ES2548987T3 - Ácido nucleico antisentido de kanamicina para el tratamiento del cáncer - Google Patents
Ácido nucleico antisentido de kanamicina para el tratamiento del cáncer Download PDFInfo
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- ES2548987T3 ES2548987T3 ES10711388.8T ES10711388T ES2548987T3 ES 2548987 T3 ES2548987 T3 ES 2548987T3 ES 10711388 T ES10711388 T ES 10711388T ES 2548987 T3 ES2548987 T3 ES 2548987T3
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- 102000039446 nucleic acids Human genes 0.000 title abstract 4
- 108020004707 nucleic acids Proteins 0.000 title abstract 4
- 150000007523 nucleic acids Chemical class 0.000 title abstract 4
- 230000000692 anti-sense effect Effects 0.000 title abstract 2
- 206010028980 Neoplasm Diseases 0.000 title description 2
- 201000011510 cancer Diseases 0.000 title description 2
- 229930027917 kanamycin Natural products 0.000 title 1
- SBUJHOSQTJFQJX-NOAMYHISSA-N kanamycin Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CN)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](N)[C@H](O)[C@@H](CO)O2)O)[C@H](N)C[C@@H]1N SBUJHOSQTJFQJX-NOAMYHISSA-N 0.000 title 1
- 229960000318 kanamycin Drugs 0.000 title 1
- 229930182823 kanamycin A Natural products 0.000 title 1
- 239000012634 fragment Substances 0.000 abstract 2
- 101710120978 Kanamycin resistance protein Proteins 0.000 abstract 1
- 241000124008 Mammalia Species 0.000 abstract 1
- 230000000295 complement effect Effects 0.000 abstract 1
- 230000028993 immune response Effects 0.000 abstract 1
- 239000002773 nucleotide Substances 0.000 abstract 1
- 125000003729 nucleotide group Chemical group 0.000 abstract 1
- 238000002560 therapeutic procedure Methods 0.000 abstract 1
- SHGAZHPCJJPHSC-YCNIQYBTSA-N all-trans-retinoic acid Chemical compound OC(=O)\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C SHGAZHPCJJPHSC-YCNIQYBTSA-N 0.000 description 45
- 239000000902 placebo Substances 0.000 description 13
- 229940068196 placebo Drugs 0.000 description 13
- 238000010276 construction Methods 0.000 description 9
- 241000699670 Mus sp. Species 0.000 description 7
- 238000010172 mouse model Methods 0.000 description 6
- 230000000694 effects Effects 0.000 description 4
- 230000001681 protective effect Effects 0.000 description 4
- 235000016496 Panda oleosa Nutrition 0.000 description 2
- 240000000220 Panda oleosa Species 0.000 description 2
- 102100021569 Apoptosis regulator Bcl-2 Human genes 0.000 description 1
- 102100039788 GTPase NRas Human genes 0.000 description 1
- 101000971171 Homo sapiens Apoptosis regulator Bcl-2 Proteins 0.000 description 1
- 101000744505 Homo sapiens GTPase NRas Proteins 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 210000005259 peripheral blood Anatomy 0.000 description 1
- 239000011886 peripheral blood Substances 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 239000013612 plasmid Substances 0.000 description 1
- 108010006693 promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein Proteins 0.000 description 1
- 230000001012 protector Effects 0.000 description 1
- 206010043554 thrombocytopenia Diseases 0.000 description 1
- 238000002255 vaccination Methods 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
- C12N15/09—Recombinant DNA-technology
- C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
- C12N15/113—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing
- C12N15/1137—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing against enzymes
-
- 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
- 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
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- 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
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2310/00—Structure or type of the nucleic acid
- C12N2310/10—Type of nucleic acid
- C12N2310/11—Antisense
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2310/00—Structure or type of the nucleic acid
- C12N2310/10—Type of nucleic acid
- C12N2310/11—Antisense
- C12N2310/111—Antisense spanning the whole gene, or a large part of it
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Genetics & Genomics (AREA)
- Engineering & Computer Science (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Biomedical Technology (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- General Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Public Health (AREA)
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- Biotechnology (AREA)
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- Microbiology (AREA)
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- Wood Science & Technology (AREA)
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- General Engineering & Computer Science (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Biophysics (AREA)
- Biochemistry (AREA)
- Physics & Mathematics (AREA)
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- Epidemiology (AREA)
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- Communicable Diseases (AREA)
- Hematology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
Abstract
Un ácido nucleico aislado para su uso en terapia, en el que dicho ácido nucleico aislado comprende una secuencia antisentido complementaria a un fragmento de la secuencia que codifica para la proteína de resistencia a la kanamicina, fragmento que es de al menos 50 nucleótidos de longitud y en el que dicho ácido nucleico aislado es capaz de provocar una respuesta inmunitaria en un mamífero.
Description
E10711388
30-09-2015
[0079] pCDNA3PML-RARαFrC (VVACS01) y pVaxPML-RARαKanAS (VVACS03) se transfectaron transitoriamente en células COS. Los experimentos de RQ-PCR demostraron que PML-RARα se expresa con ambas construcciones.
[0080] Se estudió el efecto de diferentes construcciones de ADN en un modelo de ratón LPA utilizando el protocolo descrito en Padua et al. (2003, Nature Medicine 9: 1413-1417). En resumen, 104 células LPA se inyectaron a ratones FVB/N. A continuación, se introdujo una pastilla de ATRA, que libera 5 mg/día de ATRA durante 21 días,
10 detrás del cuello de los ratones con un trocar. Se inyectó ADN (2 x 50 microgramos de plásmido) el día después de la introducción de la pastilla de ATRA, y cada 20 días para un total de tres inyecciones. Se inyectaron las siguientes construcciones de ADN a los ratones:
-la construcción pVaxKanAS, también denominado pVax14;
15 -la construcción pCDNA3PML-RARαFrC (VVACS01); -la construcción pVaxPML-RARαFrC; y -la construcción pCDNA3PML-RARαASFrC (VVACS04).
[0081] Como placebo se usó una pastilla adquirida del fabricante de la pastilla de ATRA (Innovative 20 Research, Sarasota, EE.UU.).
[0082] Se hizo un seguimiento de los ratones durante dos años y se construyeron curvas de Kaplan-Meier.
[0083] Los resultados se muestran en Figura 2 y en la Tabla 1 a continuación. Se aplicaron los ensayos log
25 rank (Mantel-Cox) y de Wilcoxon general a las curvas de Kaplan-Meier. Los dos ensayos estadísticos condujeron a idénticas conclusiones en términos de importancia.
Tabla 1
- log-rank (Mantel-Cox)
- Wilcoxon general
- Valor Chi-2
- valor de p Valor Chi-2 valor de p
- ATRA vs. ATRA + pCDNA3PML-RARαASFrC
- 8,7257E+00 3,1375E03 p < 0,005 7,1234E+00 7,6086E-03 p < 0,01
- ATRA vs. ATRA + pCDNA3PML-RARαFrC
- 1,7729E+01 2,5473E05 p < 0,0001 1,0263E+01 1,3571E-03 p < 0,005
- ATRA vs. ATRA + pVaxPML-RARαFrC
- 5,0145E+00 2,5136E02 p < 0,05 5,1840E+00 2,2796E-02 p < 0,05
- ATRA vs. ATRA + pVaxKanAS
- 6,5927E+00 1,0240E02 p < 0,05 2,3055E+00 1,2892E-01 n.s.
- ATRA vs. placebo
- 6,0018E+01 9,3994E15 p < 0,0001 5,1827E+01 6,0611 E13 p < 0,0001
- ATRA vs. placebo+ADN
- 8,7059E+00 3,1718E03 p < 0,005 1,6318E+01 5,3547E-05 p < 0,0001
- ATRA + pCDNA3PML-RARαASFrC vs. ATRA + pCDNA3PML-RARαFrC
- 2,9314E-02 8,6406E01 n.s. 7,4390E-03 9,3127E-01 n.s.
- ATRA + pCDNA3PML-RARαASFrC vs. ATRA + pVaxPML-RARαFrC
- 2,3666E+00 1,2395E01 n.s. 1,0271E+00 3,1085E-01 n.s.
- ATRA + pCDNA3PML-RARαASFrC vs. ATRA + pVaxKanAS
- 6,0339E-05 9,9380E01 n.s. 8,7577E-02 7,6728E-01 n.s.
- ATRA + pCDNA3PML-RARαASFrC vs. placebo
- 3,1948E+01 1,5838E08 p < 0,0001 2,4578E+01 7,1365E-07 p < 0,0001
- ATRA + pCDNA3PML-RARαASFrC vs. placebo+ADN
- 1,3354E+01 2,5792E04 p < 0,0005 1,3575E+01 2,2917E-04 p < 0,0005
- ATRA + pCDNA3PML
- 3,8212E+00 5,0608E n.s. 1,0797E+00 2,9876E-01 n.s.
12
E10711388
30-09-2015
- RARαFrC vs. ATRA + pVaxPML-RARαFrC
- 02
- ATRA + pCDNA3PML-RARαFrC vs. ATRA + pVaxKanAS
- 1,3756E-02 9,0663E01 n.s. 2,5419E-01 6,1414E-01 n.s.
- ATRA + pCDNA3PML-RARαFrC vs. placebo
- 7,3553E+01 9,7951E18 p < 0,0001 6,4450E+01 9,9035E-16 p < 0,0001
- ATRA + pCDNA3PML-RARαFrC vs. placebo+ADN
- 2,9433E+01 5,7887E08 p < 0,0001 3,0640E+01 3,1065E-08 p < 0,0001
- ATRA + pVaxPML-RARαFrC vs. ATRA + pVaxKanAS
- 2,2960E+00 1,2971E01 n.s. 5,2380E-01 4,6923E-01 n.s.
- ATRA + pVaxPML-RARαFrC vs. placebo
- 2,6830E+01 2,2214E07 p < 0,0001 2,1359E+01 3,8082E-06 p < 0,0001
- ATRA + pVaxPML-RARαFrC vs. placebo+ADN
- 1,0216E+01 1,3921E03 p < 0,005 1,0704E+01 1,0688E-03 p < 0,005
- ATRA + pVaxKanAS vs. placebo
- 1,7202E+01 3,3607E05 p < 0,0001 1,2455E+01 4,1695E-04 p < 0,0005
- ATRA + pVaxKanAS vs. placebo+AND
- 7,8950E+00 4,9572E03 p < 0,005 6,2853E+00 1,2174E-02 p < 0,05
- placebo vs. placebo+ADN
- 4,0649E+00 4,3783E02 p < 0,05 4,1371 E+00 4,1953E-02 p < 0,05
[0084] Así, la construcción pVaxKanAS, administrada en combinación con ATRA, tiene un efecto protector en el modelo de ratón LPA. Aproximadamente el 40 % de los ratones fueron rescatados de la muerte. Este efecto protector es comparable con el efecto protector de la construcción pCDNA3PML-RARαFrC. Por otra parte, el efecto
5 protector de la construcción pVaxKanAS es significativamente diferente del ATRA solo (p = <0,05 para ATRA vs. ATRA + pVaxKanAS).
[0085] Se llevó a cabo un experimento separado para estudiar el efecto de la construcción de PMLRARαKanAS (también denominado pVax15). El protocolo fue el mismo que el anterior, excepto por el hecho de que 10 las células LPA usadas para este experimento se habían sometido a más pasos y más agresivos, y que el seguimiento de los ratones fue de nueve meses.
[0086] Los resultados se muestran en la Figura 3 y en la Tabla 2 a continuación.
15 Tabla 2
- log-rank (Mantel-Cox)
- Valor Chi-2
- valor de p
- ATRA vs. ATRA + pCDNA3PML-RARαFrC
- 9,883 0,0017
- ATRA vs. ATRA + pVAXKanASFrC
- 11,080 0,0009
- ATRA + pCDNA3PML-RARαFrC vs. ATRA + pVAXKanAS
- 0,004 0,9482
[0087] La construcción PML-RARαKanAS también tiene un efecto protector en comparación con el ATRA solo (p = 0,0009). La construcción PML-RARαKanAS es al menos tan eficaz como la construcción pCDNA3PML
20 RARaFrC.
[0088] Se utilizó el modelo de ratón SMD descrito en Omidvar et al. (2007, Cancer Res 67: 11657-67) para
25 estudiar el efecto de KanAS en SMD. Este modelo de ratón se basa en el uso de ratones portadores de NRAS mutante con BCL-2, a los que se hace un seguimiento hasta que presentan un recuento plaquetario reducido indicativo de trombocitopenia y muerte inminente.
[0089] El protocolo de vacunación era el siguiente: se administraron 2 x 50 microgramos de ADN el día
30 después del diagnóstico (día 0), que correspondía a la fecha en la que el recuento de plaquetas en sangre periférica cayó por debajo de lo normal (<105/microlitro). El día 20 y el día 40, se volvieron a inyectar 2 x 50 microgramos de ADN.
13
Claims (1)
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imagen1 imagen2 imagen3
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP09290224 | 2009-03-27 | ||
| EP09290224 | 2009-03-27 | ||
| PCT/EP2010/054039 WO2010109016A1 (en) | 2009-03-27 | 2010-03-26 | Kanamycin antisense nucleic acid for the treatment of cancer |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| ES2548987T3 true ES2548987T3 (es) | 2015-10-22 |
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ID=40935598
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| ES10711388.8T Active ES2548987T3 (es) | 2009-03-27 | 2010-03-26 | Ácido nucleico antisentido de kanamicina para el tratamiento del cáncer |
Country Status (7)
| Country | Link |
|---|---|
| US (1) | US9029135B2 (es) |
| EP (1) | EP2411519B1 (es) |
| JP (1) | JP2012521749A (es) |
| CN (1) | CN102439150A (es) |
| CA (1) | CA2756070C (es) |
| ES (1) | ES2548987T3 (es) |
| WO (1) | WO2010109016A1 (es) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1356820A1 (en) * | 2002-04-26 | 2003-10-29 | Institut National De La Sante Et De La Recherche Medicale (Inserm) | DNA vaccine combined with an inducer of tumor cell apoptosis |
| CN102925558B (zh) * | 2012-09-29 | 2014-09-17 | 童永清 | 一种检测PML-RARa融合基因mRNA表达量的试剂盒 |
| WO2024200831A1 (en) * | 2023-03-30 | 2024-10-03 | Vivadju | Pvax14 nucleic acid in combination with all-trans retinoic acid (atra) and a checkpoint inhibitor for the treatment of cancer |
| WO2024200829A1 (en) * | 2023-03-30 | 2024-10-03 | Vivadju | Pvax14 nucleic acid formulated with nano-vehicle in combination with all-trans retinoic acid (atra) for activating immune pathways |
Family Cites Families (19)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4945050A (en) | 1984-11-13 | 1990-07-31 | Cornell Research Foundation, Inc. | Method for transporting substances into living cells and tissues and apparatus therefor |
| ZA8681B (en) | 1985-01-07 | 1987-08-26 | Syntex Inc | 1,2-dialkoxy-omega-trialkylammonium cationic surfactants |
| US5015580A (en) | 1987-07-29 | 1991-05-14 | Agracetus | Particle-mediated transformation of soybean plants and lines |
| DE69034168T3 (de) | 1989-03-21 | 2013-04-11 | Vical, Inc. | Expression von exogenen Polynukleotidsequenzen in Wirbeltieren |
| AU5856790A (en) | 1989-06-26 | 1991-01-17 | Agracetus, Inc. | Particle-mediated transformation of animal somatic cells |
| US5279833A (en) | 1990-04-04 | 1994-01-18 | Yale University | Liposomal transfection of nucleic acids into animal cells |
| US5283185A (en) | 1991-08-28 | 1994-02-01 | University Of Tennessee Research Corporation | Method for delivering nucleic acids into cells |
| CA2102918C (en) | 1992-03-11 | 2007-05-08 | Joel R. Haynes | Genetic vaccine for immunodeficiency viruses |
| EP0632722A4 (en) | 1992-03-20 | 1997-07-30 | Baylor College Medicine | DNA TRANSPORTATION SYSTEM AND INSTRUCTIONS FOR USE. |
| DK0636028T3 (da) | 1992-04-03 | 2004-07-12 | Univ California | Selvorganiserende polynucleotidleveringssystem omfattende et amfipatisk kationisk peptid |
| PT681483E (pt) | 1993-01-26 | 2005-11-30 | Wyeth Corp | Composicoes e metodos para distribuicao de material genetico |
| TW360548B (en) | 1993-04-08 | 1999-06-11 | Powderject Res Ltd | Products for therapeutic use |
| SG54115A1 (en) | 1993-04-27 | 1998-11-16 | Gerber Scient Products Inc | Thermal printing apparatus with improved power supply |
| EP0708637B1 (en) | 1993-07-14 | 2004-01-28 | The Regents of the University of California | Self-assembling polynucleotide delivery system comprising dendrimer polycations |
| US5651981A (en) | 1994-03-29 | 1997-07-29 | Northwestern University | Cationic phospholipids for transfection |
| US5527928A (en) | 1994-09-30 | 1996-06-18 | Nantz; Michael H. | Cationic transport reagents |
| DE69841578D1 (de) * | 1997-09-16 | 2010-05-06 | Centocor Inc | Methoden zur kompletten chemischen Synthese und Zusammensetzung von Genen und Genomen |
| EP1356820A1 (en) * | 2002-04-26 | 2003-10-29 | Institut National De La Sante Et De La Recherche Medicale (Inserm) | DNA vaccine combined with an inducer of tumor cell apoptosis |
| US20050260619A1 (en) * | 2004-02-11 | 2005-11-24 | Roland Brousseau | DNA microarray for fingerprinting and characterization of microorganisms in microbial communities |
-
2010
- 2010-03-26 ES ES10711388.8T patent/ES2548987T3/es active Active
- 2010-03-26 EP EP10711388.8A patent/EP2411519B1/en active Active
- 2010-03-26 CN CN2010800213883A patent/CN102439150A/zh active Pending
- 2010-03-26 WO PCT/EP2010/054039 patent/WO2010109016A1/en not_active Ceased
- 2010-03-26 JP JP2012501318A patent/JP2012521749A/ja active Pending
- 2010-03-26 US US13/258,173 patent/US9029135B2/en active Active
- 2010-03-26 CA CA2756070A patent/CA2756070C/en active Active
Also Published As
| Publication number | Publication date |
|---|---|
| CA2756070A1 (en) | 2010-09-30 |
| CA2756070C (en) | 2019-08-20 |
| CN102439150A (zh) | 2012-05-02 |
| EP2411519B1 (en) | 2015-07-22 |
| WO2010109016A1 (en) | 2010-09-30 |
| US20120076828A1 (en) | 2012-03-29 |
| US9029135B2 (en) | 2015-05-12 |
| EP2411519A1 (en) | 2012-02-01 |
| JP2012521749A (ja) | 2012-09-20 |
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