JP4472520B2 - Mhc分子に結合する腫瘍関連ペプチド - Google Patents
Mhc分子に結合する腫瘍関連ペプチド Download PDFInfo
- Publication number
- JP4472520B2 JP4472520B2 JP2004509714A JP2004509714A JP4472520B2 JP 4472520 B2 JP4472520 B2 JP 4472520B2 JP 2004509714 A JP2004509714 A JP 2004509714A JP 2004509714 A JP2004509714 A JP 2004509714A JP 4472520 B2 JP4472520 B2 JP 4472520B2
- Authority
- JP
- Japan
- Prior art keywords
- peptide
- cells
- tumor
- ctl
- seq
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
- 108090000765 processed proteins & peptides Proteins 0.000 title claims abstract description 217
- 206010028980 Neoplasm Diseases 0.000 title claims abstract description 78
- 102000004196 processed proteins & peptides Human genes 0.000 title claims abstract description 59
- 210000004027 cell Anatomy 0.000 claims abstract description 96
- 108700018351 Major Histocompatibility Complex Proteins 0.000 claims abstract description 26
- 230000020382 suppression by virus of host antigen processing and presentation of peptide antigen via MHC class I Effects 0.000 claims abstract description 26
- 108020004707 nucleic acids Proteins 0.000 claims abstract description 9
- 102000039446 nucleic acids Human genes 0.000 claims abstract description 9
- 150000007523 nucleic acids Chemical class 0.000 claims abstract description 9
- 239000013598 vector Substances 0.000 claims abstract description 5
- 206010006187 Breast cancer Diseases 0.000 claims abstract description 3
- 208000026310 Breast neoplasm Diseases 0.000 claims abstract description 3
- 208000008839 Kidney Neoplasms Diseases 0.000 claims abstract 2
- 206010038389 Renal cancer Diseases 0.000 claims abstract 2
- 208000005718 Stomach Neoplasms Diseases 0.000 claims abstract 2
- 206010017758 gastric cancer Diseases 0.000 claims abstract 2
- 201000010982 kidney cancer Diseases 0.000 claims abstract 2
- 201000011549 stomach cancer Diseases 0.000 claims abstract 2
- 210000001744 T-lymphocyte Anatomy 0.000 claims description 20
- 150000001413 amino acids Chemical class 0.000 claims description 15
- 210000000612 antigen-presenting cell Anatomy 0.000 claims description 12
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 9
- 239000008194 pharmaceutical composition Substances 0.000 claims description 9
- 238000011282 treatment Methods 0.000 claims description 9
- 239000002671 adjuvant Substances 0.000 claims description 8
- 230000027455 binding Effects 0.000 claims description 8
- 238000004519 manufacturing process Methods 0.000 claims description 7
- 201000010099 disease Diseases 0.000 claims description 6
- 208000003200 Adenoma Diseases 0.000 claims description 4
- 206010001233 Adenoma benign Diseases 0.000 claims description 4
- 210000000481 breast Anatomy 0.000 claims description 3
- 239000003153 chemical reaction reagent Substances 0.000 claims description 3
- 210000003734 kidney Anatomy 0.000 claims description 3
- 210000000265 leukocyte Anatomy 0.000 claims description 3
- 210000000496 pancreas Anatomy 0.000 claims description 3
- 210000002784 stomach Anatomy 0.000 claims description 3
- 210000003932 urinary bladder Anatomy 0.000 claims description 3
- 230000001461 cytolytic effect Effects 0.000 claims description 2
- 208000024313 Testicular Neoplasms Diseases 0.000 claims 2
- 206010057644 Testis cancer Diseases 0.000 claims 2
- 125000003275 alpha amino acid group Chemical group 0.000 claims 2
- 201000003120 testicular cancer Diseases 0.000 claims 2
- 206010005003 Bladder cancer Diseases 0.000 claims 1
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims 1
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 claims 1
- 239000003814 drug Substances 0.000 claims 1
- 230000001747 exhibiting effect Effects 0.000 claims 1
- 238000002372 labelling Methods 0.000 claims 1
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims 1
- 208000008443 pancreatic carcinoma Diseases 0.000 claims 1
- 230000004936 stimulating effect Effects 0.000 claims 1
- 229940124597 therapeutic agent Drugs 0.000 claims 1
- 201000005112 urinary bladder cancer Diseases 0.000 claims 1
- 230000009089 cytolysis Effects 0.000 abstract description 32
- 210000004443 dendritic cell Anatomy 0.000 abstract description 24
- 238000003556 assay Methods 0.000 abstract description 23
- 230000006698 induction Effects 0.000 abstract description 12
- 210000003819 peripheral blood mononuclear cell Anatomy 0.000 abstract description 11
- 210000001151 cytotoxic T lymphocyte Anatomy 0.000 abstract description 9
- 201000011510 cancer Diseases 0.000 abstract description 8
- 201000001441 melanoma Diseases 0.000 abstract description 6
- 229960005486 vaccine Drugs 0.000 abstract description 5
- 230000000694 effects Effects 0.000 abstract description 3
- 102000000588 Interleukin-2 Human genes 0.000 abstract description 2
- 108010002350 Interleukin-2 Proteins 0.000 abstract description 2
- 239000012636 effector Substances 0.000 abstract description 2
- 239000000824 cytostatic agent Substances 0.000 abstract 1
- 230000001085 cytostatic effect Effects 0.000 abstract 1
- 230000003013 cytotoxicity Effects 0.000 abstract 1
- 231100000135 cytotoxicity Toxicity 0.000 abstract 1
- 238000010348 incorporation Methods 0.000 abstract 1
- 230000010534 mechanism of action Effects 0.000 abstract 1
- 210000005259 peripheral blood Anatomy 0.000 abstract 1
- 239000011886 peripheral blood Substances 0.000 abstract 1
- 210000004881 tumor cell Anatomy 0.000 description 47
- 102000017794 Perilipin-2 Human genes 0.000 description 43
- 108010067163 Perilipin-2 Proteins 0.000 description 43
- 239000000427 antigen Substances 0.000 description 38
- 108091007433 antigens Proteins 0.000 description 38
- 102000036639 antigens Human genes 0.000 description 38
- FWMNVWWHGCHHJJ-SKKKGAJSSA-N 4-amino-1-[(2r)-6-amino-2-[[(2r)-2-[[(2r)-2-[[(2r)-2-amino-3-phenylpropanoyl]amino]-3-phenylpropanoyl]amino]-4-methylpentanoyl]amino]hexanoyl]piperidine-4-carboxylic acid Chemical compound C([C@H](C(=O)N[C@H](CC(C)C)C(=O)N[C@H](CCCCN)C(=O)N1CCC(N)(CC1)C(O)=O)NC(=O)[C@H](N)CC=1C=CC=CC=1)C1=CC=CC=C1 FWMNVWWHGCHHJJ-SKKKGAJSSA-N 0.000 description 33
- 239000003446 ligand Substances 0.000 description 33
- 108010075704 HLA-A Antigens Proteins 0.000 description 29
- 102000011786 HLA-A Antigens Human genes 0.000 description 29
- 108090000623 proteins and genes Proteins 0.000 description 24
- 230000001404 mediated effect Effects 0.000 description 19
- 102000004169 proteins and genes Human genes 0.000 description 18
- 235000018102 proteins Nutrition 0.000 description 17
- 210000001519 tissue Anatomy 0.000 description 17
- 238000000338 in vitro Methods 0.000 description 15
- 239000003112 inhibitor Substances 0.000 description 12
- 238000000034 method Methods 0.000 description 12
- 235000001014 amino acid Nutrition 0.000 description 11
- 229940024606 amino acid Drugs 0.000 description 11
- 102100033421 Keratin, type I cytoskeletal 18 Human genes 0.000 description 10
- 108010066327 Keratin-18 Proteins 0.000 description 10
- 230000028993 immune response Effects 0.000 description 9
- 230000001472 cytotoxic effect Effects 0.000 description 8
- 230000005764 inhibitory process Effects 0.000 description 8
- 239000002609 medium Substances 0.000 description 8
- 230000004044 response Effects 0.000 description 8
- 102100028976 HLA class I histocompatibility antigen, B alpha chain Human genes 0.000 description 7
- 108010058607 HLA-B Antigens Proteins 0.000 description 7
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 description 7
- 102000043129 MHC class I family Human genes 0.000 description 7
- 108091054437 MHC class I family Proteins 0.000 description 7
- 108010002687 Survivin Proteins 0.000 description 7
- KZSNJWFQEVHDMF-UHFFFAOYSA-N Valine Natural products CC(C)C(N)C(O)=O KZSNJWFQEVHDMF-UHFFFAOYSA-N 0.000 description 7
- AGPKZVBTJJNPAG-UHFFFAOYSA-N isoleucine Chemical group CCC(C)C(N)C(O)=O AGPKZVBTJJNPAG-UHFFFAOYSA-N 0.000 description 7
- 229960000310 isoleucine Drugs 0.000 description 7
- 239000004474 valine Substances 0.000 description 7
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical group C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 6
- AGPKZVBTJJNPAG-WHFBIAKZSA-N L-isoleucine Chemical group CC[C@H](C)[C@H](N)C(O)=O AGPKZVBTJJNPAG-WHFBIAKZSA-N 0.000 description 6
- KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical group CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 description 6
- 102000000763 Survivin Human genes 0.000 description 6
- 235000004279 alanine Nutrition 0.000 description 6
- 239000012634 fragment Substances 0.000 description 6
- 102000004149 Annexin A2 Human genes 0.000 description 5
- 108090000668 Annexin A2 Proteins 0.000 description 5
- 208000010839 B-cell chronic lymphocytic leukemia Diseases 0.000 description 5
- 102100022623 Hepatocyte growth factor receptor Human genes 0.000 description 5
- 101000972946 Homo sapiens Hepatocyte growth factor receptor Proteins 0.000 description 5
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 description 5
- 210000003719 b-lymphocyte Anatomy 0.000 description 5
- 238000002474 experimental method Methods 0.000 description 5
- 230000002401 inhibitory effect Effects 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 102000004457 Granulocyte-Macrophage Colony-Stimulating Factor Human genes 0.000 description 4
- 108010017213 Granulocyte-Macrophage Colony-Stimulating Factor Proteins 0.000 description 4
- 208000031422 Lymphocytic Chronic B-Cell Leukemia Diseases 0.000 description 4
- 102000007079 Peptide Fragments Human genes 0.000 description 4
- 108010033276 Peptide Fragments Proteins 0.000 description 4
- 208000032852 chronic lymphocytic leukemia Diseases 0.000 description 4
- 238000009169 immunotherapy Methods 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 108700028369 Alleles Proteins 0.000 description 3
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 3
- 102000004127 Cytokines Human genes 0.000 description 3
- 108090000695 Cytokines Proteins 0.000 description 3
- 108020004414 DNA Proteins 0.000 description 3
- 102000043131 MHC class II family Human genes 0.000 description 3
- 108091054438 MHC class II family Proteins 0.000 description 3
- 108010088865 Nicotinamide N-Methyltransferase Proteins 0.000 description 3
- 102000009063 Nicotinamide N-methyltransferase Human genes 0.000 description 3
- 239000012980 RPMI-1640 medium Substances 0.000 description 3
- 208000006265 Renal cell carcinoma Diseases 0.000 description 3
- 239000003242 anti bacterial agent Substances 0.000 description 3
- 229940088710 antibiotic agent Drugs 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- 239000010432 diamond Substances 0.000 description 3
- 238000004520 electroporation Methods 0.000 description 3
- 239000012091 fetal bovine serum Substances 0.000 description 3
- 210000000987 immune system Anatomy 0.000 description 3
- 230000002163 immunogen Effects 0.000 description 3
- 238000001727 in vivo Methods 0.000 description 3
- 229930182817 methionine Chemical group 0.000 description 3
- 210000001616 monocyte Anatomy 0.000 description 3
- 230000002269 spontaneous effect Effects 0.000 description 3
- 210000001550 testis Anatomy 0.000 description 3
- 238000002560 therapeutic procedure Methods 0.000 description 3
- 108010078791 Carrier Proteins Proteins 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- 102000000794 Galectin 2 Human genes 0.000 description 2
- 108010001496 Galectin 2 Proteins 0.000 description 2
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 2
- 108010074032 HLA-A2 Antigen Proteins 0.000 description 2
- 102000025850 HLA-A2 Antigen Human genes 0.000 description 2
- 102000002812 Heat-Shock Proteins Human genes 0.000 description 2
- 108010004889 Heat-Shock Proteins Proteins 0.000 description 2
- 102000008949 Histocompatibility Antigens Class I Human genes 0.000 description 2
- 108010088652 Histocompatibility Antigens Class I Proteins 0.000 description 2
- 241000701044 Human gammaherpesvirus 4 Species 0.000 description 2
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical group CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 2
- 108091008874 T cell receptors Proteins 0.000 description 2
- 230000005867 T cell response Effects 0.000 description 2
- 102000016266 T-Cell Antigen Receptors Human genes 0.000 description 2
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 2
- 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 230000001464 adherent effect Effects 0.000 description 2
- 230000030741 antigen processing and presentation Effects 0.000 description 2
- 238000013459 approach Methods 0.000 description 2
- 210000004899 c-terminal region Anatomy 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 229910003460 diamond Inorganic materials 0.000 description 2
- 108010048367 enhanced green fluorescent protein Proteins 0.000 description 2
- 210000003743 erythrocyte Anatomy 0.000 description 2
- 235000013922 glutamic acid Nutrition 0.000 description 2
- 239000004220 glutamic acid Substances 0.000 description 2
- 210000005260 human cell Anatomy 0.000 description 2
- 230000008076 immune mechanism Effects 0.000 description 2
- 230000003053 immunization Effects 0.000 description 2
- 238000002955 isolation Methods 0.000 description 2
- 210000003292 kidney cell Anatomy 0.000 description 2
- 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 2
- 230000036210 malignancy Effects 0.000 description 2
- 239000003550 marker Substances 0.000 description 2
- 238000004949 mass spectrometry Methods 0.000 description 2
- 230000035772 mutation Effects 0.000 description 2
- 239000013642 negative control Substances 0.000 description 2
- 238000012856 packing Methods 0.000 description 2
- 239000013612 plasmid Substances 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 230000002829 reductive effect Effects 0.000 description 2
- 238000004007 reversed phase HPLC Methods 0.000 description 2
- 239000000523 sample Substances 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 230000032258 transport Effects 0.000 description 2
- 102000003730 Alpha-catenin Human genes 0.000 description 1
- 108090000020 Alpha-catenin Proteins 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- 208000030808 Clear cell renal carcinoma Diseases 0.000 description 1
- 206010009944 Colon cancer Diseases 0.000 description 1
- 102000006311 Cyclin D1 Human genes 0.000 description 1
- 108010058546 Cyclin D1 Proteins 0.000 description 1
- 108700039887 Essential Genes Proteins 0.000 description 1
- 229920001917 Ficoll Polymers 0.000 description 1
- 108010029526 HLA-A28 antigen Proteins 0.000 description 1
- 102000018713 Histocompatibility Antigens Class II Human genes 0.000 description 1
- 108010027412 Histocompatibility Antigens Class II Proteins 0.000 description 1
- 241000725303 Human immunodeficiency virus Species 0.000 description 1
- 101900297506 Human immunodeficiency virus type 1 group M subtype B Reverse transcriptase/ribonuclease H Proteins 0.000 description 1
- 108060003951 Immunoglobulin Proteins 0.000 description 1
- 108090000978 Interleukin-4 Proteins 0.000 description 1
- 102000011782 Keratins Human genes 0.000 description 1
- 108010076876 Keratins Proteins 0.000 description 1
- 239000004472 Lysine Chemical group 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Chemical group NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 208000034578 Multiple myelomas Diseases 0.000 description 1
- 208000034179 Neoplasms, Glandular and Epithelial Diseases 0.000 description 1
- 108700020796 Oncogene Proteins 0.000 description 1
- 206010035226 Plasma cell myeloma Diseases 0.000 description 1
- 108700020978 Proto-Oncogene Proteins 0.000 description 1
- 102000052575 Proto-Oncogene Human genes 0.000 description 1
- 108091034057 RNA (poly(A)) Proteins 0.000 description 1
- 238000011530 RNeasy Mini Kit Methods 0.000 description 1
- 102000007056 Recombinant Fusion Proteins Human genes 0.000 description 1
- 108010008281 Recombinant Fusion Proteins Proteins 0.000 description 1
- 208000000453 Skin Neoplasms Diseases 0.000 description 1
- 108010090804 Streptavidin Proteins 0.000 description 1
- 230000024932 T cell mediated immunity Effects 0.000 description 1
- 210000000173 T-lymphoid precursor cell Anatomy 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
- 108091023040 Transcription factor Proteins 0.000 description 1
- 102000040945 Transcription factor Human genes 0.000 description 1
- 102000013127 Vimentin Human genes 0.000 description 1
- 108010065472 Vimentin Proteins 0.000 description 1
- 210000001789 adipocyte Anatomy 0.000 description 1
- 230000000735 allogeneic effect Effects 0.000 description 1
- WNROFYMDJYEPJX-UHFFFAOYSA-K aluminium hydroxide Chemical compound [OH-].[OH-].[OH-].[Al+3] WNROFYMDJYEPJX-UHFFFAOYSA-K 0.000 description 1
- 230000006023 anti-tumor response Effects 0.000 description 1
- 239000008365 aqueous carrier 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
- 125000000637 arginyl group Chemical group N[C@@H](CCCNC(N)=N)C(=O)* 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 102000028861 calmodulin binding Human genes 0.000 description 1
- 108091000084 calmodulin binding Proteins 0.000 description 1
- 238000009566 cancer vaccine Methods 0.000 description 1
- 229940022399 cancer vaccine Drugs 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 230000022534 cell killing Effects 0.000 description 1
- 230000006037 cell lysis Effects 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 208000024207 chronic leukemia Diseases 0.000 description 1
- 206010073251 clear cell renal cell carcinoma Diseases 0.000 description 1
- 208000029742 colonic neoplasm Diseases 0.000 description 1
- 238000012875 competitive assay Methods 0.000 description 1
- 230000000295 complement effect Effects 0.000 description 1
- 239000002299 complementary DNA Substances 0.000 description 1
- 230000000139 costimulatory effect Effects 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 208000035250 cutaneous malignant susceptibility to 1 melanoma Diseases 0.000 description 1
- 210000000172 cytosol Anatomy 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 238000000432 density-gradient centrifugation Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 238000012137 double-staining Methods 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 230000012202 endocytosis Effects 0.000 description 1
- 210000002472 endoplasmic reticulum Anatomy 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000010195 expression analysis Methods 0.000 description 1
- 229960000390 fludarabine Drugs 0.000 description 1
- GIUYCYHIANZCFB-FJFJXFQQSA-N fludarabine phosphate Chemical compound C1=NC=2C(N)=NC(F)=NC=2N1[C@@H]1O[C@H](COP(O)(O)=O)[C@@H](O)[C@@H]1O GIUYCYHIANZCFB-FJFJXFQQSA-N 0.000 description 1
- 238000013467 fragmentation Methods 0.000 description 1
- 238000006062 fragmentation reaction Methods 0.000 description 1
- 238000002523 gelfiltration Methods 0.000 description 1
- 230000014509 gene expression Effects 0.000 description 1
- 238000011223 gene expression profiling Methods 0.000 description 1
- 238000012252 genetic analysis Methods 0.000 description 1
- 230000000762 glandular Effects 0.000 description 1
- 125000000291 glutamic acid group Chemical group N[C@@H](CCC(O)=O)C(=O)* 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 210000002443 helper t lymphocyte Anatomy 0.000 description 1
- 108091008147 housekeeping proteins Proteins 0.000 description 1
- 210000004408 hybridoma Anatomy 0.000 description 1
- 238000002649 immunization Methods 0.000 description 1
- 230000005847 immunogenicity Effects 0.000 description 1
- 102000018358 immunoglobulin Human genes 0.000 description 1
- 230000003308 immunostimulating effect Effects 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 238000007373 indentation Methods 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 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 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- 230000002934 lysing effect Effects 0.000 description 1
- 230000002101 lytic effect Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 125000001360 methionine group Chemical group N[C@@H](CCSC)C(=O)* 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 230000009149 molecular binding Effects 0.000 description 1
- 239000000178 monomer Substances 0.000 description 1
- 210000000822 natural killer cell Anatomy 0.000 description 1
- 201000011330 nonpapillary renal cell carcinoma Diseases 0.000 description 1
- 238000010899 nucleation Methods 0.000 description 1
- 210000001672 ovary Anatomy 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 239000013610 patient sample Substances 0.000 description 1
- 108010011903 peptide receptors Proteins 0.000 description 1
- 102000014187 peptide receptors Human genes 0.000 description 1
- 238000010647 peptide synthesis reaction Methods 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- 239000013600 plasmid vector Substances 0.000 description 1
- 238000004094 preconcentration Methods 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 229930182490 saponin Natural products 0.000 description 1
- 150000007949 saponins Chemical class 0.000 description 1
- 235000017709 saponins Nutrition 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 150000003377 silicon compounds Chemical class 0.000 description 1
- 201000000849 skin cancer Diseases 0.000 description 1
- PXLIDIMHPNPGMH-UHFFFAOYSA-N sodium chromate Chemical compound [Na+].[Na+].[O-][Cr]([O-])(=O)=O PXLIDIMHPNPGMH-UHFFFAOYSA-N 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000010186 staining Methods 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- 238000001890 transfection Methods 0.000 description 1
- 108010060175 trypsinogen activation peptide Proteins 0.000 description 1
- 230000037455 tumor specific immune response Effects 0.000 description 1
- 238000002255 vaccination Methods 0.000 description 1
- 125000002987 valine group Chemical group [H]N([H])C([H])(C(*)=O)C([H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 210000005048 vimentin Anatomy 0.000 description 1
Images
Classifications
-
- 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
-
- 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
-
- 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
- A61K39/464448—Regulators of development
- A61K39/46445—Apoptosis related proteins, e.g. survivin or livin
-
- 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
- A61K39/464452—Transcription factors, e.g. SOX or c-MYC
-
- 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
- A61K39/464838—Viral antigens
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/18—Drugs for disorders of the alimentary tract or the digestive system for pancreatic disorders, e.g. pancreatic enzymes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/10—Drugs for disorders of the urinary system of the bladder
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/14—Drugs for genital or sexual disorders; Contraceptives for lactation disorders, e.g. galactorrhoea
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/04—Immunostimulants
-
- 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
-
- 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
- G01N33/5005—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells
- G01N33/5008—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics
- G01N33/5044—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics involving specific cell types
- G01N33/5047—Cells of the immune system
- G01N33/505—Cells of the immune system involving T-cells
-
- 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
- G01N33/569—Immunoassay; Biospecific binding assay; Materials therefor for microorganisms, e.g. protozoa, bacteria, viruses
- G01N33/56966—Animal cells
- G01N33/56977—HLA or MHC typing
-
- 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
-
- 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
- A61K2239/00—Indexing codes associated with cellular immunotherapy of group A61K39/46
- A61K2239/46—Indexing codes associated with cellular immunotherapy of group A61K39/46 characterised by the cancer treated
- A61K2239/48—Blood cells, e.g. leukemia or lymphoma
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10S530/00—Chemistry: natural resins or derivatives; peptides or proteins; lignins or reaction products thereof
- Y10S530/827—Proteins from mammals or birds
- Y10S530/828—Cancer
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Immunology (AREA)
- Engineering & Computer Science (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Cell Biology (AREA)
- Molecular Biology (AREA)
- Pharmacology & Pharmacy (AREA)
- Urology & Nephrology (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Biomedical Technology (AREA)
- Hematology (AREA)
- Microbiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biochemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Physics & Mathematics (AREA)
- Pathology (AREA)
- Food Science & Technology (AREA)
- Biotechnology (AREA)
- Analytical Chemistry (AREA)
- General Physics & Mathematics (AREA)
- Epidemiology (AREA)
- Mycology (AREA)
- Oncology (AREA)
- Toxicology (AREA)
- Zoology (AREA)
- Biophysics (AREA)
- Genetics & Genomics (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Tropical Medicine & Parasitology (AREA)
- Virology (AREA)
- Endocrinology (AREA)
Description
このようなペプチドは、例えば、腫瘍関連疾患(tumor−associated diseases)の免疫療法に用いられる。
MHCクラスII分子は、専門的な抗原提示細胞(APC)にのみ存在し、エンドサイト−シスの間に取り込まれて加工される外来性タンパク質のペプチドを提示する。ペプチド/MHCクラスI分子複合体は、CD8陽性の細胞傷害性Tリンパ球によって認識され、ペプチド/MHCクラスII分子複合体は、CD4ヘルパーT細胞によって認識される。
本発明の基礎をなす課題は、これにより、完全に達成される。
ここでは、ペプチドは、CTL集団中に特異的にそのペプチドに向かうCTLが存在するかどうか、又は、CTLが治療により誘導されたかどうかを知るために用いることができる。
1.1 患者サンプル
組織学的に確認された腎臓細胞の悪性腫瘍を有する患者のサンプルは、ティュービンゲン大学の泌尿器科から入手した。患者はいずれも術前治療を受けていない。患者番号1(以下、RCC01と記す)は、以下のHLA型を有していた:HLA−A*02 A*68 B*18 B*44;患者番号2(以下、RCC13と記す):HLA−A*02 A*24 B*07 B*40。
ショック冷凍(shock−frozen)した腫瘍サンプルは、Schirle,M.らの記載「新規T細胞−非依存アプローチによる、腫瘍関連MHCクラスIリガンドの同定(Identification of tumor-associated MHC-class I ligands by a novel T cell-independent approach)」2000,European Journal of Immunology,30:2216-2225に従い処理した。ペプチドは、クラスIHLAに特異的なモノクローナル抗体W6/32、又は、HLA−A2に特異的なモノクローナル抗体BB7.2を用いて標準的な手順により単離された。これらの抗体の生産方法と使用方法は、Barnstable, C.J.らの「グループA赤血球、HLAおよび他のヒト細胞表面抗原に対するモノクローナル抗体の生産−遺伝的解析のための新規ツール(Production of monoclonal antibodies to group A erythrocytes,HLA and other human cell surface antigens-New tools for genetic analysis.)」1978,Cell,14:9-20、及び、Parham, P.及びBrodsky F.M.の「BB7.2の部分精製および特性。HLA−A2およびHLA−A28の変異体に対する特異性を持つ細胞傷害性モノクローナル抗体(Partial purification and some properties of BB7.2.A cytotoxic monoclonal antibody with specificity for HLA-A2 and a variant of HLA-A28)」1981,Hum.Immunol.,3:277-299による。
患者RCC01の腫瘍組織由来のペプチドは、逆相HPLC(SMART−system, μRPC C2/C18 SC 2.1/19, Amersham Pharmacia Biotech)により分離され、フラクションはnanoESI MSを用いて分析された。これに際し、手順はSchirle,M.等の報告に記載されている方法で実施した(Identification of tumor-associated MHC-class I ligand by a novel T
cell-independent approach, 2000,European Journal of Immunology, 30:2216-2225)。
添付した表1に、HLA−A*02、HLA−A*68、HLA−B*18、又は、HLA−B*44に結合したリガンドを示した。HLA−A*02に結合したペプチドは、対立遺伝子に特異的なペプチドモチーフを示した:ポジション2がロイシン、バリン、イソロイシン、アラニン又はメチオニンで、C末端がロイシン、バリン、イソロイシン又はアラニンである。多くのリガンドは、いわゆるハウスキーピングタンパク質由来であるが、腫瘍関連グループと報告されているタンパク質由来のリガンドも検出された。
患者RCC13の腫瘍組織にも、患者RCC01において確認された同じリガンドが同定された、プロトオンコジーン(c−Met)とケラチン18由来のリガンドと同じリガンドが確認された:配列番号1と3を有するペプチドである。更に、この腫瘍組織からは、別のリガンドが得られ、ニコチンアミド−N−メチルトランスフェラーゼ(NNMT)に由来するリガンドが確認された;この遺伝子は、全ての腎臓悪性腫瘍の95%以上において過剰発現される。更に、その他のリガンドのいくつかは、RCC01のペプチドのレパートリーと共通している。
健康な患者由来の末梢血単核細胞を、アディポフィリン−、ケラチン18−又はmet−プロトオンコジーン(c−Met)ペプチドと共に折り畳まれたHLA−A*0201四量体で染色した:四量体の生成のため、組換えHLA−A*0201分子は、試験管内(インビトロ)でSVASTITGV(配列番号2、アディポフィリン),ALLNIKVKL(配列番号3、ケラチン18)又はYVDPVITSI(配列番号1、met−プロトオンコジーン、c−Met)と共に折り畳まれ、ゲルろ過により精製され、単量体を連結するためにビオチン化され、ストレプトアビジンと混合された。
腫瘍細胞による配列番号1(YVDPVITSI)(c−Metオンコジーンのペプチド断片)及び配列番号2(アディポフィリンのペプチド断片)のペプチドの提示、及び、CTLによるそれらの認識について分析するため、c−Metペプチド(配列番号1のペプチド)に特異的なCTLとアディポフィリンペプチド(配列番号2のペプチド)に特異的なCTLが、試験管内で誘導された。この操作において、健康なHLA−A*02陽性ドナー由来の樹状細胞(DC)が用いられた。
末梢血単核細胞(PBMNC)は、テュービンゲン大学の血液バンクの健康なボランティアの軟膜層(buffy coat)の調製物から得られたヘパリン化された血液を、Ficoll/Paque(Biochrom, Berlin, Germany)を用いて、密度勾配遠心分離することにより単離された。細胞は、RP10培地(RPMI 1640、熱で不活化したウシ胎児の血清10%と抗生物質を添加した)を使用した6穴のプレート(Falcon, Heidelberg, Germany)に植えられた(1穴あたり1×107細胞/3ml)。37℃、5%CO2で2時間インキュベーションしたあと、非粘着性の細胞を除去し、以下のサイトカインを添加したRP10培地で粘着性の血液の単球を培養した:ヒト組換えGM−CSF(顆粒球マクロファージコロニー刺激因子;Leukomax, Novartis; 100ng/ml)、インターロイキン IL−4(R&D Systems, Wiesbaden, Germany, 1000 IU/ml)及びTNF−α(腫瘍壊死因子α)(R&D Systems, Wiesbaden, Germany, 10ng/ml)。
典型的な、2つのHLA−A*02結合ペプチド(上述したように同定されたc−Met (配列番号1、YVDPVITSI)又はアディポフィリン(配列番号2,SVASTITGV))は、標準F−moc試薬を用いてペプチド合成機(432A, Applied Biosystems,Weiterstadt, Germany)で合成され、逆相HPLCと質量分析により分析された。この方法で、同定されたペプチドの充分量を得ることができる。
CTL誘導のため、ステップ2.1で得られたDC(5×105)を、ステップ2.2で得られた配列番号1又は配列番号2のペプチド各50μl/mlと共に2時間パルスし、洗浄し、自己由来の2.5×106のPBMNCとRP10培地中でインキュベートした。
CTLアッセイにおいて、腫瘍細胞、異なる細胞株のペプチド−パルス細胞及び自己由来のDCが標的細胞として用いられた。ペプチド−パルス細胞は、50μg/mlのペプチド(配列番号1又は配列番号2)と共に2時間パルスされた。全ての標的細胞は、RP10培地(RPMI 1640、熱で不活化したウシ胎児の血清10%と抗生物質を添加した)中で〔51Cr〕クロム酸ナトリウムを用いて、1時間の間37℃でラベルされた。その後、1穴あたり104の細胞を96穴の丸底プレートに移した。最終体積が200μlとなるようにCTLの数を変化させて加えて、4時間37℃でインキュベートした。アッセイの終わりに、上澄み(1穴あたり50μl)を採取して、ベータ−プレートカウンターで数えた。特異的な溶解の割合は、次のように計算した:100×((実験に基づく放出数)−(自然放出数))/((最大放出数)−(自然放出数))。自然放出数及び最大放出数は、それぞれ培地又は2%Triron X−100いずれかの存在下で決定した。
a) ペプチド−パルスDCに対するCTL細胞傷害活性
図2には、T2−又はDC−細胞に対する誘導されたCTL(項目2.3参照)の細胞傷害活性に関する51Cr放出アッセイの結果を示す。T2−細胞株はHLA−A*02陽性で、TAP(抗原処理に関連する輸送体)欠損である;(TAPペプチド輸送体は、タンパク質性のペプチド断片を細胞質ゾルから小胞体に輸送し、そこでそれらはMHC分子と結合する)。
次いで、再び標準的な腫瘍51Cr放出アッセイにおいて、配列番号1のc−Metペプチド又は配列番号2のアディポフィリンペプチドに特異的なCTLが、細胞内でc−Met−プロトオンコジーン又はアディポフィリンを発現している腫瘍細胞を認識し、溶解するかどうかを調べた。
試験管内で誘導されたCTLの抗原特異性とMHC制限を更に確かめるため、51Crでラベルしていない(cold)阻害細胞株を用いて阻害アッセイを行った。
次の実験では、自己セッティング(autologous setting) CTL細胞傷害活性について分析した。そこでは、CTL誘導のために用いられた(項目2.2.参照)のと同じPBMNCから生成した自己由来のDCが標的細胞として用いられた。CTLアッセイに先立って、DCは、腫瘍細胞株から予め単離されたRNA又はコントロールRNAに相当するRNA(試験管内で転写されたEGFP−RNA、強化緑色蛍光タンパク質RNA;プラスミド:pSP64 Poly(A) EGFPII、Van Tendeloo、アントワープ、ベルギーより入手)を用いてエレクトロポレートされた。腫瘍細胞の全RNAはQIAGEN Rneasy Mini Kit(QIAGEN、Hilden、ドイツ)を用いて、製造者の手順に従って単離された。RNA量と純度は、分光学的手法により決定し、等分して−80℃で貯蔵した。
更なる研究において、HLA−A*0201陽性の慢性リンパ性白血病(CLL)患者のPBMNCからCTLが生じ、これは配列番号2のアディポフィリンペプチドに特異的であった。この患者は、フルダラビンで治療後、症状が軽減した。更に、この患者由来のCLL細胞及びDCが、51Crでラベルされる標的としてアッセイで用いられた。このアッセイでは、ペプチドに誘導されるCTLにより51Crの放出が媒介される。
Claims (16)
- 添付した配列プロトコルの配列番号1のアミノ酸配列を含み、ヒト主要組織適合複合体(MHC)クラスI分子に結合することができ、腫瘍細胞溶解活性を有するT細胞刺激能を示すことを特徴とする腫瘍関連ペプチド。
- N末端又はC末端に1つの付加的なアミノ酸を含むことを特徴とする請求項1に記載のペプチド。
- 1つのアミノ酸が欠損していることを特徴とする請求項1又は2に記載のペプチド。
- 腫瘍疾患及び/又はアデノーマ疾患の治療薬の製造のための、請求項1〜3のいずれかに記載の1又は2以上のペプチドの使用。
- 疾患が、腎臓、***、膵臓、胃、膀胱、及び/又は精巣のがんであることを特徴とする請求項4記載のペプチドの使用。
- 請求項1〜3のいずれかに記載のペプチドを1又は2以上含むことを特徴とする腫瘍疾患及び/又はアデノーマ疾患の治療のための医薬組成物。
- 疾患が、腎臓、***、膵臓、胃、膀胱、及び/又は精巣のがんであることを特徴とする請求項6記載の医薬組成物。
- さらに、アジュバントを含むことを特徴とする請求項6又は7記載の医薬組成物。
- 抗原提示細胞上に結合されたペプチドが使用されることを特徴とする請求項6〜8のいずれかに記載の医薬組成物。
- 白血球をラベルするために用いられることを特徴とする請求項1〜3のいずれかに記載のペプチドの使用。
- 請求項1〜3のいずれかに記載のペプチドを1又は2以上含むことを特徴とする診断試薬。
- 抗体を製造するための、請求項1〜3のいずれかに記載のペプチドの使用。
- 請求項1〜3のいずれかに記載のペプチドを1つ又は2以上含むことを特徴とする医薬組成物。
- 請求項1〜3のいずれかに記載のペプチドをコードしていることを特徴とする核酸分子。
- 請求項14に記載の核酸分子を含むことを特徴とするベクター。
- 請求項14に記載の核酸分子又は請求項15に記載のベクターにより遺伝子的に修飾されていることを特徴とする、請求項1〜3のいずれかに記載のペプチドを製造するための細胞。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE10225144A DE10225144A1 (de) | 2002-05-29 | 2002-05-29 | An MHC-Moleküle bindende Tumor-assoziierte Peptide |
PCT/EP2003/003181 WO2003102023A1 (de) | 2002-05-29 | 2003-03-27 | An mhc-moleküle bindende tumor-assoziierte peptide |
Related Child Applications (4)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2009283584A Division JP5042301B2 (ja) | 2002-05-29 | 2009-12-15 | Mhc分子に結合する腫瘍関連ペプチド |
JP2009283585A Division JP5042302B2 (ja) | 2002-05-29 | 2009-12-15 | Mhc分子に結合する腫瘍関連ペプチド |
JP2009283586A Division JP5042303B2 (ja) | 2002-05-29 | 2009-12-15 | Mhc分子に結合する腫瘍関連ペプチド |
JP2009283583A Division JP5042300B2 (ja) | 2002-05-29 | 2009-12-15 | Mhc分子に結合する腫瘍関連ペプチド |
Publications (3)
Publication Number | Publication Date |
---|---|
JP2006511196A JP2006511196A (ja) | 2006-04-06 |
JP2006511196A5 JP2006511196A5 (ja) | 2009-09-03 |
JP4472520B2 true JP4472520B2 (ja) | 2010-06-02 |
Family
ID=29557592
Family Applications (5)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2004509714A Expired - Fee Related JP4472520B2 (ja) | 2002-05-29 | 2003-03-27 | Mhc分子に結合する腫瘍関連ペプチド |
JP2009283583A Expired - Fee Related JP5042300B2 (ja) | 2002-05-29 | 2009-12-15 | Mhc分子に結合する腫瘍関連ペプチド |
JP2009283586A Expired - Fee Related JP5042303B2 (ja) | 2002-05-29 | 2009-12-15 | Mhc分子に結合する腫瘍関連ペプチド |
JP2009283585A Expired - Fee Related JP5042302B2 (ja) | 2002-05-29 | 2009-12-15 | Mhc分子に結合する腫瘍関連ペプチド |
JP2009283584A Expired - Fee Related JP5042301B2 (ja) | 2002-05-29 | 2009-12-15 | Mhc分子に結合する腫瘍関連ペプチド |
Family Applications After (4)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2009283583A Expired - Fee Related JP5042300B2 (ja) | 2002-05-29 | 2009-12-15 | Mhc分子に結合する腫瘍関連ペプチド |
JP2009283586A Expired - Fee Related JP5042303B2 (ja) | 2002-05-29 | 2009-12-15 | Mhc分子に結合する腫瘍関連ペプチド |
JP2009283585A Expired - Fee Related JP5042302B2 (ja) | 2002-05-29 | 2009-12-15 | Mhc分子に結合する腫瘍関連ペプチド |
JP2009283584A Expired - Fee Related JP5042301B2 (ja) | 2002-05-29 | 2009-12-15 | Mhc分子に結合する腫瘍関連ペプチド |
Country Status (15)
Country | Link |
---|---|
US (5) | US7396904B2 (ja) |
EP (5) | EP1734048B1 (ja) |
JP (5) | JP4472520B2 (ja) |
AT (5) | ATE416188T1 (ja) |
AU (2) | AU2003224001B2 (ja) |
CA (5) | CA2736972C (ja) |
CY (5) | CY1108507T1 (ja) |
DE (6) | DE10225144A1 (ja) |
DK (5) | DK2014673T3 (ja) |
ES (5) | ES2350461T3 (ja) |
HR (1) | HRP20041108B1 (ja) |
PL (5) | PL211159B1 (ja) |
PT (5) | PT1507795E (ja) |
SI (5) | SI1507795T1 (ja) |
WO (1) | WO2003102023A1 (ja) |
Families Citing this family (42)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7892559B2 (en) | 2002-01-30 | 2011-02-22 | Survac Aps | Survivin-derived peptides and use thereof |
DE10225139A1 (de) * | 2002-05-29 | 2004-02-26 | Immatics Biotechnologies Gmbh | Verfahren zur Identifizierung von immunreaktiven Peptiden |
US20050221350A1 (en) | 2002-05-29 | 2005-10-06 | Toni Weinschenk | Method for identifying immunoreactive peptides |
US7670604B2 (en) | 2002-12-13 | 2010-03-02 | Aurelium Biopharma, Inc. | Vimentin directed diagnostics and therapeutics for multidrug resistant neoplastic disease |
PT2359841E (pt) * | 2003-01-30 | 2015-02-10 | Survac Aps | Péptidos derivados de survivina e a sua utilização |
DE10313819A1 (de) * | 2003-03-24 | 2004-10-07 | Immatics Biotechnologies Gmbh | An MHC-Moleküle bindende Tumor-assoziierte Peptide |
CA2549185C (en) | 2003-12-01 | 2012-10-30 | Meiji Dairies Corporation | Peptide inhibiting angiotensin converting enzyme |
EP1695089A1 (en) * | 2003-12-15 | 2006-08-30 | Aurelium Biopharma Inc. | Vimentin directed diagnostics and therapeutics for multidrug resistant neoplastic disease |
DE102004011503A1 (de) * | 2004-01-28 | 2005-09-15 | Immatics Biotechnologies Gmbh | Verfahren zur Identifizierung und Quantifizierung von tumor-assoziierten Peptiden |
DE102004026135A1 (de) | 2004-05-25 | 2006-01-05 | Immatics Biotechnologies Gmbh | An MHC-Moleküle bindende Tumor-assoziierte Peptide |
DE602004019215D1 (de) * | 2004-10-02 | 2009-03-12 | Immatics Biotechnologies Gmbh | Immunogene T-Helfer Epitope von menschlichen Tumorantigenen und deren Verwendung in immunotherapeutischen Methoden |
IL172896A0 (en) * | 2005-12-29 | 2006-06-11 | Yeda Res & Dev | Cxcr4 inhibition |
US20090004213A1 (en) * | 2007-03-26 | 2009-01-01 | Immatics Biotechnologies Gmbh | Combination therapy using active immunotherapy |
HUE026142T2 (en) | 2007-07-27 | 2016-05-30 | Immatics Biotechnologies Gmbh | New immunogenic epitope for immunotherapy |
WO2009129498A2 (en) * | 2008-04-17 | 2009-10-22 | Immuneregen Biosciences, Inc. | Substance p and analogs thereof as a cancer immunogenic composition adjuvant |
PL2119726T5 (pl) | 2008-05-14 | 2018-04-30 | Immatics Biotechnologies Gmbh | Nowe i silne peptydy MHC klasy II pochodzące z surwiwiny i neurokanu |
CN101451975B (zh) * | 2008-12-29 | 2012-01-25 | 浙江大学 | 一种检测胃癌预后与分期血清蛋白质的方法 |
US8075895B2 (en) * | 2009-09-22 | 2011-12-13 | Janssen Pharmaceutica N.V. | Identification of antigenic peptides from multiple myeloma cells |
GB201004575D0 (en) | 2010-03-19 | 2010-05-05 | Immatics Biotechnologies Gmbh | Composition of tumor associated peptides and related anti cancer vaccine for the treatment of gastric cancer and other cancers |
GB201009222D0 (en) * | 2010-06-02 | 2010-07-21 | Immatics Biotechnologies Gmbh | Improved cancer therapy based on tumour associated antigens derived from cyclin D1 |
US9555074B2 (en) | 2010-10-08 | 2017-01-31 | Regents Of The University Of Minnesota | Annexin II compositions |
RS62602B1 (sr) | 2013-08-05 | 2021-12-31 | Immatics Biotechnologies Gmbh | Nova imunoterapija za lečenje nekoliko tumora, kao što je rak pluća, uključujući nsclc |
US20160310583A1 (en) * | 2013-10-03 | 2016-10-27 | Sumitomo Dainippon Pharma Co., Ltd. | Tumor antigen peptide |
US10206986B2 (en) | 2013-11-13 | 2019-02-19 | Regents Of The University Of Minnesota | Annexin II variant compositions and methods |
GB201505305D0 (en) | 2015-03-27 | 2015-05-13 | Immatics Biotechnologies Gmbh | Novel Peptides and combination of peptides for use in immunotherapy against various tumors |
MD3388075T2 (ro) | 2015-03-27 | 2023-10-31 | Immatics Biotechnologies Gmbh | Noi peptide și combinații de peptide pentru utilizare în imunoterapia împotriva unor diverse tumori (SEQ ID 25 - MXRA5-003) |
NL2014935B1 (en) | 2015-06-08 | 2017-02-03 | Applied Immune Tech Ltd | T cell receptor like antibodies having fine specificity. |
GB201511546D0 (en) | 2015-07-01 | 2015-08-12 | Immatics Biotechnologies Gmbh | Novel peptides and combination of peptides for use in immunotherapy against ovarian cancer and other cancers |
MA42294B1 (fr) | 2015-07-01 | 2020-11-30 | Immatics Biotechnologies Gmbh | Nouveaux peptides et combinaison de peptides à utiliser en immunothérapie contre le cancer de l'ovaire et d'autres cancers |
GB201520550D0 (en) | 2015-11-23 | 2016-01-06 | Immunocore Ltd & Adaptimmune Ltd | Peptides |
GB201520568D0 (en) | 2015-11-23 | 2016-01-06 | Immunocore Ltd | Peptides |
GB201520558D0 (en) * | 2015-11-23 | 2016-01-06 | Immunocore Ltd & Adaptimmune Ltd | Peptides |
GB201521746D0 (en) * | 2015-12-10 | 2016-01-27 | Immatics Biotechnologies Gmbh | Novel peptides and combination of peptides for use in immunotherapy against CLL and other cancers |
SG10202111399YA (en) | 2015-12-22 | 2021-11-29 | Immatics Biotechnologies Gmbh | Peptides and combination of peptides for use in immunotherapy against breast cancer and other cancers |
DE102016005550A1 (de) | 2016-05-09 | 2017-11-09 | Emc Microcollections Gmbh | Adjuvans zur lnduzierung einer zellulären lmmunantwort |
JP7075125B2 (ja) | 2016-05-25 | 2022-05-25 | イマティクス バイオテクノロジーズ ゲーエムベーハー | 標的としてのおよび胆嚢がんおよび胆管がんおよびその他のがんに対する免疫療法で使用するための新規ペプチド、ペプチド組み合わせ |
GB201609193D0 (en) | 2016-05-25 | 2016-07-06 | Immatics Biotechnologies Gmbh | Novel peptides, combination of peptides as targets for use in immunotherapy against gallbladder cancer and cholangiocarcinoma and other cancers |
KR102639592B1 (ko) | 2016-12-08 | 2024-02-21 | 이매틱스 바이오테크놀로지스 게엠베하 | 짝짓기가 향상된 t 세포 수용체 |
DE102016123893A1 (de) | 2016-12-08 | 2018-06-14 | Immatics Biotechnologies Gmbh | T-Zellrezeptoren mit verbesserter Bindung |
WO2019160383A1 (ko) * | 2018-02-19 | 2019-08-22 | 고려대학교 산학협력단 | 열충격단백질의 에피토프를 포함하는 백신 및 이의 용도 |
KR102184377B1 (ko) | 2018-02-19 | 2020-11-30 | 고려대학교 산학협력단 | 열충격단백질의 에피토프를 포함하는 백신 및 이의 용도 |
BR102018010523A2 (pt) * | 2018-05-23 | 2020-04-28 | Univ Estadual Campinas Unicamp | peptídeo, composição farmacêutica compreendendo o mesmo e uso |
Family Cites Families (13)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4810781A (en) * | 1987-01-15 | 1989-03-07 | The George Washington University | Methods of preparing epitopes of tumor associated antigens |
US5739009A (en) * | 1996-12-12 | 1998-04-14 | Incyte Pharmaceuticals, Inc. | Adipocyte-specific differentiation-related protein |
US6977074B2 (en) * | 1997-07-10 | 2005-12-20 | Mannkind Corporation | Method of inducing a CTL response |
DE19837015C2 (de) * | 1998-08-14 | 2003-03-20 | Vasopharm Biotech Gmbh | Isolierte und gereinigte humane lösliche Guanylylcyclase alpha1/beta1 (hsGCalpha1/beta1) |
US6809179B1 (en) | 1999-08-04 | 2004-10-26 | Boehringer Ingelheim International Gmbh | Tumor-associated antigen (R11) |
DE19936563A1 (de) | 1999-08-04 | 2001-02-08 | Boehringer Ingelheim Int | Tumorassoziiertes Antigen |
WO2001063294A2 (en) * | 2000-02-24 | 2001-08-30 | Oxford Glycosciences (Uk) Limited | Diagnosis of bipolar affective disorder (bad) and unipolar depression |
AU2001295582A1 (en) * | 2000-12-20 | 2002-07-01 | GlaxoSmithKline Biologicals (s.a.) | Tumour-related antigens |
US20030170719A1 (en) * | 2000-12-28 | 2003-09-11 | Akio Matsuda | NF-kappa B activating gene |
AU2002309583A1 (en) * | 2001-04-18 | 2002-11-05 | Protein Desing Labs, Inc. | Methods of diagnosis of lung cancer, compositions and methods of screening for modulators of lung cancer |
US6867283B2 (en) * | 2001-05-16 | 2005-03-15 | Technion Research & Development Foundation Ltd. | Peptides capable of binding to MHC molecules, cells presenting such peptides, and pharmaceutical compositions comprising such peptides and/or cells |
US7125663B2 (en) * | 2001-06-13 | 2006-10-24 | Millenium Pharmaceuticals, Inc. | Genes, compositions, kits and methods for identification, assessment, prevention, and therapy of cervical cancer |
AU2002346613A1 (en) * | 2001-12-03 | 2003-06-17 | Michael Bowen | Polynucleotides and polypeptides associated with the development of rheumatoid arthritis |
-
2002
- 2002-05-29 DE DE10225144A patent/DE10225144A1/de not_active Ceased
-
2003
- 2003-03-27 AT AT06015806T patent/ATE416188T1/de active
- 2003-03-27 DE DE50310882T patent/DE50310882D1/de not_active Expired - Lifetime
- 2003-03-27 EP EP06015805A patent/EP1734048B1/de not_active Expired - Lifetime
- 2003-03-27 EP EP06015806A patent/EP1734049B1/de not_active Expired - Lifetime
- 2003-03-27 PL PL390817A patent/PL211159B1/pl unknown
- 2003-03-27 DK DK08014305.0T patent/DK2014673T3/da active
- 2003-03-27 DK DK06015806T patent/DK1734049T3/da active
- 2003-03-27 JP JP2004509714A patent/JP4472520B2/ja not_active Expired - Fee Related
- 2003-03-27 ES ES08014304T patent/ES2350461T3/es not_active Expired - Lifetime
- 2003-03-27 ES ES06015806T patent/ES2317379T3/es not_active Expired - Lifetime
- 2003-03-27 SI SI200331412T patent/SI1507795T1/sl unknown
- 2003-03-27 PT PT03720376T patent/PT1507795E/pt unknown
- 2003-03-27 PL PL390816A patent/PL210356B1/pl unknown
- 2003-03-27 CA CA2736972A patent/CA2736972C/en not_active Expired - Fee Related
- 2003-03-27 AT AT03720376T patent/ATE410442T1/de active
- 2003-03-27 PT PT06015806T patent/PT1734049E/pt unknown
- 2003-03-27 ES ES03720376T patent/ES2314196T3/es not_active Expired - Lifetime
- 2003-03-27 AU AU2003224001A patent/AU2003224001B2/en not_active Ceased
- 2003-03-27 CA CA2487137A patent/CA2487137C/en not_active Expired - Fee Related
- 2003-03-27 DK DK06015805T patent/DK1734048T3/da active
- 2003-03-27 CA CA2736974A patent/CA2736974C/en not_active Expired - Fee Related
- 2003-03-27 EP EP03720376A patent/EP1507795B1/de not_active Expired - Lifetime
- 2003-03-27 DE DE50310952T patent/DE50310952D1/de not_active Expired - Lifetime
- 2003-03-27 PT PT06015805T patent/PT1734048E/pt unknown
- 2003-03-27 DK DK03720376T patent/DK1507795T3/da active
- 2003-03-27 EP EP08014304A patent/EP2006294B1/de not_active Expired - Lifetime
- 2003-03-27 DE DE50312701T patent/DE50312701D1/de not_active Expired - Lifetime
- 2003-03-27 SI SI200331848T patent/SI2014673T1/sl unknown
- 2003-03-27 AT AT08014305T patent/ATE466872T1/de active
- 2003-03-27 ES ES06015805T patent/ES2317378T3/es not_active Expired - Lifetime
- 2003-03-27 SI SI200331885T patent/SI2006294T1/sl unknown
- 2003-03-27 PL PL390815A patent/PL211158B1/pl unknown
- 2003-03-27 DK DK08014304.3T patent/DK2006294T3/da active
- 2003-03-27 AT AT08014304T patent/ATE478088T1/de active
- 2003-03-27 SI SI200331430T patent/SI1734049T1/sl unknown
- 2003-03-27 PT PT08014305T patent/PT2014673E/pt unknown
- 2003-03-27 DE DE50313004T patent/DE50313004D1/de not_active Expired - Lifetime
- 2003-03-27 AT AT06015805T patent/ATE417859T1/de active
- 2003-03-27 DE DE50310613T patent/DE50310613D1/de not_active Expired - Lifetime
- 2003-03-27 PL PL390814A patent/PL211157B1/pl unknown
- 2003-03-27 CA CA2736926A patent/CA2736926C/en not_active Expired - Fee Related
- 2003-03-27 CA CA2736921A patent/CA2736921C/en not_active Expired - Fee Related
- 2003-03-27 WO PCT/EP2003/003181 patent/WO2003102023A1/de active Application Filing
- 2003-03-27 SI SI200331451T patent/SI1734048T1/sl unknown
- 2003-03-27 EP EP08014305A patent/EP2014673B1/de not_active Expired - Lifetime
- 2003-03-27 ES ES08014305T patent/ES2348468T3/es not_active Expired - Lifetime
- 2003-03-27 PL PL373700A patent/PL206306B1/pl unknown
- 2003-03-27 PT PT08014304T patent/PT2006294E/pt unknown
-
2004
- 2004-11-23 HR HRP20041108AA patent/HRP20041108B1/hr not_active IP Right Cessation
- 2004-11-29 US US10/999,364 patent/US7396904B2/en not_active Expired - Lifetime
-
2007
- 2007-08-30 US US11/848,062 patent/US7763711B2/en not_active Expired - Lifetime
- 2007-08-30 US US11/848,110 patent/US7666984B2/en not_active Expired - Lifetime
-
2008
- 2008-11-13 CY CY20081101297T patent/CY1108507T1/el unknown
- 2008-12-09 CY CY20081101425T patent/CY1108673T1/el unknown
- 2008-12-30 CY CY20081101508T patent/CY1108680T1/el unknown
-
2009
- 2009-12-15 JP JP2009283583A patent/JP5042300B2/ja not_active Expired - Fee Related
- 2009-12-15 JP JP2009283586A patent/JP5042303B2/ja not_active Expired - Fee Related
- 2009-12-15 JP JP2009283585A patent/JP5042302B2/ja not_active Expired - Fee Related
- 2009-12-15 JP JP2009283584A patent/JP5042301B2/ja not_active Expired - Fee Related
-
2010
- 2010-01-22 US US12/632,463 patent/US8399613B2/en not_active Expired - Lifetime
- 2010-01-22 US US12/632,541 patent/US8536304B2/en not_active Expired - Lifetime
- 2010-02-25 AU AU2010200689A patent/AU2010200689B2/en not_active Ceased
- 2010-07-30 CY CY20101100714T patent/CY1110723T1/el unknown
- 2010-11-03 CY CY20101100991T patent/CY1111174T1/el unknown
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP4472520B2 (ja) | Mhc分子に結合する腫瘍関連ペプチド | |
KR101284237B1 (ko) | Bcl-2 패밀리에 속한 단백질들, 그들의 단편들 및 암 환자에 대한 그들의 용도 | |
HRP20050808A2 (en) | Tumour-associated peptides binding to mhc molecules | |
JP2012165743A (ja) | 無差別的にヒト白血球抗体(hla)クラスii分子に結合する腫瘍関連ペプチド | |
JP2012147787A (ja) | 無差別的にヒト白血球抗体(hla)クラスii分子に結合する腫瘍関連ペプチド |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20060116 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20090324 |
|
A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20090623 |
|
A602 | Written permission of extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A602 Effective date: 20090630 |
|
A524 | Written submission of copy of amendment under article 19 pct |
Free format text: JAPANESE INTERMEDIATE CODE: A524 Effective date: 20090714 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20090715 |
|
A02 | Decision of refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A02 Effective date: 20090818 |
|
RD02 | Notification of acceptance of power of attorney |
Free format text: JAPANESE INTERMEDIATE CODE: A7422 Effective date: 20091110 |
|
RD04 | Notification of resignation of power of attorney |
Free format text: JAPANESE INTERMEDIATE CODE: A7424 Effective date: 20091111 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20091214 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20091215 |
|
A911 | Transfer to examiner for re-examination before appeal (zenchi) |
Free format text: JAPANESE INTERMEDIATE CODE: A911 Effective date: 20100121 |
|
TRDD | Decision of grant or rejection written | ||
A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20100218 |
|
A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20100303 |
|
FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20130312 Year of fee payment: 3 |
|
R150 | Certificate of patent or registration of utility model |
Ref document number: 4472520 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20140312 Year of fee payment: 4 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
LAPS | Cancellation because of no payment of annual fees |