WO2010037539A1 - Composition comprising a complexed (m)rna and a naked mrna for providing or enhancing an immunostimulatory response in a mammal and uses thereof - Google Patents
Composition comprising a complexed (m)rna and a naked mrna for providing or enhancing an immunostimulatory response in a mammal and uses thereof Download PDFInfo
- Publication number
- WO2010037539A1 WO2010037539A1 PCT/EP2009/007032 EP2009007032W WO2010037539A1 WO 2010037539 A1 WO2010037539 A1 WO 2010037539A1 EP 2009007032 W EP2009007032 W EP 2009007032W WO 2010037539 A1 WO2010037539 A1 WO 2010037539A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- rna
- mage
- immunostimulatory composition
- antigens
- sequence
- Prior art date
Links
- 230000003308 immunostimulating effect Effects 0.000 title claims abstract description 136
- 239000000203 mixture Substances 0.000 title claims abstract description 88
- 108020004999 messenger RNA Proteins 0.000 title claims abstract description 64
- 108091032973 (ribonucleotides)n+m Proteins 0.000 title claims abstract description 40
- 241000124008 Mammalia Species 0.000 title claims abstract description 15
- 230000004044 response Effects 0.000 title description 9
- 230000002708 enhancing effect Effects 0.000 title description 3
- 239000002671 adjuvant Substances 0.000 claims abstract description 101
- 108090000623 proteins and genes Proteins 0.000 claims abstract description 70
- 102000004169 proteins and genes Human genes 0.000 claims abstract description 68
- 239000000427 antigen Substances 0.000 claims abstract description 51
- 102000036639 antigens Human genes 0.000 claims abstract description 48
- 108091007433 antigens Proteins 0.000 claims abstract description 47
- 125000002091 cationic group Chemical group 0.000 claims abstract description 38
- 150000001875 compounds Chemical class 0.000 claims abstract description 36
- 238000000034 method Methods 0.000 claims abstract description 19
- 230000033289 adaptive immune response Effects 0.000 claims abstract description 14
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 12
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 7
- 229960005486 vaccine Drugs 0.000 claims abstract description 7
- 238000011282 treatment Methods 0.000 claims abstract description 4
- -1 Bac715-24 Proteins 0.000 claims description 202
- 235000018102 proteins Nutrition 0.000 claims description 67
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 47
- 102000004196 processed proteins & peptides Human genes 0.000 claims description 31
- 150000001413 amino acids Chemical group 0.000 claims description 14
- 108091034117 Oligonucleotide Proteins 0.000 claims description 13
- 229920000642 polymer Polymers 0.000 claims description 12
- 229940024606 amino acid Drugs 0.000 claims description 11
- 108020005544 Antisense RNA Proteins 0.000 claims description 10
- 206010028980 Neoplasm Diseases 0.000 claims description 9
- 102000007327 Protamines Human genes 0.000 claims description 9
- 108010007568 Protamines Proteins 0.000 claims description 9
- 230000001580 bacterial effect Effects 0.000 claims description 9
- 229940048914 protamine Drugs 0.000 claims description 9
- 108010051109 Cell-Penetrating Peptides Proteins 0.000 claims description 8
- 102000020313 Cell-Penetrating Peptides Human genes 0.000 claims description 8
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 claims description 8
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 claims description 8
- 229920002873 Polyethylenimine Polymers 0.000 claims description 8
- 239000003184 complementary RNA Substances 0.000 claims description 8
- 108090000538 Caspase-8 Proteins 0.000 claims description 7
- 102100038358 Prostate-specific antigen Human genes 0.000 claims description 7
- 108020004459 Small interfering RNA Proteins 0.000 claims description 7
- 230000027455 binding Effects 0.000 claims description 7
- 235000000346 sugar Nutrition 0.000 claims description 7
- 102100025064 Cellular tumor antigen p53 Human genes 0.000 claims description 6
- 102100041003 Glutamate carboxypeptidase 2 Human genes 0.000 claims description 6
- 229920006317 cationic polymer Polymers 0.000 claims description 6
- 239000000412 dendrimer Substances 0.000 claims description 6
- 229920000736 dendritic polymer Polymers 0.000 claims description 6
- 229920000729 poly(L-lysine) polymer Polymers 0.000 claims description 6
- 229920000962 poly(amidoamine) Polymers 0.000 claims description 6
- ATHGHQPFGPMSJY-UHFFFAOYSA-N spermidine Chemical compound NCCCCNCCCN ATHGHQPFGPMSJY-UHFFFAOYSA-N 0.000 claims description 6
- LKKMLIBUAXYLOY-UHFFFAOYSA-N 3-Amino-1-methyl-5H-pyrido[4,3-b]indole Chemical compound N1C2=CC=CC=C2C2=C1C=C(N)N=C2C LKKMLIBUAXYLOY-UHFFFAOYSA-N 0.000 claims description 5
- 102100024423 Carbonic anhydrase 9 Human genes 0.000 claims description 5
- 108091026890 Coding region Proteins 0.000 claims description 5
- 101001133056 Homo sapiens Mucin-1 Proteins 0.000 claims description 5
- 101001131990 Homo sapiens Peroxidasin homolog Proteins 0.000 claims description 5
- 102100031413 L-dopachrome tautomerase Human genes 0.000 claims description 5
- 101710093778 L-dopachrome tautomerase Proteins 0.000 claims description 5
- 102100034256 Mucin-1 Human genes 0.000 claims description 5
- 102100034601 Peroxidasin homolog Human genes 0.000 claims description 5
- 108010072866 Prostate-Specific Antigen Proteins 0.000 claims description 5
- 102100036234 Synaptonemal complex protein 1 Human genes 0.000 claims description 5
- 108010053099 Vascular Endothelial Growth Factor Receptor-2 Proteins 0.000 claims description 5
- 102100033177 Vascular endothelial growth factor receptor 2 Human genes 0.000 claims description 5
- PFNFFQXMRSDOHW-UHFFFAOYSA-N spermine Chemical compound NCCCNCCCCNCCCN PFNFFQXMRSDOHW-UHFFFAOYSA-N 0.000 claims description 5
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 claims description 4
- 102100021305 Acyl-CoA:lysophosphatidylglycerol acyltransferase 1 Human genes 0.000 claims description 4
- 239000004475 Arginine Substances 0.000 claims description 4
- 102100026548 Caspase-8 Human genes 0.000 claims description 4
- 229920001661 Chitosan Polymers 0.000 claims description 4
- 102100037362 Fibronectin Human genes 0.000 claims description 4
- 101001042227 Homo sapiens Acyl-CoA:lysophosphatidylglycerol acyltransferase 1 Proteins 0.000 claims description 4
- 101000892862 Homo sapiens Glutamate carboxypeptidase 2 Proteins 0.000 claims description 4
- 101000628547 Homo sapiens Metalloreductase STEAP1 Proteins 0.000 claims description 4
- 101000610208 Homo sapiens Poly(A) polymerase gamma Proteins 0.000 claims description 4
- 101001130763 Homo sapiens Protein OS-9 Proteins 0.000 claims description 4
- 101000880770 Homo sapiens Protein SSX2 Proteins 0.000 claims description 4
- 101000842302 Homo sapiens Protein-cysteine N-palmitoyltransferase HHAT Proteins 0.000 claims description 4
- 102100027735 Hyaluronan mediated motility receptor Human genes 0.000 claims description 4
- 102100022430 Melanocyte protein PMEL Human genes 0.000 claims description 4
- 102100026712 Metalloreductase STEAP1 Human genes 0.000 claims description 4
- 101100368144 Mus musculus Synb gene Proteins 0.000 claims description 4
- 241000737052 Naso hexacanthus Species 0.000 claims description 4
- 108010038807 Oligopeptides Proteins 0.000 claims description 4
- 102000015636 Oligopeptides Human genes 0.000 claims description 4
- 102100040153 Poly(A) polymerase gamma Human genes 0.000 claims description 4
- 229920001212 Poly(beta amino esters) Polymers 0.000 claims description 4
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Chemical compound OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 claims description 4
- ATUOYWHBWRKTHZ-UHFFFAOYSA-N Propane Chemical compound CCC ATUOYWHBWRKTHZ-UHFFFAOYSA-N 0.000 claims description 4
- 101710120463 Prostate stem cell antigen Proteins 0.000 claims description 4
- 102100036735 Prostate stem cell antigen Human genes 0.000 claims description 4
- 102100037686 Protein SSX2 Human genes 0.000 claims description 4
- 101710173694 Short transient receptor potential channel 2 Proteins 0.000 claims description 4
- 101710192266 Tegument protein VP22 Proteins 0.000 claims description 4
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 claims description 4
- 229910052757 nitrogen Inorganic materials 0.000 claims description 4
- 229960005489 paracetamol Drugs 0.000 claims description 4
- 108010043655 penetratin Proteins 0.000 claims description 4
- MCYTYTUNNNZWOK-LCLOTLQISA-N penetratin Chemical compound C([C@H](NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H]([C@@H](C)CC)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](N)CCCNC(N)=N)[C@@H](C)CC)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(N)=O)C1=CC=CC=C1 MCYTYTUNNNZWOK-LCLOTLQISA-N 0.000 claims description 4
- 108010011110 polyarginine Proteins 0.000 claims description 4
- 230000003612 virological effect Effects 0.000 claims description 4
- SSOORFWOBGFTHL-OTEJMHTDSA-N (4S)-5-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-6-amino-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[2-[(2S)-2-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-6-amino-1-[[(2S)-1-[[(2S)-1-[[(2S,3S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-6-amino-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-5-amino-1-[[(2S)-1-[[(2S)-1-[[(2S)-6-amino-1-[[(2S)-6-amino-1-[[(2S)-1-[[(2S)-1-[[(2S)-5-amino-1-[[(2S)-5-carbamimidamido-1-[[(2S)-5-carbamimidamido-1-[[(1S)-4-carbamimidamido-1-carboxybutyl]amino]-1-oxopentan-2-yl]amino]-1-oxopentan-2-yl]amino]-1,5-dioxopentan-2-yl]amino]-5-carbamimidamido-1-oxopentan-2-yl]amino]-5-carbamimidamido-1-oxopentan-2-yl]amino]-1-oxohexan-2-yl]amino]-1-oxohexan-2-yl]amino]-5-carbamimidamido-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-1,5-dioxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-hydroxy-1-oxopropan-2-yl]amino]-3-hydroxy-1-oxopropan-2-yl]amino]-3-hydroxy-1-oxopropan-2-yl]amino]-1-oxopropan-2-yl]amino]-1-oxohexan-2-yl]amino]-3-hydroxy-1-oxopropan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-3-methyl-1-oxopentan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]amino]-5-carbamimidamido-1-oxopentan-2-yl]amino]-1-oxohexan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]amino]-5-carbamimidamido-1-oxopentan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-1-oxopropan-2-yl]amino]-5-carbamimidamido-1-oxopentan-2-yl]carbamoyl]pyrrolidin-1-yl]-2-oxoethyl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-5-carbamimidamido-1-oxopentan-2-yl]amino]-1-oxohexan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]amino]-5-carbamimidamido-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-3-(1H-imidazol-4-yl)-1-oxopropan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-4-[[(2S)-2-[[(2S)-2-[[(2S)-2,6-diaminohexanoyl]amino]-3-methylbutanoyl]amino]propanoyl]amino]-5-oxopentanoic acid Chemical compound CC[C@H](C)[C@H](NC(=O)[C@@H](NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@@H]1CCCN1C(=O)CNC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@@H](N)CCCCN)C(C)C)C(C)C)C(C)C)C(C)C)C(C)C)C(C)C)C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O SSOORFWOBGFTHL-OTEJMHTDSA-N 0.000 claims description 3
- BJHCYTJNPVGSBZ-YXSASFKJSA-N 1-[4-[6-amino-5-[(Z)-methoxyiminomethyl]pyrimidin-4-yl]oxy-2-chlorophenyl]-3-ethylurea Chemical compound CCNC(=O)Nc1ccc(Oc2ncnc(N)c2\C=N/OC)cc1Cl BJHCYTJNPVGSBZ-YXSASFKJSA-N 0.000 claims description 3
- 102100030310 5,6-dihydroxyindole-2-carboxylic acid oxidase Human genes 0.000 claims description 3
- 102100037982 Alpha-1,6-mannosylglycoprotein 6-beta-N-acetylglucosaminyltransferase A Human genes 0.000 claims description 3
- 102000052587 Anaphase-Promoting Complex-Cyclosome Apc3 Subunit Human genes 0.000 claims description 3
- 108700004606 Anaphase-Promoting Complex-Cyclosome Apc3 Subunit Proteins 0.000 claims description 3
- 102100021569 Apoptosis regulator Bcl-2 Human genes 0.000 claims description 3
- 102000036365 BRCA1 Human genes 0.000 claims description 3
- 108700020463 BRCA1 Proteins 0.000 claims description 3
- 101150072950 BRCA1 gene Proteins 0.000 claims description 3
- 108700020462 BRCA2 Proteins 0.000 claims description 3
- 102100021663 Baculoviral IAP repeat-containing protein 5 Human genes 0.000 claims description 3
- 101150008921 Brca2 gene Proteins 0.000 claims description 3
- 102100029894 Bromodomain testis-specific protein Human genes 0.000 claims description 3
- 101150108242 CDC27 gene Proteins 0.000 claims description 3
- 102100039510 Cancer/testis antigen 2 Human genes 0.000 claims description 3
- 102100025475 Carcinoembryonic antigen-related cell adhesion molecule 5 Human genes 0.000 claims description 3
- 102100038916 Caspase-5 Human genes 0.000 claims description 3
- 108010025464 Cyclin-Dependent Kinase 4 Proteins 0.000 claims description 3
- 108010009392 Cyclin-Dependent Kinase Inhibitor p16 Proteins 0.000 claims description 3
- 102100036252 Cyclin-dependent kinase 4 Human genes 0.000 claims description 3
- 102100024458 Cyclin-dependent kinase inhibitor 2A Human genes 0.000 claims description 3
- 101100216227 Dictyostelium discoideum anapc3 gene Proteins 0.000 claims description 3
- 101150084967 EPCAM gene Proteins 0.000 claims description 3
- 102100039788 GTPase NRas Human genes 0.000 claims description 3
- 102100032530 Glypican-3 Human genes 0.000 claims description 3
- 208000009889 Herpes Simplex Diseases 0.000 claims description 3
- 101000794028 Homo sapiens Bromodomain testis-specific protein Proteins 0.000 claims description 3
- 101000889345 Homo sapiens Cancer/testis antigen 2 Proteins 0.000 claims description 3
- 101000914324 Homo sapiens Carcinoembryonic antigen-related cell adhesion molecule 5 Proteins 0.000 claims description 3
- 101000721661 Homo sapiens Cellular tumor antigen p53 Proteins 0.000 claims description 3
- 101000744505 Homo sapiens GTPase NRas Proteins 0.000 claims description 3
- 101001014668 Homo sapiens Glypican-3 Proteins 0.000 claims description 3
- 101001055144 Homo sapiens Interleukin-2 receptor subunit alpha Proteins 0.000 claims description 3
- 101001057156 Homo sapiens Melanoma-associated antigen C2 Proteins 0.000 claims description 3
- 101000617725 Homo sapiens Pregnancy-specific beta-1-glycoprotein 2 Proteins 0.000 claims description 3
- 101000591201 Homo sapiens Receptor-type tyrosine-protein phosphatase kappa Proteins 0.000 claims description 3
- 101000914484 Homo sapiens T-lymphocyte activation antigen CD80 Proteins 0.000 claims description 3
- 101000648075 Homo sapiens Trafficking protein particle complex subunit 1 Proteins 0.000 claims description 3
- 101000851376 Homo sapiens Tumor necrosis factor receptor superfamily member 8 Proteins 0.000 claims description 3
- 108010002616 Interleukin-5 Proteins 0.000 claims description 3
- 102100028389 Melanoma antigen recognized by T-cells 1 Human genes 0.000 claims description 3
- 102100027252 Melanoma-associated antigen C2 Human genes 0.000 claims description 3
- 102100027347 Neural cell adhesion molecule 1 Human genes 0.000 claims description 3
- 102100033174 Neutrophil elastase Human genes 0.000 claims description 3
- 102100036961 Nuclear mitotic apparatus protein 1 Human genes 0.000 claims description 3
- 102100031492 Protein OS-9 Human genes 0.000 claims description 3
- 102100034089 Receptor-type tyrosine-protein phosphatase kappa Human genes 0.000 claims description 3
- 108010002687 Survivin Proteins 0.000 claims description 3
- 102100027222 T-lymphocyte activation antigen CD80 Human genes 0.000 claims description 3
- 108700019889 TEL-AML1 fusion Proteins 0.000 claims description 3
- 102100025256 Trafficking protein particle complex subunit 1 Human genes 0.000 claims description 3
- 102100036857 Tumor necrosis factor receptor superfamily member 8 Human genes 0.000 claims description 3
- 201000011510 cancer Diseases 0.000 claims description 3
- 102000052116 epidermal growth factor receptor activity proteins Human genes 0.000 claims description 3
- 108700015053 epidermal growth factor receptor activity proteins Proteins 0.000 claims description 3
- 230000001965 increasing effect Effects 0.000 claims description 3
- PUPNJSIFIXXJCH-UHFFFAOYSA-N n-(4-hydroxyphenyl)-2-(1,1,3-trioxo-1,2-benzothiazol-2-yl)acetamide Chemical compound C1=CC(O)=CC=C1NC(=O)CN1S(=O)(=O)C2=CC=CC=C2C1=O PUPNJSIFIXXJCH-UHFFFAOYSA-N 0.000 claims description 3
- YOHYSYJDKVYCJI-UHFFFAOYSA-N n-[3-[[6-[3-(trifluoromethyl)anilino]pyrimidin-4-yl]amino]phenyl]cyclopropanecarboxamide Chemical compound FC(F)(F)C1=CC=CC(NC=2N=CN=C(NC=3C=C(NC(=O)C4CC4)C=CC=3)C=2)=C1 YOHYSYJDKVYCJI-UHFFFAOYSA-N 0.000 claims description 3
- 229920001282 polysaccharide Polymers 0.000 claims description 3
- 239000005017 polysaccharide Substances 0.000 claims description 3
- 229940063673 spermidine Drugs 0.000 claims description 3
- 101150047061 tag-72 gene Proteins 0.000 claims description 3
- CPCWCRHPTDMVFU-UHFFFAOYSA-N (2-hydroxy-4,5-dioctadecoxypentyl)-dimethylazanium;chloride Chemical compound [Cl-].CCCCCCCCCCCCCCCCCCOCC(CC(O)C[NH+](C)C)OCCCCCCCCCCCCCCCCCC CPCWCRHPTDMVFU-UHFFFAOYSA-N 0.000 claims description 2
- WMLBMYGMIFJTCS-HUROMRQRSA-N (2r,3s,5r)-2-[(9-phenylxanthen-9-yl)oxymethyl]-5-purin-9-yloxolan-3-ol Chemical compound C([C@H]1O[C@H](C[C@@H]1O)N1C2=NC=NC=C2N=C1)OC1(C2=CC=CC=C2OC2=CC=CC=C21)C1=CC=CC=C1 WMLBMYGMIFJTCS-HUROMRQRSA-N 0.000 claims description 2
- 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 2
- SNKAWJBJQDLSFF-NVKMUCNASA-N 1,2-dioleoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCC\C=C/CCCCCCCC SNKAWJBJQDLSFF-NVKMUCNASA-N 0.000 claims description 2
- 102100039583 116 kDa U5 small nuclear ribonucleoprotein component Human genes 0.000 claims description 2
- LDGWQMRUWMSZIU-LQDDAWAPSA-M 2,3-bis[(z)-octadec-9-enoxy]propyl-trimethylazanium;chloride Chemical compound [Cl-].CCCCCCCC\C=C/CCCCCCCCOCC(C[N+](C)(C)C)OCCCCCCCC\C=C/CCCCCCCC LDGWQMRUWMSZIU-LQDDAWAPSA-M 0.000 claims description 2
- WALUVDCNGPQPOD-UHFFFAOYSA-M 2,3-di(tetradecoxy)propyl-(2-hydroxyethyl)-dimethylazanium;bromide Chemical compound [Br-].CCCCCCCCCCCCCCOCC(C[N+](C)(C)CCO)OCCCCCCCCCCCCCC WALUVDCNGPQPOD-UHFFFAOYSA-M 0.000 claims description 2
- GVDKLYIMIVTKOA-UHFFFAOYSA-N 2-(2,3-dihexadecoxypropoxymethoxy)ethyl-trimethylazanium Chemical compound CCCCCCCCCCCCCCCCOCC(COCOCC[N+](C)(C)C)OCCCCCCCCCCCCCCCC GVDKLYIMIVTKOA-UHFFFAOYSA-N 0.000 claims description 2
- LTHJXDSHSVNJKG-UHFFFAOYSA-N 2-[2-[2-[2-(2-methylprop-2-enoyloxy)ethoxy]ethoxy]ethoxy]ethyl 2-methylprop-2-enoate Chemical compound CC(=C)C(=O)OCCOCCOCCOCCOC(=O)C(C)=C LTHJXDSHSVNJKG-UHFFFAOYSA-N 0.000 claims description 2
- HYRQVGHJHUTCJL-UHFFFAOYSA-M 3,3-di(tetradecoxy)propyl-(2-hydroxyethyl)-dimethylazanium;bromide Chemical compound [Br-].CCCCCCCCCCCCCCOC(CC[N+](C)(C)CCO)OCCCCCCCCCCCCCC HYRQVGHJHUTCJL-UHFFFAOYSA-M 0.000 claims description 2
- WEVYNIUIFUYDGI-UHFFFAOYSA-N 3-[6-[4-(trifluoromethoxy)anilino]-4-pyrimidinyl]benzamide Chemical compound NC(=O)C1=CC=CC(C=2N=CN=C(NC=3C=CC(OC(F)(F)F)=CC=3)C=2)=C1 WEVYNIUIFUYDGI-UHFFFAOYSA-N 0.000 claims description 2
- 101710163881 5,6-dihydroxyindole-2-carboxylic acid oxidase Proteins 0.000 claims description 2
- 102100033793 ALK tyrosine kinase receptor Human genes 0.000 claims description 2
- 102100032959 Alpha-actinin-4 Human genes 0.000 claims description 2
- 102100036526 Anoctamin-7 Human genes 0.000 claims description 2
- 108700031308 Antennapedia Homeodomain Proteins 0.000 claims description 2
- 108091023037 Aptamer Proteins 0.000 claims description 2
- 102100038080 B-cell receptor CD22 Human genes 0.000 claims description 2
- 102100024222 B-lymphocyte antigen CD19 Human genes 0.000 claims description 2
- 102100022005 B-lymphocyte antigen CD20 Human genes 0.000 claims description 2
- 102100027522 Baculoviral IAP repeat-containing protein 7 Human genes 0.000 claims description 2
- 108010064528 Basigin Proteins 0.000 claims description 2
- 102000015279 Basigin Human genes 0.000 claims description 2
- 102000015735 Beta-catenin Human genes 0.000 claims description 2
- 108060000903 Beta-catenin Proteins 0.000 claims description 2
- 108700012439 CA9 Proteins 0.000 claims description 2
- 102100024217 CAMPATH-1 antigen Human genes 0.000 claims description 2
- 108010065524 CD52 Antigen Proteins 0.000 claims description 2
- 101150116874 CML28 gene Proteins 0.000 claims description 2
- 108060001064 Calcitonin Proteins 0.000 claims description 2
- 102100039532 Calcium-activated chloride channel regulator 2 Human genes 0.000 claims description 2
- 102100029968 Calreticulin Human genes 0.000 claims description 2
- 241000282836 Camelus dromedarius Species 0.000 claims description 2
- 108090000994 Catalytic RNA Proteins 0.000 claims description 2
- 102000053642 Catalytic RNA Human genes 0.000 claims description 2
- 102100039361 Chondrosarcoma-associated gene 2/3 protein Human genes 0.000 claims description 2
- 102100025680 Complement decay-accelerating factor Human genes 0.000 claims description 2
- 229920000858 Cyclodextrin Polymers 0.000 claims description 2
- XULFJDKZVHTRLG-JDVCJPALSA-N DOSPA trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F.CCCCCCCC\C=C/CCCCCCCCOCC(C[N+](C)(C)CCNC(=O)C(CCCNCCCN)NCCCN)OCCCCCCCC\C=C/CCCCCCCC XULFJDKZVHTRLG-JDVCJPALSA-N 0.000 claims description 2
- 102100040606 Dermatan-sulfate epimerase Human genes 0.000 claims description 2
- 229920002307 Dextran Polymers 0.000 claims description 2
- 108700006830 Drosophila Antp Proteins 0.000 claims description 2
- 101100219190 Drosophila melanogaster byn gene Proteins 0.000 claims description 2
- 102100037238 E3 ubiquitin-protein ligase UBR4 Human genes 0.000 claims description 2
- 102100035078 ETS-related transcription factor Elf-2 Human genes 0.000 claims description 2
- 108010055196 EphA2 Receptor Proteins 0.000 claims description 2
- 108010055191 EphA3 Receptor Proteins 0.000 claims description 2
- 102100030340 Ephrin type-A receptor 2 Human genes 0.000 claims description 2
- 102100030324 Ephrin type-A receptor 3 Human genes 0.000 claims description 2
- 101100129584 Escherichia coli (strain K12) trg gene Proteins 0.000 claims description 2
- 102100038975 Exosome complex component RRP46 Human genes 0.000 claims description 2
- 102100028043 Fibroblast growth factor 3 Human genes 0.000 claims description 2
- 102100028073 Fibroblast growth factor 5 Human genes 0.000 claims description 2
- 108090000382 Fibroblast growth factor 6 Proteins 0.000 claims description 2
- 102100028075 Fibroblast growth factor 6 Human genes 0.000 claims description 2
- 102000003817 Fos-related antigen 1 Human genes 0.000 claims description 2
- 108090000123 Fos-related antigen 1 Proteins 0.000 claims description 2
- 102100039717 G antigen 1 Human genes 0.000 claims description 2
- 102100040003 G antigen 2D Human genes 0.000 claims description 2
- 102100039699 G antigen 4 Human genes 0.000 claims description 2
- 102100039698 G antigen 5 Human genes 0.000 claims description 2
- 101710092267 G antigen 5 Proteins 0.000 claims description 2
- 102100039713 G antigen 6 Human genes 0.000 claims description 2
- 101710092269 G antigen 6 Proteins 0.000 claims description 2
- 102100024405 GPI-linked NAD(P)(+)-arginine ADP-ribosyltransferase 1 Human genes 0.000 claims description 2
- 101710144640 GPI-linked NAD(P)(+)-arginine ADP-ribosyltransferase 1 Proteins 0.000 claims description 2
- JZNWSCPGTDBMEW-UHFFFAOYSA-N Glycerophosphorylethanolamin Natural products NCCOP(O)(=O)OCC(O)CO JZNWSCPGTDBMEW-UHFFFAOYSA-N 0.000 claims description 2
- 108010074032 HLA-A2 Antigen Proteins 0.000 claims description 2
- 102000025850 HLA-A2 Antigen Human genes 0.000 claims description 2
- 229920000209 Hexadimethrine bromide Polymers 0.000 claims description 2
- 102100038970 Histone-lysine N-methyltransferase EZH2 Human genes 0.000 claims description 2
- 102000006947 Histones Human genes 0.000 claims description 2
- 108010033040 Histones Proteins 0.000 claims description 2
- 101000608799 Homo sapiens 116 kDa U5 small nuclear ribonucleoprotein component Proteins 0.000 claims description 2
- 101000928370 Homo sapiens Anoctamin-7 Proteins 0.000 claims description 2
- 101000971171 Homo sapiens Apoptosis regulator Bcl-2 Proteins 0.000 claims description 2
- 101000884305 Homo sapiens B-cell receptor CD22 Proteins 0.000 claims description 2
- 101000980825 Homo sapiens B-lymphocyte antigen CD19 Proteins 0.000 claims description 2
- 101000897405 Homo sapiens B-lymphocyte antigen CD20 Proteins 0.000 claims description 2
- 101000888580 Homo sapiens Calcium-activated chloride channel regulator 2 Proteins 0.000 claims description 2
- 101000914321 Homo sapiens Carcinoembryonic antigen-related cell adhesion molecule 7 Proteins 0.000 claims description 2
- 101000741072 Homo sapiens Caspase-5 Proteins 0.000 claims description 2
- 101000745414 Homo sapiens Chondrosarcoma-associated gene 2/3 protein Proteins 0.000 claims description 2
- 101000856022 Homo sapiens Complement decay-accelerating factor Proteins 0.000 claims description 2
- 101000807547 Homo sapiens E3 ubiquitin-protein ligase UBR4 Proteins 0.000 claims description 2
- 101000877377 Homo sapiens ETS-related transcription factor Elf-2 Proteins 0.000 claims description 2
- 101100389965 Homo sapiens EXOSC5 gene Proteins 0.000 claims description 2
- 101000886137 Homo sapiens G antigen 1 Proteins 0.000 claims description 2
- 101000886678 Homo sapiens G antigen 2D Proteins 0.000 claims description 2
- 101000886136 Homo sapiens G antigen 4 Proteins 0.000 claims description 2
- 101000893968 Homo sapiens G antigen 7 Proteins 0.000 claims description 2
- 101000882127 Homo sapiens Histone-lysine N-methyltransferase EZH2 Proteins 0.000 claims description 2
- 101001081176 Homo sapiens Hyaluronan mediated motility receptor Proteins 0.000 claims description 2
- 101001057504 Homo sapiens Interferon-stimulated gene 20 kDa protein Proteins 0.000 claims description 2
- 101001054842 Homo sapiens Leucine zipper protein 4 Proteins 0.000 claims description 2
- 101000578943 Homo sapiens MAGE-like protein 2 Proteins 0.000 claims description 2
- 101001014223 Homo sapiens MAPK/MAK/MRK overlapping kinase Proteins 0.000 claims description 2
- 101000578784 Homo sapiens Melanoma antigen recognized by T-cells 1 Proteins 0.000 claims description 2
- 101001036689 Homo sapiens Melanoma-associated antigen B5 Proteins 0.000 claims description 2
- 101001036675 Homo sapiens Melanoma-associated antigen B6 Proteins 0.000 claims description 2
- 101001036406 Homo sapiens Melanoma-associated antigen C1 Proteins 0.000 claims description 2
- 101001057159 Homo sapiens Melanoma-associated antigen C3 Proteins 0.000 claims description 2
- 101001057154 Homo sapiens Melanoma-associated antigen D2 Proteins 0.000 claims description 2
- 101000623901 Homo sapiens Mucin-16 Proteins 0.000 claims description 2
- 101001133081 Homo sapiens Mucin-2 Proteins 0.000 claims description 2
- 101000934338 Homo sapiens Myeloid cell surface antigen CD33 Proteins 0.000 claims description 2
- 101000581981 Homo sapiens Neural cell adhesion molecule 1 Proteins 0.000 claims description 2
- 101001024605 Homo sapiens Next to BRCA1 gene 1 protein Proteins 0.000 claims description 2
- 101001109282 Homo sapiens NudC domain-containing protein 1 Proteins 0.000 claims description 2
- 101000721757 Homo sapiens Olfactory receptor 51E2 Proteins 0.000 claims description 2
- 101001114052 Homo sapiens P antigen family member 4 Proteins 0.000 claims description 2
- 101000741896 Homo sapiens POTE ankyrin domain family member D Proteins 0.000 claims description 2
- 101000619805 Homo sapiens Peroxiredoxin-5, mitochondrial Proteins 0.000 claims description 2
- 101001091365 Homo sapiens Plasma kallikrein Proteins 0.000 claims description 2
- 101000874141 Homo sapiens Probable ATP-dependent RNA helicase DDX43 Proteins 0.000 claims description 2
- 101001095095 Homo sapiens Proline-rich acidic protein 1 Proteins 0.000 claims description 2
- 101000605534 Homo sapiens Prostate-specific antigen Proteins 0.000 claims description 2
- 101001109419 Homo sapiens RNA-binding protein NOB1 Proteins 0.000 claims description 2
- 101001073409 Homo sapiens Retrotransposon-derived protein PEG10 Proteins 0.000 claims description 2
- 101000711466 Homo sapiens SAM pointed domain-containing Ets transcription factor Proteins 0.000 claims description 2
- 101000821981 Homo sapiens Sarcoma antigen 1 Proteins 0.000 claims description 2
- 101000643620 Homo sapiens Synaptonemal complex protein 1 Proteins 0.000 claims description 2
- 101000716102 Homo sapiens T-cell surface glycoprotein CD4 Proteins 0.000 claims description 2
- 101000904724 Homo sapiens Transmembrane glycoprotein NMB Proteins 0.000 claims description 2
- 101000955999 Homo sapiens V-set domain-containing T-cell activation inhibitor 1 Proteins 0.000 claims description 2
- 108050002021 Integrator complex subunit 2 Proteins 0.000 claims description 2
- 102100038356 Kallikrein-2 Human genes 0.000 claims description 2
- 102100034872 Kallikrein-4 Human genes 0.000 claims description 2
- 108010063045 Lactoferrin Proteins 0.000 claims description 2
- 102100032241 Lactotransferrin Human genes 0.000 claims description 2
- 108010000851 Laminin Receptors Proteins 0.000 claims description 2
- 102000002297 Laminin Receptors Human genes 0.000 claims description 2
- 102100026910 Leucine zipper protein 4 Human genes 0.000 claims description 2
- 239000004472 Lysine Substances 0.000 claims description 2
- 102100028333 MAGE-like protein 2 Human genes 0.000 claims description 2
- 102100031520 MAPK/MAK/MRK overlapping kinase Human genes 0.000 claims description 2
- 108010047702 MPG peptide Proteins 0.000 claims description 2
- 102100028123 Macrophage colony-stimulating factor 1 Human genes 0.000 claims description 2
- 102100039475 Melanoma-associated antigen B5 Human genes 0.000 claims description 2
- 102100039483 Melanoma-associated antigen B6 Human genes 0.000 claims description 2
- 102100039447 Melanoma-associated antigen C1 Human genes 0.000 claims description 2
- 102100027248 Melanoma-associated antigen C3 Human genes 0.000 claims description 2
- 102100027251 Melanoma-associated antigen D2 Human genes 0.000 claims description 2
- 102100023123 Mucin-16 Human genes 0.000 claims description 2
- 102100034263 Mucin-2 Human genes 0.000 claims description 2
- 101100348669 Mus musculus Nkx3-1 gene Proteins 0.000 claims description 2
- 102100025243 Myeloid cell surface antigen CD33 Human genes 0.000 claims description 2
- 102000003505 Myosin Human genes 0.000 claims description 2
- 108060008487 Myosin Proteins 0.000 claims description 2
- PHSRRHGYXQCRPU-AWEZNQCLSA-N N-(3-oxododecanoyl)-L-homoserine lactone Chemical compound CCCCCCCCCC(=O)CC(=O)N[C@H]1CCOC1=O PHSRRHGYXQCRPU-AWEZNQCLSA-N 0.000 claims description 2
- 102100022913 NAD-dependent protein deacetylase sirtuin-2 Human genes 0.000 claims description 2
- 102100022475 NudC domain-containing protein 1 Human genes 0.000 claims description 2
- 102100025128 Olfactory receptor 51E2 Human genes 0.000 claims description 2
- 102100023240 P antigen family member 4 Human genes 0.000 claims description 2
- 102100038762 POTE ankyrin domain family member D Human genes 0.000 claims description 2
- 108060006580 PRAME Proteins 0.000 claims description 2
- 102000036673 PRAME Human genes 0.000 claims description 2
- 102100034640 PWWP domain-containing DNA repair factor 3A Human genes 0.000 claims description 2
- 108050007154 PWWP domain-containing DNA repair factor 3A Proteins 0.000 claims description 2
- 101710124046 Palmitoyl-acyl carrier protein thioesterase, chloroplastic Proteins 0.000 claims description 2
- 108010088535 Pep-1 peptide Proteins 0.000 claims description 2
- 102100022078 Peroxiredoxin-5, mitochondrial Human genes 0.000 claims description 2
- 239000004952 Polyamide Substances 0.000 claims description 2
- 239000004698 Polyethylene Substances 0.000 claims description 2
- 102100022019 Pregnancy-specific beta-1-glycoprotein 2 Human genes 0.000 claims description 2
- 102100035724 Probable ATP-dependent RNA helicase DDX43 Human genes 0.000 claims description 2
- 101710088675 Proline-rich peptide Proteins 0.000 claims description 2
- 102100038280 Prostaglandin G/H synthase 2 Human genes 0.000 claims description 2
- 108050003267 Prostaglandin G/H synthase 2 Proteins 0.000 claims description 2
- 102100033514 Prostate and testis expressed protein 1 Human genes 0.000 claims description 2
- 102100030616 Protein-cysteine N-palmitoyltransferase HHAT Human genes 0.000 claims description 2
- 108010017121 Proto-Oncogene Proteins c-pim-1 Proteins 0.000 claims description 2
- 102000004433 Proto-Oncogene Proteins c-pim-1 Human genes 0.000 claims description 2
- 102100022491 RNA-binding protein NOB1 Human genes 0.000 claims description 2
- 101100443768 Rattus norvegicus Dock9 gene Proteins 0.000 claims description 2
- 102100035844 Retrotransposon-derived protein PEG10 Human genes 0.000 claims description 2
- 108020004422 Riboswitch Proteins 0.000 claims description 2
- 102100034018 SAM pointed domain-containing Ets transcription factor Human genes 0.000 claims description 2
- 108050003189 SH2B adapter protein 1 Proteins 0.000 claims description 2
- 102100021466 Sarcoma antigen 1 Human genes 0.000 claims description 2
- 108010041216 Sirtuin 2 Proteins 0.000 claims description 2
- 102100037253 Solute carrier family 45 member 3 Human genes 0.000 claims description 2
- 102100035748 Squamous cell carcinoma antigen recognized by T-cells 3 Human genes 0.000 claims description 2
- 101800001271 Surface protein Proteins 0.000 claims description 2
- 101710143177 Synaptonemal complex protein 1 Proteins 0.000 claims description 2
- 102100036011 T-cell surface glycoprotein CD4 Human genes 0.000 claims description 2
- 102100034030 Transient receptor potential cation channel subfamily M member 8 Human genes 0.000 claims description 2
- 102100023935 Transmembrane glycoprotein NMB Human genes 0.000 claims description 2
- 102100027244 U4/U6.U5 tri-snRNP-associated protein 1 Human genes 0.000 claims description 2
- 102100031358 Urokinase-type plasminogen activator Human genes 0.000 claims description 2
- 102100038929 V-set domain-containing T-cell activation inhibitor 1 Human genes 0.000 claims description 2
- 102000005789 Vascular Endothelial Growth Factors Human genes 0.000 claims description 2
- 108010019530 Vascular Endothelial Growth Factors Proteins 0.000 claims description 2
- AZCCDRNDKZSNBW-UHFFFAOYSA-M [2-[bis(2-tetradecanoyloxyethyl)amino]-2-oxoethyl]-trimethylazanium;chloride Chemical compound [Cl-].CCCCCCCCCCCCCC(=O)OCCN(C(=O)C[N+](C)(C)C)CCOC(=O)CCCCCCCCCCCCC AZCCDRNDKZSNBW-UHFFFAOYSA-M 0.000 claims description 2
- NYDLOCKCVISJKK-WRBBJXAJSA-N [3-(dimethylamino)-2-[(z)-octadec-9-enoyl]oxypropyl] (z)-octadec-9-enoate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC(CN(C)C)OC(=O)CCCCCCC\C=C/CCCCCCCC NYDLOCKCVISJKK-WRBBJXAJSA-N 0.000 claims description 2
- 150000001252 acrylic acid derivatives Chemical class 0.000 claims description 2
- 108010034034 alpha-1,6-mannosylglycoprotein beta 1,6-N-acetylglucosaminyltransferase Proteins 0.000 claims description 2
- 230000000845 anti-microbial effect Effects 0.000 claims description 2
- 108010025307 buforin II Proteins 0.000 claims description 2
- WERYXYBDKMZEQL-UHFFFAOYSA-N butane-1,4-diol Chemical class OCCCCO WERYXYBDKMZEQL-UHFFFAOYSA-N 0.000 claims description 2
- 150000004985 diamines Chemical class 0.000 claims description 2
- 108010003425 hyaluronan-mediated motility receptor Proteins 0.000 claims description 2
- 230000002209 hydrophobic effect Effects 0.000 claims description 2
- 108040006849 interleukin-2 receptor activity proteins Proteins 0.000 claims description 2
- 108010024383 kallikrein 4 Proteins 0.000 claims description 2
- CSSYQJWUGATIHM-IKGCZBKSSA-N l-phenylalanyl-l-lysyl-l-cysteinyl-l-arginyl-l-arginyl-l-tryptophyl-l-glutaminyl-l-tryptophyl-l-arginyl-l-methionyl-l-lysyl-l-lysyl-l-leucylglycyl-l-alanyl-l-prolyl-l-seryl-l-isoleucyl-l-threonyl-l-cysteinyl-l-valyl-l-arginyl-l-arginyl-l-alanyl-l-phenylal Chemical compound C([C@H](N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CS)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)C1=CC=CC=C1 CSSYQJWUGATIHM-IKGCZBKSSA-N 0.000 claims description 2
- 229940078795 lactoferrin Drugs 0.000 claims description 2
- 235000021242 lactoferrin Nutrition 0.000 claims description 2
- 235000015250 liver sausages Nutrition 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims description 2
- 108010036112 nuclear matrix protein 22 Proteins 0.000 claims description 2
- 150000008104 phosphatidylethanolamines Chemical class 0.000 claims description 2
- 229920001559 poly(2-methyloxazoline)-block-poly(dimethylsiloxane) Polymers 0.000 claims description 2
- 229920000083 poly(allylamine) Polymers 0.000 claims description 2
- 229920001308 poly(aminoacid) Polymers 0.000 claims description 2
- 229920000333 poly(propyleneimine) Polymers 0.000 claims description 2
- 229920002246 poly[2-(dimethylamino)ethyl methacrylate] polymer Polymers 0.000 claims description 2
- 229920002647 polyamide Polymers 0.000 claims description 2
- 229920002851 polycationic polymer Polymers 0.000 claims description 2
- 229920000573 polyethylene Polymers 0.000 claims description 2
- 229920001184 polypeptide Polymers 0.000 claims description 2
- 239000001294 propane Substances 0.000 claims description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 108091092562 ribozyme Proteins 0.000 claims description 2
- XYSQXZCMOLNHOI-UHFFFAOYSA-N s-[2-[[4-(acetylsulfamoyl)phenyl]carbamoyl]phenyl] 5-pyridin-1-ium-1-ylpentanethioate;bromide Chemical compound [Br-].C1=CC(S(=O)(=O)NC(=O)C)=CC=C1NC(=O)C1=CC=CC=C1SC(=O)CCCC[N+]1=CC=CC=C1 XYSQXZCMOLNHOI-UHFFFAOYSA-N 0.000 claims description 2
- 235000002020 sage Nutrition 0.000 claims description 2
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 claims description 2
- 229940063675 spermine Drugs 0.000 claims description 2
- 238000010361 transduction Methods 0.000 claims description 2
- 230000026683 transduction Effects 0.000 claims description 2
- 108010062760 transportan Proteins 0.000 claims description 2
- PBKWZFANFUTEPS-CWUSWOHSSA-N transportan Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N[C@H](C(=O)N[C@@H](CC(N)=O)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(=O)N[C@@H](C)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(C)C)C(N)=O)[C@@H](C)CC)NC(=O)CNC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)CN)[C@@H](C)O)C1=CC=C(O)C=C1 PBKWZFANFUTEPS-CWUSWOHSSA-N 0.000 claims description 2
- 102100025570 Cancer/testis antigen 1 Human genes 0.000 claims 2
- 208000035473 Communicable disease Diseases 0.000 claims 2
- 108050006400 Cyclin Proteins 0.000 claims 2
- 102000016736 Cyclin Human genes 0.000 claims 2
- 101000856237 Homo sapiens Cancer/testis antigen 1 Proteins 0.000 claims 2
- 208000026935 allergic disease Diseases 0.000 claims 2
- KSXTUUUQYQYKCR-LQDDAWAPSA-M 2,3-bis[[(z)-octadec-9-enoyl]oxy]propyl-trimethylazanium;chloride Chemical compound [Cl-].CCCCCCCC\C=C/CCCCCCCC(=O)OCC(C[N+](C)(C)C)OC(=O)CCCCCCC\C=C/CCCCCCCC KSXTUUUQYQYKCR-LQDDAWAPSA-M 0.000 claims 1
- OULMZHKWILMJEK-UHFFFAOYSA-N 2-[4-(2,3-dihexadecoxypropoxy)-4-oxobutanoyl]oxyethyl-trimethylazanium Chemical compound CCCCCCCCCCCCCCCCOCC(COC(=O)CCC(=O)OCC[N+](C)(C)C)OCCCCCCCCCCCCCCCC OULMZHKWILMJEK-UHFFFAOYSA-N 0.000 claims 1
- 101800000504 3C-like protease Proteins 0.000 claims 1
- 102100036464 Activated RNA polymerase II transcriptional coactivator p15 Human genes 0.000 claims 1
- 101710115256 Alpha-actinin-4 Proteins 0.000 claims 1
- 208000023275 Autoimmune disease Diseases 0.000 claims 1
- 102000052609 BRCA2 Human genes 0.000 claims 1
- 101710177963 Baculoviral IAP repeat-containing protein 7 Proteins 0.000 claims 1
- 101100123850 Caenorhabditis elegans her-1 gene Proteins 0.000 claims 1
- 101100314454 Caenorhabditis elegans tra-1 gene Proteins 0.000 claims 1
- 108090000549 Calreticulin Proteins 0.000 claims 1
- 102000004225 Cathepsin B Human genes 0.000 claims 1
- 108090000712 Cathepsin B Proteins 0.000 claims 1
- 102400001321 Cathepsin L Human genes 0.000 claims 1
- 108090000624 Cathepsin L Proteins 0.000 claims 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims 1
- 102100031552 Coactosin-like protein Human genes 0.000 claims 1
- 101710105549 Coactosin-like protein Proteins 0.000 claims 1
- 102000008186 Collagen Human genes 0.000 claims 1
- 108010035532 Collagen Proteins 0.000 claims 1
- 102100021307 Cyclic AMP-responsive element-binding protein 3-like protein 4 Human genes 0.000 claims 1
- 101710174221 Cyclic AMP-responsive element-binding protein 3-like protein 4 Proteins 0.000 claims 1
- 101710127030 Dermatan-sulfate epimerase Proteins 0.000 claims 1
- 101150029707 ERBB2 gene Proteins 0.000 claims 1
- 108090000380 Fibroblast growth factor 5 Proteins 0.000 claims 1
- 101710113436 GTPase KRas Proteins 0.000 claims 1
- 108060003393 Granulin Proteins 0.000 claims 1
- 108010088729 HLA-A*02:01 antigen Proteins 0.000 claims 1
- 108010035452 HLA-A1 Antigen Proteins 0.000 claims 1
- 102000004989 Hepsin Human genes 0.000 claims 1
- 108090001101 Hepsin Proteins 0.000 claims 1
- 101000971605 Homo sapiens Kita-kyushu lung cancer antigen 1 Proteins 0.000 claims 1
- 101001057131 Homo sapiens Melanoma-associated antigen D4 Proteins 0.000 claims 1
- 101001057132 Homo sapiens Melanoma-associated antigen F1 Proteins 0.000 claims 1
- 241000713772 Human immunodeficiency virus 1 Species 0.000 claims 1
- 206010020751 Hypersensitivity Diseases 0.000 claims 1
- 108090000723 Insulin-Like Growth Factor I Proteins 0.000 claims 1
- 102000004218 Insulin-Like Growth Factor I Human genes 0.000 claims 1
- 102100027268 Interferon-stimulated gene 20 kDa protein Human genes 0.000 claims 1
- 101710176220 Kallikrein-2 Proteins 0.000 claims 1
- 102100021533 Kita-kyushu lung cancer antigen 1 Human genes 0.000 claims 1
- 108010010995 MART-1 Antigen Proteins 0.000 claims 1
- 108010046938 Macrophage Colony-Stimulating Factor Proteins 0.000 claims 1
- 102000005727 Mammaglobin A Human genes 0.000 claims 1
- 108010031030 Mammaglobin A Proteins 0.000 claims 1
- 244000137850 Marrubium vulgare Species 0.000 claims 1
- 102100027257 Melanoma-associated antigen D4 Human genes 0.000 claims 1
- 102100027258 Melanoma-associated antigen F1 Human genes 0.000 claims 1
- 102000003735 Mesothelin Human genes 0.000 claims 1
- 108090000015 Mesothelin Proteins 0.000 claims 1
- 102000004067 Osteocalcin Human genes 0.000 claims 1
- 108090000573 Osteocalcin Proteins 0.000 claims 1
- 102000004264 Osteopontin Human genes 0.000 claims 1
- 108010081689 Osteopontin Proteins 0.000 claims 1
- 101001128814 Pandinus imperator Pandinin-1 Proteins 0.000 claims 1
- 102000004179 Plasminogen Activator Inhibitor 2 Human genes 0.000 claims 1
- 108090000614 Plasminogen Activator Inhibitor 2 Proteins 0.000 claims 1
- 102000004879 Racemases and epimerases Human genes 0.000 claims 1
- 108090001066 Racemases and epimerases Proteins 0.000 claims 1
- 101710173693 Short transient receptor potential channel 1 Proteins 0.000 claims 1
- 101710185775 Squamous cell carcinoma antigen recognized by T-cells 3 Proteins 0.000 claims 1
- LVTKHGUGBGNBPL-UHFFFAOYSA-N Trp-P-1 Chemical compound N1C2=CC=CC=C2C2=C1C(C)=C(N)N=C2C LVTKHGUGBGNBPL-UHFFFAOYSA-N 0.000 claims 1
- 102000003425 Tyrosinase Human genes 0.000 claims 1
- 108060008724 Tyrosinase Proteins 0.000 claims 1
- 101710155955 U4/U6.U5 tri-snRNP-associated protein 1 Proteins 0.000 claims 1
- 102100031929 UDP-N-acetylglucosamine-peptide N-acetylglucosaminyltransferase 110 kDa subunit Human genes 0.000 claims 1
- 101710117112 UDP-N-acetylglucosamine-peptide N-acetylglucosaminyltransferase 110 kDa subunit Proteins 0.000 claims 1
- 230000007815 allergy Effects 0.000 claims 1
- 239000005516 coenzyme A Substances 0.000 claims 1
- 229940093530 coenzyme a Drugs 0.000 claims 1
- 229920001436 collagen Polymers 0.000 claims 1
- 208000037765 diseases and disorders Diseases 0.000 claims 1
- 239000003937 drug carrier Substances 0.000 claims 1
- 108010066416 multidrug resistance-associated protein 3 Proteins 0.000 claims 1
- 101800000607 p15 Proteins 0.000 claims 1
- 238000011321 prophylaxis Methods 0.000 claims 1
- 108010079891 prostein Proteins 0.000 claims 1
- 239000003981 vehicle Substances 0.000 claims 1
- 238000002360 preparation method Methods 0.000 abstract description 8
- 239000013566 allergen Substances 0.000 abstract description 5
- 201000010099 disease Diseases 0.000 abstract description 5
- ISAKRJDGNUQOIC-UHFFFAOYSA-N Uracil Chemical compound O=C1C=CNC(=O)N1 ISAKRJDGNUQOIC-UHFFFAOYSA-N 0.000 description 244
- DRTQHJPVMGBUCF-XVFCMESISA-N Uridine Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-XVFCMESISA-N 0.000 description 166
- 150000007523 nucleic acids Chemical class 0.000 description 145
- 239000002773 nucleotide Substances 0.000 description 144
- 125000003729 nucleotide group Chemical group 0.000 description 144
- OPTASPLRGRRNAP-UHFFFAOYSA-N cytosine Chemical group NC=1C=CNC(=O)N=1 OPTASPLRGRRNAP-UHFFFAOYSA-N 0.000 description 130
- 229940035893 uracil Drugs 0.000 description 116
- 102000039446 nucleic acids Human genes 0.000 description 114
- 108020004707 nucleic acids Proteins 0.000 description 114
- 229940045145 uridine Drugs 0.000 description 84
- DRTQHJPVMGBUCF-PSQAKQOGSA-N beta-L-uridine Natural products O[C@H]1[C@@H](O)[C@H](CO)O[C@@H]1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-PSQAKQOGSA-N 0.000 description 81
- DRTQHJPVMGBUCF-UHFFFAOYSA-N uracil arabinoside Natural products OC1C(O)C(CO)OC1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-UHFFFAOYSA-N 0.000 description 81
- NYHBQMYGNKIUIF-UUOKFMHZSA-N Guanosine Chemical class C1=NC=2C(=O)NC(N)=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O NYHBQMYGNKIUIF-UUOKFMHZSA-N 0.000 description 66
- 239000002777 nucleoside Substances 0.000 description 65
- 229940104302 cytosine Drugs 0.000 description 62
- UYTPUPDQBNUYGX-UHFFFAOYSA-N guanine Chemical compound O=C1NC(N)=NC2=C1N=CN2 UYTPUPDQBNUYGX-UHFFFAOYSA-N 0.000 description 60
- UHDGCWIWMRVCDJ-ZAKLUEHWSA-N cytidine Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O1 UHDGCWIWMRVCDJ-ZAKLUEHWSA-N 0.000 description 50
- UHDGCWIWMRVCDJ-UHFFFAOYSA-N 1-beta-D-Xylofuranosyl-NH-Cytosine Natural products O=C1N=C(N)C=CN1C1C(O)C(O)C(CO)O1 UHDGCWIWMRVCDJ-UHFFFAOYSA-N 0.000 description 48
- UHDGCWIWMRVCDJ-PSQAKQOGSA-N Cytidine Natural products O=C1N=C(N)C=CN1[C@@H]1[C@@H](O)[C@@H](O)[C@H](CO)O1 UHDGCWIWMRVCDJ-PSQAKQOGSA-N 0.000 description 48
- OIRDTQYFTABQOQ-KQYNXXCUSA-N adenosine Chemical group C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O OIRDTQYFTABQOQ-KQYNXXCUSA-N 0.000 description 46
- 125000003835 nucleoside group Chemical group 0.000 description 44
- 108091028043 Nucleic acid sequence Proteins 0.000 description 35
- IQFYYKKMVGJFEH-XLPZGREQSA-N Thymidine Chemical group O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](O)C1 IQFYYKKMVGJFEH-XLPZGREQSA-N 0.000 description 35
- NYHBQMYGNKIUIF-UHFFFAOYSA-N D-guanosine Natural products C1=2NC(N)=NC(=O)C=2N=CN1C1OC(CO)C(O)C1O NYHBQMYGNKIUIF-UHFFFAOYSA-N 0.000 description 31
- MIKUYHXYGGJMLM-GIMIYPNGSA-N Crotonoside Natural products C1=NC2=C(N)NC(=O)N=C2N1[C@H]1O[C@@H](CO)[C@H](O)[C@@H]1O MIKUYHXYGGJMLM-GIMIYPNGSA-N 0.000 description 30
- 229940029575 guanosine Drugs 0.000 description 30
- RWQNBRDOKXIBIV-UHFFFAOYSA-N thymine Chemical compound CC1=CNC(=O)NC1=O RWQNBRDOKXIBIV-UHFFFAOYSA-N 0.000 description 30
- VTIYIXJVHDMAGD-GWTDSMLYSA-N 2-amino-3,7-dihydropurin-6-one;2-amino-9-[(2r,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-3h-purin-6-one Chemical class O=C1NC(N)=NC2=C1NC=N2.C1=NC=2C(=O)NC(N)=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O VTIYIXJVHDMAGD-GWTDSMLYSA-N 0.000 description 27
- 229930024421 Adenine Natural products 0.000 description 25
- GFFGJBXGBJISGV-UHFFFAOYSA-N Adenine Chemical compound NC1=NC=NC2=C1N=CN2 GFFGJBXGBJISGV-UHFFFAOYSA-N 0.000 description 25
- 229960000643 adenine Drugs 0.000 description 25
- 239000002126 C01EB10 - Adenosine Chemical group 0.000 description 23
- 229960005305 adenosine Drugs 0.000 description 23
- 150000003833 nucleoside derivatives Chemical class 0.000 description 21
- 102000040650 (ribonucleotides)n+m Human genes 0.000 description 20
- 102000002689 Toll-like receptor Human genes 0.000 description 20
- 108020000411 Toll-like receptor Proteins 0.000 description 20
- 102000004127 Cytokines Human genes 0.000 description 18
- 108090000695 Cytokines Proteins 0.000 description 18
- 108020004414 DNA Proteins 0.000 description 18
- DWRXFEITVBNRMK-UHFFFAOYSA-N Beta-D-1-Arabinofuranosylthymine Chemical group O=C1NC(=O)C(C)=CN1C1C(O)C(O)C(CO)O1 DWRXFEITVBNRMK-UHFFFAOYSA-N 0.000 description 17
- IQFYYKKMVGJFEH-UHFFFAOYSA-N beta-L-thymidine Chemical group O=C1NC(=O)C(C)=CN1C1OC(CO)C(O)C1 IQFYYKKMVGJFEH-UHFFFAOYSA-N 0.000 description 17
- 210000004027 cell Anatomy 0.000 description 17
- 230000015788 innate immune response Effects 0.000 description 17
- 229940104230 thymidine Drugs 0.000 description 17
- 239000003446 ligand Substances 0.000 description 15
- 229940113082 thymine Drugs 0.000 description 15
- 244000052769 pathogen Species 0.000 description 14
- 102000053602 DNA Human genes 0.000 description 13
- 230000001717 pathogenic effect Effects 0.000 description 13
- 102000005962 receptors Human genes 0.000 description 11
- 108020003175 receptors Proteins 0.000 description 11
- 238000013519 translation Methods 0.000 description 11
- 241000282414 Homo sapiens Species 0.000 description 10
- 210000005006 adaptive immune system Anatomy 0.000 description 10
- 210000005007 innate immune system Anatomy 0.000 description 10
- 239000002253 acid Substances 0.000 description 9
- 210000003719 b-lymphocyte Anatomy 0.000 description 9
- 230000028993 immune response Effects 0.000 description 9
- 230000003252 repetitive effect Effects 0.000 description 9
- 101000763579 Homo sapiens Toll-like receptor 1 Proteins 0.000 description 8
- 102100027010 Toll-like receptor 1 Human genes 0.000 description 8
- 230000000536 complexating effect Effects 0.000 description 8
- 210000000987 immune system Anatomy 0.000 description 8
- 108020004682 Single-Stranded DNA Proteins 0.000 description 7
- 235000001014 amino acid Nutrition 0.000 description 7
- 239000002299 complementary DNA Substances 0.000 description 7
- 125000000524 functional group Chemical group 0.000 description 7
- 238000000338 in vitro Methods 0.000 description 7
- DAZSWUUAFHBCGE-KRWDZBQOSA-N n-[(2s)-3-methyl-1-oxo-1-pyrrolidin-1-ylbutan-2-yl]-3-phenylpropanamide Chemical compound N([C@@H](C(C)C)C(=O)N1CCCC1)C(=O)CCC1=CC=CC=C1 DAZSWUUAFHBCGE-KRWDZBQOSA-N 0.000 description 7
- 108010049048 Cholera Toxin Proteins 0.000 description 6
- 102000009016 Cholera Toxin Human genes 0.000 description 6
- 229910019142 PO4 Inorganic materials 0.000 description 6
- 150000004702 methyl esters Chemical class 0.000 description 6
- 102000007863 pattern recognition receptors Human genes 0.000 description 6
- 108010089193 pattern recognition receptors Proteins 0.000 description 6
- 239000010452 phosphate Substances 0.000 description 6
- 230000011664 signaling Effects 0.000 description 6
- 238000013518 transcription Methods 0.000 description 6
- 230000035897 transcription Effects 0.000 description 6
- 241000894006 Bacteria Species 0.000 description 5
- HMFHBZSHGGEWLO-SOOFDHNKSA-N D-ribofuranose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@@H]1O HMFHBZSHGGEWLO-SOOFDHNKSA-N 0.000 description 5
- 101000763537 Homo sapiens Toll-like receptor 10 Proteins 0.000 description 5
- 108010065805 Interleukin-12 Proteins 0.000 description 5
- 102000013462 Interleukin-12 Human genes 0.000 description 5
- 108090001005 Interleukin-6 Proteins 0.000 description 5
- 108700018351 Major Histocompatibility Complex Proteins 0.000 description 5
- 238000012228 RNA interference-mediated gene silencing Methods 0.000 description 5
- PYMYPHUHKUWMLA-LMVFSUKVSA-N Ribose Natural products OC[C@@H](O)[C@@H](O)[C@@H](O)C=O PYMYPHUHKUWMLA-LMVFSUKVSA-N 0.000 description 5
- 102100027009 Toll-like receptor 10 Human genes 0.000 description 5
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 5
- 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 description 5
- HMFHBZSHGGEWLO-UHFFFAOYSA-N alpha-D-Furanose-Ribose Natural products OCC1OC(O)C(O)C1O HMFHBZSHGGEWLO-UHFFFAOYSA-N 0.000 description 5
- 230000000295 complement effect Effects 0.000 description 5
- 238000009472 formulation Methods 0.000 description 5
- 230000009368 gene silencing by RNA Effects 0.000 description 5
- 238000001727 in vivo Methods 0.000 description 5
- 125000004433 nitrogen atom Chemical group N* 0.000 description 5
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 5
- 235000021317 phosphate Nutrition 0.000 description 5
- 230000020382 suppression by virus of host antigen processing and presentation of peptide antigen via MHC class I Effects 0.000 description 5
- XUNKPNYCNUKOAU-VXJRNSOOSA-N (2s)-2-[[(2s)-2-[[(2s)-2-[[(2s)-2-[[(2s)-2-[[(2s)-2-[[(2s)-2-[[(2s)-2-[[(2s)-2-amino-5-(diaminomethylideneamino)pentanoyl]amino]-5-(diaminomethylideneamino)pentanoyl]amino]-5-(diaminomethylideneamino)pentanoyl]amino]-5-(diaminomethylideneamino)pentanoyl]a Chemical compound NC(N)=NCCC[C@H](N)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CCCN=C(N)N)C(O)=O XUNKPNYCNUKOAU-VXJRNSOOSA-N 0.000 description 4
- 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 description 4
- RHFUOMFWUGWKKO-XVFCMESISA-N 2-thiocytidine Chemical compound S=C1N=C(N)C=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 RHFUOMFWUGWKKO-XVFCMESISA-N 0.000 description 4
- 102100037435 Antiviral innate immune response receptor RIG-I Human genes 0.000 description 4
- 101710127675 Antiviral innate immune response receptor RIG-I Proteins 0.000 description 4
- 108010017213 Granulocyte-Macrophage Colony-Stimulating Factor Proteins 0.000 description 4
- 102100039620 Granulocyte-macrophage colony-stimulating factor Human genes 0.000 description 4
- 101000959820 Homo sapiens Interferon alpha-1/13 Proteins 0.000 description 4
- 101000669447 Homo sapiens Toll-like receptor 4 Proteins 0.000 description 4
- 101000669402 Homo sapiens Toll-like receptor 7 Proteins 0.000 description 4
- 102000000588 Interleukin-2 Human genes 0.000 description 4
- 108010002350 Interleukin-2 Proteins 0.000 description 4
- 102000004889 Interleukin-6 Human genes 0.000 description 4
- 210000001744 T-lymphocyte Anatomy 0.000 description 4
- 102100039360 Toll-like receptor 4 Human genes 0.000 description 4
- 102100039390 Toll-like receptor 7 Human genes 0.000 description 4
- 108020004566 Transfer RNA Proteins 0.000 description 4
- 108020000999 Viral RNA Proteins 0.000 description 4
- 241000700605 Viruses Species 0.000 description 4
- 230000004913 activation Effects 0.000 description 4
- 230000004888 barrier function Effects 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 238000004422 calculation algorithm Methods 0.000 description 4
- 150000001767 cationic compounds Chemical class 0.000 description 4
- 230000001413 cellular effect Effects 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- 238000010668 complexation reaction Methods 0.000 description 4
- SSJJWVREPZVNBF-DGXVIIAXSA-N dG10 Chemical compound C1=NC(C(NC(N)=N2)=O)=C2N1[C@H](O[C@@H]1COP(O)(=O)O[C@@H]2[C@H](O[C@H](C2)N2C3=C(C(NC(N)=N3)=O)N=C2)COP(O)(=O)O[C@@H]2[C@H](O[C@H](C2)N2C3=C(C(NC(N)=N3)=O)N=C2)COP(O)(=O)O[C@@H]2[C@H](O[C@H](C2)N2C3=C(C(NC(N)=N3)=O)N=C2)COP(O)(=O)O[C@@H]2[C@H](O[C@H](C2)N2C3=C(C(NC(N)=N3)=O)N=C2)COP(O)(=O)O[C@@H]2[C@H](O[C@H](C2)N2C3=C(C(NC(N)=N3)=O)N=C2)COP(O)(=O)O[C@@H]2[C@H](O[C@H](C2)N2C3=C(C(NC(N)=N3)=O)N=C2)COP(O)(=O)O[C@@H]2[C@H](O[C@H](C2)N2C3=C(C(NC(N)=N3)=O)N=C2)COP(O)(=O)O[C@@H]2[C@H](O[C@H](C2)N2C3=C(C(NC(N)=N3)=O)N=C2)CO)C[C@@H]1OP(O)(=O)OC[C@@H](O1)[C@@H](O)C[C@@H]1N1C(N=C(NC2=O)N)=C2N=C1 SSJJWVREPZVNBF-DGXVIIAXSA-N 0.000 description 4
- 230000007123 defense Effects 0.000 description 4
- 230000001419 dependent effect Effects 0.000 description 4
- 210000001163 endosome Anatomy 0.000 description 4
- 238000005755 formation reaction Methods 0.000 description 4
- 230000006698 induction Effects 0.000 description 4
- 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 description 4
- 230000008569 process Effects 0.000 description 4
- 108020004418 ribosomal RNA Proteins 0.000 description 4
- RHFUOMFWUGWKKO-UHFFFAOYSA-N s2C Natural products S=C1N=C(N)C=CN1C1C(O)C(O)C(CO)O1 RHFUOMFWUGWKKO-UHFFFAOYSA-N 0.000 description 4
- UTAIYTHAJQNQDW-KQYNXXCUSA-N 1-methylguanosine Chemical compound C1=NC=2C(=O)N(C)C(N)=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O UTAIYTHAJQNQDW-KQYNXXCUSA-N 0.000 description 3
- ZLOIGESWDJYCTF-UHFFFAOYSA-N 4-Thiouridine Natural products OC1C(O)C(CO)OC1N1C(=O)NC(=S)C=C1 ZLOIGESWDJYCTF-UHFFFAOYSA-N 0.000 description 3
- ZLOIGESWDJYCTF-XVFCMESISA-N 4-thiouridine Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=S)C=C1 ZLOIGESWDJYCTF-XVFCMESISA-N 0.000 description 3
- UVGCZRPOXXYZKH-QADQDURISA-N 5-(carboxyhydroxymethyl)uridine Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(C(O)C(O)=O)=C1 UVGCZRPOXXYZKH-QADQDURISA-N 0.000 description 3
- VSCNRXVDHRNJOA-PNHWDRBUSA-N 5-(carboxymethylaminomethyl)uridine Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(CNCC(O)=O)=C1 VSCNRXVDHRNJOA-PNHWDRBUSA-N 0.000 description 3
- AGFIRQJZCNVMCW-UAKXSSHOSA-N 5-bromouridine Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(Br)=C1 AGFIRQJZCNVMCW-UAKXSSHOSA-N 0.000 description 3
- VKLFQTYNHLDMDP-PNHWDRBUSA-N 5-carboxymethylaminomethyl-2-thiouridine Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=S)NC(=O)C(CNCC(O)=O)=C1 VKLFQTYNHLDMDP-PNHWDRBUSA-N 0.000 description 3
- FHIDNBAQOFJWCA-UAKXSSHOSA-N 5-fluorouridine Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(F)=C1 FHIDNBAQOFJWCA-UAKXSSHOSA-N 0.000 description 3
- RJUNHHFZFRMZQQ-FDDDBJFASA-N 5-methoxyaminomethyl-2-thiouridine Chemical compound S=C1NC(=O)C(CNOC)=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 RJUNHHFZFRMZQQ-FDDDBJFASA-N 0.000 description 3
- ZXIATBNUWJBBGT-JXOAFFINSA-N 5-methoxyuridine Chemical compound O=C1NC(=O)C(OC)=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 ZXIATBNUWJBBGT-JXOAFFINSA-N 0.000 description 3
- SNNBPMAXGYBMHM-JXOAFFINSA-N 5-methyl-2-thiouridine Chemical compound S=C1NC(=O)C(C)=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 SNNBPMAXGYBMHM-JXOAFFINSA-N 0.000 description 3
- ZXQHKBUIXRFZBV-FDDDBJFASA-N 5-methylaminomethyluridine Chemical compound O=C1NC(=O)C(CNC)=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 ZXQHKBUIXRFZBV-FDDDBJFASA-N 0.000 description 3
- 241000588832 Bordetella pertussis Species 0.000 description 3
- 102100035875 C-C chemokine receptor type 5 Human genes 0.000 description 3
- 102100032937 CD40 ligand Human genes 0.000 description 3
- 102000004091 Caspase-8 Human genes 0.000 description 3
- 102000019034 Chemokines Human genes 0.000 description 3
- 108010012236 Chemokines Proteins 0.000 description 3
- 102100029140 Cyclic nucleotide-gated cation channel beta-3 Human genes 0.000 description 3
- 241000196324 Embryophyta Species 0.000 description 3
- 101710146739 Enterotoxin Proteins 0.000 description 3
- 102100031940 Epithelial cell adhesion molecule Human genes 0.000 description 3
- 241000233866 Fungi Species 0.000 description 3
- 101000771083 Homo sapiens Cyclic nucleotide-gated cation channel beta-3 Proteins 0.000 description 3
- 101001043594 Homo sapiens Low-density lipoprotein receptor-related protein 5 Proteins 0.000 description 3
- 101000604123 Homo sapiens Noggin Proteins 0.000 description 3
- 101000854060 Homo sapiens Oxygen-regulated protein 1 Proteins 0.000 description 3
- 101001131829 Homo sapiens P protein Proteins 0.000 description 3
- 101001064282 Homo sapiens Platelet-activating factor acetylhydrolase IB subunit beta Proteins 0.000 description 3
- 101001003584 Homo sapiens Prelamin-A/C Proteins 0.000 description 3
- 101000904173 Homo sapiens Progonadoliberin-1 Proteins 0.000 description 3
- 101001012157 Homo sapiens Receptor tyrosine-protein kinase erbB-2 Proteins 0.000 description 3
- 101000617738 Homo sapiens Survival motor neuron protein Proteins 0.000 description 3
- 101000831567 Homo sapiens Toll-like receptor 2 Proteins 0.000 description 3
- 101000831496 Homo sapiens Toll-like receptor 3 Proteins 0.000 description 3
- 101000669460 Homo sapiens Toll-like receptor 5 Proteins 0.000 description 3
- 101000800483 Homo sapiens Toll-like receptor 8 Proteins 0.000 description 3
- 229930010555 Inosine Natural products 0.000 description 3
- UGQMRVRMYYASKQ-KQYNXXCUSA-N Inosine Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C2=NC=NC(O)=C2N=C1 UGQMRVRMYYASKQ-KQYNXXCUSA-N 0.000 description 3
- 102100027353 Interferon-induced helicase C domain-containing protein 1 Human genes 0.000 description 3
- 101710085994 Interferon-induced helicase C domain-containing protein 1 Proteins 0.000 description 3
- 108090000172 Interleukin-15 Proteins 0.000 description 3
- 102000003812 Interleukin-15 Human genes 0.000 description 3
- 102000004890 Interleukin-8 Human genes 0.000 description 3
- 108090001007 Interleukin-8 Proteins 0.000 description 3
- 102100021926 Low-density lipoprotein receptor-related protein 5 Human genes 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- 102100031545 Microsomal triglyceride transfer protein large subunit Human genes 0.000 description 3
- 102100038895 Myc proto-oncogene protein Human genes 0.000 description 3
- 108010077432 Myeloid Differentiation Factor 88 Proteins 0.000 description 3
- 102000010168 Myeloid Differentiation Factor 88 Human genes 0.000 description 3
- 102100038454 Noggin Human genes 0.000 description 3
- 102100035714 Oxygen-regulated protein 1 Human genes 0.000 description 3
- 102100034574 P protein Human genes 0.000 description 3
- 108091081548 Palindromic sequence Proteins 0.000 description 3
- 108010081690 Pertussis Toxin Proteins 0.000 description 3
- 102100030655 Platelet-activating factor acetylhydrolase IB subunit beta Human genes 0.000 description 3
- 102100026531 Prelamin-A/C Human genes 0.000 description 3
- 102100024028 Progonadoliberin-1 Human genes 0.000 description 3
- 102100030086 Receptor tyrosine-protein kinase erbB-2 Human genes 0.000 description 3
- 102100021947 Survival motor neuron protein Human genes 0.000 description 3
- RYYWUUFWQRZTIU-UHFFFAOYSA-N Thiophosphoric acid Chemical class OP(O)(S)=O RYYWUUFWQRZTIU-UHFFFAOYSA-N 0.000 description 3
- 102000008235 Toll-Like Receptor 9 Human genes 0.000 description 3
- 108010060818 Toll-Like Receptor 9 Proteins 0.000 description 3
- 102100024333 Toll-like receptor 2 Human genes 0.000 description 3
- 102100024324 Toll-like receptor 3 Human genes 0.000 description 3
- 102100039357 Toll-like receptor 5 Human genes 0.000 description 3
- 102100033110 Toll-like receptor 8 Human genes 0.000 description 3
- 102100023931 Transcriptional regulator ATRX Human genes 0.000 description 3
- 102100031988 Tumor necrosis factor ligand superfamily member 6 Human genes 0.000 description 3
- 241000251539 Vertebrata <Metazoa> Species 0.000 description 3
- 230000021736 acetylation Effects 0.000 description 3
- 238000006640 acetylation reaction Methods 0.000 description 3
- 230000003044 adaptive effect Effects 0.000 description 3
- 150000001973 desoxyriboses Chemical class 0.000 description 3
- ZPTBLXKRQACLCR-XVFCMESISA-N dihydrouridine Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)CC1 ZPTBLXKRQACLCR-XVFCMESISA-N 0.000 description 3
- 239000000147 enterotoxin Substances 0.000 description 3
- 231100000655 enterotoxin Toxicity 0.000 description 3
- 229920001519 homopolymer Polymers 0.000 description 3
- 230000033444 hydroxylation Effects 0.000 description 3
- 238000005805 hydroxylation reaction Methods 0.000 description 3
- 229960003786 inosine Drugs 0.000 description 3
- 230000007246 mechanism Effects 0.000 description 3
- KDOXVZUBMTZPGI-VUBKMPIKSA-N methyl 3-[(2r,3s,4r,5r)-5-(2,4-dioxopyrimidin-1-yl)-3,4-dihydroxyoxolan-2-yl]-3-hydroxypropanoate Chemical compound O[C@@H]1[C@H](O)[C@@H](C(O)CC(=O)OC)O[C@H]1N1C(=O)NC(=O)C=C1 KDOXVZUBMTZPGI-VUBKMPIKSA-N 0.000 description 3
- 230000011987 methylation Effects 0.000 description 3
- 238000007069 methylation reaction Methods 0.000 description 3
- YACKEPLHDIMKIO-UHFFFAOYSA-N methylphosphonic acid Chemical class CP(O)(O)=O YACKEPLHDIMKIO-UHFFFAOYSA-N 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 150000004713 phosphodiesters Chemical group 0.000 description 3
- 150000008298 phosphoramidates Chemical class 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 230000000087 stabilizing effect Effects 0.000 description 3
- 230000000638 stimulation Effects 0.000 description 3
- 210000001519 tissue Anatomy 0.000 description 3
- 238000001890 transfection Methods 0.000 description 3
- RDPUKVRQKWBSPK-UHFFFAOYSA-N 3-Methylcytidine Natural products O=C1N(C)C(=N)C=CN1C1C(O)C(O)C(CO)O1 RDPUKVRQKWBSPK-UHFFFAOYSA-N 0.000 description 2
- RDPUKVRQKWBSPK-ZOQUXTDFSA-N 3-methylcytidine Chemical compound O=C1N(C)C(=N)C=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 RDPUKVRQKWBSPK-ZOQUXTDFSA-N 0.000 description 2
- BCZUPRDAAVVBSO-MJXNYTJMSA-N 4-acetylcytidine Chemical compound C1=CC(C(=O)C)(N)NC(=O)N1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 BCZUPRDAAVVBSO-MJXNYTJMSA-N 0.000 description 2
- 102100033051 40S ribosomal protein S19 Human genes 0.000 description 2
- 102100038222 60 kDa heat shock protein, mitochondrial Human genes 0.000 description 2
- 102100036512 7-dehydrocholesterol reductase Human genes 0.000 description 2
- OGHAROSJZRTIOK-KQYNXXCUSA-O 7-methylguanosine Chemical compound C1=2N=C(N)NC(=O)C=2[N+](C)=CN1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O OGHAROSJZRTIOK-KQYNXXCUSA-O 0.000 description 2
- 102100028187 ATP-binding cassette sub-family C member 6 Human genes 0.000 description 2
- 108010083528 Adenylate Cyclase Toxin Proteins 0.000 description 2
- 102100020775 Adenylosuccinate lyase Human genes 0.000 description 2
- 108700040193 Adenylosuccinate lyases Proteins 0.000 description 2
- 102100022524 Alpha-1-antichymotrypsin Human genes 0.000 description 2
- 102100035991 Alpha-2-antiplasmin Human genes 0.000 description 2
- 102100026882 Alpha-synuclein Human genes 0.000 description 2
- 102100034452 Alternative prion protein Human genes 0.000 description 2
- 102100039109 Amelogenin, Y isoform Human genes 0.000 description 2
- 102100030346 Antigen peptide transporter 1 Human genes 0.000 description 2
- 102100022977 Antithrombin-III Human genes 0.000 description 2
- 102100029470 Apolipoprotein E Human genes 0.000 description 2
- 102100040124 Apoptosis-inducing factor 1, mitochondrial Human genes 0.000 description 2
- 101100332654 Arabidopsis thaliana ECA1 gene Proteins 0.000 description 2
- 102100029361 Aromatase Human genes 0.000 description 2
- 102000007372 Ataxin-1 Human genes 0.000 description 2
- 108010032963 Ataxin-1 Proteins 0.000 description 2
- 102000007370 Ataxin2 Human genes 0.000 description 2
- 108010032951 Ataxin2 Proteins 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 102100021631 B-cell lymphoma 6 protein Human genes 0.000 description 2
- 108010077805 Bacterial Proteins Proteins 0.000 description 2
- 102100036597 Basement membrane-specific heparan sulfate proteoglycan core protein Human genes 0.000 description 2
- 102100022794 Bestrophin-1 Human genes 0.000 description 2
- 102100026189 Beta-galactosidase Human genes 0.000 description 2
- 102100035631 Bloom syndrome protein Human genes 0.000 description 2
- 102100025422 Bone morphogenetic protein receptor type-2 Human genes 0.000 description 2
- 102100026008 Breakpoint cluster region protein Human genes 0.000 description 2
- 102100025399 Breast cancer type 2 susceptibility protein Human genes 0.000 description 2
- 102100031151 C-C chemokine receptor type 2 Human genes 0.000 description 2
- 101710149870 C-C chemokine receptor type 5 Proteins 0.000 description 2
- 102100023703 C-C motif chemokine 15 Human genes 0.000 description 2
- 102100036846 C-C motif chemokine 21 Human genes 0.000 description 2
- 102100039398 C-X-C motif chemokine 2 Human genes 0.000 description 2
- 102100036150 C-X-C motif chemokine 5 Human genes 0.000 description 2
- 102100036153 C-X-C motif chemokine 6 Human genes 0.000 description 2
- 108010029697 CD40 Ligand Proteins 0.000 description 2
- 101150013553 CD40 gene Proteins 0.000 description 2
- 102100022002 CD59 glycoprotein Human genes 0.000 description 2
- 208000036875 CNGB3-related retinopathy Diseases 0.000 description 2
- 102100029801 Calcium-transporting ATPase type 2C member 1 Human genes 0.000 description 2
- 241000282472 Canis lupus familiaris Species 0.000 description 2
- 102100035023 Carboxypeptidase B2 Human genes 0.000 description 2
- 108090000397 Caspase 3 Proteins 0.000 description 2
- 102100029855 Caspase-3 Human genes 0.000 description 2
- 102100033601 Collagen alpha-1(I) chain Human genes 0.000 description 2
- 102100029136 Collagen alpha-1(II) chain Human genes 0.000 description 2
- 102100036213 Collagen alpha-2(I) chain Human genes 0.000 description 2
- 102100040496 Collagen alpha-2(VIII) chain Human genes 0.000 description 2
- 108700040183 Complement C1 Inhibitor Proteins 0.000 description 2
- 102000055157 Complement C1 Inhibitor Human genes 0.000 description 2
- 102100037077 Complement C1q subcomponent subunit A Human genes 0.000 description 2
- 102100037085 Complement C1q subcomponent subunit B Human genes 0.000 description 2
- 102100025849 Complement C1q subcomponent subunit C Human genes 0.000 description 2
- 102100033269 Cyclin-dependent kinase inhibitor 1C Human genes 0.000 description 2
- 102100024332 Cytochrome P450 11B1, mitochondrial Human genes 0.000 description 2
- 102100027417 Cytochrome P450 1B1 Human genes 0.000 description 2
- 102100029363 Cytochrome P450 2C19 Human genes 0.000 description 2
- 102100038698 Cytochrome P450 7B1 Human genes 0.000 description 2
- 102100026234 Cytokine receptor common subunit gamma Human genes 0.000 description 2
- 102100039498 Cytotoxic T-lymphocyte protein 4 Human genes 0.000 description 2
- 102100031868 DNA excision repair protein ERCC-8 Human genes 0.000 description 2
- 102100037700 DNA mismatch repair protein Msh3 Human genes 0.000 description 2
- 102100022307 DNA polymerase alpha catalytic subunit Human genes 0.000 description 2
- 102100023319 Dihydrolipoyl dehydrogenase, mitochondrial Human genes 0.000 description 2
- 101100316028 Drosophila melanogaster Uggt gene Proteins 0.000 description 2
- 102000012199 E3 ubiquitin-protein ligase Mdm2 Human genes 0.000 description 2
- 108050002772 E3 ubiquitin-protein ligase Mdm2 Proteins 0.000 description 2
- 102100021765 E3 ubiquitin-protein ligase RNF139 Human genes 0.000 description 2
- 102100029503 E3 ubiquitin-protein ligase TRIM32 Human genes 0.000 description 2
- 102100035094 Enamelin Human genes 0.000 description 2
- 241000588724 Escherichia coli Species 0.000 description 2
- 108010067306 Fibronectins Proteins 0.000 description 2
- 102100026561 Filamin-A Human genes 0.000 description 2
- 102100021084 Forkhead box protein C1 Human genes 0.000 description 2
- 102100022277 Fructose-bisphosphate aldolase A Human genes 0.000 description 2
- 102100039397 Gap junction beta-3 protein Human genes 0.000 description 2
- 102100039401 Gap junction beta-6 protein Human genes 0.000 description 2
- 102100039684 Glucose-6-phosphate exchanger SLC37A4 Human genes 0.000 description 2
- 102000001398 Granzyme Human genes 0.000 description 2
- 108060005986 Granzyme Proteins 0.000 description 2
- 102100035368 Growth/differentiation factor 6 Human genes 0.000 description 2
- 102100034154 Guanine nucleotide-binding protein G(i) subunit alpha-2 Human genes 0.000 description 2
- 102100034471 H(+)/Cl(-) exchange transporter 5 Human genes 0.000 description 2
- 102100028972 HLA class I histocompatibility antigen, A alpha chain Human genes 0.000 description 2
- 108010075704 HLA-A Antigens Proteins 0.000 description 2
- 102100034051 Heat shock protein HSP 90-alpha Human genes 0.000 description 2
- 108010004889 Heat-Shock Proteins Proteins 0.000 description 2
- 102000002812 Heat-Shock Proteins Human genes 0.000 description 2
- 102100027685 Hemoglobin subunit alpha Human genes 0.000 description 2
- 102100030500 Heparin cofactor 2 Human genes 0.000 description 2
- 102100022103 Histone-lysine N-methyltransferase 2A Human genes 0.000 description 2
- 102100027345 Homeobox protein SIX3 Human genes 0.000 description 2
- 101000866618 Homo sapiens 3-beta-hydroxysteroid-Delta(8),Delta(7)-isomerase Proteins 0.000 description 2
- 101000733040 Homo sapiens 40S ribosomal protein S19 Proteins 0.000 description 2
- 101000928720 Homo sapiens 7-dehydrocholesterol reductase Proteins 0.000 description 2
- 101000986621 Homo sapiens ATP-binding cassette sub-family C member 6 Proteins 0.000 description 2
- 101000678026 Homo sapiens Alpha-1-antichymotrypsin Proteins 0.000 description 2
- 101000783712 Homo sapiens Alpha-2-antiplasmin Proteins 0.000 description 2
- 101000834898 Homo sapiens Alpha-synuclein Proteins 0.000 description 2
- 101000924727 Homo sapiens Alternative prion protein Proteins 0.000 description 2
- 101000959107 Homo sapiens Amelogenin, Y isoform Proteins 0.000 description 2
- 101000890622 Homo sapiens Apoptosis-inducing factor 1, mitochondrial Proteins 0.000 description 2
- 101000971234 Homo sapiens B-cell lymphoma 6 protein Proteins 0.000 description 2
- 101001000001 Homo sapiens Basement membrane-specific heparan sulfate proteoglycan core protein Proteins 0.000 description 2
- 101000903449 Homo sapiens Bestrophin-1 Proteins 0.000 description 2
- 101000765010 Homo sapiens Beta-galactosidase Proteins 0.000 description 2
- 101000934635 Homo sapiens Bone morphogenetic protein receptor type-2 Proteins 0.000 description 2
- 101000933320 Homo sapiens Breakpoint cluster region protein Proteins 0.000 description 2
- 101000978376 Homo sapiens C-C motif chemokine 15 Proteins 0.000 description 2
- 101000889128 Homo sapiens C-X-C motif chemokine 2 Proteins 0.000 description 2
- 101000947186 Homo sapiens C-X-C motif chemokine 5 Proteins 0.000 description 2
- 101000897400 Homo sapiens CD59 glycoprotein Proteins 0.000 description 2
- 101000728145 Homo sapiens Calcium-transporting ATPase type 2C member 1 Proteins 0.000 description 2
- 101000771163 Homo sapiens Collagen alpha-1(II) chain Proteins 0.000 description 2
- 101000875067 Homo sapiens Collagen alpha-2(I) chain Proteins 0.000 description 2
- 101000749886 Homo sapiens Collagen alpha-2(VIII) chain Proteins 0.000 description 2
- 101000740726 Homo sapiens Complement C1q subcomponent subunit A Proteins 0.000 description 2
- 101000740680 Homo sapiens Complement C1q subcomponent subunit B Proteins 0.000 description 2
- 101000933636 Homo sapiens Complement C1q subcomponent subunit C Proteins 0.000 description 2
- 101000725164 Homo sapiens Cytochrome P450 1B1 Proteins 0.000 description 2
- 101000957674 Homo sapiens Cytochrome P450 7B1 Proteins 0.000 description 2
- 101001055227 Homo sapiens Cytokine receptor common subunit gamma Proteins 0.000 description 2
- 101000920778 Homo sapiens DNA excision repair protein ERCC-8 Proteins 0.000 description 2
- 101000902558 Homo sapiens DNA polymerase alpha catalytic subunit Proteins 0.000 description 2
- 101001106970 Homo sapiens E3 ubiquitin-protein ligase RNF139 Proteins 0.000 description 2
- 101000634982 Homo sapiens E3 ubiquitin-protein ligase TRIM32 Proteins 0.000 description 2
- 101000877410 Homo sapiens Enamelin Proteins 0.000 description 2
- 101000918311 Homo sapiens Exostosin-1 Proteins 0.000 description 2
- 101000913549 Homo sapiens Filamin-A Proteins 0.000 description 2
- 101000818310 Homo sapiens Forkhead box protein C1 Proteins 0.000 description 2
- 101000755879 Homo sapiens Fructose-bisphosphate aldolase A Proteins 0.000 description 2
- 101000889136 Homo sapiens Gap junction beta-3 protein Proteins 0.000 description 2
- 101000886173 Homo sapiens Glucose-6-phosphate exchanger SLC37A4 Proteins 0.000 description 2
- 101001023964 Homo sapiens Growth/differentiation factor 6 Proteins 0.000 description 2
- 101000710225 Homo sapiens H(+)/Cl(-) exchange transporter 5 Proteins 0.000 description 2
- 101001009007 Homo sapiens Hemoglobin subunit alpha Proteins 0.000 description 2
- 101001082432 Homo sapiens Heparin cofactor 2 Proteins 0.000 description 2
- 101001045846 Homo sapiens Histone-lysine N-methyltransferase 2A Proteins 0.000 description 2
- 101000651928 Homo sapiens Homeobox protein SIX3 Proteins 0.000 description 2
- 101001056180 Homo sapiens Induced myeloid leukemia cell differentiation protein Mcl-1 Proteins 0.000 description 2
- 101000982538 Homo sapiens Inositol polyphosphate 5-phosphatase OCRL Proteins 0.000 description 2
- 101000976075 Homo sapiens Insulin Proteins 0.000 description 2
- 101001011446 Homo sapiens Interferon regulatory factor 6 Proteins 0.000 description 2
- 101001033312 Homo sapiens Interleukin-4 receptor subunit alpha Proteins 0.000 description 2
- 101000677891 Homo sapiens Iron-sulfur clusters transporter ABCB7, mitochondrial Proteins 0.000 description 2
- 101001046960 Homo sapiens Keratin, type II cytoskeletal 1 Proteins 0.000 description 2
- 101001137074 Homo sapiens Long-wave-sensitive opsin 1 Proteins 0.000 description 2
- 101001051093 Homo sapiens Low-density lipoprotein receptor Proteins 0.000 description 2
- 101001039035 Homo sapiens Lutropin-choriogonadotropic hormone receptor Proteins 0.000 description 2
- 101001004953 Homo sapiens Lysosomal acid lipase/cholesteryl ester hydrolase Proteins 0.000 description 2
- 101000634835 Homo sapiens M1-specific T cell receptor alpha chain Proteins 0.000 description 2
- 101000573901 Homo sapiens Major prion protein Proteins 0.000 description 2
- 101000614988 Homo sapiens Mediator of RNA polymerase II transcription subunit 12 Proteins 0.000 description 2
- 101000598987 Homo sapiens Medium-wave-sensitive opsin 1 Proteins 0.000 description 2
- 101000620359 Homo sapiens Melanocyte protein PMEL Proteins 0.000 description 2
- 101000588130 Homo sapiens Microsomal triglyceride transfer protein large subunit Proteins 0.000 description 2
- 101000957756 Homo sapiens Microtubule-associated protein RP/EB family member 2 Proteins 0.000 description 2
- 101001030243 Homo sapiens Myosin-7 Proteins 0.000 description 2
- 101000997654 Homo sapiens N-acetylmannosamine kinase Proteins 0.000 description 2
- 101001109052 Homo sapiens NADH-ubiquinone oxidoreductase chain 4 Proteins 0.000 description 2
- 101000973618 Homo sapiens NF-kappa-B essential modulator Proteins 0.000 description 2
- 101000979216 Homo sapiens Necdin Proteins 0.000 description 2
- 101000985296 Homo sapiens Neuron-specific calcium-binding protein hippocalcin Proteins 0.000 description 2
- 101000851058 Homo sapiens Neutrophil elastase Proteins 0.000 description 2
- 101000945735 Homo sapiens Parafibromin Proteins 0.000 description 2
- 101001000631 Homo sapiens Peripheral myelin protein 22 Proteins 0.000 description 2
- 101000610652 Homo sapiens Peripherin-2 Proteins 0.000 description 2
- 101001073025 Homo sapiens Peroxisomal targeting signal 1 receptor Proteins 0.000 description 2
- 101001099372 Homo sapiens Peroxisome biogenesis factor 1 Proteins 0.000 description 2
- 101000595674 Homo sapiens Pituitary homeobox 3 Proteins 0.000 description 2
- 101001096159 Homo sapiens Pituitary-specific positive transcription factor 1 Proteins 0.000 description 2
- 101000582950 Homo sapiens Platelet factor 4 Proteins 0.000 description 2
- 101000595193 Homo sapiens Podocin Proteins 0.000 description 2
- 101001105683 Homo sapiens Pre-mRNA-processing-splicing factor 8 Proteins 0.000 description 2
- 101000928339 Homo sapiens Progressive ankylosis protein homolog Proteins 0.000 description 2
- 101001038300 Homo sapiens Protein ERGIC-53 Proteins 0.000 description 2
- 101000573199 Homo sapiens Protein PML Proteins 0.000 description 2
- 101001123986 Homo sapiens Protein-serine O-palmitoleoyltransferase porcupine Proteins 0.000 description 2
- 101000896576 Homo sapiens Putative cytochrome P450 2D7 Proteins 0.000 description 2
- 101000665882 Homo sapiens Retinol-binding protein 4 Proteins 0.000 description 2
- 101001125551 Homo sapiens Ribose-phosphate pyrophosphokinase 1 Proteins 0.000 description 2
- 101000711796 Homo sapiens Sclerostin Proteins 0.000 description 2
- 101000836983 Homo sapiens Secretoglobin family 1D member 1 Proteins 0.000 description 2
- 101000628575 Homo sapiens Serine/threonine-protein kinase 19 Proteins 0.000 description 2
- 101000821972 Homo sapiens Solute carrier family 4 member 11 Proteins 0.000 description 2
- 101000861263 Homo sapiens Steroid 21-hydroxylase Proteins 0.000 description 2
- 101000634836 Homo sapiens T cell receptor alpha chain MC.7.G5 Proteins 0.000 description 2
- 101000713600 Homo sapiens T-box transcription factor TBX22 Proteins 0.000 description 2
- 101000809875 Homo sapiens TYRO protein tyrosine kinase-binding protein Proteins 0.000 description 2
- 101000653005 Homo sapiens Thromboxane-A synthase Proteins 0.000 description 2
- 101000645320 Homo sapiens Titin Proteins 0.000 description 2
- 101000669406 Homo sapiens Toll-like receptor 6 Proteins 0.000 description 2
- 101000679575 Homo sapiens Trafficking protein particle complex subunit 2 Proteins 0.000 description 2
- 101001050288 Homo sapiens Transcription factor Jun Proteins 0.000 description 2
- 101001074042 Homo sapiens Transcriptional activator GLI3 Proteins 0.000 description 2
- 101001051166 Homo sapiens Transcriptional activator MN1 Proteins 0.000 description 2
- 101000801433 Homo sapiens Trophoblast glycoprotein Proteins 0.000 description 2
- 101000850794 Homo sapiens Tropomyosin alpha-3 chain Proteins 0.000 description 2
- 101000764260 Homo sapiens Troponin T, cardiac muscle Proteins 0.000 description 2
- 101000772173 Homo sapiens Tubby-related protein 1 Proteins 0.000 description 2
- 101000625842 Homo sapiens Tubulin-specific chaperone E Proteins 0.000 description 2
- 101000610605 Homo sapiens Tumor necrosis factor receptor superfamily member 10A Proteins 0.000 description 2
- 101000610604 Homo sapiens Tumor necrosis factor receptor superfamily member 10B Proteins 0.000 description 2
- 101000610602 Homo sapiens Tumor necrosis factor receptor superfamily member 10C Proteins 0.000 description 2
- 101000679903 Homo sapiens Tumor necrosis factor receptor superfamily member 25 Proteins 0.000 description 2
- 101000611023 Homo sapiens Tumor necrosis factor receptor superfamily member 6 Proteins 0.000 description 2
- 101000823316 Homo sapiens Tyrosine-protein kinase ABL1 Proteins 0.000 description 2
- 101000772888 Homo sapiens Ubiquitin-protein ligase E3A Proteins 0.000 description 2
- 101000867848 Homo sapiens Voltage-dependent L-type calcium channel subunit alpha-1F Proteins 0.000 description 2
- 101001104102 Homo sapiens X-linked retinitis pigmentosa GTPase regulator Proteins 0.000 description 2
- 101000772560 Homo sapiens Zinc finger transcription factor Trps1 Proteins 0.000 description 2
- 108090000144 Human Proteins Proteins 0.000 description 2
- 102000003839 Human Proteins Human genes 0.000 description 2
- 102100026539 Induced myeloid leukemia cell differentiation protein Mcl-1 Human genes 0.000 description 2
- 102100026724 Inositol polyphosphate 5-phosphatase OCRL Human genes 0.000 description 2
- 102100023915 Insulin Human genes 0.000 description 2
- 102100026720 Interferon beta Human genes 0.000 description 2
- 102100030130 Interferon regulatory factor 6 Human genes 0.000 description 2
- 108010047761 Interferon-alpha Proteins 0.000 description 2
- 102000006992 Interferon-alpha Human genes 0.000 description 2
- 108090000467 Interferon-beta Proteins 0.000 description 2
- 102100026878 Interleukin-2 receptor subunit alpha Human genes 0.000 description 2
- 102000004388 Interleukin-4 Human genes 0.000 description 2
- 108090000978 Interleukin-4 Proteins 0.000 description 2
- 102100039078 Interleukin-4 receptor subunit alpha Human genes 0.000 description 2
- 102100039897 Interleukin-5 Human genes 0.000 description 2
- 102100021592 Interleukin-7 Human genes 0.000 description 2
- 108010002586 Interleukin-7 Proteins 0.000 description 2
- 108010002335 Interleukin-9 Proteins 0.000 description 2
- 102100026871 Interleukin-9 Human genes 0.000 description 2
- 102100021504 Iron-sulfur clusters transporter ABCB7, mitochondrial Human genes 0.000 description 2
- 102100022905 Keratin, type II cytoskeletal 1 Human genes 0.000 description 2
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 2
- 108090000581 Leukemia inhibitory factor Proteins 0.000 description 2
- 108010028921 Lipopeptides Proteins 0.000 description 2
- 102100035576 Long-wave-sensitive opsin 1 Human genes 0.000 description 2
- 102100024640 Low-density lipoprotein receptor Human genes 0.000 description 2
- 102100040788 Lutropin-choriogonadotropic hormone receptor Human genes 0.000 description 2
- 102100026001 Lysosomal acid lipase/cholesteryl ester hydrolase Human genes 0.000 description 2
- 102100033472 Lysosomal-trafficking regulator Human genes 0.000 description 2
- 241001082241 Lythrum hyssopifolia Species 0.000 description 2
- 102100026553 Mannose-binding protein C Human genes 0.000 description 2
- 102100021070 Mediator of RNA polymerase II transcription subunit 12 Human genes 0.000 description 2
- 108010023335 Member 2 Subfamily B ATP Binding Cassette Transporter Proteins 0.000 description 2
- 102100039364 Metalloproteinase inhibitor 1 Human genes 0.000 description 2
- 102100030157 Microphthalmia-associated transcription factor Human genes 0.000 description 2
- 102100030173 Muellerian-inhibiting factor Human genes 0.000 description 2
- 241001529936 Murinae Species 0.000 description 2
- 101100481581 Mus musculus Tlr13 gene Proteins 0.000 description 2
- 101710135898 Myc proto-oncogene protein Proteins 0.000 description 2
- 102100038934 Myosin-7 Human genes 0.000 description 2
- RSPURTUNRHNVGF-IOSLPCCCSA-N N(2),N(2)-dimethylguanosine Chemical compound C1=NC=2C(=O)NC(N(C)C)=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O RSPURTUNRHNVGF-IOSLPCCCSA-N 0.000 description 2
- SLEHROROQDYRAW-KQYNXXCUSA-N N(2)-methylguanosine Chemical compound C1=NC=2C(=O)NC(NC)=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O SLEHROROQDYRAW-KQYNXXCUSA-N 0.000 description 2
- 102100033341 N-acetylmannosamine kinase Human genes 0.000 description 2
- 102100021506 NADH-ubiquinone oxidoreductase chain 4 Human genes 0.000 description 2
- 102100022219 NF-kappa-B essential modulator Human genes 0.000 description 2
- 102100023064 Nectin-1 Human genes 0.000 description 2
- 102100028669 Neuron-specific calcium-binding protein hippocalcin Human genes 0.000 description 2
- 108700026244 Open Reading Frames Proteins 0.000 description 2
- 101710116435 Outer membrane protein Proteins 0.000 description 2
- 102100034743 Parafibromin Human genes 0.000 description 2
- 102100028467 Perforin-1 Human genes 0.000 description 2
- 102100040375 Peripherin-2 Human genes 0.000 description 2
- 102100036598 Peroxisomal targeting signal 1 receptor Human genes 0.000 description 2
- 102100038881 Peroxisome biogenesis factor 1 Human genes 0.000 description 2
- 201000005702 Pertussis Diseases 0.000 description 2
- 102100036088 Pituitary homeobox 3 Human genes 0.000 description 2
- 102100037914 Pituitary-specific positive transcription factor 1 Human genes 0.000 description 2
- 102100030304 Platelet factor 4 Human genes 0.000 description 2
- 102100036037 Podocin Human genes 0.000 description 2
- 102100021231 Pre-mRNA-processing-splicing factor 8 Human genes 0.000 description 2
- 208000034255 Primary dystonia, DYT2 type Diseases 0.000 description 2
- 102100036812 Progressive ankylosis protein homolog Human genes 0.000 description 2
- 102100040252 Protein ERGIC-53 Human genes 0.000 description 2
- 102100026375 Protein PML Human genes 0.000 description 2
- 102100028680 Protein patched homolog 1 Human genes 0.000 description 2
- 102100028119 Protein-serine O-palmitoleoyltransferase porcupine Human genes 0.000 description 2
- 102100030060 Pulmonary surfactant-associated protein A1 Human genes 0.000 description 2
- 102100021702 Putative cytochrome P450 2D7 Human genes 0.000 description 2
- 102100038042 Retinoblastoma-associated protein Human genes 0.000 description 2
- 102100023606 Retinoic acid receptor alpha Human genes 0.000 description 2
- 102100038246 Retinol-binding protein 4 Human genes 0.000 description 2
- 102100029508 Ribose-phosphate pyrophosphokinase 1 Human genes 0.000 description 2
- 102000001332 SRC Human genes 0.000 description 2
- 101001128051 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) 60S ribosomal protein L3 Proteins 0.000 description 2
- 102100028294 Saccharopine dehydrogenase Human genes 0.000 description 2
- 102100034201 Sclerostin Human genes 0.000 description 2
- 102100023105 Sialin Human genes 0.000 description 2
- 102100034803 Small nuclear ribonucleoprotein-associated protein N Human genes 0.000 description 2
- 102100023536 Solute carrier family 2, facilitated glucose transporter member 1 Human genes 0.000 description 2
- 102100021475 Solute carrier family 4 member 11 Human genes 0.000 description 2
- 102100032929 Son of sevenless homolog 1 Human genes 0.000 description 2
- 108010049356 Steroid 11-beta-Hydroxylase Proteins 0.000 description 2
- 102100021719 Steroid 17-alpha-hydroxylase/17,20 lyase Human genes 0.000 description 2
- 102100027545 Steroid 21-hydroxylase Human genes 0.000 description 2
- 102100029454 T cell receptor alpha chain MC.7.G5 Human genes 0.000 description 2
- 102100036839 T-box transcription factor TBX22 Human genes 0.000 description 2
- 101150057140 TACSTD1 gene Proteins 0.000 description 2
- 102100038717 TYRO protein tyrosine kinase-binding protein Human genes 0.000 description 2
- 102100034195 Thrombopoietin Human genes 0.000 description 2
- 102100030973 Thromboxane-A synthase Human genes 0.000 description 2
- 102100026260 Titin Human genes 0.000 description 2
- 102100039387 Toll-like receptor 6 Human genes 0.000 description 2
- 102100022613 Trafficking protein particle complex subunit 2 Human genes 0.000 description 2
- 102100023132 Transcription factor Jun Human genes 0.000 description 2
- 102100035559 Transcriptional activator GLI3 Human genes 0.000 description 2
- 102100024592 Transcriptional activator MN1 Human genes 0.000 description 2
- 101710150448 Transcriptional regulator Myc Proteins 0.000 description 2
- 108090001012 Transforming Growth Factor beta Proteins 0.000 description 2
- 102100030742 Transforming growth factor beta-1 proprotein Human genes 0.000 description 2
- 102100034902 Transmembrane 4 L6 family member 1 Human genes 0.000 description 2
- 102100033579 Trophoblast glycoprotein Human genes 0.000 description 2
- 102100033080 Tropomyosin alpha-3 chain Human genes 0.000 description 2
- 102100026893 Troponin T, cardiac muscle Human genes 0.000 description 2
- 102100029293 Tubby-related protein 1 Human genes 0.000 description 2
- 102100024769 Tubulin-specific chaperone E Human genes 0.000 description 2
- 102100040113 Tumor necrosis factor receptor superfamily member 10A Human genes 0.000 description 2
- 102100040112 Tumor necrosis factor receptor superfamily member 10B Human genes 0.000 description 2
- 102100040115 Tumor necrosis factor receptor superfamily member 10C Human genes 0.000 description 2
- 102100022203 Tumor necrosis factor receptor superfamily member 25 Human genes 0.000 description 2
- 102100040245 Tumor necrosis factor receptor superfamily member 5 Human genes 0.000 description 2
- 102100040403 Tumor necrosis factor receptor superfamily member 6 Human genes 0.000 description 2
- 102100024250 Ubiquitin carboxyl-terminal hydrolase CYLD Human genes 0.000 description 2
- 102100030434 Ubiquitin-protein ligase E3A Human genes 0.000 description 2
- 102100035336 Werner syndrome ATP-dependent helicase Human genes 0.000 description 2
- 102100040092 X-linked retinitis pigmentosa GTPase regulator Human genes 0.000 description 2
- 102100039662 Xaa-Pro dipeptidase Human genes 0.000 description 2
- 102100030619 Zinc finger transcription factor Trps1 Human genes 0.000 description 2
- JLCPHMBAVCMARE-UHFFFAOYSA-N [3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-hydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methyl [5-(6-aminopurin-9-yl)-2-(hydroxymethyl)oxolan-3-yl] hydrogen phosphate Polymers Cc1cn(C2CC(OP(O)(=O)OCC3OC(CC3OP(O)(=O)OCC3OC(CC3O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c3nc(N)[nH]c4=O)C(COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3CO)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cc(C)c(=O)[nH]c3=O)n3cc(C)c(=O)[nH]c3=O)n3ccc(N)nc3=O)n3cc(C)c(=O)[nH]c3=O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)O2)c(=O)[nH]c1=O JLCPHMBAVCMARE-UHFFFAOYSA-N 0.000 description 2
- 208000003012 achromatopsia 3 Diseases 0.000 description 2
- 108010029483 alpha 1 Chain Collagen Type I Proteins 0.000 description 2
- 238000013459 approach Methods 0.000 description 2
- 229960003121 arginine Drugs 0.000 description 2
- 235000009697 arginine Nutrition 0.000 description 2
- 108050002883 beta-defensin Proteins 0.000 description 2
- 102000012265 beta-defensin Human genes 0.000 description 2
- 230000004154 complement system Effects 0.000 description 2
- 108091036078 conserved sequence Proteins 0.000 description 2
- 210000001151 cytotoxic T lymphocyte Anatomy 0.000 description 2
- 230000006378 damage Effects 0.000 description 2
- 108010057167 dimethylaniline monooxygenase (N-oxide forming) Proteins 0.000 description 2
- 230000006870 function Effects 0.000 description 2
- 230000014509 gene expression Effects 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 230000036039 immunity Effects 0.000 description 2
- 230000006054 immunological memory Effects 0.000 description 2
- 230000001771 impaired effect Effects 0.000 description 2
- 230000001939 inductive effect Effects 0.000 description 2
- 208000015181 infectious disease Diseases 0.000 description 2
- 210000004698 lymphocyte Anatomy 0.000 description 2
- 230000015654 memory Effects 0.000 description 2
- 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 description 2
- 230000032361 posttranscriptional gene silencing Effects 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- 102000016914 ras Proteins Human genes 0.000 description 2
- 108010014186 ras Proteins Proteins 0.000 description 2
- 238000010532 solid phase synthesis reaction Methods 0.000 description 2
- 241000894007 species Species 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- 201000003353 torsion dystonia 2 Diseases 0.000 description 2
- 238000011144 upstream manufacturing Methods 0.000 description 2
- 238000002255 vaccination Methods 0.000 description 2
- GKJZMAHZJGSBKD-NMMTYZSQSA-N (10E,12Z)-octadecadienoic acid Chemical compound CCCCC\C=C/C=C/CCCCCCCCC(O)=O GKJZMAHZJGSBKD-NMMTYZSQSA-N 0.000 description 1
- UDPGUMQDCGORJQ-UHFFFAOYSA-N (2-chloroethyl)phosphonic acid Chemical compound OP(O)(=O)CCCl UDPGUMQDCGORJQ-UHFFFAOYSA-N 0.000 description 1
- XOYCLJDJUKHHHS-LHBOOPKSSA-N (2s,3s,4s,5r,6r)-6-[[(2s,3s,5r)-3-amino-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy]-3,4,5-trihydroxyoxane-2-carboxylic acid Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO[C@H]2[C@@H]([C@@H](O)[C@H](O)[C@H](O2)C(O)=O)O)[C@@H](N)C1 XOYCLJDJUKHHHS-LHBOOPKSSA-N 0.000 description 1
- LAQPKDLYOBZWBT-NYLDSJSYSA-N (2s,4s,5r,6r)-5-acetamido-2-{[(2s,3r,4s,5s,6r)-2-{[(2r,3r,4r,5r)-5-acetamido-1,2-dihydroxy-6-oxo-4-{[(2s,3s,4r,5s,6s)-3,4,5-trihydroxy-6-methyloxan-2-yl]oxy}hexan-3-yl]oxy}-3,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy}-4-hydroxy-6-[(1r,2r)-1,2,3-trihydrox Chemical compound O[C@H]1[C@H](O)[C@H](O)[C@H](C)O[C@H]1O[C@H]([C@@H](NC(C)=O)C=O)[C@@H]([C@H](O)CO)O[C@H]1[C@H](O)[C@@H](O[C@]2(O[C@H]([C@H](NC(C)=O)[C@@H](O)C2)[C@H](O)[C@H](O)CO)C(O)=O)[C@@H](O)[C@@H](CO)O1 LAQPKDLYOBZWBT-NYLDSJSYSA-N 0.000 description 1
- GWMHBZDOVFZVQC-UHFFFAOYSA-N 1,5,6-trimethylimidazo[4,5-b]pyridin-2-amine Chemical compound N1=C(C)C(C)=CC2=C1N=C(N)N2C GWMHBZDOVFZVQC-UHFFFAOYSA-N 0.000 description 1
- WEYNBWVKOYCCQT-UHFFFAOYSA-N 1-(3-chloro-4-methylphenyl)-3-{2-[({5-[(dimethylamino)methyl]-2-furyl}methyl)thio]ethyl}urea Chemical compound O1C(CN(C)C)=CC=C1CSCCNC(=O)NC1=CC=C(C)C(Cl)=C1 WEYNBWVKOYCCQT-UHFFFAOYSA-N 0.000 description 1
- 102100038369 1-acyl-sn-glycerol-3-phosphate acyltransferase beta Human genes 0.000 description 1
- GFYLSDSUCHVORB-IOSLPCCCSA-N 1-methyladenosine Chemical compound C1=NC=2C(=N)N(C)C=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O GFYLSDSUCHVORB-IOSLPCCCSA-N 0.000 description 1
- WJNGQIYEQLPJMN-IOSLPCCCSA-N 1-methylinosine Chemical compound C1=NC=2C(=O)N(C)C=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O WJNGQIYEQLPJMN-IOSLPCCCSA-N 0.000 description 1
- 102100024341 10 kDa heat shock protein, mitochondrial Human genes 0.000 description 1
- 102100031236 11-beta-hydroxysteroid dehydrogenase type 2 Human genes 0.000 description 1
- 108010020567 12E7 Antigen Proteins 0.000 description 1
- 102000008482 12E7 Antigen Human genes 0.000 description 1
- 102100020928 14 kDa phosphohistidine phosphatase Human genes 0.000 description 1
- 101710082470 14 kDa phosphohistidine phosphatase Proteins 0.000 description 1
- 102100022585 17-beta-hydroxysteroid dehydrogenase type 3 Human genes 0.000 description 1
- RSMRWWHFJMENJH-LQDDAWAPSA-M 2,3-bis[[(z)-octadec-9-enoyl]oxy]propyl-trimethylazanium;methyl sulfate Chemical compound COS([O-])(=O)=O.CCCCCCCC\C=C/CCCCCCCC(=O)OCC(C[N+](C)(C)C)OC(=O)CCCCCCC\C=C/CCCCCCCC RSMRWWHFJMENJH-LQDDAWAPSA-M 0.000 description 1
- 102100021403 2,4-dienoyl-CoA reductase [(3E)-enoyl-CoA-producing], mitochondrial Human genes 0.000 description 1
- 102100027962 2-5A-dependent ribonuclease Human genes 0.000 description 1
- IQZWKGWOBPJWMX-UHFFFAOYSA-N 2-Methyladenosine Natural products C12=NC(C)=NC(N)=C2N=CN1C1OC(CO)C(O)C1O IQZWKGWOBPJWMX-UHFFFAOYSA-N 0.000 description 1
- HVANFPMHKAMILB-XKNCWEQSSA-N 2-[(8s,9s,10s,11s,13s,14s,17r)-13-formyl-11-hydroxy-10-methyl-3-oxo-1,2,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydrocyclopenta[a]phenanthren-17-yl]ethyl hydrogen sulfate Chemical compound C([C@@]1([C@@H](CCOS(O)(=O)=O)CC[C@H]1[C@@H]1CC2)C=O)[C@H](O)[C@@H]1[C@]1(C)C2CC(=O)CC1 HVANFPMHKAMILB-XKNCWEQSSA-N 0.000 description 1
- AKEMIRQFANFFKU-NCYRAAIKSA-N 2-[[(2s,4as,6ar,6as,6br,8ar,10s,12as)-10-(2-carboxybenzoyl)oxy-2,4a,6a,6b,9,9,12a-heptamethyl-1,3,4,5,6,6a,7,8,8a,10,11,12-dodecahydropicen-2-yl]methoxycarbonyl]benzoic acid Chemical compound C([C@]1(C)CC2=C3[C@@]([C@@]4(CC[C@H]5C(C)(C)[C@@H](OC(=O)C=6C(=CC=CC=6)C(O)=O)CC[C@]5(C)[C@H]4C=C3)C)(C)CC[C@@]2(C)CC1)OC(=O)C1=CC=CC=C1C(O)=O AKEMIRQFANFFKU-NCYRAAIKSA-N 0.000 description 1
- 101710186725 2-acylglycerol O-acyltransferase 2 Proteins 0.000 description 1
- LTXJQOCWTBTJMW-UPVQRQRKSA-N 2-amino-1,7-dihydropurin-6-one 2-amino-9-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-1H-purin-6-one 1-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]pyrimidine-2,4-dione 1H-pyrimidine-2,4-dione Chemical compound O=C1C=CNC(=O)N1.O=C1NC(N)=NC2=C1NC=N2.O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C=C1.C1=NC=2C(=O)NC(N)=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O LTXJQOCWTBTJMW-UPVQRQRKSA-N 0.000 description 1
- IQZWKGWOBPJWMX-IOSLPCCCSA-N 2-methyladenosine Chemical compound C12=NC(C)=NC(N)=C2N=CN1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O IQZWKGWOBPJWMX-IOSLPCCCSA-N 0.000 description 1
- 108010030844 2-methylcitrate synthase Proteins 0.000 description 1
- VZQXUWKZDSEQRR-SDBHATRESA-N 2-methylthio-N(6)-(Delta(2)-isopentenyl)adenosine Chemical compound C12=NC(SC)=NC(NCC=C(C)C)=C2N=CN1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O VZQXUWKZDSEQRR-SDBHATRESA-N 0.000 description 1
- 102100026936 2-oxoglutarate dehydrogenase, mitochondrial Human genes 0.000 description 1
- 102100035352 2-oxoisovalerate dehydrogenase subunit alpha, mitochondrial Human genes 0.000 description 1
- 102100035315 2-oxoisovalerate dehydrogenase subunit beta, mitochondrial Human genes 0.000 description 1
- 108010073030 25-Hydroxyvitamin D3 1-alpha-Hydroxylase Proteins 0.000 description 1
- 102100036285 25-hydroxyvitamin D-1 alpha hydroxylase, mitochondrial Human genes 0.000 description 1
- 102100023817 26S proteasome complex subunit SEM1 Human genes 0.000 description 1
- 102100032303 26S proteasome non-ATPase regulatory subunit 2 Human genes 0.000 description 1
- 208000017858 2q37 microdeletion syndrome Diseases 0.000 description 1
- 108010067083 3 beta-hydroxysteroid dehydrogenase type II Proteins 0.000 description 1
- 108020005345 3' Untranslated Regions Proteins 0.000 description 1
- 102100027824 3'(2'),5'-bisphosphate nucleotidase 1 Human genes 0.000 description 1
- TVZRAEYQIKYCPH-UHFFFAOYSA-N 3-(trimethylsilyl)propane-1-sulfonic acid Chemical compound C[Si](C)(C)CCCS(O)(=O)=O TVZRAEYQIKYCPH-UHFFFAOYSA-N 0.000 description 1
- AMQVHASIFJZFOS-UHFFFAOYSA-N 3-[(4-chlorophenyl)-(4-hydroxy-2-oxochromen-3-yl)methyl]-4-hydroxychromen-2-one Chemical compound O=C1OC=2C=CC=CC=2C(O)=C1C(C=1C(OC2=CC=CC=C2C=1O)=O)C1=CC=C(Cl)C=C1 AMQVHASIFJZFOS-UHFFFAOYSA-N 0.000 description 1
- XPRGFWCOARUGAL-UHFFFAOYSA-N 3-anilino-1-phenylpyrrolidine-2,5-dione Chemical compound O=C1N(C=2C=CC=CC=2)C(=O)CC1NC1=CC=CC=C1 XPRGFWCOARUGAL-UHFFFAOYSA-N 0.000 description 1
- 102100029103 3-ketoacyl-CoA thiolase Human genes 0.000 description 1
- 102100039217 3-ketoacyl-CoA thiolase, peroxisomal Human genes 0.000 description 1
- 101710082567 3-methylorcinaldehyde synthase Proteins 0.000 description 1
- 102100033875 3-oxo-5-alpha-steroid 4-dehydrogenase 2 Human genes 0.000 description 1
- INZOTETZQBPBCE-NYLDSJSYSA-N 3-sialyl lewis Chemical compound O[C@H]1[C@H](O)[C@H](O)[C@H](C)O[C@H]1O[C@H]([C@H](O)CO)[C@@H]([C@@H](NC(C)=O)C=O)O[C@H]1[C@H](O)[C@@H](O[C@]2(O[C@H]([C@H](NC(C)=O)[C@@H](O)C2)[C@H](O)[C@H](O)CO)C(O)=O)[C@@H](O)[C@@H](CO)O1 INZOTETZQBPBCE-NYLDSJSYSA-N 0.000 description 1
- RHKWIGHJGOEUSM-UHFFFAOYSA-N 3h-imidazo[4,5-h]quinoline Chemical class C1=CN=C2C(N=CN3)=C3C=CC2=C1 RHKWIGHJGOEUSM-UHFFFAOYSA-N 0.000 description 1
- SXXLKZCNJHJYFL-UHFFFAOYSA-N 4,5,6,7-tetrahydro-[1,2]oxazolo[4,5-c]pyridin-5-ium-3-olate Chemical compound C1CNCC2=C1ONC2=O SXXLKZCNJHJYFL-UHFFFAOYSA-N 0.000 description 1
- GMOGICAFJFPMNS-UHFFFAOYSA-N 4-(1,4,8,11-tetrazacyclotetradec-1-ylmethyl)benzoic acid Chemical compound C1=CC(C(=O)O)=CC=C1CN1CCNCCCNCCNCCC1 GMOGICAFJFPMNS-UHFFFAOYSA-N 0.000 description 1
- KFVINGKPXQSPNP-UHFFFAOYSA-N 4-amino-2-[2-(diethylamino)ethyl]-n-propanoylbenzamide Chemical compound CCN(CC)CCC1=CC(N)=CC=C1C(=O)NC(=O)CC KFVINGKPXQSPNP-UHFFFAOYSA-N 0.000 description 1
- 102100035923 4-aminobutyrate aminotransferase, mitochondrial Human genes 0.000 description 1
- KEWSCDNULKOKTG-UHFFFAOYSA-N 4-cyano-4-ethylsulfanylcarbothioylsulfanylpentanoic acid Chemical compound CCSC(=S)SC(C)(C#N)CCC(O)=O KEWSCDNULKOKTG-UHFFFAOYSA-N 0.000 description 1
- 102100035277 4-galactosyl-N-acetylglucosaminide 3-alpha-L-fucosyltransferase FUT6 Human genes 0.000 description 1
- 108010068327 4-hydroxyphenylpyruvate dioxygenase Proteins 0.000 description 1
- MXCVHSXCXPHOLP-UHFFFAOYSA-N 4-oxo-6-propylchromene-2-carboxylic acid Chemical compound O1C(C(O)=O)=CC(=O)C2=CC(CCC)=CC=C21 MXCVHSXCXPHOLP-UHFFFAOYSA-N 0.000 description 1
- 102100037563 40S ribosomal protein S2 Human genes 0.000 description 1
- 102100034088 40S ribosomal protein S4, X isoform Human genes 0.000 description 1
- 102100028550 40S ribosomal protein S4, Y isoform 1 Human genes 0.000 description 1
- 108020003589 5' Untranslated Regions Proteins 0.000 description 1
- 102100024626 5'-AMP-activated protein kinase subunit gamma-2 Human genes 0.000 description 1
- 102100031020 5-aminolevulinate synthase, erythroid-specific, mitochondrial Human genes 0.000 description 1
- 101710163573 5-hydroxyisourate hydrolase Proteins 0.000 description 1
- 102100024959 5-hydroxytryptamine receptor 2C Human genes 0.000 description 1
- USVMJSALORZVDV-UHFFFAOYSA-N 6-(gamma,gamma-dimethylallylamino)purine riboside Natural products C1=NC=2C(NCC=C(C)C)=NC=NC=2N1C1OC(CO)C(O)C1O USVMJSALORZVDV-UHFFFAOYSA-N 0.000 description 1
- AAHNBILIYONQLX-UHFFFAOYSA-N 6-fluoro-3-[4-[3-methoxy-4-(4-methylimidazol-1-yl)phenyl]triazol-1-yl]-1-(2,2,2-trifluoroethyl)-4,5-dihydro-3h-1-benzazepin-2-one Chemical compound COC1=CC(C=2N=NN(C=2)C2C(N(CC(F)(F)F)C3=CC=CC(F)=C3CC2)=O)=CC=C1N1C=NC(C)=C1 AAHNBILIYONQLX-UHFFFAOYSA-N 0.000 description 1
- 101710154868 60 kDa heat shock protein, mitochondrial Proteins 0.000 description 1
- VJUPMOPLUQHMLE-UUOKFMHZSA-N 8-Bromoadenosine Chemical compound BrC1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O VJUPMOPLUQHMLE-UUOKFMHZSA-N 0.000 description 1
- JBYXPOFIGCOSSB-GOJKSUSPSA-N 9-cis,11-trans-octadecadienoic acid Chemical compound CCCCCC\C=C\C=C/CCCCCCCC(O)=O JBYXPOFIGCOSSB-GOJKSUSPSA-N 0.000 description 1
- FWXNJWAXBVMBGL-UHFFFAOYSA-N 9-n,9-n,10-n,10-n-tetrakis(4-methylphenyl)anthracene-9,10-diamine Chemical compound C1=CC(C)=CC=C1N(C=1C2=CC=CC=C2C(N(C=2C=CC(C)=CC=2)C=2C=CC(C)=CC=2)=C2C=CC=CC2=1)C1=CC=C(C)C=C1 FWXNJWAXBVMBGL-UHFFFAOYSA-N 0.000 description 1
- MSSXOMSJDRHRMC-UHFFFAOYSA-N 9H-purine-2,6-diamine Chemical compound NC1=NC(N)=C2NC=NC2=N1 MSSXOMSJDRHRMC-UHFFFAOYSA-N 0.000 description 1
- 102100032290 A disintegrin and metalloproteinase with thrombospondin motifs 13 Human genes 0.000 description 1
- 102100027399 A disintegrin and metalloproteinase with thrombospondin motifs 2 Human genes 0.000 description 1
- 101150092476 ABCA1 gene Proteins 0.000 description 1
- 101150060184 ACHE gene Proteins 0.000 description 1
- 108091005670 ADAMTS13 Proteins 0.000 description 1
- 108091005662 ADAMTS2 Proteins 0.000 description 1
- 102100032533 ADP/ATP translocase 1 Human genes 0.000 description 1
- 102100026396 ADP/ATP translocase 2 Human genes 0.000 description 1
- 102100026397 ADP/ATP translocase 3 Human genes 0.000 description 1
- 102000017919 ADRB2 Human genes 0.000 description 1
- 102000017918 ADRB3 Human genes 0.000 description 1
- 108060003355 ADRB3 Proteins 0.000 description 1
- 101150012579 ADSL gene Proteins 0.000 description 1
- 102100024379 AF4/FMR2 family member 1 Human genes 0.000 description 1
- 102100024378 AF4/FMR2 family member 2 Human genes 0.000 description 1
- 102000010553 ALAD Human genes 0.000 description 1
- 101150082527 ALAD gene Proteins 0.000 description 1
- 102100032123 AMP deaminase 1 Human genes 0.000 description 1
- 102100032898 AMP deaminase 3 Human genes 0.000 description 1
- 102100037651 AP-2 complex subunit sigma Human genes 0.000 description 1
- 102100033936 AP-3 complex subunit beta-1 Human genes 0.000 description 1
- 101150063992 APOC2 gene Proteins 0.000 description 1
- 101150037123 APOE gene Proteins 0.000 description 1
- 102100030840 AT-rich interactive domain-containing protein 4B Human genes 0.000 description 1
- 102000000872 ATM Human genes 0.000 description 1
- 108700005241 ATP Binding Cassette Transporter 1 Proteins 0.000 description 1
- 102100021921 ATP synthase subunit a Human genes 0.000 description 1
- 102100028161 ATP-binding cassette sub-family C member 2 Human genes 0.000 description 1
- 102100028162 ATP-binding cassette sub-family C member 3 Human genes 0.000 description 1
- 102100024645 ATP-binding cassette sub-family C member 8 Human genes 0.000 description 1
- 102100024643 ATP-binding cassette sub-family D member 1 Human genes 0.000 description 1
- 102100020973 ATP-binding cassette sub-family D member 3 Human genes 0.000 description 1
- 102100033106 ATP-binding cassette sub-family G member 5 Human genes 0.000 description 1
- 102100033092 ATP-binding cassette sub-family G member 8 Human genes 0.000 description 1
- 102100032922 ATP-dependent 6-phosphofructokinase, muscle type Human genes 0.000 description 1
- 102100027452 ATP-dependent DNA helicase Q4 Human genes 0.000 description 1
- 102100033350 ATP-dependent translocase ABCB1 Human genes 0.000 description 1
- 101150020330 ATRX gene Proteins 0.000 description 1
- 208000012861 AVSD 1 Diseases 0.000 description 1
- 102100039164 Acetyl-CoA carboxylase 1 Human genes 0.000 description 1
- 102100030913 Acetylcholine receptor subunit alpha Human genes 0.000 description 1
- 102100022725 Acetylcholine receptor subunit beta Human genes 0.000 description 1
- 102100040963 Acetylcholine receptor subunit epsilon Human genes 0.000 description 1
- 102100033639 Acetylcholinesterase Human genes 0.000 description 1
- 102100029271 Acetylcholinesterase collagenic tail peptide Human genes 0.000 description 1
- 102100027446 Acetylserotonin O-methyltransferase Human genes 0.000 description 1
- 102100024005 Acid ceramidase Human genes 0.000 description 1
- 208000034012 Acid sphingomyelinase deficiency Diseases 0.000 description 1
- 101150091203 Acot1 gene Proteins 0.000 description 1
- 201000011244 Acrocallosal syndrome Diseases 0.000 description 1
- 102100039819 Actin, alpha cardiac muscle 1 Human genes 0.000 description 1
- 102100026656 Actin, alpha skeletal muscle Human genes 0.000 description 1
- 108010085238 Actins Proteins 0.000 description 1
- 102000007469 Actins Human genes 0.000 description 1
- 102100040430 Active breakpoint cluster region-related protein Human genes 0.000 description 1
- 102100025854 Acyl-coenzyme A thioesterase 1 Human genes 0.000 description 1
- 102100035886 Adenine DNA glycosylase Human genes 0.000 description 1
- 108090001079 Adenine Nucleotide Translocator 1 Proteins 0.000 description 1
- 102100029457 Adenine phosphoribosyltransferase Human genes 0.000 description 1
- 108010024223 Adenine phosphoribosyltransferase Proteins 0.000 description 1
- 102100036664 Adenosine deaminase Human genes 0.000 description 1
- 102100020925 Adenosylhomocysteinase Human genes 0.000 description 1
- 102100027236 Adenylate kinase isoenzyme 1 Human genes 0.000 description 1
- 101710137115 Adenylyl cyclase-associated protein 1 Proteins 0.000 description 1
- 102100040152 Adenylyl-sulfate kinase Human genes 0.000 description 1
- 102100022455 Adrenocorticotropic hormone receptor Human genes 0.000 description 1
- 208000008190 Agammaglobulinemia Diseases 0.000 description 1
- 208000006704 Aland Island eye disease Diseases 0.000 description 1
- 102100027211 Albumin Human genes 0.000 description 1
- 102100034042 Alcohol dehydrogenase 1C Human genes 0.000 description 1
- 108020002663 Aldehyde Dehydrogenase Proteins 0.000 description 1
- 102100026608 Aldehyde dehydrogenase family 3 member A2 Human genes 0.000 description 1
- 102100033816 Aldehyde dehydrogenase, mitochondrial Human genes 0.000 description 1
- 102100024321 Alkaline phosphatase, placental type Human genes 0.000 description 1
- 102100025683 Alkaline phosphatase, tissue-nonspecific isozyme Human genes 0.000 description 1
- 102100034112 Alkyldihydroxyacetonephosphate synthase, peroxisomal Human genes 0.000 description 1
- 102100034044 All-trans-retinol dehydrogenase [NAD(+)] ADH1B Human genes 0.000 description 1
- 102100024296 Alpha-1,6-mannosyl-glycoprotein 2-beta-N-acetylglucosaminyltransferase Human genes 0.000 description 1
- 102100022463 Alpha-1-acid glycoprotein 1 Human genes 0.000 description 1
- 102100022712 Alpha-1-antitrypsin Human genes 0.000 description 1
- 102100035028 Alpha-L-iduronidase Human genes 0.000 description 1
- 102100031317 Alpha-N-acetylgalactosaminidase Human genes 0.000 description 1
- 102100034561 Alpha-N-acetylglucosaminidase Human genes 0.000 description 1
- 102100024085 Alpha-aminoadipic semialdehyde dehydrogenase Human genes 0.000 description 1
- 102100040743 Alpha-crystallin B chain Human genes 0.000 description 1
- 102100038910 Alpha-enolase Human genes 0.000 description 1
- 102100021761 Alpha-mannosidase 2 Human genes 0.000 description 1
- 102100040410 Alpha-methylacyl-CoA racemase Human genes 0.000 description 1
- 108010044434 Alpha-methylacyl-CoA racemase Proteins 0.000 description 1
- 102100030685 Alpha-sarcoglycan Human genes 0.000 description 1
- 102100031663 Alpha-tocopherol transfer protein Human genes 0.000 description 1
- 101710085003 Alpha-tubulin N-acetyltransferase Proteins 0.000 description 1
- 101710085461 Alpha-tubulin N-acetyltransferase 1 Proteins 0.000 description 1
- 102100032047 Alsin Human genes 0.000 description 1
- 102100032360 Alstrom syndrome protein 1 Human genes 0.000 description 1
- 201000000541 Ambras type hypertrichosis universalis congenita Diseases 0.000 description 1
- 102100039088 Amelogenin, X isoform Human genes 0.000 description 1
- 102100037242 Amiloride-sensitive sodium channel subunit alpha Human genes 0.000 description 1
- 102100037232 Amiloride-sensitive sodium channel subunit beta Human genes 0.000 description 1
- 102100022534 Amiloride-sensitive sodium channel subunit gamma Human genes 0.000 description 1
- 102100028661 Amine oxidase [flavin-containing] A Human genes 0.000 description 1
- 102100028116 Amine oxidase [flavin-containing] B Human genes 0.000 description 1
- 102100020895 Ammonium transporter Rh type A Human genes 0.000 description 1
- 102100030988 Angiotensin-converting enzyme Human genes 0.000 description 1
- 101710185050 Angiotensin-converting enzyme Proteins 0.000 description 1
- 102100034280 Ankyrin repeat domain-containing protein 26 Human genes 0.000 description 1
- 102100031366 Ankyrin-1 Human genes 0.000 description 1
- 102100023086 Anosmin-1 Human genes 0.000 description 1
- 102100025511 Anti-Muellerian hormone type-2 receptor Human genes 0.000 description 1
- 102100030343 Antigen peptide transporter 2 Human genes 0.000 description 1
- 108700042778 Antimicrobial Peptides Proteins 0.000 description 1
- 102000044503 Antimicrobial Peptides Human genes 0.000 description 1
- 102100033715 Apolipoprotein A-I Human genes 0.000 description 1
- 102100030942 Apolipoprotein A-II Human genes 0.000 description 1
- 102100040202 Apolipoprotein B-100 Human genes 0.000 description 1
- 102100039998 Apolipoprotein C-II Human genes 0.000 description 1
- 102100030970 Apolipoprotein C-III Human genes 0.000 description 1
- 102000011899 Aquaporin 2 Human genes 0.000 description 1
- 108010036221 Aquaporin 2 Proteins 0.000 description 1
- 101000686547 Arabidopsis thaliana 30S ribosomal protein S1, chloroplastic Proteins 0.000 description 1
- 101100454193 Arabidopsis thaliana AAA1 gene Proteins 0.000 description 1
- 101100165034 Arabidopsis thaliana AZF2 gene Proteins 0.000 description 1
- 101100059333 Arabidopsis thaliana CYCA1-2 gene Proteins 0.000 description 1
- 101100226366 Arabidopsis thaliana EXT3 gene Proteins 0.000 description 1
- 101100018371 Arabidopsis thaliana ICR5 gene Proteins 0.000 description 1
- 101100404726 Arabidopsis thaliana NHX7 gene Proteins 0.000 description 1
- 101100517192 Arabidopsis thaliana NRPD1 gene Proteins 0.000 description 1
- 101100407152 Arabidopsis thaliana PBL7 gene Proteins 0.000 description 1
- 101100298412 Arabidopsis thaliana PCMP-H73 gene Proteins 0.000 description 1
- 101001125931 Arabidopsis thaliana Plastidial pyruvate kinase 2 Proteins 0.000 description 1
- 101000719121 Arabidopsis thaliana Protein MEI2-like 1 Proteins 0.000 description 1
- 101100038200 Arabidopsis thaliana RPD1 gene Proteins 0.000 description 1
- 101100536545 Arabidopsis thaliana TCL2 gene Proteins 0.000 description 1
- 101100102990 Arabidopsis thaliana WOX3 gene Proteins 0.000 description 1
- 102100024003 Arf-GAP with SH3 domain, ANK repeat and PH domain-containing protein 1 Human genes 0.000 description 1
- 108700040066 Argininosuccinate lyases Proteins 0.000 description 1
- 102100020999 Argininosuccinate synthase Human genes 0.000 description 1
- 108010078554 Aromatase Proteins 0.000 description 1
- 102100026789 Aryl hydrocarbon receptor repressor Human genes 0.000 description 1
- 108020005224 Arylamine N-acetyltransferase Proteins 0.000 description 1
- 102100031491 Arylsulfatase B Human genes 0.000 description 1
- 102100023943 Arylsulfatase L Human genes 0.000 description 1
- 101150025804 Asl gene Proteins 0.000 description 1
- 102100023927 Asparagine synthetase [glutamine-hydrolyzing] Human genes 0.000 description 1
- 102100032948 Aspartoacylase Human genes 0.000 description 1
- 101001099437 Aspergillus niger Pectin lyase D Proteins 0.000 description 1
- 108010004586 Ataxia Telangiectasia Mutated Proteins Proteins 0.000 description 1
- 102100021321 Ataxin-3 Human genes 0.000 description 1
- 102000007371 Ataxin-3 Human genes 0.000 description 1
- 108010032947 Ataxin-3 Proteins 0.000 description 1
- 108010032953 Ataxin-7 Proteins 0.000 description 1
- 102100027766 Atlastin-1 Human genes 0.000 description 1
- 101150074725 Atxn3 gene Proteins 0.000 description 1
- 241000972773 Aulopiformes Species 0.000 description 1
- 102100036465 Autoimmune regulator Human genes 0.000 description 1
- 208000035669 Autosomal dominant Charcot-Marie-Tooth disease type 2B Diseases 0.000 description 1
- 208000035665 Autosomal dominant Charcot-Marie-Tooth disease type 2D Diseases 0.000 description 1
- 208000031629 Autosomal dominant spastic paraplegia type 4 Diseases 0.000 description 1
- 208000036075 Autosomal dominant tubulointerstitial kidney disease Diseases 0.000 description 1
- 208000031721 Autosomal recessive spastic paraplegia type 23 Diseases 0.000 description 1
- 208000031627 Autosomal recessive spastic paraplegia type 5A Diseases 0.000 description 1
- 102100035683 Axin-2 Human genes 0.000 description 1
- 102100035526 B melanoma antigen 1 Human genes 0.000 description 1
- 108700024832 B-Cell CLL-Lymphoma 10 Proteins 0.000 description 1
- 108700009171 B-Cell Lymphoma 3 Proteins 0.000 description 1
- 102100035634 B-cell linker protein Human genes 0.000 description 1
- 102100021570 B-cell lymphoma 3 protein Human genes 0.000 description 1
- 102100037598 B-cell lymphoma/leukemia 10 Human genes 0.000 description 1
- 101150074953 BCL10 gene Proteins 0.000 description 1
- 108091012583 BCL2 Proteins 0.000 description 1
- 231100000699 Bacterial toxin Toxicity 0.000 description 1
- 102100021264 Band 3 anion transport protein Human genes 0.000 description 1
- 102100033949 Basic salivary proline-rich protein 3 Human genes 0.000 description 1
- 102100022440 Battenin Human genes 0.000 description 1
- 101150072667 Bcl3 gene Proteins 0.000 description 1
- 208000014596 Berardinelli-Seip congenital lipodystrophy Diseases 0.000 description 1
- 102100027321 Beta-1,4-galactosyltransferase 7 Human genes 0.000 description 1
- 102100030802 Beta-2-glycoprotein 1 Human genes 0.000 description 1
- 102100027314 Beta-2-microglobulin Human genes 0.000 description 1
- 102100023658 Beta-chimaerin Human genes 0.000 description 1
- 102100029334 Beta-crystallin A3 Human genes 0.000 description 1
- 102100029388 Beta-crystallin B2 Human genes 0.000 description 1
- 102100026031 Beta-glucuronidase Human genes 0.000 description 1
- 102100022548 Beta-hexosaminidase subunit alpha Human genes 0.000 description 1
- 102100022549 Beta-hexosaminidase subunit beta Human genes 0.000 description 1
- 102100032487 Beta-mannosidase Human genes 0.000 description 1
- 102100030686 Beta-sarcoglycan Human genes 0.000 description 1
- 208000012922 Beukes hip dysplasia Diseases 0.000 description 1
- 208000008225 Beukes type hip dysplasia Diseases 0.000 description 1
- 102100030401 Biglycan Human genes 0.000 description 1
- 102100028282 Bile salt export pump Human genes 0.000 description 1
- 102100033743 Biotin-[acetyl-CoA-carboxylase] ligase Human genes 0.000 description 1
- 102100026044 Biotinidase Human genes 0.000 description 1
- 108010029692 Bisphosphoglycerate mutase Proteins 0.000 description 1
- 102100036200 Bisphosphoglycerate mutase Human genes 0.000 description 1
- 102100027058 Bleomycin hydrolase Human genes 0.000 description 1
- 102100027544 Blood group Rh(D) polypeptide Human genes 0.000 description 1
- 108091009167 Bloom syndrome protein Proteins 0.000 description 1
- 208000006146 Borjeson-Forssman-Lehmann syndrome Diseases 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 101000988373 Burkholderia cepacia Phthalate dioxygenase reductase Proteins 0.000 description 1
- 101710149815 C-C chemokine receptor type 2 Proteins 0.000 description 1
- 102100036841 C-C motif chemokine 1 Human genes 0.000 description 1
- 102100023702 C-C motif chemokine 13 Human genes 0.000 description 1
- 101710112613 C-C motif chemokine 13 Proteins 0.000 description 1
- 102100023705 C-C motif chemokine 14 Human genes 0.000 description 1
- 102100023700 C-C motif chemokine 16 Human genes 0.000 description 1
- 102100023698 C-C motif chemokine 17 Human genes 0.000 description 1
- 102100023701 C-C motif chemokine 18 Human genes 0.000 description 1
- 102100036850 C-C motif chemokine 23 Human genes 0.000 description 1
- 102100021936 C-C motif chemokine 27 Human genes 0.000 description 1
- 101710112538 C-C motif chemokine 27 Proteins 0.000 description 1
- 102100032367 C-C motif chemokine 5 Human genes 0.000 description 1
- 102100032366 C-C motif chemokine 7 Human genes 0.000 description 1
- 101710155834 C-C motif chemokine 7 Proteins 0.000 description 1
- 102100034871 C-C motif chemokine 8 Human genes 0.000 description 1
- 101710155833 C-C motif chemokine 8 Proteins 0.000 description 1
- 102100022291 C-Jun-amino-terminal kinase-interacting protein 1 Human genes 0.000 description 1
- 102100025248 C-X-C motif chemokine 10 Human genes 0.000 description 1
- 102100025279 C-X-C motif chemokine 11 Human genes 0.000 description 1
- 102100025277 C-X-C motif chemokine 13 Human genes 0.000 description 1
- 102100039396 C-X-C motif chemokine 16 Human genes 0.000 description 1
- 102100036189 C-X-C motif chemokine 3 Human genes 0.000 description 1
- 101710085504 C-X-C motif chemokine 6 Proteins 0.000 description 1
- 102100036170 C-X-C motif chemokine 9 Human genes 0.000 description 1
- 102100037084 C4b-binding protein alpha chain Human genes 0.000 description 1
- 101710159767 C4b-binding protein alpha chain Proteins 0.000 description 1
- 102000014817 CACNA1A Human genes 0.000 description 1
- 102000014812 CACNA1F Human genes 0.000 description 1
- 102000014832 CACNA1S Human genes 0.000 description 1
- 101150052962 CACNA1S gene Proteins 0.000 description 1
- 208000036320 CAPN5-related vitreoretinopathy Diseases 0.000 description 1
- 101710134031 CCAAT/enhancer-binding protein beta Proteins 0.000 description 1
- 108010046080 CD27 Ligand Proteins 0.000 description 1
- 102100027207 CD27 antigen Human genes 0.000 description 1
- 102000049320 CD36 Human genes 0.000 description 1
- 108010045374 CD36 Antigens Proteins 0.000 description 1
- 102100032912 CD44 antigen Human genes 0.000 description 1
- 108010058905 CD44v6 antigen Proteins 0.000 description 1
- 108010062802 CD66 antigens Proteins 0.000 description 1
- 102100025221 CD70 antigen Human genes 0.000 description 1
- 102100027221 CD81 antigen Human genes 0.000 description 1
- 208000011597 CGF1 Diseases 0.000 description 1
- 101150110330 CRAT gene Proteins 0.000 description 1
- 102100021975 CREB-binding protein Human genes 0.000 description 1
- 108091011896 CSF1 Proteins 0.000 description 1
- 101100170001 Caenorhabditis elegans ddb-1 gene Proteins 0.000 description 1
- 101100205174 Caenorhabditis elegans lars-1 gene Proteins 0.000 description 1
- 101100181137 Caenorhabditis elegans pkc-3 gene Proteins 0.000 description 1
- 101100356682 Caenorhabditis elegans rho-1 gene Proteins 0.000 description 1
- 102100027557 Calcipressin-1 Human genes 0.000 description 1
- 102100038518 Calcitonin Human genes 0.000 description 1
- 102100038520 Calcitonin receptor Human genes 0.000 description 1
- 108010050543 Calcium-Sensing Receptors Proteins 0.000 description 1
- 102100034279 Calcium-binding mitochondrial carrier protein Aralar2 Human genes 0.000 description 1
- 102100025338 Calcium-binding tyrosine phosphorylation-regulated protein Human genes 0.000 description 1
- 102100024436 Caldesmon Human genes 0.000 description 1
- 102100025580 Calmodulin-1 Human genes 0.000 description 1
- 102000007590 Calpain Human genes 0.000 description 1
- 108010032088 Calpain Proteins 0.000 description 1
- 102100032539 Calpain-3 Human genes 0.000 description 1
- 102100030006 Calpain-5 Human genes 0.000 description 1
- 101100449736 Candida albicans (strain SC5314 / ATCC MYA-2876) ZCF23 gene Proteins 0.000 description 1
- 101000809436 Candida albicans Sterol O-acyltransferase 2 Proteins 0.000 description 1
- 101100507655 Canis lupus familiaris HSPA1 gene Proteins 0.000 description 1
- 102100033868 Cannabinoid receptor 1 Human genes 0.000 description 1
- 101710187010 Cannabinoid receptor 1 Proteins 0.000 description 1
- 241000283707 Capra Species 0.000 description 1
- 102100038783 Carbohydrate sulfotransferase 6 Human genes 0.000 description 1
- 102100024644 Carbonic anhydrase 4 Human genes 0.000 description 1
- 101710134395 Carboxy-terminal domain RNA polymerase II polypeptide A small phosphatase 1 Proteins 0.000 description 1
- 108090000201 Carboxypeptidase B2 Proteins 0.000 description 1
- 102100024533 Carcinoembryonic antigen-related cell adhesion molecule 1 Human genes 0.000 description 1
- 102100036357 Carnitine O-acetyltransferase Human genes 0.000 description 1
- 102100027943 Carnitine O-palmitoyltransferase 1, liver isoform Human genes 0.000 description 1
- 102100024853 Carnitine O-palmitoyltransferase 2, mitochondrial Human genes 0.000 description 1
- 102100027473 Cartilage oligomeric matrix protein Human genes 0.000 description 1
- 101710176668 Cartilage oligomeric matrix protein Proteins 0.000 description 1
- 108090000425 Caspase 6 Proteins 0.000 description 1
- 102000004018 Caspase 6 Human genes 0.000 description 1
- 108090000567 Caspase 7 Proteins 0.000 description 1
- 108090000426 Caspase-1 Proteins 0.000 description 1
- 102100035904 Caspase-1 Human genes 0.000 description 1
- 108090000572 Caspase-10 Proteins 0.000 description 1
- 102100026549 Caspase-10 Human genes 0.000 description 1
- 108090000552 Caspase-2 Proteins 0.000 description 1
- 102100032616 Caspase-2 Human genes 0.000 description 1
- 101710090338 Caspase-4 Proteins 0.000 description 1
- 102100025597 Caspase-4 Human genes 0.000 description 1
- 101710090333 Caspase-5 Proteins 0.000 description 1
- 102100038902 Caspase-7 Human genes 0.000 description 1
- 108090000566 Caspase-9 Proteins 0.000 description 1
- 102100026550 Caspase-9 Human genes 0.000 description 1
- 102000011727 Caspases Human genes 0.000 description 1
- 108010076667 Caspases Proteins 0.000 description 1
- 108020002739 Catechol O-methyltransferase Proteins 0.000 description 1
- 102100040999 Catechol O-methyltransferase Human genes 0.000 description 1
- 102100028914 Catenin beta-1 Human genes 0.000 description 1
- 102100021633 Cathepsin B Human genes 0.000 description 1
- 102100024940 Cathepsin K Human genes 0.000 description 1
- 102100037182 Cation-independent mannose-6-phosphate receptor Human genes 0.000 description 1
- 102100032212 Caveolin-3 Human genes 0.000 description 1
- 102000011068 Cdc42 Human genes 0.000 description 1
- 108050001278 Cdc42 Proteins 0.000 description 1
- 102100025175 Cellular communication network factor 6 Human genes 0.000 description 1
- 208000016615 Central areolar choroidal dystrophy Diseases 0.000 description 1
- 102100023441 Centromere protein J Human genes 0.000 description 1
- 241000282693 Cercopithecidae Species 0.000 description 1
- 102100035360 Cerebellar degeneration-related antigen 1 Human genes 0.000 description 1
- 102100034505 Ceroid-lipofuscinosis neuronal protein 5 Human genes 0.000 description 1
- 102100034480 Ceroid-lipofuscinosis neuronal protein 6 Human genes 0.000 description 1
- 101710163595 Chaperone protein DnaK Proteins 0.000 description 1
- 108010059013 Chaperonin 10 Proteins 0.000 description 1
- 108010058432 Chaperonin 60 Proteins 0.000 description 1
- 201000009744 Charcot-Marie-Tooth disease X-linked recessive 2 Diseases 0.000 description 1
- 201000009733 Charcot-Marie-Tooth disease X-linked recessive 3 Diseases 0.000 description 1
- 201000009729 Charcot-Marie-Tooth disease X-linked recessive 4 Diseases 0.000 description 1
- 201000009009 Charcot-Marie-Tooth disease type 1A Diseases 0.000 description 1
- 201000008973 Charcot-Marie-Tooth disease type 2B Diseases 0.000 description 1
- 201000008958 Charcot-Marie-Tooth disease type 2D Diseases 0.000 description 1
- 201000008889 Charcot-Marie-Tooth disease type 4A Diseases 0.000 description 1
- 101710171922 Cheilanthifoline synthase Proteins 0.000 description 1
- 108010083702 Chemokine CCL21 Proteins 0.000 description 1
- 108010055166 Chemokine CCL5 Proteins 0.000 description 1
- 102000016950 Chemokine CXCL1 Human genes 0.000 description 1
- 108010014419 Chemokine CXCL1 Proteins 0.000 description 1
- 102000006573 Chemokine CXCL12 Human genes 0.000 description 1
- 108010008951 Chemokine CXCL12 Proteins 0.000 description 1
- 102100030099 Chloride anion exchanger Human genes 0.000 description 1
- 102100023457 Chloride channel protein 1 Human genes 0.000 description 1
- 102100023459 Chloride channel protein ClC-Kb Human genes 0.000 description 1
- 102100037637 Cholesteryl ester transfer protein Human genes 0.000 description 1
- 102100032404 Cholinesterase Human genes 0.000 description 1
- 102100028757 Chondroitin sulfate proteoglycan 4 Human genes 0.000 description 1
- 102100032765 Chordin-like protein 1 Human genes 0.000 description 1
- 102100031196 Choriogonadotropin subunit beta 3 Human genes 0.000 description 1
- 108010005939 Ciliary Neurotrophic Factor Proteins 0.000 description 1
- 102100031614 Ciliary neurotrophic factor Human genes 0.000 description 1
- 101710082464 Cis-aconitate decarboxylase Proteins 0.000 description 1
- 101100328088 Cladosporium cladosporioides cla3 gene Proteins 0.000 description 1
- 102100031060 Clarin-1 Human genes 0.000 description 1
- 102100039585 Claudin-16 Human genes 0.000 description 1
- 102100029057 Coagulation factor XIII A chain Human genes 0.000 description 1
- 102100029058 Coagulation factor XIII B chain Human genes 0.000 description 1
- 102100040996 Cochlin Human genes 0.000 description 1
- 102100024484 Codanin-1 Human genes 0.000 description 1
- 108091033380 Coding strand Proteins 0.000 description 1
- 102100032368 Coiled-coil domain-containing protein 110 Human genes 0.000 description 1
- 102100031611 Collagen alpha-1(III) chain Human genes 0.000 description 1
- 102100031457 Collagen alpha-1(V) chain Human genes 0.000 description 1
- 102100031519 Collagen alpha-1(VI) chain Human genes 0.000 description 1
- 102100024335 Collagen alpha-1(VII) chain Human genes 0.000 description 1
- 102100033825 Collagen alpha-1(XI) chain Human genes 0.000 description 1
- 102100028256 Collagen alpha-1(XVII) chain Human genes 0.000 description 1
- 102100030781 Collagen alpha-1(XXIII) chain Human genes 0.000 description 1
- 102100030976 Collagen alpha-2(IX) chain Human genes 0.000 description 1
- 102100031502 Collagen alpha-2(V) chain Human genes 0.000 description 1
- 102100031518 Collagen alpha-2(VI) chain Human genes 0.000 description 1
- 102100033885 Collagen alpha-2(XI) chain Human genes 0.000 description 1
- 102100033780 Collagen alpha-3(IV) chain Human genes 0.000 description 1
- 102100030977 Collagen alpha-3(IX) chain Human genes 0.000 description 1
- 102100024338 Collagen alpha-3(VI) chain Human genes 0.000 description 1
- 102100033779 Collagen alpha-4(IV) chain Human genes 0.000 description 1
- 102100033775 Collagen alpha-5(IV) chain Human genes 0.000 description 1
- 102100033773 Collagen alpha-6(IV) chain Human genes 0.000 description 1
- 102100025406 Complement C1s subcomponent Human genes 0.000 description 1
- 108020004635 Complementary DNA Proteins 0.000 description 1
- 102100029362 Cone-rod homeobox protein Human genes 0.000 description 1
- 201000006705 Congenital generalized lipodystrophy Diseases 0.000 description 1
- 208000034717 Congenital hereditary endothelial dystrophy type II Diseases 0.000 description 1
- 208000033708 Congenital muscular dystrophy type 1B Diseases 0.000 description 1
- 108010069176 Connexin 30 Proteins 0.000 description 1
- 102100040998 Conserved oligomeric Golgi complex subunit 6 Human genes 0.000 description 1
- 108010022637 Copper-Transporting ATPases Proteins 0.000 description 1
- 102100027587 Copper-transporting ATPase 1 Human genes 0.000 description 1
- 102100027591 Copper-transporting ATPase 2 Human genes 0.000 description 1
- 108010024682 Core Binding Factor Alpha 1 Subunit Proteins 0.000 description 1
- 102100021752 Corticoliberin Human genes 0.000 description 1
- 102100032323 Corticosteroid-binding globulin Human genes 0.000 description 1
- 102100032165 Corticotropin-releasing factor-binding protein Human genes 0.000 description 1
- 241000699800 Cricetinae Species 0.000 description 1
- 102100031096 Cubilin Human genes 0.000 description 1
- 102100029142 Cyclic nucleotide-gated cation channel alpha-3 Human genes 0.000 description 1
- 102100021430 Cyclic pyranopterin monophosphate synthase Human genes 0.000 description 1
- 108010058546 Cyclin D1 Proteins 0.000 description 1
- 108010016788 Cyclin-Dependent Kinase Inhibitor p21 Proteins 0.000 description 1
- 108010017222 Cyclin-Dependent Kinase Inhibitor p57 Proteins 0.000 description 1
- 102100037912 Cyclin-dependent kinase 11A Human genes 0.000 description 1
- 102100037916 Cyclin-dependent kinase 11B Human genes 0.000 description 1
- 102100033270 Cyclin-dependent kinase inhibitor 1 Human genes 0.000 description 1
- 108010045283 Cystathionine gamma-lyase Proteins 0.000 description 1
- 102100026891 Cystatin-B Human genes 0.000 description 1
- 102100026897 Cystatin-C Human genes 0.000 description 1
- 102100031089 Cystinosin Human genes 0.000 description 1
- 108010074918 Cytochrome P-450 CYP1A1 Proteins 0.000 description 1
- 108010074922 Cytochrome P-450 CYP1A2 Proteins 0.000 description 1
- 108010026925 Cytochrome P-450 CYP2C19 Proteins 0.000 description 1
- 108010000543 Cytochrome P-450 CYP2C9 Proteins 0.000 description 1
- 108010001237 Cytochrome P-450 CYP2D6 Proteins 0.000 description 1
- 108010081668 Cytochrome P-450 CYP3A Proteins 0.000 description 1
- 102100031476 Cytochrome P450 1A1 Human genes 0.000 description 1
- 102100026533 Cytochrome P450 1A2 Human genes 0.000 description 1
- 102100036194 Cytochrome P450 2A6 Human genes 0.000 description 1
- 102100029358 Cytochrome P450 2C9 Human genes 0.000 description 1
- 102100021704 Cytochrome P450 2D6 Human genes 0.000 description 1
- 102100039205 Cytochrome P450 3A4 Human genes 0.000 description 1
- 102100025287 Cytochrome b Human genes 0.000 description 1
- 102100025621 Cytochrome b-245 heavy chain Human genes 0.000 description 1
- 102100025620 Cytochrome b-245 light chain Human genes 0.000 description 1
- 102100039924 Cytochrome b-c1 complex subunit 1, mitochondrial Human genes 0.000 description 1
- 102100031655 Cytochrome b5 Human genes 0.000 description 1
- 102100030878 Cytochrome c oxidase subunit 1 Human genes 0.000 description 1
- 102100039061 Cytokine receptor common subunit beta Human genes 0.000 description 1
- 101710199286 Cytosol aminopeptidase Proteins 0.000 description 1
- 102100020756 D(2) dopamine receptor Human genes 0.000 description 1
- 102100029815 D(4) dopamine receptor Human genes 0.000 description 1
- 102100037579 D-3-phosphoglycerate dehydrogenase Human genes 0.000 description 1
- 102100021246 DDIT3 upstream open reading frame protein Human genes 0.000 description 1
- 101150013449 DHS gene Proteins 0.000 description 1
- 102100024810 DNA (cytosine-5)-methyltransferase 3B Human genes 0.000 description 1
- 101710123222 DNA (cytosine-5)-methyltransferase 3B Proteins 0.000 description 1
- 102100021122 DNA damage-binding protein 2 Human genes 0.000 description 1
- 102100031866 DNA excision repair protein ERCC-5 Human genes 0.000 description 1
- 108010035476 DNA excision repair protein ERCC-5 Proteins 0.000 description 1
- 102100031867 DNA excision repair protein ERCC-6 Human genes 0.000 description 1
- 102100038026 DNA fragmentation factor subunit alpha Human genes 0.000 description 1
- 101710182628 DNA fragmentation factor subunit alpha Proteins 0.000 description 1
- 101710147299 DNA fragmentation factor subunit beta Proteins 0.000 description 1
- 102100034157 DNA mismatch repair protein Msh2 Human genes 0.000 description 1
- 102100021147 DNA mismatch repair protein Msh6 Human genes 0.000 description 1
- 102100029766 DNA polymerase theta Human genes 0.000 description 1
- 101710082494 DNA protection during starvation protein Proteins 0.000 description 1
- 102100034490 DNA repair and recombination protein RAD54B Human genes 0.000 description 1
- 102100029094 DNA repair endonuclease XPF Human genes 0.000 description 1
- 102100024607 DNA topoisomerase 1 Human genes 0.000 description 1
- 102100033587 DNA topoisomerase 2-alpha Human genes 0.000 description 1
- 102100020986 DNA-binding protein RFX5 Human genes 0.000 description 1
- 102100021044 DNA-binding protein RFXANK Human genes 0.000 description 1
- 102100022204 DNA-dependent protein kinase catalytic subunit Human genes 0.000 description 1
- 101100067112 Danio rerio foxn4 gene Proteins 0.000 description 1
- 102100038713 Death domain-containing protein CRADD Human genes 0.000 description 1
- 102100032501 Death-inducer obliterator 1 Human genes 0.000 description 1
- 102100031262 Deleted in malignant brain tumors 1 protein Human genes 0.000 description 1
- 102100022283 Delta-1-pyrroline-5-carboxylate dehydrogenase, mitochondrial Human genes 0.000 description 1
- 102100036466 Delta-like protein 3 Human genes 0.000 description 1
- 102100021790 Delta-sarcoglycan Human genes 0.000 description 1
- 201000008163 Dentatorubral pallidoluysian atrophy Diseases 0.000 description 1
- 102100029792 Dentin sialophosphoprotein Human genes 0.000 description 1
- 101800000026 Dentin sialoprotein Proteins 0.000 description 1
- 102100031242 Deoxyhypusine synthase Human genes 0.000 description 1
- 108700023218 Deoxyhypusine synthases Proteins 0.000 description 1
- 102100030012 Deoxyribonuclease-1 Human genes 0.000 description 1
- 102100034579 Desmoglein-1 Human genes 0.000 description 1
- 102100038199 Desmoplakin Human genes 0.000 description 1
- 108010086291 Deubiquitinating Enzyme CYLD Proteins 0.000 description 1
- 102100037981 Dickkopf-like protein 1 Human genes 0.000 description 1
- 101710125833 Dickkopf-like protein 1 Proteins 0.000 description 1
- 101000797456 Dictyostelium discoideum AMP deaminase Proteins 0.000 description 1
- 101000779375 Dictyostelium discoideum Alpha-protein kinase 1 Proteins 0.000 description 1
- 101000745420 Dictyostelium discoideum Contact site A protein Proteins 0.000 description 1
- 101100226017 Dictyostelium discoideum repD gene Proteins 0.000 description 1
- 102100024746 Dihydrofolate reductase Human genes 0.000 description 1
- 102100027152 Dihydrolipoyllysine-residue acetyltransferase component of pyruvate dehydrogenase complex, mitochondrial Human genes 0.000 description 1
- 102100022317 Dihydropteridine reductase Human genes 0.000 description 1
- 102100036238 Dihydropyrimidinase Human genes 0.000 description 1
- 102100022334 Dihydropyrimidine dehydrogenase [NADP(+)] Human genes 0.000 description 1
- 102100035041 Dimethylaniline monooxygenase [N-oxide-forming] 3 Human genes 0.000 description 1
- 102100035046 Dimethylaniline monooxygenase [N-oxide-forming] 4 Human genes 0.000 description 1
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 1
- 102100020743 Dipeptidase 1 Human genes 0.000 description 1
- 102100029921 Dipeptidyl peptidase 1 Human genes 0.000 description 1
- 102100031675 DnaJ homolog subfamily C member 5 Human genes 0.000 description 1
- 108010044266 Dopamine Plasma Membrane Transport Proteins Proteins 0.000 description 1
- 101100504104 Drosophila melanogaster Gbeta76C gene Proteins 0.000 description 1
- 101100181139 Drosophila melanogaster Pkcdelta gene Proteins 0.000 description 1
- 101100269980 Drosophila melanogaster aPKC gene Proteins 0.000 description 1
- 101100310386 Drosophila melanogaster sli gene Proteins 0.000 description 1
- 208000003556 Dry Eye Syndromes Diseases 0.000 description 1
- 102100029638 Dual serine/threonine and tyrosine protein kinase Human genes 0.000 description 1
- 208000030772 Duane syndrome type 1 Diseases 0.000 description 1
- 102100032248 Dysferlin Human genes 0.000 description 1
- 102100035374 Dystrophia myotonica WD repeat-containing protein Human genes 0.000 description 1
- 102100024108 Dystrophin Human genes 0.000 description 1
- 102100023227 E3 SUMO-protein ligase EGR2 Human genes 0.000 description 1
- 101710197780 E3 ubiquitin-protein ligase LAP Proteins 0.000 description 1
- 102100040068 E3 ubiquitin-protein ligase TRIM37 Human genes 0.000 description 1
- 102100025027 E3 ubiquitin-protein ligase TRIM69 Human genes 0.000 description 1
- 102100022207 E3 ubiquitin-protein ligase parkin Human genes 0.000 description 1
- 102000017930 EDNRB Human genes 0.000 description 1
- 102100031814 EGF-containing fibulin-like extracellular matrix protein 1 Human genes 0.000 description 1
- 101150110503 END3 gene Proteins 0.000 description 1
- 102000012804 EPCAM Human genes 0.000 description 1
- 101150105460 ERCC2 gene Proteins 0.000 description 1
- 102100032057 ETS domain-containing protein Elk-1 Human genes 0.000 description 1
- 102100039563 ETS translocation variant 1 Human genes 0.000 description 1
- 208000033707 Early-onset X-linked optic atrophy Diseases 0.000 description 1
- 102100037354 Ectodysplasin-A Human genes 0.000 description 1
- 102100030695 Electron transfer flavoprotein subunit alpha, mitochondrial Human genes 0.000 description 1
- 102100027262 Electron transfer flavoprotein subunit beta Human genes 0.000 description 1
- 102100031804 Electron transfer flavoprotein-ubiquinone oxidoreductase, mitochondrial Human genes 0.000 description 1
- 102100037074 Ellis-van Creveld syndrome protein Human genes 0.000 description 1
- 102100039246 Elongator complex protein 1 Human genes 0.000 description 1
- 102100037241 Endoglin Human genes 0.000 description 1
- 102100023387 Endoribonuclease Dicer Human genes 0.000 description 1
- 102100029109 Endothelin-3 Human genes 0.000 description 1
- 102100029112 Endothelin-converting enzyme 1 Human genes 0.000 description 1
- 101710147220 Ent-copalyl diphosphate synthase, chloroplastic Proteins 0.000 description 1
- 101100007581 Entamoeba histolytica CPP1 gene Proteins 0.000 description 1
- 102100029727 Enteropeptidase Human genes 0.000 description 1
- 102100028471 Eosinophil peroxidase Human genes 0.000 description 1
- 102100030322 Ephrin type-A receptor 1 Human genes 0.000 description 1
- 102100021793 Epsilon-sarcoglycan Human genes 0.000 description 1
- 241000283074 Equus asinus Species 0.000 description 1
- 101001028319 Escherichia coli (strain K12) 2,4-dienoyl-CoA reductase [(2E)-enoyl-CoA-producing] Proteins 0.000 description 1
- 101001039702 Escherichia coli (strain K12) Methyl-accepting chemotaxis protein I Proteins 0.000 description 1
- 102100038595 Estrogen receptor Human genes 0.000 description 1
- 241000206602 Eukaryota Species 0.000 description 1
- 102100034174 Eukaryotic translation initiation factor 2-alpha kinase 3 Human genes 0.000 description 1
- 102100029055 Exostosin-1 Human genes 0.000 description 1
- 102100029074 Exostosin-2 Human genes 0.000 description 1
- 102100035650 Extracellular calcium-sensing receptor Human genes 0.000 description 1
- 102100027186 Extracellular superoxide dismutase [Cu-Zn] Human genes 0.000 description 1
- 102100030863 Eyes absent homolog 1 Human genes 0.000 description 1
- 102100028147 F-box/WD repeat-containing protein 4 Human genes 0.000 description 1
- 101710191461 F420-dependent glucose-6-phosphate dehydrogenase Proteins 0.000 description 1
- 102100026693 FAS-associated death domain protein Human genes 0.000 description 1
- 201000003727 FG syndrome Diseases 0.000 description 1
- 208000035855 Familial platelet disorder with associated myeloid malignancy Diseases 0.000 description 1
- 108010033305 Fanconi Anemia Complementation Group G protein Proteins 0.000 description 1
- 102100034555 Fanconi anemia group G protein Human genes 0.000 description 1
- 108010039471 Fas Ligand Protein Proteins 0.000 description 1
- 102100026748 Fatty acid-binding protein, intestinal Human genes 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 102100020760 Ferritin heavy chain Human genes 0.000 description 1
- 102100038652 Ferritin heavy polypeptide-like 17 Human genes 0.000 description 1
- 102100021062 Ferritin light chain Human genes 0.000 description 1
- 102100031509 Fibrillin-1 Human genes 0.000 description 1
- 102100031510 Fibrillin-2 Human genes 0.000 description 1
- BWGVNKXGVNDBDI-UHFFFAOYSA-N Fibrin monomer Chemical class CNC(=O)CNC(=O)CN BWGVNKXGVNDBDI-UHFFFAOYSA-N 0.000 description 1
- 108010049003 Fibrinogen Proteins 0.000 description 1
- 102000008946 Fibrinogen Human genes 0.000 description 1
- 102100035290 Fibroblast growth factor 13 Human genes 0.000 description 1
- 102100035307 Fibroblast growth factor 16 Human genes 0.000 description 1
- 108090000379 Fibroblast growth factor 2 Proteins 0.000 description 1
- 102100024802 Fibroblast growth factor 23 Human genes 0.000 description 1
- 102100023593 Fibroblast growth factor receptor 1 Human genes 0.000 description 1
- 102100023600 Fibroblast growth factor receptor 2 Human genes 0.000 description 1
- 101710182389 Fibroblast growth factor receptor 2 Proteins 0.000 description 1
- 102100027842 Fibroblast growth factor receptor 3 Human genes 0.000 description 1
- 101710182396 Fibroblast growth factor receptor 3 Proteins 0.000 description 1
- 102100032596 Fibrocystin Human genes 0.000 description 1
- 108010040721 Flagellin Proteins 0.000 description 1
- 102100027627 Follicle-stimulating hormone receptor Human genes 0.000 description 1
- 102100027909 Folliculin Human genes 0.000 description 1
- 102100040977 Follitropin subunit beta Human genes 0.000 description 1
- 108010010285 Forkhead Box Protein L2 Proteins 0.000 description 1
- 102100037042 Forkhead box protein E1 Human genes 0.000 description 1
- 102100035137 Forkhead box protein L2 Human genes 0.000 description 1
- 102100023371 Forkhead box protein N1 Human genes 0.000 description 1
- 102100035416 Forkhead box protein O4 Human genes 0.000 description 1
- 102100020997 Fractalkine Human genes 0.000 description 1
- 102100020714 Fragile X mental retardation 1 neighbor protein Human genes 0.000 description 1
- 102100027525 Frataxin, mitochondrial Human genes 0.000 description 1
- 102100037181 Fructose-1,6-bisphosphatase 1 Human genes 0.000 description 1
- 102100022272 Fructose-bisphosphate aldolase B Human genes 0.000 description 1
- 108010058643 Fungal Proteins Proteins 0.000 description 1
- 108091006027 G proteins Proteins 0.000 description 1
- 108010038179 G-protein beta3 subunit Proteins 0.000 description 1
- 102100024165 G1/S-specific cyclin-D1 Human genes 0.000 description 1
- 102100032340 G2/mitotic-specific cyclin-B1 Human genes 0.000 description 1
- 102000017694 GABRA3 Human genes 0.000 description 1
- 102100025101 GATA-type zinc finger protein 1 Human genes 0.000 description 1
- 108010003163 GDP dissociation inhibitor 1 Proteins 0.000 description 1
- 108010013942 GMP Reductase Proteins 0.000 description 1
- 102100021188 GMP reductase 1 Human genes 0.000 description 1
- 101150016162 GSM1 gene Proteins 0.000 description 1
- 102000030782 GTP binding Human genes 0.000 description 1
- 102100027346 GTP cyclohydrolase 1 Human genes 0.000 description 1
- 108091000058 GTP-Binding Proteins 0.000 description 1
- 102100029974 GTPase HRas Human genes 0.000 description 1
- 102100030708 GTPase KRas Human genes 0.000 description 1
- 102100028496 Galactocerebrosidase Human genes 0.000 description 1
- 102100037777 Galactokinase Human genes 0.000 description 1
- 102100036291 Galactose-1-phosphate uridylyltransferase Human genes 0.000 description 1
- 102100039835 Galactoside alpha-(1,2)-fucosyltransferase 1 Human genes 0.000 description 1
- 102100040837 Galactoside alpha-(1,2)-fucosyltransferase 2 Human genes 0.000 description 1
- 101100476713 Gallus gallus SAX1 gene Proteins 0.000 description 1
- 102100039331 Gamma-crystallin A Human genes 0.000 description 1
- 102100027813 Gamma-crystallin C Human genes 0.000 description 1
- 102100027812 Gamma-crystallin D Human genes 0.000 description 1
- 102100028652 Gamma-enolase Human genes 0.000 description 1
- 101710191797 Gamma-enolase Proteins 0.000 description 1
- 101710115997 Gamma-tubulin complex component 2 Proteins 0.000 description 1
- 102100023364 Ganglioside GM2 activator Human genes 0.000 description 1
- 102100024411 Ganglioside-induced differentiation-associated protein 1 Human genes 0.000 description 1
- 102100021337 Gap junction alpha-1 protein Human genes 0.000 description 1
- 102100030526 Gap junction alpha-3 protein Human genes 0.000 description 1
- 102100025283 Gap junction alpha-8 protein Human genes 0.000 description 1
- 102100037260 Gap junction beta-1 protein Human genes 0.000 description 1
- 102100037156 Gap junction beta-2 protein Human genes 0.000 description 1
- 102100037391 Gasdermin-E Human genes 0.000 description 1
- 108010004460 Gastric Inhibitory Polypeptide Proteins 0.000 description 1
- 102400000921 Gastrin Human genes 0.000 description 1
- 102100021022 Gastrin Human genes 0.000 description 1
- 102100030671 Gastrin-releasing peptide receptor Human genes 0.000 description 1
- 108090001064 Gelsolin Proteins 0.000 description 1
- 102000004878 Gelsolin Human genes 0.000 description 1
- 102100028953 Gelsolin Human genes 0.000 description 1
- 102100031885 General transcription and DNA repair factor IIH helicase subunit XPB Human genes 0.000 description 1
- 102100035184 General transcription and DNA repair factor IIH helicase subunit XPD Human genes 0.000 description 1
- 102100032865 General transcription factor IIH subunit 5 Human genes 0.000 description 1
- 102100037410 Gigaxonin Human genes 0.000 description 1
- 102000034615 Glial cell line-derived neurotrophic factor Human genes 0.000 description 1
- 108091010837 Glial cell line-derived neurotrophic factor Proteins 0.000 description 1
- 102100039289 Glial fibrillary acidic protein Human genes 0.000 description 1
- 101710193519 Glial fibrillary acidic protein Proteins 0.000 description 1
- 101710174134 Globin CTT-Z Proteins 0.000 description 1
- 102100025894 Glomulin Human genes 0.000 description 1
- 102100040890 Glucagon receptor Human genes 0.000 description 1
- 102100033417 Glucocorticoid receptor Human genes 0.000 description 1
- 102100036264 Glucose-6-phosphatase catalytic subunit 1 Human genes 0.000 description 1
- 102100035172 Glucose-6-phosphate 1-dehydrogenase Human genes 0.000 description 1
- 101710155861 Glucose-6-phosphate 1-dehydrogenase Proteins 0.000 description 1
- 101710174622 Glucose-6-phosphate 1-dehydrogenase, chloroplastic Proteins 0.000 description 1
- 101710137456 Glucose-6-phosphate 1-dehydrogenase, cytoplasmic isoform Proteins 0.000 description 1
- 102100021223 Glucosidase 2 subunit beta Human genes 0.000 description 1
- 102100034009 Glutamate dehydrogenase 1, mitochondrial Human genes 0.000 description 1
- 102100036646 Glutamyl-tRNA(Gln) amidotransferase subunit A, mitochondrial Human genes 0.000 description 1
- 102100028603 Glutaryl-CoA dehydrogenase, mitochondrial Human genes 0.000 description 1
- 102100033366 Glutathione hydrolase 1 proenzyme Human genes 0.000 description 1
- 102100036442 Glutathione reductase, mitochondrial Human genes 0.000 description 1
- 101710155270 Glycerate 2-kinase Proteins 0.000 description 1
- 102100030395 Glycerol-3-phosphate dehydrogenase, mitochondrial Human genes 0.000 description 1
- 102100025506 Glycine cleavage system H protein, mitochondrial Human genes 0.000 description 1
- 102100033495 Glycine dehydrogenase (decarboxylating), mitochondrial Human genes 0.000 description 1
- 102100036589 Glycine-tRNA ligase Human genes 0.000 description 1
- 102100039264 Glycogen [starch] synthase, liver Human genes 0.000 description 1
- 102100039262 Glycogen [starch] synthase, muscle Human genes 0.000 description 1
- 102100029481 Glycogen phosphorylase, liver form Human genes 0.000 description 1
- 102100029492 Glycogen phosphorylase, muscle form Human genes 0.000 description 1
- 102100035716 Glycophorin-A Human genes 0.000 description 1
- 102100023849 Glycophorin-C Human genes 0.000 description 1
- 102100030648 Glyoxylate reductase/hydroxypyruvate reductase Human genes 0.000 description 1
- 102100033851 Gonadotropin-releasing hormone receptor Human genes 0.000 description 1
- 108010017080 Granulocyte Colony-Stimulating Factor Proteins 0.000 description 1
- 102100039619 Granulocyte colony-stimulating factor Human genes 0.000 description 1
- 102100039622 Granulocyte colony-stimulating factor receptor Human genes 0.000 description 1
- 102100028113 Granulocyte-macrophage colony-stimulating factor receptor subunit alpha Human genes 0.000 description 1
- 102100036717 Growth hormone variant Human genes 0.000 description 1
- 102100033365 Growth hormone-releasing hormone receptor Human genes 0.000 description 1
- 102100034221 Growth-regulated alpha protein Human genes 0.000 description 1
- 102100035379 Growth/differentiation factor 5 Human genes 0.000 description 1
- 102100040579 Guanidinoacetate N-methyltransferase Human genes 0.000 description 1
- 102100035346 Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-3 Human genes 0.000 description 1
- 102100032610 Guanine nucleotide-binding protein G(s) subunit alpha isoforms XLas Human genes 0.000 description 1
- 102100039261 Guanine nucleotide-binding protein G(t) subunit alpha-1 Human genes 0.000 description 1
- 102100036738 Guanine nucleotide-binding protein subunit alpha-11 Human genes 0.000 description 1
- 102100033969 Guanylyl cyclase-activating protein 1 Human genes 0.000 description 1
- 102100031249 H/ACA ribonucleoprotein complex subunit DKC1 Human genes 0.000 description 1
- 102100028971 HLA class I histocompatibility antigen, C alpha chain Human genes 0.000 description 1
- 102100031618 HLA class II histocompatibility antigen, DP beta 1 chain Human genes 0.000 description 1
- 102100040505 HLA class II histocompatibility antigen, DR alpha chain Human genes 0.000 description 1
- 108010036972 HLA-A11 Antigen Proteins 0.000 description 1
- 108010045483 HLA-DPB1 antigen Proteins 0.000 description 1
- 108010067802 HLA-DR alpha-Chains Proteins 0.000 description 1
- 102100039330 HMG box-containing protein 1 Human genes 0.000 description 1
- 108700039143 HMGA2 Proteins 0.000 description 1
- 101710094895 HTLV-1 basic zipper factor Proteins 0.000 description 1
- 101710178376 Heat shock 70 kDa protein Proteins 0.000 description 1
- 101710152018 Heat shock cognate 70 kDa protein Proteins 0.000 description 1
- 102100034047 Heat shock factor protein 4 Human genes 0.000 description 1
- 102100026973 Heat shock protein 75 kDa, mitochondrial Human genes 0.000 description 1
- 101710113864 Heat shock protein 90 Proteins 0.000 description 1
- 102100028006 Heme oxygenase 1 Human genes 0.000 description 1
- 102100021519 Hemoglobin subunit beta Human genes 0.000 description 1
- 102100039894 Hemoglobin subunit delta Human genes 0.000 description 1
- 102100030826 Hemoglobin subunit epsilon Human genes 0.000 description 1
- 102100038614 Hemoglobin subunit gamma-1 Human genes 0.000 description 1
- 102100038617 Hemoglobin subunit gamma-2 Human genes 0.000 description 1
- 102100030378 Hemoglobin subunit theta-1 Human genes 0.000 description 1
- 102100030387 Hemoglobin subunit zeta Human genes 0.000 description 1
- 101800000637 Hemokinin Proteins 0.000 description 1
- 102100031415 Hepatic triacylglycerol lipase Human genes 0.000 description 1
- 102100022623 Hepatocyte growth factor receptor Human genes 0.000 description 1
- 102100022123 Hepatocyte nuclear factor 1-beta Human genes 0.000 description 1
- 102100022054 Hepatocyte nuclear factor 4-alpha Human genes 0.000 description 1
- 208000021236 Hereditary diffuse leukoencephalopathy with axonal spheroids and pigmented glia Diseases 0.000 description 1
- 102100028902 Hermansky-Pudlak syndrome 1 protein Human genes 0.000 description 1
- 101710121996 Hexon protein p72 Proteins 0.000 description 1
- 102100038009 High affinity immunoglobulin epsilon receptor subunit beta Human genes 0.000 description 1
- 102100035108 High affinity nerve growth factor receptor Human genes 0.000 description 1
- 102100028999 High mobility group protein HMGI-C Human genes 0.000 description 1
- 208000023075 Hip dysplasia, Beukes type Diseases 0.000 description 1
- 102100021628 Histatin-3 Human genes 0.000 description 1
- 102100038885 Histone acetyltransferase p300 Human genes 0.000 description 1
- 102100021454 Histone deacetylase 4 Human genes 0.000 description 1
- 108091016366 Histone-lysine N-methyltransferase EHMT1 Proteins 0.000 description 1
- 101150073387 Hmga2 gene Proteins 0.000 description 1
- 102100035009 Holocytochrome c-type synthase Human genes 0.000 description 1
- 102100034633 Homeobox expressed in ES cells 1 Human genes 0.000 description 1
- 102100022376 Homeobox protein DLX-3 Human genes 0.000 description 1
- 102100023830 Homeobox protein EMX2 Human genes 0.000 description 1
- 102100030309 Homeobox protein Hox-A1 Human genes 0.000 description 1
- 102100040227 Homeobox protein Hox-D13 Human genes 0.000 description 1
- 102100028707 Homeobox protein MSX-1 Human genes 0.000 description 1
- 102100040615 Homeobox protein MSX-2 Human genes 0.000 description 1
- 102100027875 Homeobox protein Nkx-2.5 Human genes 0.000 description 1
- 102100033798 Homeobox protein aristaless-like 4 Human genes 0.000 description 1
- 102100031159 Homeobox protein prophet of Pit-1 Human genes 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 101000605571 Homo sapiens 1-acyl-sn-glycerol-3-phosphate acyltransferase beta Proteins 0.000 description 1
- 101000845090 Homo sapiens 11-beta-hydroxysteroid dehydrogenase type 2 Proteins 0.000 description 1
- 101001045211 Homo sapiens 17-beta-hydroxysteroid dehydrogenase type 3 Proteins 0.000 description 1
- 101001041661 Homo sapiens 2,4-dienoyl-CoA reductase [(3E)-enoyl-CoA-producing], mitochondrial Proteins 0.000 description 1
- 101001080057 Homo sapiens 2-5A-dependent ribonuclease Proteins 0.000 description 1
- 101000982656 Homo sapiens 2-oxoglutarate dehydrogenase, mitochondrial Proteins 0.000 description 1
- 101000597665 Homo sapiens 2-oxoisovalerate dehydrogenase subunit alpha, mitochondrial Proteins 0.000 description 1
- 101000597680 Homo sapiens 2-oxoisovalerate dehydrogenase subunit beta, mitochondrial Proteins 0.000 description 1
- 101000684297 Homo sapiens 26S proteasome complex subunit SEM1 Proteins 0.000 description 1
- 101000590272 Homo sapiens 26S proteasome non-ATPase regulatory subunit 2 Proteins 0.000 description 1
- 101000728693 Homo sapiens 28S ribosomal protein S11, mitochondrial Proteins 0.000 description 1
- 101000841262 Homo sapiens 3-ketoacyl-CoA thiolase Proteins 0.000 description 1
- 101000670146 Homo sapiens 3-ketoacyl-CoA thiolase, peroxisomal Proteins 0.000 description 1
- 101000640851 Homo sapiens 3-oxo-5-alpha-steroid 4-dehydrogenase 2 Proteins 0.000 description 1
- 101001000686 Homo sapiens 4-aminobutyrate aminotransferase, mitochondrial Proteins 0.000 description 1
- 101001022175 Homo sapiens 4-galactosyl-N-acetylglucosaminide 3-alpha-L-fucosyltransferase FUT6 Proteins 0.000 description 1
- 101001098029 Homo sapiens 40S ribosomal protein S2 Proteins 0.000 description 1
- 101000732165 Homo sapiens 40S ribosomal protein S4, X isoform Proteins 0.000 description 1
- 101000696103 Homo sapiens 40S ribosomal protein S4, Y isoform 1 Proteins 0.000 description 1
- 101000760987 Homo sapiens 5'-AMP-activated protein kinase subunit gamma-2 Proteins 0.000 description 1
- 101000773083 Homo sapiens 5,6-dihydroxyindole-2-carboxylic acid oxidase Proteins 0.000 description 1
- 101001083755 Homo sapiens 5-aminolevulinate synthase, erythroid-specific, mitochondrial Proteins 0.000 description 1
- 101000761348 Homo sapiens 5-hydroxytryptamine receptor 2C Proteins 0.000 description 1
- 101000833180 Homo sapiens AF4/FMR2 family member 1 Proteins 0.000 description 1
- 101000833172 Homo sapiens AF4/FMR2 family member 2 Proteins 0.000 description 1
- 101000779641 Homo sapiens ALK tyrosine kinase receptor Proteins 0.000 description 1
- 101000775844 Homo sapiens AMP deaminase 1 Proteins 0.000 description 1
- 101000797462 Homo sapiens AMP deaminase 3 Proteins 0.000 description 1
- 101000806914 Homo sapiens AP-2 complex subunit sigma Proteins 0.000 description 1
- 101000779239 Homo sapiens AP-3 complex subunit beta-1 Proteins 0.000 description 1
- 101000792935 Homo sapiens AT-rich interactive domain-containing protein 4B Proteins 0.000 description 1
- 101000753741 Homo sapiens ATP synthase subunit a Proteins 0.000 description 1
- 101000986633 Homo sapiens ATP-binding cassette sub-family C member 3 Proteins 0.000 description 1
- 101000760570 Homo sapiens ATP-binding cassette sub-family C member 8 Proteins 0.000 description 1
- 101000783770 Homo sapiens ATP-binding cassette sub-family D member 3 Proteins 0.000 description 1
- 101000730838 Homo sapiens ATP-dependent 6-phosphofructokinase, muscle type Proteins 0.000 description 1
- 101000580577 Homo sapiens ATP-dependent DNA helicase Q4 Proteins 0.000 description 1
- 101000598552 Homo sapiens Acetyl-CoA acetyltransferase, mitochondrial Proteins 0.000 description 1
- 101000963424 Homo sapiens Acetyl-CoA carboxylase 1 Proteins 0.000 description 1
- 101000726895 Homo sapiens Acetylcholine receptor subunit alpha Proteins 0.000 description 1
- 101000678746 Homo sapiens Acetylcholine receptor subunit beta Proteins 0.000 description 1
- 101000965233 Homo sapiens Acetylcholine receptor subunit epsilon Proteins 0.000 description 1
- 101000770471 Homo sapiens Acetylcholinesterase collagenic tail peptide Proteins 0.000 description 1
- 101000936718 Homo sapiens Acetylserotonin O-methyltransferase Proteins 0.000 description 1
- 101000975753 Homo sapiens Acid ceramidase Proteins 0.000 description 1
- 101000959247 Homo sapiens Actin, alpha cardiac muscle 1 Proteins 0.000 description 1
- 101000834207 Homo sapiens Actin, alpha skeletal muscle Proteins 0.000 description 1
- 101000964363 Homo sapiens Active breakpoint cluster region-related protein Proteins 0.000 description 1
- 101000594506 Homo sapiens Acyl-coenzyme A diphosphatase NUDT19 Proteins 0.000 description 1
- 101001000351 Homo sapiens Adenine DNA glycosylase Proteins 0.000 description 1
- 101000924577 Homo sapiens Adenomatous polyposis coli protein Proteins 0.000 description 1
- 101000929495 Homo sapiens Adenosine deaminase Proteins 0.000 description 1
- 101000716952 Homo sapiens Adenosylhomocysteinase Proteins 0.000 description 1
- 101001057251 Homo sapiens Adenylate kinase isoenzyme 1 Proteins 0.000 description 1
- 101000610212 Homo sapiens Adenylyl-sulfate kinase Proteins 0.000 description 1
- 101000678419 Homo sapiens Adrenocorticotropic hormone receptor Proteins 0.000 description 1
- 101000693913 Homo sapiens Albumin Proteins 0.000 description 1
- 101000780463 Homo sapiens Alcohol dehydrogenase 1C Proteins 0.000 description 1
- 101000717967 Homo sapiens Aldehyde dehydrogenase family 3 member A2 Proteins 0.000 description 1
- 101000574445 Homo sapiens Alkaline phosphatase, tissue-nonspecific isozyme Proteins 0.000 description 1
- 101000799143 Homo sapiens Alkyldihydroxyacetonephosphate synthase, peroxisomal Proteins 0.000 description 1
- 101000780453 Homo sapiens All-trans-retinol dehydrogenase [NAD(+)] ADH1B Proteins 0.000 description 1
- 101000951392 Homo sapiens Alpha-1,6-mannosylglycoprotein 6-beta-N-acetylglucosaminyltransferase A Proteins 0.000 description 1
- 101000678195 Homo sapiens Alpha-1-acid glycoprotein 1 Proteins 0.000 description 1
- 101000823116 Homo sapiens Alpha-1-antitrypsin Proteins 0.000 description 1
- 101001019502 Homo sapiens Alpha-L-iduronidase Proteins 0.000 description 1
- 101000588435 Homo sapiens Alpha-N-acetylgalactosaminidase Proteins 0.000 description 1
- 101000797282 Homo sapiens Alpha-actinin-4 Proteins 0.000 description 1
- 101000891982 Homo sapiens Alpha-crystallin B chain Proteins 0.000 description 1
- 101000882335 Homo sapiens Alpha-enolase Proteins 0.000 description 1
- 101000615953 Homo sapiens Alpha-mannosidase 2 Proteins 0.000 description 1
- 101000703500 Homo sapiens Alpha-sarcoglycan Proteins 0.000 description 1
- 101000776160 Homo sapiens Alsin Proteins 0.000 description 1
- 101000797795 Homo sapiens Alstrom syndrome protein 1 Proteins 0.000 description 1
- 101000959114 Homo sapiens Amelogenin, X isoform Proteins 0.000 description 1
- 101000740448 Homo sapiens Amiloride-sensitive sodium channel subunit alpha Proteins 0.000 description 1
- 101000740426 Homo sapiens Amiloride-sensitive sodium channel subunit beta Proteins 0.000 description 1
- 101000822373 Homo sapiens Amiloride-sensitive sodium channel subunit gamma Proteins 0.000 description 1
- 101000694718 Homo sapiens Amine oxidase [flavin-containing] A Proteins 0.000 description 1
- 101000768078 Homo sapiens Amine oxidase [flavin-containing] B Proteins 0.000 description 1
- 101001075525 Homo sapiens Ammonium transporter Rh type A Proteins 0.000 description 1
- 101000780116 Homo sapiens Ankyrin repeat domain-containing protein 26 Proteins 0.000 description 1
- 101000796140 Homo sapiens Ankyrin-1 Proteins 0.000 description 1
- 101000928344 Homo sapiens Ankyrin-2 Proteins 0.000 description 1
- 101001050039 Homo sapiens Anosmin-1 Proteins 0.000 description 1
- 101000693801 Homo sapiens Anti-Muellerian hormone type-2 receptor Proteins 0.000 description 1
- 101000757319 Homo sapiens Antithrombin-III Proteins 0.000 description 1
- 101000733802 Homo sapiens Apolipoprotein A-I Proteins 0.000 description 1
- 101000793406 Homo sapiens Apolipoprotein A-II Proteins 0.000 description 1
- 101000889953 Homo sapiens Apolipoprotein B-100 Proteins 0.000 description 1
- 101000793223 Homo sapiens Apolipoprotein C-III Proteins 0.000 description 1
- 101000771674 Homo sapiens Apolipoprotein E Proteins 0.000 description 1
- 101000752037 Homo sapiens Arginase-1 Proteins 0.000 description 1
- 101000784014 Homo sapiens Argininosuccinate synthase Proteins 0.000 description 1
- 101000919395 Homo sapiens Aromatase Proteins 0.000 description 1
- 101000690533 Homo sapiens Aryl hydrocarbon receptor repressor Proteins 0.000 description 1
- 101000884399 Homo sapiens Arylamine N-acetyltransferase 2 Proteins 0.000 description 1
- 101000923070 Homo sapiens Arylsulfatase B Proteins 0.000 description 1
- 101000975827 Homo sapiens Arylsulfatase L Proteins 0.000 description 1
- 101000975992 Homo sapiens Asparagine synthetase [glutamine-hydrolyzing] Proteins 0.000 description 1
- 101000797251 Homo sapiens Aspartoacylase Proteins 0.000 description 1
- 101000936983 Homo sapiens Atlastin-1 Proteins 0.000 description 1
- 101000928549 Homo sapiens Autoimmune regulator Proteins 0.000 description 1
- 101000874569 Homo sapiens Axin-2 Proteins 0.000 description 1
- 101000874316 Homo sapiens B melanoma antigen 1 Proteins 0.000 description 1
- 101000803266 Homo sapiens B-cell linker protein Proteins 0.000 description 1
- 101100272581 Homo sapiens BIRC7 gene Proteins 0.000 description 1
- 101001068638 Homo sapiens Basic salivary proline-rich protein 3 Proteins 0.000 description 1
- 101000901683 Homo sapiens Battenin Proteins 0.000 description 1
- 101000937508 Homo sapiens Beta-1,4-galactosyltransferase 7 Proteins 0.000 description 1
- 101000959437 Homo sapiens Beta-2 adrenergic receptor Proteins 0.000 description 1
- 101000793425 Homo sapiens Beta-2-glycoprotein 1 Proteins 0.000 description 1
- 101000937544 Homo sapiens Beta-2-microglobulin Proteins 0.000 description 1
- 101000919139 Homo sapiens Beta-crystallin A3 Proteins 0.000 description 1
- 101000919250 Homo sapiens Beta-crystallin B2 Proteins 0.000 description 1
- 101000933465 Homo sapiens Beta-glucuronidase Proteins 0.000 description 1
- 101001045440 Homo sapiens Beta-hexosaminidase subunit alpha Proteins 0.000 description 1
- 101001045433 Homo sapiens Beta-hexosaminidase subunit beta Proteins 0.000 description 1
- 101001016707 Homo sapiens Beta-mannosidase Proteins 0.000 description 1
- 101000703495 Homo sapiens Beta-sarcoglycan Proteins 0.000 description 1
- 101001126865 Homo sapiens Biglycan Proteins 0.000 description 1
- 101000871771 Homo sapiens Biotin-[acetyl-CoA-carboxylase] ligase Proteins 0.000 description 1
- 101000984541 Homo sapiens Bleomycin hydrolase Proteins 0.000 description 1
- 101000580024 Homo sapiens Blood group Rh(D) polypeptide Proteins 0.000 description 1
- 101000803270 Homo sapiens Bloom syndrome protein Proteins 0.000 description 1
- 101000777599 Homo sapiens C-C chemokine receptor type 2 Proteins 0.000 description 1
- 101000946926 Homo sapiens C-C chemokine receptor type 5 Proteins 0.000 description 1
- 101000978381 Homo sapiens C-C motif chemokine 14 Proteins 0.000 description 1
- 101000978375 Homo sapiens C-C motif chemokine 16 Proteins 0.000 description 1
- 101000978362 Homo sapiens C-C motif chemokine 17 Proteins 0.000 description 1
- 101000978371 Homo sapiens C-C motif chemokine 18 Proteins 0.000 description 1
- 101000713085 Homo sapiens C-C motif chemokine 21 Proteins 0.000 description 1
- 101000713081 Homo sapiens C-C motif chemokine 23 Proteins 0.000 description 1
- 101001046660 Homo sapiens C-Jun-amino-terminal kinase-interacting protein 1 Proteins 0.000 description 1
- 101000858088 Homo sapiens C-X-C motif chemokine 10 Proteins 0.000 description 1
- 101000858060 Homo sapiens C-X-C motif chemokine 11 Proteins 0.000 description 1
- 101000858064 Homo sapiens C-X-C motif chemokine 13 Proteins 0.000 description 1
- 101000889133 Homo sapiens C-X-C motif chemokine 16 Proteins 0.000 description 1
- 101000947193 Homo sapiens C-X-C motif chemokine 3 Proteins 0.000 description 1
- 101000947177 Homo sapiens C-X-C motif chemokine 6 Proteins 0.000 description 1
- 101000947172 Homo sapiens C-X-C motif chemokine 9 Proteins 0.000 description 1
- 101000914211 Homo sapiens CASP8 and FADD-like apoptosis regulator Proteins 0.000 description 1
- 101000942590 Homo sapiens CCR4-NOT transcription complex subunit 9 Proteins 0.000 description 1
- 101000914511 Homo sapiens CD27 antigen Proteins 0.000 description 1
- 101000868215 Homo sapiens CD40 ligand Proteins 0.000 description 1
- 101000868273 Homo sapiens CD44 antigen Proteins 0.000 description 1
- 101000914479 Homo sapiens CD81 antigen Proteins 0.000 description 1
- 101000896987 Homo sapiens CREB-binding protein Proteins 0.000 description 1
- 101000794587 Homo sapiens Cadherin-5 Proteins 0.000 description 1
- 101000580357 Homo sapiens Calcipressin-1 Proteins 0.000 description 1
- 101000741445 Homo sapiens Calcitonin Proteins 0.000 description 1
- 101000932890 Homo sapiens Calcitonin gene-related peptide 1 Proteins 0.000 description 1
- 101000741435 Homo sapiens Calcitonin receptor Proteins 0.000 description 1
- 101000935132 Homo sapiens Calcium-binding tyrosine phosphorylation-regulated protein Proteins 0.000 description 1
- 101000867715 Homo sapiens Calpain-3 Proteins 0.000 description 1
- 101000793666 Homo sapiens Calpain-5 Proteins 0.000 description 1
- 101000793651 Homo sapiens Calreticulin Proteins 0.000 description 1
- 101000855412 Homo sapiens Carbamoyl-phosphate synthase [ammonia], mitochondrial Proteins 0.000 description 1
- 101000882998 Homo sapiens Carbohydrate sulfotransferase 6 Proteins 0.000 description 1
- 101000760567 Homo sapiens Carbonic anhydrase 4 Proteins 0.000 description 1
- 101000946518 Homo sapiens Carboxypeptidase B2 Proteins 0.000 description 1
- 101000859570 Homo sapiens Carnitine O-palmitoyltransferase 1, liver isoform Proteins 0.000 description 1
- 101000909313 Homo sapiens Carnitine O-palmitoyltransferase 2, mitochondrial Proteins 0.000 description 1
- 101000916173 Homo sapiens Catenin beta-1 Proteins 0.000 description 1
- 101000898449 Homo sapiens Cathepsin B Proteins 0.000 description 1
- 101000761509 Homo sapiens Cathepsin K Proteins 0.000 description 1
- 101001028831 Homo sapiens Cation-independent mannose-6-phosphate receptor Proteins 0.000 description 1
- 101000869042 Homo sapiens Caveolin-3 Proteins 0.000 description 1
- 101000934310 Homo sapiens Cellular communication network factor 6 Proteins 0.000 description 1
- 101000737793 Homo sapiens Cerebellar degeneration-related antigen 1 Proteins 0.000 description 1
- 101000710208 Homo sapiens Ceroid-lipofuscinosis neuronal protein 5 Proteins 0.000 description 1
- 101000710215 Homo sapiens Ceroid-lipofuscinosis neuronal protein 6 Proteins 0.000 description 1
- 101000851684 Homo sapiens Chimeric ERCC6-PGBD3 protein Proteins 0.000 description 1
- 101000906651 Homo sapiens Chloride channel protein 1 Proteins 0.000 description 1
- 101000906654 Homo sapiens Chloride channel protein ClC-Kb Proteins 0.000 description 1
- 101000880514 Homo sapiens Cholesteryl ester transfer protein Proteins 0.000 description 1
- 101000943274 Homo sapiens Cholinesterase Proteins 0.000 description 1
- 101000916489 Homo sapiens Chondroitin sulfate proteoglycan 4 Proteins 0.000 description 1
- 101000941971 Homo sapiens Chordin-like protein 1 Proteins 0.000 description 1
- 101000776619 Homo sapiens Choriogonadotropin subunit beta 3 Proteins 0.000 description 1
- 101000895818 Homo sapiens Chorionic somatomammotropin hormone 1 Proteins 0.000 description 1
- 101000992973 Homo sapiens Clarin-1 Proteins 0.000 description 1
- 101000888608 Homo sapiens Claudin-16 Proteins 0.000 description 1
- 101000918350 Homo sapiens Coagulation factor XIII B chain Proteins 0.000 description 1
- 101000748988 Homo sapiens Cochlin Proteins 0.000 description 1
- 101000980888 Homo sapiens Codanin-1 Proteins 0.000 description 1
- 101000868824 Homo sapiens Coiled-coil domain-containing protein 110 Proteins 0.000 description 1
- 101000993285 Homo sapiens Collagen alpha-1(III) chain Proteins 0.000 description 1
- 101000941708 Homo sapiens Collagen alpha-1(V) chain Proteins 0.000 description 1
- 101000941581 Homo sapiens Collagen alpha-1(VI) chain Proteins 0.000 description 1
- 101000909498 Homo sapiens Collagen alpha-1(VII) chain Proteins 0.000 description 1
- 101000710623 Homo sapiens Collagen alpha-1(XI) chain Proteins 0.000 description 1
- 101000860679 Homo sapiens Collagen alpha-1(XVII) chain Proteins 0.000 description 1
- 101000920176 Homo sapiens Collagen alpha-1(XXIII) chain Proteins 0.000 description 1
- 101000919645 Homo sapiens Collagen alpha-2(IX) chain Proteins 0.000 description 1
- 101000941594 Homo sapiens Collagen alpha-2(V) chain Proteins 0.000 description 1
- 101000941585 Homo sapiens Collagen alpha-2(VI) chain Proteins 0.000 description 1
- 101000710619 Homo sapiens Collagen alpha-2(XI) chain Proteins 0.000 description 1
- 101000710873 Homo sapiens Collagen alpha-3(IV) chain Proteins 0.000 description 1
- 101000919644 Homo sapiens Collagen alpha-3(IX) chain Proteins 0.000 description 1
- 101000909506 Homo sapiens Collagen alpha-3(VI) chain Proteins 0.000 description 1
- 101000710870 Homo sapiens Collagen alpha-4(IV) chain Proteins 0.000 description 1
- 101000710886 Homo sapiens Collagen alpha-5(IV) chain Proteins 0.000 description 1
- 101000710885 Homo sapiens Collagen alpha-6(IV) chain Proteins 0.000 description 1
- 101000934958 Homo sapiens Complement C1s subcomponent Proteins 0.000 description 1
- 101000919370 Homo sapiens Cone-rod homeobox protein Proteins 0.000 description 1
- 101000876012 Homo sapiens Conserved oligomeric Golgi complex subunit 4 Proteins 0.000 description 1
- 101000748957 Homo sapiens Conserved oligomeric Golgi complex subunit 6 Proteins 0.000 description 1
- 101000936280 Homo sapiens Copper-transporting ATPase 2 Proteins 0.000 description 1
- 101000895481 Homo sapiens Corticoliberin Proteins 0.000 description 1
- 101000868967 Homo sapiens Corticosteroid-binding globulin Proteins 0.000 description 1
- 101000921095 Homo sapiens Corticotropin-releasing factor-binding protein Proteins 0.000 description 1
- 101000922080 Homo sapiens Cubilin Proteins 0.000 description 1
- 101000771071 Homo sapiens Cyclic nucleotide-gated cation channel alpha-3 Proteins 0.000 description 1
- 101000969676 Homo sapiens Cyclic pyranopterin monophosphate synthase Proteins 0.000 description 1
- 101000738403 Homo sapiens Cyclin-dependent kinase 11A Proteins 0.000 description 1
- 101000738400 Homo sapiens Cyclin-dependent kinase 11B Proteins 0.000 description 1
- 101000912191 Homo sapiens Cystatin-B Proteins 0.000 description 1
- 101000912205 Homo sapiens Cystatin-C Proteins 0.000 description 1
- 101000922034 Homo sapiens Cystinosin Proteins 0.000 description 1
- 101000875170 Homo sapiens Cytochrome P450 2A6 Proteins 0.000 description 1
- 101000896586 Homo sapiens Cytochrome P450 2D6 Proteins 0.000 description 1
- 101000858267 Homo sapiens Cytochrome b Proteins 0.000 description 1
- 101000856723 Homo sapiens Cytochrome b-245 light chain Proteins 0.000 description 1
- 101000607486 Homo sapiens Cytochrome b-c1 complex subunit 1, mitochondrial Proteins 0.000 description 1
- 101000922386 Homo sapiens Cytochrome b5 Proteins 0.000 description 1
- 101000919849 Homo sapiens Cytochrome c oxidase subunit 1 Proteins 0.000 description 1
- 101001033280 Homo sapiens Cytokine receptor common subunit beta Proteins 0.000 description 1
- 101000889276 Homo sapiens Cytotoxic T-lymphocyte protein 4 Proteins 0.000 description 1
- 101000931901 Homo sapiens D(2) dopamine receptor Proteins 0.000 description 1
- 101000865206 Homo sapiens D(4) dopamine receptor Proteins 0.000 description 1
- 101000739890 Homo sapiens D-3-phosphoglycerate dehydrogenase Proteins 0.000 description 1
- 101001041466 Homo sapiens DNA damage-binding protein 2 Proteins 0.000 description 1
- 101000920783 Homo sapiens DNA excision repair protein ERCC-6 Proteins 0.000 description 1
- 101001134036 Homo sapiens DNA mismatch repair protein Msh2 Proteins 0.000 description 1
- 101001027762 Homo sapiens DNA mismatch repair protein Msh3 Proteins 0.000 description 1
- 101000968658 Homo sapiens DNA mismatch repair protein Msh6 Proteins 0.000 description 1
- 101001094607 Homo sapiens DNA polymerase eta Proteins 0.000 description 1
- 101000865085 Homo sapiens DNA polymerase theta Proteins 0.000 description 1
- 101000712511 Homo sapiens DNA repair and recombination protein RAD54-like Proteins 0.000 description 1
- 101001132263 Homo sapiens DNA repair and recombination protein RAD54B Proteins 0.000 description 1
- 101000830681 Homo sapiens DNA topoisomerase 1 Proteins 0.000 description 1
- 101001075432 Homo sapiens DNA-binding protein RFX5 Proteins 0.000 description 1
- 101001075464 Homo sapiens DNA-binding protein RFXANK Proteins 0.000 description 1
- 101000619536 Homo sapiens DNA-dependent protein kinase catalytic subunit Proteins 0.000 description 1
- 101000957914 Homo sapiens Death domain-containing protein CRADD Proteins 0.000 description 1
- 101000869896 Homo sapiens Death-inducer obliterator 1 Proteins 0.000 description 1
- 101000844721 Homo sapiens Deleted in malignant brain tumors 1 protein Proteins 0.000 description 1
- 101000755868 Homo sapiens Delta-1-pyrroline-5-carboxylate dehydrogenase, mitochondrial Proteins 0.000 description 1
- 101000928513 Homo sapiens Delta-like protein 3 Proteins 0.000 description 1
- 101000616408 Homo sapiens Delta-sarcoglycan Proteins 0.000 description 1
- 101000865404 Homo sapiens Dentin sialophosphoprotein Proteins 0.000 description 1
- 101000863721 Homo sapiens Deoxyribonuclease-1 Proteins 0.000 description 1
- 101000816698 Homo sapiens Dermatan-sulfate epimerase Proteins 0.000 description 1
- 101000924316 Homo sapiens Desmoglein-1 Proteins 0.000 description 1
- 101000620808 Homo sapiens Dexamethasone-induced Ras-related protein 1 Proteins 0.000 description 1
- 101000908058 Homo sapiens Dihydrolipoyl dehydrogenase, mitochondrial Proteins 0.000 description 1
- 101001122360 Homo sapiens Dihydrolipoyllysine-residue acetyltransferase component of pyruvate dehydrogenase complex, mitochondrial Proteins 0.000 description 1
- 101000902365 Homo sapiens Dihydropteridine reductase Proteins 0.000 description 1
- 101000930818 Homo sapiens Dihydropyrimidinase Proteins 0.000 description 1
- 101000902632 Homo sapiens Dihydropyrimidine dehydrogenase [NADP(+)] Proteins 0.000 description 1
- 101000932213 Homo sapiens Dipeptidase 1 Proteins 0.000 description 1
- 101000793922 Homo sapiens Dipeptidyl peptidase 1 Proteins 0.000 description 1
- 101000929429 Homo sapiens Discoidin domain-containing receptor 2 Proteins 0.000 description 1
- 101000805864 Homo sapiens Divergent protein kinase domain 2A Proteins 0.000 description 1
- 101000845893 Homo sapiens DnaJ homolog subfamily C member 5 Proteins 0.000 description 1
- 101000865739 Homo sapiens Dual serine/threonine and tyrosine protein kinase Proteins 0.000 description 1
- 101000722054 Homo sapiens Dynamin-like 120 kDa protein, mitochondrial Proteins 0.000 description 1
- 101001016184 Homo sapiens Dysferlin Proteins 0.000 description 1
- 101000804521 Homo sapiens Dystrophia myotonica WD repeat-containing protein Proteins 0.000 description 1
- 101001053946 Homo sapiens Dystrophin Proteins 0.000 description 1
- 101001049692 Homo sapiens E3 SUMO-protein ligase EGR2 Proteins 0.000 description 1
- 101000610400 Homo sapiens E3 ubiquitin-protein ligase TRIM37 Proteins 0.000 description 1
- 101000830203 Homo sapiens E3 ubiquitin-protein ligase TRIM69 Proteins 0.000 description 1
- 101000619542 Homo sapiens E3 ubiquitin-protein ligase parkin Proteins 0.000 description 1
- 101001065272 Homo sapiens EGF-containing fibulin-like extracellular matrix protein 1 Proteins 0.000 description 1
- 101000813729 Homo sapiens ETS translocation variant 1 Proteins 0.000 description 1
- 101000880080 Homo sapiens Ectodysplasin-A Proteins 0.000 description 1
- 101001010541 Homo sapiens Electron transfer flavoprotein subunit alpha, mitochondrial Proteins 0.000 description 1
- 101001057122 Homo sapiens Electron transfer flavoprotein subunit beta Proteins 0.000 description 1
- 101000920874 Homo sapiens Electron transfer flavoprotein-ubiquinone oxidoreductase, mitochondrial Proteins 0.000 description 1
- 101000881890 Homo sapiens Ellis-van Creveld syndrome protein Proteins 0.000 description 1
- 101000813117 Homo sapiens Elongator complex protein 1 Proteins 0.000 description 1
- 101000881679 Homo sapiens Endoglin Proteins 0.000 description 1
- 101000907904 Homo sapiens Endoribonuclease Dicer Proteins 0.000 description 1
- 101000967299 Homo sapiens Endothelin receptor type B Proteins 0.000 description 1
- 101000841213 Homo sapiens Endothelin-3 Proteins 0.000 description 1
- 101000841259 Homo sapiens Endothelin-converting enzyme 1 Proteins 0.000 description 1
- 101001012451 Homo sapiens Enteropeptidase Proteins 0.000 description 1
- 101000987586 Homo sapiens Eosinophil peroxidase Proteins 0.000 description 1
- 101000938354 Homo sapiens Ephrin type-A receptor 1 Proteins 0.000 description 1
- 101000920667 Homo sapiens Epithelial cell adhesion molecule Proteins 0.000 description 1
- 101000616437 Homo sapiens Epsilon-sarcoglycan Proteins 0.000 description 1
- 101000882584 Homo sapiens Estrogen receptor Proteins 0.000 description 1
- 101000926508 Homo sapiens Eukaryotic translation initiation factor 2-alpha kinase 3 Proteins 0.000 description 1
- 101000918275 Homo sapiens Exostosin-2 Proteins 0.000 description 1
- 101000836222 Homo sapiens Extracellular superoxide dismutase [Cu-Zn] Proteins 0.000 description 1
- 101000938435 Homo sapiens Eyes absent homolog 1 Proteins 0.000 description 1
- 101001060244 Homo sapiens F-box/WD repeat-containing protein 4 Proteins 0.000 description 1
- 101000911074 Homo sapiens FAS-associated death domain protein Proteins 0.000 description 1
- 101001065295 Homo sapiens Fas-binding factor 1 Proteins 0.000 description 1
- 101000911337 Homo sapiens Fatty acid-binding protein, intestinal Proteins 0.000 description 1
- 101001002987 Homo sapiens Ferritin heavy chain Proteins 0.000 description 1
- 101001031604 Homo sapiens Ferritin heavy polypeptide-like 17 Proteins 0.000 description 1
- 101000818390 Homo sapiens Ferritin light chain Proteins 0.000 description 1
- 101000846893 Homo sapiens Fibrillin-1 Proteins 0.000 description 1
- 101000846890 Homo sapiens Fibrillin-2 Proteins 0.000 description 1
- 101000878123 Homo sapiens Fibroblast growth factor 16 Proteins 0.000 description 1
- 101001051973 Homo sapiens Fibroblast growth factor 23 Proteins 0.000 description 1
- 101001060267 Homo sapiens Fibroblast growth factor 5 Proteins 0.000 description 1
- 101000827746 Homo sapiens Fibroblast growth factor receptor 1 Proteins 0.000 description 1
- 101000730595 Homo sapiens Fibrocystin Proteins 0.000 description 1
- 101000862396 Homo sapiens Follicle-stimulating hormone receptor Proteins 0.000 description 1
- 101001060703 Homo sapiens Folliculin Proteins 0.000 description 1
- 101000893054 Homo sapiens Follitropin subunit beta Proteins 0.000 description 1
- 101001029304 Homo sapiens Forkhead box protein E1 Proteins 0.000 description 1
- 101000907576 Homo sapiens Forkhead box protein N1 Proteins 0.000 description 1
- 101000877683 Homo sapiens Forkhead box protein O4 Proteins 0.000 description 1
- 101000854520 Homo sapiens Fractalkine Proteins 0.000 description 1
- 101000932499 Homo sapiens Fragile X mental retardation 1 neighbor protein Proteins 0.000 description 1
- 101000861386 Homo sapiens Frataxin, mitochondrial Proteins 0.000 description 1
- 101000885581 Homo sapiens Frizzled-4 Proteins 0.000 description 1
- 101001028852 Homo sapiens Fructose-1,6-bisphosphatase 1 Proteins 0.000 description 1
- 101000755933 Homo sapiens Fructose-bisphosphate aldolase B Proteins 0.000 description 1
- 101000868643 Homo sapiens G2/mitotic-specific cyclin-B1 Proteins 0.000 description 1
- 101000862581 Homo sapiens GTP cyclohydrolase 1 Proteins 0.000 description 1
- 101000584633 Homo sapiens GTPase HRas Proteins 0.000 description 1
- 101000584612 Homo sapiens GTPase KRas Proteins 0.000 description 1
- 101000860395 Homo sapiens Galactocerebrosidase Proteins 0.000 description 1
- 101001024874 Homo sapiens Galactokinase Proteins 0.000 description 1
- 101001021379 Homo sapiens Galactose-1-phosphate uridylyltransferase Proteins 0.000 description 1
- 101000885616 Homo sapiens Galactoside alpha-(1,2)-fucosyltransferase 1 Proteins 0.000 description 1
- 101000893710 Homo sapiens Galactoside alpha-(1,2)-fucosyltransferase 2 Proteins 0.000 description 1
- 101000893321 Homo sapiens Gamma-aminobutyric acid receptor subunit alpha-3 Proteins 0.000 description 1
- 101000745534 Homo sapiens Gamma-crystallin A Proteins 0.000 description 1
- 101000859938 Homo sapiens Gamma-crystallin C Proteins 0.000 description 1
- 101000859943 Homo sapiens Gamma-crystallin D Proteins 0.000 description 1
- 101000685969 Homo sapiens Ganglioside GM2 activator Proteins 0.000 description 1
- 101000833509 Homo sapiens Ganglioside-induced differentiation-associated protein 1 Proteins 0.000 description 1
- 101000894966 Homo sapiens Gap junction alpha-1 protein Proteins 0.000 description 1
- 101000726577 Homo sapiens Gap junction alpha-3 protein Proteins 0.000 description 1
- 101000858024 Homo sapiens Gap junction alpha-8 protein Proteins 0.000 description 1
- 101000954104 Homo sapiens Gap junction beta-1 protein Proteins 0.000 description 1
- 101000954092 Homo sapiens Gap junction beta-2 protein Proteins 0.000 description 1
- 101000889125 Homo sapiens Gap junction beta-6 protein Proteins 0.000 description 1
- 101001026269 Homo sapiens Gasdermin-E Proteins 0.000 description 1
- 101001002317 Homo sapiens Gastrin Proteins 0.000 description 1
- 101001010479 Homo sapiens Gastrin-releasing peptide receptor Proteins 0.000 description 1
- 101000920748 Homo sapiens General transcription and DNA repair factor IIH helicase subunit XPB Proteins 0.000 description 1
- 101000655402 Homo sapiens General transcription factor IIH subunit 5 Proteins 0.000 description 1
- 101001025761 Homo sapiens Gigaxonin Proteins 0.000 description 1
- 101000857303 Homo sapiens Glomulin Proteins 0.000 description 1
- 101001040075 Homo sapiens Glucagon receptor Proteins 0.000 description 1
- 101000926939 Homo sapiens Glucocorticoid receptor Proteins 0.000 description 1
- 101000930910 Homo sapiens Glucose-6-phosphatase catalytic subunit 1 Proteins 0.000 description 1
- 101001040875 Homo sapiens Glucosidase 2 subunit beta Proteins 0.000 description 1
- 101000870042 Homo sapiens Glutamate dehydrogenase 1, mitochondrial Proteins 0.000 description 1
- 101001072655 Homo sapiens Glutamyl-tRNA(Gln) amidotransferase subunit A, mitochondrial Proteins 0.000 description 1
- 101001058943 Homo sapiens Glutaryl-CoA dehydrogenase, mitochondrial Proteins 0.000 description 1
- 101000997558 Homo sapiens Glutathione hydrolase 1 proenzyme Proteins 0.000 description 1
- 101001009678 Homo sapiens Glycerol-3-phosphate dehydrogenase, mitochondrial Proteins 0.000 description 1
- 101000856845 Homo sapiens Glycine cleavage system H protein, mitochondrial Proteins 0.000 description 1
- 101000998096 Homo sapiens Glycine dehydrogenase (decarboxylating), mitochondrial Proteins 0.000 description 1
- 101001072736 Homo sapiens Glycine-tRNA ligase Proteins 0.000 description 1
- 101001036117 Homo sapiens Glycogen [starch] synthase, liver Proteins 0.000 description 1
- 101001036130 Homo sapiens Glycogen [starch] synthase, muscle Proteins 0.000 description 1
- 101000700616 Homo sapiens Glycogen phosphorylase, liver form Proteins 0.000 description 1
- 101000700475 Homo sapiens Glycogen phosphorylase, muscle form Proteins 0.000 description 1
- 101001074244 Homo sapiens Glycophorin-A Proteins 0.000 description 1
- 101000905336 Homo sapiens Glycophorin-C Proteins 0.000 description 1
- 101001038874 Homo sapiens Glycoprotein hormones alpha chain Proteins 0.000 description 1
- 101001010442 Homo sapiens Glyoxylate reductase/hydroxypyruvate reductase Proteins 0.000 description 1
- 101000996727 Homo sapiens Gonadotropin-releasing hormone receptor Proteins 0.000 description 1
- 101000746364 Homo sapiens Granulocyte colony-stimulating factor receptor Proteins 0.000 description 1
- 101000916625 Homo sapiens Granulocyte-macrophage colony-stimulating factor receptor subunit alpha Proteins 0.000 description 1
- 101000642577 Homo sapiens Growth hormone variant Proteins 0.000 description 1
- 101000997535 Homo sapiens Growth hormone-releasing hormone receptor Proteins 0.000 description 1
- 101001069921 Homo sapiens Growth-regulated alpha protein Proteins 0.000 description 1
- 101001023988 Homo sapiens Growth/differentiation factor 5 Proteins 0.000 description 1
- 101000893897 Homo sapiens Guanidinoacetate N-methyltransferase Proteins 0.000 description 1
- 101001070508 Homo sapiens Guanine nucleotide-binding protein G(i) subunit alpha-2 Proteins 0.000 description 1
- 101001014590 Homo sapiens Guanine nucleotide-binding protein G(s) subunit alpha isoforms XLas Proteins 0.000 description 1
- 101001014594 Homo sapiens Guanine nucleotide-binding protein G(s) subunit alpha isoforms short Proteins 0.000 description 1
- 101000888178 Homo sapiens Guanine nucleotide-binding protein G(t) subunit alpha-1 Proteins 0.000 description 1
- 101001072407 Homo sapiens Guanine nucleotide-binding protein subunit alpha-11 Proteins 0.000 description 1
- 101001068480 Homo sapiens Guanylyl cyclase-activating protein 1 Proteins 0.000 description 1
- 101000844866 Homo sapiens H/ACA ribonucleoprotein complex subunit DKC1 Proteins 0.000 description 1
- 101000986084 Homo sapiens HLA class I histocompatibility antigen, C alpha chain Proteins 0.000 description 1
- 101000930800 Homo sapiens HLA class II histocompatibility antigen, DQ beta 1 chain Proteins 0.000 description 1
- 101001035846 Homo sapiens HMG box-containing protein 1 Proteins 0.000 description 1
- 101001016879 Homo sapiens Heat shock factor protein 4 Proteins 0.000 description 1
- 101000763352 Homo sapiens Heat shock protein 75 kDa, mitochondrial Proteins 0.000 description 1
- 101001016865 Homo sapiens Heat shock protein HSP 90-alpha Proteins 0.000 description 1
- 101001079623 Homo sapiens Heme oxygenase 1 Proteins 0.000 description 1
- 101000899111 Homo sapiens Hemoglobin subunit beta Proteins 0.000 description 1
- 101001035503 Homo sapiens Hemoglobin subunit delta Proteins 0.000 description 1
- 101001083591 Homo sapiens Hemoglobin subunit epsilon Proteins 0.000 description 1
- 101001031977 Homo sapiens Hemoglobin subunit gamma-1 Proteins 0.000 description 1
- 101001031961 Homo sapiens Hemoglobin subunit gamma-2 Proteins 0.000 description 1
- 101000843063 Homo sapiens Hemoglobin subunit theta-1 Proteins 0.000 description 1
- 101000941289 Homo sapiens Hepatic triacylglycerol lipase Proteins 0.000 description 1
- 101000972946 Homo sapiens Hepatocyte growth factor receptor Proteins 0.000 description 1
- 101001045758 Homo sapiens Hepatocyte nuclear factor 1-beta Proteins 0.000 description 1
- 101001045740 Homo sapiens Hepatocyte nuclear factor 4-alpha Proteins 0.000 description 1
- 101000838926 Homo sapiens Hermansky-Pudlak syndrome 1 protein Proteins 0.000 description 1
- 101000878594 Homo sapiens High affinity immunoglobulin epsilon receptor subunit beta Proteins 0.000 description 1
- 101000596894 Homo sapiens High affinity nerve growth factor receptor Proteins 0.000 description 1
- 101000898505 Homo sapiens Histatin-3 Proteins 0.000 description 1
- 101000882390 Homo sapiens Histone acetyltransferase p300 Proteins 0.000 description 1
- 101000899259 Homo sapiens Histone deacetylase 4 Proteins 0.000 description 1
- 101000634050 Homo sapiens Histone-lysine N-methyltransferase, H3 lysine-36 specific Proteins 0.000 description 1
- 101000946589 Homo sapiens Holocytochrome c-type synthase Proteins 0.000 description 1
- 101001067288 Homo sapiens Homeobox expressed in ES cells 1 Proteins 0.000 description 1
- 101000901646 Homo sapiens Homeobox protein DLX-3 Proteins 0.000 description 1
- 101001048970 Homo sapiens Homeobox protein EMX2 Proteins 0.000 description 1
- 101001083156 Homo sapiens Homeobox protein Hox-A1 Proteins 0.000 description 1
- 101001037168 Homo sapiens Homeobox protein Hox-D13 Proteins 0.000 description 1
- 101000985653 Homo sapiens Homeobox protein MSX-1 Proteins 0.000 description 1
- 101000967222 Homo sapiens Homeobox protein MSX-2 Proteins 0.000 description 1
- 101000632178 Homo sapiens Homeobox protein Nkx-2.1 Proteins 0.000 description 1
- 101000632197 Homo sapiens Homeobox protein Nkx-2.5 Proteins 0.000 description 1
- 101000596925 Homo sapiens Homeobox protein TGIF1 Proteins 0.000 description 1
- 101000779608 Homo sapiens Homeobox protein aristaless-like 4 Proteins 0.000 description 1
- 101000706471 Homo sapiens Homeobox protein prophet of Pit-1 Proteins 0.000 description 1
- 101000872475 Homo sapiens Homogentisate 1,2-dioxygenase Proteins 0.000 description 1
- 101000867099 Homo sapiens Humanin Proteins 0.000 description 1
- 101000962530 Homo sapiens Hyaluronidase-1 Proteins 0.000 description 1
- 101001047912 Homo sapiens Hydroxymethylglutaryl-CoA lyase, mitochondrial Proteins 0.000 description 1
- 101001077647 Homo sapiens IQ motif and SEC7 domain-containing protein 2 Proteins 0.000 description 1
- 101000840540 Homo sapiens Iduronate 2-sulfatase Proteins 0.000 description 1
- 101000961146 Homo sapiens Immunoglobulin heavy constant gamma 2 Proteins 0.000 description 1
- 101000840257 Homo sapiens Immunoglobulin kappa constant Proteins 0.000 description 1
- 101001047811 Homo sapiens Inactive heparanase-2 Proteins 0.000 description 1
- 101000878213 Homo sapiens Inactive peptidyl-prolyl cis-trans isomerase FKBP6 Proteins 0.000 description 1
- 101000580021 Homo sapiens Inactive rhomboid protein 2 Proteins 0.000 description 1
- 101001044118 Homo sapiens Inosine-5'-monophosphate dehydrogenase 1 Proteins 0.000 description 1
- 101000852815 Homo sapiens Insulin receptor Proteins 0.000 description 1
- 101000599951 Homo sapiens Insulin-like growth factor I Proteins 0.000 description 1
- 101001050468 Homo sapiens Integral membrane protein 2B Proteins 0.000 description 1
- 101001078133 Homo sapiens Integrin alpha-2 Proteins 0.000 description 1
- 101000994365 Homo sapiens Integrin alpha-6 Proteins 0.000 description 1
- 101001078143 Homo sapiens Integrin alpha-IIb Proteins 0.000 description 1
- 101000935040 Homo sapiens Integrin beta-2 Proteins 0.000 description 1
- 101001015004 Homo sapiens Integrin beta-3 Proteins 0.000 description 1
- 101001015006 Homo sapiens Integrin beta-4 Proteins 0.000 description 1
- 101000599852 Homo sapiens Intercellular adhesion molecule 1 Proteins 0.000 description 1
- 101001001420 Homo sapiens Interferon gamma receptor 1 Proteins 0.000 description 1
- 101000994815 Homo sapiens Interleukin-1 receptor accessory protein-like 1 Proteins 0.000 description 1
- 101000852255 Homo sapiens Interleukin-1 receptor-associated kinase-like 2 Proteins 0.000 description 1
- 101001033233 Homo sapiens Interleukin-10 Proteins 0.000 description 1
- 101001003142 Homo sapiens Interleukin-12 receptor subunit beta-1 Proteins 0.000 description 1
- 101001076430 Homo sapiens Interleukin-13 Proteins 0.000 description 1
- 101000853009 Homo sapiens Interleukin-24 Proteins 0.000 description 1
- 101001033279 Homo sapiens Interleukin-3 Proteins 0.000 description 1
- 101000998120 Homo sapiens Interleukin-3 receptor subunit alpha Proteins 0.000 description 1
- 101001043809 Homo sapiens Interleukin-7 receptor subunit alpha Proteins 0.000 description 1
- 101001055222 Homo sapiens Interleukin-8 Proteins 0.000 description 1
- 101000998711 Homo sapiens Inversin Proteins 0.000 description 1
- 101000944277 Homo sapiens Inward rectifier potassium channel 2 Proteins 0.000 description 1
- 101001026582 Homo sapiens KAT8 regulatory NSL complex subunit 3 Proteins 0.000 description 1
- 101000971351 Homo sapiens KRR1 small subunit processome component homolog Proteins 0.000 description 1
- 101000605528 Homo sapiens Kallikrein-2 Proteins 0.000 description 1
- 101000975474 Homo sapiens Keratin, type I cytoskeletal 10 Proteins 0.000 description 1
- 101000975472 Homo sapiens Keratin, type I cytoskeletal 12 Proteins 0.000 description 1
- 101000614627 Homo sapiens Keratin, type I cytoskeletal 13 Proteins 0.000 description 1
- 101000614442 Homo sapiens Keratin, type I cytoskeletal 16 Proteins 0.000 description 1
- 101001050274 Homo sapiens Keratin, type I cytoskeletal 9 Proteins 0.000 description 1
- 101001026977 Homo sapiens Keratin, type II cuticular Hb6 Proteins 0.000 description 1
- 101001046936 Homo sapiens Keratin, type II cytoskeletal 2 epidermal Proteins 0.000 description 1
- 101001056469 Homo sapiens Keratin, type II cytoskeletal 3 Proteins 0.000 description 1
- 101001056466 Homo sapiens Keratin, type II cytoskeletal 4 Proteins 0.000 description 1
- 101001056473 Homo sapiens Keratin, type II cytoskeletal 5 Proteins 0.000 description 1
- 101001056445 Homo sapiens Keratin, type II cytoskeletal 6B Proteins 0.000 description 1
- 101000934758 Homo sapiens Keratin, type II cytoskeletal 72 Proteins 0.000 description 1
- 101001050606 Homo sapiens Ketohexokinase Proteins 0.000 description 1
- 101000971697 Homo sapiens Kinesin-like protein KIF1B Proteins 0.000 description 1
- 101001027628 Homo sapiens Kinesin-like protein KIF21A Proteins 0.000 description 1
- 101001091610 Homo sapiens Krev interaction trapped protein 1 Proteins 0.000 description 1
- 101001021858 Homo sapiens Kynureninase Proteins 0.000 description 1
- 101001090713 Homo sapiens L-lactate dehydrogenase A chain Proteins 0.000 description 1
- 101001051207 Homo sapiens L-lactate dehydrogenase B chain Proteins 0.000 description 1
- 101001130171 Homo sapiens L-lactate dehydrogenase C chain Proteins 0.000 description 1
- 101000918657 Homo sapiens L-xylulose reductase Proteins 0.000 description 1
- 101001020452 Homo sapiens LIM/homeobox protein Lhx3 Proteins 0.000 description 1
- 101000876418 Homo sapiens Laforin Proteins 0.000 description 1
- 101000882389 Homo sapiens Laforin, isoform 9 Proteins 0.000 description 1
- 101000972491 Homo sapiens Laminin subunit alpha-2 Proteins 0.000 description 1
- 101001023271 Homo sapiens Laminin subunit gamma-2 Proteins 0.000 description 1
- 101001054649 Homo sapiens Latent-transforming growth factor beta-binding protein 2 Proteins 0.000 description 1
- 101001054646 Homo sapiens Latent-transforming growth factor beta-binding protein 3 Proteins 0.000 description 1
- 101001008411 Homo sapiens Lebercilin Proteins 0.000 description 1
- 101000967918 Homo sapiens Left-right determination factor 2 Proteins 0.000 description 1
- 101000966742 Homo sapiens Leucine-rich PPR motif-containing protein, mitochondrial Proteins 0.000 description 1
- 101000978210 Homo sapiens Leukotriene C4 synthase Proteins 0.000 description 1
- 101000966257 Homo sapiens Limb region 1 protein homolog Proteins 0.000 description 1
- 101001003687 Homo sapiens Lipoma-preferred partner Proteins 0.000 description 1
- 101000581802 Homo sapiens Lithostathine-1-alpha Proteins 0.000 description 1
- 101000841267 Homo sapiens Long chain 3-hydroxyacyl-CoA dehydrogenase Proteins 0.000 description 1
- 101000677545 Homo sapiens Long-chain specific acyl-CoA dehydrogenase, mitochondrial Proteins 0.000 description 1
- 101000780202 Homo sapiens Long-chain-fatty-acid-CoA ligase 6 Proteins 0.000 description 1
- 101000917826 Homo sapiens Low affinity immunoglobulin gamma Fc region receptor II-a Proteins 0.000 description 1
- 101000917824 Homo sapiens Low affinity immunoglobulin gamma Fc region receptor II-b Proteins 0.000 description 1
- 101000917858 Homo sapiens Low affinity immunoglobulin gamma Fc region receptor III-A Proteins 0.000 description 1
- 101001088879 Homo sapiens Lysine-specific demethylase 5D Proteins 0.000 description 1
- 101000997662 Homo sapiens Lysosomal acid glucosylceramidase Proteins 0.000 description 1
- 101000979046 Homo sapiens Lysosomal alpha-mannosidase Proteins 0.000 description 1
- 101001122938 Homo sapiens Lysosomal protective protein Proteins 0.000 description 1
- 101001018064 Homo sapiens Lysosomal-trafficking regulator Proteins 0.000 description 1
- 101000983747 Homo sapiens MHC class II transactivator Proteins 0.000 description 1
- 101001028659 Homo sapiens MORC family CW-type zinc finger protein 1 Proteins 0.000 description 1
- 101000916644 Homo sapiens Macrophage colony-stimulating factor 1 receptor Proteins 0.000 description 1
- 101000578262 Homo sapiens Magnesium transporter NIPA1 Proteins 0.000 description 1
- 101000918777 Homo sapiens Malonyl-CoA decarboxylase, mitochondrial Proteins 0.000 description 1
- 101000739168 Homo sapiens Mammaglobin-B Proteins 0.000 description 1
- 101001056128 Homo sapiens Mannose-binding protein C Proteins 0.000 description 1
- 101000577105 Homo sapiens Mannosyl-oligosaccharide glucosidase Proteins 0.000 description 1
- 101000573510 Homo sapiens McKusick-Kaufman/Bardet-Biedl syndromes putative chaperonin Proteins 0.000 description 1
- 101001120868 Homo sapiens Meckel syndrome type 1 protein Proteins 0.000 description 1
- 101000760730 Homo sapiens Medium-chain specific acyl-CoA dehydrogenase, mitochondrial Proteins 0.000 description 1
- 101000978418 Homo sapiens Melanocortin receptor 4 Proteins 0.000 description 1
- 101001012669 Homo sapiens Melanoma inhibitory activity protein 2 Proteins 0.000 description 1
- 101000583150 Homo sapiens Membrane-associated phosphatidylinositol transfer protein 3 Proteins 0.000 description 1
- 101000581514 Homo sapiens Membrane-bound transcription factor site-2 protease Proteins 0.000 description 1
- 101000954986 Homo sapiens Merlin Proteins 0.000 description 1
- 101000576802 Homo sapiens Mesothelin Proteins 0.000 description 1
- 101000669513 Homo sapiens Metalloproteinase inhibitor 1 Proteins 0.000 description 1
- 101000645296 Homo sapiens Metalloproteinase inhibitor 2 Proteins 0.000 description 1
- 101001013648 Homo sapiens Methionine synthase Proteins 0.000 description 1
- 101001116314 Homo sapiens Methionine synthase reductase Proteins 0.000 description 1
- 101000581533 Homo sapiens Methylcrotonoyl-CoA carboxylase beta chain, mitochondrial Proteins 0.000 description 1
- 101000587058 Homo sapiens Methylenetetrahydrofolate reductase Proteins 0.000 description 1
- 101000581289 Homo sapiens Microcephalin Proteins 0.000 description 1
- 101001011628 Homo sapiens Microphthalmia-associated transcription factor Proteins 0.000 description 1
- 101000891579 Homo sapiens Microtubule-associated protein tau Proteins 0.000 description 1
- 101000615613 Homo sapiens Mineralocorticoid receptor Proteins 0.000 description 1
- 101000697649 Homo sapiens Mitochondrial chaperone BCS1 Proteins 0.000 description 1
- 101000763951 Homo sapiens Mitochondrial import inner membrane translocase subunit Tim8 A Proteins 0.000 description 1
- 101000960626 Homo sapiens Mitochondrial inner membrane protease subunit 2 Proteins 0.000 description 1
- 101000577080 Homo sapiens Mitochondrial-processing peptidase subunit alpha Proteins 0.000 description 1
- 101000896657 Homo sapiens Mitotic checkpoint serine/threonine-protein kinase BUB1 Proteins 0.000 description 1
- 101000591936 Homo sapiens Molybdopterin synthase catalytic subunit Proteins 0.000 description 1
- 101000963255 Homo sapiens Molybdopterin synthase sulfur carrier subunit Proteins 0.000 description 1
- 101000987117 Homo sapiens Monocarboxylate transporter 8 Proteins 0.000 description 1
- 101000576323 Homo sapiens Motor neuron and pancreas homeobox protein 1 Proteins 0.000 description 1
- 101000972286 Homo sapiens Mucin-4 Proteins 0.000 description 1
- 101000972282 Homo sapiens Mucin-5AC Proteins 0.000 description 1
- 101001030211 Homo sapiens Myc proto-oncogene protein Proteins 0.000 description 1
- 101000982010 Homo sapiens Myelin proteolipid protein Proteins 0.000 description 1
- 101001115699 Homo sapiens Myelin-oligodendrocyte glycoprotein Proteins 0.000 description 1
- 101001090860 Homo sapiens Myeloblastin Proteins 0.000 description 1
- 101000585663 Homo sapiens Myocilin Proteins 0.000 description 1
- 101000635878 Homo sapiens Myosin light chain 3 Proteins 0.000 description 1
- 101000629029 Homo sapiens Myosin regulatory light chain 2, ventricular/cardiac muscle isoform Proteins 0.000 description 1
- 101000588964 Homo sapiens Myosin-14 Proteins 0.000 description 1
- 101000958741 Homo sapiens Myosin-6 Proteins 0.000 description 1
- 101000982032 Homo sapiens Myosin-binding protein C, cardiac-type Proteins 0.000 description 1
- 101001132874 Homo sapiens Myotubularin Proteins 0.000 description 1
- 101000966872 Homo sapiens Myotubularin-related protein 2 Proteins 0.000 description 1
- 101001066305 Homo sapiens N-acetylgalactosamine-6-sulfatase Proteins 0.000 description 1
- 101001072470 Homo sapiens N-acetylglucosamine-1-phosphotransferase subunits alpha/beta Proteins 0.000 description 1
- 101000829992 Homo sapiens N-acetylglucosamine-6-sulfatase Proteins 0.000 description 1
- 101000829958 Homo sapiens N-acetyllactosaminide beta-1,6-N-acetylglucosaminyl-transferase Proteins 0.000 description 1
- 101001090919 Homo sapiens N-acylglucosamine 2-epimerase Proteins 0.000 description 1
- 101000983292 Homo sapiens N-fatty-acyl-amino acid synthase/hydrolase PM20D1 Proteins 0.000 description 1
- 101000651201 Homo sapiens N-sulphoglucosamine sulphohydrolase Proteins 0.000 description 1
- 101001128138 Homo sapiens NACHT, LRR and PYD domains-containing protein 2 Proteins 0.000 description 1
- 101001109465 Homo sapiens NACHT, LRR and PYD domains-containing protein 3 Proteins 0.000 description 1
- 101000973778 Homo sapiens NAD(P)H dehydrogenase [quinone] 1 Proteins 0.000 description 1
- 101001111187 Homo sapiens NADH dehydrogenase [ubiquinone] flavoprotein 2, mitochondrial Proteins 0.000 description 1
- 101000601581 Homo sapiens NADH dehydrogenase [ubiquinone] iron-sulfur protein 4, mitochondrial Proteins 0.000 description 1
- 101000979227 Homo sapiens NADH dehydrogenase [ubiquinone] iron-sulfur protein 7, mitochondrial Proteins 0.000 description 1
- 101000636705 Homo sapiens NADH dehydrogenase [ubiquinone] iron-sulfur protein 8, mitochondrial Proteins 0.000 description 1
- 101000998623 Homo sapiens NADH-cytochrome b5 reductase 3 Proteins 0.000 description 1
- 101000604411 Homo sapiens NADH-ubiquinone oxidoreductase chain 1 Proteins 0.000 description 1
- 101000632748 Homo sapiens NADH-ubiquinone oxidoreductase chain 2 Proteins 0.000 description 1
- 101000598279 Homo sapiens NADH-ubiquinone oxidoreductase chain 5 Proteins 0.000 description 1
- 101000632623 Homo sapiens NADH-ubiquinone oxidoreductase chain 6 Proteins 0.000 description 1
- 101001124388 Homo sapiens NPC intracellular cholesterol transporter 1 Proteins 0.000 description 1
- 101001109579 Homo sapiens NPC intracellular cholesterol transporter 2 Proteins 0.000 description 1
- 101100241084 Homo sapiens NRTN gene Proteins 0.000 description 1
- 101001128156 Homo sapiens Nanos homolog 3 Proteins 0.000 description 1
- 101000780028 Homo sapiens Natriuretic peptides A Proteins 0.000 description 1
- 101000979306 Homo sapiens Nectin-1 Proteins 0.000 description 1
- 101000978730 Homo sapiens Nephrin Proteins 0.000 description 1
- 101000978743 Homo sapiens Nephrocystin-1 Proteins 0.000 description 1
- 101001051490 Homo sapiens Neural cell adhesion molecule L1 Proteins 0.000 description 1
- 101001128694 Homo sapiens Neuroendocrine convertase 1 Proteins 0.000 description 1
- 101001014610 Homo sapiens Neuroendocrine secretory protein 55 Proteins 0.000 description 1
- 101001111338 Homo sapiens Neurofilament heavy polypeptide Proteins 0.000 description 1
- 101000745167 Homo sapiens Neuronal acetylcholine receptor subunit alpha-4 Proteins 0.000 description 1
- 101000720704 Homo sapiens Neuronal migration protein doublecortin Proteins 0.000 description 1
- 101001112229 Homo sapiens Neutrophil cytosol factor 1 Proteins 0.000 description 1
- 101001112224 Homo sapiens Neutrophil cytosol factor 2 Proteins 0.000 description 1
- 101000981336 Homo sapiens Nibrin Proteins 0.000 description 1
- 101001124309 Homo sapiens Nitric oxide synthase, endothelial Proteins 0.000 description 1
- 101000979761 Homo sapiens Norrin Proteins 0.000 description 1
- 101000597425 Homo sapiens Nuclear RNA export factor 2 Proteins 0.000 description 1
- 101000598160 Homo sapiens Nuclear mitotic apparatus protein 1 Proteins 0.000 description 1
- 101001103036 Homo sapiens Nuclear receptor ROR-alpha Proteins 0.000 description 1
- 101000603323 Homo sapiens Nuclear receptor subfamily 0 group B member 1 Proteins 0.000 description 1
- 101000979629 Homo sapiens Nucleoside diphosphate kinase A Proteins 0.000 description 1
- 101000836873 Homo sapiens Nucleotide exchange factor SIL1 Proteins 0.000 description 1
- 101000812677 Homo sapiens Nucleotide pyrophosphatase Proteins 0.000 description 1
- 101000598921 Homo sapiens Orexin Proteins 0.000 description 1
- 101000807596 Homo sapiens Orotidine 5'-phosphate decarboxylase Proteins 0.000 description 1
- 101001086210 Homo sapiens Osteocalcin Proteins 0.000 description 1
- 101000613820 Homo sapiens Osteopontin Proteins 0.000 description 1
- 101001134169 Homo sapiens Otoferlin Proteins 0.000 description 1
- 101001021103 Homo sapiens Oxygen-dependent coproporphyrinogen-III oxidase, mitochondrial Proteins 0.000 description 1
- 101000720693 Homo sapiens Oxysterol-binding protein-related protein 1 Proteins 0.000 description 1
- 101001114051 Homo sapiens P antigen family member 5 Proteins 0.000 description 1
- 101001120086 Homo sapiens P2Y purinoceptor 12 Proteins 0.000 description 1
- 101000692980 Homo sapiens PHD finger protein 6 Proteins 0.000 description 1
- 101001074571 Homo sapiens PIN2/TERF1-interacting telomerase inhibitor 1 Proteins 0.000 description 1
- 101000738901 Homo sapiens PMS1 protein homolog 1 Proteins 0.000 description 1
- 101000572950 Homo sapiens POU domain, class 3, transcription factor 4 Proteins 0.000 description 1
- 101001094737 Homo sapiens POU domain, class 4, transcription factor 3 Proteins 0.000 description 1
- 101000613577 Homo sapiens Paired box protein Pax-2 Proteins 0.000 description 1
- 101000613490 Homo sapiens Paired box protein Pax-3 Proteins 0.000 description 1
- 101000601661 Homo sapiens Paired box protein Pax-7 Proteins 0.000 description 1
- 101000601664 Homo sapiens Paired box protein Pax-8 Proteins 0.000 description 1
- 101000735484 Homo sapiens Paired box protein Pax-9 Proteins 0.000 description 1
- 101001134456 Homo sapiens Pancreatic triacylglycerol lipase Proteins 0.000 description 1
- 101000981502 Homo sapiens Pantothenate kinase 2, mitochondrial Proteins 0.000 description 1
- 101000610206 Homo sapiens Pappalysin-1 Proteins 0.000 description 1
- 101000629361 Homo sapiens Paraplegin Proteins 0.000 description 1
- 101000589873 Homo sapiens Parathyroid hormone/parathyroid hormone-related peptide receptor Proteins 0.000 description 1
- 101000891031 Homo sapiens Peptidyl-prolyl cis-trans isomerase FKBP10 Proteins 0.000 description 1
- 101000987581 Homo sapiens Perforin-1 Proteins 0.000 description 1
- 101001095085 Homo sapiens Periaxin Proteins 0.000 description 1
- 101000619708 Homo sapiens Peroxiredoxin-6 Proteins 0.000 description 1
- 101000987700 Homo sapiens Peroxisomal biogenesis factor 3 Proteins 0.000 description 1
- 101001082860 Homo sapiens Peroxisomal membrane protein 2 Proteins 0.000 description 1
- 101000579352 Homo sapiens Peroxisomal membrane protein PEX13 Proteins 0.000 description 1
- 101000730779 Homo sapiens Peroxisome assembly factor 2 Proteins 0.000 description 1
- 101001126498 Homo sapiens Peroxisome biogenesis factor 10 Proteins 0.000 description 1
- 101000693847 Homo sapiens Peroxisome biogenesis factor 2 Proteins 0.000 description 1
- 101000741790 Homo sapiens Peroxisome proliferator-activated receptor gamma Proteins 0.000 description 1
- 101000873719 Homo sapiens Phakinin Proteins 0.000 description 1
- 101001038051 Homo sapiens Phlorizin hydrolase Proteins 0.000 description 1
- 101000955481 Homo sapiens Phosphatidylcholine translocator ABCB4 Proteins 0.000 description 1
- 101001130226 Homo sapiens Phosphatidylcholine-sterol acyltransferase Proteins 0.000 description 1
- 101000595513 Homo sapiens Phosphatidylinositol 4-phosphate 5-kinase type-1 beta Proteins 0.000 description 1
- 101000595489 Homo sapiens Phosphatidylinositol N-acetylglucosaminyltransferase subunit A Proteins 0.000 description 1
- 101000734579 Homo sapiens Phosphoenolpyruvate carboxykinase [GTP], mitochondrial Proteins 0.000 description 1
- 101000734572 Homo sapiens Phosphoenolpyruvate carboxykinase, cytosolic [GTP] Proteins 0.000 description 1
- 101000579123 Homo sapiens Phosphoglycerate kinase 1 Proteins 0.000 description 1
- 101000600392 Homo sapiens Phosphoglycerate mutase 2 Proteins 0.000 description 1
- 101000983161 Homo sapiens Phospholipase A2, membrane associated Proteins 0.000 description 1
- 101000701363 Homo sapiens Phospholipid-transporting ATPase IC Proteins 0.000 description 1
- 101001094831 Homo sapiens Phosphomannomutase 2 Proteins 0.000 description 1
- 101000731078 Homo sapiens Phosphorylase b kinase gamma catalytic chain, liver/testis isoform Proteins 0.000 description 1
- 101000945272 Homo sapiens Phosphorylase b kinase regulatory subunit alpha, liver isoform Proteins 0.000 description 1
- 101000945267 Homo sapiens Phosphorylase b kinase regulatory subunit alpha, skeletal muscle isoform Proteins 0.000 description 1
- 101001137939 Homo sapiens Phosphorylase b kinase regulatory subunit beta Proteins 0.000 description 1
- 101000633511 Homo sapiens Photoreceptor-specific nuclear receptor Proteins 0.000 description 1
- 101000595669 Homo sapiens Pituitary homeobox 2 Proteins 0.000 description 1
- 101001125939 Homo sapiens Plakophilin-1 Proteins 0.000 description 1
- 101000728115 Homo sapiens Plasma membrane calcium-transporting ATPase 3 Proteins 0.000 description 1
- 101001081555 Homo sapiens Plasma protease C1 inhibitor Proteins 0.000 description 1
- 101000605403 Homo sapiens Plasminogen Proteins 0.000 description 1
- 101000947178 Homo sapiens Platelet basic protein Proteins 0.000 description 1
- 101001116302 Homo sapiens Platelet endothelial cell adhesion molecule Proteins 0.000 description 1
- 101001071312 Homo sapiens Platelet glycoprotein IX Proteins 0.000 description 1
- 101001070790 Homo sapiens Platelet glycoprotein Ib alpha chain Proteins 0.000 description 1
- 101001070786 Homo sapiens Platelet glycoprotein Ib beta chain Proteins 0.000 description 1
- 101001097889 Homo sapiens Platelet-activating factor acetylhydrolase Proteins 0.000 description 1
- 101000692455 Homo sapiens Platelet-derived growth factor receptor beta Proteins 0.000 description 1
- 101000692464 Homo sapiens Platelet-derived growth factor receptor-like protein Proteins 0.000 description 1
- 101001126471 Homo sapiens Plectin Proteins 0.000 description 1
- 101000609211 Homo sapiens Polyadenylate-binding protein 2 Proteins 0.000 description 1
- 101001074439 Homo sapiens Polycystin-2 Proteins 0.000 description 1
- 101000611427 Homo sapiens Polyglutamine-binding protein 1 Proteins 0.000 description 1
- 101001067140 Homo sapiens Porphobilinogen deaminase Proteins 0.000 description 1
- 101000974720 Homo sapiens Potassium voltage-gated channel subfamily E member 2 Proteins 0.000 description 1
- 101001047090 Homo sapiens Potassium voltage-gated channel subfamily H member 2 Proteins 0.000 description 1
- 101000994648 Homo sapiens Potassium voltage-gated channel subfamily KQT member 4 Proteins 0.000 description 1
- 101000610107 Homo sapiens Pre-B-cell leukemia transcription factor 1 Proteins 0.000 description 1
- 101000617708 Homo sapiens Pregnancy-specific beta-1-glycoprotein 1 Proteins 0.000 description 1
- 101000617536 Homo sapiens Presenilin-1 Proteins 0.000 description 1
- 101000617546 Homo sapiens Presenilin-2 Proteins 0.000 description 1
- 101001000545 Homo sapiens Probable hydrolase PNKD Proteins 0.000 description 1
- 101000808590 Homo sapiens Probable ubiquitin carboxyl-terminal hydrolase FAF-Y Proteins 0.000 description 1
- 101000983583 Homo sapiens Procathepsin L Proteins 0.000 description 1
- 101000595904 Homo sapiens Procollagen-lysine,2-oxoglutarate 5-dioxygenase 1 Proteins 0.000 description 1
- 101000611936 Homo sapiens Programmed cell death protein 1 Proteins 0.000 description 1
- 101000945496 Homo sapiens Proliferation marker protein Ki-67 Proteins 0.000 description 1
- 101000611614 Homo sapiens Proline-rich protein PRCC Proteins 0.000 description 1
- 101000610551 Homo sapiens Prominin-1 Proteins 0.000 description 1
- 101001098989 Homo sapiens Propionyl-CoA carboxylase alpha chain, mitochondrial Proteins 0.000 description 1
- 101001098982 Homo sapiens Propionyl-CoA carboxylase beta chain, mitochondrial Proteins 0.000 description 1
- 101001091094 Homo sapiens Prorelaxin H1 Proteins 0.000 description 1
- 101001091088 Homo sapiens Prorelaxin H2 Proteins 0.000 description 1
- 101000605122 Homo sapiens Prostaglandin G/H synthase 1 Proteins 0.000 description 1
- 101000920629 Homo sapiens Protein 4.1 Proteins 0.000 description 1
- 101000920625 Homo sapiens Protein 4.2 Proteins 0.000 description 1
- 101000959489 Homo sapiens Protein AF-9 Proteins 0.000 description 1
- 101000797903 Homo sapiens Protein ALEX Proteins 0.000 description 1
- 101000797623 Homo sapiens Protein AMBP Proteins 0.000 description 1
- 101000710213 Homo sapiens Protein CLN8 Proteins 0.000 description 1
- 101000925651 Homo sapiens Protein ENL Proteins 0.000 description 1
- 101000969776 Homo sapiens Protein Mpv17 Proteins 0.000 description 1
- 101000821884 Homo sapiens Protein S100-G Proteins 0.000 description 1
- 101000874364 Homo sapiens Protein SCO2 homolog, mitochondrial Proteins 0.000 description 1
- 101000880769 Homo sapiens Protein SSX1 Proteins 0.000 description 1
- 101000880774 Homo sapiens Protein SSX4 Proteins 0.000 description 1
- 101000642815 Homo sapiens Protein SSXT Proteins 0.000 description 1
- 101000781361 Homo sapiens Protein XRP2 Proteins 0.000 description 1
- 101000726148 Homo sapiens Protein crumbs homolog 1 Proteins 0.000 description 1
- 101000928791 Homo sapiens Protein diaphanous homolog 1 Proteins 0.000 description 1
- 101000928408 Homo sapiens Protein diaphanous homolog 2 Proteins 0.000 description 1
- 101001072202 Homo sapiens Protein disulfide-isomerase Proteins 0.000 description 1
- 101000994437 Homo sapiens Protein jagged-1 Proteins 0.000 description 1
- 101001051777 Homo sapiens Protein kinase C alpha type Proteins 0.000 description 1
- 101000695187 Homo sapiens Protein patched homolog 1 Proteins 0.000 description 1
- 101000685914 Homo sapiens Protein transport protein Sec23B Proteins 0.000 description 1
- 101001123332 Homo sapiens Proteoglycan 4 Proteins 0.000 description 1
- 101000615238 Homo sapiens Proto-oncogene DBL Proteins 0.000 description 1
- 101000579425 Homo sapiens Proto-oncogene tyrosine-protein kinase receptor Ret Proteins 0.000 description 1
- 101000919980 Homo sapiens Protoheme IX farnesyltransferase, mitochondrial Proteins 0.000 description 1
- 101001123245 Homo sapiens Protoporphyrinogen oxidase Proteins 0.000 description 1
- 101000655540 Homo sapiens Protransforming growth factor alpha Proteins 0.000 description 1
- 101001125901 Homo sapiens Pterin-4-alpha-carbinolamine dehydratase Proteins 0.000 description 1
- 101000864780 Homo sapiens Pulmonary surfactant-associated protein A1 Proteins 0.000 description 1
- 101001086862 Homo sapiens Pulmonary surfactant-associated protein B Proteins 0.000 description 1
- 101000612671 Homo sapiens Pulmonary surfactant-associated protein C Proteins 0.000 description 1
- 101000632467 Homo sapiens Pulmonary surfactant-associated protein D Proteins 0.000 description 1
- 101001082131 Homo sapiens Pumilio homolog 3 Proteins 0.000 description 1
- 101000730612 Homo sapiens Puratrophin-1 Proteins 0.000 description 1
- 101000737669 Homo sapiens Putative cat eye syndrome critical region protein 9 Proteins 0.000 description 1
- 101000584293 Homo sapiens Putative myc-like protein MYCLP1 Proteins 0.000 description 1
- 101000701517 Homo sapiens Putative protein ATXN8OS Proteins 0.000 description 1
- 101000873438 Homo sapiens Putative protein SEM1, isoform 2 Proteins 0.000 description 1
- 101000912352 Homo sapiens Putative uncharacterized protein DANCR Proteins 0.000 description 1
- 101001091536 Homo sapiens Pyruvate kinase PKLR Proteins 0.000 description 1
- 101000725943 Homo sapiens RNA polymerase II subunit A C-terminal domain phosphatase Proteins 0.000 description 1
- 101000668165 Homo sapiens RNA-binding motif, single-stranded-interacting protein 1 Proteins 0.000 description 1
- 101000743264 Homo sapiens RNA-binding protein 6 Proteins 0.000 description 1
- 101001092166 Homo sapiens RPE-retinal G protein-coupled receptor Proteins 0.000 description 1
- 101000620777 Homo sapiens Rab proteins geranylgeranyltransferase component A 1 Proteins 0.000 description 1
- 101000620788 Homo sapiens Rab proteins geranylgeranyltransferase component A 2 Proteins 0.000 description 1
- 101001130509 Homo sapiens Ras GTPase-activating protein 1 Proteins 0.000 description 1
- 101000686227 Homo sapiens Ras-related protein R-Ras2 Proteins 0.000 description 1
- 101000584785 Homo sapiens Ras-related protein Rab-7a Proteins 0.000 description 1
- 101001062222 Homo sapiens Receptor-binding cancer antigen expressed on SiSo cells Proteins 0.000 description 1
- 101000710137 Homo sapiens Recoverin Proteins 0.000 description 1
- 101001075466 Homo sapiens Regulatory factor X-associated protein Proteins 0.000 description 1
- 101000899806 Homo sapiens Retinal guanylyl cyclase 1 Proteins 0.000 description 1
- 101000801643 Homo sapiens Retinal-specific phospholipid-transporting ATPase ABCA4 Proteins 0.000 description 1
- 101001078886 Homo sapiens Retinaldehyde-binding protein 1 Proteins 0.000 description 1
- 101001104199 Homo sapiens Retinitis pigmentosa 9 protein Proteins 0.000 description 1
- 101000742859 Homo sapiens Retinoblastoma-associated protein Proteins 0.000 description 1
- 101001112293 Homo sapiens Retinoic acid receptor alpha Proteins 0.000 description 1
- 101001099922 Homo sapiens Retinoic acid-induced protein 1 Proteins 0.000 description 1
- 101000729271 Homo sapiens Retinoid isomerohydrolase Proteins 0.000 description 1
- 101000742950 Homo sapiens Retinol dehydrogenase 5 Proteins 0.000 description 1
- 101000927796 Homo sapiens Rho guanine nucleotide exchange factor 7 Proteins 0.000 description 1
- 101000611338 Homo sapiens Rhodopsin Proteins 0.000 description 1
- 101001125547 Homo sapiens Ribose-phosphate pyrophosphokinase 2 Proteins 0.000 description 1
- 101000945090 Homo sapiens Ribosomal protein S6 kinase alpha-3 Proteins 0.000 description 1
- 101000609947 Homo sapiens Rod cGMP-specific 3',5'-cyclic phosphodiesterase subunit alpha Proteins 0.000 description 1
- 101000609949 Homo sapiens Rod cGMP-specific 3',5'-cyclic phosphodiesterase subunit beta Proteins 0.000 description 1
- 101001106432 Homo sapiens Rod outer segment membrane protein 1 Proteins 0.000 description 1
- 101000857677 Homo sapiens Runt-related transcription factor 1 Proteins 0.000 description 1
- 101100095198 Homo sapiens SCARB2 gene Proteins 0.000 description 1
- 101000761644 Homo sapiens SH3 domain-binding protein 2 Proteins 0.000 description 1
- 101100477520 Homo sapiens SHOX gene Proteins 0.000 description 1
- 101000633786 Homo sapiens SLAM family member 6 Proteins 0.000 description 1
- 101000652133 Homo sapiens STE20-like serine/threonine-protein kinase Proteins 0.000 description 1
- 101000724404 Homo sapiens Saccharopine dehydrogenase Proteins 0.000 description 1
- 101000740205 Homo sapiens Sal-like protein 1 Proteins 0.000 description 1
- 101000936731 Homo sapiens Sarcoplasmic/endoplasmic reticulum calcium ATPase 1 Proteins 0.000 description 1
- 101000936922 Homo sapiens Sarcoplasmic/endoplasmic reticulum calcium ATPase 2 Proteins 0.000 description 1
- 101000740659 Homo sapiens Scavenger receptor class B member 1 Proteins 0.000 description 1
- 101000739195 Homo sapiens Secretoglobin family 1D member 2 Proteins 0.000 description 1
- 101000898985 Homo sapiens Seipin Proteins 0.000 description 1
- 101000823955 Homo sapiens Serine palmitoyltransferase 1 Proteins 0.000 description 1
- 101000610626 Homo sapiens Serine protease 33 Proteins 0.000 description 1
- 101000872580 Homo sapiens Serine protease hepsin Proteins 0.000 description 1
- 101000629622 Homo sapiens Serine-pyruvate aminotransferase Proteins 0.000 description 1
- 101000771237 Homo sapiens Serine/threonine-protein kinase A-Raf Proteins 0.000 description 1
- 101000984753 Homo sapiens Serine/threonine-protein kinase B-raf Proteins 0.000 description 1
- 101000777277 Homo sapiens Serine/threonine-protein kinase Chk2 Proteins 0.000 description 1
- 101001026882 Homo sapiens Serine/threonine-protein kinase D2 Proteins 0.000 description 1
- 101000601460 Homo sapiens Serine/threonine-protein kinase Nek4 Proteins 0.000 description 1
- 101000987315 Homo sapiens Serine/threonine-protein kinase PAK 3 Proteins 0.000 description 1
- 101000742986 Homo sapiens Serine/threonine-protein kinase WNK4 Proteins 0.000 description 1
- 101001036145 Homo sapiens Serine/threonine-protein kinase greatwall Proteins 0.000 description 1
- 101000799194 Homo sapiens Serine/threonine-protein kinase receptor R3 Proteins 0.000 description 1
- 101000915806 Homo sapiens Serine/threonine-protein phosphatase 2A 55 kDa regulatory subunit B beta isoform Proteins 0.000 description 1
- 101000869480 Homo sapiens Serum amyloid A-1 protein Proteins 0.000 description 1
- 101001094647 Homo sapiens Serum paraoxonase/arylesterase 1 Proteins 0.000 description 1
- 101000621061 Homo sapiens Serum paraoxonase/arylesterase 2 Proteins 0.000 description 1
- 101000826130 Homo sapiens Sex-determining region Y protein Proteins 0.000 description 1
- 101000760716 Homo sapiens Short-chain specific acyl-CoA dehydrogenase, mitochondrial Proteins 0.000 description 1
- 101001120990 Homo sapiens Short-wave-sensitive opsin 1 Proteins 0.000 description 1
- 101001123859 Homo sapiens Sialidase-1 Proteins 0.000 description 1
- 101000685690 Homo sapiens Sialin Proteins 0.000 description 1
- 101000703681 Homo sapiens Single-minded homolog 1 Proteins 0.000 description 1
- 101000864098 Homo sapiens Small muscular protein Proteins 0.000 description 1
- 101000657580 Homo sapiens Small nuclear ribonucleoprotein-associated protein N Proteins 0.000 description 1
- 101000631760 Homo sapiens Sodium channel protein type 1 subunit alpha Proteins 0.000 description 1
- 101000693993 Homo sapiens Sodium channel protein type 4 subunit alpha Proteins 0.000 description 1
- 101000694017 Homo sapiens Sodium channel protein type 5 subunit alpha Proteins 0.000 description 1
- 101000684813 Homo sapiens Sodium channel subunit beta-1 Proteins 0.000 description 1
- 101000713305 Homo sapiens Sodium-coupled neutral amino acid transporter 1 Proteins 0.000 description 1
- 101000631929 Homo sapiens Sodium-dependent serotonin transporter Proteins 0.000 description 1
- 101000685678 Homo sapiens Solute carrier family 22 member 18 Proteins 0.000 description 1
- 101000829127 Homo sapiens Somatostatin receptor type 2 Proteins 0.000 description 1
- 101000868152 Homo sapiens Son of sevenless homolog 1 Proteins 0.000 description 1
- 101000664527 Homo sapiens Spastin Proteins 0.000 description 1
- 101000881267 Homo sapiens Spectrin alpha chain, erythrocytic 1 Proteins 0.000 description 1
- 101000881247 Homo sapiens Spectrin beta chain, erythrocytic Proteins 0.000 description 1
- 101000825248 Homo sapiens Sperm protein associated with the nucleus on the X chromosome C Proteins 0.000 description 1
- 101000652359 Homo sapiens Spermatogenesis-associated protein 2 Proteins 0.000 description 1
- 101000881206 Homo sapiens Spermine synthase Proteins 0.000 description 1
- 101000785978 Homo sapiens Sphingomyelin phosphodiesterase Proteins 0.000 description 1
- 101000873927 Homo sapiens Squamous cell carcinoma antigen recognized by T-cells 3 Proteins 0.000 description 1
- 101000697578 Homo sapiens Statherin Proteins 0.000 description 1
- 101000896517 Homo sapiens Steroid 17-alpha-hydroxylase/17,20 lyase Proteins 0.000 description 1
- 101000875401 Homo sapiens Sterol 26-hydroxylase, mitochondrial Proteins 0.000 description 1
- 101000617830 Homo sapiens Sterol O-acyltransferase 1 Proteins 0.000 description 1
- 101000820460 Homo sapiens Stomatin Proteins 0.000 description 1
- 101000617130 Homo sapiens Stromal cell-derived factor 1 Proteins 0.000 description 1
- 101000951145 Homo sapiens Succinate dehydrogenase [ubiquinone] cytochrome b small subunit, mitochondrial Proteins 0.000 description 1
- 101000685323 Homo sapiens Succinate dehydrogenase [ubiquinone] flavoprotein subunit, mitochondrial Proteins 0.000 description 1
- 101000654245 Homo sapiens Succinate dehydrogenase assembly factor 2, mitochondrial Proteins 0.000 description 1
- 101000829168 Homo sapiens Succinate-semialdehyde dehydrogenase, mitochondrial Proteins 0.000 description 1
- 101000716763 Homo sapiens Succinyl-CoA:3-ketoacid coenzyme A transferase 1, mitochondrial Proteins 0.000 description 1
- 101000643865 Homo sapiens Sulfite oxidase, mitochondrial Proteins 0.000 description 1
- 101000880098 Homo sapiens Sushi repeat-containing protein SRPX Proteins 0.000 description 1
- 101000821100 Homo sapiens Synapsin-1 Proteins 0.000 description 1
- 101000828537 Homo sapiens Synaptic functional regulator FMR1 Proteins 0.000 description 1
- 101000695522 Homo sapiens Synaptophysin Proteins 0.000 description 1
- 101000714470 Homo sapiens Synaptotagmin-1 Proteins 0.000 description 1
- 101000666775 Homo sapiens T-box transcription factor TBX3 Proteins 0.000 description 1
- 101000800488 Homo sapiens T-cell leukemia homeobox protein 1 Proteins 0.000 description 1
- 101000980827 Homo sapiens T-cell surface glycoprotein CD1a Proteins 0.000 description 1
- 101000716149 Homo sapiens T-cell surface glycoprotein CD1b Proteins 0.000 description 1
- 101000716124 Homo sapiens T-cell surface glycoprotein CD1c Proteins 0.000 description 1
- 101000946860 Homo sapiens T-cell surface glycoprotein CD3 epsilon chain Proteins 0.000 description 1
- 101000738413 Homo sapiens T-cell surface glycoprotein CD3 gamma chain Proteins 0.000 description 1
- 101000738335 Homo sapiens T-cell surface glycoprotein CD3 zeta chain Proteins 0.000 description 1
- 101000914514 Homo sapiens T-cell-specific surface glycoprotein CD28 Proteins 0.000 description 1
- 101000712674 Homo sapiens TGF-beta receptor type-1 Proteins 0.000 description 1
- 101000595548 Homo sapiens TIR domain-containing adapter molecule 1 Proteins 0.000 description 1
- 101000595554 Homo sapiens TIR domain-containing adapter molecule 2 Proteins 0.000 description 1
- 101100207070 Homo sapiens TNFSF8 gene Proteins 0.000 description 1
- 101000597193 Homo sapiens Telethonin Proteins 0.000 description 1
- 101000626155 Homo sapiens Tensin-4 Proteins 0.000 description 1
- 101000596845 Homo sapiens Testis-expressed protein 15 Proteins 0.000 description 1
- 101000612838 Homo sapiens Tetraspanin-7 Proteins 0.000 description 1
- 101000799388 Homo sapiens Thiopurine S-methyltransferase Proteins 0.000 description 1
- 101000802084 Homo sapiens Thiosulfate sulfurtransferase Proteins 0.000 description 1
- 101000830956 Homo sapiens Three-prime repair exonuclease 1 Proteins 0.000 description 1
- 101000763314 Homo sapiens Thrombomodulin Proteins 0.000 description 1
- 101000799461 Homo sapiens Thrombopoietin Proteins 0.000 description 1
- 101000715050 Homo sapiens Thromboxane A2 receptor Proteins 0.000 description 1
- 101000837626 Homo sapiens Thyroid hormone receptor alpha Proteins 0.000 description 1
- 101000712600 Homo sapiens Thyroid hormone receptor beta Proteins 0.000 description 1
- 101000772267 Homo sapiens Thyrotropin receptor Proteins 0.000 description 1
- 101000633601 Homo sapiens Thyrotropin subunit beta Proteins 0.000 description 1
- 101000893741 Homo sapiens Tissue alpha-L-fucosidase Proteins 0.000 description 1
- 101000801481 Homo sapiens Tissue-type plasminogen activator Proteins 0.000 description 1
- 101000662686 Homo sapiens Torsin-1A Proteins 0.000 description 1
- 101000819111 Homo sapiens Trans-acting T-cell-specific transcription factor GATA-3 Proteins 0.000 description 1
- 101000891321 Homo sapiens Transcobalamin-2 Proteins 0.000 description 1
- 101000891649 Homo sapiens Transcription elongation factor A protein-like 1 Proteins 0.000 description 1
- 101000837845 Homo sapiens Transcription factor E3 Proteins 0.000 description 1
- 101001121409 Homo sapiens Transcription factor Ovo-like 2 Proteins 0.000 description 1
- 101000664703 Homo sapiens Transcription factor SOX-10 Proteins 0.000 description 1
- 101000711846 Homo sapiens Transcription factor SOX-9 Proteins 0.000 description 1
- 101000596093 Homo sapiens Transcription initiation factor TFIID subunit 1 Proteins 0.000 description 1
- 101000674717 Homo sapiens Transcription initiation factor TFIID subunit 7-like Proteins 0.000 description 1
- 101000636213 Homo sapiens Transcriptional activator Myb Proteins 0.000 description 1
- 101000635938 Homo sapiens Transforming growth factor beta-1 proprotein Proteins 0.000 description 1
- 101000712663 Homo sapiens Transforming growth factor beta-3 proprotein Proteins 0.000 description 1
- 101000894525 Homo sapiens Transforming growth factor-beta-induced protein ig-h3 Proteins 0.000 description 1
- 101000800463 Homo sapiens Transketolase Proteins 0.000 description 1
- 101000658574 Homo sapiens Transmembrane 4 L6 family member 1 Proteins 0.000 description 1
- 101000801040 Homo sapiens Transmembrane channel-like protein 1 Proteins 0.000 description 1
- 101000892344 Homo sapiens Transmembrane protein 185A Proteins 0.000 description 1
- 101000772194 Homo sapiens Transthyretin Proteins 0.000 description 1
- 101000891326 Homo sapiens Treacle protein Proteins 0.000 description 1
- 101000795130 Homo sapiens Trehalase Proteins 0.000 description 1
- 101000801701 Homo sapiens Tropomyosin alpha-1 chain Proteins 0.000 description 1
- 101000851334 Homo sapiens Troponin I, cardiac muscle Proteins 0.000 description 1
- 101000713585 Homo sapiens Tubulin beta-4A chain Proteins 0.000 description 1
- 101000800287 Homo sapiens Tubulointerstitial nephritis antigen-like Proteins 0.000 description 1
- 101000889756 Homo sapiens Tudor domain-containing protein 1 Proteins 0.000 description 1
- 101000611183 Homo sapiens Tumor necrosis factor Proteins 0.000 description 1
- 101000638161 Homo sapiens Tumor necrosis factor ligand superfamily member 6 Proteins 0.000 description 1
- 101000798130 Homo sapiens Tumor necrosis factor receptor superfamily member 11B Proteins 0.000 description 1
- 101000801228 Homo sapiens Tumor necrosis factor receptor superfamily member 1A Proteins 0.000 description 1
- 101000920026 Homo sapiens Tumor necrosis factor receptor superfamily member EDAR Proteins 0.000 description 1
- 101000850748 Homo sapiens Tumor necrosis factor receptor type 1-associated DEATH domain protein Proteins 0.000 description 1
- 101000613251 Homo sapiens Tumor susceptibility gene 101 protein Proteins 0.000 description 1
- 101000693985 Homo sapiens Twinkle mtDNA helicase Proteins 0.000 description 1
- 101000773184 Homo sapiens Twist-related protein 1 Proteins 0.000 description 1
- 101001053773 Homo sapiens Type I iodothyronine deiodinase Proteins 0.000 description 1
- 101000690425 Homo sapiens Type-1 angiotensin II receptor Proteins 0.000 description 1
- 101000606090 Homo sapiens Tyrosinase Proteins 0.000 description 1
- 101000934996 Homo sapiens Tyrosine-protein kinase JAK3 Proteins 0.000 description 1
- 101000818543 Homo sapiens Tyrosine-protein kinase ZAP-70 Proteins 0.000 description 1
- 101001103033 Homo sapiens Tyrosine-protein kinase transmembrane receptor ROR2 Proteins 0.000 description 1
- 101000610557 Homo sapiens U4/U6 small nuclear ribonucleoprotein Prp31 Proteins 0.000 description 1
- 101000836268 Homo sapiens U4/U6.U5 tri-snRNP-associated protein 1 Proteins 0.000 description 1
- 101000819146 Homo sapiens UDP-glucose 4-epimerase Proteins 0.000 description 1
- 101000841498 Homo sapiens UDP-glucuronosyltransferase 1A1 Proteins 0.000 description 1
- 101000608653 Homo sapiens UbiA prenyltransferase domain-containing protein 1 Proteins 0.000 description 1
- 101000831708 Homo sapiens Ubiquitin carboxyl-terminal hydrolase CYLD Proteins 0.000 description 1
- 101000807344 Homo sapiens Ubiquitin-conjugating enzyme E2 A Proteins 0.000 description 1
- 101000807306 Homo sapiens Ubiquitin-like modifier-activating enzyme 1 Proteins 0.000 description 1
- 101000911513 Homo sapiens Uncharacterized protein FAM215A Proteins 0.000 description 1
- 101001000116 Homo sapiens Unconventional myosin-Ig Proteins 0.000 description 1
- 101000583031 Homo sapiens Unconventional myosin-Va Proteins 0.000 description 1
- 101000585635 Homo sapiens Unconventional myosin-XV Proteins 0.000 description 1
- 101000808114 Homo sapiens Uroplakin-1b Proteins 0.000 description 1
- 101000910482 Homo sapiens Uroporphyrinogen decarboxylase Proteins 0.000 description 1
- 101000805941 Homo sapiens Usherin Proteins 0.000 description 1
- 101001061851 Homo sapiens V(D)J recombination-activating protein 2 Proteins 0.000 description 1
- 101000670953 Homo sapiens V-type proton ATPase subunit B, kidney isoform Proteins 0.000 description 1
- 101000803527 Homo sapiens Vacuolar ATPase assembly integral membrane protein VMA21 Proteins 0.000 description 1
- 101000667092 Homo sapiens Vacuolar protein sorting-associated protein 13A Proteins 0.000 description 1
- 101000667110 Homo sapiens Vacuolar protein sorting-associated protein 13B Proteins 0.000 description 1
- 101000807859 Homo sapiens Vasopressin V2 receptor Proteins 0.000 description 1
- 101000760747 Homo sapiens Very long-chain specific acyl-CoA dehydrogenase, mitochondrial Proteins 0.000 description 1
- 101000854936 Homo sapiens Visual system homeobox 1 Proteins 0.000 description 1
- 101000854931 Homo sapiens Visual system homeobox 2 Proteins 0.000 description 1
- 101000742236 Homo sapiens Vitamin K-dependent gamma-carboxylase Proteins 0.000 description 1
- 101001125402 Homo sapiens Vitamin K-dependent protein C Proteins 0.000 description 1
- 101000983956 Homo sapiens Voltage-dependent L-type calcium channel subunit beta-2 Proteins 0.000 description 1
- 101000983947 Homo sapiens Voltage-dependent L-type calcium channel subunit beta-4 Proteins 0.000 description 1
- 101000935117 Homo sapiens Voltage-dependent P/Q-type calcium channel subunit alpha-1A Proteins 0.000 description 1
- 101000740755 Homo sapiens Voltage-dependent calcium channel subunit alpha-2/delta-1 Proteins 0.000 description 1
- 101000771618 Homo sapiens WD repeat-containing protein 62 Proteins 0.000 description 1
- 101000804798 Homo sapiens Werner syndrome ATP-dependent helicase Proteins 0.000 description 1
- 101000621427 Homo sapiens Wiskott-Aldrich syndrome protein Proteins 0.000 description 1
- 101001104110 Homo sapiens X-linked retinitis pigmentosa GTPase regulator-interacting protein 1 Proteins 0.000 description 1
- 101000606589 Homo sapiens Xaa-Pro dipeptidase Proteins 0.000 description 1
- 101000788669 Homo sapiens Zinc finger MYM-type protein 2 Proteins 0.000 description 1
- 101000788739 Homo sapiens Zinc finger MYM-type protein 3 Proteins 0.000 description 1
- 101000759185 Homo sapiens Zinc finger X-chromosomal protein Proteins 0.000 description 1
- 101000964566 Homo sapiens Zinc finger Y-chromosomal protein Proteins 0.000 description 1
- 101000760175 Homo sapiens Zinc finger protein 35 Proteins 0.000 description 1
- 101000760181 Homo sapiens Zinc finger protein 41 Proteins 0.000 description 1
- 101000964741 Homo sapiens Zinc finger protein 711 Proteins 0.000 description 1
- 101000976643 Homo sapiens Zinc finger protein ZIC 2 Proteins 0.000 description 1
- 101000976645 Homo sapiens Zinc finger protein ZIC 3 Proteins 0.000 description 1
- 101000685830 Homo sapiens Zinc transporter ZIP4 Proteins 0.000 description 1
- 101001026573 Homo sapiens cAMP-dependent protein kinase type I-alpha regulatory subunit Proteins 0.000 description 1
- 101000883219 Homo sapiens cGMP-gated cation channel alpha-1 Proteins 0.000 description 1
- 102100034782 Homogentisate 1,2-dioxygenase Human genes 0.000 description 1
- 101150051916 Hsd3b3 gene Proteins 0.000 description 1
- 102100031450 Humanin Human genes 0.000 description 1
- 102100039283 Hyaluronidase-1 Human genes 0.000 description 1
- 108010052919 Hydroxyethylthiazole kinase Proteins 0.000 description 1
- 102100024004 Hydroxymethylglutaryl-CoA lyase, mitochondrial Human genes 0.000 description 1
- 108010027436 Hydroxymethylpyrimidine kinase Proteins 0.000 description 1
- 102000026633 IL6 Human genes 0.000 description 1
- 102100025141 IQ motif and SEC7 domain-containing protein 2 Human genes 0.000 description 1
- 102100029199 Iduronate 2-sulfatase Human genes 0.000 description 1
- 102100021711 Ileal sodium/bile acid cotransporter Human genes 0.000 description 1
- 102100039346 Immunoglobulin heavy constant gamma 2 Human genes 0.000 description 1
- 102100029572 Immunoglobulin kappa constant Human genes 0.000 description 1
- 102100024022 Inactive heparanase-2 Human genes 0.000 description 1
- 102100027537 Inactive rhomboid protein 2 Human genes 0.000 description 1
- 102100026214 Indian hedgehog protein Human genes 0.000 description 1
- 101710139099 Indian hedgehog protein Proteins 0.000 description 1
- 208000027646 Infantile-onset X-linked spinal muscular atrophy Diseases 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 102100021602 Inosine-5'-monophosphate dehydrogenase 1 Human genes 0.000 description 1
- 102100036721 Insulin receptor Human genes 0.000 description 1
- 102100037852 Insulin-like growth factor I Human genes 0.000 description 1
- 102100023350 Integral membrane protein 2B Human genes 0.000 description 1
- 102100025305 Integrin alpha-2 Human genes 0.000 description 1
- 102100032816 Integrin alpha-6 Human genes 0.000 description 1
- 102100032832 Integrin alpha-7 Human genes 0.000 description 1
- 102100025306 Integrin alpha-IIb Human genes 0.000 description 1
- 108010030506 Integrin alpha6beta4 Proteins 0.000 description 1
- 102100025390 Integrin beta-2 Human genes 0.000 description 1
- 102100032999 Integrin beta-3 Human genes 0.000 description 1
- 102100033000 Integrin beta-4 Human genes 0.000 description 1
- 108010064600 Intercellular Adhesion Molecule-3 Proteins 0.000 description 1
- 102100037877 Intercellular adhesion molecule 1 Human genes 0.000 description 1
- 102100037871 Intercellular adhesion molecule 3 Human genes 0.000 description 1
- 108010014726 Interferon Type I Proteins 0.000 description 1
- 102000002227 Interferon Type I Human genes 0.000 description 1
- 102100040019 Interferon alpha-1/13 Human genes 0.000 description 1
- 102100035678 Interferon gamma receptor 1 Human genes 0.000 description 1
- 102100034170 Interferon-induced, double-stranded RNA-activated protein kinase Human genes 0.000 description 1
- 101710089751 Interferon-induced, double-stranded RNA-activated protein kinase Proteins 0.000 description 1
- 102000000589 Interleukin-1 Human genes 0.000 description 1
- 108010002352 Interleukin-1 Proteins 0.000 description 1
- 102000003777 Interleukin-1 beta Human genes 0.000 description 1
- 108090000193 Interleukin-1 beta Proteins 0.000 description 1
- 102100034413 Interleukin-1 receptor accessory protein-like 1 Human genes 0.000 description 1
- 102100036433 Interleukin-1 receptor-associated kinase-like 2 Human genes 0.000 description 1
- 102000003814 Interleukin-10 Human genes 0.000 description 1
- 108090000174 Interleukin-10 Proteins 0.000 description 1
- 102100039068 Interleukin-10 Human genes 0.000 description 1
- 102100020790 Interleukin-12 receptor subunit beta-1 Human genes 0.000 description 1
- 102100026011 Interleukin-13 Human genes 0.000 description 1
- 102100020793 Interleukin-13 receptor subunit alpha-2 Human genes 0.000 description 1
- 101710112634 Interleukin-13 receptor subunit alpha-2 Proteins 0.000 description 1
- 101800003050 Interleukin-16 Proteins 0.000 description 1
- 102000049772 Interleukin-16 Human genes 0.000 description 1
- 102000003810 Interleukin-18 Human genes 0.000 description 1
- 108090000171 Interleukin-18 Proteins 0.000 description 1
- 102100030703 Interleukin-22 Human genes 0.000 description 1
- 102100036671 Interleukin-24 Human genes 0.000 description 1
- 102100039064 Interleukin-3 Human genes 0.000 description 1
- 108010002386 Interleukin-3 Proteins 0.000 description 1
- 102000000646 Interleukin-3 Human genes 0.000 description 1
- 102100033493 Interleukin-3 receptor subunit alpha Human genes 0.000 description 1
- 102100021593 Interleukin-7 receptor subunit alpha Human genes 0.000 description 1
- 102100026236 Interleukin-8 Human genes 0.000 description 1
- 102100033257 Inversin Human genes 0.000 description 1
- 102100033114 Inward rectifier potassium channel 2 Human genes 0.000 description 1
- 208000034613 Isolated polycystic liver disease Diseases 0.000 description 1
- 102100025392 Isovaleryl-CoA dehydrogenase, mitochondrial Human genes 0.000 description 1
- 101710201965 Isovaleryl-CoA dehydrogenase, mitochondrial Proteins 0.000 description 1
- 102100037489 KAT8 regulatory NSL complex subunit 3 Human genes 0.000 description 1
- 108010006746 KCNQ2 Potassium Channel Proteins 0.000 description 1
- 108010038888 KCNQ3 Potassium Channel Proteins 0.000 description 1
- 102100021559 KRR1 small subunit processome component homolog Human genes 0.000 description 1
- 241001397173 Kali <angiosperm> Species 0.000 description 1
- 108010093811 Kazal Pancreatic Trypsin Inhibitor Proteins 0.000 description 1
- 102100023970 Keratin, type I cytoskeletal 10 Human genes 0.000 description 1
- 102100023967 Keratin, type I cytoskeletal 12 Human genes 0.000 description 1
- 102100040487 Keratin, type I cytoskeletal 13 Human genes 0.000 description 1
- 102100040441 Keratin, type I cytoskeletal 16 Human genes 0.000 description 1
- 102100023129 Keratin, type I cytoskeletal 9 Human genes 0.000 description 1
- 102100037382 Keratin, type II cuticular Hb6 Human genes 0.000 description 1
- 102100022854 Keratin, type II cytoskeletal 2 epidermal Human genes 0.000 description 1
- 102100025759 Keratin, type II cytoskeletal 3 Human genes 0.000 description 1
- 102100025758 Keratin, type II cytoskeletal 4 Human genes 0.000 description 1
- 102100025756 Keratin, type II cytoskeletal 5 Human genes 0.000 description 1
- 102100025655 Keratin, type II cytoskeletal 6B Human genes 0.000 description 1
- 102100025380 Keratin, type II cytoskeletal 72 Human genes 0.000 description 1
- 102100023418 Ketohexokinase Human genes 0.000 description 1
- 102100021524 Kinesin-like protein KIF1B Human genes 0.000 description 1
- 102100037688 Kinesin-like protein KIF21A Human genes 0.000 description 1
- 101100193693 Kirsten murine sarcoma virus K-RAS gene Proteins 0.000 description 1
- 102100035878 Krev interaction trapped protein 1 Human genes 0.000 description 1
- 102100036091 Kynureninase Human genes 0.000 description 1
- 102100034671 L-lactate dehydrogenase A chain Human genes 0.000 description 1
- 102100024580 L-lactate dehydrogenase B chain Human genes 0.000 description 1
- 102100031357 L-lactate dehydrogenase C chain Human genes 0.000 description 1
- 101710159002 L-lactate oxidase Proteins 0.000 description 1
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 1
- 102100036106 LIM/homeobox protein Lhx3 Human genes 0.000 description 1
- 102100035192 Laforin Human genes 0.000 description 1
- 108010021099 Lamin Type A Proteins 0.000 description 1
- 102000008201 Lamin Type A Human genes 0.000 description 1
- 108010021101 Lamin Type B Proteins 0.000 description 1
- 208000037161 Laminin subunit alpha 2-related congenital muscular dystrophy Diseases 0.000 description 1
- 102100022745 Laminin subunit alpha-2 Human genes 0.000 description 1
- 102100022743 Laminin subunit alpha-4 Human genes 0.000 description 1
- 102100024629 Laminin subunit beta-3 Human genes 0.000 description 1
- 102100035159 Laminin subunit gamma-2 Human genes 0.000 description 1
- 101710084021 Large envelope protein Proteins 0.000 description 1
- 102100027017 Latent-transforming growth factor beta-binding protein 2 Human genes 0.000 description 1
- 208000002180 Laurin-Sandrow syndrome Diseases 0.000 description 1
- 102100027443 Lebercilin Human genes 0.000 description 1
- 101710197072 Lectin 1 Proteins 0.000 description 1
- 102100040511 Left-right determination factor 2 Human genes 0.000 description 1
- 208000010994 Lethal infantile mitochondrial myopathy Diseases 0.000 description 1
- 102100040589 Leucine-rich PPR motif-containing protein, mitochondrial Human genes 0.000 description 1
- 102100032352 Leukemia inhibitory factor Human genes 0.000 description 1
- 102100023758 Leukotriene C4 synthase Human genes 0.000 description 1
- 102100040547 Limb region 1 protein homolog Human genes 0.000 description 1
- 108010013563 Lipoprotein Lipase Proteins 0.000 description 1
- 108010033266 Lipoprotein(a) Proteins 0.000 description 1
- 102100027361 Lithostathine-1-alpha Human genes 0.000 description 1
- 102100029107 Long chain 3-hydroxyacyl-CoA dehydrogenase Human genes 0.000 description 1
- 102100021644 Long-chain specific acyl-CoA dehydrogenase, mitochondrial Human genes 0.000 description 1
- 102100034337 Long-chain-fatty-acid-CoA ligase 6 Human genes 0.000 description 1
- 102100029204 Low affinity immunoglobulin gamma Fc region receptor II-a Human genes 0.000 description 1
- 102100029205 Low affinity immunoglobulin gamma Fc region receptor II-b Human genes 0.000 description 1
- 102100029193 Low affinity immunoglobulin gamma Fc region receptor III-A Human genes 0.000 description 1
- 102100040947 Lutropin subunit beta Human genes 0.000 description 1
- 102000008072 Lymphokines Human genes 0.000 description 1
- 108010074338 Lymphokines Proteins 0.000 description 1
- 108090000542 Lymphotoxin-alpha Proteins 0.000 description 1
- 102000004083 Lymphotoxin-alpha Human genes 0.000 description 1
- 102100026894 Lymphotoxin-beta Human genes 0.000 description 1
- 102100033143 Lysine-specific demethylase 5D Human genes 0.000 description 1
- 102100033342 Lysosomal acid glucosylceramidase Human genes 0.000 description 1
- 101710204480 Lysosomal acid phosphatase Proteins 0.000 description 1
- 102100023231 Lysosomal alpha-mannosidase Human genes 0.000 description 1
- 102100028524 Lysosomal protective protein Human genes 0.000 description 1
- 108010009491 Lysosomal-Associated Membrane Protein 2 Proteins 0.000 description 1
- 102100020983 Lysosome membrane protein 2 Human genes 0.000 description 1
- 102100038225 Lysosome-associated membrane glycoprotein 2 Human genes 0.000 description 1
- 101150083522 MECP2 gene Proteins 0.000 description 1
- 208000035177 MELAS Diseases 0.000 description 1
- 102100026371 MHC class II transactivator Human genes 0.000 description 1
- 102100037200 MORC family CW-type zinc finger protein 1 Human genes 0.000 description 1
- 102000046961 MRE11 Homologue Human genes 0.000 description 1
- 108700019589 MRE11 Homologue Proteins 0.000 description 1
- 229910015837 MSH2 Inorganic materials 0.000 description 1
- 102100028198 Macrophage colony-stimulating factor 1 receptor Human genes 0.000 description 1
- 101000687334 Magnaporthe oryzae (strain 70-15 / ATCC MYA-4617 / FGSC 8958) NAD(P)H-dependent pentose reductase Proteins 0.000 description 1
- 102100028112 Magnesium transporter NIPA1 Human genes 0.000 description 1
- 101710175243 Major antigen Proteins 0.000 description 1
- 101710125418 Major capsid protein Proteins 0.000 description 1
- 101710122864 Major tegument protein Proteins 0.000 description 1
- 102100029461 Malonyl-CoA decarboxylase, mitochondrial Human genes 0.000 description 1
- 102100037267 Mammaglobin-B Human genes 0.000 description 1
- 102100026046 Mannan-binding lectin serine protease 2 Human genes 0.000 description 1
- 101710117460 Mannan-binding lectin serine protease 2 Proteins 0.000 description 1
- 101001129124 Mannheimia haemolytica Outer membrane lipoprotein 1 Proteins 0.000 description 1
- 101710110798 Mannose-binding protein C Proteins 0.000 description 1
- 102100025315 Mannosyl-oligosaccharide glucosidase Human genes 0.000 description 1
- 108010000684 Matrix Metalloproteinases Proteins 0.000 description 1
- 102000002274 Matrix Metalloproteinases Human genes 0.000 description 1
- 102100026300 McKusick-Kaufman/Bardet-Biedl syndromes putative chaperonin Human genes 0.000 description 1
- 102100026048 Meckel syndrome type 1 protein Human genes 0.000 description 1
- 102100024590 Medium-chain specific acyl-CoA dehydrogenase, mitochondrial Human genes 0.000 description 1
- 102100037812 Medium-wave-sensitive opsin 1 Human genes 0.000 description 1
- 102100023724 Melanocortin receptor 4 Human genes 0.000 description 1
- 102100029778 Melanoma inhibitory activity protein 2 Human genes 0.000 description 1
- 102000000440 Melanoma-associated antigen Human genes 0.000 description 1
- 108050008953 Melanoma-associated antigen Proteins 0.000 description 1
- 102000056430 Member 1 Solute Carrier Family 12 Human genes 0.000 description 1
- 108010047230 Member 1 Subfamily B ATP Binding Cassette Transporter Proteins 0.000 description 1
- 108010049137 Member 1 Subfamily D ATP Binding Cassette Transporter Proteins 0.000 description 1
- 108010093662 Member 11 Subfamily B ATP Binding Cassette Transporter Proteins 0.000 description 1
- 102000056548 Member 3 Solute Carrier Family 12 Human genes 0.000 description 1
- 108010090837 Member 5 Subfamily G ATP Binding Cassette Transporter Proteins 0.000 description 1
- 108010090822 Member 8 Subfamily G ATP Binding Cassette Transporter Proteins 0.000 description 1
- 102000018697 Membrane Proteins Human genes 0.000 description 1
- 108010052285 Membrane Proteins Proteins 0.000 description 1
- 102100039373 Membrane cofactor protein Human genes 0.000 description 1
- 102100030351 Membrane-associated phosphatidylinositol transfer protein 3 Human genes 0.000 description 1
- 102100027382 Membrane-bound transcription factor site-2 protease Human genes 0.000 description 1
- 102100037106 Merlin Human genes 0.000 description 1
- 102100025096 Mesothelin Human genes 0.000 description 1
- 102100026262 Metalloproteinase inhibitor 2 Human genes 0.000 description 1
- 102100026261 Metalloproteinase inhibitor 3 Human genes 0.000 description 1
- 102100031551 Methionine synthase Human genes 0.000 description 1
- 102100024614 Methionine synthase reductase Human genes 0.000 description 1
- 102100039124 Methyl-CpG-binding protein 2 Human genes 0.000 description 1
- 102100027320 Methylcrotonoyl-CoA carboxylase beta chain, mitochondrial Human genes 0.000 description 1
- 102100029684 Methylenetetrahydrofolate reductase Human genes 0.000 description 1
- 102100022259 Mevalonate kinase Human genes 0.000 description 1
- 108700040132 Mevalonate kinases Proteins 0.000 description 1
- 102100027632 Microcephalin Human genes 0.000 description 1
- 108010050345 Microphthalmia-Associated Transcription Factor Proteins 0.000 description 1
- 102100040243 Microtubule-associated protein tau Human genes 0.000 description 1
- 102100021316 Mineralocorticoid receptor Human genes 0.000 description 1
- 108010074346 Mismatch Repair Endonuclease PMS2 Proteins 0.000 description 1
- 102000008071 Mismatch Repair Endonuclease PMS2 Human genes 0.000 description 1
- 108010009513 Mitochondrial Aldehyde Dehydrogenase Proteins 0.000 description 1
- 102100038738 Mitochondrial carnitine/acylcarnitine carrier protein Human genes 0.000 description 1
- 102100027891 Mitochondrial chaperone BCS1 Human genes 0.000 description 1
- 102100026808 Mitochondrial import inner membrane translocase subunit Tim8 A Human genes 0.000 description 1
- 102100039840 Mitochondrial inner membrane protease subunit 2 Human genes 0.000 description 1
- 101710151805 Mitochondrial intermediate peptidase 1 Proteins 0.000 description 1
- 102100030108 Mitochondrial ornithine transporter 1 Human genes 0.000 description 1
- 102100028192 Mitogen-activated protein kinase kinase kinase kinase 2 Human genes 0.000 description 1
- 101710144533 Mitogen-activated protein kinase kinase kinase kinase 2 Proteins 0.000 description 1
- 102100021691 Mitotic checkpoint serine/threonine-protein kinase BUB1 Human genes 0.000 description 1
- 102100027983 Molybdenum cofactor sulfurase Human genes 0.000 description 1
- 101710132461 Molybdenum cofactor sulfurase Proteins 0.000 description 1
- 102100039428 Molybdopterin synthase sulfur carrier subunit Human genes 0.000 description 1
- 102100027871 Monocarboxylate transporter 8 Human genes 0.000 description 1
- 102100025744 Mothers against decapentaplegic homolog 1 Human genes 0.000 description 1
- 102100025725 Mothers against decapentaplegic homolog 4 Human genes 0.000 description 1
- 102100025170 Motor neuron and pancreas homeobox protein 1 Human genes 0.000 description 1
- 102100022693 Mucin-4 Human genes 0.000 description 1
- 102100022496 Mucin-5AC Human genes 0.000 description 1
- 101710122877 Muellerian-inhibiting factor Proteins 0.000 description 1
- 108010066419 Multidrug Resistance-Associated Protein 2 Proteins 0.000 description 1
- MSFSPUZXLOGKHJ-UHFFFAOYSA-N Muraminsaeure Natural products OC(=O)C(C)OC1C(N)C(O)OC(CO)C1O MSFSPUZXLOGKHJ-UHFFFAOYSA-N 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 101100381649 Mus musculus Bik gene Proteins 0.000 description 1
- 101100382264 Mus musculus Ca14 gene Proteins 0.000 description 1
- 101000933115 Mus musculus Caspase-4 Proteins 0.000 description 1
- 101100112373 Mus musculus Ctsm gene Proteins 0.000 description 1
- 101100447665 Mus musculus Gas2 gene Proteins 0.000 description 1
- 101100460492 Mus musculus Nkx1-2 gene Proteins 0.000 description 1
- 101100198353 Mus musculus Rnasel gene Proteins 0.000 description 1
- 101001123852 Mus musculus Sialidase-2 Proteins 0.000 description 1
- 101100207071 Mus musculus Tnfsf8 gene Proteins 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 101000944608 Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv) Chaperonin GroEL 2 Proteins 0.000 description 1
- 101000891671 Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv) Medium/long-chain-fatty-acid-CoA ligase FadD6 Proteins 0.000 description 1
- 102100026784 Myelin proteolipid protein Human genes 0.000 description 1
- 102100023302 Myelin-oligodendrocyte glycoprotein Human genes 0.000 description 1
- 102100034681 Myeloblastin Human genes 0.000 description 1
- 102100029839 Myocilin Human genes 0.000 description 1
- 108010009047 Myosin VIIa Proteins 0.000 description 1
- 102100030971 Myosin light chain 3 Human genes 0.000 description 1
- 102100026925 Myosin regulatory light chain 2, ventricular/cardiac muscle isoform Human genes 0.000 description 1
- 102100032972 Myosin-14 Human genes 0.000 description 1
- 102100038319 Myosin-6 Human genes 0.000 description 1
- 102100026771 Myosin-binding protein C, cardiac-type Human genes 0.000 description 1
- 108010052185 Myotonin-Protein Kinase Proteins 0.000 description 1
- 102100022437 Myotonin-protein kinase Human genes 0.000 description 1
- 102100033817 Myotubularin Human genes 0.000 description 1
- 102100040602 Myotubularin-related protein 2 Human genes 0.000 description 1
- USVMJSALORZVDV-SDBHATRESA-N N(6)-(Delta(2)-isopentenyl)adenosine Chemical compound C1=NC=2C(NCC=C(C)C)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O USVMJSALORZVDV-SDBHATRESA-N 0.000 description 1
- VQAYFKKCNSOZKM-IOSLPCCCSA-N N(6)-methyladenosine Chemical compound C1=NC=2C(NC)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O VQAYFKKCNSOZKM-IOSLPCCCSA-N 0.000 description 1
- 102100031688 N-acetylgalactosamine-6-sulfatase Human genes 0.000 description 1
- 102100036710 N-acetylglucosamine-1-phosphotransferase subunits alpha/beta Human genes 0.000 description 1
- 102100023282 N-acetylglucosamine-6-sulfatase Human genes 0.000 description 1
- 102100023315 N-acetyllactosaminide beta-1,6-N-acetylglucosaminyl-transferase Human genes 0.000 description 1
- 102100034977 N-acylglucosamine 2-epimerase Human genes 0.000 description 1
- 102100026783 N-alpha-acetyltransferase 16, NatA auxiliary subunit Human genes 0.000 description 1
- 102100027661 N-sulphoglucosamine sulphohydrolase Human genes 0.000 description 1
- 102100022691 NACHT, LRR and PYD domains-containing protein 3 Human genes 0.000 description 1
- 102100022365 NAD(P)H dehydrogenase [quinone] 1 Human genes 0.000 description 1
- 102100023964 NADH dehydrogenase [ubiquinone] flavoprotein 2, mitochondrial Human genes 0.000 description 1
- 102100037519 NADH dehydrogenase [ubiquinone] iron-sulfur protein 4, mitochondrial Human genes 0.000 description 1
- 102100023212 NADH dehydrogenase [ubiquinone] iron-sulfur protein 7, mitochondrial Human genes 0.000 description 1
- 102100031919 NADH dehydrogenase [ubiquinone] iron-sulfur protein 8, mitochondrial Human genes 0.000 description 1
- 102100033153 NADH-cytochrome b5 reductase 3 Human genes 0.000 description 1
- 102100038625 NADH-ubiquinone oxidoreductase chain 1 Human genes 0.000 description 1
- 102100028488 NADH-ubiquinone oxidoreductase chain 2 Human genes 0.000 description 1
- 102100036971 NADH-ubiquinone oxidoreductase chain 5 Human genes 0.000 description 1
- 102100028386 NADH-ubiquinone oxidoreductase chain 6 Human genes 0.000 description 1
- 108010082739 NADPH Oxidase 2 Proteins 0.000 description 1
- 101150114886 NECTIN1 gene Proteins 0.000 description 1
- 101150079937 NEUROD1 gene Proteins 0.000 description 1
- 108010057466 NF-kappa B Proteins 0.000 description 1
- 108010059419 NIMA-Interacting Peptidylprolyl Isomerase Proteins 0.000 description 1
- 102000005591 NIMA-Interacting Peptidylprolyl Isomerase Human genes 0.000 description 1
- 102100029565 NPC intracellular cholesterol transporter 1 Human genes 0.000 description 1
- 102100022737 NPC intracellular cholesterol transporter 2 Human genes 0.000 description 1
- VQAYFKKCNSOZKM-UHFFFAOYSA-N NSC 29409 Natural products C1=NC=2C(NC)=NC=NC=2N1C1OC(CO)C(O)C1O VQAYFKKCNSOZKM-UHFFFAOYSA-N 0.000 description 1
- 102100034296 Natriuretic peptides A Human genes 0.000 description 1
- 102100023210 Necdin Human genes 0.000 description 1
- 102100023195 Nephrin Human genes 0.000 description 1
- 102100023187 Nephrocystin-1 Human genes 0.000 description 1
- 108010069196 Neural Cell Adhesion Molecules Proteins 0.000 description 1
- 102100024964 Neural cell adhesion molecule L1 Human genes 0.000 description 1
- 108700020297 NeuroD Proteins 0.000 description 1
- 102100032132 Neuroendocrine convertase 1 Human genes 0.000 description 1
- 102000007530 Neurofibromin 1 Human genes 0.000 description 1
- 108010085793 Neurofibromin 1 Proteins 0.000 description 1
- 102100024007 Neurofilament heavy polypeptide Human genes 0.000 description 1
- 201000004009 Neurogenic arthrogryposis multiplex congenita Diseases 0.000 description 1
- 102100032063 Neurogenic differentiation factor 1 Human genes 0.000 description 1
- 102100039909 Neuronal acetylcholine receptor subunit alpha-4 Human genes 0.000 description 1
- 101001122350 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) Dihydrolipoyllysine-residue acetyltransferase component of pyruvate dehydrogenase complex, mitochondrial Proteins 0.000 description 1
- 102100021584 Neurturin Human genes 0.000 description 1
- 102100027341 Neutral and basic amino acid transport protein rBAT Human genes 0.000 description 1
- 102100023620 Neutrophil cytosol factor 1 Human genes 0.000 description 1
- 102100023618 Neutrophil cytosol factor 2 Human genes 0.000 description 1
- 102100024403 Nibrin Human genes 0.000 description 1
- 102100028452 Nitric oxide synthase, endothelial Human genes 0.000 description 1
- 108700002045 Nod2 Signaling Adaptor Proteins 0.000 description 1
- 101150083031 Nod2 gene Proteins 0.000 description 1
- 108091092724 Noncoding DNA Proteins 0.000 description 1
- 108010049586 Norepinephrine Plasma Membrane Transport Proteins Proteins 0.000 description 1
- 102100025036 Norrin Human genes 0.000 description 1
- 102000001759 Notch1 Receptor Human genes 0.000 description 1
- 108010029755 Notch1 Receptor Proteins 0.000 description 1
- 102000001760 Notch3 Receptor Human genes 0.000 description 1
- 108010029756 Notch3 Receptor Proteins 0.000 description 1
- 102100035403 Nuclear RNA export factor 2 Human genes 0.000 description 1
- 102100023050 Nuclear factor NF-kappa-B p105 subunit Human genes 0.000 description 1
- 102000007399 Nuclear hormone receptor Human genes 0.000 description 1
- 102100039614 Nuclear receptor ROR-alpha Human genes 0.000 description 1
- 102100039019 Nuclear receptor subfamily 0 group B member 1 Human genes 0.000 description 1
- 102000011931 Nucleoproteins Human genes 0.000 description 1
- 108010061100 Nucleoproteins Proteins 0.000 description 1
- VZQXUWKZDSEQRR-UHFFFAOYSA-N Nucleosid Natural products C12=NC(SC)=NC(NCC=C(C)C)=C2N=CN1C1OC(CO)C(O)C1O VZQXUWKZDSEQRR-UHFFFAOYSA-N 0.000 description 1
- 102100023252 Nucleoside diphosphate kinase A Human genes 0.000 description 1
- 102100027096 Nucleotide exchange factor SIL1 Human genes 0.000 description 1
- 102100039306 Nucleotide pyrophosphatase Human genes 0.000 description 1
- 102100029441 Nucleotide-binding oligomerization domain-containing protein 2 Human genes 0.000 description 1
- PVFRBOFKMUXLLW-WFIJOQBCSA-N O=C1C=CNC(=O)N1.NC1=NC=NC2=C1NC=N2.O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C=C1 Chemical compound O=C1C=CNC(=O)N1.NC1=NC=NC2=C1NC=N2.O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C=C1 PVFRBOFKMUXLLW-WFIJOQBCSA-N 0.000 description 1
- 101000761187 Odontomachus monticola U-poneritoxin(01)-Om1a Proteins 0.000 description 1
- 108700006385 OmpF Proteins 0.000 description 1
- 101710148753 Ornithine aminotransferase Proteins 0.000 description 1
- 102100027177 Ornithine aminotransferase, mitochondrial Human genes 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 101100335694 Oryza sativa subsp. japonica G1L6 gene Proteins 0.000 description 1
- 102100031475 Osteocalcin Human genes 0.000 description 1
- 102100040557 Osteopontin Human genes 0.000 description 1
- 102100034198 Otoferlin Human genes 0.000 description 1
- 101710160102 Outer membrane protein B Proteins 0.000 description 1
- 101710195703 Oxygen-dependent coproporphyrinogen-III oxidase Proteins 0.000 description 1
- 101710146072 Oxygen-independent coproporphyrinogen III oxidase Proteins 0.000 description 1
- 102100023238 P antigen family member 5 Human genes 0.000 description 1
- 102100026171 P2Y purinoceptor 12 Human genes 0.000 description 1
- 108010032788 PAX6 Transcription Factor Proteins 0.000 description 1
- KJWZYMMLVHIVSU-IYCNHOCDSA-N PGK1 Chemical compound CCCCC[C@H](O)\C=C\[C@@H]1[C@@H](CCCCCCC(O)=O)C(=O)CC1=O KJWZYMMLVHIVSU-IYCNHOCDSA-N 0.000 description 1
- 102100026365 PHD finger protein 6 Human genes 0.000 description 1
- 101150096217 PHYH gene Proteins 0.000 description 1
- 108091007960 PI3Ks Proteins 0.000 description 1
- 102000038030 PI3Ks Human genes 0.000 description 1
- 108700043304 PKC-3 Proteins 0.000 description 1
- 102100037482 PMS1 protein homolog 1 Human genes 0.000 description 1
- 102100026450 POU domain, class 3, transcription factor 4 Human genes 0.000 description 1
- 102100035398 POU domain, class 4, transcription factor 3 Human genes 0.000 description 1
- 108010011536 PTEN Phosphohydrolase Proteins 0.000 description 1
- 101710148592 PTS system fructose-like EIIA component Proteins 0.000 description 1
- 101710169713 PTS system fructose-specific EIIA component Proteins 0.000 description 1
- 102100040852 Paired box protein Pax-2 Human genes 0.000 description 1
- 102100040891 Paired box protein Pax-3 Human genes 0.000 description 1
- 102100037506 Paired box protein Pax-6 Human genes 0.000 description 1
- 102100037503 Paired box protein Pax-7 Human genes 0.000 description 1
- 102100037502 Paired box protein Pax-8 Human genes 0.000 description 1
- 102100034901 Paired box protein Pax-9 Human genes 0.000 description 1
- 102100041030 Pancreas/duodenum homeobox protein 1 Human genes 0.000 description 1
- 102100033359 Pancreatic triacylglycerol lipase Human genes 0.000 description 1
- 102100040156 Pappalysin-1 Human genes 0.000 description 1
- 102100027006 Paraplegin Human genes 0.000 description 1
- 108090000445 Parathyroid hormone Proteins 0.000 description 1
- 102100032256 Parathyroid hormone/parathyroid hormone-related peptide receptor Human genes 0.000 description 1
- 108010065129 Patched-1 Receptor Proteins 0.000 description 1
- 108010071083 Patched-2 Receptor Proteins 0.000 description 1
- 208000024787 Patella aplasia/hypoplasia Diseases 0.000 description 1
- 102100035278 Pendrin Human genes 0.000 description 1
- 108010013639 Peptidoglycan Proteins 0.000 description 1
- 102100040349 Peptidyl-prolyl cis-trans isomerase FKBP10 Human genes 0.000 description 1
- 108010056995 Perforin Proteins 0.000 description 1
- KHGNFPUMBJSZSM-UHFFFAOYSA-N Perforine Natural products COC1=C2CCC(O)C(CCC(C)(C)O)(OC)C2=NC2=C1C=CO2 KHGNFPUMBJSZSM-UHFFFAOYSA-N 0.000 description 1
- 102100035917 Peripheral myelin protein 22 Human genes 0.000 description 1
- 102100022239 Peroxiredoxin-6 Human genes 0.000 description 1
- 108010077056 Peroxisomal Targeting Signal 2 Receptor Proteins 0.000 description 1
- 102100029577 Peroxisomal biogenesis factor 3 Human genes 0.000 description 1
- 102100030564 Peroxisomal membrane protein 2 Human genes 0.000 description 1
- 102100028223 Peroxisomal membrane protein PEX13 Human genes 0.000 description 1
- 102100032924 Peroxisomal targeting signal 2 receptor Human genes 0.000 description 1
- 102100032931 Peroxisome assembly factor 2 Human genes 0.000 description 1
- 102100030554 Peroxisome biogenesis factor 10 Human genes 0.000 description 1
- 102100025516 Peroxisome biogenesis factor 2 Human genes 0.000 description 1
- 102100038825 Peroxisome proliferator-activated receptor gamma Human genes 0.000 description 1
- 102100035832 Phakinin Human genes 0.000 description 1
- 102100038223 Phenylalanine-4-hydroxylase Human genes 0.000 description 1
- 101710125939 Phenylalanine-4-hydroxylase Proteins 0.000 description 1
- 102100040402 Phlorizin hydrolase Human genes 0.000 description 1
- 102100039032 Phosphatidylcholine translocator ABCB4 Human genes 0.000 description 1
- 102100031538 Phosphatidylcholine-sterol acyltransferase Human genes 0.000 description 1
- 102100032543 Phosphatidylinositol 3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase PTEN Human genes 0.000 description 1
- 102100036081 Phosphatidylinositol 4-phosphate 5-kinase type-1 beta Human genes 0.000 description 1
- 102100036050 Phosphatidylinositol N-acetylglucosaminyltransferase subunit A Human genes 0.000 description 1
- 101710169596 Phosphatidylinositol-binding clathrin assembly protein Proteins 0.000 description 1
- 102100034792 Phosphoenolpyruvate carboxykinase [GTP], mitochondrial Human genes 0.000 description 1
- 102100034796 Phosphoenolpyruvate carboxykinase, cytosolic [GTP] Human genes 0.000 description 1
- 102100028251 Phosphoglycerate kinase 1 Human genes 0.000 description 1
- 102100037385 Phosphoglycerate mutase 2 Human genes 0.000 description 1
- 102100026831 Phospholipase A2, membrane associated Human genes 0.000 description 1
- 102100033616 Phospholipid-transporting ATPase ABCA1 Human genes 0.000 description 1
- 102100030448 Phospholipid-transporting ATPase IC Human genes 0.000 description 1
- 102100035362 Phosphomannomutase 2 Human genes 0.000 description 1
- 102100032391 Phosphorylase b kinase gamma catalytic chain, liver/testis isoform Human genes 0.000 description 1
- 102100033548 Phosphorylase b kinase regulatory subunit alpha, liver isoform Human genes 0.000 description 1
- 102100033547 Phosphorylase b kinase regulatory subunit alpha, skeletal muscle isoform Human genes 0.000 description 1
- 102100020854 Phosphorylase b kinase regulatory subunit beta Human genes 0.000 description 1
- 102100029533 Photoreceptor-specific nuclear receptor Human genes 0.000 description 1
- 102100039421 Phytanoyl-CoA dioxygenase, peroxisomal Human genes 0.000 description 1
- 102100036090 Pituitary homeobox 2 Human genes 0.000 description 1
- 102100029331 Plakophilin-1 Human genes 0.000 description 1
- 102100029744 Plasma membrane calcium-transporting ATPase 3 Human genes 0.000 description 1
- 102100027637 Plasma protease C1 inhibitor Human genes 0.000 description 1
- 102100038124 Plasminogen Human genes 0.000 description 1
- 108010022233 Plasminogen Activator Inhibitor 1 Proteins 0.000 description 1
- 102100039418 Plasminogen activator inhibitor 1 Human genes 0.000 description 1
- 101100205354 Plasmodium falciparum (isolate 3D7) proRS gene Proteins 0.000 description 1
- 102100036154 Platelet basic protein Human genes 0.000 description 1
- 102100024616 Platelet endothelial cell adhesion molecule Human genes 0.000 description 1
- 102100036851 Platelet glycoprotein IX Human genes 0.000 description 1
- 102100034173 Platelet glycoprotein Ib alpha chain Human genes 0.000 description 1
- 102100034168 Platelet glycoprotein Ib beta chain Human genes 0.000 description 1
- 102100037518 Platelet-activating factor acetylhydrolase Human genes 0.000 description 1
- 102100026547 Platelet-derived growth factor receptor beta Human genes 0.000 description 1
- 102100026554 Platelet-derived growth factor receptor-like protein Human genes 0.000 description 1
- 102100040990 Platelet-derived growth factor subunit B Human genes 0.000 description 1
- 102100030477 Plectin Human genes 0.000 description 1
- 101710179684 Poly [ADP-ribose] polymerase Proteins 0.000 description 1
- 102100023712 Poly [ADP-ribose] polymerase 1 Human genes 0.000 description 1
- 229920000776 Poly(Adenosine diphosphate-ribose) polymerase Polymers 0.000 description 1
- 229920002730 Poly(butyl cyanoacrylate) Polymers 0.000 description 1
- 102100039427 Polyadenylate-binding protein 2 Human genes 0.000 description 1
- 102100036142 Polycystin-2 Human genes 0.000 description 1
- 102100040748 Polyglutamine-binding protein 1 Human genes 0.000 description 1
- 229920000331 Polyhydroxybutyrate Polymers 0.000 description 1
- 229920012196 Polyoxymethylene Copolymer Polymers 0.000 description 1
- 108010013381 Porins Proteins 0.000 description 1
- 102000017033 Porins Human genes 0.000 description 1
- 102100034391 Porphobilinogen deaminase Human genes 0.000 description 1
- 101710189720 Porphobilinogen deaminase Proteins 0.000 description 1
- 101710170827 Porphobilinogen deaminase, chloroplastic Proteins 0.000 description 1
- 102100022752 Potassium voltage-gated channel subfamily E member 2 Human genes 0.000 description 1
- 102100022807 Potassium voltage-gated channel subfamily H member 2 Human genes 0.000 description 1
- 101710163352 Potassium voltage-gated channel subfamily H member 4 Proteins 0.000 description 1
- 102100034354 Potassium voltage-gated channel subfamily KQT member 2 Human genes 0.000 description 1
- 102100034360 Potassium voltage-gated channel subfamily KQT member 3 Human genes 0.000 description 1
- 102100034363 Potassium voltage-gated channel subfamily KQT member 4 Human genes 0.000 description 1
- 102100040171 Pre-B-cell leukemia transcription factor 1 Human genes 0.000 description 1
- 102100022033 Presenilin-1 Human genes 0.000 description 1
- 102100022036 Presenilin-2 Human genes 0.000 description 1
- 108010050254 Presenilins Proteins 0.000 description 1
- 102000015499 Presenilins Human genes 0.000 description 1
- 208000033377 Primary dystonia, DYT4 type Diseases 0.000 description 1
- 108010069820 Pro-Opiomelanocortin Proteins 0.000 description 1
- 102100022661 Pro-neuregulin-1, membrane-bound isoform Human genes 0.000 description 1
- 102100027467 Pro-opiomelanocortin Human genes 0.000 description 1
- 102100032251 Pro-thyrotropin-releasing hormone Human genes 0.000 description 1
- 101710119292 Probable D-lactate dehydrogenase, mitochondrial Proteins 0.000 description 1
- 101710145525 Probable cinnamyl alcohol dehydrogenase Proteins 0.000 description 1
- 101710089118 Probable cytosol aminopeptidase Proteins 0.000 description 1
- 102100035920 Probable hydrolase PNKD Human genes 0.000 description 1
- 102100036829 Probable peptidyl-tRNA hydrolase Human genes 0.000 description 1
- 101710100896 Probable porphobilinogen deaminase Proteins 0.000 description 1
- 102100038600 Probable ubiquitin carboxyl-terminal hydrolase FAF-Y Human genes 0.000 description 1
- 102100026534 Procathepsin L Human genes 0.000 description 1
- 102100035202 Procollagen-lysine,2-oxoglutarate 5-dioxygenase 1 Human genes 0.000 description 1
- 102000011195 Profilin Human genes 0.000 description 1
- 108050001408 Profilin Proteins 0.000 description 1
- 102100034836 Proliferation marker protein Ki-67 Human genes 0.000 description 1
- 102100028772 Proline dehydrogenase 1, mitochondrial Human genes 0.000 description 1
- 102100040829 Proline-rich protein PRCC Human genes 0.000 description 1
- 102100040120 Prominin-1 Human genes 0.000 description 1
- 102100039022 Propionyl-CoA carboxylase alpha chain, mitochondrial Human genes 0.000 description 1
- 102100039025 Propionyl-CoA carboxylase beta chain, mitochondrial Human genes 0.000 description 1
- 102100034945 Prorelaxin H1 Human genes 0.000 description 1
- 102100034949 Prorelaxin H2 Human genes 0.000 description 1
- 102100038277 Prostaglandin G/H synthase 1 Human genes 0.000 description 1
- 102100031952 Protein 4.1 Human genes 0.000 description 1
- 102100031953 Protein 4.2 Human genes 0.000 description 1
- 102100039686 Protein AF-9 Human genes 0.000 description 1
- 102100032859 Protein AMBP Human genes 0.000 description 1
- 102100034479 Protein CLN8 Human genes 0.000 description 1
- 102100033813 Protein ENL Human genes 0.000 description 1
- 102100023602 Protein Hook homolog 1 Human genes 0.000 description 1
- 102100021486 Protein S100-G Human genes 0.000 description 1
- 102100035546 Protein SCO2 homolog, mitochondrial Human genes 0.000 description 1
- 102100037687 Protein SSX1 Human genes 0.000 description 1
- 102100037727 Protein SSX4 Human genes 0.000 description 1
- 102100035586 Protein SSXT Human genes 0.000 description 1
- 101710137284 Protein STPG4 Proteins 0.000 description 1
- 102100033154 Protein XRP2 Human genes 0.000 description 1
- 102100027331 Protein crumbs homolog 1 Human genes 0.000 description 1
- 102100036490 Protein diaphanous homolog 1 Human genes 0.000 description 1
- 102100036469 Protein diaphanous homolog 2 Human genes 0.000 description 1
- 102100036352 Protein disulfide-isomerase Human genes 0.000 description 1
- 102100032702 Protein jagged-1 Human genes 0.000 description 1
- 102100024924 Protein kinase C alpha type Human genes 0.000 description 1
- 102100036894 Protein patched homolog 2 Human genes 0.000 description 1
- 102100023366 Protein transport protein Sec23B Human genes 0.000 description 1
- 102100030944 Protein-glutamine gamma-glutamyltransferase K Human genes 0.000 description 1
- 102100028965 Proteoglycan 4 Human genes 0.000 description 1
- 108010071563 Proto-Oncogene Proteins c-fos Proteins 0.000 description 1
- 102000007568 Proto-Oncogene Proteins c-fos Human genes 0.000 description 1
- 108010019674 Proto-Oncogene Proteins c-sis Proteins 0.000 description 1
- 102100021384 Proto-oncogene DBL Human genes 0.000 description 1
- 102100028286 Proto-oncogene tyrosine-protein kinase receptor Ret Human genes 0.000 description 1
- 102100030729 Protoheme IX farnesyltransferase, mitochondrial Human genes 0.000 description 1
- 102100029028 Protoporphyrinogen oxidase Human genes 0.000 description 1
- 108010042038 Protozoan Proteins Proteins 0.000 description 1
- 102100032350 Protransforming growth factor alpha Human genes 0.000 description 1
- 208000022366 Pseudohypoaldosteronism type 2A Diseases 0.000 description 1
- 102100029333 Pterin-4-alpha-carbinolamine dehydratase Human genes 0.000 description 1
- 108010007100 Pulmonary Surfactant-Associated Protein A Proteins 0.000 description 1
- 102100032617 Pulmonary surfactant-associated protein B Human genes 0.000 description 1
- 102100040971 Pulmonary surfactant-associated protein C Human genes 0.000 description 1
- 102100027845 Pulmonary surfactant-associated protein D Human genes 0.000 description 1
- 102100027358 Pumilio homolog 3 Human genes 0.000 description 1
- 101710156592 Putative TATA-binding protein pB263R Proteins 0.000 description 1
- 102100035369 Putative cat eye syndrome critical region protein 9 Human genes 0.000 description 1
- 102100030632 Putative myc-like protein MYCLP1 Human genes 0.000 description 1
- 101710183548 Pyridoxal 5'-phosphate synthase subunit PdxS Proteins 0.000 description 1
- 102100039233 Pyrin Human genes 0.000 description 1
- 108010059278 Pyrin Proteins 0.000 description 1
- 102100034909 Pyruvate kinase PKLR Human genes 0.000 description 1
- 101150058540 RAC1 gene Proteins 0.000 description 1
- 102000001183 RAG-1 Human genes 0.000 description 1
- 108060006897 RAG1 Proteins 0.000 description 1
- 101150111584 RHOA gene Proteins 0.000 description 1
- 108091034057 RNA (poly(A)) Proteins 0.000 description 1
- 108090000944 RNA Helicases Proteins 0.000 description 1
- 102000004409 RNA Helicases Human genes 0.000 description 1
- 102100027669 RNA polymerase II subunit A C-terminal domain phosphatase Human genes 0.000 description 1
- 102100038150 RNA-binding protein 6 Human genes 0.000 description 1
- 102000004229 RNA-binding protein EWS Human genes 0.000 description 1
- 108090000740 RNA-binding protein EWS Proteins 0.000 description 1
- 208000036448 RPGR-related retinopathy Diseases 0.000 description 1
- 102000004913 RYR1 Human genes 0.000 description 1
- 108060007240 RYR1 Proteins 0.000 description 1
- 102100034335 Rab GDP dissociation inhibitor alpha Human genes 0.000 description 1
- 102100022881 Rab proteins geranylgeranyltransferase component A 1 Human genes 0.000 description 1
- 102100022880 Rab proteins geranylgeranyltransferase component A 2 Human genes 0.000 description 1
- 102100022851 Rab5 GDP/GTP exchange factor Human genes 0.000 description 1
- 102100035582 Ral-GDS-related protein Human genes 0.000 description 1
- 102100031426 Ras GTPase-activating protein 1 Human genes 0.000 description 1
- 102100022122 Ras-related C3 botulinum toxin substrate 1 Human genes 0.000 description 1
- 102100025003 Ras-related protein R-Ras2 Human genes 0.000 description 1
- 102100039767 Ras-related protein Rab-27A Human genes 0.000 description 1
- 102100030019 Ras-related protein Rab-7a Human genes 0.000 description 1
- 108010038036 Receptor Activator of Nuclear Factor-kappa B Proteins 0.000 description 1
- 101710100969 Receptor tyrosine-protein kinase erbB-3 Proteins 0.000 description 1
- 102100029986 Receptor tyrosine-protein kinase erbB-3 Human genes 0.000 description 1
- 102100029165 Receptor-binding cancer antigen expressed on SiSo cells Human genes 0.000 description 1
- 102100034572 Recoverin Human genes 0.000 description 1
- 102100021043 Regulatory factor X-associated protein Human genes 0.000 description 1
- 101710203837 Replication-associated protein Proteins 0.000 description 1
- 102100022663 Retinal guanylyl cyclase 1 Human genes 0.000 description 1
- 102100033617 Retinal-specific phospholipid-transporting ATPase ABCA4 Human genes 0.000 description 1
- 102100028001 Retinaldehyde-binding protein 1 Human genes 0.000 description 1
- 201000000582 Retinoblastoma Diseases 0.000 description 1
- 101710124357 Retinoblastoma-associated protein Proteins 0.000 description 1
- 102100038470 Retinoic acid-induced protein 1 Human genes 0.000 description 1
- 102100031176 Retinoid isomerohydrolase Human genes 0.000 description 1
- 102100038053 Retinol dehydrogenase 5 Human genes 0.000 description 1
- 101001030849 Rhinella marina Mesotocin receptor Proteins 0.000 description 1
- 101100497944 Rhizopus delemar (strain RA 99-880 / ATCC MYA-4621 / FGSC 9543 / NRRL 43880) cyp11 gene Proteins 0.000 description 1
- 102100040756 Rhodopsin Human genes 0.000 description 1
- 102100029509 Ribose-phosphate pyrophosphokinase 2 Human genes 0.000 description 1
- 102100033643 Ribosomal protein S6 kinase alpha-3 Human genes 0.000 description 1
- 102100039177 Rod cGMP-specific 3',5'-cyclic phosphodiesterase subunit alpha Human genes 0.000 description 1
- 102100039174 Rod cGMP-specific 3',5'-cyclic phosphodiesterase subunit beta Human genes 0.000 description 1
- 102100021424 Rod outer segment membrane protein 1 Human genes 0.000 description 1
- 241000283984 Rodentia Species 0.000 description 1
- 102100025373 Runt-related transcription factor 1 Human genes 0.000 description 1
- 102100025368 Runt-related transcription factor 2 Human genes 0.000 description 1
- 108010055623 S-Phase Kinase-Associated Proteins Proteins 0.000 description 1
- 102100034374 S-phase kinase-associated protein 2 Human genes 0.000 description 1
- 101150097162 SERPING1 gene Proteins 0.000 description 1
- 102100027720 SH2 domain-containing protein 1A Human genes 0.000 description 1
- 102100024865 SH3 domain-binding protein 2 Human genes 0.000 description 1
- 102100029197 SLAM family member 6 Human genes 0.000 description 1
- 108091006614 SLC10A2 Proteins 0.000 description 1
- 108091006621 SLC12A1 Proteins 0.000 description 1
- 108091006623 SLC12A3 Proteins 0.000 description 1
- 108091006633 SLC12A6 Proteins 0.000 description 1
- 108091006161 SLC17A5 Proteins 0.000 description 1
- 108091006736 SLC22A5 Proteins 0.000 description 1
- 108091006418 SLC25A13 Proteins 0.000 description 1
- 108091006411 SLC25A15 Proteins 0.000 description 1
- 108091006422 SLC25A20 Proteins 0.000 description 1
- 108091006716 SLC25A4 Proteins 0.000 description 1
- 108091006715 SLC25A5 Proteins 0.000 description 1
- 108091006495 SLC25A6 Proteins 0.000 description 1
- 108091006505 SLC26A2 Proteins 0.000 description 1
- 108091006504 SLC26A3 Proteins 0.000 description 1
- 108091006507 SLC26A4 Proteins 0.000 description 1
- 108091006296 SLC2A1 Proteins 0.000 description 1
- 108091006299 SLC2A2 Proteins 0.000 description 1
- 108091006300 SLC2A4 Proteins 0.000 description 1
- 108091006311 SLC3A1 Proteins 0.000 description 1
- 101150105729 SLC45A3 gene Proteins 0.000 description 1
- 108091006318 SLC4A1 Proteins 0.000 description 1
- 108091006262 SLC4A4 Proteins 0.000 description 1
- 108091006277 SLC5A1 Proteins 0.000 description 1
- 108091006273 SLC5A5 Proteins 0.000 description 1
- 102000005030 SLC6A2 Human genes 0.000 description 1
- 102000005029 SLC6A3 Human genes 0.000 description 1
- 102000005038 SLC6A4 Human genes 0.000 description 1
- 108091006236 SLC7A7 Proteins 0.000 description 1
- 108091006239 SLC7A9 Proteins 0.000 description 1
- 101700032040 SMAD1 Proteins 0.000 description 1
- 101150019443 SMAD4 gene Proteins 0.000 description 1
- 108700028341 SMARCB1 Proteins 0.000 description 1
- 101150008214 SMARCB1 gene Proteins 0.000 description 1
- 108700022176 SOS1 Proteins 0.000 description 1
- 108060006706 SRC Proteins 0.000 description 1
- 102100030571 STE20-like serine/threonine-protein kinase Human genes 0.000 description 1
- 102100025746 SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily B member 1 Human genes 0.000 description 1
- 101001053942 Saccharolobus solfataricus (strain ATCC 35092 / DSM 1617 / JCM 11322 / P2) Diphosphomevalonate decarboxylase Proteins 0.000 description 1
- 101000677914 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) 40S ribosomal protein S5 Proteins 0.000 description 1
- 101000677924 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) 40S ribosomal protein S6-A Proteins 0.000 description 1
- 101001114408 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) 40S ribosomal protein S6-B Proteins 0.000 description 1
- 101000733871 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) 60S ribosomal protein L4-A Proteins 0.000 description 1
- 101000733875 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) 60S ribosomal protein L4-B Proteins 0.000 description 1
- 101000853650 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) 60S ribosomal protein L8-A Proteins 0.000 description 1
- 101000853649 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) 60S ribosomal protein L8-B Proteins 0.000 description 1
- 101100121588 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) GCY1 gene Proteins 0.000 description 1
- 101100017043 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) HIR3 gene Proteins 0.000 description 1
- 101100071231 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) HMS1 gene Proteins 0.000 description 1
- 101100189627 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) PTC5 gene Proteins 0.000 description 1
- 101100197320 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) RPL35A gene Proteins 0.000 description 1
- 101100473190 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) RPN1 gene Proteins 0.000 description 1
- 101100042631 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) SIN3 gene Proteins 0.000 description 1
- 101100477614 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) SIR4 gene Proteins 0.000 description 1
- 102100037204 Sal-like protein 1 Human genes 0.000 description 1
- 101100094962 Salmo salar salarin gene Proteins 0.000 description 1
- 208000025802 Sanfilippo syndrome type C Diseases 0.000 description 1
- 102100027697 Sarcoplasmic/endoplasmic reticulum calcium ATPase 1 Human genes 0.000 description 1
- 102100027732 Sarcoplasmic/endoplasmic reticulum calcium ATPase 2 Human genes 0.000 description 1
- 102100023363 Sarcosine dehydrogenase, mitochondrial Human genes 0.000 description 1
- 101150028021 Sardh gene Proteins 0.000 description 1
- 208000019937 Scapuloperoneal spinal muscular atrophy Diseases 0.000 description 1
- 102100037118 Scavenger receptor class B member 1 Human genes 0.000 description 1
- 101100347609 Schizosaccharomyces pombe (strain 972 / ATCC 24843) myo3 gene Proteins 0.000 description 1
- 101100082911 Schizosaccharomyces pombe (strain 972 / ATCC 24843) ppp1 gene Proteins 0.000 description 1
- 201000004224 Schnyder corneal dystrophy Diseases 0.000 description 1
- 208000018675 Schwartz-Jampel syndrome Diseases 0.000 description 1
- 208000036451 Schwartz-Jampel syndrome type 1 Diseases 0.000 description 1
- 102100037279 Secretoglobin family 1D member 2 Human genes 0.000 description 1
- 102100021463 Seipin Human genes 0.000 description 1
- 108010005020 Serine Peptidase Inhibitor Kazal-Type 5 Proteins 0.000 description 1
- 102100022068 Serine palmitoyltransferase 1 Human genes 0.000 description 1
- 102100040342 Serine protease 33 Human genes 0.000 description 1
- 102100034801 Serine protease hepsin Human genes 0.000 description 1
- 102100025144 Serine protease inhibitor Kazal-type 1 Human genes 0.000 description 1
- 102100025420 Serine protease inhibitor Kazal-type 5 Human genes 0.000 description 1
- 102100026842 Serine-pyruvate aminotransferase Human genes 0.000 description 1
- 102100029437 Serine/threonine-protein kinase A-Raf Human genes 0.000 description 1
- 102100027103 Serine/threonine-protein kinase B-raf Human genes 0.000 description 1
- 102100031075 Serine/threonine-protein kinase Chk2 Human genes 0.000 description 1
- 102100027939 Serine/threonine-protein kinase PAK 2 Human genes 0.000 description 1
- 101710148167 Serine/threonine-protein kinase PAK 2 Proteins 0.000 description 1
- 102100027911 Serine/threonine-protein kinase PAK 3 Human genes 0.000 description 1
- 102100038101 Serine/threonine-protein kinase WNK4 Human genes 0.000 description 1
- 102100034136 Serine/threonine-protein kinase receptor R3 Human genes 0.000 description 1
- 102100029014 Serine/threonine-protein phosphatase 2A 55 kDa regulatory subunit B beta isoform Human genes 0.000 description 1
- 108010012996 Serotonin Plasma Membrane Transport Proteins Proteins 0.000 description 1
- 101100174184 Serratia marcescens fosA gene Proteins 0.000 description 1
- 102100032277 Serum amyloid A-1 protein Human genes 0.000 description 1
- 102100035476 Serum paraoxonase/arylesterase 1 Human genes 0.000 description 1
- 102100022824 Serum paraoxonase/arylesterase 2 Human genes 0.000 description 1
- 108010089417 Sex Hormone-Binding Globulin Proteins 0.000 description 1
- 102100030758 Sex hormone-binding globulin Human genes 0.000 description 1
- 102100022978 Sex-determining region Y protein Human genes 0.000 description 1
- 108700025071 Short Stature Homeobox Proteins 0.000 description 1
- 102100029992 Short stature homeobox protein Human genes 0.000 description 1
- 102100024639 Short-chain specific acyl-CoA dehydrogenase, mitochondrial Human genes 0.000 description 1
- 102100026557 Short-wave-sensitive opsin 1 Human genes 0.000 description 1
- 102100028760 Sialidase-1 Human genes 0.000 description 1
- 108010011033 Signaling Lymphocytic Activation Molecule Associated Protein Proteins 0.000 description 1
- 102000013970 Signaling Lymphocytic Activation Molecule Associated Protein Human genes 0.000 description 1
- BLRPTPMANUNPDV-UHFFFAOYSA-N Silane Chemical group [SiH4] BLRPTPMANUNPDV-UHFFFAOYSA-N 0.000 description 1
- 208000003874 Simpson-Golabi-Behmel syndrome Diseases 0.000 description 1
- 102100031980 Single-minded homolog 1 Human genes 0.000 description 1
- 108700031298 Smad4 Proteins 0.000 description 1
- 102100029873 Small muscular protein Human genes 0.000 description 1
- 102100028910 Sodium channel protein type 1 subunit alpha Human genes 0.000 description 1
- 102100027195 Sodium channel protein type 4 subunit alpha Human genes 0.000 description 1
- 102100027198 Sodium channel protein type 5 subunit alpha Human genes 0.000 description 1
- 102100023732 Sodium channel subunit beta-1 Human genes 0.000 description 1
- 102000006633 Sodium-Bicarbonate Symporters Human genes 0.000 description 1
- 102000058090 Sodium-Glucose Transporter 1 Human genes 0.000 description 1
- 102100028874 Sodium-dependent serotonin transporter Human genes 0.000 description 1
- 102100020886 Sodium/iodide cotransporter Human genes 0.000 description 1
- 102100034245 Solute carrier family 12 member 6 Human genes 0.000 description 1
- 102100023537 Solute carrier family 2, facilitated glucose transporter member 2 Human genes 0.000 description 1
- 102100033939 Solute carrier family 2, facilitated glucose transporter member 4 Human genes 0.000 description 1
- 102100023102 Solute carrier family 22 member 18 Human genes 0.000 description 1
- 102100036924 Solute carrier family 22 member 5 Human genes 0.000 description 1
- 102100023802 Somatostatin receptor type 2 Human genes 0.000 description 1
- 102100021796 Sonic hedgehog protein Human genes 0.000 description 1
- 101710113849 Sonic hedgehog protein Proteins 0.000 description 1
- 101150100839 Sos1 gene Proteins 0.000 description 1
- 102100038829 Spastin Human genes 0.000 description 1
- 102100037608 Spectrin alpha chain, erythrocytic 1 Human genes 0.000 description 1
- 102100037613 Spectrin beta chain, erythrocytic Human genes 0.000 description 1
- 102100026503 Sperm mitochondrial-associated cysteine-rich protein Human genes 0.000 description 1
- 102100022322 Sperm protein associated with the nucleus on the X chromosome C Human genes 0.000 description 1
- 102100037616 Spermine synthase Human genes 0.000 description 1
- 101000942604 Sphingomonas wittichii (strain DC-6 / KACC 16600) Chloroacetanilide N-alkylformylase, oxygenase component Proteins 0.000 description 1
- 108010061312 Sphingomyelin Phosphodiesterase Proteins 0.000 description 1
- 102000011971 Sphingomyelin Phosphodiesterase Human genes 0.000 description 1
- 102100026263 Sphingomyelin phosphodiesterase Human genes 0.000 description 1
- 208000009415 Spinocerebellar Ataxias Diseases 0.000 description 1
- 102100028026 Statherin Human genes 0.000 description 1
- 108010015330 Steroid 17-alpha-Hydroxylase Proteins 0.000 description 1
- 102100039081 Steroid Delta-isomerase Human genes 0.000 description 1
- 108010048349 Steroidogenic Factor 1 Proteins 0.000 description 1
- 102100029856 Steroidogenic factor 1 Human genes 0.000 description 1
- 102100036325 Sterol 26-hydroxylase, mitochondrial Human genes 0.000 description 1
- 102100021993 Sterol O-acyltransferase 1 Human genes 0.000 description 1
- 102100021685 Stomatin Human genes 0.000 description 1
- 102100021669 Stromal cell-derived factor 1 Human genes 0.000 description 1
- 102100038014 Succinate dehydrogenase [ubiquinone] cytochrome b small subunit, mitochondrial Human genes 0.000 description 1
- 102100023155 Succinate dehydrogenase [ubiquinone] flavoprotein subunit, mitochondrial Human genes 0.000 description 1
- 102100031715 Succinate dehydrogenase assembly factor 2, mitochondrial Human genes 0.000 description 1
- 102100023673 Succinate-semialdehyde dehydrogenase, mitochondrial Human genes 0.000 description 1
- 102100020868 Succinyl-CoA:3-ketoacid coenzyme A transferase 1, mitochondrial Human genes 0.000 description 1
- 102100030113 Sulfate transporter Human genes 0.000 description 1
- 102100020951 Sulfite oxidase, mitochondrial Human genes 0.000 description 1
- 108010021188 Superoxide Dismutase-1 Proteins 0.000 description 1
- 102100038836 Superoxide dismutase [Cu-Zn] Human genes 0.000 description 1
- 102100032891 Superoxide dismutase [Mn], mitochondrial Human genes 0.000 description 1
- 108060007963 Surf-1 Proteins 0.000 description 1
- 102000046669 Surf-1 Human genes 0.000 description 1
- 241000282898 Sus scrofa Species 0.000 description 1
- 101000996723 Sus scrofa Gonadotropin-releasing hormone receptor Proteins 0.000 description 1
- 102100037352 Sushi repeat-containing protein SRPX Human genes 0.000 description 1
- 102100021905 Synapsin-1 Human genes 0.000 description 1
- 102100023532 Synaptic functional regulator FMR1 Human genes 0.000 description 1
- 102100028706 Synaptophysin Human genes 0.000 description 1
- 108091008874 T cell receptors Proteins 0.000 description 1
- 102000016266 T-Cell Antigen Receptors Human genes 0.000 description 1
- 108010014480 T-box transcription factor 5 Proteins 0.000 description 1
- 102100038409 T-box transcription factor TBX3 Human genes 0.000 description 1
- 102100024755 T-box transcription factor TBX5 Human genes 0.000 description 1
- 102100033111 T-cell leukemia homeobox protein 1 Human genes 0.000 description 1
- 102100024219 T-cell surface glycoprotein CD1a Human genes 0.000 description 1
- 102100035794 T-cell surface glycoprotein CD3 epsilon chain Human genes 0.000 description 1
- 102100037911 T-cell surface glycoprotein CD3 gamma chain Human genes 0.000 description 1
- 102100037906 T-cell surface glycoprotein CD3 zeta chain Human genes 0.000 description 1
- 102100027213 T-cell-specific surface glycoprotein CD28 Human genes 0.000 description 1
- 108700012457 TACSTD2 Proteins 0.000 description 1
- 108010032166 TARP Proteins 0.000 description 1
- 102100040296 TATA-box-binding protein Human genes 0.000 description 1
- 101710145783 TATA-box-binding protein Proteins 0.000 description 1
- 102100033456 TGF-beta receptor type-1 Human genes 0.000 description 1
- 102100033455 TGF-beta receptor type-2 Human genes 0.000 description 1
- 102100036073 TIR domain-containing adapter molecule 1 Human genes 0.000 description 1
- 102100036074 TIR domain-containing adapter molecule 2 Human genes 0.000 description 1
- 101150031162 TM4SF1 gene Proteins 0.000 description 1
- 108090000925 TNF receptor-associated factor 2 Proteins 0.000 description 1
- 102100033082 TNF receptor-associated factor 3 Human genes 0.000 description 1
- 102100034779 TRAF family member-associated NF-kappa-B activator Human genes 0.000 description 1
- 101150097293 TSC3 gene Proteins 0.000 description 1
- 101800000849 Tachykinin-associated peptide 2 Proteins 0.000 description 1
- 102100026508 Tafazzin Human genes 0.000 description 1
- 101710175789 Tafazzin Proteins 0.000 description 1
- 101710199973 Tail tube protein Proteins 0.000 description 1
- 102100035155 Telethonin Human genes 0.000 description 1
- 208000028911 Temporomandibular Joint disease Diseases 0.000 description 1
- 102100024545 Tensin-4 Human genes 0.000 description 1
- 102100035116 Testis-expressed protein 15 Human genes 0.000 description 1
- 108010055044 Tetanus Toxin Proteins 0.000 description 1
- 102100040952 Tetraspanin-7 Human genes 0.000 description 1
- 101150050472 Tfr2 gene Proteins 0.000 description 1
- 101000874827 Thermus thermophilus (strain ATCC 27634 / DSM 579 / HB8) Dephospho-CoA kinase Proteins 0.000 description 1
- 102100034162 Thiopurine S-methyltransferase Human genes 0.000 description 1
- 108010022173 Thiosulfate sulfurtransferase Proteins 0.000 description 1
- 102100024855 Three-prime repair exonuclease 1 Human genes 0.000 description 1
- 102100026966 Thrombomodulin Human genes 0.000 description 1
- 208000007536 Thrombosis Diseases 0.000 description 1
- 102100036704 Thromboxane A2 receptor Human genes 0.000 description 1
- 102400000160 Thymopentin Human genes 0.000 description 1
- 101800001703 Thymopentin Proteins 0.000 description 1
- 101100505910 Thymus vulgaris TPS3 gene Proteins 0.000 description 1
- 102100028702 Thyroid hormone receptor alpha Human genes 0.000 description 1
- 102100033451 Thyroid hormone receptor beta Human genes 0.000 description 1
- 101710113649 Thyroid peroxidase Proteins 0.000 description 1
- 102100029337 Thyrotropin receptor Human genes 0.000 description 1
- 102100029530 Thyrotropin subunit beta Human genes 0.000 description 1
- 101800004623 Thyrotropin-releasing hormone Proteins 0.000 description 1
- 108010031429 Tissue Inhibitor of Metalloproteinase-3 Proteins 0.000 description 1
- 108090000373 Tissue Plasminogen Activator Proteins 0.000 description 1
- 102100040526 Tissue alpha-L-fucosidase Human genes 0.000 description 1
- 102100033571 Tissue-type plasminogen activator Human genes 0.000 description 1
- 102100037454 Torsin-1A Human genes 0.000 description 1
- 241000223997 Toxoplasma gondii Species 0.000 description 1
- 102100021386 Trans-acting T-cell-specific transcription factor GATA-3 Human genes 0.000 description 1
- 102100040423 Transcobalamin-2 Human genes 0.000 description 1
- 108010057666 Transcription Factor CHOP Proteins 0.000 description 1
- 102000040945 Transcription factor Human genes 0.000 description 1
- 108091023040 Transcription factor Proteins 0.000 description 1
- 102000004893 Transcription factor AP-2 Human genes 0.000 description 1
- 108090001039 Transcription factor AP-2 Proteins 0.000 description 1
- 102100028507 Transcription factor E3 Human genes 0.000 description 1
- 102100026385 Transcription factor Ovo-like 2 Human genes 0.000 description 1
- 102100038808 Transcription factor SOX-10 Human genes 0.000 description 1
- 102100034204 Transcription factor SOX-9 Human genes 0.000 description 1
- 102100035222 Transcription initiation factor TFIID subunit 1 Human genes 0.000 description 1
- 102100021172 Transcription initiation factor TFIID subunit 7-like Human genes 0.000 description 1
- 102100030780 Transcriptional activator Myb Human genes 0.000 description 1
- 102100026143 Transferrin receptor protein 2 Human genes 0.000 description 1
- 102000004887 Transforming Growth Factor beta Human genes 0.000 description 1
- 108010082684 Transforming Growth Factor-beta Type II Receptor Proteins 0.000 description 1
- 102100033460 Transforming growth factor beta-3 proprotein Human genes 0.000 description 1
- 102100021398 Transforming growth factor-beta-induced protein ig-h3 Human genes 0.000 description 1
- 108060008539 Transglutaminase Proteins 0.000 description 1
- 208000008963 Transient myeloproliferative syndrome Diseases 0.000 description 1
- 102100033055 Transketolase Human genes 0.000 description 1
- 102100033690 Transmembrane channel-like protein 1 Human genes 0.000 description 1
- 102100040666 Transmembrane protein 185A Human genes 0.000 description 1
- 102100029290 Transthyretin Human genes 0.000 description 1
- 102100040421 Treacle protein Human genes 0.000 description 1
- 102100029677 Trehalase Human genes 0.000 description 1
- 101100395211 Trichoderma harzianum his3 gene Proteins 0.000 description 1
- 206010044628 Trichothiodystrophy Diseases 0.000 description 1
- 108010039203 Tripeptidyl-Peptidase 1 Proteins 0.000 description 1
- 102100034197 Tripeptidyl-peptidase 1 Human genes 0.000 description 1
- 102100033632 Tropomyosin alpha-1 chain Human genes 0.000 description 1
- 102100036859 Troponin I, cardiac muscle Human genes 0.000 description 1
- 102100036788 Tubulin beta-4A chain Human genes 0.000 description 1
- 102100033469 Tubulointerstitial nephritis antigen-like Human genes 0.000 description 1
- 102100040192 Tudor domain-containing protein 1 Human genes 0.000 description 1
- 108010078814 Tumor Suppressor Protein p53 Proteins 0.000 description 1
- 102100040247 Tumor necrosis factor Human genes 0.000 description 1
- 108050002568 Tumor necrosis factor ligand superfamily member 6 Proteins 0.000 description 1
- 102100032100 Tumor necrosis factor ligand superfamily member 8 Human genes 0.000 description 1
- 102100028787 Tumor necrosis factor receptor superfamily member 11A Human genes 0.000 description 1
- 102100032236 Tumor necrosis factor receptor superfamily member 11B Human genes 0.000 description 1
- 102100033732 Tumor necrosis factor receptor superfamily member 1A Human genes 0.000 description 1
- 102100033733 Tumor necrosis factor receptor superfamily member 1B Human genes 0.000 description 1
- 101710187830 Tumor necrosis factor receptor superfamily member 1B Proteins 0.000 description 1
- 102100022153 Tumor necrosis factor receptor superfamily member 4 Human genes 0.000 description 1
- 101710165473 Tumor necrosis factor receptor superfamily member 4 Proteins 0.000 description 1
- 102100030810 Tumor necrosis factor receptor superfamily member EDAR Human genes 0.000 description 1
- 102100033081 Tumor necrosis factor receptor type 1-associated DEATH domain protein Human genes 0.000 description 1
- 102100027881 Tumor protein 63 Human genes 0.000 description 1
- 101710140697 Tumor protein 63 Proteins 0.000 description 1
- 102100040879 Tumor susceptibility gene 101 protein Human genes 0.000 description 1
- 102100027212 Tumor-associated calcium signal transducer 2 Human genes 0.000 description 1
- 102100027193 Twinkle mtDNA helicase Human genes 0.000 description 1
- 102100030398 Twist-related protein 1 Human genes 0.000 description 1
- 108010046308 Type II DNA Topoisomerases Proteins 0.000 description 1
- 102100026803 Type-1 angiotensin II receptor Human genes 0.000 description 1
- 102100039094 Tyrosinase Human genes 0.000 description 1
- 102100021869 Tyrosine aminotransferase Human genes 0.000 description 1
- 101710175714 Tyrosine aminotransferase Proteins 0.000 description 1
- 102100022596 Tyrosine-protein kinase ABL1 Human genes 0.000 description 1
- 102100029823 Tyrosine-protein kinase BTK Human genes 0.000 description 1
- 102100025387 Tyrosine-protein kinase JAK3 Human genes 0.000 description 1
- 102100021125 Tyrosine-protein kinase ZAP-70 Human genes 0.000 description 1
- 102100040118 U4/U6 small nuclear ribonucleoprotein Prp31 Human genes 0.000 description 1
- 102100021436 UDP-glucose 4-epimerase Human genes 0.000 description 1
- 102100029152 UDP-glucuronosyltransferase 1A1 Human genes 0.000 description 1
- 102100020797 UMP-CMP kinase Human genes 0.000 description 1
- 101150076392 UOX gene Proteins 0.000 description 1
- 102100039547 UbiA prenyltransferase domain-containing protein 1 Human genes 0.000 description 1
- 108010005656 Ubiquitin Thiolesterase Proteins 0.000 description 1
- 102100025038 Ubiquitin carboxyl-terminal hydrolase isozyme L1 Human genes 0.000 description 1
- 102100037261 Ubiquitin-conjugating enzyme E2 A Human genes 0.000 description 1
- 102100037160 Ubiquitin-like modifier-activating enzyme 1 Human genes 0.000 description 1
- 102100026728 Uncharacterized protein FAM215A Human genes 0.000 description 1
- 102100035824 Unconventional myosin-Ig Human genes 0.000 description 1
- 102100031835 Unconventional myosin-VIIa Human genes 0.000 description 1
- 102100030409 Unconventional myosin-Va Human genes 0.000 description 1
- 102100029836 Unconventional myosin-XV Human genes 0.000 description 1
- 108091023045 Untranslated Region Proteins 0.000 description 1
- 101710166980 Uridylate kinase Proteins 0.000 description 1
- 102100038853 Uroplakin-1b Human genes 0.000 description 1
- 102100024118 Uroporphyrinogen decarboxylase Human genes 0.000 description 1
- 108020000963 Uroporphyrinogen-III synthase Proteins 0.000 description 1
- 102100034397 Uroporphyrinogen-III synthase Human genes 0.000 description 1
- 201000008554 Usher syndrome type 3A Diseases 0.000 description 1
- 102100037930 Usherin Human genes 0.000 description 1
- 102100029591 V(D)J recombination-activating protein 2 Human genes 0.000 description 1
- 102100039468 V-type proton ATPase subunit B, kidney isoform Human genes 0.000 description 1
- 101150045640 VWF gene Proteins 0.000 description 1
- 102100035048 Vacuolar ATPase assembly integral membrane protein VMA21 Human genes 0.000 description 1
- 102100039114 Vacuolar protein sorting-associated protein 13A Human genes 0.000 description 1
- 102100022962 Vam6/Vps39-like protein Human genes 0.000 description 1
- 108010053096 Vascular Endothelial Growth Factor Receptor-1 Proteins 0.000 description 1
- 108010053100 Vascular Endothelial Growth Factor Receptor-3 Proteins 0.000 description 1
- 102100033178 Vascular endothelial growth factor receptor 1 Human genes 0.000 description 1
- 102100033179 Vascular endothelial growth factor receptor 3 Human genes 0.000 description 1
- 102100037108 Vasopressin V2 receptor Human genes 0.000 description 1
- 102100024591 Very long-chain specific acyl-CoA dehydrogenase, mitochondrial Human genes 0.000 description 1
- 108010067390 Viral Proteins Proteins 0.000 description 1
- 102100020676 Visual system homeobox 2 Human genes 0.000 description 1
- 102100038182 Vitamin K-dependent gamma-carboxylase Human genes 0.000 description 1
- 102100029477 Vitamin K-dependent protein C Human genes 0.000 description 1
- 102100033031 Voltage-dependent L-type calcium channel subunit alpha-1F Human genes 0.000 description 1
- 102100025807 Voltage-dependent L-type calcium channel subunit beta-2 Human genes 0.000 description 1
- 102100025836 Voltage-dependent L-type calcium channel subunit beta-4 Human genes 0.000 description 1
- 102100037059 Voltage-dependent calcium channel subunit alpha-2/delta-1 Human genes 0.000 description 1
- 102100029478 WD repeat-containing protein 62 Human genes 0.000 description 1
- 201000003263 Waardenburg syndrome type 2A Diseases 0.000 description 1
- 208000008256 Waardenburg syndrome type 2B Diseases 0.000 description 1
- 108010007135 Werner Syndrome Helicase Proteins 0.000 description 1
- 102100023034 Wiskott-Aldrich syndrome protein Human genes 0.000 description 1
- 108091007416 X-inactive specific transcript Proteins 0.000 description 1
- 208000032470 X-linked 1 intellectual disability Diseases 0.000 description 1
- 208000034576 X-linked 14 intellectual disability Diseases 0.000 description 1
- 208000032009 X-linked 2 intellectual disability Diseases 0.000 description 1
- 208000034560 X-linked 20 intellectual disability Diseases 0.000 description 1
- 208000031691 X-linked Charcot-Marie-Tooth disease type 2 Diseases 0.000 description 1
- 208000031692 X-linked Charcot-Marie-Tooth disease type 3 Diseases 0.000 description 1
- 108700042462 X-linked Nuclear Proteins 0.000 description 1
- 201000002380 X-linked amelogenesis imperfecta hypoplastic/hypomaturation 2 Diseases 0.000 description 1
- 208000002564 X-linked cardiac valvular dysplasia Diseases 0.000 description 1
- 201000000467 X-linked cone-rod dystrophy 1 Diseases 0.000 description 1
- 201000000465 X-linked cone-rod dystrophy 2 Diseases 0.000 description 1
- 208000029823 X-linked deafness 1 Diseases 0.000 description 1
- 208000029828 X-linked deafness 3 Diseases 0.000 description 1
- 208000029830 X-linked deafness 4 Diseases 0.000 description 1
- 201000003426 X-linked dystonia-parkinsonism Diseases 0.000 description 1
- 208000032344 X-linked myopia 1 Diseases 0.000 description 1
- 102100040089 X-linked retinitis pigmentosa GTPase regulator-interacting protein 1 Human genes 0.000 description 1
- 208000014914 X-linked spinal muscular atrophy 2 Diseases 0.000 description 1
- 108091035715 XIST (gene) Proteins 0.000 description 1
- 108700031763 Xeroderma Pigmentosum Group D Proteins 0.000 description 1
- 102100032726 Y+L amino acid transporter 1 Human genes 0.000 description 1
- 102100025085 Zinc finger MYM-type protein 2 Human genes 0.000 description 1
- 102100025417 Zinc finger MYM-type protein 3 Human genes 0.000 description 1
- 102100023405 Zinc finger X-chromosomal protein Human genes 0.000 description 1
- 102100040802 Zinc finger Y-chromosomal protein Human genes 0.000 description 1
- 102100024672 Zinc finger protein 35 Human genes 0.000 description 1
- 102100024669 Zinc finger protein 41 Human genes 0.000 description 1
- 102100040724 Zinc finger protein 711 Human genes 0.000 description 1
- 102100023492 Zinc finger protein ZIC 2 Human genes 0.000 description 1
- 102100023495 Zinc finger protein ZIC 3 Human genes 0.000 description 1
- 102100023140 Zinc transporter ZIP4 Human genes 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 102000035181 adaptor proteins Human genes 0.000 description 1
- 108091005764 adaptor proteins Proteins 0.000 description 1
- 230000000240 adjuvant effect Effects 0.000 description 1
- 208000025531 adult-onset foveomacular vitelliform dystrophy Diseases 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229960004784 allergens Drugs 0.000 description 1
- 230000000172 allergic effect Effects 0.000 description 1
- 108010075843 alpha-2-HS-Glycoprotein Proteins 0.000 description 1
- 102000012005 alpha-2-HS-Glycoprotein Human genes 0.000 description 1
- 108010009380 alpha-N-acetyl-D-glucosaminidase Proteins 0.000 description 1
- 229940037003 alum Drugs 0.000 description 1
- WNROFYMDJYEPJX-UHFFFAOYSA-K aluminium hydroxide Chemical compound [OH-].[OH-].[OH-].[Al+3] WNROFYMDJYEPJX-UHFFFAOYSA-K 0.000 description 1
- 229910021502 aluminium hydroxide Inorganic materials 0.000 description 1
- 235000021120 animal protein Nutrition 0.000 description 1
- 208000026753 anterior segment dysgenesis Diseases 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 108010036226 antigen CYFRA21.1 Proteins 0.000 description 1
- 230000030741 antigen processing and presentation Effects 0.000 description 1
- 230000000890 antigenic effect Effects 0.000 description 1
- 230000001640 apoptogenic effect Effects 0.000 description 1
- 201000002496 arrhythmogenic right ventricular dysplasia 1 Diseases 0.000 description 1
- 101150085047 asd-1 gene Proteins 0.000 description 1
- 208000037741 atherosclerosis susceptibility Diseases 0.000 description 1
- 208000010668 atopic eczema Diseases 0.000 description 1
- 230000003190 augmentative effect Effects 0.000 description 1
- 208000030759 autism susceptibility 1 Diseases 0.000 description 1
- 230000001363 autoimmune Effects 0.000 description 1
- 208000031592 autosomal dominant myopia 2 Diseases 0.000 description 1
- 208000021033 autosomal dominant polycystic liver disease Diseases 0.000 description 1
- 208000036479 autosomal dominant scapuloperoneal spinal muscular atrophy Diseases 0.000 description 1
- 201000006257 autosomal recessive nonsyndromic deafness 5 Diseases 0.000 description 1
- 208000031397 autosomal recessive nonsyndromic hearing loss 5 Diseases 0.000 description 1
- 201000003291 autosomal recessive osteopetrosis 1 Diseases 0.000 description 1
- 102100021298 b(0,+)-type amino acid transporter 1 Human genes 0.000 description 1
- 239000000688 bacterial toxin Substances 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 201000008181 benign familial infantile epilepsy Diseases 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000001185 bone marrow Anatomy 0.000 description 1
- 102100037490 cAMP-dependent protein kinase type I-alpha regulatory subunit Human genes 0.000 description 1
- 102100038623 cGMP-gated cation channel alpha-1 Human genes 0.000 description 1
- 201000009828 cataract 10 multiple types Diseases 0.000 description 1
- 201000009912 cataract 32 multiple types Diseases 0.000 description 1
- 101150055276 ced-3 gene Proteins 0.000 description 1
- 101150039936 ced-9 gene Proteins 0.000 description 1
- 230000030833 cell death Effects 0.000 description 1
- 208000031406 ceroid lipofuscinosis, neuronal, 4 (Kufs type) Diseases 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 208000008403 chondrocalcinosis 1 Diseases 0.000 description 1
- 201000008675 chorea-acanthocytosis Diseases 0.000 description 1
- 208000029659 chromosome 2q37 deletion syndrome Diseases 0.000 description 1
- 230000024203 complement activation Effects 0.000 description 1
- 208000003908 cone-rod dystrophy 1 Diseases 0.000 description 1
- 208000005011 cone-rod dystrophy 5 Diseases 0.000 description 1
- 208000035443 congenital autosomal dominant nystagmus 2 Diseases 0.000 description 1
- 208000031350 congenital autosomal dominant nystagmus 4 Diseases 0.000 description 1
- 208000027332 congenital dyserythropoietic anemia type II Diseases 0.000 description 1
- 208000012231 congenital dyserythropoietic anemia type III Diseases 0.000 description 1
- 201000000728 congenital hereditary endothelial dystrophy of cornea Diseases 0.000 description 1
- 208000028494 congenital hereditary endothelial dystrophy type I Diseases 0.000 description 1
- 201000006948 congenital merosin-deficient muscular dystrophy 1A Diseases 0.000 description 1
- 201000006953 congenital muscular dystrophy 1B Diseases 0.000 description 1
- 208000028889 congenital nystagmus 2 Diseases 0.000 description 1
- 208000028886 congenital nystagmus 4 Diseases 0.000 description 1
- 239000013256 coordination polymer Substances 0.000 description 1
- 230000000139 costimulatory effect Effects 0.000 description 1
- 238000004690 coupled electron pair approximation Methods 0.000 description 1
- 101150044687 crm gene Proteins 0.000 description 1
- 238000009109 curative therapy Methods 0.000 description 1
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 1
- 125000000151 cysteine group Chemical group N[C@@H](CS)C(=O)* 0.000 description 1
- 108010012052 cytochrome P-450 CYP2C subfamily Proteins 0.000 description 1
- 210000000805 cytoplasm Anatomy 0.000 description 1
- 108091007930 cytoplasmic receptors Proteins 0.000 description 1
- 230000001086 cytosolic effect Effects 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 230000005860 defense response to virus Effects 0.000 description 1
- 229940127276 delta-like ligand 3 Drugs 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 208000036969 diffuse hereditary with spheroids 1 leukoencephalopathy Diseases 0.000 description 1
- 230000029087 digestion Effects 0.000 description 1
- 108020001096 dihydrofolate reductase Proteins 0.000 description 1
- 238000010494 dissociation reaction Methods 0.000 description 1
- 230000005593 dissociations Effects 0.000 description 1
- 208000013984 distal hereditary motor neuronopathy type 2 Diseases 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 208000001321 ectrodactyly, ectodermal dysplasia, and cleft lip-palate syndrome 1 Diseases 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 108060002564 ependymin Proteins 0.000 description 1
- 238000011067 equilibration Methods 0.000 description 1
- 208000027386 essential tremor 1 Diseases 0.000 description 1
- 201000001267 familial hypocalciuric hypercalcemia 2 Diseases 0.000 description 1
- 201000001265 familial hypocalciuric hypercalcemia 3 Diseases 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- WDQNIWFZKXZFAY-UHFFFAOYSA-M fentin acetate Chemical compound CC([O-])=O.C1=CC=CC=C1[Sn+](C=1C=CC=CC=1)C1=CC=CC=C1 WDQNIWFZKXZFAY-UHFFFAOYSA-M 0.000 description 1
- VLMZMRDOMOGGFA-WDBKCZKBSA-N festuclavine Chemical compound C1=CC([C@H]2C[C@H](CN(C)[C@@H]2C2)C)=C3C2=CNC3=C1 VLMZMRDOMOGGFA-WDBKCZKBSA-N 0.000 description 1
- 239000000246 fibrin derivative Substances 0.000 description 1
- 229940012952 fibrinogen Drugs 0.000 description 1
- 208000030376 fibronectin glomerulopathy Diseases 0.000 description 1
- 108700014844 flt3 ligand Proteins 0.000 description 1
- 108010006620 fodrin Proteins 0.000 description 1
- 101150078861 fos gene Proteins 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 230000002538 fungal effect Effects 0.000 description 1
- 108010066264 gastrin 17 Proteins 0.000 description 1
- GKDWRERMBNGKCZ-RNXBIMIWSA-N gastrin-17 Chemical compound C([C@@H](C(=O)NCC(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@H](C)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H]1N(CCC1)C(=O)CNC(=O)[C@H]1NC(=O)CC1)C1=CC=C(O)C=C1 GKDWRERMBNGKCZ-RNXBIMIWSA-N 0.000 description 1
- 102000034356 gene-regulatory proteins Human genes 0.000 description 1
- 108091006104 gene-regulatory proteins Proteins 0.000 description 1
- 230000002068 genetic effect Effects 0.000 description 1
- 210000005046 glial fibrillary acidic protein Anatomy 0.000 description 1
- 208000030377 glomuvenous malformation Diseases 0.000 description 1
- XLXSAKCOAKORKW-UHFFFAOYSA-N gonadorelin Chemical compound C1CCC(C(=O)NCC(N)=O)N1C(=O)C(CCCN=C(N)N)NC(=O)C(CC(C)C)NC(=O)CNC(=O)C(NC(=O)C(CO)NC(=O)C(CC=1C2=CC=CC=C2NC=1)NC(=O)C(CC=1NC=NC=1)NC(=O)C1NC(=O)CC1)CC1=CC=C(O)C=C1 XLXSAKCOAKORKW-UHFFFAOYSA-N 0.000 description 1
- 229940037467 helicobacter pylori Drugs 0.000 description 1
- 210000002443 helper t lymphocyte Anatomy 0.000 description 1
- 101150055960 hemB gene Proteins 0.000 description 1
- 210000003958 hematopoietic stem cell Anatomy 0.000 description 1
- 108010080417 hemozoin Proteins 0.000 description 1
- 201000007787 hereditary spastic paraplegia 23 Diseases 0.000 description 1
- 201000007474 hereditary spastic paraplegia 3A Diseases 0.000 description 1
- 201000007473 hereditary spastic paraplegia 4 Diseases 0.000 description 1
- 201000007104 hereditary spastic paraplegia 5A Diseases 0.000 description 1
- 108010044853 histidine-rich proteins Proteins 0.000 description 1
- 201000008665 holoprosencephaly 1 Diseases 0.000 description 1
- 208000008777 holoprosencephaly 2 Diseases 0.000 description 1
- 230000008348 humoral response Effects 0.000 description 1
- 108010074834 hydroxyneurosporene desaturase Proteins 0.000 description 1
- 201000010551 hypertrophic cardiomyopathy 2 Diseases 0.000 description 1
- 201000010517 hypertrophic cardiomyopathy 6 Diseases 0.000 description 1
- 208000031813 idiopathic 1 basal ganglia calcification Diseases 0.000 description 1
- 230000001900 immune effect Effects 0.000 description 1
- 208000011635 immunodeficiency 61 Diseases 0.000 description 1
- 230000001976 improved effect Effects 0.000 description 1
- 201000006747 infectious mononucleosis Diseases 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 108010092830 integrin alpha7beta1 Proteins 0.000 description 1
- 230000010468 interferon response Effects 0.000 description 1
- 108010074108 interleukin-21 Proteins 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 102000027411 intracellular receptors Human genes 0.000 description 1
- 108091008582 intracellular receptors Proteins 0.000 description 1
- 230000004068 intracellular signaling Effects 0.000 description 1
- 108010028309 kalinin Proteins 0.000 description 1
- 108010045069 keyhole-limpet hemocyanin Proteins 0.000 description 1
- 230000002147 killing effect Effects 0.000 description 1
- 108010008094 laminin alpha 3 Proteins 0.000 description 1
- 230000021633 leukocyte mediated immunity Effects 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 230000005923 long-lasting effect Effects 0.000 description 1
- 210000002751 lymph Anatomy 0.000 description 1
- 210000002540 macrophage Anatomy 0.000 description 1
- 201000006010 major affective disorder 1 Diseases 0.000 description 1
- 201000006009 major affective disorder 2 Diseases 0.000 description 1
- 210000004962 mammalian cell Anatomy 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- AEUKDPKXTPNBNY-XEYRWQBLSA-N mcp 2 Chemical compound C([C@@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CS)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)NC(=O)CNC(=O)[C@H](C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CC(C)C)NC(=O)[C@H](CS)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CS)NC(=O)[C@H](C)NC(=O)[C@H](CS)NC(=O)[C@@H](NC(=O)[C@@H](N)C(C)C)C(C)C)C1=CC=CC=C1 AEUKDPKXTPNBNY-XEYRWQBLSA-N 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 229910044991 metal oxide Inorganic materials 0.000 description 1
- 150000004706 metal oxides Chemical class 0.000 description 1
- 238000012737 microarray-based gene expression Methods 0.000 description 1
- 244000000010 microbial pathogen Species 0.000 description 1
- 101150071637 mre11 gene Proteins 0.000 description 1
- 208000005340 mucopolysaccharidosis III Diseases 0.000 description 1
- 208000036707 mucopolysaccharidosis type 3C Diseases 0.000 description 1
- 208000012224 mucopolysaccharidosis type IIIC Diseases 0.000 description 1
- 108010066052 multidrug resistance-associated protein 1 Proteins 0.000 description 1
- 208000033573 multinodular 1 with or without Sertoli-Leydig cell tumors goiter Diseases 0.000 description 1
- 201000006417 multiple sclerosis Diseases 0.000 description 1
- 208000034420 multiple type III exostoses Diseases 0.000 description 1
- 238000012243 multiplex automated genomic engineering Methods 0.000 description 1
- 101150091791 mvk gene Proteins 0.000 description 1
- LBCGUKCXRVUULK-QGZVFWFLSA-N n-[2-(1,3-benzodioxol-5-yl)ethyl]-1-[2-(1h-imidazol-1-yl)-6-methylpyrimidin-4-yl]-d-prolinamide Chemical compound N=1C(C)=CC(N2[C@H](CCC2)C(=O)NCCC=2C=C3OCOC3=CC=2)=NC=1N1C=CN=C1 LBCGUKCXRVUULK-QGZVFWFLSA-N 0.000 description 1
- AEMBWNDIEFEPTH-UHFFFAOYSA-N n-tert-butyl-n-ethylnitrous amide Chemical compound CCN(N=O)C(C)(C)C AEMBWNDIEFEPTH-UHFFFAOYSA-N 0.000 description 1
- 208000031580 neurogenic type arthrogryposis multiplex congenita 2 Diseases 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 208000033581 nocturnal 1 enuresis Diseases 0.000 description 1
- 208000023876 non-syndromic X-linked intellectual disability 1 Diseases 0.000 description 1
- 208000024746 non-syndromic X-linked intellectual disability 14 Diseases 0.000 description 1
- 208000024707 non-syndromic X-linked intellectual disability 2 Diseases 0.000 description 1
- 208000024733 non-syndromic X-linked intellectual disability 20 Diseases 0.000 description 1
- 102000044158 nucleic acid binding protein Human genes 0.000 description 1
- 108700020942 nucleic acid binding protein Proteins 0.000 description 1
- 238000011330 nucleic acid test Methods 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 208000033298 open angle B glaucoma 1 Diseases 0.000 description 1
- 208000000895 ophthalmoplegia, external, and myopia Diseases 0.000 description 1
- 208000027014 optic atrophy 1 Diseases 0.000 description 1
- 208000025019 optic atrophy 2 Diseases 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 201000006284 orofacial cleft 1 Diseases 0.000 description 1
- 201000001937 osteoporosis-pseudoglioma syndrome Diseases 0.000 description 1
- 208000007138 otopalatodigital syndrome type 1 Diseases 0.000 description 1
- 208000037346 otosclerosis 1 Diseases 0.000 description 1
- 244000045947 parasite Species 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 101150008465 pdb1 gene Proteins 0.000 description 1
- 229930192851 perforin Natural products 0.000 description 1
- 210000001539 phagocyte Anatomy 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 108010031345 placental alkaline phosphatase Proteins 0.000 description 1
- 210000002381 plasma Anatomy 0.000 description 1
- 229920002791 poly-4-hydroxybutyrate Polymers 0.000 description 1
- 208000030151 polycystic kidney disease 3 with or without polycystic liver disease Diseases 0.000 description 1
- 201000010065 polycystic ovary syndrome Diseases 0.000 description 1
- 108040000983 polyphosphate:AMP phosphotransferase activity proteins Proteins 0.000 description 1
- 208000036335 preeclampsia/eclampsia 1 Diseases 0.000 description 1
- 201000001682 primary autosomal recessive microcephaly 2 with or without cortical malformations Diseases 0.000 description 1
- 208000032288 primary infantile B glaucoma 3 Diseases 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000000770 proinflammatory effect Effects 0.000 description 1
- 108020004930 proline dehydrogenase Proteins 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 108020001580 protein domains Proteins 0.000 description 1
- 230000017854 proteolysis Effects 0.000 description 1
- 108010033990 rab27 GTP-Binding Proteins Proteins 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000009711 regulatory function Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 108091008726 retinoic acid receptors α Proteins 0.000 description 1
- 210000003705 ribosome Anatomy 0.000 description 1
- 108020000318 saccharopine dehydrogenase Proteins 0.000 description 1
- 235000019515 salmon Nutrition 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 201000000381 schizophrenia 1 Diseases 0.000 description 1
- 201000000379 schizophrenia 2 Diseases 0.000 description 1
- 201000000377 schizophrenia 3 Diseases 0.000 description 1
- 201000000372 schizophrenia 4 Diseases 0.000 description 1
- 201000000370 schizophrenia 6 Diseases 0.000 description 1
- 206010051951 scimitar syndrome Diseases 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 102000030938 small GTPase Human genes 0.000 description 1
- 108060007624 small GTPase Proteins 0.000 description 1
- 108010039827 snRNP Core Proteins Proteins 0.000 description 1
- 201000003624 spinocerebellar ataxia type 1 Diseases 0.000 description 1
- 201000003262 split hand-foot malformation 1 Diseases 0.000 description 1
- 208000004452 split hand-foot malformation 2 Diseases 0.000 description 1
- 201000003268 split hand-foot malformation 3 Diseases 0.000 description 1
- 108010087686 src-Family Kinases Proteins 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- CXVGEDCSTKKODG-UHFFFAOYSA-N sulisobenzone Chemical compound C1=C(S(O)(=O)=O)C(OC)=CC(O)=C1C(=O)C1=CC=CC=C1 CXVGEDCSTKKODG-UHFFFAOYSA-N 0.000 description 1
- 108010045815 superoxide dismutase 2 Proteins 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 229920003002 synthetic resin Polymers 0.000 description 1
- 239000000057 synthetic resin Substances 0.000 description 1
- WWJZWCUNLNYYAU-UHFFFAOYSA-N temephos Chemical compound C1=CC(OP(=S)(OC)OC)=CC=C1SC1=CC=C(OP(=S)(OC)OC)C=C1 WWJZWCUNLNYYAU-UHFFFAOYSA-N 0.000 description 1
- 229940118376 tetanus toxin Drugs 0.000 description 1
- ZRKFYGHZFMAOKI-QMGMOQQFSA-N tgfbeta Chemical compound C([C@H](NC(=O)[C@H](C(C)C)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CC(C)C)NC(=O)CNC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CCSC)C(C)C)[C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O)C1=CC=C(O)C=C1 ZRKFYGHZFMAOKI-QMGMOQQFSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- PSWFFKRAVBDQEG-YGQNSOCVSA-N thymopentin Chemical compound NC(N)=NCCC[C@H](N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 PSWFFKRAVBDQEG-YGQNSOCVSA-N 0.000 description 1
- 229960004517 thymopentin Drugs 0.000 description 1
- 201000003315 torsion dystonia 4 Diseases 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 208000037918 transfusion-transmitted disease Diseases 0.000 description 1
- 102000003601 transglutaminase Human genes 0.000 description 1
- 108010058734 transglutaminase 1 Proteins 0.000 description 1
- 201000003569 transient neonatal diabetes mellitus Diseases 0.000 description 1
- 102000035160 transmembrane proteins Human genes 0.000 description 1
- 108091005703 transmembrane proteins Proteins 0.000 description 1
- 108010020589 trehalose-6-phosphate synthase Proteins 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 208000035408 type 1 diabetes mellitus 1 Diseases 0.000 description 1
- 201000007906 type 1 diabetes mellitus 2 Diseases 0.000 description 1
- 102000009310 vitamin D receptors Human genes 0.000 description 1
- 108050000156 vitamin D receptors Proteins 0.000 description 1
- 208000020939 vitelliform macular dystrophy 1 Diseases 0.000 description 1
- 102100036537 von Willebrand factor Human genes 0.000 description 1
- WCNMEQDMUYVWMJ-JPZHCBQBSA-N wybutoxosine Chemical compound C1=NC=2C(=O)N3C(CC([C@H](NC(=O)OC)C(=O)OC)OO)=C(C)N=C3N(C)C=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O WCNMEQDMUYVWMJ-JPZHCBQBSA-N 0.000 description 1
- 108010073629 xeroderma pigmentosum group F protein Proteins 0.000 description 1
- 208000036381 Åland Islands eye disease Diseases 0.000 description 1
Classifications
-
- 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
- A61K39/39—Medicinal preparations containing antigens or antibodies characterised by the immunostimulating additives, e.g. chemical adjuvants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/0005—Vertebrate antigens
- A61K39/0011—Cancer antigens
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/0005—Vertebrate antigens
- A61K39/0011—Cancer antigens
- A61K39/001102—Receptors, cell surface antigens or cell surface determinants
- A61K39/001103—Receptors for growth factors
- A61K39/001106—Her-2/neu/ErbB2, Her-3/ErbB3 or Her 4/ErbB4
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/0005—Vertebrate antigens
- A61K39/0011—Cancer antigens
- A61K39/001102—Receptors, cell surface antigens or cell surface determinants
- A61K39/001103—Receptors for growth factors
- A61K39/001109—Vascular endothelial growth factor receptors [VEGFR]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/0005—Vertebrate antigens
- A61K39/0011—Cancer antigens
- A61K39/001102—Receptors, cell surface antigens or cell surface determinants
- A61K39/001111—Immunoglobulin superfamily
- A61K39/001112—CD19 or B4
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/0005—Vertebrate antigens
- A61K39/0011—Cancer antigens
- A61K39/001102—Receptors, cell surface antigens or cell surface determinants
- A61K39/001111—Immunoglobulin superfamily
- A61K39/001113—CD22, BL-CAM, siglec-2 or sialic acid- binding Ig-related lectin 2
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/0005—Vertebrate antigens
- A61K39/0011—Cancer antigens
- A61K39/001102—Receptors, cell surface antigens or cell surface determinants
- A61K39/001116—Receptors for cytokines
- A61K39/001117—Receptors for tumor necrosis factors [TNF], e.g. lymphotoxin receptor [LTR] or CD30
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/0005—Vertebrate antigens
- A61K39/0011—Cancer antigens
- A61K39/001102—Receptors, cell surface antigens or cell surface determinants
- A61K39/001122—Ephrin Receptors [Eph]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/0005—Vertebrate antigens
- A61K39/0011—Cancer antigens
- A61K39/001102—Receptors, cell surface antigens or cell surface determinants
- A61K39/001124—CD20
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/0005—Vertebrate antigens
- A61K39/0011—Cancer antigens
- A61K39/001102—Receptors, cell surface antigens or cell surface determinants
- A61K39/001129—Molecules with a "CD" designation not provided for elsewhere
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/0005—Vertebrate antigens
- A61K39/0011—Cancer antigens
- A61K39/00113—Growth factors
- A61K39/001132—Fibroblast growth factors [FGF]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/0005—Vertebrate antigens
- A61K39/0011—Cancer antigens
- A61K39/00113—Growth factors
- A61K39/001134—Transforming growth factor [TGF]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/0005—Vertebrate antigens
- A61K39/0011—Cancer antigens
- A61K39/00113—Growth factors
- A61K39/001135—Vascular endothelial growth factor [VEGF]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/0005—Vertebrate antigens
- A61K39/0011—Cancer antigens
- A61K39/001136—Cytokines
- A61K39/00114—Interleukins [IL]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/0005—Vertebrate antigens
- A61K39/0011—Cancer antigens
- A61K39/001148—Regulators of development
- A61K39/001149—Cell cycle regulated proteins, e.g. cyclin, CDC, CDK or INK-CCR
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/0005—Vertebrate antigens
- A61K39/0011—Cancer antigens
- A61K39/001148—Regulators of development
- A61K39/00115—Apoptosis related proteins, e.g. survivin or livin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/0005—Vertebrate antigens
- A61K39/0011—Cancer antigens
- A61K39/001148—Regulators of development
- A61K39/00115—Apoptosis related proteins, e.g. survivin or livin
- A61K39/001151—Apoptosis related proteins, e.g. survivin or livin p53
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/0005—Vertebrate antigens
- A61K39/0011—Cancer antigens
- A61K39/001152—Transcription factors, e.g. SOX or c-MYC
- A61K39/001153—Wilms tumor 1 [WT1]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/0005—Vertebrate antigens
- A61K39/0011—Cancer antigens
- A61K39/001154—Enzymes
- A61K39/001156—Tyrosinase and tyrosinase related proteinases [TRP-1 or TRP-2]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/0005—Vertebrate antigens
- A61K39/0011—Cancer antigens
- A61K39/001154—Enzymes
- A61K39/001158—Proteinases
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/0005—Vertebrate antigens
- A61K39/0011—Cancer antigens
- A61K39/001154—Enzymes
- A61K39/001158—Proteinases
- A61K39/001159—Matrix metalloproteinases [MMP]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/0005—Vertebrate antigens
- A61K39/0011—Cancer antigens
- A61K39/001154—Enzymes
- A61K39/001162—Kinases, e.g. Raf or Src
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/0005—Vertebrate antigens
- A61K39/0011—Cancer antigens
- A61K39/001154—Enzymes
- A61K39/001164—GTPases, e.g. Ras or Rho
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/0005—Vertebrate antigens
- A61K39/0011—Cancer antigens
- A61K39/001166—Adhesion molecules, e.g. NRCAM, EpCAM or cadherins
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/0005—Vertebrate antigens
- A61K39/0011—Cancer antigens
- A61K39/001166—Adhesion molecules, e.g. NRCAM, EpCAM or cadherins
- A61K39/001168—Mesothelin [MSLN]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/0005—Vertebrate antigens
- A61K39/0011—Cancer antigens
- A61K39/001169—Tumor associated carbohydrates
- A61K39/00117—Mucins, e.g. MUC-1
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/0005—Vertebrate antigens
- A61K39/0011—Cancer antigens
- A61K39/001176—Heat shock proteins
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/0005—Vertebrate antigens
- A61K39/0011—Cancer antigens
- A61K39/00118—Cancer antigens from embryonic or fetal origin
- A61K39/001182—Carcinoembryonic antigen [CEA]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/0005—Vertebrate antigens
- A61K39/0011—Cancer antigens
- A61K39/001184—Cancer testis antigens, e.g. SSX, BAGE, GAGE or SAGE
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/0005—Vertebrate antigens
- A61K39/0011—Cancer antigens
- A61K39/001184—Cancer testis antigens, e.g. SSX, BAGE, GAGE or SAGE
- A61K39/001186—MAGE
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/0005—Vertebrate antigens
- A61K39/0011—Cancer antigens
- A61K39/001184—Cancer testis antigens, e.g. SSX, BAGE, GAGE or SAGE
- A61K39/001188—NY-ESO
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/0005—Vertebrate antigens
- A61K39/0011—Cancer antigens
- A61K39/00119—Melanoma antigens
- A61K39/001191—Melan-A/MART
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/0005—Vertebrate antigens
- A61K39/0011—Cancer antigens
- A61K39/00119—Melanoma antigens
- A61K39/001192—Glycoprotein 100 [Gp100]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/0005—Vertebrate antigens
- A61K39/0011—Cancer antigens
- A61K39/001193—Prostate associated antigens e.g. Prostate stem cell antigen [PSCA]; Prostate carcinoma tumor antigen [PCTA]; PAP or PSGR
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/0005—Vertebrate antigens
- A61K39/0011—Cancer antigens
- A61K39/001193—Prostate associated antigens e.g. Prostate stem cell antigen [PSCA]; Prostate carcinoma tumor antigen [PCTA]; PAP or PSGR
- A61K39/001194—Prostate specific antigen [PSA]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/0005—Vertebrate antigens
- A61K39/0011—Cancer antigens
- A61K39/001193—Prostate associated antigens e.g. Prostate stem cell antigen [PSCA]; Prostate carcinoma tumor antigen [PCTA]; PAP or PSGR
- A61K39/001195—Prostate specific membrane antigen [PSMA]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/0005—Vertebrate antigens
- A61K39/0011—Cancer antigens
- A61K39/001196—Fusion proteins originating from gene translocation in cancer cells
- A61K39/001197—Breakpoint cluster region-abelson tyrosine kinase [BCR-ABL]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- 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
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
-
- 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
-
- 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
- A61P31/12—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
- A61P37/02—Immunomodulators
-
- 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
-
- 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
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
-
- 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
- A61P37/08—Antiallergic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/51—Medicinal preparations containing antigens or antibodies comprising whole cells, viruses or DNA/RNA
- A61K2039/53—DNA (RNA) vaccination
-
- 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
- A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
- A61K2039/55511—Organic adjuvants
Definitions
- composition comprising a complexed (m)RNA and a naked mRNA for providing or enhancing an immunostimulatory response in a mammal and uses thereof
- the present invention relates to an immunostimulatory composition
- an immunostimulatory composition comprising a) an adjuvant component, comprising or consisting of at least one (m)RNA, complexed with a cationic or polycationic compound, and b) at least one free mRNA, encoding at least one therapeutically active protein, antigen, allergen and/or antibody, wherein the immunostimulatory composition is capable to elicit or enhance an innate and optionally an adaptive immune response in a mammal.
- the inventive immunostimulatory composition may be a pharmaceutical composition or a vaccine.
- the invention furthermore relates to a method of preparation of the inventive immunostimulatory composition.
- the invention also relates to the use of the inventive immunostimulatory composition or its components (for the preparation of a pharmaceutical composition or a vaccine) for the treatment of various diseases.
- the invention relates to kits containing the inventive immunostimulatory composition, its components and/or the pharmaceutical composition or vaccine.
- Induction and/or enhancement of immune responses of the innate and/or the adaptive immune system plays an important role in the treatment and prevention of numerous diseases.
- the immune system is typically modulated by, e.g., administration of an immunostimulatory agent or an adjuvant.
- the immune system of vertebrates such as humans is very complex and finely regulated. It consists of many types of proteins, cells, organs, and tissues, which interact in an elaborate and dynamic network.
- the immune system typically protects these organisms from infection with layered defenses of increasing specificity.
- One layer of defense comprises physical or chemical barriers and allows an a priori elimination of at least some pathogens and antigens.
- a further layer of defense includes the innate and the adaptive immune system.
- the innate immune system as part of the immune system is the dominant system of host defense in most organisms and comprises barriers such as humoral and chemical barriers including, e.g., inflammation, the complement system and cellular barriers.
- the innate immune system is typically based on a small number of receptors, called pattern recognition receptors. They recognize conserved molecular patterns that distinguish foreign organisms, like viruses, bacteria, fungi and parasites from cells of their hosts. Such pathogen-associated molecular patterns include viral nucleic acids, components of bacterial and fungal walls, flagellar proteins, and more.
- TLR Toll-like receptor
- TLRs 1 - 10 Toll-like receptors
- TLRs 1 - 13 Toll-like receptors
- TLRs 1 - 13 Those Toll-like receptors (TLRs) in human include TLR1 -TLR2 (known ligand: Triacyl lipopeptide), TLR1 -TLR6 (known ligand: Diacyl lipopeptide), TLR2 (known ligand: Peptidoglycan), TLR3 (known ligand: dsRNA), TLR4 (known ligand: LPS (lipopolysachharide) of Gram-negative bacteria)), TLR5 (known ligand: bacterial flagellin(s)), TLR7/8 (known ligands: imidazoquinolines, guanosine analogs and ssRNA), TLR9 (known ligands: CpG DNA of bacteria, viruses and protozoans and malaria pigment hemozoin (product of digestion of haemoglobin)) and TLR10.
- TLRs After recognition of microbial pathogens, these TLRs typically trigger intracellular signalling pathways that result in induction of inflammatory cytokines (e.g. TNF-alpha, IL-6, IL-1 -beta and IL-12), type I interferon (IFN-beta and multiple IFN-alpha) and chemokines (Kawai, T. and S. Akira (2006). "TLR signaling.” Cell Death Differ 13(5): 816-25).
- inflammatory cytokines e.g. TNF-alpha, IL-6, IL-1 -beta and IL-12
- IFN-beta and multiple IFN-alpha type I interferon
- chemokines Yamanes, T. and S. Akira (2006). "TLR signaling.” Cell Death Differ 13(5): 816-25).
- the immune system adapts over time to recognize particular pathogens or antigens more efficiently. This adaptation process creates immunological memories and allows even more effective protection during future encounters with these pathogens.
- This process of adaptive or acquired immunity forms the basis for vaccination strategies.
- the adaptive immune system is antigen-specific and requires the recognition of specific "self” or "non-self” antigens during a process called antigen presentation.
- the adaptive immune system confers long-lasting or protective immunity to the host and thus allows a more tailored response to specific pathogens, pathogen-infected cells or antigens.
- the ability to mount these tailored responses is maintained in the body by so called “memory cells”. Should an antigen or a pathogen enter/infect the body more than once, these specific memory cells are used to quickly eliminate it.
- the adaptive immune system thus allows for a stronger immune response as well as an immunological memory, wherein different immune responses are possible in favor of specific diseases.
- each pathogen is "remembered” by a signature antigen, whereas in case of cancer diseases tumor antigens or self-antigens may be recognized and neutralized by the adaptive immune system.
- lymphocytes as cellular components of the adaptive immune system include B cells and T cells which are derived from hematopoietic stem cells in the bone marrow. B cells are involved in the humoral response, whereas T cells are involved in the cell mediated immune response. Both B cells and T cells carry receptor molecules that recognize specific targets. T cells recognize a "non-self" target, such as a pathogenic target structure, only after antigens (e.g. small fragments of a pathogen) have been processed and presented in combination with a "self" receptor called a major histocompatibility complex (MHC) molecule.
- MHC major histocompatibility complex
- the B cell antigen-specific receptor is an antibody molecule on the B cell surface, and recognizes pathogens as such when antibodies on its surface bind to a specific foreign antigen.
- This antigen/antibody complex is taken up by the B cell and processed by proteolysis into peptides.
- the B cell displays these antigenic peptides on its surface MHC class Il molecules.
- This combination of MHC and antigen attracts a matching helper T cell, which releases lymphokines and activates the B cell. As the activated B cell then begins to divide, its offspring secretes millions of copies of the antibody that recognizes this antigen.
- cytotoxic T cells CD8 +
- CD8 + -T cells carry out their killing function by releasing cytotoxic proteins in the cell.
- Both basic mechanisms of the immune system i.e. the innate immune system as well as the adaptive immune system, may thus form targets for curative treatments and prevention of numerous diseases.
- Appropriate methods which are presently known in the art, either utilize adjuvants to elicit an innate immune response or utilize antigens, pathogens or immunogens in order to evoke an adaptive immune response, or, in some rare cases, both.
- an adaptive immune response may be elicited by administering the cells or the host organism a specific foreign antigen as described above either in the form of the peptide or protein antigens or the antigen may be encoded by a nucleic acid, e.g. a cDNA or a messenger RNA.
- advantagoeus e.g. when providing an unspecific stimulus parallel to the antigen specific signal.
- the parallel unspecific stimulus turns the immune system into an activated state, which improves an adaptive immune response.
- Compounds capable of providing such an unspecific immune response are typically termed "adjuvants".
- adjuvants for example Freund's adjuvant, metal oxides, e.g. alum (aluminium hydroxide), inorganic chelates or salts thereof, various paraffin-like oils, synthetic resins, alginates, mucoids, polysaccharide compounds, caseinates, as well as compounds isolated from blood and/or blood clots, such as, for example, fibrin derivatives, etc.
- adjuvants typically may be used in combination with other compounds, such as e.g. proteins, peptides, DNA- or RNA-molecules or other therapeutically active compounds, dependent on the result to be achieved.
- mRNA molecules, cDNAs or nucleic acids in general which may encode a specific antigen or any other therapeutically active protein, suitable for a specific therapy, typically do not show a significant or even no immunostimulatory properties. Nevertheless, such immunostimulatory properties may be conferred to the mRNA molecule, the cDNA or the nucleic acid, when complexed with a peptide or protein, such as protamin or a nucleic acid binding protein.
- the mRNA molecule or the nucleic acid may be formulated such, that a complex is formed between the mRNA molecule or the nucleic acid and the peptide or protein, wherein different complexes may be formed between the mRNA molecule or the nucleic acid and the peptide or protein.
- Particularly strong (adjuvant) complexes can occur, when the nucleic acid, which is usually negatively charged at neutral pH, is bound by a cationic or polycationic peptide or protein.
- the complexed mRNA or nucleic acid molecules will have to be released from the complex with the (cationic) peptide or protein subsequent to transfection of the complex into the cells to allow efficient translation of the mRNA. Unfortunatlely, this does not occur in most cases.
- complexing the mRNA molecule or the nucleic acid with a cationic or polycationic compound may even prevent the nucleic acid from translation or at least significantly reduces the translation rate in vivo due to the strong binding of the polycationic compound to the mRNA molecule, cDNA or nucleic acid molecule in general. Accordingly, it is difficult to obtain a good immunostimulatory property of the composition with regard to the innate immune system taking these compounds and to ensure in parallel an efficient translation of the mRNA molecule, cDNA or nucleic acid molecule in general when using such a formulation.
- One possibility to circumvent the above problem may be the administration of an adjuvant and mRNA in separated formulations. This, however, renders the administration much more complicated. It is also preferred that the adjuvant and the antigen-encoding mRNA enter the same cell to achieve an optimal immune response. Furthermore, an adjuvant beneficially supports the induction of an adaptive immune response, if it induces an innate immune response in the same cell, in which the antigen is expressen by the encoding mRNA. Another possibility to circumvent the above problem may be the excluxive administration of naked mRNA, cDNA or nucleic acid.
- an immunostimulatory composition comprising a) an adjuvant component comprising or consisting of at least one (m)RNA, complexed with a cationic or polycationic compound, and b) at least one free mRNA, encoding at least one therapeutically active protein, antigen, allergen and/or antibody, wherein the immunostimulatory composition is capable to elicit or enhance an innate and optionally an adaptive immune response in a mammal.
- a mammal may be selected from any mammal, preferably from a mammal, selected from the group comprising, without being limited thereto, e.g. goat, cattle, swine, dog, cat, donkey, monkey, ape, a rodent such as a mouse, hamster, rabbit, and, in particular, human.
- the main advantage of the inventive immunostimulatory composition is that an innate and optionally an adaptive immune response may be efficiently elicited in a mammal, wherein the translation of the at least one free mRNA, encoding at least one therapeutically active protein, is not impaired by the adjuvant component, particularly the complexation of the at least one (m)RNA with a cationic or polycationic compound.
- the adjuvant component is formed by using a cationic or polycationic compound for complexation, which typically leads to a strong complex between the RNA and the cationic compound, that barely releases the RNA, with which it is complexed.
- the free mRNA is no-more disturbed by the cationic compound, even though the administration of the adjuvant component and the free mRNA together in one formulation also leads to a significantly improved transfection and expression in vivo of the free mRNA.
- the solution according to the present invention utilizes the surprising finding of the inventors of the present invention, that both properties of the immunostimulatory composition, i.e. an efficient immunostimulatory property and an efficient translation of the RNA, may be achieved in one and the same formulation, if the formulation per se is prepared in two separate steps. This solution is even more convincing as it allows mixing of the adjuvant component with any free mRNA without losing free mRNA by complexation with the cationic compound of the adjuvant component.
- the solution may be even stored for a considerable time without leading to an equilibration reaction between the complexed RNA and the free mRNA.
- there is no dissociation of the formed adjuvant component which may lead to a binding of free mRNA by the cationic compound of the adjuvant component and to a release of bound RNA from the complex.
- the inventive immunostimulatory composition comprises a so called “adjuvant component", comprising or consisting of at least one (m)RNA, complexed with a cationic or polycationic compound.
- the so called "adjuvant component” is prepared according to a first step by complexing the at least one (m)RNA of the adjuvant component with a cationic or polycationic compound in a specific ratio to form a stable complex.
- a cationic or polycationic compound in a specific ratio to form a stable complex.
- the ratio of the (m)RNA and the cationic or polycationic compound in the adjuvant component is typically selected in a range that the (m)RNA is entirely complexed and no free cationic or polycationic compound or only a neclectably small amount remains in the composition.
- the ratio of the adjuvant component i.e.
- the ratio of the (m)RNA to the cationic or polycationic compound is selected from a range of about 6:1 (w/w) to about 0,25:1 (w/w), more preferably from about 5:1 (w/w) to about 0,5:1 (w/w), even more preferably of about 4:1 (w/w) to about 1 :1 (w/w) or of about 3:1 (w/w) to about 1 :1 (w/w), and most preferably a ratio of about 3:1 (w/w) to about 2:1 (w/w).
- the ratio of the m(RNA) to the cationic or polycationic compound in the adjuvant component may also be calculated on the basis of the nitrogen/phosphate ratio (N/P-ratio) of the entire RNA complex.
- N/P-ratio nitrogen/phosphate ratio
- 1 ⁇ g RNA typically contains about 3 nmol phosphate residues, provided the RNA exhibits a statistical distribution of bases.
- 1 ⁇ g peptide typically contains about x nmol nitrogen residues, dependent on the molecular weight and the number of basic amino acids.
- protamine molecular weight about 4250 g/mol, 21 nitrogen atoms, when protamine from salmon is used
- N/P ratio of about 0.81 can be calculated.
- mass ratio of about 8:1 RNA/protamine an N/P ratio of about 0.2 can be calculated.
- an N/P-ratio is preferably in the range of about 0.1 -10, preferably in a range of about 0.3-4 and most preferably in a range of about 0.5-2 or 0.7-2 regarding the ratio of RNA:peptide in the complex, and most preferably in the range of about 0.7-1 .5.
- a cationic or polycationic compound is preferably selected from any cationic or polycationic compound, suitable for complexing and thereby stabilizing a nucleic acid, particularly the at least one (m)RNA, e.g. by associating the at least one (m)RNA with the cationic or polycationic compound.
- a cationic or polycationic compound per se does not need to exhibit any adjuvant properties, since an adjuvant property, particularly the capability of inducing an innate immune response, is preferably created upon complexing the at least one (m)RNA with the cationic or polycationic compound.
- the adjuvant component is formed.
- cationic or polycationic peptides or proteins as component P 2 may be selected from protamine, nucleoline, spermine or spermidine, poly-L-lysine (PLL), basic polypeptides, poly-arginine, cell penetrating peptides (CPPs), chimeric CPPs, such as Transportan, or MPG peptides, HIV-binding peptides, Tat, HIV-I Tat (HIV), Tat-derived peptides, oligoarginines, members of the penetratin family, e.g.
- Penetratin Antennapedia-derived peptides (particularly from Drosophila antennapedia), pAntp, plsl, etc., antimicrobial-derived CPPs e.g. Buforin-2, Bac715-24, SynB, SynB(1 ), pVEC, hCT-derived peptides, SAP, MAP, KALA, PpTG20, Proline-rich peptides, L-oligomers, Argi nine-rich peptides, Calcitonin-peptides, FGF, Lactoferrin, poly-L-Lysine, poly-Arginine, histones, VP22 derived or analog peptides, HSV, VP22 (Herpes simplex), MAP, KALA or protein transduction domains (PTDs, PpT620, prolin-rich peptides, arginine-rich peptides, lysine-rich peptides, Pep-1 , Calcitonin peptide(
- oligoarginines in this context are e.g. Arg 7 , Argg, Arg 9 , Arg 7 , H 3 R 9 , R 9 H 3 , H 3 R 9 H 3 , YSSR 9 SSY, (RKH) 4 , Y(RKH) 2 R, etc.
- Further preferred cationic or polycationic compounds, which can be used for complexing the at least one (m)RNA of the adjuvant component above may include cationic polysaccharides, for example chitosan, polybrene, cationic polymers, e.g. polyethyleneimine (PEI), cationic lipids, e.g.
- PEI polyethyleneimine
- DOTMA [1 - (2,3-sioleyloxy)propyl)]-N,N,N-trimethylammonium chloride, DMRIE, di-C14-amidine, DOTIM, SAINT, DC-Choi, BGTC, CTAP, DOPC, DODAP, DOPE: Dioleyl phosphatidylethanol-amine, DOSPA, DODAB, DOIC, DMEPC, DOGS: Dioctadecylamidoglicylspermin, DIMRI: Dimyristo-oxypropyl dimethyl hydroxyethyl ammonium bromide, DOTAP: dioleoyloxy-3-(trimethylammonio)propane, DC-6-14: O,O- ditetradecanoyl-N-( ⁇ -trimethylammonioacetyl)diethanolamine chloride, CLIP!
- CLIP6 rac-[2(2,3- dihexadecyloxypropyl-oxymethyloxy)ethyl]trimethylammonium
- CLI P9 rac-[2(2,3- dihexadecyloxypropyl-oxysuccinyloxyjethyll-trimethylammonium, oligofectamine, or cationic or polycationic polymers, e.g.
- modified polyaminoacids such as ⁇ -aminoacid- polymers or reversed polyamides, etc.
- modified polyethylenes such as PVP (poly(N-ethyl- 4-vinylpyridinium bromide)), etc.
- modified acrylates such as pDMAEMA (poly(dimethylaminoethyl methylacrylate)), etc.
- modified Amidoamines such as pAMAM (poly(amidoamine)), etc., modified polybetaaminoester (PBAE), such as diamine end modified 1 ,4 butanediol diacrylate-co-5-amino-1 -pentanol polymers, etc.
- dendrimers such as polypropylamine dendrimers or pAMAM based dendrimers, etc.
- polyimine(s) such as PEI: poly(ethyleneimine), poly(propyleneimine), etc., polyallylamine, sugar backbone based poly
- association or complexing the modified (m)RNA of the inventive immunostimulatory composition with cationic or polycationic compounds preferably provides adjuvant properties to the (m)RNA and confers a stabilizing effect to the (m)RNA of the adjuvant component by complexation.
- the procedure for stabilizing the modified (m)RNA is in general described in EP-A-1083232, the disclosure of which is incorporated by reference into the present invention in its entirety.
- cationic or polycationic compounds are compounds selected from the group consisting of protamine, nucleoline, spermin, spermidine, oligoarginines as defined above, such as Arg 7 , Argg, Arg 9 , Arg 7 , H 3 R 9 , R 9 H 3 , H 3 R 9 H 3 , YSSR 9 SSY, (RKH) 4 , Y(RKH) 2 R, etc.
- the at least one (m)RNA of the "adjuvant component" of the inventive immunostimulatory composition may be any RNA, preferably, without being limited thereto, a short RNA oligonucleotide, a coding RNA, an immunostimulatory RNA, an siRNA, an antisense RNA, or riboswitches, ribozymes or aptamers.
- the at least one (m)RNA of the adjuvant component may be a single- or a double-stranded RNA (which may also be regarded as an RNA (molecule) due to non-covalent association of two single-stranded RNA (molecules)) or a partially double- stranded or partially single stranded RNA, which are at least partially self complementary (both of these partially double-stranded or partially single stranded RNA molecules are typically formed by a longer and a shorter single-stranded RNA molecule or by two single stranded RNA-molecules, which are about equal in length, wherein one single-stranded RNA molecule is in part complementary to the other single-stranded RNA molecule and both thus form a double-stranded RNA molecule in this region, i.e.
- the at least one (m)RNA of the adjuvant component may be a single-stranded RNA.
- the at least one (m)RNA of the adjuvant component may be a circular or linear RNA, preferably a linear RNA. More preferably, the at least one (m)RNA of the adjuvant component may be a (linear) single- stranded RNA.
- the at least one (m)RNA of the adjuvant component may be a ribosomal RNA (rRNA), a transfer RNA (tRNA), a messenger RNA (mRNA), or a viral RNA (vRNA), more preferably an mRNA.
- an mRNA is typically an RNA, which is composed of several structural elements, e.g. an optional 5'-UTR region, an upstream positioned ribosomal binding site followed by a coding region, an optional 3'-UTR region, which may be followed by a poly-A tail (and/or a poly-C-tail).
- An mRNA may occur as a mono-, di-, or even multicistronic RNA, i.e. an RNA which carries the coding sequences of one, two or more proteins or peptides. Such coding sequences in di-, or even multicistronic mRNA may be separated by at least one IRES sequence, e.g. as defined herein.
- the at least one (m)RNA of the adjuvant component of the inventive immunostimulatory composition comprises a length of about 5 to about 20,000, or 100 to about 20,000 nucleotides, preferably of about 250 to about 20,000 nucleotides, more preferably of about 500 to about 10,000, even more preferably of about 500 to about 5,000, most preferably a length of about 100 to 10,000 nucleotides or a length of about 100 to 5,000 nucleotides.
- the at least one (m)RNA of the adjuvant component of the inventive immunostimulatory composition may be a short RNA oligonucleotide.
- Short RNA oligonucleotides in the context of the present invention may comprise any RNA as defined above.
- the short RNA oligonucleotide may be a single- or a double-stranded RNA oligonuclotide, more preferably a single-stranded RNA oligonucleotide.
- the short RNA oligonucleotide may be a linear single-stranded RNA oligonucleotide.
- the short RNA oligonucleotides as used herein may comprise a length as defined above in general for RNA molecules, more preferably a length of 5 to 100, of 5 to 50, or of 5 of 30, and even more preferably a length of 20 to 100, of 20 to 80, or of 20 of 60 nucleotides.
- the at least one (m)RNA of the adjuvant component of the inventive immunostimulatory composition may be an immunostimulatory RNA, i.e. an RNA derived from an immunostimulatory RNA, which triggers or increases an (innate) immune response.
- the at least one (m)RNA of the adjuvant component of the inventive immunostimulatory composition may be a single-stranded, a double-stranded or a partially double-stranded or partially single-stranded RNA, more preferably a single- stranded RNA, and/or a circular or linear RNA, more preferably a linear RNA.
- the at least one (m)RNA of the adjuvant component may be a (linear) single- stranded RNA. Even more preferably, the at least one (m)RNA of the adjuvant component may be a ((linear) single-stranded) messenger RNA (mRNA).
- the at least one (m)RNA of the adjuvant component of the inventive immunostimulatory composition may also occur as a short RNA oligonucleotide as defined above.
- the at least one (m)RNA of the adjuvant component of the inventive immunostimulatory composition may furthermore be selected from any class of RNA molecules, found in nature or being prepared synthetically, and which can induce an innate immune response.
- the adjuvant component of the inventive immunostimulatory composition typically elicits an innate immune response
- the free mRNA of the inventive immunostimulatory composition may elicit an adaptive immune response, particularly if the free mRNA encodes an antigen or allergen as described herein or any further molecule, which is capable to elicit an adaptive immune response.
- those classes of RNA molecules, which can induce an innate immune response may be selected from ligands of Toll-like receptors (TLRs).
- the at least one immunostimulatory RNA of the adjuvant component of the inventive immunostimulatory composition may thus comprise any RNA sequence known to be immunostimulatory, including, without being limited thereto, RNA sequences representing and/or encoding ligands of TLRs, preferably selected from human family members TLR1 - TLR10 or murine family members TLR1 - TLR13, more preferably from TLR7 and TLR8, ligands for intracellular receptors for RNA (such as RIG-I or MDA-5, etc.) (see e.g. Meylan, E., Tschopp, J. (2006). Toll-like receptors and RNA helicases: two parallel ways to trigger antiviral responses. MoI. Cell 22, 561 -569), or any other immunostimulatory RNA sequence.
- RNA sequences representing and/or encoding ligands of TLRs preferably selected from human family members TLR1 - TLR10 or murine family members TLR1 - TLR13, more
- the immunostimulatory RNA used as an at least one (m)RNA of the adjuvant component of the inventive immunostimulatory composition may comprise a length as defined above in general for RNA molecules of the RNA of the adjuvant component of the inventive immunostimulatory composition.
- the RNA may have a length of 1000 to 5000, of 500 to 5000, of 5 to 5000, or of 5 to 1000, 5 to 500, 5 to 250, of 5 to 100, of 5 to 50 or of 5 to 30 nucleotides.
- immunostimulatory sequences may comprise e.g. a nucleic acid of formula (I):
- X m G n wherein: G is guanosine, uracil or an analogue of guanosine or uracil;
- X is guanosine, uracil, adenosine, thymidine, cytosine or an analogue of the above- mentioned nucleotides;
- immunostimulatory sequences may also comprise e.g. a nucleic acid of formula (II):
- C is cytosine, uracil or an analogue of cytosine or uracil
- X is guanosine, uracil, adenosine, thymidine, cytosine or an analogue of the above- mentioned nucleotides
- nucleic acids of formula (I) or (II), which may be used for the at least one (m)RNA of the adjuvant component of the inventive immunostimulatory composition are typically relatively short nucleic acid molecules and typically hav a length of approximately from 5 to 100 (but may also be longer than 100 nucleotides for specific embodiments, e.g. up to 200 nucleotides), from 5 to 90 or from 5 to 80 nucleotides, preferably a length of approximately from 5 to 70, more preferably a length of approximately from 8 to 60 and, more preferably a length of approximately from 15 to 60 nucleotides, more preferably from 20 to 60, most preferably from 30 to 60 nucleotides.
- the number of nucleotides G in the nucleic acid of formula (I) is determined by I or n.
- a nucleotide adjacent to X m in the nucleic acid of formula (I) according to the invention is preferably not a uracil.
- the number of nucleotides C in the nucleic acid of formula (II) according to the invention is determined by I or n.
- a nucleotide adjacent to X m in the nucleic acid of formula (II) according to the invention is preferably not a uracil.
- I or n > 1 at least 60%, 70%, 80%, 90% or even 100% of the nucleotides are guanosine or an analogue thereof, as defined above.
- the remaining nucleotides to 100% (when guanosine constitutes less than 100% of the nucleotides) in the flanking sequences G 1 and/or G n are uracil or an analogue thereof, as defined hereinbefore.
- I and n independently of one another, are each an integer from 2 to 30, more preferably an integer from 2 to 20 and yet more preferably an integer from 2 to 15.
- the lower limit of I or n can be varied if necessary and is at least 1 , preferably at least 2, more preferably at least 3, 4, 5, 6, 7, 8, 9 or 10. This definition applies correspondingly to formula (II).
- a nucleic acid according to any of formulas (I) or (II) above which may be used for the at least one (m)RNA of the adjuvant component of the inventive immunostimulatory composition, may be selected from a sequence consisting or comprising any of the following sequences:
- the term "identity" in the present application means that the sequences are compared in relation to a reference sequence and the percentage identity is determined by comparing them.
- the sequences can first be arranged relative to one another (alignment) in order to permit subsequent comparison of the sequences.
- gaps can be introduced into the sequence of the first nucleic acid sequence and the nucleotides can be compared with the corresponding position of the second nucleic acid sequence.
- the percentage identity between two sequences is a function of the number of identical positions divided by the sequences. If, for example, a specific sequence identity is assumed for a particular nucleic acid in comparison with a reference nucleic acid having a defined length, then this percentage identity is indicated relatively in relation to the reference nucleic acid. Therefore, starting, for example, from a nucleic acid sequence that has 50% sequence identity with a reference nucleic acid sequence having a length of 100 nucleotides, that nucleic acid sequence can represent a nucleic acid sequence having a length of 50 nucleotides that is wholly identical with a section of the reference nucleic acid sequence having a length of 50 nucleotides.
- nucleic acid sequence having a length of 100 nucleotides that has 50% identity that is to say in this case 50% identical nucleic acids
- nucleic acid sequence can be a nucleic acid sequence having a length of 200 nucleotides that, in a section of the nucleic acid sequence having a length of 100 nucleotides, is wholly identical with the reference nucleic acid sequence having a length of 100 nucleotides.
- nucleic acid sequences naturally fulfil these criteria equally.
- the determination of the percentage identity of two sequences can be carried out by means of a mathematical algorithm.
- a preferred but non-limiting example of a mathematical algorithm which can be used for comparing two sequences is the algorithm of Karlin et a/. (1993), PNAS USA, 90:5873-5877. Such an algorithm is integrated into the NBLAST program, with which sequences having a desired identity with the sequences of the present invention can be identified.
- the "Gapped BLAST" program can be used, as described in Altschul eta/. (1997), Nucleic Acids Res, 25:3389-3402.
- the default parameters of the particular program e.g.
- NBLAST NBLAST
- the sequences can further be aligned using version 9 of GAP (global alignment program) from "Genetic Computing Group", using the default (BLOSUM62) matrix (values -4 to +1 1 ) with a gap open penalty of -12 (for the first zero of a gap) and a gap extension penalty of -4 (for each additional successive zero in the gap).
- GAP global alignment program
- BLOSUM62 default matrix
- the percentage identity is calculated by expressing the number of correspondences as a percentage of the nucleic acids in the claimed sequence.
- the described methods for determining the percentage identity of two nucleic acid sequences can also be applied correspondingly to amino acid sequences using the appropriate programs.
- immunostimulatory sequences may also comprise e.g. a nucleic acid (molecule) of formula (III):
- G is guanosine (guanine), uridine (uracil) or an analogue of guanosine (guanine) or uridine (uracil), preferably guanosine (guanine) or an analogue thereof
- X is guanosine (guanine), uridine (uracil), adenosine (adenine), thymidine (thymine), cytidine (cytosine), or an analogue of these nucleotides (nucleosides), preferably uridine (uracil) or an analogue thereof;
- N is a nucleic acid sequence having a length of about 4 to 50, preferably of about 4 to
- nucleic acids each N independently being selected from guanosine (guanine), uridine (uracil), adenosine (adenine), thymidine (thymine), cytidine (cytosine) or an analogue of these nucleotides (nucleosides);
- a is an integer from 1 to 20, preferably from 1 to 15, most preferably from 1 to 10;
- u,v may be independently from each other an integer from 0 to 50,
- the structure (N 1J GiX m G n N v ) 3 of formula (III) according to the present invention comprises the element G
- a molecule according to formula (III) i.e.
- X m G n N v a molecule comprising the above core structure G
- This molecule design is particularly advantageous when preparing a molecule according structure (N u G
- G in the nucleic acid molecule of formula (III) (and of formula (I) and (M)) is a nucleotide or deoxynucleotide or comprises a nucleoside, wherein the nucleotide (nucleoside) is guanosine (guanine) or uridine (uracil) or an analogue thereof, more preferably guanosine (guanine) or an analogue thereof.
- guanosine (guanine) or uridine (uracil) nucleotide (nucleoside) analogues are defined as non-natively occurring variants of the naturally occurring nucleotides (nucleoside) guanosine (guanine) and uridine (uracil).
- guanosine (guanine) or uridine (uracil) analogues are typically chemically derivatized nucleotides (nucleoside) with non-natively occurring functional groups or components, which are preferably added to, modified or deleted from the naturally occurring guanosine (guanine) or uridine (uracil) nucleotide or which substitute the naturally occurring functional groups or components of a naturally occurring guanosine (guanine) or uridine (uracil) nucleotide.
- each functional group or component of the naturally occurring guanosine (guanine) or uridine (uracil) nucleotide may be modified or deleted therefrom, namely the base component, the sugar (ribose) component, any naturally occurring functional side group and/or the phosphate component forming the oligonucleotide's backbone.
- the phosphate moieties may be substituted by e.g. phosphoramidates, phosphorothioates, peptide nucleotides, methylphosphonates etc., however, naturally occurring phosphodiester backbones still being preferred in the context of the present invention.
- the sugar (ribose) component is selected from a desoxyribose, particularly the nucleic acid is an RNA as defined above, wherein the sugar (ribose) component is selected from a desoxyribose.
- analogues of guanosine (guanine) or uridine (uracil) include, without implying any limitation, any naturally occurring or non-naturally occurring guanosine (guanine) or uridine (uracil) that has been altered chemically, for example by acetylation, methylation, hydroxylation, etc., including, for example, 1 -methyl-guanosine (guanine), 2-methyl- guanosine (guanine), 2,2-dimethyl-guanosine (guanine), 7-methyl-guanosine (guanine), dihydro-uridine (uracil), 4-thio-uridine (uracil), 5-carboxymethylaminomethyl-2-thio-uridine (uracil), 5-(carboxy-hydroxylmethyl)-uridine (uracil), 5-fluoro-uridine (uracil), 5-bromo- uridine (uracil), 5-carboxymethylaminomethyl-uridine (uracil), 5-
- At least one guanosine (guanine) or uridine (uracil) or an analogue thereof can occur in the core structure elements G
- and/or G n contains at least one analogue of a naturally occurring guanosine (guanine) and/or a naturally occurring uridine (uracil) at all.
- and/or G n are analogues, which may - most preferably - be identical analogues for the same type of nucleotides (nucleosides) (e.g. all guanosine (guanine) nucleotides are provided as 1 -methyl-guanosine (guanine)) or they may be distinct (e.g. at least two different guanosin analogues substitute the naturally occurring guanosin nucleotide).
- and/or G n ) in the nucleic acid molecule of formula (III) (and of formula (I) and (II)) is determined by I and n.
- I and n independently of one another, are each an integer from 1 to 100, 1 to 90, 1 to 80, 1 to 70, 1 to 60, preferably 1 to 50, yet more preferably 1 to 40, and even more preferably 1 to 30, wherein the lower limit of these ranges may be 1, but alternatively also 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 1 6, 1 7, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, or even more.
- G is guanosine (guanine) or an analogue thereof
- I or n > 1 at least 50%, more preferably at least 50%, 60%, 70%, 80%, 90% or even 100% of the nucleotides (nucleosides) of core structure element G (G
- and/or G n directly adjacent to X m in the nucleic acid molecule of formula (III) (and of formula (I) and (II)) is preferably not an uridine (uracil) or an analogue therof.
- and/or G n directly adjacent to X m in the nucleic acid molecule of formula (III) are at least one guanosine (guanine) or an analogue thereof, more preferably a stretch of at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 1 7, 18, 19 or even 20 or more guanosines (guanines) or an analogue thereof.
- and/or G n directly adjacent to N e.g.
- N ⁇ , and/or N v (or N w1 or N w2 as defined below) in the nucleic acid molecule of formula (III) (and of formula (I) and (II)) is preferably not an uridine (uracil) or an analogue therof. More preferably, nucleotides (nucleosides) of core structure elements G
- N ⁇ , and/or N v (or N wl or N w2 as defined below) in the nucleic acid molecule of formula (III) (and of formula (I) and (II)) are at least one guanosine (guanine) or an analogue thereof, more preferably a stretch of at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 1 7, 18, 19 or even 20 or more guanosines (guanines) or an analogue thereof.
- and/or G n are guanosine (guanine) or an analogue thereof, as defined above.
- and/or G n may then be uridine (uracil) or an analogue thereof, as defined hereinbefore.
- X, particularly X m , in the nucleic acid molecule of formula (III) (and of formula (I) and (II)) is also a core structure element and is a nucleotide or deoxynucleotide or comprises a nucleoside, wherein the nucleotide (nucleoside) is typically selected from guanosine (guanine), uridine (uracil), adenosine (adenine), thymidine (thymine), cytidine (cytosine) or an analogue thereof, preferably uridine (uracil) or an analogue thereof.
- nucleotide (nucleoside) analogues are defined as non-natively occurring variants of naturally occurring nucleotides (nucleosides). Accordingly, analogues are chemically derivatized nucleotides (nucleosides) with non-natively occurring functional groups, which are preferably added to or deleted from the naturally occurring nucleotide (nucleoside) or which substitute the naturally occurring functional groups of a nucleotide (nucleoside).
- each component of the naturally occurring nucleotide may be modified, namely the base component, the sugar (ribose or desoxyribose) component and/or the phosphate component forming the oligonucleotide's backbone.
- the phosphate moieties may be substituted by e.g. phosphoramidates, phosphorothioates, peptide nucleotides, methylphosphonates etc., wherein, however, the naturally occurring phosphodiester backbone is still preferred.
- At least 10%, more preferably at least 20 %, more preferably at least 30%, more preferably at least 50%, more preferably at least 70% and even more preferably at least 90% of all "X" nucleotides may exhibit properties of an analogue as defined herein, if the immunostimulatory sequence contains at least one analogue at all.
- the analogues substituting a specific nucleotide type within the core structure element "X m " may be identical, e.g. all cytidine (cytosine) nucleotides (nucleosides) occurring in the core structure element "X n ,” are formed by a specific cytidine (cytosine) analogue, e.g.
- 2-thio-cytidine or they may be distinct for a specific nucleotide (nucleosides), e.g. at least two distinct cytidine (cytosine) analogues are contained within the core structure element "X *m".
- Analogues of guanosine (guanine), uridine (uracil), adenosine (adenine), thymidine (thymine), cytidine (cytosine) include, without implying any limitation, any naturally occurring or non-naturally occurring guanosine (guanine), uridine (uracil), adenosine (adenine), thymidine (thymine) or cytidine (cytosine) that has been altered chemically, for example by acetylation, methylation, hydroxylation, etc., including 1 -methyl-adenosine (adenine), 2-methyl-adenosine (adenine), 2-methylthio-N6-isopentenyl-adenosine (adenine), N6-methyl-adenosine (adenine), N6-isopentenyl-adenosine (adenine), 2-thio-cytidine (cytosine), 3-methyl-cyt
- the number of core structure element X in the nucleic acid molecule of formula (III) (and of formula (I) and (M)) is determined by m.
- a monotonic uridine (uracil) sequence typically has a length of at least 3, 4, 5, 6, 7, 8, 9 or 10, 1 1 , 12, 13, 14, 15, 16, 1 7, 18, 19, 20, 20 to 30, 30 to 40, 40 to 50, 50 to 60, 60 to 70, 70 to 80, 80 to 90, 90 to 100, 100 to 150, 150 to 200 uridines (uracils) or optionally analogues of uridine (uracil) as defined above.
- Such a monotonic uridine (uracil) sequence occurs at least once in the core structure element X of the nucleic acid molecule of formula (III) (and of formula (I) and (II)). It is therefore possible, for example, for 1 , 2, 3, 4, 5 or more monotonic uridine (uracil) sequences having at least 3 or more uridines (uracils) or analogues thereof to occur, which monotonic uridine (uracil) sequences can be interruped in the core structure element X by at least one guanosine (guanine), adenosine (adenine), thymidine (thymine), cytidine (cytosine) or an analogue thereof, preferably 2, 3, 4, 5 or more.
- X m is a UUU.
- X m can be, for example, without implying any limitation, a UUUA, UUUG, UUUC, UUUU, AUUU, GUUU or CUUU, etc.
- n 10
- X n can be, for example, without implying any limitation, a UUUAAUUUUC, UUUUGUUUUA, UUUGUUUGUU, UUGUUUUGUU, UUUUUUUU, etc.
- the nucleotides of X m adjacent to G, or G n of the nucleic acid molecule of formula (III) preferably comprise uridine (uracil) or analogues thereof.
- uridine uracil
- m > 3 typically at least 50%, preferably at least 60%, 70%, 80%, 90% or even 100%, of the nucleotides of X m are uridine (uracil) or an analogue thereof, as defined above.
- nucleotides of X n to 100% (where there is less than 100% uridine (uracil) in the sequence X m ) are then guanosine (guanine), uridine (uracil), adenosine (adenine), thymidine (thymine), cytidine (cytosine) or an analogue thereof, as defined above.
- the immunostimulatory sequence according formula (III) above also contains bordering element N.
- the bordering element N is typically a nucleic acid sequence having a length of about 4 to 50, preferably of about 4 to 40, more preferably of about 4 to 30 nucleotides (nucleosides), even more preferably of about 4 to 20 nucleotides (nucleosides), wherein the lower limit of these ranges alternatively also may be 5, 6, 7, 8, 9, 10, or more.
- the nucleotides (nucleosides) of each N are independently selected from guanosine (guanine), uridine (uracil), adenosine (adenine), thymidine (thymine), cytidine (cytosine) and/or an analogue thereof.
- bordering element N in the nucleic acid molecule of formula (III) according to the present invention may be a sequence, which may be composed of any (random) sequence, available in the art, each N independently selected from guanosine (guanine), uridine (uracil), adenosine (adenine), thymidine (thymine), cytidine (cytosine) and/or an analogue of these nucleotides, or from a homopolymer of these nucleotides (nucleosides), in each case provided, that such a sequence has a length of about 4 to 50, preferably of about 4 to 40, more preferably of about 4 to 30 nucleotides (nucleosides) and even more preferably of about 4 to 30 or 4 to 20 nucleotides (nucleosides)according to the above definition.
- N may be a nucleic acid sequence within the above definitions, wherein the sequence typically comprises not more than 2 identical nucleotides (nucleosides) as defined above in a directly neighboring position, i.e. the sequence typically comprises no stretches of more than two identical nucleotides (nucleosides) selected from adenosine (adenine), cytidine (cytosine), uridine (uracil) and/or guanosine (guanine), and/or an analogue thereof (i.e. a stretch of "aa”, “cc", “uu”, “gg” and/or an analogue thereof), more preferably no such stretch, i.e.
- N may be a nucleic acid sequence within the above definitions, wherein the sequence typically comprises a content of adenosine (adenine) or an analogue thereof preferably of about 0 to 50%, 5 to 45%, or 10 to 40%, more preferably of about 15 to 35%, even more preferably of about 20 to 30%, and most preferably of about 25%; a content of uridine (uracil) or an analogue thereof preferably of about 0 to 50%, 5 to 45%, or 10 to 40%, more preferably of about 15 to 35%, even more preferably of about 20 to 30%, and most preferably of about 25%; a content of cytidine (cytosine) or an analogue thereof preferably of about 0 to 50%, 5 to 45%, or 10 to 40%, more preferably of about 15 to 35%, even more preferably of about 20 to 30%, and most preferably of about 25%; a
- N may be a nucleic acid sequence within the above definitions, wherein the sequence typically comprises a content of each adenosine (adenine), guanosine (guanine), cytidine (cytosine) and uridine (uracil) of about 25%.
- sequences of N include e.g.
- the number of bordering element N in the nucleic acid molecule of formula (III), i.e. its repetition, is determined by integers u and/or v.
- N in the nucleic acid molecule of formula (III) may occur as a (repetitive) bordering element N u and/or N v , wherein u and/or v may be, independently from each other, an integer from 0 or 1 to 100, more preferably from
- 0 or 1 to 50 even more preferably from 0 or 1 to 40, and most preferably from 0 or 1 to 30, e.g. 0 or 1 to 5, 10, 20, 25, or 30; or from 5 to 10, 10 to 15, 15 to 20, 20 to 25 or 25 to 30.
- At least one (repetitive) bordering element N y and/or N v may be present in formula (III), i.e. either u or v are not 0, more preferably, both (repetitive) bordering elements N u and/or N v are present, even more preferably in the above definitions.
- the combination of core structure elements and bordering elements to the element N u GiX n1 G n N v may occur as repetitive elements according to the immunostimulatory sequence of formula (III), (N u G
- a is an integer from about 1 to 100, 1 to 50, 1 to 20, more preferably an integer from about 1 to 15, most preferably an integer from about 1 to 10.
- X m G n N v may be equal or different from each other.
- the immunostimulatory sequence of formula (III) (N u G
- immunostimulatory sequences as defined herein may also comprise e.g. a nucleic acid (molecule) of formula (Ilia)
- C is cytidine (cytosine), uridine (uracil) or an analogue of cytidine (cytosine) or uridine
- uracil preferably cytidine (cytosine) or an analogue thereof
- X is guanosine (guanine), uridine (uracil), adenosine (adenine), thymidine (thymine), cytidine (cytosine) or an analogue of the above-mentioned nucleotides (nucleosides), preferably uridine (uracil) or an analogue thereof;
- N is each a nucleic acid sequence having independent from each other a length of about 4 to 50, preferably of about 4 to 40, more preferably of about 4 to 30 or 4 to
- nucleic acids each N independently being selected from guanosine (guanine), uridine (uracil), adenosine (adenine), thymidine (thymine), cytidine (cytosine) or an analogue of these nucleotides (nucleosides);
- a is an integer from 1 to 20, preferably from 1 to 15, most preferably from 1 to 10;
- the definition of bordering elements N u and N v is identical to the definitions given above for N u and N v .
- C in the nucleic acid molecule of formula (Ilia) is a nucleotide or deoxynucleotide or comprises a nucleoside, wherein the nucleotide (nucleoside) is typically cytidine (cytosine) or uridine (uracil) or an analogue thereof.
- cytidine (cytosine) or uridine (uracil) nucleotide analogues are defined as non-natively occurring variants of naturally occurring cytidine (cytosine) or uridine (uracil) nucleotides.
- cytidine (cytosine) or uridine (uracil) analogues are chemically derivatized nucleotides (nucleosides) with non-natively occurring functional groups, which are preferably added to or deleted from the naturally occurring cytidine (cytosine) or uridine (uracil) nucleotide (nucleoside) or which substitute the naturally occurring functional groups of a cytidine (cytosine) or uridine (uracil) nucleotide (nucleoside).
- each component of the naturally occurring cytidine (cytosine) or uridine (uracil) nucleotide may be modified, namely the base component, the sugar (ribose) component and/or the phosphate component forming the oligonucleotide's backbone.
- the phosphate moieties may be substituted by e.g. phosphoramidates, phosphorothioates, peptide nucleotides, methylphosphonates etc., wherein the naturally occurring phosphodiester backbone is still preferred.
- analogues of cytidine (cytosine) or uridine (uracil) include, without implying any limitation, any naturally occurring or non-naturally occurring cytidine (cytosine) or uridine (uracil) that has been altered chemically, for example by acetylation, methylation, hydroxylation, etc., including, for example, 2-thio-cytidine (cytosine), 3-methyl-cytidine (cytosine), 4-acetyl-cytidine (cytosine), dihydro-uridine (uracil), 4-thio-uridine (uracil), 5- carboxymethylaminomethyl-2-thio-uridine (uracil), 5-(carboxy-hydroxylmethyl)-uridine (uracil), 5-fluoro-uridine (uracil), 5-bromo-uridine (uracil), 5-carboxymethylaminomethyl- uridine (uracil), 5-methyl-2-thio-uridine (uracil), N-ur
- At least one cytidine (cytosine) or uridine (uracil) or an analogue thereof can occur in the core structure elements Q and/or C n , optionally at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80% 90% or even 100% of the nucleotides (nucleosides) of the core structure elements Q and/or C n are a naturally occurring cytidine (cytosine), a naturally occurring uridine (uracil), and/or an analogue thereof and/or exhibit properties of an analogue thereof as defined herein.
- the core structure element Q and/or C n contains at least one analogue of a naturally occurring cytidine (cytosine) and/or a naturally occurring uridine (uracil) at all.
- all nucleotides (nucleosides) of these core structure elements Q and/or C n are analogues, which may - most preferably - be identical analogues for the same type of nucleotides (nucleosides) (e.g. all cytidine (cytosine) nucleotides are provided as 2-thio- cytidine (cytosine)) or they may be distinct (e.g. at least two different cytidine (cytosine) analogues substitute the naturally occurring cytidine (cytosine) nucleotide).
- the number of nucleotides (nucleosides) of core structure element C (Q and/or C n ) in the nucleic acid molecule of formula (Ilia) is determined by I and n.
- I and n independently of one another, are each an integer from 1 to 90, 1 to 80, 1 to 70, 1 to 60, preferably 1 to 50, yet more preferably 1 to 40, and even more preferably 1 to 30, wherein the lower limit of these ranges may be 1 , but alternatively also 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 1 7, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, or even more.
- C is cytidine (cytosine) or an analogue thereof
- I or n > 1 at least 50%, more preferably at least 50%, 60%, 70%, 80%, 90% or even 100% of the nucleotides (nucleosides) of core structure element C (Q and/or C n ) are cytidine (cytosine) or an analogue thereof.
- a nucleotide (nucleoside) of core structure elements Q and/or C n directly adjacent to X n , in the nucleic acid molecule of formula (Ilia) is preferably not an uridine (uracil) or an analogue therof.
- nucleotides (nucleosides) of core structure elements Q and/or C n directly adjacent to X m in the nucleic acid molecule of formula (Ilia) are at least one cytidine (cytosine) or an analogue thereof, more preferably a stretch of at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19 or even 20 or more cytidines (cytosines) or an analogue thereof.
- a nucleotide (nucleoside) of core structure elements Q and/or C n directly adjacent to N e.g.
- N 11 , and/or N v (or N wl or N w2 as defined below) in the nucleic acid molecule of formula (Ilia) is preferably not an uridine (uracil) or an analogue therof. More preferably, nucleotides (nucleosides) of core structure elements Q and/or C n directly adjacent to N, e.g.
- N u , and/or N v (or N w1 or N w2 as defined below) in the nucleic acid molecule of formula (Ilia) are at least one cytidine (cytosine) or an analogue thereof, more preferably a stretch of at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 1 7, 18, 19 or even 20 or more cytidines (cytosines) or an analogue thereof.
- nucleotides of the core structure elements C, and/or C n when I or n > 1 , at least 60%, 70%, 80%, 90% or even 100% of the nucleotides of the core structure elements C, and/or C n are cytidine (cytosine) or an analogue thereof, as defined above.
- the remaining nucleotides (nucleosides) to 100% in the core structure elements Q and/or C n when cytidine (cytosine) constitutes less than 100% of these nucleotides (nucleosides) may then be uridine (uracil) or an analogue thereof, as defined hereinbefore.
- X, particularly X m , as a further core structure element in the immunostimulatory sequence according to formula (Ilia), is preferably as defined above for formula (III).
- the number of core structure element X in the nucleic acid molecule of formula (Ilia) is determined by m.
- a sequence of at least 3 or more directly successive uridines (uracils) is referred to in connection with this application as a "monotonic uridine (uracil) sequence".
- a monotonic uridine (uracil) sequence typically has a length of at least 3, 4, 5, 6, 7, 8, 9 or 10, 1 1 , 12, 13, 14, 15, 16, 1 7, 18, 19, 20, 20 to 30, 30 to 40, 40 to 50, 50 to 60, 60 to 70, 70 to 80, 80 to 90, 90 to 100, 100 to 150, 150 to 200 uridines (uracils) or optionally analogues of uridine (uracil) as defined above.
- Such a monotonic uridine (uracil) sequence occurs at least once in the core structure element X of the nucleic acid molecule of formula (Ilia).
- monotonic uridine (uracil) sequences having at least 3 or more uridines (uracils) or analogues thereof to occur, which monotonic uridine (uracil) sequences can be interruped in the core structure element X by at least one guanosine (guanine), adenosine (adenine), thymidine (thymine), cytidine (cytosine) or an analogue thereof, preferably 2, 3, 4, 5 or more.
- guanosine guanine
- adenosine adenine
- thymidine thymine
- cytidine cytosine
- X m can be, for example, without implying any limitation, a UUUA, UUUG, UUUC, UUUU, AUUU, GUUU or CUUU, etc.
- X n can be, for example, without implying any limitation, a UUUAAUUUUC, UUUUGUUUUA, UUUGUUUGUU, UUGUUUUGUU, UUUUUUUUU, etc.
- the nucleotides (nucleosides) of X m adjacent to C 1 or C n of the nucleic acid molecule of formula (Ilia) preferably comprise uridine (uracil) or analogues thereof.
- uridine uracil
- m > 3 typically at least 50%, preferably at least 60%, 70%, 80%, 90% or even 100%, of the nucleotides of X m are uridine (uracil) or an analogue thereof, as defined above.
- nucleosides of X m to 100% may then be guanosine (guanine), uridine (uracil), adenosine (adenine), thymidine (thymine), cytidine (cytosine) or an analogue thereof, as defined above.
- the immunostimulatory sequence according formula (Ilia) above contains a bordering element N, particularly N u and/or N v , wherein the bordering element N, particularly N u and/or N v , as well as integers x and y are as defined above.
- the element N u QX m C n N v may occur as a repetitive element according to the immunostimulatory sequence of formula (Ilia) (N u QX m C n N v ) a , as defined above, wherein the number of repetitions of this element according to formula (Ilia) (N u QX m C n N v ) a is determined by the integer a.
- a is an integer from about 1 to 100, 1 to 50, 1 to 20, more preferably an integer from about 1 to 15, most preferably an integer from about 1 to 10.
- X m C n N v may be equal or different from each other.
- the immunostimulatory sequence of formula (Ilia) (N u C
- X m G n N v (or N u QX m C n N v ) thereof, may be single-stranded, double- stranded or partially double-stranded, etc. as defined for formula (III) in general.
- immunostimulatory sequence is a single- stranded nucleic acid molecule, the sequence is typically single-stranded over its entire length.
- the immunostimulatory sequence according to either formula (III) (or (HIa)) is a double-stranded nucleic acid molecule, the sequence is typically double-stranded over its entire length.
- the immunostimulatory sequence according to either formula (III) (or (MIa)) is a partially double-stranded nucleic acid molecule
- the nucleic acid sequence of a nucleic acid molecule of either formula (III) (or (MIa)) may be single-stranded in the region outside the core structure G
- the core structure G,X m G n (or QX m C n ) of (either) formula (III) (or (MIa)) may be double-stranded in such a region of the core structure, wherein a stretch of uridines (uracils) occurs, most preferably over the entire uridine (uracil) stretch or at least 60%, 70%, 80%, 90%, 95%, 98% or 99% thereof.
- the immunostimulatory sequence according to either formula (III) or (IMa) is a partially double-stranded nucleic acid molecule
- other parts (than the core structure G,X m G n ) of the immunostimulatory sequence according to formula (III) or (Ilia) as defined above may be double-stranded.
- the nucleic acid sequence of a nucleic acid molecule of either formula (III) or (Ilia) may be double-stranded in the region outside the core structure G
- X m G n (or QX 1n C n ), preferably selected from at least one of the above defined sequences of SEQ ID NOs: 1 -83.
- at least one of the bordering elements N v and/or N v may be double-stranded, whereas the remaining elements of either formula (III) or (MIa), e.g. the core structure G
- the immunostimulatory sequence according to formula (III) may be selected from a mixture of a single-stranded nucleic acid molecule according to either formula (III) or (Ilia) and a (partially) double-stranded nucleic acid molecule according to either formula (III) (or (HIa)), preferably in a ratio of about 1 :10 to 10:1 , more preferably in a ratio of 1 :3 to 3:1 .
- the immunostimulatory sequence according to formula (III) may be selected from e.g. any of the following sequences:
- the immunostimulatory sequence according to formula (Ilia) may be selected from e.g. any of the following sequences:
- the immunostimulatory sequence according to formula (III) may be modified with a poly(X) sequence (modifying element).
- Such immunostimulatory sequences may comprise e.g. a nucleic acid molecule according to formula (IV):
- nucleic acid molecule of formula (IV) likewise has a length of at least 50 nucleotides, preferably of at least 100 nucleotides, more preferably of at least 150 nucleotides, even more preferably of at least 200 nucleotides and most preferably of at least 250 nucleotides.
- a modifying element poly(IV), particularly poly(IV) s and/or poly(IV) t , of an immunostimulatory sequence according to formula (IV) is typically a single-stranded, a double-stranded or a partially double-stranded nucleic acid sequence, e.g a DNA or RNA sequence as defined above in general.
- the modifying element poly(IV), particularly poly(IV) s and/or poly(IV) t is a homopolymeric stretch of nucleic acids, wherein X may be any nucleotide or deoxynucleotide or comprises a nucleoside as defined above for X of an immunostimulatory sequence according to formula (III) or (Ilia).
- X may selected independently for each poly(IV), particularly poly(IV) s and/or poly(IV),, from a nucleotide or deoxynucleotide or comprises a nucleoside, wherein the nucleotide (nucleoside)is selected from guanosine (guanine), uridine (uracil), adenosine (adenine), thymidine (thymine), cytidine (cytosine), inosine or an analogue of these nucleotides, e.g.
- cytosines cytosines
- poly(Q) cytidines
- guanosine guanine
- poly(G) guanosine
- adenosine adenine
- poly(U) uridines
- inosines poly(lll)
- cytoines poly(lll:Q)
- adenosine adenine
- uridines uracils
- poly(A:U) a homopolymeric double- stranded stretch of inosines and cytidines
- the homoplymeric sequence particularly poly(lll:C) and/or poly(A:U)
- modifying element poly(IV), particularly poly(IV) 5 and/or poly(IV),, of the immunostimulatory sequence of formula (IV) is determined by integers s and/or t, wherein s and/or t, independent from each other, may be an integer from about 5 to 100, preferably about 5 to 70, more preferably about 5 to 50, even more preferably about 5 to 30 and most preferably about 5 to 20.
- a nucleic acid molecule according to formula (IV) as defined above may specifically comprise e.g. a nucleic acid molecule according to formula (IVa),
- all other definitions apply as set forth for formula (IV) or (III) above.
- said formulas (IV), (IVa) and (IVb) may be defined on basis of a formula according to formula (1Mb), i.e. introducing the core structure QX m C n .
- poly(X) in an immunostimulatory sequence according to either formula (IV), (IVa) and/or (IVb) may be selected from a poly(IV) as defined above, more preferably from poly(l:C) and/or from poly(A:U).
- These modifying elements poly(X), particularly poly(l:C) and/or poly(A:U) may be coupled to the sequence according to formula (IV), (IVa) and/or (IVb) via any of its strands, e.g. either using the poly-C, the poly-G, the poly-l, the poly-A or the poly-U sequence.
- the immunostimulatory sequence according to either formula (IV), (IVa) and/or (IVb) may be a single-stranded, a double-stranded or a partially double-stranded nucleic acid molecule, as defined above.
- immunostimulatory sequence according to formula (IV), (IVa) and/or (IVb) is a single- stranded nucleic acid molecule, the sequence is typically single-stranded over its entire length.
- the immunostimulatory sequence according to either formula (IV), (IVa) and/or (IVb) is a double-stranded nucleic acid molecule, the sequence is typically double-stranded over its entire length. If the immunostimulatory sequence according to either formula (IV), (IVa) and/or (IVb) is a partially double-stranded nucleic acid molecule, the nucleic acid sequence of a nucleic acid molecule of either formula (IV), (IVa) and/or (IVb) may be single-stranded in the region outside the core structure G
- X m C n ) of either formula (III) (or (MIa)) may be double-stranded in such a region of the core structure, wherein a stretch of uridines (uracils) occurs, most preferably over the entire uridine (uracil) stretch or at least 60%, 70%, 80%, 90%, 95%, 98 or 99% thereof.
- the immunostimulatory sequence according to either formula (IV), (IVa) and/or (IVb) is a partially double-stranded nucleic acid molecule
- X m G n ) of the immunostimulatory sequence according to either formula (IV), (IVa) and/or (IVb) as defined above may be double-stranded.
- the nucleic acid sequence of a nucleic acid molecule of either formula (IV), (IVa) and/or (IVb) may be double- stranded in the region outside the core structure G
- the modifying element poly(X) e.g. poly(X) s and or poly(X), (such as e.g. a poly(l:C) or poly(A:U) sequence), and e.g. single-stranded in the region of said core structure, the core structure G
- the bordering elements N u and/or N v and/or at least one of the modifying elements poly(IV), e.g.
- poly(IV) s and or poly(IV), may be double-stranded, whereas the remaining elements of either formula (IV), (IVa) and/or (IVb), e.g. the core structure G
- the immunostimulatory sequence according to either formula (IV), (IVa) and/or (IVb) may be selected from e.g. any of the following sequences: - CCCCCCCCCCCCCC GG UUUUU UUUUU UUUUU GGG (SEQ ID NO: 88)
- An immunostimulatory sequence according to formula (III) (or (HIa)) as defined above may also be modified by inserting a stem or a stem loop, e.g. leading to a nucleic acid molecule according to formula (Va),
- nucleic acid molecule of either formula (Va) and/or (Vb) has a length of at least 100 nucleotides, more preferably of at least 150 nucleotides, even more preferably of at least
- formulas (Va) and (Vb) may be defined on basis of formula (MIb), i.e. by introducing the core structure
- the immunostimulatory sequences of either formula (Va) and/or (Vb) represent variants of formula (III) as defined above.
- the bordering elements N i.e. N u and/or N v , bordering the core structure G
- the elements G, X and N particularly, the core structure G
- X m G n , and the integers a, I, m, n, u and v are as defined above. More preferably integer a 1 .
- elements N w) and N w2 adjacent to stem loop elements stemi and stem2, represent further bordering elements, which are defined as described above for bordering elements N 11 and/or N v .
- bordering element N in general is as described above for N in formula (III) above, and integers w1 and w2 are independently selected from each other and are defined as above in formula (III) for integers u and/or v.
- a stem or stem loop structure is an intramolecular base pairing that can occur in single-stranded DNA or, more commonly, in RNA.
- the structure is also known as a hairpin or hairpin loop. It occurs when two regions of the same molecule, e.g. stem loop elements stemi and stem2, usually palindromic sequence elements in nucleic acid sequences, form base-pairs with each other, leading to (a double helix that ends in) an unpaired loop.
- the unpaired loop thereby typically represents a region of the nucleic acid, which shows no or nearly no identity or homology with the sequence of either stemi or stem2 and is thus not capable of base pairing with any of these stem loop elements.
- the resulting lollipop-shaped structure is a key building block of many RNA secondary structures.
- the formation of a stem-loop structure is thus dependent on the stability of the resulting helix and loop regions, wherein the first prerequisite is typically the presence of a sequence that can fold back on itself to form a paired double helix.
- the stability of paired stem loop elements is determined by the length, the number of mismatches or bulges it contains (a small number of mismatches is typically tolerable, especially in a long helix), and the base composition of the paired region.
- guanosine (guanine) and cytidine (cytosine) may be more preferred in such sequences, since they have three hydrogen bonds and are more stable compared to adenosine (adenine)-uridine (uracil) pairings, which have only two.
- adenosine (adenine)-uridine (uracil) pairings which have only two.
- uracil adenosine-uridine pairings featuring two hydrogen bonds
- the stability of the loop also influences the formation of the stem-loop structure. "Loops" (i.e. only the loop not containing stem loop elements stemi and stem2) that are less than three bases long are sterically less preferable. However, stems, i.e.
- optimal loop length tends to be about 4-100 bases long, more preferably 4 to 50 or even 4 to 30 or even 4 to 20 bases.
- stem loop elements stemi and stem2 typically represent parts of one stem or stem loop structure, wherein the stem or stem loop structure may be formed by stem loop elements stemi and stem2, and a loop may be formed by a sequence, which is located between these stem loop elements.
- the stem or stem loop may have the form of a helix in the base-paired region.
- Each stem loop element stemi and stem2 is preferably a nucleic acid as defined above, more preferably an RNA, and most preferably a single-stranded RNA, wherein any of nucleotides (nucleosides) or analogs as defined above for core structure element X may be used as a nucleotides (nucleosides) for either stemi and/or stem2.
- stem loop element stemi represents a palindromic sequence of stem loop element stem2. Both sequences are therefore preferably capable of base pairing with each other and thus together form basis for a stem or stem loop.
- stem loop elements stemi or stem2 may be selected pairwise from any nucleic acid sequence, provided that stem loop elements stemi or stem2 are palindromic to each other, i.e. that one sequence is equal to the other (complementary) sequence read backwards or shows a identiy or homology to this sequence of at least 90%, more preferably of at least 95%, and most preferably of at least 99% to the other sequence, when read backwards.
- Such palindromic sequences stemi and stem2 may be formed each by a nucleic acid sequence having a length of about 5 to 50, more preferably about 5 to 40 and most preferably about 5 to 30 nucleic acids, selected from adenosine (adenine), guanosine (guanine), cytidine (cytosine), uridine (uracil), thymidine (thymine), or an anologue thereof as defined herein.
- Exemplary sequences for stem loop elements stemi and stem2 may include e.g.: a) for stemi :
- stem 1 UAGGUCCAAGAGCUUCGCUA (SEQ ID NO: 96) b) for stem 1:
- stem 1 UAGCGAAGCUCUUGGACCUA (SEQ ID NO: 95) c) for stem 1:
- X m G n may be located within the stem loop structure, i.e. the core structure G
- Such a nucleic acid molecule is resembled by formula (Va), having the composition (N u stem1 G[X m G n stem2 N v ) a , as defined above.
- formula (Va) may lead to a specific nucleic acid molecule "stemi G
- X m G n may be located outside the stem loop structure, wherein likewise stem loop elements stemi and stem2 may be separated from each other by a sequence, preferably a bordering element N, e.g. N wl or N w2 , which then may form a loop structure upon base pairing of stem loop elements stemi and stem2.
- stem loop elements 1 and/or 1 adjacent to the core structure G
- such a nucleic acid is resembled by formula (Vb), having the composition (N u G,X m G n N v ) a stemi N w1 stem2 N w2 , as defined above.
- the immunostimulatory sequence according to either formula (Va) and/or (Vb) may be single-stranded, or partially double-stranded. If the immunostimulatory sequence according to either formula (Va) and/or (Vb) is a single-stranded nucleic acid molecule, the sequence is typically single-stranded over its entire length.
- the immunostimulatory sequence according to either formula (Va) and/or (Vb) is a partially double-stranded nucleic acid molecule
- the nucleic acid molecule of either formula (Va) and/or (Vb) preferably may be single-stranded in the region of the stem loop elements stemi and stem2 and in the regions of the loop formed by either the core structure G
- N w1 or N w2 may then be, independent from each other, single or double-stranded.
- the immunostimulatory sequence according to either formula (Va) and/or (Vb), respectively may be selected from e.g. any of the following sequences:
- the immunostimulatory sequence of formula (I), (II), (III), (Ilia), (IV), (IVa), (IVb), (Va) and/or (Vb) as defined above, is typically a nucleic acid, which may be in the form of any DNA or RNA, preferably, without being limited thereto, a circular or linear DNA or RNA, a single- or a double-stranded DNA or RNA (which may also be regarded as an DNA or RNA due to non-covalent association of two single-stranded DNAs or RNAs) or a partially double- stranded DNA or RNA (which is typically formed by a longer and at least one shorter single- stranded DNA or RNA molecule or by at least two single-stranded DNA or RNA-molecules, which are about equal in length, wherein one or more single-stranded DNA or RNA molecules are in part complementary to one or more other single-stranded DNA or RNA molecules and thus form a double-stranded RNA in this
- nucleic acid molecule of formula (I), (II), (III), (Ilia), (IV), (IVa), (IVb), (Va) and/or (Vb) as defined above may be in the form of a single- or a double-stranded DNA or RNA, more preferably a partially double-stranded DNA or RNA.
- immunostimulatory sequence of formula (I), (II), (III), (Ilia), (IV), (IVa), (IVb), (Va) and/or (Vb) as defined above is in the form of a mixture of a single-stranded nucleic and double stranded DNA or RNA.
- the immunostimulatory sequence of formula (I), (II), (III), (Ilia), (IV), (IVa), (IVb), (Va) and/or (Vb) as defined above is a partially double-stranded nucleic acid molecule, since such a (partially double-stranded) immunostimulatory sequence according to formula (I), (II), (III), (Ilia), (IV), (IVa), (IVb), (Va) and/or (Vb) as defined above), can positively stimulate the innate immune response in a patient to be treated by addressing the PAMP-(pathogen associated molecular pattern) receptors for single-stranded RNA (TLR-7 and TLR-8) as well as the PAMP-receptors for double-stranded RNA (TLR-3, RIG-I and MDA-5).
- TLR-7 and TLR-8 the PAMP-receptors for double-stranded RNA
- Receptors TLR-3, TLR-7 and TLR-8 are located in the endosome and are activated by RNA taken up by the endosome.
- RIG-I and MDA-5 are cytoplasmic receptors, which are activated by RNA, which was directly taken up into the cytoplasm or which has been released from the endosomes (endosomal release or endosomal escape). Accordingly, any partially double-stranded immunostimulatory sequence of formula (I), (II), (III), (Ilia), (IV), (IVa), (IVb), (Va) and/or (Vb) as defined above is capable of activating different signal cascades of immunostimulation and thus leads to an innate immune response or enhances such a response significantly.
- Nucleic acid molecules of either formula (I), (II), (III), (Ilia), (IV), (IVa), (IVb), (Va) and/or (Vb) as defined above may be prepared using any method known in the art, including synthetic methods such as e.g. solid phase synthesis, as well as in vitro methods such as in vitro transcription reactions. Preferably, an in vitro transcription is used for preparation of the immunostimulatory sequences.
- nucleic acid molecules of either formula (I), (II), (III), (Ilia), (IV), (IVa), (IVb), (Va) and/or (Vb) as defined above show an even better stimulation of the innate immune system, when prepared by an in vitro transcription due to its 5'-phosphate, when compared to nucleic acid molecules of either formula (I), (II), (III), (Ilia), (IV), (IVa), (IVb), (Va) and/or (Vb) prepared by synthetic methods.
- Such a stimulation of the innate immune system is, without being bound thereto, contributed to the activation of the receptor RIG-1 .
- nucleic acid molecules of either formula (I), (II), (III), (Ilia), (IV), (IVa), (IVb), (Va) and/or (Vb) as defined above are particularly preferred, when prepared by an in vitro transcription reaction.
- RNA molecules which may be used for the at least one (m)RNA of the adjuvant component of the inventive immunostimulatory composition, may include any other RNA capable of eliciting an immune response.
- an immunostimulatory RNA may include ribosomal RNA (rRNA), transfer RNA (tRNA), messenger RNA (mRNA), and viral RNA (vRNA).
- the at least one (m)RNA of the adjuvant component of the inventive immunostimulatory composition may be an siRNA.
- An siRNA is of interest particularly in connection with the phenomenon of RNA interference. Attention was drawn to the phenomenon of RNA interference in the course of immunological research. In recent years, an RNA-based defence mechanism has been discovered, which occurs both in the kingdom of the fungi and in the plant and animal kingdom and acts as an "immune system of the genome". The system was originally described in various species independently of one another, first in C.
- RNA-mediated virus resistance in plants RNA-mediated virus resistance in plants
- PTGS posttranscriptional gene silencing
- RNA interference in eukaryotes are accordingly based on a common procedure.
- the in vitro technique of RNA interference (RNAi) is based on double-stranded RNA molecules (dsRNA), which trigger the sequence- specific suppression of gene expression (Zamore (2001 ) Nat. Struct. Biol. 9: 746-750; Sharp (2001 ) Genes Dev. 5:485-490: Hannon (2002) Nature 41 : 244-251 ).
- dsRNA molecules have also been used in vivo (McCaffrey et a/. (2002), Nature 418: 38-39; Xia et a/. (2002), Nature Biotech. 20: 1006-1010; Brummelkamp et a/. (2002), Cancer Cell 2: 243-247).
- an siRNA used for the at least one (m)RNA of the adjuvant component of the inventive immunostimulatory composition may be an immunostimulatory RNA, and typically comprises a (single- or) double stranded, preferably a double-stranded, RNA sequence with about 8 to 30 nucleotides, preferably 17 to 25 nucleotides, even more preferably from 20 to 25 and most preferably from 21 to 23 nucleotides.
- all the sections having a length of from 1 7 to 29, preferably from 19 to 25, most preferably from 21 to 23 base pairs that occur in the coding region of an RNA sequence as mentioned above can serve as target sequence for such an siRNA.
- siRNAs can also be directed against nucleotide sequences of a protein, particularly of regulatory proteins, which negatively regulate induction of an (innate or adaptive) immune response, that do not lie in the coding region, in particular in the 5' non-coding region of the RNA, for example, therefore, against non-coding regions of an RNA having a regulatory function.
- the target sequence of the si RNA, used as the at least one (m)RNA of the adjuvant component of the inventive immunostimulatory composition can therefore lie in the translated and/or untranslated region of the nucleotide sequence of such a protein as defined above and/or in the region of its control elements.
- the target sequence of an si RNA as defined above can also lie in the overlapping region of untranslated and translated sequence; in particular, the target sequence can comprise at least one nucleotide upstream of the start triplet of the coding region of the RNA.
- the at least one (m)RNA of the adjuvant component of the inventive immunostimulatory composition may be an antisense RNA.
- an antisense RNA is preferably a (single-stranded) RNA molecule transcribed off the coding, rather than the template, strand of a DNA, so that (preferably) the (entire) anti-sense mRNA sequence is complementary to the sense (messenger) RNA.
- An antisense RNA as defined herein typically forms a duplex between the sense and antisense RNA molecules and is thus capable to block transcription of the coding strand.
- An antisense RNA used as the at least one (m)RNA of the adjuvant component of the inventive immunostimulatory composition can be directed against the nucleotide sequences, e.g. a (naturally occurring) mRNA or genomic sequence encoding a protein or peptide, which may be selected from any protein or peptide sequence suitable for that purpose.
- the antisense RNA used herein as at least one (m)RNA of the adjuvant component of the inventive immunostimulatory composition comprises a length as defined above in general for RNA molecules, more preferably a length of 1000 to 5000, of 500 to 5000, of 5 to 5000, or of 5 to 1000, 5 to 500, 5 to 250, of 5 to 100, of 5 to 50 or of 5 to 30 nucleotides.
- the at least one (m)RNA of the adjuvant component of the inventive immunostimulatory composition may be a coding RNA.
- a coding RNA may be any RNA as defined above.
- such a coding RNA may be a single- or a double-stranded RNA, more preferably a single-stranded RNA, and/or a circular or linear RNA, more preferably a linear RNA.
- the coding RNA may be a (linear) single-stranded RNA.
- the coding RNA may be a ((linear) single- stranded) messenger RNA (mRNA).
- the coding RNA used as the at least one (m)RNA of the adjuvant component of the inventive immunostimulatory composition may further encode a protein or a peptide, which may be selected, without being restricted thereto, e.g. from therapeutically active proteins or peptides, from antigens, e.g. tumor antigens, pathogenic antigens (e.g.
- RNA used as the at least one (m)RNA of the adjuvant component of the inventive immunostimulatory composition may be transported into a cell, a tissue or an organism and the protein may be expressed subsequently in this cell, tissue or organism.
- therapeutically active proteins encoded by the at least one (m)RNA of the adjuvant component of the immunostimulatory composition may be selected from any naturally occurring recombinant or isolated proteins known to a skilled person from the prior art.
- therapeutically active proteins may comprise proteins, capable of stimulating or inhibiting the signal transduction in the cell, e.g. cytokines, antibodies, etc.
- Therapeutically active proteins may thus comprise cytokines of class I of the family of cytokines, having 4 positionally conserved cysteine residues
- Cytokines of class I of the family of cytokines comprise the GM-CSF subfamily, e.g. IL-3, IL-5, GM-CSF, the IL-6-subfamily, e.g. IL-6, IL- 1 1 , IL-12, or the IL-2 -subfamily, e.g. IL-2, IL-4, IL-7, IL-9, IL-15, etc., or the cytokines IL- 1 alpha, IL-1 beta, IL-10 etc.
- Therapeutically active proteins may also comprise cytokines of class Il of the family of cytokines, which also comprise 4 positionally conserved cystein residues (CCCC), but no conserved sequence motif Trp-Ser-X-Trp-Ser (WSXWS). Cytokines of class Il of the family of cytokines comprise e.g. IFN-alpha, IFN-beta, IFN- gamma, etc. Therapeutically active proteins may additionally comprise cytokines of the family of tumor necrose factors, e.g. TNF-alpha, TNF-beta, etc., or cytokines of the family of chemokines, which comprise 7 transmembrane helices and interact with G-protein, e.g.
- Therapeutically active proteins encoded by the at least one (m)RNA of the adjuvant component of the immunostimulatory composition may also be selected from any of the proteins given in the following: 0ATL3, 0FC3, 0PA3, 0PD2, 4-1 BBL, 5T4, 6Ckine, 707- AP, 9D7, A2M, AA, AAAS, AACT, AASS, ABAT, ABCA1, ABCA4, ABCB1, ABCB11,
- CARD15 CASP-5/m, CASP-8, CASP-8/m, CASR, CAT, CATM, CAV3, CB1, CBBM, CBS, CCA1, CCAL2, CCAL1, CCAT, CCL-1, CCL-11, CCL-12, CCL-13, CCL-14, CCL-15, CCL- 16, CCL-17, CCL-18, CCL-19, CCL-2, CCL-20, CCL-21, CCL-22, CCL-23, CCL-24, CCL- 25, CCL-27, CCL-3, CCL-4, CCL-5, CCL-7, CCL-8, CCM1, CCNB1, CCND1, CCO, CCR2, CCR5, CCT, CCV, CCZS, CD1, CD19, CD20, CD22, CD25, CD27, CD27L, cD3, CD30, CD30, CD30L, CD33, CD36, CD3E, CD3G, CD3Z, CD4, CD40, CD40L, CD44, CD44v, CD44v6, CD52, CD
- CMDJ CMD1A, CMD1B, CMH2, MH3, CMH6, CMKBR2, CMKBR5, CML28, CML66, CMM, CMT2B, CMT2D, CMT4A, CMT1A, CMTX2, CMTX3, C-MYC, CNA1, CND, CNGA3, CNGA1, CNGB3, CNSN, CNTF, COA-1/m, COCH, COD2, COD1, COHl, COL10A, COL2A2, COL11A2, COL17A1, COL1A1, COL1A2, COL2A1, COL3A1, COL4A3, COL4A4, COL4A5, COL4A6, COL5A1, COL5A2, COL6A1, COL6A2,
- DISCI DKC1, DLAT, DLD, DLL3, DLX3, DMBT1, DMD, DMI, DMPK, DMWD, DNAH, DNASE1, DNMT3B, DPEP1, DPYD, DPYS, DRD2, DRD4, DRPLA, DSCR1, DSG1, DSP, DSPP, DSS, DTDP2, DTR, DURS1, DWS, DYS, DYSF, DYT2, DYT3, DYT4, DYT2, DYT1, DYX1, EBAF, EBM, EBNA, EBP, EBR3, EBSl, ECA1, ECB2, ECE1, ECGFl, ECT, ED2, ED4, EDA, EDAR, ECA1, EDN3, EDNRB, EEC1, EEF1A1L14, EEGV1, EFEMP1, EFTUD2/m, EGFR, EGFR/Herl, EGI, EGR2, EIF2AK3, elF4G, EK
- G250/CAIX G6PC, G6PD, G6PT1, G6PT2, GAA, GABRA3, GAGE-1, GAGE-2, GAGE-3, GAGE-4, GAGE-5, GAGE-6, GAGE-7b, GAGE-8, GALC, GALE, GALK1, GALNS, GALT, GAMT, GAN, GAST, GASTRIN17, GATA3, GATA, GBA, GBE, GC, GCDH, GCGR, GCH1, GCK, GCP-2, GCS1, G-CSF, GCSH, GCSL, GCY, GDEP,GDF5, GDI1, GDNF, GDXY, GFAP, GFND, GGCX, GGT1, GH2, GH1, GHR, GHRHR, GHS, GIF, GINGF,
- GIP GJA3, GJA8, GJB2, GJB3, GJB6, GJB1, GK, GLA, GLB, GLB1, GLC3B, GLC1B, GLC1C, GLDC, GLI3, GLP1, GLRAl, GLUD1, GM1 (fuc-GMI), GM2A, GM-CSF, GMPR, GNAI2, GNAS, GNAT1, GNB3, GNE, GNPTA, GNRH, GNRH1, GNRHR, GNS, GnT-V, gp100, GP1BA, GP1BB, GP9, GPC3, GPD2, GPDS1, GPI, GP1 BA, GPN1LW, GPNMB/m, GPSC, GPXI, GRHPR, GRKI, GRO ⁇ , GRO ⁇ , GRO ⁇ , GRPR, GSE, GSM1,
- GSN GSR, GSS, GTD, GTS, GUCA1A, GUCY2D, GULOP, GUSB, GUSM, GUST, GYPA, GYPC, GYS1, GYS2, H0KPP2, H0MG2, HADHA, HADHB, HAGE, HAGH, HAL, HAST-2, HB 1, HBA2, HBA1, HBB, HBBPl, HBD, HBE1, HBG2, HBG1, HBHR, HBP1, HBQ1, HBZ, HBZP, HCA, HCC-1, HCC-4, HCF2, HCG, HCL2, HCL1, HCR, HCVS, HD, HPN, HER2, HER2/NEU, HER3, HERV-K-MEL, HESX1, HEXA, HEXB, HF1, HFE, HF1,
- HGD HHC2, HHC3, HHG, HK1 HLA-A, HLA-A*0201-R170l, HLA-A11/m, HLA-A2/m, HLA-DPB1 HLA-DRA, HLCS, HLXB9, HMBS, HMGA2, HMGCL, HMI, HMN2, HMOX1, HMS1 HMW-MAA, HND, HNE, HNF4A, HOAC, HOMEOBOX NKX 3.1, HOM-TES- 14/SCP-1, HOM-TES-85, HOXA1 HOXD13, HP, HPC1, HPD, HPE2, HPE1, HPFH, HPFH2, HPRTI, HPS1, HPT, HPV-E6, HPV-E7, HR, HRAS, HRD, HRG, HRPT2, HRPT1, HRX, HSD11B2, HSD17B3, HSDl 7B4, HSD3B2, HSD3B3, HSN1, HSP70-2M,
- MOV18 MPD1, MPE, MPFD, MPI, MPIF-1, MPL, MPO, MPS3C, MPZ, MRE11A, MROS, MRP1, MRP2, MRP3, MRSD, MRX14, MRX2, MRX20, MRX3, MRX40, MRXA, MRX1, MS, MS4A2, MSD, MSH2, MSH3, MSH6, MSS, MSSE, MSX2, MSX1, MTATP6, MTC03, MTCO1, MTCYB, MTHFR, MTM1, MTMR2, MTND2, MTND4, MTND5, MTND6, MTND1, MTP, MTR, MTRNR2, MTRNRI, MTRR,MTTE, MTTG, MTTI, MTTK, MTTL2,
- MTTLI MTTLI, MTTN, MTTP, MTTSI, MUC1,MUC2, MUC4, MUC5AC, MUM-I, MUM-1/m, MUM-2, MUM-2/m, MUM-3, MUM-3/m, MUT, mutant p21 ras, MUTYH, MVK, MX2, MXH, MY05A, MYB, MYBPC3, MYC, MYCL2, MYH6, MYH7, MYL2, MYL3, MYMY, MYO15A, MYO1G, MYO5A, MYO7A, MYOC, Myosin/m, MYP2, MYP1, NA88-A, N- acetylglucosaminyltransferase-V, NAGA, NAGLU, NAMSD, NAPB, NAT2, NAT, NBIA1,
- PDHAI PDR, PDX1, PECAM1, PEE1, PEO1, PEPD, PEX10, PEXI 2, PEX13, PEX3, PEX5, PEX6, PEX7, PEX1, PF4, PFBI, PFC, PFKFBI, PFKM, PGAM2, PGD, PGK1, PGK1P1, PGL2, PGR, PGS, PHA2A, PHB, PHEX, PHGDH, PHKA2, PHKA1, PHKB, PHKG2, PHP, PHYH, Pl, PI3, PIGA, PIM1 -KINASE, PIN1, PIP5K1B, PITX2, PITX3, PKD2, PKD3, PKD1, PKDTS, PKHD1, PKLR, PKP1, PKU1, PLA2G2A, PLA2G7, PLAT, PLEC1, PLG, PLI, PLOD, PLP1, PMEL17, PML, PML/RAR ⁇ , PMM2, PMP22,
- PPTl PRAME, PRB, PRB3, PRCA1, PRCC, PRD, PRDX5/m, PRF1, PRG4, PRKAR1A, PRKCA, PRKDC, PRKWNK4, PRNP, PROC, PRODH, PROM1, PROP1, PROSI, PRST, PRP8, PRPF31, PRPF8, PRPH2, PRPS2, PRPS1, PRS, PRSS7, PRSSl, PRTN3, PRX, PSA, PSAP, PSCA, PSEN2, PSEN1, PSG1, PSGR, PSM, PSMA, PSORS1, PTC, PTCH, PTCH1, PTCH2, PTEN, PTGS1, PTH, PTHR1, PTLAH, PTOS1, PTPNl 2, PTPNI I, PTPRK,
- SIRT2/m SIX3, SJS1, SKP2, SLC10A2, SLC12A1, SLC12A3, SLC17A5, SLCl 9A2, SLC22A1L, SLC22A5, SLC25A13, SLC25A15, SLC25A20, SLC25A4, SLC25A5, SLC25A6, SLC26A2, SLC26A3, SLC26A4, SLC2A1, SLC2A2, SLC2A4, SLC3A1, SLC4A1, SLC4A4, SLC5A1, SLC5A5, SLC6A2, SLC6A3, SLC6A4, SLC7A7, SLC7A9, SLCl 1A1, SLOS, SMA, SMAD1, SMAL, SMARCB1, SMAX2, SMCR, SMCY, SM1, SMN2, SMN1, SMPD1, SNCA,
- SNRPN SOD2, SOD3, SOD1, SOS1, SOST, SOX9, SOX10, Sp17, SPANXC, SPG23, SPG3A, SPG4, SPG5A, SPG5B, SPG6, SPG7, SPINK1, SPINK5, SPPK, SPPM, SPSMA, SPTA1, SPTB, SPTLCl, SRC, SRD5A2, SRPX, SRS, SRY, ⁇ hCG, SSTR2, SSX1, SSX2 (HOM- MEL-40/SSX2), SSX4, ST8, STAMP-1, STAR, STARPI, STATH, STEAP, STK2, STKlI, STn/ KLH, STO, STOM, STS, SUOX, SURF1, SURVIVIN-2B, SYCP1, SYM1, SYN1, SYNS1, SYP, SYT/SSX, SYT-SSX-1, SYT-SSX-2, TA-90, TAAL
- WHN WISP3, WMS, WRN, WS2A, WS2B, WSN, WSS, WT2, WT3, WT1, WTS, WWS, XAGE, XDH, XIC, XIST, XK, XM, XPA, XPC, XRCC9, XS, ZAP70, ZFHX1 B, ZFX, ZFY, ZIC2, ZIC3, ZNFl 45, ZNF261, ZNF35, ZNF41, ZNF6, ZNF198, ZWS1.
- Therapeutically active proteins may further be selected from apoptotic factors or apoptosis related proteins including AIF, Apaf e.g. Apaf-1, Apaf-2, Apaf-3, oder APO-2 (L), APO-3 (L), Apopain, Bad, Bak, Bax, Bcl-2, Bcl-x L , Bcl-x s , bik, CAD, Calpain, Caspase e.g.
- a therapeutically active protein which may be encoded by the at least one (m)RNA of the adjuvant component of the inventive immunostimulatory composition, can also be an adjuvant protein.
- an adjuvant protein is preferably to be understood as any protein, which is capable to elicit an innate immune response as defined herein.
- such an innate immune response comprises activation of a pattern recognition receptor, such as e.g. a receptor selected from the Toll-like receptor (TLR) familiy, including e.g. a Toll like receptor selected from human TLRl to TLR10 or from murine
- TLR Toll-like receptor
- the adjuvant protein is selected from human adjuvant proteins or from pathogenic adjuvant proteins, in particular from bacterial adjuvant proteins.
- mRNA encoding human proteins involved in adjuvant effects may be used as well.
- Human adjuvant proteins which may be encoded by the at least one (m)RNA of the adjuvant component of the inventive immunostimulatory composition, typically comprise any human protein, which is capable of eliciting an innate immune response (in a mammal), e.g. as a reaction of the binding of an exogenous TLR ligand to a TLR.
- human adjuvant proteins encoded by the at least one modified (m)RNA of the inventive immunostimulatory composition are selected from the group consisting of, without being limited thereto, cytokines which induce or enhance an innate immune response, including IL-2, IL-12, IL-15, IL-18, IL-21 CCL21 , GM-CSF and TNF-alpha; cytokines which are released from macrophages, including IL-I , IL-6, IL-8, IL-12 and
- TNF-alpha from components of the complement system including C1 q, MBL, C1 r, C1 s, C2b, Bb, D, MASP-I , MASP-2, C4b, C3b, C5a, C3a, C4a, C5b, C6, QJ, C8, C9, CR1 , CR2, CR3, CR4, C1 qR, C1 INH, C4bp, MCP, DAF, H, I, P and CD59; from proteins which are components of the signalling networks of the pattern recognition receptors including TLR and IL-I R1 , whereas the components are ligands of the pattern recognition receptors including IL-I alpha, I L-I beta, Beta-defensin, heat shock proteins, such as HSP10, HSP60, HSP65, HSP70, HSP75 and HSP90, gp96, Fibrinogen, Typlll repeat extra domain A of fibronectin; the receptors, including IL-
- NF- ⁇ B, c-Fos, c-Jun, c-Myc e.g. IL-I alpha, IL-I beta, Beta-Defensin, IL-6, IFN gamma, IFN alpha and IFN beta; from costimulatory molecules, including CD28 or CD40-ligand or PD1 ; protein domains, including LAMP; cell surface proteins; or human adjuvant proteins including CD80, CD81 , CD86, trif, flt-3 ligand, thymopentin, Gp96 or fibronectin, etc., or any species homolog of any of the above human adjuvant proteins.
- Pathogenic adjuvant proteins which may be encoded by the at least one (m)RNA of the adjuvant component of the inventive immunostimulatory composition, typically comprise any pathogenic (adjuvant) protein, which is capable of eliciting an innate immune response (in a mammal), more preferably selected from pathogenic (adjuvant) proteins derived from bacteria, protozoa, viruses, or fungi, animals, etc., and even more preferably from pathogenic adjuvant proteins selected from the group consisting of, without being limited thereto, bacterial proteins, protozoan proteins (e.g. profilin - like protein of Toxoplasma gondii), viral proteins, or fungal proteins, animal proteins, etc.
- pathogenic (adjuvant) protein which is capable of eliciting an innate immune response (in a mammal)
- pathogenic (adjuvant) proteins derived from bacteria, protozoa, viruses, or fungi, animals, etc. and even more preferably from pathogenic adjuvant proteins selected from the
- bacterial (adjuvant) proteins which may be encoded by the at least one (m)RNA of the adjuvant component of the inventive immunostimulatory composition, may comprise any bacterial protein, which is capable of eliciting an innate immune response (preferably in a mammal) or shows an adjuvant character.
- such bacterial (adjuvant) proteins are selected from the group consisting of bacterial heat shock proteins or chaperons, including Hsp60, Hsp70, Hsp90, Hsp100; OmpA (Outer membrane protein) from gram-negative bacteria; bacterial porins, including OmpF; bacterial toxins, including pertussis toxin (PT) from Bordetella pertussis, pertussis adenylate cyclase toxin CyaA and CyaC from Bordetella pertussis, PT-9K/129G mutant from pertussis toxin, pertussis adenylate cyclase toxin CyaA and CyaC from Bordetella pertussis, tetanus toxin, cholera toxin (CT), cholera toxin B-subunit, CTK63 mutant from cholera toxin, CTE1 12K mutant from CT, Escherichia coli heat-labile entero
- CT
- Bacterial (adjuvant) proteins which may be encoded by the at least one (m)RNA of the adjuvant component of the inventive immunostimulatory composition, may also be selected from bacterial adjuvant proteins, even more preferably selected from the group consisting of, without being limited thereto, bacterial flagellins, including flagellins from organisms including Agrobacterium, Aquifex, Azospirillum, Bacillus, Bartonella, Bordetella, Borrelia, Burkholderia, Campylobacter, Caulobacte, Clostridium, Escherichia, Helicobacter, Lachnospiraceae, Legionella, Listeria, Proteus, Pseudomonas, Rhizobium, Rhodobacter, Roseburia, Salmonella, Serpulina, Serratia, Shigella, Treponema, Vibrio,
- Helicobacter pylori Lachnospiraceae bacterium, Legionella pneumophila, Listeria monocytogenes, Proteus mirabilis, Pseudomonas aeroguinosa, Pseudomonas syringae, Rhizobium meliloti, Rhodobacter sphaeroides, Roseburia diarrhea during Roseburis hominis, Salmonella typhimurium, Salmonella bongori, Salmonella typhi, Salmonella enteritidis, Serpulina hyodysenteriae, Serratia marcescens, Shigella boydii, Treponema phagedenis,
- Vibrio alginolyticus Vibrio cholerae, Vibrio parahaemolyticus, Wolinella succinogenes and Yersinia enterocolitica.
- Bacterial flagellins which may be encoded by the at least one (m)RNA of the adjuvant component of the inventive immunostimulatory composition, even more preferably comprise a sequence selected from the group comprising any of the following sequences as referred to their accession numbers:
- Protozoan proteins which may also be encoded by the at least one (m)RNA of the adjuvant component of the inventive immunostimulatory composition, may be selected from any protozoan protein showing adjuvant character, more preferably, from the group consisting of, without being limited thereto, Tc52 from Trypanosoma cruzi, PFTG from Trypanosoma gondii, Protozoan heat shock proteins, LeIF from Leishmania spp., profilin- I ike protein from Toxoplasma gondii, etc.
- Viral proteins which may be encoded by the at least one (m)RNA of the adjuvant component of the inventive immunostimulatory composition, may be selected from any viral protein showing adjuvant character, more preferably, from the group consisting of, without being limited thereto, Respiratory Syncytial Virus fusion glycoprotein (F-protein), envelope protein from MMT virus, mouse leukemia virus protein, Hemagglutinin protein of wild-type measles virus, etc.
- F-protein Respiratory Syncytial Virus fusion glycoprotein
- Fungal proteins which may be encoded by the at least one (m)RNA of the adjuvant component of the inventive immunostimulatory composition, may be selected from any fungal protein showing adjuvant character, more preferably, from the group consisting of, without being limited thereto, fungal immunomodulatory protein (FIP; LZ-8), etc.
- FIP fungal immunomodulatory protein
- pathogenic adjuvant proteins which may be encoded by the at least one (m)RNA of the adjuvant component of the inventive immunostimulatory composition, may finally be selected from any further pathogenic protein showing adjuvant character, more preferably, from the group consisting of, without being limited thereto, Keyhole limpet hemocyanin (KLH), OspA, etc.
- KLH Keyhole limpet hemocyanin
- OspA OspA
- the at least one (m)RNA of the adjuvant component of the immunostimulatory composition may alternatively encode an antigen.
- the term "antigen" refers to a substance which is recognized by the immune system and is capable of triggering an antigen-specific immune response, e.g. by formation of antibodies as part of an adaptive immune response or antigen-specific T-cells.
- the first step of an adaptive immune response is the activation of na ⁇ ve antigen- specific T cells by antigen-presenting cells. This occurs in the lymphoid tissues and organs through which na ⁇ ve T cells are constantly passing.
- the three cell types that can serve as antigen-presenting cells are dendritic cells, macrophages, and B cells.
- Tissue dendritic cells take up antigens by phagocytosis and macropinocytosis and are stimulated by infection to migrate to the local lymphoid tissue, where they differentiate into mature dendritic cells. Macrophages ingest particulate antigens such as bacteria and are induced by infectious agents to express MHC class Il molecules. The unique ability of B cells to bind and internalize soluble protein antigens via their receptors may be important to induce T cells. By presenting the antigen on MHC molecules leads to activation of T cells which induces their proliferation and differentiation into armed effector T cells.
- effector T cells The most important function of effector T cells is the killing of infected cells by CD8 cytotoxic T cells and the activation of macrophages by TH1 cells which together make up cell- mediated immunity, and the activation of B cells by both TH2 and TH1 cells to produce different classes of antibody, thus driving the humoral immune response.
- T cells recognize an antigen by their T cell receptors which does not recognize and bind antigen directly, but instead recognize short peptide fragments e.g. of pathogens' protein antigens, which are bound to MHC molecules on the surfaces of other cells.
- T cells fall into two major classes that have different effector functions.
- the two classes are distinguished by the expression of the cell-surface proteins CD4 and CD8. These two types of T cells differ in the class of MHC molecule that they recognize.
- MHC molecule- MHC class I and MHC class II- which differ in their structure and expression pattern on tissues of the body.
- CD4 T cells bind to the MHC class Il molecule and CD8 T cells to the MHC class I molecule.
- MHC class I and MHC class Il have distinct distributions among cells that reflect the different effector functions of the T cells that recognize them.
- MHC class I molecules present peptides from pathogens, commonly viruses to CD8 T cells, which differentiate into cytotoxic T cells that are specialized to kill any cell that they specifically recognize.
- MHC class I molecules Almost all cells express MHC class I molecules, although the level of constitutive expression varies from one cell type to the next. But not only pathogenic peptides from viruses are presented by MHC class I molecules, also self-antigens like tumour antigens are presented by them. MHC class I molecules bind peptides from proteins degraded in the cytosol and transported in the endoplasmic reticulum. Thereby MHC class I molecules on the surface of cells infected with viruses or other cytosolic pathogens display peptides from these pathogen.
- the CD8 T cells that recognize MHC classkpeptide complexes are specialized to kill any cells displaying foreign peptides and so rid the body of cells infected with viruses and other cytosolic pathogens.
- CD4 T cells CD4 helper T cells
- MHC class Il molecules are normally found on B lymphocytes, dendritic cells, and macrophages, cells that participate in immune responses, but not on other tissue cells.
- Macrophages for example, are activated to kill the intravesicular pathogens they harbour, and B cells to secrete immunoglobulins against foreign molecules.
- MHC class Il molecules are prevented from binding to peptides in the endoplasmic reticulum and thus MHC class Il molecules bind peptides from proteins which are degraded in endosomes. They can capture peptides from pathogens that have entered the vesicular system of macrophages, or from antigens internalized by immature dendritic cells or the immunoglobulin receptors of B cells.
- TH1 cells activate the microbicidal properties of macrophages and induce B cells to make IgG antibodies that are very effective of opsonising extracellular pathogens for ingestion by phagocytic cells
- TH2 cells initiate the humoral response by activating na ⁇ ve B cells to secrete IgM, and induce the production of weakly opsonising antibodes such as IgGI and lgG3 (mouse) and lgG2 and lgG4 (human) as well as IgA and IgE (mouse and human).
- antigens as encoded by the at least one (m)RNA of the adjuvant component of the inventive immunostimulatory composition typically comprise any antigen, falling under the above definition, more preferably protein and peptide antigens, e.g. tumor antigens, allergy antigens, auto-immune self-antigens, pathogenic anigens, etc.
- antigens as encoded by the at least one (m)RNA of the adjuvant component of the inventive immunostimulatory composition may be antigens generated outside the cell, more typically antigens not derived from the host organism (e.g. a human) itself (i.e. non-self antigens) but rather derived from host cells outside the host organism, e.g.
- Allergy antigens are typically antigens, which cause an allergy in a human and may be derived from either a human or other sources.
- Antigens as encoded by the at least one (m)RNA of the adjuvant component of the inventive immunostimulatory composition may be furthermore antigens generated inside the cell, the tissue or the body, e.g. by secretion of proteins, their degradation, metabolism, etc..
- Such antigens include antigens derived from the host organism (e.g. a human) itself, e.g.
- tumor antigens self-antigens or auto-antigens, such as auto-immune self-antigens, etc., but also (non-self) antigens as defined above, which have been originally been derived from host cells outside the host organism, but which are fragmented or degraded inside the body, tissue or cell, e.g. by (protease) degradation, metabolism, etc.
- Pathogenic antigens particularly comprise e.g. antigens from influenza, including hemagglutinin (HA), neuroamidase (NA), matrix protein 1 (M1 ), ion channel protein M2 (M2), nucleoprotein (NP), etc; or e.g. antigens from respiratory syncytial virus (RSV), including F-protein, G-protein, etc.
- HA hemagglutinin
- NA neuroamidase
- M1 matrix protein 1
- M2 ion channel protein M2
- NP nucleoprotein
- RSV respiratory syncytial virus
- Antigens as encoded by the at least one (m)RNA of the adjuvant component of the inventive immunostimulatory composition may furthermore comprise fragments of such antigens as mentioned herein, particularly of protein or peptide antigens. Fragments of such antigens in the context of the present invention may comprise fragments preferably having a length of about 6 to about 20 or even more amino acids, e.g. fragments as processed and presented by MHC class I molecules, preferably having a length of about 8 to about 10 amino acids, e.g. 8, 9, or 10, (or even 1 1 , or 12 amino acids), or fragments as processed and presented by MHC class Il molecules, preferably having a length of about
- amino acids e.g. 13, 14, 15, 16, 17, 18, 19, 20 or even more amiono acids, wherein these fragments may be selected from any part of the amino acid sequence.
- fragments are typically recognized by T-cells in form of a complex consisting of the peptide fragment and an MHC molecule, i.e. the fragments are typically not recognized in their na ⁇ ve form.
- Fragments of antigens as defined herein may also comprise epitopes of those antigens.
- Epitopes also called “antigen determinants” are typically fragments located on the outer surface of (na ⁇ ve) protein or peptide antigens as defined herein, preferably having 5 to 15 amino acids, more preferably having 5 to 12 amino acids, even more preferably having 6 to 9 amino acids, which may be recognized by antibodies, i.e. in their na ⁇ ve form.
- One class of antigens as encoded by the at least one (m)RNA of the adjuvant component of the inventive immunostimulatory composition comprises tumor antigens.
- Tuor antigens are preferably located on the surface of the (tumor) cell.
- Tumor antigens may also be selected from proteins, which are overexpressed in tumor cells compared to a normal cell. Furthermore, tumor antigens also includes antigens expressed in cells which are (were) not themselves (or originally not themselves) degenerate but are associated with the supposed tumor. Antigens which are connected with tumor-supplying vessels or (re)formation thereof, in particular those antigens which are associated with neovascularization, e.g. growth factors, such as VEGF, bFGF etc., are also included herein. Antigens connected with a tumor furthermore include antigens from cells or tissues, typically embedding the tumor.
- tumor antigens are expressed in patients suffering (knowingly or not-knowingly) from a cancer disease and they occur in increased concentrations in the body fluids of said patients. These substances are also referred to as “tumor antigens", however they are not antigens in the stringent meaning of an immune response inducing substance.
- the class of tumor antigens can be divided further into tumor-specific antigens (TSAs) and tumor-associated- antigens (TAAs).
- TSAs can only be presented by tumor cells and never by normal "healthy" cells. They typically result from a tumor specific mutation.
- TAAs which are more common, are usually presented by both tumor and healthy cells. These antigens are recognized and the antigen-presenting cell can be destroyed by cytotoxic T cells.
- tumor antigens can also occur on the surface of the tumor in the form of, e.g., a mutated receptor. In this case, they can be recognized by antibodies.
- tumor antigens as encoded by the at least one (m)RNA of the adjuvant component of the inventive immunostimulatory composition are shown in Tables 1 and 2 below. These tables illustrate specific (protein) antigens (i.e. "tumor antigens") with respect to the cancer disease, they are associated with. According to the invention, the terms “cancer diseases” and “tumor diseases” are used synonymously herein.
- the tumor antigens as encoded by the at least one (m)RNA of the adjuvant component of the inventive immunostimulatory composition are selected from the group consisting of 5T4, 707-AP, 9D7, AFP, AlbZIP HPG1 , alpha-5-beta-1 -integrin, alpha-5-beta-6-integrin, alpha-actinin- 4/m, alpha-methylacyl-coenzyme A racemase, ART-4, ARTC1/m, B7H4, BAGE-1 , BCL-2, bcr/abl, beta-eaten in/m, BING-4, BRCAI/m, BRCA2/m, CA 15-3/CA 27-29, CA 19-9, CA72-4, CA125, calreticulin, CAMEL, CASP-8/m, cathepsin B, cathepsin L, CD19, CD20, CD22, CD25, CDE30, CD33, CD4, CD52, CD55,
- Neo-PAP Neo-PAP/m, NFYQm, NGEP, NMP22, NPM/ALK, N-Ras/m, NSE, NY-ESO- 1 , NY-ESO-B, OA1, OFA-iLRP, OGT, OGT/m, OS-9, OS-9/m, osteocalcin, osteopontin, p15, p190 minor bcr-abl, p53, p53/m, PAGE-4, PAI-I , PAI-2, PART-1, PATE, PDEF, Pim- 1 -Kinase, Pin-1 , Pml/PARalpha, POTE, PRAME, PRDX5/m, prostein, proteinase-3, PSA, PSCA, PSGR, PSM, PSMA, PTPRK/m, RAGE-1 , RBAF600/m, RHAMM/CD168, RU1 , RU2,
- the tumor antigens as encoded by the at least one (m)RNA of the adjuvant component of the inventive immunostimulatory composition are selected from the group consisting of MAGE-A1 (e.g. MAGE-A1 according to accession number M77481 ), MAGE-A2, MAGE-A3, MAGE-A6 (e.g. MAGE-A6 according to accession number NM_005363), MAGE-C1 , MAGE-C2, melan-A (e.g. melan-A according to accession number NM_00551 1 ), GP100 (e.g. GP100 according to accession number M77348), tyrosinase (e.g.
- tyrosinase according to accession number NM_000372
- survivin e.g. survivin according to accession number AF077350
- CEA e.g. CEA according to accession number NM_004363
- Her-2/neu e.g. Her-2/neu according to accession number M11730
- WT1 e.g. WT1 according to accession number NM_0003708
- PRAME e.g. PRAME according to accession number NM_0061 15
- EGFRI epidermal growth factor receptor 1
- EGFRI epidermal growth factor receptor 1
- mucin-1 e.g.
- mucin-1 according to accession number NM_002456
- SEC61 G e.g. SEC61 G according to accession number NM_014302
- hTERT e.g. hTERT accession number NM_198253
- 5T4 e.g. 5T4 according to accession number NM_006670
- NY-Eso-1 e.g. NY-Eso1 according to accession number NM_001327)
- TRP-2 e.g. TRP-2 according to accession number NM_001922
- STEAP PCA
- PSA PSMA
- PSMA etc.
- the tumor antigens as encoded by the at least one (m)RNA of the adjuvant component of the inventive immunostimulatory composition may form a cocktail of antigens, e.g. in an active
- the at least one (m)RNA of the adjuvant component of the inventive immunostimulatory composition is preferably at least one RNA, more preferably at least one mRNA, which may encode at least one, preferably two, three or even four (preferably different) antigens of the following group of antigens:
- PSA Prostate-Specific Antigen
- KLK3 Kallikrein-3
- the tumor antigens as encoded by the at least one (m)RNA of the adjuvant component of the inventive immunostimulatory composition may form a cocktail of antigens, e.g. in an active (immunostimulatory) composition or a kit of parts (wherein preferably each antigen is contained in one part of the kit), preferably for eliciting an (adaptive) immune response for the treatment of non-small cell lung cancers (NSCLC), preferably selected from the three main sub-types squamous cell lung carcinoma, adenocarcinoma and large cell lung carcinoma, or of disorders related thereto.
- NSCLC non-small cell lung cancers
- the at least one (m)RNA of the adjuvant component of the inventive immunostimulatory composition is preferably at least one mRNA, which may encode at least one, preferably two, three, four, five, six, seven, eight, nine, ten eleven or twelve (preferably different) antigens of the following group of antigens:
- the tumor antigens as encoded by the at least one (m)RNA of the adjuvant component of the inventive immunostimulatory composition may form a cocktail of antigens, e.g. in an active
- kits of parts wherein preferably each antigen is contained in one part of the kit, preferably for eliciting an (adaptive) immune response for the treatment of non-small cell lung cancers (NSCLC), preferably selected from the three main sub-types squamous cell lung carcinoma, adenocarcinoma and large cell lung carcinoma, or of disorders related thereto.
- NSCLC non-small cell lung cancers
- the at least one (m)RNA of the adjuvant component of the inventive immunostimulatory composition is preferably at least one RNA, more preferably at least one mRNA, which may encode at least two (preferably different) antigens, a) wherein at least one, preferably at least two, three, four, five or even six, of these at least two antigens is (are) selected from: • 5T4
- the further antigen(s) is (are) selected from at least one antigen as defined herein, preferably in any of the herein mentioned combinations, groups or subgroups of antigens, e.g. the further antigen(s) is (are) selected from, e.g.: • hTERT,
- each of the above defined proteins e.g. therapeutically active proteins, antibodies, antigens, etc., as defined herein may be encoded by one (monocistronic) RNA, preferably one (monocistronic) mRNA.
- the at least one (m)RNA of the adjuvant component of the inventive immunostimulatory composition may comprise at least two (monocistronic) RNAs, preferably mRNAs, wherein each of these at least two (monocistronic) RNAs, preferably mRNAs, may encode, e.g. just one (preferably different) protein, e.g. an antigen, preferably selected from one of the above mentioned antigen combinations.
- the at least one (m)RNA of the adjuvant component of the inventive immunostimulatory composition may comprise (at least) one bi- or even multicistronic RNA, preferably mRNA, i.e. (at least) one RNA which carries, e.g. two or even more of the coding sequences of at least two (preferably different) proteins, e.g. antigens, preferably selected from one of the above mentioned antigen combinations.
- coding sequences, e.g. of the at least two (preferably different) proteins, e.g. antigens, of the (at least) one bi- or even multicistronic RNA may be separated by at least one IRES (internal ribosomal entry site) sequence, as defined below.
- the term "encoding at least two (preferably different) proteins” may mean, without being limited thereto, that the (at least) one (bi- or even multicistronic) RNA, preferably an mRNA, may encode e.g. at least two, three, four, five, six, seven, eight, nine, ten, eleven or twelve or more (preferably different) proteins, e.g. antigens of the above mentioned group(s) of antigens, or their fragments or variants, therapeutically active proteins, antibodies, adjuvant proteins, etc. More preferably, without being limited thereto, the (at least) one (bi- or even multicistronic) RNA, preferably mRNA, may encode e.g.
- IRES internal ribosomal entry site
- IRES sequences can function as a sole ribosome binding site, but it can also serve to provide a bi- or even multicistronic RNA as defined herein which codes for several proteins, which are to be translated by the ribosomes independently of one another.
- IRES sequences which can be used according to the invention are those from picornaviruses (e.g.
- FMDV pestiviruses
- CFFV pestiviruses
- PV polioviruses
- ECMV encephalomyocarditis viruses
- FMDV foot and mouth disease viruses
- HCV hepatitis C viruses
- CSFV classical swine fever viruses
- MLV mouse leukoma virus
- SIV simian immunodeficiency viruses
- CrPV cricket paralysis viruses
- the at least one (m)RNA of the adjuvant component of the inventive immunostimulatory composition may comprise a mixture of at least one monocistronic RNA, preferably mRNA, as defined herein, and at least one bi- or even multicistronic RNA, preferably mRNA, as defined herein.
- the at least one monocistronic RNA and/or the at least one bi- or even multicistronic RNA preferably encode different proteins, e.g. antigens, or their fragments or variants, the antigens preferably being selected from one of the above mentioned groups or subgroups of antigens, more preferably in one of the above mentioned combinations.
- the at least one monocistronic RNA and the at least one bi- or even multicistronic RNA may preferably also encode (in part) identical proteins as defined herein, e.g. antigens selected from one of the above mentioned groups or subgroups of antigens, preferably in one of the above mentioned combinations, provided that the at least one (m)RNA of the adjuvant component of the inventive immunostimulatory composition as a whole provides at least two (preferably different) proteins, e.g. antigens, as defined herein.
- Such an embodiment may be advantageous e.g. for a staggered, e.g. time dependent, administration of one or several of the at least one (m)RNA of the adjuvant component of the inventive immunostimulatory composition, e.g.
- RNAs encoding the at least two (preferably different) proteins may be e.g. contained in (different parts of) a kit of parts composition or may be e.g. administered separately as components of different pharmaceutical compositions according to the present invention.
- One further class of antigens as encoded by the at least one (m)RNA of the adjuvant component of the inventive immunostimulatory composition comprises allergy antigens.
- allergy antigens may be selected from antigens derived from different sources, e.g. from animals, plants, fungi, bacteria, etc. Allergens in this context include e.g. grasses, pollens, molds, drugs, or numerous environmental triggers, etc. Allergy antigens typically belong to different classes of compounds, such as nucleic acids and their fragments, proteins or peptides and their fragments, carbohydrates, polysaccharides, sugars, lipids, phospholipids, etc.
- antigens which are encoded by the at least one (m)RNA of the adjuvant component of the inventive immunostimulatory composition, i.e. protein or peptide antigens and their fragments or epitopes, or nucleic acids and their fragments, particularly nucleic acids and their fragments, encoding such protein or peptide antigens and their fragments or epitopes.
- antigens derived from animals which are encoded by the at least one (m)RNA of the adjuvant component of the inventive immunostimulatory composition, may include antigens derived from, without being limited thereto, insects, such as mite (e.g. house dust mites), mosquito, bee (e.g. honey bee, bumble bee), cockroache, tick, moth (e.g.
- mite e.g. house dust mites
- mosquito e.g. honey bee, bumble bee
- cockroache e.g.
- Antigens derived from plants, which are encoded by the at least one (m)RNA of the adjuvant component of the inventive immunostimulatory composition may include antigens derived from, without being limited thereto, fruits, such as kiwi, pineapple, jackfruit,papaya, lemon, orange, mandarin, melon, sharon fruit, strawberry, lychee, apple, cherryados apple, mango, passion fruit, plum, apricot, nectarine, pear, passion fruit, raspberry, grape, from vegetables, such as garlic, onion, leek, soya bean, celery, cauliflower, turnip, paprika, chickpea, fennel, zucchini, cucumber, carrot, yam, bean, pea, olive, tomato, potato, lentil, lettuce, avocado, parsley, horseradish, chirimoya, beet, pumkin, spinach, from spices, such as mustard, coriander, saffron, pepper, aniseed, from crop, such as oat,
- Antigens derived from fungi which are encoded by the at least one (m)RNA of the adjuvant component of the inventive immunostimulatory composition, may include antigens derived from, without being limited thereto, e.g. Altemia sp., Aspergillus sp.,
- Beauveria sp. Candida sp., Cladosporium sp., Endothia sp., Curcularia sp., Embellisia sp., Epicoccum sp., Fusarium sp., Malassezia sp., Penicillum sp., Pleospora sp., Saccharomyces sp., etc.
- Antigens derived from bacteria which are encoded by the at least one (m)RNA of the adjuvant component of the inventive immunostimulatory composition, may include antigens derived from, without being limited thereto, e.g. Bacillus tetani, Staphylococcus aureus, Streptomyces griseus, etc..
- the at least one (m)RNA of the adjuvant component of the inventive immunostimulatory composition may encode an antibody.
- an antibody may be selected from any antibody, e.g. any recombinantly produced or naturally occurring antibodies, known in the art, in particular antibodies suitable for therapeutic, diagnostic or scientific purposes, or antibodies which have been identified in relation to specific cancer diseases.
- the term "antibody” is used in its broadest sense and specifically covers monoclonal and polyclonal antibodies (including agonist, antagonist, and blocking or neutralizing antibodies) and antibody species with polyepitopic specificity.
- “antibody” typically comprises any antibody known in the art (e.g.
- IgM, IgD, IgG, IgA and IgE antibodies such as naturally occurring antibodies, antibodies generated by immunization in a host organism, antibodies which were isolated and identified from naturally occurring antibodies or antibodies generated by immunization in a host organism and recombinantly produced by biomolecular methods known in the art, as well as chimeric antibodies, human antibodies, humanized antibodies, bispecific antibodies, intrabodies, i.e. antibodies expressed in cells and optionally localized in specific cell compartments, and fragments and variants of the aforementioned antibodies.
- an antibody consists of a light chain and a heavy chain both having variable and constant domains.
- the light chain consists of an N-terminal variable domain, V L , and a C-terminal constant domain, Q.
- the heavy chain of the IgG antibody for example, is comprised of an N-terminal variable domain, V H , and three constant domains, C H 1 , C H 2 und C H 3.
- Single chain antibodies may be encoded by the RNA of the modified (m)RNA of the invention as well, preferably by a single-stranded RNA, more preferably by an mRNA.
- the at least one (m)RNA of the adjuvant component of the inventive immunostimulatory composition may encode a polyclonal antibody.
- polyclonal antibody typically means mixtures of antibodies directed to specific antigens or immunogens or epitopes of a protein which were generated by immunization of a host organism, such as a mammal, e.g. including goat, cattle, swine, dog, cat, donkey, monkey, ape, a rodent such as a mouse, hamster and rabbit.
- a host organism such as a mammal, e.g. including goat, cattle, swine, dog, cat, donkey, monkey, ape, a rodent such as a mouse, hamster and rabbit.
- Polyclonal antibodies are generally not identical, and thus usually recognize different epitopes or regions from the same antigen.
- RNAs typically a mixture (a composition) of different RNAs will be used as the at least one (m)RNA of the adjuvant component of the inventive immunostimulatory composition, each RNA encoding a specific (monoclonal) antibody being directed to specific antigens or immunogens or epitopes of a protein.
- the at least one (m)RNA of the adjuvant component of the inventive immunostimulatory composition may encode a monoclonal antibody.
- monoclonal antibody typically refers to an antibody obtained from a population of substantially homogeneous antibodies, i.e., the individual antibodies comprising the population are identical except for possible naturally-occurring mutations that may be present in minor amounts. Monoclonal antibodies are highly specific, being directed to a single antigenic site. Furthermore, in contrast to conventional (polyclonal) antibody preparations which typically include different antibodies directed to different determinants (epitopes), each monoclonal antibody is directed to a single determinant on the antigen.
- monoclonal antibodies as defined above may be made by the hybridoma method first described by Kohler and Milstein, Nature, 256:495 (1975), or may be made by recombinant DNA methods, e.g. as described in U.S. Pat. No. 4,816,567.
- “Monoclonal antibodies” may also be isolated from phage libraries generated using the techniques described in McCafferty et al., Nature, 348:552-554 (1990), for example.
- an immunogen (antigen) of interest is injected into a host such as a mouse and B-cell lymphocytes produced in response to the immunogen are harvested after a period of time.
- the B-cells are combined with myeloma cells obtained from mouse and introduced into a medium which permits the B-cells to fuse with the myeloma cells, producing hybridomas. These fused cells (hybridomas) are then placed into separate wells of microtiter plates and grown to produce monoclonal antibodies. The monoclonal antibodies are tested to determine which of them are suitable for detecting the antigen of interest. After being selected, the monoclonal antibodies can be grown in cell cultures or by injecting the hybridomas into mice.
- the peptide sequences of these monoclonal antibodies have to be sequenced and the RNA sequences encoding these antibodies can be used as the at least one (m)RNA of the adjuvant component of the inventive immunostimulatory composition, which can be prepared according to procedures well known in the art.
- non-human monoclonal or polyclonal antibodies such as murine antibodies may also be encoded by the at least one (m)RNA of the adjuvant component of the inventive immunostimulatory composition.
- such antibodies are typically only of limited use, since they generally induce an immune response by production of human antibodies directed to the said non-human antibodies, in the human body. Therefore, a particular non-human antibody can only be administered once to the human.
- chimeric, humanized non- human and human antibodies are also envisaged encoded by the at least one (m)RNA of the adjuvant component of the inventive immunostimulatory composition.
- “Chimeric” antibodies which may be encoded by the at least one (m)RNA of the adjuvant component of the inventive immunostimulatory composition, are preferably antibodies in which the constant domains of an antibody described above are replaced by sequences of antibodies from other organisms, preferably human sequences.
- “Humanized” (non- human) antibodies which may be also encoded by the at least one (m)RNA of the adjuvant component of the inventive immunostimulatory composition, are antibodies in which the constant and variable domains (except for the hypervariable domains) described above of an antibody are replaced by human sequences.
- the at least one (m)RNA of the adjuvant component of the inventive immunostimulatory composition may encode human antibodies, i.e. antibodies having only human sequences.
- Such human antibodies can be isolated from human tissues or from immunized non-human host organisms which are transgene for the human IgG gene locus, and RNA sequences may be prepared according to procedures well known in the art. Additionally, human antibodies can be provided by the use of a phage display.
- the at least one (m)RNA of the adjuvant component of the inventive immunostimulatory composition may encode bispecific antibodies.
- Bispecific antibodies in context of the invention are preferably antibodies which act as an adaptor between an effector and a respective target by two different F ⁇ -domains, e.g.
- Bispecific antibodies as described herein are, in general, configured to recognize by two different F ⁇ -domains, e.g. two different antigens, immunogens, epitopes, drugs, cells (or receptors on cells), or other molecules (or structures) as described above. Bispecificity means herewith that the antigen-binding regions of the antibodies are specific for two different epitopes. Thus, different antigens, immunogens or epitopes, etc. can be brought close together, what, optionally, allows a direct interaction of the two components. For example, different cells such as effector cells and target cells can be connected via a bispecific antibody.
- Encompassed, but not limited, by the present invention are antibodies or fragments thereof which bind, on the one hand, a soluble antigen as described herein, and, on the other hand, an antigen or receptor on the surface of a tumor cell.
- the at least one (m)RNA of the adjuvant component of the inventive immunostimulatory composition may also encode intrabodies, wherein these intrabodies may be antibodies as defined above. Since these antibodies are intracellular expressed antibodies, i.e. antibodies which are encoded by nucleic acids localized in specific areas of the cell and also expressed there, such antibodies may be termed intrabodies.
- Antibodies as encoded by the at least one (m)RNA of the adjuvant component of the inventive immunostimulatory composition may preferably comprise full-length antibodies, i.e. antibodies composed of the full heavy and full light chains, as described above. However, derivatives of antibodies such as antibody fragments, variants or adducts may also be encoded by the at least one (m)RNA of the adjuvant component of the inventive immunostimulatory composition.
- the at least one (m)RNA of the adjuvant component of the inventive immunostimulator ⁇ composition may also encode antibody fragments selected from Fab, Fab', F(ab') 2 , Fc, Facb, pFc', Fd and Fv fragments of the aforementioned (full-length) antibodies.
- antibody fragments are known in the art.
- an Fab fragment, antigen binding
- the two variable domains bind the epitope on specific antigens.
- the two chains are connected via a disulfide linkage.
- An scFv single chain variable fragment
- the domains are linked by an artificial linkage, in general a polypeptide linkage such as a peptide composed of 15-25 glycine, proline and/or serine residues.
- the inventive immunostimulatory composition comprises at least one free mRNA, encoding at least one therapeutically active protein or peptide as defined herein, at least one antigen as defined herein, e.g. tumor antigens, pathogenic antigens (e.g. selected from pathogenic proteins as defined above or from animal antigens, viral antigens, protozoal antigens, bacterial antigens, allergic antigens), autoimmune antigens, or further antigens, at least one allergen as defined herein, at least one antibody as defined herein, at least one antigen-specific T-cell receptor as defined herein, or at least one other protein or peptide suitable for a specific (therapeutic) application as defined herein.
- an antigen as defined herein e.g. tumor antigens, pathogenic antigens (e.g. selected from pathogenic proteins as defined above or from animal antigens, viral antigens, protozoal antigens, bacterial antigens, allergic antigens), autoimmune antigens, or further antigen
- This second component is added (according to a second step of preparation of the inventive immunostimulatory composition) to the above prepared "adjuvant component" to form the inventive immunostimulatory composition.
- the at least one free mRNA is not complexed and will preferably not undergo any detectable or significant complexation reaction upon the addition of the adjuvant component. This is due to the strong binding of the cationic or polycationic compound to the above described at least one (m)RNA in the adjuvant component.
- the at least one free mRNA, encoding the therapeutically active protein is added to the "adjuvant component", preferably no free or substantially no free cationic or polycationic compound is present, which may form a complex with the at least one free mRNA.
- the at least one free mRNA which is the second component of the inventive immunostimulatory composition, is a messenger RNA, encoding at least one therapeutically active protein or peptide as defined herein, at least one antigen as defined herein, e.g. tumor antigens, pathogenic antigens (e.g.
- an mRNA is in general defined as above for the adjuvant component as an RNA, which is composed of several structural elements, e.g.
- the at least one free mRNA may occur as a mono-, di-, or even multicistronic RNA, i.e. an RNA which carries the coding sequences of one, two or more proteins.
- Such coding sequences in di-, or even multicistronic mRNA may be separated by at least one IRES sequence, e.g. as defined herein.
- the at least one free mRNA, provided as a second component of the inventive immunostimulatory composition may encode at least one therapeutically active protein.
- a therapeutically active protein preferably may be any protein or peptide, suitable for a therapeutic purpose, more preferably may be selected from any recombinant or isolated protein known to a skilled person from the prior art and even more preferably may be selected from any therapeutically active protein as defined above for the adjuvant component of the inventive immunostimulatory composition.
- Such therapeutically active proteins as defined above include, without being limited thereto, e.g. proteins, capable of stimulating or inhibiting the signal transduction in the cell, e.g.
- cytokines, antibodies, etc. apoptotic factors or apoptosis related proteins
- adjuvant proteins e.g. selected from human adjuvant proteins or from pathogenic adjuvant proteins, in particular from bacterial adjuvant proteins, etc.
- the at least one free mRNA, provided as a second component of the inventive immunostimulatory composition may furthermore encode at least one antibody or antibody fragment.
- the at least one free mRNA, provided as a second component of the inventive immunostimulatory composition may encode any antibody or antibody fragment as defined above for the adjuvant component of the inventive immunostimulatory composition.
- the at least one free mRNA, provided as a second component of the inventive immunostimulatory composition may also encode at least one antigen as defined above.
- a (tumor) antigen or in general the term "antigen” is defined as described above for the adjuvant component of the inventive immunostimulatory composition and typically refers to a substance which is recognized by the immune system and is capable of triggering an antigen-specific immune response, e.g. by formation of antibodies as part of an adaptive immune response.
- the at least one free mRNA, provided as a second component of the inventive immunostimulatory composition may encode any antigen as defined above for the adjuvant component of the inventive immunostimulatory composition.
- such antigens may be selected from tumor antigens as defined above for the adjuvant component of the inventive immunostimulatory composition, e.g. tumor-specific antigens (TSAs) and tumor-associated-antigens (TAAs) as defined above, etc.
- TSAs tumor-specific antigens
- TAAs tumor-associated-antigens
- the at least one free mRNA, which is provided as a second component of the inventive immunostimulatory composition may be identical or different to the at least one (m)RNA of the adjuvant component of the inventive immunostimulatory composition, dependent on the specific requirements of therapy. Even more preferably, the at least one free mRNA, which is provided as a second component of the inventive immunostimulatory composition, is identical to the at least one (m)RNA of the adjuvant component of the inventive immunostimulatory composition.
- the ratio of the first component (i.e. the adjuvant component comprising or consisting of at least one (m)RNA complexed with a cationic or polycationic compound) and the second component (i.e. the at least one free mRNA) may be selected in the inventive immunostimulatory composition according to the specific requirements of a particular therapy, e.g. a cancer therapy, etc.
- the ratio of adjuvant component and the at least one free mRNA (adjuvant component : free mRNA) of the inventive immunostimulatory composition is selected such that a significant stimulation of the innate immune system is elicited due to the adjuvant component.
- the ratio is selected such that a significant amount of the at least one free mRNA can be provided in vivo leading to an efficient translation and concentration of the expressed protein in vivo.
- the at least one antibody, antigen and/or therapeutically active protein, etc. as defined above.
- the ratio of adjuvant component : free mRNA in the inventive immunostimulatory composition is selected from a range of about 5:1 (w/w) to about 1 :10 (w/w), more preferably from a range of about 4:1 (w/w) to about 1 :8 (w/w), even more preferably from a range of about 3:1 (w/w) to about 1 :5 (w/w) or 1 :3 (w/w), and most preferably the ratio of adjuvant component : free mRNA in the inventive immunostimulatory composition is selected from a ratio of about 1 :1 (w/w).
- the ratio of the first component i.e. the adjuvant component comprising or consisting of at least one (m)RNA complexed with a cationic or polycationic compound
- the second component i.e. the at least one free mRNA
- N/P-ratio nitrogen/phosphate ratio
- an N/P-ratio is preferably in the range of about 0.1 -10, preferably in a range of about 0.3-4 and most preferably in a range of about 0.5-2 or 0.7-2 regarding the ratio of RNA:peptide in the complex, and most preferably in the range of about 0.7-1.5.
- the ratio of the first component (i.e. the adjuvant component comprising or consisting of at least one (m)RNA complexed with a cationic or polycationic compound) and the second component (i.e. the at least one free mRNA) may also be selected in the inventive immunostimulatory composition on the basis of the molar ratio of both RNAs to each other, i.e. the (m)RNA of the adjuvant component, being complexed with a cationic or polycationic compound) and the at least one free mRNA of the second component.
- the molar ratio of the (m)RNA of the adjuvant component to the at least one free mRNA of the second component may be selected such, that the molar ratio suffices the above (w/w) and/or N/P-definitions. More preferably, the molar ratio of the (m)RNA of the adjuvant component to the at least one free mRNA of the second component may be selected e.g.
- the molar ratio of the (m)RNA of the adjuvant component to the at least one free mRNA of the second component may be selected e.g. from a range of about 0.01 :1 to 1 :0.01. Most preferably, the molar ratio of the (m)RNA of the adjuvant component to the at least one free mRNA of the second component may be selected e.g. from a molar ratio of about 1:1. Any of the above definitions with regard to (w/w) and/or N/P ratio may also apply.
- the at least one (m)RNA of the adjuvant component and/or the at least one free mRNA of the inventive immunostimulatory composition as defined above, encoding a protein, e.g. a therapeutically active protein, antibody and/or antigen, may also encode fragments and/or variants of the aforementioned proteins, wherein the fragments and/or variants may have a sequence identity to one of the aforementioned proteins of at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80% or 85%, preferably at least 90%, more preferably at least 95% and most preferably at least 99% over the whole length of the (coding) nucleic acid sequences encoding these proteins.
- a fragment of such a protein is to be understood as a truncated protein thereof, i.e. an amino acid sequence, which is N-terminally, C-terminally and/or intrasequentially truncated compared to the amino acid sequence of the original (native) protein.
- fragments including an antigenic epitope are preferred.
- fragments and epitopes are preferably as specifically defined above for antigens.
- a “variant” in the context of the present invention refers to a protein as defined above, e.g. a therapeutically active protein, adjuvant protein, antigen or antibody as defined above (or its encoding mRNA or (m)RNA sequence), wherein nucleic acids of the at least one (m)RNA of the adjuvant component of the inventive immunostimulatory composition or nucleic acids of the at least one free mRNA of the inventive immunostimulatory composition, encoding e.g. a therapeutically active protein, antibody and/or antigen, etc., are exchanged.
- a therapeutically active protein, adjuvant protein, antigen or antibody is generated, having an amino acid sequence which differs from the original sequence in one or more mutation(s), such as one or more substituted, inserted and/or deleted amino acid(s).
- the fragments and/or variants have the same biological function or specific activity compared to the full-length native proteins, e.g. therapeutically active proteins, antigens or antibodies.
- biological function include e.g. the specific binding capacity (e.g. of particular antigens), catalytic activity of these proteins, e.g. of therapeutically active proteins, etc.
- biological function of antibodies as described herein also comprises neutralization of antigens, complement activation or opsonization.
- antibodies typically recognize either native epitopes on the cell surface or free antigens.
- Antibodies as defined above can interact with the cell-presenting antigens and initiate different defense mechanisms.
- the antibody can initiate signaling mechanisms in the targeted cell that leads to the cell's self-destruction (apoptosis).
- apoptosis On the other hand, it can mark the cell in such a way that other components or effector cells of the body's immune system can recognize and attack.
- the attack mechanisms are referred to as antibody-dependent complement-mediated cytotoxicity (CMC) and antibody-dependent cellular cytotoxicity (ADCC).
- ADCC involves a recognition of the antibody by immune cells that engage the antibody-marked cells and either through their direct action, or through the recruitment of other cell types, lead to the tagged-cell's death.
- CMC is a process where a cascade of different complement proteins becomes activated, usually when several antibodies are in close proximity to each other, either resulting in cell lysis or attracting other immune cells to this location for effector cell function.
- the antibody can bind an antigen and neutralize the same.
- Such neutralization reaction leads in general to blocking of the antibody.
- the antibody can bind only one antigen, or, in case of a bispecific antibody, two antigens.
- scFv antibody fragments are useful for neutralization reactions because they don't contain the functionalities of the constant domain of an antibody.
- the complex system of complement proteins can be activated via binding of an antibody which is independent of the Fc part of an antibody.
- End products of the complement cascade result in lysis of the cell and generation of an inflammatory milieu.
- pathogens or other non-cellular particles are made accessible to phagocytes via binding the constant domain of an antibody.
- cells recognized as foreign can be lysed via antibody- dependent cell-mediated cytotoxicity (ADCC).
- ADCC antibody- dependent cell-mediated cytotoxicity
- NK-cells can display lysis functions by activating Fc receptors.
- the sequences can be aligned in order to be subsequently compared to one another. Therefore, as an example, e.g. gaps can be inserted into the sequence of the first sequence (e.g. (m)RNA or mRNA) and the component at the corresponding position of the second sequence (e.g. (m)RNA or mRNA) can be compared. If a position in the first sequence (e.g. (m)RNA or mRNA) sequence is occupied by the same component as is the case at a position in the second sequence (e.g.
- (m)RNA or mRNA the two sequences are identical at this position.
- the percentage to which two (m)RNA (or mRNA) sequences are identical is a function of the number of identical positions divided by the total number of positions. The same, of course also applies accordingly to DNA sequences or the encoded amino acid sequences.
- the percentage to which two sequences, such as the at least one (m)RNA of the adjuvant component of the inventive immunostimulatory composition and/or the at least one free mRNA of the inventive immunostimulatory composition, or their encoded amino acid sequences, are identical can be determined using a mathematical algorithm.
- a preferred, but not limiting, example of a mathematical algorithm which can be used is the algorithm of Karlin et a/. (1993), PNAS USA, 90:5873-5877 or Altschul et a/. (1997), Nucleic Acids Res, 25:3389-3402. Such an algorithm is integrated in the BLAST or NBLAST program.
- Sequences which are identical to the sequences of the at least one (m)RNA of the adjuvant component of the inventive immunostimulatory composition or of the at least one free mRNA of the inventive immunostimulatory composition (or to the coding regions thereof) to a certain extent can be identified by these programmes.
- RNA sequences corresponding to the at least one (m)RNA of the adjuvant component or the at least one free mRNA of the inventive immunostimulatory composition encoding amino acid sequences which have (a) conservative substitution(s) compared to the physiological, i.e. native and non-modified, sequence in particular fall under the term "variants".
- substitutions in which encoded amino acids which originate from the same class are exchanged for one another are called conservative substitutions.
- these are encoded amino acids, encoded aliphatic side chains, positively or negatively charged side chains, aromatic groups in the side chains or encoded amino acids, the side chains of which can enter into hydrogen bridges, e.g. side chains which have a hydroxyl function. This means that e.g.
- an amino acid having a polar side chain is replaced by another amino acid having a likewise polar side chain, or, for example, an amino acid characterized by a hydrophobic side chain is substituted by another amino acid having a likewise hydrophobic side chain (e.g. serine (threonine) by threonine (serine) or leucine (isoleucine) by isoleucine (leucine)).
- Insertions and substitutions are possible, in particular, at those sequence positions which cause no modification of the three-dimensional structure or do not affect the binding region or the catalytic domain. Modifications of the three-dimensional structure by insertion(s) or deletion(s) can easily be determined e.g.
- CD spectra circular dichroism spectra
- RNA sequences corresponding to the at least one (m)RNA of the adjuvant component of the inventive immunostimulatory composition or to the at least one free mRNA of the inventive immunostimulatory composition, which encode amino acid sequences as defined above, may occur as a mono-, di-, or even multicistronic RNA, i.e. an RNA which carries the coding sequences of one, two or more proteins as defined above, e.g. therapeutically active proteins, adjuvant proteins, (protein) antigens or antibodies as defined above.
- an RNA sequence corresponding to the at least one (m)RNA of the adjuvant component and/or the at least one free mRNA of the inventive immunostimulatory composition within the above definition encodes at least one protein as defined above, e.g. two, three or more of a therapeutically active protein, adjuvant protein, antigen or antibody as defined above, each of these proteins may be selected from the same or a (preferably) different protein as defined above.
- each protein encoded by an RNA sequence corresponding to the at least one (m)RNA of the adjuvant component of the inventive immunostimulatory composition and/or the at least one free mRNA of the inventive immunostimulatory composition may be selected independently.
- the inventive immunostimulatory composition of the present invention may comprise as the at least one free mRNA or as the the at least one (m)RNA of the adjuvant component at least one bi- or even multicistronic RNA sequence as defined above.
- Each coding sequence in these bi- or even multicistronic RNA sequences as defined above may be separated by at least one so-called IRES (internal ribosomal entry site) sequence.
- IRES internal ribosomal entry site
- an IRES sequence can function as a sole ribosome binding site, but it can also serve to provide a bi- or even multicistronic RNA sequence as defined above which encodes several proteins which are to be translated by the ribosomes independently of one another.
- IRES sequences which can be used according to the invention are those from picornavi ruses (e.g. FMDV), pestiviruses (CFFV), polioviruses (PV), encephalomyocarditis viruses (ECMV), foot and mouth disease viruses (FMDV), hepatitis C viruses (HCV), classical swine fever viruses (CSFV), mouse leukoma virus (MLV), simian immunodeficiency viruses (SIV) or cricket paralysis viruses (CrPV).
- picornavi ruses e.g. FMDV
- CFFV pestiviruses
- PV polioviruses
- ECMV encephalomyocarditis viruses
- FMDV foot and mouth disease viruses
- HCV hepatitis C viruses
- CSFV classical swine fever viruses
- MMV mouse leukoma virus
- SIV simian immunodeficiency viruses
- CrPV cricket paralysis viruses
- the immunostimulatory composition of the present invention may also comprise as the at least one (m)RNA of the adjuvant component and/or the at least one free mRNA, a mixture of different RNA sequences, wherein the mixture comprises e.g. at least one monocistronic mRNA encoding a protein as defined above, and/or at least one bi- or even multicistronic mRNA, encoding the same or different proteins as defined above, e.g. a therapeutically active protein, an adjuvant protein, an antigen and/or an antibody as defined above.
- the at least one (m)RNA of the adjuvant component of the inventive immunostimulatory composition and/or the at least one free mRNA of the inventive immunostimulatory composition may be provided as a "stabilized RNA", preferably a stabilized mRNA, that is to say as an RNA that is essentially resistant to in vivo degradation by various approaches (e.g. by an exo- or endo-nuclease). It is known in the art that instability and (fast) degradation of mRNA or of RNA in vivo in general may represent a serious problem in the application of RNA based compositions.
- RNAases RNA-degrading enzymes
- RNase contaminations may be generally removed by special treatment prior to use of said compositions, in particular with diethyl pyrocarbonate (DEPC).
- DEPC diethyl pyrocarbonate
- cap structure a modified guanosine nucleotide
- poly-A tail a sequence of up to 200 adenosine nucleotides
- the at least one (m)RNA of the adjuvant component of the inventive immunostimulatory composition and/or the at least one free mRNA of the inventive immunostimulatory composition, particularly if provided as an mRNA can therefore be stabilized against degradation by RNases by the addition of a so- called "5' cap” structure.
- a so-called "5' cap” structure Particular preference is given in this connection to an m7G(5')ppp (5'(A,G(5')ppp(5')A or G(5')ppp(5')G as the 5' cap" structure.
- the at least one (m)RNA of the adjuvant component of the inventive immunostimulatory composition and/or the at least one free mRNA of the inventive immunostimulatory composition may contain, especially if the RNA is in the form of an mRNA, a poly-A tail at its 3' terminus of typically about 10 to 200 adenosine nucleotides, preferably about 10 to 100 adenosine nucleotides, more preferably about 20 to 100 adenosine nucleotides or even more preferably about 40 to 80 adenosine nucleotides.
- the at least one (m)RNA of the adjuvant component of the inventive immunostimulatory composition and/or the at least one free mRNA of the inventive immunostimulatory composition may contain, especially if the RNA is in the form of an mRNA, a poly-C tail at its 3' terminus of typically about 10 to 200 cytosine nucleotides, preferably about 10 to 100 cytosine nucleotides, more preferably about 20 to 70 cytosine nucleotides or even more preferably about 20 to 60 or even 10 to 40 cytosine nucleotides.
- the at least one (m)RNA of the adjuvant component of the inventive immunostimulatory composition and/or the at least one free mRNA of the inventive immunostimulatory composition may furthermore be GC-modified or modified in another form.
- Some modifications of the RNA may be, dependent on the type of RNA, more suitable for an RNA in general, or, e.g. in the case of GC-modified (m)RNA or mRNA sequences, be more suitable for a coding RNA, preferably an (m)RNA and/or mRNA as defined above.
- Such further modifications as defined herein preferably lead to a stabilized (m)RNA and/or mRNA as defined above.
- such a stabilized RNA may be prepared by modifying the G/C content of the coding region of the RNA sequences mentioned herein, e.g. an RNA sequence corresponding to the at least one (m)RNA of the adjuvant component and/or to the at least one free mRNA of the inventive immunostimulatory composition.
- the G/C content of the coding region of the at least one (m)RNA of the adjuvant component and/or the at least one free mRNA of the inventive immunostimulatory composition is altered, preferably increased, compared to the G/C content of the coding region of the corresponding non- modified RNA (in the following "native RNA").
- the encoded amino acid sequence of this G/C-increased RNA sequence corresponding to the at least one (m)RNA of the adjuvant component or the at least one free mRNA of the inventive immunostimulatory composition is preferably not altered compared to the corresponding native RNA.
- Such alteration of the GC-sequence may be termed in the following GC-stabilization.
- This G/C-stabilization of the at least one (m)RNA of the adjuvant component of the inventive immunostimulatory composition and/or of the at least one free mRNA of the inventive immunostimulatory composition is based on the fact that the sequence of any RNA region to be translated is important for efficient translation of that RNA.
- the sequence of various nucleotides is important.
- sequences having an increased G (guanosine)/C (cytosine) content are more stable than sequences having an increased A (adenosine)/U (uracil) content.
- the codons the at least one (m)RNA of the adjuvant component of the inventive immunostimulatory composition or of the at least one free mRNA of the inventive immunostimulatory composition are therefore varied compared to its native RNA sequence, while retaining the translated amino acid sequence, such that they include an increased amount of G/C nucleotides.
- the most favorable codons for the stability can be determined (so-called alternative codon usage).
- the amino acid to be encoded by the at least one (m)RNA of the adjuvant component of the inventive immunostimulatory composition and/or the at least one free mRNA of the inventive immunostimulatory composition there are various possibilities for
- codons which contain A and/or U nucleotides can be G/C-modified by substitution of other codons which code for the same amino acids but contain no A and/or U. Examples of these are:
- the codons for Pro can be G/C-modified from CCU or CCA to CCC or CCG; the codons for Arg can be G/C-modified from CGU or CGA or AGA or AGG to CGC or CGG; the codons for Ala can be G/C-modified from GCU or GCA to GCC or GCG; the codons for GIy can be G/C-modified from GGU or GGA to GGC or GGG.
- the codons for Phe can be G/C-modified from UUU to UUC; the codons for Leu can be G/C-modified from UUA, UUG, CUU or CUA to CUC or CUG; the codons for Ser can be G/C-modified from UCU or UCA or AGU to UCC, UCG or AGC; the codon for Tyr can be G/C-modified from UAU to UAC; the codon for Cys can be G/C-modified from UGU to UGC; the codon for His can be G/C-modified from CAU to CAC; the codon for GIn can be G/C-modified from CAA to CAG; the codons for He can be G/C-modified from AUU or AUA to AUC; the codons for Thr can be G/C-modified from ACU or ACA to ACC or ACG; the codon for Asn can be G/C-modified from AAU to AAC; the codon for Lys can
- substitutions listed above can be used either individually or in all possible combinations to increase the G/C content of the at least one (m)RNA of the adjuvant component of the inventive immunostimulatory composition and/or the at least one free mRNA of the inventive immunostimulatory composition compared to its particular native RNA (i.e. the non-modified sequence).
- all codons for Thr occurring in the native sequence can be G/C-modified to ACC (or ACG).
- combinations of the above substitution possibilities are used:
- the G/C content of the coding region of an RNA sequence corresponding to the at least one (m)RNA of the adjuvant component and/or the at least one free mRNA of the inventive immunostimulatory composition is increased by at least 7%, more preferably by at least 15%, particularly preferably by at least 20%, compared to the G/C content of the coding region of the native RNA which codes for a protein.
- at least 60%, more preferably at least 70 %, even more preferably at least 80% and most preferably at least 90%, 95% or even 100% of the substitutable codons in the region coding for a protein or the whole sequence of the native RNA sequence are substituted, thereby increasing the GC/content of said sequence.
- the G/C content of the native RNA of the at least one (m)RNA of the adjuvant component of the inventive immunostimulatory composition and/or the at least one free mRNA of the inventive immunostimulatory composition is particularly preferable to increase the G/C content of the native RNA of the at least one (m)RNA of the adjuvant component of the inventive immunostimulatory composition and/or the at least one free mRNA of the inventive immunostimulatory composition, to the maximum (i.e. 100% of the substitutable codons of the native RNA), in particular in the region coding for a protein.
- a further preferred modification of the at least one (m)RNA of the adjuvant component of the inventive immunostimulatory composition and/or the at least one free mRNA of the inventive immunostimulatory composition is based on the finding that the translation efficiency is also determined by a different frequency in the occurrence of tRNAs in cells.
- the corresponding G/C-stabilized or native RNA sequence may be translated to a significantly poorer degree than in the case, where codons coding for relatively "frequent" tRNAs are present.
- the region in the at least one (m)RNA of the adjuvant component of the inventive immunostimulatory composition and/or the at least one free mRNA of the inventive immunostimulatory composition, which code for a protein is preferably GC-stabilized compared to the corresponding region of the respective native RNA such that at least one codon of the native sequence which codes for a tRNA which is relatively rare in the cell is exchanged for a codon which codes for a tRNA which is relatively frequent in the cell and carries the same amino acid as the relatively rare tRNA.
- the native RNA sequences are GC-stabilized such that codons for which frequently occurring tRNAs are available are inserted.
- the sequential G/C content which is increased, in particular maximized, in the GC-stabilized RNA sequence of the at least one (m)RNA of the adjuvant component and/or the at least one free mRNA of the inventive immunostimulatory composition, with the "frequent" codons without modifying the amino acid sequence of the protein encoded by the coding region of the native RNA.
- This preferred embodiment allows provision of a particularly efficiently translated and GC- stabilized RNA sequence of the at least one (m)RNA of the inventive immunostimulatory composition of the adjuvant component and/or the at least one free mRNA of the inventive immunostimulatory composition.
- the determination of the necessary (and/or possible) GC modification of the at least one (m)RNA of the adjuvant component of the inventive immunostimulatory composition and/or the at least one free mRNA of the inventive immunostimulatory composition, as described above can be carried out using the computer program as explained in WO 02/098443 - the disclosure content of which is included in its full scope in the present invention.
- the nucleotide sequence of any desired coding RNA as defined above can be GC-stabilized with the aid of the genetic code or the degenerative nature thereof such that a maximum G/C content results.
- the amino acid sequence coded by the GC-stabilized RNA sequence of the at least one (m)RNA of the adjuvant component and/or the at least one free mRNA of the inventive immunostimulatory composition is preferably not further modified compared to their native RNA sequence.
- the source code in Visual Basic 6.0 (development environment used: Microsoft Visual Studio Enterprise 6.0 with Servicepack 3) is also described in WO 02/098443.
- the at least one (m)RNA of the adjuvant component of the inventive immunostimulatory composition and/or the at least one free mRNA of the inventive immunostimulatory composition may be provided as a stabilized RNA, that is essentially resistant to in vivo degradation (e.g. by an exo- or endo-nuclease), by modifying the phosphate backbone of this (these) RNA sequence(s) as defined herein.
- Nucleotides that may be preferably used in this connection contain a phosphorothioate- modified phosphate backbone, preferably at least one of the phosphate oxygens contained in the phosphate backbone being replaced by a sulfur atom.
- a stabilized RNA sequence as defined herein may further include, for example: non-ionic phosphate analogues, such as, for example, alkyl and aryl phosphonates, in which the charged phosphonate oxygen is replaced by an alkyl or aryl group, or phosphodiesters and alkylphosphotriesters, in which the charged oxygen residue is present in alkylated form.
- non-ionic phosphate analogues such as, for example, alkyl and aryl phosphonates, in which the charged phosphonate oxygen is replaced by an alkyl or aryl group
- phosphodiesters and alkylphosphotriesters in which the charged oxygen residue is present in alkylated form.
- the phosphate moieties may preferably be substituted by, e.g., phosphorami dates, phosphorothioates, peptide nucleotides, methylphosphonates etc.
- an RNA sequence as defined herein preferably the at least one (m)RNA of the adjuvant component of the inventive immunostimulatory composition and/or the at least one free mRNA of the inventive immunostimulatory composition, can likewise be modified (and preferably stabilized) by introducing modified nucleotides containing modifications of their ribose or base moieties into the RNA sequence.
- nucleotide analogues are defined as non-natively occurring variants of naturally occurring nucleotides. Accordingly, analogues are chemically derivatized nucleotides with non-natively occurring functional groups, which are preferably added to or deleted from the naturally occurring nucleotide or which substitute the naturally occurring functional groups of a nucleotide. Accordingly, each component of the naturally occurring nucleotide may be modified, namely the base component, the sugar (ribose) component and/or the phosphate component forming the backbone of the RNA sequence to be modified.
- Analogues of guanosine, uracil, adenosine, and cytosine include, without implying any limitation, any naturally occurring or non-naturally occurring guanosine, uracil, adenosine, thymidine or cytosine that has been altered chemically, for example by acetylation, methylation, hydroxylation, etc., including 1 -methyl-adenosine, 1 -methyl-guanosine, 1 - methyl-inosine, 2,2-dimethyl-guanosine, 2,6-diaminopurine, 2'-Amino-2'-deoxyadenosine, T- Amino-2'-deoxycytidine, 2'-Amino-2'-deoxyguanosine, 2'-Amino-2'-deoxyuridine, 2-Amino-6- chloropurineriboside, 2-Aminopurine-riboside, 2'-Araadenosine, 2
- an analogue as described above particular preference is given according to the invention to those analogues that increase the immunogenity of an RNA sequence as defined herein, preferably the at least one (m)RNA of the adjuvant component of the inventive immunostimulatory composition and/or the at least one free mRNA of the inventive immunostimulatory composition, and/or do not interfere with a further modification of the RNA that has been introduced.
- An RNA sequence of the inventive immunostimulatory composition as defined herein, preferably the at least one (m)RNA of the adjuvant component and/or the at least one free mRNA of the inventive immunostimulatory composition may contain backbone modifications.
- a backbone modification in connection with the present invention is a modification in which phosphates of the backbone of the nucleotides contained in the RNA are chemically modified.
- Such backbone modifications typically include, without implying any limitation, modifications from the group consisting of methylphosphonates, phosphoramidates and phosphorothioates (e.g. cytidine-5'-O-(1 -thiophosphate)).
- RNA sequence of the inventive immunostimulatory composition as defined herein may additionally or alternatively also contain sugar modifications.
- a sugar modification in connection with the present invention is a chemical modification of the sugar of the nucleotides present and typically includes, without implying any limitation, sugar modifications selected from the group consisting of 2'-deoxy-2'-fluoro-oligoribonucleotide (2'-fluoro-2'-deoxycytidine-5'- tri phosphate, 2 ' -f I uoro-2 ' -deoxy u ridi ne-5 ' -tri phosphate), 2 ' -deoxy-2 ' -deam i ne oligoribonucleotide (2 '-amino-2'-deoxycytidine-5 '-triphosphate, 2'-amino-2'-deoxyuridine- 5 '
- Significant in this case means an increase in the expression of the protein compared with the expression of the native RNA sequence by at least 20%, preferably at least 30%, 40%, 50% or 60%, more preferably by at least 70%, 80%, 90% or even 100% and most preferably by at least 150%, 200% or even 300%.
- a nucleotide having a base modification is preferably selected from the group of the base-modified nucleotides consisting of 2-amino-6- chloropurineriboside-5'-triphosphate, 2-aminoadenosine-5'-triphosphate, 2-thiocytidine-5'- triphosphate, 2-thiouridine-5 '-triphosphate, 4-thiouridine-5'-triphosphate, 5- aminoallylcytidine-5 '-triphosphate, 5-aminoallyluridine-5'-triphosphate, 5-bromocytidine- 5 '-triphosphate, 5-bromouridine-5 '-triphosphate, 5-iodocytidine-5'-triphosphate, 5- iodouridine-5 '-triphosphate, 5-methylcytidine-5 '-triphosphate, 5-methyluridine-5'- triphosphate, 6-azacytidine-5'-triphosphate, 6-azauridine-5 '-triphosphate, 6- chlor
- nucleotides for base modifications selected from the group of base-modified nucleotides consisting of 5- methylcytidine-5 '-triphosphate, 7-deazaguanosine-5 '-triphosphate, 5-bromocytidine-5'- triphosphate, and pseudouridine-5'-triphosphate.
- an RNA sequence as defined herein, preferably the at least one (m)RNA of the adjuvant component of the inventive immunostimulatory composition and/or the at least one free mRNA of the inventive immunostimulatory composition comprises between 0.1 % and 100% (modified) nucleotides selected from (modified) nucleotides as defined above with respect to the non-modified, i.e.
- native RNA sequence wherein preferably between 0.1 % and 100% of each natively occurring non-modified ATP, GTP, CTP, UTP (and/or TTP) nucleotide of an RNA sequence as defined herein, preferably of the at least one (m)RNA of the adjuvant component of the inventive immunostimulatory composition and/or of the at least one free mRNA of the inventive immunostimulatory composition, or of its corresponding DNA-template, may be modified using a corresponding modified nucleotide as defined above, more preferably between 0,1 % and 20%, between 10% and 30%, between 20% and 40%, between 30% and 50%, between 40% and 60%, between 50% and 70%, between 60% and 80%, between 70% and 90%, or between 80% and 100% or at least 10%, more preferably at least 30%, more preferably at least 40%, more preferably at least 60%, more preferably at least 70%, more preferably at least 80% and more preferably at least 90% and most preferably 100% of each natively occurring non-modified ATP, GTP CTP, U
- the A/U content in the environment of the ribosome binding site of an (optionally already GC-stabilized) RNA sequence as defined herein, preferably the at least one (m)RNA of the adjuvant component of the inventive immunostimulatory composition and/or the at least one free mRNA of the inventive immunostimulatory composition is increased compared to the A/U content in the environment of the ribosome binding site of its particular native RNA sequence.
- This modification (an increased A/U content around the ribosome binding site) increases the efficiency of ribosome binding to the RNA sequence.
- an RNA sequence as defined herein preferably the at least one (m)RNA of the adjuvant component of the inventive immunostimulatory composition and/or the at least one free mRNA of the inventive immunostimulatory composition, may be further modified with respect to potentially destabilizing sequence elements.
- the coding region and/or the 5' and/or 3' untranslated region of the RNA sequence as defined herein may be further modified compared to the particular native RNA sequence such that is contains no destabilizing sequence elements, the coded amino acid sequence of the RNA sequence as defined herein preferably not being modified compared to its particular native RNA.
- DSE destabilizing sequence elements
- DSEs present in the untranslated regions (3'- and/or 5'-UTR) can also be eliminated from an RNA sequence as defined herein, preferably from the at least one (m)RNA of the adjuvant component of the inventive immunostimulatory composition and/or from the at least one free mRNA of the inventive immunostimulatory composition, by such further modifications.
- Such destabilizing sequences are e.g. AU-rich sequences (AURES), which occur in 3'-UTR sections of numerous unstable RNAs (Caput et a/., Proc. Natl. Acad. Sci. USA 1986, 83: 1670 to 1674).
- An RNA sequence as defined herein, preferably the at least one (m)RNA of the adjuvant component of the inventive immunostimulatory composition and/or the at least one free mRNA of the inventive immunostimulatory composition is therefore preferably (further) modified compared to the native RNA such that the modified RNA contains no such destabilizing sequences.
- sequence motifs which are recognized by possible endonucleases, e.g.
- sequence GAACAAG which is contained in the 3'-UTR segment of the gene which codes for the transferrin receptor (Binder et a/., EMBO J. 1994, 13: 1969 to 1980).
- sequence motifs are also preferably removed according to the invention in the RNA sequence as defined herein, preferably the at least one (m)RNA of the adjuvant component of the inventive immunostimulatory composition and/or the at least one free mRNA of the inventive immunostimulatory composition.
- an RNA sequence as defined herein preferably the at least one (m)RNA of the adjuvant component of the inventive immunostimulatory composition and/or the at least one free mRNA of the inventive immunostimulatory composition, has, in a further modified form at least one IRES as defined above and/or at least one 5' and/or 3' stabilizing sequence, e.g. to enhance ribosome binding or to allow expression of different encoded proteins, e.g., antibodies, therapeutically active proteins or antigens, as defined above, located on an at least one (bi- or even multicistronic) RNA as defined above.
- IRES as defined above
- 5' and/or 3' stabilizing sequence e.g. to enhance ribosome binding or to allow expression of different encoded proteins, e.g., antibodies, therapeutically active proteins or antigens, as defined above, located on an at least one (bi- or even multicistronic) RNA as defined above.
- an RNA sequence as defined herein preferably the at least one (m)RNA of the adjuvant component of the inventive immunostimulatory composition and/or the at least one free mRNA of the inventive immunostimulatory composition, furthermore preferably may have at least one 5' and/or 3' stabilizing sequence.
- These stabilizing sequences in the 5' and/or 3' untranslated regions have the effect of increasing the half-life of the RNA as defined herein in the cytosol.
- These stabilizing sequences can have 100% sequence homology to naturally occurring sequences which occur in viruses, bacteria and eukaryotes, but can also be partly or completely synthetic.
- the untranslated sequences (UTR) of the globin gene e.g.
- RNA sequence as defined herein, preferably a further stabilized at least one (m)RNA of the adjuvant component of the inventive immunostimulatory composition and/or a further stabilized at least one free mRNA of the inventive immunostimulatory composition.
- stabilizing sequence has the general formula (C/U)CCAN x CCC(U/A)Py x UC(C/U)CC (SEQ ID NO: 123), which is contained in the 3'UTR of the very stable RNA which codes for globin, (l)-collagen, 15- lipoxygenase or for tyrosine hydroxylase (cf. Holcik et a/., Proc. Natl. Acad. Sci. USA 1997, 94: 2410 to 2414).
- Such stabilizing sequences can of course be used individually or in combination with one another and also in combination with other stabilizing sequences known to a person skilled in the art.
- RNA sequence as defined herein preferably the at least one (m)RNA of the adjuvant component of the inventive immunostimulatory composition and/or the at least one free mRNA of the inventive immunostimulatory composition, is therefore preferably present as globin UTR (untranslated regions)-stabilized RNA.
- any of the above modifications may be applied to an RNA sequence as defined herein, preferably the at least one (m)RNA of the adjuvant component of the inventive immunostimulatory composition and/or the at least one free mRNA of the inventive immunostimulatory composition, and further to any RNA as used in the context of the present invention and may be, if suitable or necessary, be combined with each other in any combination, provided, these combinations of modifications do not interfere with each other in the respective modified RNA.
- a person skilled in the art will be able to take his choice accordingly.
- an RNA sequence as defined herein preferably the at least one (m)RNA of the adjuvant component of the inventive immunostimulatory composition and/or the at least one free mRNA of the inventive immunostimulatory composition, may be prepared using any naturally or synthetic DNA or RNA sequence available in the art as a template, i.e. any suitable (desoxy)ribonucleic acid.
- Such naturally or synthetic DNA or RNA sequences may be obtained from any synthetic or naturally occurring source, which is available to a skilled person, e.g. may be derived from a protein or peptide library or may be transcribed from a nucleic acid library, such as a cDNA library, or may be obtained from any living or dead tissue, from a sample obtained from e.g.
- an RNA sequence as defined herein preferably the at least one (m)RNA of the adjuvant component of the inventive immunostimulatory composition and/or the at least one free mRNA of the inventive immunostimulatory composition, may be prepared synthetically by methods known to a person skilled in the art, e.g., by solid phase synthesis or any other suitable method for preparing nucleic acid sequences, particularly RNA sequences.
- substitutions, additions or eliminations of nucleotides or bases in these sequences are preferably carried out using a DNA matrix for preparation of the RNA as defined herein or by techniques of the well known site directed mutagenesis or with an oligonucleotide ligation strategy (see e.g.
- RNA sequence as defined herein preferably the at least one (m)RNA of the adjuvant component of the inventive immunostimulatory composition and/or the at least one free mRNA of the inventive immunostimulatory composition, can also be introduced into the RNA by means of further methods known to a person skilled in the art. Suitable methods are, for example, synthesis methods using (automatic or semiautomatic) oligonucleotide synthesis devices, biochemical methods, such as, for example, in vitro transcription methods, etc.
- the inventive immunostimulatory composition comprises a) an adjuvant component and b) at least one free mRNA.
- the inventive immunostimulatory composition may comprise an additional adjuvant, i.e. an adjuvant which is contained in the inventive immunostimulatory composition additional to the adjuvant component defined above.
- an adjuvant may be understood as any compound, which is suitable to support administration and optionally delivery of the inventive immunostimulatory composition according to the invention.
- an adjuvant may, without being bound thereto, initiate or increase an immune response of the innate immune system, i.e. a non-specific immune response.
- the inventive immunostimulatory composition when administered, typically elicits an innate immune response due to the adjuvant component, comprising or consisting of the at least one (m)RNA complexed with a cationic or polycationic compound as defined above.
- an innate immune response may be enhanced by adding an additional adjuvant, as defined in the following.
- Such an additional adjuvant may be selected from any adjuvant known to a skilled person and suitable for the present case, i.e. supporting the induction of an innate immune response in a mammal, except of cationic or polycationic compounds as defined above in order to prevent complexation of the at least one free mRNA.
- the adjuvant may be selected from the group consisting of, without being limited thereto, including chitosan, TDM, MDP, muramyl dipeptide, pluronics, alum solution, aluminium hydroxide, ADJUMERTM (polyphosphazene); aluminium phosphate gel; glucans from algae; algammulin; aluminium hydroxide gel (alum); highly protein-adsorbing aluminium hydroxide gel; low viscosity aluminium hydroxide gel; AF or SPT (emulsion of squalane (5%), Tween 80 (0.2%), Pluronic L121 (1 .25%), phosphate-buffered saline, pH 7.4); AVRIDINETM (propanediamine); BAY R1005TM ((N-(2-deoxy-2-L-leucylamino-b-D- glucopyranosyl)-N-octadecyl-dodecanoyl-amide hydroa
- TM liposomes
- LOXORIBINETM (7-allyl-8-oxoguanosine); LT oral adjuvant ⁇ E.coli labile enterotoxin-protoxin); microspheres and microparticles of any composition
- MF59TM serum emulsion
- MONTANIDE ISA 51TM purified incomplete Freund's adjuvant
- MONTANIDE ISA 720TM metabolisable oil adjuvant
- MPLTM (3-Q-desacyl-4'-monophosphoryl lipid A
- MTP-PE and MTP-PE liposomes ((N-acetyl-L-alanyl-D-isoglutaminyl-L-alanine ⁇ -O ⁇ -dipalmitoyl-sn-glycero-S- (hydroxyphosphoryloxy))-ethylamide, monosodium salt);
- MURAMETIDETM Nac-Mur-L-Ala- D-GIn-OCH 3
- Suitable adjuvants may furthermore be selected from lipid modified nucleic acids or from any of the immunostimulatory sequences of formula (I), (II), (III), (MIa), (IV), (IVa), (IVb), (Va) and/or (Vb) as defined above.
- the present invention also provides a pharmaceutical composition, comprising the inventive immunostimulatory composition as defined above and optionally a pharmaceutically acceptable carrier and/or vehicle.
- the inventive pharmaceutical composition comprises the inventive immunostimulatory composition as defined above, i.e. an a) adjuvant component, comprising or consisting of at least one (m)RNA, complexed with a cationic or polycationic compound, and b) at least one free mRNA, encoding at least one therapeutically active protein, antigen and/or antibody, wherein the immunostimulatory composition is capable to elicit or enhance an innate and optionally an adaptive immune response in a mammal.
- the inventive pharmaceutical composition typically supports an innate immune response and optionally an adaptive immune response of the immune system of a patient to be treated.
- inventive pharmaceutical composition may comprise a pharmaceutically acceptable carrier and/or vehicle.
- a pharmaceutically acceptable carrier typically includes the liquid or non-liquid basis of the inventive inventive pharmaceutical composition. If the inventive pharmaceutical composition is provided in liquid form, the carrier will typically be pyrogen-free water; isotonic saline or buffered (aqueous) solutions, e.g phosphate, citrate etc. buffered solutions.
- water or preferably a buffer preferably an aqueous buffer
- a sodium salt preferably at least 50 mM of a sodium salt
- a calcium salt preferably at least 0,01 mM of a calcium salt
- optionally a potassium salt preferably at least 3 mM of a potassium salt.
- the sodium, calcium and, optionally, potassium salts may occur in the form of their halogenides, e.g. chlorides, iodides, or bromides, in the form of their hydroxides, carbonates, hydrogen carbonates, or sulfates, etc.
- examples of sodium salts include e.g.
- examples of the optional potassium salts include e.g. KCI, Kl, KBr, K 2 CO 3 , KHCO 3 , K 2 SO 4
- examples of calcium salts include e.g. CaCI 2 , CaI 2 , CaBr 2 , CaCO 3 , CaSO 4 , Ca(OH) 2 .
- organic anions of the aforementioned cations may be contained in the buffer.
- the buffer suitable for injection purposes as defined above may contain salts selected from sodium chloride (NaCI), calcium chloride (CaCI 2 ) and optionally potassium chloride (KCI), wherein further anions may be present additional to the chlorides.
- CaCI 2 can also be replaced by another salt like KCl.
- the salts in the injection buffer are present in a concentration of at least 50 mM sodium chloride (NaCI), at least 3 itiM potassium chloride (KCI) and at least 0,01 mM calcium chloride (CaCl 2 ).
- the injection buffer may be hypertonic, isotonic or hypotonic with reference to the specific reference medium, i.e.
- the buffer may have a higher, identical or lower salt content with reference to the specific reference medium, wherein preferably such concentrations of the afore mentioned salts may be used, which do not lead to damage of cells due to osmosis or other concentration effects.
- Reference media are e.g. liquids occurring in "in vivd' methods, such as blood, lymph, cytosolic liquids, or other body liquids, or e.g. liquids, which may be used as reference media in "in vitrd' methods, such as common buffers or liquids.
- Such common buffers or liquids are known to a skilled person. Ringer or Ringer-Lactate solution is particularly preferred as a liquid basis.
- compatible solid or liquid fillers or diluents or encapsulating compounds may be used as well for the inventive pharmaceutical composition, which are suitable for administration to a patient to be treated.
- the term "compatible” as used here means that these constituents of the inventive pharmaceutical composition are capable of being mixed with an RNA sequence as defined herein, preferably the at least one (m)RNA of the adjuvant component of the inventive immunostimulatory composition complexed with a cationic or polycationic compound, and the at least one free mRNA of the inventive immunostimulatory composition, in such a manner that no interaction occurs which would substantially reduce the pharmaceutical effectiveness of the inventive pharmaceutical composition under typical use conditions.
- Pharmaceutically acceptable carriers, fillers and diluents must, of course, have sufficiently high purity and sufficiently low toxicity to make them suitable for administration to a person to be treated.
- Some examples of compounds which can be used as pharmaceutically acceptable carriers, fillers or constituents thereof are sugars, such as, for example, lactose, glucose and sucrose; starches, such as, for example, corn starch or potato starch; cellulose and its derivatives, such as, for example, sodium carboxymethylcellulose, ethylcellulose, cellulose acetate; powdered tragacanth; malt; gelatin; tallow; solid glidants, such as, for example, stearic acid, magnesium stearate; calcium sulfate; vegetable oils, such as, for example, groundnut oil, cottonseed oil, sesame oil, olive oil, corn oil and oil from theobroma; polyols, such as, for example, polypropylene glycol, glycerol, sorbitol, mannito
- inventive pharmaceutical composition may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir.
- parenteral as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional, intracranial, transdermal, intradermal, intrapulmonal, intraperitoneal, intracardial, intraarterial, and sublingual injection or infusion techniques.
- the inventive pharmaceutical composition may be administered by parenteral injection, more preferably by subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional, intracranial, transdermal, intradermal, intrapulmonal, intraperitoneal, intracardial, intraarterial, and sublingual injection or via infusion techniques.
- Sterile injectable forms of the inventive pharmaceutical compositions may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents.
- the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenteral ly-acceptable diluent or solvent, for example as a solution in 1 ,3-butanediol.
- a non-toxic parenteral ly-acceptable diluent or solvent for example as a solution in 1 ,3-butanediol.
- acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
- sterile, fixed oils are conventionally employed as a solvent or suspending medium.
- any bland fixed oil may be employed including synthetic mono- or di- glycerides.
- Fatty acids such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutical ly-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions.
- These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents that are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions.
- Other commonly used surfactants such as Tweens, Spans and other emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation of the inventive pharmaceutical composition.
- inventive pharmaceutical composition as defined above may also be administered orally in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions.
- carriers commonly used include lactose and corn starch.
- Lubricating agents, such as magnesium stearate, are also typically added.
- useful diluents include lactose and dried cornstarch.
- the at least one (m)RNA of the adjuvant component of the inventive immunostimulatory composition and/or the at least one free mRANA of the inventive immunostimulatory composition forming part of the inventive pharmaceutical composition as defined above is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added.
- inventive pharmaceutical composition may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, e.g. including diseases of the skin or of any other accessible epithelial tissue.
- Suitable topical formulations are readily prepared for each of these areas or organs.
- the inventive pharmaceutical composition may be formulated in a suitable ointment, containing the inventive immunostimulatory composition, particularly its components as defined above, suspended or dissolved in one or more carriers.
- Carriers for topical administration include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water.
- the inventive pharmaceutical composition can be formulated in a suitable lotion or cream.
- suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.
- the inventive pharmaceutical composition typically comprises a "safe and effective amount" of the components of the inventive pharmaceutical composition, particularly of the at least one (m)RNA of the adjuvant component of the inventive immunostimulatory composition complexed with a cationic or polycationic compound, and/or of the at least one free mRNA of the inventive immunostimulatory composition.
- a "safe and effective amount” means an amount of the at least one (m)RNA of the adjuvant component of the inventive immunostimulatory composition complexed with a cationic or polycationic compound, and/or of the at least one free mRNA of the inventive immunostimulatory composition, that is sufficient to significantly induce a positive modification of a disease or disorder as defined herein.
- a "safe and effective amount” is small enough to avoid serious side-effects, that is to say to permit a sensible relationship between advantage and risk. The determination of these limits typically lies within the scope of sensible medical judgment.
- a "safe and effective amount" of the components of the inventive pharmaceutical composition, particularly of the at least one (m)RNA of the adjuvant component of the inventive immunostimulatory composition complexed with a cationic or polycationic compound, and/or of the at least one free mRNA of the inventive immunostimulatory composition, herein will furthermore vary in connection with the particular condition to be treated and also with the age and physical condition of the patient to be treated, the body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, the activity of the specific (m)RNA or mRNA as defined herein employed, the severity of the condition, the duration of the treatment, the nature of the accompanying therapy, of the particular pharmaceutically acceptable carrier used, and similar factors, within the knowledge and experience of the accompanying doctor.
- the inventive pharmaceutical composition may be used for human and also for veterinary medical purposes, preferably for human medical purposes, as a pharmaceutical composition in general or as a vaccine.
- the inventive pharmaceutical composition may be provided as a vaccine.
- Such an inventive vaccine is typically composed like the inventive pharmaceutical composition and preferably supports at least an innate immune response of the immune system of a patient to be treated. Additionally, the inventive vaccine furthermore may also elicit an adaptive immune response, preferably, if the (at least one (m)RNA of the adjuvant component of the inventive immunostimulatory composition complexed with a cationic or polycationic compound, and/or preferably the) at least one free mRNA of the inventive immunostimulatory composition encodes any of the above mentioned antigens (or antibodies), which elicit an adaptive immune response.
- the inventive vaccine may also comprise a pharmaceutically acceptable carrier, adjuvant, and/or vehicle as defined above for the inventive pharmaceutical composition.
- a pharmaceutically acceptable carrier is determined in principle by the manner in which the inventive vaccine is administered.
- the inventive vaccine can be administered, for example, systemically or locally. Routes for systemic administration in general include, for example, transdermal, oral, parenteral routes, including subcutaneous, intravenous, intramuscular, intraarterial, intradermal and intraperitoneal injections and/or intranasal administration routes.
- Routes for local administration in general include, for example, topical administration routes but also intradermal, transdermal, subcutaneous, or intramuscular injections or intralesional, intracranial, intrapulmonal, intracardial, and sublingual injections. More preferably, vaccines may be administered by an intradermal, subcutaneous, or intramuscular route. Inventive vaccines are therefore preferably formulated in liquid (or sometimes in solid) form. The suitable amount of the inventive vaccine to be administered can be determined by routine experiments with animal models. Such models include, without implying any limitation, rabbit, sheep, mouse, rat, dog and non-human primate models. Preferred unit dose forms for injection include sterile solutions of water, physiological saline or mixtures thereof. The pH of such solutions should be adjusted to about 7.4.
- Suitable carriers for injection include hydrogels, devices for controlled or delayed release, polylactic acid and collagen matrices.
- Suitable pharmaceutically acceptable carriers for topical application include those which are suitable for use in lotions, creams, gels and the like. If the inventive vaccine is to be administered orally, tablets, capsules and the like are the preferred unit dose form.
- the pharmaceutically acceptable carriers for the preparation of unit dose forms which can be used for oral administration are well known in the prior art. The choice thereof will depend on secondary considerations such as taste, costs and storability, which are not critical for the purposes of the present invention, and can be made without difficulty by a person skilled in the art.
- the inventive vaccine can additionally contain one or more auxiliary substances in order to further increase its immunogenicity.
- a synergistic action of the at least one (m)RNA of the adjuvant component of the inventive immunostimulatory composition complexed with a cationic or polycationic compound, and/or of the at least one free mRNA of the inventive immunostimulatory composition, as defined above, and of an auxiliary substance, which may be optionally contained in the inventive vaccine as described above, is preferably achieved thereby.
- auxiliary substances various mechanisms can come into consideration in this respect.
- DCs dendritic cells
- TNF-alpha or CD40 ligand form a first class of suitable auxiliary substances.
- auxiliary substance any agent that influences the immune system in the manner of a "danger signal" (LPS, GP96, etc.) or cytokines, such as GM-CFS, which allow an immune response produced by the immune-stimulating adjuvant according to the invention to be enhanced and/or influenced in a targeted manner.
- a "danger signal” LPS, GP96, etc.
- cytokines such as GM-CFS
- auxiliary substances are cytokines, such as monokines, lymphokines, interleukins or chemokines, that further promote the innate immune response, such as IL-I , IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-12, IL-13, IL-14, IL-15, IL-16, IL-I 7, IL-18, IL-19, IL-20, IL-21 , IL-22, IL- 23, IL-24, IL-25, IL-26, IL-27, IL-28, IL-29, IL-30, IL-31 , IL-32, IL-33, INF-alpha, IFN-beta, INF-gamma, GM-CSF, G-CSF, M-CSF, LT-beta or TNF-alpha, growth factors, such as hGH.
- cytokines such as monokines, lymphokines,
- emulsifiers such as, for example, Tween ® ; wetting agents, such as, for example, sodium lauryl sulfate; colouring agents; taste-imparting agents, pharmaceutical carriers; tablet-forming agents; stabilizers; antioxidants; preservatives.
- the inventive vaccine can also additionally contain any further compound, which is known to be immune-stimulating due to its binding affinity (as ligands) to human Toll-like receptors TLRl , TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, TLR10, or due to its binding affinity (as ligands) to murine Toll-like receptors TLR1 , TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, TLR10, TLR1 1 , TLR12 or TLR13.
- any further compound which is known to be immune-stimulating due to its binding affinity (as ligands) to human Toll-like receptors TLRl , TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, TLR10, TLR1 1 , TLR12 or TLR13.
- CpG nucleic acids in particular CpG-RNA or CpG-DNA.
- a CpG-RNA or CpG- DNA can be a single-stranded CpG-DNA (ss CpG-DNA), a double-stranded CpG-DNA (dsDNA), a single-stranded CpG-RNA (ss CpG-RNA) or a double-stranded CpG-RNA (ds CpG-RNA).
- the CpG nucleic acid is preferably in the form of CpG-RNA, more preferably in the form of single-stranded CpG-RNA (ss CpG-RNA).
- the CpG nucleic acid preferably contains at least one or more (mitogenic) cytosine/guanine dinucleotide sequence(s) (CpG motif(s)).
- CpG motif(s) cytosine/guanine dinucleotide sequence(s)
- at least one CpG motif contained in these sequences that is to say the C (cytosine) and the G (guanine) of the CpG motif, is unmethylated. All further cytosines or guanines optionally contained in these sequences can be either methylated or unmethylated.
- the C (cytosine) and the G (guanine) of the CpG motif can also be present in methylated form.
- the inventive immunostimulatory composition preferably the components of the inventive immunostimulatory composition, i.e. the at least one (m)RNA of the adjuvant component of the inventive immunostimulatory composition complexed with a cationic or polycationic compound, together with the at least one free mRNA of the inventive immunostimulatory composition, may be used for the preparation of a pharmaceutical composition or a vaccine, preferably all as defined herein, for the prophylaxis, treatment and/or amelioration of any of the diseases and disorders as defined herein.
- a pharmaceutical composition or a vaccine preferably all as defined herein, for the prophylaxis, treatment and/or amelioration of any of the diseases and disorders as defined herein.
- inventive immunostimulatory composition the inventive pharmaceutical composition or the inventive vaccine, or the at least one (m)RNA of the adjuvant component of the inventive immunostimulatory composition complexed with a cationic or polycationic compound, together with the at least one free mRNA of the inventive immunostimulatory composition, may be used for (the preparation of a medicament for) the prophylaxis, treatment and/or amelioration of e.g.
- cervical carcinoma cervical cancer
- inventive immunostimulatory composition may be used for (the preparation of a medicament for) the prophylaxis, treatment, and/or amelioration of e.g. infectious diseases, preferably (viral, bacterial or protozoological) infectious diseases.
- infectious diseases preferably (viral, bacterial or protozoological) infectious diseases.
- infectious diseases are typically selected from influenza, malaria, SARS, yellow fever, AIDS, Lyme borreliosis, Leishmaniasis, anthrax, meningitis, viral infectious diseases such as AIDS, Condyloma acuminata, hollow warts, Dengue fever, three-day fever, Ebola virus, cold, early summer meningoencephalitis (FSME), flu, shingles, hepatitis, herpes simplex type I, herpes simplex type II, Herpes zoster, influenza, Japanese encephalitis, Lassa fever, Marburg virus, measles, foot-and-mouth disease, mononucleosis, mumps, Norwalk virus infection, Pfeiffer's glandular fever, smallpox, polio (childhood lameness), pseudo-croup, fifth disease, rabies, warts, West Nile fever, chickenpox, cytomegalic virus
- inventive immunostimulatory composition may be used for (the preparation of a medicament for) the prophylaxis, treatment, and/or amelioration of e.g. autoimmune diseases.
- Autoimmune diseases can be broadly divided into systemic and organ-specific or localised autoimmune disorders, depending on the principal clinico-pathologic features of each disease.
- Autoimmune diseases may be divided into the categories of systemic syndromes, including systemic lupus erythematosus (SLE), Sjogren's syndrome, Scleroderma, Rheumatoid Arthritis and polymyositis or local syndromes which may be endocrinologic (type I diabetes (Diabetes mellitus Type 1 ), Hashimoto's thyroiditis, Addison's disease etc.), dermatologic (pemphigus vulgaris), haematologic (autoimmune haemolytic anaemia), neural (multiple sclerosis) or can involve virtually any circumscribed mass of body tissue.
- SLE systemic lupus erythematosus
- Sjogren's syndrome Sjogren's syndrome
- Scleroderma Scleroderma
- Rheumatoid Arthritis and polymyositis or local syndromes
- endocrinologic type I diabetes (Diabetes mellitus Type 1 ), Hashimoto's thyroiditis, Add
- the autoimmune diseases to be treated may be selected from the group consisting of type I autoimmune diseases or type Il autoimmune diseases or type III autoimmune diseases or type IV autoimmune diseases, such as, for example, multiple sclerosis (MS), rheumatoid arthritis, diabetes, type I diabetes (Diabetes mellitus Type 1 ), chronic polyarthritis, Basedow's disease, autoimmune forms of chronic hepatitis, colitis ulcerosa, type I allergy diseases, type Il allergy diseases, type III allergy diseases, type IV allergy diseases, fibromyalgia, hair loss, Bechterew's disease, Crohn's disease, Myasthenia gravis, neurodermitis, Polymyalgia rheumatica, progressive systemic sclerosis (PSS), Reiter's syndrome, rheumatic arthritis, psoriasis, vasculitis, etc, or type Il diabetes.
- MS multiple sclerosis
- rheumatoid arthritis diabetes
- type I diabetes Diabetes mell
- the autoreaction may be due to a T-CeII bypass.
- a normal immune system requires the activation of B-cells by T-cells before the former can produce antibodies in large quantities.
- This requirement of a T-cell can be by-passed in rare instances, such as infection by organisms producing super- antigens, which are capable of initiating polyclonal activation of B-cells, or even of T-cells, by directly binding to the ⁇ -subunit of T-cell receptors in a non-specific fashion.
- autoimmune diseases from a Molecular Mimicry.
- An exogenous antigen may share structural similarities with certain host antigens; thus, any antibody produced against this antigen (which mimics the self-antigens) can also, in theory, bind to the host antigens and amplify the immune response.
- the most striking form of molecular mimicry is observed in Group A beta-haemolytic streptococci, which shares antigens with human myocardium, and is responsible for the cardiac manifestations of rheumatic fever.
- inventive immunostimulatory composition may be used for (the preparation of a medicament for) the prophylaxis, treatment, and/or amelioration of allergies or allergic diseases, i.e. diseases related to allergies.
- Allergy is a condition that typically involves an abnormal, acquired immunological hypersensitivity to certain foreign antigens or allergens, such as the allergy antigens as defined above.
- allergy antigens or allergens may be selected from allergy antigens as defined above antigens derived from different sources, e.g. from animals, plants, fungi, bacteria, etc.
- Allergens in this context include e.g. grasses, pollens, molds, drugs, or numerous environmental triggers, etc. Allergies normally result in a local or systemic inflammatory response to these antigens or allergens and lead to an immunity in the body against these allergens.
- allergies Without being bound to theory, several different disease mechanisms are supposed to be involved in the development of allergies. According to a classification scheme by P. GeII and R. Coombs the word "allergy" was restricted to type I hypersensitivities, which are caused by the classical IgE mechanism.
- Type I hypersensitivity is characterised by excessive activation of mast cells and basophils by IgE, resulting in a systemic inflammatory response that can result in symptoms as benign as a runny nose, to life-threatening anaphylactic shock and death.
- Well known types of allergies include, without being limited thereto, allergic asthma (leading to swelling of the nasal mucosa), allergic conjunctivitis (leading to redness and itching of the conjunctiva), allergic rhinitis ("hay fever”), anaphylaxis, angiodema, atopic dermatitis (eczema), urticaria (hives), eosinophilia, respiratory, allergies to insect stings, skin allergies (leading to and including various rashes, such as eczema, hives (urticaria) and (contact) dermatitis), food allergies, allergies to medicine, etc.
- the inventive immunostimulatory composition, the inventive pharmaceutical composition or the inventive vaccine, or the at least one (m)RNA of the adjuvant component of the inventive immunostimulatory composition complexed with a cationic or polycationic compound, together with the at least one free mRNA of the inventive immunostimulatory composition may be used for the treatment of such allergic disorders or diseases, preferably by desensitizing the immune reaction which triggers a specific immune response.
- desensitizing may be carried out by administering an effective amount of the allergen or allergic antigen encoded by a RNA of the inventive immunostimulatory composition, preferably the at least one free mRNA, to induce a slight immune reaction.
- the amount of the allergen or allergic antigen may then be raised step by step in subsequent administrations until the immune system of the patient to be treated tolerates a specific amount of allergen or allergic antigen.
- the invention furthermore relates also to the use of the inventive immunostimulatory composition, the inventive pharmaceutical composition or the inventive vaccine, or the at least one (m)RNA of the adjuvant component of the inventive immunostimulatory composition complexed with a cationic or polycationic compound, together with the at least one free mRNA of the inventive immunostimulatory composition, for the prophylaxis, treatment, and/or amelioration of diseases or disorders as mentioned herein.
- inventive immunostimulatory composition typically comprises administering the described pharmaceutical composition to a patient in need thereof (e.g.
- inventive pharmaceutical compositions suffering from any of the above diseases or showing symptoms thereof), in particular to a human being, preferably in a "safe and effective amount" and in one of the above formulations as described above for inventive pharmaceutical compositions.
- the administration mode also may be as described above for inventive pharmaceutical compositions or vaccines.
- the present invention relates also to an in vitro transcription method for the preparation of the at least one (m)RNA, to be complexed with a cationic or polycationic compound, or the at least one free mRNA, respectively, encoding at least one therapeutically active protein, antigen and/or antibody, both as defined above, comprising the following steps: a) preparation/provision of a (desoxy)ribonucleic acid as a template for the inventive at least one (m)RNA, to be complexed with a cationic or polycationic compound, or the at least one free mRNA, respectively, encoding at least one therapeutically active protein, antigen and/or antibody, both as described above; b) addition of the (desoxy)ribonucleic acid to an in vitro transcription medium comprising a RNA polymerase, a suitable buffer, a nucleotide mix, the nucleotide mix optionally comprising one or more nucleotides with chemically modified nucleosides selected from the chemically modified nucle
- a (desoxy)ribonucleic acid as described in step a) of the inventive in vitro transcription method can be any nucleic acid as described above that may be used as a template for the preparation of the at least one (m)RNA, to be complexed with a cationic or polycationic compound, and/or the at least one free mRNA, respectively, encoding at least one therapeutically active protein, antigen and/or antibody.
- DNA sequences are used, for example genomic DNA or fragments thereof, or plasmids, or RNA sequences (corresponding thereto), for example mRNA sequences, preferably in linearized form.
- the in vitro transcription reaction can usually be carried out using a vector having a RNA polymerase binding site.
- any vectors known in the art for example commercially available vectors (see above). Preference is given, for example, to those vectors that have a SP6 or a T7 or T3 binding site upstream and/or downstream of the cloning site. Accordingly, the (desoxy)ribonucleic acid sequences used can be transcribed later, as desired, depending on the chosen RNA polymerase.
- the plasmid Prior to transcription, the plasmid is typically cleaved with restriction enzymes at the site at which the future 3' end of the at least one (m)RNA of the adjuvant component as defined above or the at least one free mRNA as defined above is to be located, using a suitable restriction enzyme, and the fragment is purified. This prevents the future at least one (m)RNA of the adjuvant component as defined above or the at least one free mRNA as defined above, from containing vector sequences, and a defined length may be obtained.
- one of the primers used for PCR typically contains the sequence of a RNA polymerase binding site. It is further preferred for the 5' end of the primer to have a length of approximately 10 to 50 further nucleotides, more preferably 15 to 30 further nucleotides and most preferably of approximately 20 nucleotides.
- the (desoxy)ribonucleic acid Prior to the in vitro transcription reaction, the (desoxy)ribonucleic acid, e.g., the specific DNA or RNA template, is typically purified and free of RNase in order to ensure a high yield. Purification can be carried out by any process known in the art, for example with a caesium chloride gradient or ion-exchange process.
- the (desoxy)ribonucleic acid is added to an in vitro transcription medium.
- a suitable in vitro transcription medium first contains a (desoxy)ribonucleic acid as prepared under step a), for example approximately from about 0.1 to about 10 ⁇ g, preferably approximately from about 1 to about 5 ⁇ g, more preferably about 2.5 ⁇ g and most preferably approximately about 1 ⁇ g, of such a nucleic acid.
- a suitable in vitro transcription medium further optionally contains a reducing agent, e.g. DTT, more preferably approximately from about 1 to about 20 ⁇ l of about 50 mM DTT, yet more preferably approximately about 5 ⁇ l of about 50 mM DTT.
- the in vitro transcription medium further contains nucleotides (AMP, GMP, UMP and/or CMP), for example a nucleotide mix.
- nucleotides AMP, GMP, UMP and/or CMP
- the nucleotides preferably comprise chemically modified nucleosides as defined above.
- Such (chemically modified) nucleotides may serve as replacement for one or more of the naturally occurring nucleotides AMP, GMP, UMP and/or CMP, and optionally one or more naturally occurring nucleotides AMP, GMP, UMP and/or CMP, if not all of the naturally occurring nucleotides AMP, GMP, UMP and/or CMP are to be replaced.
- the nucleotides AMP, GMP, UMP and/or CMP are typically present in the nucleotide mix in a concentration of typically approximately from 0.1 to 10 mM per nucleotide, preferably from 0.1 to 1 mM per nucleotide, preferably approximately 4 mM in total.
- (Chemically) modified nucleotides as described above are typically added in such an amount that the native nucleotide is replaced completely by the (modified) nucleotide(s) comprising a chemically modified nucleoside as defined above.
- the content, that is to say the occurrence and amount, of the desired nucleotide modification in the transcribed inventive at least one (m)RNA, to be complexed with a cationic or polycationic compound, or the at least one free mRNA, encoding at least one therapeutically active protein, antigen and/or antibody can therefore be controlled.
- a suitable in vitro transcription medium likewise contains a RNA polymerase, e.g. T7-RNA polymerase (e.g.
- T7-Opti mRNA Kit CureVac, Tubingen, Germany
- T3-RNA polymerase or SP6 typically approximately from 10 to 500 U, preferably approximately from 25 to 250 U, more preferably approximately from 50 to 150 U, and most preferably approximately 100 U of RNA polymerase.
- the in vitro transcription medium is further preferably kept free of RNase in order to avoid degradation of the transcribed (m)RNA.
- a suitable in vitro transcription medium therefore optionally contains in addition an RNase inhibitor.
- step c) of the inventive in vitro transcription method the (desoxy)ribonucleic acid of step b) is incubated and transcribed in the in vitro transcription medium, typically for approximately 30 to 120 minutes, preferably for approximately 40 to 90 minutes and most preferably for approximately 60 minutes, at approximately 30 to 45°C, preferably at 37 to 42°C.
- the incubation temperature is governed by the RNA polymerase that is used, for example in the case of T7 RNA polymerase it is approximately 37°C.
- the nucleic acid obtained by the transcription is preferably the at least one (m)RNA, to be complexed with a cationic or polycationic compound, or the at least one free mRNA, encoding at least one therapeutically active protein, antigen and/or antibody, respectively, both as defined herein.
- step d) of the in vitro transcription method according to the invention can optionally take place in step d) of the in vitro transcription method according to the invention.
- any suitable process known in the art can be used, for example chromatographic purification processes, e.g. affinity chromatography, gel filtration, etc.
- chromatographic purification processes e.g. affinity chromatography, gel filtration, etc.
- non-incorporated, i.e. excess, nucleotides can be removed from the in vitro transcription medium.
- Any suitable method known in the prior art e.g. chromatographic purification methods, e.g. affinity chromatography, gel filtration etc., can be used for this.
- a clean transcribed RNA of an RNA sequence as defined herein e.g.
- RNA an at least one (m)RNA, to be complexed with a cationic or polycationic compound, or of the at least one free mRNA, encoding at least one therapeutically active protein, antigen and/or antibody, respectively.
- the reaction mixture containing the transcribed RNA can typically be digested with DNase in order to remove the DNA template still contained in the reaction mixture.
- the transcribed RNA can be subsequently or alternatively precipitated with LiCI. Purification of the transcribed RNA can then take place via ion-pair reversed phase (IP RP)-HPLC. This renders it possible in particular to separate longer and shorter fragments from one another effectively.
- IP RP ion-pair reversed phase
- the purification takes place via a method for purification of the RNA on a preparative scale, which is distinguished in that the RNA as defined herein, particularly the at least one (m)RNA, to be complexed with a cationic or polycationic compound, or the at least one free mRNA, encoding at least one therapeutically active protein, antigen and/or antibody, respectively, is purified by means of HPLC using a porous reverse phase as the stationary phase (PURE Messenger).
- a reverse phase can be employed as the stationary phase for the HPLC purification.
- a non-polar compound typically serves as stationary phase, and a polar solvent, such as mixtures of water, which is usually employed in the form of buffers, with acetonitrile and/or methanol, serves as the mobile phase for the elution.
- a polar solvent such as mixtures of water, which is usually employed in the form of buffers, with acetonitrile and/or methanol, serves as the mobile phase for the elution.
- the porous reverse phase has a particle size of 8.0 ⁇ 2 ⁇ m, preferably ⁇ 1 ⁇ m, more preferably +/- 0.5 ⁇ m.
- the reverse phase material can be in the form of beads.
- the purification can be carried out in a particularly favourable manner with a porous reverse phase having this particle size, optionally in the form of beads, particularly good separation results being obtained.
- the reverse phase employed is preferably porous since with stationary reverse phases which are not porous, such as are described, e.g., by Azarani A. and Hecker K.H., pressures which are too high are built up, so that preparative purification of the RNA as defined herein, particularly the at least one (m)RNA, to be complexed with a cationic or polycationic compound, or the at least one free mRNA, encoding at least one therapeutically active protein, antigen and/or antibody, respectively, is possible, if at all, only with great difficulty.
- the reverse phase preferably has a pore size of from 200 A to 5,000 A, in particular a pore size of from 300 A to 4,000 A.
- Particularly preferred pore sizes for the reverse phases are 200 A - 400 A, 800 A - 1 ,200 A and 3,500 A - 4,500 ⁇ . With a reverse phase having these pore sizes, particularly good results are achieved in respect of the purification of the RNA as defined herein in process step d).
- the material for the reverse phase is preferably a polystyrene-divinylbenzene, and non-alkylated polystyrene-divinylbenzenes can be employed in particular. Stationary phases with polystyrene-divinylbenzene are known per se.
- the polystyrene-divinylbenzenes which are known per se and already employed for HPLC methods and are commercially obtainable can be used.
- a non-alkylated porous polystyrene-divinylbenzene which in particular has a particle size of 8.0 ⁇ 0.5 ⁇ m and a pore size of 250 ⁇ - 300 A, 900 A - 1 ,100 A or 3,500 A - 4,500 A is very particularly preferably used for the purification in method step d).
- the advantages described above can be achieved in a particularly favourable manner with this material for the reverse phases.
- the HPLC purification can be carried out by the ion pair method, an ion having a positive charge being added to the mobile phase as a counter-ion to the negatively charged RNA.
- An ion pair having a lipophilic character which is slowed down by the non-polar stationary phase of the reverse phase system, is formed in this manner.
- the precise conditions for the ion pair method must be worked out empirically for each concrete separation problem.
- the size of the counter-ion, its concentration and the pH of the solution contribute greatly towards the result of the separation.
- alkylammonium salts such as triethylammonium acetate and/or tetraalkylammonium compounds, such as tetrabutylammonium
- 0.1 M triethylammonium acetate is added and the pH is adjusted to about 7.
- the choice of mobile phase depends on the nature of the desired separation. This means that the mobile phase found for a specific separation, such as can be known, for example, from the prior art, cannot be transferred readily to another separation problem with adequate prospect of success.
- the ideal elution conditions, in particular the mobile phase used must be determined for each separation problem by empirical experiments.
- a mixture of an aqueous solvent and an organic solvent can be employed as the mobile phase for elution of the RNA as defined herein, particularly the at least one (m)RNA, complexed with a cationic or polycationic compound, or the at least one free mRNA, encoding at least one therapeutically active protein, antigen and/or antibody, respectively, by the HPLC method.
- a buffer which has, in particular, a pH of about 7, for example 6.5 - 7.5, e.g.
- the buffer triethylammonium acetate is used, particularly preferably a 0.1 M triethylammonium acetate buffer which, as described above, also acts as a counter-ion to RNA as defined herein in the ion pair method.
- the organic solvent employed in the mobile phase can be acetonitrile, methanol or a mixture of these two, very particularly preferably acetonitrile.
- the purification of the RNA as defined herein in method step d) using an HPLC method as described, particularly purification of the at least one (m)RNA, to be complexed with a cationic or polycationic compound, or of the at least one free mRNA, encoding at least one therapeutically active protein, antigen and/or antibody, respectively, is carried out in a particularly favourable manner with these organic solvents.
- the mobile phase is particularly preferably a mixture of 0.1 M triethylammonium acetate, pH 7, and acetonitrile.
- the mobile phase contains 5.0 vol.% to 20.0 vol.% of organic solvent, based on the mobile phase, and the remainder to make up 100 vol.% is the aqueous solvent. It is very particularly favourable for the method according to the invention if the mobile phase contains 9.5 vol.% to 14.5 vol.% of organic solvent, based on the mobile phase, and the remainder to make up 100 vol.% is the aqueous solvent.
- Elution of the RNA as defined herein, particularly the at least one (m)RNA, to be complexed with a cationic or polycationic compound, or the at least one free mRNA, encoding at least one therapeutically active protein, antigen and/or antibody, respectively, can subsequently be carried out isocratically or by means of a gradient separation.
- elution of the RNA as defined herein is carried out with a single eluting agent or a mixture of several eluting agents which remains constant, it being possible for the solvents described above in detail to be employed as the eluting agent.
- the present patent application also provides a method of transfecting and optionally administering the inventive immunostimulatory composition or its components as defined above, the inventive pharmaceutical composition or the inventive vaccine, as defined above, comprising the following steps:
- blood cells are preferably understood according to the invention as meaning a mixture or an enriched to substantially pure population of red blood cells, granulocytes, mononuclear cells (PBMCs) and/or blood platelets from whole blood, blood serum or another source, e.g. from the spleen or lymph nodes, only a small proportion of professional APCs being present.
- APCs professional antigen presenting cells
- DCs dendritic cells
- blood cells are preferably understood according to the invention as meaning a mixture or an enriched to substantially pure population of red blood cells, granulocytes, mononuclear cells (PBMCs) and/or blood platelets from whole blood, blood serum or another source, e.g. from the spleen or lymph nodes, only a small proportion of professional APCs being present.
- blood cells in the present invention are typically characterized in that they contain a small proportion of well- differentiated professional antigen presenting cells (APCs), especially dendritic cells (DCs).
- the blood cells as used according to the present invention may be preferably fresh blood cells, i.e. the period between collection of the blood cells (especially blood withdrawal) and transfection being only short, e.g. less than 12 h, preferably less than 6 h, particularly preferably less than 2 h and very particularly preferably less than 1 h.
- the blood cells as used according to the present invention may also be blood cells obtained upon withdrawal of blood prior to need, e.g. an operation or a treatment as defined herein, and which are stored subsequently until use.
- Blood cells may be collected from an animal or human patient by standard methods, for example. Thus whole blood can easily be obtained by puncturing a suitable vessel. Serum is obtained in known manner by coagulating the solid blood constituents.
- PBMCs may be mentioned as an example of an enriched partial population of blood cells. These are conventionally isolated by a method first described by B ⁇ yum (Nature 204, 793-794, 1964; Scan. J. Lab. Clin. Invest. Suppl. 97, 1967). This is generally done by withdrawing blood from the individual and adding it e.g. to a solution of density 1.077 g/ml (25°C), conventionally containing Ficoll and sodium diatrizoate, for density gradient centrifugation.
- the PBMCs collect at the Ficoll/blood interface whereas the red blood cells and the remaining white blood cells are sedimented.
- the interface with the PBMCs is recovered and conventionally washed with a suitable buffer, e.g. sterile PBS.
- the PBMCs are preferably subjected to a short isotonic treatment with an aqueous solution of e.g. ammonium chloride.
- the PBMCs are washed a further one or more times with a buffer such as PBS (sterile).
- PBS sterile
- the blood cells immediately prior to transfection are fresh blood cells, i.e. there is only a short period between the collection of blood cells (especially blood withdrawal) in step (a) and the transfection according to step (b), e.g. less than 12 h, preferably less than 6 h, particularly preferably less than 2 h and very particularly preferably less than 1 h.
- dendritic cells are typically potent antigen presenting cells (APCs) that typically possess the ability to stimulate na ⁇ ve T cells. They comprise a system of leukocytes widely distributed in all tissues, especially in those that provide an environmental interface. DCs posses a heterogeneous haemopoietic lineage, in that subsets from different tissues have been shown to posses a differential morphology, phenotype and function. The ability to stimulate na ⁇ ve T cell proliferation appears to be shared between these various DC subsets.
- APCs antigen presenting cells
- DCs are derived from bone marrow progenitors and circulate in the blood as immature precursors prior to migration into peripheral tissues. Within different tissues, DCs differentiate and become active in the taking up and processing of antigens, and their subsequent presentation on the cell surface linked to major histocompatibility (MHC) molecules. Upon appropriate stimulation, DCs undergo further maturation and migrate to secondary lymphoid tissues where they present antigens to T cells and induce an immune response.
- MHC major histocompatibility
- DCs are receiving increasing scientific and clinical interest due to their key role in anti-cancer host responses and potential use as biological adjuvants in tumour vaccines, as well as their involvement in the immunobiology of tolerance and autoimmunity.
- DCs Dendritic cells
- Such dendritic cells (DCs), as defined above, may be isolated from different tissues as mentioned above or from blood, particularly from blood samples as described above.
- the blood cells, professional antigen presenting cells (APCs), especially dendritic cells (DCs), used for the inventive method of transfection and optionally administration pharmaceutical composition or the vaccine according to the invention originate from the actual patient who will be treated with the pharmaceutical composition of the present invention (autologous cells).
- the pharmaceutical composition or the vaccine according to the invention therefore preferably contain autologous blood cells, professional antigen presenting cells (APCs), especially dendritic cells (DCs).
- the transfection of the blood cells, professional antigen presenting cells (APCs), especially dendritic cells (DCs), is likewise carried out by common methods, e.g. by means of electroporation or chemical methods, especially lipofection, preferably only by administration of the inventive composition without further transfection reagents.
- APCs professional antigen presenting cells
- DCs dendritic cells
- RNA as defined herein particularly the at least one (m)RNA, complexed with a cationic or polycationic compound, and the at least one free mRNA, encoding at least one therapeutically active protein, antigen and/or antibody, respectively, used for the in vitro transfection according to step (b) is prepared by methods known to those skilled in the art, especially by chemical synthesis or particularly preferably by means of molecular biological methods which have already been mentioned above.
- an organism typically means mammals, selected from, without being restricted thereto, the group comprising humans, and animals, including e.g.
- living tissues as mentioned above, are preferably derived from these organisms.
- Administration of the transfected cells to those living tissues and/or organisms may occur via any suitable administration route, e.g. systemically, and include e.g. intra- or transdermal, oral, parenteral, including subcutaneous, intramuscular or intravenous injections, topical and/or intranasal routes as defined above.
- the present invention also provides a method for the preparation of the inventive immunostimulatroy composition, comprising following steps: a) preparing an "adjuvant component" comprising or consisting of at least one (m)RNA as defined above, complexed with a cationic or polycationic compound, as defined above, preferably by mixing the at least one (m)RNA as defined above in a specific ratio with the cationic or polycationic compound, as defined above; and b) preparing the inventive immunostimulatory composition by adding in a specific ratio as defined above the at least one free mRNA as defined above to the adjuvant component prepared according to step a), wherein the at least one free mRNA as defined above, encodes at least one therapeutically active protein, antigen and/or antibody as defined above.
- the so called "adjuvant component” is prepared according to a step a) of the inventive method of preparation by complexing the at least one (m)RNA of the adjuvant component with a cationic or polycationic compound preferably in a specific ratio to form a stable complex.
- a cationic or polycationic compound preferably in a specific ratio to form a stable complex.
- the ratio of the (m)RNA and the cationic or polycationic compound in the adjuvant component is typically selected such that the (m)RNA is entirely complexed and no free cationic or polycationic compound or only a neclectably small amount remains in the composition.
- the ratio of the adjuvant component i.e. the ratio of the (m)RNA to the cationic or polycationic compound is selected in a range of about
- the ratio of the first component i.e. the adjuvant component comprising or consisting of at least one (m)RNA complexed with a cationic or polycationic compound
- the second component i.e. the at least one free mRNA
- N/P-ratio nitrogen/phosphate ratio
- an N/P-ratio is preferably in the range of about 0.1 -10, preferably in a range of about 0.3-4 and most preferably in a range of about 0.5-2 or 0.7-2 regarding the ratio of RNA:peptide in the complex, and most preferably in the range of about 0.7-1.5.
- the ratio of the first component (i.e. the adjuvant component comprising or consisting of at least one (m)RNA complexed with a cationic or polycationic compound) and the second component (i.e. the at least one free mRNA) may also be selected in the inventive immunostimulatory composition on the basis of the molar ratio of both RNAs to each other, i.e. the (m)RNA of the adjuvant component, being complexed with a cationic or polycationic compound) and the at least one free mRNA of the second component.
- the molar ratio of the (m)RNA of the adjuvant component to the at least one free mRNA of the second component may be selected such, that the molar ratio suffices the above (w/w) and/or N/P-definitions. More preferably, the molar ratio of the (m)RNA of the adjuvant component to the at least one free mRNA of the second component may be selected e.g. from a molar ratio of as defined above, e.g.
- the molar ratio of the (m)RNA of the adjuvant component to the at least one free mRNA of the second component may be selected e.g. from a range of about 0.01 :1 to 1 :0.01 .
- the molar ratio of the (m)RNA of the adjuvant component to the at least one free mRNA of the second component may be selected e.g. from a molar ratio of about 1 :1.
- any of the above definitions with regard to (w/w) and/or N/P ratio may also apply.
- the cationic or polycationic compound is preferably selected from a cationic or polycationic compound as defined above, suitable for complexing and thereby stabilizing a nucleic acid, particularly an (m)RNA, e.g. by associating the nucleic acid with the cationic or polycationic compound.
- Association or complexing the modified (m)RNA of the inventive immunostimulatory composition with cationic or polycationic compounds as defined above preferably provides adjuvant properties to the (m)RNA and confers a stabilizing effect to the (m)RNA of the adjuvant component by complexation.
- the procedure for stabilizing the modified (m)RNA is in general described in EP-A-1083232, the disclosure of which is incorporated by reference into the present invention in its entirety, but also may be carried out by any suitable procedure known in the art.
- the inventive immunostimulatory composition is obtained by adding in a specific ratio an at least one free mRNA as defined above to the adjuvant component prepared according to step a), wherein the at least one free mRNA as defined above encodes at least one therapeutically active protein, antigen and/or antibody, as defined above.
- the ratio of the adjuvant component (comprising at least one (m)RNA complexed with a cationic or polycationic compound) and the second component (at least one free mRNA) in the inventive immunostimulatory composition may be selected according to the specific requirements of a particular therapy, e.g.
- the ratio of the adjuvant component and the second component of the inventive immunostimulatory composition is selected such that a significant stimulation of the innate immune system is elicited due to the adjuvant component.
- the ratio is selected such that a significant amount of the at least one free mRNA can be provided in vivo leading to an efficient translation of the expressed protein in vivo.
- the ratio of adjuvant component : free mRNA in the inventive immunostimulatory composition is selected from a range as defined above, e.g.
- the ratio of adjuvant component : free mRNA in the inventive immunostimulatory composition is selected from a ratio of about 1 :1 (w/w).
- kits particularly kits of parts, comprising as components alone or in combination, the inventive immunostimulatroy composition or its components, i.e. the at least one (m)RNA, complexed with a cationic or polycationic compound, and the at least one free mRNA, encoding at least one therapeutically active protein, antigen and/or antibody, respectively, and/or an inventive pharmaceutical composition or vaccine, and optionally technical instructions with information on the administration and dosage of these components.
- kits preferably kits of parts, may be applied, e.g., for any of the above mentioned applications or uses.
- Figure 1 depicts the results of the expression of luciferase after intradermal injection of mRNA encoding luciferase in vivo, wherein a composition comprising an amount of 10 ⁇ g free mRNA coding for luciferase (Pp Luc) with or without combination with LacZ-mRNA (wt LacZ) complexed with protamine (2:1 and 1 :1 ) were prepared and injected intradermal Iy into the ear pinna.
- LacZ-mRNA:protamine complexes which have been formulated in a ratio of 1 :1 or 2:1 , respectively, had no negative influence on the expression of luciferase, i.e.
- Figure 2 shows the results of a vaccination reaction in the E.G7-OVA-model for therapeutic purposes.
- 300,000 E.G7-OVA tumor cells were implanted in C57 BL/6 mice and the mice were vaccinated 8 times within 2 weeks with the inventive immunostimulatory composition comprising 20 ⁇ g GC-enriched mRNA coding for Gallus gallus Ovalbumin.
- RNA was used, which was entirely complexed with protamine in a ratio of 3:1 or an RNA, wherein the complexed RNA was mixed with free RNA in a ratio of 1 :1 , 1 :4 and 1 :8 (w/w).
- free RNA as well as protamine alone do not exhibit any effect on tumor growth in comparison to the buffer control (Ringer-lactate solution).
- a vaccination with a protamine complexed RNA in a ratio of 3:1 (RNA:protamine) significantly reduces tumor growth.
- Figure 3 describes the results of a vaccination reaction in the E.G7-OVA-model for therapeutic purposes similar to the Experiment in Figure 2.
- an RNA was used, which was entirely complexed with protamine in a ratio of 3:1 or an RNA according to an improved protocol, wherein the complexed RNA was mixed with free RNA in a ratio of RNA:protamine 3:1 + free RNA (1 :1 )).
- the combination of complexed RNA and free RNA leads to an improved tumor defense.
- Figure 4 shows the statistical (mathematical) analysis of the experiment according to
- Figure 4 particularly shows that the difference between the groups are significant.
- the statistical (mathematical) analysis was carried out with the GraphPad Prism Software and the p values were determined using the Mann Whitney test. The analysis underlines the results shown in Figure 3.
- Figure 5 depicts the results of the detection of immunostimulatory properties and the stimulation of hPBMC with mRNA (CAP-GgOva(GQ-muag-A70-C30).
- mRNA CAP-GgOva(GQ-muag-A70-C30).
- 2 x 10 5 hPBMCs were seeded in 200 ⁇ l medium per well in 96 well plates and 50 ⁇ l of the inventive composition, comprising 10 ⁇ g mRNA coding for Gallus gallus ovalbumin were added to stimulate cytokine release over night at 37°C.
- Figure 6 describes the results of the induction of a humoral immune response in vivo, wherein C57 BL/6 mice were vacinated 8-times with each 16 ⁇ g GC- enrichen mRNA (CAP-GgOva(GC)-muag-A70-C30) coding for Gallus gallus Ovalbumine or an "irrelevant" control RNA (pB-Luc RNA).
- CAP-GgOva(GC)-muag-A70-C30 16 ⁇ g GC- enrichen mRNA
- pB-Luc RNA an "irrelevant" control RNA
- Figure 6 shows the combination of a complexed RNA with a free RNA, particularly in a ratio of (1 :1 ) leads to an elevated humoral immune response compared to the vaccination with an entirely complexed RNA.
- Figure 7 shows the mRNA sequence according to SEQ ID NO: 120, which exhibits a length of 1365 nuclotides and was termed "CAP-GgOva(GC)-muag-A70- C30".
- the mRNA sequence CAP-GgOva(GC)-muag-A70-C30 contained following sequence elements:
- muag mutated alpha-globin-3'-UTR 70 x adenosine at the 3'-terminal end (poly-A-tail), 30 x cytosine at the 3'- terminal end (poly-C-tail).
- the ORF is indicated in italic letters, muag (mutated alpha-globin-3'-UTR is indicated with a dotted line, the poly-A-tail is underlined with a single line and the poly-C-tail is underlined with a double line.
- Figure 8 depicts the mRNA sequence according to SEQ ID NO: 121 , which exhibits a length of 1816 nucleotides and was termed "T7TS-Ppluc(wt)-A70".
- the coding sequence (CDS) of the entire mRNA sequence is indicated in italic letters, the poly-A-tail is underlined with a single line.
- Figure 9 shows the statistical analysis of the expression of luciferase in Balb/c mice. The statistical analysis was carried out with the GraphPad Prism Software and the p values were determined using the Mann Whitney test. The results in Figure 9 show that the RNA complexed according to the invention (2:1 (50%) + free (50%) exhibits the same expression when compared to naked RNA and RNA which is complexed in the ratio of 4:1 with protamine. As can be seen, differences between the relevant groups are not significant (ns).
- an immune stimulation can be efficiently provided with the inventive complexed RNA wherein expression level is maintained compared to naked RNA and RNA which is complexed in the ratio of 4:1 with protamine (see als Figure 10).
- Figure 10 depicts the statistical analysis of induction of IL-12 in Balb/c mice. The statistical analysis was carried out with the GraphPad Prism Software and the p values were determined using the Mann Whitney test. The results show that the difference between the inventive complexed RNA (2:1 (50% + free (50%)) and the group 4:1 (100%) which comprises the same amount of RNA and protamine is significant. Thus, an immune stimulation can be efficiently provided with the inventive complexed RNA wherein expression level is maintained compared to naked RNA and RNA which is complexed in the ratio of 4:1 with protamine (see also Figure 9).
- Figure 1 1 shows the induction of lgG2a antibodies against the Influenza antigen hemagglutinin (HA). Therefore mice were vaccinated 2 times with 20 ⁇ g GC- enriched mRNA coding for hemagglutinin (HA) naked or formulated with protamine hydrochloride (Prot. VaI) or protamine sulphate (Prot. Leo) as indicated.
- protamine hydrochloride Prot. VaI
- Protamine sulphate Prot. Leo
- Figure 12 illustrates the induction of lgG2a-specific antibodies against the Influenza antigen HA over 15 weeks after immunization. Therefore mice were vaccinated 2 times with 20 ⁇ g GC-enriched mRNA coding for hemagglutinin (HA) naked or complexed with protamine (RNA:Protamine 2:1 + free RNA (1 :1 ) (w/w)) and lgG2a antibodies were measured at the indicated time points. Sera from different time points after immunization were analysed by
- Hemagglutinin-specific antibody titers of the lgG2a subtype are plotted for the groups treated with buffer (80% RiLa), naked or complexed HA mRNA.
- Figure 13 depicts the induction of antibodies against the influenza antigen HA by HAI assay. Therefore mice were vaccinated 2 times with 20 ⁇ g GC-enriched mRNA coding for hemagglutinin (HA) naked or formulated with protamine (RNA: Protamine 2:1 + free RNA (1 :1 ) (w/w)) and the HAI assay was performed at the indicated time points.
- HA hemagglutinin
- protamine RNA: Protamine 2:1 + free RNA (1 :1 ) (w/w)
- Figure 14 shows the mRNA sequence encoding the pathogenic antigen hemagglutinin (HA) from influenza virus.
- HA hemagglutinin
- GC-optimized sequence for a better codon usage and stabilization muag (mutated alpha-globin-3'-UTR) 70 x adenosine at the 3'-terminal end (poly-A-tail), 30 x cytosine at the 3'- terminal end (poly-C-tail).
- the recombinant plasmid DNA was linearized and subsequently in vitro transcribed using the T7 RNA polymerase.
- the DNA template was then degraded by DNAsel digestion.
- the RNA was recovered by LiCl precipitation and further cleaned by HPLC extraction (PUREMessenger ® , CureVac GmbH, Tubingen, Germany).
- Example 4 Making of the inventive composition:
- the mRNA used in the experiments below was complexed with protamine by addition of protamine to the mRNA in the indicated ratios (1 :1 -1 :4) (w/w). After incubation for 10 min, the free RNA was added.
- compositions comprising readily prepared mRNA:protamine complexes and/or free mRNA on the translation was investigated. Therefore, a composition comprising an amount of 10 ⁇ g free mRNA coding for luciferase (Pp Luc) with or without combination with LacZ-mRNA complexed with protamine (2:1 and 1 :1 ) were prepared and injected intradermal Iy into the ear pinna.
- the mRNA encoding Pp Luciferase was prepared as described above.
- the composition to be administered contained either no further complexed RNA, lacZ-mRNA:protamine in a concentration of 2:1 or lacZ-mRNA:protamine in a concentration of 1 :1 .
- a composition was administered containing no mRNA encoding Pp Luciferase (Photin ⁇ s pyra/is). Protamine was used as a control.
- lacZ- mRNA was formulated in a first step with protamine in different amounts and ratios (2:1 und 1 :1 (w/w)) and added as a first component. Then, free Pp Luc mRNA was added 10 minutes later to the composition.
- the ear pinna were removed and frozen in liquid nitrogen.
- the samples were placed in a TissueLyser for 3 min at 30 s "1 .
- 800 ⁇ l lysis-buffer 25 mM Tris-HCI pH (7.5 - 7.8); 2 mM EDTA; 10% (w/v) Glycerol; 1 % (w/v) Triton-X-100; 2 mM DTT; 1 mM PMSF
- samples are placed again in the TissueLyser for 6 min at 30 s '1 . Samples are centrifuged for 10 min at 13500 rpm and 4°C.
- the supernatant is removed and stored at -80 0 C until luciferase measurement.
- Supernatants were mixed with Luciferin Buffer (25 mM Glycylglycin, 15 mM MgSO 4 , 5 mM ATP, 62.5 ⁇ M Luciferin) and the luminescence was measured with a luminometer (Lumat LB 9507; Berthold Technologies, Bad Wildbad, Germany).
- LacZ-mRNA:protamine complexes which have been formulated in a ratio of 1 :1 or 2:1 , respectively, had no negative influence on the expression of luciferase, i.e. no free protamine was present in the solution or only a very small amount, which had no negative influence on the translation. Accordingly, no complex formation between protamine and ppLuc mRNA was possible, which indicates the stability of the already formed LacZ-mRNA:protamine complexes.
- Example 6 Vaccination in the E.G7-OVA-model for therapeutic purposes
- 300000 E.G7-OVA tumor cells were implanted in C57 BL/6 mice. In the following 3 weeks the mice were vaccinated 8 times within 3 weeks with the inventive composition comprising 20 ⁇ g GC-enriched mRNA coding for Gallus gallus Ovalbumine. The tumor size was measured 18 days after the implantation of the tumor cells.
- RNA was used, which was entirely complexed with protamine in a ratio of 3:1 or an RNA according to an improved protocol, wherein the complexed RNA was mixed with free RNA in a ratio of RNA:Protamin 3:1 + free RNA (1 :1 )).
- hPBMC were isolated by centrifugation on Ficoll (20 min at 2000 rpm) and subsequently washed two times in PBS. hPBMC were then resuspended in FCS, 10% DMSO at a density of 5 x 10 7 /ml. 1 ml aliquots were frozen and stored at -80 0 C.
- hPBMc Prior to the experiment, hPBMc were thawed by resuspending in PBS, followed by two washes in PBS. hPBMC were then suspended in X-Vivo 15, 1 % glutamine, 1 % Pen/Strep at a density of 1 x 10 6 / ml. After seeding hPBMCs at 2 x 10 5 per well in 96 well plates, 50 ⁇ l of the inventive composition, comprising 8 ⁇ g mRNA coding for Gallus gallus ovalbumin were added to stimulate cytokine release over night at 37°C.
- RNA encoding Callus gallus Ovalbumin (OVA)
- Ovalbumin complexed with protamine (3:1 ) plus 50% free RNA (formulated as follows: RNA:protamine 3:1 + free RNA (1 :1 ) (w/w)).
- cytokines TNFalpha and IL6
- TNFalpha and IL6 quantification Maxisorb plates were coated over night (4°C) with capture antibody (1 ⁇ g/ml) and subsequently blocked with 1 % BSA for 1 hour at room temperature (RT). After three washes with 0.05% Tween, 50 ⁇ l (TNF ⁇ ) or 50 ⁇ l (IL-6) hPBMC supernatant, adjusted with blocking buffer 15 to 100 ⁇ l, were added to the wells. Binding was allowed to proceed for two hours (RT). The plate was then washed and 100 ⁇ l streptavidin-conjugated horseradish peroxidise was added. After incubation for 30 minutes and washing a colorimetric substrate (TMB, Perbio Science) was added. Optical densities were measured at 450 nm using a Tecan ELISA plate reader. All incubations were performed at room temperature and washing steps include at least 3 steps using PBS/Tween20 (0.05% v/v).
- compositions comprising complexed and free RNA exhibit an immunostimulatory property, which is reflected by a significant secretion of TNFalpha and IL-6 in hPBMCs.
- Example 8 Induction of a humoral immune response
- mice were vacinated 8-times with each 16 ⁇ g GC-enriched mRNA coding for Gallus gallus Ovalbumine or an "irrelevant" control RNA (pB-Luc RNA).
- the RNA was either formulated entirely with protamine in a ratio of 2:1 or the ratio was according to an improved protocol RNA:Protamin 2:1 + tier RNA (1 :1 ) (w/w))). 2 weeks after the last vaccination blood samples were collected and expression of Ovalbumin-specific antibodies was determined.
- Example 9 Statistical analysis of the expression of luciferase in Balb/c mice.
- mice were injeceted on 4 different sites intradermal Iy with
- composition comprising Luc-RNA complexed with protamine in the ration 4:1 , (3) 100% free Luc-RNA, or
- Each sample comprised 10 ⁇ g mRNA coding for luciferase (Luc-RNA, i.e. the above described construct "T7TS-Ppluc(wt)-A70" according to SEQ ID NO: 121 ) in 50 ⁇ l Ringer- Lactate buffer.
- the first and the second group comprised also the same amount of protamine, but they were different formulated.
- the immunostimulatory composition of group (1 ) was prepared according to the invention. The results are shown in Figure 9.
- Figure 9 shows the statistical analysis of the expression of luciferase in Balb/c mice. The statistical analysis was carried out with the GraphPad Prism Software and the p values were determined using the Mann Whitney test.
- Figure 10 depicts the statistical analysis of induction of IL-12 in Balb/c mice according to Example 10. The statistical analysis was carried out with the GraphPad Prism Software and the p values were determined using the Mann Whitney test. The results show that the difference between the inventive immunostimulatory composition (2:1 (50%) + free (50%)) and the group 4:1 (100%), which comprises the same amount of RNA and protamine, is in fact significant. Thus, an immune stimulation can be efficiently provided with the inventive immunostimulatory composition wherein expression level is maintained compared to naked RNA and RNA, which is complexed in the ratio of 4:1 with protamine (see also Figure 9).
- Example 1 1 - Induction of a humoral immune response against a viral antigen
- RNA was either formulated entirely with protamine in a ratio of 2:1 or the ratio was according to the invention RNA:Protamin 2:1 + free RNA (1 :1 ) (w/w).
- protamine hydrochloride Protamin Valeant
- protamine sulphate Protamin LEO
- FIG. 1 1 The results of analysis of sera obtained two weeks after immunization are shown in Figure 1 1.
- Figure 1 1 the combination of a complexed RNA with free RNA leads to an elevated humoral immune response compared to the vaccination with an entirely complexed RNA.
- complexed RNA leads to higher lgG2a antibody titers, an indicator of the Th1 driven response.
- Complexation of RNA with protamine hydrochloride has a stronger effect than complexation with protamine sulphate.
- HAI assay Sera of immunized mice were also analysed by HAI assay. In an HAI assay, antibodies that neutralize the virus by blocking the interaction of the viral hemagglutinin and the sialic acid on the host cell are detected.
- Sera were inactivated at 56 0 C for 10 min to destroy complement and HAI inhibitors. Sera were further incubated with kaolin for 20 min and preadsorbed to chicken red blood cells for 30min to remove unspecific factors that influence hemagglutination. Pre-treated serum samples were added to a 96 well, U-bottom plate in serial dilution and duplicates. 25 ⁇ l containing 4 hemagglutinating units of inactivated PR8 in PBS and 50 ⁇ l of 0.5 % chicken red blood cells were then added and incubated at room temperature for 45 min. Endpoint HAI titers were defined as the reciprocal of the highest serum dilution that completely inhibited hemagglutination of the red blood cells.
- Titers of sera from different time points after immunization are plotted for the groups treated with buffer (80% RiLa), naked or complexed HA mRNA.
- the complexation was done with Protamin Valeant and the improved protocol RNA:Protamin 2:1 + free RNA (1 :1 ) (w/w).
- a titre of 40 is assumed to be protective in case of influenza infection. Mice immunized with complexed HA RNA show an enduring HAI titer of more than 40, whereas naked HA mRNA led to titers in average lower than the protective titer of 40.
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Immunology (AREA)
- Epidemiology (AREA)
- Mycology (AREA)
- Microbiology (AREA)
- Oncology (AREA)
- Cell Biology (AREA)
- Developmental Biology & Embryology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Molecular Biology (AREA)
- Vascular Medicine (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Inorganic Chemistry (AREA)
- Gynecology & Obstetrics (AREA)
- Genetics & Genomics (AREA)
- Pregnancy & Childbirth (AREA)
- Reproductive Health (AREA)
- Communicable Diseases (AREA)
- Virology (AREA)
- Tropical Medicine & Parasitology (AREA)
- Transplantation (AREA)
- Pulmonology (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
Claims
Priority Applications (17)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
BRPI0915844-8A BRPI0915844B1 (en) | 2008-09-30 | 2009-09-30 | COMPOSITION COMPRISING A COMPLEX (M)RNA AND A PURE MRNA FOR THE PROVISION OR INTENSIFICATION OF AN IMMUNOSTIMULATORY RESPONSE IN A MAMMALS AND USES THEREOF |
KR1020117001541A KR101343043B1 (en) | 2008-09-30 | 2009-09-30 | Composition comprising a complexed (m)RNA and a naked mRNA for providing or enhancing an immunostimulatory response in a mammal and uses thereof |
CN200980131936.5A CN102123733B (en) | 2008-09-30 | 2009-09-30 | For providing or strengthen the compositions comprising compound mRNA and naked mRNA and the application thereof of immunostimulatory response in mammal |
SI200930990T SI2331129T1 (en) | 2008-09-30 | 2009-09-30 | Composition comprising a complexed (m)rna and a naked mrna for providing or enhancing an immunostimulatory response in a mammal and uses thereof |
CA2730261A CA2730261C (en) | 2008-09-30 | 2009-09-30 | Composition comprising a complexed (m)rna and a naked mrna for providing or enhancing an immunostimulatory response in a mammal and uses thereof |
MX2010013071A MX2010013071A (en) | 2008-09-30 | 2009-09-30 | Composition comprising a complexed (m)rna and a naked mrna for providing or enhancing an immunostimulatory response in a mammal and uses thereof. |
US12/994,407 US9572874B2 (en) | 2008-09-30 | 2009-09-30 | Composition comprising a complexed (M)RNA and a naked mRNA for providing or enhancing an immunostimulatory response in a mammal and uses thereof |
EP09736823.7A EP2331129B1 (en) | 2008-09-30 | 2009-09-30 | Composition comprising a complexed (m)rna and a naked mrna for providing or enhancing an immunostimulatory response in a mammal and uses thereof |
RU2011116931/15A RU2545756C2 (en) | 2008-09-30 | 2009-09-30 | Composition containing complex (m)rna and free mrna for implementing or improving immunostimulatory response in mammals and using it |
JP2011526423A JP5859853B2 (en) | 2008-09-30 | 2009-09-30 | Compositions comprising complexed (m) RNA and naked mRNA for providing or enhancing an immune stimulating response in mammals and uses thereof |
PL09736823T PL2331129T3 (en) | 2008-09-30 | 2009-09-30 | Composition comprising a complexed (m)rna and a naked mrna for providing or enhancing an immunostimulatory response in a mammal and uses thereof |
DK09736823.7T DK2331129T3 (en) | 2008-09-30 | 2009-09-30 | COMPOSITION comprising a complex (M) RNA and a sufficient mRNA to provide or enhance an immunostimulatory response in a mammal and its uses |
AU2009300113A AU2009300113B2 (en) | 2008-09-30 | 2009-09-30 | Composition comprising a complexed (m)RNA and a naked mRNA for providing or enhancing an immunostimulatory response in a mammal and uses thereof |
ES09736823.7T ES2502915T3 (en) | 2008-09-30 | 2009-09-30 | Composition comprising a complex RNA (m) and a bare mRNA to provide or improve the immunostimulatory response in a mammal and uses thereof |
HRP20140763AT HRP20140763T1 (en) | 2008-09-30 | 2014-08-12 | Composition comprising a complexed (m)rna and a naked mrna for providing or enhancing an immunostimulatory response in a mammal and uses thereof |
US15/408,339 US20170202957A1 (en) | 2008-09-30 | 2017-01-17 | COMPOSITION COMPRISING A COMPLEXED (m)RNA AND A NAKED mRNA FOR PROVIDING OR ENHANCING AN IMMUNOSTIMULATORY RESPONSE IN A MAMMAL AND USES THEREOF |
US16/907,130 US20210046179A1 (en) | 2008-09-30 | 2020-06-19 | COMPOSITION COMPRISING A COMPLEXED (m)RNA AND A NAKED mRNA FOR PROVIDING OR ENHANCING AN IMMUNOSTIMULATORY RESPONSE IN A MAMMAL AND USES THEREOF |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
PCT/EP2008/008304 WO2010037408A1 (en) | 2008-09-30 | 2008-09-30 | Composition comprising a complexed (m)rna and a naked mrna for providing or enhancing an immunostimulatory response in a mammal and uses thereof |
EPPCT/EP2008/008304 | 2008-09-30 |
Related Child Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US12/994,407 A-371-Of-International US9572874B2 (en) | 2008-09-30 | 2009-09-30 | Composition comprising a complexed (M)RNA and a naked mRNA for providing or enhancing an immunostimulatory response in a mammal and uses thereof |
US15/408,339 Continuation US20170202957A1 (en) | 2008-09-30 | 2017-01-17 | COMPOSITION COMPRISING A COMPLEXED (m)RNA AND A NAKED mRNA FOR PROVIDING OR ENHANCING AN IMMUNOSTIMULATORY RESPONSE IN A MAMMAL AND USES THEREOF |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2010037539A1 true WO2010037539A1 (en) | 2010-04-08 |
Family
ID=40685915
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/EP2008/008304 WO2010037408A1 (en) | 2008-09-30 | 2008-09-30 | Composition comprising a complexed (m)rna and a naked mrna for providing or enhancing an immunostimulatory response in a mammal and uses thereof |
PCT/EP2009/007032 WO2010037539A1 (en) | 2008-09-30 | 2009-09-30 | Composition comprising a complexed (m)rna and a naked mrna for providing or enhancing an immunostimulatory response in a mammal and uses thereof |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/EP2008/008304 WO2010037408A1 (en) | 2008-09-30 | 2008-09-30 | Composition comprising a complexed (m)rna and a naked mrna for providing or enhancing an immunostimulatory response in a mammal and uses thereof |
Country Status (17)
Country | Link |
---|---|
US (3) | US9572874B2 (en) |
EP (2) | EP2331129B1 (en) |
JP (2) | JP5859853B2 (en) |
KR (1) | KR101343043B1 (en) |
CN (1) | CN102123733B (en) |
AU (1) | AU2009300113B2 (en) |
BR (1) | BRPI0915844B1 (en) |
CA (1) | CA2730261C (en) |
DK (1) | DK2331129T3 (en) |
ES (1) | ES2502915T3 (en) |
HR (1) | HRP20140763T1 (en) |
MX (1) | MX2010013071A (en) |
PL (1) | PL2331129T3 (en) |
PT (1) | PT2331129E (en) |
RU (1) | RU2545756C2 (en) |
SI (1) | SI2331129T1 (en) |
WO (2) | WO2010037408A1 (en) |
Cited By (177)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP2216028A2 (en) | 2002-07-03 | 2010-08-11 | CureVac GmbH | Immunostimulation by chemically modified RNA |
US8216582B2 (en) | 2006-06-23 | 2012-07-10 | Alethia Biotherapeutics Inc. | Polynucleotides and polypeptide sequences involved in cancer |
EP2548960A1 (en) * | 2008-01-31 | 2013-01-23 | CureVac GmbH | Nucleic acids comprising formula (NuGIXmGnNv)a and derivatives thereof as an immunostimulating agents/adjuvant |
WO2013113502A1 (en) | 2012-01-31 | 2013-08-08 | Curevac Gmbh | Negatively charged nucleic acid comprising complexes for immunostimulation |
WO2013143683A1 (en) | 2012-03-26 | 2013-10-03 | Biontech Ag | Rna formulation for immunotherapy |
US8580257B2 (en) | 2008-11-03 | 2013-11-12 | Alethia Biotherapeutics Inc. | Antibodies that specifically block the biological activity of kidney associated antigen 1 (KAAG1) |
US8664194B2 (en) | 2011-12-16 | 2014-03-04 | Moderna Therapeutics, Inc. | Method for producing a protein of interest in a primate |
JP2014508152A (en) * | 2011-02-09 | 2014-04-03 | キュアバック ゲーエムベーハー | Vaccination in newborns and infants |
JP2014508153A (en) * | 2011-03-02 | 2014-04-03 | キュアバック ゲーエムベーハー | Vaccination in elderly patients |
US8710200B2 (en) | 2011-03-31 | 2014-04-29 | Moderna Therapeutics, Inc. | Engineered nucleic acids encoding a modified erythropoietin and their expression |
US20140186398A1 (en) * | 2011-07-18 | 2014-07-03 | Icahn School Of Medicine At Mount Sinai | BACTERIAL RNAs AS VACCINE ADJUVANTS |
US8822663B2 (en) | 2010-08-06 | 2014-09-02 | Moderna Therapeutics, Inc. | Engineered nucleic acids and methods of use thereof |
US8937163B2 (en) | 2011-03-31 | 2015-01-20 | Alethia Biotherapeutics Inc. | Antibodies against kidney associated antigen 1 and antigen binding fragments thereof |
US8940298B2 (en) | 2007-09-04 | 2015-01-27 | The Regents Of The University Of California | High affinity anti-prostate stem cell antigen (PSCA) antibodies for cancer targeting and detection |
US8940871B2 (en) | 2006-03-20 | 2015-01-27 | The Regents Of The University Of California | Engineered anti-prostate stem cell antigen (PSCA) antibodies for cancer targeting |
US8968746B2 (en) | 2010-07-30 | 2015-03-03 | Curevac Gmbh | Complexation of nucleic acids with disulfide-crosslinked cationic components for transfection and immunostimulation |
US8980864B2 (en) | 2013-03-15 | 2015-03-17 | Moderna Therapeutics, Inc. | Compositions and methods of altering cholesterol levels |
US8999380B2 (en) | 2012-04-02 | 2015-04-07 | Moderna Therapeutics, Inc. | Modified polynucleotides for the production of biologics and proteins associated with human disease |
WO2015101415A1 (en) | 2013-12-30 | 2015-07-09 | Curevac Gmbh | Artificial nucleic acid molecules |
WO2015101414A2 (en) | 2013-12-30 | 2015-07-09 | Curevac Gmbh | Artificial nucleic acid molecules |
US9107886B2 (en) | 2012-04-02 | 2015-08-18 | Moderna Therapeutics, Inc. | Modified polynucleotides encoding basic helix-loop-helix family member E41 |
WO2015149944A3 (en) * | 2014-04-01 | 2015-11-26 | Curevac Ag | Polymeric carrier cargo complex for use as an immunostimulating agent or as an adjuvant |
US9283287B2 (en) | 2012-04-02 | 2016-03-15 | Moderna Therapeutics, Inc. | Modified polynucleotides for the production of nuclear proteins |
US9314535B2 (en) | 2009-09-03 | 2016-04-19 | Curevac Ag | Disulfide-linked polyethyleneglycol/peptide conjugates for the transfection of nucleic acids |
US9334328B2 (en) | 2010-10-01 | 2016-05-10 | Moderna Therapeutics, Inc. | Modified nucleosides, nucleotides, and nucleic acids, and uses thereof |
US9421255B2 (en) | 2011-02-21 | 2016-08-23 | Curevac Ag | Vaccine composition comprising complexed immunostimulatory nucleic acids and antigens packaged with disulfide-linked polyethyleneglycol/peptide conjugates |
US9428535B2 (en) | 2011-10-03 | 2016-08-30 | Moderna Therapeutics, Inc. | Modified nucleosides, nucleotides, and nucleic acids, and uses thereof |
US9464124B2 (en) | 2011-09-12 | 2016-10-11 | Moderna Therapeutics, Inc. | Engineered nucleic acids and methods of use thereof |
WO2016165831A1 (en) | 2015-04-17 | 2016-10-20 | Curevac Ag | Lyophilization of rna |
WO2016170176A1 (en) | 2015-04-22 | 2016-10-27 | Curevac Ag | Rna containing composition for treatment of tumor diseases |
EP2101823B1 (en) | 2007-01-09 | 2016-11-23 | CureVac AG | Rna-coded antibody |
WO2016184822A1 (en) | 2015-05-15 | 2016-11-24 | Curevac Ag | Prime-boost regimens involving administration of at least one mrna construct |
US9572897B2 (en) | 2012-04-02 | 2017-02-21 | Modernatx, Inc. | Modified polynucleotides for the production of cytoplasmic and cytoskeletal proteins |
US9572874B2 (en) | 2008-09-30 | 2017-02-21 | Curevac Ag | Composition comprising a complexed (M)RNA and a naked mRNA for providing or enhancing an immunostimulatory response in a mammal and uses thereof |
US9597380B2 (en) | 2012-11-26 | 2017-03-21 | Modernatx, Inc. | Terminally modified RNA |
WO2017049245A2 (en) | 2015-09-17 | 2017-03-23 | Modernatx, Inc. | Compounds and compositions for intracellular delivery of therapeutic agents |
EP2680881B1 (en) | 2011-03-02 | 2017-04-05 | CureVac AG | Vaccination in elderly patients |
WO2017066782A1 (en) | 2015-10-16 | 2017-04-20 | Modernatx, Inc. | Hydrophobic mrna cap analogs |
WO2017066789A1 (en) | 2015-10-16 | 2017-04-20 | Modernatx, Inc. | Mrna cap analogs with modified sugar |
WO2017066791A1 (en) | 2015-10-16 | 2017-04-20 | Modernatx, Inc. | Sugar substituted mrna cap analogs |
WO2017066793A1 (en) | 2015-10-16 | 2017-04-20 | Modernatx, Inc. | Mrna cap analogs and methods of mrna capping |
WO2017066781A1 (en) | 2015-10-16 | 2017-04-20 | Modernatx, Inc. | Mrna cap analogs with modified phosphate linkage |
WO2017112865A1 (en) | 2015-12-22 | 2017-06-29 | Modernatx, Inc. | Compounds and compositions for intracellular delivery of agents |
WO2017070616A3 (en) * | 2015-10-22 | 2017-07-27 | Modernatx, Inc. | Sexually transmitted disease vaccines |
US9796762B2 (en) | 2013-04-10 | 2017-10-24 | 4D Pharma Research Limited | Polypeptide and immune modulation |
WO2017182634A1 (en) | 2016-04-22 | 2017-10-26 | Curevac Ag | Rna encoding a tumor antigen |
WO2017191274A2 (en) | 2016-05-04 | 2017-11-09 | Curevac Ag | Rna encoding a therapeutic protein |
WO2017191264A1 (en) | 2016-05-04 | 2017-11-09 | Curevac Ag | Nucleic acid molecules and uses thereof |
WO2017218704A1 (en) | 2016-06-14 | 2017-12-21 | Modernatx, Inc. | Stabilized formulations of lipid nanoparticles |
WO2018033254A2 (en) | 2016-08-19 | 2018-02-22 | Curevac Ag | Rna for cancer therapy |
WO2018041921A1 (en) | 2016-08-31 | 2018-03-08 | Curevac Ag | Mixing device for the production of a liquid nucleic acid composition |
US9937211B2 (en) | 2011-10-07 | 2018-04-10 | 4D Pharma Research Limited | Composition of Roseburia hominis |
WO2018078053A1 (en) | 2016-10-26 | 2018-05-03 | Curevac Ag | Lipid nanoparticle mrna vaccines |
WO2018089540A1 (en) | 2016-11-08 | 2018-05-17 | Modernatx, Inc. | Stabilized formulations of lipid nanoparticles |
WO2018104540A1 (en) | 2016-12-08 | 2018-06-14 | Curevac Ag | Rnas for wound healing |
WO2018104538A1 (en) | 2016-12-08 | 2018-06-14 | Curevac Ag | Rna for treatment or prophylaxis of a liver disease |
WO2018115525A1 (en) | 2016-12-23 | 2018-06-28 | Curevac Ag | Lassa virus vaccine |
WO2018115527A2 (en) | 2016-12-23 | 2018-06-28 | Curevac Ag | Mers coronavirus vaccine |
WO2018115507A2 (en) | 2016-12-23 | 2018-06-28 | Curevac Ag | Henipavirus vaccine |
RU2662962C2 (en) * | 2012-09-25 | 2018-07-31 | Джензим Корпорейшн | Peptide-linked morpholino antisense oligonucleotides for treatment of myotonic dystrophy |
WO2018144082A1 (en) * | 2017-02-01 | 2018-08-09 | Modernatx, Inc. | Rna cancer vaccines |
US10064935B2 (en) | 2015-10-22 | 2018-09-04 | Modernatx, Inc. | Human cytomegalovirus RNA vaccines |
US10064934B2 (en) | 2015-10-22 | 2018-09-04 | Modernatx, Inc. | Combination PIV3/hMPV RNA vaccines |
WO2018167320A1 (en) | 2017-03-17 | 2018-09-20 | Curevac Ag | Rna vaccine and immune checkpoint inhibitors for combined anticancer therapy |
WO2018170306A1 (en) | 2017-03-15 | 2018-09-20 | Modernatx, Inc. | Compounds and compositions for intracellular delivery of therapeutic agents |
WO2018170336A1 (en) | 2017-03-15 | 2018-09-20 | Modernatx, Inc. | Lipid nanoparticle formulation |
WO2018172556A1 (en) | 2017-03-24 | 2018-09-27 | Curevac Ag | Nucleic acids encoding crispr-associated proteins and uses thereof |
US10111967B2 (en) | 2007-09-04 | 2018-10-30 | Curevac Ag | Complexes of RNA and cationic peptides for transfection and for immunostimulation |
US10124055B2 (en) | 2015-10-22 | 2018-11-13 | Modernatx, Inc. | Zika virus RNA vaccines |
WO2018232120A1 (en) | 2017-06-14 | 2018-12-20 | Modernatx, Inc. | Compounds and compositions for intracellular delivery of agents |
EP3424524A2 (en) | 2017-07-04 | 2019-01-09 | CureVac AG | Cancer rna-vaccine |
EP3427723A1 (en) * | 2012-03-26 | 2019-01-16 | BioNTech RNA Pharmaceuticals GmbH | Rna formulation for immunotherapy |
WO2019036638A1 (en) | 2017-08-18 | 2019-02-21 | Modernatx, Inc. | Methods of preparing modified rna |
WO2019038332A1 (en) | 2017-08-22 | 2019-02-28 | Curevac Ag | Bunyavirales vaccine |
WO2019046809A1 (en) | 2017-08-31 | 2019-03-07 | Modernatx, Inc. | Methods of making lipid nanoparticles |
EP3461498A1 (en) | 2013-08-21 | 2019-04-03 | CureVac AG | Rabies vaccine |
WO2019077001A1 (en) | 2017-10-19 | 2019-04-25 | Curevac Ag | Novel artificial nucleic acid molecules |
US10273269B2 (en) | 2017-02-16 | 2019-04-30 | Modernatx, Inc. | High potency immunogenic zika virus compositions |
WO2019092153A1 (en) | 2017-11-08 | 2019-05-16 | Curevac Ag | Rna sequence adaptation |
EP3494982A1 (en) | 2014-12-30 | 2019-06-12 | CureVac AG | Artificial nucleic acid molecules |
EP3495486A1 (en) | 2013-12-30 | 2019-06-12 | CureVac AG | Artificial nucleic acid molecules |
US10322151B2 (en) | 2015-06-15 | 2019-06-18 | 4D Pharma Research Limited | Compositions comprising bacterial strains |
US10323076B2 (en) | 2013-10-03 | 2019-06-18 | Modernatx, Inc. | Polynucleotides encoding low density lipoprotein receptor |
WO2019115635A1 (en) | 2017-12-13 | 2019-06-20 | Curevac Ag | Flavivirus vaccine |
EP2714071B1 (en) | 2011-05-24 | 2019-07-10 | BioNTech RNA Pharmaceuticals GmbH | Individualized vaccines for cancer |
US10391128B2 (en) | 2015-11-23 | 2019-08-27 | 4D Pharma Research Limited | Compositions comprising bacterial strains |
US10391130B2 (en) | 2015-06-15 | 2019-08-27 | 4D Pharma Research Limited | Compositions comprising bacterial strains |
WO2019193183A2 (en) | 2018-04-05 | 2019-10-10 | Curevac Ag | Novel yellow fever nucleic acid molecules for vaccination |
US10449244B2 (en) | 2015-07-21 | 2019-10-22 | Modernatx, Inc. | Zika RNA vaccines |
US10456444B2 (en) | 2014-12-23 | 2019-10-29 | 4D Pharma Research Limited | Pirin polypeptide and immune modulation |
US10471108B2 (en) | 2015-11-20 | 2019-11-12 | 4D Pharma Research Limited | Compositions comprising bacterial strains |
US10485830B2 (en) | 2016-12-12 | 2019-11-26 | 4D Pharma Plc | Compositions comprising bacterial strains |
US10493112B2 (en) | 2015-06-15 | 2019-12-03 | 4D Pharma Research Limited | Compositions comprising bacterial strains |
US10500237B2 (en) | 2015-06-15 | 2019-12-10 | 4D Pharma Research Limited | Compositions comprising bacterial strains |
EP3586871A2 (en) | 2013-08-21 | 2020-01-01 | CureVac AG | Respiratory syncytial virus (rsv) vaccine |
WO2020002525A1 (en) | 2018-06-27 | 2020-01-02 | Curevac Ag | Novel lassa virus rna molecules and compositions for vaccination |
US10583158B2 (en) | 2016-03-04 | 2020-03-10 | 4D Pharma Plc | Compositions comprising bacterial strains |
WO2020061457A1 (en) | 2018-09-20 | 2020-03-26 | Modernatx, Inc. | Preparation of lipid nanoparticles and methods of administration thereof |
WO2020061367A1 (en) | 2018-09-19 | 2020-03-26 | Modernatx, Inc. | Compounds and compositions for intracellular delivery of therapeutic agents |
US10610548B2 (en) | 2016-07-13 | 2020-04-07 | 4D Pharma Plc | Compositions comprising bacterial strains |
US10610550B2 (en) | 2015-11-20 | 2020-04-07 | 4D Pharma Research Limited | Compositions comprising bacterial strains |
US10653767B2 (en) | 2017-09-14 | 2020-05-19 | Modernatx, Inc. | Zika virus MRNA vaccines |
WO2020128031A2 (en) | 2018-12-21 | 2020-06-25 | Curevac Ag | Rna for malaria vaccines |
US10695419B2 (en) | 2016-10-21 | 2020-06-30 | Modernatx, Inc. | Human cytomegalovirus vaccine |
WO2020160430A1 (en) | 2019-01-31 | 2020-08-06 | Modernatx, Inc. | Vortex mixers and associated methods, systems, and apparatuses thereof |
WO2020160397A1 (en) | 2019-01-31 | 2020-08-06 | Modernatx, Inc. | Methods of preparing lipid nanoparticles |
US10736926B2 (en) | 2015-06-15 | 2020-08-11 | 4D Pharma Research Limited | Compositions comprising bacterial strains |
US10738355B2 (en) | 2011-05-24 | 2020-08-11 | Tron-Translationale Onkologie An Der Universitätsmedizin Der Johannes Gutenberg-Universität Mainz Ggmbh | Individualized vaccines for cancer |
WO2020161342A1 (en) | 2019-02-08 | 2020-08-13 | Curevac Ag | Coding rna administered into the suprachoroidal space in the treatment of ophtalmic diseases |
US10744166B2 (en) | 2015-11-23 | 2020-08-18 | 4D Pharma Research Limited | Compositions comprising bacterial strains |
EP3701963A1 (en) | 2015-12-22 | 2020-09-02 | CureVac AG | Method for producing rna molecule compositions |
US10815291B2 (en) | 2013-09-30 | 2020-10-27 | Modernatx, Inc. | Polynucleotides encoding immune modulating polypeptides |
WO2020254535A1 (en) | 2019-06-18 | 2020-12-24 | Curevac Ag | Rotavirus mrna vaccine |
CN112194719A (en) * | 2020-09-01 | 2021-01-08 | 中日友好医院(中日友好临床医学研究所) | Preparation and application of CRT antigen and MAGE-A1 antigen |
US10987387B2 (en) | 2017-05-24 | 2021-04-27 | 4D Pharma Research Limited | Compositions comprising bacterial strain |
US11007233B2 (en) | 2017-06-14 | 2021-05-18 | 4D Pharma Research Limited | Compositions comprising a bacterial strain of the genus Megasphera and uses thereof |
US11013773B2 (en) | 2011-07-14 | 2021-05-25 | 4D Pharma Research Limited | Lactic acid bacterial strains |
EP3838294A1 (en) | 2012-01-31 | 2021-06-23 | CureVac AG | Negatively charged nucleic acid comprising complexes for immunostimulation |
WO2021123332A1 (en) | 2019-12-20 | 2021-06-24 | Curevac Ag | Lipid nanoparticles for delivery of nucleic acids |
US11084872B2 (en) | 2012-01-09 | 2021-08-10 | Adc Therapeutics Sa | Method for treating breast cancer |
WO2021156267A1 (en) | 2020-02-04 | 2021-08-12 | Curevac Ag | Coronavirus vaccine |
EP3019619B1 (en) | 2013-07-11 | 2021-08-25 | ModernaTX, Inc. | Compositions comprising synthetic polynucleotides encoding crispr related proteins and synthetic sgrnas and methods of use |
US11103578B2 (en) | 2016-12-08 | 2021-08-31 | Modernatx, Inc. | Respiratory virus nucleic acid vaccines |
US11123379B2 (en) | 2017-06-14 | 2021-09-21 | 4D Pharma Research Limited | Compositions comprising bacterial strains |
US11123378B2 (en) | 2017-05-22 | 2021-09-21 | 4D Pharma Research Limited | Compositions comprising bacterial strains |
WO2021204179A1 (en) | 2020-04-09 | 2021-10-14 | Suzhou Abogen Biosciences Co., Ltd. | Nucleic acid vaccines for coronavirus |
WO2021204175A1 (en) | 2020-04-09 | 2021-10-14 | Suzhou Abogen Biosciences Co., Ltd. | Lipid nanoparticle composition |
EP3916091A2 (en) | 2015-05-20 | 2021-12-01 | CureVac AG | Dry powder composition comprising long-chain rna |
WO2021239880A1 (en) | 2020-05-29 | 2021-12-02 | Curevac Ag | Nucleic acid based combination vaccines |
EP3134131B1 (en) | 2014-04-23 | 2021-12-22 | ModernaTX, Inc. | Nucleic acid vaccines |
EP3928800A2 (en) | 2015-05-20 | 2021-12-29 | CureVac AG | Dry powder composition comprising long-chain rna |
WO2022002040A1 (en) | 2020-06-30 | 2022-01-06 | Suzhou Abogen Biosciences Co., Ltd. | Lipid compounds and lipid nanoparticle compositions |
US11224620B2 (en) | 2016-07-13 | 2022-01-18 | 4D Pharma Plc | Compositions comprising bacterial strains |
DE202015009961U1 (en) | 2014-12-12 | 2022-01-25 | Curevac Ag | Artificial nucleic acid molecules for improved protein expression |
WO2022037652A1 (en) | 2020-08-20 | 2022-02-24 | Suzhou Abogen Biosciences Co., Ltd. | Lipid compounds and lipid nanoparticle compositions |
WO2022043551A2 (en) | 2020-08-31 | 2022-03-03 | Curevac Ag | Multivalent nucleic acid based coronavirus vaccines |
US20220152193A1 (en) * | 2013-08-21 | 2022-05-19 | Curevac Ag | Combination vaccine |
US11351242B1 (en) | 2019-02-12 | 2022-06-07 | Modernatx, Inc. | HMPV/hPIV3 mRNA vaccine composition |
US11364292B2 (en) | 2015-07-21 | 2022-06-21 | Modernatx, Inc. | CHIKV RNA vaccines |
US11364259B2 (en) | 2016-12-27 | 2022-06-21 | The University Of Tokyo | MRNA functionalization method |
WO2022152109A2 (en) | 2021-01-14 | 2022-07-21 | Suzhou Abogen Biosciences Co., Ltd. | Lipid compounds and lipid nanoparticle compositions |
WO2022152141A2 (en) | 2021-01-14 | 2022-07-21 | Suzhou Abogen Biosciences Co., Ltd. | Polymer conjugated lipid compounds and lipid nanoparticle compositions |
EP4035659A1 (en) | 2016-11-29 | 2022-08-03 | PureTech LYT, Inc. | Exosomes for delivery of therapeutic agents |
WO2022162027A2 (en) | 2021-01-27 | 2022-08-04 | Curevac Ag | Method of reducing the immunostimulatory properties of in vitro transcribed rna |
US11406703B2 (en) | 2020-08-25 | 2022-08-09 | Modernatx, Inc. | Human cytomegalovirus vaccine |
WO2022233880A1 (en) | 2021-05-03 | 2022-11-10 | Curevac Ag | Improved nucleic acid sequence for cell type specific expression |
US11497807B2 (en) | 2017-03-17 | 2022-11-15 | Modernatx, Inc. | Zoonotic disease RNA vaccines |
WO2022247755A1 (en) | 2021-05-24 | 2022-12-01 | Suzhou Abogen Biosciences Co., Ltd. | Lipid compounds and lipid nanoparticle compositions |
EP4066855B1 (en) | 2010-08-31 | 2022-12-28 | GlaxoSmithKline Biologicals SA | Pegylated liposomes for delivery of immunogen-encoding rna |
EP4108774A1 (en) | 2015-08-28 | 2022-12-28 | CureVac AG | Artificial nucleic acid molecules |
EP4043040B1 (en) | 2010-08-31 | 2023-01-11 | GlaxoSmithKline Biologicals SA | Small liposomes for delivery of immunogen-encoding rna |
WO2023006999A2 (en) | 2021-07-30 | 2023-02-02 | CureVac SE | Mrnas for treatment or prophylaxis of liver diseases |
WO2023031392A2 (en) | 2021-09-03 | 2023-03-09 | CureVac SE | Novel lipid nanoparticles for delivery of nucleic acids comprising phosphatidylserine |
WO2023031394A1 (en) | 2021-09-03 | 2023-03-09 | CureVac SE | Novel lipid nanoparticles for delivery of nucleic acids |
WO2023044333A1 (en) | 2021-09-14 | 2023-03-23 | Renagade Therapeutics Management Inc. | Cyclic lipids and methods of use thereof |
WO2023044343A1 (en) | 2021-09-14 | 2023-03-23 | Renagade Therapeutics Management Inc. | Acyclic lipids and methods of use thereof |
EP4162950A1 (en) | 2021-10-08 | 2023-04-12 | Suzhou Abogen Biosciences Co., Ltd. | Nucleic acid vaccines for coronavirus |
WO2023056914A1 (en) | 2021-10-08 | 2023-04-13 | Suzhou Abogen Biosciences Co., Ltd. | Lipid compounds and lipid nanoparticle compositions |
WO2023056917A1 (en) | 2021-10-08 | 2023-04-13 | Suzhou Abogen Biosciences Co., Ltd. | Lipid compounds and lipid nanoparticle compositions |
WO2023116804A1 (en) | 2021-12-23 | 2023-06-29 | 苏州艾博生物科技有限公司 | Lipid compound and lipid nanoparticle composition |
WO2023122752A1 (en) | 2021-12-23 | 2023-06-29 | Renagade Therapeutics Management Inc. | Constrained lipids and methods of use thereof |
US11690910B2 (en) | 2012-01-31 | 2023-07-04 | CureVac SE | Pharmaceutical composition comprising a polymeric carrier cargo complex and at least one protein or peptide antigen |
WO2023144193A1 (en) | 2022-01-25 | 2023-08-03 | CureVac SE | Mrnas for treatment of hereditary tyrosinemia type i |
US11723933B2 (en) | 2014-12-23 | 2023-08-15 | Cj Bioscience, Inc. | Composition of bacteroides thetaiotaomicron for immune modulation |
EP4227319A1 (en) | 2018-04-17 | 2023-08-16 | CureVac SE | Novel rsv rna molecules and compositions for vaccination |
US11739125B2 (en) | 2013-08-21 | 2023-08-29 | Cure Vac SE | Respiratory syncytial virus (RSV) vaccine |
EP4233898A2 (en) | 2016-05-04 | 2023-08-30 | CureVac SE | Influenza mrna vaccines |
WO2023196931A1 (en) | 2022-04-07 | 2023-10-12 | Renagade Therapeutics Management Inc. | Cyclic lipids and lipid nanoparticles (lnp) for the delivery of nucleic acids or peptides for use in vaccinating against infectious agents |
US11814627B2 (en) * | 2016-06-20 | 2023-11-14 | The Board Of The Leland Stanford Junior University | Circular RNAs and their use in immunomodulation |
WO2024015803A2 (en) | 2022-07-11 | 2024-01-18 | Autonomous Therapeutics, Inc. | Encrypted rna and methods of its use |
WO2024037578A1 (en) | 2022-08-18 | 2024-02-22 | Suzhou Abogen Biosciences Co., Ltd. | Composition of lipid nanoparticles |
EP4353257A2 (en) | 2015-04-13 | 2024-04-17 | CureVac Manufacturing GmbH | Method for producing rna compositions |
US12048720B2 (en) | 2017-06-14 | 2024-07-30 | Cj Bioscience, Inc. | Compositions comprising bacterial strains |
US12070495B2 (en) | 2019-03-15 | 2024-08-27 | Modernatx, Inc. | HIV RNA vaccines |
WO2024192291A1 (en) | 2023-03-15 | 2024-09-19 | Renagade Therapeutics Management Inc. | Delivery of gene editing systems and methods of use thereof |
WO2024192277A2 (en) | 2023-03-15 | 2024-09-19 | Renagade Therapeutics Management Inc. | Lipid nanoparticles comprising coding rna molecules for use in gene editing and as vaccines and therapeutic agents |
US12109275B2 (en) | 2010-08-13 | 2024-10-08 | CureVac SE | Nucleic acid comprising or coding for a histone stem-loop and a poly(A) sequence or a polyadenylation signal for increasing the expression of an encoded protein |
Families Citing this family (139)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE102005023170A1 (en) * | 2005-05-19 | 2006-11-23 | Curevac Gmbh | Optimized formulation for mRNA |
WO2008014979A2 (en) | 2006-07-31 | 2008-02-07 | Curevac Gmbh | NUCLEIC ACID OF FORMULA (I): GIXmGn, OR (II): CIXmCn, IN PARTICULAR AS AN IMMUNE-STIMULATING AGENT/ADJUVANT |
EP2478922B1 (en) | 2007-02-19 | 2017-02-01 | Marine Polymer Technologies, Inc. | Hemostatic compositions and therapeutic regimens |
ES2460899T3 (en) | 2008-03-03 | 2014-05-14 | The University Of Miami | Immunotherapy based on allogenic cancer cells |
TR201901311T4 (en) | 2009-12-01 | 2019-02-21 | Translate Bio Inc | Steroid derivative for delivery of mRNA in human genetic diseases. |
WO2011069529A1 (en) | 2009-12-09 | 2011-06-16 | Curevac Gmbh | Mannose-containing solution for lyophilization, transfection and/or injection of nucleic acids |
EP2338520A1 (en) | 2009-12-21 | 2011-06-29 | Ludwig Maximilians Universität | Conjugate with targeting ligand and use of same |
CN102892783B (en) * | 2010-02-25 | 2016-11-09 | 杜克大学 | The method of the generation of eliciting protective anti-HIV-1 antibody |
EA027315B1 (en) | 2010-11-12 | 2017-07-31 | Дзе Трастиз Оф Дзе Юниверсити Оф Пенсильвания | Nucleic acid molecule and protein for inducing immune response against prostate cancer antigen, plasmid, expression vector, method of treatment and pharmaceutical composition |
WO2012089225A1 (en) | 2010-12-29 | 2012-07-05 | Curevac Gmbh | Combination of vaccination and inhibition of mhc class i restricted antigen presentation |
BR112013031553A2 (en) | 2011-06-08 | 2020-11-10 | Shire Human Genetic Therapies, Inc. | compositions, mrna encoding a gland and its use, use of at least one mrna molecule and a vehicle for transfer and use of an mrna encoding for exogenous protein |
CN102973950B (en) * | 2011-09-06 | 2015-05-27 | 四川百利药业有限责任公司 | PRAME and WT1 bivalent tumor DNA vaccine |
WO2013039857A1 (en) * | 2011-09-12 | 2013-03-21 | modeRNA Therapeutics | Engineered nucleic acids and methods of use thereof |
CN102344974A (en) * | 2011-11-22 | 2012-02-08 | 王旋 | Chicken infectious anemia virus LAMP (loop-mediated isothermal amplification) detection kit and detection method thereof |
CN103184221B (en) * | 2011-12-30 | 2016-03-30 | 复旦大学 | Core switch aac and preparing the application in microbiotic |
WO2013120498A1 (en) | 2012-02-15 | 2013-08-22 | Curevac Gmbh | Nucleic acid comprising or coding for a histone stem-loop and a poly(a) sequence or a polyadenylation signal for increasing the expression of an encoded allergenic antigen or an autoimmune self-antigen |
WO2013120500A1 (en) | 2012-02-15 | 2013-08-22 | Curevac Gmbh | Nucleic acid comprising or coding for a histone stem-loop and a poly(a) sequence or a polyadenylation signal for increasing the expression of an encoded tumour antigen |
WO2013120499A1 (en) | 2012-02-15 | 2013-08-22 | Curevac Gmbh | Nucleic acid comprising or coding for a histone stem-loop and a poly (a) sequence or a polyadenylation signal for increasing the expression of an encoded pathogenic antigen |
WO2013120497A1 (en) | 2012-02-15 | 2013-08-22 | Curevac Gmbh | Nucleic acid comprising or coding for a histone stem-loop and a poly(a) sequence or a polyadenylation signal for increasing the expression of an encoded therapeutic protein |
CN102526725B (en) * | 2012-02-22 | 2013-09-04 | 中国医学科学院医学生物学研究所 | Adenosine triphosphate (ATP) and aluminium hydroxide composite adjuvant and vaccine containing same |
WO2013139972A1 (en) * | 2012-03-23 | 2013-09-26 | Laboratorios Del Dr. Esteve, S.A. | Method for monitoring hiv specific t cell responses |
US9683233B2 (en) | 2012-03-27 | 2017-06-20 | Curevac Ag | Artificial nucleic acid molecules for improved protein or peptide expression |
CA2866945C (en) | 2012-03-27 | 2021-05-04 | Curevac Gmbh | Artificial nucleic acid molecules comprising a 5'top utr |
MX357803B (en) | 2012-03-27 | 2018-07-24 | Curevac Ag | Artificial nucleic acid molecules. |
PL2844282T3 (en) * | 2012-05-04 | 2019-11-29 | Pfizer | Prostate-associated antigens and vaccine-based immunotherapy regimens |
US8735359B2 (en) | 2012-05-24 | 2014-05-27 | Orban Biotech Llc | Combinations of modalities for the treatment of diabetes |
EP3800254A1 (en) * | 2012-06-08 | 2021-04-07 | Ethris GmbH | Pulmonary delivery of messenger rna |
US10245229B2 (en) | 2012-06-08 | 2019-04-02 | Translate Bio, Inc. | Pulmonary delivery of mRNA to non-lung target cells |
CN113138279A (en) | 2012-06-27 | 2021-07-20 | 法姆制药有限责任公司 | Application of fusion protein composition |
BR122021025267B1 (en) | 2013-02-22 | 2023-12-05 | Curevac Ag | KIT PARTS AND PHARMACEUTICAL COMPOSITION COMPRISING A PD-1 PATHWAY INHIBITOR |
CN105073135A (en) * | 2013-02-22 | 2015-11-18 | 库瑞瓦格有限责任公司 | Combination of vaccination and inhibition of the PD-1 pathway |
WO2014152774A1 (en) | 2013-03-14 | 2014-09-25 | Shire Human Genetic Therapies, Inc. | Methods and compositions for delivering mrna coded antibodies |
CN105142676B (en) | 2013-03-14 | 2022-06-28 | 夏尔人类遗传性治疗公司 | CFTR MRNA compositions and related methods and uses |
US10077439B2 (en) * | 2013-03-15 | 2018-09-18 | Modernatx, Inc. | Removal of DNA fragments in mRNA production process |
RS57316B1 (en) | 2013-03-15 | 2018-08-31 | Translate Bio Inc | Synergistic enhancement of the delivery of nucleic acids via blended formulations |
CN103160608A (en) * | 2013-04-11 | 2013-06-19 | 中华人民共和国上海出入境检验检疫局 | Food allergen lupin component LAMP (loop-mediated isothermal amplification) field quick detection method |
WO2015023775A1 (en) * | 2013-08-13 | 2015-02-19 | Baylor College Of Medicine | A novel plga-modified polyethylenimine self-assembly nanotechnology for nucleic acid and drug delivery |
KR20160042935A (en) * | 2013-08-21 | 2016-04-20 | 큐어백 아게 | Composition and Vaccine for Treating Lung Cancer |
CN105451779A (en) | 2013-08-21 | 2016-03-30 | 库瑞瓦格股份公司 | Method for increasing expression of RNA-encoded proteins |
AU2014310931B2 (en) | 2013-08-21 | 2019-12-19 | CureVac SE | Rabies vaccine |
WO2015042229A2 (en) * | 2013-09-20 | 2015-03-26 | Landegren Nils | A novel autoantigen |
NZ718817A (en) | 2013-10-22 | 2020-07-31 | Massachusetts Inst Technology | Lipid formulations for delivery of messenger rna |
WO2015065097A1 (en) * | 2013-10-31 | 2015-05-07 | 에스케이텔레콤 주식회사 | Composition for diagnosing pancreatic cancer and method for diagnosing pancreatic cancer using same |
CA2925021A1 (en) | 2013-11-01 | 2015-05-07 | Curevac Ag | Modified rna with decreased immunostimulatory properties |
US11254951B2 (en) | 2014-12-30 | 2022-02-22 | Curevac Ag | Artificial nucleic acid molecules |
SG11201604198YA (en) | 2013-12-30 | 2016-07-28 | Curevac Ag | Methods for rna analysis |
GB2523399B (en) | 2014-02-25 | 2019-03-13 | Orban Tihamer | A composition comprising ten overlapping peptide fragments of the entire preproinsulin sequence |
ES2754239T3 (en) | 2014-03-12 | 2020-04-16 | Curevac Ag | Combination of vaccination and OX40 agonists |
US10022455B2 (en) | 2014-05-30 | 2018-07-17 | Translate Bio, Inc. | Biodegradable lipids for delivery of nucleic acids |
JP6748579B2 (en) | 2014-06-10 | 2020-09-02 | キュアバック リアル エステート ゲゼルシャフト ミット ベシュレンクテル ハフツング | Methods and means for enhancing RNA production |
AU2015279968B2 (en) | 2014-06-24 | 2019-11-14 | Translate Bio, Inc. | Stereochemically enriched compositions for delivery of nucleic acids |
ES2931832T3 (en) | 2014-06-25 | 2023-01-03 | Acuitas Therapeutics Inc | Novel lipids and lipid nanoparticle formulations for nucleic acid delivery |
CN104537150A (en) * | 2014-12-01 | 2015-04-22 | 艾法能源工程股份有限公司 | Statistical method for pipe support materials in PDMS |
CN104826130B (en) * | 2015-02-06 | 2018-06-22 | 中国人民解放军第二军医大学 | MSX3 gene specifics induce the selectively polarized method and its application of microglia |
RU2680527C1 (en) * | 2015-02-27 | 2019-02-22 | Те Асан Фаундейшн | Compositions containing dpp-4 inhibitor for prevention or treatment of valve calcification |
JP2018516847A (en) * | 2015-03-25 | 2018-06-28 | ザ リージェンツ オブ ザ ユニバーシティ オブ ミシガン | Compositions and methods for delivering biopolymer drugs |
US11384375B2 (en) | 2015-04-30 | 2022-07-12 | Curevac Ag | Immobilized poly(n)polymerase |
EP3294885B1 (en) | 2015-05-08 | 2020-07-01 | CureVac Real Estate GmbH | Method for producing rna |
ES2960429T3 (en) | 2015-05-29 | 2024-03-04 | Curevac Mfg Gmbh | Method for producing and purifying RNA, comprising at least one tangential flow filtration step |
WO2016193226A1 (en) | 2015-05-29 | 2016-12-08 | Curevac Ag | Method for adding cap structures to rna using immobilized enzymes |
CN105087647B (en) * | 2015-06-17 | 2018-10-02 | 深圳益世康宁生物科技有限公司 | A kind of recombined glandulae correlation viral vectors carrying Survivin antigen genes and its construction method and application |
US20180296663A1 (en) * | 2015-06-17 | 2018-10-18 | Curevac Ag | Vaccine composition |
CN105087648B (en) * | 2015-06-17 | 2018-05-25 | 深圳益世康宁生物科技有限公司 | The recombined glandulae correlation viral vectors and construction method of carrying MAGE-A3 antigen genes and application |
CN105969804B (en) * | 2015-06-17 | 2018-10-02 | 深圳益世康宁生物科技有限公司 | A kind of recombined glandulae correlation viral vectors carrying SCC antigen genes and its construction method and application |
US10221127B2 (en) | 2015-06-29 | 2019-03-05 | Acuitas Therapeutics, Inc. | Lipids and lipid nanoparticle formulations for delivery of nucleic acids |
US10501768B2 (en) | 2015-07-13 | 2019-12-10 | Curevac Ag | Method of producing RNA from circular DNA and corresponding template DNA |
EP3362576A1 (en) | 2015-10-12 | 2018-08-22 | CureVac AG | Automated method for isolation, selection and/or detection of microorganisms or cells comprised in a solution |
WO2017066797A1 (en) | 2015-10-16 | 2017-04-20 | Modernatx, Inc. | Trinucleotide mrna cap analogs |
WO2017067592A1 (en) * | 2015-10-21 | 2017-04-27 | Biontech Ag | Cytotoxic immunostimulating particles and uses thereof |
TN2018000152A1 (en) | 2015-10-22 | 2019-10-04 | Modernatx Inc | Nucleic acid vaccines for varicella zoster virus (vzv) |
CA3003055C (en) | 2015-10-28 | 2023-08-01 | Acuitas Therapeutics, Inc. | Lipids and lipid nanoparticle formulations for delivery of nucleic acids |
WO2017081110A1 (en) | 2015-11-09 | 2017-05-18 | Curevac Ag | Rotavirus vaccines |
US11248223B2 (en) | 2015-12-23 | 2022-02-15 | Curevac Ag | Method of RNA in vitro transcription using a buffer containing a dicarboxylic acid or tricarboxylic acid or a salt thereof |
MX2018009917A (en) | 2016-02-17 | 2019-08-14 | Curevac Ag | Zika virus vaccine. |
EP3423595A1 (en) | 2016-03-03 | 2019-01-09 | CureVac AG | Rna analysis by total hydrolysis |
JP7150608B6 (en) | 2016-04-08 | 2022-11-11 | トランスレイト バイオ, インコーポレイテッド | Multimer-encoding nucleic acid and use thereof |
EP3448427A1 (en) | 2016-04-29 | 2019-03-06 | CureVac AG | Rna encoding an antibody |
CN107475355A (en) * | 2016-06-08 | 2017-12-15 | 益善生物技术股份有限公司 | Lung cancer early screening kit |
JP7145579B2 (en) | 2016-06-09 | 2022-10-03 | キュアバック アーゲー | Hybrid carrier for nucleic acid cargo |
US10835583B2 (en) | 2016-06-13 | 2020-11-17 | Translate Bio, Inc. | Messenger RNA therapy for the treatment of ornithine transcarbamylase deficiency |
CN114176043B (en) * | 2016-06-14 | 2024-04-23 | 明尼苏达大学董事会 | Genetically modified cells, tissues and organs for the treatment of diseases |
CN105994197A (en) * | 2016-06-16 | 2016-10-12 | 嵊泗县景晟贻贝产业发展有限公司 | Thick shell mussel disengaging machine |
CA3042015A1 (en) * | 2016-10-26 | 2018-05-03 | Modernatx, Inc. | Messenger ribonucleic acids for enhancing immune responses and methods of use thereof |
MA46766A (en) | 2016-11-11 | 2019-09-18 | Modernatx Inc | INFLUENZA VACCINE |
WO2018096179A1 (en) | 2016-11-28 | 2018-05-31 | Curevac Ag | Method for purifying rna |
EP4309739A3 (en) * | 2017-01-27 | 2024-04-17 | The Methodist Hospital | Core/shell structure platform for immunotherapy |
CN117224710A (en) | 2017-02-01 | 2023-12-15 | 莫得纳特斯公司 | Immunomodulatory therapeutic MRNA compositions encoding mutant peptides that activate oncogenes |
AU2018224326B2 (en) | 2017-02-27 | 2024-01-04 | Translate Bio, Inc. | Novel codon-optimized CFTR mRNA |
TW201842921A (en) | 2017-02-28 | 2018-12-16 | 法商賽諾菲公司 | Therapeutic rna |
EP3595713A4 (en) | 2017-03-15 | 2021-01-13 | ModernaTX, Inc. | Respiratory syncytial virus vaccine |
EP3609534A4 (en) | 2017-03-15 | 2021-01-13 | ModernaTX, Inc. | Broad spectrum influenza virus vaccine |
WO2018170256A1 (en) | 2017-03-15 | 2018-09-20 | Modernatx, Inc. | Herpes simplex virus vaccine |
WO2018170270A1 (en) | 2017-03-15 | 2018-09-20 | Modernatx, Inc. | Varicella zoster virus (vzv) vaccine |
AU2018246292A1 (en) | 2017-03-31 | 2019-10-10 | Accanis Biotech F&E Gmbh & Co Kg | Prevention and treatment of non-melanoma skin cancer (NMSC) |
US11905525B2 (en) | 2017-04-05 | 2024-02-20 | Modernatx, Inc. | Reduction of elimination of immune responses to non-intravenous, e.g., subcutaneously administered therapeutic proteins |
WO2018191657A1 (en) | 2017-04-13 | 2018-10-18 | Acuitas Therapeutics, Inc. | Lipids for delivery of active agents |
WO2018200892A1 (en) | 2017-04-27 | 2018-11-01 | The Trustees Of The University Of Pennsylvania | NUCLEOSIDE-MODIFIED mRNA-LIPID NANOPARTICLE LINEAGE VACCINE FOR HEPATITIS C VIRUS |
ES2981244T3 (en) | 2017-04-28 | 2024-10-07 | Acuitas Therapeutics Inc | Novel formulations of lipid carbonyl nanoparticles and lipids for nucleic acid delivery |
MA49138A (en) | 2017-05-16 | 2020-03-25 | Translate Bio Inc | TREATMENT OF CYSTIC FIBROSIS BY ADMINISTRATION OF CODON-OPTIMIZED MRNA CODING FOR CFTR |
JP7284101B2 (en) | 2017-05-31 | 2023-05-30 | ウルトラジェニクス ファーマシューティカル インク. | Therapeutic agents for glycogen storage disease type III |
EP3437650A1 (en) | 2017-07-31 | 2019-02-06 | Accanis Biotech F&E GmbH & Co KG | Treatment of local skin hypotrophy conditions |
US11639329B2 (en) | 2017-08-16 | 2023-05-02 | Acuitas Therapeutics, Inc. | Lipids for use in lipid nanoparticle formulations |
WO2019036030A1 (en) | 2017-08-17 | 2019-02-21 | Acuitas Therapeutics, Inc. | Lipids for use in lipid nanoparticle formulations |
EP3668834B1 (en) | 2017-08-17 | 2024-10-02 | Acuitas Therapeutics, Inc. | Lipids for use in lipid nanoparticle formulations |
WO2019036028A1 (en) | 2017-08-17 | 2019-02-21 | Acuitas Therapeutics, Inc. | Lipids for use in lipid nanoparticle formulations |
CN107653313B (en) * | 2017-09-12 | 2021-07-09 | 首都医科大学附属北京胸科医院 | Application of RETN and KLK1 as tuberculosis detection markers |
CN111511405A (en) * | 2017-10-16 | 2020-08-07 | 阿迪根有限公司 | Peptides and nanoparticles for intracellular delivery of mRNA |
AU2018392716A1 (en) | 2017-12-20 | 2020-06-18 | Translate Bio, Inc. | Improved composition and methods for treatment of ornithine transcarbamylase deficiency |
US11525158B2 (en) | 2017-12-21 | 2022-12-13 | CureVac SE | Linear double stranded DNA coupled to a single support or a tag and methods for producing said linear double stranded DNA |
KR20200103750A (en) | 2017-12-21 | 2020-09-02 | 바제클리크 게엠베하 | Click-modified mRNA |
WO2019148101A1 (en) | 2018-01-29 | 2019-08-01 | Modernatx, Inc. | Rsv rna vaccines |
CN108611310A (en) * | 2018-04-28 | 2018-10-02 | 中国药科大学 | A kind of recombination Hsp65 and STEAP1186-193The structure of the genetic engineering bacterium of fusion protein |
CN108714213A (en) * | 2018-06-04 | 2018-10-30 | 北京工业大学 | The preparation method and application of a kind of nanometer adjuvant of self assembly and the nano vaccine formed by the adjuvant |
EP4299750A3 (en) | 2018-12-06 | 2024-07-10 | Arcturus Therapeutics, Inc. | Compositions and methods for treating ornithine transcarbamylase deficiency |
CN111499758B (en) * | 2019-01-31 | 2023-01-31 | 中国科学院脑科学与智能技术卓越创新中心 | Method for screening human potassium ion channel modulators |
CN110241116B (en) * | 2019-05-21 | 2023-02-07 | 中国医学科学院放射医学研究所 | Circular RNA and application thereof in promoting DNA damage repair |
CN110305866A (en) * | 2019-07-09 | 2019-10-08 | 江苏省人民医院(南京医科大学第一附属医院) | Method for constructing EFTUD2 single allele knockout HepG2.2.15 cell strain by using Cas9 technology |
CN110592033B (en) * | 2019-07-28 | 2022-04-12 | 中国海洋大学 | Paralichthys olivaceus streptococcus iniae PDHA1 multi-epitope polypeptide |
CN110804662B (en) * | 2019-09-30 | 2021-07-13 | 中山大学 | Method for screening anti-blue-ear disease pigs based on SIRT2 expression quantity |
US20240277830A1 (en) | 2020-02-04 | 2024-08-22 | CureVac SE | Coronavirus vaccine |
US11241493B2 (en) | 2020-02-04 | 2022-02-08 | Curevac Ag | Coronavirus vaccine |
MX2022011504A (en) | 2020-03-19 | 2022-10-07 | Baseclick Gmbh | Modified mrnas for vaccine development. |
EP3964576A1 (en) | 2020-09-04 | 2022-03-09 | baseclick GmbH | Modified mrnas for vaccine development |
JP2021147353A (en) * | 2020-03-19 | 2021-09-27 | 国立大学法人信州大学 | Composition, lipid particle manufacturing kit, substance delivery method, and detection method |
WO2021263081A2 (en) * | 2020-06-26 | 2021-12-30 | National Breast Cancer Coalition | Breast cancer vaccine |
CN111875699B (en) * | 2020-07-03 | 2022-07-05 | 江南大学 | Method for improving bacillus subtilis ovalbumin expression level |
CN111973616A (en) * | 2020-07-15 | 2020-11-24 | 中山大学 | Application of vibrio parahaemolyticus 23S rRNA and/or conserved sequence VP13 thereof in improving immunity of fish |
US11976019B2 (en) | 2020-07-16 | 2024-05-07 | Acuitas Therapeutics, Inc. | Cationic lipids for use in lipid nanoparticles |
CN111965353B (en) * | 2020-08-18 | 2022-08-19 | 四川农业大学 | Application of psoroptes ovis cysteine protease inhibitor and ELISA kit |
CN112011501B (en) * | 2020-08-26 | 2022-11-08 | 福建省医学科学研究院 | HCM specificity induced pluripotent stem cell line carrying c.3369-3370 insC mutation |
RU2761876C1 (en) * | 2020-11-27 | 2021-12-13 | Федеральное государственное бюджетное образовательное учреждение высшего образования "Московский государственный университет имени М.В.Ломоносова" (МГУ) | Humanised 5d3hu antibody binding to the prame tumour antigen, dna fragments encoding said antibody, and antigen-binding fragment of the antibody |
CN112637884B (en) * | 2020-12-08 | 2022-09-20 | 广西电网有限责任公司电力科学研究院 | Model prediction control method of WSN (Wireless sensor network) based on extended state observer |
AU2021405281A1 (en) | 2020-12-22 | 2023-07-06 | CureVac SE | Rna vaccine against sars-cov-2 variants |
KR20220117133A (en) | 2021-02-15 | 2022-08-23 | 주식회사 바이오파마 | Vaccine composition for the prevention of COVID-19 containing ion complex of cationic molecular carrier and SARS-CoV-2 mRNA |
WO2023034957A1 (en) * | 2021-09-03 | 2023-03-09 | University Of Connecticut | Stabilization of antigens for long term administration in transdermal microneedle patches |
WO2024020451A2 (en) * | 2022-07-21 | 2024-01-25 | Thomas Jefferson University | Methods and compositions for selectively modulating gene expression in megakaryocytes and platelets |
CN115414494B (en) * | 2022-08-17 | 2024-04-26 | 南京中医药大学 | Polypeptide nanometer vaccine and preparation method and application thereof |
KR102624969B1 (en) * | 2023-04-03 | 2024-01-16 | 한국과학기술원 | mRNA 3'UTR sequences leading to increase mRNA translation |
CN116693708B (en) * | 2023-04-28 | 2024-08-30 | 百珍堂生物科技(浙江)有限公司 | High-activity abalone visceral polysaccharide and eutectic solvent extraction method thereof |
Citations (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4373071A (en) | 1981-04-30 | 1983-02-08 | City Of Hope Research Institute | Solid-phase synthesis of polynucleotides |
US4401796A (en) | 1981-04-30 | 1983-08-30 | City Of Hope Research Institute | Solid-phase synthesis of polynucleotides |
US4415732A (en) | 1981-03-27 | 1983-11-15 | University Patents, Inc. | Phosphoramidite compounds and processes |
US4458066A (en) | 1980-02-29 | 1984-07-03 | University Patents, Inc. | Process for preparing polynucleotides |
US4500707A (en) | 1980-02-29 | 1985-02-19 | University Patents, Inc. | Nucleosides useful in the preparation of polynucleotides |
US4668777A (en) | 1981-03-27 | 1987-05-26 | University Patents, Inc. | Phosphoramidite nucleoside compounds |
US4816567A (en) | 1983-04-08 | 1989-03-28 | Genentech, Inc. | Recombinant immunoglobin preparations |
US4973679A (en) | 1981-03-27 | 1990-11-27 | University Patents, Inc. | Process for oligonucleo tide synthesis using phosphormidite intermediates |
EP1083232A1 (en) | 1999-09-09 | 2001-03-14 | Jung, Günther, Prof. Dr. | Transfer of mRNA using polycationic compounds |
DE102006007433A1 (en) | 2006-02-17 | 2007-08-23 | Curevac Gmbh | Immunostimulant adjuvant useful in vaccines against cancer or infectious diseases comprises a lipid-modified nucleic acid |
WO2008014979A2 (en) | 2006-07-31 | 2008-02-07 | Curevac Gmbh | NUCLEIC ACID OF FORMULA (I): GIXmGn, OR (II): CIXmCn, IN PARTICULAR AS AN IMMUNE-STIMULATING AGENT/ADJUVANT |
EP1905844A2 (en) | 2001-12-19 | 2008-04-02 | CureVac GmbH | Application of mRNA for use as a therapeutic agent against tumours |
Family Cites Families (103)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3906092A (en) | 1971-11-26 | 1975-09-16 | Merck & Co Inc | Stimulation of antibody response |
DE3314999A1 (en) | 1983-04-26 | 1985-03-14 | Behringwerke Ag, 3550 Marburg | USE OF THE DITERPEN DERIVATE FORSKOLIN FOR IMMUNE STIMULATION |
US5663163A (en) | 1987-09-07 | 1997-09-02 | Fujisawa Pharmaceutical Co., Ltd. | Cephem compounds and processes for preparation thereof |
CA1320446C (en) | 1988-06-20 | 1993-07-20 | William A. Carter | Modulation of lymphokine-resistant cellular states by dsrnas |
DE69029738T2 (en) | 1989-10-11 | 1997-08-14 | Hem Pharma Corp | PROTECTION AGAINST SHOCK DUE TO DAMAGE FROM DOUBLE-STRANDED RNA'S |
NZ262254A (en) | 1993-01-25 | 1997-10-24 | Hybridon Inc | Oligonucleotide analogue containing a ribonucleotide alkylphosphon(ate or thioate), gene repression |
AU6764794A (en) | 1993-01-27 | 1994-08-29 | Affymax Technologies N.V. | Compositions and methods for transdermal drug delivery |
US5516652A (en) | 1993-10-06 | 1996-05-14 | Merck Frosst Canada Inc. | DNA encoding prostaglandin receptor IP |
HUT76094A (en) | 1994-03-18 | 1997-06-30 | Lynx Therapeutics | Oligonucleotide n3'-p5' phosphoramidates: synthesis and compounds; hybridization and nuclease resistance properties |
WO1995026204A1 (en) | 1994-03-25 | 1995-10-05 | Isis Pharmaceuticals, Inc. | Immune stimulation by phosphorothioate oligonucleotide analogs |
US5874560A (en) | 1994-04-22 | 1999-02-23 | The United States Of America As Represented By The Department Of Health And Human Services | Melanoma antigens and their use in diagnostic and therapeutic methods |
DE69535036T3 (en) | 1994-07-15 | 2011-07-07 | The University of Iowa Research Foundation, IA | IMMUNOMODULATIVE OLIGONUCLEOTIDES |
US6239116B1 (en) | 1994-07-15 | 2001-05-29 | University Of Iowa Research Foundation | Immunostimulatory nucleic acid molecules |
US6689757B1 (en) | 1996-02-12 | 2004-02-10 | M.L. Laboratories Plc | Methods for vaccination and vaccines therefor |
US6090391A (en) | 1996-02-23 | 2000-07-18 | Aviron | Recombinant tryptophan mutants of influenza |
DE69733020T2 (en) | 1996-10-11 | 2006-02-16 | The Regents Of The University Of California, Oakland | IMMUNOSTIMULATING OLIGONUCLEOTIDE CONJUGATES |
EP0839912A1 (en) | 1996-10-30 | 1998-05-06 | Instituut Voor Dierhouderij En Diergezondheid (Id-Dlo) | Infectious clones of RNA viruses and vaccines and diagnostic assays derived thereof |
GB9623051D0 (en) | 1996-11-06 | 1997-01-08 | Schacht Etienne H | Delivery of DNA to target cells in biological systems |
EP0855184A1 (en) | 1997-01-23 | 1998-07-29 | Grayson B. Dr. Lipford | Pharmaceutical composition comprising a polynucleotide and an antigen especially for vaccination |
US6406705B1 (en) | 1997-03-10 | 2002-06-18 | University Of Iowa Research Foundation | Use of nucleic acids containing unmethylated CpG dinucleotide as an adjuvant |
AU6972798A (en) | 1997-04-18 | 1998-11-13 | University Of Medicine And Dentistry Of New Jersey | Inhibition of hiv-1 replication by a tat rna-binding domain peptide analog |
DE69819150T3 (en) | 1997-06-06 | 2007-12-20 | Dynavax Technologies Corp., San Diego | IMMUNOSTIMULATING OLIGONUCLEOTIDES, COMPOSITIONS THEREOF, AND METHOD OF USE THEREOF |
US6589940B1 (en) | 1997-06-06 | 2003-07-08 | Dynavax Technologies Corporation | Immunostimulatory oligonucleotides, compositions thereof and methods of use thereof |
US20040006034A1 (en) | 1998-06-05 | 2004-01-08 | Eyal Raz | Immunostimulatory oligonucleotides, compositions thereof and methods of use thereof |
EP1374894A3 (en) | 1997-06-06 | 2004-09-22 | Dynavax Technologies Corporation | Immunostimulatory oligonucleotides, compositions thereof and methods of use thereof |
PT1009413E (en) | 1997-09-05 | 2007-05-31 | Univ California | Use of immunostimulatory oligonucleotides for preventing or treating asthma |
US6096307A (en) | 1997-12-11 | 2000-08-01 | A. Glenn Braswell | Compositions for immunostimulation containing Echinacea angustofolia, bromelain, and lysozyme |
WO1999051259A2 (en) | 1998-04-03 | 1999-10-14 | University Of Iowa Research Foundation | Methods and products for stimulating the immune system using immunotherapeutic oligonucleotides and cytokines |
EP1071472A4 (en) | 1998-04-23 | 2002-04-17 | Univ Michigan Technology Man W | Peptides for efficient gene transfer |
US6833438B1 (en) | 1999-06-01 | 2004-12-21 | Agensys, Inc. | Serpentine transmembrane antigens expressed in human cancers and uses thereof |
WO2000049158A2 (en) | 1999-02-18 | 2000-08-24 | Compugen Ltd. | Psa and klk-2 splicing variants |
EP1196558A1 (en) | 1999-06-08 | 2002-04-17 | Aventis Pasteur | Immunostimulant oligonucleotide |
US6514948B1 (en) | 1999-07-02 | 2003-02-04 | The Regents Of The University Of California | Method for enhancing an immune response |
WO2001004135A2 (en) | 1999-07-13 | 2001-01-18 | The Regents Of The University Of Michigan | Crosslinked dna condensate compositions and gene delivery methods |
AU6158700A (en) | 1999-07-13 | 2001-01-30 | Corixa Corporation | Vaccine |
US20030104622A1 (en) | 1999-09-01 | 2003-06-05 | Robbins Paul D. | Identification of peptides that facilitate uptake and cytoplasmic and/or nuclear transport of proteins, DNA and viruses |
AU775366B2 (en) | 1999-12-06 | 2004-07-29 | Agensys, Inc. | Serpentine transmembrane antigens expressed in human cancers and uses thereof |
AU2001231245A1 (en) | 2000-01-31 | 2001-08-07 | The Regents Of The University Of California | Immunomodulatory polynucleotides in treatment of an infection by an intracellular pathogen |
CA2404890C (en) | 2000-03-30 | 2013-11-19 | Whitehead Institute For Biomedical Research | Rna sequence-specific mediators of rna interference |
JP2004530629A (en) | 2000-06-07 | 2004-10-07 | バイオシネクサス インコーポレーテッド | Immunostimulatory RNA / DNA hybrid molecule |
CA2410371C (en) | 2000-06-22 | 2015-11-17 | University Of Iowa Research Foundation | Methods for enhancing antibody-induced cell lysis and treating cancer |
WO2002000694A2 (en) | 2000-06-23 | 2002-01-03 | American Cyanamid Company | Modified morbillivirus v proteins |
US6376704B1 (en) | 2000-06-28 | 2002-04-23 | 3M Innovative Properties Company | Naphthyoxyalkyl(meth)acrylates with high refractive indices and low glass transition temperatures |
US6716434B1 (en) | 2000-09-19 | 2004-04-06 | Daniel R. Ansley | Composition and method for immunostimulation in non- mammalian vertebrates |
GB0025577D0 (en) | 2000-10-18 | 2000-12-06 | Smithkline Beecham Biolog | Vaccine |
DE60235297D1 (en) | 2001-04-02 | 2010-03-25 | Univ South Florida | LPS-RESISTANT CHS1 / BEIGE-SIMILAR ANCHOR GENES AND THERAPEUTIC APPLICATIONS THEREOF |
EP2842964A1 (en) * | 2001-06-05 | 2015-03-04 | Curevac GmbH | Virtual method of determining a modified mRNA sequence |
US7785610B2 (en) | 2001-06-21 | 2010-08-31 | Dynavax Technologies Corporation | Chimeric immunomodulatory compounds and methods of using the same—III |
AR045702A1 (en) | 2001-10-03 | 2005-11-09 | Chiron Corp | COMPOSITIONS OF ASSISTANTS. |
DE10148886A1 (en) | 2001-10-04 | 2003-04-30 | Avontec Gmbh | Inhibition of STAT-1 |
WO2003035836A2 (en) | 2001-10-24 | 2003-05-01 | Hybridon Inc. | Modulation of immunostimulatory properties of oligonucleotide-based compounds by optimal presentation of 5' ends |
US7276489B2 (en) | 2002-10-24 | 2007-10-02 | Idera Pharmaceuticals, Inc. | Modulation of immunostimulatory properties of oligonucleotide-based compounds by optimal presentation of 5′ ends |
AU2002358803A1 (en) | 2001-12-31 | 2003-07-15 | Asm Automation Sensorik Messtechnik Gmbh | Magnetostrictive sensor element |
WO2003059381A2 (en) * | 2002-01-18 | 2003-07-24 | Curevac Gmbh | Immunogenic preparations and vaccines on the basis of mrna |
KR100468534B1 (en) | 2002-01-31 | 2005-01-27 | 주식회사 엑스넷 | Realtime convention event management system using wireless communication |
PL373567A1 (en) | 2002-03-01 | 2005-09-05 | The Administrators Of The Tulane Educational Fund | Conjugates of therapeutic or cytotoxic agents and biologically active peptides |
NZ573064A (en) | 2002-04-04 | 2011-02-25 | Coley Pharm Gmbh | Immunostimulatory G,U-containing oligoribonucleotides |
JP2006512047A (en) | 2002-06-11 | 2006-04-13 | グラクソスミスクライン バイオロジカルズ ソシエテ アノニム | Immunogenic composition |
DE10229872A1 (en) | 2002-07-03 | 2004-01-29 | Curevac Gmbh | Immune stimulation through chemically modified RNA |
EP1393745A1 (en) | 2002-07-29 | 2004-03-03 | Hybridon, Inc. | Modulation of immunostimulatory properties of oligonucleotide-based compounds by optimal presentation of 5'ends |
EP2181595A1 (en) | 2002-08-16 | 2010-05-05 | Yeda Research And Development Company Ltd. | Tumor associated antigen, peptides thereof, and use of same as anti-tumor vaccines |
EP1625140A4 (en) | 2002-12-23 | 2008-06-18 | Dynavax Tech Corp | Branched immunomodulatory compounds and methods of using the same |
EP1601789A4 (en) | 2003-01-16 | 2007-10-31 | Idera Pharmaceuticals Inc | Modulation of immunostimulatory properties of oligonucleotide-based compounds by utilizing modified immunostimulatory dinucleotides |
EP1587837B1 (en) | 2003-01-28 | 2012-06-13 | Proscan RX Pharma Inc. | Epitope sequences for prostate cancer diagnosis and treatment |
US20040242502A1 (en) | 2003-04-08 | 2004-12-02 | Galenica Pharmaceuticals, Inc. | Semi-synthetic saponin analogs with carrier and immune stimulatory activities for DNA and RNA vaccines |
WO2005001022A2 (en) | 2003-04-10 | 2005-01-06 | 3M Innovative Properties Company | Methods and compositions for enhancing immune response |
WO2005000887A1 (en) | 2003-06-30 | 2005-01-06 | Universite De Lausanne | Rasgap derived peptide for selectively killing cancer cells |
AU2004276226B2 (en) | 2003-08-05 | 2009-07-30 | Avi Biopharma, Inc. | Oligonucleotide analog and method for treating flavivirus infections |
DE10335833A1 (en) | 2003-08-05 | 2005-03-03 | Curevac Gmbh | Transfection of blood cells with mRNA for immune stimulation and gene therapy |
AU2004275876B2 (en) | 2003-09-25 | 2011-03-31 | Coley Pharmaceutical Gmbh | Nucleic acid-lipophilic conjugates |
DE10346721A1 (en) | 2003-10-08 | 2005-05-04 | Holger Kalthoff | New oligonucleotides, useful for treating cancer, especially of the pancreas, are not species specific but induce apoptosis or inhibit proliferation |
JP2007530449A (en) | 2003-12-08 | 2007-11-01 | イデラ ファーマシューティカルズ インコーポレイテッド | Modulation of immunostimulatory properties by compounds based on small oligonucleotides |
EP1720568A2 (en) | 2004-02-19 | 2006-11-15 | Coley Pharmaceutical Group, Inc. | Immunostimulatory viral rna oligonucleotides |
CA2563735C (en) | 2004-04-22 | 2020-07-14 | Agensys, Inc. | Antibodies and molecules derived therefrom that bind to steap-1 proteins |
WO2006046978A2 (en) | 2004-06-28 | 2006-05-04 | Argos Therapeutics, Inc. | Cationic peptide-mediated transformation |
DE102004035227A1 (en) | 2004-07-21 | 2006-02-16 | Curevac Gmbh | mRNA mixture for vaccination against tumor diseases |
DE102004042546A1 (en) | 2004-09-02 | 2006-03-09 | Curevac Gmbh | Combination therapy for immune stimulation |
WO2006029223A2 (en) | 2004-09-08 | 2006-03-16 | Children's Medical Center Corporation | Method for stimulating the immune response of newborns |
WO2006097993A1 (en) | 2005-03-14 | 2006-09-21 | Fujitsu Limited | Liquid crystal display device and method for manufacturing liquid crystal display device |
WO2006118458A2 (en) | 2005-05-04 | 2006-11-09 | Single Buoy Moorings Inc. | Large distance offshore lng export terminal with boil-off vapour collection and utilization capacities |
DE102005023170A1 (en) | 2005-05-19 | 2006-11-23 | Curevac Gmbh | Optimized formulation for mRNA |
WO2007026338A2 (en) | 2005-09-02 | 2007-03-08 | The Procter & Gamble Company | Efficacious scalp health predictor |
WO2007031322A1 (en) | 2005-09-14 | 2007-03-22 | Gunther Hartmann | Compositions comprising immunostimulatory rna oligonucleotides and methods for producing said rna oligonucleotides |
EP1764107A1 (en) | 2005-09-14 | 2007-03-21 | Gunther Hartmann | Compositions comprising immunostimulatory RNA oligonucleotides and methods for producing said RNA oligonucleotides |
WO2007035690A2 (en) | 2005-09-19 | 2007-03-29 | Veridex, Llc | Methods for diagnosing pancreatic cancer |
US20090169472A1 (en) | 2005-10-12 | 2009-07-02 | Cancer Research Technology Ltd. | Methods and compositions for treating immune disorders |
CN101346393B (en) | 2005-11-02 | 2015-07-22 | 普洛体维生物治疗公司 | Modified siRNA molecules and uses thereof |
US7470674B2 (en) | 2005-11-07 | 2008-12-30 | Idera Pharmaceuticals, Inc. | Immunostimulatory properties of oligonucleotide-based compounds comprising modified immunostimulatory dinucleotides |
AU2006325030B2 (en) | 2005-12-16 | 2012-07-26 | Cellectis | Cell penetrating peptide conjugates for delivering nucleic acids into cells |
PL2027158T3 (en) | 2006-05-02 | 2013-02-28 | Carviar Aps | Method for immunizing an avian species |
DE102006035618A1 (en) * | 2006-07-31 | 2008-02-07 | Curevac Gmbh | New nucleic acid useful as immuno-stimulating adjuvant for manufacture of a composition for treatment of cancer diseases e.g. colon carcinomas and infectious diseases e.g. influenza and malaria |
WO2008022046A2 (en) | 2006-08-18 | 2008-02-21 | Nastech Pharmaceutical Company Inc. | Dicer substrate rna peptide conjugates and methods for rna therapeutics |
US20080071711A1 (en) | 2006-09-20 | 2008-03-20 | Siemens Corporate Research, Inc. | Method and System for Object Detection Using Probabilistic Boosting Cascade Tree |
DE102006061015A1 (en) | 2006-12-22 | 2008-06-26 | Curevac Gmbh | Process for the purification of RNA on a preparative scale by HPLC |
DE102007001370A1 (en) | 2007-01-09 | 2008-07-10 | Curevac Gmbh | RNA-encoded antibodies |
WO2009030254A1 (en) | 2007-09-04 | 2009-03-12 | Curevac Gmbh | Complexes of rna and cationic peptides for transfection and for immunostimulation |
WO2009046738A1 (en) | 2007-10-09 | 2009-04-16 | Curevac Gmbh | Composition for treating lung cancer, particularly of non-small lung cancers (nsclc) |
WO2009046739A1 (en) | 2007-10-09 | 2009-04-16 | Curevac Gmbh | Composition for treating prostate cancer (pca) |
WO2009053700A1 (en) | 2007-10-23 | 2009-04-30 | Cancer Research Technology Limited | Modification of nucleic acid-containing biological entities |
EP2247308A4 (en) | 2008-01-10 | 2012-04-18 | Nventa Biopharmaceuticals Corp | Adjuvant compositions comprising poly-ic and a cationic polymer |
PL2176408T3 (en) | 2008-01-31 | 2015-08-31 | Curevac Gmbh | NUCLEIC ACIDS COMPRISING FORMULA (NuGiXmGnNv)a AND DERIVATIVES THEREOF AS AN IMMUNOSTIMULATING AGENTS /ADJUVANTS |
WO2010037408A1 (en) | 2008-09-30 | 2010-04-08 | Curevac Gmbh | Composition comprising a complexed (m)rna and a naked mrna for providing or enhancing an immunostimulatory response in a mammal and uses thereof |
US20110053829A1 (en) | 2009-09-03 | 2011-03-03 | Curevac Gmbh | Disulfide-linked polyethyleneglycol/peptide conjugates for the transfection of nucleic acids |
-
2008
- 2008-09-30 WO PCT/EP2008/008304 patent/WO2010037408A1/en active Application Filing
-
2009
- 2009-09-30 PT PT97368237T patent/PT2331129E/en unknown
- 2009-09-30 CN CN200980131936.5A patent/CN102123733B/en not_active Expired - Fee Related
- 2009-09-30 WO PCT/EP2009/007032 patent/WO2010037539A1/en active Application Filing
- 2009-09-30 JP JP2011526423A patent/JP5859853B2/en not_active Expired - Fee Related
- 2009-09-30 BR BRPI0915844-8A patent/BRPI0915844B1/en not_active IP Right Cessation
- 2009-09-30 SI SI200930990T patent/SI2331129T1/en unknown
- 2009-09-30 MX MX2010013071A patent/MX2010013071A/en active IP Right Grant
- 2009-09-30 DK DK09736823.7T patent/DK2331129T3/en active
- 2009-09-30 EP EP09736823.7A patent/EP2331129B1/en active Active
- 2009-09-30 KR KR1020117001541A patent/KR101343043B1/en active IP Right Grant
- 2009-09-30 AU AU2009300113A patent/AU2009300113B2/en not_active Ceased
- 2009-09-30 RU RU2011116931/15A patent/RU2545756C2/en active
- 2009-09-30 ES ES09736823.7T patent/ES2502915T3/en active Active
- 2009-09-30 CA CA2730261A patent/CA2730261C/en not_active Expired - Fee Related
- 2009-09-30 US US12/994,407 patent/US9572874B2/en active Active
- 2009-09-30 EP EP13005251.7A patent/EP2762165B1/en not_active Not-in-force
- 2009-09-30 PL PL09736823T patent/PL2331129T3/en unknown
-
2014
- 2014-05-07 JP JP2014096387A patent/JP5931120B2/en not_active Expired - Fee Related
- 2014-08-12 HR HRP20140763AT patent/HRP20140763T1/en unknown
-
2017
- 2017-01-17 US US15/408,339 patent/US20170202957A1/en not_active Abandoned
-
2020
- 2020-06-19 US US16/907,130 patent/US20210046179A1/en not_active Abandoned
Patent Citations (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4458066A (en) | 1980-02-29 | 1984-07-03 | University Patents, Inc. | Process for preparing polynucleotides |
US4500707A (en) | 1980-02-29 | 1985-02-19 | University Patents, Inc. | Nucleosides useful in the preparation of polynucleotides |
US4415732A (en) | 1981-03-27 | 1983-11-15 | University Patents, Inc. | Phosphoramidite compounds and processes |
US4668777A (en) | 1981-03-27 | 1987-05-26 | University Patents, Inc. | Phosphoramidite nucleoside compounds |
US4973679A (en) | 1981-03-27 | 1990-11-27 | University Patents, Inc. | Process for oligonucleo tide synthesis using phosphormidite intermediates |
US4373071A (en) | 1981-04-30 | 1983-02-08 | City Of Hope Research Institute | Solid-phase synthesis of polynucleotides |
US4401796A (en) | 1981-04-30 | 1983-08-30 | City Of Hope Research Institute | Solid-phase synthesis of polynucleotides |
US4816567A (en) | 1983-04-08 | 1989-03-28 | Genentech, Inc. | Recombinant immunoglobin preparations |
EP1083232A1 (en) | 1999-09-09 | 2001-03-14 | Jung, Günther, Prof. Dr. | Transfer of mRNA using polycationic compounds |
EP1905844A2 (en) | 2001-12-19 | 2008-04-02 | CureVac GmbH | Application of mRNA for use as a therapeutic agent against tumours |
DE102006007433A1 (en) | 2006-02-17 | 2007-08-23 | Curevac Gmbh | Immunostimulant adjuvant useful in vaccines against cancer or infectious diseases comprises a lipid-modified nucleic acid |
WO2008014979A2 (en) | 2006-07-31 | 2008-02-07 | Curevac Gmbh | NUCLEIC ACID OF FORMULA (I): GIXmGn, OR (II): CIXmCn, IN PARTICULAR AS AN IMMUNE-STIMULATING AGENT/ADJUVANT |
Non-Patent Citations (33)
Title |
---|
AKASHI, CURR. OPIN. GENET. DEV., 2001 |
ALTSCHUL ET AL., NUCLEIC ACIDS RES, vol. 25, 1997, pages 3389 - 3402 |
ALTSCHUL, NUCLEIC ACIDS RES, vol. 25, 1997, pages 3389 - 3402 |
BINDER ET AL., EMBO J., vol. 13, 1994, pages 1969 - 1980 |
BRUMMELKAMP ET AL., CANCERCELL, vol. 2, 2002, pages 243 - 247 |
CAPUT ET AL., PROC. NATL. ACAD. SCI. USA, vol. 83, 1986, pages 1670 - 1674 |
FISHER; WILSON, BIOCHEM. J., vol. 321, 1997, pages 49 - 58 |
HAMM ET AL., INTERNATIONAL IMMUNOLOGY, vol. 19, no. 3, pages 1297 - 1304 |
HANNON, NATURE, vol. 41, 2002, pages 244 - 251 |
HE; KATZE, VIRAL LMMUNOL., vol. 15, 2002, pages 95 - 119 |
HELL F ET AL: "Species-specific recognition of single-stranded RNA via Toll-like receptor 7 and 8", SCIENCE, AMERICAN ASSOCIATION FOR THE ADVANCEMENT OF SCIENCE, US, WASHINGTON, DC, vol. 303, 5 March 2004 (2004-03-05), pages 1526 - 1529, XP002358689, ISSN: 0036-8075 * |
HOLCIK, PROC. NATL. ACAD. SCI. USA, vol. 94, 1997, pages 2410 - 2414 |
KARLIN, PNAS USA, vol. 90, 1993, pages 5873 - 5877 |
KAWAI, T.; S. AKIRA: "TLR signaling", CELL DEATH DIFFER, vol. 13, no. 5, 2006, pages 816 - 25 |
KOHLER; MILSTEIN, NATURE, vol. 256, 1975, pages 495 |
KONTERMANN R.E., ACTA PHARMACOL. SIN, vol. 26, no. 1, 2005, pages 1 - 9 |
LOCHMANN D ET AL: "Drug delivery of oligonucleotides by peptides", EUROPEAN JOURNAL OF PHARMACEUTICS AND BIOPHARMACEUTICS, ELSEVIER SCIENCE PUBLISHERS B.V., AMSTERDAM, NL, vol. 58, no. 2, 1 September 2004 (2004-09-01), pages 237 - 251, XP004526309, ISSN: 0939-6411 * |
MANIATIS: "Molecular Cloning: A Laboratory Manual", 2001, COLD SPRING HARBOR LABORATORY PRESS |
MCCAFFERTY ET AL., NATURE, vol. 348, 1990, pages 552 - 554 |
MCCAFFREY ET AL., NATURE, vol. 418, 2002, pages 38 - 39 |
MEYLAN, E.: "Intracellular pattern recognition receptors in the host response", J. TSCHOPP, 2006 |
MEYLAN, E.; TSCHOPP, J.: "Toll-like receptors and RNA helicases: two parallel ways to trigger antiviral responses", MOL. CELL, vol. 22, 2006, pages 561 - 569 |
NATURE, vol. 442, no. 7098, pages 39 - 44 |
SCHEEL BIRGIT ET AL: "Therapeutic anti-tumor immunity triggered by injections of immunostimulating single-stranded RNA", EUROPEAN JOURNAL OF IMMUNOLOGY, WILEY - V C H VERLAG GMBH & CO. KGAA, DE, vol. 36, no. 10, 1 October 2006 (2006-10-01), pages 2807 - 2816, XP002462635, ISSN: 0014-2980 * |
SCHEEL BIRGIT ET AL: "Toll-like receptor-dependent activation of several human blood cell types by protamine-condensed mRNA", EUROPEAN JOURNAL OF IMMUNOLOGY, WILEY - V C H VERLAG GMBH & CO. KGAA, DE, vol. 35, no. 5, 1 May 2005 (2005-05-01), pages 1557 - 1566, XP002462636, ISSN: 0014-2980 * |
SCHEEL ET AL., EUROPEAN JOURNAL IMMUNOL., vol. 35, 2005, pages 1557 - 1566 |
SHARP, GENES DEV., vol. 5, 2001, pages 485 - 490 |
SHIFFMAN ET AL., NUCLEIC ACIDS RESEARCH, vol. 5, no. 9, 1978, pages 3409 - 3426 |
STARK, ANNU. REV. BIOCHEM., vol. 67, 1998, pages 227 - 264 |
URRY ET AL.: "Modern Physical Methods in Biochemistry", 1985, ELSEVIER, article "Absorption, Circular Dichroism and ORD of Polypeptides" |
XIA ET AL., NATURE BIOTECH., vol. 20, 2002, pages 1006 - 1010 |
ZAMORE, NAT. STRUCT. BIOL., vol. 9, 2001, pages 746 - 750 |
ZOHRA ET AL., BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, vol. 358, 2007, pages 373 - 378 |
Cited By (330)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1685844B1 (en) | 2002-07-03 | 2015-03-18 | CureVac GmbH | Immunostimulation by chemically modified RNA |
EP2216028A2 (en) | 2002-07-03 | 2010-08-11 | CureVac GmbH | Immunostimulation by chemically modified RNA |
US8940871B2 (en) | 2006-03-20 | 2015-01-27 | The Regents Of The University Of California | Engineered anti-prostate stem cell antigen (PSCA) antibodies for cancer targeting |
US8216582B2 (en) | 2006-06-23 | 2012-07-10 | Alethia Biotherapeutics Inc. | Polynucleotides and polypeptide sequences involved in cancer |
US11421038B2 (en) | 2007-01-09 | 2022-08-23 | Curevac Ag | RNA-coded antibody |
EP2101823B1 (en) | 2007-01-09 | 2016-11-23 | CureVac AG | Rna-coded antibody |
US9527919B2 (en) | 2007-09-04 | 2016-12-27 | The Regents Of The University Of California | High affinity anti-prostate stem cell antigen (PSCA) antibodies for cancer targeting and detection |
US10111967B2 (en) | 2007-09-04 | 2018-10-30 | Curevac Ag | Complexes of RNA and cationic peptides for transfection and for immunostimulation |
US8940298B2 (en) | 2007-09-04 | 2015-01-27 | The Regents Of The University Of California | High affinity anti-prostate stem cell antigen (PSCA) antibodies for cancer targeting and detection |
US9226959B2 (en) | 2008-01-31 | 2016-01-05 | Curevac Ag | Nucleic acids comprising formula (NuGlXmGnNv)a and derivatives thereof as immunostimulating agent/adjuvant |
EP2548960A1 (en) * | 2008-01-31 | 2013-01-23 | CureVac GmbH | Nucleic acids comprising formula (NuGIXmGnNv)a and derivatives thereof as an immunostimulating agents/adjuvant |
EP3346005A1 (en) * | 2008-01-31 | 2018-07-11 | CureVac AG | Nucleic acids of formula (i) (nuglxmgnnv)a and derivatives thereof as an immunostimulating agent/adjuvant |
US9572874B2 (en) | 2008-09-30 | 2017-02-21 | Curevac Ag | Composition comprising a complexed (M)RNA and a naked mRNA for providing or enhancing an immunostimulatory response in a mammal and uses thereof |
US9855291B2 (en) | 2008-11-03 | 2018-01-02 | Adc Therapeutics Sa | Anti-kidney associated antigen 1 (KAAG1) antibodies |
US8580257B2 (en) | 2008-11-03 | 2013-11-12 | Alethia Biotherapeutics Inc. | Antibodies that specifically block the biological activity of kidney associated antigen 1 (KAAG1) |
US9907862B2 (en) | 2009-09-03 | 2018-03-06 | Curevac Ag | Disulfide-linked polyethyleneglycol/peptide conjugates for the transfection of nucleic acids |
US9314535B2 (en) | 2009-09-03 | 2016-04-19 | Curevac Ag | Disulfide-linked polyethyleneglycol/peptide conjugates for the transfection of nucleic acids |
US10751424B2 (en) | 2009-09-03 | 2020-08-25 | Curevac Ag | Disulfide-linked polyethyleneglycol/peptide conjugates for the transfection of nucleic acids |
US8968746B2 (en) | 2010-07-30 | 2015-03-03 | Curevac Gmbh | Complexation of nucleic acids with disulfide-crosslinked cationic components for transfection and immunostimulation |
US9937233B2 (en) | 2010-08-06 | 2018-04-10 | Modernatx, Inc. | Engineered nucleic acids and methods of use thereof |
US8822663B2 (en) | 2010-08-06 | 2014-09-02 | Moderna Therapeutics, Inc. | Engineered nucleic acids and methods of use thereof |
US9447164B2 (en) | 2010-08-06 | 2016-09-20 | Moderna Therapeutics, Inc. | Engineered nucleic acids and methods of use thereof |
US9181319B2 (en) | 2010-08-06 | 2015-11-10 | Moderna Therapeutics, Inc. | Engineered nucleic acids and methods of use thereof |
US12109275B2 (en) | 2010-08-13 | 2024-10-08 | CureVac SE | Nucleic acid comprising or coding for a histone stem-loop and a poly(A) sequence or a polyadenylation signal for increasing the expression of an encoded protein |
EP4043040B1 (en) | 2010-08-31 | 2023-01-11 | GlaxoSmithKline Biologicals SA | Small liposomes for delivery of immunogen-encoding rna |
EP4066855B1 (en) | 2010-08-31 | 2022-12-28 | GlaxoSmithKline Biologicals SA | Pegylated liposomes for delivery of immunogen-encoding rna |
US9334328B2 (en) | 2010-10-01 | 2016-05-10 | Moderna Therapeutics, Inc. | Modified nucleosides, nucleotides, and nucleic acids, and uses thereof |
US9657295B2 (en) | 2010-10-01 | 2017-05-23 | Modernatx, Inc. | Modified nucleosides, nucleotides, and nucleic acids, and uses thereof |
US10064959B2 (en) | 2010-10-01 | 2018-09-04 | Modernatx, Inc. | Modified nucleosides, nucleotides, and nucleic acids, and uses thereof |
JP2014508152A (en) * | 2011-02-09 | 2014-04-03 | キュアバック ゲーエムベーハー | Vaccination in newborns and infants |
US9421255B2 (en) | 2011-02-21 | 2016-08-23 | Curevac Ag | Vaccine composition comprising complexed immunostimulatory nucleic acids and antigens packaged with disulfide-linked polyethyleneglycol/peptide conjugates |
US10568958B2 (en) | 2011-02-21 | 2020-02-25 | Curevac Ag | Vaccine composition comprising complexed immunostimulatory nucleic acids and antigens packaged with disulfide-linked polyethyleneglycol/peptide conjugates |
EP2680881B1 (en) | 2011-03-02 | 2017-04-05 | CureVac AG | Vaccination in elderly patients |
EP2680880B2 (en) † | 2011-03-02 | 2021-11-10 | CureVac AG | Vaccination in newborns and infants |
US10596252B2 (en) | 2011-03-02 | 2020-03-24 | Curevac Ag | Vaccination in newborns and infants |
US11975064B2 (en) | 2011-03-02 | 2024-05-07 | CureVac SE | Vaccination with mRNA-coded antigens |
US10729761B2 (en) | 2011-03-02 | 2020-08-04 | Curevac Ag | Vaccination in newborns and infants |
EP3473265A1 (en) * | 2011-03-02 | 2019-04-24 | CureVac AG | Vaccination in elderly patients |
US12036277B2 (en) | 2011-03-02 | 2024-07-16 | CureVac SE | Vaccination with mRNA-coded antigens |
US10172935B2 (en) | 2011-03-02 | 2019-01-08 | Curevac Ag | Vaccination in newborns and infants |
JP2017149744A (en) * | 2011-03-02 | 2017-08-31 | キュアバック アーゲー | Vaccination in newborn and infant |
JP2017149743A (en) * | 2011-03-02 | 2017-08-31 | キュアバック アーゲー | Vaccination in elderly patient |
JP2014508153A (en) * | 2011-03-02 | 2014-04-03 | キュアバック ゲーエムベーハー | Vaccination in elderly patients |
EP3473266A1 (en) * | 2011-03-02 | 2019-04-24 | CureVac AG | Vaccination in newborns and infants |
JP2019059774A (en) * | 2011-03-02 | 2019-04-18 | キュアバック アーゲー | Vaccination in newborn and infant |
US9623095B2 (en) | 2011-03-02 | 2017-04-18 | Curevac Ag | Vaccination in newborns and infants |
EP2680880B1 (en) | 2011-03-02 | 2017-04-26 | CureVac AG | Vaccination in newborns and infants |
JP2021191783A (en) * | 2011-03-02 | 2021-12-16 | キュアバック アーゲー | Vaccination in newborns and infants |
US11672856B2 (en) | 2011-03-02 | 2023-06-13 | CureVac SE | Vaccination in newborns and infants |
US9950068B2 (en) | 2011-03-31 | 2018-04-24 | Modernatx, Inc. | Delivery and formulation of engineered nucleic acids |
US9393302B2 (en) | 2011-03-31 | 2016-07-19 | Alethia Biotherapeutics Inc. | Antibodies against kidney associated antigen 1 and antigen binding fragments thereof |
US8710200B2 (en) | 2011-03-31 | 2014-04-29 | Moderna Therapeutics, Inc. | Engineered nucleic acids encoding a modified erythropoietin and their expression |
US10597450B2 (en) | 2011-03-31 | 2020-03-24 | Adc Therapeutics Sa | Antibodies against kidney associated antigen 1 and antigen binding fragments thereof |
US9828426B2 (en) | 2011-03-31 | 2017-11-28 | Adc Therapeutics Sa | Antibodies against kidney associated antigen 1 and antigen binding fragments thereof |
US8937163B2 (en) | 2011-03-31 | 2015-01-20 | Alethia Biotherapeutics Inc. | Antibodies against kidney associated antigen 1 and antigen binding fragments thereof |
US9533047B2 (en) | 2011-03-31 | 2017-01-03 | Modernatx, Inc. | Delivery and formulation of engineered nucleic acids |
EP2714071B1 (en) | 2011-05-24 | 2019-07-10 | BioNTech RNA Pharmaceuticals GmbH | Individualized vaccines for cancer |
EP3892295B1 (en) | 2011-05-24 | 2023-04-26 | BioNTech SE | Individualized vaccines for cancer |
US11248264B2 (en) | 2011-05-24 | 2022-02-15 | Tron-Translationale Onkologie An Der Universitätsmedizin Der Johannes Gutenberg-Universität Mainz Ggmbh | Individualized vaccines for cancer |
US10738355B2 (en) | 2011-05-24 | 2020-08-11 | Tron-Translationale Onkologie An Der Universitätsmedizin Der Johannes Gutenberg-Universität Mainz Ggmbh | Individualized vaccines for cancer |
EP3473267B1 (en) | 2011-05-24 | 2021-09-08 | BioNTech RNA Pharmaceuticals GmbH | Individualized vaccines for cancer |
US11013773B2 (en) | 2011-07-14 | 2021-05-25 | 4D Pharma Research Limited | Lactic acid bacterial strains |
US20140186398A1 (en) * | 2011-07-18 | 2014-07-03 | Icahn School Of Medicine At Mount Sinai | BACTERIAL RNAs AS VACCINE ADJUVANTS |
US9844592B2 (en) * | 2011-07-18 | 2017-12-19 | Icahn School Of Medicine At Mount Sinai | Bacterial RNAs as vaccine adjuvants |
US10588964B2 (en) | 2011-07-18 | 2020-03-17 | Cornell University | Bacterial RNAs as vaccine adjuvants |
US10022425B2 (en) | 2011-09-12 | 2018-07-17 | Modernatx, Inc. | Engineered nucleic acids and methods of use thereof |
US9464124B2 (en) | 2011-09-12 | 2016-10-11 | Moderna Therapeutics, Inc. | Engineered nucleic acids and methods of use thereof |
US10751386B2 (en) | 2011-09-12 | 2020-08-25 | Modernatx, Inc. | Engineered nucleic acids and methods of use thereof |
US9428535B2 (en) | 2011-10-03 | 2016-08-30 | Moderna Therapeutics, Inc. | Modified nucleosides, nucleotides, and nucleic acids, and uses thereof |
US11266698B2 (en) | 2011-10-07 | 2022-03-08 | 4D Pharma Research Limited | Bacterium for use as a probiotic for nutritional and medical applications |
US9937211B2 (en) | 2011-10-07 | 2018-04-10 | 4D Pharma Research Limited | Composition of Roseburia hominis |
US8680069B2 (en) | 2011-12-16 | 2014-03-25 | Moderna Therapeutics, Inc. | Modified polynucleotides for the production of G-CSF |
US9186372B2 (en) | 2011-12-16 | 2015-11-17 | Moderna Therapeutics, Inc. | Split dose administration |
US8754062B2 (en) | 2011-12-16 | 2014-06-17 | Moderna Therapeutics, Inc. | DLIN-KC2-DMA lipid nanoparticle delivery of modified polynucleotides |
US9295689B2 (en) | 2011-12-16 | 2016-03-29 | Moderna Therapeutics, Inc. | Formulation and delivery of PLGA microspheres |
US9271996B2 (en) | 2011-12-16 | 2016-03-01 | Moderna Therapeutics, Inc. | Formulation and delivery of PLGA microspheres |
US8664194B2 (en) | 2011-12-16 | 2014-03-04 | Moderna Therapeutics, Inc. | Method for producing a protein of interest in a primate |
US11084872B2 (en) | 2012-01-09 | 2021-08-10 | Adc Therapeutics Sa | Method for treating breast cancer |
US11690910B2 (en) | 2012-01-31 | 2023-07-04 | CureVac SE | Pharmaceutical composition comprising a polymeric carrier cargo complex and at least one protein or peptide antigen |
WO2013113502A1 (en) | 2012-01-31 | 2013-08-08 | Curevac Gmbh | Negatively charged nucleic acid comprising complexes for immunostimulation |
EP3838294A1 (en) | 2012-01-31 | 2021-06-23 | CureVac AG | Negatively charged nucleic acid comprising complexes for immunostimulation |
WO2013113325A1 (en) * | 2012-01-31 | 2013-08-08 | Curevac Gmbh | Negatively charged nucleic acid comprising complexes for immunostimulation |
EP2830593B1 (en) * | 2012-03-26 | 2019-02-27 | BioNTech RNA Pharmaceuticals GmbH | Rna formulation for immunotherapy |
US11559587B2 (en) | 2012-03-26 | 2023-01-24 | Tron-Translationale Onkologie An Der Universitätsmedizin Der Johannes Gutenberg-Universität Mainz Ggmbh | RNA formulation for immunotherapy |
US10485884B2 (en) | 2012-03-26 | 2019-11-26 | Biontech Rna Pharmaceuticals Gmbh | RNA formulation for immunotherapy |
WO2013143683A1 (en) | 2012-03-26 | 2013-10-03 | Biontech Ag | Rna formulation for immunotherapy |
EP3777840A1 (en) * | 2012-03-26 | 2021-02-17 | BioNTech RNA Pharmaceuticals GmbH | Rna formulation for immunotherapy |
CN109331176B (en) * | 2012-03-26 | 2022-12-02 | 生物技术公司 | RNA formulations for immunotherapy |
EP3427723A1 (en) * | 2012-03-26 | 2019-01-16 | BioNTech RNA Pharmaceuticals GmbH | Rna formulation for immunotherapy |
CN109331176A (en) * | 2012-03-26 | 2019-02-15 | 生物技术Rna制药有限公司 | RNA preparation for immunization therapy |
US9221891B2 (en) | 2012-04-02 | 2015-12-29 | Moderna Therapeutics, Inc. | In vivo production of proteins |
US9114113B2 (en) | 2012-04-02 | 2015-08-25 | Moderna Therapeutics, Inc. | Modified polynucleotides encoding citeD4 |
US9828416B2 (en) | 2012-04-02 | 2017-11-28 | Modernatx, Inc. | Modified polynucleotides for the production of secreted proteins |
US9878056B2 (en) | 2012-04-02 | 2018-01-30 | Modernatx, Inc. | Modified polynucleotides for the production of cosmetic proteins and peptides |
US9827332B2 (en) | 2012-04-02 | 2017-11-28 | Modernatx, Inc. | Modified polynucleotides for the production of proteins |
US9814760B2 (en) | 2012-04-02 | 2017-11-14 | Modernatx, Inc. | Modified polynucleotides for the production of biologics and proteins associated with human disease |
US8999380B2 (en) | 2012-04-02 | 2015-04-07 | Moderna Therapeutics, Inc. | Modified polynucleotides for the production of biologics and proteins associated with human disease |
US9050297B2 (en) | 2012-04-02 | 2015-06-09 | Moderna Therapeutics, Inc. | Modified polynucleotides encoding aryl hydrocarbon receptor nuclear translocator |
US9061059B2 (en) | 2012-04-02 | 2015-06-23 | Moderna Therapeutics, Inc. | Modified polynucleotides for treating protein deficiency |
US9782462B2 (en) | 2012-04-02 | 2017-10-10 | Modernatx, Inc. | Modified polynucleotides for the production of proteins associated with human disease |
US9675668B2 (en) | 2012-04-02 | 2017-06-13 | Moderna Therapeutics, Inc. | Modified polynucleotides encoding hepatitis A virus cellular receptor 2 |
US9089604B2 (en) | 2012-04-02 | 2015-07-28 | Moderna Therapeutics, Inc. | Modified polynucleotides for treating galactosylceramidase protein deficiency |
US9095552B2 (en) | 2012-04-02 | 2015-08-04 | Moderna Therapeutics, Inc. | Modified polynucleotides encoding copper metabolism (MURR1) domain containing 1 |
US9107886B2 (en) | 2012-04-02 | 2015-08-18 | Moderna Therapeutics, Inc. | Modified polynucleotides encoding basic helix-loop-helix family member E41 |
US9149506B2 (en) | 2012-04-02 | 2015-10-06 | Moderna Therapeutics, Inc. | Modified polynucleotides encoding septin-4 |
US9192651B2 (en) | 2012-04-02 | 2015-11-24 | Moderna Therapeutics, Inc. | Modified polynucleotides for the production of secreted proteins |
US9216205B2 (en) | 2012-04-02 | 2015-12-22 | Moderna Therapeutics, Inc. | Modified polynucleotides encoding granulysin |
US9587003B2 (en) | 2012-04-02 | 2017-03-07 | Modernatx, Inc. | Modified polynucleotides for the production of oncology-related proteins and peptides |
US9220755B2 (en) | 2012-04-02 | 2015-12-29 | Moderna Therapeutics, Inc. | Modified polynucleotides for the production of proteins associated with blood and lymphatic disorders |
US9572897B2 (en) | 2012-04-02 | 2017-02-21 | Modernatx, Inc. | Modified polynucleotides for the production of cytoplasmic and cytoskeletal proteins |
US9303079B2 (en) | 2012-04-02 | 2016-04-05 | Moderna Therapeutics, Inc. | Modified polynucleotides for the production of cytoplasmic and cytoskeletal proteins |
US9301993B2 (en) | 2012-04-02 | 2016-04-05 | Moderna Therapeutics, Inc. | Modified polynucleotides encoding apoptosis inducing factor 1 |
US9220792B2 (en) | 2012-04-02 | 2015-12-29 | Moderna Therapeutics, Inc. | Modified polynucleotides encoding aquaporin-5 |
US9283287B2 (en) | 2012-04-02 | 2016-03-15 | Moderna Therapeutics, Inc. | Modified polynucleotides for the production of nuclear proteins |
US9255129B2 (en) | 2012-04-02 | 2016-02-09 | Moderna Therapeutics, Inc. | Modified polynucleotides encoding SIAH E3 ubiquitin protein ligase 1 |
US9254311B2 (en) | 2012-04-02 | 2016-02-09 | Moderna Therapeutics, Inc. | Modified polynucleotides for the production of proteins |
US9233141B2 (en) | 2012-04-02 | 2016-01-12 | Moderna Therapeutics, Inc. | Modified polynucleotides for the production of proteins associated with blood and lymphatic disorders |
RU2662962C2 (en) * | 2012-09-25 | 2018-07-31 | Джензим Корпорейшн | Peptide-linked morpholino antisense oligonucleotides for treatment of myotonic dystrophy |
US10111962B2 (en) | 2012-09-25 | 2018-10-30 | Genzyme Corporation | Peptide-linked morpholino antisense oligonucleotides for treatment of myotonic dystrophy |
US9597380B2 (en) | 2012-11-26 | 2017-03-21 | Modernatx, Inc. | Terminally modified RNA |
US8980864B2 (en) | 2013-03-15 | 2015-03-17 | Moderna Therapeutics, Inc. | Compositions and methods of altering cholesterol levels |
US10851137B2 (en) | 2013-04-10 | 2020-12-01 | 4D Pharma Research Limited | Polypeptide and immune modulation |
US11414463B2 (en) | 2013-04-10 | 2022-08-16 | 4D Pharma Research Limited | Polypeptide and immune modulation |
US9796762B2 (en) | 2013-04-10 | 2017-10-24 | 4D Pharma Research Limited | Polypeptide and immune modulation |
EP3019619B1 (en) | 2013-07-11 | 2021-08-25 | ModernaTX, Inc. | Compositions comprising synthetic polynucleotides encoding crispr related proteins and synthetic sgrnas and methods of use |
EP4043032A1 (en) | 2013-08-21 | 2022-08-17 | CureVac AG | Rabies vaccine |
EP3586871A2 (en) | 2013-08-21 | 2020-01-01 | CureVac AG | Respiratory syncytial virus (rsv) vaccine |
US20220152193A1 (en) * | 2013-08-21 | 2022-05-19 | Curevac Ag | Combination vaccine |
US11965000B2 (en) | 2013-08-21 | 2024-04-23 | CureVac SE | Respiratory syncytial virus (RSV) vaccine |
EP3461498A1 (en) | 2013-08-21 | 2019-04-03 | CureVac AG | Rabies vaccine |
US11739125B2 (en) | 2013-08-21 | 2023-08-29 | Cure Vac SE | Respiratory syncytial virus (RSV) vaccine |
US10815291B2 (en) | 2013-09-30 | 2020-10-27 | Modernatx, Inc. | Polynucleotides encoding immune modulating polypeptides |
US10323076B2 (en) | 2013-10-03 | 2019-06-18 | Modernatx, Inc. | Polynucleotides encoding low density lipoprotein receptor |
WO2015101414A2 (en) | 2013-12-30 | 2015-07-09 | Curevac Gmbh | Artificial nucleic acid molecules |
WO2015101415A1 (en) | 2013-12-30 | 2015-07-09 | Curevac Gmbh | Artificial nucleic acid molecules |
EP3495486A1 (en) | 2013-12-30 | 2019-06-12 | CureVac AG | Artificial nucleic acid molecules |
EP3842537A1 (en) | 2013-12-30 | 2021-06-30 | CureVac AG | Artificial nucleic acid molecules |
WO2015149944A3 (en) * | 2014-04-01 | 2015-11-26 | Curevac Ag | Polymeric carrier cargo complex for use as an immunostimulating agent or as an adjuvant |
US10369216B2 (en) | 2014-04-01 | 2019-08-06 | Curevac Ag | Polymeric carrier cargo complex for use as an immunostimulating agent or as an adjuvant |
US11110166B2 (en) | 2014-04-01 | 2021-09-07 | Curevac Ag | Polymeric carrier cargo complex for use as an immunostimulating agent or as an adjuvant |
EP3134131B1 (en) | 2014-04-23 | 2021-12-22 | ModernaTX, Inc. | Nucleic acid vaccines |
DE202015009974U1 (en) | 2014-12-12 | 2022-02-17 | Curevac Ag | Artificial nucleic acid molecules for improved protein expression |
US11761009B2 (en) | 2014-12-12 | 2023-09-19 | CureVac SE | Artificial nucleic acid molecules for improved protein expression |
DE202015010001U1 (en) | 2014-12-12 | 2023-07-03 | CureVac SE | Artificial nucleic acid molecules for improved protein expression |
DE202015010000U1 (en) | 2014-12-12 | 2023-07-03 | CureVac SE | Artificial nucleic acid molecules for improved protein expression |
EP3708668B1 (en) | 2014-12-12 | 2022-07-27 | CureVac AG | Artificial nucleic acid molecules for improved protein expression |
DE202015009961U1 (en) | 2014-12-12 | 2022-01-25 | Curevac Ag | Artificial nucleic acid molecules for improved protein expression |
EP4023755A1 (en) | 2014-12-12 | 2022-07-06 | CureVac AG | Artificial nucleic acid molecules for improved protein expression |
EP4241784A2 (en) | 2014-12-12 | 2023-09-13 | CureVac SE | Artificial nucleic acid molecules for improved protein expression |
EP4023755B1 (en) | 2014-12-12 | 2023-04-26 | CureVac SE | Artificial nucleic acid molecules for improved protein expression |
US11723933B2 (en) | 2014-12-23 | 2023-08-15 | Cj Bioscience, Inc. | Composition of bacteroides thetaiotaomicron for immune modulation |
US10456444B2 (en) | 2014-12-23 | 2019-10-29 | 4D Pharma Research Limited | Pirin polypeptide and immune modulation |
US10973872B2 (en) | 2014-12-23 | 2021-04-13 | 4D Pharma Research Limited | Pirin polypeptide and immune modulation |
EP3494982A1 (en) | 2014-12-30 | 2019-06-12 | CureVac AG | Artificial nucleic acid molecules |
EP4353257A2 (en) | 2015-04-13 | 2024-04-17 | CureVac Manufacturing GmbH | Method for producing rna compositions |
EP4026568A1 (en) | 2015-04-17 | 2022-07-13 | CureVac Real Estate GmbH | Lyophilization of rna |
WO2016165831A1 (en) | 2015-04-17 | 2016-10-20 | Curevac Ag | Lyophilization of rna |
EP3326641A1 (en) | 2015-04-22 | 2018-05-30 | CureVac AG | Rna containing composition for treatment of tumor diseases |
WO2016170176A1 (en) | 2015-04-22 | 2016-10-27 | Curevac Ag | Rna containing composition for treatment of tumor diseases |
EP3603661A2 (en) | 2015-04-22 | 2020-02-05 | CureVac AG | Rna containing composition for treatment of tumor diseases |
EP3173092A2 (en) | 2015-04-22 | 2017-05-31 | CureVac AG | Rna containing composition for treatment of tumor diseases |
WO2016184822A1 (en) | 2015-05-15 | 2016-11-24 | Curevac Ag | Prime-boost regimens involving administration of at least one mrna construct |
US11559570B2 (en) | 2015-05-15 | 2023-01-24 | CureVac SE | Prime-boost regimens involving administration of at least one mRNA construct |
RU2742993C2 (en) * | 2015-05-15 | 2021-02-12 | Куревак Аг | Prime-boost modes involving introduction of at least one mrna structure |
CN107810009A (en) * | 2015-05-15 | 2018-03-16 | 库瑞瓦格股份公司 | It is related to and exempts from strengthened scheme using at least one the first of mRNA constructs |
US20180125952A1 (en) * | 2015-05-15 | 2018-05-10 | Curevac Ag | PRIME-BOOST REGIMENS INVOLVING ADMINISTRATION OF AT LEAST ONE mRNA CONSTRUCT |
EP3928800A2 (en) | 2015-05-20 | 2021-12-29 | CureVac AG | Dry powder composition comprising long-chain rna |
EP3916091A2 (en) | 2015-05-20 | 2021-12-01 | CureVac AG | Dry powder composition comprising long-chain rna |
US10736926B2 (en) | 2015-06-15 | 2020-08-11 | 4D Pharma Research Limited | Compositions comprising bacterial strains |
US10500237B2 (en) | 2015-06-15 | 2019-12-10 | 4D Pharma Research Limited | Compositions comprising bacterial strains |
US10322151B2 (en) | 2015-06-15 | 2019-06-18 | 4D Pharma Research Limited | Compositions comprising bacterial strains |
US10780134B2 (en) | 2015-06-15 | 2020-09-22 | 4D Pharma Research Limited | Compositions comprising bacterial strains |
US10744167B2 (en) | 2015-06-15 | 2020-08-18 | 4D Pharma Research Limited | Compositions comprising bacterial strains |
US11273185B2 (en) | 2015-06-15 | 2022-03-15 | 4D Pharma Research Limited | Compositions comprising bacterial strains |
US10493112B2 (en) | 2015-06-15 | 2019-12-03 | 4D Pharma Research Limited | Compositions comprising bacterial strains |
US11331352B2 (en) | 2015-06-15 | 2022-05-17 | 4D Pharma Research Limited | Compositions comprising bacterial strains |
US10864236B2 (en) | 2015-06-15 | 2020-12-15 | 4D Pharma Research Limited | Compositions comprising bacterial strains |
US10391130B2 (en) | 2015-06-15 | 2019-08-27 | 4D Pharma Research Limited | Compositions comprising bacterial strains |
US11389493B2 (en) | 2015-06-15 | 2022-07-19 | 4D Pharma Research Limited | Compositions comprising bacterial strains |
US11433106B2 (en) | 2015-06-15 | 2022-09-06 | 4D Pharma Research Limited | Compositions comprising bacterial strains |
US11040075B2 (en) | 2015-06-15 | 2021-06-22 | 4D Pharma Research Limited | Compositions comprising bacterial strains |
US11364292B2 (en) | 2015-07-21 | 2022-06-21 | Modernatx, Inc. | CHIKV RNA vaccines |
US10702597B2 (en) | 2015-07-21 | 2020-07-07 | Modernatx, Inc. | CHIKV RNA vaccines |
US11007260B2 (en) | 2015-07-21 | 2021-05-18 | Modernatx, Inc. | Infectious disease vaccines |
US10449244B2 (en) | 2015-07-21 | 2019-10-22 | Modernatx, Inc. | Zika RNA vaccines |
EP4108774A1 (en) | 2015-08-28 | 2022-12-28 | CureVac AG | Artificial nucleic acid molecules |
EP3736261A1 (en) | 2015-09-17 | 2020-11-11 | ModernaTX, Inc. | Compounds and compositions for intracellular delivery of therapeutic agents |
WO2017049245A2 (en) | 2015-09-17 | 2017-03-23 | Modernatx, Inc. | Compounds and compositions for intracellular delivery of therapeutic agents |
EP4286012A2 (en) | 2015-09-17 | 2023-12-06 | ModernaTX, Inc. | Compounds and compositions for intracellular delivery of therapeutic agents |
EP4086269A1 (en) | 2015-10-16 | 2022-11-09 | ModernaTX, Inc. | Mrna cap analogs with modified phosphate linkage |
WO2017066791A1 (en) | 2015-10-16 | 2017-04-20 | Modernatx, Inc. | Sugar substituted mrna cap analogs |
WO2017066793A1 (en) | 2015-10-16 | 2017-04-20 | Modernatx, Inc. | Mrna cap analogs and methods of mrna capping |
WO2017066789A1 (en) | 2015-10-16 | 2017-04-20 | Modernatx, Inc. | Mrna cap analogs with modified sugar |
WO2017066781A1 (en) | 2015-10-16 | 2017-04-20 | Modernatx, Inc. | Mrna cap analogs with modified phosphate linkage |
WO2017066782A1 (en) | 2015-10-16 | 2017-04-20 | Modernatx, Inc. | Hydrophobic mrna cap analogs |
US10716846B2 (en) | 2015-10-22 | 2020-07-21 | Modernatx, Inc. | Human cytomegalovirus RNA vaccines |
US10517940B2 (en) | 2015-10-22 | 2019-12-31 | Modernatx, Inc. | Zika virus RNA vaccines |
US10272150B2 (en) | 2015-10-22 | 2019-04-30 | Modernatx, Inc. | Combination PIV3/hMPV RNA vaccines |
US11235052B2 (en) | 2015-10-22 | 2022-02-01 | Modernatx, Inc. | Chikungunya virus RNA vaccines |
US10493143B2 (en) | 2015-10-22 | 2019-12-03 | Modernatx, Inc. | Sexually transmitted disease vaccines |
US10064934B2 (en) | 2015-10-22 | 2018-09-04 | Modernatx, Inc. | Combination PIV3/hMPV RNA vaccines |
US20180289792A1 (en) * | 2015-10-22 | 2018-10-11 | ModernaTX. Inc. | Sexually transmitted disease vaccines |
WO2017070616A3 (en) * | 2015-10-22 | 2017-07-27 | Modernatx, Inc. | Sexually transmitted disease vaccines |
US10238731B2 (en) | 2015-10-22 | 2019-03-26 | Modernatx, Inc. | Chikagunya virus RNA vaccines |
US11872278B2 (en) | 2015-10-22 | 2024-01-16 | Modernatx, Inc. | Combination HMPV/RSV RNA vaccines |
US10124055B2 (en) | 2015-10-22 | 2018-11-13 | Modernatx, Inc. | Zika virus RNA vaccines |
US10064935B2 (en) | 2015-10-22 | 2018-09-04 | Modernatx, Inc. | Human cytomegalovirus RNA vaccines |
US10933127B2 (en) | 2015-10-22 | 2021-03-02 | Modernatx, Inc. | Betacoronavirus mRNA vaccine |
US10543269B2 (en) | 2015-10-22 | 2020-01-28 | Modernatx, Inc. | hMPV RNA vaccines |
US11278611B2 (en) | 2015-10-22 | 2022-03-22 | Modernatx, Inc. | Zika virus RNA vaccines |
US10383937B2 (en) | 2015-10-22 | 2019-08-20 | Modernatx, Inc. | Human cytomegalovirus RNA vaccines |
US11484590B2 (en) | 2015-10-22 | 2022-11-01 | Modernatx, Inc. | Human cytomegalovirus RNA vaccines |
US10702600B1 (en) | 2015-10-22 | 2020-07-07 | Modernatx, Inc. | Betacoronavirus mRNA vaccine |
US10702599B2 (en) | 2015-10-22 | 2020-07-07 | Modernatx, Inc. | HPIV3 RNA vaccines |
US10675342B2 (en) | 2015-10-22 | 2020-06-09 | Modernatx, Inc. | Chikungunya virus RNA vaccines |
US11058732B2 (en) | 2015-11-20 | 2021-07-13 | 4D Pharma Research Limited | Compositions comprising bacterial strains |
US10471108B2 (en) | 2015-11-20 | 2019-11-12 | 4D Pharma Research Limited | Compositions comprising bacterial strains |
US10610550B2 (en) | 2015-11-20 | 2020-04-07 | 4D Pharma Research Limited | Compositions comprising bacterial strains |
US10744166B2 (en) | 2015-11-23 | 2020-08-18 | 4D Pharma Research Limited | Compositions comprising bacterial strains |
US10391128B2 (en) | 2015-11-23 | 2019-08-27 | 4D Pharma Research Limited | Compositions comprising bacterial strains |
EP4036079A2 (en) | 2015-12-22 | 2022-08-03 | ModernaTX, Inc. | Compounds and compositions for intracellular delivery of agents |
EP3701963A1 (en) | 2015-12-22 | 2020-09-02 | CureVac AG | Method for producing rna molecule compositions |
WO2017112865A1 (en) | 2015-12-22 | 2017-06-29 | Modernatx, Inc. | Compounds and compositions for intracellular delivery of agents |
US10583158B2 (en) | 2016-03-04 | 2020-03-10 | 4D Pharma Plc | Compositions comprising bacterial strains |
WO2017182634A1 (en) | 2016-04-22 | 2017-10-26 | Curevac Ag | Rna encoding a tumor antigen |
EP3777881A1 (en) | 2016-04-22 | 2021-02-17 | CureVac AG | Rna encoding a tumor antigen |
EP4233898A2 (en) | 2016-05-04 | 2023-08-30 | CureVac SE | Influenza mrna vaccines |
WO2017191264A1 (en) | 2016-05-04 | 2017-11-09 | Curevac Ag | Nucleic acid molecules and uses thereof |
WO2017191274A2 (en) | 2016-05-04 | 2017-11-09 | Curevac Ag | Rna encoding a therapeutic protein |
WO2017218704A1 (en) | 2016-06-14 | 2017-12-21 | Modernatx, Inc. | Stabilized formulations of lipid nanoparticles |
US11814627B2 (en) * | 2016-06-20 | 2023-11-14 | The Board Of The Leland Stanford Junior University | Circular RNAs and their use in immunomodulation |
US10960031B2 (en) | 2016-07-13 | 2021-03-30 | 4D Pharma Plc | Compositions comprising bacterial strains |
US10967010B2 (en) | 2016-07-13 | 2021-04-06 | 4D Pharma Plc | Compositions comprising bacterial strains |
US10610548B2 (en) | 2016-07-13 | 2020-04-07 | 4D Pharma Plc | Compositions comprising bacterial strains |
US10610549B2 (en) | 2016-07-13 | 2020-04-07 | 4D Pharma Plc | Composition comprising bacterial strains |
US11224620B2 (en) | 2016-07-13 | 2022-01-18 | 4D Pharma Plc | Compositions comprising bacterial strains |
WO2018033254A2 (en) | 2016-08-19 | 2018-02-22 | Curevac Ag | Rna for cancer therapy |
WO2018041921A1 (en) | 2016-08-31 | 2018-03-08 | Curevac Ag | Mixing device for the production of a liquid nucleic acid composition |
US11197927B2 (en) | 2016-10-21 | 2021-12-14 | Modernatx, Inc. | Human cytomegalovirus vaccine |
US11541113B2 (en) | 2016-10-21 | 2023-01-03 | Modernatx, Inc. | Human cytomegalovirus vaccine |
US10695419B2 (en) | 2016-10-21 | 2020-06-30 | Modernatx, Inc. | Human cytomegalovirus vaccine |
WO2018078053A1 (en) | 2016-10-26 | 2018-05-03 | Curevac Ag | Lipid nanoparticle mrna vaccines |
WO2018089540A1 (en) | 2016-11-08 | 2018-05-17 | Modernatx, Inc. | Stabilized formulations of lipid nanoparticles |
EP4035659A1 (en) | 2016-11-29 | 2022-08-03 | PureTech LYT, Inc. | Exosomes for delivery of therapeutic agents |
WO2018104540A1 (en) | 2016-12-08 | 2018-06-14 | Curevac Ag | Rnas for wound healing |
EP3808380A1 (en) | 2016-12-08 | 2021-04-21 | CureVac AG | Rna for treatment or prophylaxis of a liver disease |
US11103578B2 (en) | 2016-12-08 | 2021-08-31 | Modernatx, Inc. | Respiratory virus nucleic acid vaccines |
WO2018104538A1 (en) | 2016-12-08 | 2018-06-14 | Curevac Ag | Rna for treatment or prophylaxis of a liver disease |
US10485830B2 (en) | 2016-12-12 | 2019-11-26 | 4D Pharma Plc | Compositions comprising bacterial strains |
WO2018115527A2 (en) | 2016-12-23 | 2018-06-28 | Curevac Ag | Mers coronavirus vaccine |
WO2018115507A2 (en) | 2016-12-23 | 2018-06-28 | Curevac Ag | Henipavirus vaccine |
WO2018115525A1 (en) | 2016-12-23 | 2018-06-28 | Curevac Ag | Lassa virus vaccine |
US11364259B2 (en) | 2016-12-27 | 2022-06-21 | The University Of Tokyo | MRNA functionalization method |
WO2018144082A1 (en) * | 2017-02-01 | 2018-08-09 | Modernatx, Inc. | Rna cancer vaccines |
US10273269B2 (en) | 2017-02-16 | 2019-04-30 | Modernatx, Inc. | High potency immunogenic zika virus compositions |
WO2018170336A1 (en) | 2017-03-15 | 2018-09-20 | Modernatx, Inc. | Lipid nanoparticle formulation |
EP4186888A1 (en) | 2017-03-15 | 2023-05-31 | ModernaTX, Inc. | Compound and compositions for intracellular delivery of therapeutic agents |
WO2018170306A1 (en) | 2017-03-15 | 2018-09-20 | Modernatx, Inc. | Compounds and compositions for intracellular delivery of therapeutic agents |
US11497807B2 (en) | 2017-03-17 | 2022-11-15 | Modernatx, Inc. | Zoonotic disease RNA vaccines |
WO2018167320A1 (en) | 2017-03-17 | 2018-09-20 | Curevac Ag | Rna vaccine and immune checkpoint inhibitors for combined anticancer therapy |
WO2018172556A1 (en) | 2017-03-24 | 2018-09-27 | Curevac Ag | Nucleic acids encoding crispr-associated proteins and uses thereof |
US11123378B2 (en) | 2017-05-22 | 2021-09-21 | 4D Pharma Research Limited | Compositions comprising bacterial strains |
US11382936B2 (en) | 2017-05-22 | 2022-07-12 | 4D Pharma Research Limited | Compositions comprising bacterial strains |
US11376284B2 (en) | 2017-05-22 | 2022-07-05 | 4D Pharma Research Limited | Compositions comprising bacterial strains |
US10987387B2 (en) | 2017-05-24 | 2021-04-27 | 4D Pharma Research Limited | Compositions comprising bacterial strain |
US11007233B2 (en) | 2017-06-14 | 2021-05-18 | 4D Pharma Research Limited | Compositions comprising a bacterial strain of the genus Megasphera and uses thereof |
US11660319B2 (en) | 2017-06-14 | 2023-05-30 | 4D Pharma Research Limited | Compositions comprising bacterial strains |
WO2018232120A1 (en) | 2017-06-14 | 2018-12-20 | Modernatx, Inc. | Compounds and compositions for intracellular delivery of agents |
US11123379B2 (en) | 2017-06-14 | 2021-09-21 | 4D Pharma Research Limited | Compositions comprising bacterial strains |
US12048720B2 (en) | 2017-06-14 | 2024-07-30 | Cj Bioscience, Inc. | Compositions comprising bacterial strains |
US11779613B2 (en) | 2017-06-14 | 2023-10-10 | Cj Bioscience, Inc. | Compositions comprising a bacterial strain of the genus Megasphera and uses thereof |
WO2019008001A1 (en) | 2017-07-04 | 2019-01-10 | Curevac Ag | Novel nucleic acid molecules |
EP3424524A2 (en) | 2017-07-04 | 2019-01-09 | CureVac AG | Cancer rna-vaccine |
WO2019036638A1 (en) | 2017-08-18 | 2019-02-21 | Modernatx, Inc. | Methods of preparing modified rna |
WO2019038332A1 (en) | 2017-08-22 | 2019-02-28 | Curevac Ag | Bunyavirales vaccine |
WO2019046809A1 (en) | 2017-08-31 | 2019-03-07 | Modernatx, Inc. | Methods of making lipid nanoparticles |
US11207398B2 (en) | 2017-09-14 | 2021-12-28 | Modernatx, Inc. | Zika virus mRNA vaccines |
US10653767B2 (en) | 2017-09-14 | 2020-05-19 | Modernatx, Inc. | Zika virus MRNA vaccines |
WO2019077001A1 (en) | 2017-10-19 | 2019-04-25 | Curevac Ag | Novel artificial nucleic acid molecules |
WO2019092153A1 (en) | 2017-11-08 | 2019-05-16 | Curevac Ag | Rna sequence adaptation |
WO2019115635A1 (en) | 2017-12-13 | 2019-06-20 | Curevac Ag | Flavivirus vaccine |
WO2019193183A2 (en) | 2018-04-05 | 2019-10-10 | Curevac Ag | Novel yellow fever nucleic acid molecules for vaccination |
EP4227319A1 (en) | 2018-04-17 | 2023-08-16 | CureVac SE | Novel rsv rna molecules and compositions for vaccination |
WO2020002525A1 (en) | 2018-06-27 | 2020-01-02 | Curevac Ag | Novel lassa virus rna molecules and compositions for vaccination |
WO2020061367A1 (en) | 2018-09-19 | 2020-03-26 | Modernatx, Inc. | Compounds and compositions for intracellular delivery of therapeutic agents |
WO2020061457A1 (en) | 2018-09-20 | 2020-03-26 | Modernatx, Inc. | Preparation of lipid nanoparticles and methods of administration thereof |
WO2020128031A2 (en) | 2018-12-21 | 2020-06-25 | Curevac Ag | Rna for malaria vaccines |
WO2020160397A1 (en) | 2019-01-31 | 2020-08-06 | Modernatx, Inc. | Methods of preparing lipid nanoparticles |
WO2020160430A1 (en) | 2019-01-31 | 2020-08-06 | Modernatx, Inc. | Vortex mixers and associated methods, systems, and apparatuses thereof |
EP4427739A2 (en) | 2019-01-31 | 2024-09-11 | ModernaTX, Inc. | Methods of preparing lipid nanoparticles |
WO2020161342A1 (en) | 2019-02-08 | 2020-08-13 | Curevac Ag | Coding rna administered into the suprachoroidal space in the treatment of ophtalmic diseases |
US11351242B1 (en) | 2019-02-12 | 2022-06-07 | Modernatx, Inc. | HMPV/hPIV3 mRNA vaccine composition |
US12070495B2 (en) | 2019-03-15 | 2024-08-27 | Modernatx, Inc. | HIV RNA vaccines |
WO2020254535A1 (en) | 2019-06-18 | 2020-12-24 | Curevac Ag | Rotavirus mrna vaccine |
WO2021123332A1 (en) | 2019-12-20 | 2021-06-24 | Curevac Ag | Lipid nanoparticles for delivery of nucleic acids |
DE202021003575U1 (en) | 2020-02-04 | 2022-01-17 | Curevac Ag | Coronavirus Vaccine |
EP4147717A1 (en) | 2020-02-04 | 2023-03-15 | CureVac SE | Coronavirus vaccine |
DE202021004130U1 (en) | 2020-02-04 | 2022-10-26 | Curevac Ag | Coronavirus Vaccine |
DE112021000012T5 (en) | 2020-02-04 | 2021-11-18 | Curevac Ag | Coronavirus vaccine |
WO2021156267A1 (en) | 2020-02-04 | 2021-08-12 | Curevac Ag | Coronavirus vaccine |
DE202021004123U1 (en) | 2020-02-04 | 2022-10-26 | Curevac Ag | Coronavirus Vaccine |
WO2021204175A1 (en) | 2020-04-09 | 2021-10-14 | Suzhou Abogen Biosciences Co., Ltd. | Lipid nanoparticle composition |
WO2021204179A1 (en) | 2020-04-09 | 2021-10-14 | Suzhou Abogen Biosciences Co., Ltd. | Nucleic acid vaccines for coronavirus |
WO2021239880A1 (en) | 2020-05-29 | 2021-12-02 | Curevac Ag | Nucleic acid based combination vaccines |
WO2022002040A1 (en) | 2020-06-30 | 2022-01-06 | Suzhou Abogen Biosciences Co., Ltd. | Lipid compounds and lipid nanoparticle compositions |
WO2022037652A1 (en) | 2020-08-20 | 2022-02-24 | Suzhou Abogen Biosciences Co., Ltd. | Lipid compounds and lipid nanoparticle compositions |
US11406703B2 (en) | 2020-08-25 | 2022-08-09 | Modernatx, Inc. | Human cytomegalovirus vaccine |
WO2022043551A2 (en) | 2020-08-31 | 2022-03-03 | Curevac Ag | Multivalent nucleic acid based coronavirus vaccines |
CN112194719A (en) * | 2020-09-01 | 2021-01-08 | 中日友好医院(中日友好临床医学研究所) | Preparation and application of CRT antigen and MAGE-A1 antigen |
WO2022152141A2 (en) | 2021-01-14 | 2022-07-21 | Suzhou Abogen Biosciences Co., Ltd. | Polymer conjugated lipid compounds and lipid nanoparticle compositions |
WO2022152109A2 (en) | 2021-01-14 | 2022-07-21 | Suzhou Abogen Biosciences Co., Ltd. | Lipid compounds and lipid nanoparticle compositions |
WO2022162027A2 (en) | 2021-01-27 | 2022-08-04 | Curevac Ag | Method of reducing the immunostimulatory properties of in vitro transcribed rna |
WO2022233880A1 (en) | 2021-05-03 | 2022-11-10 | Curevac Ag | Improved nucleic acid sequence for cell type specific expression |
WO2022247755A1 (en) | 2021-05-24 | 2022-12-01 | Suzhou Abogen Biosciences Co., Ltd. | Lipid compounds and lipid nanoparticle compositions |
WO2023006999A2 (en) | 2021-07-30 | 2023-02-02 | CureVac SE | Mrnas for treatment or prophylaxis of liver diseases |
WO2023031394A1 (en) | 2021-09-03 | 2023-03-09 | CureVac SE | Novel lipid nanoparticles for delivery of nucleic acids |
WO2023031392A2 (en) | 2021-09-03 | 2023-03-09 | CureVac SE | Novel lipid nanoparticles for delivery of nucleic acids comprising phosphatidylserine |
WO2023044343A1 (en) | 2021-09-14 | 2023-03-23 | Renagade Therapeutics Management Inc. | Acyclic lipids and methods of use thereof |
WO2023044333A1 (en) | 2021-09-14 | 2023-03-23 | Renagade Therapeutics Management Inc. | Cyclic lipids and methods of use thereof |
WO2023056917A1 (en) | 2021-10-08 | 2023-04-13 | Suzhou Abogen Biosciences Co., Ltd. | Lipid compounds and lipid nanoparticle compositions |
WO2023056914A1 (en) | 2021-10-08 | 2023-04-13 | Suzhou Abogen Biosciences Co., Ltd. | Lipid compounds and lipid nanoparticle compositions |
EP4162950A1 (en) | 2021-10-08 | 2023-04-12 | Suzhou Abogen Biosciences Co., Ltd. | Nucleic acid vaccines for coronavirus |
WO2023116804A1 (en) | 2021-12-23 | 2023-06-29 | 苏州艾博生物科技有限公司 | Lipid compound and lipid nanoparticle composition |
WO2023122752A1 (en) | 2021-12-23 | 2023-06-29 | Renagade Therapeutics Management Inc. | Constrained lipids and methods of use thereof |
WO2023144193A1 (en) | 2022-01-25 | 2023-08-03 | CureVac SE | Mrnas for treatment of hereditary tyrosinemia type i |
WO2023196931A1 (en) | 2022-04-07 | 2023-10-12 | Renagade Therapeutics Management Inc. | Cyclic lipids and lipid nanoparticles (lnp) for the delivery of nucleic acids or peptides for use in vaccinating against infectious agents |
WO2024015803A2 (en) | 2022-07-11 | 2024-01-18 | Autonomous Therapeutics, Inc. | Encrypted rna and methods of its use |
WO2024037578A1 (en) | 2022-08-18 | 2024-02-22 | Suzhou Abogen Biosciences Co., Ltd. | Composition of lipid nanoparticles |
WO2024192277A2 (en) | 2023-03-15 | 2024-09-19 | Renagade Therapeutics Management Inc. | Lipid nanoparticles comprising coding rna molecules for use in gene editing and as vaccines and therapeutic agents |
WO2024192291A1 (en) | 2023-03-15 | 2024-09-19 | Renagade Therapeutics Management Inc. | Delivery of gene editing systems and methods of use thereof |
Also Published As
Publication number | Publication date |
---|---|
WO2010037408A1 (en) | 2010-04-08 |
BRPI0915844B1 (en) | 2021-07-13 |
AU2009300113B2 (en) | 2013-04-18 |
JP5859853B2 (en) | 2016-02-16 |
CN102123733B (en) | 2016-01-13 |
AU2009300113A1 (en) | 2010-04-08 |
RU2011116931A (en) | 2012-11-10 |
JP2012502074A (en) | 2012-01-26 |
DK2331129T3 (en) | 2014-08-25 |
JP5931120B2 (en) | 2016-06-08 |
US20110250225A1 (en) | 2011-10-13 |
KR101343043B1 (en) | 2013-12-20 |
PL2331129T3 (en) | 2014-11-28 |
CA2730261A1 (en) | 2010-04-08 |
CN102123733A (en) | 2011-07-13 |
KR20110023889A (en) | 2011-03-08 |
PT2331129E (en) | 2014-08-26 |
ES2502915T3 (en) | 2014-10-06 |
US20170202957A1 (en) | 2017-07-20 |
EP2762165A2 (en) | 2014-08-06 |
SI2331129T1 (en) | 2014-09-30 |
US20210046179A1 (en) | 2021-02-18 |
JP2014196306A (en) | 2014-10-16 |
BRPI0915844A2 (en) | 2015-11-03 |
US9572874B2 (en) | 2017-02-21 |
EP2331129B1 (en) | 2014-06-18 |
HRP20140763T1 (en) | 2014-11-07 |
RU2545756C2 (en) | 2015-04-10 |
MX2010013071A (en) | 2010-12-20 |
EP2762165B1 (en) | 2017-08-09 |
EP2331129A1 (en) | 2011-06-15 |
EP2762165A3 (en) | 2014-10-29 |
CA2730261C (en) | 2016-11-29 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US20210046179A1 (en) | COMPOSITION COMPRISING A COMPLEXED (m)RNA AND A NAKED mRNA FOR PROVIDING OR ENHANCING AN IMMUNOSTIMULATORY RESPONSE IN A MAMMAL AND USES THEREOF | |
US20210060175A1 (en) | Methods of immunostimulation with complexes of rna and cationic carriers | |
US9616084B2 (en) | Mannose-containing solution for lyophilization, transfection and/or injection of nucleic acids | |
US20110053829A1 (en) | Disulfide-linked polyethyleneglycol/peptide conjugates for the transfection of nucleic acids | |
WO2010088927A1 (en) | Use of pei for the improvement of endosomal release and expression of transfected nucleic acids, complexed with cationic or polycationic compounds | |
WO2011069587A1 (en) | Lyophilization of nucleic acids in lactate-containing solutions | |
EP2510100B1 (en) | Mannose-containing solution for lyophilization, transfection and/or injection of nucleic acids |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
WWE | Wipo information: entry into national phase |
Ref document number: 200980131936.5 Country of ref document: CN |
|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 09736823 Country of ref document: EP Kind code of ref document: A1 |
|
ENP | Entry into the national phase |
Ref document number: 2730261 Country of ref document: CA |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2009300113 Country of ref document: AU |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2009736823 Country of ref document: EP |
|
WWE | Wipo information: entry into national phase |
Ref document number: 12994407 Country of ref document: US |
|
WWE | Wipo information: entry into national phase |
Ref document number: 8454/DELNP/2010 Country of ref document: IN Ref document number: MX/A/2010/013071 Country of ref document: MX |
|
ENP | Entry into the national phase |
Ref document number: 2009300113 Country of ref document: AU Date of ref document: 20090930 Kind code of ref document: A |
|
ENP | Entry into the national phase |
Ref document number: 20117001541 Country of ref document: KR Kind code of ref document: A |
|
ENP | Entry into the national phase |
Ref document number: 2011526423 Country of ref document: JP Kind code of ref document: A |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2011116931 Country of ref document: RU |
|
ENP | Entry into the national phase |
Ref document number: PI0915844 Country of ref document: BR Kind code of ref document: A2 Effective date: 20110110 |