TWI446921B - 基於表現於抗原-表現細胞之樹突細胞免疫受體(dcir)之標的抗原之疫苗 - Google Patents
基於表現於抗原-表現細胞之樹突細胞免疫受體(dcir)之標的抗原之疫苗 Download PDFInfo
- Publication number
- TWI446921B TWI446921B TW097104113A TW97104113A TWI446921B TW I446921 B TWI446921 B TW I446921B TW 097104113 A TW097104113 A TW 097104113A TW 97104113 A TW97104113 A TW 97104113A TW I446921 B TWI446921 B TW I446921B
- Authority
- TW
- Taiwan
- Prior art keywords
- dcir
- antigen
- specific antibody
- functional fragment
- cells
- Prior art date
Links
- 239000000427 antigen Substances 0.000 title claims description 263
- 108091007433 antigens Proteins 0.000 title claims description 256
- 102000036639 antigens Human genes 0.000 title claims description 256
- 229960005486 vaccine Drugs 0.000 title claims description 46
- 210000000612 antigen-presenting cell Anatomy 0.000 title claims description 7
- 230000008685 targeting Effects 0.000 title description 4
- 101150085274 CLEC4A gene Proteins 0.000 title 1
- 210000004443 dendritic cell Anatomy 0.000 claims description 112
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 83
- 210000004027 cell Anatomy 0.000 claims description 65
- 108090000623 proteins and genes Proteins 0.000 claims description 58
- 239000012634 fragment Substances 0.000 claims description 54
- 102000004169 proteins and genes Human genes 0.000 claims description 54
- 238000000034 method Methods 0.000 claims description 35
- 230000001580 bacterial effect Effects 0.000 claims description 27
- 206010028980 Neoplasm Diseases 0.000 claims description 26
- 210000001744 T-lymphocyte Anatomy 0.000 claims description 22
- 102000015696 Interleukins Human genes 0.000 claims description 21
- 108010063738 Interleukins Proteins 0.000 claims description 21
- 230000027455 binding Effects 0.000 claims description 21
- 108020001507 fusion proteins Proteins 0.000 claims description 18
- 230000028993 immune response Effects 0.000 claims description 18
- 238000002255 vaccination Methods 0.000 claims description 18
- 102000010780 Platelet-Derived Growth Factor Human genes 0.000 claims description 17
- 108010038512 Platelet-Derived Growth Factor Proteins 0.000 claims description 17
- 102000037865 fusion proteins Human genes 0.000 claims description 17
- 102000009618 Transforming Growth Factors Human genes 0.000 claims description 15
- 108010009583 Transforming Growth Factors Proteins 0.000 claims description 15
- 230000002538 fungal effect Effects 0.000 claims description 15
- -1 IL14 Proteins 0.000 claims description 14
- 229940047122 interleukins Drugs 0.000 claims description 14
- 230000000890 antigenic effect Effects 0.000 claims description 13
- 102000004196 processed proteins & peptides Human genes 0.000 claims description 13
- 102000018233 Fibroblast Growth Factor Human genes 0.000 claims description 12
- 108050007372 Fibroblast Growth Factor Proteins 0.000 claims description 12
- 102100039620 Granulocyte-macrophage colony-stimulating factor Human genes 0.000 claims description 12
- 229940126864 fibroblast growth factor Drugs 0.000 claims description 12
- 108010017213 Granulocyte-Macrophage Colony-Stimulating Factor Proteins 0.000 claims description 11
- 230000001225 therapeutic effect Effects 0.000 claims description 11
- 102000039446 nucleic acids Human genes 0.000 claims description 10
- 108020004707 nucleic acids Proteins 0.000 claims description 10
- 150000007523 nucleic acids Chemical class 0.000 claims description 10
- 239000003053 toxin Substances 0.000 claims description 10
- 231100000765 toxin Toxicity 0.000 claims description 10
- 108700012359 toxins Proteins 0.000 claims description 10
- 230000003612 virological effect Effects 0.000 claims description 10
- 108010029697 CD40 Ligand Proteins 0.000 claims description 9
- 102100032937 CD40 ligand Human genes 0.000 claims description 9
- 108010002350 Interleukin-2 Proteins 0.000 claims description 9
- 239000002671 adjuvant Substances 0.000 claims description 9
- 201000011510 cancer Diseases 0.000 claims description 9
- 230000000295 complement effect Effects 0.000 claims description 9
- 239000000758 substrate Substances 0.000 claims description 9
- 102000004190 Enzymes Human genes 0.000 claims description 8
- 108090000790 Enzymes Proteins 0.000 claims description 8
- 108090000978 Interleukin-4 Proteins 0.000 claims description 8
- 102000004388 Interleukin-4 Human genes 0.000 claims description 8
- 229940088598 enzyme Drugs 0.000 claims description 8
- 239000003102 growth factor Substances 0.000 claims description 8
- 230000001900 immune effect Effects 0.000 claims description 8
- 238000004519 manufacturing process Methods 0.000 claims description 8
- 101000930762 Sulfolobus acidocaldarius (strain ATCC 33909 / DSM 639 / JCM 8929 / NBRC 15157 / NCIMB 11770) Signal recognition particle receptor FtsY Proteins 0.000 claims description 7
- 210000003719 b-lymphocyte Anatomy 0.000 claims description 7
- 239000003153 chemical reaction reagent Substances 0.000 claims description 7
- 230000001681 protective effect Effects 0.000 claims description 7
- 102000001706 Immunoglobulin Fab Fragments Human genes 0.000 claims description 6
- 108010054477 Immunoglobulin Fab Fragments Proteins 0.000 claims description 6
- 108090000723 Insulin-Like Growth Factor I Proteins 0.000 claims description 6
- 102000014429 Insulin-like growth factor Human genes 0.000 claims description 6
- 108090000172 Interleukin-15 Proteins 0.000 claims description 6
- 102000003812 Interleukin-15 Human genes 0.000 claims description 6
- 102100032101 Tumor necrosis factor ligand superfamily member 9 Human genes 0.000 claims description 6
- 230000004913 activation Effects 0.000 claims description 6
- VBEQCZHXXJYVRD-GACYYNSASA-N uroanthelone Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CS)C(=O)N[C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)C(C)C)[C@@H](C)O)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CCSC)NC(=O)[C@H](CS)NC(=O)[C@@H](NC(=O)CNC(=O)CNC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CS)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CS)NC(=O)CNC(=O)[C@H]1N(CCC1)C(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC(N)=O)C(C)C)[C@@H](C)CC)C1=CC=C(O)C=C1 VBEQCZHXXJYVRD-GACYYNSASA-N 0.000 claims description 6
- OFMQLVRLOGHAJI-FGHAYEPSSA-N (4r,7s,10s,13r,16s,19r)-n-[(2s,3r)-1-amino-3-hydroxy-1-oxobutan-2-yl]-19-[[(2r)-2-amino-3-phenylpropanoyl]amino]-10-[3-(diaminomethylideneamino)propyl]-7-[(1r)-1-hydroxyethyl]-16-[(4-hydroxyphenyl)methyl]-13-(1h-indol-3-ylmethyl)-3,3-dimethyl-6,9,12,15,18 Chemical compound C([C@H]1C(=O)N[C@H](CC=2C3=CC=CC=C3NC=2)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@H](C(=O)N[C@@H](C(SSC[C@@H](C(=O)N1)NC(=O)[C@H](N)CC=1C=CC=CC=1)(C)C)C(=O)N[C@@H]([C@H](O)C)C(N)=O)[C@@H](C)O)C1=CC=C(O)C=C1 OFMQLVRLOGHAJI-FGHAYEPSSA-N 0.000 claims description 5
- 108010059616 Activins Proteins 0.000 claims description 5
- 102100037362 Fibronectin Human genes 0.000 claims description 5
- 108010067306 Fibronectins Proteins 0.000 claims description 5
- 102100026818 Inhibin beta E chain Human genes 0.000 claims description 5
- 108010002586 Interleukin-7 Proteins 0.000 claims description 5
- 239000000488 activin Substances 0.000 claims description 5
- 108010035886 connective tissue-activating peptide Proteins 0.000 claims description 5
- 210000004962 mammalian cell Anatomy 0.000 claims description 5
- MZOFCQQQCNRIBI-VMXHOPILSA-N (3s)-4-[[(2s)-1-[[(2s)-1-[[(1s)-1-carboxy-2-hydroxyethyl]amino]-4-methyl-1-oxopentan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-3-[[2-[[(2s)-2,6-diaminohexanoyl]amino]acetyl]amino]-4-oxobutanoic acid Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@@H](N)CCCCN MZOFCQQQCNRIBI-VMXHOPILSA-N 0.000 claims description 4
- 108010017080 Granulocyte Colony-Stimulating Factor Proteins 0.000 claims description 4
- 102000004269 Granulocyte Colony-Stimulating Factor Human genes 0.000 claims description 4
- 102100037850 Interferon gamma Human genes 0.000 claims description 4
- 108010074328 Interferon-gamma Proteins 0.000 claims description 4
- 108010065805 Interleukin-12 Proteins 0.000 claims description 4
- 102000013462 Interleukin-12 Human genes 0.000 claims description 4
- 108060008682 Tumor Necrosis Factor Proteins 0.000 claims description 4
- 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 claims description 4
- 230000002708 enhancing effect Effects 0.000 claims description 4
- 230000012010 growth Effects 0.000 claims description 4
- 150000002632 lipids Chemical class 0.000 claims description 4
- 108010082808 4-1BB Ligand Proteins 0.000 claims description 3
- 102000010825 Actinin Human genes 0.000 claims description 3
- 108010063503 Actinin Proteins 0.000 claims description 3
- 102400000068 Angiostatin Human genes 0.000 claims description 3
- 108010079709 Angiostatins Proteins 0.000 claims description 3
- 108010049931 Bone Morphogenetic Protein 2 Proteins 0.000 claims description 3
- 108010049951 Bone Morphogenetic Protein 3 Proteins 0.000 claims description 3
- 108010049955 Bone Morphogenetic Protein 4 Proteins 0.000 claims description 3
- 108010049976 Bone Morphogenetic Protein 5 Proteins 0.000 claims description 3
- 108010049974 Bone Morphogenetic Protein 6 Proteins 0.000 claims description 3
- 108010049870 Bone Morphogenetic Protein 7 Proteins 0.000 claims description 3
- 108010007726 Bone Morphogenetic Proteins Proteins 0.000 claims description 3
- 102000007350 Bone Morphogenetic Proteins Human genes 0.000 claims description 3
- 102100028728 Bone morphogenetic protein 1 Human genes 0.000 claims description 3
- 108090000654 Bone morphogenetic protein 1 Proteins 0.000 claims description 3
- 102100024506 Bone morphogenetic protein 2 Human genes 0.000 claims description 3
- 102100024504 Bone morphogenetic protein 3 Human genes 0.000 claims description 3
- 102100024505 Bone morphogenetic protein 4 Human genes 0.000 claims description 3
- 102100022526 Bone morphogenetic protein 5 Human genes 0.000 claims description 3
- 102100022525 Bone morphogenetic protein 6 Human genes 0.000 claims description 3
- 102100022544 Bone morphogenetic protein 7 Human genes 0.000 claims description 3
- 102100022545 Bone morphogenetic protein 8B Human genes 0.000 claims description 3
- 101710098275 C-X-C motif chemokine 10 Proteins 0.000 claims description 3
- 101150093802 CXCL1 gene Proteins 0.000 claims description 3
- 108010071942 Colony-Stimulating Factors Proteins 0.000 claims description 3
- 108010053187 Diphtheria Toxin Proteins 0.000 claims description 3
- 102000016607 Diphtheria Toxin Human genes 0.000 claims description 3
- 102100040897 Embryonic growth/differentiation factor 1 Human genes 0.000 claims description 3
- 108010079505 Endostatins Proteins 0.000 claims description 3
- 102000003951 Erythropoietin Human genes 0.000 claims description 3
- 108090000394 Erythropoietin Proteins 0.000 claims description 3
- 101001043796 Gallus gallus Interleukin-8 Proteins 0.000 claims description 3
- 108010090296 Growth Differentiation Factor 1 Proteins 0.000 claims description 3
- 101000899368 Homo sapiens Bone morphogenetic protein 8B Proteins 0.000 claims description 3
- 101000998146 Homo sapiens Interleukin-17A Proteins 0.000 claims description 3
- 101000764294 Homo sapiens Lymphotoxin-beta Proteins 0.000 claims description 3
- 101000582950 Homo sapiens Platelet factor 4 Proteins 0.000 claims description 3
- 101000638251 Homo sapiens Tumor necrosis factor ligand superfamily member 9 Proteins 0.000 claims description 3
- 102000026633 IL6 Human genes 0.000 claims description 3
- 102000017727 Immunoglobulin Variable Region Human genes 0.000 claims description 3
- 108010067060 Immunoglobulin Variable Region Proteins 0.000 claims description 3
- 102100026720 Interferon beta Human genes 0.000 claims description 3
- 108010047761 Interferon-alpha Proteins 0.000 claims description 3
- 102000006992 Interferon-alpha Human genes 0.000 claims description 3
- 108090000467 Interferon-beta Proteins 0.000 claims description 3
- 102100020881 Interleukin-1 alpha Human genes 0.000 claims description 3
- 108090000174 Interleukin-10 Proteins 0.000 claims description 3
- 102000003814 Interleukin-10 Human genes 0.000 claims description 3
- 108090000177 Interleukin-11 Proteins 0.000 claims description 3
- 102100030694 Interleukin-11 Human genes 0.000 claims description 3
- 108090000176 Interleukin-13 Proteins 0.000 claims description 3
- 102000003816 Interleukin-13 Human genes 0.000 claims description 3
- 101800003050 Interleukin-16 Proteins 0.000 claims description 3
- 102000049772 Interleukin-16 Human genes 0.000 claims description 3
- 102100033461 Interleukin-17A Human genes 0.000 claims description 3
- 102000003810 Interleukin-18 Human genes 0.000 claims description 3
- 108090000171 Interleukin-18 Proteins 0.000 claims description 3
- 102100039064 Interleukin-3 Human genes 0.000 claims description 3
- 102000000743 Interleukin-5 Human genes 0.000 claims description 3
- 108010002616 Interleukin-5 Proteins 0.000 claims description 3
- 108090001005 Interleukin-6 Proteins 0.000 claims description 3
- 102000000704 Interleukin-7 Human genes 0.000 claims description 3
- 102000004890 Interleukin-8 Human genes 0.000 claims description 3
- 108090001007 Interleukin-8 Proteins 0.000 claims description 3
- 102000000585 Interleukin-9 Human genes 0.000 claims description 3
- 108010002335 Interleukin-9 Proteins 0.000 claims description 3
- 102000004083 Lymphotoxin-alpha Human genes 0.000 claims description 3
- 108090000542 Lymphotoxin-alpha Proteins 0.000 claims description 3
- 108010046938 Macrophage Colony-Stimulating Factor Proteins 0.000 claims description 3
- 102000007651 Macrophage Colony-Stimulating Factor Human genes 0.000 claims description 3
- 102000015336 Nerve Growth Factor Human genes 0.000 claims description 3
- 108010025020 Nerve Growth Factor Proteins 0.000 claims description 3
- 108010039491 Ricin Proteins 0.000 claims description 3
- 108010055044 Tetanus Toxin Proteins 0.000 claims description 3
- 102000046299 Transforming Growth Factor beta1 Human genes 0.000 claims description 3
- 102000011117 Transforming Growth Factor beta2 Human genes 0.000 claims description 3
- 101800002279 Transforming growth factor beta-1 Proteins 0.000 claims description 3
- 101800000304 Transforming growth factor beta-2 Proteins 0.000 claims description 3
- 102000056172 Transforming growth factor beta-3 Human genes 0.000 claims description 3
- 108090000097 Transforming growth factor beta-3 Proteins 0.000 claims description 3
- 102000005789 Vascular Endothelial Growth Factors Human genes 0.000 claims description 3
- 108010019530 Vascular Endothelial Growth Factors Proteins 0.000 claims description 3
- 108010023082 activin A Proteins 0.000 claims description 3
- 108010023079 activin B Proteins 0.000 claims description 3
- 239000002870 angiogenesis inducing agent Substances 0.000 claims description 3
- FZCSTZYAHCUGEM-UHFFFAOYSA-N aspergillomarasmine B Natural products OC(=O)CNC(C(O)=O)CNC(C(O)=O)CC(O)=O FZCSTZYAHCUGEM-UHFFFAOYSA-N 0.000 claims description 3
- 108091008324 binding proteins Proteins 0.000 claims description 3
- 229940112869 bone morphogenetic protein Drugs 0.000 claims description 3
- 150000001720 carbohydrates Chemical class 0.000 claims description 3
- 235000014633 carbohydrates Nutrition 0.000 claims description 3
- 230000024245 cell differentiation Effects 0.000 claims description 3
- 230000003399 chemotactic effect Effects 0.000 claims description 3
- 230000004069 differentiation Effects 0.000 claims description 3
- 229940105423 erythropoietin Drugs 0.000 claims description 3
- 102000055414 human LTB Human genes 0.000 claims description 3
- 108010067471 inhibin A Proteins 0.000 claims description 3
- 108010067479 inhibin B Proteins 0.000 claims description 3
- 230000002297 mitogenic effect Effects 0.000 claims description 3
- OHDXDNUPVVYWOV-UHFFFAOYSA-N n-methyl-1-(2-naphthalen-1-ylsulfanylphenyl)methanamine Chemical compound CNCC1=CC=CC=C1SC1=CC=CC2=CC=CC=C12 OHDXDNUPVVYWOV-UHFFFAOYSA-N 0.000 claims description 3
- OXCMYAYHXIHQOA-UHFFFAOYSA-N potassium;[2-butyl-5-chloro-3-[[4-[2-(1,2,4-triaza-3-azanidacyclopenta-1,4-dien-5-yl)phenyl]phenyl]methyl]imidazol-4-yl]methanol Chemical compound [K+].CCCCC1=NC(Cl)=C(CO)N1CC1=CC=C(C=2C(=CC=CC=2)C2=N[N-]N=N2)C=C1 OXCMYAYHXIHQOA-UHFFFAOYSA-N 0.000 claims description 3
- 229940118376 tetanus toxin Drugs 0.000 claims description 3
- 229930195730 Aflatoxin Natural products 0.000 claims description 2
- XWIYFDMXXLINPU-UHFFFAOYSA-N Aflatoxin G Chemical compound O=C1OCCC2=C1C(=O)OC1=C2C(OC)=CC2=C1C1C=COC1O2 XWIYFDMXXLINPU-UHFFFAOYSA-N 0.000 claims description 2
- 101710092462 Alpha-hemolysin Proteins 0.000 claims description 2
- 101710197219 Alpha-toxin Proteins 0.000 claims description 2
- 241000193830 Bacillus <bacterium> Species 0.000 claims description 2
- 108030001720 Bontoxilysin Proteins 0.000 claims description 2
- 108010049048 Cholera Toxin Proteins 0.000 claims description 2
- 102000009016 Cholera Toxin Human genes 0.000 claims description 2
- 101000867232 Escherichia coli Heat-stable enterotoxin II Proteins 0.000 claims description 2
- 108010090290 Growth Differentiation Factor 2 Proteins 0.000 claims description 2
- 102100040892 Growth/differentiation factor 2 Human genes 0.000 claims description 2
- 102100039939 Growth/differentiation factor 8 Human genes 0.000 claims description 2
- 102100032813 Hepatocyte growth factor-like protein Human genes 0.000 claims description 2
- 102100031000 Hepatoma-derived growth factor Human genes 0.000 claims description 2
- 101001083798 Homo sapiens Hepatoma-derived growth factor Proteins 0.000 claims description 2
- 108010092277 Leptin Proteins 0.000 claims description 2
- 102000016267 Leptin Human genes 0.000 claims description 2
- 231100000678 Mycotoxin Toxicity 0.000 claims description 2
- 108010056852 Myostatin Proteins 0.000 claims description 2
- 101710124951 Phospholipase C Proteins 0.000 claims description 2
- 108010079723 Shiga Toxin Proteins 0.000 claims description 2
- 239000005409 aflatoxin Substances 0.000 claims description 2
- 239000002776 alpha toxin Substances 0.000 claims description 2
- 210000000988 bone and bone Anatomy 0.000 claims description 2
- 229940053031 botulinum toxin Drugs 0.000 claims description 2
- 108010045512 cohesins Proteins 0.000 claims description 2
- 102000027596 immune receptors Human genes 0.000 claims description 2
- 108091008915 immune receptors Proteins 0.000 claims description 2
- 229940039781 leptin Drugs 0.000 claims description 2
- NRYBAZVQPHGZNS-ZSOCWYAHSA-N leptin Chemical compound O=C([C@H](CO)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)CNC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](N)CC(C)C)CCSC)N1CCC[C@H]1C(=O)NCC(=O)N[C@@H](CS)C(O)=O NRYBAZVQPHGZNS-ZSOCWYAHSA-N 0.000 claims description 2
- 108010053292 macrophage stimulating protein Proteins 0.000 claims description 2
- 229910052751 metal Inorganic materials 0.000 claims description 2
- 239000002184 metal Substances 0.000 claims description 2
- 239000002636 mycotoxin Substances 0.000 claims description 2
- RPQXVSUAYFXFJA-HGRQIUPRSA-N saxitoxin Chemical compound NC(=O)OC[C@@H]1N=C(N)N2CCC(O)(O)[C@@]22N=C(N)N[C@@H]12 RPQXVSUAYFXFJA-HGRQIUPRSA-N 0.000 claims description 2
- RPQXVSUAYFXFJA-UHFFFAOYSA-N saxitoxin hydrate Natural products NC(=O)OCC1N=C(N)N2CCC(O)(O)C22NC(N)=NC12 RPQXVSUAYFXFJA-UHFFFAOYSA-N 0.000 claims description 2
- 239000003998 snake venom Substances 0.000 claims description 2
- 239000002708 spider venom Substances 0.000 claims description 2
- CFMYXEVWODSLAX-QOZOJKKESA-N tetrodotoxin Chemical compound O([C@@]([C@H]1O)(O)O[C@H]2[C@@]3(O)CO)[C@H]3[C@@H](O)[C@]11[C@H]2[C@@H](O)N=C(N)N1 CFMYXEVWODSLAX-QOZOJKKESA-N 0.000 claims description 2
- 229950010357 tetrodotoxin Drugs 0.000 claims description 2
- CFMYXEVWODSLAX-UHFFFAOYSA-N tetrodotoxin Natural products C12C(O)NC(=N)NC2(C2O)C(O)C3C(CO)(O)C1OC2(O)O3 CFMYXEVWODSLAX-UHFFFAOYSA-N 0.000 claims description 2
- 125000000539 amino acid group Chemical group 0.000 claims 9
- 108010040897 Microfilament Proteins Proteins 0.000 claims 2
- 102000002151 Microfilament Proteins Human genes 0.000 claims 2
- 108010066676 Abrin Proteins 0.000 claims 1
- 102000007644 Colony-Stimulating Factors Human genes 0.000 claims 1
- 102400001047 Endostatin Human genes 0.000 claims 1
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 claims 1
- 102000000588 Interleukin-2 Human genes 0.000 claims 1
- 108010049746 Microcystins Proteins 0.000 claims 1
- 241000219094 Vitaceae Species 0.000 claims 1
- 102000023732 binding proteins Human genes 0.000 claims 1
- 229940047120 colony stimulating factors Drugs 0.000 claims 1
- 235000021021 grapes Nutrition 0.000 claims 1
- 150000002739 metals Chemical class 0.000 claims 1
- 206010022000 influenza Diseases 0.000 description 93
- 239000000203 mixture Substances 0.000 description 45
- 102000005962 receptors Human genes 0.000 description 43
- 108020003175 receptors Proteins 0.000 description 43
- 239000013598 vector Substances 0.000 description 42
- 210000001266 CD8-positive T-lymphocyte Anatomy 0.000 description 32
- 108020004414 DNA Proteins 0.000 description 21
- 230000028327 secretion Effects 0.000 description 17
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 15
- 239000006228 supernatant Substances 0.000 description 15
- 241000725303 Human immunodeficiency virus Species 0.000 description 13
- 102100034922 T-cell surface glycoprotein CD8 alpha chain Human genes 0.000 description 13
- 238000009472 formulation Methods 0.000 description 13
- 230000003321 amplification Effects 0.000 description 12
- 239000000872 buffer Substances 0.000 description 12
- 210000004408 hybridoma Anatomy 0.000 description 12
- 238000003199 nucleic acid amplification method Methods 0.000 description 12
- 108091034117 Oligonucleotide Proteins 0.000 description 11
- 238000002965 ELISA Methods 0.000 description 10
- 241000699666 Mus <mouse, genus> Species 0.000 description 10
- 230000003053 immunization Effects 0.000 description 10
- 238000002649 immunization Methods 0.000 description 10
- 108091033319 polynucleotide Proteins 0.000 description 10
- 102000040430 polynucleotide Human genes 0.000 description 10
- 239000002157 polynucleotide Substances 0.000 description 10
- 238000011282 treatment Methods 0.000 description 10
- 108020004705 Codon Proteins 0.000 description 9
- 102100031573 Hematopoietic progenitor cell antigen CD34 Human genes 0.000 description 9
- 101000777663 Homo sapiens Hematopoietic progenitor cell antigen CD34 Proteins 0.000 description 9
- 238000004458 analytical method Methods 0.000 description 9
- 230000000694 effects Effects 0.000 description 9
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 9
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 8
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 8
- 101000946889 Homo sapiens Monocyte differentiation antigen CD14 Proteins 0.000 description 8
- 108010001336 Horseradish Peroxidase Proteins 0.000 description 8
- 102100020873 Interleukin-2 Human genes 0.000 description 8
- 102100035877 Monocyte differentiation antigen CD14 Human genes 0.000 description 8
- 239000004480 active ingredient Substances 0.000 description 8
- 239000011780 sodium chloride Substances 0.000 description 8
- 208000023275 Autoimmune disease Diseases 0.000 description 7
- 238000001943 fluorescence-activated cell sorting Methods 0.000 description 7
- 201000001441 melanoma Diseases 0.000 description 7
- 239000002773 nucleotide Substances 0.000 description 7
- 125000003729 nucleotide group Chemical group 0.000 description 7
- 239000002953 phosphate buffered saline Substances 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- 230000004044 response Effects 0.000 description 7
- 150000003839 salts Chemical class 0.000 description 7
- 210000003491 skin Anatomy 0.000 description 7
- 108091026890 Coding region Proteins 0.000 description 6
- 102000004895 Lipoproteins Human genes 0.000 description 6
- 108090001030 Lipoproteins Proteins 0.000 description 6
- 239000011324 bead Substances 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 6
- 238000004132 cross linking Methods 0.000 description 6
- 238000011161 development Methods 0.000 description 6
- 230000018109 developmental process Effects 0.000 description 6
- 230000036039 immunity Effects 0.000 description 6
- 244000052769 pathogen Species 0.000 description 6
- 108020001580 protein domains Proteins 0.000 description 6
- 238000000746 purification Methods 0.000 description 6
- 238000003786 synthesis reaction Methods 0.000 description 6
- 101001069692 Dickeya chrysanthemi Serralysin G Proteins 0.000 description 5
- 101000716102 Homo sapiens T-cell surface glycoprotein CD4 Proteins 0.000 description 5
- 108060003951 Immunoglobulin Proteins 0.000 description 5
- 241000725643 Respiratory syncytial virus Species 0.000 description 5
- 229920002684 Sepharose Polymers 0.000 description 5
- 102100036011 T-cell surface glycoprotein CD4 Human genes 0.000 description 5
- 230000003213 activating effect Effects 0.000 description 5
- 150000001413 amino acids Chemical group 0.000 description 5
- 239000003795 chemical substances by application Substances 0.000 description 5
- 230000004927 fusion Effects 0.000 description 5
- 102000018358 immunoglobulin Human genes 0.000 description 5
- 238000000338 in vitro Methods 0.000 description 5
- 239000000825 pharmaceutical preparation Substances 0.000 description 5
- 229920001184 polypeptide Polymers 0.000 description 5
- 238000002415 sodium dodecyl sulfate polyacrylamide gel electrophoresis Methods 0.000 description 5
- 238000010186 staining Methods 0.000 description 5
- 230000000638 stimulation Effects 0.000 description 5
- 102000007592 Apolipoproteins Human genes 0.000 description 4
- 108010071619 Apolipoproteins Proteins 0.000 description 4
- 241000894006 Bacteria Species 0.000 description 4
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 4
- ULGZDMOVFRHVEP-RWJQBGPGSA-N Erythromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 ULGZDMOVFRHVEP-RWJQBGPGSA-N 0.000 description 4
- 239000004471 Glycine Substances 0.000 description 4
- 241000222722 Leishmania <genus> Species 0.000 description 4
- 102000043129 MHC class I family Human genes 0.000 description 4
- 108091054437 MHC class I family Proteins 0.000 description 4
- 241000712079 Measles morbillivirus Species 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 4
- 101100042687 Mus musculus Slamf1 gene Proteins 0.000 description 4
- 241001460678 Napo <wasp> Species 0.000 description 4
- 108010058846 Ovalbumin Proteins 0.000 description 4
- 101710199789 Oxidized low-density lipoprotein receptor 1 Proteins 0.000 description 4
- 102100025386 Oxidized low-density lipoprotein receptor 1 Human genes 0.000 description 4
- 239000004698 Polyethylene Substances 0.000 description 4
- 108010072866 Prostate-Specific Antigen Proteins 0.000 description 4
- 102100038358 Prostate-specific antigen Human genes 0.000 description 4
- 108010076504 Protein Sorting Signals Proteins 0.000 description 4
- 239000007983 Tris buffer Substances 0.000 description 4
- 241000700605 Viruses Species 0.000 description 4
- 238000001042 affinity chromatography Methods 0.000 description 4
- 230000037396 body weight Effects 0.000 description 4
- 210000004899 c-terminal region Anatomy 0.000 description 4
- 239000002299 complementary DNA Substances 0.000 description 4
- 239000012228 culture supernatant Substances 0.000 description 4
- 201000010099 disease Diseases 0.000 description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 150000004676 glycans Chemical class 0.000 description 4
- 210000002865 immune cell Anatomy 0.000 description 4
- 210000000987 immune system Anatomy 0.000 description 4
- 239000002609 medium Substances 0.000 description 4
- 229940092253 ovalbumin Drugs 0.000 description 4
- 230000001717 pathogenic effect Effects 0.000 description 4
- 239000008194 pharmaceutical composition Substances 0.000 description 4
- 229940127557 pharmaceutical product Drugs 0.000 description 4
- 239000013612 plasmid Substances 0.000 description 4
- 229920001282 polysaccharide Polymers 0.000 description 4
- 239000005017 polysaccharide Substances 0.000 description 4
- 210000001938 protoplast Anatomy 0.000 description 4
- 238000012216 screening Methods 0.000 description 4
- 125000006850 spacer group Chemical group 0.000 description 4
- 210000001519 tissue Anatomy 0.000 description 4
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 4
- 210000000605 viral structure Anatomy 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 3
- 241000238876 Acari Species 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 101150075175 Asgr1 gene Proteins 0.000 description 3
- 241000193738 Bacillus anthracis Species 0.000 description 3
- 102100021943 C-C motif chemokine 2 Human genes 0.000 description 3
- 101710155857 C-C motif chemokine 2 Proteins 0.000 description 3
- 108090000342 C-Type Lectins Proteins 0.000 description 3
- 102000003930 C-Type Lectins Human genes 0.000 description 3
- 102100028667 C-type lectin domain family 4 member A Human genes 0.000 description 3
- 230000004568 DNA-binding Effects 0.000 description 3
- 201000004624 Dermatitis Diseases 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- 241000606768 Haemophilus influenzae Species 0.000 description 3
- 101710154606 Hemagglutinin Proteins 0.000 description 3
- 101000766908 Homo sapiens C-type lectin domain family 4 member A Proteins 0.000 description 3
- 101000917858 Homo sapiens Low affinity immunoglobulin gamma Fc region receptor III-A Proteins 0.000 description 3
- 101000917839 Homo sapiens Low affinity immunoglobulin gamma Fc region receptor III-B Proteins 0.000 description 3
- 101000738771 Homo sapiens Receptor-type tyrosine-protein phosphatase C Proteins 0.000 description 3
- 206010020751 Hypersensitivity Diseases 0.000 description 3
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 description 3
- 241000710842 Japanese encephalitis virus Species 0.000 description 3
- 102100029185 Low affinity immunoglobulin gamma Fc region receptor III-B Human genes 0.000 description 3
- 108010063954 Mucins Proteins 0.000 description 3
- 102000015728 Mucins Human genes 0.000 description 3
- 101710093908 Outer capsid protein VP4 Proteins 0.000 description 3
- 101710135467 Outer capsid protein sigma-1 Proteins 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 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
- 101710176177 Protein A56 Proteins 0.000 description 3
- 102100037422 Receptor-type tyrosine-protein phosphatase C Human genes 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 108091081024 Start codon Proteins 0.000 description 3
- 108090000631 Trypsin Proteins 0.000 description 3
- 102000004142 Trypsin Human genes 0.000 description 3
- 238000010521 absorption reaction Methods 0.000 description 3
- 239000013543 active substance Substances 0.000 description 3
- 230000007815 allergy Effects 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- 238000005119 centrifugation Methods 0.000 description 3
- 239000003937 drug carrier Substances 0.000 description 3
- 229940047650 haemophilus influenzae Drugs 0.000 description 3
- 239000000185 hemagglutinin Substances 0.000 description 3
- 108010037896 heparin-binding hemagglutinin Proteins 0.000 description 3
- 208000006454 hepatitis Diseases 0.000 description 3
- 231100000283 hepatitis Toxicity 0.000 description 3
- 229940088597 hormone Drugs 0.000 description 3
- 239000005556 hormone Substances 0.000 description 3
- 230000002163 immunogen Effects 0.000 description 3
- 238000001727 in vivo Methods 0.000 description 3
- 230000001939 inductive effect Effects 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 230000003993 interaction Effects 0.000 description 3
- 238000002372 labelling Methods 0.000 description 3
- 230000000670 limiting effect Effects 0.000 description 3
- 210000001165 lymph node Anatomy 0.000 description 3
- 229940049954 penicillin Drugs 0.000 description 3
- 239000002243 precursor Substances 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 239000013615 primer Substances 0.000 description 3
- 210000002966 serum Anatomy 0.000 description 3
- 230000004936 stimulating effect Effects 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 235000000346 sugar Nutrition 0.000 description 3
- 239000000829 suppository Substances 0.000 description 3
- 229940124597 therapeutic agent Drugs 0.000 description 3
- 239000012588 trypsin Substances 0.000 description 3
- 229960001322 trypsin Drugs 0.000 description 3
- MYPYJXKWCTUITO-UHFFFAOYSA-N vancomycin Natural products O1C(C(=C2)Cl)=CC=C2C(O)C(C(NC(C2=CC(O)=CC(O)=C2C=2C(O)=CC=C3C=2)C(O)=O)=O)NC(=O)C3NC(=O)C2NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(CC(C)C)NC)C(O)C(C=C3Cl)=CC=C3OC3=CC2=CC1=C3OC1OC(CO)C(O)C(O)C1OC1CC(C)(N)C(O)C(C)O1 MYPYJXKWCTUITO-UHFFFAOYSA-N 0.000 description 3
- XBMULXNXJLWLLD-UHFFFAOYSA-N 4,5-bis(4-methoxyphenyl)-2-thiophen-2-yl-1h-imidazole Chemical compound C1=CC(OC)=CC=C1C1=C(C=2C=CC(OC)=CC=2)NC(C=2SC=CC=2)=N1 XBMULXNXJLWLLD-UHFFFAOYSA-N 0.000 description 2
- XHVDVFNHQJLOBV-UHFFFAOYSA-N 5-[(4-fluoroimidazol-1-yl)methyl]quinolin-8-ol Chemical compound Oc1ccc(Cn2cnc(F)c2)c2cccnc12 XHVDVFNHQJLOBV-UHFFFAOYSA-N 0.000 description 2
- 102100038222 60 kDa heat shock protein, mitochondrial Human genes 0.000 description 2
- STQGQHZAVUOBTE-UHFFFAOYSA-N 7-Cyan-hept-2t-en-4,6-diinsaeure Natural products C1=2C(O)=C3C(=O)C=4C(OC)=CC=CC=4C(=O)C3=C(O)C=2CC(O)(C(C)=O)CC1OC1CC(N)C(O)C(C)O1 STQGQHZAVUOBTE-UHFFFAOYSA-N 0.000 description 2
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 2
- 102000007469 Actins Human genes 0.000 description 2
- 108010085238 Actins Proteins 0.000 description 2
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 2
- 102100035526 B melanoma antigen 1 Human genes 0.000 description 2
- 102100024222 B-lymphocyte antigen CD19 Human genes 0.000 description 2
- 102100022005 B-lymphocyte antigen CD20 Human genes 0.000 description 2
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 2
- 102000017420 CD3 protein, epsilon/gamma/delta subunit Human genes 0.000 description 2
- 108050005493 CD3 protein, epsilon/gamma/delta subunit Proteins 0.000 description 2
- 102000014914 Carrier Proteins Human genes 0.000 description 2
- 108010058432 Chaperonin 60 Proteins 0.000 description 2
- 108010009685 Cholinergic Receptors Proteins 0.000 description 2
- 241000223203 Coccidioides Species 0.000 description 2
- 102100031162 Collagen alpha-1(XVIII) chain Human genes 0.000 description 2
- 208000011231 Crohn disease Diseases 0.000 description 2
- 241000701022 Cytomegalovirus Species 0.000 description 2
- 108010037897 DC-specific ICAM-3 grabbing nonintegrin Proteins 0.000 description 2
- 238000001712 DNA sequencing Methods 0.000 description 2
- 208000001490 Dengue Diseases 0.000 description 2
- 206010012310 Dengue fever Diseases 0.000 description 2
- 108010008655 Epstein-Barr Virus Nuclear Antigens Proteins 0.000 description 2
- 238000012413 Fluorescence activated cell sorting analysis Methods 0.000 description 2
- 108091022930 Glutamate decarboxylase Proteins 0.000 description 2
- 102000025850 HLA-A2 Antigen Human genes 0.000 description 2
- 108010074032 HLA-A2 Antigen Proteins 0.000 description 2
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 description 2
- 241000700721 Hepatitis B virus Species 0.000 description 2
- 101000874316 Homo sapiens B melanoma antigen 1 Proteins 0.000 description 2
- 101000980825 Homo sapiens B-lymphocyte antigen CD19 Proteins 0.000 description 2
- 101000897405 Homo sapiens B-lymphocyte antigen CD20 Proteins 0.000 description 2
- 101001002634 Homo sapiens Interleukin-1 alpha Proteins 0.000 description 2
- 101001033279 Homo sapiens Interleukin-3 Proteins 0.000 description 2
- 101000581981 Homo sapiens Neural cell adhesion molecule 1 Proteins 0.000 description 2
- 101001012157 Homo sapiens Receptor tyrosine-protein kinase erbB-2 Proteins 0.000 description 2
- 101000946843 Homo sapiens T-cell surface glycoprotein CD8 alpha chain Proteins 0.000 description 2
- 241000701806 Human papillomavirus Species 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 108091058560 IL8 Proteins 0.000 description 2
- 108010004250 Inhibins Proteins 0.000 description 2
- 206010024229 Leprosy Diseases 0.000 description 2
- 102000043131 MHC class II family Human genes 0.000 description 2
- 108091054438 MHC class II family Proteins 0.000 description 2
- 108010031099 Mannose Receptor Proteins 0.000 description 2
- 101710085938 Matrix protein Proteins 0.000 description 2
- 101710127721 Membrane protein Proteins 0.000 description 2
- 102100027347 Neural cell adhesion molecule 1 Human genes 0.000 description 2
- 208000001132 Osteoporosis Diseases 0.000 description 2
- 201000005702 Pertussis Diseases 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 241000223960 Plasmodium falciparum Species 0.000 description 2
- 206010037742 Rabies Diseases 0.000 description 2
- 241000711798 Rabies lyssavirus Species 0.000 description 2
- 102100030086 Receptor tyrosine-protein kinase erbB-2 Human genes 0.000 description 2
- 102000007056 Recombinant Fusion Proteins Human genes 0.000 description 2
- 108010008281 Recombinant Fusion Proteins Proteins 0.000 description 2
- 108010073443 Ribi adjuvant Proteins 0.000 description 2
- 241000606701 Rickettsia Species 0.000 description 2
- 241000702670 Rotavirus Species 0.000 description 2
- 238000012300 Sequence Analysis Methods 0.000 description 2
- 241000700584 Simplexvirus Species 0.000 description 2
- 208000021386 Sjogren Syndrome Diseases 0.000 description 2
- 108010023197 Streptokinase Proteins 0.000 description 2
- 102000019197 Superoxide Dismutase Human genes 0.000 description 2
- 108010012715 Superoxide dismutase Proteins 0.000 description 2
- 230000005867 T cell response Effects 0.000 description 2
- 206010043376 Tetanus Diseases 0.000 description 2
- 102000011923 Thyrotropin Human genes 0.000 description 2
- 108010061174 Thyrotropin Proteins 0.000 description 2
- 101710120037 Toxin CcdB Proteins 0.000 description 2
- 241000223996 Toxoplasma Species 0.000 description 2
- 206010052779 Transplant rejections Diseases 0.000 description 2
- 229920004929 Triton X-114 Polymers 0.000 description 2
- 241000700647 Variola virus Species 0.000 description 2
- 108010067390 Viral Proteins Proteins 0.000 description 2
- 102000034337 acetylcholine receptors Human genes 0.000 description 2
- 229960001138 acetylsalicylic acid Drugs 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 108060000200 adenylate cyclase Proteins 0.000 description 2
- 102000030621 adenylate cyclase Human genes 0.000 description 2
- 239000013566 allergen Substances 0.000 description 2
- 210000004727 amygdala Anatomy 0.000 description 2
- 229940035676 analgesics Drugs 0.000 description 2
- 239000000730 antalgic agent Substances 0.000 description 2
- 239000003242 anti bacterial agent Substances 0.000 description 2
- 239000002260 anti-inflammatory agent Substances 0.000 description 2
- 229940121363 anti-inflammatory agent Drugs 0.000 description 2
- 230000001754 anti-pyretic effect Effects 0.000 description 2
- 229940088710 antibiotic agent Drugs 0.000 description 2
- 239000003146 anticoagulant agent Substances 0.000 description 2
- 229940127219 anticoagulant drug Drugs 0.000 description 2
- 239000002246 antineoplastic agent Substances 0.000 description 2
- 239000002221 antipyretic Substances 0.000 description 2
- 229940125716 antipyretic agent Drugs 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 208000006673 asthma Diseases 0.000 description 2
- 239000011575 calcium Substances 0.000 description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 239000013522 chelant Substances 0.000 description 2
- STQGQHZAVUOBTE-VGBVRHCVSA-N daunorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(C)=O)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 STQGQHZAVUOBTE-VGBVRHCVSA-N 0.000 description 2
- 238000012217 deletion Methods 0.000 description 2
- 230000037430 deletion Effects 0.000 description 2
- 208000025729 dengue disease Diseases 0.000 description 2
- 206010012601 diabetes mellitus Diseases 0.000 description 2
- 206010013023 diphtheria Diseases 0.000 description 2
- 231100000655 enterotoxin Toxicity 0.000 description 2
- 229960003276 erythromycin Drugs 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000013613 expression plasmid Substances 0.000 description 2
- 239000013604 expression vector Substances 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 239000012091 fetal bovine serum Substances 0.000 description 2
- MHMNJMPURVTYEJ-UHFFFAOYSA-N fluorescein-5-isothiocyanate Chemical compound O1C(=O)C2=CC(N=C=S)=CC=C2C21C1=CC=C(O)C=C1OC1=CC(O)=CC=C21 MHMNJMPURVTYEJ-UHFFFAOYSA-N 0.000 description 2
- 239000012737 fresh medium Substances 0.000 description 2
- 239000000499 gel Substances 0.000 description 2
- 238000001415 gene therapy Methods 0.000 description 2
- 210000001280 germinal center Anatomy 0.000 description 2
- 229960002897 heparin Drugs 0.000 description 2
- 229920000669 heparin Polymers 0.000 description 2
- 208000002672 hepatitis B Diseases 0.000 description 2
- JYGXADMDTFJGBT-VWUMJDOOSA-N hydrocortisone Chemical compound O=C1CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 JYGXADMDTFJGBT-VWUMJDOOSA-N 0.000 description 2
- 229960001680 ibuprofen Drugs 0.000 description 2
- 230000001976 improved effect Effects 0.000 description 2
- 208000015181 infectious disease Diseases 0.000 description 2
- 239000000893 inhibin Substances 0.000 description 2
- ZPNFWUPYTFPOJU-LPYSRVMUSA-N iniprol Chemical compound C([C@H]1C(=O)NCC(=O)NCC(=O)N[C@H]2CSSC[C@H]3C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@H](C(N[C@H](C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=4C=CC(O)=CC=4)C(=O)N[C@@H](CC=4C=CC=CC=4)C(=O)N[C@@H](CC=4C=CC(O)=CC=4)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CC=4C=CC=CC=4)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](CCCNC(N)=N)NC2=O)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](CC=2C=CC=CC=2)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H]2N(CCC2)C(=O)[C@@H](N)CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N2[C@@H](CCC2)C(=O)N2[C@@H](CCC2)C(=O)N[C@@H](CC=2C=CC(O)=CC=2)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(=O)N2[C@@H](CCC2)C(=O)N3)C(=O)NCC(=O)NCC(=O)N[C@@H](C)C(O)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@H](C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@H](C(=O)N1)C(C)C)[C@@H](C)O)[C@@H](C)CC)=O)[C@@H](C)CC)C1=CC=C(O)C=C1 ZPNFWUPYTFPOJU-LPYSRVMUSA-N 0.000 description 2
- 206010023332 keratitis Diseases 0.000 description 2
- 201000010666 keratoconjunctivitis Diseases 0.000 description 2
- 208000032839 leukemia Diseases 0.000 description 2
- 239000002502 liposome Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 230000007774 longterm Effects 0.000 description 2
- 210000004072 lung Anatomy 0.000 description 2
- 239000012516 mab select resin Substances 0.000 description 2
- 108700025647 major vault Proteins 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 244000005700 microbiome Species 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 229960000988 nystatin Drugs 0.000 description 2
- VQOXZBDYSJBXMA-NQTDYLQESA-N nystatin A1 Chemical compound O[C@H]1[C@@H](N)[C@H](O)[C@@H](C)O[C@H]1O[C@H]1/C=C/C=C/C=C/C=C/CC/C=C/C=C/[C@H](C)[C@@H](O)[C@@H](C)[C@H](C)OC(=O)C[C@H](O)C[C@H](O)C[C@H](O)CC[C@@H](O)[C@H](O)C[C@](O)(C[C@H](O)[C@H]2C(O)=O)O[C@H]2C1 VQOXZBDYSJBXMA-NQTDYLQESA-N 0.000 description 2
- 210000000056 organ Anatomy 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 235000005985 organic acids Nutrition 0.000 description 2
- 230000002188 osteogenic effect Effects 0.000 description 2
- 230000037361 pathway Effects 0.000 description 2
- 210000005105 peripheral blood lymphocyte Anatomy 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 238000012545 processing Methods 0.000 description 2
- 230000035755 proliferation Effects 0.000 description 2
- 230000000069 prophylactic effect Effects 0.000 description 2
- 210000002307 prostate Anatomy 0.000 description 2
- 230000002829 reductive effect Effects 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 239000011347 resin Substances 0.000 description 2
- 229920005989 resin Polymers 0.000 description 2
- 230000001177 retroviral effect Effects 0.000 description 2
- 206010039073 rheumatoid arthritis Diseases 0.000 description 2
- 201000004409 schistosomiasis Diseases 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 230000009870 specific binding Effects 0.000 description 2
- 210000000952 spleen Anatomy 0.000 description 2
- 210000003046 sporozoite Anatomy 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- 229960005202 streptokinase Drugs 0.000 description 2
- 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 2
- 239000000725 suspension Substances 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- 241001529453 unidentified herpesvirus Species 0.000 description 2
- 241000712461 unidentified influenza virus Species 0.000 description 2
- JWDFQMWEFLOOED-UHFFFAOYSA-N (2,5-dioxopyrrolidin-1-yl) 3-(pyridin-2-yldisulfanyl)propanoate Chemical compound O=C1CCC(=O)N1OC(=O)CCSSC1=CC=CC=N1 JWDFQMWEFLOOED-UHFFFAOYSA-N 0.000 description 1
- PJRSUKFWFKUDTH-JWDJOUOUSA-N (2s)-6-amino-2-[[2-[[(2s)-2-[[(2s,3s)-2-[[(2s)-2-[[2-[[(2s)-2-[[(2s)-6-amino-2-[[(2s)-2-[[(2s)-2-[[(2s)-2-[(2-aminoacetyl)amino]-4-methylsulfanylbutanoyl]amino]propanoyl]amino]-3-hydroxypropanoyl]amino]hexanoyl]amino]propanoyl]amino]acetyl]amino]propanoyl Chemical compound CSCC[C@H](NC(=O)CN)C(=O)N[C@@H](C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(=O)NCC(=O)N[C@@H](C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(N)=O PJRSUKFWFKUDTH-JWDJOUOUSA-N 0.000 description 1
- YYGNTYWPHWGJRM-UHFFFAOYSA-N (6E,10E,14E,18E)-2,6,10,15,19,23-hexamethyltetracosa-2,6,10,14,18,22-hexaene Chemical compound CC(C)=CCCC(C)=CCCC(C)=CCCC=C(C)CCC=C(C)CCC=C(C)C YYGNTYWPHWGJRM-UHFFFAOYSA-N 0.000 description 1
- FDKXTQMXEQVLRF-ZHACJKMWSA-N (E)-dacarbazine Chemical compound CN(C)\N=N\c1[nH]cnc1C(N)=O FDKXTQMXEQVLRF-ZHACJKMWSA-N 0.000 description 1
- ASNTZYQMIUCEBV-UHFFFAOYSA-N 2,5-dioxo-1-[6-[3-(pyridin-2-yldisulfanyl)propanoylamino]hexanoyloxy]pyrrolidine-3-sulfonic acid Chemical compound O=C1C(S(=O)(=O)O)CC(=O)N1OC(=O)CCCCCNC(=O)CCSSC1=CC=CC=N1 ASNTZYQMIUCEBV-UHFFFAOYSA-N 0.000 description 1
- MIJDSYMOBYNHOT-UHFFFAOYSA-N 2-(ethylamino)ethanol Chemical compound CCNCCO MIJDSYMOBYNHOT-UHFFFAOYSA-N 0.000 description 1
- KISWVXRQTGLFGD-UHFFFAOYSA-N 2-[[2-[[6-amino-2-[[2-[[2-[[5-amino-2-[[2-[[1-[2-[[6-amino-2-[(2,5-diamino-5-oxopentanoyl)amino]hexanoyl]amino]-5-(diaminomethylideneamino)pentanoyl]pyrrolidine-2-carbonyl]amino]-3-hydroxypropanoyl]amino]-5-oxopentanoyl]amino]-5-(diaminomethylideneamino)p Chemical compound C1CCN(C(=O)C(CCCN=C(N)N)NC(=O)C(CCCCN)NC(=O)C(N)CCC(N)=O)C1C(=O)NC(CO)C(=O)NC(CCC(N)=O)C(=O)NC(CCCN=C(N)N)C(=O)NC(CO)C(=O)NC(CCCCN)C(=O)NC(C(=O)NC(CC(C)C)C(O)=O)CC1=CC=C(O)C=C1 KISWVXRQTGLFGD-UHFFFAOYSA-N 0.000 description 1
- WUBBRNOQWQTFEX-UHFFFAOYSA-N 4-aminosalicylic acid Chemical compound NC1=CC=C(C(O)=O)C(O)=C1 WUBBRNOQWQTFEX-UHFFFAOYSA-N 0.000 description 1
- UHPMCKVQTMMPCG-UHFFFAOYSA-N 5,8-dihydroxy-2-methoxy-6-methyl-7-(2-oxopropyl)naphthalene-1,4-dione Chemical compound CC1=C(CC(C)=O)C(O)=C2C(=O)C(OC)=CC(=O)C2=C1O UHPMCKVQTMMPCG-UHFFFAOYSA-N 0.000 description 1
- WJQDJDVDXAAXSB-UHFFFAOYSA-N 5-sulfanylidenepyrrolidin-2-one Chemical compound O=C1CCC(=S)N1 WJQDJDVDXAAXSB-UHFFFAOYSA-N 0.000 description 1
- 101100220718 Acetivibrio thermocellus (strain ATCC 27405 / DSM 1237 / JCM 9322 / NBRC 103400 / NCIMB 10682 / NRRL B-4536 / VPI 7372) cipA gene Proteins 0.000 description 1
- 102100034540 Adenomatous polyposis coli protein Human genes 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- OGSPWJRAVKPPFI-UHFFFAOYSA-N Alendronic Acid Chemical compound NCCCC(O)(P(O)(O)=O)P(O)(O)=O OGSPWJRAVKPPFI-UHFFFAOYSA-N 0.000 description 1
- 102100035248 Alpha-(1,3)-fucosyltransferase 4 Human genes 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound 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 GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 229940122450 Altered peptide ligand Drugs 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- APKFDSVGJQXUKY-KKGHZKTASA-N Amphotericin-B Natural products O[C@H]1[C@@H](N)[C@H](O)[C@@H](C)O[C@H]1O[C@H]1C=CC=CC=CC=CC=CC=CC=C[C@H](C)[C@@H](O)[C@@H](C)[C@H](C)OC(=O)C[C@H](O)C[C@H](O)CC[C@@H](O)[C@H](O)C[C@H](O)C[C@](O)(C[C@H](O)[C@H]2C(O)=O)O[C@H]2C1 APKFDSVGJQXUKY-KKGHZKTASA-N 0.000 description 1
- 229930182536 Antimycin Natural products 0.000 description 1
- 108020005544 Antisense RNA Proteins 0.000 description 1
- 206010002965 Aplasia pure red cell Diseases 0.000 description 1
- 208000032467 Aplastic anaemia Diseases 0.000 description 1
- 102100021569 Apoptosis regulator Bcl-2 Human genes 0.000 description 1
- 101100446590 Arabidopsis thaliana FIM5 gene Proteins 0.000 description 1
- 241000712891 Arenavirus Species 0.000 description 1
- 206010003399 Arthropod bite Diseases 0.000 description 1
- 206010003571 Astrocytoma Diseases 0.000 description 1
- 206010003645 Atopy Diseases 0.000 description 1
- 102100022717 Atypical chemokine receptor 1 Human genes 0.000 description 1
- 208000032116 Autoimmune Experimental Encephalomyelitis Diseases 0.000 description 1
- 238000011725 BALB/c mouse Methods 0.000 description 1
- 241000304886 Bacilli Species 0.000 description 1
- 101100399280 Bacillus subtilis (strain 168) licH gene Proteins 0.000 description 1
- 208000008439 Biliary Liver Cirrhosis Diseases 0.000 description 1
- 208000033222 Biliary cirrhosis primary Diseases 0.000 description 1
- 206010005003 Bladder cancer Diseases 0.000 description 1
- 108010006654 Bleomycin Proteins 0.000 description 1
- 208000018084 Bone neoplasm Diseases 0.000 description 1
- 101800004538 Bradykinin Proteins 0.000 description 1
- 208000003174 Brain Neoplasms Diseases 0.000 description 1
- 208000014644 Brain disease Diseases 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- 102100028668 C-type lectin domain family 4 member C Human genes 0.000 description 1
- 102100028672 C-type lectin domain family 4 member D Human genes 0.000 description 1
- 102100028681 C-type lectin domain family 4 member K Human genes 0.000 description 1
- 101710183165 C-type lectin domain family 4 member K Proteins 0.000 description 1
- 102100040840 C-type lectin domain family 7 member A Human genes 0.000 description 1
- 101150013553 CD40 gene Proteins 0.000 description 1
- 102100032912 CD44 antigen Human genes 0.000 description 1
- 102100035793 CD83 antigen Human genes 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 241000222120 Candida <Saccharomycetales> Species 0.000 description 1
- 241000282461 Canis lupus Species 0.000 description 1
- 241000283707 Capra Species 0.000 description 1
- 108090000994 Catalytic RNA Proteins 0.000 description 1
- 102000053642 Catalytic RNA Human genes 0.000 description 1
- 108010039939 Cell Wall Skeleton Proteins 0.000 description 1
- 229930186147 Cephalosporin Natural products 0.000 description 1
- 206010008342 Cervix carcinoma Diseases 0.000 description 1
- 102000019034 Chemokines Human genes 0.000 description 1
- 108010012236 Chemokines Proteins 0.000 description 1
- 101710091342 Chemotactic peptide Proteins 0.000 description 1
- 241000606161 Chlamydia Species 0.000 description 1
- 208000002691 Choroiditis Diseases 0.000 description 1
- 206010008909 Chronic Hepatitis Diseases 0.000 description 1
- 108090000317 Chymotrypsin Proteins 0.000 description 1
- 108010038061 Chymotrypsinogen Proteins 0.000 description 1
- 206010009900 Colitis ulcerative Diseases 0.000 description 1
- 108010035532 Collagen Proteins 0.000 description 1
- 102000008186 Collagen Human genes 0.000 description 1
- 108060005980 Collagenase Proteins 0.000 description 1
- 102000029816 Collagenase Human genes 0.000 description 1
- 206010009944 Colon cancer Diseases 0.000 description 1
- 206010010741 Conjunctivitis Diseases 0.000 description 1
- 241000711573 Coronaviridae Species 0.000 description 1
- 239000004971 Cross linker Substances 0.000 description 1
- 240000005109 Cryptomeria japonica Species 0.000 description 1
- SRUWWOSWHXIIIA-UKPGNTDSSA-N Cyanoginosin Chemical compound N1C(=O)[C@H](CCCN=C(N)N)NC(=O)[C@@H](C)[C@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)C(=C)N(C)C(=O)CC[C@H](C(O)=O)N(C)C(=O)[C@@H](C)[C@@H]1\C=C\C(\C)=C\[C@H](C)[C@@H](O)CC1=CC=CC=C1 SRUWWOSWHXIIIA-UKPGNTDSSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- 108020001019 DNA Primers Proteins 0.000 description 1
- 230000008836 DNA modification Effects 0.000 description 1
- 239000003155 DNA primer Substances 0.000 description 1
- WEAHRLBPCANXCN-UHFFFAOYSA-N Daunomycin Natural products CCC1(O)CC(OC2CC(N)C(O)C(C)O2)c3cc4C(=O)c5c(OC)cccc5C(=O)c4c(O)c3C1 WEAHRLBPCANXCN-UHFFFAOYSA-N 0.000 description 1
- 206010011891 Deafness neurosensory Diseases 0.000 description 1
- 241000725619 Dengue virus Species 0.000 description 1
- 206010012435 Dermatitis and eczema Diseases 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 206010012735 Diarrhoea Diseases 0.000 description 1
- 208000002699 Digestive System Neoplasms Diseases 0.000 description 1
- BWGNESOTFCXPMA-UHFFFAOYSA-N Dihydrogen disulfide Chemical compound SS BWGNESOTFCXPMA-UHFFFAOYSA-N 0.000 description 1
- 102100023431 E3 ubiquitin-protein ligase TRIM21 Human genes 0.000 description 1
- 101710164941 E3 ubiquitin-protein ligase TRIM21 Proteins 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 101150029707 ERBB2 gene Proteins 0.000 description 1
- 206010014596 Encephalitis Japanese B Diseases 0.000 description 1
- 208000032274 Encephalopathy Diseases 0.000 description 1
- 101001095863 Enterobacteria phage T4 RNA ligase 1 Proteins 0.000 description 1
- 101710146739 Enterotoxin Proteins 0.000 description 1
- 241000991587 Enterovirus C Species 0.000 description 1
- 101710126487 Envelope glycoprotein B Proteins 0.000 description 1
- 101710204837 Envelope small membrane protein Proteins 0.000 description 1
- 206010015150 Erythema Diseases 0.000 description 1
- 241000588724 Escherichia coli Species 0.000 description 1
- 101100113310 Escherichia coli (strain K12) chbR gene Proteins 0.000 description 1
- 241001198387 Escherichia coli BL21(DE3) Species 0.000 description 1
- 101001065501 Escherichia phage MS2 Lysis protein Proteins 0.000 description 1
- 208000000461 Esophageal Neoplasms Diseases 0.000 description 1
- 101150106011 FIM2 gene Proteins 0.000 description 1
- 101150048576 FIM3 gene Proteins 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 101710154643 Filamentous hemagglutinin Proteins 0.000 description 1
- 108010029961 Filgrastim Proteins 0.000 description 1
- 102000012673 Follicle Stimulating Hormone Human genes 0.000 description 1
- 108010079345 Follicle Stimulating Hormone Proteins 0.000 description 1
- 241000223218 Fusarium Species 0.000 description 1
- 101710177291 Gag polyprotein Proteins 0.000 description 1
- 102100021260 Galactosylgalactosylxylosylprotein 3-beta-glucuronosyltransferase 1 Human genes 0.000 description 1
- 208000022072 Gallbladder Neoplasms Diseases 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 102000008214 Glutamate decarboxylase Human genes 0.000 description 1
- 108010070675 Glutathione transferase Proteins 0.000 description 1
- 229930186217 Glycolipid Natural products 0.000 description 1
- 102000003886 Glycoproteins Human genes 0.000 description 1
- 108090000288 Glycoproteins Proteins 0.000 description 1
- 102000004457 Granulocyte-Macrophage Colony-Stimulating Factor Human genes 0.000 description 1
- 206010072579 Granulomatosis with polyangiitis Diseases 0.000 description 1
- 208000003084 Graves Ophthalmopathy Diseases 0.000 description 1
- 108010051696 Growth Hormone Proteins 0.000 description 1
- QXZGBUJJYSLZLT-UHFFFAOYSA-N H-Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg-OH Natural products NC(N)=NCCCC(N)C(=O)N1CCCC1C(=O)N1C(C(=O)NCC(=O)NC(CC=2C=CC=CC=2)C(=O)NC(CO)C(=O)N2C(CCC2)C(=O)NC(CC=2C=CC=CC=2)C(=O)NC(CCCN=C(N)N)C(O)=O)CCC1 QXZGBUJJYSLZLT-UHFFFAOYSA-N 0.000 description 1
- 241000197306 H1N1 subtype Species 0.000 description 1
- 102000006354 HLA-DR Antigens Human genes 0.000 description 1
- 108010058597 HLA-DR Antigens Proteins 0.000 description 1
- 208000030836 Hashimoto thyroiditis Diseases 0.000 description 1
- 241000590002 Helicobacter pylori Species 0.000 description 1
- 102100029100 Hematopoietic prostaglandin D synthase Human genes 0.000 description 1
- 241000711549 Hepacivirus C Species 0.000 description 1
- 208000005176 Hepatitis C Diseases 0.000 description 1
- 206010019755 Hepatitis chronic active Diseases 0.000 description 1
- 102000007625 Hirudins Human genes 0.000 description 1
- 108010007267 Hirudins Proteins 0.000 description 1
- 102100034523 Histone H4 Human genes 0.000 description 1
- 108010033040 Histones Proteins 0.000 description 1
- 208000017604 Hodgkin disease Diseases 0.000 description 1
- 208000010747 Hodgkins lymphoma Diseases 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 101000924577 Homo sapiens Adenomatous polyposis coli protein Proteins 0.000 description 1
- 101001022185 Homo sapiens Alpha-(1,3)-fucosyltransferase 4 Proteins 0.000 description 1
- 101000971171 Homo sapiens Apoptosis regulator Bcl-2 Proteins 0.000 description 1
- 101000678879 Homo sapiens Atypical chemokine receptor 1 Proteins 0.000 description 1
- 101000766907 Homo sapiens C-type lectin domain family 4 member C Proteins 0.000 description 1
- 101000766905 Homo sapiens C-type lectin domain family 4 member D Proteins 0.000 description 1
- 101100220044 Homo sapiens CD34 gene Proteins 0.000 description 1
- 101000868273 Homo sapiens CD44 antigen Proteins 0.000 description 1
- 101000946856 Homo sapiens CD83 antigen Proteins 0.000 description 1
- 101000894906 Homo sapiens Galactosylgalactosylxylosylprotein 3-beta-glucuronosyltransferase 1 Proteins 0.000 description 1
- 101001046686 Homo sapiens Integrin alpha-M Proteins 0.000 description 1
- 101000935043 Homo sapiens Integrin beta-1 Proteins 0.000 description 1
- 101000935040 Homo sapiens Integrin beta-2 Proteins 0.000 description 1
- 101000599852 Homo sapiens Intercellular adhesion molecule 1 Proteins 0.000 description 1
- 101000608935 Homo sapiens Leukosialin Proteins 0.000 description 1
- 101000972485 Homo sapiens Lupus La protein Proteins 0.000 description 1
- 101001063392 Homo sapiens Lymphocyte function-associated antigen 3 Proteins 0.000 description 1
- 101000578784 Homo sapiens Melanoma antigen recognized by T-cells 1 Proteins 0.000 description 1
- 101000934346 Homo sapiens T-cell surface antigen CD2 Proteins 0.000 description 1
- 241000700588 Human alphaherpesvirus 1 Species 0.000 description 1
- 241000701074 Human alphaherpesvirus 2 Species 0.000 description 1
- 241000701085 Human alphaherpesvirus 3 Species 0.000 description 1
- 108010003272 Hyaluronate lyase Proteins 0.000 description 1
- 102000001974 Hyaluronidases Human genes 0.000 description 1
- XQFRJNBWHJMXHO-RRKCRQDMSA-N IDUR Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(I)=C1 XQFRJNBWHJMXHO-RRKCRQDMSA-N 0.000 description 1
- 206010021245 Idiopathic thrombocytopenic purpura Diseases 0.000 description 1
- 108010073807 IgG Receptors Proteins 0.000 description 1
- 102000009490 IgG Receptors Human genes 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
- 206010061218 Inflammation Diseases 0.000 description 1
- 241001539805 Influenza A virus (A/Puerto Rico/8/1934(H1N1)) Species 0.000 description 1
- 241000797260 Influenza A virus (A/Viet Nam/1203/2004(H5N1)) Species 0.000 description 1
- 208000002979 Influenza in Birds Diseases 0.000 description 1
- 102100034353 Integrase Human genes 0.000 description 1
- 102100022338 Integrin alpha-M Human genes 0.000 description 1
- 102100025304 Integrin beta-1 Human genes 0.000 description 1
- 102100025390 Integrin beta-2 Human genes 0.000 description 1
- 108010064593 Intercellular Adhesion Molecule-1 Proteins 0.000 description 1
- 102000015271 Intercellular Adhesion Molecule-1 Human genes 0.000 description 1
- 102100037877 Intercellular adhesion molecule 1 Human genes 0.000 description 1
- 102000010789 Interleukin-2 Receptors Human genes 0.000 description 1
- 108010038453 Interleukin-2 Receptors Proteins 0.000 description 1
- 208000029523 Interstitial Lung disease Diseases 0.000 description 1
- 201000005807 Japanese encephalitis Diseases 0.000 description 1
- 208000008839 Kidney Neoplasms Diseases 0.000 description 1
- 102100035792 Kininogen-1 Human genes 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 1
- 229930182816 L-glutamine Natural products 0.000 description 1
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 description 1
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 206010023825 Laryngeal cancer Diseases 0.000 description 1
- 240000007472 Leucaena leucocephala Species 0.000 description 1
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 1
- 102100039564 Leukosialin Human genes 0.000 description 1
- OJMMVQQUTAEWLP-UHFFFAOYSA-N Lincomycin Natural products CN1CC(CCC)CC1C(=O)NC(C(C)O)C1C(O)C(O)C(O)C(SC)O1 OJMMVQQUTAEWLP-UHFFFAOYSA-N 0.000 description 1
- 206010062038 Lip neoplasm Diseases 0.000 description 1
- 241000209082 Lolium Species 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- 102100022742 Lupus La protein Human genes 0.000 description 1
- 102000009151 Luteinizing Hormone Human genes 0.000 description 1
- 108010073521 Luteinizing Hormone Proteins 0.000 description 1
- 208000016604 Lyme disease Diseases 0.000 description 1
- 102100030984 Lymphocyte function-associated antigen 3 Human genes 0.000 description 1
- 102000008072 Lymphokines Human genes 0.000 description 1
- 108010074338 Lymphokines Proteins 0.000 description 1
- 206010025323 Lymphomas Diseases 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 208000032271 Malignant tumor of penis Diseases 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 201000005505 Measles Diseases 0.000 description 1
- 102100028389 Melanoma antigen recognized by T-cells 1 Human genes 0.000 description 1
- 108010057081 Merozoite Surface Protein 1 Proteins 0.000 description 1
- 208000003445 Mouth Neoplasms Diseases 0.000 description 1
- 108010008707 Mucin-1 Proteins 0.000 description 1
- 102100034256 Mucin-1 Human genes 0.000 description 1
- 102100034263 Mucin-2 Human genes 0.000 description 1
- 108010008705 Mucin-2 Proteins 0.000 description 1
- 208000034578 Multiple myelomas Diseases 0.000 description 1
- 108010085220 Multiprotein Complexes Proteins 0.000 description 1
- 102000007474 Multiprotein Complexes Human genes 0.000 description 1
- 241001529936 Murinae Species 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 241000187479 Mycobacterium tuberculosis Species 0.000 description 1
- 101000944608 Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv) Chaperonin GroEL 2 Proteins 0.000 description 1
- 241000204031 Mycoplasma Species 0.000 description 1
- 102000047918 Myelin Basic Human genes 0.000 description 1
- 102000055324 Myelin Proteolipid Human genes 0.000 description 1
- 101710107068 Myelin basic protein Proteins 0.000 description 1
- 101710094913 Myelin proteolipid protein Proteins 0.000 description 1
- 108700020354 N-acetylmuramyl-threonyl-isoglutamine Proteins 0.000 description 1
- 101800000135 N-terminal protein Proteins 0.000 description 1
- 208000001894 Nasopharyngeal Neoplasms Diseases 0.000 description 1
- 206010061306 Nasopharyngeal cancer Diseases 0.000 description 1
- 241001644525 Nastus productus Species 0.000 description 1
- 241000588652 Neisseria gonorrhoeae Species 0.000 description 1
- 241000588650 Neisseria meningitidis Species 0.000 description 1
- 108010006232 Neuraminidase Proteins 0.000 description 1
- 102000005348 Neuraminidase Human genes 0.000 description 1
- 208000015914 Non-Hodgkin lymphomas Diseases 0.000 description 1
- 108091028043 Nucleic acid sequence Proteins 0.000 description 1
- 108091005461 Nucleic proteins Proteins 0.000 description 1
- 102000011931 Nucleoproteins Human genes 0.000 description 1
- 108010061100 Nucleoproteins Proteins 0.000 description 1
- 206010030155 Oesophageal carcinoma Diseases 0.000 description 1
- 102000043276 Oncogene Human genes 0.000 description 1
- 108700020796 Oncogene Proteins 0.000 description 1
- 241000713112 Orthobunyavirus Species 0.000 description 1
- 102000004067 Osteocalcin Human genes 0.000 description 1
- 108090000573 Osteocalcin Proteins 0.000 description 1
- 101710160107 Outer membrane protein A Proteins 0.000 description 1
- 206010033128 Ovarian cancer Diseases 0.000 description 1
- 206010061535 Ovarian neoplasm Diseases 0.000 description 1
- 101800001452 P1 proteinase Proteins 0.000 description 1
- 102000036673 PRAME Human genes 0.000 description 1
- 108060006580 PRAME Proteins 0.000 description 1
- 229930012538 Paclitaxel Natural products 0.000 description 1
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 1
- 108090000445 Parathyroid hormone Proteins 0.000 description 1
- 102000003982 Parathyroid hormone Human genes 0.000 description 1
- 208000002471 Penile Neoplasms Diseases 0.000 description 1
- 206010034299 Penile cancer Diseases 0.000 description 1
- 108010081690 Pertussis Toxin Proteins 0.000 description 1
- 208000009565 Pharyngeal Neoplasms Diseases 0.000 description 1
- 206010034811 Pharyngeal cancer Diseases 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- 108010004729 Phycoerythrin Proteins 0.000 description 1
- 241000709664 Picornaviridae Species 0.000 description 1
- 206010035226 Plasma cell myeloma Diseases 0.000 description 1
- 102000013566 Plasminogen Human genes 0.000 description 1
- 108010051456 Plasminogen Proteins 0.000 description 1
- 241000224016 Plasmodium Species 0.000 description 1
- 102100024616 Platelet endothelial cell adhesion molecule Human genes 0.000 description 1
- 101710183389 Pneumolysin Proteins 0.000 description 1
- 208000000474 Poliomyelitis Diseases 0.000 description 1
- 206010065159 Polychondritis Diseases 0.000 description 1
- 108091036414 Polyinosinic:polycytidylic acid Proteins 0.000 description 1
- 208000003971 Posterior uveitis Diseases 0.000 description 1
- 208000012654 Primary biliary cholangitis Diseases 0.000 description 1
- 206010036774 Proctitis Diseases 0.000 description 1
- 102000003946 Prolactin Human genes 0.000 description 1
- 108010057464 Prolactin Proteins 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
- 229940124158 Protease/peptidase inhibitor Drugs 0.000 description 1
- 101710194807 Protective antigen Proteins 0.000 description 1
- 241000125945 Protoparvovirus Species 0.000 description 1
- 201000004681 Psoriasis Diseases 0.000 description 1
- 201000001263 Psoriatic Arthritis Diseases 0.000 description 1
- 208000036824 Psoriatic arthropathy Diseases 0.000 description 1
- 239000012980 RPMI-1640 medium Substances 0.000 description 1
- 101000766906 Rattus norvegicus C-type lectin domain family 4 member A Proteins 0.000 description 1
- 108020004511 Recombinant DNA Proteins 0.000 description 1
- 208000015634 Rectal Neoplasms Diseases 0.000 description 1
- 206010038389 Renal cancer Diseases 0.000 description 1
- 241000702263 Reovirus sp. Species 0.000 description 1
- 101710088839 Replication initiation protein Proteins 0.000 description 1
- 206010039085 Rhinitis allergic Diseases 0.000 description 1
- 108010081734 Ribonucleoproteins Proteins 0.000 description 1
- 102000004389 Ribonucleoproteins Human genes 0.000 description 1
- 241000710799 Rubella virus Species 0.000 description 1
- 241000193448 Ruminiclostridium thermocellum Species 0.000 description 1
- 101000999689 Saimiriine herpesvirus 2 (strain 11) Transcriptional regulator ICP22 homolog Proteins 0.000 description 1
- 241000607142 Salmonella Species 0.000 description 1
- 206010039710 Scleroderma Diseases 0.000 description 1
- 206010039897 Sedation Diseases 0.000 description 1
- 208000009966 Sensorineural Hearing Loss Diseases 0.000 description 1
- 241000607768 Shigella Species 0.000 description 1
- 208000000453 Skin Neoplasms Diseases 0.000 description 1
- 102100038803 Somatotropin Human genes 0.000 description 1
- 101001039853 Sonchus yellow net virus Matrix protein Proteins 0.000 description 1
- 241000191940 Staphylococcus Species 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 206010042033 Stevens-Johnson syndrome Diseases 0.000 description 1
- 231100000168 Stevens-Johnson syndrome Toxicity 0.000 description 1
- 208000005718 Stomach Neoplasms Diseases 0.000 description 1
- 108010090804 Streptavidin Proteins 0.000 description 1
- 241000193998 Streptococcus pneumoniae Species 0.000 description 1
- 101800001271 Surface protein Proteins 0.000 description 1
- 230000024932 T cell mediated immunity Effects 0.000 description 1
- 230000006052 T cell proliferation Effects 0.000 description 1
- 102100025237 T-cell surface antigen CD2 Human genes 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 208000024313 Testicular Neoplasms Diseases 0.000 description 1
- 206010057644 Testis cancer Diseases 0.000 description 1
- 239000004098 Tetracycline Substances 0.000 description 1
- BHEOSNUKNHRBNM-UHFFFAOYSA-N Tetramethylsqualene Natural products CC(=C)C(C)CCC(=C)C(C)CCC(C)=CCCC=C(C)CCC(C)C(=C)CCC(C)C(C)=C BHEOSNUKNHRBNM-UHFFFAOYSA-N 0.000 description 1
- 108010034949 Thyroglobulin Proteins 0.000 description 1
- 102000009843 Thyroglobulin Human genes 0.000 description 1
- 208000024770 Thyroid neoplasm Diseases 0.000 description 1
- 108700019146 Transgenes Proteins 0.000 description 1
- 102000005937 Tropomyosin Human genes 0.000 description 1
- 108010030743 Tropomyosin Proteins 0.000 description 1
- 241000223109 Trypanosoma cruzi Species 0.000 description 1
- 108010027252 Trypsinogen Proteins 0.000 description 1
- 102000018690 Trypsinogen Human genes 0.000 description 1
- 208000034784 Tularaemia Diseases 0.000 description 1
- 102100040245 Tumor necrosis factor receptor superfamily member 5 Human genes 0.000 description 1
- 241001467018 Typhis Species 0.000 description 1
- 102100039094 Tyrosinase Human genes 0.000 description 1
- 108060008724 Tyrosinase Proteins 0.000 description 1
- 201000006704 Ulcerative Colitis Diseases 0.000 description 1
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 description 1
- 102000003990 Urokinase-type plasminogen activator Human genes 0.000 description 1
- 108090000435 Urokinase-type plasminogen activator Proteins 0.000 description 1
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 description 1
- 208000002495 Uterine Neoplasms Diseases 0.000 description 1
- 206010046914 Vaginal infection Diseases 0.000 description 1
- 201000008100 Vaginitis Diseases 0.000 description 1
- 244000126014 Valeriana officinalis Species 0.000 description 1
- 235000013832 Valeriana officinalis Nutrition 0.000 description 1
- 108010059993 Vancomycin Proteins 0.000 description 1
- 241000607626 Vibrio cholerae Species 0.000 description 1
- JXLYSJRDGCGARV-WWYNWVTFSA-N Vinblastine Natural products O=C(O[C@H]1[C@](O)(C(=O)OC)[C@@H]2N(C)c3c(cc(c(OC)c3)[C@]3(C(=O)OC)c4[nH]c5c(c4CCN4C[C@](O)(CC)C[C@H](C3)C4)cccc5)[C@@]32[C@H]2[C@@]1(CC)C=CCN2CC3)C JXLYSJRDGCGARV-WWYNWVTFSA-N 0.000 description 1
- 108010059722 Viral Fusion Proteins Proteins 0.000 description 1
- 208000036142 Viral infection Diseases 0.000 description 1
- 241000710886 West Nile virus Species 0.000 description 1
- 208000003152 Yellow Fever Diseases 0.000 description 1
- 241000607479 Yersinia pestis Species 0.000 description 1
- 235000011054 acetic acid Nutrition 0.000 description 1
- 239000012190 activator Substances 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 230000033289 adaptive immune response Effects 0.000 description 1
- 229940009456 adriamycin Drugs 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 239000011543 agarose gel Substances 0.000 description 1
- 229940062527 alendronate Drugs 0.000 description 1
- 201000009961 allergic asthma Diseases 0.000 description 1
- 230000000172 allergic effect Effects 0.000 description 1
- 201000010105 allergic rhinitis Diseases 0.000 description 1
- 208000004631 alopecia areata Diseases 0.000 description 1
- WNROFYMDJYEPJX-UHFFFAOYSA-K aluminium hydroxide Chemical compound [OH-].[OH-].[OH-].[Al+3] WNROFYMDJYEPJX-UHFFFAOYSA-K 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- DKNWSYNQZKUICI-UHFFFAOYSA-N amantadine Chemical compound C1C(C2)CC3CC2CC1(N)C3 DKNWSYNQZKUICI-UHFFFAOYSA-N 0.000 description 1
- 229960003805 amantadine Drugs 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 229940024606 amino acid Drugs 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 229960004909 aminosalicylic acid Drugs 0.000 description 1
- 239000000908 ammonium hydroxide Substances 0.000 description 1
- APKFDSVGJQXUKY-INPOYWNPSA-N amphotericin B Chemical compound O[C@H]1[C@@H](N)[C@H](O)[C@@H](C)O[C@H]1O[C@H]1/C=C/C=C/C=C/C=C/C=C/C=C/C=C/[C@H](C)[C@@H](O)[C@@H](C)[C@H](C)OC(=O)C[C@H](O)C[C@H](O)CC[C@@H](O)[C@H](O)C[C@H](O)C[C@](O)(C[C@H](O)[C@H]2C(O)=O)O[C@H]2C1 APKFDSVGJQXUKY-INPOYWNPSA-N 0.000 description 1
- 229960003942 amphotericin b Drugs 0.000 description 1
- 230000003698 anagen phase Effects 0.000 description 1
- 230000014102 antigen processing and presentation of exogenous peptide antigen via MHC class I Effects 0.000 description 1
- 229960005475 antiinfective agent Drugs 0.000 description 1
- 239000004599 antimicrobial Substances 0.000 description 1
- CQIUKKVOEOPUDV-IYSWYEEDSA-N antimycin Chemical compound OC1=C(C(O)=O)C(=O)C(C)=C2[C@H](C)[C@@H](C)OC=C21 CQIUKKVOEOPUDV-IYSWYEEDSA-N 0.000 description 1
- 239000003443 antiviral agent Substances 0.000 description 1
- 208000002399 aphthous stomatitis Diseases 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- 206010003246 arthritis Diseases 0.000 description 1
- 208000010668 atopic eczema Diseases 0.000 description 1
- 230000003190 augmentative effect Effects 0.000 description 1
- 230000001363 autoimmune Effects 0.000 description 1
- 201000003710 autoimmune thrombocytopenic purpura Diseases 0.000 description 1
- 201000004982 autoimmune uveitis Diseases 0.000 description 1
- 206010064097 avian influenza Diseases 0.000 description 1
- 230000008901 benefit Effects 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
- 230000002146 bilateral effect Effects 0.000 description 1
- 210000003445 biliary tract Anatomy 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 239000012148 binding buffer Substances 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000008033 biological extinction Effects 0.000 description 1
- 230000006287 biotinylation Effects 0.000 description 1
- 238000007413 biotinylation Methods 0.000 description 1
- OWMVSZAMULFTJU-UHFFFAOYSA-N bis-tris Chemical compound OCCN(CCO)C(CO)(CO)CO OWMVSZAMULFTJU-UHFFFAOYSA-N 0.000 description 1
- 229960001561 bleomycin Drugs 0.000 description 1
- OYVAGSVQBOHSSS-UAPAGMARSA-O bleomycin A2 Chemical compound N([C@H](C(=O)N[C@H](C)[C@@H](O)[C@H](C)C(=O)N[C@@H]([C@H](O)C)C(=O)NCCC=1SC=C(N=1)C=1SC=C(N=1)C(=O)NCCC[S+](C)C)[C@@H](O[C@H]1[C@H]([C@@H](O)[C@H](O)[C@H](CO)O1)O[C@@H]1[C@H]([C@@H](OC(N)=O)[C@H](O)[C@@H](CO)O1)O)C=1N=CNC=1)C(=O)C1=NC([C@H](CC(N)=O)NC[C@H](N)C(N)=O)=NC(N)=C1C OYVAGSVQBOHSSS-UAPAGMARSA-O 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- QXZGBUJJYSLZLT-FDISYFBBSA-N bradykinin Chemical compound NC(=N)NCCC[C@H](N)C(=O)N1CCC[C@H]1C(=O)N1[C@H](C(=O)NCC(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CO)C(=O)N2[C@@H](CCC2)C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)CCC1 QXZGBUJJYSLZLT-FDISYFBBSA-N 0.000 description 1
- 238000010804 cDNA synthesis Methods 0.000 description 1
- 229910052791 calcium Inorganic materials 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
- 208000020670 canker sore Diseases 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 101150072516 cbhA gene Proteins 0.000 description 1
- 101150072511 celD gene Proteins 0.000 description 1
- 230000020411 cell activation Effects 0.000 description 1
- 230000007910 cell fusion Effects 0.000 description 1
- 239000013592 cell lysate Substances 0.000 description 1
- 230000011748 cell maturation Effects 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 238000001516 cell proliferation assay Methods 0.000 description 1
- 210000004520 cell wall skeleton Anatomy 0.000 description 1
- 230000030570 cellular localization Effects 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 229940124587 cephalosporin Drugs 0.000 description 1
- 150000001780 cephalosporins Chemical class 0.000 description 1
- 201000010881 cervical cancer Diseases 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- JQXXHWHPUNPDRT-BQVAUQFYSA-N chembl1523493 Chemical compound O([C@](C1=O)(C)O\C=C/[C@@H]([C@H]([C@@H](OC(C)=O)[C@H](C)[C@H](O)[C@H](C)[C@@H](O)[C@@H](C)/C=C\C=C(C)/C(=O)NC=2C(O)=C3C(O)=C4C)C)OC)C4=C1C3=C(O)C=2C=NN1CCN(C)CC1 JQXXHWHPUNPDRT-BQVAUQFYSA-N 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 229960005091 chloramphenicol Drugs 0.000 description 1
- WIIZWVCIJKGZOK-RKDXNWHRSA-N chloramphenicol Chemical compound ClC(Cl)C(=O)N[C@H](CO)[C@H](O)C1=CC=C([N+]([O-])=O)C=C1 WIIZWVCIJKGZOK-RKDXNWHRSA-N 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 229960002376 chymotrypsin Drugs 0.000 description 1
- 229960002227 clindamycin Drugs 0.000 description 1
- KDLRVYVGXIQJDK-AWPVFWJPSA-N clindamycin Chemical compound CN1C[C@H](CCC)C[C@H]1C(=O)N[C@H]([C@H](C)Cl)[C@@H]1[C@H](O)[C@H](O)[C@@H](O)[C@@H](SC)O1 KDLRVYVGXIQJDK-AWPVFWJPSA-N 0.000 description 1
- 238000003501 co-culture Methods 0.000 description 1
- 229920001436 collagen Polymers 0.000 description 1
- 229960002424 collagenase Drugs 0.000 description 1
- 208000029742 colonic neoplasm Diseases 0.000 description 1
- 239000003184 complementary RNA Substances 0.000 description 1
- 238000010668 complexation reaction Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000004624 confocal microscopy Methods 0.000 description 1
- 210000002808 connective tissue Anatomy 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 208000004921 cutaneous lupus erythematosus Diseases 0.000 description 1
- 230000009089 cytolysis Effects 0.000 description 1
- 210000000805 cytoplasm Anatomy 0.000 description 1
- 229960003901 dacarbazine Drugs 0.000 description 1
- 229960000975 daunorubicin Drugs 0.000 description 1
- 108010025838 dectin 1 Proteins 0.000 description 1
- 210000004207 dermis Anatomy 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 229960003957 dexamethasone Drugs 0.000 description 1
- UREBDLICKHMUKA-CXSFZGCWSA-N dexamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-CXSFZGCWSA-N 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- 238000000502 dialysis Methods 0.000 description 1
- 229960005423 diatrizoate Drugs 0.000 description 1
- 229960001259 diclofenac Drugs 0.000 description 1
- DCOPUUMXTXDBNB-UHFFFAOYSA-N diclofenac Chemical compound OC(=O)CC1=CC=CC=C1NC1=C(Cl)C=CC=C1Cl DCOPUUMXTXDBNB-UHFFFAOYSA-N 0.000 description 1
- 238000009792 diffusion process Methods 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
- 108010007093 dispase Proteins 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- PRAKJMSDJKAYCZ-UHFFFAOYSA-N dodecahydrosqualene Natural products CC(C)CCCC(C)CCCC(C)CCCCC(C)CCCC(C)CCCC(C)C PRAKJMSDJKAYCZ-UHFFFAOYSA-N 0.000 description 1
- 229960004679 doxorubicin Drugs 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000000428 dust Substances 0.000 description 1
- 230000002500 effect on skin Effects 0.000 description 1
- 239000012636 effector Substances 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 238000005538 encapsulation Methods 0.000 description 1
- 239000002158 endotoxin Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 239000000147 enterotoxin Substances 0.000 description 1
- 108010078428 env Gene Products Proteins 0.000 description 1
- 108700004025 env Genes Proteins 0.000 description 1
- 101150030339 env gene Proteins 0.000 description 1
- 210000002615 epidermis Anatomy 0.000 description 1
- 239000006167 equilibration buffer Substances 0.000 description 1
- 231100000321 erythema Toxicity 0.000 description 1
- 201000004101 esophageal cancer Diseases 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 238000000855 fermentation Methods 0.000 description 1
- 230000004151 fermentation Effects 0.000 description 1
- 230000001605 fetal effect Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- YLQWCDOCJODRMT-UHFFFAOYSA-N fluoren-9-one Chemical compound C1=CC=C2C(=O)C3=CC=CC=C3C2=C1 YLQWCDOCJODRMT-UHFFFAOYSA-N 0.000 description 1
- 229940028334 follicle stimulating hormone Drugs 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 108700004026 gag Genes Proteins 0.000 description 1
- 101150098622 gag gene Proteins 0.000 description 1
- 201000010175 gallbladder cancer Diseases 0.000 description 1
- 210000000973 gametocyte Anatomy 0.000 description 1
- 150000002270 gangliosides Chemical class 0.000 description 1
- 206010017758 gastric cancer Diseases 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- 238000010353 genetic engineering Methods 0.000 description 1
- 208000005017 glioblastoma Diseases 0.000 description 1
- 229930182478 glucoside Natural products 0.000 description 1
- 150000008131 glucosides Chemical class 0.000 description 1
- 239000000122 growth hormone Substances 0.000 description 1
- 201000010536 head and neck cancer Diseases 0.000 description 1
- 208000014829 head and neck neoplasm Diseases 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 210000002216 heart Anatomy 0.000 description 1
- 229940037467 helicobacter pylori Drugs 0.000 description 1
- 230000002489 hematologic effect Effects 0.000 description 1
- 230000002008 hemorrhagic effect Effects 0.000 description 1
- 208000005252 hepatitis A Diseases 0.000 description 1
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 1
- 229940006607 hirudin Drugs 0.000 description 1
- WQPDUTSPKFMPDP-OUMQNGNKSA-N hirudin Chemical compound C([C@@H](C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1C=CC(OS(O)(=O)=O)=CC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCCN)NC(=O)[C@H]1N(CCC1)C(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)CNC(=O)[C@@H](NC(=O)[C@@H](NC(=O)[C@H]1NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CCC(O)=O)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)CNC(=O)[C@H](CC(C)C)NC(=O)[C@H]([C@@H](C)CC)NC(=O)[C@@H]2CSSC[C@@H](C(=O)N[C@@H](CCC(O)=O)C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@H](C(=O)N[C@H](C(NCC(=O)N[C@@H](CCC(N)=O)C(=O)NCC(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)N2)=O)CSSC1)C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H]1NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)CNC(=O)[C@H](CO)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CC=2C=CC(O)=CC=2)NC(=O)[C@@H](NC(=O)[C@@H](N)C(C)C)C(C)C)[C@@H](C)O)CSSC1)C(C)C)[C@@H](C)O)[C@@H](C)O)C1=CC=CC=C1 WQPDUTSPKFMPDP-OUMQNGNKSA-N 0.000 description 1
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 1
- 108010007811 human immunodeficiency virus p17 gag peptide Proteins 0.000 description 1
- 230000028996 humoral immune response Effects 0.000 description 1
- 229960002773 hyaluronidase Drugs 0.000 description 1
- 229960000890 hydrocortisone Drugs 0.000 description 1
- 229960004716 idoxuridine Drugs 0.000 description 1
- 230000002519 immonomodulatory effect Effects 0.000 description 1
- 238000003018 immunoassay Methods 0.000 description 1
- 229940072221 immunoglobulins Drugs 0.000 description 1
- 230000003308 immunostimulating effect Effects 0.000 description 1
- 238000009169 immunotherapy Methods 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 239000000411 inducer Substances 0.000 description 1
- 230000002458 infectious effect Effects 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 208000037797 influenza A Diseases 0.000 description 1
- 108010061181 influenza matrix peptide (58-66) Proteins 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 239000002054 inoculum Substances 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 201000004614 iritis Diseases 0.000 description 1
- 235000014413 iron hydroxide Nutrition 0.000 description 1
- NCNCGGDMXMBVIA-UHFFFAOYSA-L iron(ii) hydroxide Chemical compound [OH-].[OH-].[Fe+2] NCNCGGDMXMBVIA-UHFFFAOYSA-L 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 229960003350 isoniazid Drugs 0.000 description 1
- QRXWMOHMRWLFEY-UHFFFAOYSA-N isoniazide Chemical compound NNC(=O)C1=CC=NC=C1 QRXWMOHMRWLFEY-UHFFFAOYSA-N 0.000 description 1
- BPHPUYQFMNQIOC-NXRLNHOXSA-N isopropyl beta-D-thiogalactopyranoside Chemical compound CC(C)S[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O BPHPUYQFMNQIOC-NXRLNHOXSA-N 0.000 description 1
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 1
- 238000005304 joining Methods 0.000 description 1
- 229960000318 kanamycin Drugs 0.000 description 1
- 229930027917 kanamycin Natural products 0.000 description 1
- SBUJHOSQTJFQJX-NOAMYHISSA-N kanamycin Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CN)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](N)[C@H](O)[C@@H](CO)O2)O)[C@H](N)C[C@@H]1N SBUJHOSQTJFQJX-NOAMYHISSA-N 0.000 description 1
- 229930182823 kanamycin A Natural products 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 201000010982 kidney cancer Diseases 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 206010023841 laryngeal neoplasm Diseases 0.000 description 1
- 201000011486 lichen planus Diseases 0.000 description 1
- 229960005287 lincomycin Drugs 0.000 description 1
- OJMMVQQUTAEWLP-KIDUDLJLSA-N lincomycin Chemical compound CN1C[C@H](CCC)C[C@H]1C(=O)N[C@H]([C@@H](C)O)[C@@H]1[C@H](O)[C@H](O)[C@@H](O)[C@@H](SC)O1 OJMMVQQUTAEWLP-KIDUDLJLSA-N 0.000 description 1
- 208000012987 lip and oral cavity carcinoma Diseases 0.000 description 1
- 201000006721 lip cancer Diseases 0.000 description 1
- 229920006008 lipopolysaccharide Polymers 0.000 description 1
- 239000006193 liquid solution Substances 0.000 description 1
- 239000006194 liquid suspension Substances 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 201000007270 liver cancer Diseases 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- 229960005375 lutein Drugs 0.000 description 1
- KBPHJBAIARWVSC-RGZFRNHPSA-N lutein Chemical compound C([C@H](O)CC=1C)C(C)(C)C=1\C=C\C(\C)=C\C=C\C(\C)=C\C=C\C=C(/C)\C=C\C=C(/C)\C=C\[C@H]1C(C)=C[C@H](O)CC1(C)C KBPHJBAIARWVSC-RGZFRNHPSA-N 0.000 description 1
- ORAKUVXRZWMARG-WZLJTJAWSA-N lutein Natural products CC(=C/C=C/C=C(C)/C=C/C=C(C)/C=C/C1=C(C)CCCC1(C)C)C=CC=C(/C)C=CC2C(=CC(O)CC2(C)C)C ORAKUVXRZWMARG-WZLJTJAWSA-N 0.000 description 1
- 235000012680 lutein Nutrition 0.000 description 1
- 239000001656 lutein Substances 0.000 description 1
- 229940040129 luteinizing hormone Drugs 0.000 description 1
- 210000004698 lymphocyte Anatomy 0.000 description 1
- 229920002521 macromolecule Polymers 0.000 description 1
- 210000002540 macrophage Anatomy 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 description 1
- 239000001095 magnesium carbonate Substances 0.000 description 1
- 229910000021 magnesium carbonate Inorganic materials 0.000 description 1
- 201000004792 malaria Diseases 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 230000035800 maturation Effects 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 229960000485 methotrexate Drugs 0.000 description 1
- 238000012737 microarray-based gene expression Methods 0.000 description 1
- 108010067094 microcystin Proteins 0.000 description 1
- 229960005225 mifamurtide Drugs 0.000 description 1
- JMUHBNWAORSSBD-WKYWBUFDSA-N mifamurtide Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@@H](OC(=O)CCCCCCCCCCCCCCC)COP(O)(=O)OCCNC(=O)[C@H](C)NC(=O)CC[C@H](C(N)=O)NC(=O)[C@H](C)NC(=O)[C@@H](C)O[C@H]1[C@H](O)[C@@H](CO)OC(O)[C@@H]1NC(C)=O JMUHBNWAORSSBD-WKYWBUFDSA-N 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- ZAHQPTJLOCWVPG-UHFFFAOYSA-N mitoxantrone dihydrochloride Chemical compound Cl.Cl.O=C1C2=C(O)C=CC(O)=C2C(=O)C2=C1C(NCCNCCO)=CC=C2NCCNCCO ZAHQPTJLOCWVPG-UHFFFAOYSA-N 0.000 description 1
- 238000003032 molecular docking Methods 0.000 description 1
- 210000001616 monocyte Anatomy 0.000 description 1
- 230000023185 monocyte chemotactic protein-1 production Effects 0.000 description 1
- 210000005087 mononuclear cell Anatomy 0.000 description 1
- 229940072709 motrin Drugs 0.000 description 1
- 238000010172 mouse model Methods 0.000 description 1
- 229940051875 mucins Drugs 0.000 description 1
- 201000006417 multiple sclerosis Diseases 0.000 description 1
- 238000012243 multiplex automated genomic engineering Methods 0.000 description 1
- 206010028417 myasthenia gravis Diseases 0.000 description 1
- QMDUPVPMPVZZGK-UHFFFAOYSA-N n,n-dimethyloctadecan-1-amine;hydrobromide Chemical compound [Br-].CCCCCCCCCCCCCCCCCC[NH+](C)C QMDUPVPMPVZZGK-UHFFFAOYSA-N 0.000 description 1
- 229940090008 naprosyn Drugs 0.000 description 1
- CMWTZPSULFXXJA-VIFPVBQESA-N naproxen Chemical compound C1=C([C@H](C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-VIFPVBQESA-N 0.000 description 1
- 230000001338 necrotic effect Effects 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 210000000653 nervous system Anatomy 0.000 description 1
- 229940029345 neupogen Drugs 0.000 description 1
- 230000000926 neurological effect Effects 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 1
- 210000004940 nucleus Anatomy 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 229940126578 oral vaccine Drugs 0.000 description 1
- 210000003463 organelle Anatomy 0.000 description 1
- 230000011164 ossification Effects 0.000 description 1
- 201000008482 osteoarthritis Diseases 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 239000006179 pH buffering agent Substances 0.000 description 1
- 229960001592 paclitaxel Drugs 0.000 description 1
- 210000000496 pancreas Anatomy 0.000 description 1
- 201000002528 pancreatic cancer Diseases 0.000 description 1
- 208000008443 pancreatic carcinoma Diseases 0.000 description 1
- 229960005489 paracetamol Drugs 0.000 description 1
- 244000045947 parasite Species 0.000 description 1
- 230000003071 parasitic effect Effects 0.000 description 1
- 239000000199 parathyroid hormone Substances 0.000 description 1
- 229960001319 parathyroid hormone Drugs 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 1
- 238000010647 peptide synthesis reaction Methods 0.000 description 1
- 230000000737 periodic effect Effects 0.000 description 1
- 210000005259 peripheral blood Anatomy 0.000 description 1
- 239000011886 peripheral blood Substances 0.000 description 1
- 210000003819 peripheral blood mononuclear cell Anatomy 0.000 description 1
- 230000002688 persistence Effects 0.000 description 1
- 150000003904 phospholipids Chemical class 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 108700004029 pol Genes Proteins 0.000 description 1
- 101150088264 pol gene Proteins 0.000 description 1
- 229920001515 polyalkylene glycol Polymers 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229940115272 polyinosinic:polycytidylic acid Drugs 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 229960005205 prednisolone Drugs 0.000 description 1
- OIGNJSKKLXVSLS-VWUMJDOOSA-N prednisolone Chemical compound O=C1C=C[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 OIGNJSKKLXVSLS-VWUMJDOOSA-N 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- 229960004919 procaine Drugs 0.000 description 1
- CPTBDICYNRMXFX-UHFFFAOYSA-N procarbazine Chemical compound CNNCC1=CC=C(C(=O)NC(C)C)C=C1 CPTBDICYNRMXFX-UHFFFAOYSA-N 0.000 description 1
- 229960000624 procarbazine Drugs 0.000 description 1
- 229940097325 prolactin Drugs 0.000 description 1
- 230000002062 proliferating effect Effects 0.000 description 1
- 239000002510 pyrogen Substances 0.000 description 1
- 238000003127 radioimmunoassay Methods 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 230000010837 receptor-mediated endocytosis Effects 0.000 description 1
- 238000010188 recombinant method Methods 0.000 description 1
- 206010038038 rectal cancer Diseases 0.000 description 1
- 201000001275 rectum cancer Diseases 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 108091008146 restriction endonucleases Proteins 0.000 description 1
- 238000010839 reverse transcription Methods 0.000 description 1
- 108091092562 ribozyme Proteins 0.000 description 1
- 229960001225 rifampicin Drugs 0.000 description 1
- 201000005404 rubella Diseases 0.000 description 1
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
- 201000000306 sarcoidosis Diseases 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000013606 secretion vector Substances 0.000 description 1
- 230000036280 sedation Effects 0.000 description 1
- 231100000879 sensorineural hearing loss Toxicity 0.000 description 1
- 208000023573 sensorineural hearing loss disease Diseases 0.000 description 1
- 230000001568 sexual effect Effects 0.000 description 1
- 238000002741 site-directed mutagenesis Methods 0.000 description 1
- 201000000849 skin cancer Diseases 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229940083542 sodium Drugs 0.000 description 1
- 239000008279 sol Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000000527 sonication Methods 0.000 description 1
- 230000001148 spastic effect Effects 0.000 description 1
- 229940031439 squalene Drugs 0.000 description 1
- TUHBEKDERLKLEC-UHFFFAOYSA-N squalene Natural products CC(=CCCC(=CCCC(=CCCC=C(/C)CCC=C(/C)CC=C(C)C)C)C)C TUHBEKDERLKLEC-UHFFFAOYSA-N 0.000 description 1
- 238000011301 standard therapy Methods 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 210000000130 stem cell Anatomy 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 201000011549 stomach cancer Diseases 0.000 description 1
- 229940031000 streptococcus pneumoniae Drugs 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 229940124530 sulfonamide Drugs 0.000 description 1
- 150000003456 sulfonamides Chemical class 0.000 description 1
- 230000001502 supplementing effect Effects 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 201000000596 systemic lupus erythematosus Diseases 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 1
- 201000003120 testicular cancer Diseases 0.000 description 1
- 229960000814 tetanus toxoid Drugs 0.000 description 1
- 229960002180 tetracycline Drugs 0.000 description 1
- 229930101283 tetracycline Natural products 0.000 description 1
- 235000019364 tetracycline Nutrition 0.000 description 1
- 150000003522 tetracyclines Chemical class 0.000 description 1
- 125000003396 thiol group Chemical group [H]S* 0.000 description 1
- 229960002175 thyroglobulin Drugs 0.000 description 1
- 201000002510 thyroid cancer Diseases 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- KBPHJBAIARWVSC-XQIHNALSSA-N trans-lutein Natural products CC(=C/C=C/C=C(C)/C=C/C=C(C)/C=C/C1=C(C)CC(O)CC1(C)C)C=CC=C(/C)C=CC2C(=CC(O)CC2(C)C)C KBPHJBAIARWVSC-XQIHNALSSA-N 0.000 description 1
- 238000001890 transfection Methods 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 238000003146 transient transfection Methods 0.000 description 1
- 238000011269 treatment regimen Methods 0.000 description 1
- XETCRXVKJHBPMK-MJSODCSWSA-N trehalose 6,6'-dimycolate Chemical compound C([C@@H]1[C@H]([C@H](O)[C@@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](COC(=O)C(CCCCCCCCCCC3C(C3)CCCCCCCCCCCCCCCCCC)C(O)CCCCCCCCCCCCCCCCCCCCCCCCC)O2)O)O1)O)OC(=O)C(C(O)CCCCCCCCCCCCCCCCCCCCCCCCC)CCCCCCCCCCC1CC1CCCCCCCCCCCCCCCCCC XETCRXVKJHBPMK-MJSODCSWSA-N 0.000 description 1
- 150000003626 triacylglycerols Chemical class 0.000 description 1
- 241000701161 unidentified adenovirus Species 0.000 description 1
- 241001430294 unidentified retrovirus Species 0.000 description 1
- 201000005112 urinary bladder cancer Diseases 0.000 description 1
- 229960005356 urokinase Drugs 0.000 description 1
- 206010046766 uterine cancer Diseases 0.000 description 1
- 206010046885 vaginal cancer Diseases 0.000 description 1
- 208000013139 vaginal neoplasm Diseases 0.000 description 1
- 235000016788 valerian Nutrition 0.000 description 1
- 229960003165 vancomycin Drugs 0.000 description 1
- MYPYJXKWCTUITO-LYRMYLQWSA-N vancomycin Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=C2C=C3C=C1OC1=CC=C(C=C1Cl)[C@@H](O)[C@H](C(N[C@@H](CC(N)=O)C(=O)N[C@H]3C(=O)N[C@H]1C(=O)N[C@H](C(N[C@@H](C3=CC(O)=CC(O)=C3C=3C(O)=CC=C1C=3)C(O)=O)=O)[C@H](O)C1=CC=C(C(=C1)Cl)O2)=O)NC(=O)[C@@H](CC(C)C)NC)[C@H]1C[C@](C)(N)[C@H](O)[C@H](C)O1 MYPYJXKWCTUITO-LYRMYLQWSA-N 0.000 description 1
- 208000020416 vascular bone neoplasm Diseases 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 229940118696 vibrio cholerae Drugs 0.000 description 1
- 229960003048 vinblastine Drugs 0.000 description 1
- JXLYSJRDGCGARV-XQKSVPLYSA-N vincaleukoblastine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 JXLYSJRDGCGARV-XQKSVPLYSA-N 0.000 description 1
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 description 1
- 229960004528 vincristine Drugs 0.000 description 1
- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
- 239000000304 virulence factor Substances 0.000 description 1
- 230000007923 virulence factor Effects 0.000 description 1
- 229960005080 warfarin Drugs 0.000 description 1
- PJVWKTKQMONHTI-UHFFFAOYSA-N warfarin Chemical compound OC=1C2=CC=CC=C2OC(=O)C=1C(CC(=O)C)C1=CC=CC=C1 PJVWKTKQMONHTI-UHFFFAOYSA-N 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 238000001262 western blot Methods 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- FJHBOVDFOQMZRV-XQIHNALSSA-N xanthophyll Natural products CC(=C/C=C/C=C(C)/C=C/C=C(C)/C=C/C1=C(C)CC(O)CC1(C)C)C=CC=C(/C)C=CC2C=C(C)C(O)CC2(C)C FJHBOVDFOQMZRV-XQIHNALSSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/2851—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the lectin superfamily, e.g. CD23, CD72
-
- 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
- A61K39/02—Bacterial 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
- A61K39/12—Viral 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
- A61K39/12—Viral antigens
- A61K39/145—Orthomyxoviridae, e.g. influenza virus
-
- 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
- A61K39/12—Viral antigens
- A61K39/21—Retroviridae, e.g. equine infectious anemia virus
-
- 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
- A61K39/4615—Dendritic 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
- A61K39/46—Cellular immunotherapy
- A61K39/462—Cellular immunotherapy characterized by the effect or the function of the cells
- A61K39/4622—Antigen presenting 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
- A61K39/46—Cellular immunotherapy
- A61K39/464—Cellular immunotherapy characterised by the antigen targeted or presented
- A61K39/4643—Vertebrate antigens
- A61K39/4644—Cancer antigens
- A61K39/464402—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
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
- A61K47/6891—Pre-targeting systems involving an antibody for targeting specific cells
- A61K47/6897—Pre-targeting systems with two or three steps using antibody conjugates; Ligand-antiligand therapies
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
- A61K47/6901—Conjugates being cells, cell fragments, viruses, ghosts, red blood cells or viral vectors
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/10—Antimycotics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
- A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
-
- 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
-
- 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
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B82—NANOTECHNOLOGY
- B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
- B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
-
- 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
- C12N5/0639—Dendritic cells, e.g. Langherhans cells in the epidermis
-
- 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
- A61K2039/60—Medicinal preparations containing antigens or antibodies characteristics by the carrier linked to the antigen
- A61K2039/6031—Proteins
- A61K2039/6056—Antibodies
-
- 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
- C12N2760/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA ssRNA viruses negative-sense
- C12N2760/00011—Details
- C12N2760/16011—Orthomyxoviridae
- C12N2760/16111—Influenzavirus A, i.e. influenza A virus
- C12N2760/16134—Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein
Description
本發明一般而言係關於疫苗接種領域,且更具體而言係關於基於表現於抗原表現細胞之樹突細胞免疫受體(DCIR)之標的抗原之疫苗。
在不限制本發明範圍之情況下,結合抗原表現闡述本發明之背景。
基於樹突細胞(DC)標的之人類疫苗係依賴於小鼠模型中令人信服之研究的新概念。此處,藉由引導至特定DC受體之抗體攜帶至DC之小劑量相對弱的抗原可激發潛在且廣泛之免疫反應。為研發該等人類疫苗需要更確切瞭解對於此抗原標的應用應使用何種DC受體。此係因為在小鼠與人類免疫系統之間並非總是精確對應,且亦因為對於此疫苗應用並非所有潛在DC受體皆經過仔細檢驗。
因此,已開始體外測試各種抗人DC受體靶之研究,例如在HLA I類及II類分子背景下經由與抵抗甘露糖受體之人mAb融合之黑素瘤抗原pmel17標的之DC可活化T細胞(Ramakrishna,Treml等人,2004)。同樣,經由人類化抗DC-SIGN mAb將模型抗原KLH標的至DC可有效誘導抗原特異性原始及劑量節約型回憶T細胞反應(Tacken,de Vries等人,2005)。除甘露糖受體及DC-SIGN之外,人DC表現抗原捕獲中所涉及之其他已知受體。該等受體中許多係C型凝集素受體(CLR),包括LOX-1、DEC205、DC-
ASGPR、Langerin、DCIR、BDCA-2、DECTIN-1及CLEC-6。該等CLR係藉由DC之不同亞類差異性地表現且其表現可隨DC成熟狀態而變化(Figdor,van Kooyk等人,2002;Geijtenbeek,van Vliet等人,2004)。
DC亞類刺激不同免疫反應,且因此,經由差異性表現的受體將抗原標的至該等亞類可激發不同免疫反應(Shortman及Liu 2002)。此外,在相同DC亞類上之不同受體可將抗原引導至單獨處理路徑(Trombetta及Mellman 2005)。最後,某些該等受體並非內在活化受體(例如DEC205(Bonifaz,Bonnyay等人,2004)),而其他可為活化受體(例如LOX-1(Delneste,Magistrelli等人,2002))或未經充分研究。伴隨抗原吸收之DC活化之重要性仍係未知。但若此係有利地,經由標的mAb活化DC可簡化標的疫苗之調配。
在該等考慮之背景下,本發明者認識到業內迫切需要藉由在體外詳細探索CD4+
及CD8+
T細胞之原始及回憶反應實施系統性比較以限定最適人DC標的受體以達成期望免疫結果。此申請案闡述特定DC受體-樹突細胞免疫受體(DCIR)-之特殊及意外特性,該等特性顯示其為達成將抗原標的至用於預防性及治療性疫苗接種之人DC之目的之理想受體。
本發明包括製備及使用疫苗之組合物及方法,該疫苗將抗原特異性標的(遞送)至抗原表現細胞以達成激發潛在且
廣泛的經引導針對該抗原之免疫反應之目的。該目的主要係引起針對自其獲得抗原之作用物(病原體或癌症)之保護性或治療性免疫反應。
更具體而言,本發明包括設計及製備靶特異性單一重組抗體(mAb)、活化蛋白、或其他抗體之組合物、方法及方法,該單一重組抗體以受控模組化結構攜帶一或多種抗原。可使用本發明之模組化rAb載體(例如)將多種抗原及/或抗原及活化細胞介素標的(經由一針對內在化人樹突細胞受體之初級重組抗體)至樹突細胞(DC)。同樣,本發明亦提供以受控及經限定方式端對端連接兩種不同重組mAb之方法。
本發明包括藉由DCIR表現抗原表現細胞提高抗原表現效力之組合物及方法,其係藉由分離及純化與經標的作用物連接形成抗體-抗原複合物之DCIR特異性抗體或其片段來達成,其中該作用物係藉由(例如)已與抗體-作用物複合物接觸之樹突細胞處理並遞呈。在一實施例中,抗原表現細胞係樹突細胞且DCIR特異性抗體或其片段係與黏連蛋白/停靠蛋白對之一半結合。DCIR特異性抗體或其片段亦可與黏連蛋白/停靠蛋白對之一半結合且抗原係與該黏連蛋白/停靠蛋白對之一半的補體結合以形成複合物。作用物之非限制性實例包括一或多種肽、蛋白質、脂類、碳水化合物、核酸及其組合。
作用物可為一或多種細胞介素,其係選自白介素、轉化生長因子(TGF)、成纖維細胞生長因子(FGF)、血小板衍生
生長因子(PDGF)、表皮生長因子(EGF)、結締組織活化肽(CTAP)、成骨因子、及該等生長因子之生物活性類似物、片段及衍生物、B/T細胞分化因子、B/T細胞生長因子、促有絲分裂細胞介素、趨化細胞介素、集落刺激因子、血管生成因子、IFN-α、IFN-β、IFN-γ、IL1、IL2、IL3、IL4、IL5、IL6、IL7、IL8、IL9、IL10、IL11、IL12、IL13、IL14、IL15、IL16、IL17、IL18等、來普汀(leptin)、筒箭毒鹼、巨噬細胞刺激蛋白、血小板衍生生長因子、TNF-α、TNF-β、NGF、CD40L、CD137L/4-1BBL、人淋巴毒素-β、G-CSF、M-CSF、GM-CSF、PDGF、IL-1α、IL1-β、IP-10、PF4、GRO、9E3、紅細胞生成素、血管內皮抑素、血管抑素、VEGF、轉化生長因子(TGF)超基因家族,其包括β轉化生長因子(例如TGF-β1、TGF-β2、TGF-β3);骨形態發生蛋白(例如BMP-1、BMP-2、BMP-3、BMP-4、BMP-5、BMP-6、BMP-7、BMP-8、BMP-9);肝素結合生長因子(成纖維細胞生長因子(FGF)、表皮生長因子(EGF)、血小板衍生生長因子(PDGF)、胰島素樣生長因子(IGF));抑制素(例如抑制素A、抑制素B);生長分化因子(例如GDF-1);及活化素(例如活化素A、活化素B、活化素AB)。在另一實施例中,作用物包含抗原,該抗原係細菌、病毒、真菌、原生動物或癌症蛋白。
本發明亦包括藉由樹突細胞提高抗原表現效力之組合物及方法,其包括結合與抗原連接形成抗體-抗原複合物之DCIR特異性抗體或其片段,其中該抗原係藉由已與抗體-
抗原複合物接觸之樹突細胞處理並遞呈。另一實施例係經引導至DCIR之抗體或其他特異性結合分子之使用,其將抗原遞送至抗原表現細胞以達成激發保護性或治療性免疫反應之目的。對DCIR具有特異性之抗原標的試劑可用於經由皮膚實施疫苗接種;對DCIR具有特異性之抗原標的試劑可與佐劑共同投與或連接以供用於疫苗接種,或可表現為重組抗原-抗體融合蛋白之特異性抗原可用於抗原標的(疫苗接種)目的。
另一實施例包括提高樹突細胞效力之方法,其係藉由以下步驟來達成:分離患者的樹突細胞;使樹突細胞曝露於活化量之抗DCIR抗體或其片段及抗原中以形成載入抗原之經活化樹突細胞;且將該載入抗原之經活化樹突細胞再引入患者中。抗原可為細菌、病毒、真菌、原生動物或癌症蛋白。本發明亦包括自哺乳動物細胞分泌之抗DCIR免疫球蛋白或其部分及與該免疫球蛋白結合之抗原。免疫球蛋白係與黏連蛋白(cohesin)/停靠蛋白(dockerin)結構域之一半結合,或其亦可包括與抗原(其與模組化rAb載體形成複合物)結合之黏連蛋白-停靠蛋白結合對之一半的補體、或抗原融合蛋白黏連蛋白-停靠蛋白結合對之一半的補體。抗原特異性結構域可為全長抗體、抗體可變區結構域、Fab片段、Fab'片段、F(ab)2片段、及Fv片段、及Fabc片段及/或具有Fc結構域部分之Fab片段。抗DCIR免疫球蛋白亦可與毒素結合,其中該毒素係選自由下述組成之群:放射性同位素、金屬、酶、肉毒桿菌毒素、破傷風毒素、
蓖麻毒素、霍亂毒素、白喉毒素、黃麴黴毒素、產氣莢膜桿菌毒素、黴菌毒素、志賀毒素(shigatoxin)、葡萄球菌腸毒素B、T2、segui毒素(seguitoxin)、石房蛤毒素、相思豆毒素、微囊藻毒素、α毒素、河豚毒素、織錦芋螺毒素(aconotoxin)、蛇毒及蜘蛛毒。抗原可為與或不與免疫球蛋白化學共價結合之融合蛋白。
另一實施例係具有與抗原連接形成抗體-抗原複合物之DCIR特異性抗體或其片段之疫苗,其中該抗原係藉由已與抗體-抗原複合物接觸之樹突細胞處理並遞呈。
儘管在下文中詳細論述本發明各實施例之製備及使用,亦應瞭解本發明提供許多可在多種具體背景下體現之可用發明概念。本文所論述之具體實施例僅闡釋製備及使用本發明之具體方式而非限制本發明之範圍。
為促進對本發明之理解,下文中定義多個術語。本文所定義術語具有本發明相關方面具有通常知識者所瞭解之通常意義。諸如"一"及"該"等詞語並非意欲僅指單一實體,而是包括可使用一具體實例進行闡釋之一般類別。本文中術語係用於闡述本發明之具體實施例,但除非在申請專利範圍中指明,否則其使用不限制本發明。
樹突細胞(DC)係抗原表現細胞,其在調節抗原特異性免疫中具有重要作用(Mellman及Steinman 2001)、(Banchereau,Briere等人,2000)、(Cella,Sallusto等人,1997)。DC捕獲抗原,將其處理為肽且將該等肽遞呈至T
細胞。因此將抗原直接遞送至DC係改良疫苗之關鍵。一如此之實例係使用自體DC之離體抗原載入研發以DC為基礎之疫苗,然後將其再投與患者(Banchereau,Schuler-Thurner等人,2001)、(Steinman及Dhodapkar 2001)。改良疫苗效率之另一策略係將與針對內在化DC特異性受體之抗體結合之抗原特異性標的至DC。藉由關鍵小鼠研究突出顯示用於疫苗接種之標的DC之潛力。在體內,經由向MHC I類路徑交叉遞呈外源抗原,用與卵白蛋白(OVA)偶聯之抗LOX-1 mAb實施標的可誘導保護性CD8+T細胞反應(Delneste,Magistrelli等人,2002)。此外,與抗DEC205 mAb結合之OVA與CD40L成熟刺激物可在體內增強受MHC I類限制之DC之遞呈且導致效應子記憶性CD8+T細胞之持久形成(Bonifaz,Bonnyay等人,2004)。兩種該等研究皆顯示顯著劑量節約(即在極低抗原劑量下之強大免疫反應)且顯示較通常使用其他類型之OVA免疫所觀察者更廣泛之反應。近期關於經由DEC205將HIV gag抗原標的至DC之研究將該等概念擴展至臨床相關抗原且證實將抗原標的至DC之法則-顯著劑量節約、來自單一疫苗接種之保護性反應、及在CD8及CD4二區室中抗原特異性T細胞之擴增(Trumpfheller,Finke等人,2006)。
本發明提供多種抗原或蛋白質(自初級mAb獨立地構建、表現及純化)以受控多變量方式與一單一初級重組mAb之複合。目前,存在構建位點特異性生物素化位點之方法,其向一初級mAb提供不同蛋白質之添加(各自經構
建分別與抗生蛋白鏈菌素連接)。然而,本發明以固定莫耳比及位置向初級mAb提供分別經構建蛋白質之多種組合之添加。
本文所用術語"模組化rAb載體"係用於闡述重組抗體系統,其經構建以向單一重組單株抗體(mAb)提供各種抗原、活化蛋白或其他抗體之受控模組化添加。rAb可為使用標準雜交瘤技術、重組抗體呈現、人類化單株抗體及諸如此類製備之單株抗體。模組化rAb載體可用於(例如)將多種抗原及/或抗原及活化細胞介素標的(經由一針對內在化受體(例如人類樹突細胞受體)之初級重組抗體)至樹突細胞(DC)。模組化rAb載體亦可用於以受控且經限定方式端對端連接兩種不同重組mAb。
"模組化rAb載體"之抗原結合部分可為一或多個可變結構域、一或多個可變及第一恆定結構域、Fab片段、Fab'片段、F(ab)2
片段、及Fv片段、及Fabc片段及/或具有Fc結構域部分之Fab片段,其中將同源模組化結合部分添加至其胺基酸序列及/或與其胺基酸序列結合。用於模組化rAb載體之抗體可具有任一同種型或類別、亞類或來自任一來源(動物及/或重組體)。
在一非限定性實例中,模組化rAb載體經構建具有一或多種模組化黏連蛋白-停靠蛋白蛋白結構域以便在經構建重組mAb背景下製備特異性及經限定蛋白複合物。mAb係包括一或多種來自mAb之抗原結合結構域之模組化黏連蛋白-停靠蛋白蛋白結構域羧基之融合蛋白之部分。甚至可
在轉移後(例如)藉由使用化學交聯劑及/或二硫鍵結來連接黏連蛋白-停靠蛋白蛋白結構域。
本文所用術語"抗原"係指可在抗原接受者中起始體液及/或細胞免疫反應之分子。抗原可用於關於本發明之兩種不同背景下:作為抗體或rAb之其他抗原識別結構域之靶或作為藉由作為與模組化rAb載體互補之停靠蛋白/黏連蛋白分子之部分的rAb攜載至及/或攜載入細胞或靶之分子。抗原通常係導致疫苗接種可有效治療之疾病之作用物。當將抗原存在於MHC上時,該肽經常具有約8至約25個胺基酸。抗原包括任一類型之生物分子,包括(例如)簡單中間代謝產物、糖、脂及激素,以及諸如複合碳水化合物、磷脂、核酸及蛋白質等大分子。抗原之一般種類包括(但不限於)病毒抗原、細菌抗原、真菌抗原、原生動物及其他寄生蟲抗原、腫瘤抗原、自身免疫性疾病、過敏症及移植排斥中所涉及抗原及其他各種抗原。
模組化rAb載體能攜載任一數量之活性試劑,例如抗生素、抗感染劑、抗病毒劑、抗腫瘤劑、退熱劑、鎮痛劑、消炎劑、骨質疏鬆症之治療藥劑、酶、細胞介素、抗凝血劑、多糖、膠原、細胞、及兩種或更多種上述活性藥劑之組合。使用本發明遞送之抗生素之實例包括(但不限於)四環素(tetracycline)、胺基葡糖苷、青黴素(penicillin)、頭孢菌素(cephalosporin)、磺胺類藥物、丁二酸鈉氯黴素、紅黴素(erythromycin)、萬古黴素(vancomycin)、林可黴素(lincomycin)、氯林肯黴素(clindamycin)、製黴菌素
(nystatin)、兩性黴素B(amphotericin B)、金剛胺(amantidine)、碘苷(idoxuridine)、對胺基水楊酸、異煙肼、利福平(rifampin)、抗黴素D(antinomycin D)、普卡黴素(mithramycin)、道諾黴素(daunomycin)、多柔比星(adriamycin)、博萊黴素(bleomycin)、長春鹼、長春新鹼、丙卡巴肼、達卡巴嗪及類似物。
使用本發明遞送之抗腫瘤劑之實例包括(但不限於)多柔比星、柔紅黴素(Daunorubicin)、紫杉酚、胺甲蝶呤及類似物。退熱劑及鎮痛劑之實例包括阿司匹林(aspirin)、芬必得(Motrin)、布洛芬(Ibuprofen)、萘普生(naprosyn)、撲熱息痛(acetaminophen)及類似物。
使用本發明遞送之消炎劑之實例包括(但不限於)NSAIDS、阿司匹林、類固醇、地塞米松(dexamethasone)、氫化可的松(hydrocortisone)、潑尼松龍(prednisolone)、雙氯芬酸Na(Diclofenac Na)及類似物。
使用本發明遞送之治療骨質疏鬆症及作用於骨及骨骼之其他因素之治療藥劑之實例包括(但不限於)鈣、阿倫膦酸鹽(alendronate)、骨GLa肽、甲狀旁腺激素及其活性片段、組蛋白H4-相關骨形成及增殖肽及其突變體、衍生物及類似物。
使用本發明遞送之酶及酶輔因子之實例包括(但不限於)腸溶胰酶膠囊、L-天冬醯胺酶、玻璃酸酶、糜蛋白酶、胰蛋白酶、tPA、鏈激酶、尿激酶、胰酶、膠原酶、胰蛋白酶原、糜蛋白酶原、血纖維蛋白溶酶原、鏈激酶、腺苷酸
環化酶、超氧化物歧化酶(SOD)及類似物。
使用本發明遞送之細胞介素之實例包括(但不限於)白介素、轉化生長因子(TGF)、成纖維細胞生長因子(FGF)、血小板衍生生長因子(PDGF)、表皮生長因子(EGF)、結締組織活化肽(CTAP)、成骨因子、及該等生長因子之生物活性類似物、片段及衍生物。細胞介素可為B/T細胞分化因子、B/T-細胞生長因子、促有絲分裂細胞介素、趨化細胞介素、集落刺激因子、血管生成因子、IFN-α、IFN-β、IFN-γ、IL1、IL2、IL3、IL4、IL5、IL6、IL7、IL8、IL9、IL10、IL11、IL12、IL13、IL14、IL15、IL16、IL17、IL18等、來普汀、筒箭毒鹼、巨噬細胞刺激蛋白、血小板衍生生長因子、TNF-α、TNF-β、NGF、CD40L、CD137L/4-1BBL、人淋巴毒素-β、G-CSF、M-CSF、GM-CSF、PDGF、IL-1α、IL1-β、IP-10、PF4、GRO、9E3、紅細胞生成素、血管內皮抑素、血管抑素、VEGF或其任一片段或組合。其他細胞介素包括轉化生長因子(TGF)超基因家族之成員,包括β轉化生長因子(例如TGF-β1、TGF-β2、TGF-β3);骨形態發生蛋白(例如BMP-1、BMP-2、BMP-3、BMP-4、BMP-5、BMP-6、BMP-7、BMP-8、BMP-9);肝素結合生長因子(例如成纖維細胞生長因子(FGF)、表皮生長因子(EGF)、血小板衍生生長因子(PDGF)、胰島素樣生長因子(IGF));抑制素(例如抑制素A、抑制素B);生長分化因子(例如GDF-1);及活化素(例如活化素A、活化素B、活化素AB)。
使用本發明遞送之生長因子之實例包括(但不限於)可自天然或自然來源分離之生長因子,例如來自哺乳動物細胞,或可以合成方式製備,例如藉由重組DNA技術或藉由各種化學方法製備。此外,可使用該等因子之類似物、片段或衍生物,前提條件係其表現至少某些天然分子之生物活性。舉例而言,可藉由使用位點特異性誘變或其他基因工程技術改變之基因之表現來製備類似物。
使用本發明遞送之抗凝血劑之實例包括(但不限於)華法林(warfarin)、肝素、水蛭素及類似物。使用本發明遞送之作用於免疫系統之因子之實例包括(但不限於)控制炎症及惡性贅生物之因子及攻擊感染性微生物之因子,例如趨化肽及緩激肽。
病毒抗原之實例包括(但不限於)(例如)逆轉錄病毒抗原,例如來自人免疫缺陷病毒(HIV)抗原之逆轉錄病毒抗原,例如gag、pol及env基因之基因產物、Nef蛋白、逆轉錄酶及其他HIV組份;肝炎病毒抗原,例如肝炎B病毒之S、M及L蛋白、肝炎B病毒之前S抗原、及其他肝炎(例如肝炎A、B及C)病毒組份,例如肝炎C病毒RNA;流感病毒抗原,例如血凝素及神經胺酸酶及其他流感病毒組份;麻疹病毒抗原,例如麻疹病毒融合蛋白及其他麻疹病毒組份;風疹病毒抗原,例如蛋白E1及E2及其他風疹病毒組份;輪狀病毒抗原,例如VP7sc及其他輪狀病毒組份;巨細胞病毒抗原,例如包膜糖蛋白B及其他巨細胞病毒抗原組份;呼吸道合胞病毒抗原,例如RSV融合蛋白、M2蛋白
及其他呼吸道合胞病毒抗原組份;單純皰疹病毒抗原,例如即刻早期蛋白、糖蛋白D及其他單純皰疹病毒抗原組份;水痘帶狀皰疹病毒抗原,例如gpI、gpII及其他水痘帶狀皰疹病毒抗原組份;日本腦炎病毒抗原,例如蛋白E、M-E、M-E-NS1、NS1、NS1-NS2A、80% E及其他日本腦炎病毒抗原組份;狂犬病病毒抗原,例如狂犬病糖蛋白、狂犬病核蛋白及其他狂犬病病毒抗原組份。病毒抗原之其他實例參見Fundamental Virology,第二版,eds.Fields,B.N.及Knipe,D.M.(Raven Press,New York,1991)。
可使用本發明之rAb-DC/DC-抗原疫苗遞送之抗原靶包括編碼諸如病毒抗原、細菌抗原、真菌抗原或寄生蟲抗原等抗原之基因。病毒包括微小核糖核酸病毒(picornavirus)、冠狀病毒(coronavirus)、披膜病毒(togavirus)、黃熱病毒(flavirvirus)、杆狀病毒(rhabdovirus)、副黏液病毒(paramyxovirus)、正黏液病毒(orthomyxovirus)、布尼亞病毒(bunyavirus)、沙粒病毒(arenavirus)、呼腸孤病毒(reovirus)、逆轉錄病毒、乳頭瘤病毒(papilomavirus)、細小病毒(parvovirus)、皰疹病毒(herpesvirus)、痘病毒(poxvirus)、肝脫氧核糖核酸病毒(hepadnavirus)及海綿狀病毒(spongiform virus)。其他病毒靶包括流感、單純皰疹病毒1及2、麻疹、登革熱(dengue)、天花、脊髓灰質炎或HIV。病原體包括錐蟲、絛蟲、蛔蟲、蠕蟲、瘧疾。可以此方式標的腫瘤標記物,例如胎兒抗原或前列腺特異性抗原。其他實例包括:HIV env蛋白及肝炎B表面抗原。出於
疫苗接種目的投與本發明載體需要載體相關抗原具有足夠非免疫原性以使得期望其具有強免疫反應之轉基因能得到長期表現。在某些情況下,個體可能僅需要低頻率疫苗接種,例如可每年或每兩年接種一次,且疫苗接種可針對致病因子提供長期免疫保護。根據本發明用於載體且最終用作抗原之生物、過敏原及核酸及胺基酸序列之具體實例可參見美國專利第6,541,011號,其相關部分(尤其匹配可用於本發明之生物及具體序列之表格)係以引用方式併入本文中。
與本文所揭示rAb疫苗一起使用之細菌抗原包括(但不限於)(例如)細菌抗原,例如百日咳毒素、絲狀血凝素、百日咳桿菌黏附素、FIM2、FIM3、腺苷酸環化酶及其他百日咳細菌抗原組份;白喉細菌抗原,例如白喉毒素或類毒素及其他白喉細菌抗原組份;破傷風細菌抗原,例如破傷風毒素或類毒素或其他破傷風細菌抗原組份;鏈球菌細菌抗原,例如M蛋白及其他鏈球菌細菌抗原組份;革蘭氏(gram)陰性桿菌細菌抗原,例如脂多糖及其他革蘭氏陰性細菌抗原組份、結核分支桿菌(Mycobacterium tuberculosis)細菌抗原,例如分支菌酸、熱激蛋白65(HSP65)、30 kDa主要分泌蛋白、抗原85A及其他分支桿菌抗原組份;幽門螺旋桿菌(Helicobacter pylori)細菌抗原組份;肺炎球菌細菌抗原,例如肺炎球菌溶血素、肺炎球菌莢膜多糖及其他肺炎球菌細菌抗原組份;流感嗜血桿菌細菌抗原,例如莢膜多糖及其他流感嗜血桿菌細菌抗原組份;炭疽細菌抗
原,例如炭疽保護性抗原及其他炭疽細菌抗原組份;立克次氏體(rickettsiae)細菌抗原,例如rompA及其他立克次氏體細菌抗原組份。本文所述細菌抗原亦包括任一其他細菌、分支桿菌、支原體、立克次氏體或衣原體抗原。部分或全部病原體亦可為:流感嗜血桿菌;惡性瘧原蟲(Plasmodium falciparum);腦膜炎雙球菌(neisseria meningitidis);肺炎鏈球菌(streptococcus pneumoniae);奈瑟氏淋病雙球菌(neisseria gonorrhoeae);血清型傷寒沙門氏菌(salmonella serotype typhi);志賀氏菌(shigella);霍亂弧菌(vibrio cholerae);登革熱(Dengue Fever);腦炎(Encephalitides);日本腦炎;萊姆病(lyme disease);鼠疫耶爾森氏菌(Yersinia pestis);西尼羅河病毒(west nile virus);黃熱病(yellow fever);土拉菌病(tularemia);肝炎(病毒;細菌);RSV(呼吸道合胞病毒);HPIV 1及HPIV 3;腺病毒;天花;過敏及癌症。
與本發明組合物及方法一起使用之真菌抗原包括(但不限於)(例如)念珠菌屬真菌抗原組份;組織漿菌真菌抗原,例如熱激蛋白60(HSP60)及其他組織漿菌真菌抗原組份;隱球菌真菌抗原,例如莢膜多糖及其他隱球菌真菌抗原組份;粗球孢子菌真菌抗原,例如小球體抗原及其他粗球孢子菌真菌抗原組份;及癬真菌抗原,例如發癬菌素及其他粗球孢子菌真菌抗原組份。
原生動物及其他寄生蟲抗原之實例包括(但不限於)(例如)惡性瘧原蟲抗原,例如裂殖子表面抗原、子孢子表面
抗原、環子孢子抗原、配子母細胞/配子表面抗原、紅內期抗原pf 155/RESA及其他瘧原蟲抗原組份;弓形體屬抗原,例如SAG-1、p30及其他弓形體抗原組份;血吸蟲抗原,例如谷胱甘肽-S-轉移酶、副肌球蛋白及其他血吸蟲抗原組份;利什曼原蟲(leishmania)主要及其他利什曼原蟲抗原,例如gp63、脂磷聚糖及其相關蛋白及其他利什曼原蟲抗原組份;及克氏錐蟲(trypanosoma cruzi)抗原,例如75-77 kDa抗原、56 kDa抗原及其他錐蟲抗原組份。
一般可根據多種因素選擇可使用本發明rAb標的之抗原,包括:內在化可能性、免疫細胞特異性程度、經標的免疫細胞類型、免疫細胞成熟度及/或活化程度及諸如此類。樹突細胞之細胞表面標記物之實例包括(但不限於)MHC I類、MHC II類、B7-2、CD18、CD29、CD31、CD43、CD44、CD45、CD54、CD58、CD83、CD86、CMRF-44、CMRF-56、DCIR及/或ASPGR及類似物;但在某些情況下亦具有CD2、CD3、CD4、CD8、CD14、CD15、CD16、CD19、CD20、CD56及/或CD57之缺失。抗原表現細胞之細胞表面標記物之實例包括(但不限於)MHC I類、MHC II類、CD40、CD45、B7-1、B7-2、IFN-γ受體及IL-2受體、ICAM-1及/或Fcγ受體。針對T細胞之細胞表面標記物之實例包括(但不限於)CD3、CD4、CD8、CD14、CD20、CD11b、CD16、CD45及HLA-DR。
用於遞送之細胞表面上之靶抗原包括腫瘤抗原之彼等特性,其通常可衍生自腫瘤組織細胞之細胞表面、細胞質、
細胞核、細胞器及類似物。本發明抗體部分之腫瘤靶之實例包括(但不限於)血液癌症(例如白血病及淋巴瘤)、神經腫瘤(例如星形細胞瘤或膠質細胞瘤)、黑素瘤、乳腺癌、肺癌、頭頸癌、胃腸腫瘤(例如胃癌或結腸癌)、肝癌、胰腺癌、生殖泌尿腫瘤(例如子宮頸癌、子宮癌、卵巢癌、陰道癌、睪丸癌、前列腺癌或陰莖癌)、骨腫瘤、血管腫瘤、或唇癌、鼻咽癌、咽及口腔癌、食道癌、直腸癌、膽囊癌、膽道系統癌、喉癌、肺及支氣管癌、膀胱癌、腎癌、大腦及神經系統其他部分之癌、甲狀腺癌、何傑金氏病(Hodgkin's disease)、非何傑金氏淋巴瘤、多發性骨髓瘤及白血病。
可使用本發明單獨或組合遞送至用於抗原表現之免疫細胞之抗原實例包括腫瘤蛋白,例如突變致癌基因;與腫瘤相關之病毒蛋白;及腫瘤黏蛋白及糖脂。抗原可為與腫瘤相關之病毒蛋白,其可為來自上述病毒類別之彼等。某些抗原可具有腫瘤特性(一亞類係通常並非由腫瘤前體細胞表現之蛋白質),或可為通常在腫瘤前體細胞中表現之蛋白質,但其具有腫瘤之突變體特性。其他抗原包括具有經改變活性或亞細胞分佈之正常蛋白質之突變變體,例如產生腫瘤抗原之基因突變體。
腫瘤抗原之具體非限制性實例包括:CEA、前列腺特異性抗原(PSA)、HER-2/neu、BAGE、GAGE、MAGE 1-4、6及12、MUC(黏蛋白)(例如MUC-1、MUC-2等)、GM2及GD2神經節苷脂、ras、myc、酪胺酸酶、MART(黑素瘤抗
原)、Pmel 17(gp100)、GnT-V內含子V序列(N-乙醯胺基葡萄糖轉移酶V內含子V序列)、前列腺Ca psm、PRAME(黑素瘤抗原)、β-連環蛋白、MUM-1-B(黑素瘤擴散變異基因產物)、GAGE(黑素瘤抗原)1、BAGE(黑素瘤抗原)2-10、c-ERB2(Her2/neu)、EBNA(Epstein-Barr病毒核抗原)1-6、gp75、人乳頭狀瘤病毒(HPV)E6及E7、p53、肺耐藥蛋白(LRP)、Bcl-2及Ki-67。此外,免疫原性分子可為自身免疫性疾病之起始及/或傳播中所涉及之自身抗原,其病理主要歸因於對由相關靶器官、組織或細胞(例如SLE或MG)表現之分子具有特異性之抗體活性。在該等疾病中,可期望將前進抗體介導之(即Th2型)免疫反應引導至針對細胞型(即Th1型)免疫反應之相關自身抗原。或者,在未患有(但懷疑其易患)相關自身免疫性疾病之受試者中可期望藉由預防性誘導針對適宜自身抗原之Th1反應來防止針對自身抗原之Th2反應水平的升高或降低該水平。目標自身抗原包括(但不限於):(a)對於SLE而言為Smith蛋白、RNP核糖核蛋白及SS-A及SS-B蛋白;及(b)對於MG而言為乙醯膽鹼受體。在一或多種類型自身免疫反應中所涉及之其他各種抗原之實例包括(例如)內源性激素,例如黃體生成激素、卵泡刺激激素、睪酮、生長激素、催乳素及其他激素。
在自身免疫性疾病、過敏症及移植排斥中所涉及之抗原可用於本發明組合物及方法中。舉例而言,在任何一或多種以下自身免疫性疾病或病症中所涉及之抗原可用於本發明中:糖尿病(diabetes,diabetes mellitus)、關節炎(包括
類風濕性關節炎、青少年型類風濕性關節炎、骨關節炎、銀屑病關節炎)、多發性硬化症、重症肌無力、全身性紅斑狼瘡、自身免疫性甲狀腺炎、皮炎(包括特應性皮炎及濕疹性皮炎)、銀屑病、薛格連氏症候群(Sjogren's Syndrome)(包括繼發於薛格連氏症候群之幹性角膜結膜炎)、斑禿、節肢動物叮咬反應誘發之過敏性鼻炎、克隆氏病(Crohn's disease)、口瘡性潰瘍、虹膜炎、結膜炎、角膜結膜炎、潰瘍性結腸炎、哮喘、過敏性哮喘、皮膚紅斑狼瘡、硬皮病、陰道炎、直腸炎、藥物性皮炎、麻風病逆轉反應、麻風結節性紅斑、自身免疫性眼葡萄膜炎、變應性腦脊髓炎、急性壞死出血性腦病、特發性兩側進行性感覺神經性聽力喪失、再生障礙性貧血、單純紅細胞再生障礙、特發性血小板減少症、多軟骨炎、韋格納氏肉芽腫病(Wegener's granulomatosis)、慢性活動性肝炎、史蒂文斯-約翰遜症候群(Stevens-Johnson syndrome)、特發性啖性腹瀉、扁平苔蘚、葛瑞夫茲式眼病(Graves ophthalmopathy)、結節病、原發性膽汁性肝硬變、後段葡萄膜炎及間質性肺纖維化。在自身免疫性疾病中所涉及之抗原之實例包括麩胺酸脫羧酶65(GAD 65)、天然DNA、髓磷脂鹼蛋白、髓磷脂蛋白脂質蛋白質、乙醯膽鹼受體組份、甲狀腺球蛋白及促甲狀腺激素(TSH)受體。過敏症中所涉及抗原之實例包括花粉抗原(例如日本雪松花粉抗原、豕草花粉抗原、黑麥草花粉抗原)、動物源抗原(例如粉塵蟎抗原及貓抗原)、組織相容性抗原、及青黴素及其他治療藥物。移植
排斥中所涉及抗原之實例包括將移植至移植接受者中之移植物之抗原性組份,例如心臟、肺、肝、胰臟、腎臟及神經移植組份。抗原可為可用於治療自身免疫性疾病之經改變肽配體。
本文所用術語"抗原決定部位"係指肽或蛋白質抗原,其包括與位於由病原體DNA或RNA編碼的多種病原體多肽中之任一種內之抗原決定部位類似之一級、二級或三級結構。一般而言相似度可達到使經引導針對該等多肽之單株或多株抗體亦可與該肽或蛋白質抗原結合、反應或識別該抗原之程度。可結合該等抗體使用各種免疫分析方法,例如西方點漬分析(Western blotting)、ELISA、RIA及諸如此類,所有該等方法皆為熟習此項技術者已知。對適用於疫苗中之病原體抗原決定部位及/或其功能性等效物之鑑別涵蓋於本發明中。分離且鑑別後可容易地獲得功能性等效物。舉例而言,可使用Hopp方法,如美國專利第4,554,101號(其係以引用方式併入本文中)所教示,其教示基於親水性自胺基酸序列鑑別及製備抗原決定部位。亦可使用若干其他論文中所述之方法及基於其之軟體程序來鑑別抗原決定部位核心序列(參見例如Jameson及Wolf,1988;Wolf等人,1988;美國專利第4,554,101號)。然後經由使用肽合成或重組技術可容易地將該等"抗原決定部位核心序列"之胺基酸序列納入肽中。
可將包括編碼本發明抗原作為活性成份之核酸之疫苗組合物製劑製備為可注射(例如液體)溶液或懸浮液;亦可在
感染前製備適用於液體溶液或液體懸浮液之固體形式。可將製劑乳化、囊封於脂質體中。通常使活性免疫原性成份與醫藥上可接受且與活性成份相容之載劑混合。
術語"醫藥上可接受之載劑"係指在其所投與之受試者中不引起過敏性反應或其他不適效應之載劑。適宜醫藥上可接受之載劑包括(例如)水、鹽水、磷酸鹽緩衝鹽水、右旋糖、甘油、乙醇或諸如此類中之一或多種及其組合。此外,若需要,疫苗可包含少量輔助劑物質,例如潤濕劑或乳化劑、pH緩衝劑及/或增強疫苗效力之佐劑。可能有效之佐劑之實例包括(但不限於):氫氧化鋁、N-乙醯基-胞壁醯基-L-蘇胺醯基-D-異麩醯胺(thr-MDP)、N-乙醯基-正-胞壁醯基-L-內胺醯基-D-異麩醯胺、MTP-PE及RIBI,其在2%角鯊烯/Tween 80乳劑中包含三種自細菌提取之組份,單磷醯脂A、海藻糖二黴菌酸酯及細胞壁骨架(MPL+TDM+CWS)。佐劑之其他實例包括DDA(二甲基二十八烷基溴化銨)、弗羅因德氏(Freund's)完全及不完全佐劑及QuilA。此外,可與本文所述佐劑組合使用免疫調節物質,例如淋巴因子(例如IFN-γ、IL-2及IL-12)或諸如聚I:C等合成IFN-γ誘導物。
醫藥產品可包括具有單一或多個拷貝之特異性核苷酸序列之裸多核苷酸,該等特異性核苷酸序列與存於本發明所述原生質脂蛋白上之載脂蛋白的特異性DNA結合位點結合。多核苷酸可編碼生物活性肽、反義RNA、或核酶且可以生理上可接受之可投與形式來提供。可自本發明獲得之
另一醫藥產品可包括根據本文所述方法自患者血液或其他來源分離之高度純化的原生質脂蛋白部分,及包含單或多拷貝特異性核苷酸序列之多核苷酸,其以生理上可接受之可投與形式與經純化脂蛋白部分預結合,且該等特異性核苷酸與存在於原生質脂蛋白上之載脂蛋白特異性DNA結合位點結合。
另一醫藥產品可包括高度純化之原生質脂蛋白部分,其包含含有單或多拷貝特異性DNA結合基序之重組載脂蛋白片段,其以生理上可接受之可投與形式與包含單或多拷貝特異性核苷酸序列之多核苷酸預結合。另一醫藥產品可包括高度純化之原生質脂蛋白部分,其包含含有單或多拷貝特異性DNA結合基序之重組載脂蛋白片段,其以生理上可接受之可投與形式與包含單或多拷貝特異性核苷酸序列之多核苷酸預結合。
待投與劑量在很大程度上取決於所治療受試者之體重及身體狀況以及投與途徑及治療頻率。可以1 μg至1 mg多核苷酸及1 μg至100 mg蛋白質之量投與醫藥組合物,其包括與高度純化之脂蛋白部分預結合之裸多核苷酸。
可遵循投與化學療法之一般方案向患者投與rAb及rAb複合物,其考慮載體之毒性(若存在)。預計可根據需要重複治療週期。亦預期可與所述基因療法組合使用各種標準療法以及外科手術。
倘若涵蓋基因療法之臨床應用,則必須將複合物製備為適用於既定應用之醫藥組合物。一般而言此可使得必須製
備實質上不含致熱原及對人類或動物可能有害之任何其他雜質之醫藥組合物。一般而言人們亦期望採用適宜鹽及緩衝液以使複合物穩定且容許靶細胞吸收複合物。
本發明之水性組合物可包括有效量之化合物,其溶解或分散於醫藥上可接受之載劑或水性介質中。該等組合物亦可稱為接種物。該等醫藥活性物質之介質及試劑之使用係為業內所熟知。除任何與活性成份不相容之習用介質或試劑之外,本發明涵蓋其於治療組合物中之使用。亦可將補加之活性成份納入組合物中。本發明組合物可包括傳統醫藥製劑。亦可於甘油、液體聚乙二醇及其混合物中以及油中製備分散液。在普通儲存及使用條件下,該等製劑包含防腐劑以防止微生物生長。
疾病狀態。端視待治療具體疾病,本發明治療組合物可經由任一一般途徑投與,只要靶組織經由該途徑可使抗原至位點之遞送最大化從而獲得最大(或在某些情況下最小)免疫反應。一般而言可藉由正位、皮內、皮下、肌內、腹膜內或靜脈注射來投與。用於遞送之其他方面包括:經口、經鼻、含服、經直腸、經陰道或外用。對於治療皮膚癌外用投與可能尤其有利。該等組合物通常可以醫藥上可接受之組合物形式投與,其包括生理上可接受之載劑、緩衝液或其他賦形劑。
可藉由注射(例如皮下注射或肌內注射)非經腸投與本發明疫苗或治療組合物。適用於其他投與模式之其他調配物包括栓劑,且在某些情況下包括口服調配物或適用於以氣
溶膠形式分配之調配物。在口服調配物情況下,使用佐劑處理T-細胞亞類、進行抗原封裝、或向各種調配物添加各細胞介素可獲得具有優化免疫反應之經改良口服疫苗。對於栓劑,傳統黏合劑及載劑可包括(例如)聚伸烷基二醇或甘油三酸酯;該等栓劑可自以0.5%-10%、較佳1%-2%之範圍包含活性成份之混合物形成。口服調配物包括該等常用賦形劑,例如醫藥級之甘露醇、乳糖、澱粉硬脂酸鎂、糖精鈉、纖維素、碳酸鎂及諸如此類。該等組合物採用溶液、懸浮液、錠劑、丸劑、膠囊、持續釋放調配物或粉末形式且包含10%-95%、較佳25-70%之活性成份。
可以中性或鹽形式將本發明編碼抗原之核酸調配至疫苗或治療組合物中。醫藥上可接受之鹽包括酸加成鹽(以肽之游離胺基形成之鹽),且該等鹽係以無機酸(例如氫氯酸或磷酸)或有機酸(例如乙酸、草酸、酒石酸、馬來酸及諸如此類)形成。以游離羧基形成之鹽亦可衍生自諸如氫氧化鈉、氫氧化鉀、氫氧化銨、氫氧化鈣、或氫氧化鐵等無機鹼及該等諸如異丙胺、三甲胺、2-乙胺基乙醇、組胺酸、普魯卡因(procaine)及諸如此類等有機鹼。
疫苗或治療組合物係以與劑量調配物相容之方式及以該可具有預防性及/或治療性效應之量來投與。待投與之量取決於待治療之受試者,包括(例如)受試者之免疫系統合成抗體之能力,及所期望保護或治療之程度。適宜劑量範圍係對於每次約0.1 mg至1000 mg(例如約1 mg至300 mg,且較佳係約10 mg至50 mg)之疫苗接種含有數百微克數量
級之活性成份。起始投與及加強注射之適宜方案亦可改變但其代表為起始投與之後實施後續接種或其他投與。投與所需活性成份之精確量取決於開業醫師之判斷且對於各受試者可能係特有的。熟習此項技術者可易知,本發明核酸分子或融合多肽之治療有效量尤其可取決於投與方案、所投與抗原之單位劑量、核酸分子或融合多肽是否係與其他治療藥劑組合投與、接受者之免疫狀態及健康情況、及具體核酸分子或融合多肽之治療活性。
組合物可以單劑量方案或以多劑量方案來給予。在多劑量方案中,疫苗接種之初始療程可包括(例如)1-10分開劑量,之後以後續時間間隔給予維持或增強免疫反應所需之其他劑量,例如在1-4個月給予第二劑量,且若需要在數月後給予後續劑量。期望以1-5年(通常3年)之間隔實施週期性加強以維持期望程度之保護性免疫。可在免疫療程後對與ESAT6或ST-CF共培養之外周血淋巴細胞(PBL)實施體外增殖分析,且量測自經初次免疫淋巴細胞釋放之IFN-γ之濃度。可使用習用標記來實施分析,例如放射性核苷酸、酶、螢光標記及諸如此類。該等技術為熟習此項技術者已知且可參見美國專利第3,791,932號、第4,174,384號及第3,949,064號,其相關部分係以引用方式併入。
端視是否使用核酸載體、是否使用最終純化蛋白或最終疫苗形式,可以一或多種"單位劑量"提供模組化rAb載體及/或經結合rAb載體-(黏連蛋白/停靠蛋白及/或停靠蛋白-黏連蛋白)-抗原複合物(rAb-DC/DC-抗原疫苗)。單位劑量
定義為包含預定量之治療組合物,該預定量經計算可產生與其投與(即適宜途徑及治療方案)相關之期望反應。待投與之量及具體途徑及調配物係為臨床領域技術人員所精通。亦可評估待治療受試者,具體而言評估受試者免疫系統狀態及所期望保護。單位劑量不必以單一注射來投與但可包括在設定時間段內連續輸注。本發明單位劑量可方便地描述為DNA/kg(或蛋白質/Kg)體重,且其投與範圍為約0.05、0.10、0.15、0.20、0.25、0.5、1、10、50、100、1,000或更高mg/DNA或蛋白質/kg體重。同樣,所遞送rAb-DC/DC-抗原疫苗之量可自約0.2至約8.0 mg/kg體重變化。因此,在具體實施例中,可將0.4 mg、0.5 mg、0.8 mg、1.0 mg、1.5 mg、2.0 mg、2.5 mg、3.0 mg、4.0 mg、5.0 mg、5.5 mg、6.0 mg、6.5 mg、7.0 mg及7.5 mg疫苗遞送至個體體內。待投與rAb-DC/DC-抗原疫苗之劑量在很大程度上取決於所治療受試者之重量及身體狀況以及投與途徑及治療頻率。可以1 μg-1 mg多核苷酸至1 μg-100 mg蛋白質之量投與醫藥組合物,其包括與脂質體或病毒遞送載體預結合之裸多核苷酸。因此,具體組合物可包括約1 μg、5 μg、10 μg、20 μg、30 μg、40 μg、50 μg、60 μg、70 μg、80 μg、100 μg、150 μg、200 μg、250 μg、500 μg、600 μg、700 μg、800 μg、900 μg或1,000 μg多核苷酸或蛋白質,其分別與1 μg、5 μg、10 μg、20 μg、3.0 μg、40 μg、50 μg、60 μg、70 μg、80 μg、100 μg、150 μg、200 μg、250 μg、500 μg、600 μg、700 μg、800 μg、900 μg、
1 mg、1.5 mg、5 mg、10 mg、20 mg、30 mg、40 mg、50 mg、60 mg、70 mg、80 mg、90 mg或100 mg載體結合。
在活體外細胞系統中檢驗本發明,其藉由已經Flu抗原標的之樹突細胞量測人Flu-特異性T細胞之免疫刺激。本文所示結果展示在於此系統中本身無效之抗原劑量下,該等抗原特異性細胞之特異性擴增。
本發明亦可用於製備模組化rAb載體,其係(例如)與來自蓖麻毒素、炭疽毒素及葡萄球菌(Staphylococcus)B腸毒素之保護性抗原複合之重組人類化mAb(經引導至特異性人樹突細胞受體)。此實體之潛在市場係所有軍事人員之疫苗接種並儲備所儲存疫苗以因應與該等作用物相關之生物感脅而投與大型人群中心。本發明可廣泛用於設計一般用於人類及動物用途二者之疫苗。目標工業包括醫藥及生物技術工業。
一般方法-限制酶及DNA修飾酶係來自NEB。質粒及DNA片段純化係藉由Qiagen產品實施。SDS-PAGE係經由用Simply Blue(Invitrogen)染色之4-12% Bis-Tris凝膠來實施。色譜柱及樹脂來自GE Healthcare。藉由DNA測序(MCLAB)來確認質粒構成物。DNA引物係來自Operon或Midland Certified Reagent公司。序列分析係經由序列分析器(Gene Codes)來實施。藉由UV吸收(NanoDrop ND-1000)來量測基於藉由ProtParam工具(2005)預測之經計算消光係數之蛋白質濃度。
抗DCIR mAb重及輕鏈信號肽及可變區序列之對準。對所預測N末端信號肽區加陰影。突出顯示變體間或密切相關序列間之序列差異。
黏連蛋白-Flex-hMART-1-肽A-6xHis蛋白之黏連蛋白結構域之C末端擴展序列。免疫顯性肽序列肽具有灰色陰影且與該肽結合之加下劃線的殘基係抗原序列所特有的。C末端His標誌有助於經由Ni++親和色譜實施純化。
抗原表現構成物-使用PCR來擴大流感A/波多黎各(Puerto Rico)/8/34/Mount Sinai(H1N1)M1蛋白之ORF,同時納入起始密碼子遠端之Nhe I位點及終止密碼子遠端之Not I位點。將經消化片段選殖至pET-28b(+)(Novagen)中,在M1 ORF框內置入His6標記,由此編碼His.Flu M1蛋白。將Flu M1 ORF置於編碼Nco I位點遠端之N末端蛋白G前體B2結構域殘基298-352(gi|124267|)之類似載體中,隨後是編碼GGSGGSGGSLD之連接體殘基。此載體表現具有Q246E變化之ProG.Flu M1蛋白。編碼來自熱纖維梭菌(C.thermocellum)且插入Nco I與Nhe I位點間之N末端169殘基黏連蛋白結構域之pET28b(+)衍生物表現Coh.His。為表現Coh.Flu M1.His,將Flu M1 ORF插入上述衍生物之Nhe I與Xho I位點之間。以類似方式製備Coh.PEP.His表現構成物,只是其使用編碼所需序列之合成DNA。在大腸桿菌(E.coli)菌株BL21(DE3)(Novagen)或T7 Express(NEB)中表現蛋白質,該等菌株係在37℃生長以選擇對卡那黴素(kanamycin)之抗性(40 μg/ml)並以200轉/min搖盪直至生長至對數生長中期時添加120 mg/L IPTG。三小時後,藉由離心收穫細胞且將其在-80℃下儲存。藉由納入Sal I位點代替起始密碼子且在載體Xho I位點插入添加遠端Xho I位
點,ProG及黏連蛋白區段取代上述AP融合分泌載體中之胞外結構域區段。'空'AP載體係藉由刪除胞外結構域區段來製備。該等構成物分別引導ProG.AP、Coh.AP及AP之分泌。
重組蛋白之表現及純化-使來自每個1 L發酵液之大腸桿菌細胞再懸浮於30 ml具有0.1 ml蛋白酶抑制劑Cocktail II(Calbiochem)之冰冷0.1 M NaPO4
(pH 7.4)(緩衝液A,用於ProG.Flu M1)或50 mM Tris、1 mM EDTA(pH 8.0)(緩衝液B,用於所有其他蛋白質)中。在冰上於設定值18處(Fisher Sonic Dismembrator 60)對細胞實施具有5 min休息期之2x 5 min超聲處理,且然後在4℃下以17,000 r.p.m.(Sorvall SA-600)將其旋轉20 min。對於ProG.Flu M1,使上清液流經在緩衝液A中平衡之5 ml Q瓊脂糖凝膠,且然後將5 ml hIgG珠添加至Q流出物中且將其在4℃下混合培養1 h。用50 ml冷PBS洗滌珠結合蛋白且用2×10 ml 0.1 M甘胺酸(pH 2.7)洗脫。用0.1 M MES(pH 5.0)緩衝液使所收集洗脫液達到pH 5且使其在經50 mM MES(pH 5.0)(緩衝液C)平衡之1 ml HiTrap S柱上運行。用緩衝液C徹底洗滌柱結合蛋白且用存於緩衝液C中之0-1 M NaCl梯度洗脫。收集峰部分。對於His.Flu M1純化,使50 ml細胞裂解物上清液部分流經5 ml Q瓊脂糖凝膠珠且將6.25 ml 160 mM Tris、40 mM咪唑、4 M NaCl(pH 7.9)添加至Q瓊脂糖凝膠流出物中。以4 ml/min將此裝載至帶有Ni++電荷之5 ml HiTrap螯合HP柱上。用20 mM NaPO4
、300 mM NaCl(pH 7.6)(緩衝液D)洗
滌柱結合蛋白,之後用100 mM H3
COONa(pH 4.0)再洗滌。用100 mM至1 M H3
COONa(pH 4.0)之梯度洗脫結合蛋白。收集峰部分且以4 ml/min將其裝載至經100 mM H3
COONa(pH 4.0)平衡之5 ml HiTrap S柱上,且用平衡緩衝液洗滌,之後用50 mM NaPO4
(pH 7.5)再洗滌。用存於50 mM NaPO4
(pH 7.5)中之0-1 M NaCl之梯度洗脫結合蛋白。收集在約500 mM NaCl洗脫之峰部分。His.Flu M1製劑具有可變量之非全長產物,其可能具有C末端部分缺失。對於Coh.Flu M1.His純化,如上所述對來自2L培養物之細胞實施超聲處理,但係在緩衝液B中實施。離心後,將2.5 ml Triton X114添加至上清液中且在冰上培養5 min。在25℃下另外培養5 min後,於25℃下離心將上清液自Triton X114分離。重複提取且使上清液流經5 ml Q瓊脂糖凝膠珠且將6.25 ml 160 mM Tris、40 mM咪唑、4 M NaCl(pH 7.9)添加至Q瓊脂糖凝膠流出物中。然後藉由如上所述Ni++螯合色譜純化蛋白質且用存於緩衝液D中之0-500 mM咪唑洗脫。
嵌合小鼠/人mAb之cDNA選殖及表現-總RNA係自雜交瘤細胞(RNeasy試劑盒,Qiagen)製備且用於cDNA合成及(SMART RACE試劑盒,BD Bioseiences)使用所提供5'引物及基因特異性3'引物之PCR中。
(mIgG,5'ggatggtgggaagatggatacagttggtgcagcatc3';mIgGλ,5'ctaggaacagtcagcacgggacaaactcttctccacagtgtgaccttc3';mIgG1,5'gtcactggctcagggaaatagcccttgaccaggcatc3';
mIgG2a,5'ccaggcatcctagagtcaccgaggagccagt3';及mIgG2b,5'ggtgctggaggggacagtcactgagctgctcatagtgt3').
選殖PCR產物(pCR2.1 TA試劑盒,Invitrogen)且藉由DNA測序來表徵。在使用鼠H及L鏈V區cDNA之經衍生序列之情況下,使用特異性引物來以PCR擴大信號肽及V區,同時納入兩側限制性位點以便將其選殖至編碼下游人IgG或IgG4H區之表現載體中。藉由擴大兩側為Xho I及Not I位點之殘基401-731(gi|63101937|)且將此插入pIRES2-DsRed2(BD Biosciences)之Xho I-Not I間隔中來構造表現嵌合mV-hIg之載體。使用PCR將mAb Vk區自附加Nhe I或Spe I位點且隨後附加CACC之起始密碼子擴增至附加Xho I位點之編碼區(例如編碼gi|76779294|之殘基126)。然後將PCR片段選殖至上述載體之Nhe I-Not I間隔中。藉由將序列5'ctagttgctggctaatggaccccaaaggctccctttcctggagaatacttctgtttctctccctggcttttgagttgtcgtacggattaattaagggcccactcgag3'插入上述載體之Nhe I-Xho I間隔中來構造使用mSLAM前導序列之嵌合mV-hIg之載體。使用PCR來擴大經預期成熟之N末端密碼子(使用SignalP 3.0服務器來定義)(Bendtsen,Nielsen等人,2004)及mV區末端(如上文所定義)之間的間隔同時附加5'tcgtacgga3'。將用Bsi WI消化之片段及Xho I插入上述載體之對應位點中。對照hIg序列對應於gi|49257887|殘基26-85及gi|21669402|殘基67-709。對照hIgG4H載體對應於具有S229P及L236E取代基之gi|19684072|之殘基12-1473,其穩定二硫鍵且清除殘留
FcR結合(Reddy,Kinney等人,2000),將其插入pIRES2-DsRed2載體Bgl II與Not I位點之間同時添加序列5'gctagctgattaattaa3'取代終止密碼子。使用PCR將mAb VH區自附加CACC且隨後附加Bgl II位點之起始密碼子擴增至gi|19684072|之殘基473之編碼區。然後將PCR片段選殖至上述載體之Bgl II-Apa I間隔中。藉由將序列5'ctagttgctggctaatggaccccaaaggctccctttcctggagaatacttctgtttctctccctggcttttgagttgtcgtacggattaattaagggccc3'插入上述載體之Nhe I-Apa I間隔中來構造使用mSLAM前導序列之嵌合mVH-hIgG4序列之載體。使用PCR擴大經預期成熟之N末端密碼子與mV區之末端之間的間隔同時附加5'tcgtacgga3'。將經Bsi WI消化之片段及Apa I插入上述載體之對應位點中。
將終止密碼子之後的兩側為近端Nhe I位點及遠端Not I位點之各種抗原編碼序列插入H鏈載體之Nhe I-Pac I-Not I間隔中。Flu HA1-1係藉由具有近端5'gctagcgatacaacagaacctgcaacacctacaacacctgtaacaa3'序列(後接編碼cipA黏連蛋白-黏連蛋白連接體殘基之序列之Nhe I位點)及遠端5'caccatcaccatcaccattgagcggccgc3'序列(編碼His6、終止密碼子及Not I位點)之流感A病毒(A/Puerto Rico/8/34(H1N1))血凝素gi|21693168|殘基82-1025(具有C982T變化)來編碼。Flu HA5-1係藉由經與Flu HA1-1相同之序列結合之gi|50296052|流感A病毒(A/Viet Nam/1203/2004(H5N1))血凝素殘基49-990來編碼。Doc係藉由具有近端Nhe I及遠端Not I位點之gi|40671|
celD殘基1923-2150來編碼。PSA係藉由具有近端序列5'gctagcgatacaacagaacctgcaacacctacaacacctgtaacaacaccgacaacaacacttctagcgc3'(Nhe I位點及cipA間隔子)及遠端Not I位點之gi|34784812|前列腺特異性抗原抗原101-832來編碼。Flu M1-PEP係藉由5'gctagccccattctgagccccctgaccaaaggcattctgggctttgtgtttaccctgaccgtgcccagcgaacgcaagggtatacttggattcgttttcacacttacttaagcggccgc3'來編碼。此肽編碼序列及所有其他肽編碼序列係經由互補合成DNA片段之混合物來產生,該等片段具有適於選殖至Nhe I及Not I限制性H鏈載體、或Nhe I-Xho I限制性Coh.His載體之末端。始終使用較佳人類密碼子,但需要將限制性位點納入CipA間隔子序列中之情況除外。
在5 ml瞬時轉染中檢驗rAb表現構成物之產生水平,其中使用約2.5 μg之每種L鏈及H鏈構成物及上述方案。藉由抗hIgG ELISA(AffiniPure Goat抗人IgG(H+L),Jackson ImmunoResearch)分析上清液。在該方案之檢驗中,所分泌rAb之產生獨立於超過每種DNA濃度約2倍(即系統經DNA飽和)之H鏈及L鏈載體濃度。
CD34-DC之生成-自正常健康捐贈者之外周血動員並收集CD34+HPC,該等捐贈者在5天內以皮下方式接受10 U/kg/日之重組G-CSF(Neupogen)。用CEPRATE SC幹細胞濃縮系統(ISOLEX)獲得CD34+
-HPC。藉由以0.5×106
/ml之濃度在補加5%自體血清、50 μM 2-β-巰基乙醇、1% L-麩胺醯胺、1%青黴素/鏈黴素(streptomycin)、及細胞介素(GM-
CSF(50 ng/ml;Immunex公司)、FLT3-L(100 ng/ml;R&D)及TNF-α(10 ng/ml;R&D))之Yssel's培養基中(Irvine Scientific,CA)培養來生成CD34-DC。在培養第5天將細胞轉移至補加細胞介素之新鮮培養基中,且在第9天收穫。
CD34-DC之分選-在培養第9天收穫CD34衍生之DC且用抗CD1a FITC(Biosource International)及抗CD14 PE(BD Biosciences)將其染色。用FACS VantageTM
(BD Biosciences)分選CD1a+
CD14-
-LC及CD1a-
CD14+
-intDC。純度通常為95-99%。
自體CD8+
T細胞之純化-在用CD14、CD19、CD16、CD56及CD4珠耗盡後藉由使用CD8磁珠(Miltenyi)自得自相同供體之PBMC陽性選擇自體CD8+T細胞。在某些實驗中,將記憶性CD8+T細胞分選為CD8+CCR7-CD45RA-。
藉由CD34-DC亞類將Flu M1蛋白交叉遞呈至CD8+
T細胞-在補加10%經熱滅活之所收集AB人類血清、10 U/ml IL-7(R&D)及與抗DC抗體交聯之減少劑量之Flu M1的Yssel's培養基中培養來自HLA-A2供體之整體或經分選CD34+DC亞類、CD1a+LC或CD14+IntDC(5×104
細胞/ml)及經純化自體CD8+T細胞(1×106
細胞/ml)。在24 h後將CD40L添加至培養物中,且在3天後添加IL-2。在8或10天後藉由分析抗原特異性CD8+T細胞增殖程度、使用特異性Flu M1、HLA-A201/pMI、藻紅蛋白結合之iTAg MHC四聚體(Beckman Coulter)來評價交叉遞呈效能。
抗人DCIR單株抗體之研發-產生受體胞外結構域hIgG(人
IgG1Fc)及HRP(辣根過氧化物酶)融合蛋白分別用於小鼠免疫及mAb之篩選。先前闡述hDCIR胞外結構域.IgG之表現構成物(Bates,Fournier等人,1999)及使用小鼠SLAM(mSLAM)信號肽引導分泌(Bendtsen,Nielsen等人,2004)。使用PCR擴大AP殘基133-1581(gb|BC009647|)同時添加近端讀框Xho I位點及遠端TGA終止密碼子及Not I位點來生成hDCIR胞外結構域.AP之表現載體。在上述hDCIR胞外結構域.IgG載體中此Xho I-Not I片段取代IgG編碼序列。藉由選殖上述DCIR胞外結構域編碼區遠端之gi|208493|殘基14-940來生成DCIR.HRP融合蛋白載體。
自哺乳動物細胞分泌之重組蛋白之表現及純化-根據製造商方案(1 mg總質粒DNA與1.3 ml 293 Fectin試劑/L之轉染)使用FreeStyleTM
293表現系統(Invitrogen)產生融合蛋白。為了產生重組抗體(rAb),共轉染編碼H及L鏈之等量載體。將經轉染細胞培養3天,收穫培養物上清液且添加新鮮培養基並繼續培養2天。藉由過濾澄清所收集上清液。藉由HiTrap蛋白A親和色譜純化受體胞外結構域.hIgG,其中用0.1 M甘胺酸(pH 2.7)洗脫且然後對PBS透析。藉由使用HiTrap MabSelectTM
柱以類似方式純化rAb。
單株抗體之生成-藉由習用細胞融合技術生成小鼠mAb。簡言之,用20 μg具有Ribi佐劑之受體胞外結構域.hIgGFc融合蛋白對6週齡BALB/c小鼠實施腹膜腔內免疫,然後在10天及15天後用20 μg抗原加強。在3個月後,在取脾臟前三天再次加強小鼠。或者,在30-40天期間每3-
4天在小鼠足墊上注射1-10 μg存於Ribi佐劑中之抗原。在最後加強後3-4天,收穫引流淋巴結。使用習用技術使來自脾臟之B細胞或淋巴結細胞與SP2/O-Ag 14細胞融合(Shulman,Wilde等人,1978)。使用ELISA篩選與單獨融合伴侶相比針對受體胞外結構域融合蛋白、或針對與AP融合之受體胞外結構域之雜交瘤上清液(Bates,Fournier等人,1999)。然後使用經編碼全長受體cDNA之表現質粒瞬時轉染之293F細胞在FACS中篩選陽性壁。
對於抗DCIR mAb之研發,篩選來自1000種雜交瘤純系之上清液:藉由Ig ELISA分析,在DCIR.Ig上90種係+藉由FACS分析,在DCIR-293細胞上64種係+62種FACS+係ELISA+ 2種係293+(且因此對DCIR無特異性)
對藉由人DC刺激細胞介素產生之抗DCIR mAb之生物學篩選-出於DC標的目的,可能期望使抗體將抗原遞送至DC且伴隨地活化DC以刺激針對所遞送抗原之獲得性免疫反應。因此直接針對DC刺激活性來篩選62種FACS陽性抗DCIR雜交瘤上清液之組。將CD34+衍生之人DC與雜交瘤上清液一起培養24小時且在24小時後分析DC培養物上清液中趨化因子MCP-1之存在。下圖顯示與對照相比,許多(但並非所有)雜交瘤上清液可激發MCP-1之特異性產生。
在上圖中用星號標記之所選擇雜交瘤(大多數刺激MCP-1產生但並非全部如此)係在CELLine燒瓶(Intergra)中單細
胞選殖並擴增。使雜交瘤上清液與等體積1.5 M甘胺酸、3 M NaCl、1x PBS,pH 7.8混合且與MabSelect樹脂一起攪拌。用結合緩衝液洗滌樹脂且用pH 2.7之0.1 M甘胺酸洗脫。在用2 M Tris中和後,將mAb對PBS透析。
純抗DCIR mAb之表徵-首先藉由ELISA(與板結合之DCIR.Ig,用HRP結合之抗人Fc試劑顯影)檢驗純mAb,然後藉由DCIR.HRP捕獲分析(與板結合之mAb,用DCIR.HRP融合蛋白顯影)來檢驗。圖2展示代表性分析結果,其顯示mAb與結合於板上之DCIR之高親和力交互作用(顯示結合特異性之對照未經展示)。在DCIR.HRP捕獲分析中,若干(但並非所有)mAb能將可溶DCIR.HRP捕獲至板表面。該等數據顯示所選抗DCIR mAb之組具有多種DCIR結合親和力及特性。
亦檢驗純mAb之FACS反應性,首先針對經編碼全長DCIR之表現質粒瞬時轉染之293細胞檢驗,然後針對所培養各種類型離體人DC檢驗。下圖展示在針對DCIR 293細胞之FACS分析中所滴定mAb之代表類型(對照細胞為負值)。
圖3顯示CD14+及CD1a+兩種亞型之CD34衍生之人DC皆表現細胞表面DCIR。在引導體液對細胞溶解免疫反應中該兩種DC亞型作用顯著不同-因此在兩種亞型上存在DCIR表明經由DCIR標的至人DC之抗原可激發兩種類型之免疫-此係經引導針對(例如)病毒感染之疫苗之重要特徵。
圖4顯示在自人類皮膚直接分離之三種人DC亞型上亦表
現DCIR。此觀察顯示對於DCIR抗原標的疫苗,因為該等DC類型皆表現受體,投與至皮膚中可係有利的。已知該等DC類型在其免疫引導特性方面類似於上述經培養人DC,且因此經由負載DCIR之皮膚DC標的抗原可有利於激發期望混合免疫反應。
自正常人類皮膚樣品純化真皮DC及LC。在4℃下將樣品於細菌蛋白酶分散酶類型2中培養18 h,且然後在37℃下培養2 h。然後分離表皮層與真皮層,將其切成小塊(約1-10 mm)且置於補加10%胎牛血清(FBS)之RPMI 1640中。2天後,收集遷移至培養基中之細胞且使用聚蔗糖(Ficoll)-泛影葡胺梯度(1.077 g/dl)使其進一步富集。在用抗CD1a FITC及抗CD14 APC mAb染色後藉由細胞分選純化DC。
在其他人類組織中DCIR之存在。圖5展示人扁桃體內生髮中心周圍細胞群之DCIR特異性染色。該等細胞可能為駐留DC或近期(例如在載入外來抗原並活化後)遷移至此位點之DC。染色顯示將DCIR標的之疫苗經由除皮膚容許通道以外之途徑投與至產生免疫性之器官中亦可有利於激發免疫反應。
使用抗DCIR mAb將抗原標的至人DC。根據製造商方案使用硫代琥珀醯亞胺6-[3'(2-吡啶基二硫)-丙醯胺]己酸鹽(磺基-LC-SPDP;Pierce)以化學方式使Flu M1蛋白與mAb交聯。多步驟方案涉及在室溫下藉由經由SPDP之NHS酯基修飾mAb之胺將mAb活化30 min,之後對PBS透析。然後,添加包含兩個游離巰基之Flu M1蛋白且在室溫下培養
過夜。藉由對比與mAb反應前Flu M1蛋白之量及交聯後mAb/Flu M1之比來評估交聯反應之效能。可計算出,平均一分子Flu M1與50%之mAb反應。圖6及7展示DCIR之交聯-Flu M1蛋白及mAb之實例。經由還原型SDS-PAGE之分析鑑別基於Flu M1/H鏈染色之比具有1-2 Flu M1/mAb之產物且將該等製劑用於體外研究中。非還原型SDS-PAGE分析(下方第二圖)顯示複合物大部分介於Flu M1與單一mAb之間,如由極大複合物之低百分比所證實。
圖6展示Coh.Flu M1與抗DCIR_2C9 mAb之交聯。藉由蛋白G瓊脂糖凝膠親和色譜純化之經交聯產物之還原型SDS-PAGE分析。自左至右係2.5 μg、1 μg Coh.Flu M1、10 μg Coh.Flu M1與mAb以1:1、2:1、4:1之比反應之產物。
圖7展示His.Flu M1與mAb之交聯。藉由蛋白G瓊脂糖凝膠親和色譜純化之經交聯產物之非還原型SDS-PAGE分析。自左至右係5 μg His.Flu M1,之後為5 μg mAb(抗CD1a_OKT6、抗LANG_2G3、抗DCIR_2C9)及5 μg mAb與5 μg His.Flu M1反應產物之對。
與Flu M1蛋白交聯之抗DC受體mAb可有效地將抗原標的至人DC-抗DC受體mAb以化學方式與Flu M1蛋白交聯且將各種劑量添加至人CD34衍生之CD1a+DC與自體CD8+T細胞之共培養物中。在24 h後將CD40L添加至培養物中以使DC活化,之後在第3天添加IL-2以使T細胞增殖。8-10天後,藉由MHC四聚體分析評價對Flu M1肽GILGFVFTL具有特異性之T細胞。圖8顯示與抗DCIR mAb交聯之Flu M1
激發Flu M1特異性細胞之增殖,而以類似劑量使用未經交聯之Flu M1及mAb時觀察到Flu M1特異性細胞之增殖顯著較低。劑量範圍顯示經交聯mAb所激發反應之效能較游離Flu M1至少高50倍。此數據表明抗原標的,即免疫反應之增強作用-在此情況下指具有特異性Flu M1抗原決定部位之記憶之T細胞之回憶。將CD34-DC分選為CD1a+LC或CD14+IntDC亞類。圖9顯示儘管在兩種細胞類型上DCIR表現水平相似,但抗DCIR標的之CD1a+LC在引導Flu M1特異性CD8+細胞之擴增上有效得多。
圖8顯示與抗DCIR mAb交聯之Flu M1較未與mAb交聯之Flu M1蛋白可更有效地誘導Flu M1特異性CD8+T細胞之擴增。將CD34衍生之CD1a+DC與CD8+T細胞及經指示濃度之與His.Flu M1交聯之DCIR_2C9 mAb一起培養,或與未經交聯之mAb一起培養。然後分析CD8+T細胞之Flu M1特異性擴增。內框指示四聚體特異性CD8+T細胞之百分比。
圖9顯示與抗DCIR mAb交聯之Flu M1經由LC較經由Int-DC可更有效地誘導Flu M1特異性CD8+T細胞之擴增。將來自HLA-A2供體及自體CD8+T細胞之LC或Int-DC與經指示濃度之與His.Flu M1交聯之抗DCIR_2C9 mAb共培養。藉由Flu M1特異性CD8+T細胞之頻率來評價交叉提成效能且用HLA-A201/pMI四聚體來分析。內框指示四聚體特異性CD8+T細胞之百分比。
研發重組抗DCIR mAb(rAb)作為原型抗原標的疫苗。研發載體用於在經瞬時轉染之哺乳動物細胞中表現經分泌抗
DC受體rAb,其係小鼠雜交瘤編碼之H及L鏈可變(V)區與人Ig或人IgG4H恆定(C)區之嵌合體。來自具有不同特異性(即來自不同抗DCIR雜交瘤)之抗DC受體mAb之L及H鏈之V區係經cDNA選殖、藉由DNA序列分析表徵、且經構建至該等載體中。圖10展示該等編碼對應於各種不同抗DCIR mAb之嵌合小鼠-人rAb之H+L鏈載體,該等抗DCIR mAb係經共轉染至293細胞中且藉由抗人FC ELISA分析rAb至培養物上清液中之分泌。
抗DCIR rAb編碼具有rAb H鏈之約9.5 kDA停靠蛋白結構域讀框。停靠蛋白結構域(稱為rAb.Doc)之目的係容許裝配特異性[rAb.Doc:Coh.抗原]複合物。在此情況下,Coh.抗原係指介於約17.5 kDa黏連蛋白結構域與抗原之間之融合蛋白。使用黏連蛋白與停靠蛋白之間之高親和力交互作用來裝配已顯示可將抗原遞送至負載受體特異性之DC表面之經限定複合物。舉例而言,下圖展示與人DC表面結合之[抗DCIR.Doc:Coh.Flu M1]複合物(此處Coh.Flu M1係經生物素化且在洗滌步驟後在細胞表面上加以檢測)。對照rAb.Doc:Coh.Flu M1複合物(在下圖中顯示為紅色)之結合程度不超過單獨的檢測抗生蛋白鏈菌素-PE試劑。
DCIR以緩慢動力學將抗原內在化且此可將其與其他DC受體區分開。諸如DC-SIGN等DC受體之特徵在於內在化之快速動力學。舉例而言,圖11顯示抗DC-SIGN/L.Doc快速地將Alexa標記之Coh.Flu M1內在化至GM-CSF/IFN培養的人DC中-大多數標記在15 min內進入細胞內部。相反,
抗DCIR.Doc極緩慢地內部化Coh.Flu M1-在3小時時仍存在顯著量之內部抗原及細胞表面抗原。此結果將DCIR辨識為緩慢內在化之DC受體且此結果與Bates等人之結論相反,其提出"與用MMR觀察到之快速動力學相反(數據未顯示),在交聯後,在單核細胞-及CD34-衍生之DC中DCIR僅緩慢且微弱地內在化。此發現說明藉由受體介導內吞作用實施Ag捕獲並非DCIR之主要功能"。
圖11顯示與抗DCIR.Doc rAb連接之Coh.Flu M1與GM/IL-15人DC特異性結合。將單核細胞衍生之GM-CSF/IL-15培養的人DC與指定濃度且與4倍莫耳過量之生物素化Coh.Flu M1預混合1小時之抗DCIR.Doc rAb一起培養。1小時後,洗滌細胞且將其與抗生蛋白鏈菌素-PE一起培養。再次洗滌後,藉由FACS分析細胞以檢測細胞相關PE。綠色曲線係抗DCIR.Doc rAb,紅色曲線係對照IgG4.Doc複合物。
圖12顯示與抗DC-SIGN/L.Doc或抗DCIR.Doc rAb連接之Coh.Flu M1與GM-CSF/IL-4人DC結合且經內部化至GM-CSF/IL-4人DC中。將單核細胞衍生之GM-CSF/IL-4培養的人DC和與4倍莫耳過量經Alexa標記之Coh.Flu M1預混合1小時之抗DCIR.Doc或抗DC-SIGN/L.Doc rAb一起培養。在冰上保持1小時後,洗滌細胞且將其置於37℃下。使用共聚焦顯微術來分析細胞相關抗原(顯示為紅色)之細胞定位。綠色標記細胞膜相關之肌動蛋白。
經由DCIR.Doc將Coh.Flu M1標的至人DC後進行鑑別發現DCIR是用於疫苗研發目的之優良受體。比較經由緩慢
內在化DCIR受體將Flu M1抗原標的至人DC與經由快速內在化ASGPR及LOX-1受體標的。所監測免疫反應係Flu M1特異性CD8+T細胞之擴增。結果顯示經由DCIR標的較經由LOX-1或ASGPR標的顯著更有效。在相似實驗中,若DC經洗滌不含殘留[rAb.Doc:Coh.抗原],之後與CD8+T細胞一起培養,則經由DCIR標的之優越性甚至更明顯。此情形可能更接近於體內情形,其中經標的DC將與殘留的所投與抗原分離而在引流淋巴結內遇到T細胞。
圖13顯示在擴增Flu M1特異性CD8+T細胞方面抗DCIR.Doc:Coh.Flu複合物較其他[抗DC受體rAb.Doc:Coh.Flu M1]複合物更有效。將CD34衍生之CD1a+DC與CD8+T細胞及8 nM(上組)或0.8 nM(下組)[抗DCIR_2C9.Doc:Coh.Flu M1]、抗LOX1_15C4.Doc、抗ASGPR_49C11.Doc或IgG4.Doc對照rAb共培養,其分別與Coh.Flu M1複合。然後分析CD8+T細胞之Flu M1特異性擴增。內框指示四聚體特異性CD8+T細胞之百分比。
圖14顯示在擴增Flu M1特異性CD8+T細胞方面在1天內投與之抗DCIR.Doc:Coh.Flu複合物較其他[抗DC受體rAb.Doc:Coh.Flu M1]複合物更有效。研究條件如上圖所示,只是在添加自體CD8+T細胞之前第1天洗滌DC。某些抗DCIR V區對在rAb H鏈C末端經融合之重要抗原之分泌尤其有利。
圖15顯示表現為與rAbH鏈之C末端融合形式之各種抗原對rAb.抗原之分泌具有內在效應。此處相同抗原編碼區在
嵌合hIgG4 rAb上被改造為具有兩種不同小鼠V區特異性。該等表現構成物係與適宜L鏈小鼠V區-hIgk構成物共轉染至293F細胞中且在3天後評價rAb之分泌。某些rAb抗原大量表現,而其他(包括Flu HA5-1)表現極微。可預期各抗原具有在rAb背景下影響分泌之內在生化特性。實際上,在所檢驗兩種V區特異性之背景下存在對表現之顯著並聯效應。
Flu HA5在針對禽流感之疫苗研發中被視為重要抗原。圖16展示意外發現:不同抗DCIR V區(衍生自不同抗DCIR mAb)在很大程度上影響期望抗DCIR.Flu HA5疫苗之分泌。在下文所示實例中,當與其他DCIR V區比較時,DCIR_25A4對此類型疫苗之分泌尤其有利。
圖16顯示端視可變區性質,抗DCIR.Flu HA5 rAb係以不同效能分泌。將編碼經由Doc(蘭色環)或HA5-1(紅色三角形)之H鏈C末端融合之嵌合小鼠V區及人C區之H及L鏈表現質粒共轉染至293細胞中,且在3天後藉由ELISA分析上清液稀釋物之IgGFc。除DCIR_2C9外,rAb.Doc一般大量表現。然而,rAb.HA5-1之表現變化很大。
抗DCIR 25A4 V區促進rAb.HA5-1分泌之獨特特性闡釋請求項5之應用。其係基於本發明,其中特定V區可影響rAb抗原之分泌。此意味著可藉由針對彼等有利於分泌之特性篩選具有期望組合特性之不同V區來克服在rAb融合蛋白背景下特定抗原之內在微弱分泌。對於任一經分泌rAb融合蛋白主張以此作為新的通用原則。
抗DCIR可增強HIV特異性CD8+T細胞之初次免疫。圖17
顯示抗DCIR mAb對樹突細胞具有增強初次免疫之特定作用-其係肽之吸收及其在表面MHC上至肽抗原特異性T細胞之遞呈。實例顯示用抗DCIR mAb連同CD40L(通常藉由同源T細胞遞送之已知DC活化信號)刺激DC可導致大大提高對添加至DC培養物中之免疫顯性HIV gag肽具有特異性之CD8+T細胞之數量。此特性對經由DC受體rAb疫苗之成功抗原標的具有高度預測性且顯示抗DCIR.抗原疫苗係優良疫苗。
圖17顯示抗DCIR mAb增強HIV抗原特異性CD8+
細胞之初次免疫。用自體IFN-DC(1×105
細胞/孔)及HLA-A201-限制性HIV肽pol(pol476-484
ILKEPVHGV,pol293-302
KYTAFTIPSI)、及gag(gag77-85
,SLYNTVATL,gag151-159
,TLNAWVKVV)(5 μM)刺激經純化總CD8+
T細胞(2×106
細胞/孔)。在24孔板中將細胞培養9天,該孔板係在4℃下經5 μg/孔抗DCIR mAb或稀釋於PBS PH 9.6中之對照單株抗體預覆蓋過夜且經徹底洗滌。在補加10%人AB血清、10 U/ml IL-7(R&D)及100 ng/ml CD40L(R&D)之Yssel's培養基中培養細胞。在第3天以10 U/ml添加IL-2。在培養階段終點藉由計數結合肽/HLA-A201四聚體(Beckman Coulter)之細胞數來測定肽特異性CD8+
T細胞之擴增。
抗DCIR mAb增強交叉初次免疫。圖18顯示抗DCIR mAb對樹突細胞具有增強交叉初次免疫之特定作用-其係肽之吸收及其在表面MHC上之正確處理及遞呈,如藉由對抗原衍生肽具有特異性之T細胞之擴增所量測。實例顯示用抗
DCIR mAb連同CD40L(通常藉由同源T細胞遞送之已知DC活化信號)刺激DC可導致大大提高對來自經添加至DC培養物中之黏連蛋白-MART-1融合蛋白之免疫顯性MART-1抗原決定部位具有特異性之CD8+T細胞之數量。此特性對經由抗DC受體rAb疫苗之抗原標的係高度期望的且表示抗DCIR.抗原疫苗係優良的。
圖18顯示抗DCIR mAb可增強HIV抗原特異性CD8+細胞之初次免疫。上圖方法與前圖相同,只是coh.MART-1肽融合蛋白取代肽。
本發明涵蓋,此說明書中所論述之任一實施例可根據本發明之任一方法、試劑盒、試劑或組合物來實施,反之亦然。而且,本發明之組合物可用於達成本發明之方法。
應理解本文所述具體實施例係藉由闡釋性方式來展示,並非作為本發明之限制。在不背離本發明範圍之條件下,本發明之主要特徵可用於各種實施例中。熟習此項技術者僅使用常規實驗即可識別或能確定本文所述具體程序之多種等效形式。該等等效形式可視為在本發明範圍內且由申請專利範圍所涵蓋。
說明書中所提及之所有出版物及專利申請案皆可顯示熟習本發明所屬領域技術者之熟練水平。所有出版物及專利申請案皆係以引用方式併入本文中,其併入程度如同將每一個別出版物或專利申請案特定且獨立地顯示為以引用方式併入。
在申請專利範圍及/或說明書中,當結合詞語"包含"使用
時,詞語"一"("a"或"an")之使用可意指"一"("one"),但其亦與"一或多"、"至少一"及"一或一以上"之含義一致。在申請專利範圍中,除非明確表明僅指選擇其一或該等選擇相互排斥,否則詞語"或"之使用係用於意指"及/或",但所揭示內容支持僅指二選一的選擇及"及/或"之定義。在整個該申請案中,詞語"約"係用來表明,一值包括用來測量該值之裝置、方法之內在誤差變化或存在於研究受試者之間之變化。
此說明書及申請專利範圍中所用詞語"包含"("comprising")(及包含之任一形式,例如"comprise"及"comprises")、"具有"("having")(及具有之任一形式,例如"have"及"has")、"包括"("including")(及包括之任一形式,例如"includes"及"include")或"含有"("containing")(及含有之任一形式,例如"contains"及"contain")皆係包括性或無限制的,且不排除其他未列述要素或方法步驟。
本文所用詞語"或其組合"係指該詞語前所列條目之所有排列及組合。舉例而言,"A、B、C、或其組合"意欲包括下述中至少一種:A、B、C、AB、AC、BC、或ABC,且若在具體上下文中順序很重要,亦包括BA、CA、CB、CBA、BCA、ACB、BAC、或CAB。繼續此實例,其明確包括含有一或多個條目或詞語之重複之組合,例如BB、AAA、MB、BBC、AAABCCCC、CBBAAA、CABABB,等等。熟習此項技術者可理解,除非在上下文中另外說明,否則通常在任一組合中不限制條目或詞語之數目。
根據本揭示內容無需過多實驗即可獲得並實施本文所揭示及主張之所有組合物及/或方法。儘管已根據較佳實施例闡述本發明之組合物及方法,但熟習此項技術者可明瞭,可在不背離本發明之概念、精神及範圍條件下改變該等組合物及/或方法及本文所述方法之步驟或步驟之順序。熟習此項技術者所顯見的所有該等類似替代物及修改皆被視為涵蓋於隨附申請專利範圍所界定的本發明之精神、範圍及概念內。
Banchereau,J.,F.Briere等人(2000)。"Immunobiology of dendritic cells." Annu Rev Immunol 18:767-811。
Banchereau,J.,A.K.Palucka等人(2001)。"Immune and clinical responses in patients with metastatic melanoma to CD34(+)progenitor-derived dendritic cell vaccine." Cancer Res 61(17):6451-8。
Banchereau,J.,B.Schuler-Thurner等人(2001)。"Dendritic cells as vectors for therapy." Cell 106(3):271-4。
Bates,E.E.,N.Fournier等人(1999)。"APCs express DCIR,a novel C-type lectin surface receptor containing an immunoreceptor tyrosine-based inhibitory motif." J Immunol 163(4):1973-83。
Bendtsen,J.D.,H.Nielsen等人(2004)。"Improved prediction of signal peptides:SignalP 3.0." J Mol Biol 340(4):783-95。
Berard,F.,P.Blanco等人(2000)。"Cross-priming of naive CD8 T cells against melanoma antigens using dendritic cells loaded with killed allogeneic melanoma cells." J Exp Med 192(11):1535-44。
Bonifaz,L.C.,D.P.Bonnyay等人(2004)。"In vivo targeting of antigens to maturing dendritic cells via the DEC-205 receptor improves T eell vaecination." J Exp Med 199(6):815-24。
Carvalho,A.L.,F.M.Dias等人(2003)。"Cellulosome assembly revealed by the crystal structure of the cohesin-dockerin complex." Proc Natl Acad Sci U S A 100(24):13809-14。
Cella,M.,F.Sallusto等人(1997)。"Origin,mafuration and antigen presenting function of dendritic cells." Curr Opin Immunol 9(1):10-6。
Delneste,Y.,G.Magistrelli等人(2002)。"Involvement of LOX-1 in dendritic cell-mediated antigen cross-presentation." Immunity 17(3):353-62。
Figdor,C.G.,Y.van Kooyk等人(2002)。"C-type lectin receptors on dendritic cells and Langerhans cells." Nat Rev Immunol 2(2):77-84。
Geijtenbeek,T.B.,S.J.van Vliet等人(2004)。"Self-and nonself-recognition by C-type lectins on dendritic cells." Annu Rev Immunol 22:33-54。
Gerwig,G.J.,J.P.Kamerling等人(1993)。"The nature of the carbohydrate-peptide linkage region in glycoproteins from the cellulosomes of Clostridium thermocellum and Bacteroides cellulosolvens." J Biol Chem 268(36):26956-60。
Mellman,I.and R.M.Steinman(2001)."Dendritic cells:specialized and regulated antigen processing machines." Cell 106(3):255-8。
Neidhardt-Berard,E.M.,F.Berard等人(2004)。"Dendritic cells loaded with killed breast cancer cells induce differentiation of tumor-specific cytotoxic T lymphocytes." Breast Cancer Res 6(4):R322-8。
Orban,J.,P.Alexander等人(1992)。"Sequence-specific 1H NMR assignments and secondary structure of the streptococcal protein G B2-domain." Biochemistry 31(14):3604-11。
Palucka,A.K.,J.Gatlin等人(2003)。"Human dendritic cell subsets in NOD/SCID mice engrafted with CD34+hematopoietic progenitors." Blood 102(9):3302-10。
Ramakrishna,V.,J.F.Treml等人(2004)。"Mannose receptor targeting of tumor antigen pmel17 to human dendritic cells directs anti-melanoma T cell responses via multiple HLA molecules." J Immunol 172(5):2845-52。
Reddy,M.P.,C.A.Kinney等人(2000)。"Elimination of Fc receptor-dependent effector functions of a modified IgG4
monoclonal antibody to human CD4." J Immunol 164(4):1925-33。
Shortman,K.and Y.J.Liu(2002)."Mouse and human dendritic cell subtypes." Nat Rev Immunol 2(3):151-61。
Shulman,M.,C.D.Wilde等人(1978)。"A better cell line for making hybridomas secreting specific antibodies." Nature 276(5685):269-70。
Steinman,R..M.and M.Dhodapkar(2001)."Active immunization against cancer with dendritic cells:the near future." Int J Cancer 94(4):459-73。
Tacken,P.J.,I.J.de Vries等人(2005)。"Effective induction of naive and recall T-cell responses by targeting antigen to human dendritic cells via a humanized anti-DC-SIGN antibody." Blood 106(4):1278-85。
Trombetta,E.S.and I.Mellman(2005)."Cell biology of antigen processing in vitro and in vivo." Annu Rev Immunol 23:975-1028。
Trumpfheller,C.,J.S.Finke等人(2006)。"Intensified and protective CD4+T cell immunity in mice with anti-dendritic cell HIV gag fusion antibody vaccine." J Exp Med 203(3):607-17。
為更全面地理解本發明之特徵及優勢,現在參照本發明之具體說明及附圖,且其中:
圖1顯示與對照相比,許多(但並非所有)雜交瘤上清液可激發MCP-1之特異性產生。
圖2藉由ELISA展示mAb與結合於板上之DCIR之高親和力交互作用;圖3展示用於FACS中之高親和力抗體之結合;圖4顯示在自人類皮膚直接分離之三種人DC亞型上亦表現DCIR;圖5展示人扁桃體內生髮中心周圍細胞群之DCIR特異性染色;圖6展示DCIR之交聯Flu M1蛋白及mAb之實例;圖7展示Coh.Flu M1與抗DCIR_2C9 mAb之交聯。
圖8顯示與抗DCIR mAb交聯之Flu M1較未與mAb連接之Flu M1蛋白可更有效地誘導Flu M1特異性CD8+ T細胞之擴增;圖9顯示與抗DCIR mAb交聯之Flu M1經由LC可較經由Int-DC更有效地誘導Flu M1特異性CD8+ T細胞之擴增;圖10展示該等編碼對應於多種不同抗DCIR mAb之嵌合小鼠-人類rAb之H+L鏈載體,該等抗DCIR mAb係共轉染至293細胞中且藉由抗人FC ELISA分析rAb至培養上清液中之分泌;圖11顯示與抗DCIR.Doc rAb連接之Coh.Flu M1與GM/IL-15人DC特異性結合;圖12顯示與抗DC-SIGN/L.Doc或抗DCIR.Doc rAb連接之Coh.Flu M1與GM-CSF/IL-4人DC結合且被內在化至GM-
CSF/IL-4人DC中;圖13顯示在擴增Flu M1特異性CD8+ T細胞方面抗DCIR.Doc:Coh.Flu複合物較其他[抗DC受體rAb.Doc:Coh.Flu M1]複合物更有效;圖14顯示在擴增Flu M1特異性CD8+ T細胞方面在1天內投與之抗DCIR.Doc:Coh.Flu複合物較其他[抗DC受體rAb.Doc:Coh.Flu M1]複合物更有效;圖15顯示表現為與rAb H鏈C末端融合之各種抗原具有對rAb.抗原分泌之內在效應;圖16顯示端視可變區性質,抗DCIR.Flu HA5 rAb以不同效能分泌;圖17顯示抗DCIR mAb增強HIV抗原特異性CD8+細胞之初次免疫;及圖18顯示抗DCIR mAb增強HIV抗原特異性CD8+細胞之初次免疫。
<110> 美商貝勒研究協會<120> 基於表現於抗原-表現細胞之樹突細胞抑制受體(DCIR)之標的抗原之疫苗<130> BHCS:1043 <140> 097104113 <141> 2008-02-01 <150> US 60/888,032 <151> 2007-02-02 <160> 64 <170> PatentIn version 3.4 <210> 1 <211> 73 <212> PRT <213> 人工<220> <223> 化學合成肽<400> 1<210> 2 <211> 73<212> PRT <213> 人工<220> <223> 化學合成肽<400> 2 <210> 3 <211> 73 <212> PRT <213> 人工<220> <223> 化學合成肽<400> 3<210> 4 <211> 73 <212> PRT <213> 人工<220> <223> 化學合成肽<400> 4<210> 5 <211> 73 <212> PRT <213> 人工<220> <223> 化學合成肽<400> 5 <210> 6 <211> 73 <212> PRT <213> 人工<220> <223> 化學合成肽<400> 6<210> 7 <211> 75 <212> PRT <213> 人工<220> <223> 化學合成肽<400> 7 <210> 8 <211> 75 <212> PRT <213> 人工<220> <223> 化學合成肽<400> 8<210> 9 <211> 68 <212> PRT <213> 人工<220> <223> 化學合成肽<400> 9<210> 10 <211> 68 <212> PRT <213> 人工<220> <223> 化學合成肽<400> 10 <210> 11 <211> 70 <212> PRT <213> 人工<220> <223> 化學合成肽<400> 11<210> 12 <211> 68 <212> PRT <213> 人工<220> <223> 化學合成肽<400> 12 <210> 13 <211> 68 <212> PRT <213> 人工<220> <223> 化學合成肽<400> 13<210> 14 <211> 72 <212> PRT <213> 人工<220> <223> 化學合成肽<400> 14<210> 15 <211> 70 <212> PRT <213> 人工<220> <223> 化學合成肽<400> 15 <210> 16 <211> 74 <212> PRT <213> 人工<220> <223> 化學合成肽<400> 16<210> 17 <211> 74 <212> PRT <213> 人工<220> <223> 化學合成肽<400> 17 <210> 18 <211> 62 <212> PRT <213> 人工<220> <223> 化學合成肽<400> 18<210> 19 <211> 62 <212> PRT <213> 人工<220> <223> 化學合成肽<400> 19<210> 20 <211> 62 <212> PRT <213> <220> <223> <400> 20 <210> 21 <211> 62 <212> PRT <213> 人工<220> <223> 化學合成肽<400> 21<210> 22 <211> 59 <212> PRT <213> 人工<220> <223> 化學合成肽<400> 22<210> 23 <211> 59 <212> PRT <213> 人工<220> <223> 化學合成肽<400> 23 <210> 24 <211> 59 <212> PRT <213> 人工<220> <223> 化學合成肽<400> 24<210> 25 <211> 58 <212> PRT <213> 人工<220> <223> 化學合成肽<400> 25<210> 26 <211> 60 <212> PRT <213> <220> <223> <400> 26 <210> 27 <211> 60 <212> PRT <213> 人工<220> <223> 化學合成肽<400> 27<210> 28 <211> 66 <212> PRT <213> 人工<220> <223> 化學合成肽<400> 28<210> 29 <211> 66 <212> PRT <213> 人工<220> <223> 化學合成肽
<400> 29<210> 30 <211> 66 <212> PRT <213> 人工<220> <223> 化學合成肽<400> 30<210> 31 <211> 66 <212> PRT <213> 人工<220> <223> 化學合成肽<400> 31 <210> 32 <211> 66 <212> PRT <213> 人工<220> <223> 化學合成肽<400> 32<210> 33 <211> 66 <212> PRT <213> 人工<220> <223> 化學合成肽<400> 33<210> 34 <211> 66 <212> PRT <213> 人工<220> <223> 化學合成肽
<400> 34<210> 35 <211> 66 <212> PRT <213> 人工<220> <223> 化學合成肽<400> 35<210> 36 <211> 65 <212> PRT <213> 人工<220> <223> 化學合成肽<400> 36 <210> 37 <211> 66 <212> PRT <213> 人工<220> <223> 化學合成肽<400> 37<210> 38 <211> 66 <212> PRT <213> 人工<220> <223> 化學合成肽<400> 38<210> 39 <211> 66 <212> PRT <213> 人工<220> <223> 化學合成肽
<400> 39<210> 40 <211> 71 <212> PRT <213> 人工<220> <223> 化學合成肽<400> 40<210> 41 <211> 11 <212> PRT <213> 人工<220> <223> 化學合成肽<400> 41<210> 42 <211> 36 <212> DNA <213> 人工<220> <223> 化學合成寡核苷酸
<400> 42<210> 43 <211> 48 <212> DNA <213> 人工<220> <223> 化學合成寡核苷酸<400> 43<210> 44 <211> 37 <212> DNA <213> 人工<220> <223> 化學合成寡核苷酸<400> 44<210> 45 <211> 31 <212> DNA <213> 人工<220> <223> 化學合成寡核苷酸<400> 45<210> 46 <211> 38 <212> DNA <213> 人工<220> <223> 化學合成寡核苷酸<400> 46<210> 47 <211> 107 <212> DNA <213> 人工<220> <223> 化學合成寡核苷酸<400> 47<210> 48 <211> 100 <212> DNA <213> 人工<220> <223> 化學合成寡核苷酸<400> 48<210> 49 <211> 46 <212> DNA <213> 人工<220> <223> 化學合成寡核苷酸<400> 49<210> 50 <211> 29 <212> DNA <213> 人工<220> <223> 化學合成寡核苷酸<400> 50<210> 51 <211> 70 <212> DNA <213> 人工<220> <223> 化學合成寡核苷酸<400> 51<210> 52 <211> 119 <212> DNA <213> 人工<220> <223> 化學合成寡核苷酸<400> 52<210> 53 <211> 9 <212> PRT <213> 人工<220> <223> 化學合成肽<400> 53<210> 54 <211> 9 <212> PRT <213> 人工
<220> <223> 化學合成肽<400> 54<210> 55 <211> 10 <212> PRT <213> 人工<220> <223> 化學合成肽<400> 55<210> 56 <211> 9 <212> PRT <213> 人工<220> <223> 化學合成肽<400> 56<210> 57 <211> 9 <212> PRT <213> 人工<220> <223> 化學合成肽<400> 57<210> 58 <211> 80 <212> PRT <213> 人工<220> <223> 化學合成肽<400> 58 <210> 59 <211> 79 <212> PRT <213> 人工<220> <223> 化學合成肽<400> 59<210> 60 <211> 80 <212> PRT <213> 人工<220> <223> 化學合成肽<400> 60<210> 61 <211> 80 <212> PRT <213> 人工<220> <223> 化學合成肽
<400> 61<210> 62 <211> 77 <212> PRT <213> 人工<220> <223> 化學合成肽<400> 62<210> 63 <211> 77 <212> PRT <213> 人工<220> <223> 化學合成肽<400> 63 <210> 64 <211> 9 <212> PRT <213> 人工<220> <223> 化學合成肽<400> 64
(無元件符號說明)
Claims (22)
- 一種藉由表現樹突細胞免疫受體(DCIR)之抗原表現細胞提高抗原表現效力之方法,其包含以下步驟:分離及純化DCIR特異性抗體或其功能性片段,其特徵在於該DCIR特異性抗體或其功能性片段能特異性地結合DCIR胺基酸殘基70至C端之胞外結構域;該DCIR特異性抗體或其功能性片段之進一步特徵在於連接經標的作用物;獲得一或多個經分離之抗原表現細胞;將該一或多個經分離之抗原表現細胞與該DCIR特異性抗體或其功能性片段接觸,其中該經標的作用物藉由已與該DCIR特異性抗體或其功能性片段接觸之抗原表現細胞內在化。
- 如請求項1之方法,其中抗原表現細胞包含樹突細胞。
- 如請求項1之方法,其中該DCIR特異性抗體或其功能性片段與黏連蛋白(Cohesin)/停靠蛋白(Dockerin)結合對之一組份結合。
- 如請求項1之方法,其中DCIR特異性抗體或其功能性片段與黏連蛋白/停靠蛋白結合對之一組份結合且該經標的作用物與該黏連蛋白/停靠蛋白結合對之補體組份結合以形成複合物。
- 如請求項1之方法,其中該經標的作用物係選自肽、蛋白質、脂、碳水化合物、核酸及其組合。
- 如請求項1之方法,其中該經標的作用物包含一或多種 選自以下之細胞介素:白介素、轉化生長因子(TGF)、成纖維細胞生長因子(FGF)、血小板衍生生長因子(PDGF)、表皮生長因子(EGF)、結締組織活化肽(CTAP)、成骨因子、及該等生長因子之生物活性類似物、片段及衍生物、B/T細胞分化因子、B/T-細胞生長因子、促有絲分裂細胞介素、趨化細胞介素、集落刺激因子、血管生成因子、IFN-α、IFN-β、IFN-γ、IL1、IL2、IL3、IL4、IL5、IL6、IL7、IL8、IL9、IL10、IL11、IL12、IL13、IL14、IL15、IL16、IL17、IL18等、來普汀(leptin)、筒箭毒鹼、巨噬細胞刺激蛋白、血小板衍生生長因子、TNF-α、TNF-β、NGF、CD40L、CD137L/4-1BBL、人類淋巴毒素-β、G-CSF、M-CSF、GM-CSF、PDGF、IL-1α、IL1-β、IP-10、PF4、GRO、9E3、紅細胞生成素、血管內皮抑素、血管抑素、VEGF、轉化生長因子(TGF)超基因家族(包括β轉化生長因子,例如TGF-β1、TGF-β2、TGF-β3)、骨形態發生蛋白(例如BMP-1、BMP-2、BMP-3、BMP-4、BMP-5、BMP-6、BMP-7、BMP-8、BMP-9)、肝素結合生長因子(成纖維細胞生長因子(FGF)、表皮生長因子(EGF)、血小板衍生生長因子(PDGF)、類胰島素生長因子(IGF))、抑制素(例如抑制素A、抑制素B)、生長分化因子(例如GDF-1)及活化素(例如活化素A、活化素B、活化素AB)。
- 如請求項1之方法,其中該經標的作用物包含細菌、病毒、真菌、原生動物或癌症蛋白。
- 一種藉由樹突細胞提高抗原表現效力之方法,其包含結合DCIR特異性抗體或其功能性片段,其特徵在於該DCIR特異性抗體或其功能性片段能特異性地結合DCIR胺基酸殘基70至C端之胞外結構域;該DCIR特異性抗體或其功能性片段之進一步特徵在於連接抗原;其中該抗原係藉由已與該DCIR特異性抗體或其功能性片段接觸之樹突細胞處理並遞呈。
- 一種能特異性地結合DCIR胺基酸殘基70至C端之胞外結構域之DCIR特異性抗體或其功能性片段之用途,其係用以製造用於將抗原遞送至抗原表現細胞以達成激發保護性或治療性免疫反應之目的之疫苗。
- 一種能特異性地結合DCIR胺基酸殘基70至C端之胞外結構域之DCIR特異性抗體或其功能性片段之用途,其係用以製造用於經由皮膚進行疫苗接種之疫苗。
- 一種能特異性地結合DCIR胺基酸殘基70至C端之胞外結構域之DCIR特異性抗體或其功能性片段之用途,其係用以製造用於疫苗接種之疫苗,其中該試劑係與經共投與或經連接佐劑結合。
- 一種能特異性地結合DCIR胺基酸殘基70至C端之胞外結構域之DCIR特異性抗體或其功能性片段之用途,其係用以製造用於特異性抗原之抗原標的(疫苗接種)目的之疫苗,其中該特異性抗原可表現為重組抗原-抗體融合蛋白。
- 一種能特異性地結合DCIR胺基酸殘基70至C端之胞外結 構域之DCIR特異性抗體或其功能性片段之用途,其係用以製造用於提高樹突細胞效力之疫苗。
- 如請求項12之用途,其中該抗原包含細菌、病毒、真菌、原生動物或癌症蛋白。
- 一種免疫組合,其包含抗DCIR抗體或其功能性部分,其特徵在於該DCIR特異性抗體或其功能性片段能特異性地結合DCIR胺基酸殘基70至C端之胞外結構域;該DCIR特異性抗體或其功能性片段之進一步特徵在於其係已自哺乳動物細胞分泌,且進一步特徵在於抗原或毒素或兩者與該DCIR特異性抗體或其功能性片段結合,其中該DCIR特異性抗體包含選自SEQ ID NO:1至17之重鏈序列及選自SEQ ID NO:18至39之輕鏈序列。
- 如請求項15之免疫組合,其中該抗體係與黏連蛋白/停靠蛋白結合對之一組份結合。
- 如請求項15之免疫組合,其另外包含與抗原結合之該黏連蛋白-停靠蛋白結合對之補體組份。
- 如請求項15之免疫組合,其另外包含該黏連蛋白-停靠蛋白結合對之補體組份,其特徵在於該黏連蛋白-停靠蛋白結合對之補體組份與抗原為融合蛋白。
- 如請求項15之免疫組合,其中該抗原特異性結構域包含全長抗體、抗體可變區結構域、Fab片段、Fab'片段、F(ab)2片段、及Fv片段、及Fabc片段及/或具有該Fc結構域之部分之Fab片段。
- 如請求項15之免疫組合,其中該毒素係選自由以下組成 之群:放射性同位素、金屬、酶、肉毒桿菌毒素、破傷風毒素、蓖麻毒素、霍亂毒素、白喉毒素、黃麴黴毒素、產氣莢膜桿菌毒素、黴菌毒素、志賀毒素(shigatoxin)、葡萄球菌腸毒素B、T2、segui毒素(seguitoxin)、石房蛤毒素、相思豆毒素、微囊藻毒素、α毒素、河豚毒素、織錦芋螺毒素、蛇毒及蜘蛛毒。
- 如請求項15之免疫組合,其中該抗原係與該抗體融合之融合蛋白。
- 一種疫苗,其包含DCIR特異性抗體或其功能性片段,其特徵在於該DCIR特異性抗體或其功能性片段能特異性地結合DCIR胺基酸殘基70至C端之胞外結構域;該DCIR特異性抗體或其功能性片段之進一步特徵在於連接抗原,其中該抗原係藉由已與該DCIR特異性抗體或其功能性片段接觸之樹突細胞處理並遞呈。
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US88803207P | 2007-02-02 | 2007-02-02 |
Publications (2)
Publication Number | Publication Date |
---|---|
TW200902061A TW200902061A (en) | 2009-01-16 |
TWI446921B true TWI446921B (zh) | 2014-08-01 |
Family
ID=39682352
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
TW097104113A TWI446921B (zh) | 2007-02-02 | 2008-02-01 | 基於表現於抗原-表現細胞之樹突細胞免疫受體(dcir)之標的抗原之疫苗 |
Country Status (15)
Country | Link |
---|---|
US (5) | US8057798B2 (zh) |
EP (2) | EP2527363A1 (zh) |
JP (1) | JP5377330B2 (zh) |
KR (1) | KR20090114430A (zh) |
CN (1) | CN101679508B (zh) |
AU (1) | AU2008214032B2 (zh) |
BR (1) | BRPI0807160A2 (zh) |
CA (1) | CA2715044A1 (zh) |
HK (1) | HK1141812A1 (zh) |
IL (1) | IL200088A0 (zh) |
MX (1) | MX2009008140A (zh) |
NZ (2) | NZ578696A (zh) |
TW (1) | TWI446921B (zh) |
WO (1) | WO2008097866A2 (zh) |
ZA (1) | ZA200905347B (zh) |
Families Citing this family (59)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7563874B2 (en) | 1998-08-31 | 2009-07-21 | The Regents Of The University Of California | Therapeutic monoclonal antibodies that neutralize botulinum neurotoxins |
DK2114985T3 (en) * | 2007-02-02 | 2015-03-30 | Baylor Res Inst | Complexes of multivariable antigens and target antibody, a humanized |
TWI422594B (zh) | 2007-02-02 | 2014-01-11 | Baylor Res Inst | 經由樹狀細胞去唾液酸糖蛋白受體(dc-asgpr)接合抗原呈現細胞之藥劑 |
EP2527363A1 (en) | 2007-02-02 | 2012-11-28 | Baylor Research Institute | Vaccines based on targeting antigen to dcir expressed on antigen-presenting cells |
US8598321B2 (en) | 2007-03-22 | 2013-12-03 | The Regents Of The University Of California | Therapeutic monoclonal antibodies that neutralize botulinum neurotoxins |
CA2633246A1 (en) | 2008-06-19 | 2009-12-19 | Universite Laval | Identification of therapeutic agents for hiv infection |
WO2010104747A2 (en) | 2009-03-10 | 2010-09-16 | Baylor Research Institute | Antigen presenting cell targeted vaccines |
AU2010222928B2 (en) * | 2008-07-16 | 2012-11-29 | Baylor Research Institute | Antigen presenting cell targeted vaccines |
WO2010014854A2 (en) | 2008-07-31 | 2010-02-04 | The Regents Of The University Of California | Antibodies that neutralize botulinum neurotoxins |
CN102186499B (zh) * | 2008-08-20 | 2015-05-20 | Ibc医药公司 | 用于癌症治疗的对接和锁定(dnl)疫苗 |
DK2406286T3 (en) | 2009-03-10 | 2016-08-22 | Baylor Res Inst | Anti-cd40 antibodies and uses thereof |
FR2955773B1 (fr) | 2010-02-01 | 2017-05-26 | Commissariat A L'energie Atomique | Complexe moleculaire de ciblage des antigenes vers les cellules presentatrices d'antigene et ses applications pour la vaccination |
US20130058957A1 (en) * | 2010-02-23 | 2013-03-07 | The University Of Tokyo | Dendritic cell immunoreceptor agonist |
MX2012012833A (es) * | 2010-05-07 | 2012-11-30 | Baylor Res Inst | Cebado cruzado de celulas t cd8 positivas humanos moderada por inmunoreceptores de celulas dendriticas (dcir). |
US9517257B2 (en) | 2010-08-10 | 2016-12-13 | Ecole Polytechnique Federale De Lausanne (Epfl) | Erythrocyte-binding therapeutics |
US9850296B2 (en) | 2010-08-10 | 2017-12-26 | Ecole Polytechnique Federale De Lausanne (Epfl) | Erythrocyte-binding therapeutics |
CN108117586A (zh) | 2010-08-10 | 2018-06-05 | 洛桑聚合联合学院 | 红细胞结合性治疗剂 |
WO2012021834A1 (en) * | 2010-08-13 | 2012-02-16 | Baylor Research Institute | Novel vaccine adjuvants based on targeting adjuvants to antibodies directly to antigen-presenting cells |
WO2012047427A2 (en) | 2010-08-31 | 2012-04-12 | The Regents Of The University Of California | Antibodies for botulinum neurotoxins |
JP6190723B2 (ja) | 2010-12-01 | 2017-08-30 | アルダーバイオ ホールディングス エルエルシー | 抗ngf組成物およびその使用 |
US9884909B2 (en) | 2010-12-01 | 2018-02-06 | Alderbio Holdings Llc | Anti-NGF compositions and use thereof |
US9078878B2 (en) | 2010-12-01 | 2015-07-14 | Alderbio Holdings Llc | Anti-NGF antibodies that selectively inhibit the association of NGF with TrkA, without affecting the association of NGF with p75 |
US9067988B2 (en) | 2010-12-01 | 2015-06-30 | Alderbio Holdings Llc | Methods of preventing or treating pain using anti-NGF antibodies |
US9539324B2 (en) | 2010-12-01 | 2017-01-10 | Alderbio Holdings, Llc | Methods of preventing inflammation and treating pain using anti-NGF compositions |
US11214610B2 (en) | 2010-12-01 | 2022-01-04 | H. Lundbeck A/S | High-purity production of multi-subunit proteins such as antibodies in transformed microbes such as Pichia pastoris |
CN103561771B (zh) | 2011-03-17 | 2019-01-04 | 伯明翰大学 | 重新定向的免疫治疗 |
WO2012135132A1 (en) | 2011-03-25 | 2012-10-04 | Baylor Research Institute | Compositions and methods to immunize against hepatitis c virus |
TW201247700A (en) * | 2011-05-05 | 2012-12-01 | Baylor Res Inst | Immunoglobulin-like transcript (ILT) receptors as CD8 antagonists |
PT2782598T (pt) * | 2011-11-23 | 2020-09-02 | In3Bio Ltd Codan Services Ltd | Proteínas recombinantes e suas utilizações terapêuticas |
AU2012351347B2 (en) * | 2011-12-12 | 2016-05-19 | Baylor College Of Medicine | Process of expanding T cells |
GB201203442D0 (en) | 2012-02-28 | 2012-04-11 | Univ Birmingham | Immunotherapeutic molecules and uses |
CN103045627B (zh) * | 2012-11-09 | 2015-04-15 | 逢甲大学 | 于细胞内制造蛋白复合物的方法 |
CN103409451A (zh) * | 2013-06-28 | 2013-11-27 | 扬州维克斯生物科技有限公司 | 一种向树突状细胞dc靶向加载肿瘤抗原肽的方法 |
CA2916694C (en) | 2013-06-28 | 2023-01-17 | Baylor Research Institute | Dendritic cell asgpr targeting immunotherapeutics for multiple sclerosis |
JP7037884B2 (ja) | 2014-01-13 | 2022-03-17 | ベイラー リサーチ インスティテュート | Hpv及びhpv関連疾患に対する新規のワクチン |
US10046056B2 (en) | 2014-02-21 | 2018-08-14 | École Polytechnique Fédérale De Lausanne (Epfl) | Glycotargeting therapeutics |
JP6744227B2 (ja) | 2014-02-21 | 2020-08-19 | エコール・ポリテクニーク・フェデラル・ドゥ・ローザンヌ(ウペエフエル)Ecole Polytechnique Federale de Lausanne (EPFL) | 糖標的化治療剤 |
US10946079B2 (en) | 2014-02-21 | 2021-03-16 | Ecole Polytechnique Federale De Lausanne | Glycotargeting therapeutics |
US10953101B2 (en) | 2014-02-21 | 2021-03-23 | École Polytechnique Fédérale De Lausanne (Epfl) | Glycotargeting therapeutics |
AR099812A1 (es) | 2014-03-21 | 2016-08-17 | Abbvie Inc | Anticuerpos y conjugados de anticuerpo y fármaco anti-egfr |
CA2949081C (en) | 2014-05-16 | 2023-03-07 | Baylor Research Institute | Methods and compositions for treating autoimmune and inflammatory conditions |
JO3664B1 (ar) * | 2014-08-19 | 2020-08-27 | Merck Sharp & Dohme | أجسام مضادة لـ tigit |
WO2016118787A1 (en) * | 2015-01-21 | 2016-07-28 | University Of Florida Research Foundation, Inc. | Engineered receptor/ligand system for delivery of therapeutic agents |
CA2971288A1 (en) | 2015-02-02 | 2016-08-11 | The University Of Birmingham | Targeting moiety peptide epitope complexes having a plurality of t-cell epitopes |
CA3003482A1 (en) | 2015-11-19 | 2017-05-26 | Revitope Limited | Functional antibody fragment complementation for a two-components system for redirected killing of unwanted cells |
WO2017201635A1 (zh) * | 2016-05-23 | 2017-11-30 | 蔡胜和 | 透明质酸酶的细胞表达及其在实体瘤细胞治疗中的应用 |
EP3835322A3 (en) | 2016-06-08 | 2021-10-06 | AbbVie Inc. | Anti-b7-h3 antibodies and antibody drug conjugates |
MX2018015285A (es) | 2016-06-08 | 2019-09-18 | Abbvie Inc | Anticuerpos anti-b7-h3 y conjugados de anticuerpo y farmaco. |
US20200002421A1 (en) | 2016-06-08 | 2020-01-02 | Abbvie Inc. | Anti-b7-h3 antibodies and antibody drug conjugates |
JP2019524651A (ja) | 2016-06-08 | 2019-09-05 | アッヴィ・インコーポレイテッド | 抗cd98抗体及び抗体薬物コンジュゲート |
CA3114549A1 (en) | 2017-02-21 | 2018-08-30 | University Of Florida Research Foundation, Incorporated | Modified aav capsid proteins and uses thereof |
CA3064697A1 (en) | 2017-04-19 | 2018-10-25 | Bluefin Biomedicine, Inc. | Anti-vtcn1 antibodies and antibody drug conjugates |
WO2018232176A1 (en) | 2017-06-16 | 2018-12-20 | The University Of Chicago | Compositions and methods for inducing immune tolerance |
US10610585B2 (en) | 2017-09-26 | 2020-04-07 | Inserm (Institut National De La Sante Et De La Recherche Medicale) | Methods and compositions for treating and preventing HIV |
CN117004573A (zh) * | 2017-12-13 | 2023-11-07 | 苏州康聚生物科技有限公司 | 一种包含肿瘤抗原识别受体的免疫细胞及其应用 |
AU2019239850A1 (en) * | 2018-03-19 | 2020-10-29 | Lanier Biotherapeutics, Inc. | High affinity neutralizing monoclonal antibodies to programmed death ligand 1 (PD-L1) and uses thereof |
WO2021055816A1 (en) | 2019-09-18 | 2021-03-25 | Molecular Templates, Inc. | Pd-l1 binding molecules comprising shiga toxin a subunit scaffolds |
CN114423793A (zh) | 2019-09-18 | 2022-04-29 | 分子模板公司 | 包含志贺菌毒素a亚基支架的pd-l1结合分子 |
AR124681A1 (es) | 2021-01-20 | 2023-04-26 | Abbvie Inc | Conjugados anticuerpo-fármaco anti-egfr |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20050037001A1 (en) * | 2001-11-30 | 2005-02-17 | Germeraad Wilfred Thomas Vincent | APC targeting conjugate, an antigen-presenting cell contacted with such conjugate, their medical use, and methods of production |
Family Cites Families (17)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
NL154600B (nl) | 1971-02-10 | 1977-09-15 | Organon Nv | Werkwijze voor het aantonen en bepalen van specifiek bindende eiwitten en hun corresponderende bindbare stoffen. |
US3949064A (en) * | 1973-10-26 | 1976-04-06 | Baxter Laboratories, Inc. | Method of detecting antigens or antibodies |
US4174384A (en) * | 1975-06-30 | 1979-11-13 | Syva Company | Fluorescence quenching with immunological pairs in immunoassays |
US4554101A (en) | 1981-01-09 | 1985-11-19 | New York Blood Center, Inc. | Identification and preparation of epitopes on antigens and allergens on the basis of hydrophilicity |
AU6497694A (en) * | 1993-04-02 | 1994-10-24 | Ribogene, Inc. | Method for selective inactivation of viral replication |
US6451995B1 (en) * | 1996-03-20 | 2002-09-17 | Sloan-Kettering Institute For Cancer Research | Single chain FV polynucleotide or peptide constructs of anti-ganglioside GD2 antibodies, cells expressing same and related methods |
US7037510B2 (en) * | 1997-04-18 | 2006-05-02 | Statens Serum Institut | Hybrids of M. tuberculosis antigens |
NZ501777A (en) * | 1997-07-09 | 2001-10-26 | Schering Corp | Polypeptides encoding DCMP1 and DCMP2, including a fusion polypeptide of both DCMP1 and DCMP2 and antibodies thereof |
US20020025315A1 (en) * | 1998-01-14 | 2002-02-28 | Naveen N. Anand | Chimeric antibodies for delivery of antigens to selected cells of the immune system |
US6541011B2 (en) | 1998-02-11 | 2003-04-01 | Maxygen, Inc. | Antigen library immunization |
EP1046651A1 (en) * | 1999-04-19 | 2000-10-25 | Koninklijke Universiteit Nijmegen | Composition and method for modulating dendritic cell-T interaction |
US20050106700A1 (en) * | 2001-10-11 | 2005-05-19 | Tsuyoshi Nomura | Method of purifying recombinant fused protein and method of producing protein using the same |
WO2007103048A2 (en) * | 2006-03-01 | 2007-09-13 | Regents Of The University Of Colorado | Tlr agonist (flagellin)/cd40 agonist/antigen protein and dna conjugates and use thereof for inducing synergistic enhancement in immunity |
EP1991264B1 (en) * | 2006-03-07 | 2015-01-07 | Vaxinnate Corporation | Compositions that include hemagglutinin, methods of making and methods of use thereof |
EP2527363A1 (en) | 2007-02-02 | 2012-11-28 | Baylor Research Institute | Vaccines based on targeting antigen to dcir expressed on antigen-presenting cells |
DK2114985T3 (en) * | 2007-02-02 | 2015-03-30 | Baylor Res Inst | Complexes of multivariable antigens and target antibody, a humanized |
EP2570137A3 (en) * | 2007-11-07 | 2013-08-21 | Celldex Therapeutics, Inc. | Antibodies that bind human dendritic and epithelial cell 205 (DEC-205) |
-
2008
- 2008-02-01 EP EP12164572A patent/EP2527363A1/en not_active Withdrawn
- 2008-02-01 NZ NZ578696A patent/NZ578696A/en not_active IP Right Cessation
- 2008-02-01 BR BRPI0807160A patent/BRPI0807160A2/pt not_active IP Right Cessation
- 2008-02-01 JP JP2009548481A patent/JP5377330B2/ja not_active Expired - Fee Related
- 2008-02-01 KR KR1020097018301A patent/KR20090114430A/ko not_active Application Discontinuation
- 2008-02-01 AU AU2008214032A patent/AU2008214032B2/en not_active Ceased
- 2008-02-01 EP EP08728868.4A patent/EP2115002B1/en active Active
- 2008-02-01 MX MX2009008140A patent/MX2009008140A/es active IP Right Grant
- 2008-02-01 CN CN200880011285.1A patent/CN101679508B/zh not_active Expired - Fee Related
- 2008-02-01 US US12/024,897 patent/US8057798B2/en active Active
- 2008-02-01 WO PCT/US2008/052850 patent/WO2008097866A2/en active Application Filing
- 2008-02-01 TW TW097104113A patent/TWI446921B/zh not_active IP Right Cessation
- 2008-02-01 CA CA2715044A patent/CA2715044A1/en not_active Abandoned
- 2008-02-01 NZ NZ593450A patent/NZ593450A/xx not_active IP Right Cessation
-
2009
- 2009-07-27 IL IL200088A patent/IL200088A0/en unknown
- 2009-07-30 ZA ZA200905347A patent/ZA200905347B/xx unknown
-
2010
- 2010-09-01 HK HK10108281.9A patent/HK1141812A1/zh not_active IP Right Cessation
-
2011
- 2011-09-16 US US13/234,914 patent/US8449888B2/en not_active Expired - Fee Related
-
2012
- 2012-04-24 US US13/454,404 patent/US8586052B2/en active Active
-
2013
- 2013-04-29 US US13/872,793 patent/US9102730B2/en active Active
- 2013-10-03 US US14/045,454 patent/US9234040B2/en active Active
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20050037001A1 (en) * | 2001-11-30 | 2005-02-17 | Germeraad Wilfred Thomas Vincent | APC targeting conjugate, an antigen-presenting cell contacted with such conjugate, their medical use, and methods of production |
Non-Patent Citations (2)
Title |
---|
Bates et al., APCS EXPRESS DCIR, A NOVEL C-TYPE LECTIN SURFACE RECEPTOR CONTAINING AN IMMUNORECEPTOR TYROSINE-BASED INHIBITORY MOTIF1, the journal of immunology, 163, 1973-1983, 1999. * |
Craig et al., Engineered proteins containing the cohesin and dockerin domains from Clostridium thermocellum provides a reversible, high affinity interaction for biotechnology applications, Journal of Biotechnology, 121, 165-173, 2006. * |
Also Published As
Publication number | Publication date |
---|---|
US9102730B2 (en) | 2015-08-11 |
US20120004643A1 (en) | 2012-01-05 |
US9234040B2 (en) | 2016-01-12 |
US20130295120A1 (en) | 2013-11-07 |
WO2008097866A2 (en) | 2008-08-14 |
AU2008214032B2 (en) | 2012-06-28 |
KR20090114430A (ko) | 2009-11-03 |
US8449888B2 (en) | 2013-05-28 |
JP5377330B2 (ja) | 2013-12-25 |
EP2115002A2 (en) | 2009-11-11 |
US20120237513A1 (en) | 2012-09-20 |
MX2009008140A (es) | 2009-10-26 |
JP2010517538A (ja) | 2010-05-27 |
AU2008214032A1 (en) | 2008-08-14 |
HK1141812A1 (zh) | 2010-11-19 |
BRPI0807160A2 (pt) | 2018-09-25 |
US8586052B2 (en) | 2013-11-19 |
NZ593450A (en) | 2012-08-31 |
ZA200905347B (en) | 2010-04-28 |
IL200088A0 (en) | 2010-04-15 |
EP2115002A4 (en) | 2010-09-01 |
TW200902061A (en) | 2009-01-16 |
US20140134168A1 (en) | 2014-05-15 |
CN101679508A (zh) | 2010-03-24 |
EP2115002B1 (en) | 2014-08-20 |
NZ578696A (en) | 2012-01-12 |
CA2715044A1 (en) | 2008-08-14 |
CN101679508B (zh) | 2014-11-05 |
US20080241170A1 (en) | 2008-10-02 |
WO2008097866A3 (en) | 2008-12-24 |
EP2527363A1 (en) | 2012-11-28 |
US8057798B2 (en) | 2011-11-15 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
TWI446921B (zh) | 基於表現於抗原-表現細胞之樹突細胞免疫受體(dcir)之標的抗原之疫苗 | |
US11173202B2 (en) | Agents that engage antigen-presenting cells through dendritic cell asialoglycoprotein receptor (DC-ASGPR) | |
EP2129773B1 (en) | Therapeutic applications of activation of human antigen-presenting cells through dectin-1 | |
AU2012245170B2 (en) | Agents that engage antigen - presenting cells through dendritic cell asialoglycoprotein receptor (dc-asgpr) | |
AU2014240262B2 (en) | Agents that engage antigen - presenting cells through dendritic cell asialoglycoprotein receptor (dc-asgpr) |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
MM4A | Annulment or lapse of patent due to non-payment of fees |