Pharmaceutical composition containing a stabilised mRNA optimised for translation in its coding regions
IPC분류정보
국가/구분
United States(US) Patent
등록
국제특허분류(IPC7판)
A61K-047/64
C07K-014/47
A61K-038/17
C12N-015/67
A61K-039/00
A61K-048/00
A61K-047/54
A61K-039/12
A61K-038/28
A61K-038/18
A61K-039/21
A61K-038/19
C12N-015/11
C12N-007/00
A61K-039/108
C07K-014/245
C07K-014/005
A61K-039/145
G06F-019/18
G06F-019/22
출원번호
US-0729830
(2003-12-05)
등록번호
US-10188748
(2019-01-29)
우선권정보
DE-101 27 283 (2001-06-05)
발명자
/ 주소
Von Der Mülbe, Florian
Hoerr, Ingmar
Pascolo, Steve
출원인 / 주소
CureVac AG
대리인 / 주소
Parker Highlander PLLC
인용정보
피인용 횟수 :
0인용 특허 :
42
초록▼
The present invention relates to a pharmaceutical composition comprising a modified mRNA that is stabilized by sequence modifications and optimized for translation. The pharmaceutical composition according to the invention is particularly well suited for use as an inoculating agent, as well as a the
The present invention relates to a pharmaceutical composition comprising a modified mRNA that is stabilized by sequence modifications and optimized for translation. The pharmaceutical composition according to the invention is particularly well suited for use as an inoculating agent, as well as a therapeutic agent for tissue regeneration. In addition, a process is described for determining sequence modifications that promote stabilization and translational efficiency of modified mRNA of the invention.
대표청구항▼
1. A cell-free mRNA pharmaceutical composition comprising at least one modified mRNA and a pharmaceutically compatible carrier, wherein the modified mRNA encodes at least one human tumour-specific antigenic polypeptide capable of stimulating an immune response in a patient against the human tumour-s
1. A cell-free mRNA pharmaceutical composition comprising at least one modified mRNA and a pharmaceutically compatible carrier, wherein the modified mRNA encodes at least one human tumour-specific antigenic polypeptide capable of stimulating an immune response in a patient against the human tumour-specific antigenic polypeptide wherein said modified mRNA encoding the human tumour-specific antigenic polypeptide has been stabilized by increasing its Guanosine/Cytosine (G/C) content by at least 7 percentage points relative to that of the wild type mRNA encoding the tumour-specific antigenic polypeptide. 2. The mRNA pharmaceutical composition according to claim 1, wherein the modified mRNA encoding the human tumour-specific antigenic polypeptide comprises a sequence wherein at least one codon of a wild type sequence recognized by a rare cellular tRNA is replaced with a codon recognized by an abundant cellular tRNA, and wherein said rare cellular tRNA and said abundant cellular tRNA recognize the same amino acid. 3. The mRNA pharmaceutical composition according to claim 2, wherein the modified mRNA encoding the human tumour-specific antigenic polypeptide comprises a maximum G/C content and a maximum number of codons recognized by abundant tRNAs. 4. The mRNA pharmaceutical composition of claim 1, wherein the modified mRNA further encodes a secretory leader. 5. The mRNA pharmaceutical composition of claim 1, which is formulated for injection. 6. The mRNA pharmaceutical composition according to claim 1, wherein the G/C content of the modified mRNA is increased by at least 15 percentage points relative to that of the wild type mRNA. 7. The mRNA pharmaceutical composition of claim 1, wherein the tumour is a malignant melanoma, colon carcinoma, lymphoma, sarcoma, small-cell lung carcinoma, or blastoma. 8. The mRNA pharmaceutical composition of claim 1, wherein the tumour is a small-cell lung carcinoma. 9. The mRNA pharmaceutical composition of claim 1, wherein the mRNA pharmaceutical composition comprises more than one modified mRNA, wherein each modified mRNA encodes a different human tumour-specific antigenic polypeptide resulting in the stimulation of an immune response in the patient against the human tumour antigenic polypeptide. 10. The mRNA pharmaceutical composition according to claim 1, wherein the at least one modified human mRNA is dissolved in the aqueous carrier material. 11. The mRNA pharmaceutical composition of claim 10, wherein the aqueous carrier material is water for injection (WFI). 12. The mRNA pharmaceutical composition of claim 10, wherein the aqueous carrier material is a buffered solution. 13. The mRNA pharmaceutical composition of claim 10, wherein the aqueous carrier material is a solution buffered with phosphate. 14. The mRNA pharmaceutical composition of claim 10, wherein the aqueous carrier material is a solution buffered with citrate. 15. The mRNA pharmaceutical composition of claim 10, wherein the aqueous carrier material is a solution buffered with acetate. 16. The mRNA pharmaceutical composition of claim 10, wherein the aqueous carrier material is a salt solution. 17. The mRNA pharmaceutical composition of claim 16, wherein the salt solution is a sodium chloride or potassium chloride solution. 18. The mRNA pharmaceutical composition of claim 10, wherein the aqueous carrier material is a solution comprising a component selected from the group consisting of human serum albumin, a polycationic protein, polysorbate 80, a sugar and an amino acid. 19. The mRNA pharmaceutical composition of claim 10, wherein the aqueous carrier material is a phosphate buffered saline solution of polycationic protein. 20. The mRNA pharmaceutical composition of claim 10, wherein the aqueous carrier material comprises GM-CSF. 21. The mRNA pharmaceutical composition of claim 10, wherein the human tumour-specific antigenic polypeptide is from a cancer selected from the group consisting of malignant melanoma, colon carcinoma, lymphoma, sarcoma, small-cell lung carcinoma, and blastoma. 22. The mRNA pharmaceutical composition according to claim 10, wherein the G/C content of the modified mRNA is increased at least by at least 15 percentage points relative to that of the wild type mRNA. 23. The mRNA pharmaceutical composition of claim 10 wherein the at least one modified mRNA encodes a human tumour-specific antigenic polypeptide selected from the group consisting of CEA, MUC1 and MAGE. 24. The mRNA pharmaceutical composition according to claim 1, wherein the G/C content of the modified mRNA is maximized. 25. The mRNA pharmaceutical composition according to claim 1, wherein the at least one modified mRNA is selected from the group consisting of mRNA encoding a PSA, PSM, MUC1, NY-ESO-1 and MAGE tumour antigen. 26. The mRNA pharmaceutical composition according to claim 25, wherein the at least one modified mRNA encodes a PSA tumour antigen. 27. The mRNA pharmaceutical composition according to claim 25, wherein the at least one modified mRNA encodes a PSM tumour antigen. 28. The mRNA pharmaceutical composition according to claim 25, wherein the at least one modified mRNA encodes a MUC1 tumour antigen. 29. The mRNA pharmaceutical composition according to claim 25, wherein the at least one modified mRNA encodes a NY-ESO-1 tumour antigen. 30. The mRNA pharmaceutical composition according to claim 25, wherein the at least one modified mRNA encodes a MAGE tumour antigen. 31. The mRNA pharmaceutical composition according to claim 1, wherein the at least one modified mRNA comprising at least one nucleotide position replaced with a nucleotide analogue selected from the group consisting of phosphorus amidates, phosphorus thioates, peptide nucleotides, methylphosphonates, 7-deazaguanosine, 5-methylcytosine and inosine. 32. A cell-free mRNA pharmaceutical composition comprising at least one modified mRNA and a pharmaceutically compatible carrier, wherein the modified mRNA encodes at least one human tumour-specific antigenic polypeptide capable of stimulating an immune response in a patient against the human tumour-specific antigenic polypeptide wherein said modified mRNA encoding the human tumour-specific antigenic polypeptide has been stabilized by increasing its Guanosine/Cytosine (G/C) content by at least 7 percentage points relative to that of the wild type mRNA encoding the tumour-specific antigenic polypeptide and wherein the tumour-specific antigenic polypeptide is selected from the group consisting of a PSA, PSM, MUC1, NY-ESO-1 and MAGE tumour antigen.
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