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| 국가/구분 | United States(US) Patent 등록 |
|---|---|
| 국제특허분류(IPC7판) |
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| 출원번호 | US-0940512 (2015-11-13) |
| 등록번호 | US-9827332 (2017-11-28) |
| 발명자 / 주소 |
|
| 출원인 / 주소 |
|
| 대리인 / 주소 |
|
| 인용정보 | 피인용 횟수 : 0 인용 특허 : 397 |
The invention relates to compositions and methods for the preparation, manufacture and therapeutic use of polynucleotides, primary transcripts and mmRNA molecules.
1. An isolated mRNA comprising; (a) a first region of linked nucleosides, said first region having at least 80% identity to SEQ ID NO: 18020 encoding a polypeptide of interest, said polypeptide of interest having the sequence of SEQ ID NO: 9254;(b) a first flanking region located at the 5′ terminus
1. An isolated mRNA comprising; (a) a first region of linked nucleosides, said first region having at least 80% identity to SEQ ID NO: 18020 encoding a polypeptide of interest, said polypeptide of interest having the sequence of SEQ ID NO: 9254;(b) a first flanking region located at the 5′ terminus of said first region comprising; (i) a sequence of linked nucleosides having the sequence of the native 5′ UTR of the nucleic acid that encodes SEQ ID NO: 9254, or having the sequence of SEQ ID NOs: 1-4; and(ii) at least one 5′ terminal cap;(c) a second flanking region located at the 3′ terminus of said first region comprising; (i′) a sequence of linked nucleosides having the sequence of the native 3′ UTR of the nucleic acid that encodes SEQ ID NO: 9254, or having the sequence of SEQ ID NOs: 5-21; and(ii′) a 3′ tailing sequence of linked nucleosides. 2. The isolated mRNA of claim 1, wherein the first region of linked nucleosides comprises at least an open reading frame of a nucleic acid sequence having the sequence of SEQ ID NO: 18020. 3. The isolated mRNA of claim 1, wherein the 3′ tailing sequence of linked nucleosides is selected from the group consisting of a poly-A tail of approximately 160 nucleotides and a polyA-G quartet. 4. The isolated mRNA of claim 1 which is purified. 5. The isolated mRNA of claim 1, wherein the at least one 5′ terminal cap is selected from the group consisting of Cap0, Cap1, ARCA, inosine, N1-methyl-guanosine, 2′fluoro-guanosine, 7-deaza-guanosine, 8-oxo-guanosine, 2-amino-guanosine, LNA-guanosine, and 2-azido-guanosine. 6. The isolated mRNA of claim 1, wherein at least one of said linked nucleosides comprises at least one modification as compared to the chemical structure of an A, G, U or C ribonucleotide. 7. The isolated mRNA of claim 6, wherein at least one said modification is located in a nucleoside base and/or sugar portion. 8. The isolated mRNA of claim 1, wherein said first region comprises n number of linked nucleosides having Formula (Ia): or a pharmaceutically acceptable salt or stereoisomer thereof, whereinU is O, S, N(RU)nu, or C(RU)nu, wherein nu is an integer from 0 to 2 and each RU is, independently, H, halo, or optionally substituted alkyl; is a single or double bond; is a single bond or absent;each of R1′, R2′, R1″, R2″, R3, R4, and R5 is, independently, H, halo, hydroxy, thiol, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkenyloxy, optionally substituted alkynyloxy, optionally substituted aminoalkoxy, optionally substituted alkoxyalkoxy, optionally substituted hydroxyalkoxy, optionally substituted amino, azido, optionally substituted aryl, optionally substituted aminoalkyl, or absent; wherein the combination of R3 with one or more of R1′, R1″, R2′, R2″, or R5 can join together to form optionally substituted alkylene or optionally substituted heteroalkylene and, taken together with the carbons to which they are attached, provide an optionally substituted heterocyclyl; wherein the combination of R5 with one or more of R1′, R1″, R2′, or R2″ can join together to form optionally substituted alkylene or optionally substituted heteroalkylene and, taken together with the carbons to which they are attached, provide an optionally substituted heterocyclyl; and wherein the combination of R4 and one or more of R1′, R1″, R2′, R2″, R3, or R5 can join together to form optionally substituted alkylene or optionally substituted heteroalkylene and, taken together with the carbons to which they are attached, provide an optionally substituted heterocyclyl;each of Y1, Y2, and y3, is, independently, O, S, —NRN1—, optionally substituted alkylene, or optionally substituted heteroalkylene, wherein RN1 is H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, or absent;each Y4 is, independently, H, hydroxy, thiol, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted alkenyloxy, optionally substituted alkynyloxy, optionally substituted thioalkoxy, optionally substituted alkoxyalkoxy, or optionally substituted amino;each Y5 is, independently, O, S, optionally substituted alkylene, or optionally substituted heteroalkylene; n is an integer from 1 to 100,000; and B is a nucleobase, wherein the combination of B and R1′, the combination of B and R2′, the combination of B and R1″, or the combination of B and R2″ can, taken together with the carbons to which they are attached, optionally form a bicyclic group or wherein the combination of B, R1″, and R3 or the combination of B, R2″, and R3 can optionally form a tricyclic or tetracyclic group. 9. The isolated mRNA of claim 8, wherein B is not pseudouridine (ψ) or 5-methyl-cytidine (m5C). 10. The isolated mRNA of claim 8, wherein U is O or C(RU)nu, wherein nu is an integer from 1 to 2 and each RU is, independently, H, halo, or optionally substituted alkyl;each of R1, R1′, R1″, R2, R2′, and R2″, if present, is, independently, H, halo, hydroxy, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkenyloxy, optionally substituted alkynyloxy, optionally substituted aminoalkoxy, optionally substituted alkoxyalkoxy, optionally substituted amino, azido, optionally substituted aryl, or optionally substituted aminoalkyl;each of R3 and R4 is, independently, H, halo, hydroxy, optionally substituted alkyl, or optionally substituted alkoxyalkoxy;each of Y1, Y2, and Y3, is, independently, O, S, —NRN1—, optionally substituted alkylene, or optionally substituted heteroalkylene, wherein RN1 is H, optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl;each Y4 is, independently, H, hydroxy, thiol, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted alkenyloxy, optionally substituted alkynyloxy, optionally substituted thioalkoxy, or optionally substituted amino;each Y5 is, independently, O or optionally substituted alkylene; andn is an integer from 10 to 10,000. 11. The isolated mRNA of claim 10, wherein each of R1, R1′, and R1″, if present, is H. 12. The isolated mRNA of claim 11, wherein each of R2, R2′, and R2″, if present, is, independently, H, halo, hydroxy, optionally substituted alkoxy, or optionally substituted alkoxyalkoxy. 13. The isolated mRNA of claim 10, wherein each of R2, R2′, and R2″, if present, is H. 14. The isolated mRNA of claim 13, wherein each of R1, R1′, and R1″, if present, is, independently, H, halo, hydroxy, optionally substituted alkoxy, or optionally substituted alkoxyalkoxy. 15. The isolated mRNA of claim 8, wherein said first region comprises n number of linked nucleotides having Formula (IIa): or a pharmaceutically acceptable salt or stereoisomer thereof. 16. The isolated mRNA of claim 8, wherein said first region comprises n number of linked nucleosides having Formula (IIk): or a pharmaceutically acceptable salt or stereoisomer thereof. 17. The isolated mRNA claim 11, wherein U is O or C(RU)nu, wherein nu is an integer from 1 to 2 and each RU is, independently, H, halo, or optionally substituted alkyl;each of R1 and R2 is, independently, H, halo, hydroxy, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkenyloxy, optionally substituted alkynyloxy, optionally substituted aminoalkoxy, optionally substituted alkoxyalkoxy, optionally substituted amino, azido, optionally substituted aryl, or optionally substituted aminoalkyl;each of R3 and R4 is, independently, H or optionally substituted alkyl;each of Y1, Y2, and y3, is, independently, O, S, —NRN1—, optionally substituted alkylene, or optionally substituted heteroalkylene, wherein RN1 is H, optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl;each Y4 is, independently, H, hydroxy, thiol, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted alkenyloxy, optionally substituted alkynyloxy, optionally substituted thioalkoxy, or optionally substituted amino;each Y5 is, independently, O or optionally substituted alkylene; andn is an integer from 10 to 10,000. 18. The mRNA of claim 8, wherein n number of B has Formula (b18)-(b20): or a pharmaceutically acceptable salt or stereoisomer thereof, whereineach V7 is, independently, O, S, N(RVe)nv, or C(RVe)nv, wherein nv is an integer from 0 to 2 and each RVe is, independently, H, halo, optionally substituted amino acid, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted alkenyloxy, or optionally substituted alkynyloxy;each R25 is, independently, H, optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl;each of R26a and R26b is, independently, H, optionally substituted acyl, optionally substituted amino acid, optionally substituted carbamoylalkyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted hydroxyalkyl, optionally substituted hydroxyalkenyl, or optionally substituted alkoxy;each R27 is, independently, H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, or optionally substituted amino;each R28 is, independently, H, optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl; andeach R29 is, independently, H, optionally substituted acyl, optionally substituted amino acid, optionally substituted carbamoylalkyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted hydroxyalkyl, optionally substituted hydroxyalkenyl, optionally substituted alkoxy, or optionally substituted amino. 19. The isolated polynucicotidc mRNA of claim 1, further comprising a targeting moiety, wherein said targeting moiety is covalently bound to said polynucleotide. 20. The isolated mRNA of claim 19, wherein said targeting moiety is an antibody, thyrotropin, melanotropin, lectin, glycoprotein, surfactant protein A, Mucin carbohydrate, multivalent lactose, multivalent galactose, N-acetyl-galactosamine, N-acetyl-gulucosamine multivalent mannose, multivalent fucose, glycosylated polyaminoacids, multivalent galactose, transferrin, bisphosphonate, polyglutamate, polyaspartate, a lipid, cholesterol, a steroid, bile acid, folate, vitamin B12, biotin, an RGD peptide, an RGD peptide mimetic, or an aptamer. 21. A pharmaceutical composition comprising the isolated mRNA of claim 1 and a pharmaceutically acceptable excipient. 22. The pharmaceutical composition of claim 21, wherein the excipient is selected from a solvent, aqueous solvent, non-aqueous solvent, dispersion media, diluent, dispersion, suspension aid, surface active agent, isotonic agent, thickening or emulsifying agent, preservative, lipid, lipidoids liposome, lipid nanoparticle, core-shell nanoparticles, polymer, lipoplex peptide, protein, cell, hyaluronidase, and mixtures thereof. 23. The pharmaceutical composition of claim 22, where the pharmaceutical composition comprises a lipid and wherein said lipid is selected from DLin-DMA, DLin-K-DMA, DLin-KC2-DMA, 98N12-5, C12-200, DLin-MC3-DMA, DODMA, DSDMA, DLenDMA, reLNPs, PLGA and PEGylated lipids and mixtures thereof. 24. A method of producing a polypeptide of interest in a mammalian cell, tissue or organism comprising administering to said cell, tissue or organism the pharmaceutical composition of claim 21. 25. The method of claim 24, wherein the isolated polynucleotide is formulated. 26. The method of claim 25, wherein the formulation comprises a lipid which is selected from one of DLin-DMA, DLin-K-DMA, DLin-KC2-DMA, 98N12-5, C12-200, DLin-MC3-DMA, DODMA, DSDMA, DLenDMA, reLNPs, PLGA, PEGylated lipids and mixtures or combinations thereof. 27. The method of claim 26, wherein the isolated polynucleotide is administered at a total daily dose of between 1 ug and 150 ug. 28. The method of claim 27, wherein administration is by injection. 29. The method of claim 27, wherein administration is intradermal or subcutaneous or intramuscular or intravitreal. 30. The method of claim 27, wherein levels of the polypeptide of interest in the serum of the mammal are at least 50 pg/mL at least two hours after administration. 31. The method of claim 27, wherein the levels of the polypeptide of interest in the serum of the mammal remain above 50 pg/mL for at least 72 hours after administration. 32. The method of claim 31, wherein the levels of the polypeptide of interest in the serum of the mammal remain above 60 pg/mL for at least 72 hours after administration. 33. The method of claim 26, wherein the resulting polynucleotide formulation has a mean particle size of 80 nm-160 nm, a PDI of between 0.02 and 0.20 and a lipid to polynucleotide ratio (wt/wt) of between 10-20.
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