Source: http://www.google.fr/patents/US9433670
Timestamp: 2018-01-20 17:13:41
Document Index: 605388615

Matched Legal Cases: ['§111', '§119', 'ART-4', 'ART-1', 'ART-1', 'ART-3']

Brevet US9433670 - Application of mRNA for use as a therapeutic against tumour diseases - Google Brevets
The present invention relates to a pharmaceutical composition comprising at least one mRNA comprising at least one coding region for at least one antigen from a tumor, in combination with an aqueous solvent and preferably a cytokine, e.g. GM-CSF, and a process for the preparation of the pharmaceutical...http://www.google.fr/patents/US9433670?utm_source=gb-gplus-shareBrevet US9433670 - Application of mRNA for use as a therapeutic against tumour diseases
Numéro de publication US9433670 B2
Numéro de demande US 14/965,551
Date de dépôt 10 déc. 2015
Autre référence de publication CA2473135A1, CA2473135C, DE10162480A1, DE50211485D1, EP1458410A2, EP1458410B1, EP1905844A2, EP1905844A3, EP1925317A1, EP2769733A1, US8217016, US9155788, US9433669, US9439956, US9463228, US9655955, US20050059624, US20110311472, US20150030633, US20160082092, US20160089424, US20160089425, US20160089426, US20160095911, US20160095912, WO2003051401A2, WO2003051401A3
Numéro de publication 14965551, 965551, US 9433670 B2, US 9433670B2, US-B2-9433670, US9433670 B2, US9433670B2
Inventeurs Ingmar Hoerr, Florian Von Der Mülbe, Steve Pascolo
Cessionnaire d'origine Curevac Ag
Citations de brevets (103), Citations hors brevets (257), Classifications (15)
US 9433670 B2
1. A method of stimulating an antitumor immune response in a subject comprising administering an effective amount of a cell-free composition comprising mRNA encoding an MAGE antigen to a subject in need thereof, thereby stimulating a T-cell mediated cytotoxic anticancer immune response in the subject.
2. The method of claim 1, wherein the subject has a cancer.
3. The method of claim 2, wherein the cancer is a lung or skin cancer.
4. The method of claim 1, wherein the composition comprises mRNA encoding at least 2, 3, 4 or 5 different tumor antigens.
5. The method of claim 1, wherein the method further comprises administering at least 2, 3, 4 or 5 different cell-free compositions comprising mRNA encoding different tumor antigens to the subject.
6. The method of claim 1, wherein the mRNA is complexed with at least one cationic or polycationic agent.
7. The method of claim 6, wherein the cationic or polycationic agent is chosen from the group consisting of protamine, poly-L-lysine, poly-L-arginine and histones.
8. The method of claim 7, wherein the mRNA is complexed with protamine.
9. The method of claim 1, further comprising administering one or more adjuvant(s) to the subject.
10. The method of claim 9, wherein the adjuvant is chosen from the group consisting of lipopolysaccharide, TNF-α, CD40 ligand, GP96, oligonucleotides with a CpG motif, aluminum hydroxide, Freund's adjuvant, a lipopeptide and a cytokine.
11. The method of claim 10, wherein the cytokine is GM-CSF.
12. The method of claim 1, wherein the mRNA encoding the antigen has a different nucleic acid sequence compared with the wild-type mRNA encoding the antigen.
13. The method of claim 1, wherein the mRNA comprises a 5′ cap structure, at least one IRES and/or a poly(A+) tail of at least 25 nucleotides.
14. The method of claim 13, wherein the mRNA comprises a 5′ cap structure and a poly(A+) tail of at least 25 nucleotides.
15. The method of claim 1, wherein the mRNA comprises at least one 5′-stabilizing sequence and/or at least one 3′-stabilizing sequence.
16. The method of claim 15, wherein the 5′- and/or the 3′-stabilizing sequence(s) is/are chosen from the group consisting of untranslated sequences (UTR) of the β-globin gene and a stabilizing sequence of the general formula (C/U)CCANxCCC(U/A)PyxUC(C/U)CC.
17. The method of claim 1, wherein the mRNA comprises at least one analog of naturally occurring nucleotide selected from the group consisting of phosphorothioates, phosphoroamidates, peptide nucleotides, methylphosphates, 7-deazaguanosine, 5-methylcytosine and inosine.
18. The method of claim 1, wherein the cell-free composition comprising mRNA is administered by injection of an aqueous solution comprising the mRNA.
19. The method of claim 1, wherein the cell-free composition comprising mRNA is administered intradermally.
20. The method of claim 1, wherein the cell-free composition comprising mRNA is administered two or more times.
This application is a continuation of U.S. application Ser. No. 14/840,305, filed Aug. 31, 2015, which is a continuation of U.S. application Ser. No. 14/325,850, filed Jul. 8, 2014, now U.S. Pat. No. 9,155,788, which is a divisional of U.S. application Ser. No. 13/106,548, filed May 12, 2011, now abandoned, which is a divisional of U.S. application Ser. No. 10/870,110, filed Jun. 18, 2004, now U.S. Pat. No. 8,217,016, which is a continuation under 35 U.S.C. §111(a) of International Application No. PCT/EP02/14577, filed Dec. 19, 2002, which claims priority under 35 U.S.C. §119 to German Patent Application No.: 101 62 480.8, filed Dec. 19, 2001. The entire text of each of the above-referenced disclosures is specifically incorporated herein by reference without disclaimer.
This application contains a Sequence Listing which has been submitted in text format via EFS-Web and is hereby incorporated by reference in its entirety. Said text file, created Dec. 9, 2015, is named CRVCP0009USC6.txt and is ˜2 KB in size.
In its use as a vaccine, the pharmaceutical composition according to the invention is to be considered in particular for treatment of cancer diseases (the mRNA preferably coding for a tumour-specific surface antigen (TSSA), e.g. for treatment of malignant melanoma, colon carcinoma, lymphomas, sarcomas, small-cell pulmonary carcinoma, blastomas etc. Specific examples of tumour antigens are, inter alia, 707-AP, AFP, ART-4, BAGE, β-catenine/m, Bcr-abl, CAMEL, CAP-1, CASP-8, CDC27/m, CDK4/m, CEA, CT, Cyp-B, DAM, ELF2M, ETV6-AML1, G250, GAGE, GnT-V, Gp100, HAGE, HER-2/neu, HLA-A*0201-R170I, HPV-E7, HSP70-2M, HAST-2, hTERT (or hTRT), iCE, KIAA0205, LAGE, LDLR/FUT, MAGE, MART-1/melan-A, MC1R, myosine/m, MUC1, MUM-1, -2, -3, NA88-A, NY-ESO-1, p190 minor bcr-ab1, Pm1/RARα, PRAME, PSA, PSM, RAGE, RU1 or RU2, SAGE, SART-1 or SART-3, TEL/AML1, TPI/m, TRP-1, TRP-2, TRP-2/INT2 and WT1.
Example 1 Tumour Vaccination with RNA in an Animal Model
The chosen genes (CEA, mucin1, Her-2/neu, telomerase, Mage-A1 and influenza matrix) are amplified via a PCR using a heat-stable high-performance enzyme (pfu, Stratagene). The genes originate from tumour cDNA (mucin1, Her-2/neu, telomerase), or they have been cloned into bacterial vectors (influenza matrix and MAGE-A1). The PCR fragments are cleaved with restriction enzymes (mucin1: BglII-SpeI; Her-2/neu: HinDIIIblunt-SpeI; telomerase: BglII-SpeI; MAGE-A1: BamHI-SpeI; influenza matrix protein: BglII-SpeI) and cloned into the T7TS-Plasmid (cf. FIG. 8) via the BglII and SpeI restriction sites. Plasmids of high purity are obtained via the Endo-free Maxipreparation Kit (Qiagen, Hilden, Germany). The sequence of the vector is controlled via a double-strand sequencing from the T7 promoter up to the PstI site and documented. Plasmids with a correct inserted gene sequence without mutations are used for the in vitro transcription. (Control via the published sequences: Accession Numbers: M11730 for Her-2/neu, NM_002456 for MUC1, NM_003219 for telomerase TERT, V01099 for influenza matrix and M77481 for MAGE-A1).
500 μg of each plasmid are linearized in a volume of 0.8 ml via digestion with the restriction enzyme PstI in a 2 ml Eppendorf reaction vessel. This cleaved construct is transferred into the RNA production unit. 1 ml of a mixture of phenol/chloroform/isoamyl alcohol is added to the linearized DNA. The reaction vessel is vortexed for 2 minutes and centrifuged at 15,000 rpm for 3 minutes. The aqueous phase is removed and mixed with 0.7 ml 2-propanol in a 2 ml reaction vessel. This vessel is centrifuged at 15,000 rpm for 15 minutes, the supernatant is discarded and 1 ml 75% ethanol is added. The reaction vessel is centrifuged at 15,000 rpm for 10 minutes and the ethanol is removed. The vessel is centrifuged for a further 2 minutes and the residues of the ethanol are removed with a microliter pipette tip. The DNA pellet is then dissolved in 1 μg/ml in RNase-free water.
The RNA treated with DNase is mixed with 20 ml of a solution of 3.3 ml 5 M NH4OAc plus 16.65 ml of ethanol. The mixture is incubated at −20° C. for 1 hour and centrifuged at 4,000 rpm for 1 hour. The supernatant is removed and the pellet is washed with 5 ml of 75% RNase-free ethanol. The vessel is centrifuged again at 4,000 rpm for 15 minutes and the supernatant is removed. The vessel is centrifuged again under the previous conditions and the ethanol which remains is removed with a microliter pipette tip. The reaction vessel is opened and the pellet is dried under a sterile bench in the sterile environment.
1 ml of RNase-free water is added to the dried RNA. The pellet is incubated at 4° C. for at least 4 hours. 2 μl of the aqueous solution are subjected to a quantitative analysis (determination of the UV absorption at 260 nm). 2 ml of a phenol/chloroform/isoamyl alcohol solution are added to 1 ml of aqueous RNA solution. The mixture is vortexed for 2 minutes and centrifuged at 4,000 rpm for 2 minutes. The aqueous phase is removed with a microliter pipette and transferred into a new reaction vessel. 4 ml of a solution of 0.66 ml 5 M NH4OAc plus 3.33 ml ethanol are added. The mixture is incubated at −20° C. for 1 hour and centrifuged at 4,000 rpm for 1 hour. The supernatant is removed and the pellet is washed with 75% RNase-free ethanol. The vessel is centrifuged again at 4,000 rpm for 15 minutes and the supernatant is removed. The vessel is centrifuged again under the previous conditions and the ethanol which remains is removed with a microliter pipette tip. The reaction vessel is opened and the pellet is dried under a sterile bench in the sterile environment.
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Example 5 Vaccination with Autologous, Amplified Tumour RNA in Patients with Malignant Melanoma
1. Tumour marker S 100 (7 ml)
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Classification internationale A61P35/04, A61K9/00, A61K39/00, A61K48/00, A61K38/19
Classification coopérative A61K2039/55522, A61K2039/54, A61K9/0021, A61K39/0011, A61K38/193, A61K2039/572, A61K2039/70, A61K2039/53, A61K48/00, A61K2300/00