CN110785183A - 用于肺癌(包括nsclc、sclc和其他癌症)免疫治疗的新型肽和肽组合物 - Google Patents
用于肺癌(包括nsclc、sclc和其他癌症)免疫治疗的新型肽和肽组合物 Download PDFInfo
- Publication number
- CN110785183A CN110785183A CN201880041940.1A CN201880041940A CN110785183A CN 110785183 A CN110785183 A CN 110785183A CN 201880041940 A CN201880041940 A CN 201880041940A CN 110785183 A CN110785183 A CN 110785183A
- Authority
- CN
- China
- Prior art keywords
- peptide
- cell
- cells
- cancer
- peptides
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 108090000765 processed proteins & peptides Proteins 0.000 title claims abstract description 681
- 102000004196 processed proteins & peptides Human genes 0.000 title claims abstract description 301
- 206010028980 Neoplasm Diseases 0.000 title claims abstract description 215
- 208000002154 non-small cell lung carcinoma Diseases 0.000 title claims description 69
- 206010041067 Small cell lung cancer Diseases 0.000 title claims description 65
- 208000020816 lung neoplasm Diseases 0.000 title claims description 59
- 206010058467 Lung neoplasm malignant Diseases 0.000 title claims description 55
- 201000005202 lung cancer Diseases 0.000 title claims description 55
- 239000000203 mixture Substances 0.000 title abstract description 39
- 238000009169 immunotherapy Methods 0.000 title abstract description 15
- 210000004027 cell Anatomy 0.000 claims abstract description 223
- 238000000034 method Methods 0.000 claims abstract description 147
- 210000001744 T-lymphocyte Anatomy 0.000 claims abstract description 121
- 102000016266 T-Cell Antigen Receptors Human genes 0.000 claims abstract description 120
- 108091008874 T cell receptors Proteins 0.000 claims abstract description 119
- 108090000623 proteins and genes Proteins 0.000 claims abstract description 116
- 230000020382 suppression by virus of host antigen processing and presentation of peptide antigen via MHC class I Effects 0.000 claims abstract description 96
- 108700018351 Major Histocompatibility Complex Proteins 0.000 claims abstract description 95
- 230000027455 binding Effects 0.000 claims abstract description 73
- 102000004169 proteins and genes Human genes 0.000 claims abstract description 59
- 201000011510 cancer Diseases 0.000 claims abstract description 55
- 150000007523 nucleic acids Chemical class 0.000 claims abstract description 48
- 238000000338 in vitro Methods 0.000 claims abstract description 46
- 102000039446 nucleic acids Human genes 0.000 claims abstract description 43
- 108020004707 nucleic acids Proteins 0.000 claims abstract description 43
- 229960005486 vaccine Drugs 0.000 claims abstract description 38
- 241000282414 Homo sapiens Species 0.000 claims description 433
- 210000001519 tissue Anatomy 0.000 claims description 104
- 239000000427 antigen Substances 0.000 claims description 79
- 108091007433 antigens Proteins 0.000 claims description 79
- 102000036639 antigens Human genes 0.000 claims description 79
- 229920001184 polypeptide Polymers 0.000 claims description 58
- 230000014509 gene expression Effects 0.000 claims description 57
- 239000012634 fragment Substances 0.000 claims description 54
- 150000001413 amino acids Chemical class 0.000 claims description 53
- 210000000612 antigen-presenting cell Anatomy 0.000 claims description 39
- 102000043129 MHC class I family Human genes 0.000 claims description 37
- 108091054437 MHC class I family Proteins 0.000 claims description 37
- 125000003275 alpha amino acid group Chemical group 0.000 claims description 37
- 150000003839 salts Chemical class 0.000 claims description 31
- 238000011282 treatment Methods 0.000 claims description 31
- 239000013604 expression vector Substances 0.000 claims description 30
- 239000003446 ligand Substances 0.000 claims description 26
- 230000005847 immunogenicity Effects 0.000 claims description 24
- 239000003814 drug Substances 0.000 claims description 22
- 108091023037 Aptamer Proteins 0.000 claims description 21
- 238000010186 staining Methods 0.000 claims description 21
- 239000008194 pharmaceutical composition Substances 0.000 claims description 20
- 230000005867 T cell response Effects 0.000 claims description 17
- 206010073071 hepatocellular carcinoma Diseases 0.000 claims description 16
- 230000035772 mutation Effects 0.000 claims description 15
- 208000015914 Non-Hodgkin lymphomas Diseases 0.000 claims description 14
- 230000002163 immunogen Effects 0.000 claims description 13
- 206010009944 Colon cancer Diseases 0.000 claims description 12
- 208000006265 Renal cell carcinoma Diseases 0.000 claims description 12
- 208000032852 chronic lymphocytic leukemia Diseases 0.000 claims description 12
- 210000004443 dendritic cell Anatomy 0.000 claims description 12
- 238000001727 in vivo Methods 0.000 claims description 12
- 238000004519 manufacturing process Methods 0.000 claims description 12
- 208000031261 Acute myeloid leukaemia Diseases 0.000 claims description 11
- 239000003085 diluting agent Substances 0.000 claims description 11
- 231100000844 hepatocellular carcinoma Toxicity 0.000 claims description 11
- 238000004949 mass spectrometry Methods 0.000 claims description 11
- 201000001441 melanoma Diseases 0.000 claims description 11
- 206010061535 Ovarian neoplasm Diseases 0.000 claims description 10
- 208000000102 Squamous Cell Carcinoma of Head and Neck Diseases 0.000 claims description 10
- 208000005718 Stomach Neoplasms Diseases 0.000 claims description 10
- 239000000872 buffer Substances 0.000 claims description 10
- 239000012636 effector Substances 0.000 claims description 10
- 206010017758 gastric cancer Diseases 0.000 claims description 10
- 201000000459 head and neck squamous cell carcinoma Diseases 0.000 claims description 10
- 201000011549 stomach cancer Diseases 0.000 claims description 10
- 208000010839 B-cell chronic lymphocytic leukemia Diseases 0.000 claims description 9
- 206010006187 Breast cancer Diseases 0.000 claims description 9
- 208000026310 Breast neoplasm Diseases 0.000 claims description 9
- 102000004127 Cytokines Human genes 0.000 claims description 9
- 108090000695 Cytokines Proteins 0.000 claims description 9
- 208000031422 Lymphocytic Chronic B-Cell Leukemia Diseases 0.000 claims description 9
- 206010030155 Oesophageal carcinoma Diseases 0.000 claims description 9
- 206010033128 Ovarian cancer Diseases 0.000 claims description 9
- 206010060862 Prostate cancer Diseases 0.000 claims description 9
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 9
- 208000002495 Uterine Neoplasms Diseases 0.000 claims description 9
- 208000006990 cholangiocarcinoma Diseases 0.000 claims description 9
- 206010005003 Bladder cancer Diseases 0.000 claims description 8
- 208000001333 Colorectal Neoplasms Diseases 0.000 claims description 8
- 208000000461 Esophageal Neoplasms Diseases 0.000 claims description 8
- 208000022072 Gallbladder Neoplasms Diseases 0.000 claims description 8
- 208000033776 Myeloid Acute Leukemia Diseases 0.000 claims description 8
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims description 8
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 claims description 8
- 238000003556 assay Methods 0.000 claims description 8
- 150000001875 compounds Chemical class 0.000 claims description 8
- 201000004101 esophageal cancer Diseases 0.000 claims description 8
- 238000010195 expression analysis Methods 0.000 claims description 8
- 108020001507 fusion proteins Proteins 0.000 claims description 8
- 102000037865 fusion proteins Human genes 0.000 claims description 8
- 201000010175 gallbladder cancer Diseases 0.000 claims description 8
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims description 8
- 201000002528 pancreatic cancer Diseases 0.000 claims description 8
- 208000008443 pancreatic carcinoma Diseases 0.000 claims description 8
- 238000012163 sequencing technique Methods 0.000 claims description 8
- 238000012360 testing method Methods 0.000 claims description 8
- 201000005112 urinary bladder cancer Diseases 0.000 claims description 8
- 206010046766 uterine cancer Diseases 0.000 claims description 8
- 238000003745 diagnosis Methods 0.000 claims description 7
- 230000003308 immunostimulating effect Effects 0.000 claims description 7
- 230000002147 killing effect Effects 0.000 claims description 7
- 208000003174 Brain Neoplasms Diseases 0.000 claims description 6
- 238000002659 cell therapy Methods 0.000 claims description 6
- 238000012258 culturing Methods 0.000 claims description 6
- 230000003211 malignant effect Effects 0.000 claims description 6
- 239000003053 toxin Substances 0.000 claims description 6
- 231100000765 toxin Toxicity 0.000 claims description 6
- 108700012359 toxins Proteins 0.000 claims description 6
- 102000006354 HLA-DR Antigens Human genes 0.000 claims description 5
- 108010058597 HLA-DR Antigens Proteins 0.000 claims description 5
- 230000009260 cross reactivity Effects 0.000 claims description 5
- 230000002018 overexpression Effects 0.000 claims description 5
- 102000005962 receptors Human genes 0.000 claims description 5
- 108020003175 receptors Proteins 0.000 claims description 5
- 238000012216 screening Methods 0.000 claims description 5
- 239000003937 drug carrier Substances 0.000 claims description 4
- 239000001963 growth medium Substances 0.000 claims description 4
- 108010028930 invariant chain Proteins 0.000 claims description 4
- 239000008176 lyophilized powder Substances 0.000 claims description 4
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 4
- 125000001429 N-terminal alpha-amino-acid group Chemical group 0.000 claims description 3
- 230000001594 aberrant effect Effects 0.000 claims description 3
- 239000004480 active ingredient Substances 0.000 claims description 3
- 239000000706 filtrate Substances 0.000 claims description 3
- 229920002477 rna polymer Polymers 0.000 claims description 3
- 229940022399 cancer vaccine Drugs 0.000 claims description 2
- 210000000822 natural killer cell Anatomy 0.000 claims description 2
- 239000003381 stabilizer Substances 0.000 claims description 2
- 238000012070 whole genome sequencing analysis Methods 0.000 claims description 2
- 230000006698 induction Effects 0.000 claims 2
- 239000012528 membrane Substances 0.000 claims 2
- 238000002493 microarray Methods 0.000 claims 2
- 238000003114 enzyme-linked immunosorbent spot assay Methods 0.000 claims 1
- 238000011502 immune monitoring Methods 0.000 claims 1
- 230000003834 intracellular effect Effects 0.000 claims 1
- 229940038309 personalized vaccine Drugs 0.000 claims 1
- 230000005975 antitumor immune response Effects 0.000 abstract description 5
- 230000001024 immunotherapeutic effect Effects 0.000 abstract description 5
- 239000008186 active pharmaceutical agent Substances 0.000 abstract description 3
- 208000000587 small cell lung carcinoma Diseases 0.000 description 63
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 59
- 235000018102 proteins Nutrition 0.000 description 54
- 235000001014 amino acid Nutrition 0.000 description 52
- 239000000523 sample Substances 0.000 description 52
- 229940024606 amino acid Drugs 0.000 description 50
- 108020004414 DNA Proteins 0.000 description 42
- 235000002639 sodium chloride Nutrition 0.000 description 33
- 210000004698 lymphocyte Anatomy 0.000 description 28
- 239000013598 vector Substances 0.000 description 28
- 230000000875 corresponding effect Effects 0.000 description 26
- 239000002671 adjuvant Substances 0.000 description 22
- 230000000638 stimulation Effects 0.000 description 22
- 238000006467 substitution reaction Methods 0.000 description 22
- 210000004881 tumor cell Anatomy 0.000 description 21
- 125000000539 amino acid group Chemical group 0.000 description 20
- 230000004044 response Effects 0.000 description 20
- 230000028993 immune response Effects 0.000 description 19
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 17
- 210000001266 CD8-positive T-lymphocyte Anatomy 0.000 description 16
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 16
- 108091054438 MHC class II family Proteins 0.000 description 15
- 208000005017 glioblastoma Diseases 0.000 description 15
- 239000000243 solution Substances 0.000 description 15
- 238000004458 analytical method Methods 0.000 description 14
- -1 clones Substances 0.000 description 14
- 238000009472 formulation Methods 0.000 description 14
- 102000040430 polynucleotide Human genes 0.000 description 14
- 108091033319 polynucleotide Proteins 0.000 description 14
- 239000002157 polynucleotide Substances 0.000 description 14
- 230000001225 therapeutic effect Effects 0.000 description 14
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 13
- 230000006870 function Effects 0.000 description 13
- 239000000047 product Substances 0.000 description 13
- 238000001514 detection method Methods 0.000 description 12
- 238000002347 injection Methods 0.000 description 12
- 239000007924 injection Substances 0.000 description 12
- 230000004048 modification Effects 0.000 description 12
- 238000012986 modification Methods 0.000 description 12
- 108060003951 Immunoglobulin Proteins 0.000 description 11
- 241000699666 Mus <mouse, genus> Species 0.000 description 11
- 208000009956 adenocarcinoma Diseases 0.000 description 11
- 210000004899 c-terminal region Anatomy 0.000 description 11
- 239000003795 chemical substances by application Substances 0.000 description 11
- 230000000694 effects Effects 0.000 description 11
- 102000018358 immunoglobulin Human genes 0.000 description 11
- 210000004072 lung Anatomy 0.000 description 11
- 210000000056 organ Anatomy 0.000 description 11
- 102100039620 Granulocyte-macrophage colony-stimulating factor Human genes 0.000 description 10
- 102000043131 MHC class II family Human genes 0.000 description 10
- 108091028043 Nucleic acid sequence Proteins 0.000 description 10
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 10
- 201000010099 disease Diseases 0.000 description 10
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 10
- 230000004547 gene signature Effects 0.000 description 10
- 239000000463 material Substances 0.000 description 10
- 239000000126 substance Substances 0.000 description 10
- 108700028369 Alleles Proteins 0.000 description 9
- 108010047041 Complementarity Determining Regions Proteins 0.000 description 9
- 108010014597 HLA-B44 Antigen Proteins 0.000 description 9
- 102000015636 Oligopeptides Human genes 0.000 description 9
- 108010038807 Oligopeptides Proteins 0.000 description 9
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 9
- 239000002585 base Substances 0.000 description 9
- 210000004556 brain Anatomy 0.000 description 9
- 210000001151 cytotoxic T lymphocyte Anatomy 0.000 description 9
- 238000011161 development Methods 0.000 description 9
- 230000018109 developmental process Effects 0.000 description 9
- 210000000987 immune system Anatomy 0.000 description 9
- 210000004185 liver Anatomy 0.000 description 9
- 239000011777 magnesium Substances 0.000 description 9
- 239000003550 marker Substances 0.000 description 9
- 239000002773 nucleotide Substances 0.000 description 9
- 125000003729 nucleotide group Chemical group 0.000 description 9
- 108010017213 Granulocyte-Macrophage Colony-Stimulating Factor Proteins 0.000 description 8
- 102100028972 HLA class I histocompatibility antigen, A alpha chain Human genes 0.000 description 8
- 102100028976 HLA class I histocompatibility antigen, B alpha chain Human genes 0.000 description 8
- 108010075704 HLA-A Antigens Proteins 0.000 description 8
- 238000013459 approach Methods 0.000 description 8
- 239000011575 calcium Substances 0.000 description 8
- 238000006243 chemical reaction Methods 0.000 description 8
- 239000002299 complementary DNA Substances 0.000 description 8
- 238000002474 experimental method Methods 0.000 description 8
- 230000004927 fusion Effects 0.000 description 8
- 230000001939 inductive effect Effects 0.000 description 8
- 210000003819 peripheral blood mononuclear cell Anatomy 0.000 description 8
- 108020004705 Codon Proteins 0.000 description 7
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 7
- 108010058607 HLA-B Antigens Proteins 0.000 description 7
- 241000238631 Hexapoda Species 0.000 description 7
- 102000018713 Histocompatibility Antigens Class II Human genes 0.000 description 7
- 241000880493 Leptailurus serval Species 0.000 description 7
- 108091034117 Oligonucleotide Proteins 0.000 description 7
- 239000002253 acid Substances 0.000 description 7
- 230000000890 antigenic effect Effects 0.000 description 7
- 230000015572 biosynthetic process Effects 0.000 description 7
- 210000000601 blood cell Anatomy 0.000 description 7
- 239000003153 chemical reaction reagent Substances 0.000 description 7
- 229940079593 drug Drugs 0.000 description 7
- 108010050848 glycylleucine Proteins 0.000 description 7
- 230000008520 organization Effects 0.000 description 7
- 238000002360 preparation method Methods 0.000 description 7
- 208000000649 small cell carcinoma Diseases 0.000 description 7
- 238000007920 subcutaneous administration Methods 0.000 description 7
- 238000001356 surgical procedure Methods 0.000 description 7
- YBJHBAHKTGYVGT-ZKWXMUAHSA-N (+)-Biotin Chemical compound N1C(=O)N[C@@H]2[C@H](CCCCC(=O)O)SC[C@@H]21 YBJHBAHKTGYVGT-ZKWXMUAHSA-N 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- 241000701022 Cytomegalovirus Species 0.000 description 6
- 102000053602 DNA Human genes 0.000 description 6
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 6
- 108010013476 HLA-A24 Antigen Proteins 0.000 description 6
- 101000662909 Homo sapiens T cell receptor beta constant 1 Proteins 0.000 description 6
- 101000662902 Homo sapiens T cell receptor beta constant 2 Proteins 0.000 description 6
- NUEHQDHDLDXCRU-GUBZILKMSA-N Ser-Pro-Arg Chemical compound OC[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCCN=C(N)N)C(O)=O NUEHQDHDLDXCRU-GUBZILKMSA-N 0.000 description 6
- 102100037272 T cell receptor beta constant 1 Human genes 0.000 description 6
- 102100037298 T cell receptor beta constant 2 Human genes 0.000 description 6
- 241000700605 Viruses Species 0.000 description 6
- JLCPHMBAVCMARE-UHFFFAOYSA-N [3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-hydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methyl [5-(6-aminopurin-9-yl)-2-(hydroxymethyl)oxolan-3-yl] hydrogen phosphate Polymers Cc1cn(C2CC(OP(O)(=O)OCC3OC(CC3OP(O)(=O)OCC3OC(CC3O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c3nc(N)[nH]c4=O)C(COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3CO)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cc(C)c(=O)[nH]c3=O)n3cc(C)c(=O)[nH]c3=O)n3ccc(N)nc3=O)n3cc(C)c(=O)[nH]c3=O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)O2)c(=O)[nH]c1=O JLCPHMBAVCMARE-UHFFFAOYSA-N 0.000 description 6
- 239000008365 aqueous carrier Substances 0.000 description 6
- 108010093581 aspartyl-proline Proteins 0.000 description 6
- 230000001580 bacterial effect Effects 0.000 description 6
- 239000000090 biomarker Substances 0.000 description 6
- 239000008280 blood Substances 0.000 description 6
- 210000004369 blood Anatomy 0.000 description 6
- 210000004204 blood vessel Anatomy 0.000 description 6
- 210000004962 mammalian cell Anatomy 0.000 description 6
- 239000000178 monomer Substances 0.000 description 6
- 238000002823 phage display Methods 0.000 description 6
- 239000013612 plasmid Substances 0.000 description 6
- 230000037452 priming Effects 0.000 description 6
- 238000011002 quantification Methods 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 230000004083 survival effect Effects 0.000 description 6
- 230000009466 transformation Effects 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 108091026890 Coding region Proteins 0.000 description 5
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 5
- 108010021625 Immunoglobulin Fragments Proteins 0.000 description 5
- 102000008394 Immunoglobulin Fragments Human genes 0.000 description 5
- 108010002350 Interleukin-2 Proteins 0.000 description 5
- 102000000588 Interleukin-2 Human genes 0.000 description 5
- 241000829100 Macaca mulatta polyomavirus 1 Species 0.000 description 5
- 241001465754 Metazoa Species 0.000 description 5
- XMBSYZWANAQXEV-UHFFFAOYSA-N N-alpha-L-glutamyl-L-phenylalanine Natural products OC(=O)CCC(N)C(=O)NC(C(O)=O)CC1=CC=CC=C1 XMBSYZWANAQXEV-UHFFFAOYSA-N 0.000 description 5
- 108700026244 Open Reading Frames Proteins 0.000 description 5
- 102000002689 Toll-like receptor Human genes 0.000 description 5
- 108020000411 Toll-like receptor Proteins 0.000 description 5
- 210000001185 bone marrow Anatomy 0.000 description 5
- 238000002512 chemotherapy Methods 0.000 description 5
- 229960004397 cyclophosphamide Drugs 0.000 description 5
- 235000018417 cysteine Nutrition 0.000 description 5
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 5
- 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 5
- 210000004602 germ cell Anatomy 0.000 description 5
- 210000002443 helper t lymphocyte Anatomy 0.000 description 5
- 229960002751 imiquimod Drugs 0.000 description 5
- DOUYETYNHWVLEO-UHFFFAOYSA-N imiquimod Chemical compound C1=CC=CC2=C3N(CC(C)C)C=NC3=C(N)N=C21 DOUYETYNHWVLEO-UHFFFAOYSA-N 0.000 description 5
- 230000001965 increasing effect Effects 0.000 description 5
- 238000007912 intraperitoneal administration Methods 0.000 description 5
- 150000002500 ions Chemical class 0.000 description 5
- 210000003734 kidney Anatomy 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 210000001165 lymph node Anatomy 0.000 description 5
- 229920001223 polyethylene glycol Polymers 0.000 description 5
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 5
- 238000012545 processing Methods 0.000 description 5
- 210000002307 prostate Anatomy 0.000 description 5
- 229950010550 resiquimod Drugs 0.000 description 5
- BXNMTOQRYBFHNZ-UHFFFAOYSA-N resiquimod Chemical compound C1=CC=CC2=C(N(C(COCC)=N3)CC(C)(C)O)C3=C(N)N=C21 BXNMTOQRYBFHNZ-UHFFFAOYSA-N 0.000 description 5
- 239000011734 sodium Substances 0.000 description 5
- 239000011780 sodium chloride Substances 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- 230000008685 targeting Effects 0.000 description 5
- 230000003612 virological effect Effects 0.000 description 5
- 229910020366 ClO 4 Inorganic materials 0.000 description 4
- 101000577881 Homo sapiens Macrophage metalloelastase Proteins 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 4
- 239000004472 Lysine Substances 0.000 description 4
- 102100027998 Macrophage metalloelastase Human genes 0.000 description 4
- 102100028389 Melanoma antigen recognized by T-cells 1 Human genes 0.000 description 4
- 241001529936 Murinae Species 0.000 description 4
- 108010067902 Peptide Library Proteins 0.000 description 4
- 239000002202 Polyethylene glycol Substances 0.000 description 4
- 108020004511 Recombinant DNA Proteins 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- 230000000735 allogeneic effect Effects 0.000 description 4
- 108010013835 arginine glutamate Proteins 0.000 description 4
- 108010077245 asparaginyl-proline Proteins 0.000 description 4
- 108010038633 aspartylglutamate Proteins 0.000 description 4
- 239000011324 bead Substances 0.000 description 4
- 210000000481 breast Anatomy 0.000 description 4
- 238000002619 cancer immunotherapy Methods 0.000 description 4
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 4
- 230000001413 cellular effect Effects 0.000 description 4
- 238000010367 cloning Methods 0.000 description 4
- 230000000295 complement effect Effects 0.000 description 4
- 230000001419 dependent effect Effects 0.000 description 4
- 230000029087 digestion Effects 0.000 description 4
- 230000009977 dual effect Effects 0.000 description 4
- 238000005516 engineering process Methods 0.000 description 4
- 210000001508 eye Anatomy 0.000 description 4
- 239000007850 fluorescent dye Substances 0.000 description 4
- 230000002068 genetic effect Effects 0.000 description 4
- 108010092114 histidylphenylalanine Proteins 0.000 description 4
- 230000003053 immunization Effects 0.000 description 4
- 239000002502 liposome Substances 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- 239000013642 negative control Substances 0.000 description 4
- 238000011275 oncology therapy Methods 0.000 description 4
- 239000002245 particle Substances 0.000 description 4
- 108010073025 phenylalanylphenylalanine Proteins 0.000 description 4
- 230000001817 pituitary effect Effects 0.000 description 4
- 108010053725 prolylvaline Proteins 0.000 description 4
- 239000002516 radical scavenger Substances 0.000 description 4
- 230000010076 replication Effects 0.000 description 4
- BNRNXUUZRGQAQC-UHFFFAOYSA-N sildenafil Chemical compound CCCC1=NN(C)C(C(N2)=O)=C1N=C2C(C(=CC=1)OCC)=CC=1S(=O)(=O)N1CCN(C)CC1 BNRNXUUZRGQAQC-UHFFFAOYSA-N 0.000 description 4
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- 210000001550 testis Anatomy 0.000 description 4
- 238000002560 therapeutic procedure Methods 0.000 description 4
- 238000013518 transcription Methods 0.000 description 4
- 230000035897 transcription Effects 0.000 description 4
- 210000003932 urinary bladder Anatomy 0.000 description 4
- 238000002255 vaccination Methods 0.000 description 4
- HLHSUNWAPXINQU-GQCTYLIASA-N (E)-3-(3,4-dihydroxyphenyl)-N-prop-2-ynylprop-2-enamide Chemical compound OC=1C=C(C=CC=1O)/C=C/C(=O)NCC#C HLHSUNWAPXINQU-GQCTYLIASA-N 0.000 description 3
- 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 3
- UULLJGQFCDXVTQ-CYDGBPFRSA-N Arg-Pro-Ile Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N1CCC[C@H]1C(=O)N[C@@H]([C@@H](C)CC)C(O)=O UULLJGQFCDXVTQ-CYDGBPFRSA-N 0.000 description 3
- 241000501754 Astronotus ocellatus Species 0.000 description 3
- 241000894006 Bacteria Species 0.000 description 3
- 210000003359 CD4-positive helper T lymphocyte Anatomy 0.000 description 3
- 108010078791 Carrier Proteins Proteins 0.000 description 3
- 229920002307 Dextran Polymers 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical group CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- 241000255581 Drosophila <fruit fly, genus> Species 0.000 description 3
- 238000002965 ELISA Methods 0.000 description 3
- 241000588724 Escherichia coli Species 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 3
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 3
- 101001027602 Homo sapiens Kinesin-like protein KIF26B Proteins 0.000 description 3
- 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 3
- 108010054477 Immunoglobulin Fab Fragments Proteins 0.000 description 3
- 102000001706 Immunoglobulin Fab Fragments Human genes 0.000 description 3
- 102000006992 Interferon-alpha Human genes 0.000 description 3
- 108010047761 Interferon-alpha Proteins 0.000 description 3
- 108010065805 Interleukin-12 Proteins 0.000 description 3
- 102000013462 Interleukin-12 Human genes 0.000 description 3
- 102100037692 Kinesin-like protein KIF26B Human genes 0.000 description 3
- DCXYFEDJOCDNAF-REOHCLBHSA-N L-asparagine Chemical compound OC(=O)[C@@H](N)CC(N)=O DCXYFEDJOCDNAF-REOHCLBHSA-N 0.000 description 3
- YLDSJJOGQNEQJK-AVGNSLFASA-N Met-Pro-Leu Chemical compound CSCC[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CC(C)C)C(O)=O YLDSJJOGQNEQJK-AVGNSLFASA-N 0.000 description 3
- 206010027476 Metastases Diseases 0.000 description 3
- 241000699670 Mus sp. Species 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 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 3
- 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 3
- 208000035823 Non-specific autoimmune cerebellar ataxia without characteristic antibodies Diseases 0.000 description 3
- 108090000526 Papain Proteins 0.000 description 3
- 229930182555 Penicillin Natural products 0.000 description 3
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 239000004365 Protease Substances 0.000 description 3
- 208000003670 Pure Red-Cell Aplasia Diseases 0.000 description 3
- 238000003559 RNA-seq method Methods 0.000 description 3
- 108010008281 Recombinant Fusion Proteins Proteins 0.000 description 3
- 102000007056 Recombinant Fusion Proteins Human genes 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 108010060818 Toll-Like Receptor 9 Proteins 0.000 description 3
- 102100033117 Toll-like receptor 9 Human genes 0.000 description 3
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 3
- 241000251539 Vertebrata <Metazoa> Species 0.000 description 3
- 230000009471 action Effects 0.000 description 3
- 230000004913 activation Effects 0.000 description 3
- 210000000577 adipose tissue Anatomy 0.000 description 3
- 210000004100 adrenal gland Anatomy 0.000 description 3
- 230000002411 adverse Effects 0.000 description 3
- 230000000259 anti-tumor effect Effects 0.000 description 3
- 239000002246 antineoplastic agent Substances 0.000 description 3
- 108010047857 aspartylglycine Proteins 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- 210000000013 bile duct Anatomy 0.000 description 3
- 239000011230 binding agent Substances 0.000 description 3
- 229960002685 biotin Drugs 0.000 description 3
- 235000020958 biotin Nutrition 0.000 description 3
- 239000011616 biotin Substances 0.000 description 3
- 231100000504 carcinogenesis Toxicity 0.000 description 3
- 238000007385 chemical modification Methods 0.000 description 3
- 238000003776 cleavage reaction Methods 0.000 description 3
- 238000007796 conventional method Methods 0.000 description 3
- 230000008878 coupling Effects 0.000 description 3
- 238000005859 coupling reaction Methods 0.000 description 3
- 230000002950 deficient Effects 0.000 description 3
- 210000003238 esophagus Anatomy 0.000 description 3
- 239000000796 flavoring agent Substances 0.000 description 3
- 235000019634 flavors Nutrition 0.000 description 3
- 238000000684 flow cytometry Methods 0.000 description 3
- 210000000232 gallbladder Anatomy 0.000 description 3
- 230000013595 glycosylation Effects 0.000 description 3
- 108010037850 glycylvaline Proteins 0.000 description 3
- 210000003128 head Anatomy 0.000 description 3
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 3
- 108010018006 histidylserine Proteins 0.000 description 3
- 238000003384 imaging method Methods 0.000 description 3
- 239000004615 ingredient Substances 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 230000000977 initiatory effect Effects 0.000 description 3
- 238000003780 insertion Methods 0.000 description 3
- 230000037431 insertion Effects 0.000 description 3
- 238000007918 intramuscular administration Methods 0.000 description 3
- 238000001990 intravenous administration Methods 0.000 description 3
- 238000010253 intravenous injection Methods 0.000 description 3
- 108010044374 isoleucyl-tyrosine Proteins 0.000 description 3
- 210000002429 large intestine Anatomy 0.000 description 3
- 108010057821 leucylproline Proteins 0.000 description 3
- 239000000314 lubricant Substances 0.000 description 3
- 239000012931 lyophilized formulation Substances 0.000 description 3
- 108010038320 lysylphenylalanine Proteins 0.000 description 3
- 210000002540 macrophage Anatomy 0.000 description 3
- 230000014759 maintenance of location Effects 0.000 description 3
- 230000007246 mechanism Effects 0.000 description 3
- 230000001404 mediated effect Effects 0.000 description 3
- 239000002609 medium Substances 0.000 description 3
- 239000011859 microparticle Substances 0.000 description 3
- 210000003739 neck Anatomy 0.000 description 3
- 210000005036 nerve Anatomy 0.000 description 3
- 210000001672 ovary Anatomy 0.000 description 3
- 210000000496 pancreas Anatomy 0.000 description 3
- 229940055729 papain Drugs 0.000 description 3
- 235000019834 papain Nutrition 0.000 description 3
- 229940049954 penicillin Drugs 0.000 description 3
- 238000010647 peptide synthesis reaction Methods 0.000 description 3
- 108010064486 phenylalanyl-leucyl-valine Proteins 0.000 description 3
- 108010051242 phenylalanylserine Proteins 0.000 description 3
- 210000002826 placenta Anatomy 0.000 description 3
- 210000004224 pleura Anatomy 0.000 description 3
- 229920000771 poly (alkylcyanoacrylate) Polymers 0.000 description 3
- 229920000642 polymer Polymers 0.000 description 3
- 239000002243 precursor Substances 0.000 description 3
- 238000004393 prognosis Methods 0.000 description 3
- 230000002062 proliferating effect Effects 0.000 description 3
- 108010031719 prolyl-serine Proteins 0.000 description 3
- 108010090894 prolylleucine Proteins 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 230000001105 regulatory effect Effects 0.000 description 3
- 239000011347 resin Substances 0.000 description 3
- 229920005989 resin Polymers 0.000 description 3
- 230000001177 retroviral effect Effects 0.000 description 3
- 238000004007 reversed phase HPLC Methods 0.000 description 3
- 230000007017 scission Effects 0.000 description 3
- 230000028327 secretion Effects 0.000 description 3
- 210000002027 skeletal muscle Anatomy 0.000 description 3
- 210000003491 skin Anatomy 0.000 description 3
- 210000000813 small intestine Anatomy 0.000 description 3
- 239000007790 solid phase Substances 0.000 description 3
- 210000000952 spleen Anatomy 0.000 description 3
- 210000002784 stomach Anatomy 0.000 description 3
- 210000001685 thyroid gland Anatomy 0.000 description 3
- 230000002103 transcriptional effect Effects 0.000 description 3
- 238000012546 transfer Methods 0.000 description 3
- 230000004614 tumor growth Effects 0.000 description 3
- 108010020532 tyrosyl-proline Proteins 0.000 description 3
- 210000000626 ureter Anatomy 0.000 description 3
- 210000005253 yeast cell Anatomy 0.000 description 3
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 description 2
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 2
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 2
- JVJFIQYAHPMBBX-UHFFFAOYSA-N 4-hydroxynonenal Chemical compound CCCCCC(O)C=CC=O JVJFIQYAHPMBBX-UHFFFAOYSA-N 0.000 description 2
- XYTNPQNAZREREP-XQXXSGGOSA-N Ala-Glu-Thr Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O XYTNPQNAZREREP-XQXXSGGOSA-N 0.000 description 2
- RGDKRCPIFODMHK-HJWJTTGWSA-N Ala-Leu-Leu-His Chemical compound C[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](C(O)=O)CC1=CN=CN1 RGDKRCPIFODMHK-HJWJTTGWSA-N 0.000 description 2
- OYJCVIGKMXUVKB-GARJFASQSA-N Ala-Leu-Pro Chemical compound C[C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N1CCC[C@@H]1C(=O)O)N OYJCVIGKMXUVKB-GARJFASQSA-N 0.000 description 2
- XWFWAXPOLRTDFZ-FXQIFTODSA-N Ala-Pro-Ser Chemical compound C[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CO)C(O)=O XWFWAXPOLRTDFZ-FXQIFTODSA-N 0.000 description 2
- KTXKIYXZQFWJKB-VZFHVOOUSA-N Ala-Thr-Ser Chemical compound [H]N[C@@H](C)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(O)=O KTXKIYXZQFWJKB-VZFHVOOUSA-N 0.000 description 2
- WKPXXXUSUHAXDE-SRVKXCTJSA-N Arg-Pro-Arg Chemical compound NC(N)=NCCC[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCCN=C(N)N)C(O)=O WKPXXXUSUHAXDE-SRVKXCTJSA-N 0.000 description 2
- YCYXHLZRUSJITQ-SRVKXCTJSA-N Arg-Pro-Pro Chemical compound NC(=N)NCCC[C@H](N)C(=O)N1CCC[C@H]1C(=O)N1[C@H](C(O)=O)CCC1 YCYXHLZRUSJITQ-SRVKXCTJSA-N 0.000 description 2
- ADPACBMPYWJJCE-FXQIFTODSA-N Arg-Ser-Asp Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(O)=O)C(O)=O ADPACBMPYWJJCE-FXQIFTODSA-N 0.000 description 2
- FMYQECOAIFGQGU-CYDGBPFRSA-N Arg-Val-Ile Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O FMYQECOAIFGQGU-CYDGBPFRSA-N 0.000 description 2
- SZNGQSBRHFMZLT-IHRRRGAJSA-N Asn-Pro-Phe Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O SZNGQSBRHFMZLT-IHRRRGAJSA-N 0.000 description 2
- BEHQTVDBCLSCBY-CFMVVWHZSA-N Asn-Tyr-Ile Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O BEHQTVDBCLSCBY-CFMVVWHZSA-N 0.000 description 2
- XEGZSHSPQNDNRH-JRQIVUDYSA-N Asn-Tyr-Thr Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H]([C@@H](C)O)C(O)=O XEGZSHSPQNDNRH-JRQIVUDYSA-N 0.000 description 2
- ILJQISGMGXRZQQ-IHRRRGAJSA-N Asp-Arg-Tyr Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O ILJQISGMGXRZQQ-IHRRRGAJSA-N 0.000 description 2
- RTXQQDVBACBSCW-CFMVVWHZSA-N Asp-Ile-Tyr Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O RTXQQDVBACBSCW-CFMVVWHZSA-N 0.000 description 2
- UJGRZQYSNYTCAX-SRVKXCTJSA-N Asp-Leu-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CC(O)=O UJGRZQYSNYTCAX-SRVKXCTJSA-N 0.000 description 2
- LTCKTLYKRMCFOC-KKUMJFAQSA-N Asp-Phe-Leu Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CC(C)C)C(O)=O LTCKTLYKRMCFOC-KKUMJFAQSA-N 0.000 description 2
- MGSVBZIBCCKGCY-ZLUOBGJFSA-N Asp-Ser-Ser Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(O)=O MGSVBZIBCCKGCY-ZLUOBGJFSA-N 0.000 description 2
- DCXYFEDJOCDNAF-UHFFFAOYSA-N Asparagine Natural products OC(=O)C(N)CC(N)=O DCXYFEDJOCDNAF-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 102100027314 Beta-2-microglobulin Human genes 0.000 description 2
- 208000005623 Carcinogenesis Diseases 0.000 description 2
- 241000282693 Cercopithecidae Species 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
- 108010071942 Colony-Stimulating Factors Proteins 0.000 description 2
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 2
- QSJXEFYPDANLFS-UHFFFAOYSA-N Diacetyl Chemical compound CC(=O)C(C)=O QSJXEFYPDANLFS-UHFFFAOYSA-N 0.000 description 2
- 241000196324 Embryophyta Species 0.000 description 2
- 206010014733 Endometrial cancer Diseases 0.000 description 2
- 206010014759 Endometrial neoplasm Diseases 0.000 description 2
- 108010040721 Flagellin Proteins 0.000 description 2
- 208000032612 Glial tumor Diseases 0.000 description 2
- 206010018338 Glioma Diseases 0.000 description 2
- 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 2
- AUTNXSQEVVHSJK-YVNDNENWSA-N Glu-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)CCC(O)=O AUTNXSQEVVHSJK-YVNDNENWSA-N 0.000 description 2
- IVGJYOOGJLFKQE-AVGNSLFASA-N Glu-Leu-Lys Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CCC(=O)O)N IVGJYOOGJLFKQE-AVGNSLFASA-N 0.000 description 2
- MIIGESVJEBDJMP-FHWLQOOXSA-N Glu-Phe-Tyr Chemical compound C([C@H](NC(=O)[C@H](CCC(O)=O)N)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(O)=O)C1=CC=CC=C1 MIIGESVJEBDJMP-FHWLQOOXSA-N 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- DUYYPIRFTLOAJQ-YUMQZZPRSA-N Gly-Asn-His Chemical compound C1=C(NC=N1)C[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)N)NC(=O)CN DUYYPIRFTLOAJQ-YUMQZZPRSA-N 0.000 description 2
- 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 2
- DBUNZBWUWCIELX-JHEQGTHGSA-N Gly-Thr-Glu Chemical compound [H]NCC(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCC(O)=O)C(O)=O DBUNZBWUWCIELX-JHEQGTHGSA-N 0.000 description 2
- 102100028971 HLA class I histocompatibility antigen, C alpha chain Human genes 0.000 description 2
- 108010052199 HLA-C Antigens Proteins 0.000 description 2
- PYNPBMCLAKTHJL-SRVKXCTJSA-N His-Pro-Glu Chemical compound [H]N[C@@H](CC1=CNC=N1)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCC(O)=O)C(O)=O PYNPBMCLAKTHJL-SRVKXCTJSA-N 0.000 description 2
- CCUSLCQWVMWTIS-IXOXFDKPSA-N His-Thr-Leu Chemical compound [H]N[C@@H](CC1=CNC=N1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(O)=O CCUSLCQWVMWTIS-IXOXFDKPSA-N 0.000 description 2
- 108010027412 Histocompatibility Antigens Class II Proteins 0.000 description 2
- 101000578784 Homo sapiens Melanoma antigen recognized by T-cells 1 Proteins 0.000 description 2
- 101001005719 Homo sapiens Melanoma-associated antigen 3 Proteins 0.000 description 2
- 101000798076 Homo sapiens T cell receptor delta constant Proteins 0.000 description 2
- 108090000144 Human Proteins Proteins 0.000 description 2
- 102000003839 Human Proteins Human genes 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- PNDMHTTXXPUQJH-RWRJDSDZSA-N Ile-Glu-Thr Chemical compound N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H]([C@H](O)C)C(=O)O PNDMHTTXXPUQJH-RWRJDSDZSA-N 0.000 description 2
- XMYURPUVJSKTMC-KBIXCLLPSA-N Ile-Ser-Gln Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(=O)N)C(=O)O)N XMYURPUVJSKTMC-KBIXCLLPSA-N 0.000 description 2
- PELCGFMHLZXWBQ-BJDJZHNGSA-N Ile-Ser-Leu Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)O)N PELCGFMHLZXWBQ-BJDJZHNGSA-N 0.000 description 2
- 102000018071 Immunoglobulin Fc Fragments Human genes 0.000 description 2
- 108010091135 Immunoglobulin Fc Fragments Proteins 0.000 description 2
- 102000008070 Interferon-gamma Human genes 0.000 description 2
- 108010074328 Interferon-gamma Proteins 0.000 description 2
- 108010002586 Interleukin-7 Proteins 0.000 description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- 150000008575 L-amino acids Chemical class 0.000 description 2
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 2
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 2
- AYFVYJQAPQTCCC-GBXIJSLDSA-N L-threonine Chemical compound C[C@@H](O)[C@H](N)C(O)=O AYFVYJQAPQTCCC-GBXIJSLDSA-N 0.000 description 2
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 2
- 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 2
- MJWVXZABPOKJJF-ACRUOGEOSA-N Leu-Phe-Phe Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O MJWVXZABPOKJJF-ACRUOGEOSA-N 0.000 description 2
- XXXXOVFBXRERQL-ULQDDVLXSA-N Leu-Pro-Phe Chemical compound CC(C)C[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 XXXXOVFBXRERQL-ULQDDVLXSA-N 0.000 description 2
- IZPVWNSAVUQBGP-CIUDSAMLSA-N Leu-Ser-Asp Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(O)=O)C(O)=O IZPVWNSAVUQBGP-CIUDSAMLSA-N 0.000 description 2
- ARNIBBOXIAWUOP-MGHWNKPDSA-N Leu-Tyr-Ile 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@@H](C)CC)C(O)=O ARNIBBOXIAWUOP-MGHWNKPDSA-N 0.000 description 2
- 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 2
- LMGNWHDWJDIOPK-DKIMLUQUSA-N Lys-Phe-Ile Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O LMGNWHDWJDIOPK-DKIMLUQUSA-N 0.000 description 2
- 108010010995 MART-1 Antigen Proteins 0.000 description 2
- 229930195725 Mannitol Natural products 0.000 description 2
- 102100025082 Melanoma-associated antigen 3 Human genes 0.000 description 2
- WYEXWKAWMNJKPN-UBHSHLNASA-N Met-Ala-Phe Chemical compound C[C@@H](C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)O)NC(=O)[C@H](CCSC)N WYEXWKAWMNJKPN-UBHSHLNASA-N 0.000 description 2
- OOSPRDCGTLQLBP-NHCYSSNCSA-N Met-Glu-Val Chemical compound [H]N[C@@H](CCSC)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(O)=O OOSPRDCGTLQLBP-NHCYSSNCSA-N 0.000 description 2
- NTYQUVLERIHPMU-HRCADAONSA-N Met-Phe-Pro Chemical compound CSCC[C@@H](C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N2CCC[C@@H]2C(=O)O)N NTYQUVLERIHPMU-HRCADAONSA-N 0.000 description 2
- AIJULSRZWUXGPQ-UHFFFAOYSA-N Methylglyoxal Chemical compound CC(=O)C=O AIJULSRZWUXGPQ-UHFFFAOYSA-N 0.000 description 2
- SITLTJHOQZFJGG-UHFFFAOYSA-N N-L-alpha-glutamyl-L-valine Natural products CC(C)C(C(O)=O)NC(=O)C(N)CCC(O)=O SITLTJHOQZFJGG-UHFFFAOYSA-N 0.000 description 2
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 2
- 241000283973 Oryctolagus cuniculus Species 0.000 description 2
- 102000002508 Peptide Elongation Factors Human genes 0.000 description 2
- 108010068204 Peptide Elongation Factors Proteins 0.000 description 2
- 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 2
- INHMISZWLJZQGH-ULQDDVLXSA-N Phe-Leu-Val Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CC1=CC=CC=C1 INHMISZWLJZQGH-ULQDDVLXSA-N 0.000 description 2
- YFXXRYFWJFQAFW-JHYOHUSXSA-N Phe-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](CC1=CC=CC=C1)N)O YFXXRYFWJFQAFW-JHYOHUSXSA-N 0.000 description 2
- BQMFWUKNOCJDNV-HJWJTTGWSA-N Phe-Val-Ile Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O BQMFWUKNOCJDNV-HJWJTTGWSA-N 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- 102000011755 Phosphoglycerate Kinase Human genes 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 239000004698 Polyethylene Substances 0.000 description 2
- 239000004793 Polystyrene Substances 0.000 description 2
- KIZQGKLMXKGDIV-BQBZGAKWSA-N Pro-Ala-Gly Chemical compound OC(=O)CNC(=O)[C@H](C)NC(=O)[C@@H]1CCCN1 KIZQGKLMXKGDIV-BQBZGAKWSA-N 0.000 description 2
- FKLSMYYLJHYPHH-UWVGGRQHSA-N Pro-Gly-Leu Chemical compound [H]N1CCC[C@H]1C(=O)NCC(=O)N[C@@H](CC(C)C)C(O)=O FKLSMYYLJHYPHH-UWVGGRQHSA-N 0.000 description 2
- KIDXAAQVMNLJFQ-KZVJFYERSA-N Pro-Thr-Ala Chemical compound C[C@@H](O)[C@H](NC(=O)[C@@H]1CCCN1)C(=O)N[C@@H](C)C(O)=O KIDXAAQVMNLJFQ-KZVJFYERSA-N 0.000 description 2
- JDJMFMVVJHLWDP-UNQGMJICSA-N Pro-Thr-Phe Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O JDJMFMVVJHLWDP-UNQGMJICSA-N 0.000 description 2
- 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 2
- VPBQDHMASPJHGY-JYJNAYRXSA-N Pro-Trp-Ser Chemical compound C1C[C@H](NC1)C(=O)N[C@@H](CC2=CNC3=CC=CC=C32)C(=O)N[C@@H](CO)C(=O)O VPBQDHMASPJHGY-JYJNAYRXSA-N 0.000 description 2
- BVRBCQBUNGAWFP-KKUMJFAQSA-N Pro-Tyr-Gln Chemical compound C1C[C@H](NC1)C(=O)N[C@@H](CC2=CC=C(C=C2)O)C(=O)N[C@@H](CCC(=O)N)C(=O)O BVRBCQBUNGAWFP-KKUMJFAQSA-N 0.000 description 2
- OQSGBXGNAFQGGS-CYDGBPFRSA-N Pro-Val-Ile Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O OQSGBXGNAFQGGS-CYDGBPFRSA-N 0.000 description 2
- 239000013614 RNA sample Substances 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- 241000283984 Rodentia Species 0.000 description 2
- FIDMVVBUOCMMJG-CIUDSAMLSA-N Ser-Asn-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](N)CO FIDMVVBUOCMMJG-CIUDSAMLSA-N 0.000 description 2
- UFKPDBLKLOBMRH-XHNCKOQMSA-N Ser-Glu-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CCC(=O)O)NC(=O)[C@H](CO)N)C(=O)O UFKPDBLKLOBMRH-XHNCKOQMSA-N 0.000 description 2
- 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 2
- KDGARKCAKHBEDB-NKWVEPMBSA-N Ser-Gly-Pro Chemical compound C1C[C@@H](N(C1)C(=O)CNC(=O)[C@H](CO)N)C(=O)O KDGARKCAKHBEDB-NKWVEPMBSA-N 0.000 description 2
- VMLONWHIORGALA-SRVKXCTJSA-N Ser-Leu-Leu Chemical compound CC(C)C[C@@H](C([O-])=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H]([NH3+])CO VMLONWHIORGALA-SRVKXCTJSA-N 0.000 description 2
- 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 2
- 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 2
- 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 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- BQCADISMDOOEFD-UHFFFAOYSA-N Silver Chemical compound [Ag] BQCADISMDOOEFD-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 241000713880 Spleen focus-forming virus Species 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 230000024932 T cell mediated immunity Effects 0.000 description 2
- 230000037453 T cell priming Effects 0.000 description 2
- 102100032272 T cell receptor delta constant Human genes 0.000 description 2
- 108700042076 T-Cell Receptor alpha Genes Proteins 0.000 description 2
- 108700042077 T-Cell Receptor beta Genes Proteins 0.000 description 2
- 101001099217 Thermotoga maritima (strain ATCC 43589 / DSM 3109 / JCM 10099 / NBRC 100826 / MSB8) Triosephosphate isomerase Proteins 0.000 description 2
- OQCXTUQTKQFDCX-HTUGSXCWSA-N Thr-Glu-Phe Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)O)N)O OQCXTUQTKQFDCX-HTUGSXCWSA-N 0.000 description 2
- NCXVJIQMWSGRHY-KXNHARMFSA-N Thr-Leu-Pro Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N1CCC[C@@H]1C(=O)O)N)O NCXVJIQMWSGRHY-KXNHARMFSA-N 0.000 description 2
- 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
- IEZVHOULSUULHD-XGEHTFHBSA-N Thr-Ser-Val Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(O)=O IEZVHOULSUULHD-XGEHTFHBSA-N 0.000 description 2
- QJIODPFLAASXJC-JHYOHUSXSA-N Thr-Thr-Phe Chemical compound C[C@H]([C@@H](C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)O)N)O QJIODPFLAASXJC-JHYOHUSXSA-N 0.000 description 2
- 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 2
- 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 2
- BIJDDZBDSJLWJY-PJODQICGSA-N Trp-Ala-Val Chemical compound [H]N[C@@H](CC1=CNC2=C1C=CC=C2)C(=O)N[C@@H](C)C(=O)N[C@@H](C(C)C)C(O)=O BIJDDZBDSJLWJY-PJODQICGSA-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
- MNWINJDPGBNOED-ULQDDVLXSA-N Tyr-Pro-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@@H](N)CC1=CC=C(O)C=C1 MNWINJDPGBNOED-ULQDDVLXSA-N 0.000 description 2
- AGDDLOQMXUQPDY-BZSNNMDCSA-N Tyr-Tyr-Ser Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CO)C(O)=O AGDDLOQMXUQPDY-BZSNNMDCSA-N 0.000 description 2
- ROLGIBMFNMZANA-GVXVVHGQSA-N Val-Glu-Leu Chemical compound CC(C)C[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)O)NC(=O)[C@H](C(C)C)N ROLGIBMFNMZANA-GVXVVHGQSA-N 0.000 description 2
- SDUBQHUJJWQTEU-XUXIUFHCSA-N Val-Ile-Lys Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](C(C)C)N SDUBQHUJJWQTEU-XUXIUFHCSA-N 0.000 description 2
- NHXZRXLFOBFMDM-AVGNSLFASA-N Val-Pro-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@@H](N)C(C)C NHXZRXLFOBFMDM-AVGNSLFASA-N 0.000 description 2
- 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 2
- 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 2
- DLRZGNXCXUGIDG-KKHAAJSZSA-N Val-Thr-Asp Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)O)NC(=O)[C@H](C(C)C)N)O DLRZGNXCXUGIDG-KKHAAJSZSA-N 0.000 description 2
- 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 2
- SVLAAUGFIHSJPK-JYJNAYRXSA-N Val-Trp-Ser Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC1=CNC2=CC=CC=C21)C(=O)N[C@@H](CO)C(=O)O)N SVLAAUGFIHSJPK-JYJNAYRXSA-N 0.000 description 2
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 125000003295 alanine group Chemical group N[C@@H](C)C(=O)* 0.000 description 2
- 108010076324 alanyl-glycyl-glycine Proteins 0.000 description 2
- 108010045023 alanyl-prolyl-tyrosine Proteins 0.000 description 2
- 108010041407 alanylaspartic acid Proteins 0.000 description 2
- 125000001931 aliphatic group Chemical group 0.000 description 2
- KOSRFJWDECSPRO-UHFFFAOYSA-N alpha-L-glutamyl-L-glutamic acid Natural products OC(=O)CCC(N)C(=O)NC(CCC(O)=O)C(O)=O KOSRFJWDECSPRO-UHFFFAOYSA-N 0.000 description 2
- 125000003277 amino group Chemical group 0.000 description 2
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 2
- 239000005557 antagonist Substances 0.000 description 2
- 230000001093 anti-cancer Effects 0.000 description 2
- 230000005875 antibody response Effects 0.000 description 2
- 230000006907 apoptotic process Effects 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 125000000637 arginyl group Chemical group N[C@@H](CCCNC(N)=N)C(=O)* 0.000 description 2
- 108010052670 arginyl-glutamyl-glutamic acid Proteins 0.000 description 2
- 108010029539 arginyl-prolyl-proline Proteins 0.000 description 2
- 235000009582 asparagine Nutrition 0.000 description 2
- 229960001230 asparagine Drugs 0.000 description 2
- 108010040443 aspartyl-aspartic acid Proteins 0.000 description 2
- 108010068265 aspartyltyrosine Proteins 0.000 description 2
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 2
- 108010081355 beta 2-Microglobulin Proteins 0.000 description 2
- 229960000397 bevacizumab Drugs 0.000 description 2
- 238000002306 biochemical method Methods 0.000 description 2
- 238000001574 biopsy Methods 0.000 description 2
- 230000000903 blocking effect Effects 0.000 description 2
- 239000008364 bulk solution Substances 0.000 description 2
- LYQFWZFBNBDLEO-UHFFFAOYSA-M caesium bromide Chemical compound [Br-].[Cs+] LYQFWZFBNBDLEO-UHFFFAOYSA-M 0.000 description 2
- AIYUHDOJVYHVIT-UHFFFAOYSA-M caesium chloride Chemical compound [Cl-].[Cs+] AIYUHDOJVYHVIT-UHFFFAOYSA-M 0.000 description 2
- 239000001506 calcium phosphate Substances 0.000 description 2
- 230000036952 cancer formation Effects 0.000 description 2
- 230000021235 carbamoylation Effects 0.000 description 2
- 210000000845 cartilage Anatomy 0.000 description 2
- 230000036755 cellular response Effects 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 238000012512 characterization method Methods 0.000 description 2
- 210000004978 chinese hamster ovary cell Anatomy 0.000 description 2
- 239000010949 copper Substances 0.000 description 2
- 238000010168 coupling process Methods 0.000 description 2
- 238000004132 cross linking Methods 0.000 description 2
- XVOYSCVBGLVSOL-UHFFFAOYSA-N cysteic acid Chemical compound OC(=O)C(N)CS(O)(=O)=O XVOYSCVBGLVSOL-UHFFFAOYSA-N 0.000 description 2
- 125000000151 cysteine group Chemical group N[C@@H](CS)C(=O)* 0.000 description 2
- 229940127089 cytotoxic agent Drugs 0.000 description 2
- 230000034994 death Effects 0.000 description 2
- 231100000517 death Toxicity 0.000 description 2
- 230000007423 decrease Effects 0.000 description 2
- 238000012217 deletion Methods 0.000 description 2
- 230000037430 deletion Effects 0.000 description 2
- 230000004041 dendritic cell maturation Effects 0.000 description 2
- 230000004069 differentiation Effects 0.000 description 2
- 108010054813 diprotin B Proteins 0.000 description 2
- 238000010494 dissociation reaction Methods 0.000 description 2
- 230000005593 dissociations Effects 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 235000019253 formic acid Nutrition 0.000 description 2
- 238000013467 fragmentation Methods 0.000 description 2
- 238000006062 fragmentation reaction Methods 0.000 description 2
- 238000004108 freeze drying Methods 0.000 description 2
- 230000002496 gastric effect Effects 0.000 description 2
- 102000054766 genetic haplotypes Human genes 0.000 description 2
- 239000011521 glass Substances 0.000 description 2
- 125000000291 glutamic acid group Chemical group N[C@@H](CCC(O)=O)C(=O)* 0.000 description 2
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 2
- 108010057083 glutamyl-aspartyl-leucine Proteins 0.000 description 2
- 238000006206 glycosylation reaction Methods 0.000 description 2
- XKUKSGPZAADMRA-UHFFFAOYSA-N glycyl-glycyl-glycine Natural products NCC(=O)NCC(=O)NCC(O)=O XKUKSGPZAADMRA-UHFFFAOYSA-N 0.000 description 2
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 2
- 229910052737 gold Inorganic materials 0.000 description 2
- 239000010931 gold Substances 0.000 description 2
- 201000010536 head and neck cancer Diseases 0.000 description 2
- 208000014829 head and neck neoplasm Diseases 0.000 description 2
- 108010085325 histidylproline Proteins 0.000 description 2
- 229920001519 homopolymer Polymers 0.000 description 2
- 210000004408 hybridoma Anatomy 0.000 description 2
- 230000002209 hydrophobic effect Effects 0.000 description 2
- 125000001165 hydrophobic group Chemical group 0.000 description 2
- 210000002865 immune cell Anatomy 0.000 description 2
- 230000006058 immune tolerance Effects 0.000 description 2
- 238000002649 immunization Methods 0.000 description 2
- 229940124452 immunizing agent Drugs 0.000 description 2
- 229940072221 immunoglobulins Drugs 0.000 description 2
- 238000003364 immunohistochemistry Methods 0.000 description 2
- 239000002955 immunomodulating agent Substances 0.000 description 2
- 230000008676 import Effects 0.000 description 2
- 238000001802 infusion Methods 0.000 description 2
- 229960003130 interferon gamma Drugs 0.000 description 2
- 108010074108 interleukin-21 Proteins 0.000 description 2
- 238000010255 intramuscular injection Methods 0.000 description 2
- 125000000741 isoleucyl group Chemical group [H]N([H])C(C(C([H])([H])[H])C([H])([H])C([H])([H])[H])C(=O)O* 0.000 description 2
- 239000007951 isotonicity adjuster Substances 0.000 description 2
- 108010045069 keyhole-limpet hemocyanin Proteins 0.000 description 2
- 108010073472 leucyl-prolyl-proline Proteins 0.000 description 2
- AMXOYNBUYSYVKV-UHFFFAOYSA-M lithium bromide Chemical compound [Li+].[Br-] AMXOYNBUYSYVKV-UHFFFAOYSA-M 0.000 description 2
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 2
- 108010003700 lysyl aspartic acid Proteins 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 239000000594 mannitol Substances 0.000 description 2
- 235000010355 mannitol Nutrition 0.000 description 2
- 210000002752 melanocyte Anatomy 0.000 description 2
- 230000009401 metastasis Effects 0.000 description 2
- 108010056582 methionylglutamic acid Proteins 0.000 description 2
- 210000001616 monocyte Anatomy 0.000 description 2
- 238000010606 normalization Methods 0.000 description 2
- 230000002611 ovarian Effects 0.000 description 2
- 210000002990 parathyroid gland Anatomy 0.000 description 2
- 229940023041 peptide vaccine Drugs 0.000 description 2
- 210000005105 peripheral blood lymphocyte Anatomy 0.000 description 2
- 210000004303 peritoneum Anatomy 0.000 description 2
- 239000000825 pharmaceutical preparation Substances 0.000 description 2
- 229940127557 pharmaceutical product Drugs 0.000 description 2
- JTJMJGYZQZDUJJ-UHFFFAOYSA-N phencyclidine Chemical compound C1CCCCN1C1(C=2C=CC=CC=2)CCCCC1 JTJMJGYZQZDUJJ-UHFFFAOYSA-N 0.000 description 2
- 239000002953 phosphate buffered saline Substances 0.000 description 2
- 108700002563 poly ICLC Proteins 0.000 description 2
- 229940115272 polyinosinic:polycytidylic acid Drugs 0.000 description 2
- 229920002223 polystyrene Polymers 0.000 description 2
- 239000013641 positive control Substances 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 108010014614 prolyl-glycyl-proline Proteins 0.000 description 2
- 108010070643 prolylglutamic acid Proteins 0.000 description 2
- 108010029020 prolylglycine Proteins 0.000 description 2
- 125000006239 protecting group Chemical group 0.000 description 2
- 238000000159 protein binding assay Methods 0.000 description 2
- 230000009145 protein modification Effects 0.000 description 2
- 238000001959 radiotherapy Methods 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 230000002441 reversible effect Effects 0.000 description 2
- 238000012552 review Methods 0.000 description 2
- 210000003705 ribosome Anatomy 0.000 description 2
- 230000003248 secreting effect Effects 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 108010026333 seryl-proline Proteins 0.000 description 2
- 230000019491 signal transduction Effects 0.000 description 2
- 229960003310 sildenafil Drugs 0.000 description 2
- 229910052709 silver Inorganic materials 0.000 description 2
- 239000004332 silver Substances 0.000 description 2
- JHJLBTNAGRQEKS-UHFFFAOYSA-M sodium bromide Chemical compound [Na+].[Br-] JHJLBTNAGRQEKS-UHFFFAOYSA-M 0.000 description 2
- DAEPDZWVDSPTHF-UHFFFAOYSA-M sodium pyruvate Chemical compound [Na+].CC(=O)C([O-])=O DAEPDZWVDSPTHF-UHFFFAOYSA-M 0.000 description 2
- 241000894007 species Species 0.000 description 2
- 230000009870 specific binding Effects 0.000 description 2
- 230000003595 spectral effect Effects 0.000 description 2
- 238000004611 spectroscopical analysis Methods 0.000 description 2
- 206010041823 squamous cell carcinoma Diseases 0.000 description 2
- 230000000087 stabilizing effect Effects 0.000 description 2
- 238000010561 standard procedure Methods 0.000 description 2
- 230000004936 stimulating effect Effects 0.000 description 2
- 229960005322 streptomycin Drugs 0.000 description 2
- 238000010254 subcutaneous injection Methods 0.000 description 2
- 239000007929 subcutaneous injection Substances 0.000 description 2
- 230000002195 synergetic effect Effects 0.000 description 2
- 238000002626 targeted therapy Methods 0.000 description 2
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 238000010998 test method Methods 0.000 description 2
- 229940021747 therapeutic vaccine Drugs 0.000 description 2
- 125000003396 thiol group Chemical group [H]S* 0.000 description 2
- 210000001541 thymus gland Anatomy 0.000 description 2
- 238000011830 transgenic mouse model Methods 0.000 description 2
- 238000013519 translation Methods 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- 108010060175 trypsinogen activation peptide Proteins 0.000 description 2
- 108010080629 tryptophan-leucine Proteins 0.000 description 2
- 108010071635 tyrosyl-prolyl-arginine Proteins 0.000 description 2
- 108010078580 tyrosylleucine Proteins 0.000 description 2
- 241001515965 unidentified phage Species 0.000 description 2
- 210000004291 uterus Anatomy 0.000 description 2
- 239000003643 water by type Substances 0.000 description 2
- 239000000080 wetting agent Substances 0.000 description 2
- HDTRYLNUVZCQOY-UHFFFAOYSA-N α-D-glucopyranosyl-α-D-glucopyranoside Natural products OC1C(O)C(O)C(CO)OC1OC1C(O)C(O)C(O)C(CO)O1 HDTRYLNUVZCQOY-UHFFFAOYSA-N 0.000 description 1
- CNKBMTKICGGSCQ-ACRUOGEOSA-N (2S)-2-[[(2S)-2-[[(2S)-2,6-diamino-1-oxohexyl]amino]-1-oxo-3-phenylpropyl]amino]-3-(4-hydroxyphenyl)propanoic acid Chemical compound C([C@H](NC(=O)[C@@H](N)CCCCN)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(O)=O)C1=CC=CC=C1 CNKBMTKICGGSCQ-ACRUOGEOSA-N 0.000 description 1
- BRPMXFSTKXXNHF-IUCAKERBSA-N (2s)-1-[2-[[(2s)-pyrrolidine-2-carbonyl]amino]acetyl]pyrrolidine-2-carboxylic acid Chemical compound OC(=O)[C@@H]1CCCN1C(=O)CNC(=O)[C@H]1NCCC1 BRPMXFSTKXXNHF-IUCAKERBSA-N 0.000 description 1
- YUXKOWPNKJSTPQ-AXWWPMSFSA-N (2s,3r)-2-amino-3-hydroxybutanoic acid;(2s)-2-amino-3-hydroxypropanoic acid Chemical compound OC[C@H](N)C(O)=O.C[C@@H](O)[C@H](N)C(O)=O YUXKOWPNKJSTPQ-AXWWPMSFSA-N 0.000 description 1
- DMQYDVBIPXAAJA-VHXPQNKSSA-N (3z)-5-[(1-ethylpiperidin-4-yl)amino]-3-[(3-fluorophenyl)-(5-methyl-1h-imidazol-2-yl)methylidene]-1h-indol-2-one Chemical compound C1CN(CC)CCC1NC1=CC=C(NC(=O)\C2=C(/C=3NC=C(C)N=3)C=3C=C(F)C=CC=3)C2=C1 DMQYDVBIPXAAJA-VHXPQNKSSA-N 0.000 description 1
- POVNCJSPYFCWJR-USZUGGBUSA-N (4s)-4-[[(2s)-2-[[(2s)-2-amino-3-(4-hydroxyphenyl)propanoyl]amino]-4-methylpentanoyl]amino]-5-[(2s)-2-[[2-[(2s)-2-[[(2s)-1-[[(2s,3r)-1-[[(1s)-1-carboxy-2-methylpropyl]amino]-3-hydroxy-1-oxobutan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]carbamoyl]pyrrolidin-1- Chemical compound C([C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N1[C@@H](CCC1)C(=O)NCC(=O)N1[C@@H](CCC1)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(O)=O)C1=CC=C(O)C=C1 POVNCJSPYFCWJR-USZUGGBUSA-N 0.000 description 1
- 102000040650 (ribonucleotides)n+m Human genes 0.000 description 1
- DHBXNPKRAUYBTH-UHFFFAOYSA-N 1,1-ethanedithiol Chemical compound CC(S)S DHBXNPKRAUYBTH-UHFFFAOYSA-N 0.000 description 1
- RKDVKSZUMVYZHH-UHFFFAOYSA-N 1,4-dioxane-2,5-dione Chemical compound O=C1COC(=O)CO1 RKDVKSZUMVYZHH-UHFFFAOYSA-N 0.000 description 1
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 1
- DURPTKYDGMDSBL-UHFFFAOYSA-N 1-butoxybutane Chemical class CCCCOCCCC DURPTKYDGMDSBL-UHFFFAOYSA-N 0.000 description 1
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 1
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 1
- GZCWLCBFPRFLKL-UHFFFAOYSA-N 1-prop-2-ynoxypropan-2-ol Chemical compound CC(O)COCC#C GZCWLCBFPRFLKL-UHFFFAOYSA-N 0.000 description 1
- NHJVRSWLHSJWIN-UHFFFAOYSA-N 2,4,6-trinitrobenzenesulfonic acid Chemical compound OS(=O)(=O)C1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O NHJVRSWLHSJWIN-UHFFFAOYSA-N 0.000 description 1
- CHHHXKFHOYLYRE-UHFFFAOYSA-M 2,4-Hexadienoic acid, potassium salt (1:1), (2E,4E)- Chemical compound [K+].CC=CC=CC([O-])=O CHHHXKFHOYLYRE-UHFFFAOYSA-M 0.000 description 1
- 150000003923 2,5-pyrrolediones Chemical class 0.000 description 1
- KFDPCYZHENQOBV-UHFFFAOYSA-N 2-(bromomethyl)-4-nitrophenol Chemical compound OC1=CC=C([N+]([O-])=O)C=C1CBr KFDPCYZHENQOBV-UHFFFAOYSA-N 0.000 description 1
- VUCNQOPCYRJCGQ-UHFFFAOYSA-N 2-[4-(hydroxymethyl)phenoxy]acetic acid Chemical class OCC1=CC=C(OCC(O)=O)C=C1 VUCNQOPCYRJCGQ-UHFFFAOYSA-N 0.000 description 1
- IOJUJUOXKXMJNF-UHFFFAOYSA-N 2-acetyloxybenzoic acid [3-(nitrooxymethyl)phenyl] ester Chemical compound CC(=O)OC1=CC=CC=C1C(=O)OC1=CC=CC(CO[N+]([O-])=O)=C1 IOJUJUOXKXMJNF-UHFFFAOYSA-N 0.000 description 1
- LJGHYPLBDBRCRZ-UHFFFAOYSA-N 3-(3-aminophenyl)sulfonylaniline Chemical compound NC1=CC=CC(S(=O)(=O)C=2C=C(N)C=CC=2)=C1 LJGHYPLBDBRCRZ-UHFFFAOYSA-N 0.000 description 1
- HXHAJRMTJXHJJZ-UHFFFAOYSA-N 3-[(4-bromo-2,6-difluorophenyl)methoxy]-5-(4-pyrrolidin-1-ylbutylcarbamoylamino)-1,2-thiazole-4-carboxamide Chemical compound S1N=C(OCC=2C(=CC(Br)=CC=2F)F)C(C(=O)N)=C1NC(=O)NCCCCN1CCCC1 HXHAJRMTJXHJJZ-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- WHNPOQXWAMXPTA-UHFFFAOYSA-N 3-methylbut-2-enamide Chemical compound CC(C)=CC(N)=O WHNPOQXWAMXPTA-UHFFFAOYSA-N 0.000 description 1
- IECMOFZIMWVOAS-UHFFFAOYSA-N 4,4-dimethylpiperidine Chemical compound CC1(C)CCNCC1 IECMOFZIMWVOAS-UHFFFAOYSA-N 0.000 description 1
- XXJWYDDUDKYVKI-UHFFFAOYSA-N 4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxy-7-[3-(1-pyrrolidinyl)propoxy]quinazoline Chemical compound COC1=CC2=C(OC=3C(=C4C=C(C)NC4=CC=3)F)N=CN=C2C=C1OCCCN1CCCC1 XXJWYDDUDKYVKI-UHFFFAOYSA-N 0.000 description 1
- AYXZIZMZXAORLO-UFLZEWODSA-N 5-[(3as,4s,6ar)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoic acid;1-hydroxypyrrolidine-2,5-dione Chemical compound ON1C(=O)CCC1=O.N1C(=O)N[C@@H]2[C@H](CCCCC(=O)O)SC[C@@H]21 AYXZIZMZXAORLO-UFLZEWODSA-N 0.000 description 1
- GOZMBJCYMQQACI-UHFFFAOYSA-N 6,7-dimethyl-3-[[methyl-[2-[methyl-[[1-[3-(trifluoromethyl)phenyl]indol-3-yl]methyl]amino]ethyl]amino]methyl]chromen-4-one;dihydrochloride Chemical compound Cl.Cl.C=1OC2=CC(C)=C(C)C=C2C(=O)C=1CN(C)CCN(C)CC(C1=CC=CC=C11)=CN1C1=CC=CC(C(F)(F)F)=C1 GOZMBJCYMQQACI-UHFFFAOYSA-N 0.000 description 1
- HWTDMFJYBAURQR-UHFFFAOYSA-N 80-82-0 Chemical compound OS(=O)(=O)C1=CC=CC=C1[N+]([O-])=O HWTDMFJYBAURQR-UHFFFAOYSA-N 0.000 description 1
- 102100032296 A disintegrin and metalloproteinase with thrombospondin motifs 12 Human genes 0.000 description 1
- 108091005671 ADAMTS12 Proteins 0.000 description 1
- ITZMJCSORYKOSI-AJNGGQMLSA-N APGPR Enterostatin Chemical compound C[C@H](N)C(=O)N1CCC[C@H]1C(=O)NCC(=O)N1[C@H](C(=O)N[C@@H](CCCN=C(N)N)C(O)=O)CCC1 ITZMJCSORYKOSI-AJNGGQMLSA-N 0.000 description 1
- 102100030841 AT-rich interactive domain-containing protein 4A Human genes 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 102000013563 Acid Phosphatase Human genes 0.000 description 1
- 108010051457 Acid Phosphatase Proteins 0.000 description 1
- 206010069754 Acquired gene mutation Diseases 0.000 description 1
- 102100022900 Actin, cytoplasmic 1 Human genes 0.000 description 1
- 108010085238 Actins Proteins 0.000 description 1
- 208000003200 Adenoma Diseases 0.000 description 1
- 206010001233 Adenoma benign Diseases 0.000 description 1
- YLTKNGYYPIWKHZ-ACZMJKKPSA-N Ala-Ala-Glu Chemical compound C[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@H](C(O)=O)CCC(O)=O YLTKNGYYPIWKHZ-ACZMJKKPSA-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
- WQVFQXXBNHHPLX-ZKWXMUAHSA-N Ala-Ala-His Chemical compound C[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](Cc1cnc[nH]1)C(O)=O WQVFQXXBNHHPLX-ZKWXMUAHSA-N 0.000 description 1
- PJNSIUPOXFBHDM-GUBZILKMSA-N Ala-Arg-Val Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C(C)C)C(O)=O PJNSIUPOXFBHDM-GUBZILKMSA-N 0.000 description 1
- 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 1
- IYCZBJXFSZSHPN-DLOVCJGASA-N Ala-Cys-Phe Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CS)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O IYCZBJXFSZSHPN-DLOVCJGASA-N 0.000 description 1
- ZDYNWWQXFRUOEO-XDTLVQLUSA-N Ala-Gln-Tyr Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O ZDYNWWQXFRUOEO-XDTLVQLUSA-N 0.000 description 1
- KXEVYGKATAMXJJ-ACZMJKKPSA-N Ala-Glu-Asp Chemical compound C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(O)=O KXEVYGKATAMXJJ-ACZMJKKPSA-N 0.000 description 1
- BGNLUHXLSAQYRQ-FXQIFTODSA-N Ala-Glu-Gln Chemical compound C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(N)=O)C(O)=O BGNLUHXLSAQYRQ-FXQIFTODSA-N 0.000 description 1
- GGNHBHYDMUDXQB-KBIXCLLPSA-N Ala-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)N GGNHBHYDMUDXQB-KBIXCLLPSA-N 0.000 description 1
- HXNNRBHASOSVPG-GUBZILKMSA-N Ala-Glu-Leu Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(O)=O HXNNRBHASOSVPG-GUBZILKMSA-N 0.000 description 1
- UHMQKOBNPRAZGB-CIUDSAMLSA-N Ala-Glu-Met Chemical compound C[C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CCSC)C(=O)O)N UHMQKOBNPRAZGB-CIUDSAMLSA-N 0.000 description 1
- 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 1
- QCTFKEJEIMPOLW-JURCDPSOSA-N Ala-Ile-Phe Chemical compound 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 QCTFKEJEIMPOLW-JURCDPSOSA-N 0.000 description 1
- HHRAXZAYZFFRAM-CIUDSAMLSA-N Ala-Leu-Asn Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(O)=O HHRAXZAYZFFRAM-CIUDSAMLSA-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
- UWIQWPWWZUHBAO-ZLIFDBKOSA-N Ala-Leu-Trp Chemical compound C1=CC=C2C(C[C@H](NC(=O)[C@@H](NC(=O)[C@H](C)N)CC(C)C)C(O)=O)=CNC2=C1 UWIQWPWWZUHBAO-ZLIFDBKOSA-N 0.000 description 1
- ZBLQIYPCUWZSRZ-QEJZJMRPSA-N Ala-Phe-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)[C@H](C)N)CC1=CC=CC=C1 ZBLQIYPCUWZSRZ-QEJZJMRPSA-N 0.000 description 1
- OSRZOHXQCUFIQG-FPMFFAJLSA-N Ala-Phe-Pro Chemical compound C([C@H](NC(=O)[C@@H]([NH3+])C)C(=O)N1[C@H](CCC1)C([O-])=O)C1=CC=CC=C1 OSRZOHXQCUFIQG-FPMFFAJLSA-N 0.000 description 1
- MAZZQZWCCYJQGZ-GUBZILKMSA-N Ala-Pro-Arg Chemical compound [H]N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCCNC(N)=N)C(O)=O MAZZQZWCCYJQGZ-GUBZILKMSA-N 0.000 description 1
- XAXHGSOBFPIRFG-LSJOCFKGSA-N Ala-Pro-His Chemical compound C[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](Cc1cnc[nH]1)C(O)=O XAXHGSOBFPIRFG-LSJOCFKGSA-N 0.000 description 1
- ADSGHMXEAZJJNF-DCAQKATOSA-N Ala-Pro-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@H](C)N ADSGHMXEAZJJNF-DCAQKATOSA-N 0.000 description 1
- CQJHFKKGZXKZBC-BPNCWPANSA-N Ala-Pro-Tyr Chemical compound C[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 CQJHFKKGZXKZBC-BPNCWPANSA-N 0.000 description 1
- YHBDGLZYNIARKJ-GUBZILKMSA-N Ala-Pro-Val Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@H](C)N YHBDGLZYNIARKJ-GUBZILKMSA-N 0.000 description 1
- HOVPGJUNRLMIOZ-CIUDSAMLSA-N Ala-Ser-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](CO)NC(=O)[C@H](C)N HOVPGJUNRLMIOZ-CIUDSAMLSA-N 0.000 description 1
- MMLHRUJLOUSRJX-CIUDSAMLSA-N Ala-Ser-Lys Chemical compound C[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@H](C(O)=O)CCCCN MMLHRUJLOUSRJX-CIUDSAMLSA-N 0.000 description 1
- PEEYDECOOVQKRZ-DLOVCJGASA-N Ala-Ser-Phe Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O PEEYDECOOVQKRZ-DLOVCJGASA-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
- WSVLPVUVIUVCRA-KPKNDVKVSA-N Alpha-lactose monohydrate Chemical compound O.O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O WSVLPVUVIUVCRA-KPKNDVKVSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 108010049777 Ankyrins Proteins 0.000 description 1
- 102000008102 Ankyrins Human genes 0.000 description 1
- 241000272478 Aquila Species 0.000 description 1
- VBFJESQBIWCWRL-DCAQKATOSA-N Arg-Ala-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CCCNC(N)=N VBFJESQBIWCWRL-DCAQKATOSA-N 0.000 description 1
- GIVATXIGCXFQQA-FXQIFTODSA-N Arg-Ala-Ser Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CCCN=C(N)N GIVATXIGCXFQQA-FXQIFTODSA-N 0.000 description 1
- QPOARHANPULOTM-GMOBBJLQSA-N Arg-Asn-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)N)NC(=O)[C@H](CCCN=C(N)N)N QPOARHANPULOTM-GMOBBJLQSA-N 0.000 description 1
- 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 1
- MTANSHNQTWPZKP-KKUMJFAQSA-N Arg-Gln-Tyr Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)N)NC(=O)[C@H](CCCN=C(N)N)N)O MTANSHNQTWPZKP-KKUMJFAQSA-N 0.000 description 1
- 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 1
- NKBQZKVMKJJDLX-SRVKXCTJSA-N Arg-Glu-Leu Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(O)=O NKBQZKVMKJJDLX-SRVKXCTJSA-N 0.000 description 1
- AUFHLLPVPSMEOG-YUMQZZPRSA-N Arg-Gly-Glu Chemical compound NC(N)=NCCC[C@H](N)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(O)=O AUFHLLPVPSMEOG-YUMQZZPRSA-N 0.000 description 1
- RFXXUWGNVRJTNQ-QXEWZRGKSA-N Arg-Gly-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)CNC(=O)[C@H](CCCN=C(N)N)N RFXXUWGNVRJTNQ-QXEWZRGKSA-N 0.000 description 1
- NVUIWHJLPSZZQC-CYDGBPFRSA-N Arg-Ile-Arg Chemical compound NC(N)=NCCC[C@H](N)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCCN=C(N)N)C(O)=O NVUIWHJLPSZZQC-CYDGBPFRSA-N 0.000 description 1
- OOIMKQRCPJBGPD-XUXIUFHCSA-N Arg-Ile-Leu Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(C)C)C(O)=O OOIMKQRCPJBGPD-XUXIUFHCSA-N 0.000 description 1
- GRRXPUAICOGISM-RWMBFGLXSA-N Arg-Lys-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CCCCN)NC(=O)[C@H](CCCN=C(N)N)N)C(=O)O GRRXPUAICOGISM-RWMBFGLXSA-N 0.000 description 1
- DTBPLQNKYCYUOM-JYJNAYRXSA-N Arg-Met-Phe Chemical compound NC(N)=NCCC[C@H](N)C(=O)N[C@@H](CCSC)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 DTBPLQNKYCYUOM-JYJNAYRXSA-N 0.000 description 1
- LXMKTIZAGIBQRX-HRCADAONSA-N Arg-Phe-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CC2=CC=CC=C2)NC(=O)[C@H](CCCN=C(N)N)N)C(=O)O LXMKTIZAGIBQRX-HRCADAONSA-N 0.000 description 1
- PRLPSDIHSRITSF-UNQGMJICSA-N Arg-Phe-Thr Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H]([C@@H](C)O)C(O)=O PRLPSDIHSRITSF-UNQGMJICSA-N 0.000 description 1
- SLQQPJBDBVPVQV-JYJNAYRXSA-N Arg-Phe-Val Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](C(C)C)C(O)=O SLQQPJBDBVPVQV-JYJNAYRXSA-N 0.000 description 1
- STHNZYKCJHWULY-AVGNSLFASA-N Arg-Pro-His Chemical compound C1C[C@H](N(C1)C(=O)[C@H](CCCN=C(N)N)N)C(=O)N[C@@H](CC2=CN=CN2)C(=O)O STHNZYKCJHWULY-AVGNSLFASA-N 0.000 description 1
- JPAWCMXVNZPJLO-IHRRRGAJSA-N Arg-Ser-Phe Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O JPAWCMXVNZPJLO-IHRRRGAJSA-N 0.000 description 1
- ASQKVGRCKOFKIU-KZVJFYERSA-N Arg-Thr-Ala Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](C)C(=O)O)NC(=O)[C@H](CCCN=C(N)N)N)O ASQKVGRCKOFKIU-KZVJFYERSA-N 0.000 description 1
- WCZXPVPHUMYLMS-VEVYYDQMSA-N Arg-Thr-Asp Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(O)=O)C(O)=O WCZXPVPHUMYLMS-VEVYYDQMSA-N 0.000 description 1
- LYJXHXGPWDTLKW-HJGDQZAQSA-N Arg-Thr-Gln Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)O)NC(=O)[C@H](CCCN=C(N)N)N)O LYJXHXGPWDTLKW-HJGDQZAQSA-N 0.000 description 1
- AUZAXCPWMDBWEE-HJGDQZAQSA-N Arg-Thr-Glu Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCC(O)=O)C(O)=O AUZAXCPWMDBWEE-HJGDQZAQSA-N 0.000 description 1
- JKRPBTQDPJSQIT-RCWTZXSCSA-N Arg-Thr-Met Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCSC)C(=O)O)NC(=O)[C@H](CCCN=C(N)N)N)O JKRPBTQDPJSQIT-RCWTZXSCSA-N 0.000 description 1
- BFDDUDQCPJWQRQ-IHRRRGAJSA-N Arg-Tyr-Cys Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)N[C@@H](CS)C(=O)O)NC(=O)[C@H](CCCN=C(N)N)N)O BFDDUDQCPJWQRQ-IHRRRGAJSA-N 0.000 description 1
- FOWOZYAWODIRFZ-JYJNAYRXSA-N Arg-Tyr-Met Chemical compound CSCC[C@@H](C(=O)O)NC(=O)[C@H](CC1=CC=C(C=C1)O)NC(=O)[C@H](CCCN=C(N)N)N FOWOZYAWODIRFZ-JYJNAYRXSA-N 0.000 description 1
- ISVACHFCVRKIDG-SRVKXCTJSA-N Arg-Val-Arg Chemical compound NC(N)=NCCC[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCN=C(N)N)C(O)=O ISVACHFCVRKIDG-SRVKXCTJSA-N 0.000 description 1
- VYZBPPBKFCHCIS-WPRPVWTQSA-N Arg-Val-Gly Chemical compound OC(=O)CNC(=O)[C@H](C(C)C)NC(=O)[C@@H](N)CCCN=C(N)N VYZBPPBKFCHCIS-WPRPVWTQSA-N 0.000 description 1
- WHLDJYNHXOMGMU-JYJNAYRXSA-N Arg-Val-Tyr Chemical compound NC(N)=NCCC[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 WHLDJYNHXOMGMU-JYJNAYRXSA-N 0.000 description 1
- ANAHQDPQQBDOBM-UHFFFAOYSA-N Arg-Val-Tyr Natural products CC(C)C(NC(=O)C(N)CCNC(=N)N)C(=O)NC(Cc1ccc(O)cc1)C(=O)O ANAHQDPQQBDOBM-UHFFFAOYSA-N 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- HZPSDHRYYIORKR-WHFBIAKZSA-N Asn-Ala-Gly Chemical compound OC(=O)CNC(=O)[C@H](C)NC(=O)[C@@H](N)CC(N)=O HZPSDHRYYIORKR-WHFBIAKZSA-N 0.000 description 1
- JRVABKHPWDRUJF-UBHSHLNASA-N Asn-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](CC(=O)N)N JRVABKHPWDRUJF-UBHSHLNASA-N 0.000 description 1
- KWQPAXYXVMHJJR-AVGNSLFASA-N Asn-Gln-Tyr Chemical compound NC(=O)C[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 KWQPAXYXVMHJJR-AVGNSLFASA-N 0.000 description 1
- SRUUBQBAVNQZGJ-LAEOZQHASA-N Asn-Gln-Val Chemical compound CC(C)[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)N)NC(=O)[C@H](CC(=O)N)N SRUUBQBAVNQZGJ-LAEOZQHASA-N 0.000 description 1
- OGMDXNFGPOPZTK-GUBZILKMSA-N Asn-Glu-His Chemical compound C1=C(NC=N1)C[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)O)NC(=O)[C@H](CC(=O)N)N OGMDXNFGPOPZTK-GUBZILKMSA-N 0.000 description 1
- DMLSCRJBWUEALP-LAEOZQHASA-N Asn-Glu-Val Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(O)=O DMLSCRJBWUEALP-LAEOZQHASA-N 0.000 description 1
- PBSQFBAJKPLRJY-BYULHYEWSA-N Asn-Gly-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)CNC(=O)[C@H](CC(=O)N)N PBSQFBAJKPLRJY-BYULHYEWSA-N 0.000 description 1
- HYQYLOSCICEYTR-YUMQZZPRSA-N Asn-Gly-Leu Chemical compound [H]N[C@@H](CC(N)=O)C(=O)NCC(=O)N[C@@H](CC(C)C)C(O)=O HYQYLOSCICEYTR-YUMQZZPRSA-N 0.000 description 1
- 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 1
- NUCUBYIUPVYGPP-XIRDDKMYSA-N Asn-Leu-Trp Chemical compound CC(C)C[C@H](NC(=O)[C@@H](N)CC(N)=O)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(O)=O NUCUBYIUPVYGPP-XIRDDKMYSA-N 0.000 description 1
- NTWOPSIUJBMNRI-KKUMJFAQSA-N Asn-Lys-Tyr Chemical compound NC(=O)C[C@H](N)C(=O)N[C@@H](CCCCN)C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 NTWOPSIUJBMNRI-KKUMJFAQSA-N 0.000 description 1
- VITDJIPIJZAVGC-VEVYYDQMSA-N Asn-Met-Thr Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CCSC)C(=O)N[C@@H]([C@@H](C)O)C(O)=O VITDJIPIJZAVGC-VEVYYDQMSA-N 0.000 description 1
- HZZIFFOVHLWGCS-KKUMJFAQSA-N Asn-Phe-Leu Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CC(C)C)C(O)=O HZZIFFOVHLWGCS-KKUMJFAQSA-N 0.000 description 1
- GFGUPLIETCNQGF-DCAQKATOSA-N Asn-Pro-His Chemical compound C1C[C@H](N(C1)C(=O)[C@H](CC(=O)N)N)C(=O)N[C@@H](CC2=CN=CN2)C(=O)O GFGUPLIETCNQGF-DCAQKATOSA-N 0.000 description 1
- VWADICJNCPFKJS-ZLUOBGJFSA-N Asn-Ser-Asp Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(O)=O)C(O)=O VWADICJNCPFKJS-ZLUOBGJFSA-N 0.000 description 1
- MKJBPDLENBUHQU-CIUDSAMLSA-N Asn-Ser-Leu Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(O)=O MKJBPDLENBUHQU-CIUDSAMLSA-N 0.000 description 1
- HPASIOLTWSNMFB-OLHMAJIHSA-N Asn-Thr-Asp Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(O)=O)C(O)=O HPASIOLTWSNMFB-OLHMAJIHSA-N 0.000 description 1
- QUMKPKWYDVMGNT-NUMRIWBASA-N Asn-Thr-Gln Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)O)NC(=O)[C@H](CC(=O)N)N)O QUMKPKWYDVMGNT-NUMRIWBASA-N 0.000 description 1
- 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 1
- PIABYSIYPGLLDQ-XVSYOHENSA-N Asn-Thr-Phe Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O PIABYSIYPGLLDQ-XVSYOHENSA-N 0.000 description 1
- KZYSHAMXEBPJBD-JRQIVUDYSA-N Asn-Thr-Tyr Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O KZYSHAMXEBPJBD-JRQIVUDYSA-N 0.000 description 1
- ATHZHGQSAIJHQU-XIRDDKMYSA-N Asn-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](CC(=O)N)N ATHZHGQSAIJHQU-XIRDDKMYSA-N 0.000 description 1
- JPPLRQVZMZFOSX-UWJYBYFXSA-N Asn-Tyr-Ala Chemical compound NC(=O)C[C@H](N)C(=O)N[C@H](C(=O)N[C@@H](C)C(O)=O)CC1=CC=C(O)C=C1 JPPLRQVZMZFOSX-UWJYBYFXSA-N 0.000 description 1
- MJIJBEYEHBKTIM-BYULHYEWSA-N Asn-Val-Asn Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)O)NC(=O)[C@H](CC(=O)N)N MJIJBEYEHBKTIM-BYULHYEWSA-N 0.000 description 1
- JNCRAQVYJZGIOW-QSFUFRPTSA-N Asn-Val-Ile Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O JNCRAQVYJZGIOW-QSFUFRPTSA-N 0.000 description 1
- CBHVAFXKOYAHOY-NHCYSSNCSA-N Asn-Val-Leu Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O CBHVAFXKOYAHOY-NHCYSSNCSA-N 0.000 description 1
- XOQYDFCQPWAMSA-KKHAAJSZSA-N Asn-Val-Thr Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O XOQYDFCQPWAMSA-KKHAAJSZSA-N 0.000 description 1
- XBQSLMACWDXWLJ-GHCJXIJMSA-N Asp-Ala-Ile Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O XBQSLMACWDXWLJ-GHCJXIJMSA-N 0.000 description 1
- RGKKALNPOYURGE-ZKWXMUAHSA-N Asp-Ala-Val Chemical compound N[C@@H](CC(=O)O)C(=O)N[C@@H](C)C(=O)N[C@@H](C(C)C)C(=O)O RGKKALNPOYURGE-ZKWXMUAHSA-N 0.000 description 1
- HRGGPWBIMIQANI-GUBZILKMSA-N Asp-Gln-Leu Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(C)C)C(O)=O HRGGPWBIMIQANI-GUBZILKMSA-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
- ZEDBMCPXPIYJLW-XHNCKOQMSA-N Asp-Glu-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CCC(=O)O)NC(=O)[C@H](CC(=O)O)N)C(=O)O ZEDBMCPXPIYJLW-XHNCKOQMSA-N 0.000 description 1
- YDJVIBMKAMQPPP-LAEOZQHASA-N Asp-Glu-Val Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(O)=O YDJVIBMKAMQPPP-LAEOZQHASA-N 0.000 description 1
- WBDWQKRLTVCDSY-WHFBIAKZSA-N Asp-Gly-Asp Chemical compound OC(=O)C[C@H](N)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(O)=O WBDWQKRLTVCDSY-WHFBIAKZSA-N 0.000 description 1
- PSLSTUMPZILTAH-BYULHYEWSA-N Asp-Gly-Ile Chemical compound CC[C@H](C)[C@@H](C(O)=O)NC(=O)CNC(=O)[C@@H](N)CC(O)=O PSLSTUMPZILTAH-BYULHYEWSA-N 0.000 description 1
- KHGPWGKPYHPOIK-QWRGUYRKSA-N Asp-Gly-Phe Chemical compound [H]N[C@@H](CC(O)=O)C(=O)NCC(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O KHGPWGKPYHPOIK-QWRGUYRKSA-N 0.000 description 1
- POTCZYQVVNXUIG-BQBZGAKWSA-N Asp-Gly-Pro Chemical compound OC(=O)C[C@H](N)C(=O)NCC(=O)N1CCC[C@H]1C(O)=O POTCZYQVVNXUIG-BQBZGAKWSA-N 0.000 description 1
- SVABRQFIHCSNCI-FOHZUACHSA-N Asp-Gly-Thr Chemical compound [H]N[C@@H](CC(O)=O)C(=O)NCC(=O)N[C@@H]([C@@H](C)O)C(O)=O SVABRQFIHCSNCI-FOHZUACHSA-N 0.000 description 1
- UBPMOJLRVMGTOQ-GARJFASQSA-N Asp-His-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CC2=CN=CN2)NC(=O)[C@H](CC(=O)O)N)C(=O)O UBPMOJLRVMGTOQ-GARJFASQSA-N 0.000 description 1
- KTTCQQNRRLCIBC-GHCJXIJMSA-N Asp-Ile-Ala Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(O)=O KTTCQQNRRLCIBC-GHCJXIJMSA-N 0.000 description 1
- GBSUGIXJAAKZOW-GMOBBJLQSA-N Asp-Ile-Arg Chemical compound OC(=O)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 GBSUGIXJAAKZOW-GMOBBJLQSA-N 0.000 description 1
- KQBVNNAPIURMPD-PEFMBERDSA-N Asp-Ile-Glu Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCC(O)=O)C(O)=O KQBVNNAPIURMPD-PEFMBERDSA-N 0.000 description 1
- MFTVXYMXSAQZNL-DJFWLOJKSA-N Asp-Ile-His Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)NC(=O)[C@H](CC(=O)O)N MFTVXYMXSAQZNL-DJFWLOJKSA-N 0.000 description 1
- PYXXJFRXIYAESU-PCBIJLKTSA-N Asp-Ile-Phe Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O PYXXJFRXIYAESU-PCBIJLKTSA-N 0.000 description 1
- KLYPOCBLKMPBIQ-GHCJXIJMSA-N Asp-Ile-Ser Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CO)C(=O)O)NC(=O)[C@H](CC(=O)O)N KLYPOCBLKMPBIQ-GHCJXIJMSA-N 0.000 description 1
- SPWXXPFDTMYTRI-IUKAMOBKSA-N Asp-Ile-Thr Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(O)=O SPWXXPFDTMYTRI-IUKAMOBKSA-N 0.000 description 1
- AYFVRYXNDHBECD-YUMQZZPRSA-N Asp-Leu-Gly Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)NCC(O)=O AYFVRYXNDHBECD-YUMQZZPRSA-N 0.000 description 1
- UMHUHHJMEXNSIV-CIUDSAMLSA-N Asp-Leu-Ser Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CC(O)=O UMHUHHJMEXNSIV-CIUDSAMLSA-N 0.000 description 1
- ORRJQLIATJDMQM-HJGDQZAQSA-N Asp-Leu-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CC(O)=O ORRJQLIATJDMQM-HJGDQZAQSA-N 0.000 description 1
- GKWFMNNNYZHJHV-SRVKXCTJSA-N Asp-Lys-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](N)CC(O)=O GKWFMNNNYZHJHV-SRVKXCTJSA-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
- YTXCCDCOHIYQFC-GUBZILKMSA-N Asp-Met-Arg Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCCN=C(N)N)C(O)=O YTXCCDCOHIYQFC-GUBZILKMSA-N 0.000 description 1
- KPSHWSWFPUDEGF-FXQIFTODSA-N Asp-Pro-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@@H]1CCCN1C(=O)[C@@H](N)CC(O)=O KPSHWSWFPUDEGF-FXQIFTODSA-N 0.000 description 1
- MVRGBQGZSDJBSM-GMOBBJLQSA-N Asp-Pro-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)[C@@H]1CCCN1C(=O)[C@H](CC(=O)O)N MVRGBQGZSDJBSM-GMOBBJLQSA-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
- VNXQRBXEQXLERQ-CIUDSAMLSA-N Asp-Ser-Lys Chemical compound C(CCN)C[C@@H](C(=O)O)NC(=O)[C@H](CO)NC(=O)[C@H](CC(=O)O)N VNXQRBXEQXLERQ-CIUDSAMLSA-N 0.000 description 1
- 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 1
- PDIYGFYAMZZFCW-JIOCBJNQSA-N Asp-Thr-Pro Chemical compound C[C@H]([C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](CC(=O)O)N)O PDIYGFYAMZZFCW-JIOCBJNQSA-N 0.000 description 1
- RSMZEHCMIOKNMW-GSSVUCPTSA-N Asp-Thr-Thr Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O RSMZEHCMIOKNMW-GSSVUCPTSA-N 0.000 description 1
- OTKUAVXGMREHRX-CFMVVWHZSA-N Asp-Tyr-Ile Chemical compound CC[C@H](C)[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)CC(O)=O)CC1=CC=C(O)C=C1 OTKUAVXGMREHRX-CFMVVWHZSA-N 0.000 description 1
- SQIARYGNVQWOSB-BZSNNMDCSA-N Asp-Tyr-Phe Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O SQIARYGNVQWOSB-BZSNNMDCSA-N 0.000 description 1
- WAEDSQFVZJUHLI-BYULHYEWSA-N Asp-Val-Asp Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(O)=O)C(O)=O WAEDSQFVZJUHLI-BYULHYEWSA-N 0.000 description 1
- SFJUYBCDQBAYAJ-YDHLFZDLSA-N Asp-Val-Phe Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 SFJUYBCDQBAYAJ-YDHLFZDLSA-N 0.000 description 1
- RKXVTTIQNKPCHU-KKHAAJSZSA-N Asp-Val-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](N)CC(O)=O RKXVTTIQNKPCHU-KKHAAJSZSA-N 0.000 description 1
- 241000228212 Aspergillus Species 0.000 description 1
- MLDQJTXFUGDVEO-UHFFFAOYSA-N BAY-43-9006 Chemical compound C1=NC(C(=O)NC)=CC(OC=2C=CC(NC(=O)NC=3C=C(C(Cl)=CC=3)C(F)(F)F)=CC=2)=C1 MLDQJTXFUGDVEO-UHFFFAOYSA-N 0.000 description 1
- 241001289141 Babr Species 0.000 description 1
- 244000063299 Bacillus subtilis Species 0.000 description 1
- 235000014469 Bacillus subtilis Nutrition 0.000 description 1
- 108020000946 Bacterial DNA Proteins 0.000 description 1
- 108020004513 Bacterial RNA Proteins 0.000 description 1
- 102100021663 Baculoviral IAP repeat-containing protein 5 Human genes 0.000 description 1
- 206010004446 Benign prostatic hyperplasia Diseases 0.000 description 1
- 102000015735 Beta-catenin Human genes 0.000 description 1
- 108060000903 Beta-catenin Proteins 0.000 description 1
- 102000004506 Blood Proteins Human genes 0.000 description 1
- 108010017384 Blood Proteins Proteins 0.000 description 1
- 229920002799 BoPET Polymers 0.000 description 1
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 1
- 125000001433 C-terminal amino-acid group Chemical group 0.000 description 1
- 210000001239 CD8-positive, alpha-beta cytotoxic T lymphocyte Anatomy 0.000 description 1
- 101100314454 Caenorhabditis elegans tra-1 gene Proteins 0.000 description 1
- 102100025570 Cancer/testis antigen 1 Human genes 0.000 description 1
- 208000017897 Carcinoma of esophagus Diseases 0.000 description 1
- 206010008342 Cervix carcinoma Diseases 0.000 description 1
- 108090000317 Chymotrypsin Proteins 0.000 description 1
- 102100040484 Claspin Human genes 0.000 description 1
- 101100007328 Cocos nucifera COS-1 gene Proteins 0.000 description 1
- 102100039551 Collagen triple helix repeat-containing protein 1 Human genes 0.000 description 1
- 241000218631 Coniferophyta Species 0.000 description 1
- 102000000529 Costimulatory and Inhibitory T-Cell Receptors Human genes 0.000 description 1
- 108010041504 Costimulatory and Inhibitory T-Cell Receptors Proteins 0.000 description 1
- 241000723655 Cowpea mosaic virus Species 0.000 description 1
- 241000699802 Cricetulus griseus Species 0.000 description 1
- 229920002785 Croscarmellose sodium Polymers 0.000 description 1
- 239000004971 Cross linker Substances 0.000 description 1
- JPVYNHNXODAKFH-UHFFFAOYSA-N Cu2+ Chemical compound [Cu+2] JPVYNHNXODAKFH-UHFFFAOYSA-N 0.000 description 1
- 241001146209 Curio rowleyanus Species 0.000 description 1
- 108010025464 Cyclin-Dependent Kinase 4 Proteins 0.000 description 1
- 102000013701 Cyclin-Dependent Kinase 4 Human genes 0.000 description 1
- RFHGRMMADHHQSA-KBIXCLLPSA-N Cys-Gln-Ile Chemical compound [H]N[C@@H](CS)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O RFHGRMMADHHQSA-KBIXCLLPSA-N 0.000 description 1
- 102100028624 Cytoskeleton-associated protein 5 Human genes 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- 150000008574 D-amino acids Chemical class 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- YVGGHNCTFXOJCH-UHFFFAOYSA-N DDT Chemical compound C1=CC(Cl)=CC=C1C(C(Cl)(Cl)Cl)C1=CC=C(Cl)C=C1 YVGGHNCTFXOJCH-UHFFFAOYSA-N 0.000 description 1
- 108091008102 DNA aptamers Proteins 0.000 description 1
- 230000004543 DNA replication Effects 0.000 description 1
- 230000006820 DNA synthesis Effects 0.000 description 1
- 102000016928 DNA-directed DNA polymerase Human genes 0.000 description 1
- 108010014303 DNA-directed DNA polymerase Proteins 0.000 description 1
- 102000004163 DNA-directed RNA polymerases Human genes 0.000 description 1
- 108090000626 DNA-directed RNA polymerases Proteins 0.000 description 1
- 241000702421 Dependoparvovirus Species 0.000 description 1
- 235000019739 Dicalciumphosphate Nutrition 0.000 description 1
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 1
- 102000001301 EGF receptor Human genes 0.000 description 1
- 108060006698 EGF receptor Proteins 0.000 description 1
- 238000012286 ELISA Assay Methods 0.000 description 1
- 102100031780 Endonuclease Human genes 0.000 description 1
- 108010042407 Endonucleases Proteins 0.000 description 1
- 108010059378 Endopeptidases Proteins 0.000 description 1
- 102000005593 Endopeptidases Human genes 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 240000008168 Ficus benjamina Species 0.000 description 1
- 241000233866 Fungi Species 0.000 description 1
- 229910052688 Gadolinium Inorganic materials 0.000 description 1
- 241001663880 Gammaretrovirus Species 0.000 description 1
- 229930182566 Gentamicin Natural products 0.000 description 1
- CEAZRRDELHUEMR-URQXQFDESA-N Gentamicin Chemical compound O1[C@H](C(C)NC)CC[C@@H](N)[C@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](NC)[C@@](C)(O)CO2)O)[C@H](N)C[C@@H]1N CEAZRRDELHUEMR-URQXQFDESA-N 0.000 description 1
- NUMFTVCBONFQIQ-DRZSPHRISA-N Gln-Ala-Phe Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O NUMFTVCBONFQIQ-DRZSPHRISA-N 0.000 description 1
- 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 1
- JFOKLAPFYCTNHW-SRVKXCTJSA-N Gln-Arg-Lys Chemical compound C(CCN)C[C@@H](C(=O)O)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CCC(=O)N)N JFOKLAPFYCTNHW-SRVKXCTJSA-N 0.000 description 1
- JESJDAAGXULQOP-CIUDSAMLSA-N Gln-Arg-Ser Chemical compound C(C[C@@H](C(=O)N[C@@H](CO)C(=O)O)NC(=O)[C@H](CCC(=O)N)N)CN=C(N)N JESJDAAGXULQOP-CIUDSAMLSA-N 0.000 description 1
- WMOMPXKOKASNBK-PEFMBERDSA-N Gln-Asn-Ile Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O WMOMPXKOKASNBK-PEFMBERDSA-N 0.000 description 1
- CRRFJBGUGNNOCS-PEFMBERDSA-N Gln-Asp-Ile Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O CRRFJBGUGNNOCS-PEFMBERDSA-N 0.000 description 1
- ZQPOVSJFBBETHQ-CIUDSAMLSA-N Gln-Glu-Gln Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(N)=O)C(O)=O ZQPOVSJFBBETHQ-CIUDSAMLSA-N 0.000 description 1
- LLRJEFPKIIBGJP-DCAQKATOSA-N Gln-Glu-His Chemical compound C1=C(NC=N1)C[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)O)NC(=O)[C@H](CCC(=O)N)N LLRJEFPKIIBGJP-DCAQKATOSA-N 0.000 description 1
- PXAFHUATEHLECW-GUBZILKMSA-N Gln-Glu-Met Chemical compound CSCC[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)O)NC(=O)[C@H](CCC(=O)N)N PXAFHUATEHLECW-GUBZILKMSA-N 0.000 description 1
- LVSYIKGMLRHKME-IUCAKERBSA-N Gln-Gly-His Chemical compound C1=C(NC=N1)C[C@@H](C(=O)O)NC(=O)CNC(=O)[C@H](CCC(=O)N)N LVSYIKGMLRHKME-IUCAKERBSA-N 0.000 description 1
- YXQCLIVLWCKCRS-RYUDHWBXSA-N Gln-Gly-Tyr Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)O)NC(=O)CNC(=O)[C@H](CCC(=O)N)N)O YXQCLIVLWCKCRS-RYUDHWBXSA-N 0.000 description 1
- LKVCNGLNTAPMSZ-JYJNAYRXSA-N Gln-His-Phe Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)O)NC(=O)[C@H](CC2=CN=CN2)NC(=O)[C@H](CCC(=O)N)N LKVCNGLNTAPMSZ-JYJNAYRXSA-N 0.000 description 1
- GXMBDEGTXHQBAO-NKIYYHGXSA-N Gln-His-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CC1=CN=CN1)NC(=O)[C@H](CCC(=O)N)N)O GXMBDEGTXHQBAO-NKIYYHGXSA-N 0.000 description 1
- RGAOLBZBLOJUTP-GRLWGSQLSA-N Gln-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](CCC(=O)N)N RGAOLBZBLOJUTP-GRLWGSQLSA-N 0.000 description 1
- FTIJVMLAGRAYMJ-MNXVOIDGSA-N Gln-Ile-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H]([C@@H](C)CC)NC(=O)[C@@H](N)CCC(N)=O FTIJVMLAGRAYMJ-MNXVOIDGSA-N 0.000 description 1
- UWKPRVKWEKEMSY-DCAQKATOSA-N Gln-Lys-Gln Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(N)=O)C(O)=O UWKPRVKWEKEMSY-DCAQKATOSA-N 0.000 description 1
- ZEEPYMXTJWIMSN-GUBZILKMSA-N Gln-Lys-Ser Chemical compound NCCCC[C@@H](C(=O)N[C@@H](CO)C(O)=O)NC(=O)[C@@H](N)CCC(N)=O ZEEPYMXTJWIMSN-GUBZILKMSA-N 0.000 description 1
- QKWBEMCLYTYBNI-GVXVVHGQSA-N Gln-Lys-Val Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](N)CCC(N)=O QKWBEMCLYTYBNI-GVXVVHGQSA-N 0.000 description 1
- KLKYKPXITJBSNI-CIUDSAMLSA-N Gln-Met-Ala Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](C)C(O)=O KLKYKPXITJBSNI-CIUDSAMLSA-N 0.000 description 1
- JNVGVECJCOZHCN-DRZSPHRISA-N Gln-Phe-Ala Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](C)C(O)=O JNVGVECJCOZHCN-DRZSPHRISA-N 0.000 description 1
- 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 1
- UTOQQOMEJDPDMX-ACZMJKKPSA-N Gln-Ser-Asp Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(O)=O)C(O)=O UTOQQOMEJDPDMX-ACZMJKKPSA-N 0.000 description 1
- VOUSELYGTNGEPB-NUMRIWBASA-N Gln-Thr-Asp Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(O)=O)C(O)=O VOUSELYGTNGEPB-NUMRIWBASA-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
- HLRLXVPRJJITSK-IFFSRLJSSA-N Gln-Thr-Val Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(O)=O HLRLXVPRJJITSK-IFFSRLJSSA-N 0.000 description 1
- YJCZUTXLPXBNIO-BHYGNILZSA-N Gln-Trp-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CC2=CNC3=CC=CC=C32)NC(=O)[C@H](CCC(=O)N)N)C(=O)O YJCZUTXLPXBNIO-BHYGNILZSA-N 0.000 description 1
- OACQOWPRWGNKTP-AVGNSLFASA-N Gln-Tyr-Asp Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC(O)=O)C(O)=O OACQOWPRWGNKTP-AVGNSLFASA-N 0.000 description 1
- CMBXOSFZCFGDLE-IHRRRGAJSA-N Gln-Tyr-Gln Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)O)NC(=O)[C@H](CCC(=O)N)N)O CMBXOSFZCFGDLE-IHRRRGAJSA-N 0.000 description 1
- WIMVKDYAKRAUCG-IHRRRGAJSA-N Gln-Tyr-Glu Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)O)NC(=O)[C@H](CCC(=O)N)N)O WIMVKDYAKRAUCG-IHRRRGAJSA-N 0.000 description 1
- QXQDADBVIBLBHN-FHWLQOOXSA-N Gln-Tyr-Phe Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O QXQDADBVIBLBHN-FHWLQOOXSA-N 0.000 description 1
- GJLXZITZLUUXMJ-NHCYSSNCSA-N Gln-Val-Met Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCSC)C(=O)O)NC(=O)[C@H](CCC(=O)N)N GJLXZITZLUUXMJ-NHCYSSNCSA-N 0.000 description 1
- RUFHOVYUYSNDNY-ACZMJKKPSA-N Glu-Ala-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@@H](N)CCC(O)=O RUFHOVYUYSNDNY-ACZMJKKPSA-N 0.000 description 1
- FHPXTPQBODWBIY-CIUDSAMLSA-N Glu-Ala-Arg Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O FHPXTPQBODWBIY-CIUDSAMLSA-N 0.000 description 1
- OGMQXTXGLDNBSS-FXQIFTODSA-N Glu-Ala-Gln Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(N)=O)C(O)=O OGMQXTXGLDNBSS-FXQIFTODSA-N 0.000 description 1
- HUWSBFYAGXCXKC-CIUDSAMLSA-N Glu-Ala-Met Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CCSC)C(O)=O HUWSBFYAGXCXKC-CIUDSAMLSA-N 0.000 description 1
- 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 1
- LTUVYLVIZHJCOQ-KKUMJFAQSA-N Glu-Arg-Phe Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O LTUVYLVIZHJCOQ-KKUMJFAQSA-N 0.000 description 1
- FLLRAEJOLZPSMN-CIUDSAMLSA-N Glu-Asn-Arg Chemical compound OC(=O)CC[C@H](N)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@H](C(O)=O)CCCN=C(N)N FLLRAEJOLZPSMN-CIUDSAMLSA-N 0.000 description 1
- NKSGKPWXSWBRRX-ACZMJKKPSA-N Glu-Asn-Cys Chemical compound C(CC(=O)O)[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CS)C(=O)O)N NKSGKPWXSWBRRX-ACZMJKKPSA-N 0.000 description 1
- RDDSZZJOKDVPAE-ACZMJKKPSA-N Glu-Asn-Ser Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CO)C(O)=O RDDSZZJOKDVPAE-ACZMJKKPSA-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
- DSPQRJXOIXHOHK-WDSKDSINSA-N Glu-Asp-Gly Chemical compound OC(=O)CC[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)NCC(O)=O DSPQRJXOIXHOHK-WDSKDSINSA-N 0.000 description 1
- JVSBYEDSSRZQGV-GUBZILKMSA-N Glu-Asp-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@@H](N)CCC(O)=O JVSBYEDSSRZQGV-GUBZILKMSA-N 0.000 description 1
- WATXSTJXNBOHKD-LAEOZQHASA-N Glu-Asp-Val Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](C(C)C)C(O)=O WATXSTJXNBOHKD-LAEOZQHASA-N 0.000 description 1
- OBIHEDRRSMRKLU-ACZMJKKPSA-N Glu-Cys-Asp Chemical compound C(CC(=O)O)[C@@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(=O)O)C(=O)O)N OBIHEDRRSMRKLU-ACZMJKKPSA-N 0.000 description 1
- OXEMJGCAJFFREE-FXQIFTODSA-N Glu-Gln-Ala Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](C)C(O)=O OXEMJGCAJFFREE-FXQIFTODSA-N 0.000 description 1
- CGOHAEBMDSEKFB-FXQIFTODSA-N Glu-Glu-Ala Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(O)=O CGOHAEBMDSEKFB-FXQIFTODSA-N 0.000 description 1
- HNVFSTLPVJWIDV-CIUDSAMLSA-N Glu-Glu-Gln Chemical compound OC(=O)CC[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(N)=O)C(O)=O HNVFSTLPVJWIDV-CIUDSAMLSA-N 0.000 description 1
- SJPMNHCEWPTRBR-BQBZGAKWSA-N Glu-Glu-Gly Chemical compound OC(=O)CC[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)NCC(O)=O SJPMNHCEWPTRBR-BQBZGAKWSA-N 0.000 description 1
- MUSGDMDGNGXULI-DCAQKATOSA-N Glu-Glu-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](N)CCC(O)=O MUSGDMDGNGXULI-DCAQKATOSA-N 0.000 description 1
- IQACOVZVOMVILH-FXQIFTODSA-N Glu-Glu-Ser Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(O)=O IQACOVZVOMVILH-FXQIFTODSA-N 0.000 description 1
- QJCKNLPMTPXXEM-AUTRQRHGSA-N Glu-Glu-Val Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](N)CCC(O)=O QJCKNLPMTPXXEM-AUTRQRHGSA-N 0.000 description 1
- CAVMESABQIKFKT-IUCAKERBSA-N Glu-Gly-His Chemical compound C1=C(NC=N1)C[C@@H](C(=O)O)NC(=O)CNC(=O)[C@H](CCC(=O)O)N CAVMESABQIKFKT-IUCAKERBSA-N 0.000 description 1
- KRGZZKWSBGPLKL-IUCAKERBSA-N Glu-Gly-Lys Chemical compound C(CCN)C[C@@H](C(=O)O)NC(=O)CNC(=O)[C@H](CCC(=O)O)N KRGZZKWSBGPLKL-IUCAKERBSA-N 0.000 description 1
- ZPASCJBSSCRWMC-GVXVVHGQSA-N Glu-His-Val Chemical compound CC(C)[C@@H](C(=O)O)NC(=O)[C@H](CC1=CN=CN1)NC(=O)[C@H](CCC(=O)O)N ZPASCJBSSCRWMC-GVXVVHGQSA-N 0.000 description 1
- ZSWGJYOZWBHROQ-RWRJDSDZSA-N Glu-Ile-Thr 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)O)C(O)=O ZSWGJYOZWBHROQ-RWRJDSDZSA-N 0.000 description 1
- IRXNJYPKBVERCW-DCAQKATOSA-N Glu-Leu-Glu Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(O)=O IRXNJYPKBVERCW-DCAQKATOSA-N 0.000 description 1
- NJCALAAIGREHDR-WDCWCFNPSA-N Glu-Leu-Thr Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O NJCALAAIGREHDR-WDCWCFNPSA-N 0.000 description 1
- GJBUAAAIZSRCDC-GVXVVHGQSA-N Glu-Leu-Val Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(O)=O GJBUAAAIZSRCDC-GVXVVHGQSA-N 0.000 description 1
- OQXDUSZKISQQSS-GUBZILKMSA-N Glu-Lys-Ala Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(O)=O OQXDUSZKISQQSS-GUBZILKMSA-N 0.000 description 1
- YKBUCXNNBYZYAY-MNXVOIDGSA-N Glu-Lys-Ile Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O YKBUCXNNBYZYAY-MNXVOIDGSA-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
- OFIHURVSQXAZIR-SZMVWBNQSA-N Glu-Lys-Trp Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC1=CNC2=C1C=CC=C2)C(O)=O OFIHURVSQXAZIR-SZMVWBNQSA-N 0.000 description 1
- SUIAHERNFYRBDZ-GVXVVHGQSA-N Glu-Lys-Val Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C(C)C)C(O)=O SUIAHERNFYRBDZ-GVXVVHGQSA-N 0.000 description 1
- LKOAAMXDJGEYMS-ZPFDUUQYSA-N Glu-Met-Ile Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCSC)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O LKOAAMXDJGEYMS-ZPFDUUQYSA-N 0.000 description 1
- FQFWFZWOHOEVMZ-IHRRRGAJSA-N Glu-Phe-Gln Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CCC(N)=O)C(O)=O FQFWFZWOHOEVMZ-IHRRRGAJSA-N 0.000 description 1
- ITVBKCZZLJUUHI-HTUGSXCWSA-N Glu-Phe-Thr Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H]([C@@H](C)O)C(O)=O ITVBKCZZLJUUHI-HTUGSXCWSA-N 0.000 description 1
- YUXIEONARHPUTK-JBACZVJFSA-N Glu-Phe-Trp Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)N[C@@H](CC2=CNC3=CC=CC=C32)C(=O)O)NC(=O)[C@H](CCC(=O)O)N YUXIEONARHPUTK-JBACZVJFSA-N 0.000 description 1
- QJVZSVUYZFYLFQ-CIUDSAMLSA-N Glu-Pro-Ala Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](C)C(O)=O QJVZSVUYZFYLFQ-CIUDSAMLSA-N 0.000 description 1
- MRWYPDWDZSLWJM-ACZMJKKPSA-N Glu-Ser-Asp Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(O)=O)C(O)=O MRWYPDWDZSLWJM-ACZMJKKPSA-N 0.000 description 1
- BXSZPACYCMNKLS-AVGNSLFASA-N Glu-Ser-Phe Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O BXSZPACYCMNKLS-AVGNSLFASA-N 0.000 description 1
- UZWUBBRJWFTHTD-LAEOZQHASA-N Glu-Val-Asn Chemical compound NC(=O)C[C@@H](C(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](N)CCC(O)=O UZWUBBRJWFTHTD-LAEOZQHASA-N 0.000 description 1
- 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 1
- 102100041003 Glutamate carboxypeptidase 2 Human genes 0.000 description 1
- SXRSQZLOMIGNAQ-UHFFFAOYSA-N Glutaraldehyde Chemical compound O=CCCCC=O SXRSQZLOMIGNAQ-UHFFFAOYSA-N 0.000 description 1
- PYTZFYUXZZHOAD-WHFBIAKZSA-N Gly-Ala-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)CN PYTZFYUXZZHOAD-WHFBIAKZSA-N 0.000 description 1
- VSVZIEVNUYDAFR-YUMQZZPRSA-N Gly-Ala-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)CN VSVZIEVNUYDAFR-YUMQZZPRSA-N 0.000 description 1
- JPWIMMUNWUKOAD-STQMWFEESA-N Gly-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)CN JPWIMMUNWUKOAD-STQMWFEESA-N 0.000 description 1
- BIRKKBCSAIHDDF-WDSKDSINSA-N Gly-Glu-Cys Chemical compound NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CS)C(O)=O BIRKKBCSAIHDDF-WDSKDSINSA-N 0.000 description 1
- STVHDEHTKFXBJQ-LAEOZQHASA-N Gly-Glu-Ile Chemical compound [H]NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O STVHDEHTKFXBJQ-LAEOZQHASA-N 0.000 description 1
- 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 1
- 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 1
- CUYLIWAAAYJKJH-RYUDHWBXSA-N Gly-Glu-Tyr Chemical compound NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 CUYLIWAAAYJKJH-RYUDHWBXSA-N 0.000 description 1
- JSNNHGHYGYMVCK-XVKPBYJWSA-N Gly-Glu-Val Chemical compound [H]NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(O)=O JSNNHGHYGYMVCK-XVKPBYJWSA-N 0.000 description 1
- QPTNELDXWKRIFX-YFKPBYRVSA-N Gly-Gly-Gln Chemical compound NCC(=O)NCC(=O)N[C@H](C(O)=O)CCC(N)=O QPTNELDXWKRIFX-YFKPBYRVSA-N 0.000 description 1
- GDOZQTNZPCUARW-YFKPBYRVSA-N Gly-Gly-Glu Chemical compound NCC(=O)NCC(=O)N[C@H](C(O)=O)CCC(O)=O GDOZQTNZPCUARW-YFKPBYRVSA-N 0.000 description 1
- 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 1
- XPJBQTCXPJNIFE-ZETCQYMHSA-N Gly-Gly-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)CNC(=O)CN XPJBQTCXPJNIFE-ZETCQYMHSA-N 0.000 description 1
- 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 1
- LPCKHUXOGVNZRS-YUMQZZPRSA-N Gly-His-Ser Chemical compound [H]NCC(=O)N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CO)C(O)=O LPCKHUXOGVNZRS-YUMQZZPRSA-N 0.000 description 1
- ALOBJFDJTMQQPW-ONGXEEELSA-N Gly-His-Val Chemical compound CC(C)[C@@H](C(=O)O)NC(=O)[C@H](CC1=CN=CN1)NC(=O)CN ALOBJFDJTMQQPW-ONGXEEELSA-N 0.000 description 1
- DGKBSGNCMCLDSL-BYULHYEWSA-N Gly-Ile-Asn Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)O)NC(=O)CN DGKBSGNCMCLDSL-BYULHYEWSA-N 0.000 description 1
- VIIBEIQMLJEUJG-LAEOZQHASA-N Gly-Ile-Gln Chemical compound [H]NCC(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCC(N)=O)C(O)=O VIIBEIQMLJEUJG-LAEOZQHASA-N 0.000 description 1
- IUZGUFAJDBHQQV-YUMQZZPRSA-N Gly-Leu-Asn Chemical compound NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(O)=O IUZGUFAJDBHQQV-YUMQZZPRSA-N 0.000 description 1
- CCBIBMKQNXHNIN-ZETCQYMHSA-N Gly-Leu-Gly Chemical compound NCC(=O)N[C@@H](CC(C)C)C(=O)NCC(O)=O CCBIBMKQNXHNIN-ZETCQYMHSA-N 0.000 description 1
- UHPAZODVFFYEEL-QWRGUYRKSA-N Gly-Leu-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)CN UHPAZODVFFYEEL-QWRGUYRKSA-N 0.000 description 1
- FHQRLHFYVZAQHU-IUCAKERBSA-N Gly-Lys-Gln Chemical compound [H]NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(N)=O)C(O)=O FHQRLHFYVZAQHU-IUCAKERBSA-N 0.000 description 1
- FXGRXIATVXUAHO-WEDXCCLWSA-N Gly-Lys-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)CN)CCCCN FXGRXIATVXUAHO-WEDXCCLWSA-N 0.000 description 1
- YHYDTTUSJXGTQK-UWVGGRQHSA-N Gly-Met-Leu Chemical compound CSCC[C@H](NC(=O)CN)C(=O)N[C@@H](CC(C)C)C(O)=O YHYDTTUSJXGTQK-UWVGGRQHSA-N 0.000 description 1
- MXIULRKNFSCJHT-STQMWFEESA-N Gly-Phe-Met Chemical compound CSCC[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)CN)CC1=CC=CC=C1 MXIULRKNFSCJHT-STQMWFEESA-N 0.000 description 1
- HJARVELKOSZUEW-YUMQZZPRSA-N Gly-Pro-Gln Chemical compound [H]NCC(=O)N1CCC[C@H]1C(=O)N[C@@H](CCC(N)=O)C(O)=O HJARVELKOSZUEW-YUMQZZPRSA-N 0.000 description 1
- HFPVRZWORNJRRC-UWVGGRQHSA-N Gly-Pro-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@@H]1CCCN1C(=O)CN HFPVRZWORNJRRC-UWVGGRQHSA-N 0.000 description 1
- GLACUWHUYFBSPJ-FJXKBIBVSA-N Gly-Pro-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)[C@@H]1CCCN1C(=O)CN GLACUWHUYFBSPJ-FJXKBIBVSA-N 0.000 description 1
- WNGHUXFWEWTKAO-YUMQZZPRSA-N Gly-Ser-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](CO)NC(=O)CN WNGHUXFWEWTKAO-YUMQZZPRSA-N 0.000 description 1
- 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
- WCORRBXVISTKQL-WHFBIAKZSA-N Gly-Ser-Ser Chemical compound NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(O)=O WCORRBXVISTKQL-WHFBIAKZSA-N 0.000 description 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
- YXTFLTJYLIAZQG-FJXKBIBVSA-N Gly-Thr-Arg Chemical compound NCC(=O)N[C@@H]([C@H](O)C)C(=O)N[C@H](C(O)=O)CCCN=C(N)N YXTFLTJYLIAZQG-FJXKBIBVSA-N 0.000 description 1
- 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 1
- MYXNLWDWWOTERK-BHNWBGBOSA-N Gly-Thr-Pro Chemical compound C[C@H]([C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)CN)O MYXNLWDWWOTERK-BHNWBGBOSA-N 0.000 description 1
- BAYQNCWLXIDLHX-ONGXEEELSA-N Gly-Val-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](C(C)C)NC(=O)CN BAYQNCWLXIDLHX-ONGXEEELSA-N 0.000 description 1
- 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 1
- 239000004471 Glycine Substances 0.000 description 1
- 102100023177 Glycoprotein endo-alpha-1,2-mannosidase Human genes 0.000 description 1
- 102100036700 Golgi reassembly-stacking protein 2 Human genes 0.000 description 1
- 108060005986 Granzyme Proteins 0.000 description 1
- 102000001398 Granzyme Human genes 0.000 description 1
- 101150009006 HIS3 gene Proteins 0.000 description 1
- 102000015789 HLA-DP Antigens Human genes 0.000 description 1
- 108010010378 HLA-DP Antigens Proteins 0.000 description 1
- ZNPRMNDAFQKATM-LKTVYLICSA-N His-Ala-Tyr Chemical compound [H]N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](C)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O ZNPRMNDAFQKATM-LKTVYLICSA-N 0.000 description 1
- WEIYKCOEVBUJQC-JYJNAYRXSA-N His-Glu-Phe Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)O)NC(=O)[C@H](CC2=CN=CN2)N WEIYKCOEVBUJQC-JYJNAYRXSA-N 0.000 description 1
- CHZRWFUGWRTUOD-IUCAKERBSA-N His-Gly-Gln Chemical compound C1=C(NC=N1)C[C@@H](C(=O)NCC(=O)N[C@@H](CCC(=O)N)C(=O)O)N CHZRWFUGWRTUOD-IUCAKERBSA-N 0.000 description 1
- WTJBVCUCLWFGAH-JUKXBJQTSA-N His-Ile-Tyr Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC1=CC=C(C=C1)O)C(=O)O)NC(=O)[C@H](CC2=CN=CN2)N WTJBVCUCLWFGAH-JUKXBJQTSA-N 0.000 description 1
- IWXMHXYOACDSIA-PYJNHQTQSA-N His-Ile-Val Chemical compound [H]N[C@@H](CC1=CNC=N1)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C(C)C)C(O)=O IWXMHXYOACDSIA-PYJNHQTQSA-N 0.000 description 1
- YAALVYQFVJNXIV-KKUMJFAQSA-N His-Leu-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CC1=CN=CN1 YAALVYQFVJNXIV-KKUMJFAQSA-N 0.000 description 1
- TWROVBNEHJSXDG-IHRRRGAJSA-N His-Leu-Val Chemical compound [H]N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(O)=O TWROVBNEHJSXDG-IHRRRGAJSA-N 0.000 description 1
- IGBBXBFSLKRHJB-BZSNNMDCSA-N His-Lys-Phe Chemical compound C([C@H](N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)C1=CN=CN1 IGBBXBFSLKRHJB-BZSNNMDCSA-N 0.000 description 1
- ZVKDCQVQTGYBQT-LSJOCFKGSA-N His-Pro-Ala Chemical compound [H]N[C@@H](CC1=CNC=N1)C(=O)N1CCC[C@H]1C(=O)N[C@@H](C)C(O)=O ZVKDCQVQTGYBQT-LSJOCFKGSA-N 0.000 description 1
- XJFITURPHAKKAI-SRVKXCTJSA-N His-Pro-Gln Chemical compound C([C@H](N)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCC(N)=O)C(O)=O)C1=CN=CN1 XJFITURPHAKKAI-SRVKXCTJSA-N 0.000 description 1
- QCBYAHHNOHBXIH-UWVGGRQHSA-N His-Pro-Gly Chemical compound C([C@H](N)C(=O)N1[C@@H](CCC1)C(=O)NCC(O)=O)C1=CN=CN1 QCBYAHHNOHBXIH-UWVGGRQHSA-N 0.000 description 1
- ABCCKUZDWMERKT-AVGNSLFASA-N His-Pro-Met Chemical compound [H]N[C@@H](CC1=CNC=N1)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCSC)C(O)=O ABCCKUZDWMERKT-AVGNSLFASA-N 0.000 description 1
- YEKYGQZUBCRNGH-DCAQKATOSA-N His-Pro-Ser Chemical compound C1C[C@H](N(C1)C(=O)[C@H](CC2=CN=CN2)N)C(=O)N[C@@H](CO)C(=O)O YEKYGQZUBCRNGH-DCAQKATOSA-N 0.000 description 1
- STGQSBKUYSPPIG-CIUDSAMLSA-N His-Ser-Asp Chemical compound OC(=O)C[C@@H](C(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC1=CN=CN1 STGQSBKUYSPPIG-CIUDSAMLSA-N 0.000 description 1
- CUEQQFOGARVNHU-VGDYDELISA-N His-Ser-Ile Chemical compound [H]N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O CUEQQFOGARVNHU-VGDYDELISA-N 0.000 description 1
- JGFWUKYIQAEYAH-DCAQKATOSA-N His-Ser-Val Chemical compound [H]N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(O)=O JGFWUKYIQAEYAH-DCAQKATOSA-N 0.000 description 1
- XHQYFGPIRUHQIB-PBCZWWQYSA-N His-Thr-Asp Chemical compound OC(=O)C[C@@H](C(O)=O)NC(=O)[C@H]([C@H](O)C)NC(=O)[C@@H](N)CC1=CN=CN1 XHQYFGPIRUHQIB-PBCZWWQYSA-N 0.000 description 1
- VXZZUXWAOMWWJH-QTKMDUPCSA-N His-Thr-Val Chemical compound [H]N[C@@H](CC1=CNC=N1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(O)=O VXZZUXWAOMWWJH-QTKMDUPCSA-N 0.000 description 1
- 108010088652 Histocompatibility Antigens Class I Proteins 0.000 description 1
- 102100024023 Histone PARylation factor 1 Human genes 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 101000792933 Homo sapiens AT-rich interactive domain-containing protein 4A Proteins 0.000 description 1
- 101000856237 Homo sapiens Cancer/testis antigen 1 Proteins 0.000 description 1
- 101000750011 Homo sapiens Claspin Proteins 0.000 description 1
- 101000746121 Homo sapiens Collagen triple helix repeat-containing protein 1 Proteins 0.000 description 1
- 101000766864 Homo sapiens Cytoskeleton-associated protein 5 Proteins 0.000 description 1
- 101000892862 Homo sapiens Glutamate carboxypeptidase 2 Proteins 0.000 description 1
- 101000978837 Homo sapiens Glycoprotein endo-alpha-1,2-mannosidase Proteins 0.000 description 1
- 101001072495 Homo sapiens Golgi reassembly-stacking protein 2 Proteins 0.000 description 1
- 101001047783 Homo sapiens Histone PARylation factor 1 Proteins 0.000 description 1
- 101001013150 Homo sapiens Interstitial collagenase Proteins 0.000 description 1
- 101001007027 Homo sapiens Keratin, type II cuticular Hb1 Proteins 0.000 description 1
- 101001026976 Homo sapiens Keratin, type II cuticular Hb3 Proteins 0.000 description 1
- 101001026979 Homo sapiens Keratin, type II cuticular Hb5 Proteins 0.000 description 1
- 101001026977 Homo sapiens Keratin, type II cuticular Hb6 Proteins 0.000 description 1
- 101001112162 Homo sapiens Kinetochore protein NDC80 homolog Proteins 0.000 description 1
- 101000971605 Homo sapiens Kita-kyushu lung cancer antigen 1 Proteins 0.000 description 1
- 101000798114 Homo sapiens Lactotransferrin Proteins 0.000 description 1
- 101000972489 Homo sapiens Laminin subunit alpha-1 Proteins 0.000 description 1
- 101000608935 Homo sapiens Leukosialin Proteins 0.000 description 1
- 101001005722 Homo sapiens Melanoma-associated antigen 6 Proteins 0.000 description 1
- 101001133056 Homo sapiens Mucin-1 Proteins 0.000 description 1
- 101001128138 Homo sapiens NACHT, LRR and PYD domains-containing protein 2 Proteins 0.000 description 1
- 101001108932 Homo sapiens Nuclear pore complex protein Nup155 Proteins 0.000 description 1
- 101000634526 Homo sapiens Nucleolar pre-ribosomal-associated protein 1 Proteins 0.000 description 1
- 101000944945 Homo sapiens Putative keratin-87 protein Proteins 0.000 description 1
- 101000984533 Homo sapiens Ribosome biogenesis protein BMS1 homolog Proteins 0.000 description 1
- 101000914514 Homo sapiens T-cell-specific surface glycoprotein CD28 Proteins 0.000 description 1
- 101000669460 Homo sapiens Toll-like receptor 5 Proteins 0.000 description 1
- 101000669402 Homo sapiens Toll-like receptor 7 Proteins 0.000 description 1
- 101000800483 Homo sapiens Toll-like receptor 8 Proteins 0.000 description 1
- 101000667110 Homo sapiens Vacuolar protein sorting-associated protein 13B Proteins 0.000 description 1
- 101000818845 Homo sapiens Zinc finger protein 439 Proteins 0.000 description 1
- 108091006905 Human Serum Albumin Proteins 0.000 description 1
- 102000008100 Human Serum Albumin Human genes 0.000 description 1
- 241000701024 Human betaherpesvirus 5 Species 0.000 description 1
- 241000341655 Human papillomavirus type 16 Species 0.000 description 1
- VAXBXNPRXPHGHG-BJDJZHNGSA-N Ile-Ala-Leu Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)O)N VAXBXNPRXPHGHG-BJDJZHNGSA-N 0.000 description 1
- 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 1
- BOTVMTSMOUSDRW-GMOBBJLQSA-N Ile-Arg-Asn Chemical compound CC[C@H](C)[C@H](N)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CC(N)=O)C(O)=O BOTVMTSMOUSDRW-GMOBBJLQSA-N 0.000 description 1
- NULSANWBUWLTKN-NAKRPEOUSA-N Ile-Arg-Ser Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CO)C(=O)O)N NULSANWBUWLTKN-NAKRPEOUSA-N 0.000 description 1
- IIXDMJNYALIKGP-DJFWLOJKSA-N Ile-Asn-His Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)N IIXDMJNYALIKGP-DJFWLOJKSA-N 0.000 description 1
- XENGULNPUDGALZ-ZPFDUUQYSA-N Ile-Asn-Leu Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CC(C)C)C(=O)O)N XENGULNPUDGALZ-ZPFDUUQYSA-N 0.000 description 1
- QIHJTGSVGIPHIW-QSFUFRPTSA-N Ile-Asn-Val Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](C(C)C)C(=O)O)N QIHJTGSVGIPHIW-QSFUFRPTSA-N 0.000 description 1
- BGZIJZJBXRVBGJ-SXTJYALSSA-N Ile-Asp-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)O)N BGZIJZJBXRVBGJ-SXTJYALSSA-N 0.000 description 1
- DMZOUKXXHJQPTL-GRLWGSQLSA-N Ile-Gln-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H]([C@@H](C)CC)C(=O)O)N DMZOUKXXHJQPTL-GRLWGSQLSA-N 0.000 description 1
- WNQKUUQIVDDAFA-ZPFDUUQYSA-N Ile-Gln-Met Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H](CCSC)C(=O)O)N WNQKUUQIVDDAFA-ZPFDUUQYSA-N 0.000 description 1
- BALLIXFZYSECCF-QEWYBTABSA-N Ile-Gln-Phe Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)O)N BALLIXFZYSECCF-QEWYBTABSA-N 0.000 description 1
- 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 1
- FUOYNOXRWPJPAN-QEWYBTABSA-N Ile-Glu-Phe Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)O)N FUOYNOXRWPJPAN-QEWYBTABSA-N 0.000 description 1
- XLCZWMJPVGRWHJ-KQXIARHKSA-N Ile-Glu-Pro Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)N1CCC[C@@H]1C(=O)O)N XLCZWMJPVGRWHJ-KQXIARHKSA-N 0.000 description 1
- NHJKZMDIMMTVCK-QXEWZRGKSA-N Ile-Gly-Arg Chemical compound CC[C@H](C)[C@H](N)C(=O)NCC(=O)N[C@H](C(O)=O)CCCN=C(N)N NHJKZMDIMMTVCK-QXEWZRGKSA-N 0.000 description 1
- KFVUBLZRFSVDGO-BYULHYEWSA-N Ile-Gly-Asp Chemical compound CC[C@H](C)[C@H](N)C(=O)NCC(=O)N[C@H](C(O)=O)CC(O)=O KFVUBLZRFSVDGO-BYULHYEWSA-N 0.000 description 1
- JLWLMGADIQFKRD-QSFUFRPTSA-N Ile-His-Ala Chemical compound CC[C@H](C)[C@H](N)C(=O)N[C@H](C(=O)N[C@@H](C)C(O)=O)CC1=CN=CN1 JLWLMGADIQFKRD-QSFUFRPTSA-N 0.000 description 1
- YBGTWSFIGHUWQE-MXAVVETBSA-N Ile-His-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)[C@@H](C)CC)CC1=CN=CN1 YBGTWSFIGHUWQE-MXAVVETBSA-N 0.000 description 1
- LNJLOZYNZFGJMM-DEQVHRJGSA-N Ile-His-Pro Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)N2CCC[C@@H]2C(=O)O)N LNJLOZYNZFGJMM-DEQVHRJGSA-N 0.000 description 1
- RIVKTKFVWXRNSJ-GRLWGSQLSA-N Ile-Ile-Gln Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCC(=O)N)C(=O)O)N RIVKTKFVWXRNSJ-GRLWGSQLSA-N 0.000 description 1
- SJLVSMMIFYTSGY-GRLWGSQLSA-N Ile-Ile-Glu Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCC(=O)O)C(=O)O)N SJLVSMMIFYTSGY-GRLWGSQLSA-N 0.000 description 1
- MTONDYJJCIBZTK-PEDHHIEDSA-N Ile-Ile-Met Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCSC)C(=O)O)N MTONDYJJCIBZTK-PEDHHIEDSA-N 0.000 description 1
- PFPUFNLHBXKPHY-HTFCKZLJSA-N Ile-Ile-Ser Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)O)N PFPUFNLHBXKPHY-HTFCKZLJSA-N 0.000 description 1
- GAZGFPOZOLEYAJ-YTFOTSKYSA-N Ile-Leu-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)O)N GAZGFPOZOLEYAJ-YTFOTSKYSA-N 0.000 description 1
- HPCFRQWLTRDGHT-AJNGGQMLSA-N Ile-Leu-Leu Chemical compound CC[C@H](C)[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O HPCFRQWLTRDGHT-AJNGGQMLSA-N 0.000 description 1
- TVYWVSJGSHQWMT-AJNGGQMLSA-N Ile-Leu-Lys Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)O)N TVYWVSJGSHQWMT-AJNGGQMLSA-N 0.000 description 1
- PWUMCBLVWPCKNO-MGHWNKPDSA-N Ile-Leu-Tyr Chemical compound CC[C@H](C)[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 PWUMCBLVWPCKNO-MGHWNKPDSA-N 0.000 description 1
- IDMNOFVUXYYZPF-DKIMLUQUSA-N Ile-Lys-Phe Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)O)N IDMNOFVUXYYZPF-DKIMLUQUSA-N 0.000 description 1
- IMRKCLXPYOIHIF-ZPFDUUQYSA-N Ile-Met-Gln Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCC(=O)N)C(=O)O)N IMRKCLXPYOIHIF-ZPFDUUQYSA-N 0.000 description 1
- FTUZWJVSNZMLPI-RVMXOQNASA-N Ile-Met-Pro Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCSC)C(=O)N1CCC[C@@H]1C(=O)O)N FTUZWJVSNZMLPI-RVMXOQNASA-N 0.000 description 1
- 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 1
- USXAYNCLFSUSBA-MGHWNKPDSA-N Ile-Phe-His Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CC2=CN=CN2)C(=O)O)N USXAYNCLFSUSBA-MGHWNKPDSA-N 0.000 description 1
- CZWANIQKACCEKW-CYDGBPFRSA-N Ile-Pro-Met Chemical compound CC[C@H](C)[C@@H](C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCSC)C(=O)O)N CZWANIQKACCEKW-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
- YCKPUHHMCFSUMD-IUKAMOBKSA-N Ile-Thr-Asp Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(=O)O)C(=O)O)N YCKPUHHMCFSUMD-IUKAMOBKSA-N 0.000 description 1
- HJDZMPFEXINXLO-QPHKQPEJSA-N Ile-Thr-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)O)N HJDZMPFEXINXLO-QPHKQPEJSA-N 0.000 description 1
- WXLYNEHOGRYNFU-URLPEUOOSA-N Ile-Thr-Phe Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)O)N WXLYNEHOGRYNFU-URLPEUOOSA-N 0.000 description 1
- GNXGAVNTVNOCLL-SIUGBPQLSA-N Ile-Tyr-Gln Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC1=CC=C(C=C1)O)C(=O)N[C@@H](CCC(=O)N)C(=O)O)N GNXGAVNTVNOCLL-SIUGBPQLSA-N 0.000 description 1
- WIYDLTIBHZSPKY-HJWJTTGWSA-N Ile-Val-Phe 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)CC1=CC=CC=C1 WIYDLTIBHZSPKY-HJWJTTGWSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 102000009786 Immunoglobulin Constant Regions Human genes 0.000 description 1
- 108010009817 Immunoglobulin Constant Regions Proteins 0.000 description 1
- 108700005091 Immunoglobulin Genes Proteins 0.000 description 1
- 102000012745 Immunoglobulin Subunits Human genes 0.000 description 1
- 108010079585 Immunoglobulin Subunits Proteins 0.000 description 1
- 108010067060 Immunoglobulin Variable Region Proteins 0.000 description 1
- 102000017727 Immunoglobulin Variable Region Human genes 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 108010064593 Intercellular Adhesion Molecule-1 Proteins 0.000 description 1
- 102100037877 Intercellular adhesion molecule 1 Human genes 0.000 description 1
- 108090000467 Interferon-beta Proteins 0.000 description 1
- 102000003996 Interferon-beta Human genes 0.000 description 1
- 108010002352 Interleukin-1 Proteins 0.000 description 1
- 102000000589 Interleukin-1 Human genes 0.000 description 1
- 102000003816 Interleukin-13 Human genes 0.000 description 1
- 108090000176 Interleukin-13 Proteins 0.000 description 1
- 108090000172 Interleukin-15 Proteins 0.000 description 1
- 102100030703 Interleukin-22 Human genes 0.000 description 1
- 108010065637 Interleukin-23 Proteins 0.000 description 1
- 108090000978 Interleukin-4 Proteins 0.000 description 1
- 102000004388 Interleukin-4 Human genes 0.000 description 1
- 108091092195 Intron Proteins 0.000 description 1
- 102100028340 Keratin, type II cuticular Hb1 Human genes 0.000 description 1
- 102100037379 Keratin, type II cuticular Hb3 Human genes 0.000 description 1
- 102100037381 Keratin, type II cuticular Hb5 Human genes 0.000 description 1
- 102100037382 Keratin, type II cuticular Hb6 Human genes 0.000 description 1
- 102100023890 Kinetochore protein NDC80 homolog Human genes 0.000 description 1
- 102100021533 Kita-kyushu lung cancer antigen 1 Human genes 0.000 description 1
- 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 1
- 108010062028 L-BLP25 Proteins 0.000 description 1
- FADYJNXDPBKVCA-UHFFFAOYSA-N L-Phenylalanyl-L-lysin Natural products NCCCCC(C(O)=O)NC(=O)C(N)CC1=CC=CC=C1 FADYJNXDPBKVCA-UHFFFAOYSA-N 0.000 description 1
- RCFDOSNHHZGBOY-UHFFFAOYSA-N L-isoleucyl-L-alanine Natural products CCC(C)C(N)C(=O)NC(C)C(O)=O RCFDOSNHHZGBOY-UHFFFAOYSA-N 0.000 description 1
- 125000000174 L-prolyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])([H])[C@@]1([H])C(*)=O 0.000 description 1
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 description 1
- LZDNBBYBDGBADK-UHFFFAOYSA-N L-valyl-L-tryptophan Natural products C1=CC=C2C(CC(NC(=O)C(N)C(C)C)C(O)=O)=CNC2=C1 LZDNBBYBDGBADK-UHFFFAOYSA-N 0.000 description 1
- 239000005551 L01XE03 - Erlotinib Substances 0.000 description 1
- 239000002147 L01XE04 - Sunitinib Substances 0.000 description 1
- 239000005511 L01XE05 - Sorafenib Substances 0.000 description 1
- 239000003798 L01XE11 - Pazopanib Substances 0.000 description 1
- 102100022746 Laminin subunit alpha-1 Human genes 0.000 description 1
- 239000004166 Lanolin Substances 0.000 description 1
- 241000713666 Lentivirus Species 0.000 description 1
- HBJZFCIVFIBNSV-DCAQKATOSA-N Leu-Arg-Asn Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CC(N)=O)C(O)=O HBJZFCIVFIBNSV-DCAQKATOSA-N 0.000 description 1
- KSZCCRIGNVSHFH-UWVGGRQHSA-N Leu-Arg-Gly Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(O)=O KSZCCRIGNVSHFH-UWVGGRQHSA-N 0.000 description 1
- UCOCBWDBHCUPQP-DCAQKATOSA-N Leu-Arg-Ser Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(O)=O UCOCBWDBHCUPQP-DCAQKATOSA-N 0.000 description 1
- 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
- OXKYZSRZKBTVEY-ZPFDUUQYSA-N Leu-Asn-Ile Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O OXKYZSRZKBTVEY-ZPFDUUQYSA-N 0.000 description 1
- JKGHDYGZRDWHGA-SRVKXCTJSA-N Leu-Asn-Leu Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(O)=O JKGHDYGZRDWHGA-SRVKXCTJSA-N 0.000 description 1
- WGNOPSQMIQERPK-UHFFFAOYSA-N Leu-Asn-Pro Natural products CC(C)CC(N)C(=O)NC(CC(=O)N)C(=O)N1CCCC1C(=O)O WGNOPSQMIQERPK-UHFFFAOYSA-N 0.000 description 1
- WXHFZJFZWNCDNB-KKUMJFAQSA-N Leu-Asn-Tyr 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=C(O)C=C1 WXHFZJFZWNCDNB-KKUMJFAQSA-N 0.000 description 1
- TWQIYNGNYNJUFM-NHCYSSNCSA-N Leu-Asn-Val Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](C(C)C)C(O)=O TWQIYNGNYNJUFM-NHCYSSNCSA-N 0.000 description 1
- MMEDVBWCMGRKKC-GARJFASQSA-N Leu-Asp-Pro Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)N1CCC[C@@H]1C(=O)O)N MMEDVBWCMGRKKC-GARJFASQSA-N 0.000 description 1
- CLVUXCBGKUECIT-HJGDQZAQSA-N Leu-Asp-Thr Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O CLVUXCBGKUECIT-HJGDQZAQSA-N 0.000 description 1
- VPKIQULSKFVCSM-SRVKXCTJSA-N Leu-Gln-Arg Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O VPKIQULSKFVCSM-SRVKXCTJSA-N 0.000 description 1
- LOLUPZNNADDTAA-AVGNSLFASA-N Leu-Gln-Leu Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(C)C)C(O)=O LOLUPZNNADDTAA-AVGNSLFASA-N 0.000 description 1
- GPICTNQYKHHHTH-GUBZILKMSA-N Leu-Gln-Ser Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CO)C(O)=O GPICTNQYKHHHTH-GUBZILKMSA-N 0.000 description 1
- QDSKNVXKLPQNOJ-GVXVVHGQSA-N Leu-Gln-Val Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](C(C)C)C(O)=O QDSKNVXKLPQNOJ-GVXVVHGQSA-N 0.000 description 1
- QVFGXCVIXXBFHO-AVGNSLFASA-N Leu-Glu-Leu Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(O)=O QVFGXCVIXXBFHO-AVGNSLFASA-N 0.000 description 1
- 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 1
- HYIFFZAQXPUEAU-QWRGUYRKSA-N Leu-Gly-Leu Chemical compound CC(C)C[C@H](N)C(=O)NCC(=O)N[C@H](C(O)=O)CC(C)C HYIFFZAQXPUEAU-QWRGUYRKSA-N 0.000 description 1
- PBGDOSARRIJMEV-DLOVCJGASA-N Leu-His-Ala Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](C)C(O)=O PBGDOSARRIJMEV-DLOVCJGASA-N 0.000 description 1
- SEMUSFOBZGKBGW-YTFOTSKYSA-N Leu-Ile-Ile Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O SEMUSFOBZGKBGW-YTFOTSKYSA-N 0.000 description 1
- PDQDCFBVYXEFSD-SRVKXCTJSA-N Leu-Leu-Asp Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(O)=O)C(O)=O PDQDCFBVYXEFSD-SRVKXCTJSA-N 0.000 description 1
- QNBVTHNJGCOVFA-AVGNSLFASA-N Leu-Leu-Glu Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](C(O)=O)CCC(O)=O QNBVTHNJGCOVFA-AVGNSLFASA-N 0.000 description 1
- LXKNSJLSGPNHSK-KKUMJFAQSA-N Leu-Leu-Lys Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)O)N LXKNSJLSGPNHSK-KKUMJFAQSA-N 0.000 description 1
- RXGLHDWAZQECBI-SRVKXCTJSA-N Leu-Leu-Ser Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(O)=O RXGLHDWAZQECBI-SRVKXCTJSA-N 0.000 description 1
- LZHJZLHSRGWBBE-IHRRRGAJSA-N Leu-Lys-Val Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C(C)C)C(O)=O LZHJZLHSRGWBBE-IHRRRGAJSA-N 0.000 description 1
- WXZOHBVPVKABQN-DCAQKATOSA-N Leu-Met-Asp Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(=O)O)C(=O)O)N WXZOHBVPVKABQN-DCAQKATOSA-N 0.000 description 1
- BJWKOATWNQJPSK-SRVKXCTJSA-N Leu-Met-Glu Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCC(=O)O)C(=O)O)N BJWKOATWNQJPSK-SRVKXCTJSA-N 0.000 description 1
- WXDRGWBQZIMJDE-ULQDDVLXSA-N Leu-Phe-Met Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CCSC)C(O)=O WXDRGWBQZIMJDE-ULQDDVLXSA-N 0.000 description 1
- QMKFDEUJGYNFMC-AVGNSLFASA-N Leu-Pro-Arg Chemical compound CC(C)C[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCCN=C(N)N)C(O)=O QMKFDEUJGYNFMC-AVGNSLFASA-N 0.000 description 1
- KWLWZYMNUZJKMZ-IHRRRGAJSA-N Leu-Pro-Leu Chemical compound CC(C)C[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CC(C)C)C(O)=O KWLWZYMNUZJKMZ-IHRRRGAJSA-N 0.000 description 1
- YRRCOJOXAJNSAX-IHRRRGAJSA-N Leu-Pro-Lys Chemical compound CC(C)C[C@@H](C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCCCN)C(=O)O)N YRRCOJOXAJNSAX-IHRRRGAJSA-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
- IRMLZWSRWSGTOP-CIUDSAMLSA-N Leu-Ser-Ala Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@@H](C)C(O)=O IRMLZWSRWSGTOP-CIUDSAMLSA-N 0.000 description 1
- 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 1
- AKVBOOKXVAMKSS-GUBZILKMSA-N Leu-Ser-Gln Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(O)=O AKVBOOKXVAMKSS-GUBZILKMSA-N 0.000 description 1
- XOWMDXHFSBCAKQ-SRVKXCTJSA-N Leu-Ser-Leu Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@H](C(O)=O)CC(C)C XOWMDXHFSBCAKQ-SRVKXCTJSA-N 0.000 description 1
- 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 1
- 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 1
- 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 1
- 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 1
- RNYLNYTYMXACRI-VFAJRCTISA-N Leu-Thr-Trp Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CNC2=C1C=CC=C2)C(O)=O RNYLNYTYMXACRI-VFAJRCTISA-N 0.000 description 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
- 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 1
- AXVIGSRGTMNSJU-YESZJQIVSA-N Leu-Tyr-Pro Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CC1=CC=C(C=C1)O)C(=O)N2CCC[C@@H]2C(=O)O)N AXVIGSRGTMNSJU-YESZJQIVSA-N 0.000 description 1
- FBNPMTNBFFAMMH-AVGNSLFASA-N Leu-Val-Arg Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@H](C(O)=O)CCCN=C(N)N FBNPMTNBFFAMMH-AVGNSLFASA-N 0.000 description 1
- FBNPMTNBFFAMMH-UHFFFAOYSA-N Leu-Val-Arg Natural products CC(C)CC(N)C(=O)NC(C(C)C)C(=O)NC(C(O)=O)CCCN=C(N)N FBNPMTNBFFAMMH-UHFFFAOYSA-N 0.000 description 1
- 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 1
- CGHXMODRYJISSK-NHCYSSNCSA-N Leu-Val-Asp Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@H](C(O)=O)CC(O)=O CGHXMODRYJISSK-NHCYSSNCSA-N 0.000 description 1
- 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 1
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 description 1
- 102100039564 Leukosialin Human genes 0.000 description 1
- 229910013684 LiClO 4 Inorganic materials 0.000 description 1
- 229910013553 LiNO Inorganic materials 0.000 description 1
- FACUGMGEFUEBTI-SRVKXCTJSA-N Lys-Asn-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](N)CCCCN FACUGMGEFUEBTI-SRVKXCTJSA-N 0.000 description 1
- QIJVAFLRMVBHMU-KKUMJFAQSA-N Lys-Asp-Phe Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O QIJVAFLRMVBHMU-KKUMJFAQSA-N 0.000 description 1
- CKSBRMUOQDNPKZ-SRVKXCTJSA-N Lys-Gln-Met Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCSC)C(O)=O CKSBRMUOQDNPKZ-SRVKXCTJSA-N 0.000 description 1
- IRRZDAIFYHNIIN-JYJNAYRXSA-N Lys-Gln-Tyr Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O IRRZDAIFYHNIIN-JYJNAYRXSA-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
- LLSUNJYOSCOOEB-GUBZILKMSA-N Lys-Glu-Asp Chemical compound NCCCC[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(O)=O LLSUNJYOSCOOEB-GUBZILKMSA-N 0.000 description 1
- GCMWRRQAKQXDED-IUCAKERBSA-N Lys-Glu-Gly Chemical compound [NH3+]CCCC[C@H]([NH3+])C(=O)N[C@@H](CCC([O-])=O)C(=O)NCC([O-])=O GCMWRRQAKQXDED-IUCAKERBSA-N 0.000 description 1
- KZOHPCYVORJBLG-AVGNSLFASA-N Lys-Glu-His Chemical compound C1=C(NC=N1)C[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)O)NC(=O)[C@H](CCCCN)N KZOHPCYVORJBLG-AVGNSLFASA-N 0.000 description 1
- LPAJOCKCPRZEAG-MNXVOIDGSA-N Lys-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)CCCCN LPAJOCKCPRZEAG-MNXVOIDGSA-N 0.000 description 1
- DUTMKEAPLLUGNO-JYJNAYRXSA-N Lys-Glu-Phe Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O DUTMKEAPLLUGNO-JYJNAYRXSA-N 0.000 description 1
- 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 1
- OIYWBDBHEGAVST-BZSNNMDCSA-N Lys-His-Tyr Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O OIYWBDBHEGAVST-BZSNNMDCSA-N 0.000 description 1
- KEPWSUPUFAPBRF-DKIMLUQUSA-N Lys-Ile-Phe Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O KEPWSUPUFAPBRF-DKIMLUQUSA-N 0.000 description 1
- MYZMQWHPDAYKIE-SRVKXCTJSA-N Lys-Leu-Ala Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C)C(O)=O MYZMQWHPDAYKIE-SRVKXCTJSA-N 0.000 description 1
- WVJNGSFKBKOKRV-AJNGGQMLSA-N Lys-Leu-Ile Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O WVJNGSFKBKOKRV-AJNGGQMLSA-N 0.000 description 1
- VUTWYNQUSJWBHO-BZSNNMDCSA-N Lys-Leu-Tyr Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O VUTWYNQUSJWBHO-BZSNNMDCSA-N 0.000 description 1
- ALGGDNMLQNFVIZ-SRVKXCTJSA-N Lys-Lys-Asp Chemical compound C(CCN)C[C@@H](C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(=O)O)C(=O)O)N ALGGDNMLQNFVIZ-SRVKXCTJSA-N 0.000 description 1
- UQRZFMQQXXJTTF-AVGNSLFASA-N Lys-Lys-Glu Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(O)=O UQRZFMQQXXJTTF-AVGNSLFASA-N 0.000 description 1
- GAHJXEMYXKLZRQ-AJNGGQMLSA-N Lys-Lys-Ile Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O GAHJXEMYXKLZRQ-AJNGGQMLSA-N 0.000 description 1
- 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 1
- WWEWGPOLIJXGNX-XUXIUFHCSA-N Lys-Met-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)[C@H](CCSC)NC(=O)[C@H](CCCCN)N WWEWGPOLIJXGNX-XUXIUFHCSA-N 0.000 description 1
- 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 1
- CENKQZWVYMLRAX-ULQDDVLXSA-N Lys-Phe-Met Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CCSC)C(O)=O CENKQZWVYMLRAX-ULQDDVLXSA-N 0.000 description 1
- CNGOEHJCLVCJHN-SRVKXCTJSA-N Lys-Pro-Glu Chemical compound NCCCC[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCC(O)=O)C(O)=O CNGOEHJCLVCJHN-SRVKXCTJSA-N 0.000 description 1
- 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 1
- MIROMRNASYKZNL-ULQDDVLXSA-N Lys-Pro-Tyr Chemical compound NCCCC[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 MIROMRNASYKZNL-ULQDDVLXSA-N 0.000 description 1
- HKXSZKJMDBHOTG-CIUDSAMLSA-N Lys-Ser-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CCCCN HKXSZKJMDBHOTG-CIUDSAMLSA-N 0.000 description 1
- UIJVKVHLCQSPOJ-XIRDDKMYSA-N Lys-Ser-Trp Chemical compound NCCCC[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(O)=O UIJVKVHLCQSPOJ-XIRDDKMYSA-N 0.000 description 1
- 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 1
- BDFHWFUAQLIMJO-KXNHARMFSA-N Lys-Thr-Pro Chemical compound C[C@H]([C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](CCCCN)N)O BDFHWFUAQLIMJO-KXNHARMFSA-N 0.000 description 1
- IMDJSVBFQKDDEQ-MGHWNKPDSA-N Lys-Tyr-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)[C@H](CC1=CC=C(C=C1)O)NC(=O)[C@H](CCCCN)N IMDJSVBFQKDDEQ-MGHWNKPDSA-N 0.000 description 1
- MIMXMVDLMDMOJD-BZSNNMDCSA-N Lys-Tyr-Leu Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC(C)C)C(O)=O MIMXMVDLMDMOJD-BZSNNMDCSA-N 0.000 description 1
- WINFHLHJTRGLCV-BZSNNMDCSA-N Lys-Tyr-Lys Chemical compound NCCCC[C@H](N)C(=O)N[C@H](C(=O)N[C@@H](CCCCN)C(O)=O)CC1=CC=C(O)C=C1 WINFHLHJTRGLCV-BZSNNMDCSA-N 0.000 description 1
- NQOQDINRVQCAKD-ULQDDVLXSA-N Lys-Tyr-Met Chemical compound CSCC[C@@H](C(=O)O)NC(=O)[C@H](CC1=CC=C(C=C1)O)NC(=O)[C@H](CCCCN)N NQOQDINRVQCAKD-ULQDDVLXSA-N 0.000 description 1
- SQRLLZAQNOQCEG-KKUMJFAQSA-N Lys-Tyr-Ser Chemical compound NCCCC[C@H](N)C(=O)N[C@H](C(=O)N[C@@H](CO)C(O)=O)CC1=CC=C(O)C=C1 SQRLLZAQNOQCEG-KKUMJFAQSA-N 0.000 description 1
- PPNCMJARTHYNEC-MEYUZBJRSA-N Lys-Tyr-Thr Chemical compound NCCCC[C@H](N)C(=O)N[C@H](C(=O)N[C@@H]([C@H](O)C)C(O)=O)CC1=CC=C(O)C=C1 PPNCMJARTHYNEC-MEYUZBJRSA-N 0.000 description 1
- NYTDJEZBAAFLLG-IHRRRGAJSA-N Lys-Val-Lys Chemical compound NCCCC[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(O)=O NYTDJEZBAAFLLG-IHRRRGAJSA-N 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 102000000380 Matrix Metalloproteinase 1 Human genes 0.000 description 1
- 102000000440 Melanoma-associated antigen Human genes 0.000 description 1
- 108050008953 Melanoma-associated antigen Proteins 0.000 description 1
- 102100025075 Melanoma-associated antigen 6 Human genes 0.000 description 1
- KUQWVNFMZLHAPA-CIUDSAMLSA-N Met-Ala-Gln Chemical compound [H]N[C@@H](CCSC)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(N)=O)C(O)=O KUQWVNFMZLHAPA-CIUDSAMLSA-N 0.000 description 1
- CHLJXFMOQGYDNH-SZMVWBNQSA-N Met-Arg-Trp Chemical compound C1=CC=C2C(C[C@H](NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@@H](N)CCSC)C(O)=O)=CNC2=C1 CHLJXFMOQGYDNH-SZMVWBNQSA-N 0.000 description 1
- CRGKLOXHKICQOL-GARJFASQSA-N Met-Gln-Pro Chemical compound CSCC[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)N1CCC[C@@H]1C(=O)O)N CRGKLOXHKICQOL-GARJFASQSA-N 0.000 description 1
- PHWSCIFNNLLUFJ-NHCYSSNCSA-N Met-Gln-Val Chemical compound CC(C)[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)N)NC(=O)[C@H](CCSC)N PHWSCIFNNLLUFJ-NHCYSSNCSA-N 0.000 description 1
- RAAVFTFEAUAVIY-DCAQKATOSA-N Met-Glu-Met Chemical compound CSCC[C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CCSC)C(=O)O)N RAAVFTFEAUAVIY-DCAQKATOSA-N 0.000 description 1
- ULLIQRYQNMAAHC-RWMBFGLXSA-N Met-His-Pro Chemical compound CSCC[C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)N2CCC[C@@H]2C(=O)O)N ULLIQRYQNMAAHC-RWMBFGLXSA-N 0.000 description 1
- MVMNUCOHQGYYKB-PEDHHIEDSA-N Met-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](CCSC)N MVMNUCOHQGYYKB-PEDHHIEDSA-N 0.000 description 1
- KMSMNUFBNCHMII-IHRRRGAJSA-N Met-Leu-Lys Chemical compound CSCC[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](C(O)=O)CCCCN KMSMNUFBNCHMII-IHRRRGAJSA-N 0.000 description 1
- AOFZWWDTTJLHOU-ULQDDVLXSA-N Met-Lys-Tyr Chemical compound CSCC[C@H](N)C(=O)N[C@@H](CCCCN)C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 AOFZWWDTTJLHOU-ULQDDVLXSA-N 0.000 description 1
- CNTNPWWHFWAZGA-JYJNAYRXSA-N Met-Met-Phe Chemical compound CSCC[C@H](N)C(=O)N[C@@H](CCSC)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 CNTNPWWHFWAZGA-JYJNAYRXSA-N 0.000 description 1
- GRKPXCKLOOUDFG-UFYCRDLUSA-N Met-Phe-Tyr Chemical compound C([C@H](NC(=O)[C@@H](N)CCSC)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(O)=O)C1=CC=CC=C1 GRKPXCKLOOUDFG-UFYCRDLUSA-N 0.000 description 1
- QEDGNYFHLXXIDC-DCAQKATOSA-N Met-Pro-Gln Chemical compound CSCC[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCC(N)=O)C(O)=O QEDGNYFHLXXIDC-DCAQKATOSA-N 0.000 description 1
- FNYBIOGBMWFQRJ-SRVKXCTJSA-N Met-Pro-Met Chemical compound CSCC[C@@H](C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCSC)C(=O)O)N FNYBIOGBMWFQRJ-SRVKXCTJSA-N 0.000 description 1
- LXCSZPUQKMTXNW-BQBZGAKWSA-N Met-Ser-Gly Chemical compound CSCC[C@H](N)C(=O)N[C@@H](CO)C(=O)NCC(O)=O LXCSZPUQKMTXNW-BQBZGAKWSA-N 0.000 description 1
- QQPMHUCGDRJFQK-RHYQMDGZSA-N Met-Thr-Leu Chemical compound CSCC[C@H](N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@H](C(O)=O)CC(C)C QQPMHUCGDRJFQK-RHYQMDGZSA-N 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 102100034256 Mucin-1 Human genes 0.000 description 1
- 101100096028 Mus musculus Smok1 gene Proteins 0.000 description 1
- 239000005041 Mylar™ Substances 0.000 description 1
- GUVMFDICMFQHSZ-UHFFFAOYSA-N N-(1-aminoethenyl)-1-[4-[[5-(4-amino-5-methyl-2-oxopyrimidin-1-yl)-3-[[5-(4-amino-5-methyl-2-oxopyrimidin-1-yl)-3-[[3-[[3-[[3-[[3-[[3-[[3-[[5-(4-amino-5-methyl-2-oxopyrimidin-1-yl)-3-[[5-(4-amino-5-methyl-2-oxopyrimidin-1-yl)-3-[[5-(4-amino-5-methyl-2-oxopyrimidin-1-yl)-3-[[5-(4-amino-5-methyl-2-oxopyrimidin-1-yl)-3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[hydroxy-[[3-[hydroxy-[[3-hydroxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy]phosphinothioyl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy]phosphinothioyl]oxyoxolan-2-yl]methoxy-hydroxyphosphinothioyl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphinothioyl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphinothioyl]oxyoxolan-2-yl]methoxy-hydroxyphosphinothioyl]oxyoxolan-2-yl]methoxy-hydroxyphosphinothioyl]oxyoxolan-2-yl]methoxy-hydroxyphosphinothioyl]oxyoxolan-2-yl]methoxy-hydroxyphosphinothioyl]oxyoxolan-2-yl]methoxy-hydroxyphosphinothioyl]oxy-5-(2-amino-6-oxo-1H-purin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphinothioyl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphinothioyl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphinothioyl]oxy-5-(2-amino-6-oxo-1H-purin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphinothioyl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphinothioyl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphinothioyl]oxyoxolan-2-yl]methoxy-hydroxyphosphinothioyl]oxyoxolan-2-yl]methoxy-hydroxyphosphinothioyl]oxy-5-[[[2-[[[2-[[[5-(2-amino-6-oxo-1H-purin-9-yl)-2-[[[5-(4-amino-2-oxopyrimidin-1-yl)-2-[[hydroxy-[2-(hydroxymethyl)-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-3-yl]oxyphosphinothioyl]oxymethyl]oxolan-3-yl]oxy-hydroxyphosphinothioyl]oxymethyl]oxolan-3-yl]oxy-hydroxyphosphinothioyl]oxymethyl]-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-3-yl]oxy-hydroxyphosphinothioyl]oxymethyl]-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-3-yl]oxy-hydroxyphosphinothioyl]oxymethyl]oxolan-2-yl]-5-methylimidazole-4-carboxamide Chemical compound CC1=C(C(=O)NC(N)=C)N=CN1C1OC(COP(O)(=S)OC2C(OC(C2)N2C(N=C(N)C=C2)=O)COP(O)(=S)OC2C(OC(C2)N2C(NC(=O)C(C)=C2)=O)COP(O)(=S)OC2C(OC(C2)N2C3=C(C(NC(N)=N3)=O)N=C2)COP(O)(=S)OC2C(OC(C2)N2C(N=C(N)C=C2)=O)COP(O)(=S)OC2C(OC(C2)N2C(NC(=O)C(C)=C2)=O)CO)C(OP(O)(=S)OCC2C(CC(O2)N2C(N=C(N)C(C)=C2)=O)OP(O)(=S)OCC2C(CC(O2)N2C(N=C(N)C(C)=C2)=O)OP(O)(=S)OCC2C(CC(O2)N2C(NC(=O)C(C)=C2)=O)OP(O)(=S)OCC2C(CC(O2)N2C(NC(=O)C(C)=C2)=O)OP(O)(=S)OCC2C(CC(O2)N2C3=C(C(NC(N)=N3)=O)N=C2)OP(O)(=S)OCC2C(CC(O2)N2C(NC(=O)C(C)=C2)=O)OP(O)(=S)OCC2C(CC(O2)N2C(N=C(N)C=C2)=O)OP(O)(=S)OCC2C(CC(O2)N2C3=C(C(NC(N)=N3)=O)N=C2)OP(O)(=S)OCC2C(CC(O2)N2C(N=C(N)C(C)=C2)=O)OP(O)(=S)OCC2C(CC(O2)N2C(N=C(N)C(C)=C2)=O)OP(O)(=S)OCC2C(CC(O2)N2C(N=C(N)C(C)=C2)=O)OP(O)(=S)OCC2C(CC(O2)N2C(N=C(N)C(C)=C2)=O)OP(O)(=S)OCC2C(CC(O2)N2C3=C(C(NC(N)=N3)=O)N=C2)OP(O)(=S)OCC2C(CC(O2)N2C(NC(=O)C(C)=C2)=O)OP(O)(=S)OCC2C(CC(O2)N2C(N=C(N)C=C2)=O)OP(O)(=S)OCC2C(CC(O2)N2C3=C(C(NC(N)=N3)=O)N=C2)OP(O)(=S)OCC2C(CC(O2)N2C(NC(=O)C(C)=C2)=O)OP(O)(=S)OCC2C(CC(O2)N2C(NC(=O)C(C)=C2)=O)O)C1 GUVMFDICMFQHSZ-UHFFFAOYSA-N 0.000 description 1
- WUGMRIBZSVSJNP-UHFFFAOYSA-N N-L-alanyl-L-tryptophan Natural products C1=CC=C2C(CC(NC(=O)C(N)C)C(O)=O)=CNC2=C1 WUGMRIBZSVSJNP-UHFFFAOYSA-N 0.000 description 1
- XZFYRXDAULDNFX-UHFFFAOYSA-N N-L-cysteinyl-L-phenylalanine Natural products SCC(N)C(=O)NC(C(O)=O)CC1=CC=CC=C1 XZFYRXDAULDNFX-UHFFFAOYSA-N 0.000 description 1
- AUEJLPRZGVVDNU-UHFFFAOYSA-N N-L-tyrosyl-L-leucine Natural products CC(C)CC(C(O)=O)NC(=O)C(N)CC1=CC=C(O)C=C1 AUEJLPRZGVVDNU-UHFFFAOYSA-N 0.000 description 1
- VIHYIVKEECZGOU-UHFFFAOYSA-N N-acetylimidazole Chemical compound CC(=O)N1C=CN=C1 VIHYIVKEECZGOU-UHFFFAOYSA-N 0.000 description 1
- KZNQNBZMBZJQJO-UHFFFAOYSA-N N-glycyl-L-proline Natural products NCC(=O)N1CCCC1C(O)=O KZNQNBZMBZJQJO-UHFFFAOYSA-N 0.000 description 1
- AJHCSUXXECOXOY-UHFFFAOYSA-N N-glycyl-L-tryptophan Natural products C1=CC=C2C(CC(NC(=O)CN)C(O)=O)=CNC2=C1 AJHCSUXXECOXOY-UHFFFAOYSA-N 0.000 description 1
- 108010084333 N-palmitoyl-S-(2,3-bis(palmitoyloxy)propyl)cysteinyl-seryl-lysyl-lysyl-lysyl-lysine Proteins 0.000 description 1
- 108010066427 N-valyltryptophan Proteins 0.000 description 1
- 102100031897 NACHT, LRR and PYD domains-containing protein 2 Human genes 0.000 description 1
- 229930193140 Neomycin Natural products 0.000 description 1
- 208000005289 Neoplastic Cell Transformation Diseases 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 102100021512 Nuclear pore complex protein Nup155 Human genes 0.000 description 1
- 108700001237 Nucleic Acid-Based Vaccines Proteins 0.000 description 1
- 102100029053 Nucleolar pre-ribosomal-associated protein 1 Human genes 0.000 description 1
- GOWLTLODGKPXMN-MEKRSRHXSA-N OM-174 Chemical compound O1[C@H](OP(O)(O)=O)[C@H](NC(=O)C[C@H](O)CCCCCCCCCCC)[C@@H](O)[C@H](O)[C@H]1CO[C@H]1[C@H](NC(=O)C[C@H](CCCCCCCCCCC)OC(=O)CCCCCCCCCCC)[C@@H](O)[C@H](OP(O)(O)=O)[C@@H](CO)O1 GOWLTLODGKPXMN-MEKRSRHXSA-N 0.000 description 1
- 108020005187 Oligonucleotide Probes Proteins 0.000 description 1
- 108700006640 OspA Proteins 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 239000012648 POLY-ICLC Substances 0.000 description 1
- 108060006580 PRAME Proteins 0.000 description 1
- 102000036673 PRAME Human genes 0.000 description 1
- 102000057297 Pepsin A Human genes 0.000 description 1
- 108090000284 Pepsin A Proteins 0.000 description 1
- 101800001442 Peptide pr Proteins 0.000 description 1
- KHGNFPUMBJSZSM-UHFFFAOYSA-N Perforine Natural products COC1=C2CCC(O)C(CCC(C)(C)O)(OC)C2=NC2=C1C=CO2 KHGNFPUMBJSZSM-UHFFFAOYSA-N 0.000 description 1
- BBDSZDHUCPSYAC-QEJZJMRPSA-N Phe-Ala-Leu Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(O)=O BBDSZDHUCPSYAC-QEJZJMRPSA-N 0.000 description 1
- CGOMLCQJEMWMCE-STQMWFEESA-N Phe-Arg-Gly Chemical compound NC(N)=NCCC[C@@H](C(=O)NCC(O)=O)NC(=O)[C@@H](N)CC1=CC=CC=C1 CGOMLCQJEMWMCE-STQMWFEESA-N 0.000 description 1
- MECSIDWUTYRHRJ-KKUMJFAQSA-N Phe-Asn-Leu Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(O)=O MECSIDWUTYRHRJ-KKUMJFAQSA-N 0.000 description 1
- KAHUBGWSIQNZQQ-KKUMJFAQSA-N Phe-Asn-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](N)CC1=CC=CC=C1 KAHUBGWSIQNZQQ-KKUMJFAQSA-N 0.000 description 1
- LXVFHIBXOWJTKZ-BZSNNMDCSA-N Phe-Asn-Tyr Chemical compound N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC1=CC=C(C=C1)O)C(=O)O LXVFHIBXOWJTKZ-BZSNNMDCSA-N 0.000 description 1
- DJPXNKUDJKGQEE-BZSNNMDCSA-N Phe-Asp-Phe Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O DJPXNKUDJKGQEE-BZSNNMDCSA-N 0.000 description 1
- RJYBHZVWJPUSLB-QEWYBTABSA-N Phe-Gln-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)N)NC(=O)[C@H](CC1=CC=CC=C1)N RJYBHZVWJPUSLB-QEWYBTABSA-N 0.000 description 1
- 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 1
- UAMFZRNCIFFMLE-FHWLQOOXSA-N Phe-Glu-Tyr Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CC2=CC=C(C=C2)O)C(=O)O)N UAMFZRNCIFFMLE-FHWLQOOXSA-N 0.000 description 1
- BVHFFNYBKRTSIU-MEYUZBJRSA-N Phe-His-Thr Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CC1=CNC=N1)C(=O)N[C@@H]([C@@H](C)O)C(O)=O BVHFFNYBKRTSIU-MEYUZBJRSA-N 0.000 description 1
- SPXWRYVHOZVYBU-ULQDDVLXSA-N Phe-His-Val Chemical compound CC(C)[C@@H](C(=O)O)NC(=O)[C@H](CC1=CN=CN1)NC(=O)[C@H](CC2=CC=CC=C2)N SPXWRYVHOZVYBU-ULQDDVLXSA-N 0.000 description 1
- GYEPCBNTTRORKW-PCBIJLKTSA-N Phe-Ile-Asp 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(O)=O)C(O)=O GYEPCBNTTRORKW-PCBIJLKTSA-N 0.000 description 1
- YKUGPVXSDOOANW-KKUMJFAQSA-N Phe-Leu-Asp Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(O)=O)C(O)=O YKUGPVXSDOOANW-KKUMJFAQSA-N 0.000 description 1
- 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 1
- KZRQONDKKJCAOL-DKIMLUQUSA-N Phe-Leu-Ile Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O KZRQONDKKJCAOL-DKIMLUQUSA-N 0.000 description 1
- YTILBRIUASDGBL-BZSNNMDCSA-N Phe-Leu-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CC1=CC=CC=C1 YTILBRIUASDGBL-BZSNNMDCSA-N 0.000 description 1
- LRBSWBVUCLLRLU-BZSNNMDCSA-N Phe-Leu-Lys Chemical compound CC(C)C[C@H](NC(=O)[C@@H](N)Cc1ccccc1)C(=O)N[C@@H](CCCCN)C(O)=O LRBSWBVUCLLRLU-BZSNNMDCSA-N 0.000 description 1
- MSHZERMPZKCODG-ACRUOGEOSA-N Phe-Leu-Phe Chemical compound C([C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)C1=CC=CC=C1 MSHZERMPZKCODG-ACRUOGEOSA-N 0.000 description 1
- 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 1
- CMHTUJQZQXFNTQ-OEAJRASXSA-N Phe-Leu-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC1=CC=CC=C1)N)O CMHTUJQZQXFNTQ-OEAJRASXSA-N 0.000 description 1
- WLYPRKLMRIYGPP-JYJNAYRXSA-N Phe-Lys-Glu Chemical compound OC(=O)CC[C@@H](C(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](N)CC1=CC=CC=C1 WLYPRKLMRIYGPP-JYJNAYRXSA-N 0.000 description 1
- DOXQMJCSSYZSNM-BZSNNMDCSA-N Phe-Lys-Leu Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(O)=O DOXQMJCSSYZSNM-BZSNNMDCSA-N 0.000 description 1
- UXQFHEKRGHYJRA-STQMWFEESA-N Phe-Met-Gly Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CCSC)C(=O)NCC(O)=O UXQFHEKRGHYJRA-STQMWFEESA-N 0.000 description 1
- OKQQWSNUSQURLI-JYJNAYRXSA-N Phe-Met-Val Chemical compound CC(C)[C@@H](C(=O)O)NC(=O)[C@H](CCSC)NC(=O)[C@H](CC1=CC=CC=C1)N OKQQWSNUSQURLI-JYJNAYRXSA-N 0.000 description 1
- CBENHWCORLVGEQ-HJOGWXRNSA-N Phe-Phe-Phe Chemical compound C([C@H](N)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)C1=CC=CC=C1 CBENHWCORLVGEQ-HJOGWXRNSA-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
- ZLAKUZDMKVKFAI-JYJNAYRXSA-N Phe-Pro-Val Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N1CCC[C@H]1C(=O)N[C@@H](C(C)C)C(O)=O ZLAKUZDMKVKFAI-JYJNAYRXSA-N 0.000 description 1
- UNBFGVQVQGXXCK-KKUMJFAQSA-N Phe-Ser-Leu Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(O)=O UNBFGVQVQGXXCK-KKUMJFAQSA-N 0.000 description 1
- XNMYNGDKJNOKHH-BZSNNMDCSA-N Phe-Ser-Tyr Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O XNMYNGDKJNOKHH-BZSNNMDCSA-N 0.000 description 1
- 239000004952 Polyamide Substances 0.000 description 1
- 102400000745 Potential peptide Human genes 0.000 description 1
- 101800001357 Potential peptide Proteins 0.000 description 1
- IFMDQWDAJUMMJC-DCAQKATOSA-N Pro-Ala-Leu Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(O)=O IFMDQWDAJUMMJC-DCAQKATOSA-N 0.000 description 1
- VCYJKOLZYPYGJV-AVGNSLFASA-N Pro-Arg-Leu Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(O)=O VCYJKOLZYPYGJV-AVGNSLFASA-N 0.000 description 1
- ZSKJPKFTPQCPIH-RCWTZXSCSA-N Pro-Arg-Thr Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(O)=O ZSKJPKFTPQCPIH-RCWTZXSCSA-N 0.000 description 1
- SWXSLPHTJVAWDF-VEVYYDQMSA-N Pro-Asn-Thr Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O SWXSLPHTJVAWDF-VEVYYDQMSA-N 0.000 description 1
- HXOLCSYHGRNXJJ-IHRRRGAJSA-N Pro-Asp-Phe Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O HXOLCSYHGRNXJJ-IHRRRGAJSA-N 0.000 description 1
- 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 1
- NXEYSLRNNPWCRN-SRVKXCTJSA-N Pro-Glu-Leu Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(O)=O NXEYSLRNNPWCRN-SRVKXCTJSA-N 0.000 description 1
- WFHYFCWBLSKEMS-KKUMJFAQSA-N Pro-Glu-Phe Chemical compound N([C@@H](CCC(=O)O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)C(=O)[C@@H]1CCCN1 WFHYFCWBLSKEMS-KKUMJFAQSA-N 0.000 description 1
- FEPSEIDIPBMIOS-QXEWZRGKSA-N Pro-Gly-Ile Chemical compound CC[C@H](C)[C@@H](C(O)=O)NC(=O)CNC(=O)[C@@H]1CCCN1 FEPSEIDIPBMIOS-QXEWZRGKSA-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
- BWCZJGJKOFUUCN-ZPFDUUQYSA-N Pro-Ile-Gln Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCC(N)=O)C(O)=O BWCZJGJKOFUUCN-ZPFDUUQYSA-N 0.000 description 1
- VZKBJNBZMZHKRC-XUXIUFHCSA-N Pro-Ile-Leu Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(C)C)C(O)=O VZKBJNBZMZHKRC-XUXIUFHCSA-N 0.000 description 1
- RUDOLGWDSKQQFF-DCAQKATOSA-N Pro-Leu-Asn Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(O)=O RUDOLGWDSKQQFF-DCAQKATOSA-N 0.000 description 1
- BRJGUPWVFXKBQI-XUXIUFHCSA-N Pro-Leu-Ile Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O BRJGUPWVFXKBQI-XUXIUFHCSA-N 0.000 description 1
- MRYUJHGPZQNOAD-IHRRRGAJSA-N Pro-Leu-Lys Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@@H]1CCCN1 MRYUJHGPZQNOAD-IHRRRGAJSA-N 0.000 description 1
- CPRLKHJUFAXVTD-ULQDDVLXSA-N Pro-Leu-Tyr Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O CPRLKHJUFAXVTD-ULQDDVLXSA-N 0.000 description 1
- SMFQZMGHCODUPQ-ULQDDVLXSA-N Pro-Lys-Phe Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O SMFQZMGHCODUPQ-ULQDDVLXSA-N 0.000 description 1
- WFIVLLFYUZZWOD-RHYQMDGZSA-N Pro-Lys-Thr Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(O)=O WFIVLLFYUZZWOD-RHYQMDGZSA-N 0.000 description 1
- RPLMFKUKFZOTER-AVGNSLFASA-N Pro-Met-Leu Chemical compound CC(C)C[C@@H](C(=O)O)NC(=O)[C@H](CCSC)NC(=O)[C@@H]1CCCN1 RPLMFKUKFZOTER-AVGNSLFASA-N 0.000 description 1
- WHNJMTHJGCEKGA-ULQDDVLXSA-N Pro-Phe-Leu Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CC(C)C)C(O)=O WHNJMTHJGCEKGA-ULQDDVLXSA-N 0.000 description 1
- KDBHVPXBQADZKY-GUBZILKMSA-N Pro-Pro-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@@H]1CCCN1C(=O)[C@H]1NCCC1 KDBHVPXBQADZKY-GUBZILKMSA-N 0.000 description 1
- LEIKGVHQTKHOLM-IUCAKERBSA-N Pro-Pro-Gly Chemical compound OC(=O)CNC(=O)[C@@H]1CCCN1C(=O)[C@H]1NCCC1 LEIKGVHQTKHOLM-IUCAKERBSA-N 0.000 description 1
- CGSOWZUPLOKYOR-AVGNSLFASA-N Pro-Pro-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@H]1NCCC1 CGSOWZUPLOKYOR-AVGNSLFASA-N 0.000 description 1
- FDMKYQQYJKYCLV-GUBZILKMSA-N Pro-Pro-Ser Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@H]1NCCC1 FDMKYQQYJKYCLV-GUBZILKMSA-N 0.000 description 1
- RTQKBZIRDWZLDF-BZSNNMDCSA-N Pro-Pro-Trp Chemical compound C([C@H]1C(=O)N[C@@H](CC=2C3=CC=CC=C3NC=2)C(=O)O)CCN1C(=O)[C@@H]1CCCN1 RTQKBZIRDWZLDF-BZSNNMDCSA-N 0.000 description 1
- AJNGQVUFQUVRQT-JYJNAYRXSA-N Pro-Pro-Tyr Chemical compound C([C@@H](C(=O)O)NC(=O)[C@H]1N(CCC1)C(=O)[C@H]1NCCC1)C1=CC=C(O)C=C1 AJNGQVUFQUVRQT-JYJNAYRXSA-N 0.000 description 1
- OWQXAJQZLWHPBH-FXQIFTODSA-N Pro-Ser-Asn Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(O)=O OWQXAJQZLWHPBH-FXQIFTODSA-N 0.000 description 1
- DCHQYSOGURGJST-FJXKBIBVSA-N Pro-Thr-Gly Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(O)=O DCHQYSOGURGJST-FJXKBIBVSA-N 0.000 description 1
- CHYAYDLYYIJCKY-OSUNSFLBSA-N Pro-Thr-Ile Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O CHYAYDLYYIJCKY-OSUNSFLBSA-N 0.000 description 1
- RJTUIDFUUHPJMP-FHWLQOOXSA-N Pro-Trp-His Chemical compound C1C[C@H](NC1)C(=O)N[C@@H](CC2=CNC3=CC=CC=C32)C(=O)N[C@@H](CC4=CN=CN4)C(=O)O RJTUIDFUUHPJMP-FHWLQOOXSA-N 0.000 description 1
- VVEQUISRWJDGMX-VKOGCVSHSA-N Pro-Trp-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)[C@H](CC1=CNC2=CC=CC=C21)NC(=O)[C@@H]3CCCN3 VVEQUISRWJDGMX-VKOGCVSHSA-N 0.000 description 1
- LZHHZYDPMZEMRX-STQMWFEESA-N Pro-Tyr-Gly Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)NCC(O)=O LZHHZYDPMZEMRX-STQMWFEESA-N 0.000 description 1
- 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 1
- XDKKMRPRRCOELJ-GUBZILKMSA-N Pro-Val-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@H](C(C)C)NC(=O)[C@@H]1CCCN1 XDKKMRPRRCOELJ-GUBZILKMSA-N 0.000 description 1
- WWXNZNWZNZPDIF-SRVKXCTJSA-N Pro-Val-Arg Chemical compound NC(N)=NCCC[C@@H](C(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H]1CCCN1 WWXNZNWZNZPDIF-SRVKXCTJSA-N 0.000 description 1
- OOZJHTXCLJUODH-QXEWZRGKSA-N Pro-Val-Asp Chemical compound OC(=O)C[C@@H](C(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H]1CCCN1 OOZJHTXCLJUODH-QXEWZRGKSA-N 0.000 description 1
- JXVXYRZQIUPYSA-NHCYSSNCSA-N Pro-Val-Gln Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(N)=O)C(O)=O JXVXYRZQIUPYSA-NHCYSSNCSA-N 0.000 description 1
- VDHGTOHMHHQSKG-JYJNAYRXSA-N Pro-Val-Phe Chemical compound CC(C)[C@H](NC(=O)[C@@H]1CCCN1)C(=O)N[C@@H](Cc1ccccc1)C(O)=O VDHGTOHMHHQSKG-JYJNAYRXSA-N 0.000 description 1
- 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 1
- 208000004403 Prostatic Hyperplasia Diseases 0.000 description 1
- 102000007327 Protamines Human genes 0.000 description 1
- 108010007568 Protamines Proteins 0.000 description 1
- 102100033527 Putative keratin-87 protein Human genes 0.000 description 1
- 108020005067 RNA Splice Sites Proteins 0.000 description 1
- 230000004570 RNA-binding Effects 0.000 description 1
- 108020005091 Replication Origin Proteins 0.000 description 1
- 101100394989 Rhodopseudomonas palustris (strain ATCC BAA-98 / CGA009) hisI gene Proteins 0.000 description 1
- 102100027057 Ribosome biogenesis protein BMS1 homolog Human genes 0.000 description 1
- 238000010847 SEQUEST Methods 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
- MMGJPDWSIOAGTH-ACZMJKKPSA-N Ser-Ala-Gln Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(N)=O)C(O)=O MMGJPDWSIOAGTH-ACZMJKKPSA-N 0.000 description 1
- 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 1
- YQHZVYJAGWMHES-ZLUOBGJFSA-N Ser-Ala-Ser Chemical compound OC[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](CO)C(O)=O YQHZVYJAGWMHES-ZLUOBGJFSA-N 0.000 description 1
- KYKKKSWGEPFUMR-NAKRPEOUSA-N Ser-Arg-Ile Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O KYKKKSWGEPFUMR-NAKRPEOUSA-N 0.000 description 1
- OYEDZGNMSBZCIM-XGEHTFHBSA-N Ser-Arg-Thr Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(O)=O OYEDZGNMSBZCIM-XGEHTFHBSA-N 0.000 description 1
- MMAPOBOTRUVNKJ-ZLUOBGJFSA-N Ser-Asp-Ser Chemical compound C([C@@H](C(=O)N[C@@H](CO)C(=O)O)NC(=O)[C@H](CO)N)C(=O)O MMAPOBOTRUVNKJ-ZLUOBGJFSA-N 0.000 description 1
- NJSPTZXVPZDRCU-UBHSHLNASA-N Ser-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](CO)N NJSPTZXVPZDRCU-UBHSHLNASA-N 0.000 description 1
- SWSRFJZZMNLMLY-ZKWXMUAHSA-N Ser-Asp-Val Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](C(C)C)C(O)=O SWSRFJZZMNLMLY-ZKWXMUAHSA-N 0.000 description 1
- COLJZWUVZIXSSS-CIUDSAMLSA-N Ser-Cys-His Chemical compound C1=C(NC=N1)C[C@@H](C(=O)O)NC(=O)[C@H](CS)NC(=O)[C@H](CO)N COLJZWUVZIXSSS-CIUDSAMLSA-N 0.000 description 1
- MOVJSUIKUNCVMG-ZLUOBGJFSA-N Ser-Cys-Ser Chemical compound C([C@@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CO)C(=O)O)N)O MOVJSUIKUNCVMG-ZLUOBGJFSA-N 0.000 description 1
- WKLJLEXEENIYQE-SRVKXCTJSA-N Ser-Cys-Tyr Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CS)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O WKLJLEXEENIYQE-SRVKXCTJSA-N 0.000 description 1
- CDVFZMOFNJPUDD-ACZMJKKPSA-N Ser-Gln-Asn Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O CDVFZMOFNJPUDD-ACZMJKKPSA-N 0.000 description 1
- 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 1
- SQBLRDDJTUJDMV-ACZMJKKPSA-N Ser-Glu-Asn Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O SQBLRDDJTUJDMV-ACZMJKKPSA-N 0.000 description 1
- GYXVUTAOICLGKJ-ACZMJKKPSA-N Ser-Glu-Cys Chemical compound C(CC(=O)O)[C@@H](C(=O)N[C@@H](CS)C(=O)O)NC(=O)[C@H](CO)N GYXVUTAOICLGKJ-ACZMJKKPSA-N 0.000 description 1
- 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 1
- YRBGKVIWMNEVCZ-WDSKDSINSA-N Ser-Glu-Gly Chemical compound OC[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)NCC(O)=O YRBGKVIWMNEVCZ-WDSKDSINSA-N 0.000 description 1
- LALNXSXEYFUUDD-GUBZILKMSA-N Ser-Glu-Leu Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(O)=O LALNXSXEYFUUDD-GUBZILKMSA-N 0.000 description 1
- QKQDTEYDEIJPNK-GUBZILKMSA-N Ser-Glu-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](N)CO QKQDTEYDEIJPNK-GUBZILKMSA-N 0.000 description 1
- GRSLLFZTTLBOQX-CIUDSAMLSA-N Ser-Glu-Met Chemical compound CSCC[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)O)NC(=O)[C@H](CO)N GRSLLFZTTLBOQX-CIUDSAMLSA-N 0.000 description 1
- DSGYZICNAMEJOC-AVGNSLFASA-N Ser-Glu-Phe Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O DSGYZICNAMEJOC-AVGNSLFASA-N 0.000 description 1
- OHKFXGKHSJKKAL-NRPADANISA-N Ser-Glu-Val Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(O)=O OHKFXGKHSJKKAL-NRPADANISA-N 0.000 description 1
- CICQXRWZNVXFCU-SRVKXCTJSA-N Ser-His-Leu Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CC(C)C)C(O)=O CICQXRWZNVXFCU-SRVKXCTJSA-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
- KCNSGAMPBPYUAI-CIUDSAMLSA-N Ser-Leu-Asn Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(O)=O KCNSGAMPBPYUAI-CIUDSAMLSA-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
- IUXGJEIKJBYKOO-SRVKXCTJSA-N Ser-Leu-His Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)NC(=O)[C@H](CO)N IUXGJEIKJBYKOO-SRVKXCTJSA-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
- 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 1
- JWOBLHJRDADHLN-KKUMJFAQSA-N Ser-Leu-Tyr Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O JWOBLHJRDADHLN-KKUMJFAQSA-N 0.000 description 1
- IXZHZUGGKLRHJD-DCAQKATOSA-N Ser-Leu-Val Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(O)=O IXZHZUGGKLRHJD-DCAQKATOSA-N 0.000 description 1
- 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 1
- PJIQEIFXZPCWOJ-FXQIFTODSA-N Ser-Pro-Asp Chemical compound [H]N[C@@H](CO)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CC(O)=O)C(O)=O PJIQEIFXZPCWOJ-FXQIFTODSA-N 0.000 description 1
- OVQZAFXWIWNYKA-GUBZILKMSA-N Ser-Pro-Met Chemical compound CSCC[C@@H](C(=O)O)NC(=O)[C@@H]1CCCN1C(=O)[C@H](CO)N OVQZAFXWIWNYKA-GUBZILKMSA-N 0.000 description 1
- 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 1
- SRSPTFBENMJHMR-WHFBIAKZSA-N Ser-Ser-Gly Chemical compound OC[C@H](N)C(=O)N[C@@H](CO)C(=O)NCC(O)=O SRSPTFBENMJHMR-WHFBIAKZSA-N 0.000 description 1
- ILZAUMFXKSIUEF-SRVKXCTJSA-N Ser-Ser-Phe Chemical compound OC[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 ILZAUMFXKSIUEF-SRVKXCTJSA-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
- 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 1
- XJDMUQCLVSCRSJ-VZFHVOOUSA-N Ser-Thr-Ala Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C)C(O)=O XJDMUQCLVSCRSJ-VZFHVOOUSA-N 0.000 description 1
- WUXCHQZLUHBSDJ-LKXGYXEUSA-N Ser-Thr-Asp Chemical compound OC[C@H](N)C(=O)N[C@@H]([C@H](O)C)C(=O)N[C@@H](CC(O)=O)C(O)=O WUXCHQZLUHBSDJ-LKXGYXEUSA-N 0.000 description 1
- FLMYSKVSDVHLEW-SVSWQMSJSA-N Ser-Thr-Ile Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O FLMYSKVSDVHLEW-SVSWQMSJSA-N 0.000 description 1
- QYBRQMLZDDJBSW-AVGNSLFASA-N Ser-Tyr-Glu Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CCC(O)=O)C(O)=O QYBRQMLZDDJBSW-AVGNSLFASA-N 0.000 description 1
- UBTNVMGPMYDYIU-HJPIBITLSA-N Ser-Tyr-Ile Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O UBTNVMGPMYDYIU-HJPIBITLSA-N 0.000 description 1
- KIEIJCFVGZCUAS-MELADBBJSA-N Ser-Tyr-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CC2=CC=C(C=C2)O)NC(=O)[C@H](CO)N)C(=O)O KIEIJCFVGZCUAS-MELADBBJSA-N 0.000 description 1
- VVKVHAOOUGNDPJ-SRVKXCTJSA-N Ser-Tyr-Ser Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CO)C(O)=O VVKVHAOOUGNDPJ-SRVKXCTJSA-N 0.000 description 1
- HNDMFDBQXYZSRM-IHRRRGAJSA-N Ser-Val-Phe Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O HNDMFDBQXYZSRM-IHRRRGAJSA-N 0.000 description 1
- JGUWRQWULDWNCM-FXQIFTODSA-N Ser-Val-Ser Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CO)C(O)=O JGUWRQWULDWNCM-FXQIFTODSA-N 0.000 description 1
- HSWXBJCBYSWBPT-GUBZILKMSA-N Ser-Val-Val Chemical compound CC(C)[C@H](NC(=O)[C@@H](NC(=O)[C@@H](N)CO)C(C)C)C(O)=O HSWXBJCBYSWBPT-GUBZILKMSA-N 0.000 description 1
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 1
- 108020004682 Single-Stranded DNA Proteins 0.000 description 1
- 108020004459 Small interfering RNA Proteins 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 108010090804 Streptavidin Proteins 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 108010002687 Survivin Proteins 0.000 description 1
- 108700005078 Synthetic Genes Proteins 0.000 description 1
- 102100027213 T-cell-specific surface glycoprotein CD28 Human genes 0.000 description 1
- 239000012163 TRI reagent Substances 0.000 description 1
- 108010017842 Telomerase Proteins 0.000 description 1
- BPEGJWRSRHCHSN-UHFFFAOYSA-N Temozolomide Chemical compound O=C1N(C)N=NC2=C(C(N)=O)N=CN21 BPEGJWRSRHCHSN-UHFFFAOYSA-N 0.000 description 1
- CBPNZQVSJQDFBE-FUXHJELOSA-N Temsirolimus Chemical compound C1C[C@@H](OC(=O)C(C)(CO)CO)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 CBPNZQVSJQDFBE-FUXHJELOSA-N 0.000 description 1
- NYTOUQBROMCLBJ-UHFFFAOYSA-N Tetranitromethane Chemical compound [O-][N+](=O)C([N+]([O-])=O)([N+]([O-])=O)[N+]([O-])=O NYTOUQBROMCLBJ-UHFFFAOYSA-N 0.000 description 1
- 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 1
- SKHPKKYKDYULDH-HJGDQZAQSA-N Thr-Asn-Leu Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(O)=O SKHPKKYKDYULDH-HJGDQZAQSA-N 0.000 description 1
- 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 1
- OHAJHDJOCKKJLV-LKXGYXEUSA-N Thr-Asp-Ser Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(O)=O OHAJHDJOCKKJLV-LKXGYXEUSA-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
- CQNFRKAKGDSJFR-NUMRIWBASA-N Thr-Glu-Asn Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CC(=O)N)C(=O)O)N)O CQNFRKAKGDSJFR-NUMRIWBASA-N 0.000 description 1
- LGNBRHZANHMZHK-NUMRIWBASA-N Thr-Glu-Asp Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CC(=O)O)C(=O)O)N)O LGNBRHZANHMZHK-NUMRIWBASA-N 0.000 description 1
- SHOMROOOQBDGRL-JHEQGTHGSA-N Thr-Glu-Gly Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCC(O)=O)C(=O)NCC(O)=O SHOMROOOQBDGRL-JHEQGTHGSA-N 0.000 description 1
- VYEHBMMAJFVTOI-JHEQGTHGSA-N Thr-Gly-Gln Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)NCC(=O)N[C@@H](CCC(N)=O)C(O)=O VYEHBMMAJFVTOI-JHEQGTHGSA-N 0.000 description 1
- DJDSEDOKJTZBAR-ZDLURKLDSA-N Thr-Gly-Ser Chemical compound C[C@@H](O)[C@H](N)C(=O)NCC(=O)N[C@@H](CO)C(O)=O DJDSEDOKJTZBAR-ZDLURKLDSA-N 0.000 description 1
- WBCCCPZIJIJTSD-TUBUOCAGSA-N Thr-His-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)[C@H](CC1=CN=CN1)NC(=O)[C@H]([C@@H](C)O)N WBCCCPZIJIJTSD-TUBUOCAGSA-N 0.000 description 1
- AMXMBCAXAZUCFA-RHYQMDGZSA-N Thr-Leu-Arg Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O AMXMBCAXAZUCFA-RHYQMDGZSA-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
- 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 1
- 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 1
- MEJHFIOYJHTWMK-VOAKCMCISA-N Thr-Leu-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)[C@@H](C)O MEJHFIOYJHTWMK-VOAKCMCISA-N 0.000 description 1
- PRNGXSILMXSWQQ-OEAJRASXSA-N Thr-Leu-Phe Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O PRNGXSILMXSWQQ-OEAJRASXSA-N 0.000 description 1
- ISLDRLHVPXABBC-IEGACIPQSA-N Thr-Leu-Trp Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC1=CNC2=C1C=CC=C2)C(O)=O ISLDRLHVPXABBC-IEGACIPQSA-N 0.000 description 1
- IJVNLNRVDUTWDD-MEYUZBJRSA-N Thr-Leu-Tyr Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O IJVNLNRVDUTWDD-MEYUZBJRSA-N 0.000 description 1
- KKPOGALELPLJTL-MEYUZBJRSA-N Thr-Lys-Tyr Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@@H](CCCCN)C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 KKPOGALELPLJTL-MEYUZBJRSA-N 0.000 description 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
- WTMPKZWHRCMMMT-KZVJFYERSA-N Thr-Pro-Ala Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](C)C(O)=O WTMPKZWHRCMMMT-KZVJFYERSA-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
- YGZWVPBHYABGLT-KJEVXHAQSA-N Thr-Pro-Tyr Chemical compound C[C@@H](O)[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 YGZWVPBHYABGLT-KJEVXHAQSA-N 0.000 description 1
- FWTFAZKJORVTIR-VZFHVOOUSA-N Thr-Ser-Ala Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(=O)N[C@@H](C)C(O)=O FWTFAZKJORVTIR-VZFHVOOUSA-N 0.000 description 1
- IVDFVBVIVLJJHR-LKXGYXEUSA-N Thr-Ser-Asp Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(O)=O)C(O)=O IVDFVBVIVLJJHR-LKXGYXEUSA-N 0.000 description 1
- BCYUHPXBHCUYBA-CUJWVEQBSA-N Thr-Ser-His Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@@H](Cc1cnc[nH]1)C(O)=O BCYUHPXBHCUYBA-CUJWVEQBSA-N 0.000 description 1
- 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 1
- ZESGVALRVJIVLZ-VFCFLDTKSA-N Thr-Thr-Pro Chemical compound C[C@H]([C@@H](C(=O)N[C@@H]([C@@H](C)O)C(=O)N1CCC[C@@H]1C(=O)O)N)O ZESGVALRVJIVLZ-VFCFLDTKSA-N 0.000 description 1
- UMFLBPIPAJMNIM-LYARXQMPSA-N Thr-Trp-Phe Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC1=CNC2=CC=CC=C21)C(=O)N[C@@H](CC3=CC=CC=C3)C(=O)O)N)O UMFLBPIPAJMNIM-LYARXQMPSA-N 0.000 description 1
- ZEJBJDHSQPOVJV-UAXMHLISSA-N Thr-Trp-Thr Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CNC2=C1C=CC=C2)C(=O)N[C@@H]([C@@H](C)O)C(O)=O ZEJBJDHSQPOVJV-UAXMHLISSA-N 0.000 description 1
- NJGMALCNYAMYCB-JRQIVUDYSA-N Thr-Tyr-Asn 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](CC(N)=O)C(O)=O NJGMALCNYAMYCB-JRQIVUDYSA-N 0.000 description 1
- OMRWDMWXRWTQIU-YJRXYDGGSA-N Thr-Tyr-Cys Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC1=CC=C(C=C1)O)C(=O)N[C@@H](CS)C(=O)O)N)O OMRWDMWXRWTQIU-YJRXYDGGSA-N 0.000 description 1
- JAWUQFCGNVEDRN-MEYUZBJRSA-N Thr-Tyr-Leu Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC1=CC=C(C=C1)O)C(=O)N[C@@H](CC(C)C)C(=O)O)N)O JAWUQFCGNVEDRN-MEYUZBJRSA-N 0.000 description 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
- XGFYGMKZKFRGAI-RCWTZXSCSA-N Thr-Val-Arg Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@H](C(O)=O)CCCN=C(N)N XGFYGMKZKFRGAI-RCWTZXSCSA-N 0.000 description 1
- BKIOKSLLAAZYTC-KKHAAJSZSA-N Thr-Val-Asn Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(N)=O)C(O)=O BKIOKSLLAAZYTC-KKHAAJSZSA-N 0.000 description 1
- 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 1
- AYFVYJQAPQTCCC-UHFFFAOYSA-N Threonine Natural products CC(O)C(N)C(O)=O AYFVYJQAPQTCCC-UHFFFAOYSA-N 0.000 description 1
- 239000004473 Threonine Substances 0.000 description 1
- 102100039357 Toll-like receptor 5 Human genes 0.000 description 1
- 102100039390 Toll-like receptor 7 Human genes 0.000 description 1
- 102100033110 Toll-like receptor 8 Human genes 0.000 description 1
- 108091023040 Transcription factor Proteins 0.000 description 1
- 102000040945 Transcription factor Human genes 0.000 description 1
- 108020004566 Transfer RNA Proteins 0.000 description 1
- HDTRYLNUVZCQOY-WSWWMNSNSA-N Trehalose Natural products O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-WSWWMNSNSA-N 0.000 description 1
- AOAMKFFPFOPMLX-BVSLBCMMSA-N Trp-Arg-Phe Chemical compound C([C@H](NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)N)C(O)=O)C1=CC=CC=C1 AOAMKFFPFOPMLX-BVSLBCMMSA-N 0.000 description 1
- CZSMNLQMRWPGQF-XEGUGMAKSA-N Trp-Gln-Ala Chemical compound [H]N[C@@H](CC1=CNC2=C1C=CC=C2)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](C)C(O)=O CZSMNLQMRWPGQF-XEGUGMAKSA-N 0.000 description 1
- MDDYTWOFHZFABW-SZMVWBNQSA-N Trp-Gln-Leu Chemical compound C1=CC=C2C(C[C@H](N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(C)C)C(O)=O)=CNC2=C1 MDDYTWOFHZFABW-SZMVWBNQSA-N 0.000 description 1
- 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 1
- QTQNGBOKNQNQLS-PMVMPFDFSA-N Trp-His-Phe Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)O)NC(=O)[C@H](CC2=CN=CN2)NC(=O)[C@H](CC3=CNC4=CC=CC=C43)N QTQNGBOKNQNQLS-PMVMPFDFSA-N 0.000 description 1
- GWBWCGITOYODER-YTQUADARSA-N Trp-Leu-Pro Chemical compound CC(C)C[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](CC2=CNC3=CC=CC=C32)N GWBWCGITOYODER-YTQUADARSA-N 0.000 description 1
- DDJHCLVUUBEIIA-BVSLBCMMSA-N Trp-Met-Phe Chemical compound C([C@H](NC(=O)[C@@H](NC(=O)[C@@H](N)CC=1C2=CC=CC=C2NC=1)CCSC)C(O)=O)C1=CC=CC=C1 DDJHCLVUUBEIIA-BVSLBCMMSA-N 0.000 description 1
- 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 1
- ZKVANNIVSDOQMG-HKUYNNGSSA-N Trp-Tyr-Gly Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)N[C@@H](CC3=CC=C(C=C3)O)C(=O)NCC(=O)O)N ZKVANNIVSDOQMG-HKUYNNGSSA-N 0.000 description 1
- 108090000631 Trypsin Proteins 0.000 description 1
- 102000004142 Trypsin Human genes 0.000 description 1
- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 description 1
- BURPTJBFWIOHEY-UWJYBYFXSA-N Tyr-Ala-Asp Chemical compound OC(=O)C[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 BURPTJBFWIOHEY-UWJYBYFXSA-N 0.000 description 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
- XMNDQSYABVWZRK-BZSNNMDCSA-N Tyr-Asn-Phe 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](CC1=CC=CC=C1)C(O)=O XMNDQSYABVWZRK-BZSNNMDCSA-N 0.000 description 1
- FJKXUIJOMUWCDD-FHWLQOOXSA-N Tyr-Gln-Tyr Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H](CC2=CC=C(C=C2)O)C(=O)O)N)O FJKXUIJOMUWCDD-FHWLQOOXSA-N 0.000 description 1
- HKYTWJOWZTWBQB-AVGNSLFASA-N Tyr-Glu-Asp Chemical compound OC(=O)C[C@@H](C(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 HKYTWJOWZTWBQB-AVGNSLFASA-N 0.000 description 1
- WVRUKYLYMFGKAN-IHRRRGAJSA-N Tyr-Glu-Glu Chemical compound OC(=O)CC[C@@H](C(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 WVRUKYLYMFGKAN-IHRRRGAJSA-N 0.000 description 1
- HVHJYXDXRIWELT-RYUDHWBXSA-N Tyr-Glu-Gly Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CCC(O)=O)C(=O)NCC(O)=O HVHJYXDXRIWELT-RYUDHWBXSA-N 0.000 description 1
- IMXAAEFAIBRCQF-SIUGBPQLSA-N Tyr-Glu-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)O)NC(=O)[C@H](CC1=CC=C(C=C1)O)N IMXAAEFAIBRCQF-SIUGBPQLSA-N 0.000 description 1
- KIJLSRYAUGGZIN-CFMVVWHZSA-N Tyr-Ile-Asp Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(O)=O)C(O)=O KIJLSRYAUGGZIN-CFMVVWHZSA-N 0.000 description 1
- AZZLDIDWPZLCCW-ZEWNOJEFSA-N Tyr-Ile-Phe Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O AZZLDIDWPZLCCW-ZEWNOJEFSA-N 0.000 description 1
- BSCBBPKDVOZICB-KKUMJFAQSA-N Tyr-Leu-Asp 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](CC(O)=O)C(O)=O BSCBBPKDVOZICB-KKUMJFAQSA-N 0.000 description 1
- KSCVLGXNQXKUAR-JYJNAYRXSA-N Tyr-Leu-Glu 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](CCC(O)=O)C(O)=O KSCVLGXNQXKUAR-JYJNAYRXSA-N 0.000 description 1
- QHLIUFUEUDFAOT-MGHWNKPDSA-N Tyr-Leu-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC1=CC=C(C=C1)O)N QHLIUFUEUDFAOT-MGHWNKPDSA-N 0.000 description 1
- WDGDKHLSDIOXQC-ACRUOGEOSA-N Tyr-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=C(O)C=C1 WDGDKHLSDIOXQC-ACRUOGEOSA-N 0.000 description 1
- ARJASMXQBRNAGI-YESZJQIVSA-N Tyr-Leu-Pro Chemical compound CC(C)C[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](CC2=CC=C(C=C2)O)N ARJASMXQBRNAGI-YESZJQIVSA-N 0.000 description 1
- CDBXVDXSLPLFMD-BPNCWPANSA-N Tyr-Pro-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@@H]1CCCN1C(=O)[C@@H](N)CC1=CC=C(O)C=C1 CDBXVDXSLPLFMD-BPNCWPANSA-N 0.000 description 1
- ARMNWLJYHCOSHE-KKUMJFAQSA-N Tyr-Pro-Gln Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCC(N)=O)C(O)=O ARMNWLJYHCOSHE-KKUMJFAQSA-N 0.000 description 1
- QKXAEWMHAAVVGS-KKUMJFAQSA-N Tyr-Pro-Glu Chemical compound N[C@@H](Cc1ccc(O)cc1)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCC(O)=O)C(O)=O QKXAEWMHAAVVGS-KKUMJFAQSA-N 0.000 description 1
- BIWVVOHTKDLRMP-ULQDDVLXSA-N Tyr-Pro-Leu Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CC(C)C)C(O)=O BIWVVOHTKDLRMP-ULQDDVLXSA-N 0.000 description 1
- YYLHVUCSTXXKBS-IHRRRGAJSA-N Tyr-Pro-Ser Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CO)C(O)=O YYLHVUCSTXXKBS-IHRRRGAJSA-N 0.000 description 1
- GQVZBMROTPEPIF-SRVKXCTJSA-N Tyr-Ser-Asp Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(O)=O)C(O)=O GQVZBMROTPEPIF-SRVKXCTJSA-N 0.000 description 1
- KWKJGBHDYJOVCR-SRVKXCTJSA-N Tyr-Ser-Cys Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CS)C(=O)O)N)O KWKJGBHDYJOVCR-SRVKXCTJSA-N 0.000 description 1
- QPOUERMDWKKZEG-HJPIBITLSA-N Tyr-Ser-Ile Chemical compound CC[C@H](C)[C@@H](C(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 QPOUERMDWKKZEG-HJPIBITLSA-N 0.000 description 1
- MWUYSCVVPVITMW-IGNZVWTISA-N Tyr-Tyr-Ala Chemical compound C([C@@H](C(=O)N[C@@H](C)C(O)=O)NC(=O)[C@@H](N)CC=1C=CC(O)=CC=1)C1=CC=C(O)C=C1 MWUYSCVVPVITMW-IGNZVWTISA-N 0.000 description 1
- RMRFSFXLFWWAJZ-HJOGWXRNSA-N Tyr-Tyr-Tyr Chemical compound C([C@H](N)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(O)=O)C1=CC=C(O)C=C1 RMRFSFXLFWWAJZ-HJOGWXRNSA-N 0.000 description 1
- NWEGIYMHTZXVBP-JSGCOSHPSA-N Tyr-Val-Gly Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](C(C)C)C(=O)NCC(O)=O NWEGIYMHTZXVBP-JSGCOSHPSA-N 0.000 description 1
- OBKOPLHSRDATFO-XHSDSOJGSA-N Tyr-Val-Pro Chemical compound CC(C)[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](CC2=CC=C(C=C2)O)N OBKOPLHSRDATFO-XHSDSOJGSA-N 0.000 description 1
- 102100039094 Tyrosinase Human genes 0.000 description 1
- 108060008724 Tyrosinase Proteins 0.000 description 1
- 108090000848 Ubiquitin Proteins 0.000 description 1
- 102000044159 Ubiquitin Human genes 0.000 description 1
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 description 1
- 241000700618 Vaccinia virus Species 0.000 description 1
- 206010046865 Vaccinia virus infection Diseases 0.000 description 1
- 102100039113 Vacuolar protein sorting-associated protein 13B Human genes 0.000 description 1
- COYSIHFOCOMGCF-UHFFFAOYSA-N Val-Arg-Gly Natural products CC(C)C(N)C(=O)NC(C(=O)NCC(O)=O)CCCN=C(N)N COYSIHFOCOMGCF-UHFFFAOYSA-N 0.000 description 1
- CVUDMNSZAIZFAE-UHFFFAOYSA-N Val-Arg-Pro Natural products NC(N)=NCCCC(NC(=O)C(N)C(C)C)C(=O)N1CCCC1C(O)=O CVUDMNSZAIZFAE-UHFFFAOYSA-N 0.000 description 1
- VMRFIKXKOFNMHW-GUBZILKMSA-N Val-Arg-Ser Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CO)C(=O)O)N VMRFIKXKOFNMHW-GUBZILKMSA-N 0.000 description 1
- DDNIHOWRDOXXPF-NGZCFLSTSA-N Val-Asp-Pro Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)N1CCC[C@@H]1C(=O)O)N DDNIHOWRDOXXPF-NGZCFLSTSA-N 0.000 description 1
- VFOHXOLPLACADK-GVXVVHGQSA-N Val-Gln-Leu Chemical compound CC(C)C[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)N)NC(=O)[C@H](C(C)C)N VFOHXOLPLACADK-GVXVVHGQSA-N 0.000 description 1
- PGBJAZDAEWPDAA-NHCYSSNCSA-N Val-Gln-Met Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H](CCSC)C(=O)O)N PGBJAZDAEWPDAA-NHCYSSNCSA-N 0.000 description 1
- UZDHNIJRRTUKKC-DLOVCJGASA-N Val-Gln-Val Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H](C(C)C)C(=O)O)N UZDHNIJRRTUKKC-DLOVCJGASA-N 0.000 description 1
- XGJLNBNZNMVJRS-NRPADANISA-N Val-Glu-Ala Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(O)=O XGJLNBNZNMVJRS-NRPADANISA-N 0.000 description 1
- KVRLNEILGGVBJX-IHRRRGAJSA-N Val-His-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)C(C)C)CC1=CN=CN1 KVRLNEILGGVBJX-IHRRRGAJSA-N 0.000 description 1
- XBRMBDFYOFARST-AVGNSLFASA-N Val-His-Val Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)N[C@@H](C(C)C)C(=O)O)N XBRMBDFYOFARST-AVGNSLFASA-N 0.000 description 1
- VHRLUTIMTDOVCG-PEDHHIEDSA-N Val-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(C)C)N VHRLUTIMTDOVCG-PEDHHIEDSA-N 0.000 description 1
- OVBMCNDKCWAXMZ-NAKRPEOUSA-N Val-Ile-Ser Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CO)C(=O)O)NC(=O)[C@H](C(C)C)N OVBMCNDKCWAXMZ-NAKRPEOUSA-N 0.000 description 1
- APQIVBCUIUDSMB-OSUNSFLBSA-N Val-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](C(C)C)N APQIVBCUIUDSMB-OSUNSFLBSA-N 0.000 description 1
- BZWUSZGQOILYEU-STECZYCISA-N Val-Ile-Tyr Chemical compound CC(C)[C@H](N)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 BZWUSZGQOILYEU-STECZYCISA-N 0.000 description 1
- ZHQWPWQNVRCXAX-XQQFMLRXSA-N Val-Leu-Pro Chemical compound CC(C)C[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](C(C)C)N ZHQWPWQNVRCXAX-XQQFMLRXSA-N 0.000 description 1
- VPGCVZRRBYOGCD-AVGNSLFASA-N Val-Lys-Val Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C(C)C)C(O)=O VPGCVZRRBYOGCD-AVGNSLFASA-N 0.000 description 1
- WSUWDIVCPOJFCX-TUAOUCFPSA-N Val-Met-Pro Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCSC)C(=O)N1CCC[C@@H]1C(=O)O)N WSUWDIVCPOJFCX-TUAOUCFPSA-N 0.000 description 1
- FMQGYTMERWBMSI-HJWJTTGWSA-N Val-Phe-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)[C@H](CC1=CC=CC=C1)NC(=O)[C@H](C(C)C)N FMQGYTMERWBMSI-HJWJTTGWSA-N 0.000 description 1
- YTNGABPUXFEOGU-SRVKXCTJSA-N Val-Pro-Arg Chemical compound CC(C)[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCCN=C(N)N)C(O)=O YTNGABPUXFEOGU-SRVKXCTJSA-N 0.000 description 1
- RYQUMYBMOJYYDK-NHCYSSNCSA-N Val-Pro-Glu Chemical compound CC(C)[C@@H](C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCC(=O)O)C(=O)O)N RYQUMYBMOJYYDK-NHCYSSNCSA-N 0.000 description 1
- USLVEJAHTBLSIL-CYDGBPFRSA-N Val-Pro-Ile Chemical compound CC[C@H](C)[C@@H](C(O)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@@H](N)C(C)C USLVEJAHTBLSIL-CYDGBPFRSA-N 0.000 description 1
- MIKHIIQMRFYVOR-RCWTZXSCSA-N Val-Pro-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@@H]1CCCN1C(=O)[C@H](C(C)C)N)O MIKHIIQMRFYVOR-RCWTZXSCSA-N 0.000 description 1
- LTTQCQRTSHJPPL-ZKWXMUAHSA-N Val-Ser-Asp Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(=O)O)C(=O)O)N LTTQCQRTSHJPPL-ZKWXMUAHSA-N 0.000 description 1
- 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 1
- WUFHZIRMAZZWRS-OSUNSFLBSA-N Val-Thr-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](C(C)C)N WUFHZIRMAZZWRS-OSUNSFLBSA-N 0.000 description 1
- 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 1
- HTONZBWRYUKUKC-RCWTZXSCSA-N Val-Thr-Val Chemical compound CC(C)[C@H](N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(O)=O HTONZBWRYUKUKC-RCWTZXSCSA-N 0.000 description 1
- ZLMFVXMJFIWIRE-FHWLQOOXSA-N Val-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](C(C)C)N ZLMFVXMJFIWIRE-FHWLQOOXSA-N 0.000 description 1
- VTIAEOKFUJJBTC-YDHLFZDLSA-N Val-Tyr-Asp Chemical compound CC(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 VTIAEOKFUJJBTC-YDHLFZDLSA-N 0.000 description 1
- RLVTVHSDKHBFQP-ULQDDVLXSA-N Val-Tyr-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)C(C)C)CC1=CC=C(O)C=C1 RLVTVHSDKHBFQP-ULQDDVLXSA-N 0.000 description 1
- PDASTHRLDFOZMG-JYJNAYRXSA-N Val-Tyr-Met Chemical compound CSCC[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)C(C)C)CC1=CC=C(O)C=C1 PDASTHRLDFOZMG-JYJNAYRXSA-N 0.000 description 1
- PMKQKNBISAOSRI-XHSDSOJGSA-N Val-Tyr-Pro Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC1=CC=C(C=C1)O)C(=O)N2CCC[C@@H]2C(=O)O)N PMKQKNBISAOSRI-XHSDSOJGSA-N 0.000 description 1
- IECQJCJNPJVUSB-IHRRRGAJSA-N Val-Tyr-Ser Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)N[C@@H](CO)C(O)=O IECQJCJNPJVUSB-IHRRRGAJSA-N 0.000 description 1
- 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 1
- SECKRCOLJRRGGV-UHFFFAOYSA-N Vardenafil Chemical compound CCCC1=NC(C)=C(C(N=2)=O)N1NC=2C(C(=CC=1)OCC)=CC=1S(=O)(=O)N1CCN(CC)CC1 SECKRCOLJRRGGV-UHFFFAOYSA-N 0.000 description 1
- 102000005789 Vascular Endothelial Growth Factors Human genes 0.000 description 1
- 108010019530 Vascular Endothelial Growth Factors Proteins 0.000 description 1
- 108020005202 Viral DNA Proteins 0.000 description 1
- 108010067390 Viral Proteins Proteins 0.000 description 1
- 108020000999 Viral RNA Proteins 0.000 description 1
- 102100021414 Zinc finger protein 439 Human genes 0.000 description 1
- 239000003070 absorption delaying agent Substances 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- KRHYYFGTRYWZRS-BJUDXGSMSA-N ac1l2y5h Chemical compound [18FH] KRHYYFGTRYWZRS-BJUDXGSMSA-N 0.000 description 1
- 159000000021 acetate salts Chemical class 0.000 description 1
- PAAZCQANMCYGAW-UHFFFAOYSA-N acetic acid;2,2,2-trifluoroacetic acid Chemical class CC(O)=O.OC(=O)C(F)(F)F PAAZCQANMCYGAW-UHFFFAOYSA-N 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 238000005903 acid hydrolysis reaction Methods 0.000 description 1
- 238000010306 acid treatment Methods 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 230000003044 adaptive effect Effects 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 238000011226 adjuvant chemotherapy Methods 0.000 description 1
- 230000000240 adjuvant effect Effects 0.000 description 1
- 238000011467 adoptive cell therapy Methods 0.000 description 1
- 239000011543 agarose gel Substances 0.000 description 1
- 235000004279 alanine Nutrition 0.000 description 1
- 108010008685 alanyl-glutamyl-aspartic acid Proteins 0.000 description 1
- 108010005233 alanylglutamic acid Proteins 0.000 description 1
- 108010047495 alanylglycine Proteins 0.000 description 1
- 108010070944 alanylhistidine Proteins 0.000 description 1
- 108010087924 alanylproline Proteins 0.000 description 1
- 108010070783 alanyltyrosine Proteins 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 239000013566 allergen Substances 0.000 description 1
- HDTRYLNUVZCQOY-LIZSDCNHSA-N alpha,alpha-trehalose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-LIZSDCNHSA-N 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 229940037003 alum Drugs 0.000 description 1
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- CEGOLXSVJUTHNZ-UHFFFAOYSA-K aluminium tristearate Chemical compound [Al+3].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CEGOLXSVJUTHNZ-UHFFFAOYSA-K 0.000 description 1
- 229940063655 aluminum stearate Drugs 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 150000003862 amino acid derivatives Chemical class 0.000 description 1
- 239000000908 ammonium hydroxide Substances 0.000 description 1
- AVKUERGKIZMTKX-NJBDSQKTSA-N ampicillin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=CC=C1 AVKUERGKIZMTKX-NJBDSQKTSA-N 0.000 description 1
- 229960000723 ampicillin Drugs 0.000 description 1
- 238000004873 anchoring Methods 0.000 description 1
- 230000033115 angiogenesis Effects 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 210000004102 animal cell Anatomy 0.000 description 1
- 125000000129 anionic group Chemical group 0.000 description 1
- 230000003042 antagnostic effect Effects 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000001772 anti-angiogenic effect Effects 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000005809 anti-tumor immunity Effects 0.000 description 1
- 239000003429 antifungal agent Substances 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 230000030741 antigen processing and presentation Effects 0.000 description 1
- 230000014102 antigen processing and presentation of exogenous peptide antigen via MHC class I Effects 0.000 description 1
- 230000008349 antigen-specific humoral response Effects 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 108010008355 arginyl-glutamine Proteins 0.000 description 1
- 108010009111 arginyl-glycyl-glutamic acid Proteins 0.000 description 1
- 108010091092 arginyl-glycyl-proline Proteins 0.000 description 1
- 108010062796 arginyllysine Proteins 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- 108010092854 aspartyllysine Proteins 0.000 description 1
- 230000006472 autoimmune response Effects 0.000 description 1
- 230000005784 autoimmunity Effects 0.000 description 1
- 238000011888 autopsy Methods 0.000 description 1
- 210000003719 b-lymphocyte Anatomy 0.000 description 1
- 230000006399 behavior Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid group Chemical group C(C1=CC=CC=C1)(=O)O WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- 230000001588 bifunctional effect Effects 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000008827 biological function Effects 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 229960000074 biopharmaceutical Drugs 0.000 description 1
- 238000001815 biotherapy Methods 0.000 description 1
- 238000005422 blasting Methods 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 238000009395 breeding Methods 0.000 description 1
- 230000001488 breeding effect Effects 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 1
- 239000000920 calcium hydroxide Substances 0.000 description 1
- 229910001861 calcium hydroxide Inorganic materials 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 238000009566 cancer vaccine Methods 0.000 description 1
- 230000005773 cancer-related death Effects 0.000 description 1
- 238000005251 capillar electrophoresis Methods 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 229920003123 carboxymethyl cellulose sodium Polymers 0.000 description 1
- 229940063834 carboxymethylcellulose sodium Drugs 0.000 description 1
- 210000002318 cardia Anatomy 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 125000002091 cationic group Chemical group 0.000 description 1
- 229920006317 cationic polymer Polymers 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 229960002412 cediranib Drugs 0.000 description 1
- RZEKVGVHFLEQIL-UHFFFAOYSA-N celecoxib Chemical compound C1=CC(C)=CC=C1C1=CC(C(F)(F)F)=NN1C1=CC=C(S(N)(=O)=O)C=C1 RZEKVGVHFLEQIL-UHFFFAOYSA-N 0.000 description 1
- 229960000590 celecoxib Drugs 0.000 description 1
- 239000006143 cell culture medium Substances 0.000 description 1
- 230000024245 cell differentiation 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
- 230000012292 cell migration Effects 0.000 description 1
- 230000005859 cell recognition Effects 0.000 description 1
- 229940030156 cell vaccine Drugs 0.000 description 1
- 230000007969 cellular immunity Effects 0.000 description 1
- 210000002230 centromere Anatomy 0.000 description 1
- 201000010881 cervical cancer Diseases 0.000 description 1
- QUPYHCHUQVNFJW-UHFFFAOYSA-M cesium;thiocyanate Chemical compound [Cs+].[S-]C#N QUPYHCHUQVNFJW-UHFFFAOYSA-M 0.000 description 1
- 239000002738 chelating agent Substances 0.000 description 1
- 125000003636 chemical group Chemical group 0.000 description 1
- 210000000349 chromosome Anatomy 0.000 description 1
- 229960002376 chymotrypsin Drugs 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 239000008119 colloidal silica Substances 0.000 description 1
- 210000001072 colon Anatomy 0.000 description 1
- 208000029742 colonic neoplasm Diseases 0.000 description 1
- 238000002648 combination therapy Methods 0.000 description 1
- 239000002131 composite material Substances 0.000 description 1
- 238000002591 computed tomography Methods 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- 238000004624 confocal microscopy Methods 0.000 description 1
- 229910001431 copper ion Inorganic materials 0.000 description 1
- 230000002596 correlated effect Effects 0.000 description 1
- 230000000139 costimulatory effect Effects 0.000 description 1
- 239000007822 coupling agent Substances 0.000 description 1
- 229960001681 croscarmellose sodium Drugs 0.000 description 1
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 1
- XLJMAIOERFSOGZ-UHFFFAOYSA-M cyanate Chemical compound [O-]C#N XLJMAIOERFSOGZ-UHFFFAOYSA-M 0.000 description 1
- ATDGTVJJHBUTRL-UHFFFAOYSA-N cyanogen bromide Chemical compound BrC#N ATDGTVJJHBUTRL-UHFFFAOYSA-N 0.000 description 1
- WZHCOOQXZCIUNC-UHFFFAOYSA-N cyclandelate Chemical compound C1C(C)(C)CC(C)CC1OC(=O)C(O)C1=CC=CC=C1 WZHCOOQXZCIUNC-UHFFFAOYSA-N 0.000 description 1
- IBTDNBUTNOKAQD-UHFFFAOYSA-N cyclohex-3-ene-1,2-dione Chemical compound O=C1CCC=CC1=O IBTDNBUTNOKAQD-UHFFFAOYSA-N 0.000 description 1
- 230000009089 cytolysis Effects 0.000 description 1
- 210000000805 cytoplasm Anatomy 0.000 description 1
- 230000001086 cytosolic effect Effects 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 125000001295 dansyl group Chemical group [H]C1=C([H])C(N(C([H])([H])[H])C([H])([H])[H])=C2C([H])=C([H])C([H])=C(C2=C1[H])S(*)(=O)=O 0.000 description 1
- 238000007405 data analysis Methods 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 229940029030 dendritic cell vaccine Drugs 0.000 description 1
- 108010017271 denileukin diftitox Proteins 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- 125000004386 diacrylate group Chemical group 0.000 description 1
- 238000002405 diagnostic procedure Methods 0.000 description 1
- 150000004985 diamines Chemical class 0.000 description 1
- NEFBYIFKOOEVPA-UHFFFAOYSA-K dicalcium phosphate Chemical compound [Ca+2].[Ca+2].[O-]P([O-])([O-])=O NEFBYIFKOOEVPA-UHFFFAOYSA-K 0.000 description 1
- 229910000390 dicalcium phosphate Inorganic materials 0.000 description 1
- 229940038472 dicalcium phosphate Drugs 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- FFYPMLJYZAEMQB-UHFFFAOYSA-N diethyl pyrocarbonate Chemical compound CCOC(=O)OC(=O)OCC FFYPMLJYZAEMQB-UHFFFAOYSA-N 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- GXGAKHNRMVGRPK-UHFFFAOYSA-N dimagnesium;dioxido-bis[[oxido(oxo)silyl]oxy]silane Chemical compound [Mg+2].[Mg+2].[O-][Si](=O)O[Si]([O-])([O-])O[Si]([O-])=O GXGAKHNRMVGRPK-UHFFFAOYSA-N 0.000 description 1
- 239000000539 dimer Substances 0.000 description 1
- 238000006471 dimerization reaction Methods 0.000 description 1
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 description 1
- 229910000396 dipotassium phosphate Inorganic materials 0.000 description 1
- 235000019797 dipotassium phosphate Nutrition 0.000 description 1
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 1
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
- 239000002612 dispersion medium Substances 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 150000002019 disulfides Chemical class 0.000 description 1
- 229950009791 durvalumab Drugs 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 210000003162 effector t lymphocyte Anatomy 0.000 description 1
- 239000003792 electrolyte Substances 0.000 description 1
- 238000001493 electron microscopy Methods 0.000 description 1
- 238000001962 electrophoresis Methods 0.000 description 1
- 238000004520 electroporation Methods 0.000 description 1
- 238000000132 electrospray ionisation Methods 0.000 description 1
- 238000001437 electrospray ionisation time-of-flight quadrupole detection Methods 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 230000012202 endocytosis Effects 0.000 description 1
- 229940088598 enzyme Drugs 0.000 description 1
- YQGOJNYOYNNSMM-UHFFFAOYSA-N eosin Chemical compound [Na+].OC(=O)C1=CC=CC=C1C1=C2C=C(Br)C(=O)C(Br)=C2OC2=C(Br)C(O)=C(Br)C=C21 YQGOJNYOYNNSMM-UHFFFAOYSA-N 0.000 description 1
- 229960001433 erlotinib Drugs 0.000 description 1
- AAKJLRGGTJKAMG-UHFFFAOYSA-N erlotinib Chemical compound C=12C=C(OCCOC)C(OCCOC)=CC2=NC=NC=1NC1=CC=CC(C#C)=C1 AAKJLRGGTJKAMG-UHFFFAOYSA-N 0.000 description 1
- 201000005619 esophageal carcinoma Diseases 0.000 description 1
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 description 1
- 210000003527 eukaryotic cell Anatomy 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 230000007717 exclusion Effects 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 238000010265 fast atom bombardment Methods 0.000 description 1
- 239000003925 fat Substances 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 210000002950 fibroblast Anatomy 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000010408 film Substances 0.000 description 1
- 108700014844 flt3 ligand Proteins 0.000 description 1
- 125000005519 fluorenylmethyloxycarbonyl group Chemical group 0.000 description 1
- GNBHRKFJIUUOQI-UHFFFAOYSA-N fluorescein Chemical compound O1C(=O)C2=CC=CC=C2C21C1=CC=C(O)C=C1OC1=CC(O)=CC=C21 GNBHRKFJIUUOQI-UHFFFAOYSA-N 0.000 description 1
- 238000001215 fluorescent labelling Methods 0.000 description 1
- 238000002594 fluoroscopy Methods 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 239000005350 fused silica glass Substances 0.000 description 1
- UIWYJDYFSGRHKR-UHFFFAOYSA-N gadolinium atom Chemical compound [Gd] UIWYJDYFSGRHKR-UHFFFAOYSA-N 0.000 description 1
- 201000008396 gallbladder adenocarcinoma Diseases 0.000 description 1
- 108010063718 gamma-glutamylaspartic acid Proteins 0.000 description 1
- 150000002270 gangliosides Chemical class 0.000 description 1
- 238000003500 gene array Methods 0.000 description 1
- 238000001415 gene therapy Methods 0.000 description 1
- 230000004077 genetic alteration Effects 0.000 description 1
- 231100000118 genetic alteration Toxicity 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 108010078144 glutaminyl-glycine Proteins 0.000 description 1
- 108010080575 glutamyl-aspartyl-alanine Proteins 0.000 description 1
- 108010013768 glutamyl-aspartyl-proline Proteins 0.000 description 1
- 108010055341 glutamyl-glutamic acid Proteins 0.000 description 1
- 108010079547 glutamylmethionine Proteins 0.000 description 1
- 150000004676 glycans Chemical class 0.000 description 1
- 229960002449 glycine Drugs 0.000 description 1
- 150000002334 glycols Chemical class 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
- 108010000434 glycyl-alanyl-leucine Proteins 0.000 description 1
- 108010026364 glycyl-glycyl-leucine Proteins 0.000 description 1
- 108010074027 glycyl-seryl-phenylalanine Proteins 0.000 description 1
- 108010010147 glycylglutamine Proteins 0.000 description 1
- 108010020688 glycylhistidine Proteins 0.000 description 1
- 108010015792 glycyllysine Proteins 0.000 description 1
- 108010077515 glycylproline Proteins 0.000 description 1
- 108010084389 glycyltryptophan Proteins 0.000 description 1
- 210000003714 granulocyte Anatomy 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 210000002216 heart Anatomy 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 208000019691 hematopoietic and lymphoid cell neoplasm Diseases 0.000 description 1
- 229920000140 heteropolymer Polymers 0.000 description 1
- 238000013537 high throughput screening Methods 0.000 description 1
- 125000000487 histidyl group Chemical group [H]N([H])C(C(=O)O*)C([H])([H])C1=C([H])N([H])C([H])=N1 0.000 description 1
- 108010025306 histidylleucine Proteins 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 102000050459 human LTF Human genes 0.000 description 1
- 238000009396 hybridization Methods 0.000 description 1
- 239000000017 hydrogel Substances 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 238000004191 hydrophobic interaction chromatography Methods 0.000 description 1
- 229920001600 hydrophobic polymer Polymers 0.000 description 1
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 1
- 229920003132 hydroxypropyl methylcellulose phthalate Polymers 0.000 description 1
- 229940031704 hydroxypropyl methylcellulose phthalate Drugs 0.000 description 1
- 229920000639 hydroxypropylmethylcellulose acetate succinate Polymers 0.000 description 1
- 230000007124 immune defense Effects 0.000 description 1
- 230000036737 immune function Effects 0.000 description 1
- 230000037451 immune surveillance Effects 0.000 description 1
- 238000003119 immunoblot Methods 0.000 description 1
- 230000016784 immunoglobulin production Effects 0.000 description 1
- 238000012151 immunohistochemical method Methods 0.000 description 1
- 238000011532 immunohistochemical staining Methods 0.000 description 1
- 239000000568 immunological adjuvant Substances 0.000 description 1
- 229940121354 immunomodulator Drugs 0.000 description 1
- 230000002584 immunomodulator Effects 0.000 description 1
- 238000001114 immunoprecipitation Methods 0.000 description 1
- 230000002637 immunotoxin Effects 0.000 description 1
- 239000002596 immunotoxin Substances 0.000 description 1
- 229940051026 immunotoxin Drugs 0.000 description 1
- 231100000608 immunotoxin Toxicity 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000011503 in vivo imaging Methods 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 229940117681 interleukin-12 Drugs 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 230000002601 intratumoral effect Effects 0.000 description 1
- PGLTVOMIXTUURA-UHFFFAOYSA-N iodoacetamide Chemical compound NC(=O)CI PGLTVOMIXTUURA-UHFFFAOYSA-N 0.000 description 1
- JDNTWHVOXJZDSN-UHFFFAOYSA-N iodoacetic acid Chemical compound OC(=O)CI JDNTWHVOXJZDSN-UHFFFAOYSA-N 0.000 description 1
- 238000004255 ion exchange chromatography Methods 0.000 description 1
- 229960005386 ipilimumab Drugs 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- JXDYKVIHCLTXOP-UHFFFAOYSA-N isatin Chemical compound C1=CC=C2C(=O)C(=O)NC2=C1 JXDYKVIHCLTXOP-UHFFFAOYSA-N 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 229960000310 isoleucine Drugs 0.000 description 1
- AGPKZVBTJJNPAG-UHFFFAOYSA-N isoleucine Natural products CCC(C)C(N)C(O)=O AGPKZVBTJJNPAG-UHFFFAOYSA-N 0.000 description 1
- 108010078274 isoleucylvaline Proteins 0.000 description 1
- 210000003292 kidney cell Anatomy 0.000 description 1
- 238000002372 labelling Methods 0.000 description 1
- 229940116108 lactase Drugs 0.000 description 1
- 229960001021 lactose monohydrate Drugs 0.000 description 1
- 229940039717 lanolin Drugs 0.000 description 1
- 235000019388 lanolin Nutrition 0.000 description 1
- 208000003849 large cell carcinoma Diseases 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- 125000001909 leucine group Chemical group [H]N(*)C(C(*)=O)C([H])([H])C(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 108010044311 leucyl-glycyl-glycine Proteins 0.000 description 1
- 108010034529 leucyl-lysine Proteins 0.000 description 1
- 210000000265 leukocyte Anatomy 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 239000012669 liquid formulation Substances 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 238000013332 literature search Methods 0.000 description 1
- 210000005265 lung cell Anatomy 0.000 description 1
- 210000003563 lymphoid tissue Anatomy 0.000 description 1
- 125000003588 lysine group Chemical group [H]N([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 description 1
- 108010045397 lysyl-tyrosyl-lysine Proteins 0.000 description 1
- 108010009298 lysylglutamic acid Proteins 0.000 description 1
- 108010054155 lysyllysine Proteins 0.000 description 1
- 108010017391 lysylvaline Proteins 0.000 description 1
- 108010051618 macrophage stimulatory lipopeptide 2 Proteins 0.000 description 1
- 239000000391 magnesium silicate Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 229940057948 magnesium stearate Drugs 0.000 description 1
- 229940099273 magnesium trisilicate Drugs 0.000 description 1
- 229910000386 magnesium trisilicate Inorganic materials 0.000 description 1
- 235000019793 magnesium trisilicate Nutrition 0.000 description 1
- 238000002595 magnetic resonance imaging Methods 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 210000001161 mammalian embryo Anatomy 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 238000001840 matrix-assisted laser desorption--ionisation time-of-flight mass spectrometry Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 230000008099 melanin synthesis Effects 0.000 description 1
- 230000001394 metastastic effect Effects 0.000 description 1
- 206010061289 metastatic neoplasm Diseases 0.000 description 1
- 108700023046 methionyl-leucyl-phenylalanine Proteins 0.000 description 1
- 108010005942 methionylglycine Proteins 0.000 description 1
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 1
- ZCQGVFNHUATAJY-UHFFFAOYSA-N methyl 2-[methyl(prop-2-enoyl)amino]acetate Chemical compound COC(=O)CN(C)C(=O)C=C ZCQGVFNHUATAJY-UHFFFAOYSA-N 0.000 description 1
- 239000011325 microbead Substances 0.000 description 1
- 230000000813 microbial effect Effects 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 239000004005 microsphere Substances 0.000 description 1
- 230000005012 migration Effects 0.000 description 1
- 238000013508 migration Methods 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000002715 modification method Methods 0.000 description 1
- 102000035118 modified proteins Human genes 0.000 description 1
- 108091005573 modified proteins Proteins 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 229940035032 monophosphoryl lipid a Drugs 0.000 description 1
- 239000004570 mortar (masonry) Substances 0.000 description 1
- 238000002703 mutagenesis Methods 0.000 description 1
- 231100000350 mutagenesis Toxicity 0.000 description 1
- 239000002105 nanoparticle Substances 0.000 description 1
- 239000005445 natural material Substances 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 229960004927 neomycin Drugs 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- FEMOMIGRRWSMCU-UHFFFAOYSA-N ninhydrin Chemical compound C1=CC=C2C(=O)C(O)(O)C(=O)C2=C1 FEMOMIGRRWSMCU-UHFFFAOYSA-N 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 229960003301 nivolumab Drugs 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 238000002414 normal-phase solid-phase extraction Methods 0.000 description 1
- 230000000269 nucleophilic effect Effects 0.000 description 1
- 239000002751 oligonucleotide probe Substances 0.000 description 1
- 229940100027 ontak Drugs 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 229960005030 other vaccine in atc Drugs 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 230000005298 paramagnetic effect Effects 0.000 description 1
- 230000000849 parathyroid Effects 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- CUIHSIWYWATEQL-UHFFFAOYSA-N pazopanib Chemical compound C1=CC2=C(C)N(C)N=C2C=C1N(C)C(N=1)=CC=NC=1NC1=CC=C(C)C(S(N)(=O)=O)=C1 CUIHSIWYWATEQL-UHFFFAOYSA-N 0.000 description 1
- 229960000639 pazopanib Drugs 0.000 description 1
- 229960002621 pembrolizumab Drugs 0.000 description 1
- 229940111202 pepsin Drugs 0.000 description 1
- 108010011903 peptide receptors Proteins 0.000 description 1
- 229930192851 perforin Natural products 0.000 description 1
- 210000005259 peripheral blood Anatomy 0.000 description 1
- 239000011886 peripheral blood Substances 0.000 description 1
- 239000012466 permeate Substances 0.000 description 1
- 230000002085 persistent effect Effects 0.000 description 1
- 239000008177 pharmaceutical agent Substances 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 108010065135 phenylalanyl-phenylalanyl-phenylalanine Proteins 0.000 description 1
- 108010084572 phenylalanyl-valine Proteins 0.000 description 1
- 108010083476 phenylalanyltryptophan Proteins 0.000 description 1
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 1
- 235000021317 phosphate Nutrition 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 230000004260 plant-type cell wall biogenesis Effects 0.000 description 1
- 239000013600 plasmid vector Substances 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 229940115270 poly iclc Drugs 0.000 description 1
- 229920000747 poly(lactic acid) Polymers 0.000 description 1
- 229920000058 polyacrylate Polymers 0.000 description 1
- 229920002647 polyamide Polymers 0.000 description 1
- 239000005020 polyethylene terephthalate Substances 0.000 description 1
- 229920000139 polyethylene terephthalate Polymers 0.000 description 1
- 238000003752 polymerase chain reaction Methods 0.000 description 1
- 229920000193 polymethacrylate Polymers 0.000 description 1
- 102000054765 polymorphisms of proteins Human genes 0.000 description 1
- 229920001451 polypropylene glycol Polymers 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 230000008092 positive effect Effects 0.000 description 1
- 238000002600 positron emission tomography Methods 0.000 description 1
- 230000004481 post-translational protein modification Effects 0.000 description 1
- 230000001323 posttranslational effect Effects 0.000 description 1
- GKKCIDNWFBPDBW-UHFFFAOYSA-M potassium cyanate Chemical compound [K]OC#N GKKCIDNWFBPDBW-UHFFFAOYSA-M 0.000 description 1
- 239000004302 potassium sorbate Substances 0.000 description 1
- 235000010241 potassium sorbate Nutrition 0.000 description 1
- 229940069338 potassium sorbate Drugs 0.000 description 1
- ZNNZYHKDIALBAK-UHFFFAOYSA-M potassium thiocyanate Chemical compound [K+].[S-]C#N ZNNZYHKDIALBAK-UHFFFAOYSA-M 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 108010066381 preproinsulin Proteins 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 108010016009 procolipase activation peptide Proteins 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 210000001236 prokaryotic cell Anatomy 0.000 description 1
- 108010020755 prolyl-glycyl-glycine Proteins 0.000 description 1
- 108010004914 prolylarginine Proteins 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 229940021993 prophylactic vaccine Drugs 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 229950008679 protamine sulfate Drugs 0.000 description 1
- 239000012474 protein marker Substances 0.000 description 1
- 230000016434 protein splicing Effects 0.000 description 1
- 230000006337 proteolytic cleavage Effects 0.000 description 1
- 239000001397 quillaja saponaria molina bark Substances 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 239000000941 radioactive substance Substances 0.000 description 1
- 238000011127 radiochemotherapy Methods 0.000 description 1
- 238000013102 re-test Methods 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 238000005932 reductive alkylation reaction Methods 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 208000019465 refractory cytopenia of childhood Diseases 0.000 description 1
- 230000022983 regulation of cell cycle Effects 0.000 description 1
- 230000003362 replicative effect Effects 0.000 description 1
- 230000001850 reproductive effect Effects 0.000 description 1
- 238000002271 resection Methods 0.000 description 1
- 108091008146 restriction endonucleases Proteins 0.000 description 1
- 238000004366 reverse phase liquid chromatography Methods 0.000 description 1
- PYWVYCXTNDRMGF-UHFFFAOYSA-N rhodamine B Chemical compound [Cl-].C=12C=CC(=[N+](CC)CC)C=C2OC2=CC(N(CC)CC)=CC=C2C=1C1=CC=CC=C1C(O)=O PYWVYCXTNDRMGF-UHFFFAOYSA-N 0.000 description 1
- 239000011435 rock Substances 0.000 description 1
- 108010029895 rubimetide Proteins 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 229930182490 saponin Natural products 0.000 description 1
- 150000007949 saponins Chemical class 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000004621 scanning probe microscopy Methods 0.000 description 1
- 238000010187 selection method Methods 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 108010048818 seryl-histidine Proteins 0.000 description 1
- 108010048397 seryl-lysyl-leucine Proteins 0.000 description 1
- 230000035939 shock Effects 0.000 description 1
- 230000011664 signaling Effects 0.000 description 1
- 238000001542 size-exclusion chromatography Methods 0.000 description 1
- 229940074386 skatole Drugs 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 230000000391 smoking effect Effects 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 229940054269 sodium pyruvate Drugs 0.000 description 1
- VGTPCRGMBIAPIM-UHFFFAOYSA-M sodium thiocyanate Chemical compound [Na+].[S-]C#N VGTPCRGMBIAPIM-UHFFFAOYSA-M 0.000 description 1
- 230000037439 somatic mutation Effects 0.000 description 1
- 229960003787 sorafenib Drugs 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 125000006850 spacer group Chemical group 0.000 description 1
- 230000010473 stable expression Effects 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 210000000130 stem cell Anatomy 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 210000002536 stromal cell Anatomy 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000005846 sugar alcohols Polymers 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 229960001796 sunitinib Drugs 0.000 description 1
- WINHZLLDWRZWRT-ATVHPVEESA-N sunitinib Chemical compound CCN(CC)CCNC(=O)C1=C(C)NC(\C=C/2C3=CC(F)=CC=C3NC\2=O)=C1C WINHZLLDWRZWRT-ATVHPVEESA-N 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 230000001502 supplementing effect Effects 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 230000009897 systematic effect Effects 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 229960000835 tadalafil Drugs 0.000 description 1
- IEHKWSGCTWLXFU-IIBYNOLFSA-N tadalafil Chemical compound C1=C2OCOC2=CC([C@@H]2C3=C([C]4C=CC=CC4=N3)C[C@H]3N2C(=O)CN(C3=O)C)=C1 IEHKWSGCTWLXFU-IIBYNOLFSA-N 0.000 description 1
- 238000004885 tandem mass spectrometry Methods 0.000 description 1
- 229960004964 temozolomide Drugs 0.000 description 1
- 229960000235 temsirolimus Drugs 0.000 description 1
- QFJCIRLUMZQUOT-UHFFFAOYSA-N temsirolimus Natural products C1CC(O)C(OC)CC1CC(C)C1OC(=O)C2CCCCN2C(=O)C(=O)C(O)(O2)C(C)CCC2CC(OC)C(C)=CC=CC=CC(C)CC(C)C(=O)C(OC)C(O)C(C)=CC(C)C(=O)C1 QFJCIRLUMZQUOT-UHFFFAOYSA-N 0.000 description 1
- 238000011285 therapeutic regimen Methods 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- RYYWUUFWQRZTIU-UHFFFAOYSA-K thiophosphate Chemical group [O-]P([O-])([O-])=S RYYWUUFWQRZTIU-UHFFFAOYSA-K 0.000 description 1
- 108010061238 threonyl-glycine Proteins 0.000 description 1
- 108010072986 threonyl-seryl-lysine Proteins 0.000 description 1
- 238000004448 titration Methods 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 231100000440 toxicity profile Toxicity 0.000 description 1
- 210000003437 trachea Anatomy 0.000 description 1
- 238000001890 transfection Methods 0.000 description 1
- 230000001131 transforming effect Effects 0.000 description 1
- 230000009261 transgenic effect Effects 0.000 description 1
- 230000010474 transient expression Effects 0.000 description 1
- 102000035160 transmembrane proteins Human genes 0.000 description 1
- 108091005703 transmembrane proteins Proteins 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 239000012588 trypsin Substances 0.000 description 1
- 108010058119 tryptophyl-glycyl-glycine Proteins 0.000 description 1
- 239000000439 tumor marker Substances 0.000 description 1
- 210000003171 tumor-infiltrating lymphocyte Anatomy 0.000 description 1
- 231100000588 tumorigenic Toxicity 0.000 description 1
- 230000000381 tumorigenic effect Effects 0.000 description 1
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 1
- 125000001493 tyrosinyl group Chemical group [H]OC1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 description 1
- 108010003137 tyrosyltyrosine Proteins 0.000 description 1
- 238000000108 ultra-filtration Methods 0.000 description 1
- 238000009281 ultraviolet germicidal irradiation Methods 0.000 description 1
- 241000701161 unidentified adenovirus Species 0.000 description 1
- 241000701447 unidentified baculovirus Species 0.000 description 1
- 241001529453 unidentified herpesvirus Species 0.000 description 1
- 241001430294 unidentified retrovirus Species 0.000 description 1
- 229940124931 vaccine adjuvant Drugs 0.000 description 1
- 239000012646 vaccine adjuvant Substances 0.000 description 1
- 208000007089 vaccinia Diseases 0.000 description 1
- IBIDRSSEHFLGSD-UHFFFAOYSA-N valinyl-arginine Natural products CC(C)C(N)C(=O)NC(C(O)=O)CCCN=C(N)N IBIDRSSEHFLGSD-UHFFFAOYSA-N 0.000 description 1
- 108010073969 valyllysine Proteins 0.000 description 1
- 108010009962 valyltyrosine Proteins 0.000 description 1
- 229960002381 vardenafil Drugs 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 108700026220 vif Genes Proteins 0.000 description 1
- 239000013603 viral vector Substances 0.000 description 1
- 238000012800 visualization Methods 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
- 239000002023 wood Substances 0.000 description 1
- 229910052727 yttrium Inorganic materials 0.000 description 1
- VWQVUPCCIRVNHF-UHFFFAOYSA-N yttrium atom Chemical compound [Y] VWQVUPCCIRVNHF-UHFFFAOYSA-N 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 150000003751 zinc Chemical class 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
- C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
- C07K14/4701—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals not used
- C07K14/4748—Tumour specific antigens; Tumour rejection antigen precursors [TRAP], e.g. MAGE
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
- A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
- A61K35/14—Blood; Artificial blood
- A61K35/17—Lymphocytes; B-cells; T-cells; Natural killer cells; Interferon-activated or cytokine-activated lymphocytes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/08—Peptides having 5 to 11 amino acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/19—Cytokines; Lymphokines; Interferons
- A61K38/193—Colony stimulating factors [CSF]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/19—Cytokines; Lymphokines; Interferons
- A61K38/20—Interleukins [IL]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/19—Cytokines; Lymphokines; Interferons
- A61K38/21—Interferons [IFN]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/0005—Vertebrate antigens
- A61K39/0011—Cancer antigens
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/0005—Vertebrate antigens
- A61K39/0011—Cancer antigens
- A61K39/001102—Receptors, cell surface antigens or cell surface determinants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/46—Cellular immunotherapy
- A61K39/461—Cellular immunotherapy characterised by the cell type used
- A61K39/4611—T-cells, e.g. tumor infiltrating lymphocytes [TIL], lymphokine-activated killer cells [LAK] or regulatory T cells [Treg]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/46—Cellular immunotherapy
- A61K39/464—Cellular immunotherapy characterised by the antigen targeted or presented
- A61K39/4643—Vertebrate antigens
- A61K39/4644—Cancer antigens
- A61K39/464499—Undefined tumor antigens, e.g. tumor lysate or antigens targeted by cells isolated from tumor
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/52—Cytokines; Lymphokines; Interferons
- C07K14/54—Interleukins [IL]
- C07K14/5434—IL-12
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
- C07K14/70503—Immunoglobulin superfamily
- C07K14/7051—T-cell receptor (TcR)-CD3 complex
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
- C07K14/70503—Immunoglobulin superfamily
- C07K14/70539—MHC-molecules, e.g. HLA-molecules
-
- 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
- C07K16/2833—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 MHC-molecules, e.g. HLA-molecules
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/2878—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the NGF-receptor/TNF-receptor superfamily, e.g. CD27, CD30, CD40, CD95
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/30—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants from tumour cells
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/04—Linear peptides containing only normal peptide links
- C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
-
- 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
- C12N15/10—Processes for the isolation, preparation or purification of DNA or RNA
- C12N15/1034—Isolating an individual clone by screening libraries
- C12N15/1062—Isolating an individual clone by screening libraries mRNA-Display, e.g. polypeptide and encoding template are connected covalently
-
- 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
- C12N15/115—Aptamers, i.e. nucleic acids binding a target molecule specifically and with high affinity without hybridising therewith ; Nucleic acids binding to non-nucleic acids, e.g. aptamers
-
- 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
- C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
- C12N5/06—Animal cells or tissues; Human cells or tissues
- C12N5/0602—Vertebrate cells
- C12N5/0634—Cells from the blood or the immune system
- C12N5/0636—T lymphocytes
- C12N5/0638—Cytotoxic T lymphocytes [CTL] or lymphokine activated killer cells [LAK]
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
- G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
- G01N33/57484—Immunoassay; Biospecific binding assay; Materials therefor for cancer involving compounds serving as markers for tumor, cancer, neoplasia, e.g. cellular determinants, receptors, heat shock/stress proteins, A-protein, oligosaccharides, metabolites
- G01N33/57492—Immunoassay; Biospecific binding assay; Materials therefor for cancer involving compounds serving as markers for tumor, cancer, neoplasia, e.g. cellular determinants, receptors, heat shock/stress proteins, A-protein, oligosaccharides, metabolites involving compounds localized on the membrane of tumor or cancer cells
-
- 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
- A61K2039/51—Medicinal preparations containing antigens or antibodies comprising whole cells, viruses or DNA/RNA
- A61K2039/515—Animal cells
- A61K2039/5158—Antigen-pulsed cells, e.g. T-cells
-
- 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
- A61K2039/57—Medicinal preparations containing antigens or antibodies characterised by the type of response, e.g. Th1, Th2
- A61K2039/572—Medicinal preparations containing antigens or antibodies characterised by the type of response, e.g. Th1, Th2 cytotoxic response
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2319/00—Fusion polypeptide
-
- 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
- C12N2501/00—Active agents used in cell culture processes, e.g. differentation
- C12N2501/50—Cell markers; Cell surface determinants
Abstract
本发明涉及用于免疫治疗方法的肽、蛋白质、核酸和细胞。特别是,本发明涉及癌症的免疫疗法。本发明还涉及单独使用或与其他肿瘤相关肽(刺激抗肿瘤免疫反应或体外刺激T细胞和转入患者的疫苗复合物的活性药物成分)联合使用的肿瘤相关T细胞(CTL)肽表位。与主要组织相容性复合体(MHC)分子结合的肽或与此同类的肽也可能是抗体、可溶性T细胞受体和其他结合分子的靶标。
Description
本发明涉及用于免疫治疗方法的肽、蛋白质、核酸和细胞。特别是,本发明涉及癌症的免疫疗法。本发明还涉及单独使用或与其他肿瘤相关肽(刺激抗肿瘤免疫反应或体外刺激T细胞和转入患者的疫苗复合物的活性药物成分)联合使用的肿瘤相关T细胞(CTL)肽表位。与主要组织相容性复合体(MHC)分子结合的肽或与此同类的肽也可能是抗体、可溶性T细胞受体和其他结合分子的靶标。
本发明涉及数种新型肽序列及其变体,它们源自人肿瘤细胞的HLA-I类分子,可用于引发抗肿瘤免疫反应的疫苗组合物中或作为开发药物/免疫活性化合物和细胞的目标。
发明背景
在男性和女性中,大多数癌症相关死亡的均为肺癌。在世界范围内,就发生率和死亡率而言,肺癌都是最常见的癌症。2012年,有超过180万的新发病例(占癌症总发病人数的13%),160万人死于肺癌(占癌症总死亡人数的20%)。肺癌是87个国家男性、26个国家女性癌症死亡的首要原因。超过三分之一的新诊断病例在中国。死亡率最高的地区为北美、欧洲和东亚(World Cancer Report,2014)。
自1987年以来,每年死于肺癌的女性超过了死于乳腺癌。从1991年至2003年,男性的死亡率持续下降,每年约下降1.9%。女性肺癌死亡率在连续增长几十年后正趋于平稳。肺癌死亡率的这些趋势反映了过去30年吸烟率的下降。
根据美国国立癌症研究所(NCI)的资料,预计2013年美国有23万新发肺癌病例,16万死于肺癌。
根据之前的经验,小细胞肺癌(SCLC)与非小细胞肺癌(NSCLC)区分,后者包括组织学类型的腺癌、鳞状细胞癌和大细胞癌。然而,在过去的十年中,由于遗传学的主要差异以及对特定治疗的反应,腺癌和鳞状细胞癌的区别已被越来越多地认识。因此,依据驱动和保持肺肿瘤发生的特定遗传改变,根据分子学亚型,肺癌被进一步分类(Travis et al.,2013)。
预后一般较差。在所有肺癌患者中,10%-15%的患者在确诊后存活五年。肺癌患者生存期差是因为(至少部分因为)80%的患者在确诊时就有转移,一半以上的患者有远端转移(SEER Stat facts,2014)。在发病时,30-40%的NSCLC病例处于四期,60%的SCLC病例处于四期。
肺癌的1年相对存活率在1975-1979年期间为35%,至2010年,略上升至44%,这主要是由于手术技术的改进和组合疗法的使用。然而,所有阶段的肺癌组合在一起,5年存活率仅为17%。对于疾病在检出时仍为局部性的病例,存活率为54%;但是仅有16%的肺癌在此早期得到确诊(SEER Stat facts,2014)。
治疗选择根据癌症的类型(小细胞和非小细胞肺癌)和阶段进行确定,包括手术、放疗、化疗、靶向生物治疗,如贝伐单抗和埃罗替尼对于局部癌,通常选择外科手术治疗。最近的研究表明,手术随后化疗可提高早期非小细胞肺癌的存活率。由于该疾病在发现时通常已经扩散,因此,常常使用放射和化疗,有时与手术联合使用。单一化疗或放化疗结合是治疗小细胞肺癌的通常选择;采用这一方案,有很大比例的患者获得缓解,在一些接受手术的病例中,缓解为持久缓解(S3-LeitlinieLungenkarzinom,2011)。
晚期肺癌也对传统的化疗产生耐药。然而,最近的研究进展依赖于组织学和遗传学在治疗方法上取得令人兴奋的进步。审查水平为:旨在区分KRAS的密码子12和13突变以及密码子12特定突变确定的不同氨基酸取代的辅助化疗试验(Shepherd et al.,2013)。
为了扩大NSCLC的治疗方案,已经研究了或正在研究不同的免疫治疗方法。虽然用L-BLP25或MAGEA3进行疫苗接种未能证明在NSCLC患者中疫苗介导的生存优势,但是同种异体细胞源性疫苗在临床研究中表现出有希望的结果。此外,针对神经节苷脂、表皮生长因子受体和其他几个抗原的进一步接种试验目前正在进行中。增强患者抗肿瘤T细胞反应的另一策略包括使用特异性抗体阻断抑制性T细胞受体或其配体。目前,正在临床试验中评估上述几种抗体(包括ipilimumab、nivolumab、pembrolizumab、MPDL3280A和MEDI-4736)在NSCLC中的治疗潜力(Reinmuth et al.,2015)
考虑到治疗癌症相关的严重副作用和费用,通常有必要确定可用于治疗癌症的因子,尤其是肺癌(包括NSCLC和SCLC)。也有必要确定代表通常癌症和肺癌(包括NSCLC和SCLC)生物标志物的因子,从而更好地诊断癌症、评估预后和预测治疗成功性。
癌症免疫治疗代表了癌症细胞特异性靶向作用的一个选项,同时最大限度地减少副作用。癌症免疫疗法利用存在的肿瘤相关抗原。
肿瘤相关抗原(TAA)的目前分类主要包括以下几组:
a)癌-睾丸抗原:T细胞能够识别的最先确认的TAA属于这一类抗原,由于其成员表达于组织学相异的人肿瘤中、正常组织中、仅在睾丸的精母细胞/精原细胞中、偶尔在胎盘中,因此,它最初被称为癌-睾丸(CT)抗原。由于睾丸细胞不表达HLA I类和II类分子,所以,在正常组织中,这些抗原不能被T细胞识别,因此在免疫学上可考虑为具有肿瘤特异性。CT抗原大家熟知的例子是MAGE家族成员和NY-ESO-1。
b)分化抗原:肿瘤和正常组织(肿瘤源自该组织)都含有TAA。大多数已知的分化抗原发现于黑色素瘤和正常黑色素细胞中。许多此类黑色素细胞谱系相关蛋白参与黑色素的生物合成,因此这些蛋白不具有肿瘤特异性,但是仍然被广泛用于癌症的免疫治疗。例子包括,但不仅限于,黑色素瘤的酪氨酸酶和Melan-A/MART-1或前列腺癌的PSA。
c)过量表达的TAA:在组织学相异的肿瘤中以及许多正常组织中都检测到了基因编码被广泛表达的TAA,一般表达水平较低。有可能许多由正常组织加工和潜在提呈的表位低于T细胞识别的阈值水平,而它们在肿瘤细胞中的过量表达能够透过打破先前确立的耐受性而引发抗癌反应。这类TAA的典型例子为Her-2/neu、生存素、端粒酶或WT1。
d)肿瘤特异性抗原:这些独特的TAA产生于正常基因(如β-catenin、CDK4等)的突变。这些分子变化中有一些与致瘤性转化和/或进展相关。肿瘤特异性抗原一般可在不对正常组织带来自体免疫反应风险的情况下诱导很强的免疫反应。另一方面,这些TAA在多数情况下只与其上确认了有TAA的确切肿瘤相关,并且通常在许多个体肿瘤之间并不都共用TAA。在含有肿瘤特定(相关)同种型蛋白的情况下,如果肽源自肿瘤(相关)外显子也可能出现肽肿瘤特异性(或相关性)。
e)由异常翻译后修饰产生的TAA:此类TAA可能由肿瘤中既不具有特异性也不过量表达的蛋白产生,但其仍然具有肿瘤相关性(该相关性由主要对肿瘤具有活性的翻译后加工所致)。此类TAA产生于变糖基化模式的改变,导致肿瘤产生针对MUC1的新型表位或在降解过程中导致诸如蛋白拼接的事件,这可能具有也可能不具有肿瘤特异性。
f)肿瘤病毒蛋白:这些TTA是病毒蛋白,可在致癌过程中发挥关键作用,并且由于它们是外源蛋白(非人源蛋白),所以能够激发T细胞反应。这类蛋白的例子有人乳头状瘤16型病毒蛋白、E6和E7,它们在宫颈癌中表达。
基于T细胞的免疫治疗靶向作用于主要组织相容性复合体(MHC)分子提呈的来源于肿瘤相关蛋白或肿瘤特异性蛋白的肽表位。肿瘤特异性T淋巴细胞所识别的抗原,即其表位,可以是源自所有蛋白类型的分子,如酶、受体、转录因子等,它们在相应肿瘤的细胞中被表达,并且与同源未变的细胞相比,其表达通常上调。
MHC分子有两类:MHC I类和MHC II类。MHC I类分子由一条α重链和β-2-微球蛋白,MHC II类分子由一条α和一条β链组成。其三位构造形成一个结合槽,用于与肽进行非共价相互作用。
大部分有核细胞上都可发现MHC-I类分子。他们提呈主要为内源性的蛋白、缺陷核糖体产物(DRIP)和较大肽裂解生成的肽。然而,源自内体结构或外源性来源的肽也经常在MHC-I类分子上发现。这种I-类分子非经典提呈方式在文献中被称为交叉提呈(Brossartand Bevan,1997;Rock et al.,1990)。MHC II类分子主要发现于专业抗原提呈细胞(APC)上,并且主要提呈,例如,在内吞作用过程中由APC占据并且随后被加工的外源性或跨膜蛋白的肽。
肽和MHC I类的复合体由负载相应T细胞受体(TCR)的CD8阳性T细胞进行识别,而肽和MHC II类分子的复合体由负载相应TCR的CD4阳性辅助T细胞进行识别。因此,TCR、肽和MHC按照1:1:1的化学计量呈现,这一点已是共识。
CD4阳性辅助T细胞在诱导和维持CD8阳性细胞毒性T细胞的有效反应中发挥重要作用。肿瘤相关抗原(TAA)衍生的CD4阳性T细胞表位的识别对开发能引发抗肿瘤免疫反应的药物产品非常重要(Gnjatic et al.,2003)。在肿瘤部位,T辅助细胞维持着对细胞毒性T细胞(CTL)友好的细胞因子环境(Mortara et al.,2006)并吸引效应细胞,如CTL、天然杀伤(NK)细胞、巨噬细胞和粒细胞(Hwang et al.,2007)。
在没有炎症的情况下,MHC II类分子的表达主要局限于免疫系统细胞,尤其是专业抗原提呈细胞(APC),例如,单核细胞、单核细胞源性细胞、巨噬细胞、树突状细胞。在癌症患者的肿瘤细胞中发现有MHC II类分子的表达(Dengjel et al.,2006)。
本发明的拉长(较长)肽可作为MHC-II类活性表位。MHC-II类表位活化的辅助T细胞在编排抗肿瘤免疫的CTL效应子功能中发挥着重要作用。触发TH1细胞反应的辅助T细胞表位支援CD8阳性杀伤T细胞的效应子功能,其中包括直接作用于肿瘤细胞的细胞毒性功能(该类肿瘤细胞表面显示有肿瘤相关肽/MHC复合体)。这样,肿瘤相关T辅助细胞表位单独使用或与其他肿瘤相关肽结合使用可作为刺激抗肿瘤免疫反应的疫苗化合物的活性药物成分。
哺乳动物(如小鼠)模型显示,即使没有CD8阳性T淋巴细胞,CD4阳性T细胞也能透过分泌干扰素-γ(IFNγ)抑制血管生成而足以抑制肿瘤的表现(Beatty and Paterson,2001;Mumberg et al.,1999)。没有CD4 T细胞作为直接抗肿瘤效应因子的证据(Braumuller et al.,2013;Tran et al.,2014)。
由于HLA II类分子的组成性表达通常仅限于免疫细胞,因此,直接从原发肿瘤中分离II类肽之前被认为是不可能的事。然而,Dengjel等人成功地在肿瘤中直接识别了多个MHC II类表位(WO 2007/028574,EP 1 760 088 B1)。
由于CD8依赖型和CD4依赖型这两种反应共同并协同地促进抗肿瘤作用,因此,确定和表征由CD8+T细胞(配体:MHC I类分子+肽表位)或CD4阳性T辅助细胞(配体:MHC II类分子)识别的肿瘤相关抗原对开发肿瘤疫苗非常重要。
对于MHC I类肽触发(引发)细胞免疫反应的肽,它也必须与MHC分子结合。这一过程依赖于MHC分子的等位基因以及肽氨基酸序列的特异性多态性。MHC-I类-结合肽的长度通常为8-12个氨基酸残基,并且在其与MHC分子相应结合沟槽相互作用的序列中通常包含两个保守残基(“锚”)。这样,每个MHC的等位基因都有“结合基序”,从而确定哪些肽能与结合沟槽特异性结合。
在MHC-I类依赖性免疫反应中,肽不仅能与肿瘤细胞表达的某些MHC-I类分子结合,而且它们之后还必须能被T细胞负载的特异性T细胞受体(TCR)识别。
对于被T淋巴细胞识别为肿瘤特异性抗原或相关性抗原以及用于治疗的蛋白质,必须具备一些条件。该抗原应主要由肿瘤细胞表达,而不由正常健康组织表达,或表达数量相对较少。在一个优选的实施方案中,与正常健康组织相比,所述肽应在肿瘤细胞中过度提呈。更为适宜的情况是,该相应抗原不仅出现于一种肿瘤中,而且浓度(即每个细胞的相应肽拷贝数目)高。肿瘤特异性抗原和肿瘤相关抗原往往是源自直接参与因细胞周期控制或凋亡抑制中的其功能而发生的正常细胞向肿瘤细胞转化的蛋白。另外,这些直接导致转化事件的蛋白的下游靶标可能会被上调,因此可能与肿瘤间接相关。这些间接肿瘤相关抗原也可能是预防接种方法的靶标(Singh-Jasuja et al.,2004)。至关重要的是,表位存在于抗原氨基酸序列中,以确保这种来自肿瘤相关抗原的肽(“免疫原性肽”)可导致体外或体内T细胞反应。
基本上,任何能与MHC分子结合的肽都可能充当一个T细胞表位。诱导体外或体内T细胞反应的前提是存在具有相应TCR的T细胞并且不存在对该特定表位的免疫耐受性。
因此,TAA是基于T细胞疗法(包括但不限于肿瘤疫苗)研发的起点。识别和表征TAA的方法通常基于对患者或健康受试者T细胞的使用情况,或基于肿瘤与正常组织肽之间差别转录特性或差别表达模式的产生。然而,对肿瘤组织或人肿瘤细胞株中过量表达或选择性表达的基因的识别并不提供在免疫疗法中使用这些基因所转录抗原的准确资讯。这是因为,有着相应TCR的T细胞必须要存在而且对这个特定表位的免疫耐受性必须不存在或为最低水平,因此,这些抗原的表位只有一部分适合这种应用。因此,在本发明的一非常优选的实施例中,只选择那些针对可发现功能性和/或增殖性T细胞情况的过量提呈或选择性提呈肽,这一点非常重要。这种功能性T细胞被定义为在以特异性抗原刺激后能够克隆地扩展并能够执行效应子功能(“效应子T细胞”)的T细胞。
在透过根据本发明的特定TCR(例如可溶性TCR)和抗体或其他结合分子(支架)靶向作用于肽-MHC的情况下,潜在肽的免疫原性是次要的。在这些情况下,提呈是决定因素。
发明简介
在本发明的第一方面,本发明涉及一种肽,包含选自包括SEQ ID NO:1至SEQ IDNO:489的组的一个氨基酸序列、或该序列的与SEQ ID NO:1至SEQ ID NO:489具有至少77%,优选至少88%同源(优选至少77%或至少88%相同)的一种变体序列(其中所述变体与MHC结合和/或诱导T细胞与所述肽发生交叉反应),或其药用盐(其中所述肽不是潜在全长多肽)。
本发明进一步涉及本发明的一种肽,包含选自包括SEQ ID NO:1至SEQ ID NO:489的组的一个序列、或与SEQ ID NO:1至SEQ ID NO:489具有至少77%、优选至少88%同源性(优选为至少77%或至少88%相同)的一种变体,其中所述肽或其变体的总长度为8至100个、优选为8至30个、最优选为8至14个氨基酸。
下表显示了根据本发明的肽、它们各自的SEQ ID NO、以及这些肽的可能源(潜在)基因。在表1中,含有SEQ ID NO:1至SEQ ID NO:83的肽与HLA-A*24结合,含有SEQ ID NO:84至SEQ ID NO:133的肽与HLA-A*02结合,含有SEQ ID NO:134至SEQ ID NO:201的肽与HLA-A*01结合,含有SEQ ID NO:202至SEQ ID NO:219的肽与HLA-A*03结合,含有SEQ ID NO:220至SEQ ID NO:295的肽与HLA-B*07肽结合,含有SEQ ID NO:296至SEQ ID NO:318的肽与HLA-B*08结合,含有SEQ ID NO:319至SEQ ID NO:374的肽与HLA-B*44结合。表2中的肽之前在大型列表中披露,作为高通量筛查结果,错误率高,或使用演算法计算出,但之前与癌症毫无关联。在表2中,含有SEQ ID NO:375至SEQ ID NO:387的肽与HLA-A*24结合,含有SEQID NO:388至SEQ ID NO:393的肽与HLA-A*02结合,含有SEQ ID NO:394至SEQ ID NO:452的肽与HLA-A*01结合,含有SEQ ID NO:453至SEQ ID NO:458的肽与HLA-A*03结合,含有SEQID NO:459至SEQ ID NO:475的肽与HLA-B*07肽结合,含有SEQ ID NO:476的肽与HLA-B*44结合。表3中的肽是可与本发明其它肽组合使用的其他肽。在表3中,含有SEQ ID NO:490至SEQ ID NO:508的肽与HLA-A*24结合,含有SEQ ID NO:509至SEQ ID NO:528的肽与HLA-A*02结合,含有SEQ ID NO:529至SEQ ID NO:530的肽与HLA-B*07结合,含有SEQ ID NO:531的肽与HLA-B*44结合。
表1:本发明的肽。
表2:本发明的其他肽,之前与癌症无已知的关联。
表3:用于例如个人化癌症疗法的本发明肽。
此外,本发明一般还涉及根据本发明肽,其用于治疗增殖性疾病,例如,急性骨髓性白血病、乳腺癌、胆管癌、脑癌、慢性淋巴细胞性白血病、结直肠癌、食管癌、胆囊癌、胃癌、头颈部鳞状细胞癌、肝细胞癌、黑色素瘤、非霍奇金淋巴瘤、卵巢癌、胰腺癌、前列腺癌、肾细胞癌、膀胱癌、子宫癌。
特别优选的是本发明的肽(单独或组合),其选自包括SEQ ID NO:1至SEQ ID NO:489的组。更优选的是所述肽(单独或组合)选自包括SEQ ID NO:1至SEQ ID NO:374的组(见表1)并且其用于免疫治疗肺癌(包括NSCLC和SCLC)、急性骨髓性白血病、乳腺癌、胆管癌、脑癌、慢性淋巴细胞白血病、结直肠癌、食管癌、胆囊癌、胃癌、头颈部鳞状细胞癌、肝细胞癌、黑色素瘤、非霍奇金淋巴瘤、卵巢癌、胰腺癌、前列腺癌、肾细胞癌、膀胱癌、子宫癌,优选为肺癌(包括NSCLC和SCLC)。
此外,本发明的另一方面涉及根据本发明肽的用途-优选联合用于治疗选自肺癌(包括NSCLC和SCLC)、急性骨髓性白血病、乳腺癌、胆管癌、脑癌、慢性淋巴细胞白血病、结直肠癌、食管癌、胆囊癌、胃癌、头颈部鳞状细胞癌、肝细胞癌、黑色素瘤、非霍奇金淋巴瘤、卵巢癌、胰腺癌、前列腺癌、肾细胞癌、膀胱癌、子宫癌组中的增殖性疾病。
本发明还涉及本发明的肽,其具有与主要组织相容性复合体(MHC)I或以拉长形式存在的例如长度变化的-MHC-II类分子结合的能力。
本发明进一步涉及本发明中的肽,其中所述肽(每种肽)系由或基本系由根据SEQID NO:1至SEQ ID NO:489的一个氨基酸序列组成。
本发明进一步涉及本发明的肽,其中所述肽被修饰和/或包含非肽键。
本发明进一步涉及本发明的肽,其中所述肽为融合蛋白的一部分,特别是与HLA-DR抗原相关不变链(Ii)的N-端氨基酸融合,或与抗体(例如,树突状细胞特定抗体)或抗体的序列融合。
本发明进一步涉及一种核酸,其编码本发明的肽。本发明进一步涉及一种本发明的核酸,为DNA、cDNA、PNA、RNA,也可能为其组合物。
本发明进一步涉及一种能表达和/或表达本发明核酸的表达载体。
本发明进一步涉及本发明的一种肽、本发明的一种核酸或本发明的一种治疗疾病的药用表达载体,特别是用于治疗癌症。
本发明进一步涉及本发明中肽或本发明中所述肽复合体(含有MHC)的特定抗体以及制造这些抗体的方法。
本发明进一步涉及本发明的T细胞受体(TCR),特别是可溶性TCR(sTCRs)和加工为自体或异体T细胞的克隆TCR,以及制造这些TCR的方法和载有所述TCR或所述TCR交叉反应的NK细胞的制造方法。
抗体和TCR是根据目前发明的肽免疫治疗用途的另外实施方案。
本发明进一步涉及含本发明核酸或前述表达载体的一种宿主细胞。本发明进一步涉及本发明的宿主细胞,其为抗原提呈细胞,优选为树突细胞。
本发明进一步涉及配制本发明一种肽的一种方法,所述方法包括培养本发明的宿主细胞和从所述宿主细胞或其培养基中分离肽。
本发明进一步涉及本发明中的所述方法,其中抗原透过与足够量的含抗原提成细胞的抗原结合被载入表达于合适抗原提呈细胞或人工抗原呈递细胞表面的I或II类MHC分子。本发明进一步涉及本发明的方法,其中抗原提呈细胞由能表达含SEQ ID NO.1至SEQ IDNO.489、优选为含SEQ ID No.1至SEQ ID No.374所述肽的一个表达载体、或一个变体氨基酸序列组成。
本发明进一步涉及以本发明方法制造的启动T细胞,其中所述T细胞有选择性地识别一种细胞,该细胞表达含一种本发明氨基酸序列的多肽。
本发明进一步涉及一种杀伤患者靶细胞的方法,其中患者的靶细胞异常表达含本发明任何氨基酸序列的多肽,该方法包括给予患者按本发明方法制造的有效量T细胞。
本发明进一步涉及任何所述肽、本发明的核酸、本发明的表达载体、本发明的细胞、本发明的作为药剂或制造药剂的启动T淋巴细胞、T细胞受体或抗体或其他肽-和/或肽-MHC结合分子的用途。所述药剂优选为具有抗癌活性。
优选情况为,所述药剂为基于可溶性TCR或抗体的细胞治疗药物、疫苗或蛋白质。
本发明进一步涉及根据本发明肽的用途,其中所述癌细胞为肺癌(包括NSCLC和SCLC)、急性骨髓性白血病、乳腺癌、胆管癌、脑癌、慢性淋巴细胞白血病、结直肠癌、食管癌、胆囊癌、胃癌、头颈部鳞状细胞癌、肝细胞癌、黑色素瘤、非霍奇金淋巴瘤、卵巢癌、胰腺癌、前列腺癌、肾细胞癌、膀胱癌、子宫癌,优选为肺癌(包括NSCLC和SCLC)细胞。
本发明进一步涉及一种基于本发明肽的生物标志物,在此成为“靶标”,其可用于诊断癌症,优选为肺癌(包括NSCLC和SCLC)。所述标志物可以肽本身过度提呈或相应基因过度表达。标志物也可以用于预测治疗成功的可能性,优选为免疫疗法,最优选为靶向作用于该生物标志物识别的相同靶标的免疫疗法。例如,抗体或可溶性TCR可用于染色肿瘤切片以检测是否存在相关肽与MHC复合。
或者,抗体具有进一步的效应子功能,如免疫刺激域或毒素。
本发明还涉及这些癌症治疗中新靶点的用途。
是否能刺激免疫反应取决于是否存在被宿主免疫系统视为异物的抗原。发现肿瘤相关抗原的存在增加了运用宿主免疫系统干预肿瘤生长的可能性。目前,针对癌症免疫治疗,正在探索利用免疫系统的体液和细胞进行免疫的各种机制。
细胞免疫反应的特定元素能特异性地识别和破坏肿瘤细胞。从肿瘤浸润细胞群或外周血中分离出的T-细胞表明,这些细胞在癌症的天然免疫防御中发挥了重要作用。CD8阳性T细胞在这种反应中发挥重要作用,TCD8+能识别通常8至10个源自蛋白或位于细胞质的缺损核糖体产物(DRIP)的氨基酸残基的主要组织相容性复合体(MHC)所载的肽中所含的I类分子。人MHC分子也称为人白细胞-抗原(HLA)。
除非另有说明,否则本文使用的所有术语定义如下。
术语“T细胞反应”是指由一种肽在体外或体内诱导的效应子功能的特异性扩散和启动。对于MHC I类限制性细胞毒性T细胞,效应子功能可能为溶解肽脉冲的、肽前体脉冲的或天然肽提呈的靶细胞、分泌细胞因子,优选为肽诱导的干扰素-γ,TNF-α或IL-2,分泌效应分子,优选为肽诱导的颗粒酶或穿孔素,或脱颗粒。
本文所用“肽”这一术语,系指一系列氨基酸残基,通常透过相邻氨基酸的α-氨基和羰基之间的肽键来连接。这些肽的长度优选为9个氨基酸,但至短可为8个氨基酸长度,至长可为10、11、或12个氨基酸或更长,如果为MHC-II类肽时(本发明肽的拉长变体),至长可为13、14、15、16、17、18、19或20个氨基酸长度或更长。
此外,“肽”这一术语应包括一系列氨基酸残基的盐,通常透过相邻氨基酸的α-氨基和羰基之间的肽键来连接。优选的情况是,盐为肽的药用盐,例如:氯化物或乙酸(三氟乙酸)盐。必须注意的是,本发明肽的盐与其体内状态的肽基本上不同,因为该不是体内的盐。
术语“肽”应也包括“寡肽”。本文使用的术语“寡肽”是指一系列氨基酸残基,通常透过相邻氨基酸的α-氨基和羰基之间的肽键来连接。寡肽的长度对于本发明来说并不十分关键,只要在寡肽中保持正确的表位即可。通常,寡肽长度约小于30个氨基酸残基,约长于15个氨基酸。
“多肽”这一术语是指一系列氨基酸残基,通常透过相邻氨基酸的α-氨基和羰基之间的肽键来连接。多肽的长度对于本发明来说并不十分关键,只要保持正确的表位即可。与术语肽或寡肽相对,“多肽”这一术语是指包含多于约30个氨基酸残基的分子。
一种肽、寡肽、蛋白质或编码该分子的核苷酸如果能诱导免疫反应,则具有“免疫原性”(因此是本发明中的一种“免疫原”)。在本发明的情况下,免疫原性的更具体定义是诱导T细胞反应的能力。因此,“免疫原”是一种能够诱导免疫反应的分子,并且在本发明的情况下,是一种能诱导T细胞反应的分子。在另一方面,所述免疫原可以是肽,肽与MHC的复合体、和/或用于提高特异性抗体或TCR抗性的蛋白。
I类T细胞“表位”要求的是一种结合至MHC I类受体上的短肽,从而形成一种三元复合体(MHC I类α链、β-2-微球蛋白和肽),其可以透过T细胞负载匹配T细胞受体与具有适当亲和力的MHC/肽复合物结合来识别。结合至MHC I类分子的肽的典型长度为8-14个氨基酸,最典型为9个氨基酸长度。
在人类中,有三种编码MHC I类分子的不同基因位点(人MHC分子也是指定的人白细胞抗原(HLA)):HLA-A、HLA-B和HLA-C。HLA-A*01、HLA-A*02和HLA-B*07是可从这些基因位点表达的不同MHC I类等位元基因的实例。
表4:HLA-A*02、HLA-A*01、HLA-A*03、HLA-A*24、HLA-B*07、HLA-B*08和HLA-B*44血清类型的表达频率F。单体型频率Gf来源于一项研究,该研究使用了来自美国超过650万名志愿捐献者登记的HLA分型资料(Gragert et al.,2013)。该单体型频率是个体染色体上独特等位元基因的频率。由于哺乳动物细胞内的二倍体染色体组,该等位元基因的基因型出现频率较高,可以使用Hardy-Weinberg定律(F=1–(1-Gf)2)进行计算。
本发明的肽,优选当如本文描述纳入本发明的疫苗时与A*02、A*01、A*03、A*24、B*07、B*08或B*44。疫苗还可能包括泛结合MHC II类肽。因此,本发明的疫苗可用于治疗A*02、A*01、A*03、A*24、B*07、B*08或B*44阳性患者中的癌症,但不因为这些肽的广泛结核性而必须选择II类MHC同种异型。
如果本发明的A*02肽与结合至另一等位基因例如A*24的肽组合,与单独的MHC I类等位基因相比,可治疗更高比例的患者群体。虽然在大多数人群中,低于50%的患者可由单独的等位基因来解决问题,但是本发明中一种含HLA-A*24和HLA-A*02表位的疫苗可以治疗任何相关人群中至少60%的患者。具体来说,各区域中,以下比例的患者这些等位基因中的至少一个有肯定效果:美国61%、西欧62%、中国75%、韩国77%、日本86%(根据www.allelefrequencies.net计算)。
表5:欧洲白人人群中HLA等位元基因覆盖(根据(Gragert et al.,2013)中所述的方法计算)。
在一项优选的实施方案中,术语“核苷酸序列”系指去氧核苷酸的杂聚物。
编码特定肽、寡肽或多肽的核苷酸序列可为天然核苷酸序列,也可为合成核苷酸序列。一般来说,编码肽、多肽以及本发明蛋白的DNA片段由cDNA片段和短寡核苷酸衔接物,或一系列寡核苷酸组成,以提供一种合成基因,该基因能够在包含源自微生物或病毒操纵子的调节元素的重组转录单元中被表达。
如本文所用的术语“肽的核苷酸编码”系指对肽进行核苷酸序列编码,其中该肽包括与将由用于产生TCR的树突细胞或另一细胞系统所表达该序列的生物系统相容的人工(人造)启动和停止密码子。
本文提到的核酸序列既包括单链核酸也包括双链核酸。因此,除非本文另有所指,否则,例如对于DNA,具体的序列是该序列的单链DNA、该序列与其互补序列的双工(双链DNA)以及该序列的互补序列。
“编码区”这一术语是指在基因的天然基因组环境中天然或正常编码该基因的表达产物的那部分基因,即,体内编码该基因的天然表达产物的区域。
编码区可来自非突变(“正常”)基因、突变基因或异常基因,甚至还可以来自DNA序列,完全可在实验室中使用本领域熟知的DNA合成方法合成。
“表达产物”这一术语是指多肽或蛋白,它是基因和遗传码退化并因而编码同样的氨基酸所造成的任何核酸序列编码同等物的翻译产物。
“片断”这一术语,当指的是一种编码序列时,表示包含非完整编码区的DNA的一部分,其表达产物与完整编码区表达产物基本上具有相同的生物学功能或活性。
“DNA片段”这一术语是指一种DNA聚合物,以单独的片段形式或一种较大DNA结构的组分形式存在,它们从至少分离过一次的DNA中以基本纯净的形式获得,即不含污染性内源性材料,并且获得的数量或浓度能够使用标准生化方法,例如使用克隆载体,进行识别、操纵和回收该片段及其组分核苷酸序列。此类片段以开放阅读框架(未被内部未翻译序列打断)或内含子(通常提呈于真核基因中)的形式存在。未翻译DNA序列可能存在于开放阅读框架的下游,在那里其不会干预编码区的操纵或表达。
“引物”这一术语表示一种短核酸序列,其可与一个DNA链配对,并在DNA聚合酶开始合成去氧核糖核酸链之处提供一个游离的3'-OH末端。
“启动子”这一术语表示参与RNA聚合酶的结合从而启动转录的DNA区域。
术语“分离”表示一种物质从其原来的环境(例如,如果是天然发生的则是天然环境)中被移走。例如,活体动物中的天然核苷酸或多肽不是分离的,但是,从天然系统中一些或所有共存物质中分离出来的核苷酸或多肽是分离的。此类多核苷酸可能是载体的一部分和/或此类多核苷酸和多肽可能是一种组合物的一部分,并且由于该载体或组合物不是其天然环境的一部分,因此它仍然是分离的。
本发明中披露的多核苷酸和重组或免疫原性多肽也可能以“纯化”的形式存在。术语“纯化”并非要求绝对的纯度;它只是一个相对的定义,可以包括高度纯化或部分纯化的制剂,相关领域技术人员能理解这些术语。例如,各个从已用传统方法纯化为具有电泳同质性的cDNA库中分离出的各种克隆物。明确考虑到将起始材料或天然物质纯化至少一个数量级,优选为两或三个数量级,更优选为四或五个数量级。此外,明确涵盖所述多肽的纯度优选为99.999%,或至少为99.99%或99.9%;甚而适宜为以重量计99%或更高。
根据本发明公开的核酸和多肽表达产物,以及包含此类核酸和/或多肽的表达载体可能以“浓缩的形式”存在。本文使用的术语“浓缩”是指材料的浓度至少是其自然浓度的大约2、5、10、100或1000倍,有优势的是,按重量计为0.01%,优选为至少0.1%。也明确考虑到,按重量计约为0.5%、1%、5%、10%和20%的浓缩制剂。序列、构型、载体、克隆物以及包含本发明的其他材料可有优势地以浓缩或分离的形式存在。“活性片段”这一术语是指产生免疫反应的片段(即具有免疫原性活性),通常是一种肽、多肽或核酸序列的片段,不论是单独或可选地与合适的佐剂一起或在载体中给予一种动物,比如哺乳动物,例如兔子或小鼠,也包括人;这种免疫反应采用的形式是在接受动物(如:人)体内刺激T细胞反应。或者,“活性片段”也可用于诱导体外T细胞反应。
本文使用的“部分”(portion)、“节段”(segment)、“片段”(fragment)这几个术语,当与多肽相关地使用时是指残基的连续序列,比如氨基酸残基,其序列形成一个较大序列的子集。例如,如果一个多肽以任一种肽链内切肽酶(如胰蛋白酶或糜蛋白酶)进行处理,则该处理获得的寡肽会代表起始多肽的部分、节段或片段。当与多核苷酸相关地使用时,这些术语系指用任何核酸内切酶处理所述多核苷酸产生的产物。
根据本发明,术语“等同度百分比”或“等同百分比”,如果指的是序列,则表示在待对比序列(“被对比序列”)与所述序列或权利要求的序列(“参考序列”)对准之后将被对比序列与所述序列或权利要求的序列进行比较。然后根据下列公式计算等同度百分比:等同度百分比=100[1-(C/R)]
其中C是参考序列与被对比序列之间对准长度上参考序列与被对比序列之间的差异数量,其中
(i)参考序列中每个堿基或氨基酸序列在被对比序列中没有对应的对准堿基或氨基酸;
(ii)参考序列中每个空隙,以及
(iii)参考序列中每个对准堿基或氨基酸与被比对比序列中对准堿基或氨基酸不同,即构成一个差异以及
(iiii)必须在对准序列的第1位置开始对准;
并且R是参考序列与被对比序列对准长度上在参考序列中产生任何空隙也计算为一个堿基或氨基酸的参考序列中的堿基或氨基酸数目。
如果“被对比序列”和“参考序列”之间存在的一个对准按上述计算的等同度百分比大致等于或大于指定的最低等同度百分比,则被对比序列与参考序列具有指定的最低等同度百分比,虽然可能存在按本文上述计算的等同度百分比低于指定等同度百分比的对准。
因此,如上所述,本发明提出了一种肽,其包括选自SEQ ID NO:1至SEQ ID NO:489群组的一个序列、或与SEQ ID NO:1至SEQ ID NO:489具有88%同源性的其变体、或诱导与该肽发生T细胞交叉反应的一个变体。本发明所述的肽具有与主要组织相容性复合体(MHC)I或所述肽拉长版本的II类分子结合的能力。
在本发明中,“同源性”一词系指两个氨基酸序列之间的同一度(参见上文的等同度百分比,如肽或多肽序列。前文所述的“同源”是透过将理想条件下调整的两个序列与待比较序列进行比对后确定的。此类序列同源性可透过使用ClustalW等演算法创建一个排列而进行计算。也可用使用一般序列分析软件,更具体地说,是Vector NTI、GENETYX或由公共资料库提供的其他工具。
本领域技术人员能评估特定肽变体诱导的T细胞是否可与该肽本身发生交叉反应(Appay et al.,2006;Colombetti et al.,2006;Fong et al.,2001;Zaremba et al.,1997)。
发明人用给定氨基酸序列的“变体”表示,一个或两个氨基酸残基等的侧链透过被另一个天然氨基酸残基的侧链或其他侧链取代而发生改变,这样,这种肽仍然能够以含有给定氨基酸序列(由SEQ ID NO:1至SEQ ID NO:489组成)的肽大致同样的方式与HLA分子结合。例如,一种肽可能被修饰以便至少维持(如没有提高)其能与HLA-A*02或-DR等合适MHC分子的结合槽相互作用和结合,以及至少维持(如没有提高)其与启动T细胞的TCR结合的能力。
随后,这些T细胞可与细胞和杀伤细胞发生交叉反应,这些细胞表达多肽(其中包含本发明中定义的同源肽的天然氨基酸序列)。正如科学文献和资料库(Rammensee etal.,1999;Godkin et al.,1997)中所述,HLA-A结合肽的某些位点通常为锚定残基,可形成一种与HLA结合槽的结合模序相称的核心序列,其定义由构成结合槽的多肽链的极性、电物理、疏水性和空间特性确定。因此,本领域技术人员能够透过保持已知的锚残基来修饰SEQID No:1至SEQ ID NO:489提出的氨基酸序列,并且能确定这些变体是否保持与MHC I或II类分子结合的能力。本发明的变体保持与启动T细胞的TCR结合的能力,随后,这些T细胞可与表达一种包含本发明定义的同源肽的天然氨基酸序列的多肽的细胞发生交叉反应并杀死该等细胞。
如果无另有说明,那么本文公开的原始(未修饰)肽可以透过在肽链内的不同(可能为选择性)位点上取代一个或多个残基而被修饰。优选情况是,这些取代位于氨基酸链的末端。此取代可能是保守性的,例如,其中一个氨基酸被具有类似结构和特点的另一个氨基酸所取代,比如其中一个疏水性氨基酸被另一个疏水性氨基酸取代。更保守的取代是具有相同或类似的大小和化学性质的氨基酸间的取代,例如,亮氨酸被异亮氨酸取代。在天然同源蛋白质家族序列变异的研究中,某些氨基酸的取代往往比其他氨基酸更具有耐受性,这些氨基酸往往表现出与原氨基酸的大小、电荷、极性和疏水性之间的相似性相关,这是确定“保守取代”的基础。
在本文中,保守取代定义为在以下五种基团之一的内部进行交换:基团1—小脂肪族、非极性或略具极性的残基(Ala,Ser,Thr,Pro,Gly);基团2—极性、带负电荷的残基及其醯胺(Asp,Asn,Glu,Gln);基团3—极性、带正电荷的残基(His,Arg,Lys);基团4—大脂肪族非极性残基(Met,Leu,Ile,Val,Cys)以及基团5—大芳香残基(Phe,Tyr,Trp)。
较不保守的取代可能涉及一个氨基酸被另一个具有类似特点但在大小上有所不同的氨基酸所取代,如:丙氨酸被异亮氨酸残基取代。高度不保守的取代可能涉及一个酸性氨基酸被另一个具有极性或什至具有碱性性质的氨基酸所取代。然而,这种“激进”取代不能认为是无效的而不予考虑,因为化学作用是不完全可预测的,激进的取代可能会带来其简单化学原理中无法预见的偶然效果。
当然,这种取代可能涉及普通L-氨基酸之外的其他结构。因此,D-氨基酸可能被本发明的抗原肽中常见的L-氨基酸取代,也仍在本公开的范围之内。此外,非标准氨基酸(即,除了常见的天然蛋白原氨基酸)也可以用于取代之目的,以生产根据本发明的免疫原和免疫原性多肽。
如果在一个以上位置上的取代发现导致肽的抗原活性基本上等于或大于以下定义值,则对这些取代的组合进行测试,以确定组合的取代是否产生对肽抗原性的叠加或协同效应。肽内被同时取代的位置最多不能超过4个。
基本上由本文所指氨基酸序列组成的一种肽可能有一个或两个非锚定氨基酸(见下面锚基序相关内容)被交换,而不存在这种情况,即相比于未修饰的肽,与人类主要组织相容性复合体(MHC)–I或II类分子的能力基本上被改变或受到不利影响。在另一实施方案中,在基本上由本文所述氨基酸序列组成的肽中,一个或两个氨基酸可与其保守交换伙伴交换(见下文),而不存在这种情况,即相比于未修饰的肽,与人类主要组织相容性复合体(MHC)–I或II类分子的能力基本上被改变或受到不利影响。
这些基本不与T细胞受体互动的氨基酸残基可透过取代其他几乎不影响T细胞反应并不妨碍与相关MHC结合的氨基酸而得到修饰。因此,除了特定限制性条件外,本发明的肽可能为任何包括给定氨基酸序列或部分或其变体的肽(发明人所用的这个术语包括寡肽或多肽)。
表6:根据SEQ ID NO:4、13、90.93、138、171、202、204、224、294、306、316、322和327的肽的变体和基序
较长(拉长)的肽也可能适合。MHC I类表位(通常长度为8至11个氨基酸)可能由肽从较长的肽或包含实际表位的蛋白中加工而产生。两侧有实际表位的残基优选为在加工过程中几乎不影响暴露实际表位所需蛋白裂解的残基。
本发明的肽可被拉长多达四个氨基酸,即1、2、3或4个氨基酸,可按照4:0与0:4之间的任何组合添加至任意一端。本发明的拉长组合可见表7。
表7:本发明肽的拉长组合
C-端 | N-端 |
4 | 0 |
3 | 0或1 |
2 | 0或1或2 |
1 | 0或1或2或3 |
0 | 0或1或2或3或4 |
N-端 | C-端 |
4 | 0 |
3 | 0或1 |
2 | 0或1或2 |
1 | 0或1或2或3 |
0 | 0或1或2或3或4 |
拉伸/延长的氨基酸可以是所述蛋白或任何其他氨基酸的原序列肽。拉长可用于增强所述肽的稳定性或溶解性。
因此,本发明所述的表位可能与天然肿瘤相关表位或肿瘤特异性表位相同,也可能包括来自参考肽的不超过四个残基的不同肽,只要它们有基本相同的抗原活性。
在一项替代实施方案中,肽的一边或双边被拉长4个以上的氨基酸,优选最多30个氨基酸的总长度。这可形成MHC-II类结合肽。结合至MHC II类肽可透过本领域中已知的方法进行测试。
因此,本发明提出了MHC I类表位的肽和变体,其中所述肽或变体的总长度为8至100、9至100、10至100、11至100、12至100,优选为8至30、9至30、10至30、11至30、12至30,最优选为8至14、9至14、10至14、11至14、12至14。本发明进一步提出了MHC I类表位的肽和变体,其中所述肽或抗体的总长度为8、9、10、11、12、13或14个氨基酸,为伸长II类结合肽时,所述长度也可为15、16、17、18、19、20、21或22个氨基酸。
当然,本发明的肽或变体能与人主要组织相容性复合体(MHC)I或II类分子结合。肽或变体与MHC复合物的结合可用本领域内的已知方法进行测试。
优选情况是,当本发明的肽特异性T细胞相比于取代肽受到检测时,如果取代肽在相对于背景肽溶解度增加达到最大值的一半,则该肽浓度不超过约1mM,优选为不超过约1μM,更优选为不超过约1nM,再优选为不超过约100pM,最优选为不超过约10pM。也优选为,取代肽被一个以上的T细胞识别,最少为2个,更优选为3个。
在本发明的一个特别优选实施方案中,肽系由或基本系由根据SEQ ID NO:1至SEQID NO:489所选的氨基酸序列组成。
基本由“...组成”系指本发明的肽,除了根据SEQ ID NO:1至SEQ ID NO:489中的任一序列或其变体组成外,还含有位于其他N和/或C端延伸处的氨基酸,而它们不一定能形成作为MHC分子表位的肽。
但这些延伸区域对有效将本发明中的肽引进细胞具有重要作用。在本发明的一实施例中,该肽为融合蛋白的一部分,含来自NCBI、GenBank登录号X00497的HLA-DR抗原相关不变链(p33,以下称为“Ii”)的80个N-端氨基酸等。在其他的融合中,本发明的肽可以被融合到本文所述的抗体、或其功能性部分,特别是融合入抗体的序列,以便所述抗体进行特异性靶向作用,或者,例如进入本文所述的树突状细胞特异性抗体。
此外,该肽或变体可进一步修饰以提高稳定性和/或与MHC分子结合,从而引发更强的免疫反应。肽序列的该类优化方法是本领域内所熟知的,包括,例如,反式肽键和非肽键的引入。
在反式肽键氨基酸中,肽(-CO-NH-)并未连接其残基,但是其肽键是反向的。这种逆向反向模拟肽(retro-inverso peptidomimetics)可透过本领域已知的方法制备,例如:Meziere等人在(Meziere et al.,1997)中所述的方法,以引用的方式并入本文。这种方法涉及制备包含骨架(而并非侧链)改变的模拟肽。Meziere等人(Meziere et al.,1997)的研究显示,这些类比肽有利于MHC的结合和辅助性T细胞的反应。以NH-CO键替代CO-NH肽键的逆向反向肽大大地提高了抗水解性能。
非肽键为-CH2-NH、-CH2S-、-CH2CH2-、-CH=CH-、-COCH2-、-CH(OH)CH2-和-CH2SO-等。美国4897445号专利提出了多肽链中非肽键(-CH2-NH)的非固相合成法,该方法涉及按标准程序合成的多肽以及透过氨基醛和一种含NaCNBH3的氨基酸相互作用而合成的非肽键。
含上述序列的肽可与其氨基和/或羧基末端的其他化学基团进行合成,从而提高肽的稳定性、生物利用度、和/或亲和力等。例如,苄氧羰基、丹醯基等疏水基团或叔丁氧羰基团可加入肽的氨基末端。同样,乙醯基或9-芴甲氧羰基可能位于肽的氨基末端。此外,疏水基团、叔丁氧羰基团或氨基团都可能被加入肽的羧基末端。
另外,本发明中的所有肽都可能经合成而改变其空间构型。例如,可能使用这些肽的一个或多个氨基酸残基的右旋体,通常不是其左旋体。更进一步地,本发明中肽的至少一个氨基酸残基可被熟知的一个非天然氨基酸残基取代。诸如此类的改变可能有助于增加本发明肽的稳定性、生物利用度和/或结合作用。
同样,本发明中的肽或变体可在合成肽之前或之后透过特异氨基酸的反应而进行化学修饰。此类修饰的实施例为本领域所熟知,例如,在R.Lundblad所著的《ChemicalReagents for Protein Modification》(3rd ed.CRC Press,2004)(Lundblad,2004)中有概述,以参考文献的方式并入本文。虽然氨基酸的化学修饰方法无限制,但其包括(但不限于)透过以下方法修饰:醯基化、脒基化、赖氨酸吡哆基化、还原烷基化、以2,4,6-三硝基苯磺酸(TNBS)三硝基苯基化氨基团、透过将半胱氨酸过甲酸氧化为磺基丙氨酸而对羧基团和巯基进行氨基修饰、形成易变衍生物、与其他巯基化合物形成混合二硫化合物、与马来醯亚胺反应,与碘乙酸或碘乙醯胺羧甲基化、在碱性pH值下与氰酸盐甲氨醯化。在这方面,技术人员参考了《Current Protocols In Protein Science》(Eds.Coligan et al.(JohnWiley and Sons NY 1995-2000))(Coligan et al.,1995)中第15章所述的在蛋白质化学修饰相关的广泛方法。
简言之,修饰蛋白质的精氨醯残基等往往基于于邻二羰基化合物(如苯甲醯甲醛、2,3–丁二酮以及1,2-烯巳二酮)的反应而形成加合物。另一个实施例是丙酮醛与精氨酸残基的反应。半胱氨酸可在赖氨酸和组氨酸等亲核位点不作随同修饰的情况下就得到修饰。因此,有大量试剂可进行半胱氨酸的修饰。Sigma-Aldrich(http://www.sigma-aldrich.com)等公司的网站含有具体试剂的资讯。
蛋白质中二硫键的选择性还原也很普遍。二硫键可在生物制药热处理中形成和氧化。伍德沃德氏试剂K可用于修饰特定的谷氨酸残基。N-(3-二甲氨基丙基)-N′-乙基-碳二亚胺可用于形成赖氨酸残基和谷氨酸残基的分子内交联。例如:焦碳酸二乙酯是修饰蛋白质组氨酸残基的试剂。组氨酸也可使用4-羟基-2-壬烯醛进行修饰。赖氨酸残基与其他α-氨基团的反应,例如,有利于肽结合到蛋白/肽的表面或交联处。赖氨酸聚是多(乙烯)乙二醇的附着点,也是蛋白质糖基化的主要修饰位点。蛋白质的蛋氨酸残基可透过碘乙醯胺、溴乙胺、氯胺T等被修饰。
四硝基甲烷和N-乙醯基咪唑可用于酪氨酸残基的修饰。经二酪氨酸形成的交联可透过过氧化氢/铜离子完成。
对色氨酸修饰的最近研究中使用了N-溴代琥珀醯亚胺、2-羟基-5-硝基苄溴或3-溴-3-甲基-2-(2–硝苯巯基)-3H-吲哚(BPNS-粪臭素)。
当蛋白与戊二醛、聚乙二醇二丙烯酸酯和甲醛的交联用于配制水凝胶时,治疗性蛋白和含聚乙二醇的肽的成功修饰往往可延长回圈半衰期。针对免疫治疗的变态反应原化学修饰往往透过氰酸钾的氨基甲醯化实现。
一种肽或变体,其中肽被修饰或含非肽键,优选为本发明的实施例。
本发明的另一实施方案涉及一种非天然肽,其中所述肽系由或基本系由根据SEQID No:1至SEQ ID No:489的一个氨基酸序列组成,幷经合成产生(即,合成)为一种药用盐。合成产生肽的方法是本领域公知的。本发明肽的盐与其体内状态的肽基本上不同,因为这些体内产生的肽不是盐。该肽的非天然盐形式介导肽的溶解度,特别是包含所述肽的药物组合物的情况下,例如,本文所公开的肽疫苗。为了向需治疗的受试者有效地提供肽,需要肽具有充分、至少基本的溶解度。优选地,盐为肽的药用盐。本发明的这些盐包括碱和碱土盐类,诸如Hofmeister系列的盐,包含阴离子PO4 3-、SO4 2-、CH3COO-、Cl-、Br-、NO3 -、ClO4 -、I-、SCN-和阳离子NH4 +、Rb+、K+、Na+、Cs+、Li+、Zn2+、Mg2+、Ca2+、Mn2+、Cu2+和Ba2+。特别地,盐选自(NH4)3PO4、(NH4)2HPO4、(NH4)H2PO4、(NH4)2SO4、NH4CH3COO、NH4Cl、NH4Br、NH4NO3、NH4CIO4、NH4I、NH4SCN、Rb3PO4、Rb2HPO4、RbH2PO4、Rb2SO4、Rb4CH3COO、Rb4Cl、Rb4Br、Rb4NO3、Rb4CIO4、Rb4I、Rb4SCN、K3PO4、K2HPO4、KH2PO4、K2SO4、KCH3COO、KCl、KBr、KNO3、KClO4、KI、KSCN、Na3PO4、Na2HPO4、NaH2PO4、Na2SO4、NaCH3COO、NaCl、NaBr、NaNO3、NaCIO4、NaI、NaSCN、ZnCI2Cs3PO4、Cs2HPO4、CsH2PO4、Cs2SO4、CsCH3COO、CsCl、CsBr、CsNO3、CsCIO4、CsI、CsSCN、Li3PO4、Li2HPO4、LiH2PO4、Li2SO4、LiCH3COO、LiCl、LiBr、LiNO3、LiClO4、LiI、LiSCN、Cu2SO4、Mg3(PO4)2、Mg2HPO4、Mg(H2PO4)2、Mg2SO4、Mg(CH3COO)2、MgCl2、MgBr2、Mg(NO3)2、Mg(ClO4)2、MgI2、Mg(SCN)2、MnCl2、Ca3(PO4),、Ca2HPO4、Ca(H2PO4)2、CaSO4、Ca(CH3COO)2、CaCl2、CaBr2、Ca(NO3)2、Ca(ClO4)2、CaI2、Ca(SCN)2、Ba3(PO4)2、Ba2HPO4、Ba(H2PO4)2、BaSO4、Ba(CH3COO)2、BaCl2、BaBr2、Ba(NO3)2、Ba(ClO4)2、BaI2和Ba(SCN)2。特别优选为NH乙酸、MgCl2、KH2PO4、Na2SO4、KCl、NaCl和CaCl2,例如:氯化物或乙酸盐(三氟乙酸)盐。
一般来说,肽和变体(至少含氨基酸残基之间的肽联接)可使用Lukas等人(Lukaset al.,1981)以及此处引用的参考文献所披露的固相肽合成Fmoc-聚醯胺模式进行合成。芴甲氧羰基(Fmoc)团对N-氨基提供临时保护。使用N,N-二甲基甲醯胺中的20%二甲基呱啶中对这种堿高度敏感的保护基团进行重复分裂。由于它们的丁基醚(在丝氨酸苏氨酸和酪氨酸的情况下)、丁基酯(在谷氨酸和天门冬氨酸的情况下)、叔丁氧羰基衍生物(在赖氨酸和组氨酸的情况下)、三苯甲基衍生物(在半胱氨酸的情况下)及4-甲氧基-2,3,6-三甲基苯磺醯基衍生物(在精氨酸的情况下),侧链功能可能会受到保护。只要谷氨醯胺和天冬醯胺为C-末端残基,侧链氨基功能保护所使用的是由4,4'-二甲氧基二苯基团。固相支撑基于聚二甲基丙烯醯胺聚合物,其由三个单体二甲基丙烯醯胺(骨架单体)、双丙烯醯乙烯二胺(交联剂)和N-丙烯醯肌胺酸甲酯(功能剂)构成。使用的肽-树脂联剂为酸敏感的4-羟甲基苯氧乙酸衍生物。所有的氨基酸衍生物均作为其预制对称酸酐衍生物加入,但是天冬醯胺和谷氨醯胺除外,它们使用被逆转的N,N-二环己基碳二亚胺/1-羟基苯并三唑介导的耦合程序而加入。所有的耦合和脱保护反应用茚三酮、硝基苯磺酸或isotin测试程序监测。合成完成后,用浓度为95%含50%清道夫混合物的三氟醋酸,从伴随去除侧链保护基团的树脂支承物中裂解肽。常用的清道夫混合物包括乙二硫醇、苯酚、苯甲醚和水,准确的选择依据合成肽的氨基酸组成。此外,固相和液相方法结合使用对肽进行合成是可能的(例如,请参阅(Bruckdorfer et al.,2004)以及本文引用的参考文献)
三氟乙酸用真空中蒸发、随后用承载粗肽的二乙基乙醚滴定进行去除。用简单萃取程序(水相冻干后,该程序制得不含清道夫混合物的肽)清除任何存在的清道夫混合物。肽合成试剂一般可从Calbiochem-Novabiochem(英国诺丁汉)获得。
纯化可透过以下技术的任何一种或组合方法进行,如:再结晶法、体积排阻色谱法、离子交换色谱法、疏水作用色谱法以及(通常)反相高效液相色谱法(如使用乙腈/水梯度分离)。
可以使用薄层色谱法、电泳特别是毛细管电泳、固相萃取(CSPE)、反相高效液相色谱法、酸解后的氨基酸分析、快原子轰击(FAB)质谱分析以及MALDI和ESI-Q-TOF质谱分析进行肽分析。
为了选择过度提呈的肽,计算了提呈图,其显示样本中位元提呈量以及复制变化。该特点使相关肿瘤实体的样本与正常组织样本的基线值并列。可透过计算调节线性混合效应模型(Pinheiro et al.,2015)的p值将以上每个特点并入过度提呈分数中,从而透过假发现率(Benjamini and Hochberg,1995)调整多项检验(参考实施例1、图1)。
对于透过质谱法对HLA配体的识别和相对定量,对来自冲击冷冻组织样本的HLA分子进行纯化并对HLA相关肽进行分离。分离的肽分开,并透过线上纳米-电喷雾-电离(nanoESI)液相色谱-谱(LC-MS)实验进行鉴定。由此产生的肽序列的验证方法是,将肺癌(包括NSCLC和SCLC)样本(N=201个样本)中记录的自然肿瘤相关肽(TUMAP)的片段模式与相同序列相应合成参考肽的片段模式进行比较。由于这些肽被直接鉴定为原发肿瘤HLA分子的配体,因此这些结果为来自201名肺癌(包括NSCLC和SCLC)患者的原发性癌组织上确定肽的自然加工和提呈提供了直接证据。
发现管道v2.1(例如,参见US 2013-0096016,并在此透过引用将其整体并入本文)考虑到识别和选择相关过量提呈的候选肽疫苗,这基于与几种不同的非癌组织和器官相比癌症或其他受感染组织的HLA限制肽水平直接相对定量结果。这透过以下方法实现:使用专有资料分析管道处理的LC-MS采集资料、结合序列识别演算法、谱聚类、计算离子、保留时间调整、充电状态卷积以及正态化而开发无标记差异化定量方法。
为每种肽和样本确立了提呈水平,包括误差估计值。肿瘤组织大量提呈的肽以及肿瘤与非肿瘤组织和器官中过量提呈的肽已经得到确定。
对来自肺癌(包括NSCLC和SCLC)组织样本的HLA肽复合物进行纯化,并且对HLA相关肽使用LC-MS进行分离和分析(见实施例1)。本申请中包含的所有TUMAP使用肺癌(包括NSCLC和SCLC)样本的方法进行鉴定,确认其在肺癌(包括NSCLC和SCLC)上的提呈。
在多个肺癌(包括NSCLC和SCLC)和正常组织上确定的TUMAP用无标记LC-MS资料的离子计数方法进行量化。该方法假定肽的LC-MS信号区域与样本中其丰度相关。各种LC-MS实验中肽的所有量化信号在集中趋势基础上进行正常化,根据每个样品进行平均,并且合并入柱状图(被称为提呈图)。提呈图整合了不同分析方法,如:蛋白资料库检索、谱聚类、充电状态卷积(除电)和保留时间校准和正态化。
除了过量提呈肽之外,也测试了潜在基因的mRNA表达。mRNA资料透过RNA测序分析正常组织和癌组织获得(参考实施例2、图2)。正常组织资料的额外来源是从3000个正常组织样本可公开获得的RNA表达资料的资料库(Lonsdale,2013)。获得自蛋白的肽在癌组织中显示高表达编码mRNA,但是在重要正常组织中非常低或不存在,这些肽作为优选肽纳入本发明。
本发明提出了有利于治疗癌症/肿瘤,优选为治疗过量提呈或只提呈本发明肽的肺癌(包括NSCLC和SCLC)。这些肽由质谱分析法直接显示出,而由HLA分子自然提呈于人原发性人肺癌(包括NSCLC和SCLC)样本中。
与正常组织相比,癌症中高度过量表达肽来源的许多源基因/蛋白质(也指定为“全长蛋白”或“潜在蛋白”)-本发明相关的“正常组织”是健康肺细胞或其他正常组织细胞,这表明肿瘤与这些源基因的高度关联性(见实施例2)。此外,这些肽本身也在肿瘤组织中过度提呈(本发明相关的“肿瘤组织”是指来自肺癌(包括NSCLC和SCLC)患者的样本),但不在正常组织中过度提呈(见实施例1)。
HLA结合肽能够被免疫系统识别,特别是T淋巴细胞。T细胞可破坏提呈被识别HLA/肽复合体的细胞,如:提呈衍生肽的肺癌(包括NSCLC和SCLC)细胞。
本发明的所有肽已被证明具有刺激T细胞反应的能力,并过量提呈,因而可用于制备本发明的抗体和/或TCR,例如可溶性TCR(参见实施例3和实施例4)。此外,肽与相应的MHC组合时,也可用于制备本发明的抗体和/或TCR,特别是sTCR。各个方法均为技术人员所熟知,并在各个文献中可找到(也参见下文)。因此,本发明的肽可用于在患者中产生免疫反应,从而能够毁灭肿瘤细胞。患者的免疫反应能够透过直接给予患者所述肽或前体物质(如,加长肽、蛋白或编码这些肽的核酸),较理想是与加强免疫原性的制剂相结合,而进行诱导。源自该治疗性疫苗的免疫反应预期能够高度特异性地对抗肿瘤细胞,因为本发明的目标肽在正常组织上提呈的复制数目较少,防止患者发生对抗正常细胞的不良自体免疫反应的风险。
本说明书还涉及包含一个α链和一个β链(“α/βTCR”)的T细胞受体(TCR)。还提供了由MHC分子提呈时可与TCR和抗体结合的本发明的肽。
本说明书还涉及由HLA分子提呈能够与本发明的肽抗原结合的本发明的TCR片段。该术语特别涉及可溶性TCR片段,例如缺失跨膜部分和/或恒定区的TCR、单链TCR及其与例如Ig的融合物。
本说明书还涉及核酸、载体和用于表达TCR的宿主细胞和本说明书的肽;以及使用它们的方法。
术语“T细胞受体”(缩写TCR)是指一种异二聚体分子,其包含一个α多肽链(α链)和一个β多肽链(β链),其中所述异二聚体受体能够结合由HLA分子提呈的肽抗原。该术语还包括所谓的γ/δTCR。
在一个实施方案中,本说明书提供了如本文中所描述的产生TCR的方法,该方法包括在适于促进TCR表达的条件下培养能够表达TCR的宿主细胞。
另一个方面,本说明书涉及一种根据本说明书的方法,其中所述抗原透过与足够量的含抗原提成细胞的抗原结合被载入表达于合适抗原提呈细胞或人工抗原呈递细胞表面的I或II类MHC分子,或该抗原透过四聚化被载入I或II类MHC四聚体/I或II类MHC复合单体。α/βTCR的α和β链和γ/δTCR的γ和δ链通常被视为各自有两个“结构域”,即可变和恒定结构域。可变结构域由可变区(V)和连接区(J)的组合。可变结构域还可能包括一个前导区(L)。β和δ链还可能包括一个多样区(D)。α和β恒定结构域还可能包括锚定α和β链至细胞膜的C末端跨膜(TM)结构域。
相对于γ/δ的TCR,如本文所用的术语“TCRγ可变域”是指无前导区(L)的TCRγV(TRGV)区与TCRγ(TRGJ)区的组合,术语TCRγ恒定结构域是指细胞外TRGC区域,或C-末端截短TRGC序列。同样地,“TCRδ可变域”是指无前导区(L)的TCRδV(TRDV)区与TCRδD/J(TRDD/TRDJ)区的组合,术语“TCRδ恒定结构域”是指细胞外TRDC区域,或C-末端截短TRDC序列。
本说明书的TCR优选结合至肽HLA分子复合体,其具有约100μM或更小、约50μM或更小、约25μM或更小或约10μM或更小的结合亲和力(KD)。更为优选的情况是具有约1μM或更小、约100nM或更小、约50nM或更小或约25nM或更小结合亲和力的高亲和力TCR。本发明TCR优选结合亲和力范围的非限制性示例包括约1nM至约10nM;约10nM至约20nM;约20nM至约30nM;约30nM至约40nM;约40nM至约50nM;约50nM至约60nM;约60nM至约70nM;约70nM至约80nM;约80nM至约90nM;以及约90nM至约100nM。
与本说明书TCR相关,本文使用的“特异性结合”及其语法变体用于表示对100μM或更小的肽-HLA分子复合体有结合亲和力(KD)的TCR。
本说明书的α/β异二聚体TCR可能具有其恒定结构域之间的引入二硫键。这种类型的优选TCR包括那些具有一个TRAC恒定域序列和TRBC1或TRBC2恒定域序列的TCR,除非TRAC的苏氨酸48和TRBC1或TRBC2的丝氨酸57被半胱氨酸残基取代,所述半胱氨酸形成TRAC恒定域序列和TCR的TRBC1或TRBC2恒定区序列之间的二硫键。
不论具有或不具有上述的引入链间键,本说明书的α/β杂二聚体TCR可能具有一个TRAC恒定域序列和一个TRBC1或TRBC2恒定结构域序列,并且TRAC恒定结构域序列和TCR的TRBC1或TRBC2恒定结构域序列可能透过TRAC外显子2的Cys4和TRBC1或TRBC2外显子2的Cys4之间的天然二硫键相连。
本说明书的TCR可能包括选自由放射性核素、萤光团和生物素组成组中的可检测标记。
本说明书的TCR可能共轭至治疗活性剂,如放射性核素、化学治疗剂或毒素。
在一个实施方案中,具有在α链中至少一个突变和/或具有在β链中至少一个突变的TCR与未突变的TCR相比,已经修改了糖基化。
在一个实施方案中,在TCRα链和/或TCRβ链中包括至少一个突变的TCR对肽HLA分子复合体有结合亲和力和/或结合半衰期,其是包含未突变TCRα链和/或未突变TCRβ链的TCR的结合亲和力的至少两倍。肿瘤特异性TCR亲和力增强及其开发依赖于存在最佳TCR亲和力的窗口。这样窗口的存在是根据观察结果:HLA-A2限制性病原体特异性TCR与HLA-A2限制性肿瘤相关自身抗原特异性TCR相比,KD值通常大约低10倍。对于与肿瘤相关的自身抗原相比限制于其他等位基因的特异于病原基因的TCR,KD值可能在稍微不同的范围内,但是不同等位基因之间在创建TCR的可能性方面一般无差异。现已知,尽管肿瘤抗原可能具有免疫原性,但是因为肿瘤来自个体自身的细胞,因此仅突变蛋白质或翻译加工改变的蛋白将被免疫系统视为外来物质。上调或过度表达(所谓的自体抗原)的抗原不一定诱导针对肿瘤的功能免疫应答:表达对这些抗原具有高度反应性的TCR的T细胞会在一种称为中枢耐受的程序中在胸腺内被不利选择,也就是说只有对自身抗原具有低亲和力TCR的细胞才仍然存在。因此,本说明书的TCR或变体对肽的亲和力可透过本领域熟知的方法来增强。
本说明书还涉及一种识别和分离本发明TCR的一种方法,所述方法包括:用HLA/肽单体孵育来自目前等位基因呈阴性的健康捐赠者的PBMC,用四聚体-藻红蛋白(PE)孵育PBMC并透过萤光启动细胞分选(FACS)–Calibur方法分析分离高亲和力T细胞。
本说明书还涉及一种识别和分离本发明TCR的一种方法,所述方法包括:获得含整个人体TCRαβ基因位点(1.1and 0.7Mb)的转基因小鼠(其T细胞表达多样化人类TCR,用于补偿小鼠TCR缺乏),用肽对小鼠进行免疫处理,用四聚体-藻红蛋白(PE)孵育从转基因小鼠中获得的PBMC,并透过萤光启动细胞分选(FACS)–Calibur方法分析分离高亲和力T细胞。
一方面,为了获得表达本说明书TCR的T细胞,编码本说明书TCR-α和/或TCR-β链的核酸被克隆入表达载体,诸如γ反转录病毒或慢病毒。重组病毒产生,然后测试功能,如抗原专一性和功能性亲合力。然后,最终产品的等分试样被用于转导靶T细胞群体(一般纯化自患者的PBMC),在输入患者前展开。另一方面,为了获得表达本说明书TCR的T细胞,TCRRNA透过本领域中已知的技术(例如,体外转录系统)合成。然后,体外合成的TCR RNA透过电穿孔来重新表达肿瘤特异性TCR-α和/或TCR-β链被引入获得自健康供体的初级CD8+T细胞。
为了增加表达,编码本说明书TCR的核酸在操作上可连接到强启动子,例如逆转录病毒长末端重复序列(LTR)、巨细胞病毒(CMV)、鼠干细胞病毒(MSCV)U3、磷酸甘油酸激酶(PGK)、β肌动蛋白、泛素蛋白和猿猴病毒40(SV40)/CD43复合启动子、延伸因子(EF)-1a和脾脏病灶形成病毒(SFFV)启动子。在一优选实施方案中,启动子与被表达的核酸异源。除了强启动子外,本说明书的TCR表达盒可能含有附加的元素,可提高转基因表达,包括中枢多聚嘌呤区(CPPT),其促进了慢病毒构建体的核易位(Follenzi et al.,2000),和土拨鼠肝炎病毒转录后调控元素(WPRE),其透过提高RNA稳定性增加转基因表达水平(Zufferey etal.,1999)。
本发明TCR的α和β链可由位于分开的载体核酸进行编码,或者可透过位于同一载体的多核苷酸编码。
实现高水平的TCR表面表达需要引入TCR的TCR-α和TCR-β链高水平转录。为了实现它,本说明书的TCR-α和TCR-β链可在单一的载体中被克隆入双顺反子构建体,其已被证明能够克服这一障碍。使用TCR-α和TCR-β链在之间的病毒核糖体间进入位元点(IRES)导致两链的协同表达,因为TCR-α和TCR-β链均由在翻译过程中分成两个蛋白质的单一转录物产生,从而确保了产生TCR-α和TCR-β链的相等摩尔比。(Schmitt et al.2009)。
编码本说明书TCR的核酸可以是被优化以从宿主细胞增加表达的密码子。遗传密码冗余让一些氨基酸被一个以上的密码子编码,但某些密码子没有其他密码子“优化”,因为匹配tRNA以及其他因子的相对可用性(Gustafsson et al.,2004)。修改TCR-α和TCR-β基因序列使得每个氨基酸被用于哺乳动物基因表达的最佳密码子编码,以及消除mRNA不稳定性基序或隐蔽剪接位元点,已显示可显著提高TCR-α和TCR-β基因表达(Scholten et al.,2006)。
此外,引入的和内源性TCR链之间的错配可能会导致获得特异性,其构成自身免疫的显著风险。例如,混合TCR二聚体的形成可能会减少可用以形成正确配对TCR复合体的CD3分子数目,因此,可以显著降低表达所引入TCR的细胞的功能性亲合力(Kuball et al.,2007)。
为了减少错配,本说明书引入的TCR链的C-末端结构域可以进行修改以促进链间亲和力,同时降低引入链与内源TCR配对的能力。这些策略可能包括用鼠配对物取代人类TCR-α和TCR-βC端结构域(鼠化C端结构域);透过引入第二个半胱氨酸残基到引入TCR的TCR-α和TCR-β链产生C末端结构域的第二个链间二硫键(半胱氨酸修饰);交换TCR-α和TCR-β链C端结构域的相互作用残基(“杵臼结构”);直接融合TCR-α和TCR-β链可变结构域至CD3ζ(CD3ζ融合)(Schmitt et al.2009)。
在一实施方案中,宿主细胞被改变结构以表达本说明书的TCR。在一优选实施方案中,宿主细胞为人T细胞或T细胞祖细胞。在一些实施方案中,T细胞或T细胞祖细胞从癌症患者中获得。在另一些实施方案中,T细胞或T细胞祖细胞从健康供体中获得。本说明书的宿主细胞相对于待治疗的患者可以为同种异体或自体的。在一实施方案中,宿主是被转化以表达α/βTCR的γ/δT细胞。
“药物组合物”是指适合在医疗机构用于人体的组合物。优选地,药物组合物为无菌状态,并根据GMP指南生产。
药物组合物包括游离形式或以一种药用盐形式存在的肽(也参见上文)。一方面,本文所述的肽为药用盐的形式。另一方面,药用盐形式的肽为结晶形式。
一方面,本文所述的药用盐是指具有在药物应用可接受范围内毒性特征的盐。
此处使用的“药用盐”系指所公开的肽的一种衍生物,其中该肽由制酸或药剂的堿盐进行改性。例如,用与适合的酸反应的游离堿(通常其中的中性药物有一个中性–NH2基团)制备酸式盐。适合制备酸盐的酸包括有机酸,如:乙酸、丙酸、羟基酸、丙酮酸、草酸、苹果酸、丙二酸、丁二酸、马来酸、富马酸、酒石酸、柠檬酸、苯甲酸酸、肉桂酸、扁桃酸、甲磺酸、甲磺酸、苯磺酸、水杨酸等等、以及无机酸,如:盐酸、氢溴酸、硫酸、硝酸和磷酸等。相反,可在一种肽上提呈的酸性基团的堿盐制剂使用药用堿基进行制备,如氢氧化钠、氢氧化钾、氢氧化铵、氢氧化钙、三甲胺等等。
一方面,药用盐可提高本文所述肽的溶解度和/或稳定性。另一方面,本文所述的药用盐可透过常规方法由相应的载体肽或复合体制备,方法例如用本文所述的肽或复合体与适当的酸或堿发生反应。另一方面,药用盐为结晶形式或半结晶形式。另一方面,药用盐可以包括例如:PH Stahl和CG Wermuth所著的《Handbook of Pharmaceutical Salts:Properties,Selection,and Use》(药用盐手册:特征、选择和使用)(Wiley-VCH 2002),LDBighley,SM Berge,DC Monkhouse,《Encyclopedia of Pharmaceutical Technology》(制剂技术百科全书).Eds.J.Swarbrick and JC Boylan,Vol.13,Marcel Dekker,Inc.,NewYork,Basel,Hong Kong 1995,pp.453-499,各参考文献透过引用整体并入本文。
在特别优选的实施方案中,药物组合物包括乙酸(醋酸盐),三氟乙酸盐或盐酸(氯化物)形式的肽。
本发明中所述的药剂优选为一种免疫治疗药剂,例如,一种疫苗。该疫苗可直接给到患者的受影响器官,也可id、im、sc、ip和iv注射方式全身给药,或体外应用到来自患者或其细胞株的细胞(随后再将这些细胞注入到患者中),或体外用于从来自患者的免疫细胞的一个细胞亚群(然后再将细胞重新给予患者)。如果核酸体外注入细胞,可能有益于细胞转染,以共同表达免疫刺激细胞因子(如白细胞介素-2)。肽可完全单独给药,也可与免疫刺激佐剂相结合(见下文)、或与免疫刺激细胞因子联合使用、或以适当的输送系统给药(例如脂质体)。该肽也可共轭形成一种合适的载体(如钥孔虫戚血蓝蛋白(KLH)或甘露)到合适的载体(参阅WO 95/18145及(Longenecker et al.,1993))。肽也可能被标记,可能是融合蛋白,或可能是杂交分子。在本发明中给出序列的肽预计能刺激CD4或CD8T细胞。然而,在有CD4T-辅助细胞的帮助时,CD8 T细胞刺激更加有效。因此,对于刺激CD8 T细胞的MHC-I类表位,一种杂合分子的融合伙伴或片段提供了刺激CD4阳性T细胞的适当表位。CD4-和CD8刺激表位为本领域所熟知、并包括本发明中确定的表位。一方面,疫苗包括至少含有SEQ ID NO:1至SEQ ID NO:489中提出的一种肽以及至少另外一种肽,优选为2至50个、更优选为2至25个、再优选为2至20个、最优选为2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17或18个肽。肽可能从一个或多个特定TAA中衍生,并且可能与MHC I类分子结合。
另一方面,本发明提出了一种编码本发明中肽或肽变体的核酸(如多聚核苷酸)。多聚核苷酸可能为,例如,DNA、cDNA、PNA、RNA或其组合物,它们可为单链和/或双链、或多聚核苷酸的原生或稳定形式(如:具有硫代磷酸骨架的多聚核苷酸),并且只要它编码肽,就可能包含也可能不包含内含子。当然,多聚核苷酸只能编码加入天然肽键并含有天然氨基酸残基的肽。另一个方面,本发明提出了一种可根据本发明表达多肽的表达载体。
对于连接多核苷酸,已经开发出多种方法,尤其是针对DNA,可透过向载体补充可连接性末端等方法进行连接。例如,可向DNA片段加入补充性均聚物轨道,之后DNA片段被插入到载体DNA。然后,透过补充性均聚物尾巴的氢键结合,将载体和DNA片段结合,从而形成重组DNA分子。
含有一个或多个酶切位点的合成接头为DNA片段与载体连接提供了另一种方法。含各种限制性核酸内切酶的合成接头可透过多种管道购得,其中包括从国际生物技术公司(International Biotechnologies Inc,New Haven,康涅狄格州,美国)购得。
编码本发明多肽的DNA理想修饰方法是使用Saiki等人(Saiki et al.,1988)所采用的聚合酶链反应方法。此方法可用于将DNA引入合适的载体(例如,透过设计合适的酶切位点),也可用于本领域已知的其他有用方法修饰DNA。如果使用病毒载体,痘病毒载体或腺病毒载体为优选。
之后,DNA(或在逆转录病毒载体情况下,RNA)可能表达于合适的宿主,从而制成含本发明肽或变体的多肽。因此,可根据已知技术使用编码本发明肽或变体的DNA,用本文所述方法适当修饰后,构建表达载体,然后表达载体用于转化合适宿主细胞,从而表达和产生本发明中的多肽。此类技术包括那些公开于,例如,美国专利4,440,859、4,530,901、4,582,800、4,677,063、4,678,751、4,704,362、4,710,463、4,757,006、4,766,075和4,810,648。
编码含本发明化合物多肽的DNA(或在逆转录病毒载体情况下,RNA)可能被加入到其他多种DNA序列,从而引入到合适的宿主中。同伴DNA将取决于宿主的性质、DNA引入宿主的方式、以及是否需要保持为游离体还是要相互结合。
一般来说,DNA可以适当的方向和正确的表达阅读框架附着到一种表达载体(如质粒)中。如有必要,该DNA可能与所需宿主所识别的相应转录和翻译调节控制核苷酸序列连接,尽管表达载体中一般存在此类控制功能。然后,该载体透过标准方法被引入宿主。一般来说,并不是所有的宿主都会被载体转化。因此,有必要选择转化过的宿主细胞。选择方法包括用任何必要的控制元素向表达载体插入一个DNA序列,该序列对转化细胞中的可选择性属性(如抗生素耐药性)进行编码。
另外,有这种选择属性的基因可在另外一个载体上,该载体用来协同转化所需的宿主细胞。
然后,本发明中的重组DNA所转化的宿主细胞在本文中所述本领域技术人员熟悉的合适条件下培养足够长的时间,从而表达之后可回收的肽。
有许多已知的表达系统,包括细菌(如大肠杆菌和枯草芽孢杆菌)、酵母(如酵母菌)、丝状真菌(如曲霉菌)、植物细胞、动物细胞及昆虫细胞。该系统可优选为哺乳动物细胞,如来自ATCC细胞生物学库(Cell Biology Collection)中的CHO细胞。
典型的哺乳动物细胞组成型表达载体质粒包括CMV或含一个合适的多聚A尾巴的SV40启动子以及抗性标志物(如新霉素)。一个实例为从Pharmacia公司(Piscataway,新泽西州,美国)获得的pSVL。一种可诱导型哺乳动物表达载体的例子是pMSG,也可以从Pharmacia公司获得。有用的酵母质粒载体是pRS403-406和pRS413-416,一般可从Stratagene Cloning Systems公司(La Jolla,加州92037,美国)获得。质粒pRS403、pRS404、pRS405和pRS406是酵母整合型质粒(YIp),并插入了酵母可选择性标记物HIS3、TRP1、LEU2和URA3。pRS413-416质粒为酵母着丝粒质粒(Ycp)。基于CMV启动子的载体(如,来自于Sigma-Aldrich公司)提供了暂态或稳定的表达、胞浆表达或分泌,以及FLAG、3xFLAG、c-myc或MATN不同组合物中的N-端或C-端标记。这些融合蛋白可用于检测、纯化及分析重组蛋白。双标融合为检测提供了灵活性。
强劲的人巨细胞病毒(CMV)启动子调控区使得COS细胞中的组成蛋白表达水平高达1mg/L。对于较弱的细胞株,蛋白水平一般低于0.1mg/L。SV40复制原点的出现将导致DNA在SV40复制容纳性COS细胞中高水平复制。例如,CMV载体可包含细菌细胞中的pMB1(pBR322的衍生物)复制原点、细菌中进行氨苄青霉素抗性选育的钙-内醯胺酶基因、hGH polyA和f1的原点。含前胰岛素原引导(PPT)序列的载体可使用抗FLAG抗体、树脂和板引导FLAG融合蛋白分泌到进行纯化的培养基中。其他与各种宿主细胞一起应用的载体和表达系统是本领域熟知众所周知的。
在另一个实施方案中,对本发明的两个或更多的肽或肽变体进行编码,因此,以一个连续顺序(类似于“一串珠子”的构建体)表达。在达到目标,所述肽或肽变体可能透过连接子氨基酸的延伸处(例如LLLLLL)连接或融合一起,也可能他们之间没有任何附加的肽而被连接。这些构建体也可用于癌症治疗,可诱导涉及MHC I和MHC II类分子的免疫应答。
本发明还涉及一种宿主细胞,其以本发明的多核苷酸载体构建转化而来。宿主细胞可为原核细胞,也可为真核细胞。在有些情况下,细菌细胞为优选原核宿主细胞,典型为大肠杆菌株,例如,大肠杆菌菌株DH5(从Bethesda Research Laboratories公司(Bethesda,马里兰州,美国)获得)和RR1(从美国菌种保藏中心(ATCC,Rockville,马里兰州,美国),ATCC编号31343获得)。首选的真核宿主细胞包括酵母、昆虫和哺乳动物细胞,优选为脊椎动物细胞,如:小鼠、大鼠、猴子或人成纤维细胞和结肠癌细胞株中的细胞。酵母宿主细胞包括YPH499、YPH500和YPH501,一般可从Stratagene Cloning Systems公司(LaJolla,加州92037,美国)获得。首选哺乳动物宿主细胞包括中国仓鼠卵巢(CHO)细胞为ATCC中的CCL61细胞、NIH瑞士小鼠胚胎细胞NIH/3T3为ATCC中的CRL 1658细胞、猴肾源性COS-1细胞为ATCC中的CRL 1650细胞以及人胚胎肾细胞的293号细胞。首选昆虫细胞为Sf9细胞,可用杆状病毒表达载体转染。有关针对表达选择合适宿主细胞的概要,可从教科书(Paulina Balbás and Argelia Lorence《Methods in Molecular Biology RecombinantGene Expression,Reviews and Protocols》Part One,Second Edition,ISBN 978-1-58829-262-9)和技术人员知道的其他文献中查到。
含本发明DNA结构的适当宿主细胞的转化可使用大家熟知的方法完成,通常取决于使用载体的类型。关于原核宿主细胞的转化,请参见,例如,Cohen等人的文献(Cohen etal.,1972)和(Green and Sambrook,2012)。酵母细胞的转化在Sherman等人的文章(Sherman et al.,1986)中进行了描述。Beggs(Beggs,1978)中所述的方法也很有用。对于脊椎动物细胞,转染这些细胞的试剂等,例如,磷酸钙和DEAE-葡聚糖或脂质体配方,可从Stratagene Cloning Systems公司或Life Technologies公司(Gaithersburg,马里兰州20877,美国)获得。电穿孔也可用于转化和/或转染细胞,是本领域用于转化酵母细胞、细菌细胞、昆虫细胞和脊椎动物细胞大家熟知的方法。
被成功转化的细胞(即含本发明DNA结构的细胞)可用大家熟知的方法(如PCR)进行识别。另外,上清液存在的蛋白可使用抗体进行检测。
应了解,本发明中的某些宿主细胞用于制备本发明中的肽,例如细菌细胞、酵母细胞和昆虫细胞。但是,其他宿主细胞可能对某些治疗方法有用。例如,抗原提呈细胞(如树突状细胞)可用于表达本发明中的肽,使他们可以加载入相应的MHC分子中。因此,本发明提出了含本发明中核酸或表达载体的一种宿主细胞。
在一个优选实施方案中,宿主细胞为抗原提呈细胞,尤其是树突状细胞或抗原提呈细胞。2010年4月29日,美国食品和药物管理局(FDA)批准载有含前列腺酸性磷酸酶(PAP)的重组融合蛋白可用于治疗无症状或症状轻微的转移性HRPC(Rini et al.,2006;Smallet al.,2006)。
另一方面,本发明提出了一种配制一种肽及其变体的方法,该方法包括培养宿主细胞和从宿主细胞或其培养基中分离肽。
在另一个实施方案中,本发明中的肽、核酸或表达载体用于药物中。例如,肽或其变体可制备为静脉(i.v.)注射剂、皮下(s.c.)注射剂、皮内(i.d.)注射剂、腹膜内(i.p.)注射剂、肌肉(i.m.)注射剂。肽注射的优选方法包括s.c.、i.d.、i.p.、i.m.和i.v.注射。DNA注射的优选方法为i.d.、i.m.、s.c.、i.p.和i.v.注射。例如,给予50μg至1.5mg,优选为125μg至500μg的肽或DNA,这取决于具体的肽或DNA。上述剂量范围在以前的试验中成功使用(Walter et al.,2012)。
用于主动免疫接种的多聚核苷酸可为基本纯化形式,也可包被于载体或输送系统。核酸可能为DNA、cDNA、PNA、RNA,也可能为其组合物。这种核酸的设计和引入方法为本领域所熟知。例如,文献中有其概述(Teufel et al.,2005)。多核苷酸疫苗很容易制备,但这些载体诱导免疫反应的作用模式尚未完全了解。合适的载体和输送系统包括病毒DNA和/或RNA,如基于腺病毒、牛痘病毒、逆转录病毒、疱疹病毒、腺相关病毒或含一种以上病毒元素的混合病毒的系统。非病毒输送系统包括阳离子脂质体和阳离子聚合物,是DNA输送所属领域内熟知的系统。也可使用物理输送系统,如透过“基因枪”。肽或核酸编码的肽可以是一种融合蛋白,例如,含刺激T细胞进行上述CDR的表位。
本发明的药剂也可能包括一种或多种佐剂。佐剂是那些非特异性地增强或加强免疫反应的物质(例如,透过CD8-阳性T细胞和辅助T(TH)细胞介导的对一种抗原的免疫应答,因此被视为对本发明的药剂有用。适合的佐剂包括(但不仅限于)1018ISS、铝盐、AS15、BCG、CP-870,893、CpG7909、CyaA、dSLIM、鞭毛蛋白或鞭毛蛋白衍生的TLR5配体、FLT3配体、GM-CSF、IC30、IC31、咪喹莫特resiquimod、ImuFactIMP321、白细胞介素IL-2、IL-13、IL-21、干扰素α或β,或其聚乙二醇衍生物、IS Patch、ISS、ISCOMATRIX、ISCOMs、LipoVac、MALP2、MF59、单磷醯脂A、Montanide IMS1312、Montanide ISA 206、Montanide ISA 50V、Montanide ISA-51、水包油和油包水乳状液、OK-432、OM-174、OM-197-MP-EC、ONTAK、OspA、载体系统、基于聚丙交酯复合乙交酯[PLG]和右旋糖苷微粒、重组人乳铁传递蛋白SRL172、病毒颗粒和其他病毒样颗粒、YF-17D、VE GF trap、R848、β-葡聚糖、Pam3Cys、源自皂角苷、分支杆菌提取物和细菌细胞壁合成模拟物的Aquila公司的QS21刺激子,以及其他专有佐剂,如:Ribi's Detox、Quil或Superfos。优选佐剂如:弗氏佐剂或GM-CSF。前人对一些树突状细胞特异性免疫佐剂(如MF59)及其制备方法进行了描述(Allison and Krummel,1995)。也可能使用细胞因子。一些细胞因子直接影响树突状细胞向淋巴组织迁移(如,TNF-),加速树突状细胞成熟为T淋巴细胞的有效抗原提呈细胞(如,GM-CSF、IL-1和IL-4)(美国5849589号专利,特别以其完整引用形式并入本文),并充当免疫佐剂(如IL-12、IL-15、IL-23、IL-7、IFN-α、IFN-β)(Gabrilovich et al.,1996)。
据报告,CpG免疫刺激寡核苷酸可提高佐剂在疫苗中的作用。如果没有理论的约束,CpG寡核苷酸可透过Toll样受体(TLR)(主要为TLR9)启动先天(非适应性)免疫系统从而起作用。CpG引发的TLR9活化作用提高了对各种抗原的抗原特异性体液和细胞反应,这些抗原包括肽或蛋白抗原、活病毒或被杀死的病毒、树突状细胞疫苗、自体细胞疫苗以及预防性和治疗性疫苗中的多糖结合物。更重要的是,它会增强树突状细胞的成熟和分化,导致TH1细胞的活化增强以及细胞毒性T淋巴细胞(CTL)生成加强,甚至CD4 T细胞说明的缺失。甚至有疫苗佐剂的存在也能维持TLR9活化作用诱发的TH1偏移,这些佐剂如:正常促进TH2偏移的明矾或弗氏不完全佐剂(IFA)。CpG寡核苷酸与以下其他佐剂或配方一起制备或联合给药时,表现出更强的佐剂活性,如微粒、纳米粒子、脂肪乳或类似制剂,当抗原相对较弱时,这些对诱发强反应尤为必要。他们还能加速免疫反应,使抗原剂量减少约两个数量级,在有些实验中,对不含CpG的全剂量疫苗也能产生类似的抗体反应(Krieg,2006)。美国7726705B1号专利对CpG寡核苷酸、非核酸佐剂和抗原结合使用促使抗原特异性免疫反应进行了描述。一种CpG TLR9拮抗剂为Mologen公司(柏林,德国)的dSLIM(双干环免疫调节剂),这是本发明药物组合物的优选成分。也可使用其他如TLR结合分子,如:RNA结合TLR7、TLR8和/或TLR9。
其他有用的佐剂例子包括(但不限于)化学修饰性CpG(如CpR、Idera)、dsRNA模拟物,如,Poly(I:C)及其衍生物(如:AmpliGen、Hiltonol、多聚-(ICLC)、多聚(IC-R)、多聚(I:C12U))、非CpG细菌性DNA或RNA以及免疫活性小分子和抗体,如:环磷醯胺、舒尼替单抗、西乐葆、NCX-4016、西地那非、他达拉非、伐地那非、索拉非尼、替莫唑胺、temsirolimus、XL-999、CP-547632、帕唑帕尼、VEGF Trap、ZD2171、AZD2171、抗-CTLA4、免疫系统的其他抗体靶向性主要结构(如:抗-CD40、抗-TGFβ、抗-TNFα受体)和SC58175,这些药物都可能有治疗作用和/或充当佐剂。技术人员无需过度进行不当实验就很容易确定本发明中有用的佐剂和添加剂的数量和浓度。
首选佐剂是抗-CD40、咪喹莫特、瑞喹莫德、GM-CSF、环磷醯胺、舒尼替尼、贝伐单抗、干扰素α、CpG寡核苷酸及衍生物、多聚(I:C)及衍生物、RNA、西地那非和PLG或病毒颗粒的微粒制剂。
本发明药物组合物的一个优选实施方案中,佐剂从含集落刺激因子制剂中选择,如粒细胞巨噬细胞集落刺激因子(GM-CSF,沙格司亭)、环磷醯胺、咪喹莫特、resiquimod和干扰素-α。
本发明药物组合物的一个优选实施方案中,佐剂从含集落刺激因子制剂中选择,如粒细胞巨噬细胞集落刺激因子(GM-CSF,沙格司亭)、环磷醯胺、咪喹莫特和resimiquimod。在本发明药物组合物的一个优选实施方案中,佐剂为环磷醯胺、咪喹莫特或resiquimod。更优选的佐剂是Montanide IMS 1312、Montanide ISA 206、Montanide ISA50V、Montanide ISA-51、聚-ICLC和抗CD40mAB或其组合物。
此组合药物为非肠道注射使用,如皮下、皮内、肌肉注射,也可口服。为此,肽和其他选择性分子在药用载体中分解或悬浮,优选为水载体。此外,组合物可包含辅料,如:缓冲剂、结合剂、冲击剂、稀释剂、香料、润滑剂等。这些肽也可与免疫刺激物质合用,如:细胞因子。可用于此类组合物的更多辅料可在从A.Kibbe所著的Handbook of PharmaceuticalExcipients(Kibbe,2000)等书中获知。此组合药物可用于阻止、预防和/或治疗腺瘤或癌性疾病。例如,EP2112253中有示例制剂。
一方面,本文所述的肽或其他分子可与水性载体组合。一方面,水性载体选自离子交换剂、氧化铝、硬脂酸铝、硬脂酸镁、卵磷脂、血清蛋白如人血清白蛋白、缓冲物质如磷酸盐、甘氨酸、山梨酸、山梨酸钾、饱和植物脂肪酸的部分甘油混合物、盐或电解质,如酯硫酸鱼精蛋白、磷酸氢二钠、磷酸二钙、磷酸氢钾、氯化钠、锌盐、胶体二氧化矽、三矽酸镁、聚乙烯基吡咯烷酮、聚乙烯吡咯烷酮-醋酸乙烯酯、纤维素类物质(例如:微晶纤维素、羟丙基甲基纤维素、羟丙基甲基纤维素乙酸琥珀酸酯、羟丙基甲基纤维素邻苯二甲酸酯)、淀粉、乳糖一水合物、甘露糖醇、海藻糖十二烷基硫酸钠和交联羧甲基纤维素钠、聚乙二醇、羧甲基纤维素钠、聚丙烯酸酯、聚甲基丙烯酸酯、蜡、聚乙烯-聚氧丙烯嵌段聚合物和羊毛脂。
一方面,水性载体含有多种组分,例如水和非水性载体组分,例如如本文所述的那些组分。另一方面,当与本文所述的肽或其他分子组合时,水性载体能够改善性质,例如改善溶解度、有效性和/或改进免疫治疗。此外,组合物可包含辅料,如:缓冲剂、结合剂、冲击剂、稀释剂、香料、润滑剂等。“药用稀释剂”例如可能包括溶剂、填充剂、稳定剂、分散介质、涂层、抗菌剂和抗真菌剂、等渗剂和吸收延迟剂等,它们在生理学上是相容的。药用稀释剂的实例包括盐水、磷酸盐缓冲盐水、右旋糖、甘油、乙醇等中的一种或多种以及它们的组合物。在许多情况下,优选在组合物中包含一种或多种等渗剂(例如:海藻糖和蔗糖等糖类)、多元醇(例如:甘露醇、山梨糖醇)或氯化钠。药用物质(如:润湿剂)或少量辅助物质(如:润湿剂或乳化剂、防腐剂或缓冲剂)也在本发明范围内。此外,组合物可能含有赋形剂,如缓冲液、粘合剂、爆破剂、稀释剂、香精和润滑剂。
重要的是要认识到,透过本发明的疫苗引发的免疫应答在不同的细胞阶段和开发的不同阶段攻击癌症。而且不同的癌症相关信号通路被攻击。这相对于其他疫苗的优势,这些疫苗只针对一个或几个靶标,这可能会导致肿瘤很容易适应于攻击(肿瘤逃逸)。此外,并非所有的个体肿瘤都表达相同模式的抗原。因此,几个肿瘤相关肽的组合确保了每个肿瘤都承担至少一些靶标。该组合物以这样的方式设计,预期每个肿瘤可表达几种抗原并覆盖肿瘤生长和维持所需要的几种独立的途径。因此,疫苗可易于“现成的”用于较大患者群体。这意味着,预选择接受疫苗治疗的患者可限制为HLA分型,无需抗原表达的任何额外的生物标志物评估,但仍然确保多个靶标同时被诱导的免疫应答攻击,这对于疗效很重要(Banchereau et al.,2001;Walter et al.,2012)。
本文所用的“支架”一词是指与(如抗原)决定因子特异性结合的分子。在一项实施方案中,支架是能够引导其所连接的实体(例如,(第二)抗原结合部分)至目标靶点,例如,至特定类型的肿瘤细胞或承载抗原决定簇的肿瘤基质(如根据目前申请中肽和MHC的复合体)。在另一项实施例中,支架能够透过其靶抗原(例如T细胞受体复合体抗原)启动信号通路。支架包括但不限于抗体及其片段,抗体的抗原结合区,其包含抗体重链可变区和抗体轻链可变区,结合的蛋白包括至少一个锚蛋白重复序列基元和单域抗原结合(SDAB)分子、适体、(可溶)TCR和(经修饰的)细胞,例如同种异体或自体T细胞。为了评估某个分子是否是结合至靶点的支架,可进行结合测定。
“特定”结合系指,与其他天然肽-MHC复合体相比,该支架与感兴趣的肽-MHC复合体更好地结合,结合程度为,拥有能够杀死承载特定靶点细胞的活性分子的支架不能够杀死无特定靶点但提呈一个或多个其他肽-MHC复合体的另一细胞。如果交叉反应性肽-MHC的肽并不是天然的,即,并非来自人HLA-多肽组,则结合至其他肽-MHC复合体是无关紧要的。评估靶细胞杀伤的测试在本领域中是公知的。它们应该含有未改变的肽-MHC提呈的靶细胞(原发细胞或细胞系)或载有肽的细胞进行,以便达到天然肽-MHC的水平。
各支架可包括一个标记,其透过确定是否存在或不存在标签所提供的信号可检测到结合支架。例如,该支架可用萤光染料或任何其他适用的细胞标记分子进行标记。此类标记分子是本领域中公知的。例如,透过萤光染料进行的萤光标记可透过萤光或镭射扫描显微术或流式细胞术提供结合适体的视觉化。
各支架可与第二个活性分子(例如IL-21、抗CD3、抗CD28)共轭。
关于多肽支架的进一步资讯,可参阅,例如,在WO 2014/071978A1背景技术部分,并作为参考文献引用。
本发明还涉及适体。适体(例如,参见WO 2014/191359及其中引用的文献)是短的单链核酸分子,其可以折叠为所定义的三维结构并识别特定的靶标结构。它们似乎是开发靶向治疗的合适替代方法。适体已显示可选择性与具有高亲和力和特异性的复合体靶标相结合。
识别细胞表面分子的适体在过去十年内已经确定,并为开发诊断和治疗方法提供了手段。由于适体已显示几乎无毒性和免疫原性,因此,它们是生物医学应用中有前景的候选物质。事实上适体,例如前列腺特异性膜抗原识别适体,已被成功地用于靶向治疗并在体内模型的异种移植物中显示出功能。此外,认识到特定肿瘤细胞系的适体也已确定。
可选择DNA适体来揭示各种癌细胞的广谱识别属性,特别是那些来自于实体瘤的细胞,而非致瘤和主要健康细胞不被识别。如果所识别的适体不仅识别肿瘤特异性子类型,而且与一系列肿瘤相互作用,这使适体适用于作为所谓的广谱诊断和治疗手段。
此外,用流式细胞仪对细胞结合行为的研究显示,适体在纳摩尔范围内显示出很好的亲和力。
适体用于诊断和治疗目的。此外,也可能显示,一些适体被肿瘤细胞吸取,因而可作为抗癌剂靶向递送的分子赋形剂,例如siRNA进入肿瘤细胞。
可选择适体针对复合体的靶标,如细胞和组织以及包含、优选包括根据任何SEQID NO 1至SEQ ID NO 489的一个序列、根据本发明的肽复合体与MHC分子,使用细胞SELEX(透过指数富集的配体系统进化)技术。
本发明中的肽可用于生成和开发出针对MHC/肽复合物的特定抗体。这些抗体可用于治疗,将毒素或放射性物质靶向病变组织。这些抗体的另一用途是为了成像之目的(如PET)将放射性核素靶向病变组织。这可有助于检测小转移灶或确定病变组织的大小和准确位置。
因此,本发明的另一方面是提出产生特异性结合至与HLA限制性抗原络合的I或II类人主要组织相容性复合体(MHC)的一种重组抗体的方法,该方法包括:用可溶形式的与HLA限制性抗原(优选为根据本发明的肽)络合的(MHC)I或II类分子对包含表达所述主要组织相容性说复合体(MHC)I或II类的基因工程非人哺乳动物进行免疫;将mRNA分子与产生所述非人哺乳动物细胞的抗体分离;产生一个噬菌体显示库,显示由所述mRNA分子编码的蛋白分子;以及将至少一个噬菌体与所述噬菌体显示库分离,所述的至少一个噬菌体显示所述抗体特异性地结合至与HLA限制性抗原络合的所述人主要组织相容性说复合体(MHC)I或II类。
因此,本发明的另一方面提出一种抗体,其特异性结合至与一种HLA限制性抗原络合的I或II类人主要组织相容性说复合体(MHC),其中该抗体优选为多克隆抗体、单克隆抗体、双特异性抗体和/或嵌合抗体。
产生这种抗体和单链I类主要组织相容性复合物的相应方法,以及产生这些抗体的其他工具在WO 03/068201、WO 2004/084798、WO 01/72768、WO 03/070752以及出版物(Cohen et al.,2003a;Cohen et al.,2003b;Denkberg et al.,2003)中进行了披露,为了本发明之目的,所有参考文献透过引用被完整地并入本文。
优选地,该抗体与复合体的结合亲和力低于20纳摩尔,优选为低于10纳摩尔,这在本发明情况下也被视为具有“特异性”。
本发明涉及一种肽,包含选自SEQ ID NO:1至SEQ ID NO:489组成的组的一个序列或该序列的与SEQ ID NO:1至SEQ ID NO:489具有88%同源性(优选为相同)的一种变体,或诱导与所述变异肽发生T细胞交叉反应的一种变体,其中,所述肽不是基本的全长多肽。
本发明进一步涉及一种肽,包含选自SEQ ID NO:1至SEQ ID NO:489组成的组的一个序列、或与SEQ ID NO:1至SEQ ID NO:489具有至少88%同源性(优选为相同)的一种变体,其中所述肽或变体的总长度为8至100个、优选为8至30个、最优选为8至14个氨基酸。
本发明进一步涉及本发明的肽,其具有与主要组织相容性复合体(MHC)I或II类分子结合的能力。
本发明进一步涉及本发明中的肽,其中肽系由或基本系由根据SEQ ID NO:1至SEQID NO:489的一个氨基酸序列组成。
本发明进一步涉及本发明的肽,其中该肽(在化学上)被修饰和/或包含非肽键。
本发明进一步涉及本发明的肽,其中该肽为融合蛋白的一部分,特别包括HLA-DR抗原相关不变链(Ii)的N-端氨基酸,或其中该肽与一种抗体(例如,树突状细胞特定抗体)融合。
本发明进一步涉及一种核酸,其编码本发明所述肽,前提是该肽并非完整(完全)的人蛋白。
本发明进一步涉及一种本发明的核酸,为DNA、cDNA、PNA、RNA,也可能为其组合物。
本发明进一步涉及一种能表达本发明核酸的表达载体。
本发明进一步涉及本发明的一种肽、本发明的一种核酸或本发明的一种药用表达载体,特别是用于治疗肺癌(包括NSCLC和SCLC)。
本发明进一步涉及含本发明核酸或本发明表达载体的一种宿主细胞。
本发明进一步涉及本发明的宿主细胞,其为抗原提呈细胞,优选为树突细胞。
本发明进一步涉及配制本发明一种肽的一种方法,所述方法包括培养本发明的宿主细胞和从所述宿主细胞或其培养基中分离肽。
本发明进一步涉及本发明中的方法,其中抗原透过与足够量的含抗原提成细胞的抗原结合被载入表达于合适抗原提呈细胞表面的I或II类MHC分子。
本发明进一步涉及本发明的方法,其中该抗原提呈细胞包括一个表达载体,该载体有能力表达含SEQ ID NO:1至SEQ ID NO:489的肽或所述变体氨基酸序列。
本发明进一步涉及以本发明方法制造的启动T细胞,其中所述T细胞有选择性地识别一种细胞,该细胞异常表达含一种本发明氨基酸序列的多肽。
本发明进一步涉及一种杀伤患者靶细胞的方法,其中患者的靶细胞异常表达含本发明任何氨基酸序列的多肽,该方法包括给予患者本发明的有效量T细胞。
本发明进一步涉及任何所述肽、本发明的一种核酸、本发明的一种表达载体、本发明的一种细胞、本发明一种作为药剂或制造药剂的启动细胞毒性T淋巴细胞的用途。本发明进一步涉及一种本发明的用途,其中药剂可有效抗癌。
本发明进一步涉及一种本发明的用途,其中该药剂为一种疫苗。本发明进一步涉及一种本发明的用途,其中药剂可有效抗癌。
本发明进一步涉及根据本发明肽的用途,其中所述癌细胞为肺癌(包括NSCLC和SCLC)细胞或其他实体或血液学肿瘤细胞,如:急性骨髓性白血病、乳腺癌、胆管癌、脑癌、慢性淋巴细胞白血病、结直肠癌、食管癌、胆囊癌、胃癌、头颈部鳞状细胞癌、肝细胞癌、黑色素瘤、非霍奇金淋巴瘤、卵巢癌、胰腺癌、前列腺癌、肾细胞癌、膀胱癌、子宫癌。本发明进一步涉及一种基于本发明肽的特定标志物蛋白和生物标志物,在此成为“靶标”,其可用于诊断和/或判断肺癌(包括NSCLC和SCLC)的预后。本发明还涉及这些供癌症治疗使用的新靶点。
本文中术语“抗体”为广义上的定义,既包括多克隆也包括单克隆抗体。除了完整或“全部”的免疫球蛋白分子,“抗体”这一术语还包括这些免疫球蛋白分子和人源化免疫球蛋白分子的片段(如,CDR、Fv、Fab和Fc片段)或聚合物,只要它们表现出本发明的任何期望属性(例如,肺癌(包括NSCLC和SCLC)标志物(多)肽的特异性结合、将毒素传递给癌症标志物基因表达水平增加时的肺癌(包括NSCLC和SCLC)细胞和/或抑制肺癌(包括NSCLC和SCLC)志物多肽的活性)。
只要有可能,本发明的抗体可从商业来源购买。本发明的抗体也可能使用已知的方法制得。技术人员会了解全长肺癌(包括NSCLC和SCLC)标志物多肽或其片段可用于制备本发明的抗体。用于产生本发明抗体的多肽可部分或全部地由天然源经纯化而得,也可利用重组DNA技术生产。
例如,本发明的编码肽的cDNA,例如,该肽为根据SEQ ID NO:1至SEQ ID NO:489多肽的肽,或其中一个变体或片段,可在原核细胞中(如:细菌)或真核细胞(如:酵母、昆虫或哺乳动物细胞)中表达,之后,可纯化重组蛋白,并用于产生一种特异性结合用于产生本发明抗体的肺癌(包括NSCLC和SCLC)标志物多肽的单克隆或多克隆抗体制剂。
本领域的技术人员会认识到,两种或两种以上不同集合的单克隆抗体或多克隆抗体能最大限度地增加获得一种含预期用途所需的特异性和亲和力(例如,ELISA法、免疫组织化学、体内成像、免疫毒素疗法)的抗体的可能性。根据抗体的用途,用已知的方法对其期望活性进行测试(例如,ELISA法、免疫组织化学、免疫治疗等;要获取产生和测试抗体的进一步指导,请参阅,例如,Greenfield,2014(Greenfield,2014))。例如,该抗体可用ELISA法或免疫印迹法、免疫组织化学染色福马林固定的癌组织或冰冻的组织切片进行检测。在初次体外表征后,用于治疗或体内诊断用途的抗体根据已知的临床测试方法进行检测。
此处使用的术语“单克隆抗体”系指从大量同质抗体中获得的一种抗体,即,由相同的抗体组成的抗体群,但可能少量提呈的自然突变除外。此处所述的单克隆抗体具体包括“嵌合”抗体,其中一部分重链和/或轻链与从特定物种中获得的抗体或属于特定抗体类型和分类型抗体的相应序列相同(同质),同时,剩余链与从其他物种中获得的抗体或属于特定抗体类型和子类型抗体的相应序列以及这些抗体的片段相同(同质),只要他们表现出预期的拮抗活性(美国4816567号专利,其在此以其整体并入)。
本发明的单克隆抗体可能使用杂交瘤方法制得。在杂交瘤方法中,老鼠或其他适当的宿主动物,通常用免疫制剂以引发产生或能产生将特异性结合至免疫制剂的抗体。或者,淋巴细胞可在体外进行免疫。
单克隆抗体也可由DNA重组方法制得,如:美国4816567号专利所述。编码本发明单克隆抗体的DNA可很容易地使用传统程序进行分离和测序(例如:透过使用能与编码鼠抗体重链和轻链的基因特异性结合的寡核苷酸探针)。
体外方法也适用于制备单价抗体。抗体消化以产生抗体的片段,尤其是Fab片段,可以透过使用本领域已知的常规技术完成。例如,可以透过使用木瓜蛋白酶完成消化。木瓜蛋白酶消化的实施例在WO 94/29348和美国4342566号专利中有描述。抗体的木瓜蛋白酶消化通常产生两种相同的抗原结合性片段,称为Fab片段(每个片段都有一个抗原结合点)和残余Fc片段。胃蛋白酶处理产生一个F(ab')2片段和一个pFc'片段。
抗体片段,不论其是否附着于其他序列,均可包括特定区域或特定氨基酸残基的插入、删除、替换、或其他选择性修饰,但前提是,片段的活性与非修饰的抗体或抗体片段相比没有显著的改变或损害。这些修饰可提供一些额外的属性,如:删除/添加可与二硫键结合的氨基酸,以增加其生物寿命、改变其分泌特性等。在任何情况下,抗体片段必须拥有生物活性的特性,如:结合活性、调节结合域的结合力等。抗体的功能性或活性区域可透过蛋白特定区域的基因突变、随后表达和测试所表达的多肽进行确定。这些方法为本行业技术人员所熟知,可包括编码抗体片段的核酸的特定位点基因突变。
本发明的抗体可进一步包括人源化抗体或人抗体。非人(如:鼠)抗体的人源化形式为嵌合抗体免疫球蛋白、免疫球蛋白链或其片段(如:Fv、Fab、Fab'或抗体的其他抗原结合序列),其中包含从非人免疫球蛋白中获得的最小序列。人源化抗体包括人免疫球蛋白(受体抗体),其中来自受体互补决定区(CDR)的残基被来自非人物种(供体抗体)(如具有与其特异性、亲和力和能力的小鼠、大鼠或兔子)CDR的残基取代。在某些情况下,人类免疫球蛋白的Fv框架(FR)残基被相应的非人残基取代。人源化抗体可能还包括既非受体抗体、也非输入CDR或框架序列中发现的残基。一般来说,人源化抗体将包括几乎所有的至少一个、通常为二个可变域,其中,全部或几乎全部的CDR区域均对应于非人免疫球蛋白的区域并且全部或几乎全部的FR区域均为人免疫球蛋白相同序列的区域。理想情况是,人源化抗体还将包括至少免疫球蛋白恒定区(Fc)的一部分,通常是人免疫球蛋白的恒定区的一部分。
人源化非人抗体的方法为本行业所熟知。一般来说,人源化抗体具有一个或多个从非人源头引入的氨基酸残基。这些非人氨基酸残基往往被称为“输入”残基,通常从“输入”可变域中获得。人源化基本上可以透过将啮齿动物CDR或CDR序列取代为相应的人抗体序列而完成。因此,这种“人源化”抗体为嵌合抗体(美国4816567号专利),其中大大少于完整的人可变域被来自于非人物种的相应序列取代。在实践中,人源化抗体通常为人抗体,其中有些CDR残基以及可能的一些FR残基被来自啮齿动物抗体中的类似位点的残基取代。
可使用免疫后在内源性免疫球蛋白产生缺失时能产生完整人抗体的转基因动物(如:小鼠)。例如,它被描述为,嵌合和种系突变小鼠中的抗体重链连接区域基因的纯合性缺失导致内源性抗体生成的完全抑制。在此种系变种小鼠中人种系免疫球蛋白基因阵列的转移在抗原挑战后将导致人抗体的生成。人抗体也可在噬菌体展示库中产生。
本发明的抗体优选为透过药用载体的形式给予受试者。通常,在制剂中使用适量的药用盐,以使制剂等渗。药用载体的例子包括生理盐水、林格氏液和葡萄糖溶液。溶液的pH值优选为约5至8,更优选为约7至7.5。此外,载体还包括缓释制剂,如:含有抗体的固体疏水性聚合物半透性基质,其中基质为有形物品形式,如:薄膜、脂质体或微粒。本行业的技术人员熟知,某些载体可能为更优选,取决于例如,抗体的给药途径和浓度。
该抗体可透过注射(如:静脉内、腹腔内、皮下、肌肉内)或透过输注等其他方法给予受试者、患者或细胞,确保其以有效的形式传输到血液中。这些抗体也可以透过瘤内或瘤周途径给予,从而发挥局部和全身的治疗作用。局部或静脉注射为优选。
抗体给药的有效剂量和时间表可根据经验确定,并且作出此类决定属本行业的技术范围内。本行业的技术人员会明白,必须给予的抗体剂量根据以下因素会有所不同,例如:接受抗体的受试者、给药途径、使用的抗体以及其他正在使用的药物的特定类型。单独使用的抗体的通常日剂量可能为约1μg/kg至最多100mg/kg体重或更多,这取决于上述因素。给予抗体,优选为肺癌(包括NSCLC和SCLC)后,治疗抗体的疗效可透过技术人员熟知的不同方法评估。例如:接受治疗的受试者癌症的大小、数量和/或分布可使用标准肿瘤成像技术进行监测。因治疗而给予的抗体与不给予抗体时的病程相比,可阻止肿瘤生长、导致肿瘤缩小、和/或阻止新肿瘤的发展,这样的抗体是一种有效治疗癌症的抗体。
本发明的另一方面提出了制备识别特异性肽-MHC复合物的可溶性T细胞受体(sTCR)的一种方法。这种可溶性T细胞受体可从特异性T细胞克隆中产生,并且它们的亲和力可以透过互补决定区靶向诱变而增加。为了T细胞受体选择之目的,可以使用噬菌体展示(美国2010/0113300,(Liddy et al.,2012))。为了在噬菌体展示期间以及实际使用为药物时稳定T细胞受体之目的,可透过非天然二硫键、其他共价键(单链T细胞受体)或透过二聚化结构域连接α和β链(Boulter et al.,2003;Card et al.,2004;Willcox et al.,1999)。T细胞受体可以连接到毒素、药物、细胞因子(参见US 2013/0115191)、域招募效应细胞,如抗CD3域等,以便对靶细胞执行特定的功能。此外,它可能表达于用于过继转移的T细胞。进一步的资讯可在WO 2004/033685A1和WO 2004/074322A1中找到。sTCR的组合在WO 2012/056407A1中进行了描述。WO 2013/057586A1中公开了制备的进一步的方法。
此外,可用本发明的肽和/或TCR或抗体或其他结合分子在活检样本的基础上验证病理师对癌症的诊断。
该抗体或TCR也可用于体内诊断实验。一般来说,抗体用放射性核素标记(如:111In、99Tc、14C、131I、3H、32P或35S),从而可免疫闪烁扫描法使肿瘤局限化。在一实施方案中,其中的抗体或片段与两个或两个以上选自包括上述蛋白的组的蛋白质靶标的细胞外域结合,并且亲和力值(Kd)低于1x 10μM。
诊断用抗体可透过各种影像学方法使用适合检测的探针进行标记。探针检测方法包括但不限于,萤光、光、共聚焦和电镜方法;磁共振成像和光谱学技术;透视、电脑断层扫描和正电子发射断层扫描。合适的探针包括但不限于,萤光素、罗丹明、曙红及其它萤光团、放射性同位素、黄金、釓和其他稀土、顺磁铁、氟-18和其他正电子发射放射性核素。此外,探针可能是双功能或多功能的,并且用一种以上的上述方法可进行检测。这些抗体可用所述的探针直接或间接进行标记。抗体探针的连接,包括探针的共价连接、将探针融合入抗体、以及螯合化合物的共价连接从而结合探针、以及其他本行业熟知的方法。对于免疫组织化学方法,疾病组织样本可能是新鲜或冷冻或可能包埋于石蜡中以及用福马林等防腐剂固定。固定或包埋的切片包括与标记一抗和二抗接触的样本,其中该抗体用于检测原位蛋白的表达。
本发明的另一方面包括一种体外制备启动的T细胞的方法,该方法包括将T细胞与载有抗原的人MHC分子进行体外连接,这些分子在合适的抗原提呈细胞表面表达足够的一段时间从而以抗原特异性方式启动T细胞,其中所述抗原为根据本发明所述的一种肽。优选情况是足够量的抗原与抗原提呈细胞一同使用。
优选情况是,哺乳动物细胞的TAP肽转运载体缺乏或水平下降或功能降低。缺乏TAP肽转运载体的适合细胞包括T2、RMA-S和果蝇细胞。TAP是与抗原加工相关的转运载体。
人体肽载入的缺陷细胞株T2从属美国菌种保藏中心(ATCC,12301ParklawnDrive,Rockville,马里兰州20852,美国)目录号CRL1992;果蝇细胞株Schneider 2号株从属ATCC目录CRL 19863;小鼠RMA-S细胞株Ljunggren等人描述过(Ljunggren and Karre,1985)。
优选情况是,宿主细胞在转染前基本上不表达MHC I类分子。刺激因子细胞还优选为表达对T细胞共刺激信号起到重要作用的分子,如,B7.1、B7.2、ICAM-1和LFA 3中的任一种分子。大量MHC I类分子和共刺激分子的核酸序列可从GenBank和EMBL资料库中公开获得。
当MHC I类表位用作一种抗原时,T细胞为CD8阳性T细胞。
如果抗原提呈细胞受到转染而表达这种表位,则优选的细胞包括一个表达载体,该载体有能力表达含SEQ ID NO:1至SEQ ID NO:489的肽或变体氨基酸序列。
可使用其他一些方法来体外生成T细胞。例如,自体肿瘤浸润性淋巴细胞可用于生成CTL。Plebanski等人在(Plebanski et al.,1995)使用自体外周血淋巴细胞(PLB)制得T细胞。另外,也可能用肽或多肽脉冲处理树突状细胞或透过与重组病毒感染而制成自体T细胞。此外,B细胞可用于制备自体T细胞。此外,用肽或多肽脉冲处理或用重组病毒感染的巨噬细胞可用于配制自体T细胞。S.Walter等人在(Walter et al.,2003)中描述了透过使用人工抗原提呈细胞(aAPC)体外启动T细胞,这也是生成作用于所选肽的T细胞的一种合适方法。在本发明中,根据生物素:链霉素生物化学方法透过将预制的MHC:肽复合物耦合到聚苯乙烯颗粒(微球)而生成aAPC。该系统实现了对aAPC上的MHC密度进行精确调节,这使得可以在血液样本中选择地引发高或低亲合力的高效抗原特异性T细胞反应。除了MHC:肽复合物外,aAPC还应携运含共刺激活性的其他蛋白,如耦合至表面的抗-CD28抗体。此外,此类基于aAPC的系统往往需要加入适当的可溶性因子,例如,诸如白细胞介素12的细胞因子。
也可用同种异体细胞制得T细胞,在WO 97/26328中详细描述了一种方法,以参考文献方式并入本文。例如,除了果蝇细胞和T2细胞,也可用其他细胞来提呈肽,如CHO细胞、杆状病毒感染的昆虫细胞、细菌、酵母、牛痘感染的靶细胞。此外,也可使用植物病毒(例如,参阅Porta等人在(Porta et al.,1994)中描述了将豇豆花叶病毒开发为一种提呈外来肽的高产系统。
被启动的T细胞直接针对本发明中的肽,有助于治疗。因此,本发明的另一方面提出了用本发明前述方法制得的启动T细胞。
按上述方法制成的启动T细胞将会有选择性地识别异常表达含SEQ ID NO:1至SEQID NO489氨基酸序列的多肽。
优选情况是,T细胞透过与其含HLA/肽复合物的TCR相互作用(如,结合)而识别该细胞。T细胞是杀伤患者靶细胞方法中有用的细胞,其靶细胞异常表达含本发明中氨基酸序列的多肽。此类患者给予有效量的启动T细胞。给予患者的T细胞可能源自该患者,并按上述方法启动(即,它们为自体T细胞)。或者,T细胞不是源自该患者,而是来自另一个人。当然,优选情况是该供体为健康人。发明人使用“健康个人”系指一个人一般状况良好,优选为免疫系统合格,更优选为无任何可很容易测试或检测到的疾病。
根据本发明,CD8-阳性T细胞的体内靶细胞可为肿瘤细胞(有时表达MHC-II类抗原)和/或肿瘤周围的基质细胞(肿瘤细胞)(有时也表达MHC-II类抗原;(Dengjel et al.,2006))。
本发明所述的T细胞可用作治疗性组合物中的活性成分。因此,本发明也提出了一种杀伤患者靶细胞的方法,其中患者的靶细胞异常表达含本发明中氨基酸序列的多肽,该方法包括给予患者上述有效量的T细胞。
发明人所用的“异常表达”的意思还包括,与正常表达水平相比,多肽过量表达,或该基因在源自肿瘤的组织中不表达但在肿瘤中表达。“过量表达”系指多肽水平至少为正常组织中的1.2倍;优选为至少为正常组织中的2倍,更优选为至少4或6倍。
T细胞可用本领域已知的方法制得(如,上述方法)。
T细胞继转移方案为本领域所熟知的方案。综述可发现于:Gattioni et al.和Morgan et al.(Gattinoni et al.,2006;Morgan et al.,2006)。
本发明的另一个方面包括使用与MHC复合的肽,以生成T细胞受体,其核酸被克隆并被引入至宿主细胞,优选为T细胞。然后,该透过基因工程改变的T细胞可转给患者用于癌症治疗。
本发明的任一分子(即肽、核酸、抗体、表达载体、细胞,启动T细胞、T细胞受体或编码核酸)都有益于治疗疾病,其特点在于细胞逃避免疫反应的打击。因此,本发明的任一分子都可用作药剂或用于制造药剂。这种分子可单独使用也可与本发明中的其他分子或已知分子联合使用。
本发明还涉及一种套件,其包括:
(a)一个容器,包含上述溶液或冻干粉形式的药物组合物;
(b)可选的第二个容器,其含有冻干粉剂型的稀释剂或重组溶液;和
(c)可选的(i)溶液使用或(ii)重组和/或冻干制剂使用的说明。
该套件还步包括一个或多个(iii)缓冲剂,(iv)稀释剂,(v)过滤液,(vi)针,或(v)注射器。容器最好是瓶子、小瓶、注射器或试管,可以为多用途容器。药物组合物最好是冻干的。
本发明中的套件优选包含一种置于合适容器中的冻干制剂以及重组和/或使用说明。适当的容器包括,例如瓶子、西林瓶(如双室瓶)、注射器(如双室注射器)和试管。该容器可能由多种材料制成,如玻璃或塑胶。试剂盒和/或容器最好有容器或关于容器的说明书,指明重组和/或使用的方向。例如,标签可能表明冻干剂型将重组为上述肽浓度。该标签可进一步表明制剂用于皮下注射。
存放制剂的容器可使用多用途西林瓶,使得可重复给予(例如,2-6次)重组剂型。该套件可进一步包括装有合适稀释剂(如碳酸氢钠溶液)的第二个容器。
稀释液和冻干制剂混合后,重组制剂中的肽终浓度优选为至少0.15mg/mL/肽(=75μg),不超过3mg/mL/肽(=1500μg)。该套件还可包括商业和用户角度来说可取的其他材料,包括其他缓冲剂、稀释剂,过滤液、针头、注射器和带有使用说明书的包装插页。
本发明中的套件可能有一个单独的容器,其中包含本发明所述的药物组合物制剂,该制剂可有其他成分(例如,其他化合物或及其药物组合物),也可无其他成分,或者每种成分都有其不同容器。
优选情况是,本发明的套件包括与本发明的一种制剂,包装后与第二种化合物(如佐剂(例如GM-CSF)、化疗药物、天然产品、激素或拮抗剂、抗血管生成剂或抑制剂、凋亡诱导剂或螯合剂)或其药物组合物联合使用。该套件的成分可进行预络合或每种成分在给予患者之前可放置于单独的不同容器。该套件的成分可以是一种或多种溶液,优选为水溶液,更优选为无菌水溶液。该套件的成分也可为固体形式,加入合适的溶剂后转换为液体,最好放置于另一个不同的容器中。
治疗套件的容器可能为西林瓶、试管、烧瓶、瓶子、注射器、或任何其他盛装固体或液体的工具。通常,当成分不只一种时,套件将包含第二个西林瓶或其他容器,使之可以单独定量。该套件还可能包含另一个装载药用液体的容器。优选情况是,治疗套件将包含一个设备(如,一个或多个针头、注射器、滴眼器、吸液管等),使得可注射本发明的药物(本套件的组合物)。
本发明的药物配方适合以任何可接受的途径进行肽给药,如口服(肠道)、鼻内、眼内、皮下、皮内、肌内,静脉或经皮给药。优选为皮下给药,最优选为皮内给药,也可透过输液泵给药。
由于本发明的肽从肺癌(包括NSCLC和SCLC)中分离而得,因此,本发明的药剂优选用于治疗肺癌(包括NSCLC和SCLC)。
本发明进一步涉及为个体患者制备个体化药物的一种方法,其中包括:制造含选自预筛选TUMAP存储库至少一种肽的药物组合物,其中药物组合物中所用的至少一种肽选择为适合于个体患者。在一项实施方案中,药物组合物为一种疫苗。该方法也可以改动以产生下游应用的T细胞克隆物,如:TCR隔离物或可溶性抗体和其他治疗选择。
“个体化药物”系指专门针对个体患者的治疗,将仅用于该等个体患者,包括个体化活性癌症疫苗以及使用自体组织的过继细胞疗法。
如本文所述,“存储库”应指已经接受免疫原性预筛查和/或在特定肿瘤类型中过量提呈的一组或一系列肽。“存储库”一词并不暗示,疫苗中包括的特定肽已预先制造并储存于物理设备中,虽然预期有这种可能性。明确预期所述肽可以用于新制造每种个体化疫苗,也可能被预先制造和储存。存储库(例如,资料库形式)由肿瘤相关肽组成,其在各种HLA-A HLA-B和HLA-C等位元基因肺癌(包括NSCLC和SCLC)患者的肿瘤组织中高度过度表达。其可能含有包括MHC I类和MHC II类肽或拉长的MHC I类肽。除了从几种肺癌(包括NSCLC和SCLC)组织中采集的肿瘤相关肽外,存储库还可能包含HLA-A*02、HLA-A*01、HLA-A*03、HLA-A*24、HLA-B*07、HLA-B*08和HLA-A*24B*44标记肽。这些肽可对TUMAP诱导的T细胞免疫进行量化比较,从而可得出疫苗抗肿瘤反应能力的重要结论。其次,在没有观察到来自患者“自身”抗原TUMAP的任何疫苗诱导的T细胞反应时,它们可作为来自“非自身”抗原的重要阳性对照肽。第三,它还可对患者的免疫功能状态得出结论。
存储库的TUMAP透过使用一种功能基因组学方法进行鉴定,该方法结合了基因表达分析、质谱法和T细胞免疫学该方法确保了只选择真实存在于高百分比肿瘤但在正常组织中不表达或仅很少量表达的TUMAP用于进一步分析。对于初始肽的选择,患者肺癌(包括NSCLC和SCLC)样本和健康供体的血液以循序渐进的方法进行分析:
1.恶性材料的HLA配体用质谱法确定
2.使用全基因组信使核糖核酸(mRNA)表达分析法用于确定恶性肿瘤组织(肺癌(包括NSCLC和SCLC))与一系列正常器官和组织相比过度表达的基因。
3.确定的HLA配体与基因表达资料进行比较。肿瘤组织上过量表达或选择性提呈的肽,优选为第2步中检测到的选择性表达或过量表达基因所编码的考虑为多肽疫苗的合适候选TUMAP。
4.文献检索以确定更多证据以支持确认为TUMP的肽的相关性
5.过度表达在mRNA水平的相关性由肿瘤组织第3步选定的TUMAP重新检测而确定,并且在健康组织上缺乏(或不经常)检测。
6.为了评估透过选定的肽诱导体内T细胞反应是否可行,使用健康供体以及肺癌(包括NSCLC和SCLC)患者的人T细胞进行体外免疫原性测定。
一方面,在将所述肽加入存储库之前,对其进行筛查以了解免疫原性。举例来说(但不限于此),纳入存储库的肽的免疫原性的确定方法包括体外T细胞启动,具体为:用装载肽/MHC复合物和抗CD28抗体的人工抗原提呈细胞反复刺激来自健康供体的CD8+T细胞。
这种方法优选用于罕见癌症以及有罕见表达谱的患者。与含目前开发为固定组分的多肽鸡尾酒相反的是,存储库可将肿瘤中抗原的实际表达于疫苗进行更高程度的匹配。在多目标方法中,每名患者将使用几种“现成”肽的选定单一肽或组合。理论上来说,基于从50抗原肽库中选择例如5种不同抗原肽的一种方法可提供大约170万种可能的药物产品(DP)组分。
在一方面,选择所述肽用于疫苗,其基于个体患者的适合性,并使用本发明此处或后文所述的方法。
HLA表型、转录和肽组学资料从患者的肿瘤材料和血液样本中收集,以确定最合适每名患者且含有“存储库”和患者独特(即突变)TUMAP的肽。将选择的那些肽选择性地或过度表达于患者肿瘤中,并且可能的情况下,如果用患者个体PBMC进行检测,则表现出很强的体外免疫原性。
优选的情况是,疫苗所包括的肽的一种确定方法包括:(a)识别由来自个体患者肿瘤样本提呈的肿瘤相关肽(TUMAP);(b)将(a)中鉴定的肽与上述肽的存储库(资料库)进行比对;且(c)从与患者中确定的肿瘤相关肽相关的存储库(资料库)中选择至少一种肽。例如,肿瘤样本提呈的TUMAP的鉴定方法有:(a1)将来自肿瘤样本的表达资料与所述肿瘤样本组织类型相对应的正常组织样本的表达资料相比对,以识别肿瘤组织中过量表达或异常表达的蛋白;以及(a2)将表达资料与结合到肿瘤样本中I类MHC和/或II类分子的MHC配体序列想关联,以确定来源于肿瘤过量表达或异常表达的蛋白质的MHC配体。优选情况是,MHC配体的序列的确定方法是:洗脱来自肿瘤样本分离的MHC分子结合肽,并测序洗脱配体。优选情况是,肿瘤样本和正常组织从同一患者获得。
除了使用存储库(资料库)模型选择肽以外,或作为一种替代方法,TUMAP可能在新患者中进行鉴定,然后列入疫苗中。作为一种实施例,患者中的候选TUMAP可透过以下方法进行鉴定:(a1)将来自肿瘤样本的表达资料与所述肿瘤样本组织类型相对应的正常组织样本的表达资料相比对,以识别肿瘤组织中过量表达或异常表达的蛋白;以及(a2)将表达资料与结合到肿瘤样本中I类MHC和/或II类分子的MHC配体序列想关联,以确定来源于肿瘤过量表达或异常表达的蛋白质的MHC配体。作为另一实施例,蛋白的鉴定方法为可包含突变,其对于肿瘤样本相对于个体患者的相应正常组织是独特的,并且TUMAP可透过特异性靶向作用于变异来鉴定。例如,肿瘤以及相应正常组织的基因组可透过全基因组测序方法进行测序:为了发现基因蛋白质编码区域的非同义突变,从肿瘤组织中萃取基因组DNA和RNA,从外周血单核细胞(PBMC)中提取正常非突变基因组种系DNA。运用的NGS方法只限于蛋白编码区的重测序(外显子组重测序)。为了这一目的,使用供应商提供的靶序列富集试剂盒来捕获来自人样本的外显子DNA,随后使用HiSeq2000(Illumina公司)进行测序。此外,对肿瘤的mRNA进行测序,以直接定量基因表达,并确认突变基因在患者肿瘤中表达。得到的数以百万计的序列读数透过软件演算法处理。输出列表中包含突变和基因表达。肿瘤特异性体突变透过与PBMC衍生的种系变化比较来确定,并进行优化。然后,为了存储库可能测试新确定的肽了解如上所述的免疫原性,并且选择具有合适免疫原性的候选TUMAP用于疫苗。
在一个示范实施方案中,疫苗中所含肽透过以下方法确定:(a)用上述方法识别由来自个体患者肿瘤样本提呈的肿瘤相关肽(TUMAP);(b)将(a)中鉴定的肽与进行肿瘤(与相应的正常组织相比)免疫原性和过量提呈预筛查肽的存储库进行比对;(c)从与患者中确定的肿瘤相关肽相关的存储库中选择至少一种肽;及(d)可选地在(a)中选择至少一种新确定的肽,确认其免疫原性。
在一个示范实施方案中,疫苗中所含肽透过以下方法确定:(a)识别由来自个体患者肿瘤样本提呈的肿瘤相关肽(TUMAP);以及(b)在(a)中选择至少一种新确定的肽,并确认其免疫原性。
一旦选定了用于个体化肽疫苗的肽时,则产生疫苗。该疫苗优选为一种液体制剂,包括溶解于20-40%DMSO之间,优选为约30-35%DMSO,例如,约33%DMSO中的个体肽。列入产品的每种肽都溶于DMSO中。单个肽溶液浓度的选择取决于要列入产品中的肽的数量。单肽-DMSO溶液均等混合,以实现一种溶液中包含所有的肽,且浓度为每肽~2.5mg/ml。然后该混合溶液按照1:3比例用注射用水进行稀释,以达到在33%DMSO中每肽0.826mg/ml的浓度。稀释的溶液透过0.22μm无菌筛检程序进行过滤。从而获得最终本体溶液。
最终本体溶液填充到小瓶中,在使用前储存于-20℃下。一个小瓶包含700μL溶液,其中每种肽含有0.578mg。其中的500μL(每种肽约400μg)将用于皮内注射。
本发明的肽除了用于治疗癌症,也可用于诊断。由于肽由肺癌(包括NSCLC和SCLC)细胞产生,并且已确定这些肽在正常组织中不存在或水平较低,因此这些肽可用于诊断癌症是否存在。
血液样本中组织活检物含权利要求的肽,可有助于病理师诊断癌症。用抗体、质谱或其他本领域内已知的方法检测某些肽可使病理师判断该组织样本为恶性的还是炎症或一般病变,也可用作肺癌(包括NSCLC和SCLC)的生物标志物。肽基团的提呈使得能对病变组织进行分类或进一步分成子类。
对病变标本中肽的检测使得能对免疫系统治疗方法的利益进行判断,特别是如果T-淋巴细胞已知或预计与作用机制有关。MHC表达的缺失是一种机制,充分说明了哪些受感染的恶性细胞逃避了免疫监视。因此,肽的提呈表明,分析过的细胞并没有利用这种机制。
本发明的肽可用于分析淋巴细胞对肽的反应(如T细胞反应),或抗体对肽或MHC分子络合的肽发生的反应。这些淋巴细胞反应可以作为预后指标,决定是否采取进一步的治疗。这些反应也可以用作免疫疗法中的替代反应指标,旨在以不同方式诱导淋巴细胞反应,如接种蛋白疫苗、核酸、自体材料、淋巴细胞过继转移。基因治疗中,淋巴细胞对肽发生的反应可以在副作用的评估中考虑。淋巴细胞反应监测也可能成为移植疗法随访检查中的一种有价值的工具,如,用于检测移植物抗宿主和宿主抗移植物疾病。
下列描述优选方案的实施例将对本发明进行说明,并参照随附图表(但是不仅限于此)。考虑到本发明的目的,文中引用的所有参考文献透过引用的方式并入在本文中。
图表
图1A至1N显示了各种肽在不同癌症组织中的过度提呈(黑点)。上面部分:根据技术重复测量值的中值MS信号强度绘制为点,单一阳性正常组织为灰色点,检测到该肽的肿瘤样本为黑点。肿瘤和正常样本按照器官起源分组,箱须图代表了多个样本归一化信号强度的中位数,第25和第75百分位(箱)以及最小值和最大值(须)。正常器官根据风险类别排列顺序(血细胞、血管、脑、肝、肺:高风险,灰色点;生殖器官、乳腺、前列腺:低风险,灰色点;所有其他器官:中等风险;灰色点)。下面部分:每个器官的相对肽检测频率显示为脊柱图。图表下面的数位表示每个器官分析的总样本数中检测到肽的样本数。如果在一个样本上检测到肽,但因技术原因无法量化,则该样本纳入检测频率图中,但图表上部分不显示任何点。图1A至1B显示与一组HLA-A*24正常样本相比各种肽在HLA-A*24癌症组织中的过量提呈(正常样本N=19,肿瘤样本N=94)。组织(从左到右):正常样本:bloodvess(血管);脑;心;肝;肺;肾脏;pituit(垂体)。肿瘤样本:GBM:胶质细胞瘤;GC:胃癌;HCC:肝细胞癌;NSCLCadeno(非小细胞肺癌腺癌);NSCLCother(非小细胞癌);NSCLCsquam(鳞状细胞非小细胞肺癌);SCLC:小细胞肺癌。图1A)基因符号:URB1,肽:LYQEILAQL(SEQ ID NO.:62),图1B)基因符号:CKAP5,肽:VYPASKMFPFI(SEQ ID NO.:65)。图1C至1D显示与一组HLA-A*02正常样本相比各种肽在HLA-A*02癌症组织中的过量提呈(正常样本N=469,肿瘤样本N=528)。组织(从左到右):正常样本:血细胞;bloodvess(血管);脑;心;肝;肺;脂肪(脂肪组织);adren.gl.(肾上腺);胆管;膀胱;BM(骨髓);esoph(食管);眼;gallb(胆囊);头颈部;肾;large_int(大肠);LN(淋巴结);神经;胰腺;parathyr(甲状旁腺);perit(腹膜);pituit(垂体);胸膜;skel.mus(骨骼肌);皮肤;small_int(小肠);脾;胃;甲状腺;气管;输尿管;乳房;卵巢;胎盘;前列腺;睾丸;胸腺;子宫。肿瘤样本:AML:急性髓性白血病;BRCA:乳腺癌;CCC:胆管细胞癌;CLL:慢性淋巴细胞白血病;CRC:结直肠癌;GBC:胆囊癌;GBM:胶质细胞瘤;GC:胃癌;GEJC:胃贲门食管癌;HCC:肝细胞癌;HNSCC:头颈癌;MEL:黑色素瘤;NHL:非霍奇金淋巴瘤;NSCLCadeno(非小细胞肺癌腺癌);NSCLCother(非小细胞癌);NSCLCsquam(鳞状细胞非小细胞肺癌);OC:卵巢癌;OSCAR:食管癌;PACA:胰腺癌;PRCA:前列腺癌;RCC:肾细胞癌;SCLC:小细胞肺癌;UBC:膀胱癌;UEC:子宫和子宫内膜癌。图1C)基因符号:BMS1,肽:VLYDKDAVYV(SEQ ID NO.:129),图1D)基因符号:GORASP2,肽:NLWGGQGLLGV(SEQ ID NO.:130)。图1E至1F显示与一组HLA-A*01正常样本相比各种肽在HLA-A*01癌症组织中的过量提呈(正常样本N=13,肿瘤样本N=40)。组织(从左到右):正常样本:血细胞;脑;心;肝;肺。肿瘤样本:GBM:胶质母细胞瘤;HCC:肝细胞癌;NSCLCadeno(非小细胞肺癌腺癌);NSCLCother(非小细胞癌);NSCLCsquam(鳞状细胞非小细胞肺癌);SCLC:小细胞肺癌。图1E)基因符号:ZNF439,肽:LLDISQKNLY(SEQ ID NO:154),图1F)基因符号:MMP12,肽:SADDIRGIQSLY(SEQID NO.:174)。图1G至1H显示与一组HLA-A*03正常样本相比各种肽在HLA-A*03癌症组织中的过量提呈(正常样本N=12,肿瘤样本N=28)。组织(从左到右):正常样本:血细胞;bloodvess(血管);脑;心;肝;肺。肿瘤样本:GBM:胶质细胞瘤;GC:胃癌;NHL:非霍奇金淋巴瘤;NSCLCadeno(非小细胞肺癌腺癌);NSCLCother(非小细胞癌);NSCLCsquam(鳞状细胞非小细胞肺癌);SCLC:小细胞肺癌。图1G)基因符号:KRT81、KRT121P、KRT83、KRT85、KRT86,肽:KLAELEGALQK(SEQ ID NO:202),图1H)基因符号:NDC80,肽:SINKPTSER(SEQ ID NO.:457)。图1I至1J显示与一组HLA-B*07正常样本相比各种肽在HLA-B*07癌症组织中的过量提呈(正常样本N=13,肿瘤样本N=36)。组织(从左到右):正常样本:血细胞;bloodvess(血管);脑;心;肝;肺。肿瘤样本:GBM:胶质母细胞瘤;NSCLCadeno(非小细胞肺癌腺癌);NSCLCother(非小细胞癌);NSCLCsquam(鳞状细胞非小细胞肺癌);OC:卵巢癌;SCLC:小细胞肺癌。图1I)基因符号:CTHRC1,肽:SPQRLRGLL(SEQ ID NO.:291),图1J)基因符号:MANEA,肽:RPHKPGLYL(SEQ ID NO.:475)。图1K至1L显示与一组HLA-B*08正常样本相比各种肽在HLA-B*08癌症组织中的过量提呈(正常样本N=1,肿瘤样本N=22)。组织(从左到右):正常样本:肺。肿瘤样本:GBM:胶质母细胞瘤;NSCLCadeno(非小细胞肺癌腺癌);NSCLCother(非小细胞癌);NSCLCsquam(鳞状细胞非小细胞肺癌);SCLC:小细胞肺癌。图1K)基因符号:VPS13B,肽:DIYQRALNL(SEQ ID NO.:315),图1L)基因符号:ARID4A,肽:LVKVKVLL(SEQ ID NO.:317)。图1M至1N显示与一组HLA-B*44正常样本相比各种肽在HLA-B*44癌症组织中的过量提呈(正常样本N=15,肿瘤样本N=25)。组织(从左到右):正常样本:脑;心;肝;肺。肿瘤样本:GBM:胶质母细胞瘤;NSCLCadeno(非小细胞肺癌腺癌);NSCLCother(非小细胞癌);NSCLCsquam(鳞状细胞非小细胞肺癌);SCLC:小细胞肺癌。图1M)基因符号:NUP155,肽:SEKGVIQVY(SEQ IDNO.:362),图1N)基因符号:CLSPN,肽:SEIGKAVGF(SEQ ID NO.:489)。
图2A至2N显示了本发明的源基因的代表性外显子表达特征,其在不同癌症样本中过度表达。肿瘤(黑点)和正常(灰色点)样本按照器官起源分组,箱须图代表了中位数、第25和第75百分位(箱)以及最小和最大(须)RPKM值。正常器官根据风险类别排列顺序。FPKM=每百万映射读数每千堿基片段。正常样本:血细胞;bloodvess:血冠;脑;心;肝;肺;脂肪:脂肪组织;adren.gl.:肾上腺;胆管;膀胱;BM:骨髓;软骨;esoph:食管;眼睛;gallb:胆囊;头颈部;肾;large_int:大肠;LN:淋巴结;神经;胰腺;parathyr:甲状旁腺;perit:腹膜;pituit:垂体;胸膜;skel.mus:骨骼肌;皮肤;small_int:小肠;脾;胃;甲状腺;气管;输尿管;乳房;卵巢;胎盘;前列腺;睾丸;胸腺;子宫。肿瘤样本:AML:急性髓性白血病;BRCA:乳腺癌;CCC:胆管细胞癌;CLL:慢性淋巴细胞白血病;CRC:结直肠癌;GBC:胆囊癌;GBM:胶质细胞瘤;GC:胃癌;HCC:肝细胞癌;HNSCC:头颈癌;MEL:黑色素瘤;NHL:非霍奇金淋巴瘤;NSCLCadeno:非小细胞肺癌腺癌;NSCLCother:非小细胞肺癌;NSCLCsquam:非小细胞肺癌鳞状细胞;OC:卵巢癌;OSCAR:食管癌;PACA:胰腺癌;PRCA:前列腺癌;RCC:肾细胞癌;SCLC:小细胞肺癌;UBC:膀胱癌;UEC:子宫和子宫内膜癌。图2A)基因符号:ADAMTS12,肽:QYDPTPLTW(SEQ ID No.:1),图2B)基因符号:MMP12,肽:VWSNVTPLKF(SEQ ID No.:2),图2C)基因符号:MMP12,肽:YVDINTFRL(SEQ ID No.:84),图2D)基因符号:KIF26B,肽:TLYPYQISQL(SEQ IDNo.:87),图2E)基因符号:CT83,肽:NTDNNLAVY(SEQ ID No.:164),图2F)基因符号:LAMA1,肽:VSDSECLSRY(SEQ ID No.:189),图2G)基因符号:KIF26B,肽:KVKDTPGLGK(SEQ ID No.:203),图2H)基因符号:SP6,肽:SLDGAARPK(SEQ ID No.:205),图2I)基因符号:PRAME,肽:SPSVSQLSVL(SEQ ID No.:220),图2J)基因符号:MMP1,肽:NPFYPEVEL(SEQ ID No.:222),图2K)基因符号:NLRP2,肽:FNKRKPLSL(SEQ ID No.:298),图2L)基因符号:KIF26B,肽:VASPKHCVL(SEQ ID No.:300),图2M)基因符号:MAGEA3、MAGEA6,肽:MEVDPIGHVYIF(SEQ IDNo.:320),图2N)基因符号:MMP12,肽:QEMQHFLGL(SEQ ID No.:326)。
图3显示了健康HLA-A*02+供体的肽特异性CD8+T细胞体外反应的示例性结果。CD8+T细胞制备的方法为:使用抗CD28 mAb和HLA-A*02涂层的人工APC分别与SeqID No520肽(KIQEMQHFL,Seq ID NO:520)(A,左图)。经过3个周期的刺激后,用A*02/SeqID No 520(A)的2D多聚体染色法对肽反应性细胞进行检测。右图(B)显示了用不相关A*02/肽复合体刺激的细胞对照染色。活单细胞透过CD8+淋巴细胞门控。Boolean门控帮助排除用不同肽特定的多聚体检测的假阳性事件。提示了特异性多聚体+细胞和CD8+淋巴细胞的频率。
图4显示了健康HLA-A*24+供体的肽特异性CD8+T细胞体外反应的示例性结果。CD8+T细胞制备的方法为:使用抗CD28 mAb和HLA-A*24涂层的人工APC分别与SeqID No504肽(A,左图)。经过3个周期的刺激后,用A*24/SeqID No 504(VYEKNGYIYF,Seq ID NO:504)(A)的2D多聚体染色法对肽反应性细胞进行检测。右图(B)显示了用不相关A*24/肽复合体刺激的细胞对照染色。活单细胞透过CD8+淋巴细胞门控。Boolean门控帮助排除用不同肽特定的多聚体检测的假阳性事件。提示了特异性多聚体+细胞和CD8+淋巴细胞的频率。
图5显示了健康HLA-A*01+供体的肽特异性CD8+T细胞体外反应的示例性结果。CD8+T细胞制备的方法为:使用抗CD28 mAb和HLA-A*01涂层的人工APC分别与SeqID No 153肽(KLDRSVFTAY,Seq ID NO:153)(A,左图)和SeqID No 173肽(RTEFNLNQY,Seq ID NO:173)(B,左图)合成。经过3个周期的刺激后,用A*01/SeqID No 153(A)或A*01/SeqID No 173进行2D多聚体染色检测肽反应性细胞。右图(A和B)显示不相关A*01/肽复合体刺激的细胞的对照染色。活单细胞在CD8+淋巴细胞上得到门控。Boolean门控帮助排除用不同肽特定的多聚体检测的假阳性事件。提示了特异性多聚体+细胞和CD8+淋巴细胞的频率。
图6显示了健康HLA-A*02+供体的肽特异性CD8+T细胞体外反应的示例性结果。CD8+T细胞制备的方法为:使用抗CD28 mAb和HLA-A*02涂层的人工APC分别与SeqID No 89肽(ILSTTMVTV,Seq ID NO:89)(A,左图)和SeqID No 88肽(VQMVITEAQKV,Seq ID NO:88)(B,左图)合成。经过3个周期的刺激后,用A*02/SeqID No 89(A)或A*02/SeqID No 88(B)的2D多聚体染色法对肽反应性细胞进行检测。右图(A和B)显示用不相关A*02/肽复合体刺激的细胞对照染色。活单细胞在CD8+淋巴细胞上得到门控。Boolean门控帮助排除用不同肽特定的多聚体检测的假阳性事件。提示了特异性多聚体+细胞和CD8+淋巴细胞的频率。
图7显示了健康HLA-A*03+供体的肽特异性CD8+T细胞体外反应的示例性结果。CD8+T细胞制备的方法为:使用抗CD28 mAb和HLA-A*03涂层的人工APC分别与SeqID No 208肽(GLASRILDAK,Seq ID NO:208)(A,左图)和SeqID No 210肽(ATSGVPVYK,Seq ID NO:210)(B,左图)处理。经过3个周期的刺激后,用A*03/SeqID No 208(A)或A*03/SeqID No 210(B)的2D多聚体染色法对肽反应性细胞进行检测。右图(A和B)显示用不相关A*03/肽复合体刺激的细胞对照染色。活单细胞在CD8+淋巴细胞上得到门控。Boolean门控帮助排除用不同肽特定的多聚体检测的假阳性事件。提示了特异性多聚体+细胞和CD8+淋巴细胞的频率。
图8显示了健康HLA-A*24+供体的肽特异性CD8+T细胞体外反应的示例性结果。CD8+T细胞制备的方法为:使用抗CD28 mAb和HLA-A*24涂层的人工APC分别与SeqID No 15肽(KYALLLQDL,Seq ID NO:15)(A,左图)和SeqID No 11肽(YYSKSVGFMQW,Seq ID NO:11)(B,左图)处理。经过3个周期的刺激后,用A*24/SeqID No 15(A)或A*24/SeqID No 11(B)的2D多聚体染色法对肽反应性细胞进行检测。右图(A和B)显示用不相关A*24/肽复合体刺激的细胞对照染色。活单细胞在CD8+淋巴细胞上得到门控。Boolean门控帮助排除用不同肽特定的多聚体检测的假阳性事件。提示了特异性多聚体+细胞和CD8+淋巴细胞的频率。
图9显示了健康HLA-B*07+供体的肽特异性CD8+T细胞体外反应的示例性结果。CD8+T细胞制备的方法为:使用抗CD28 mAb和HLA-B*07涂层的人工APC分别与SeqID No 225肽(LPFDGPGGIL,Seq ID NO:225)(A,左图)和SeqID No 248肽(IPNWARQDL,Seq ID NO:248)(B,左图)处理。经过3个周期的刺激后,用B*07/SeqID No 225(A)或B*07/SeqID No 248(B)的2D多聚体染色法对肽反应性细胞进行检测。右图(A和B)显示用不相关B*07/肽复合体刺激的细胞对照染色。活单细胞在CD8+淋巴细胞上得到门控。Boolean门控帮助排除用不同肽特定的多聚体检测的假阳性事件。提示了特异性多聚体+细胞和CD8+淋巴细胞的频率。
图10显示了健康HLA-B*08+供体的肽特异性CD8+T细胞体外反应的示例性结果。CD8+T细胞制备的方法为:使用抗CD28 mAb和HLA-B*08涂层的人工APC分别与SeqID No 299肽(MAQFKEISL,Seq ID NO:299)(A,左图)和SeqID No 297肽(RAQLKLVAL,Seq ID NO:297)(B,左图)处理。经过3个周期的刺激后,用B*08/SeqID No 299(A)或B*08/SeqID No 297(B)的2D多聚体染色法对肽反应性细胞进行检测。右图(A和B)显示用不相关B*08/肽复合体刺激的细胞对照染色。活单细胞在CD8+淋巴细胞上得到门控。Boolean门控帮助排除用不同肽特定的多聚体检测的假阳性事件。提示了特异性多聚体+细胞和CD8+淋巴细胞的频率。
图11显示了健康HLA-B*44+供体的肽特异性CD8+T细胞体外反应的示例性结果。CD8+T细胞制备的方法为:使用抗CD28 mAb和HLA-B*44涂层的人工APC分别与SeqID No 325肽(QEQDVDLVQKY,Seq ID NO:325)(A,左图)和SeqID No 331肽(EDAQGHIW,Seq ID NO:331)(B,左图)处理。经过3个周期的刺激后,用2D多聚体染色法对肽反应性细胞进行检测,用B*44/SeqID No 325(A)或B*44/SeqID No 331(B)对单个细胞进行CD8+淋巴细胞进行门控。右图(A和B)显示用不相关B*44/肽复合体刺激的细胞对照染色。活单细胞在CD8+淋巴细胞上得到门控。Boolean门控帮助排除用不同肽特定的多聚体检测的假阳性事件。提示了特异性多聚体+细胞和CD8+淋巴细胞的频率。
实施例
实施例1
细胞表面提呈的肿瘤相关肽的识别和定量
组织样本
患者的肿瘤组织获得自:Asterand(Detroit,密西根州,美国&Royston,赫特福德郡,英国)、Bio-Options Inc.(Brea,加州,美国)、Geneticist Inc.(Glendale,加州,美国)、海德堡大学医院(海德堡,德国)、ProteoGenex Inc.(Culver City,加州,美国)、Tissue Solutions Ltd(格拉斯哥,英国)、慕尼克大学医院(慕尼克,德国)。正常组织获得自Asterand(Detroit,密西根州,美国&Royston,赫特福德郡,英国)、BioCat GmbH(海德堡,德国)、Bio-Options Inc.(Brea,加州,美国)、Bio-Options Inc.(Brea,加州,美国)、BioServe(Beltsville,马里兰州,美国)、Capital BioScience Inc.(Rockville,马里兰州,美国)、蒂宾根临床输血医疗中心(蒂宾根,德国)、Geneticist Inc.(Glendale,加州,美国)、京都府立医科大学(KPUM)(京都,日本)、大阪市立大学(OCU)(大阪,日本)、ProteoGenex Inc.(Culver City,加州,美国)、Tissue Solutions Ltd(格拉斯哥,英国)、日内瓦大学医院(日内瓦,瑞士)、海德堡大学医院(海德堡,德国)、蒂宾根大学医院(蒂宾根,德国)、慕尼克大学医院(慕尼克,德国)。所有患者在手术或尸检前都获得了书面知情同意。切除后组织立即进行急速冷冻处理,在分离TUMAP前储存于-70℃或以下。
从组织样本中分离HLA肽
根据方案(Falk et al.,1991;Seeger et al.,1999)略加修改,使用HLA-A*02特异性抗体BB7.2、HLA-A、HLA-B、HLA-特异性抗体W6/32、HLA-DR特异性L243和HLA DP特异性抗体B7/21、CNBr活化的琼脂糖凝胶、酸处理和超滤方法以免疫沉淀法获得了来自实体组织的快速冷冻组织样本的HLA肽库。
质谱分析
获得的HLA肽库根据其疏水性用反相色谱(nanoAcquity UPLC system,Waters)分离,洗脱肽用装有电喷雾源的LTQ-velos融合杂交质谱(ThermoElectron)进行了分析。肽库被直接载入填充有1.7μm C18反相材料(Waters)的分析用熔炼石英微毛细管柱(75μm内径x250mm),应用流速为400nL每分钟。随后,使用来自流速为300nL每分钟、浓度为10%至33%溶剂B中的两步180分钟二元梯度法对肽进行分离。梯度由溶剂A(含0.1%甲酸的水)和溶剂B(含0.1%甲酸的乙腈)。金镀膜玻璃毛细管(PicoTip,New Objective)用于引入到纳升电喷雾源。使用前5(TOP5)策略在资料依赖模式下操作LTQ-Orbitrap质谱仪。简言之,首先以高精确品质完全扫描在orbitrap开始一个扫描周期(R=30 000),之后用先前选定离子的动态排除技术在orbitrap中对5种含量最为丰富的前体离子进行MS/MS扫描(R=7500)。串联质谱由SEQUEST以固定的错误发现率(q≤0.05)和额外的手动控制器进行解读。在确定的肽序列不确定的情况下,透过比较生成的天然肽片段化模式与合成序列相同参考肽的片段化模式,进一步验证所述肽序列。
无标记相对LC-MS定量透过离子计数(即透过LC-MS功能提取和分析)来进行(Mueller et al.,2007)。该方法假定肽的LC-MS信号区域与样本中其丰度相关。提取的特征透过充电状态去卷积和保留时间校准进行进一步处理(Mueller et al.,2008;Sturm etal.,2008)。最后,所有的LC-MS特征与序列鉴定结果交叉引用,以将不同样本和组织的定量资料与肽呈递特征结合。定量资料根据集中资料以两层方式进行正态化处理,以说明技术和生物学复制变异。因此,每个被识别的肽均可与定量资料相关,从而可得出样本和组织之间的相对定量。此外,对候选肽获得的所有定量资料进行手动检查,以确保资料的一致性,并验证自动化分析的准确度。对于每种肽,计算了提呈图,其显示样本平均提呈量以及复制变化。这些特征使癌症样本与正常组织样本的基线值并列。在肿瘤上示例性过度提呈或专门提呈的肽的提呈谱示于图1中。
表8显示选定肽在各种癌症实体中的提呈,因此显示所提及的肽特别相关性用于诊断和/或治疗所示的癌症(例如:肝细胞癌为肽SEQ ID No.3,黑色素瘤、卵巢癌和子宫癌为肽SEQ ID No.11)。
表8:本发明选定肿瘤相关肽在各实体中提呈概述。AML=急性骨髓性白血病,BRCA=乳腺癌,CCC=胆管癌,GBM=脑癌,CLL=慢性淋巴细胞白血病,CRC=结直肠癌,OSCAR=食管癌,GBC=胆囊腺癌,GC=胃癌,HNSCC=头颈部鳞状细胞癌,HCC=肝细胞癌,MEL=黑色素瘤,NHL=非霍奇金淋巴瘤,OC=卵巢癌,PACA=胰腺癌,PRCA=前列腺癌和良性前列腺增生,RCC=肾细胞癌,UBC=膀胱癌,UEC=子宫癌。
实施例2
编码本发明肽的基因的表达谱
与正常细胞相比在肿瘤细胞上一种肽过度提呈或特定提呈足够其在免疫治疗中有效使用,一些肽为肿瘤特异性的,尽管存在其源蛋白也存在于正常组织中。但是,mRNA表达谱增加了免疫治疗目标肽选择中其他级别的安全性。特别是对于具有高安全性风险的治疗选择,诸如亲和力成熟的TCR,理想的目标肽将来源于对该肿瘤独一无二且不出现于正常组织中的蛋白。
RNA来源与制备
手术切除组织标本按如上所述(参见实施例1)在获得每名患者的书面知情同意后提供。手术后立即速冻肿瘤组织标本,之后在液态氮中用杵臼匀浆。使用TRI试剂(Ambion公司,Darmstadt,德国)之后用RNeasy(QIAGEN公司,Hilden,德国)清理从这些样本中制备总RNA;这两种方法都根据制造商的方案进行。
用于RNASeq实验来自健康人体组织的总RNA获得自:Asterand(底特律,密西根州,美国&Royston,赫特福德郡,英国)、Bio-Options Inc.(Brea,加州,美国)、BioCat GmbH(海德堡,德国)、(Beltsville,马里兰州,美国)、Geneticist Inc.(Glendale,加州,美国)、海德堡大学医院(Thoraxklinik,海德堡,德国)、Istituto Nazionale Tumori“Pascale”(那不勒斯,意大利)、ProteoGenex Inc.(Culver City,加州,美国)。
用于RNASeq实验来自肿瘤组织的总RNA获得自:Asterand(底特律,密西根州,美国&Royston,赫特福德郡,英国)、Geneticist Inc.(Glendale,加州,美国)、ProteoGenexInc.(Culver City,加州,美国)、Tissue Solutions Ltd(格拉斯哥,英国)、波恩大学医院(波恩,德国)、蒂宾根大学医院(蒂宾根,德国)。
所有RNA样本的品质和数量都在Agilent 2100Bioanalyzer分析仪(Agilent公司,Waldbronn,德国)上使用RNA 6000Pico LabChip Kit试剂盒(Agilent公司)进行评估。
RNAseq实验
透过新一代测序技术(RNAseq)由CeGaT(蒂宾根,德国)对肿瘤和正常组织的RNA样本进行基因表达分析。简言之,根据供应商的方案(Illumina Inc.,San Diego,加州,美国),其中包括RNA碎片化、cDNA转化和测序适配器的加入,利用Illumina HiSeq v4试剂盒准备测序文库。从多个样本获得的文库根据制造商的说明等摩尔混合并在Illumina HiSeq2500定序器上测序,产生50bp的单端读数。处理的读数使用STAR软件映射至人类基因组(GRCh38)。根据ENSEMBL序列资料库的说明(Ensembl77),表达资料在转录水平设置为RPKM(每百万映射读数每千堿基读数,由Cufflinks软件生成)并在外显子水平上设置(总读数,由Bedtools软件生成)。外显子读数被归为外显子长度和校准尺寸,以获得RPKM值。
本发明的代表性源基因在肺癌(包括NSCLC和SCLC)中高度过量表达的表达谱如图2所示。进一步代表性基因的表达分数见表9。
表9:表达分数。该表列出了来自与一系列正常组织相比在肺癌组织(NSCLCadeno=非小细胞肺癌腺癌;NSCLCsquam=非小细胞肺癌鳞状细胞;NSCLCother=非小细胞肺癌,其他亚型;SCLC=小细胞肺癌)中非常高度过量表达(+++)、与一系列正常组织相比在肿瘤上高度过量表达(++)或与一系列正常组织相比在肿瘤上过量表达(+)的基因的肽。本基线得分根据以下相关正常组织的测量值计算:脂肪组织、肾上腺、胆管、血细胞、血管、骨髓、脑、软骨、食管、眼、胆囊、心脏、头颈、肾、大肠、肝、肺、淋巴结、神经、甲状旁腺、胰腺、垂体、胸膜、骨胳肌、皮肤、小肠、脾、胃、甲状腺、气管、膀胱、输尿管。如果获得同一组织类型几个样本的表达数据,则使用各样本的算术平均值进行计算。
实施例3
MHC-I类提呈肽的体外免疫原性
为了获得关于本发明TUMAP的免疫原性资讯,发明人使用体外T细胞扩增分析方法进行了研究,其中该分析方法基于使用装载肽/MHC复合物和抗CD28抗体的人工抗原提呈细胞(aAPC)进行反复刺激。用这种方法,发明人可显示出本发明的HLA-A*02:01、HLA-A*24:02、HLA-A*01:01、HLA-A*03:01、HLA-B*07:02、HLA-B*08:01和HLA-B*44:02限制TUMAP具有免疫原性,这表明这些肽为对抗人CD8+前体T细胞的T细胞表位(表10a和表10b)。
CD8+T细胞体外启动
为了用载有肽-MHC复合物(pMHC)和抗CD28抗体的人工抗原提呈细胞进行体外刺激,发明人首先从德国曼海姆大学诊所(University clinics Mannheim)中获取健康供体CD8微珠(Miltenyi Biotec,伯吉斯格拉德巴赫,德国)透过积极选择白细胞清除术后新鲜HLA-A*02、HLA-A*24、HLA-A*01、HLA-A*03、HLA-B*07、HLA-B*08或HLA-B*44产物而分离出CD8+T细胞。
PBMC和分离出的CD8+淋巴细胞使用前在T细胞培养基(TCM)中培养,培养基包括RPMI-Glutamax(Invitrogen公司,卡尔斯鲁厄,德国)并补充10%热灭活人AB血清(PAN-Biotech公司,艾登巴赫,德国)、100U/ml青霉素/100μg/ml链霉素(Cambrex公司,科隆,德国),1mM丙酮酸钠(CC Pro公司,Oberdorla,德国)和20μg/ml庆大霉素(Cambrex公司)。在此步骤,2.5ng/ml的IL-7(PromoCell公司,海德堡,德国)和10U/ml的IL-2(Novartis Pharma公司,纽伦堡,德国)也加入TCM。
对于pMHC/抗-CD28涂层珠的生成、T细胞的刺激和读出,使用每刺激条件四个不同pMHC分子以及每个读出条件8个不同的pMHC分子在高度限定的体外系统中进行。
纯化的共刺激小鼠IgG2a抗人CD28抗体9.3(Jung et al.,1987)使用制造商(Perbio公司,波恩,德国)推荐的N-羟基琥珀醯亚胺生物素进行化学生物素化处理。所用珠为5.6μm的链霉抗生物素蛋白包裹的多聚苯乙烯颗粒(Bangs Labooratories,伊利诺州,美国)。
用于阳性和阴性对照刺激物的pMHC分别为A*02:01/MLA-001(从Melan-A/MART-1中修饰制得的肽ELAGIGILTV(SEQ ID NO.532))和A*02:01/DDX5-001(从DDX5中获得的YLLPAIVHI(SEQ ID NO.533))。
800.000珠/200μl包裹于含有4x 12.5ng不同生物素-pMHC的96孔板、进行洗涤,随后加入体积为200μl的600ng生物素抗-CD28。在37℃下,在含5ng/ml IL-12(PromoCell)的200μl TCM中共培养1x106 CD8+T细胞与2x105的清洗涂层珠3天,从而启动刺激。之后,一半培养基与补充80U/ml IL-2的新鲜TCM进行交换,并且培养在37℃下持续4天。这种刺激性周期总共进行3次。对于使用每条件8种不同pMHC分子的pMHC多聚体读出,二维组合编码方法如前述使用(Andersen et al.,2012),稍作修饰,涵盖耦合至5种不同的萤光染料。最后,用Live/dead near IR染料(Invitrogen公司,卡尔斯鲁厄,德国)、CD8-FITC抗体克隆SK1(BD公司,海德堡,德国)和萤光pMHC多聚体而执行多聚体分析。对于分析,使用了配有合适镭射仪和筛检程序的BD LSRII SORP细胞仪。肽特异性细胞以占总CD8+细胞的百分比形式进行计算。多聚体分析结果使用FlowJo软件(Tree Star公司,俄勒冈州,美国)进行评估。特定多聚体+CD8+淋巴细胞的体外填装用与阴性对照刺激组比较而进行检测。如果健康供体中的至少一个可评价的体外刺激孔在体外刺激后发现含有特异性CD8+T细胞株(即该孔包含至少1%特定多聚体+CD8+T细胞,并且特定多聚体+的百分比至少为阴性对照刺激中位数的10倍),则检测给定抗原的免疫原性。
肺癌(包括NSCLC和SCLC)肽体外免疫原性
对于受到测试的HLA-I类肽,可透过肽特异性T细胞株的生成证明其体外免疫原性。TUMAP特异性多聚体对本发明的16种肽染色后流式细胞仪检测的典型结果如图3至11所示,同时也含有相应的阴性对照资讯。本发明152种肽的结果汇总于表10a和表10b。
表10a:本发明中HLA I类肽的体外免疫原性
申请人对本发明的肽所做的体外免疫原性实验的示例性结果。<20%=+;20%-49%=++;50%-69%=+++;>=70%=++++
表10b:本发明中HLA I类肽的体外免疫原性
申请人对本发明的肽所做的体外免疫原性实验的示例性结果。<20%=+;20%-49%=++;50%-69%=+++;>=70%=++++
实施例4
肽的合成
所有的肽透过使用Fmoc策略以标准、广为接受的固相肽合成法合成。每个肽的身份和纯度已使用质谱和RP-HPLC分析法确定。用冻干法(三氟乙酸盐)获得白色至类白色的肽,纯度为>50%。所有的TUMAP优选作为三氟乙酸盐或乙酸盐进行给药,其他药用盐形式也可以。
实施例5
MHC结合测定
本发明基于T细胞疗法的候选肽进一步测试其MHC结合能力(亲和性)。单个肽-MHC复合体透过UV-配体交换产生,其中,紫外线敏感肽经紫外线照射后裂解,与分析的相关肽交换。只有能够有效地结合并稳定肽接受MHC分子的候选肽才能阻止MHC复合物的解离。为了确定交换反应的产率,将基于稳定MHC复合物轻链(β2m)的检测结果进行ELISA测定。检测总体上按照Rodenko等人在(Rodenko et al.,2006)中描述的方法进行。
96孔Maxisorp板(NUNC)在室温下在PBS中以2ug/ml链霉包被过夜,用4倍洗涤并在37℃下在含封闭缓冲液的2%BSA中封闭1小时。折叠的HLA-A*02:01/MLA-001单体作为标准品,涵盖15-500ng/ml的范围。紫外线交换反应的肽-MHC单体在封闭缓冲液中稀释100倍。样本在37℃下孵育1小时,洗涤四次,在37℃下以2ug/ml HRP缀合抗-β2m温育1小时,再次洗涤,并以NH2SO4封堵的TMB溶液进行检测。在450nm处测量吸收。在生成和产生抗体或其片段时和/或T细胞受体或其片段时,通常优选显示为高交换产率(优选为高于50%,最优选为高于75%)的候选肽,这是因为它们对MHC分子表现出足够的亲合力,并能防止MHC复合物的解离。
表11:MHC-I类结合分数。HLA-I类限制肽与HLA-A*01的结合根据肽交换产量分类:>10%=+;>20%=++;>50=+++;>75%=++++
表12:MHC-I类结合分数。HLA-I类限制肽与HLA-A*02的结合根据肽交换产量分类:>10%=+;>20%=++;>50=+++;>75%=++++
表13:MHC-I类结合分数。HLA-I类限制肽与HLA-A*03的结合根据肽交换产量分类:>10%=+;>20%=++;>50=+++;>75%=++++
序列ID号 | 序列 | 肽交换 |
202 | KLAELEGALQK | "++++" |
203 | KVKDTPGLGK | "++++" |
204 | AVFDKFIRY | "++++" |
205 | SLDGAARPK | "++++" |
206 | KLIDLSQVMY | "++++" |
207 | RSFNGLLTMY | "++++" |
208 | GLASRILDAK | "++++" |
209 | RTQIPMSEK | "++++" |
210 | ATSGVPVYK | "++++" |
211 | TVNPVAIHK | "++++" |
212 | KAYEQVMHY | "++++" |
214 | RTMSEAALVRK | "++++" |
215 | MMFSGPQILKL | "++++" |
216 | KLYAWELAF | "+++" |
217 | RILNQILYY | "++++" |
218 | KTLVAELLILK | "+++" |
219 | RLRSSLVFK | "++++" |
453 | AINTSIKNK | "++++" |
454 | KVYTPSISK | "++++" |
455 | RIADIFVKK | "++++" |
456 | SMFTAILKK | "++++" |
457 | SINKPTSER | "++++" |
458 | GIADFVLKY | "++++" |
表14:MHC-I类结合分数。HLA-I类限制肽与HLA-A*24的结合根据肽交换产量分类:>10%=+;>20%=++;>50=+++;>75%=++++
表15:MHC-I类结合分数。HLA-I类限制肽与HLA-B*07的结合根据肽交换产量分类:>10%=+;>20%=++;>50=+++;>75%=++++
表16:MHC-I类结合分数。HLA-I类限制肽与HLA-B*08的结合根据肽交换产量分类:>10%=+;>20%=++;>50=+++;>75%=++++
表17:MHC-I类结合分数。HLA-I类限制肽与HLA-B*44的结合根据肽交换产量进行范围划分:>10%=+;>20%=++;>50=+++;>75%=++++
参考文献列表
Allison,J.P.et al.,Science 270(1995):932-933
Andersen,R.S.et al.,Nat.Protoc.7(2012):891-902
Appay,V.et al.,Eur.J Immunol.36(2006):1805-1814
Banchereau,J.et al.,Cell 106(2001):271-274
Beatty,G.et al.,J Immunol 166(2001):2276-2282
Beggs,J.D.,Nature 275(1978):104-109
Benjamini,Y.et al.,Journal of the Royal Statistical Society.Series B(Methodological),Vol.57(1995):289-300
Boulter,J.M.et al.,Protein Eng 16(2003):707-711
Braumuller,H.et al.,Nature(2013)
Brossart,P.et al.,Blood 90(1997):1594-1599
Bruckdorfer,T.et al.,Curr.Pharm.Biotechnol.5(2004):29-43
Card,K.F.et al.,Cancer Immunol Immunother.53(2004):345-357
Cohen,C.J.et al.,J Mol Recognit.16(2003a):324-332
Cohen,C.J.et al.,J Immunol 170(2003b):4349-4361
Cohen,S.N.et al.,Proc.Natl.Acad.Sci.U.S.A 69(1972):2110-2114
Coligan,J.E.et al.,Current Protocols in Protein Science(1995)
Colombetti,S.et al.,J Immunol.176(2006):2730-2738
Dengjel,J.et al.,Clin Cancer Res 12(2006):4163-4170
Denkberg,G.et al.,J Immunol 171(2003):2197-2207
Falk,K.et al.,Nature 351(1991):290-296
Follenzi,A.et al.,Nat Genet.25(2000):217-222
Fong,L.et al.,Proc.Natl.Acad.Sci.U.S.A 98(2001):8809-8814
Gabrilovich,D.I.et al.,Nat Med.2(1996):1096-1103
Gattinoni,L.et al.,Nat Rev.Immunol 6(2006):383-393
Gnjatic,S.et al.,Proc Natl.Acad.Sci.U.S.A 100(2003):8862-8867
Godkin,A.et al.,Int.Immunol 9(1997):905-911
Gragert,L.et al.,Hum.Immunol.74(2013):1313-1320
Green,M.R.et al.,Molecular Cloning,A Laboratory Manual 4th(2012)
Greenfield,E.A.,Antibodies:A Laboratory Manual 2nd(2014)
Gustafsson,C.et al.,Trends Biotechnol.22(2004):346-353
Hwang,M.L.et al.,J Immunol.179(2007):5829-5838
Jung,G.et al.,Proc Natl Acad Sci U S A 84(1987):4611-4615
Kibbe,A.H.,Handbook of Pharmaceutical Excipients rd(2000)
Krieg,A.M.,Nat Rev.Drug Discov.5(2006):471-484
Kuball,J.et al.,Blood 109(2007):2331-2338
Liddy,N.et al.,Nat Med.18(2012):980-987
Ljunggren,H.G.et al.,J Exp.Med.162(1985):1745-1759
Longenecker,B.M.et al.,Ann N.Y.Acad.Sci.690(1993):276-291
Lonsdale,J.,Nat.Genet.45(2013):580-585
Lukas,T.J.et al.,Proc.Natl.Acad.Sci.U.S.A 78(1981):2791-2795
Lundblad,R.L.,Chemical Reagents for Protein Modification 3rd(2004)
Meziere,C.et al.,J Immunol 159(1997):3230-3237
Morgan,R.A.et al.,Science 314(2006):126-129
Mortara,L.et al.,Clin Cancer Res.12(2006):3435-3443
Mueller,L.N.et al.,J Proteome.Res 7(2008):51-61
Mueller,L.N.et al.,Proteomics.7(2007):3470-3480
Mumberg,D.et al.,Proc.Natl.Acad.Sci.U.S.A 96(1999):8633-8638
Pinheiro,J.et al.,nlme:Linear and Nonlinear Mixed Effects Models(http://CRAN.R-project.org/packe=nlme)(2015)
Plebanski,M.et al.,Eur.J Immunol 25(1995):1783-1787
Porta,C.et al.,Virology 202(1994):949-955
Rammensee,H.et al.,Immunogenetics 50(1999):213-219
Reinmuth,N.et al.,Dtsch.Med.Wochenschr.140(2015):329-333
Rini,B.I.et al.,Cancer 107(2006):67-74
Rock,K.L.et al.,Science 249(1990):918-921
Rodenko,B.et al.,Nat Protoc.1(2006):1120-1132
S3-Leitlinie Lungenkarzinom,020/007,(2011)
Saiki,R.K.et al.,Science 239(1988):487-491
Schmitt,T.M.et al.,Hum.Gene Ther.20(2009):1240-1248
Scholten,K.B.et al.,Clin Immunol.119(2006):135-145
Seeger,F.H.et al.,Immunogenetics 49(1999):571-576
SEER Stat facts,(2014),http://seer.cancer.gov/
Shepherd,F.A.et al.,J Clin.Oncol.31(2013):2173-2181
Sherman,F.et al.,Laboratory Course Manual for Methods in YeastGenetics(1986)
Singh-Jasuja,H.et al.,Cancer Immunol.Immunother.53(2004):187-195
Small,E.J.et al.,J Clin Oncol.24(2006):3089-3094
Sturm,M.et al.,BMC.Bioinformatics.9(2008):163
Teufel,R.et al.,Cell Mol Life Sci.62(2005):1755-1762
Tran,E.et al.,Science 344(2014):641-645
Travis,W.D.et al.,J Clin.Oncol.31(2013):992-1001
Walter,S.et al.,J Immunol 171(2003):4974-4978
Walter,S.et al.,Nat Med.18(2012):1254-1261
Willcox,B.E.et al.,Protein Sci.8(1999):2418-2423
World Cancer Report,(2014)
Zaremba,S.et al.,Cancer Res.57(1997):4570-4577
Zufferey,R.et al.,J Virol.73(1999):2886-2892
序列名单
<110> Immatics biotechnologies GmbH
<120> 用于肺癌(包括 NSCLC、SCLC 和其他癌症)免疫治疗的新型肽和肽组合物
<130> I33040WO
<150> DE 10 2017 115 301.2
<151> 2017-07-07
<150> US 62/529,758
<151> 2017-07-07
<160> 533
<170> PatentIn version 3.5
<210> 1
<211> 9
<212> PRT
<213> Homo sapiens
<400> 1
Gln Tyr Asp Pro Thr Pro Leu Thr Trp
1 5
<210> 2
<211> 10
<212> PRT
<213> Homo sapiens
<400> 2
Val Trp Ser Asn Val Thr Pro Leu Lys Phe
1 5 10
<210> 3
<211> 8
<212> PRT
<213> Homo sapiens
<400> 3
Tyr Leu Glu Lys Phe Tyr Gly Leu
1 5
<210> 4
<211> 9
<212> PRT
<213> Homo sapiens
<400> 4
Ser Tyr Glu Lys Val Ile Asn Tyr Leu
1 5
<210> 5
<211> 9
<212> PRT
<213> Homo sapiens
<400> 5
Arg Tyr Met Lys Lys Asp Tyr Leu Ile
1 5
<210> 6
<211> 9
<212> PRT
<213> Homo sapiens
<400> 6
Lys Tyr Lys Asp Tyr Phe Pro Val Ile
1 5
<210> 7
<211> 9
<212> PRT
<213> Homo sapiens
<400> 7
Val Gln Gln Trp Ser Val Ala Val Phe
1 5
<210> 8
<211> 10
<212> PRT
<213> Homo sapiens
<400> 8
Pro Phe Leu Pro Pro Ala Ala Cys Phe Phe
1 5 10
<210> 9
<211> 9
<212> PRT
<213> Homo sapiens
<400> 9
Arg Ile Leu Arg Phe Pro Trp Gln Leu
1 5
<210> 10
<211> 10
<212> PRT
<213> Homo sapiens
<400> 10
Val Trp Ser Asp Val Thr Pro Leu Asn Phe
1 5 10
<210> 11
<211> 11
<212> PRT
<213> Homo sapiens
<400> 11
Tyr Tyr Ser Lys Ser Val Gly Phe Met Gln Trp
1 5 10
<210> 12
<211> 10
<212> PRT
<213> Homo sapiens
<400> 12
Ser Thr Ile Arg Gly Glu Leu Phe Phe Phe
1 5 10
<210> 13
<211> 9
<212> PRT
<213> Homo sapiens
<400> 13
His Tyr Thr Tyr Ile Leu Glu Val Phe
1 5
<210> 14
<211> 8
<212> PRT
<213> Homo sapiens
<400> 14
Ser Tyr Ser Ser Cys Tyr Ser Phe
1 5
<210> 15
<211> 9
<212> PRT
<213> Homo sapiens
<400> 15
Lys Tyr Ala Leu Leu Leu Gln Asp Leu
1 5
<210> 16
<211> 9
<212> PRT
<213> Homo sapiens
<400> 16
Thr Tyr Asn Pro Asp Phe Ser Ser Leu
1 5
<210> 17
<211> 11
<212> PRT
<213> Homo sapiens
<400> 17
Tyr Tyr Ala Asp Lys Lys Thr Phe Ile Val Leu
1 5 10
<210> 18
<211> 9
<212> PRT
<213> Homo sapiens
<400> 18
Asp Tyr Ile Gly Ser Val Glu Lys Trp
1 5
<210> 19
<211> 9
<212> PRT
<213> Homo sapiens
<400> 19
Ile Leu Lys Glu Asp Pro Phe Leu Phe
1 5
<210> 20
<211> 9
<212> PRT
<213> Homo sapiens
<400> 20
Glu Phe Thr Thr Val Leu Tyr Asn Phe
1 5
<210> 21
<211> 8
<212> PRT
<213> Homo sapiens
<400> 21
Ser Tyr Glu Val Arg Ser Thr Phe
1 5
<210> 22
<211> 9
<212> PRT
<213> Homo sapiens
<400> 22
Thr Gln Pro Gly Asp Trp Thr Leu Phe
1 5
<210> 23
<211> 9
<212> PRT
<213> Homo sapiens
<400> 23
Lys Phe Ile Ile Ser Asp Trp Arg Phe
1 5
<210> 24
<211> 10
<212> PRT
<213> Homo sapiens
<400> 24
Met Tyr Pro Asp Leu Ser Glu Leu Leu Met
1 5 10
<210> 25
<211> 9
<212> PRT
<213> Homo sapiens
<400> 25
Ser Tyr Asn Gly Tyr Val Phe Tyr Leu
1 5
<210> 26
<211> 9
<212> PRT
<213> Homo sapiens
<400> 26
Lys Thr Pro Thr Asn Tyr Tyr Leu Phe
1 5
<210> 27
<211> 9
<212> PRT
<213> Homo sapiens
<400> 27
Asn Tyr Thr Leu Tyr Pro Ile Thr Phe
1 5
<210> 28
<211> 9
<212> PRT
<213> Homo sapiens
<400> 28
Tyr Tyr Ser Ile Ile Ser His Thr Leu
1 5
<210> 29
<211> 10
<212> PRT
<213> Homo sapiens
<400> 29
Val Tyr Pro Leu Leu Ser Arg Leu Tyr Trp
1 5 10
<210> 30
<211> 10
<212> PRT
<213> Homo sapiens
<400> 30
Gln Tyr Leu Pro Gly Trp Thr Val Leu Phe
1 5 10
<210> 31
<211> 9
<212> PRT
<213> Homo sapiens
<400> 31
Gln Tyr Gln Asn Val Leu Thr Leu Trp
1 5
<210> 32
<211> 9
<212> PRT
<213> Homo sapiens
<400> 32
Ser Leu Pro Asp Leu Thr Pro Thr Phe
1 5
<210> 33
<211> 10
<212> PRT
<213> Homo sapiens
<400> 33
Lys Ser Ser Val Ile Ala Ser Leu Leu Phe
1 5 10
<210> 34
<211> 9
<212> PRT
<213> Homo sapiens
<400> 34
Met Gln Pro Arg Met Phe Phe Leu Phe
1 5
<210> 35
<211> 9
<212> PRT
<213> Homo sapiens
<400> 35
Lys Tyr Leu Glu Glu Ser Val Trp Leu
1 5
<210> 36
<211> 10
<212> PRT
<213> Homo sapiens
<400> 36
Lys Gln Met Glu Asp Gly His Thr Leu Phe
1 5 10
<210> 37
<211> 10
<212> PRT
<213> Homo sapiens
<400> 37
Gln Trp Pro Trp Gln Ala Ser Leu Gln Phe
1 5 10
<210> 38
<211> 9
<212> PRT
<213> Homo sapiens
<400> 38
Lys Tyr Thr Asn Trp Lys Ala Phe Leu
1 5
<210> 39
<211> 9
<212> PRT
<213> Homo sapiens
<400> 39
Leu Ile Phe Met Leu Ala Asn Val Phe
1 5
<210> 40
<211> 12
<212> PRT
<213> Homo sapiens
<400> 40
Gln Tyr Glu Pro Pro Ser Ala Pro Ser Thr Thr Phe
1 5 10
<210> 41
<211> 9
<212> PRT
<213> Homo sapiens
<400> 41
Val Ile Tyr Phe Met Gly Ala Ile Phe
1 5
<210> 42
<211> 9
<212> PRT
<213> Homo sapiens
<400> 42
Thr Leu Pro Asn Thr Ile Tyr Arg Phe
1 5
<210> 43
<211> 9
<212> PRT
<213> Homo sapiens
<400> 43
Ile Gln Met Asp Glu Pro Met Ala Phe
1 5
<210> 44
<211> 9
<212> PRT
<213> Homo sapiens
<400> 44
Ala Tyr Leu Ser Ala Val Gly Thr Phe
1 5
<210> 45
<211> 9
<212> PRT
<213> Homo sapiens
<400> 45
Lys Tyr Phe Val Pro Pro Gln Leu Phe
1 5
<210> 46
<211> 11
<212> PRT
<213> Homo sapiens
<400> 46
Ala Phe Pro Val Thr Ser Ile Phe His Thr Phe
1 5 10
<210> 47
<211> 9
<212> PRT
<213> Homo sapiens
<400> 47
Lys Tyr Ala Asp Tyr Phe Leu Glu Val
1 5
<210> 48
<211> 11
<212> PRT
<213> Homo sapiens
<400> 48
Val Phe Ile Asp His Pro Val His Leu Lys Phe
1 5 10
<210> 49
<211> 9
<212> PRT
<213> Homo sapiens
<400> 49
Leu Tyr Ile Ser Glu Val Arg Asn Ile
1 5
<210> 50
<211> 10
<212> PRT
<213> Homo sapiens
<400> 50
Ser Tyr Pro Glu Leu Val Lys Met Val Trp
1 5 10
<210> 51
<211> 9
<212> PRT
<213> Homo sapiens
<400> 51
Lys Tyr Ala Leu Leu Leu Gln Glu Leu
1 5
<210> 52
<211> 9
<212> PRT
<213> Homo sapiens
<400> 52
Lys Tyr Met Lys Ile Phe His Lys Phe
1 5
<210> 53
<211> 9
<212> PRT
<213> Homo sapiens
<400> 53
Lys Tyr Ile Thr Asn Leu Glu Asp Leu
1 5
<210> 54
<211> 9
<212> PRT
<213> Homo sapiens
<400> 54
Leu Leu Ile Lys Leu Leu Gln Thr Phe
1 5
<210> 55
<211> 9
<212> PRT
<213> Homo sapiens
<400> 55
Arg Trp Met Asp Gln Arg Leu Val Phe
1 5
<210> 56
<211> 9
<212> PRT
<213> Homo sapiens
<400> 56
Val Tyr Met Ile Glu Pro Leu Glu Leu
1 5
<210> 57
<211> 8
<212> PRT
<213> Homo sapiens
<400> 57
Tyr Pro Ser Ile Ile Gln Glu Phe
1 5
<210> 58
<211> 11
<212> PRT
<213> Homo sapiens
<400> 58
Gln Phe Ala Ala Pro Leu Arg Gly Ile Tyr Phe
1 5 10
<210> 59
<211> 9
<212> PRT
<213> Homo sapiens
<400> 59
Lys Tyr Ser Thr Thr Phe Phe Met Val
1 5
<210> 60
<211> 9
<212> PRT
<213> Homo sapiens
<400> 60
Thr Tyr Leu Ser Ile Phe Asp Gln Leu
1 5
<210> 61
<211> 9
<212> PRT
<213> Homo sapiens
<400> 61
Asn Tyr Ala Glu Asn Ile Leu Thr Leu
1 5
<210> 62
<211> 9
<212> PRT
<213> Homo sapiens
<400> 62
Leu Tyr Gln Glu Ile Leu Ala Gln Leu
1 5
<210> 63
<211> 9
<212> PRT
<213> Homo sapiens
<400> 63
Val Met Pro Ser Asp Ser Phe Phe Phe
1 5
<210> 64
<211> 11
<212> PRT
<213> Homo sapiens
<400> 64
Asn Tyr Ala Ile Phe Asp Glu Gly His Met Leu
1 5 10
<210> 65
<211> 11
<212> PRT
<213> Homo sapiens
<400> 65
Val Tyr Pro Ala Ser Lys Met Phe Pro Phe Ile
1 5 10
<210> 66
<211> 9
<212> PRT
<213> Homo sapiens
<400> 66
Ile Tyr Phe Arg Asp Ser Ser Phe Leu
1 5
<210> 67
<211> 9
<212> PRT
<213> Homo sapiens
<400> 67
Arg Tyr Pro Gly Lys Phe Tyr Arg Val
1 5
<210> 68
<211> 9
<212> PRT
<213> Homo sapiens
<400> 68
Ile Tyr Gln Gln Ile Ile Gln Thr Tyr
1 5
<210> 69
<211> 9
<212> PRT
<213> Homo sapiens
<400> 69
Ile Met Pro Glu Lys Phe Glu Phe Trp
1 5
<210> 70
<211> 9
<212> PRT
<213> Homo sapiens
<400> 70
Pro Tyr Thr Asn Tyr Thr Phe Asp Phe
1 5
<210> 71
<211> 9
<212> PRT
<213> Homo sapiens
<400> 71
Ser Tyr Met Val Leu Ala Pro Val Phe
1 5
<210> 72
<211> 9
<212> PRT
<213> Homo sapiens
<400> 72
Arg Tyr Glu Gly Ile Leu Tyr Thr Ile
1 5
<210> 73
<211> 9
<212> PRT
<213> Homo sapiens
<400> 73
Ser Tyr Ile Gly Leu Pro Leu Thr Leu
1 5
<210> 74
<211> 9
<212> PRT
<213> Homo sapiens
<400> 74
Val Tyr Asp Gln Tyr Phe Ile Thr Leu
1 5
<210> 75
<211> 9
<212> PRT
<213> Homo sapiens
<400> 75
Asn Tyr Ile Tyr Ser Ile Ser Val Phe
1 5
<210> 76
<211> 9
<212> PRT
<213> Homo sapiens
<400> 76
Trp Tyr Gly Trp His Phe Pro Glu Leu
1 5
<210> 77
<211> 10
<212> PRT
<213> Homo sapiens
<400> 77
Ala Tyr Thr Leu Leu Gly His Glu Phe Val
1 5 10
<210> 78
<211> 10
<212> PRT
<213> Homo sapiens
<400> 78
Thr Trp Phe Pro Lys Thr Pro Met Leu Phe
1 5 10
<210> 79
<211> 9
<212> PRT
<213> Homo sapiens
<400> 79
Arg Tyr Leu Ala Asp Leu Pro Thr Leu
1 5
<210> 80
<211> 9
<212> PRT
<213> Homo sapiens
<400> 80
Tyr Tyr Ser Pro Leu Arg Asp Leu Leu
1 5
<210> 81
<211> 9
<212> PRT
<213> Homo sapiens
<400> 81
Leu Tyr Pro Glu Gly Leu Arg Leu Leu
1 5
<210> 82
<211> 9
<212> PRT
<213> Homo sapiens
<400> 82
Arg Phe Leu Pro Ser Pro Val Val Ile
1 5
<210> 83
<211> 9
<212> PRT
<213> Homo sapiens
<400> 83
Thr Tyr Cys Gln Asn Ile Lys Glu Phe
1 5
<210> 84
<211> 9
<212> PRT
<213> Homo sapiens
<400> 84
Tyr Val Asp Ile Asn Thr Phe Arg Leu
1 5
<210> 85
<211> 9
<212> PRT
<213> Homo sapiens
<400> 85
Tyr Ile Asp Glu Phe Gln Ser Leu Val
1 5
<210> 86
<211> 9
<212> PRT
<213> Homo sapiens
<400> 86
Phe Val Ile Asp Gly Phe Asp Glu Leu
1 5
<210> 87
<211> 10
<212> PRT
<213> Homo sapiens
<400> 87
Thr Leu Tyr Pro Tyr Gln Ile Ser Gln Leu
1 5 10
<210> 88
<211> 11
<212> PRT
<213> Homo sapiens
<400> 88
Val Gln Met Val Ile Thr Glu Ala Gln Lys Val
1 5 10
<210> 89
<211> 9
<212> PRT
<213> Homo sapiens
<400> 89
Ile Leu Ser Thr Thr Met Val Thr Val
1 5
<210> 90
<211> 8
<212> PRT
<213> Homo sapiens
<400> 90
Phe Leu Leu Met His Pro Ser Ile
1 5
<210> 91
<211> 9
<212> PRT
<213> Homo sapiens
<400> 91
Phe Ala Leu Pro Gly Leu Leu His Ala
1 5
<210> 92
<211> 9
<212> PRT
<213> Homo sapiens
<400> 92
Asn Leu Arg Asp Leu Leu Ser Glu Val
1 5
<210> 93
<211> 9
<212> PRT
<213> Homo sapiens
<400> 93
Thr Leu Gln Glu Lys Ile Leu Gln Val
1 5
<210> 94
<211> 11
<212> PRT
<213> Homo sapiens
<400> 94
Val Leu Pro Asp Ile Glu Thr Leu Ile Gly Val
1 5 10
<210> 95
<211> 9
<212> PRT
<213> Homo sapiens
<400> 95
Ile Thr Ile Gly Val Leu Ala Arg Val
1 5
<210> 96
<211> 9
<212> PRT
<213> Homo sapiens
<400> 96
His Leu Val Gly Gly Leu His Thr Val
1 5
<210> 97
<211> 9
<212> PRT
<213> Homo sapiens
<400> 97
Val Leu Ala Leu Val Asn Ser Thr Val
1 5
<210> 98
<211> 10
<212> PRT
<213> Homo sapiens
<400> 98
Leu Gln Ser Ser Gly Leu Thr Leu Leu Leu
1 5 10
<210> 99
<211> 9
<212> PRT
<213> Homo sapiens
<400> 99
Phe Leu Lys Glu Lys Val Pro Gly Ile
1 5
<210> 100
<211> 9
<212> PRT
<213> Homo sapiens
<400> 100
Arg Gln Tyr Pro Thr Pro Phe Gln Leu
1 5
<210> 101
<211> 10
<212> PRT
<213> Homo sapiens
<400> 101
Phe Ile Ile Ser Asp Trp Arg Phe Val Leu
1 5 10
<210> 102
<211> 9
<212> PRT
<213> Homo sapiens
<400> 102
Ser Leu Leu Glu Gln Ala Ile Ala Leu
1 5
<210> 103
<211> 9
<212> PRT
<213> Homo sapiens
<400> 103
Phe Leu Tyr Tyr Pro Asp Pro Val Leu
1 5
<210> 104
<211> 9
<212> PRT
<213> Homo sapiens
<400> 104
Gly Met Leu Asp Ile Phe Trp Gly Val
1 5
<210> 105
<211> 9
<212> PRT
<213> Homo sapiens
<400> 105
Ser Leu Leu Thr His Ile Pro Thr Ala
1 5
<210> 106
<211> 11
<212> PRT
<213> Homo sapiens
<400> 106
Phe Ile Ile Asp Thr Thr Tyr Pro Ala Tyr Val
1 5 10
<210> 107
<211> 9
<212> PRT
<213> Homo sapiens
<400> 107
Leu Leu Gln Gly Ala Ile Glu Ser Val
1 5
<210> 108
<211> 9
<212> PRT
<213> Homo sapiens
<400> 108
Met Ile Ile Ala Leu Ser Leu Tyr Ile
1 5
<210> 109
<211> 11
<212> PRT
<213> Homo sapiens
<400> 109
Leu Leu Leu Gly Ser Ile Gly Leu Leu Gly Val
1 5 10
<210> 110
<211> 9
<212> PRT
<213> Homo sapiens
<400> 110
Leu Leu Ala Asp Phe Gln Ala Leu Leu
1 5
<210> 111
<211> 9
<212> PRT
<213> Homo sapiens
<400> 111
Ala Leu Cys Leu Leu Leu His Leu Leu
1 5
<210> 112
<211> 9
<212> PRT
<213> Homo sapiens
<400> 112
Ser Val Ser Asp Gly Ile His Ser Val
1 5
<210> 113
<211> 9
<212> PRT
<213> Homo sapiens
<400> 113
Ala Val Leu Thr Gly Leu Val Glu Val
1 5
<210> 114
<211> 9
<212> PRT
<213> Homo sapiens
<400> 114
Ile Leu Asp Glu Arg Gln Val Leu Leu
1 5
<210> 115
<211> 11
<212> PRT
<213> Homo sapiens
<400> 115
Met Leu Leu Glu Thr Gln Asp Ala Leu Tyr Val
1 5 10
<210> 116
<211> 9
<212> PRT
<213> Homo sapiens
<400> 116
Val Leu Met Glu Glu Asn Ser Lys Leu
1 5
<210> 117
<211> 10
<212> PRT
<213> Homo sapiens
<400> 117
Phe Leu Asp Pro Asn Ala Arg Pro Leu Val
1 5 10
<210> 118
<211> 9
<212> PRT
<213> Homo sapiens
<400> 118
Ala Leu Ser Ser Val Leu His Ser Ile
1 5
<210> 119
<211> 9
<212> PRT
<213> Homo sapiens
<400> 119
Arg Thr Ala Asp Ile Thr Val Thr Val
1 5
<210> 120
<211> 9
<212> PRT
<213> Homo sapiens
<400> 120
Ala Leu Leu Ala Asn Leu Pro Ala Val
1 5
<210> 121
<211> 9
<212> PRT
<213> Homo sapiens
<400> 121
Ala Leu Val Asp Thr Leu Thr Gly Ile
1 5
<210> 122
<211> 11
<212> PRT
<213> Homo sapiens
<400> 122
Ala Leu Leu Glu Met Phe Pro Glu Ile Thr Val
1 5 10
<210> 123
<211> 9
<212> PRT
<213> Homo sapiens
<400> 123
Leu Met Ala Phe Phe Leu Ala Val Val
1 5
<210> 124
<211> 9
<212> PRT
<213> Homo sapiens
<400> 124
Ser Val Ala Ser Val Leu Leu Tyr Leu
1 5
<210> 125
<211> 9
<212> PRT
<213> Homo sapiens
<400> 125
Val Leu Gln Pro Phe Leu Pro Ser Ile
1 5
<210> 126
<211> 8
<212> PRT
<213> Homo sapiens
<400> 126
Phe Leu Ser Thr Val Thr Ser Val
1 5
<210> 127
<211> 9
<212> PRT
<213> Homo sapiens
<400> 127
Gly Leu Asp Gly Ser Leu Val Phe Leu
1 5
<210> 128
<211> 8
<212> PRT
<213> Homo sapiens
<400> 128
Phe Leu Gly Thr Thr Pro Thr Leu
1 5
<210> 129
<211> 10
<212> PRT
<213> Homo sapiens
<400> 129
Val Leu Tyr Asp Lys Asp Ala Val Tyr Val
1 5 10
<210> 130
<211> 11
<212> PRT
<213> Homo sapiens
<400> 130
Asn Leu Trp Gly Gly Gln Gly Leu Leu Gly Val
1 5 10
<210> 131
<211> 9
<212> PRT
<213> Homo sapiens
<400> 131
Leu Leu Lys Glu Phe Val Gln Arg Val
1 5
<210> 132
<211> 10
<212> PRT
<213> Homo sapiens
<400> 132
Ala Leu Trp Leu Val Asp Pro Leu Thr Val
1 5 10
<210> 133
<211> 11
<212> PRT
<213> Homo sapiens
<400> 133
Met Thr Leu Pro Val Asp Ala Val Ile Ser Val
1 5 10
<210> 134
<211> 11
<212> PRT
<213> Homo sapiens
<400> 134
Ala Ala Glu Ile Gly Asp Lys Ser Trp Leu Tyr
1 5 10
<210> 135
<211> 9
<212> PRT
<213> Homo sapiens
<400> 135
Ala Ser Glu Asp Ser Val Leu Leu Tyr
1 5
<210> 136
<211> 10
<212> PRT
<213> Homo sapiens
<400> 136
Ala Thr Asp Leu Val Val Leu Asp Arg Tyr
1 5 10
<210> 137
<211> 9
<212> PRT
<213> Homo sapiens
<400> 137
Ala Thr Ser Lys Phe Met Glu Phe Tyr
1 5
<210> 138
<211> 9
<212> PRT
<213> Homo sapiens
<400> 138
Asp Ser Asp Ser Cys His Phe Asn Tyr
1 5
<210> 139
<211> 9
<212> PRT
<213> Homo sapiens
<400> 139
Glu Cys Asp Met Ala Phe His Ile Tyr
1 5
<210> 140
<211> 9
<212> PRT
<213> Homo sapiens
<400> 140
Glu Ser Asp Arg Glu Glu Leu Asn Tyr
1 5
<210> 141
<211> 9
<212> PRT
<213> Homo sapiens
<400> 141
Glu Ser Asp Val Gly Val Val Val Tyr
1 5
<210> 142
<211> 12
<212> PRT
<213> Homo sapiens
<400> 142
Glu Val Ala Glu Pro Ser Val Leu Phe Asp Leu Tyr
1 5 10
<210> 143
<211> 10
<212> PRT
<213> Homo sapiens
<400> 143
Phe Ile Asp Tyr Pro Lys Lys Glu Asp Tyr
1 5 10
<210> 144
<211> 10
<212> PRT
<213> Homo sapiens
<400> 144
Phe Leu Asp Ser Gln Asn Leu Ser Ala Tyr
1 5 10
<210> 145
<211> 8
<212> PRT
<213> Homo sapiens
<400> 145
Phe Val Asp Lys Pro Val Ala Tyr
1 5
<210> 146
<211> 10
<212> PRT
<213> Homo sapiens
<400> 146
Gly Leu Asn Thr Gly Ser Ala Leu Ser Tyr
1 5 10
<210> 147
<211> 11
<212> PRT
<213> Homo sapiens
<400> 147
Gly Ser Ser Asp Ser Ser Thr Leu Pro Lys Leu
1 5 10
<210> 148
<211> 9
<212> PRT
<213> Homo sapiens
<400> 148
Gly Thr Glu Phe Thr Thr Ile Leu Tyr
1 5
<210> 149
<211> 9
<212> PRT
<213> Homo sapiens
<400> 149
Gly Thr Glu Phe Thr Thr Val Leu Tyr
1 5
<210> 150
<211> 9
<212> PRT
<213> Homo sapiens
<400> 150
Gly Thr Glu Leu Leu Ser Leu Val Tyr
1 5
<210> 151
<211> 9
<212> PRT
<213> Homo sapiens
<400> 151
His Ser Asp Leu Lys Val Gly Glu Tyr
1 5
<210> 152
<211> 9
<212> PRT
<213> Homo sapiens
<400> 152
His Thr Asp Ser Leu His Leu Leu Ile
1 5
<210> 153
<211> 10
<212> PRT
<213> Homo sapiens
<400> 153
Lys Leu Asp Arg Ser Val Phe Thr Ala Tyr
1 5 10
<210> 154
<211> 10
<212> PRT
<213> Homo sapiens
<400> 154
Leu Leu Asp Ile Ser Gln Lys Asn Leu Tyr
1 5 10
<210> 155
<211> 9
<212> PRT
<213> Homo sapiens
<400> 155
Leu Leu Asp Pro Asn Pro His Met Tyr
1 5
<210> 156
<211> 9
<212> PRT
<213> Homo sapiens
<400> 156
Leu Leu Asp Ser Leu Arg Glu Gln Tyr
1 5
<210> 157
<211> 8
<212> PRT
<213> Homo sapiens
<400> 157
Leu Met Asp Arg Pro Ile Phe Tyr
1 5
<210> 158
<211> 9
<212> PRT
<213> Homo sapiens
<400> 158
Leu Ser Asp Leu Leu Lys Gln Gly Tyr
1 5
<210> 159
<211> 10
<212> PRT
<213> Homo sapiens
<400> 159
Leu Ser Asp Thr Ser Val Ile Gln Phe Tyr
1 5 10
<210> 160
<211> 9
<212> PRT
<213> Homo sapiens
<400> 160
Leu Thr Glu Ala Val Leu Asn Arg Tyr
1 5
<210> 161
<211> 10
<212> PRT
<213> Homo sapiens
<400> 161
Leu Val Asp Asp Gly Thr His Gly Gln Tyr
1 5 10
<210> 162
<211> 11
<212> PRT
<213> Homo sapiens
<400> 162
Leu Val Asp Asn Ser Ile Arg Glu Leu Gln Tyr
1 5 10
<210> 163
<211> 12
<212> PRT
<213> Homo sapiens
<400> 163
Asn Ser Asp Ser Ser Leu Thr Leu Arg Glu Phe Tyr
1 5 10
<210> 164
<211> 9
<212> PRT
<213> Homo sapiens
<400> 164
Asn Thr Asp Asn Asn Leu Ala Val Tyr
1 5
<210> 165
<211> 9
<212> PRT
<213> Homo sapiens
<400> 165
Asn Thr Asp Pro Thr Ala Pro Pro Tyr
1 5
<210> 166
<211> 10
<212> PRT
<213> Homo sapiens
<400> 166
Asn Thr Gln Ile Thr Asp Ile Gly Arg Tyr
1 5 10
<210> 167
<211> 11
<212> PRT
<213> Homo sapiens
<400> 167
Gln Ser Asp Pro Gly Thr Ser Val Leu Gly Tyr
1 5 10
<210> 168
<211> 12
<212> PRT
<213> Homo sapiens
<400> 168
Gln Thr Asp His Pro Gln Pro Ile Leu Asp Arg Tyr
1 5 10
<210> 169
<211> 10
<212> PRT
<213> Homo sapiens
<400> 169
Arg Leu Asp Thr Pro Leu Tyr Phe Ser Tyr
1 5 10
<210> 170
<211> 9
<212> PRT
<213> Homo sapiens
<400> 170
Arg Ser Asp Asp Thr Ala Val Tyr Tyr
1 5
<210> 171
<211> 11
<212> PRT
<213> Homo sapiens
<400> 171
Arg Ser Asp Pro Val Thr Leu Asn Val Leu Tyr
1 5 10
<210> 172
<211> 12
<212> PRT
<213> Homo sapiens
<400> 172
Arg Thr Asp Ser Cys Ser Ser Ala Gln Ala Gln Tyr
1 5 10
<210> 173
<211> 9
<212> PRT
<213> Homo sapiens
<400> 173
Arg Thr Glu Phe Asn Leu Asn Gln Tyr
1 5
<210> 174
<211> 12
<212> PRT
<213> Homo sapiens
<400> 174
Ser Ala Asp Asp Ile Arg Gly Ile Gln Ser Leu Tyr
1 5 10
<210> 175
<211> 8
<212> PRT
<213> Homo sapiens
<400> 175
Ser Asp Val Thr Pro Leu Thr Phe
1 5
<210> 176
<211> 10
<212> PRT
<213> Homo sapiens
<400> 176
Ser Arg Thr Ile Asn Val Ser Asn Leu Tyr
1 5 10
<210> 177
<211> 10
<212> PRT
<213> Homo sapiens
<400> 177
Ser Ser Asp Glu Val Asn Phe Leu Val Tyr
1 5 10
<210> 178
<211> 10
<212> PRT
<213> Homo sapiens
<400> 178
Ser Ser Asp Ser Ser Thr Leu Pro Lys Leu
1 5 10
<210> 179
<211> 10
<212> PRT
<213> Homo sapiens
<400> 179
Ser Thr Ala Lys Ser Ala Thr Trp Thr Tyr
1 5 10
<210> 180
<211> 10
<212> PRT
<213> Homo sapiens
<400> 180
Ser Thr Asp Pro Trp Ile Gln Met Ala Tyr
1 5 10
<210> 181
<211> 9
<212> PRT
<213> Homo sapiens
<400> 181
Thr Ala Asp Gly Lys Thr Tyr Tyr Tyr
1 5
<210> 182
<211> 8
<212> PRT
<213> Homo sapiens
<400> 182
Thr Asp Tyr His Val Arg Val Tyr
1 5
<210> 183
<211> 11
<212> PRT
<213> Homo sapiens
<400> 183
Thr Leu Glu Asp Ile Ala Thr Ser His Leu Tyr
1 5 10
<210> 184
<211> 11
<212> PRT
<213> Homo sapiens
<400> 184
Thr Ser Ala His Pro Glu Asp Ser Ser Phe Tyr
1 5 10
<210> 185
<211> 9
<212> PRT
<213> Homo sapiens
<400> 185
Thr Ser Asp Ser Asn Leu Asn Lys Tyr
1 5
<210> 186
<211> 8
<212> PRT
<213> Homo sapiens
<400> 186
Thr Thr Asp Ile Ile Glu Lys Tyr
1 5
<210> 187
<211> 9
<212> PRT
<213> Homo sapiens
<400> 187
Val Ala Asp Leu His Leu Tyr Leu Tyr
1 5
<210> 188
<211> 9
<212> PRT
<213> Homo sapiens
<400> 188
Val Ser Asp Ala Lys Leu Asp Lys Tyr
1 5
<210> 189
<211> 10
<212> PRT
<213> Homo sapiens
<400> 189
Val Ser Asp Ser Glu Cys Leu Ser Arg Tyr
1 5 10
<210> 190
<211> 12
<212> PRT
<213> Homo sapiens
<400> 190
Val Thr Asp Gly Ile Asn Pro Leu Ile Asp Arg Tyr
1 5 10
<210> 191
<211> 12
<212> PRT
<213> Homo sapiens
<400> 191
Val Thr Asp Gly Ser Leu Tyr Glu Gly Val Ala Tyr
1 5 10
<210> 192
<211> 11
<212> PRT
<213> Homo sapiens
<400> 192
Val Thr Glu Glu Ser Phe Asp Ser Lys Phe Tyr
1 5 10
<210> 193
<211> 9
<212> PRT
<213> Homo sapiens
<400> 193
Val Thr Glu Phe Ser Leu Asn Thr Tyr
1 5
<210> 194
<211> 10
<212> PRT
<213> Homo sapiens
<400> 194
Val Val Ala Asp Thr Lys Met Ile Glu Tyr
1 5 10
<210> 195
<211> 10
<212> PRT
<213> Homo sapiens
<400> 195
Val Val Asp Ser Val Gly Gly Tyr Leu Tyr
1 5 10
<210> 196
<211> 8
<212> PRT
<213> Homo sapiens
<400> 196
Trp Met Phe Phe Val Ile Asn Tyr
1 5
<210> 197
<211> 10
<212> PRT
<213> Homo sapiens
<400> 197
Tyr Ala Asp Thr Val Arg Pro Glu Phe Tyr
1 5 10
<210> 198
<211> 10
<212> PRT
<213> Homo sapiens
<400> 198
Tyr Leu Asp Pro Val Gln Arg Asp Leu Tyr
1 5 10
<210> 199
<211> 10
<212> PRT
<213> Homo sapiens
<400> 199
Tyr Leu Pro Gln His Thr Ile Glu Thr Tyr
1 5 10
<210> 200
<211> 9
<212> PRT
<213> Homo sapiens
<400> 200
Tyr Ser Asp Glu Asp Val Thr Lys Tyr
1 5
<210> 201
<211> 9
<212> PRT
<213> Homo sapiens
<400> 201
Tyr Val Gly Lys Glu His Met Phe Tyr
1 5
<210> 202
<211> 11
<212> PRT
<213> Homo sapiens
<400> 202
Lys Leu Ala Glu Leu Glu Gly Ala Leu Gln Lys
1 5 10
<210> 203
<211> 10
<212> PRT
<213> Homo sapiens
<400> 203
Lys Val Lys Asp Thr Pro Gly Leu Gly Lys
1 5 10
<210> 204
<211> 9
<212> PRT
<213> Homo sapiens
<400> 204
Ala Val Phe Asp Lys Phe Ile Arg Tyr
1 5
<210> 205
<211> 9
<212> PRT
<213> Homo sapiens
<400> 205
Ser Leu Asp Gly Ala Ala Arg Pro Lys
1 5
<210> 206
<211> 10
<212> PRT
<213> Homo sapiens
<400> 206
Lys Leu Ile Asp Leu Ser Gln Val Met Tyr
1 5 10
<210> 207
<211> 10
<212> PRT
<213> Homo sapiens
<400> 207
Arg Ser Phe Asn Gly Leu Leu Thr Met Tyr
1 5 10
<210> 208
<211> 10
<212> PRT
<213> Homo sapiens
<400> 208
Gly Leu Ala Ser Arg Ile Leu Asp Ala Lys
1 5 10
<210> 209
<211> 9
<212> PRT
<213> Homo sapiens
<400> 209
Arg Thr Gln Ile Pro Met Ser Glu Lys
1 5
<210> 210
<211> 9
<212> PRT
<213> Homo sapiens
<400> 210
Ala Thr Ser Gly Val Pro Val Tyr Lys
1 5
<210> 211
<211> 9
<212> PRT
<213> Homo sapiens
<400> 211
Thr Val Asn Pro Val Ala Ile His Lys
1 5
<210> 212
<211> 9
<212> PRT
<213> Homo sapiens
<400> 212
Lys Ala Tyr Glu Gln Val Met His Tyr
1 5
<210> 213
<211> 12
<212> PRT
<213> Homo sapiens
<400> 213
Leu Asn Ile Asn Met Thr Ser Pro Met Gly Thr Lys
1 5 10
<210> 214
<211> 11
<212> PRT
<213> Homo sapiens
<400> 214
Arg Thr Met Ser Glu Ala Ala Leu Val Arg Lys
1 5 10
<210> 215
<211> 11
<212> PRT
<213> Homo sapiens
<400> 215
Met Met Phe Ser Gly Pro Gln Ile Leu Lys Leu
1 5 10
<210> 216
<211> 9
<212> PRT
<213> Homo sapiens
<400> 216
Lys Leu Tyr Ala Trp Glu Leu Ala Phe
1 5
<210> 217
<211> 9
<212> PRT
<213> Homo sapiens
<400> 217
Arg Ile Leu Asn Gln Ile Leu Tyr Tyr
1 5
<210> 218
<211> 11
<212> PRT
<213> Homo sapiens
<400> 218
Lys Thr Leu Val Ala Glu Leu Leu Ile Leu Lys
1 5 10
<210> 219
<211> 9
<212> PRT
<213> Homo sapiens
<400> 219
Arg Leu Arg Ser Ser Leu Val Phe Lys
1 5
<210> 220
<211> 10
<212> PRT
<213> Homo sapiens
<400> 220
Ser Pro Ser Val Ser Gln Leu Ser Val Leu
1 5 10
<210> 221
<211> 9
<212> PRT
<213> Homo sapiens
<400> 221
Val Pro Asp Val Ala Gln Phe Val Leu
1 5
<210> 222
<211> 9
<212> PRT
<213> Homo sapiens
<400> 222
Asn Pro Phe Tyr Pro Glu Val Glu Leu
1 5
<210> 223
<211> 9
<212> PRT
<213> Homo sapiens
<400> 223
Tyr Pro Lys Asp Ile Tyr Ser Ser Phe
1 5
<210> 224
<211> 9
<212> PRT
<213> Homo sapiens
<400> 224
Gly Pro Gln Pro Trp His Ala Ala Leu
1 5
<210> 225
<211> 10
<212> PRT
<213> Homo sapiens
<400> 225
Leu Pro Phe Asp Gly Pro Gly Gly Ile Leu
1 5 10
<210> 226
<211> 11
<212> PRT
<213> Homo sapiens
<400> 226
Ser Pro Arg Met Ser Gly Leu Leu Ser Gln Thr
1 5 10
<210> 227
<211> 11
<212> PRT
<213> Homo sapiens
<400> 227
Tyr Pro Arg Gly Asn His Trp Ala Val Gly His
1 5 10
<210> 228
<211> 12
<212> PRT
<213> Homo sapiens
<400> 228
Tyr Pro Arg Gly Asn His Trp Ala Val Gly His Leu
1 5 10
<210> 229
<211> 10
<212> PRT
<213> Homo sapiens
<400> 229
Val Pro Leu Pro Ala Gly Gly Gly Thr Val
1 5 10
<210> 230
<211> 11
<212> PRT
<213> Homo sapiens
<400> 230
Val Pro Leu Pro Ala Gly Gly Gly Thr Val Leu
1 5 10
<210> 231
<211> 10
<212> PRT
<213> Homo sapiens
<400> 231
Arg Pro Arg Ala Leu Arg Asp Leu Gln Leu
1 5 10
<210> 232
<211> 11
<212> PRT
<213> Homo sapiens
<400> 232
Arg Pro Arg Ala Leu Arg Asp Leu Gln Leu Leu
1 5 10
<210> 233
<211> 9
<212> PRT
<213> Homo sapiens
<400> 233
Lys Pro Tyr Gln Gly Asn Pro Thr Phe
1 5
<210> 234
<211> 9
<212> PRT
<213> Homo sapiens
<400> 234
Arg Ala Lys Asn Ala Gly Val Thr Ile
1 5
<210> 235
<211> 9
<212> PRT
<213> Homo sapiens
<400> 235
Met Pro Leu Lys His Tyr Leu Leu Leu
1 5
<210> 236
<211> 12
<212> PRT
<213> Homo sapiens
<400> 236
Arg Val Arg Gly Gly Glu Asp Gly Asp Arg Ala Leu
1 5 10
<210> 237
<211> 10
<212> PRT
<213> Homo sapiens
<400> 237
Arg Pro Ala Ala Thr Ala Val Ile Ser Leu
1 5 10
<210> 238
<211> 9
<212> PRT
<213> Homo sapiens
<400> 238
Lys Pro Gly Pro Pro Trp Ala Ala Phe
1 5
<210> 239
<211> 10
<212> PRT
<213> Homo sapiens
<400> 239
Tyr Val Pro Ser Ala Ser Leu Phe Met Leu
1 5 10
<210> 240
<211> 9
<212> PRT
<213> Homo sapiens
<400> 240
Ser Pro Arg Glu Val Thr Thr Val Leu
1 5
<210> 241
<211> 9
<212> PRT
<213> Homo sapiens
<400> 241
Ser Ala Arg Leu Ala Thr Asp Ala Leu
1 5
<210> 242
<211> 9
<212> PRT
<213> Homo sapiens
<400> 242
Ser Pro Arg Trp Leu Pro Val Ser Leu
1 5
<210> 243
<211> 10
<212> PRT
<213> Homo sapiens
<400> 243
Arg Pro Ile Glu Asn Arg Ile Leu Ile Leu
1 5 10
<210> 244
<211> 9
<212> PRT
<213> Homo sapiens
<400> 244
Phe Pro Tyr Val Arg Asp Phe Val Met
1 5
<210> 245
<211> 9
<212> PRT
<213> Homo sapiens
<400> 245
Arg Ile Arg Glu His Val Pro Gln Leu
1 5
<210> 246
<211> 9
<212> PRT
<213> Homo sapiens
<400> 246
Thr Pro Leu Pro Ala Val Ile Val Leu
1 5
<210> 247
<211> 9
<212> PRT
<213> Homo sapiens
<400> 247
Arg Ala Leu Leu Ala Arg Leu Leu Leu
1 5
<210> 248
<211> 9
<212> PRT
<213> Homo sapiens
<400> 248
Ile Pro Asn Trp Ala Arg Gln Asp Leu
1 5
<210> 249
<211> 9
<212> PRT
<213> Homo sapiens
<400> 249
Val Pro Ser Ser Arg Ile Leu Gln Leu
1 5
<210> 250
<211> 9
<212> PRT
<213> Homo sapiens
<400> 250
Ser Pro Arg Asp Phe Leu Ser Gly Leu
1 5
<210> 251
<211> 9
<212> PRT
<213> Homo sapiens
<400> 251
Val Pro Arg Ser Ser Gly Gln Thr Val
1 5
<210> 252
<211> 9
<212> PRT
<213> Homo sapiens
<400> 252
Ser Pro Asp Ile Arg Asn Thr Thr Val
1 5
<210> 253
<211> 10
<212> PRT
<213> Homo sapiens
<400> 253
Arg Val Ile Asp Ala Val Arg Phe Thr Leu
1 5 10
<210> 254
<211> 9
<212> PRT
<213> Homo sapiens
<400> 254
Asn Pro Phe Pro His Leu Ile Thr Leu
1 5
<210> 255
<211> 9
<212> PRT
<213> Homo sapiens
<400> 255
Met Pro Leu Leu Glu Asn Leu Tyr Leu
1 5
<210> 256
<211> 9
<212> PRT
<213> Homo sapiens
<400> 256
Ser Pro Arg Val Pro Ser Ile Glu Leu
1 5
<210> 257
<211> 9
<212> PRT
<213> Homo sapiens
<400> 257
Leu Pro Arg Ile Pro Phe Ala Asp Val
1 5
<210> 258
<211> 9
<212> PRT
<213> Homo sapiens
<400> 258
Leu Pro Arg Gly Pro Leu Ala Ser Leu
1 5
<210> 259
<211> 12
<212> PRT
<213> Homo sapiens
<400> 259
Arg Pro Pro Ala Ala Gly Leu Arg Gly Ile Ser Leu
1 5 10
<210> 260
<211> 9
<212> PRT
<213> Homo sapiens
<400> 260
Tyr Pro Gln His Pro Gly Leu Asn Ala
1 5
<210> 261
<211> 9
<212> PRT
<213> Homo sapiens
<400> 261
Ala Pro Ser Ala Arg Val Gly Val Cys
1 5
<210> 262
<211> 9
<212> PRT
<213> Homo sapiens
<400> 262
Ser Ala Tyr Pro Gln Arg Leu Glu Ile
1 5
<210> 263
<211> 9
<212> PRT
<213> Homo sapiens
<400> 263
His Pro Ala Pro Tyr Gly Asp Leu Leu
1 5
<210> 264
<211> 9
<212> PRT
<213> Homo sapiens
<400> 264
Arg Pro Ile Leu Ile Ile Ile Thr Leu
1 5
<210> 265
<211> 9
<212> PRT
<213> Homo sapiens
<400> 265
Ser Pro Arg Gln Pro Pro Arg Leu Val
1 5
<210> 266
<211> 9
<212> PRT
<213> Homo sapiens
<400> 266
His Ala Tyr Pro Pro Gly Pro Gly Leu
1 5
<210> 267
<211> 10
<212> PRT
<213> Homo sapiens
<400> 267
His Pro Glu Leu Val Asn His Ile Val Phe
1 5 10
<210> 268
<211> 9
<212> PRT
<213> Homo sapiens
<400> 268
Tyr Pro Leu Phe Arg Gly Ile Asn Leu
1 5
<210> 269
<211> 9
<212> PRT
<213> Homo sapiens
<400> 269
Ala Pro Arg Ala Pro Arg Leu Met Leu
1 5
<210> 270
<211> 9
<212> PRT
<213> Homo sapiens
<400> 270
Ala Pro Gly Pro Arg Phe Leu Val Thr
1 5
<210> 271
<211> 10
<212> PRT
<213> Homo sapiens
<400> 271
Met Pro Leu Pro Trp Ser Leu Ala Leu Pro
1 5 10
<210> 272
<211> 11
<212> PRT
<213> Homo sapiens
<400> 272
Met Pro Leu Pro Trp Ser Leu Ala Leu Pro Leu
1 5 10
<210> 273
<211> 9
<212> PRT
<213> Homo sapiens
<400> 273
Met Pro Leu Leu Trp Leu Arg Gly Phe
1 5
<210> 274
<211> 9
<212> PRT
<213> Homo sapiens
<400> 274
Thr Pro Tyr Gln Glu His Val Ala Leu
1 5
<210> 275
<211> 9
<212> PRT
<213> Homo sapiens
<400> 275
Ala Pro His Pro Pro Leu Ser Val Val
1 5
<210> 276
<211> 9
<212> PRT
<213> Homo sapiens
<400> 276
Leu Pro Arg Ala Gly Gly Ala Phe Leu
1 5
<210> 277
<211> 9
<212> PRT
<213> Homo sapiens
<400> 277
Met Pro Leu Phe Glu Pro Arg Val Phe
1 5
<210> 278
<211> 12
<212> PRT
<213> Homo sapiens
<400> 278
His Pro Met Ile Asp Ile Asn Gly Ile Ile Val Phe
1 5 10
<210> 279
<211> 9
<212> PRT
<213> Homo sapiens
<400> 279
Ser Pro Ala Arg Ala Ser Pro Ala Leu
1 5
<210> 280
<211> 11
<212> PRT
<213> Homo sapiens
<400> 280
Val Pro Ile Ser Glu Glu Gly Thr Pro Val Leu
1 5 10
<210> 281
<211> 9
<212> PRT
<213> Homo sapiens
<400> 281
Arg Pro Arg Ala Pro Val Thr Pro Ala
1 5
<210> 282
<211> 10
<212> PRT
<213> Homo sapiens
<400> 282
Met Pro Gln Ile Glu Thr Arg Val Ile Leu
1 5 10
<210> 283
<211> 9
<212> PRT
<213> Homo sapiens
<400> 283
Arg Pro His Ser Leu Ser Ser Glu Leu
1 5
<210> 284
<211> 10
<212> PRT
<213> Homo sapiens
<400> 284
Phe Pro Val Thr Ser Ile Phe His Thr Phe
1 5 10
<210> 285
<211> 9
<212> PRT
<213> Homo sapiens
<400> 285
Phe Pro Ser Phe Leu Thr Asn Ser Leu
1 5
<210> 286
<211> 8
<212> PRT
<213> Homo sapiens
<400> 286
Val Pro Thr Leu Arg Ser Glu Leu
1 5
<210> 287
<211> 10
<212> PRT
<213> Homo sapiens
<400> 287
Ala Pro Arg Glu Glu Gln Gln Arg Ser Leu
1 5 10
<210> 288
<211> 9
<212> PRT
<213> Homo sapiens
<400> 288
Phe Pro Gln Lys Phe Ile Asp Leu Leu
1 5
<210> 289
<211> 9
<212> PRT
<213> Homo sapiens
<400> 289
Val Pro Glu Asn His Ser Val Ala Leu
1 5
<210> 290
<211> 10
<212> PRT
<213> Homo sapiens
<400> 290
Ala Pro Tyr Arg Pro Pro Asp Ile Ser Leu
1 5 10
<210> 291
<211> 9
<212> PRT
<213> Homo sapiens
<400> 291
Ser Pro Gln Arg Leu Arg Gly Leu Leu
1 5
<210> 292
<211> 10
<212> PRT
<213> Homo sapiens
<400> 292
Ser Pro Gln Arg Leu Arg Gly Leu Leu Leu
1 5 10
<210> 293
<211> 12
<212> PRT
<213> Homo sapiens
<400> 293
Arg Pro Arg Ser Ala Leu Pro Arg Leu Leu Leu Pro
1 5 10
<210> 294
<211> 10
<212> PRT
<213> Homo sapiens
<400> 294
Gly Pro Thr Pro Asn Thr Gly Ala Ala Leu
1 5 10
<210> 295
<211> 9
<212> PRT
<213> Homo sapiens
<400> 295
Lys Pro Glu Gly Thr Arg Ile Ala Val
1 5
<210> 296
<211> 8
<212> PRT
<213> Homo sapiens
<400> 296
Met Pro Met Gln Asp Ile Lys Met
1 5
<210> 297
<211> 9
<212> PRT
<213> Homo sapiens
<400> 297
Arg Ala Gln Leu Lys Leu Val Ala Leu
1 5
<210> 298
<211> 9
<212> PRT
<213> Homo sapiens
<400> 298
Phe Asn Lys Arg Lys Pro Leu Ser Leu
1 5
<210> 299
<211> 9
<212> PRT
<213> Homo sapiens
<400> 299
Met Ala Gln Phe Lys Glu Ile Ser Leu
1 5
<210> 300
<211> 9
<212> PRT
<213> Homo sapiens
<400> 300
Val Ala Ser Pro Lys His Cys Val Leu
1 5
<210> 301
<211> 8
<212> PRT
<213> Homo sapiens
<400> 301
Tyr Met His Lys Leu Leu Val Leu
1 5
<210> 302
<211> 9
<212> PRT
<213> Homo sapiens
<400> 302
His Leu Leu Gln Lys Gln Thr Ser Ile
1 5
<210> 303
<211> 8
<212> PRT
<213> Homo sapiens
<400> 303
Leu Pro Phe Pro Lys Phe Thr Val
1 5
<210> 304
<211> 9
<212> PRT
<213> Homo sapiens
<400> 304
Glu Leu Lys Lys Leu Tyr Cys Gln Ile
1 5
<210> 305
<211> 9
<212> PRT
<213> Homo sapiens
<400> 305
Ala Leu Lys Leu Arg Val Ala Val Leu
1 5
<210> 306
<211> 8
<212> PRT
<213> Homo sapiens
<400> 306
Ile Leu Lys Val Lys Val Gly Leu
1 5
<210> 307
<211> 9
<212> PRT
<213> Homo sapiens
<400> 307
Ile Leu Leu Pro Arg Thr Val Ser Leu
1 5
<210> 308
<211> 9
<212> PRT
<213> Homo sapiens
<400> 308
Met Leu Lys Gln Lys Val Glu Glu Leu
1 5
<210> 309
<211> 9
<212> PRT
<213> Homo sapiens
<400> 309
Asp Ala Ile Gln Arg Lys Tyr Ser Cys
1 5
<210> 310
<211> 8
<212> PRT
<213> Homo sapiens
<400> 310
Leu Pro Pro Lys Lys Phe Val Leu
1 5
<210> 311
<211> 9
<212> PRT
<213> Homo sapiens
<400> 311
Glu Ile Arg Ile Arg Val Val Gln Met
1 5
<210> 312
<211> 9
<212> PRT
<213> Homo sapiens
<400> 312
Glu Ala Met Leu Arg Asn Lys Glu Leu
1 5
<210> 313
<211> 10
<212> PRT
<213> Homo sapiens
<400> 313
Glu Leu Lys Lys Lys Glu Tyr Glu Glu Leu
1 5 10
<210> 314
<211> 9
<212> PRT
<213> Homo sapiens
<400> 314
Ala Ile Ile Ser Arg Leu Val Ala Leu
1 5
<210> 315
<211> 9
<212> PRT
<213> Homo sapiens
<400> 315
Asp Ile Tyr Gln Arg Ala Leu Asn Leu
1 5
<210> 316
<211> 9
<212> PRT
<213> Homo sapiens
<400> 316
Val Ile Lys Glu Lys Ala Leu Thr Leu
1 5
<210> 317
<211> 8
<212> PRT
<213> Homo sapiens
<400> 317
Leu Val Lys Val Lys Val Leu Leu
1 5
<210> 318
<211> 9
<212> PRT
<213> Homo sapiens
<400> 318
Glu Ala Ala Ile Arg Ser Val Glu Leu
1 5
<210> 319
<211> 11
<212> PRT
<213> Homo sapiens
<400> 319
Ala Glu Met Leu Glu Arg Val Ile Lys Asn Tyr
1 5 10
<210> 320
<211> 12
<212> PRT
<213> Homo sapiens
<400> 320
Met Glu Val Asp Pro Ile Gly His Val Tyr Ile Phe
1 5 10
<210> 321
<211> 11
<212> PRT
<213> Homo sapiens
<400> 321
Ala Glu Met Leu Glu Ser Val Ile Lys Asn Tyr
1 5 10
<210> 322
<211> 10
<212> PRT
<213> Homo sapiens
<400> 322
Lys Glu Val Asp Pro Ala Gly His Ser Tyr
1 5 10
<210> 323
<211> 8
<212> PRT
<213> Homo sapiens
<400> 323
Ser Glu Phe Met Gln Val Ile Phe
1 5
<210> 324
<211> 9
<212> PRT
<213> Homo sapiens
<400> 324
Thr Asp Ser Ile His Ala Trp Thr Phe
1 5
<210> 325
<211> 11
<212> PRT
<213> Homo sapiens
<400> 325
Gln Glu Gln Asp Val Asp Leu Val Gln Lys Tyr
1 5 10
<210> 326
<211> 9
<212> PRT
<213> Homo sapiens
<400> 326
Gln Glu Met Gln His Phe Leu Gly Leu
1 5
<210> 327
<211> 10
<212> PRT
<213> Homo sapiens
<400> 327
Tyr Glu Ile Glu Ala Arg Asn Gln Val Phe
1 5 10
<210> 328
<211> 10
<212> PRT
<213> Homo sapiens
<400> 328
Phe Glu Tyr Asp Phe Leu Leu Gln Arg Ile
1 5 10
<210> 329
<211> 8
<212> PRT
<213> Homo sapiens
<400> 329
Asn Glu His Pro Ser Asn Asn Trp
1 5
<210> 330
<211> 10
<212> PRT
<213> Homo sapiens
<400> 330
Lys Glu Gly Asp Leu Gly Gly Lys Gln Trp
1 5 10
<210> 331
<211> 8
<212> PRT
<213> Homo sapiens
<400> 331
Glu Asp Ala Gln Gly His Ile Trp
1 5
<210> 332
<211> 8
<212> PRT
<213> Homo sapiens
<400> 332
Met Glu Val Pro Val Ile Lys Ile
1 5
<210> 333
<211> 9
<212> PRT
<213> Homo sapiens
<400> 333
Ala Glu Thr Leu Ser Thr Ile Gln Ile
1 5
<210> 334
<211> 10
<212> PRT
<213> Homo sapiens
<400> 334
Ala Glu Asp Glu Pro Ala Ala Ala His Leu
1 5 10
<210> 335
<211> 9
<212> PRT
<213> Homo sapiens
<400> 335
Lys Glu Leu Glu Ala Thr Lys Gln Tyr
1 5
<210> 336
<211> 10
<212> PRT
<213> Homo sapiens
<400> 336
Ala Ser Ser Ser Gly Pro Met Arg Trp Trp
1 5 10
<210> 337
<211> 9
<212> PRT
<213> Homo sapiens
<400> 337
Thr Glu Asn Arg Tyr Cys Val Gln Leu
1 5
<210> 338
<211> 12
<212> PRT
<213> Homo sapiens
<400> 338
Ser Glu Gly Ser Glu Pro Ala Leu Leu His Ser Trp
1 5 10
<210> 339
<211> 9
<212> PRT
<213> Homo sapiens
<400> 339
Ser Glu Pro Ala Leu Leu His Ser Trp
1 5
<210> 340
<211> 8
<212> PRT
<213> Homo sapiens
<400> 340
Thr Glu Phe Ser Leu Asn Thr Tyr
1 5
<210> 341
<211> 12
<212> PRT
<213> Homo sapiens
<400> 341
Glu Glu Ile Glu Gly Lys Gly Ser Phe Thr Tyr Phe
1 5 10
<210> 342
<211> 9
<212> PRT
<213> Homo sapiens
<400> 342
His Glu Phe Ser Ser Pro Ser His Leu
1 5
<210> 343
<211> 8
<212> PRT
<213> Homo sapiens
<400> 343
Thr Glu Phe Thr Thr Val Leu Tyr
1 5
<210> 344
<211> 10
<212> PRT
<213> Homo sapiens
<400> 344
Glu Glu Ala Thr Gly Gln Phe His Val Tyr
1 5 10
<210> 345
<211> 9
<212> PRT
<213> Homo sapiens
<400> 345
Ile Glu Phe Ile His Pro Gln Ala Phe
1 5
<210> 346
<211> 11
<212> PRT
<213> Homo sapiens
<400> 346
Val Glu Ala Pro Gly Pro Val His Val Tyr Trp
1 5 10
<210> 347
<211> 9
<212> PRT
<213> Homo sapiens
<400> 347
Ala Leu Asn Pro Tyr Gln Tyr Gln Tyr
1 5
<210> 348
<211> 10
<212> PRT
<213> Homo sapiens
<400> 348
Ala Glu Ile Gln Gly Asn Ile Asn His Val
1 5 10
<210> 349
<211> 10
<212> PRT
<213> Homo sapiens
<400> 349
Ala Glu Gln Asp Met Arg Glu Leu Thr Tyr
1 5 10
<210> 350
<211> 10
<212> PRT
<213> Homo sapiens
<400> 350
Gly Glu Cys Asp Val Phe Lys Glu Ile Leu
1 5 10
<210> 351
<211> 9
<212> PRT
<213> Homo sapiens
<400> 351
Glu Glu Val Asn Tyr Ile Asn Thr Phe
1 5
<210> 352
<211> 9
<212> PRT
<213> Homo sapiens
<400> 352
Asn Glu Val Leu Thr Tyr Ile Lys Phe
1 5
<210> 353
<211> 9
<212> PRT
<213> Homo sapiens
<400> 353
Gly Glu Ile Ile Met Gln Asn Asn Trp
1 5
<210> 354
<211> 9
<212> PRT
<213> Homo sapiens
<400> 354
Thr Glu Asp Pro Thr Ile Leu Arg Ile
1 5
<210> 355
<211> 9
<212> PRT
<213> Homo sapiens
<400> 355
Ser Asp Met Val Arg Phe His Leu Phe
1 5
<210> 356
<211> 8
<212> PRT
<213> Homo sapiens
<400> 356
Glu Glu Gly Arg Val Tyr Leu Phe
1 5
<210> 357
<211> 10
<212> PRT
<213> Homo sapiens
<400> 357
Arg Glu Leu Glu Asn Cys Phe Gln Ile Gln
1 5 10
<210> 358
<211> 9
<212> PRT
<213> Homo sapiens
<400> 358
Lys Glu Ala Asp Ile His Phe Leu Ile
1 5
<210> 359
<211> 9
<212> PRT
<213> Homo sapiens
<400> 359
Asp Glu Leu Phe Ser Ile Ala Leu Tyr
1 5
<210> 360
<211> 9
<212> PRT
<213> Homo sapiens
<400> 360
Ala Glu Val Pro Thr Gly Val Ile Ile
1 5
<210> 361
<211> 9
<212> PRT
<213> Homo sapiens
<400> 361
Ser Glu Asn Leu Phe Phe Ala Ser Phe
1 5
<210> 362
<211> 9
<212> PRT
<213> Homo sapiens
<400> 362
Ser Glu Lys Gly Val Ile Gln Val Tyr
1 5
<210> 363
<211> 9
<212> PRT
<213> Homo sapiens
<400> 363
Ala Glu Leu Asp Lys Leu Thr Ser Val
1 5
<210> 364
<211> 9
<212> PRT
<213> Homo sapiens
<400> 364
Ala Glu Thr Pro Ile Gln Asn Val Ile
1 5
<210> 365
<211> 9
<212> PRT
<213> Homo sapiens
<400> 365
Ser Glu Met Asn Val Asn Met Lys Tyr
1 5
<210> 366
<211> 8
<212> PRT
<213> Homo sapiens
<400> 366
Ala Glu Asn Leu Phe Arg Ala Phe
1 5
<210> 367
<211> 9
<212> PRT
<213> Homo sapiens
<400> 367
Gly Glu Val His Pro Ser Glu Met Ile
1 5
<210> 368
<211> 9
<212> PRT
<213> Homo sapiens
<400> 368
Gly Glu Phe Pro Val Arg Val Gln Val
1 5
<210> 369
<211> 9
<212> PRT
<213> Homo sapiens
<400> 369
Glu Glu Ile Glu Arg Phe Phe Lys Leu
1 5
<210> 370
<211> 8
<212> PRT
<213> Homo sapiens
<400> 370
Tyr Glu Asp Leu Ser Gln Lys Tyr
1 5
<210> 371
<211> 9
<212> PRT
<213> Homo sapiens
<400> 371
Gly Glu Leu Ala Leu Lys Lys Lys Ile
1 5
<210> 372
<211> 9
<212> PRT
<213> Homo sapiens
<400> 372
Thr Glu Gly Ile Ile Met Lys Asp Phe
1 5
<210> 373
<211> 9
<212> PRT
<213> Homo sapiens
<400> 373
Met Glu Met Gln Lys Ser Pro Val Phe
1 5
<210> 374
<211> 8
<212> PRT
<213> Homo sapiens
<400> 374
Asp Glu Val Asn Phe Leu Val Tyr
1 5
<210> 375
<211> 10
<212> PRT
<213> Homo sapiens
<400> 375
Val Tyr Ser Asp Leu His Ala Phe Tyr Tyr
1 5 10
<210> 376
<211> 9
<212> PRT
<213> Homo sapiens
<400> 376
Lys Tyr Val Lys Asp Phe His Lys Phe
1 5
<210> 377
<211> 9
<212> PRT
<213> Homo sapiens
<400> 377
Val Tyr Val Gly Ala Val Asn Arg Ile
1 5
<210> 378
<211> 11
<212> PRT
<213> Homo sapiens
<400> 378
Lys Phe Leu Gly Pro Ala Glu His Leu Thr Phe
1 5 10
<210> 379
<211> 10
<212> PRT
<213> Homo sapiens
<400> 379
Asn Tyr Ile Val Pro Asp Lys Gln Ile Phe
1 5 10
<210> 380
<211> 9
<212> PRT
<213> Homo sapiens
<400> 380
Val Phe Gln Glu Lys His His Val Ile
1 5
<210> 381
<211> 9
<212> PRT
<213> Homo sapiens
<400> 381
Thr Tyr Ser Lys Lys His Phe Arg Ile
1 5
<210> 382
<211> 9
<212> PRT
<213> Homo sapiens
<400> 382
Ile Tyr His Ser His His Pro Thr Leu
1 5
<210> 383
<211> 9
<212> PRT
<213> Homo sapiens
<400> 383
Arg Tyr Lys Gln Asp Val Glu Arg Phe
1 5
<210> 384
<211> 9
<212> PRT
<213> Homo sapiens
<400> 384
Lys Tyr Val Lys Val Phe Asp Lys Phe
1 5
<210> 385
<211> 9
<212> PRT
<213> Homo sapiens
<400> 385
Met Tyr Ile Asn Glu Val Glu Arg Leu
1 5
<210> 386
<211> 10
<212> PRT
<213> Homo sapiens
<400> 386
Val Tyr Asn Asp His Ser Ile Tyr Val Trp
1 5 10
<210> 387
<211> 11
<212> PRT
<213> Homo sapiens
<400> 387
Arg Trp Leu Pro Gln Lys Asn Ala Ala Gln Phe
1 5 10
<210> 388
<211> 11
<212> PRT
<213> Homo sapiens
<400> 388
Phe Ser Ile Pro Glu Gly Ala Leu Val Ala Val
1 5 10
<210> 389
<211> 10
<212> PRT
<213> Homo sapiens
<400> 389
Thr Leu Met Glu Gln Pro Leu Thr Thr Leu
1 5 10
<210> 390
<211> 9
<212> PRT
<213> Homo sapiens
<400> 390
His Ile Met Pro Thr Val His Thr Val
1 5
<210> 391
<211> 11
<212> PRT
<213> Homo sapiens
<400> 391
Ser Leu Ile Asp Met Arg Gly Ile Glu Thr Val
1 5 10
<210> 392
<211> 9
<212> PRT
<213> Homo sapiens
<400> 392
Ser Leu Phe Lys Asp Gln Met Glu Leu
1 5
<210> 393
<211> 9
<212> PRT
<213> Homo sapiens
<400> 393
Ile Leu Leu Pro Tyr Leu Gln Thr Leu
1 5
<210> 394
<211> 10
<212> PRT
<213> Homo sapiens
<400> 394
Ala Ser Glu Ala Glu Met Arg Leu Phe Tyr
1 5 10
<210> 395
<211> 10
<212> PRT
<213> Homo sapiens
<400> 395
Ala Ser Glu Ala Ser Arg Leu Ala His Tyr
1 5 10
<210> 396
<211> 10
<212> PRT
<213> Homo sapiens
<400> 396
Ala Ser Glu Phe Gly Asn His Tyr Leu Tyr
1 5 10
<210> 397
<211> 12
<212> PRT
<213> Homo sapiens
<400> 397
Ala Ser Glu Ile Thr Ser Lys Gly Ala Ser Leu Tyr
1 5 10
<210> 398
<211> 12
<212> PRT
<213> Homo sapiens
<400> 398
Ala Ser Glu Gln Gln Ala Leu His Thr Val Gln Tyr
1 5 10
<210> 399
<211> 9
<212> PRT
<213> Homo sapiens
<400> 399
Ala Thr Asp Ile Pro Cys Leu Leu Tyr
1 5
<210> 400
<211> 10
<212> PRT
<213> Homo sapiens
<400> 400
Ala Thr Asp Ile Ser Arg Gln Asn Glu Tyr
1 5 10
<210> 401
<211> 12
<212> PRT
<213> Homo sapiens
<400> 401
Asp Ser Asp Glu Ser Tyr Met Glu Lys Ser Leu Tyr
1 5 10
<210> 402
<211> 9
<212> PRT
<213> Homo sapiens
<400> 402
Asp Thr Asp Ser Gln Arg Leu Ala Tyr
1 5
<210> 403
<211> 11
<212> PRT
<213> Homo sapiens
<400> 403
Glu Leu Asp Ser Lys Val Glu Val Leu Thr Tyr
1 5 10
<210> 404
<211> 9
<212> PRT
<213> Homo sapiens
<400> 404
Glu Thr Ala Arg Lys Phe Leu Tyr Tyr
1 5
<210> 405
<211> 10
<212> PRT
<213> Homo sapiens
<400> 405
Glu Thr Glu Glu Gly Ile Tyr Trp Arg Tyr
1 5 10
<210> 406
<211> 10
<212> PRT
<213> Homo sapiens
<400> 406
Glu Thr Glu Gln Thr Lys Phe Trp Asp Tyr
1 5 10
<210> 407
<211> 10
<212> PRT
<213> Homo sapiens
<400> 407
Phe Ser Asp Asn Asp Lys Leu Tyr Leu Tyr
1 5 10
<210> 408
<211> 9
<212> PRT
<213> Homo sapiens
<400> 408
Phe Thr Glu Gln Trp Thr Asp Gly Tyr
1 5
<210> 409
<211> 9
<212> PRT
<213> Homo sapiens
<400> 409
Phe Val Asp Pro Leu Val Thr Asn Tyr
1 5
<210> 410
<211> 12
<212> PRT
<213> Homo sapiens
<400> 410
Gly Ser Asp His Gln Ser Pro Ser Ser Ser Ser Tyr
1 5 10
<210> 411
<211> 9
<212> PRT
<213> Homo sapiens
<400> 411
Gly Thr Val Tyr Glu Asp Leu Arg Tyr
1 5
<210> 412
<211> 9
<212> PRT
<213> Homo sapiens
<400> 412
Ile Leu Asp Glu Val Ile Met Gly Tyr
1 5
<210> 413
<211> 10
<212> PRT
<213> Homo sapiens
<400> 413
Ile Ser Asp Arg Tyr Tyr Thr Ala Leu Tyr
1 5 10
<210> 414
<211> 9
<212> PRT
<213> Homo sapiens
<400> 414
Lys Thr Asp Glu Ser Leu Thr Lys Tyr
1 5
<210> 415
<211> 10
<212> PRT
<213> Homo sapiens
<400> 415
Leu Leu Asp Pro Arg Ser Tyr His Thr Tyr
1 5 10
<210> 416
<211> 10
<212> PRT
<213> Homo sapiens
<400> 416
Leu Leu Asp Thr Ala Gln Lys Asn Leu Tyr
1 5 10
<210> 417
<211> 10
<212> PRT
<213> Homo sapiens
<400> 417
Leu Leu Glu Asp Lys His Phe Gln Ser Tyr
1 5 10
<210> 418
<211> 10
<212> PRT
<213> Homo sapiens
<400> 418
Leu Ser Asp Pro Ser Gly Pro Lys Ser Tyr
1 5 10
<210> 419
<211> 9
<212> PRT
<213> Homo sapiens
<400> 419
Leu Ser Glu Leu Lys Pro Met Ser Tyr
1 5
<210> 420
<211> 10
<212> PRT
<213> Homo sapiens
<400> 420
Leu Thr Glu Asp Lys Glu Thr Leu Gln Tyr
1 5 10
<210> 421
<211> 11
<212> PRT
<213> Homo sapiens
<400> 421
Leu Thr Glu Leu Leu Glu Arg Ala Ala Phe Tyr
1 5 10
<210> 422
<211> 9
<212> PRT
<213> Homo sapiens
<400> 422
Met Ile Asp Val Thr Lys Ser Tyr Tyr
1 5
<210> 423
<211> 12
<212> PRT
<213> Homo sapiens
<400> 423
Asn Leu Asp Ala Val His Asp Ile Thr Val Ala Tyr
1 5 10
<210> 424
<211> 10
<212> PRT
<213> Homo sapiens
<400> 424
Asn Leu Asp Glu Glu Lys Gln Leu Leu Tyr
1 5 10
<210> 425
<211> 9
<212> PRT
<213> Homo sapiens
<400> 425
Asn Leu Asp Ile Ile Gln Gln Glu Tyr
1 5
<210> 426
<211> 10
<212> PRT
<213> Homo sapiens
<400> 426
Asn Leu Asp Gln Ala Thr Arg Val Ala Tyr
1 5 10
<210> 427
<211> 12
<212> PRT
<213> Homo sapiens
<400> 427
Asn Ser Asp Glu Gln Lys Ile Thr Glu Met Val Tyr
1 5 10
<210> 428
<211> 9
<212> PRT
<213> Homo sapiens
<400> 428
Asn Ser Glu Leu Ser Cys Gln Leu Tyr
1 5
<210> 429
<211> 12
<212> PRT
<213> Homo sapiens
<400> 429
Asn Thr Glu Asp Ser Ser Met Ser Gly Tyr Leu Tyr
1 5 10
<210> 430
<211> 9
<212> PRT
<213> Homo sapiens
<400> 430
Asn Thr Glu Gly Leu His His Leu Tyr
1 5
<210> 431
<211> 11
<212> PRT
<213> Homo sapiens
<400> 431
Asn Thr Ser Asp Met Met Gly Arg Met Ser Tyr
1 5 10
<210> 432
<211> 9
<212> PRT
<213> Homo sapiens
<400> 432
Asn Val Asp Pro Val Gln His Thr Tyr
1 5
<210> 433
<211> 9
<212> PRT
<213> Homo sapiens
<400> 433
Gln Ile Asp Thr Gly Glu Asn Leu Tyr
1 5
<210> 434
<211> 10
<212> PRT
<213> Homo sapiens
<400> 434
Gln Thr Asp Cys Ala Pro Asn Asn Gly Tyr
1 5 10
<210> 435
<211> 10
<212> PRT
<213> Homo sapiens
<400> 435
Gln Thr Asp Asp Thr Trp Arg Thr Glu Tyr
1 5 10
<210> 436
<211> 11
<212> PRT
<213> Homo sapiens
<400> 436
Gln Thr Glu Thr Gly Thr Pro Tyr Met Leu Tyr
1 5 10
<210> 437
<211> 10
<212> PRT
<213> Homo sapiens
<400> 437
Ser Thr Asp Gly Lys His Trp Trp Glu Tyr
1 5 10
<210> 438
<211> 9
<212> PRT
<213> Homo sapiens
<400> 438
Ser Thr Asp Asn Phe Asn Cys Lys Tyr
1 5
<210> 439
<211> 10
<212> PRT
<213> Homo sapiens
<400> 439
Thr Leu Asp Ala Gly Lys Phe Gln Ile Tyr
1 5 10
<210> 440
<211> 10
<212> PRT
<213> Homo sapiens
<400> 440
Thr Leu Asp Glu Asn Pro Gly Val Arg Tyr
1 5 10
<210> 441
<211> 12
<212> PRT
<213> Homo sapiens
<400> 441
Thr Leu Asp Ser Ala Leu Asn Ala Ala Ser Tyr Tyr
1 5 10
<210> 442
<211> 10
<212> PRT
<213> Homo sapiens
<400> 442
Thr Ser Asp Phe Ser Arg Phe Thr Asn Tyr
1 5 10
<210> 443
<211> 12
<212> PRT
<213> Homo sapiens
<400> 443
Thr Thr Asp Phe Pro Ser Glu Ser Ser Phe Glu Tyr
1 5 10
<210> 444
<211> 9
<212> PRT
<213> Homo sapiens
<400> 444
Thr Thr Asp Thr Val Ile Arg Ser Tyr
1 5
<210> 445
<211> 10
<212> PRT
<213> Homo sapiens
<400> 445
Val Leu Asp Gln Gly Lys Ile Thr Glu Tyr
1 5 10
<210> 446
<211> 11
<212> PRT
<213> Homo sapiens
<400> 446
Val Thr Ala Gln Val Val Gly Thr Glu Arg Tyr
1 5 10
<210> 447
<211> 10
<212> PRT
<213> Homo sapiens
<400> 447
Val Val Asp Glu Asp His Glu Leu Ile Tyr
1 5 10
<210> 448
<211> 9
<212> PRT
<213> Homo sapiens
<400> 448
Tyr Leu Asp Ile Pro Asn Pro Arg Tyr
1 5
<210> 449
<211> 12
<212> PRT
<213> Homo sapiens
<400> 449
Tyr Leu Asp Arg Gly Thr Gly Asn Val Ser Phe Tyr
1 5 10
<210> 450
<211> 11
<212> PRT
<213> Homo sapiens
<400> 450
Tyr Ser Asp Asp Gly Gln Lys Trp Thr Val Tyr
1 5 10
<210> 451
<211> 10
<212> PRT
<213> Homo sapiens
<400> 451
Tyr Ser Asp Ser Leu Val Gln Lys Gly Tyr
1 5 10
<210> 452
<211> 12
<212> PRT
<213> Homo sapiens
<400> 452
Tyr Val Asp Ala Val Leu Gly Lys Gly His Gln Tyr
1 5 10
<210> 453
<211> 9
<212> PRT
<213> Homo sapiens
<400> 453
Ala Ile Asn Thr Ser Ile Lys Asn Lys
1 5
<210> 454
<211> 9
<212> PRT
<213> Homo sapiens
<400> 454
Lys Val Tyr Thr Pro Ser Ile Ser Lys
1 5
<210> 455
<211> 9
<212> PRT
<213> Homo sapiens
<400> 455
Arg Ile Ala Asp Ile Phe Val Lys Lys
1 5
<210> 456
<211> 9
<212> PRT
<213> Homo sapiens
<400> 456
Ser Met Phe Thr Ala Ile Leu Lys Lys
1 5
<210> 457
<211> 9
<212> PRT
<213> Homo sapiens
<400> 457
Ser Ile Asn Lys Pro Thr Ser Glu Arg
1 5
<210> 458
<211> 9
<212> PRT
<213> Homo sapiens
<400> 458
Gly Ile Ala Asp Phe Val Leu Lys Tyr
1 5
<210> 459
<211> 10
<212> PRT
<213> Homo sapiens
<400> 459
Arg Pro Met Gln Gln Ala Arg Ala Gln Leu
1 5 10
<210> 460
<211> 10
<212> PRT
<213> Homo sapiens
<400> 460
Met Pro Met Ala Gly Asp Met Asn Gly Leu
1 5 10
<210> 461
<211> 9
<212> PRT
<213> Homo sapiens
<400> 461
Arg Pro Ile Leu Ile Ile Val Thr Leu
1 5
<210> 462
<211> 9
<212> PRT
<213> Homo sapiens
<400> 462
Arg Pro Phe His Thr Arg Ala Thr Val
1 5
<210> 463
<211> 8
<212> PRT
<213> Homo sapiens
<400> 463
Thr Pro Lys Ala Gly Pro Thr Leu
1 5
<210> 464
<211> 9
<212> PRT
<213> Homo sapiens
<400> 464
Tyr Pro Arg Pro Gly Thr Pro Ala Ala
1 5
<210> 465
<211> 9
<212> PRT
<213> Homo sapiens
<400> 465
Val Pro Arg Pro Ile Phe Ser Gln Leu
1 5
<210> 466
<211> 9
<212> PRT
<213> Homo sapiens
<400> 466
Ala Pro Tyr Lys Ser Val Thr Ser Leu
1 5
<210> 467
<211> 9
<212> PRT
<213> Homo sapiens
<400> 467
Lys Pro Phe Ser Ser Phe Thr Ser Met
1 5
<210> 468
<211> 9
<212> PRT
<213> Homo sapiens
<400> 468
Ser Pro Met Tyr Gly Gln Ala Gly Leu
1 5
<210> 469
<211> 9
<212> PRT
<213> Homo sapiens
<400> 469
Tyr Pro Glu Asn Gly Val Val Gln Met
1 5
<210> 470
<211> 9
<212> PRT
<213> Homo sapiens
<400> 470
Ser Pro Asn Ser Tyr Phe Arg Val Leu
1 5
<210> 471
<211> 10
<212> PRT
<213> Homo sapiens
<400> 471
Lys Pro Arg Pro Asp Val Thr Asn Glu Leu
1 5 10
<210> 472
<211> 9
<212> PRT
<213> Homo sapiens
<400> 472
Asn Pro Arg Ala Thr Asp Ala Gln Leu
1 5
<210> 473
<211> 9
<212> PRT
<213> Homo sapiens
<400> 473
Leu Pro Arg Ala Leu Leu Ser Ser Leu
1 5
<210> 474
<211> 8
<212> PRT
<213> Homo sapiens
<400> 474
Leu Pro Arg Leu Leu Pro Ala Leu
1 5
<210> 475
<211> 9
<212> PRT
<213> Homo sapiens
<400> 475
Arg Pro His Lys Pro Gly Leu Tyr Leu
1 5
<210> 476
<211> 9
<212> PRT
<213> Homo sapiens
<400> 476
Ala Glu Glu Glu Ile Met Lys Lys Ile
1 5
<210> 477
<211> 9
<212> PRT
<213> Homo sapiens
<400> 477
Gln Glu Asn Ser Tyr Gln Ser Arg Leu
1 5
<210> 478
<211> 10
<212> PRT
<213> Homo sapiens
<400> 478
Ser Glu Ile Glu Gln Glu Ile Gly Ser Leu
1 5 10
<210> 479
<211> 9
<212> PRT
<213> Homo sapiens
<400> 479
Ala Glu Ile Gln Pro Gln Thr Gln Val
1 5
<210> 480
<211> 10
<212> PRT
<213> Homo sapiens
<400> 480
Gly Glu Val Ser Gly Leu Thr Lys Asp Phe
1 5 10
<210> 481
<211> 9
<212> PRT
<213> Homo sapiens
<400> 481
Arg Glu Leu Gln His Glu His Ser Leu
1 5
<210> 482
<211> 9
<212> PRT
<213> Homo sapiens
<400> 482
Thr Glu Arg Glu Trp Ala Asp Glu Trp
1 5
<210> 483
<211> 10
<212> PRT
<213> Homo sapiens
<400> 483
Glu Glu Asn Asp Gln Ser Thr His Lys Trp
1 5 10
<210> 484
<211> 9
<212> PRT
<213> Homo sapiens
<400> 484
Ala Glu Val Gly Phe Val Arg Phe Phe
1 5
<210> 485
<211> 11
<212> PRT
<213> Homo sapiens
<400> 485
Ser Glu Ile Glu Asp Ser Thr Lys Gln Val Phe
1 5 10
<210> 486
<211> 9
<212> PRT
<213> Homo sapiens
<400> 486
Ser Glu Asp Asp Pro Ile Leu Gln Ile
1 5
<210> 487
<211> 9
<212> PRT
<213> Homo sapiens
<400> 487
Ala Glu Asp Gln Leu His His Ser Phe
1 5
<210> 488
<211> 9
<212> PRT
<213> Homo sapiens
<400> 488
Thr Glu Phe Pro Ile Ile Lys Met Tyr
1 5
<210> 489
<211> 9
<212> PRT
<213> Homo sapiens
<400> 489
Ser Glu Ile Gly Lys Ala Val Gly Phe
1 5
<210> 490
<211> 9
<212> PRT
<213> Homo sapiens
<400> 490
Ser Tyr Val Lys Val Leu His His Leu
1 5
<210> 491
<211> 9
<212> PRT
<213> Homo sapiens
<400> 491
Lys Tyr Leu Glu Lys Tyr Tyr Asn Leu
1 5
<210> 492
<211> 9
<212> PRT
<213> Homo sapiens
<400> 492
Asn Tyr Glu Asp His Phe Pro Leu Leu
1 5
<210> 493
<211> 10
<212> PRT
<213> Homo sapiens
<400> 493
Thr Tyr Lys Tyr Val Asp Ile Asn Thr Phe
1 5 10
<210> 494
<211> 9
<212> PRT
<213> Homo sapiens
<400> 494
Arg Tyr Leu Glu Lys Phe Tyr Gly Leu
1 5
<210> 495
<211> 9
<212> PRT
<213> Homo sapiens
<400> 495
Ser Tyr Asn Asp Ala Leu Leu Thr Phe
1 5
<210> 496
<211> 10
<212> PRT
<213> Homo sapiens
<400> 496
Val Phe Met Lys Asp Gly Phe Phe Tyr Phe
1 5 10
<210> 497
<211> 9
<212> PRT
<213> Homo sapiens
<400> 497
Asn Tyr Pro Lys Ser Ile His Ser Phe
1 5
<210> 498
<211> 9
<212> PRT
<213> Homo sapiens
<400> 498
Glu Tyr Ile Arg Ala Leu Gln Gln Leu
1 5
<210> 499
<211> 9
<212> PRT
<213> Homo sapiens
<400> 499
Val Tyr Phe Val Ala Pro Ala Lys Phe
1 5
<210> 500
<211> 10
<212> PRT
<213> Homo sapiens
<400> 500
Val Trp Ser Asp Val Thr Pro Leu Thr Phe
1 5 10
<210> 501
<211> 9
<212> PRT
<213> Homo sapiens
<400> 501
Gly Tyr Ile Asp Asn Val Thr Leu Ile
1 5
<210> 502
<211> 9
<212> PRT
<213> Homo sapiens
<400> 502
Ser Val His Lys Ile Thr Ser Thr Phe
1 5
<210> 503
<211> 12
<212> PRT
<213> Homo sapiens
<400> 503
Val His Phe Glu Asp Thr Gly Lys Thr Leu Leu Phe
1 5 10
<210> 504
<211> 10
<212> PRT
<213> Homo sapiens
<400> 504
Val Tyr Glu Lys Asn Gly Tyr Ile Tyr Phe
1 5 10
<210> 505
<211> 9
<212> PRT
<213> Homo sapiens
<400> 505
Ala Tyr Ile Ser Gly Leu Asp Val Phe
1 5
<210> 506
<211> 9
<212> PRT
<213> Homo sapiens
<400> 506
Arg Tyr Val Phe Pro Leu Pro Tyr Leu
1 5
<210> 507
<211> 9
<212> PRT
<213> Homo sapiens
<400> 507
Val Tyr Ile Ala Glu Leu Glu Lys Ile
1 5
<210> 508
<211> 9
<212> PRT
<213> Homo sapiens
<400> 508
Ile Tyr Val Thr Gly Gly His Leu Phe
1 5
<210> 509
<211> 9
<212> PRT
<213> Homo sapiens
<400> 509
Ala Leu Leu Glu Glu Glu Glu Gly Val
1 5
<210> 510
<211> 9
<212> PRT
<213> Homo sapiens
<400> 510
Lys Val Leu Glu His Val Val Arg Val
1 5
<210> 511
<211> 11
<212> PRT
<213> Homo sapiens
<400> 511
Lys Ile Trp Glu Glu Leu Ser Val Leu Glu Val
1 5 10
<210> 512
<211> 9
<212> PRT
<213> Homo sapiens
<400> 512
Val Leu Gly Glu Glu Gln Glu Gly Val
1 5
<210> 513
<211> 9
<212> PRT
<213> Homo sapiens
<400> 513
Lys Leu Val Glu Leu Glu His Thr Leu
1 5
<210> 514
<211> 11
<212> PRT
<213> Homo sapiens
<400> 514
Val Gln Leu Asp Ser Ile Glu Asp Leu Glu Val
1 5 10
<210> 515
<211> 9
<212> PRT
<213> Homo sapiens
<400> 515
Lys Ile Phe Glu Met Leu Glu Gly Val
1 5
<210> 516
<211> 9
<212> PRT
<213> Homo sapiens
<400> 516
Tyr Thr Phe Ser Gly Asp Val Gln Leu
1 5
<210> 517
<211> 11
<212> PRT
<213> Homo sapiens
<400> 517
Thr Leu Tyr Asn Pro Glu Arg Thr Ile Thr Val
1 5 10
<210> 518
<211> 11
<212> PRT
<213> Homo sapiens
<400> 518
Gly Leu Leu Glu Asp Glu Arg Ala Leu Gln Leu
1 5 10
<210> 519
<211> 9
<212> PRT
<213> Homo sapiens
<400> 519
Lys Ile Gln Glu Ile Leu Thr Gln Val
1 5
<210> 520
<211> 9
<212> PRT
<213> Homo sapiens
<400> 520
Lys Ile Gln Glu Met Gln His Phe Leu
1 5
<210> 521
<211> 9
<212> PRT
<213> Homo sapiens
<400> 521
Phe Val Tyr Gly Glu Pro Arg Glu Leu
1 5
<210> 522
<211> 9
<212> PRT
<213> Homo sapiens
<400> 522
Thr Leu Asp Glu Lys Val Ala Glu Leu
1 5
<210> 523
<211> 9
<212> PRT
<213> Homo sapiens
<400> 523
His Leu Ile Ala Glu Ile His Thr Ala
1 5
<210> 524
<211> 9
<212> PRT
<213> Homo sapiens
<400> 524
Lys Val Trp Ser Asp Val Thr Pro Leu
1 5
<210> 525
<211> 9
<212> PRT
<213> Homo sapiens
<400> 525
Arg Leu Asp Asp Leu Lys Met Thr Val
1 5
<210> 526
<211> 9
<212> PRT
<213> Homo sapiens
<400> 526
Val Leu Ser Pro Phe Ile Leu Thr Leu
1 5
<210> 527
<211> 8
<212> PRT
<213> Homo sapiens
<400> 527
Leu Leu Asp Ser Val Ser Arg Leu
1 5
<210> 528
<211> 9
<212> PRT
<213> Homo sapiens
<400> 528
Arg Leu Leu Asp Ser Val Ser Arg Leu
1 5
<210> 529
<211> 9
<212> PRT
<213> Homo sapiens
<400> 529
His Pro Ser Ala His Asp Val Ile Leu
1 5
<210> 530
<211> 10
<212> PRT
<213> Homo sapiens
<400> 530
Ala Pro Ala Ala Trp Leu Arg Ser Ala Ala
1 5 10
<210> 531
<211> 9
<212> PRT
<213> Homo sapiens
<400> 531
Ala Glu Ile Glu Ala Asp Arg Ser Tyr
1 5
<210> 532
<211> 10
<212> PRT
<213> Homo sapiens
<400> 532
Glu Leu Ala Gly Ile Gly Ile Leu Thr Val
1 5 10
<210> 533
<211> 9
<212> PRT
<213> Homo sapiens
<400> 533
Tyr Leu Leu Pro Ala Ile Val His Ile
1 5
Claims (32)
1.一种肽,其包括选自SEQ ID No.1至SEQ ID No.489组成群组的一个氨基酸序列、以及与SEQ ID No.1至SEQ ID No.489具有至少88%同源性的其变体序列、其中所述变体与主要组织相容性复合体(MHC)结合和/或诱导与该变体肽发生T细胞交叉反应,及其一种药用盐,其中所述肽不是一种全长多肽。
2.根据权利要求1中所述的肽,其中所述肽有能力与MHC-I或-II类分子结合,其中所述肽与MHC结合时能够被CD4和/或CD8 T细胞识别。
3.根据权利要求1或2中所述的肽或其变体,其中氨基酸序列包括任意SEQ ID No.1至SEQ ID No.489的一个连续的氨基酸延伸区。
4.根据权利要求1至3任一项中所述的肽或其变体,其中所述肽或其变体的总长度为8至100个氨基酸、优选为8至30个氨基酸、更优选为8至16个氨基酸、最优选为该肽该肽系由或基本系由根据任意SEQ ID No.1至SEQ ID No.489的氨基酸序列组成。
5.根据权利要求1至4任一项中所述的肽或其变体,其中所述肽被修饰和/或包含非肽键。
6.根据权利要求1至5任一项所述的肽或其变体,其中所述肽为融合蛋白的一部分,尤其包含HLA-DR抗原相关不变链(Ii)的N-端氨基酸。
7.一种抗体,特别是可溶性或膜结合性抗体,优选为单克隆抗体或其片段,其特异性地识别根据权利要求1至5任一项所述的肽或其变体,与MHC分子结合时优选为根据权利要求1至5中任一项所述的肽或变体。
8.一种T细胞受体,优选为可溶性或膜结合性受体或其片段,其与HLA配体反应,其中所述配体是根据权利要求1至5任一项所述的肽或其变体,与MHC分子结合时优选为根据权利要求1至5中任一项所述的肽或变体。
9.根据权利要求8所述的T细胞受体,其中所述配体氨基酸序列与SEQ ID No.1至SEQID No.489中任一个至少88%相同,或其中所述配体氨基酸序列包括SEQ ID No.1至SEQ IDNo.489任何之一。
10.根据权利要求8或9中任何一项所述的T细胞受体,其中所述T细胞受体作为可溶性分子提供并任选具有进一步的效应子功能,如免疫刺激结构域或毒素。
11.一种适体,其特异性地识别根据权利要求1至5中的肽或其变体,优选为根据权利要求1至5中任一项所述的、与MHC分子结合的肽或变体。
12.一种核酸,其编码根据权利要求1至5中任一项所述的肽或其变体,根据权利要求7所述的抗体或其片段,根据权利要求8或9所述的T细胞受体或其片段,任选连接到异源启动子序列或表达所述核酸的表达载体。
13.一种重组宿主细胞,其包含根据权利要求1至6中任一项所述的肽,根据权利要求7所述的抗体或其片段,根据权利要求8或9所述的T细胞受体或其片段,或根据权利要求12所述的核酸或表达载体,其中所述宿主细胞优选为选自抗原提呈细胞,例如树突细胞、T细胞或NK细胞。
14.一种体外制备启动的T淋巴细胞的方法,该方法包括将T细胞与载有抗原的人I或II类MHC分子进行体外连接,这些分子在合适的抗原提呈细胞表面或人工类比的抗原提呈细胞结构表面上表达足够的一段时间从而以抗原特异性方式启动T细胞,其中所述抗原为权利要求1至4任一项中所述的肽。
15.根据权利要求14中所述的方法制成的启动T淋巴细胞,其有选择性地识别一种细胞,该细胞提呈含权利要求1至4任一项中给定氨基酸序列的多肽。
16.一种药物组合物,其包括至少一种活性成分,该成分选自根据权利要求1至6任一项中所述的肽、根据权利要求7中所述的抗体或其片段、根据权利要求8或9中所述的T细胞受体或其片段、根据权利要求11中所述的适体、根据权利要求12中所述的核酸或表达载体、根据权利要求13中所述的宿主细胞或根据权利要求15中所述的活化T淋巴细胞,或共轭或标记的活性成分以及一种药用载体和任选的药用赋形剂和/或稳定剂。
17.一种用于制备根据权利要求1至6任一项中所述的肽或其变体、根据权利要求7所述的抗体或其片段或根据权利要求8或9所述的T细胞受体或其片段的方法,所述方法包括培养根据权利要求13所述的宿主细胞以及从所述宿主细胞和/或其培养基中分离出所述肽或其变体、所述抗体或其片段或所述T细胞受体或其片段。
18.根据权利要求1至6任一项中所述的肽、根据权利要求7中所述的抗体或其片段、根据权利要求8或9中所述的T细胞受体或其片段、根据权利要求11中所述的适体、根据权利要求12中所述的核酸或表达载体、根据权利要求13中所述的宿主细胞或根据权利要求15中所述的活化T淋巴细胞在药物中的用途。
19.一种杀灭患者体内靶向细胞的方法,其中靶向细胞提呈一种多肽,该多肽含权利要求1至4任一项中给定的氨基酸序列;一种给药方法,其中包括给予患者权利要求15中定义的有效量T细胞。
20.根据权利要求1至6任一项中所述的肽、根据权利要求7中所述的抗体或其片段、根据权利要求8或9中所述的T细胞受体或其片段、根据权利要求11中所述的适体、根据权利要求12中所述的核酸或表达载体、根据权利要求13中所述的宿主细胞或根据权利要求15中所述的活化T淋巴细胞在癌症诊断和/或治疗或制造抗癌药物中的用途。
21.根据权利要求20所述的用途,其中所述癌症为选自肺癌(包括NSCLC和SCLC)、急性骨髓性白血病、乳腺癌、胆管癌、脑癌、慢性淋巴细胞白血病、结直肠癌、食管癌、胆囊癌、胃癌、头颈部鳞状细胞癌、肝细胞癌、黑色素瘤、非霍奇金淋巴瘤、卵巢癌、胰腺癌、前列腺癌、肾细胞癌、膀胱癌、子宫癌和其他肿瘤的组,这些肿瘤显示过度表达来自根据SEQ ID No.1至SEQ ID No.489的一种蛋白所衍生的肽。
22.一种套件,包括:
a)包含药物组合物的容器,所述药物组合物包含根据权利要求1至6任一项中所述的肽、根据权利要求7中所述的抗体或其片段、根据权利要求8或9中所述的T细胞受体或其片段、根据权利要求11中所述的适体、根据权利要求12中所述的核酸或表达载体、根据权利要求13中所述的宿主细胞或根据权利要求15中所述的溶液或冻干形式的活化T淋巴细胞。
b)可选地,第二个容器,其含有冻干粉剂型的稀释剂或重组溶液;
c)可选的至少一种以上肽,选自由SEQ ID No.1至SEQ ID No.531基团,以及
d)可选地,(i)使用溶液或(ii)重组和/或使用冻干粉剂型的说明书。
23.根据权利要求22所述的药盒套件,进一步包括一个或多个(iii)缓冲剂,(iv)稀释剂,(v)过滤液,(vi)针,或(v)注射器。
24.一种用于生产用作个体患者的个性化抗癌疫苗或基于化合物的和/或细胞疗法,所述方法包括:
a)识别所述个体患者肿瘤样本提呈的肿瘤相关肽(TUMAP);
b)将a)中确定的肽与已经接受过免疫原性预筛查和/或与正常组织相比在肿瘤中过度提呈的存储库的肽进行比较。
c)选择与患者中识别的TUMAP匹配的存储库中的至少一种肽;和
d)生产和/或构想基于步骤c)的所述个性化疫苗或基于化合物的和/或细胞疗法。
25.根据权利要求24中所述的方法,其中所述TUMAP透过以下方法识别:
a1)将肿瘤样本的表达资料与肿瘤样本组织类型相应的正常组织样本的表达资料进行比较,以识别在肿瘤样本中过度表达或异常表达的蛋白;和
a2)将表达资料与肿瘤样本中MHC I类和/或II类分子结合的MHC配体序列相关联,以识别肿瘤过度表达或异常的蛋白质衍生的MHC配体。
26.根据权利要求24或25所述的方法,其中MHC配体的序列的确定方法是:洗脱来自肿瘤样本分离的MHC分子结合肽,并测序洗脱配体。
27.根据权利要求24至26任一项所述的方法,其中该类型肿瘤样本相应的正常组织样本获得自同一患者。
28.根据权利要求24至27任一项中所述的方法,其中存储库包含的肽用基于以下步骤进行识别:
aa.透过高度并行的方法,例如微阵列或基于测序的表达谱,进行全基因组信使核糖核酸(mRNA)表达分析,其包括识别相较于正常组织在恶性组织中过度表达的基因;
ab.选择步骤aa检测到的特异性表达或过量表达的基因所编码的肽,以及
ac.透过选定的肽确定诱导体内T细胞反应,包括使用健康供体或所述患者的人类T细胞的体外免疫原性测定;或
ba.用质谱法识别来自所述肿瘤样本的HLA配体;
bb.透过高度并行的方法,例如微阵列或基于测序的表达谱,进行全基因组信使核糖核酸(mRNA)表达分析,其包括识别相较于正常组织在恶性组织中过度表达的基因;
bc.比较识别的HLA配体与所述基因表达资料;
bd.选择步骤bc检测到的特异性表达或过量表达的基因所编码的肽;
be.重新检测肿瘤组织上来自步骤bd的选定TUMAP、其在健康组织上缺乏或不经常检测到,并确定在mRNA水平上过度表达的相关性;以及
bf.透过选定的肽确定诱导体内T细胞反应,包括使用健康供体或所述患者的人类T细胞的体外免疫原性测定。
29.根据权利要求24至28任一项所述的方法,其中存储库是否包括肽免疫原性由含有体外免疫原性实验、个体HLA结合性患者免疫监测、MHC多聚体染色、ELISPOT分析和/或细胞内细胞因子染色的一种方法确定。
30.根据权利要求24至29任一项所述的方法,其中所述存储库包括选自SEQ ID No.1至SEQ ID No.531组成的组团的多个肽。
31.根据权利要求24至30任一项所述的方法,其进一步包括以下步骤:识别与该个体患者相应正常组织相比对所述肿瘤样本具有唯一性的至少一种突变,以及选择与突变相关并包含于疫苗或用于产生细胞疗法的一种肽。
32.根据权利要求31中所述的方法,其中所述至少一种突变使用全基因组测序鉴定。
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201762529758P | 2017-07-07 | 2017-07-07 | |
US62/529,758 | 2017-07-07 | ||
DE102017115301 | 2017-07-07 | ||
DE102017115301.2 | 2017-07-07 | ||
PCT/EP2018/067979 WO2019007974A1 (en) | 2017-07-07 | 2018-07-03 | NOVEL PEPTIDES AND COMBINATION OF PEPTIDES FOR USE IN IMMUNOTHERAPY OF LUNG CANCER, INCLUDING NSCLC, CPPC AND OTHER CANCERS |
Publications (1)
Publication Number | Publication Date |
---|---|
CN110785183A true CN110785183A (zh) | 2020-02-11 |
Family
ID=62904428
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201880041940.1A Pending CN110785183A (zh) | 2017-07-07 | 2018-07-03 | 用于肺癌(包括nsclc、sclc和其他癌症)免疫治疗的新型肽和肽组合物 |
Country Status (17)
Country | Link |
---|---|
US (47) | US10472402B2 (zh) |
EP (2) | EP4316597A2 (zh) |
JP (2) | JP2020530759A (zh) |
KR (1) | KR20200026898A (zh) |
CN (1) | CN110785183A (zh) |
AU (3) | AU2018297578C1 (zh) |
BR (1) | BR112019028070A2 (zh) |
CA (1) | CA3068852A1 (zh) |
CL (3) | CL2020000020A1 (zh) |
CO (1) | CO2020001141A2 (zh) |
CR (4) | CR20200059A (zh) |
IL (2) | IL271895A (zh) |
MX (2) | MX2019015879A (zh) |
PE (1) | PE20200693A1 (zh) |
PH (1) | PH12020500051A1 (zh) |
SG (1) | SG11201913302SA (zh) |
TW (1) | TW201906859A (zh) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN111732629A (zh) * | 2020-06-19 | 2020-10-02 | 完美(广东)日用品有限公司 | 一种寡肽、减肥组合物及制备方法和应用 |
CN114019165A (zh) * | 2022-01-05 | 2022-02-08 | 首都医科大学附属北京妇产医院 | 多肽芯片或试剂盒及其在诊断非小细胞肺癌中的应用 |
CN115785212A (zh) * | 2022-06-10 | 2023-03-14 | 河北博海生物工程开发有限公司 | 肺癌特异性分子靶标03及其用途 |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US10800823B2 (en) * | 2017-07-07 | 2020-10-13 | Immatics Biotechnologies Gmbh | Peptides and combination of peptides for use in immunotherapy against lung cancer, including NSCLC, SCLC and other cancers |
CR20200059A (es) | 2017-07-07 | 2020-06-01 | Immatics Biotechnologies Gmbh | Nuevos péptidos y nuevas combinaciones de péptidos para el uso en la inmunoterapia contra el cáncer de pulmón, incluyendo el nsclc, el sclc y otros cánceres |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2015018805A1 (en) * | 2013-08-05 | 2015-02-12 | Immatics Biotechnologies Gmbh | Novel immunotherapy against several tumors, such as lung cancer, including nsclc |
WO2017060169A1 (en) * | 2015-10-05 | 2017-04-13 | Immatics Biotechnologies Gmbh | Peptides and combination of peptides for use in immunotherapy against small cell lung cancer and other cancers |
CN111533796A (zh) * | 2017-04-10 | 2020-08-14 | 伊玛提克斯生物技术有限公司 | 用于癌症免疫治疗的肽及其肽组合物 |
CN111533799A (zh) * | 2017-04-10 | 2020-08-14 | 伊玛提克斯生物技术有限公司 | 用于白血病和其他癌症免疫治疗的肽和肽组合物 |
CN112512538A (zh) * | 2018-05-18 | 2021-03-16 | 国家儿童医疗中心 | 改进的靶向t细胞疗法 |
Family Cites Families (51)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4440859A (en) | 1977-05-27 | 1984-04-03 | The Regents Of The University Of California | Method for producing recombinant bacterial plasmids containing the coding sequences of higher organisms |
US4704362A (en) | 1977-11-08 | 1987-11-03 | Genentech, Inc. | Recombinant cloning vehicle microbial polypeptide expression |
ES8105035A1 (es) | 1978-12-22 | 1981-05-16 | Biogen Nv | Un metodo para producir al menos un polipeptido que muestra antigenicidad de hbv |
US4530901A (en) | 1980-01-08 | 1985-07-23 | Biogen N.V. | Recombinant DNA molecules and their use in producing human interferon-like polypeptides |
US4342566A (en) | 1980-02-22 | 1982-08-03 | Scripps Clinic & Research Foundation | Solid phase anti-C3 assay for detection of immune complexes |
US4678751A (en) | 1981-09-25 | 1987-07-07 | Genentech, Inc. | Hybrid human leukocyte interferons |
US4766075A (en) | 1982-07-14 | 1988-08-23 | Genentech, Inc. | Human tissue plasminogen activator |
US4582800A (en) | 1982-07-12 | 1986-04-15 | Hoffmann-La Roche Inc. | Novel vectors and method for controlling interferon expression |
US4816567A (en) | 1983-04-08 | 1989-03-28 | Genentech, Inc. | Recombinant immunoglobin preparations |
US4757006A (en) | 1983-10-28 | 1988-07-12 | Genetics Institute, Inc. | Human factor VIII:C gene and recombinant methods for production |
US4677063A (en) | 1985-05-02 | 1987-06-30 | Cetus Corporation | Human tumor necrosis factor |
US4810648A (en) | 1986-01-08 | 1989-03-07 | Rhone Poulenc Agrochimie | Haloarylnitrile degrading gene, its use, and cells containing the gene |
US4897445A (en) | 1986-06-27 | 1990-01-30 | The Administrators Of The Tulane Educational Fund | Method for synthesizing a peptide containing a non-peptide bond |
ES2138662T3 (es) | 1993-06-03 | 2000-01-16 | Therapeutic Antibodies Inc | Produccion de fragmentos de anticuerpos. |
AUPM322393A0 (en) | 1993-12-24 | 1994-01-27 | Austin Research Institute, The | Mucin carbohydrate compounds and their use in immunotherapy |
DE69723230T2 (de) | 1996-01-17 | 2004-05-27 | Imperial College Innovations Ltd. | Immunotherapie mit verwendung von zytotoxischen t lymphozyten (ctl) |
US5849589A (en) | 1996-03-11 | 1998-12-15 | Duke University | Culturing monocytes with IL-4, TNF-α and GM-CSF TO induce differentiation to dendric cells |
US6406705B1 (en) | 1997-03-10 | 2002-06-18 | University Of Iowa Research Foundation | Use of nucleic acids containing unmethylated CpG dinucleotide as an adjuvant |
JP2003512814A (ja) | 1999-03-02 | 2003-04-08 | ルードヴィッヒ インスティテュート フォー キャンサー リサーチ | MAGE5、8、9および11のcDNAのクローニングならびに癌の診断におけるそれらの使用 |
WO2001031034A1 (en) | 1999-10-25 | 2001-05-03 | Millennium Pharmaceuticals, Inc. | 27875 a human adam-ts homolog |
US6934639B1 (en) | 2000-02-25 | 2005-08-23 | Wyeth | Methods for designing agents that interact with MMP-13 |
US20040191260A1 (en) | 2003-03-26 | 2004-09-30 | Technion Research & Development Foundation Ltd. | Compositions capable of specifically binding particular human antigen presenting molecule/pathogen-derived antigen complexes and uses thereof |
IL151860A0 (en) | 2000-03-27 | 2003-04-10 | Technion Res & Dev Foundation | Single chain class i major histocompatibility complexes, constructs encoding same and methods of generating same |
AUPQ776100A0 (en) * | 2000-05-26 | 2000-06-15 | Australian National University, The | Synthetic molecules and uses therefor |
WO2001093913A2 (en) | 2000-06-05 | 2001-12-13 | Sunol Molecular Corporation | T cell receptor fusions and conjugates and methods of use thereof |
US20040142325A1 (en) | 2001-09-14 | 2004-07-22 | Liat Mintz | Methods and systems for annotating biomolecular sequences |
US6992176B2 (en) | 2002-02-13 | 2006-01-31 | Technion Research & Development Foundation Ltd. | Antibody having a T-cell receptor-like specificity, yet higher affinity, and the use of same in the detection and treatment of cancer, viral infection and autoimmune disease |
JP2005533486A (ja) | 2002-02-20 | 2005-11-10 | ダイアックス、コープ | Mhc−ペプチド複合体結合リガンド |
US7569664B2 (en) | 2002-10-09 | 2009-08-04 | Immunocore Limited | Single chain recombinant T cell receptors |
ATE432290T1 (de) | 2002-11-09 | 2009-06-15 | Immunocore Ltd | T ZELL REZEPTOR ßDISPLAYß |
GB0304068D0 (en) | 2003-02-22 | 2003-03-26 | Avidex Ltd | Substances |
DE102005013846A1 (de) * | 2005-03-24 | 2006-10-05 | Ganymed Pharmaceuticals Ag | Identifizierung von Oberflächen-assoziierten Antigenen für die Tumordiagnose und -therapie |
DE102005041616B4 (de) | 2005-09-01 | 2011-03-17 | Johannes-Gutenberg-Universität Mainz | Melanom-assoziierte MHC Klasse I assoziierte Oligopeptide und für diese kodierende Polynukleotide und deren Verwendungen |
PT1806359E (pt) | 2005-09-05 | 2010-05-25 | Immatics Biotechnologies Gmbh | Peptídeos associados a tumor ligando promiscuamente às moléculas do antigénio de leucócitos humanos (hla) da classe ii |
EP2305827A1 (en) | 2005-11-14 | 2011-04-06 | Université Laval | Cancer antigen MAGE-A9 and uses thereof |
US20090263574A1 (en) | 2008-04-21 | 2009-10-22 | Quinn Daniel E | Method of restoring an article |
GB0910725D0 (en) | 2009-06-22 | 2009-08-05 | Heptares Therapeutics Ltd | Mutant proteins and methods for producing them |
GB201006360D0 (en) | 2010-04-16 | 2010-06-02 | Immatics Biotechnologies Gmbh | Method for differentially quantifying naturally processed HLA-restricted peptides for cancer, autoimmune and infectious diseases immunotherapy development |
US8987423B2 (en) | 2010-07-22 | 2015-03-24 | Glaxosmithkline Biologicals, S.A. | MAGE antigen binding proteins |
BR112013010213A2 (pt) | 2010-10-26 | 2019-09-24 | Technion Research & Development Foundation Ltd | anticorpos que unem ligantes solúveis de receptores de célula t |
WO2013057586A1 (en) | 2011-10-19 | 2013-04-25 | Oslo Universitetssykehus Hf | Compositions and methods for producing soluble t - cell receptors |
WO2013096862A2 (en) | 2011-12-21 | 2013-06-27 | Integrated Diagnostics, Inc. | Selected reaction monitoring assays |
AU2013243948A1 (en) * | 2012-04-02 | 2014-10-30 | Moderna Therapeutics, Inc. | Modified polynucleotides for the production of proteins associated with human disease |
ES2603589T3 (es) | 2012-11-08 | 2017-02-28 | F. Hoffmann-La Roche Ag | Ácidos nucleicos que codifican polipéptidos quiméricos para la identificación sistemática de bibliotecas |
EP2808392A1 (en) | 2013-05-28 | 2014-12-03 | Rheinische Friedrich-Wilhelms-Universität Bonn | Aptamers and use of the aptamers in the diagnosis and treatment of cancer |
GB201319446D0 (en) | 2013-11-04 | 2013-12-18 | Immatics Biotechnologies Gmbh | Personalized immunotherapy against several neuronal and brain tumors |
CA2984234C (en) | 2015-05-01 | 2023-10-10 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Methods of isolating t cells and t cell receptors having antigenic specificity for a cancer-specific mutation from peripheral blood |
GB201520559D0 (en) * | 2015-11-23 | 2016-01-06 | Immunocore Ltd & Adaptimmune Ltd | Peptides |
GB201520579D0 (en) | 2015-11-23 | 2016-01-06 | Immunocore Ltd & Adaptimmune Ltd | Peptides |
CR20200059A (es) | 2017-07-07 | 2020-06-01 | Immatics Biotechnologies Gmbh | Nuevos péptidos y nuevas combinaciones de péptidos para el uso en la inmunoterapia contra el cáncer de pulmón, incluyendo el nsclc, el sclc y otros cánceres |
US11945850B2 (en) * | 2018-09-17 | 2024-04-02 | Immatics Biotechnologies Gmbh | B*44 restricted peptides for use in immunotherapy against cancers and related methods |
-
2018
- 2018-07-03 CR CR20200059A patent/CR20200059A/es unknown
- 2018-07-03 CR CR20210169A patent/CR20210169A/es unknown
- 2018-07-03 PE PE2020000025A patent/PE20200693A1/es unknown
- 2018-07-03 CR CR20210168A patent/CR20210168A/es unknown
- 2018-07-03 TW TW107122872A patent/TW201906859A/zh unknown
- 2018-07-03 SG SG11201913302SA patent/SG11201913302SA/en unknown
- 2018-07-03 AU AU2018297578A patent/AU2018297578C1/en not_active Expired - Fee Related
- 2018-07-03 EP EP23216393.1A patent/EP4316597A2/en active Pending
- 2018-07-03 EP EP18740138.5A patent/EP3648790A1/en active Pending
- 2018-07-03 BR BR112019028070-7A patent/BR112019028070A2/pt unknown
- 2018-07-03 JP JP2019571705A patent/JP2020530759A/ja active Pending
- 2018-07-03 CN CN201880041940.1A patent/CN110785183A/zh active Pending
- 2018-07-03 CA CA3068852A patent/CA3068852A1/en active Pending
- 2018-07-03 CR CR20210167A patent/CR20210167A/es unknown
- 2018-07-03 MX MX2019015879A patent/MX2019015879A/es unknown
- 2018-07-03 KR KR1020207001447A patent/KR20200026898A/ko not_active Application Discontinuation
-
2019
- 2019-04-18 US US16/387,610 patent/US10472402B2/en active Active
- 2019-09-26 US US16/584,022 patent/US10597434B2/en active Active
- 2019-12-20 MX MX2022005897A patent/MX2022005897A/es unknown
-
2020
- 2020-01-03 CL CL2020000020A patent/CL2020000020A1/es unknown
- 2020-01-06 PH PH12020500051A patent/PH12020500051A1/en unknown
- 2020-01-07 IL IL271895A patent/IL271895A/en unknown
- 2020-01-29 US US16/776,244 patent/US10711048B2/en active Active
- 2020-01-31 CO CONC2020/0001141A patent/CO2020001141A2/es unknown
- 2020-05-01 US US16/864,897 patent/US10836806B2/en active Active
-
2021
- 2021-07-09 US US17/371,826 patent/US11279740B2/en active Active
- 2021-07-09 US US17/371,871 patent/US11279741B2/en active Active
- 2021-07-16 US US17/377,905 patent/US11261224B2/en active Active
- 2021-07-16 US US17/377,867 patent/US11292821B2/en active Active
- 2021-09-02 US US17/465,597 patent/US11352401B1/en active Active
- 2021-09-17 US US17/477,869 patent/US11370817B2/en active Active
- 2021-12-23 US US17/561,051 patent/US11414470B2/en active Active
-
2022
- 2022-01-07 US US17/570,943 patent/US11407798B2/en active Active
- 2022-01-14 US US17/576,714 patent/US11618774B2/en active Active
- 2022-01-21 US US17/581,260 patent/US11414471B2/en active Active
- 2022-01-28 US US17/587,387 patent/US11414472B2/en active Active
- 2022-02-04 US US17/665,199 patent/US11414473B2/en active Active
- 2022-02-11 US US17/669,601 patent/US11427622B2/en active Active
- 2022-02-18 US US17/674,910 patent/US11459365B2/en active Active
- 2022-02-25 US US17/681,107 patent/US11459366B2/en active Active
- 2022-03-04 US US17/687,307 patent/US11498948B2/en active Active
- 2022-03-11 US US17/693,316 patent/US11479589B2/en active Active
- 2022-03-16 CL CL2022000642A patent/CL2022000642A1/es unknown
- 2022-03-16 CL CL2022000641A patent/CL2022000641A1/es unknown
- 2022-05-16 AU AU2022203259A patent/AU2022203259B2/en active Active
- 2022-06-17 US US17/843,733 patent/US20230040789A1/en active Pending
- 2022-07-08 US US17/860,827 patent/US20220348622A1/en active Pending
- 2022-07-08 US US17/860,840 patent/US20230100686A1/en active Pending
- 2022-07-08 US US17/860,600 patent/US20220348621A1/en active Pending
- 2022-07-08 US US17/860,803 patent/US20220363729A1/en active Pending
- 2022-07-22 US US17/871,615 patent/US20220389068A1/en active Pending
- 2022-07-22 US US17/871,724 patent/US20230125179A1/en active Pending
- 2022-07-29 US US17/877,535 patent/US20230051523A1/en active Pending
- 2022-07-29 US US17/877,515 patent/US20220363730A1/en active Pending
- 2022-08-12 US US17/886,752 patent/US20230002461A1/en active Pending
- 2022-08-12 US US17/819,470 patent/US20230287069A1/en active Pending
- 2022-08-18 US US17/820,824 patent/US20230174602A1/en active Pending
- 2022-08-18 US US17/820,821 patent/US20230148369A1/en active Pending
- 2022-08-26 US US17/822,653 patent/US20230094553A1/en active Pending
- 2022-08-26 US US17/822,657 patent/US20230021673A1/en active Pending
- 2022-09-02 US US17/929,344 patent/US20230094286A1/en active Pending
- 2022-09-02 US US17/929,347 patent/US20230116279A1/en active Pending
- 2022-09-09 US US17/930,891 patent/US20230035702A1/en active Pending
- 2022-09-19 US US17/933,353 patent/US20230109584A1/en active Pending
- 2022-09-19 US US17/933,298 patent/US20230043654A1/en active Pending
- 2022-09-23 US US17/934,673 patent/US20230046543A1/en active Pending
- 2022-09-23 US US17/934,663 patent/US20230192791A1/en active Pending
- 2022-09-23 US US17/934,747 patent/US20230042253A1/en active Pending
-
2023
- 2023-04-07 US US18/297,076 patent/US20230279066A1/en active Pending
- 2023-05-10 US US18/314,878 patent/US20230340046A1/en active Pending
- 2023-07-04 AU AU2023204282A patent/AU2023204282A1/en active Pending
- 2023-07-09 IL IL304321A patent/IL304321A/en unknown
- 2023-08-11 US US18/448,614 patent/US20230382964A1/en active Pending
- 2023-09-20 JP JP2023152293A patent/JP2024001045A/ja active Pending
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2015018805A1 (en) * | 2013-08-05 | 2015-02-12 | Immatics Biotechnologies Gmbh | Novel immunotherapy against several tumors, such as lung cancer, including nsclc |
WO2017060169A1 (en) * | 2015-10-05 | 2017-04-13 | Immatics Biotechnologies Gmbh | Peptides and combination of peptides for use in immunotherapy against small cell lung cancer and other cancers |
CN111533796A (zh) * | 2017-04-10 | 2020-08-14 | 伊玛提克斯生物技术有限公司 | 用于癌症免疫治疗的肽及其肽组合物 |
CN111533799A (zh) * | 2017-04-10 | 2020-08-14 | 伊玛提克斯生物技术有限公司 | 用于白血病和其他癌症免疫治疗的肽和肽组合物 |
CN112512538A (zh) * | 2018-05-18 | 2021-03-16 | 国家儿童医疗中心 | 改进的靶向t细胞疗法 |
Non-Patent Citations (1)
Title |
---|
陈志国等: "医学免疫学", 辽宁大学出版社, pages: 118 - 122 * |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN111732629A (zh) * | 2020-06-19 | 2020-10-02 | 完美(广东)日用品有限公司 | 一种寡肽、减肥组合物及制备方法和应用 |
CN114019165A (zh) * | 2022-01-05 | 2022-02-08 | 首都医科大学附属北京妇产医院 | 多肽芯片或试剂盒及其在诊断非小细胞肺癌中的应用 |
CN114019165B (zh) * | 2022-01-05 | 2022-04-01 | 首都医科大学附属北京妇产医院 | 多肽芯片或试剂盒及其在诊断非小细胞肺癌中的应用 |
CN115785212A (zh) * | 2022-06-10 | 2023-03-14 | 河北博海生物工程开发有限公司 | 肺癌特异性分子靶标03及其用途 |
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN114040921A (zh) | 用于不同类型癌症免疫治疗的非经典来源的肽和肽组合 | |
CN112512639A (zh) | B*07限制肽和肽组合的抗癌免疫治疗和相关方法 | |
CN111533798A (zh) | 用于癌症免疫治疗的肽及其肽组合物 | |
US11292821B2 (en) | Peptides and combination of peptides for use in immunotherapy against lung cancer, including NSCLC, SCLC and other cancers | |
CN112789285A (zh) | B*44 限制肽在抗癌免疫治疗的用途和相关方法 | |
US11168122B2 (en) | Peptides and combination of peptides for use in immunotherapy against lung cancer, including NSCLC, SCLC and other cancers | |
CN113164569A (zh) | A*01限制肽和肽组合物在抗癌免疫治疗中的用途和相关方法 | |
CN113444148A (zh) | A*03限制肽在抗癌免疫治疗和相关方法中的用途 | |
CN113260376A (zh) | B*08限制肽和肽组合物抗癌免疫治疗和相关方法 | |
CN112135629A (zh) | 用于抗癌免疫治疗的肽 | |
CN112920257A (zh) | 用于不同类型癌症免疫治疗的非经典来源的肽和肽组合 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination |