val Ala Thr Leu Ser Cys Gly His Asn Val Ser Val Glu Glu Leu
465 470 475 480
Ala Gln Thr Arg Ile Tyr Trp Gln Lys Glu Lys Lys Met Val Leu Thr
485 490 495
Met Met Ser Gly Asp Met Asn Ile Trp Pro Glu Tyr Lys Asn Arg Thr
500 505 510
Ile Phe Asp Ile Thr Asn Asn Leu Ser Ile Val Ile Leu Ala Leu Arg
515 520 525
Pro Ser Asp Glu Gly Thr Tyr Glu Cys Val Val Leu Lys Tyr Glu Lys
530 535 540
Asp Ala Phe Lys Arg Glu His Leu Ala Glu Val Thr Leu Ser Val Lys
545 550 555 560
Ala Asp Phe Pro Thr Pro Ser Ile Ser Asp Phe Glu Ile Pro Thr Ser
565 570 575
Asn Ile Arg Arg Ile Ile Cys Ser Thr Ser Gly Gly Phe Pro Glu Pro
580 585 590
His Leu Ser Trp Leu Glu Asn Gly Glu Glu Leu Asn Ala Ile Asn Thr
595 600 605
Thr Val Ser Gln Asp Pro Glu Thr Glu Leu Tyr Ala Val Ser Ser Lys
610 615 620
Leu Asp Phe Asn Met Thr Thr Asn His Ser Phe Met Cys Leu Ile Lys
625 630 635 640
Tyr Gly His Leu Arg Val Asn Gln Thr Phe Asn Trp Asn
645 650
<210> 127
<211> 214
<212> PRT
<213> Artificial Sequence
<220>
<223> Light chain amino acid sequence of Control protein 2
<400> 127
Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Tyr
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Tyr Asp Ala Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro
65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Ser Ser Asn Trp Pro Arg
85 90 95
Thr Phe Gly Gln 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> 128
<211> 657
<212> PRT
<213> Artificial Sequence
<220>
<223> Heavy chain amino acid sequence of Control protein 3
<400> 128
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Asp Cys Lys Ala Ser Gly Ile Thr Phe Ser Asn Ser
20 25 30
Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Val Ile Trp Tyr Asp Gly Ser Lys Arg Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Phe
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Thr Asn Asp Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser
100 105 110
Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser
115 120 125
Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp
130 135 140
Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr
145 150 155 160
Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr
165 170 175
Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys
180 185 190
Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp
195 200 205
Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala
210 215 220
Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
225 230 235 240
Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
245 250 255
Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val
260 265 270
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln
275 280 285
Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln
290 295 300
Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly
305 310 315 320
Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
325 330 335
Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr
340 345 350
Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser
355 360 365
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
370 375 380
Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr
385 390 395 400
Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe
405 410 415
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
420 425 430
Ser Leu Ser Leu Ser Leu Gly Lys Gly Gly Gly Gly Ser Gly Gly Gly
435 440 445
Gly Ser Gly Gly Gly Gly Ser Gly Arg Pro Phe Val Glu Met Tyr Ser
450 455 460
Glu Ile Pro Glu Ile Ile His Met Thr Glu Gly Arg Glu Leu Val Ile
465 470 475 480
Pro Cys Arg Val Thr Ser Pro Asn Ile Thr Val Thr Leu Lys Lys Phe
485 490 495
Pro Leu Asp Thr Leu Ile Pro Asp Gly Lys Arg Ile Ile Trp Asp Ser
500 505 510
Arg Lys Gly Phe Ile Ile Ser Asn Ala Thr Tyr Lys Glu Ile Gly Leu
515 520 525
Leu Thr Cys Glu Ala Thr Val Asn Gly His Leu Tyr Lys Thr Asn Tyr
530 535 540
Leu Thr His Arg Gln Thr Asn Thr Ile Ile Asp Val Val Leu Ser Pro
545 550 555 560
Ser His Gly Ile Glu Leu Ser Val Gly Glu Lys Leu Val Leu Asn Cys
565 570 575
Thr Ala Arg Thr Glu Leu Asn Val Gly Ile Asp Phe Asn Trp Glu Tyr
580 585 590
Pro Ser Ser Lys His Gln His Lys Lys Leu Val Asn Arg Asp Leu Lys
595 600 605
Thr Gln Ser Gly Ser Glu Met Lys Lys Phe Leu Ser Thr Leu Thr Ile
610 615 620
Asp Gly Val Thr Arg Ser Asp Gln Gly Leu Tyr Thr Cys Ala Ala Ser
625 630 635 640
Ser Gly Leu Met Thr Lys Lys Asn Ser Thr Phe Val Arg Val His Glu
645 650 655
Pro
<210> 129
<211> 214
<212> PRT
<213> Artificial Sequence
<220>
<223> Light chain amino acid sequence of Control protein 3
<400> 129
Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Tyr
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Tyr Asp Ala Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro
65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Ser Ser Asn Trp Pro Arg
85 90 95
Thr Phe Gly Gln 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> 130
<211> 202
<212> PRT
<213> Artificial Sequence
<220>
<223> VEGF-R fragment
<400> 130
Gly Arg Pro Phe Val Glu Met Tyr Ser Glu Ile Pro Glu Ile Ile His
1 5 10 15
Met Thr Glu Gly Arg Glu Leu Val Ile Pro Cys Arg Val Thr Ser Pro
20 25 30
Asn Ile Thr Val Thr Leu Lys Lys Phe Pro Leu Asp Thr Leu Ile Pro
35 40 45
Asp Gly Lys Arg Ile Ile Trp Asp Ser Arg Lys Gly Phe Ile Ile Ser
50 55 60
Asn Ala Thr Tyr Lys Glu Ile Gly Leu Leu Thr Cys Glu Ala Thr Val
65 70 75 80
Asn Gly His Leu Tyr Lys Thr Asn Tyr Leu Thr His Arg Gln Thr Asn
85 90 95
Thr Ile Ile Asp Val Val Leu Ser Pro Ser His Gly Ile Glu Leu Ser
100 105 110
Val Gly Glu Lys Leu Val Leu Asn Cys Thr Ala Arg Thr Glu Leu Asn
115 120 125
Val Gly Ile Asp Phe Asn Trp Glu Tyr Pro Ser Ser Lys His Gln His
130 135 140
Lys Lys Leu Val Asn Arg Asp Leu Lys Thr Gln Ser Gly Ser Glu Met
145 150 155 160
Lys Lys Phe Leu Ser Thr Leu Thr Ile Asp Gly Val Thr Arg Ser Asp
165 170 175
Gln Gly Leu Tyr Thr Cys Ala Ala Ser Ser Gly Leu Met Thr Lys Lys
180 185 190
Asn Ser Thr Phe Val Arg Val His Glu Pro
195 200
<210> 131
<211> 117
<212> PRT
<213> Artificial Sequence
<220>
<223> Human TGF-betaRII
<400> 131
Gly Ala Val Lys Phe Pro Gln Leu Cys Lys Phe Cys Asp Val Arg Phe
1 5 10 15
Ser Thr Cys Asp Asn Gln Lys Ser Cys Met Ser Asn Cys Ser Ile Thr
20 25 30
Ser Ile Cys Glu Lys Pro Gln Glu Val Cys Val Ala Val Trp Arg Lys
35 40 45
Asn Asp Glu Asn Ile Thr Leu Glu Thr Val Cys His Asp Pro Lys Leu
50 55 60
Pro Tyr His Asp Phe Ile Leu Glu Asp Ala Ala Ser Pro Lys Cys Ile
65 70 75 80
Met Lys Glu Lys Lys Lys Pro Gly Glu Thr Phe Phe Met Cys Ser Cys
85 90 95
Ser Ser Asp Glu Cys Asn Asp Asn Ile Ile Phe Ser Glu Glu Tyr Asn
100 105 110
Thr Ser Asn Pro Asp
115
<210> 132
<211> 115
<212> PRT
<213> Artificial Sequence
<220>
<223> Human TGF-betaRII
<400> 132
Val Lys Phe Pro Gln Leu Cys Lys Phe Cys Asp Val Arg Phe Ser Thr
1 5 10 15
Cys Asp Asn Gln Lys Ser Cys Met Ser Asn Cys Ser Ile Thr Ser Ile
20 25 30
Cys Glu Lys Pro Gln Glu Val Cys Val Ala Val Trp Arg Lys Asn Asp
35 40 45
Glu Asn Ile Thr Leu Glu Thr Val Cys His Asp Pro Lys Leu Pro Tyr
50 55 60
His Asp Phe Ile Leu Glu Asp Ala Ala Ser Pro Lys Cys Ile Met Lys
65 70 75 80
Glu Lys Lys Lys Pro Gly Glu Thr Phe Phe Met Cys Ser Cys Ser Ser
85 90 95
Asp Glu Cys Asn Asp Asn Ile Ile Phe Ser Glu Glu Tyr Asn Thr Ser
100 105 110
Asn Pro Asp
115
<210> 133
<211> 112
<212> PRT
<213> Artificial Sequence
<220>
<223> CD80 ECD
<400> 133
Val Ile His Val Thr Lys Glu Val Lys Glu Val Ala Thr Leu Ser Cys
1 5 10 15
Gly His Asn Val Ser Val Glu Glu Leu Ala Gln Thr Arg Ile Tyr Trp
20 25 30
Gln Lys Glu Lys Lys Met Val Leu Thr Met Met Ser Gly Asp Met Asn
35 40 45
Ile Trp Pro Glu Tyr Lys Asn Arg Thr Ile Phe Asp Ile Thr Asn Asn
50 55 60
Leu Ser Ile Val Ile Leu Ala Leu Arg Pro Ser Asp Glu Gly Thr Tyr
65 70 75 80
Glu Cys Val Val Leu Lys Tyr Glu Lys Asp Ala Phe Lys Arg Glu His
85 90 95
Leu Ala Glu Val Thr Leu Ser Val Lys Ala Asp Phe Pro Thr Pro Ser
100 105 110
<210> 134
<211> 288
<212> PRT
<213> Artificial Sequence
<220>
<223> CD80
<400> 134
Met Gly His Thr Arg Arg Gln Gly Thr Ser Pro Ser Lys Cys Pro Tyr
1 5 10 15
Leu Asn Phe Phe Gln Leu Leu Val Leu Ala Gly Leu Ser His Phe Cys
20 25 30
Ser Gly Val Ile His Val Thr Lys Glu Val Lys Glu Val Ala Thr Leu
35 40 45
Ser Cys Gly His Asn Val Ser Val Glu Glu Leu Ala Gln Thr Arg Ile
50 55 60
Tyr Trp Gln Lys Glu Lys Lys Met Val Leu Thr Met Met Ser Gly Asp
65 70 75 80
Met Asn Ile Trp Pro Glu Tyr Lys Asn Arg Thr Ile Phe Asp Ile Thr
85 90 95
Asn Asn Leu Ser Ile Val Ile Leu Ala Leu Arg Pro Ser Asp Glu Gly
100 105 110
Thr Tyr Glu Cys Val Val Leu Lys Tyr Glu Lys Asp Ala Phe Lys Arg
115 120 125
Glu His Leu Ala Glu Val Thr Leu Ser Val Lys Ala Asp Phe Pro Thr
130 135 140
Pro Ser Ile Ser Asp Phe Glu Ile Pro Thr Ser Asn Ile Arg Arg Ile
145 150 155 160
Ile Cys Ser Thr Ser Gly Gly Phe Pro Glu Pro His Leu Ser Trp Leu
165 170 175
Glu Asn Gly Glu Glu Leu Asn Ala Ile Asn Thr Thr Val Ser Gln Asp
180 185 190
Pro Glu Thr Glu Leu Tyr Ala Val Ser Ser Lys Leu Asp Phe Asn Met
195 200 205
Thr Thr Asn His Ser Phe Met Cys Leu Ile Lys Tyr Gly His Leu Arg
210 215 220
Val Asn Gln Thr Phe Asn Trp Asn Thr Thr Lys Gln Glu His Phe Pro
225 230 235 240
Asp Asn Leu Leu Pro Ser Trp Ala Ile Thr Leu Ile Ser Val Asn Gly
245 250 255
Ile Phe Val Ile Cys Cys Leu Thr Tyr Cys Phe Ala Pro Arg Cys Arg
260 265 270
Glu Arg Arg Arg Asn Glu Arg Leu Arg Arg Glu Ser Val Arg Pro Val
275 280 285
<210> 135
<211> 256
<212> PRT
<213> Artificial Sequence
<220>
<223> CD80
<400> 135
Met Gly His Thr Arg Arg Gln Gly Thr Ser Pro Ser Lys Cys Pro Tyr
1 5 10 15
Leu Asn Phe Phe Gln Leu Leu Val Leu Ala Gly Leu Ser His Phe Cys
20 25 30
Ser Gly Val Ile His Val Thr Lys Glu Val Lys Glu Val Ala Thr Leu
35 40 45
Ser Cys Gly His Asn Val Ser Val Glu Glu Leu Ala Gln Thr Arg Ile
50 55 60
Tyr Trp Gln Lys Glu Lys Lys Met Val Leu Thr Met Met Ser Gly Asp
65 70 75 80
Met Asn Ile Trp Pro Glu Tyr Lys Asn Arg Thr Ile Phe Asp Ile Thr
85 90 95
Asn Asn Leu Ser Ile Val Ile Leu Ala Leu Arg Pro Ser Asp Glu Gly
100 105 110
Thr Tyr Glu Cys Val Val Leu Lys Tyr Glu Lys Asp Ala Phe Lys Arg
115 120 125
Glu His Leu Ala Glu Val Thr Leu Ser Val Lys Ala Asp Phe Pro Thr
130 135 140
Pro Ser Ile Ser Asp Phe Glu Ile Pro Thr Ser Asn Ile Arg Arg Ile
145 150 155 160
Ile Cys Ser Thr Ser Gly Gly Phe Pro Glu Pro His Leu Ser Trp Leu
165 170 175
Glu Asn Gly Glu Glu Leu Asn Ala Ile Asn Thr Thr Val Ser Gln Asp
180 185 190
Pro Glu Thr Glu Leu Tyr Ala Val Ser Ser Lys Leu Asp Phe Asn Met
195 200 205
Thr Thr Asn His Ser Phe Met Cys Leu Ile Lys Tyr Gly His Leu Arg
210 215 220
Val Asn Gln Thr Phe Asn Trp Asn Thr Ser Phe Ala Pro Arg Cys Arg
225 230 235 240
Glu Arg Arg Arg Asn Glu Arg Leu Arg Arg Glu Ser Val Arg Pro Val
245 250 255
<210> 136
<211> 162
<212> PRT
<213> Artificial Sequence
<220>
<223> CD80
<400> 136
Met Gly His Thr Arg Arg Gln Gly Thr Ser Pro Ser Lys Cys Pro Tyr
1 5 10 15
Leu Asn Phe Phe Gln Leu Leu Val Leu Ala Gly Leu Ser His Phe Cys
20 25 30
Ser Gly Val Ile His Val Thr Lys Glu Val Lys Glu Val Ala Thr Leu
35 40 45
Ser Cys Gly His Asn Val Ser Val Glu Glu Leu Ala Gln Thr Arg Ile
50 55 60
Tyr Trp Gln Lys Glu Lys Lys Met Val Leu Thr Met Met Ser Gly Asp
65 70 75 80
Met Asn Ile Trp Pro Glu Tyr Lys Asn Arg Thr Ile Phe Asp Ile Thr
85 90 95
Asn Asn Leu Ser Ile Val Ile Leu Ala Leu Arg Pro Ser Asp Glu Gly
100 105 110
Thr Tyr Glu Cys Val Val Leu Lys Tyr Glu Lys Asp Ala Phe Lys Arg
115 120 125
Glu His Leu Ala Glu Val Thr Leu Ser Val Lys Gly Phe Ala Pro Arg
130 135 140
Cys Arg Glu Arg Arg Arg Asn Glu Arg Leu Arg Arg Glu Ser Val Arg
145 150 155 160
Pro Val
<210> 137
<211> 137
<212> PRT
<213> Artificial Sequence
<220>
<223> TGF-betaRII extracellular region fragment
<400> 137
Thr Ile Pro Pro His Val Gln Lys Ser Val Asn Asn Asp Met Ile Val
1 5 10 15
Thr Asp Asn Asn Gly Ala Val Lys Phe Pro Gln Leu Cys Lys Phe Cys
20 25 30
Asp Val Arg Phe Ser Thr Cys Asp Asn Gln Lys Ser Cys Met Ser Asn
35 40 45
Cys Ser Ile Thr Ser Ile Cys Glu Lys Pro Gln Glu Val Cys Val Ala
50 55 60
Val Trp Arg Lys Asn Asp Glu Asn Ile Thr Leu Glu Thr Val Cys His
65 70 75 80
Asp Pro Lys Leu Pro Tyr His Asp Phe Ile Leu Glu Asp Ala Ala Ser
85 90 95
Pro Lys Cys Ile Met Lys Glu Lys Lys Lys Pro Gly Glu Thr Phe Phe
100 105 110
Met Cys Ser Cys Ser Ser Asp Glu Cys Asn Asp Asn Ile Ile Phe Ser
115 120 125
Glu Glu Tyr Asn Thr Ser Asn Pro Asp
130 135
Claims (45)
- 이중특이성 융합 단백질로서,
상기 융합 단백질은 제2 결합 도메인이 전체 길이의 면역글로불린 G(IgG)의 힌지 영역에 임의의 펩타이드 링커를 통해 삽입된 구조를 갖고, 상기 IgG의 Fab 영역이 제1 결합 도메인이며;
상기 제2 결합 도메인이 삽입된 후, 상기 IgG의 중쇄는 상기 융합 단백질의 중쇄이고, 상기 IgG의 경쇄는 상기 융합 단백질의 경쇄이고;
상기 제2 결합 도메인은 인간 수용체 또는 리간드, 상기 수용체 또는 리간드의 단편, 및 상기 수용체 또는 리간드의 단편 조합으로부터 선택되고;
상기 수용체 또는 리간드는 자연 신호전달 경로에서 이량체화 또는 다량체화 구조를 형성하여 신호전달 경로를 활성화 또는 억제하고, 상기 제2 결합 도메인 및 제1 결합 도메인은 상이한 표적을 표적화하는 것인, 이중특이성 융합 단백질.
- 제1항에 있어서, 상기 제1 결합 도메인은 면역 관문 분자 또는 종양 항원을 표적으로 하여 결합하는 것인, 융합 단백질.
- 제2항에 있어서, 상기 면역 관문 분자는 PD-1, PD-L1, CTLA-4, LAG-3, FGL1, TIM-3, 갈렉틴-9, TIGIT, CD155 및 CD47; 그리고 클라우딘 18.2, HER-2, 메조텔린, BCMA, SSTR2, GPRC5D, PSMA, FCRH5, CD33, CD123, CD20, A33, CEA, CD28, DLL3, EGFR, VEGFR, VEGFR2, VEGF-A, Nectin-4, FGFR, C-met, RANKL, PDGF, PDGFR, PDGFRα, DLL4, Ang-1 및 Ang-2을 포함하는 종양 항원을 포함하는 것인, 융합 단백질.
- 제3항에 있어서, 상기 제2 결합 도메인은 인간 TGF-β, CTLA-4, VEGF, LAG3, CD27, 4-1BB, OX40, CD47, FGL1, TLT-2, CD28, HGF, CSF1, CXCL1, CXCL2, CXCL3, CXCL5, CXCL6, CXCL7, CXCL8, CXCL9, CXCL10, CXCL12, GITR, EGF 및 ICOSL을 표적으로 하여 결합하는 것인, 융합 단백질.
- 제4항에 있어서, 상기 수용체 또는 리간드는 인간 TGF-β 수용체(TGF-βR), CD80, CD86, VEGFR, VEGF-트랩, FGL1, CD70, 4-1BBL, OX40L, SIRPα, B7-H3 , C-met, CSF1R, CXCR2, CXCR3, CXCR4, GITRL, EGFR 및 ICOS인 것인, 융합 단백질.
- 제4항에 있어서, 상기 제1 결합 도메인 및 제2 결합 도메인은 하기 조합으로부터 선택되는 것인 융합 단백질:
(1) 상기 제1결합 도메인은 PD-L1을 표적으로 하여 결합하고, 상기 제2결합 도메인은 인간 TGF-β, VEGF, FGL1, CD47, CD155, HGF, CSF1, CXCL1, CXCL2, CXCL3, CXCL5, CXCL6, CXCL7, CXCL8, CXCL9, CXCL10, CXCL12, EGF 또는 ICOSL을 표적으로 하여 결합하거나; 또는
(2) 상기 제1결합 도메인은 PD-1을 표적으로 하여 결합하고, 상기 제2결합 도메인은 인간 CTLA-4, VEGF, HGF, EGF, CD28, LAG3, CD27, 4-1BB 또는 OX40을 표적으로 하여 결합하거나; 또는
(3) 상기 제1 결합 도메인은 CTLA-4를 표적으로 하여 결합하고, 상기 제2 결합 도메인은 인간 CD28, VEGF, HGF, EGF, LAG3, CD27, 4-1BB 또는 OX40을 표적으로 하여 결합하거나; 또는
(4) 상기 제1 결합 도메인은 LAG-3을 표적으로 하여 결합하고, 상기 제2 결합 도메인은 인간 CD28, VEGF, HGF, EGF, CTLA-4, CD27, 4-1BB 또는 OX40을 표적으로 하여 결합하거나; 또는
(5) 상기 제1 결합 도메인은 FGL1을 표적으로 하여 결합하고, 상기 제2 결합 도메인은 인간 TGF-β, VEGF, CD47, CD155, HGF, CSF1, CXCL1, CXCL2, CXCL3, CXCL5, CXCL6, CXCL7, CXCL8, CXCL9, CXCL10, CXCL12, EGF 또는 ICOSL 을 표적으로 하여 결합하거나; 또는
(6) 상기 제1 결합 도메인은 TIM-3을 표적으로 하여 결합하고, 상기 제2 결합 도메인은 인간 VEGF, HGF, EGF, LAG3, CD27, 4-1BB 또는 OX40을 표적으로 하여 결합하거나; 또는
(7) 상기 제1 결합 도메인은 갈렉틴-9를 표적으로 하여 결합하고, 상기 제2 결합 도메인은 인간 TGF-β, VEGF, CD47, CD155, HGF, CSF1, CXCL1, CXCL2, CXCL3, CXCL5, CXCL6, CXCL7, CXCL8, CXCL9, CXCL10, CXCL12, EGF 또는 ICOSL 을 표적으로 하여 결합하거나; 또는
(8) 상기 제1 결합 도메인은 TIGIT를 표적으로 하여 결합하고, 상기 제2 결합 도메인은 인간 TGF-β, HGF, EGF 또는 VEGF를 표적으로 하여 결합하거나; 또는
(9) 상기 제1 결합 도메인은 CD155를 표적으로 하여 결합하고, 상기 제2 결합 도메인은 인간 TGF-β, VEGF, HGF, EGF, CD47 또는 CD155를 표적으로 하여 결합하거나; 또는
(10) 상기 제1 결합 도메인은 클라우딘 18.2, HER-2, 메조텔린, BCMA, SSTR2, GPRC5D, PSMA, FCRH5, CD33, CD123, CD20, A33, CEA, CD28, DLL3, EGFR, VEGFR, VEGFR2, VEGF-A, 넥틴-4, FGFR, C-met, RANKL, PDGF, PDGFR, PDGFRα, DLL-4, Ang-1 또는 Ang-2를 표적으로 하여 결합하고, 상기 제2 결합 도메인은 인간 CTLA-4, TGF-β, VEGF, FGL1, LAG3, 4-1BB, OX40, CD27, CD28, CD47, CD155, HGF, CSF1, CXCL1, CXCL2, CXCL3, CXCL5, CXCL6, CXCL7, CXCL8, CXCL9, CXCL10, CXCL12, EGF 또는 ICOSL 를 표적으로 하여 결합한다.
- 제6항에 있어서, 상기 제1 결합 도메인 및 상기 수용체 또는 리간드가 하기 조합으로부터 선택되는 융합 단백질:
(1) 상기 제1 결합 도메인은 PD-L1을 표적으로 하여 결합하고, 상기 수용체 또는 리간드는 TGF-βRII, VEGFR, LAG-3, SIRPα, TIGIT, C-MET, CSF1R, CXCR2, CXCR3, CXCR4, EGFR 또는 ICOS 로부터 선택되거나; 또는
(2) 상기 제1 결합 도메인은 PD-1을 표적으로 하여 결합하고, 상기 수용체 또는 리간드는 인간 CD80, CD86, VEGFR, c-MET, EGFR, FGL1, CD70, 4-1BBL 또는 OX40L로부터 선택되거나; 또는
(3) 상기 제1 결합 도메인은 CTLA-4를 표적으로 하여 결합하고, 상기 수용체 또는 리간드는 인간 CD80, CD86, VEGFR, c-MET, EGFR, FGL1, CD70, 4-1BBL 또는 OX40L로부터 선택되거나; 또는
(4) 상기 제1 결합 도메인은 LAG-3을 표적으로 하여 결합하고, 상기 수용체 또는 리간드는 인간 VEGFR, c-MET, EGFR, CD80, CD86, CD70, 4-1BBL 또는 OX40L로부터 선택되거나; 또는
(5) 상기 제1 결합 도메인은 FGL1을 표적으로 하여 결합하고, 상기 수용체 또는 리간드는 인간 TGF-βRII, VEGFR, SIRPα, TIGIT, c-MET, CSF1R, CXCR2, CXCR3, CXCR4, EGFR 또는 ICOS로부터 선택되거나; 또는
(6) 상기 제1 결합 도메인은 TIM-3을 표적으로 하여 결합하고, 상기 수용체 또는 리간드는 인간 VEGFR, c-MET, EGFR, FGL1, CD70, 4-1BBL 또는 OX40L로부터 선택되거나; 또는
(7) 상기 제1 결합 도메인은 갈렉틴-9를 표적으로 하여 결합하고, 상기 수용체 또는 리간드는 인간 TGF-βRII, VEGFR, SIRPα, TIGIT, c-MET, CSF1R, CXCR2, CXCR3, CXCR4, EGFR 또는 ICOS로부터 선택되거나; 또는
(8) 상기 제1 결합 도메인은 TIGIT를 표적으로 하여 결합하고, 상기 수용체 또는 리간드는 인간 TGF-βRII, c-MET, EGFR 또는 VEGFR로부터 선택되거나; 또는
(9) 상기 제1 결합 도메인은 CD155를 표적으로 하여 결합하고, 상기 수용체 또는 리간드는 인간 TGF-βRII, VEGFR, c-MET, EGFR, SIRPα 또는 TIGIT로부터 선택되거나; 또는
(10) 상기 제1 결합 도메인은 클라우딘 18.2, HER-2, 메조텔린, BCMA, SSTR2, GPRC5D, PSMA, FCRH5, CD33, CD123, CD20, A33, CEA, CD28, DLL3, EGFR, VEGFR, VEGFR2, Nectin-4, FGFR, c-MET, RANKL, PDGF, PDGFR, PDGFRα, DLL4, Ang-1 또는 Ang-2를 표적으로 하여 결합하고, 상기 수용체 또는 리간드는 인간 CTLA-4, CD80, CD86, TGF-βRII, VEGFR, FGL1, LAG3, 4-1BB, OX40, CD27, CD28, CD70, c-MET, SIRPα, TIGIT, CSF1R, CXCR2, CXCR3, CXCR4, EGFR 또는 ICOS에서 선택된다.
- 제1항 내지 제7항 중 어느 한 항에 있어서, 상기 수용체 또는 리간드의 단편이 세포외 영역의 단편 및 상기 수용체 또는 리간드의 결합 도메인의 단편을 포함하는 것인, 융합 단백질.
- 제7항에 있어서, 상기 제1 결합 도메인은 PD-L1을 표적으로 하여 결합하고; 상기 제2 결합 도메인은 인간 TGF-βRII의 단편이거나; 또는 상기 제1 결합 도메인은 PD-1을 표적으로 하여 결합하고, 상기 제2 결합 도메인은 인간 CD80 ECD, CD80 IgV 영역, 인간 CD80 IgVIgC, VEGFR1 ECD, VEGFR2 ECD 또는 VEGFR1의 제2 세포외 영역 및 VEGFR2의 제3 세포외 영역의 조합으로부터 선택되거나; 또는 상기 제1 결합 도메인은 클라우딘 18.2, HER-2 또는 EGFR을 표적으로 하여 결합하고, 상기 제2 결합 도메인은 인간 CD80 ECD, CD80 IgV 영역, 인간 CD80 IgVIgC, VEGFR1 ECD, VEGFR2 ECD 또는 VEGFR1의 제2 세포외 영역 및 VEGFR2의 제3세포외 영역의 조합으로부터 선택되는 것인, 융합 단백질.
- 제9항에 있어서, 상기 제2 결합 도메인은 하기로부터 선택되는 것인 융합 단백질:
(1) 서열번호 31, 131 또는 132에 나타낸 서열, 또는 서열번호 31, 131 또는 132에 나타낸 서열과 비교하여 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% 이상의 상동성을 갖는 서열, 또는 서열번호 31, 131 또는 132에 나타낸 서열 상의 1, 2, 3, 4, 5, 6, 7, 8, 9 또는 10개의 아미노산 치환 또는 결실된 아미노산 서열을 포함하는, 인간 TGF-βRII; 또는
(2) 서열번호 32 또는 133에 나타낸 서열, 또는 서열번호 32 또는 133에 나타낸 서열과 비교하여 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% 이상의 상동성을 갖는 서열, 또는 서열번호 32 또는 133에 나타낸 서열에서 1, 2, 3, 4, 5, 6, 7, 8, 9, 또는 10개의 아미노산 치환 또는 결실을 갖는 아미노산 서열을 포함하는 CD80 ECD; 또는
(3) VEGFR1의 제2 세포외 영역 및 VEGFR2의 제3 세포외 영역의 조합으로서, 서열번호 33에 나타낸 서열, 또는 서열번호 33에 나타낸 서열과 비교하여 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% 이상의 상동성을 갖는 서열, 또는 서열번호 33에 나타낸 서열 상의 1, 2, 3, 4, 5, 6, 7, 8, 9, 또는 10개의 아미노산 치환 또는 결실을 포함하는 조합.
- 제9항 또는 제10항에 있어서, 상기 제1 결합 도메인이 PD-L1을 표적으로 하여 결합하고, 상기 IgG의 Fab에서 상기 중쇄 가변 영역의 CDR 및/또는 상기 경쇄 가변 영역의 CDR이 하기 서열로 정의된 항체와 동일한 CDR 서열을 가지거나, 또는 하기 서열로 정의된 항체의 CDR 에 1-2개의 아미노산 치환을 갖고, 상기 항체는 다음과 같이 정의되는 것인, 융합 단백질:
(1) 서열번호 66의 중쇄 가변영역의 아미노산 서열; 및/또는
(2) 서열번호 67의 경쇄 가변영역의 아미노산 서열.
- 제11항에 있어서, 상기 IgG의 Fab에서 상기 중쇄 가변영역의 CDR 및/또는 상기 경쇄 가변영역의 CDR은 다음을 특징으로 하는 융합단백질:
(1) 중쇄 가변 영역의 경우, CDR1의 아미노산 서열은 서열번호 1-5 및 서열번호 1-5에 1 또는 2개의 아미노산 치환을 갖는 아미노산 서열로부터 선택되고; CDR2의 아미노산 서열은 서열번호 6-10 및 서열번호 6-10에서 1 또는 2개의 아미노산 치환을 갖는 아미노산 서열로부터 선택되고; CDR3의 아미노산 서열은 서열번호 11-15 및 서열번호 11-15에서 1 또는 2개의 아미노산 치환을 갖는 아미노산 서열로부터 선택되고; 및/또는
(2) 경쇄 가변 영역의 경우, CDR1의 아미노산 서열은 서열번호 16-20 및 서열번호 16-20에 1 또는 2개의 아미노산 치환을 갖는 아미노산 서열로부터 선택되고; CDR2의 아미노산 서열은 서열번호 21-25 및 서열번호 21-25에서 1 또는 2개의 아미노산 치환을 갖는 아미노산 서열로부터 선택되고; CDR3의 아미노산 서열은 서열번호 26-30 및 서열번호 26-30에서 1 또는 2개의 아미노산 치환을 갖는 아미노산 서열로부터 선택된다.
- 제12항에 있어서,
(1) 상기 중쇄 가변영역의 CDR 1-3의 아미노산 서열은 서열번호 1, 6, 11, 또는 서열번호 1, 6, 11에 1 또는 2개의 아미노산 치환을 갖는 아미노산 서열이고; 및/또는 상기 경쇄 가변 영역의 CDR 1-3의 아미노산 서열은 서열번호 16, 21, 26, 또는 서열번호 16, 21, 26에 1 또는 2개의 아미노산 치환을 갖는 아미노산 서열이거나; 또는
(2) 상기 중쇄 가변영역의 CDR 1-3의 아미노산 서열은 서열번호 2, 7, 12, 또는 서열번호 2, 7, 12에 1 또는 2개의 아미노산 치환을 갖는 아미노산 서열이고; 및/또는 상기 경쇄 가변 영역의 CDR 1-3의 아미노산 서열은 서열번호 17, 22, 27, 또는 서열번호: 17, 22, 27에서 1 또는 2개의 아미노산 치환을 갖는 아미노산 서열이거나; 또는
(3) 상기 중쇄 가변영역의 CDR 1-3의 아미노산 서열은 서열번호 3, 8, 13 또는 서열번호 3, 8, 13에 1 또는 2개의 아미노산 치환을 갖는 아미노산 서열이고; 및/또는 상기 경쇄 가변 영역의 CDR 1-3의 아미노산 서열은 서열번호 18, 23, 28, 또는 서열번호 18, 23, 28에 1 또는 2개의 아미노산 치환을 갖는 아미노산 서열이거나; 또는
(4) 상기 중쇄 가변영역의 CDR 1-3의 아미노산 서열은 서열번호 4, 9, 14, 또는 서열번호 4, 9, 14에 1 또는 2개의 아미노산 치환을 갖는 아미노산 서열이고; 및/또는 상기 경쇄 가변 영역의 CDR 1-3의 아미노산 서열은 서열번호 19, 24, 29, 또는 서열번호: 19, 24, 29에 1 또는 2개의 아미노산 치환을 갖는 아미노산 서열이거나; 또는
(5) 상기 중쇄 가변영역의 CDR 1-3의 아미노산 서열은 서열번호 5, 10, 15 또는 서열번호 5, 10, 15에 1 또는 2개의 아미노산 치환을 갖는 아미노산 서열이고; 및/또는 상기 경쇄 가변 영역의 CDR 1-3의 아미노산 서열은 서열번호 20, 25, 30, 또는 서열번호 20, 25, 30에서 1 또는 2개의 아미노산 치환을 갖는 아미노산 서열인 것인, 융합 단백질.
- 제13항에 있어서, 상기 중쇄 가변영역의 CDR 1-3의 아미노산 서열은 서열번호 3, 8, 13이고; 및/또는 상기 경쇄 가변 영역의 CDR 1-3의 아미노산 서열은 서열번호 18, 23, 28인 것인, 융합 단백질.
- 제14항에 있어서,
(1) 상기 중쇄 가변영역은 서열번호 66에 나타낸 서열, 또는 서열번호 66과 동일한 CDR 1-3을 갖고, 서열번호 66과 비교하여 상동성이 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% 이상인 서열을 갖고; 및/또는
(2) 경쇄 가변영역은 서열번호 67에 나타낸 서열, 또는 서열번호 67과 동일한 CDR 1-3을 갖고, 서열번호 67과 비교하여 상동성이 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% 이상인 서열을 갖는 것인, 융합 단백질.
- 제15항에 있어서,
(1) 상기 융합 단백질의 중쇄는 서열번호 72 에 나타낸 아미노산 서열, 또는 서열번호 72와 비교하여 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% 이상의 상동성을 갖는 서열을 가지고;
(2) 상기 융합 단백질의 경쇄는 서열번호 73 에 나타낸 아미노산 서열, 또는 서열번호 73과 비교하여 상동성이80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 이상인 서열을 갖는 것인, 융합 단백질.
- 제16항에 있어서,
(1) 상기 융합 단백질의 중쇄의 아미노산 서열은 서열번호 72와 비교하여 1-15개의 아미노산 부위 돌연변이를 가지거나 대체 펩타이드 링커를 갖고;
(2) 상기 융합 단백질의 경쇄의 아미노산 서열은 서열번호 73과 비교하여 1-10개의 아미노산 부위 돌연변이를 갖는 것인, 융합 단백질.
- 제9항에 있어서,
상기 제1 결합 도메인은 PD-1을 표적으로 하여 결합하고, 상기 IgG의 Fab에서 중쇄 가변 영역의 CDR 및/또는 경쇄 가변 영역의 CDR은 하기 서열에 의해 정의된 항체와 동일한 CDR 서열, 또는 하기 서열에 의해 정의된 항체의 CDR 상에 1-2개의 아미노산 치환을 갖고, 상기 항체는 다음과 같이 정의 되는 것인, 융합 단백질:
(1) 서열번호 64의 중쇄 가변영역의 아미노산 서열; 및/또는
(2) 서열번호 65의 경쇄 가변영역의 아미노산 서열.
- 제18항에 있어서, 상기 IgG의 Fab에서 중쇄 가변 영역의 CDR 및/또는 경쇄 가변 영역의 CDR은 하기와 같은 융합 단백질:
(1) 상기 중쇄 가변 영역의 경우, CDR1의 아미노산 서열은 서열번호 34-38 및 서열번호 34-38에서 1 또는 2개의 아미노산 치환을 갖는 아미노산 서열로부터 선택되고; CDR2의 아미노산 서열은 서열번호 39-43 및 서열번호 39-43에서 1 또는 2개의 아미노산 치환을 갖는 아미노산 서열로부터 선택되고; CDR3의 아미노산 서열은 서열번호 44-48 및 서열번호 44-48에서 1 또는 2개의 아미노산 치환을 갖는 아미노산 서열로부터 선택되고; 및/또는
(2) 상기 경쇄 가변 영역의 경우, CDR1의 아미노산 서열은 서열번호 49-53 및 서열번호 49-53에서 1 또는 2개의 아미노산 치환을 갖는 아미노산 서열로부터 선택되고; CDR2의 아미노산 서열은 서열번호 54-58 및 서열번호 54-58에서 1 또는 2개의 아미노산 치환을 갖는 아미노산 서열로부터 선택되고; CDR3의 아미노산 서열은 서열번호 59-63 및 서열번호 59-63에서 1 또는 2개의 아미노산 치환을 갖는 아미노산 서열로부터 선택된다.
- 제19항에 있어서,
(1) 상기 중쇄 가변영역의 CDR 1-3의 아미노산 서열은 서열번호 34, 39, 44 또는 서열번호 34, 39, 44에 1 또는 2개의 아미노산 치환을 갖는 아미노산 서열이고; 및/또는 상기 경쇄 가변 영역의 CDR 1-3의 아미노산 서열은 서열번호 49, 54, 59, 또는 서열번호 49, 54, 59에서 1 또는 2개의 아미노산 치환을 갖는 아미노산 서열이거나; 또는
(2) 상기 중쇄 가변영역의 CDR 1-3의 아미노산 서열은 서열번호 35, 40, 45, 또는 서열번호 35, 40, 45에 1 또는 2개의 아미노산 치환을 갖는 아미노산 서열이고; 및/또는 상기 경쇄 가변 영역의 CDR 1-3의 아미노산 서열은 서열번호 50, 55, 60, 또는 서열번호 50, 55, 60에서 1 또는 2개의 아미노산 치환을 갖는 아미노산 서열이거나; 또는
(3) 상기 중쇄 가변영역의 CDR 1-3의 아미노산 서열은 서열번호 36, 41, 46 또는 서열번호 36, 41, 46에 1 또는 2개의 아미노산 치환을 갖는 아미노산 서열이고; 및/또는 상기 경쇄 가변 영역의 CDR 1-3의 아미노산 서열은 서열번호 51, 56, 61, 또는 서열번호 51, 56, 61에서 1 또는 2개의 아미노산 치환을 갖는 아미노산 서열이거나; 또는
(4) 상기 중쇄 가변영역의 CDR 1-3의 아미노산 서열은 서열번호 37, 42, 47, 또는 서열번호 37, 42, 47에 1 또는 2개의 아미노산 치환을 갖는 아미노산 서열이고; 및/또는 상기 경쇄 가변 영역의 CDR 1-3의 아미노산 서열은 서열번호 52, 57, 62, 또는 서열번호 52, 57, 62에 1 또는 2개의 아미노산 치환을 갖는 아미노산 서열이거나; 또는
(5) 상기 중쇄 가변영역의 CDR 1-3의 아미노산 서열은 서열번호 38, 43, 48 또는 서열번호 38, 43, 48에 1 또는 2개의 아미노산 치환을 갖는 아미노산 서열이고; 및/또는 상기 경쇄 가변 영역의 CDR 1-3의 아미노산 서열은 서열번호 53, 58, 63, 또는 서열번호 53, 58, 63에서 1 또는 2개의 아미노산 치환을 갖는 아미노산 서열인 것인, 융합 단백질.
- 제20항에 있어서, 상기 중쇄 가변 영역의 CDR 1-3의 아미노산 서열은 서열번호 36, 41, 46이고; 및/또는 상기 경쇄 가변 영역의 CDR 1-3의 아미노산 서열은 서열번호 51, 56, 61인 것인, 융합 단백질.
- 제21항에 있어서,
(1) 상기 중쇄 가변영역은 서열번호 64에 나타낸 서열, 또는 서열번호 64와 동일한 CDR 1-3을 갖고 서열번호 64와 비교하여 상동성이 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% 이상인 서열이고; 및/또는
(2) 상기 경쇄 가변영역은 서열번호 65 에 나타낸 서열, 또는 서열번호 65와 동일한 CDR 1-3을 갖고 서열번호 65와 비교하여 상동성이 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% 이상인 것인, 융합 단백질.
- 제22항에 있어서,
(1) 상기 융합 단백질의 중쇄는 서열번호 68 에 나타낸 아미노산 서열, 또는 서열번호 68와 비교하여 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% 이상의 상동성을 갖는 서열을 가지고;
(2) 상기 융합 단백질의 경쇄는 서열번호 69 에 나타낸 아미노산 서열, 또는 서열번호 69와 비교하여 상동성이 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% 이상인 서열을 갖는 것인, 융합 단백질.
- 제23항에 있어서,
(1) 상기 융합 단백질의 중쇄의 아미노산 서열은 서열번호 68과 비교하여 1-15개의 아미노산 부위 돌연변이를 갖거나 대체 펩타이드 링커를 갖고;
(2) 상기 융합 단백질의 경쇄의 아미노산 서열은 서열번호 69와 비교하여 1-10개의 아미노산 부위 돌연변이를 갖는 것인, 융합 단백질.
- 제22항에 있어서,
(1) 융합 단백질의 중쇄는 서열번호 70 에 나타낸 아미노산 서열, 또는 서열번호 70과 비교하여 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% 이상의 상동성을 갖는 서열을 가지고;
(2) 융합 단백질의 경쇄는 서열번호 71에 나타낸 아미노산 서열, 또는 서열번호 71과 비교하여 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% 이상의 상동성을 갖는 서열을 갖는 것인, 융합 단백질.
- 제25항에 있어서,
(1) 융합 단백질의 중쇄의 아미노산 서열은 서열번호 70과 비교하여 1-15개의 아미노산 부위 돌연변이를 가지거나 대체 펩타이드 링커를 갖고;
(2) 융합 단백질의 경쇄의 아미노산 서열은 서열번호 71과 비교하여 1-10개의 아미노산 부위 돌연변이를 갖는 것인, 융합 단백질.
- 제1항 내지 제10항 중 어느 한 항에 있어서, 상기 IgG는 아테졸리주맙, 아벨루맙, 더발루맙, 니볼루맙, 펨브롤리주맙, 세미플리맙 또는 이필리무맙인 것인, 융합 단백질.
- 제1항 내지 제27항 중 어느 한 항에 있어서, 상기 제2 결합 도메인의 C-말단 또는/및 N-말단은 펩타이드 링커를 갖고, 상기 펩타이드 링커는 2-30개의 아미노산으로 이루어진 것인 융합 단백질.
- 제28항에 있어서, 상기 펩타이드 링커는
(1) (GGGGS)n; 또는
(2) AKTTPKLEEEGEFSEAR(서열번호 80); 또는
(3) AKTTPKLEEEGEFSEARV(서열번호 81); 또는
(4) AKTTPKLGG(서열번호 82); 또는
(5) SAKTTPKLGG(서열번호 83); 또는
(6) SAKTTP(서열번호 84); 또는
(7) RADAAP(서열번호 85); 또는
(8) RADAAPTVS(서열번호 86); 또는
(9) RADAAAAGGPGS(서열번호 87); 또는
(10) RADAAAA(서열번호 88); 또는
(11) SAKTTPKLEEEGEFSEARV(서열번호 89); 또는
(12) ADAAP(서열번호 90); 또는
(13) DAAPTVSIFPP(서열번호 91); 또는
(14) TVAAP(서열번호 92); 또는
(15) TVAAPSVFIFFP(서열번호 93); 또는
(16) QPKAAP(서열번호 94); 또는
(17) QPKAAPSVTLFPP(서열번호 95); 또는
(18) AKTTPP(서열번호 96); 또는
(19) AKTTPPSVTPLAP(서열번호 97); 또는
(20) AKTTAP(서열번호 98); 또는
(21) AKTTAPSVYPLAP(서열번호 99); 또는
(22) ASTKGP(서열번호 100); 또는
(23) ASTKGPSVFPLAP(서열번호 101); 또는
(24) GENKVEYAPALMALS(서열번호 102); 또는
(25) GPAKELTPLKEAKVS(서열번호 103); 또는
(26) GHEAAAVMQVQYPAS(서열번호 104); 또는
(27) GGGGSGGGGSGGGGSA(서열번호 105) 이고,
상기 n은 1, 2, 3 또는 4인 것인, 융합 단백질.
- 제1항 내지 제29항 중 어느 한 항에 있어서, 상기 삽입된 제2 결합 도메인의 크기가 300개의 아미노산을 초과하지 않는 것인, 융합 단백질.
- 제1항 내지 제30항 중 어느 한 항에 있어서, 상기 제2 결합 도메인의 삽입 부위가 힌지 영역의 전면 중앙부에 위치하고, 상기 삽입 부위가 면역글로불린의 이황화 결합 형성에 영향을 미치지 않는 것인, 융합 단백질.
- 제 31항에 있어서, 상기 힌지영역의 전면 중앙부는 231A의 이전 부분을 의미하는 것인, 융합단백질.
- 제1항 내지 제32항 중 어느 한 항에 있어서, 상기 삽입 부위 전후의 힌지 영역의 아미노산의 일부가 치환 또는 결실되어 있는, 융합 단백질.
- 제33항에 있어서, 상기 힌지 영역이 D221G 및/또는 C220V 돌연변이를 포함하는 것인, 융합 단백질.
- 제1항 내지 제34항 중 어느 한 항에 있어서, 상기 IgG는 포유동물 IgG, 인간화 IgG 및 인간 IgG로부터 선택되고, 상기 포유동물에는 마우스, 래트 및 토끼가 포함되고; 바람직하게는 상기 IgG는 IgG1, IgG2, IgG3 또는 IgG4인 것인, 융합 단백질.
- 제1항 내지 제35항 중 어느 한 항에 있어서, 상기 융합 단백질의 Fc 영역이 비글리코실화 또는 탈글리코실화되거나, 푸코실화가 감소되거나 또는 비푸코실화되는 것인, 융합 단백질.
- 제1항 내지 제36항 중 어느 한 항에 따른 융합 단백질을 코딩하는 분리된 폴리뉴클레오티드.
- 제37항에 따른 폴리뉴클레오티드를 포함하는 핵산 구조체로서, 바람직하게 상기 핵산 구조체는 벡터인 것인, 핵산 구조체.
- 제37항에 따른 폴리뉴클레오티드 또는 제38항에 따른 핵산 구축물 또는 벡터를 포함하는 숙주 세포로서, 바람직하게 상기 세포는 원핵 세포, 진핵 세포, 효모 세포, 포유동물 세포, 대장균 세포 또는 CHO 세포, NS0 세포 , Sp2/0 세포 또는 BHK 세포인 것인, 세포.
- 제1항 내지 제36항 중 어느 한 항에 따른 융합 단백질 및 약학적으로 허용되는 담체를 포함하는, 약학 조성물.
- 제1항 내지 제36항 중 어느 한 항에 따른 융합 단백질 또는 제40항에 따른 약학 조성물을, 치료 또는 완화가 필요한 대상체에게 투여하는 단계를 포함하는, 종양 또는 암의 치료 방법.
- 제1항 내지 제36항 중 어느 한 항에 따른 융합 단백질, 제37항에 따른 폴리뉴클레오타이드, 제38항에 따른 핵산 구조체 또는 벡터, 또는 제40항에 따른 약학 조성물의, 종양 또는 암의 치료 또는 예방을 위한 의약 제조에서의 용도.
- 제42항에 있어서, 상기 종양 또는 암은 고형 종양 또는 비-고형 종양을 포함하는 것인, 용도.
- 제1항 내지 제36항 중 어느 한 항에 따른 융합 단백질을 포함하는 진단 키트.
- 제1항 내지 제36항 중 어느 한 항에 따른 융합 단백질의 제조 방법으로서,
제38항에 따른 핵산 구조체의 발현이 가능한 조건 하에 제39항에 따른 숙주 세포를 배양하는 단계, 및 생산된 융합 단백질을 상기 배양물로부터 회수하는 단계를 포함하는, 융합 단백질의 제조 방법.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202010199036 | 2020-03-20 | ||
CN202010199036.2 | 2020-03-20 | ||
PCT/CN2021/081659 WO2021185337A1 (zh) | 2020-03-20 | 2021-03-19 | 一种双特异性融合蛋白及其应用 |
Publications (1)
Publication Number | Publication Date |
---|---|
KR20220107257A true KR20220107257A (ko) | 2022-08-02 |
Family
ID=77769172
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
KR1020227022059A KR20220107257A (ko) | 2020-03-20 | 2021-03-19 | 이중특이성 융합 단백질 및 그의 응용 |
Country Status (9)
Country | Link |
---|---|
US (1) | US20220204626A1 (ko) |
EP (1) | EP4056596A4 (ko) |
JP (1) | JP7489468B2 (ko) |
KR (1) | KR20220107257A (ko) |
CN (1) | CN114466868A (ko) |
AU (1) | AU2021237513B2 (ko) |
CA (1) | CA3137211A1 (ko) |
TW (1) | TW202136315A (ko) |
WO (1) | WO2021185337A1 (ko) |
Families Citing this family (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
BR112021016512A2 (pt) * | 2019-08-29 | 2022-03-15 | Remegen Co Ltd | Anticorpo anti pd-l1 e uso do mesmo |
EP4410842A1 (en) * | 2021-10-21 | 2024-08-07 | Adlai Nortye Biopharma Co., Ltd. | Fusion polypeptide and use thereof |
WO2024028386A1 (en) * | 2022-08-02 | 2024-02-08 | Ose Immunotherapeutics | Multifunctional molecule directed against cd28 |
WO2024114605A1 (zh) * | 2022-11-29 | 2024-06-06 | 杭州阿诺生物医药科技有限公司 | 一种融合多肽及其用途 |
CN117986367B (zh) * | 2024-04-02 | 2024-07-16 | 上海美迪西生物医药股份有限公司 | 靶点为Nectin-4的抗体及其应用 |
Family Cites Families (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
PE20161096A1 (es) * | 2014-02-10 | 2016-10-22 | Merck Patent Gmbh | INHIBICION DIRIGIDA DEL FACTOR DE CRECIMIENTO TRANSFORMADOR ß (TGFß) |
CN108779176A (zh) * | 2016-01-11 | 2018-11-09 | 印希比股份有限公司 | 多价和多特异性41bb结合融合蛋白 |
AR108377A1 (es) | 2016-05-06 | 2018-08-15 | Medimmune Llc | Proteínas de unión biespecíficas y sus usos |
CN111372950A (zh) | 2017-10-12 | 2020-07-03 | 免疫苏醒公司 | Vegfr-抗体轻链融合蛋白 |
CN109721657B (zh) * | 2017-10-27 | 2021-11-02 | 北京比洋生物技术有限公司 | 阻断pd-1/pd-l1信号传导途径且活化t细胞的融合蛋白及其用途 |
WO2020006511A1 (en) * | 2018-06-29 | 2020-01-02 | Gensun Biopharma, Inc. | Trispecific antagonists |
CA3105750A1 (en) * | 2018-07-09 | 2020-01-16 | Precigen, Inc. | Fusion constructs and methods of using thereof |
-
2021
- 2021-03-19 CN CN202180005265.9A patent/CN114466868A/zh active Pending
- 2021-03-19 WO PCT/CN2021/081659 patent/WO2021185337A1/zh unknown
- 2021-03-19 JP JP2022539415A patent/JP7489468B2/ja active Active
- 2021-03-19 KR KR1020227022059A patent/KR20220107257A/ko unknown
- 2021-03-19 TW TW110110024A patent/TW202136315A/zh unknown
- 2021-03-19 EP EP21770764.5A patent/EP4056596A4/en active Pending
- 2021-03-19 CA CA3137211A patent/CA3137211A1/en active Pending
- 2021-03-19 US US17/594,768 patent/US20220204626A1/en active Pending
- 2021-03-19 AU AU2021237513A patent/AU2021237513B2/en active Active
Also Published As
Publication number | Publication date |
---|---|
CA3137211A1 (en) | 2021-09-23 |
JP2023509005A (ja) | 2023-03-06 |
AU2021237513A1 (en) | 2021-11-11 |
JP7489468B2 (ja) | 2024-05-23 |
WO2021185337A1 (zh) | 2021-09-23 |
EP4056596A1 (en) | 2022-09-14 |
US20220204626A1 (en) | 2022-06-30 |
TW202136315A (zh) | 2021-10-01 |
EP4056596A4 (en) | 2023-01-25 |
CN114466868A (zh) | 2022-05-10 |
AU2021237513B2 (en) | 2024-08-15 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
AU2021237513B2 (en) | Bispecific fusion protein and application thereof | |
US20220106397A1 (en) | Multivalent and Multispecific OX40-Binding Fusion Proteins | |
US20230416387A1 (en) | Multivalent and Multispecific 41BB-Binding Proteins | |
US20220041746A1 (en) | Anti-cd38 antibodies and methods of use | |
CA2953818C (en) | Covalently bonded diabodies having immunoreactivity with pd-1 and lag-3, and methods of use thereof | |
DK2536764T3 (en) | ANTI-CD28 HUMANIZED ANTIBODIES | |
US12024559B2 (en) | Fusions with CD8 antigen binding molecules for modulating immune cell function | |
US10745466B2 (en) | Type III secretion system targeting molecules | |
TW202313684A (zh) | 抗ccr8抗體及其用途 | |
RU2801528C2 (ru) | Биспецифичный слитый белок и его применение |