Application of mRNA for use as a therapeutic agent for tumorous diseases
원문보기
IPC분류정보
국가/구분
United States(US) Patent
등록
국제특허분류(IPC7판)
G06F-017/00
A61K-048/00
출원번호
US-0870110
(2004-06-18)
등록번호
US-8217016
(2012-07-10)
우선권정보
DE-101 62 480 (2001-12-19)
발명자
/ 주소
Hoerr, Ingmar
Von Der Mulbe, Florian
Pascolo, Steve
출원인 / 주소
CUREVAC GmbH
대리인 / 주소
Farelli Haag & Kilger PLLC
인용정보
피인용 횟수 :
76인용 특허 :
40
초록▼
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 tumour, in combination with an aqueous solvent and preferably a cytokine, e.g. GM-CSF, and a process for the preparation of the pharmaceuti
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 tumour, in combination with an aqueous solvent and preferably a cytokine, e.g. GM-CSF, and a process for the preparation of the pharmaceutical composition. The pharmaceutical composition according to the invention is used in particular for therapy and/or prophylaxis against cancer.
대표청구항▼
1. A method for preparing a pharmaceutical composition comprising an RNA which codes for an antigen from a tumour comprising: (a) preparing a tumour tissue cDNA library from tumour tissue from a patient comprising: (i) comparing the sequences of a cDNA library from healthy tissue to the sequences of
1. A method for preparing a pharmaceutical composition comprising an RNA which codes for an antigen from a tumour comprising: (a) preparing a tumour tissue cDNA library from tumour tissue from a patient comprising: (i) comparing the sequences of a cDNA library from healthy tissue to the sequences of the cDNA from tumour tissue; and(ii) identifying cDNA sequences which are present exclusively in the tumour tissue cDNA library and code for tumour-specific antigens of said patient based upon an alignment with the cDNA library from healthy tissue,wherein the tumour tissue cDNA library is a subtraction library of the entire cDNA library from healthy tissue;(b) preparing a matrix for in vitro transcription of RNA using the tumour tissue cDNA library which is present exclusively in the tumour tissue cDNA library and codes for tumour-specific antigens of the patient;(c) transcribing the matrix in vitro; and(d) formulating the transcribed RNA into a pharmaceutical composition which does not comprise cells;wherein the tumour specific antigens are not present in non-tumour tissue. 2. A process according to claim 1, wherein the tumour specific antigens comprise one or more antigens selected from the group consisting of 707-AP, β-catenin/m, Bcr-abl, CASP-8, CDC27/m, CDK4/m, ELF2M, ETV6-AML1, G250, HLA-A*0201-R1701, HPV-E7, HSP70-2M, HAST-2, KIAA0205, LDLR/FUT, myosin/m, MUM-I, -2, -3, p190 minor bcr-abl, Pml/RARα, TEL/AML1, TPI/m, and TRP-2/INT2. 3. A process according to claim 1 wherein the RNA molecules are provided with a 5′ cap structure and/or a poly(A *) tail of at least about 25 nucleotides and/or at least one IRES and/or at least one 5′-stabilizing sequence and/or at least one 3′-stabilizing sequence. 4. A process according to claim 1, wherein one or more adjuvants are included in the pharmaceutical composition. 5. A process according to claim 4, wherein the one or more adjuvant is selected from the group consisting of lipopolysaccharide, TNF-α, CD40 ligand, GP96, oligonucleotides with the CpG motif, aluminum hydroxide, Freund's adjuvant, lipopeptides and cytokines. 6. A process according to claim 5, wherein the cytokine is GM-CSF. 7. A process according to claim 1, wherein the RNA molecules are complexed or condensed with at least one cationic or polycationic agent in said pharmaceutical composition. 8. A process according to claim 7, wherein the cationic or polycationic agent is selected from the group consisting of protamine, poly-L-lysine, poly-L-arginine and histones. 9. A process according to claim 1, wherein at least one RNase inhibitor is included in the pharmaceutical composition. 10. A process according to claim 9, wherein the RNase inhibitor is RNasin. 11. A process according to claim 1, wherein the pharmaceutical composition includes at least one further pharmaceutically acceptable carrier and/or at least one further pharmaceutically acceptable vehicle. 12. A process according to claim 1, wherein the alignment comprises a comparison of the expression patterns of healthy and tumour tissue. 13. A process according to claim 12, wherein the determination of the sequences of the tumour-specific antigens is performed using microarray. 14. A process according to claim 1, wherein the expression patterns are compared at the nucleic acid level. 15. A method for preparing a pharmaceutical composition comprising at least one tumour-specific RNA which codes for an antigen expressed in a tumour in a patient comprising: (a) preparing a cDNA library from a portion of tumour tissue to obtain a tumour cDNA library;(b) preparing a cDNA library from a portion of non-tumour tissue to obtain a non-tumour cDNA library;(c) comparing the tumour cDNA library with the non-tumour cDNA library;(d) identifying cDNA sequences which are present exclusively in the tumour cDNA library and not present in the non-tumour cDNA library to obtain at least one tumour-specific cDNA which corresponds to an mRNA expressed exclusively in the tumour;(e) transcribing the at least one tumour-specific cDNA to obtain tumour-specific RNA which codes for tumour-specific antigens of the patient; and(f) formulating the tumour-specific RNA into a pharmaceutical composition which does not comprise cells;wherein the tumour specific antigens are not present in non-tumour tissue. 16. A process according to claim 15, wherein the tumour specific antigens comprise one or more antigens selected from the group consisting of 707-AP, β-catenin/m, Bcr-abl, CASP-8, CDC27/m, CDK4/m, ELF2M, ETV6-AML1, G250, HLA-A*0201-R1701, HPV-E7, HSP70-2M, HAST-2, KIAA0205, LDLR/FUT, myosin/m, MUM-I, -2, -3, p190 minor bcr-abl, Pml/RARα, TEL/AML1, TPI/m, and TRP-2/INT2. 17. A process according to claim 15 wherein the RNA is provided with a 5′ cap structure and/or a poly(A *) tail of at least about 25 nucleotides and/or at least one IRES and/or at least one 5′-stabilizing sequence and/or at least one 3′-stabilizing sequence. 18. A process according to claim 15, wherein one or more adjuvants are included in the pharmaceutical composition. 19. A process according to claim 18, wherein the one or more adjuvant is selected from the group consisting of lipopolysaccharide, TNF-α, CD40 ligand, GP96, oligonucleotides with the CpG motif, aluminum hydroxide, Freund's adjuvant, lipopeptides and cytokines. 20. A process according to claim 19, wherein the cytokine is GM-CSF. 21. A process according to claim 15, wherein the RNA is complexed or condensed with at least one cationic or polycationic agent in said pharmaceutical composition. 22. A process according to claim 21, wherein the cationic or polycationic agent is selected from the group consisting of protamine, poly-L-lysine, poly-L-arginine and histones. 23. A process according to claim 15, wherein at least one RNase inhibitor is included in the pharmaceutical composition. 24. A process according to claim 23, wherein the RNase inhibitor is RNasin. 25. A process according to claim 15, wherein the pharmaceutical composition includes at least one further pharmaceutically acceptable carrier and/or at least one further pharmaceutically acceptable vehicle. 26. A process according to claim 15, wherein the identification of the tumour-specific cDNA is performed by an alignment comprising a comparison of the expression patterns of the tumour tissue and the healthy tissue. 27. A process according to claim 26, wherein the determination of the sequences of the tumour-specific antigens is performed using a microarray.
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