Oligoribonucleotides and uses thereof
AssigneeColey Pharmaceutical GmbH
InventorsMarion Jurk, Jorg Vollmer, Eugen Uhlmann
Life of this patent
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Abstract
The invention relates to immunostimulatory RNA oligonucleotides (ORN). In particular the ORN have an immunostimulatory ORN motif directly or indirectly flanked by a 3′ poly G motif and optionally a 5′ poly-G motif. The invention also relates to methods including therapeutic methods and screening methods and related kits for use of the ORN.
Claims83
An RNA oligonucleotide (ORN) of 10-100 ribonucleotides in length comprising:
- GG(R1)n (U)4-20(R2)m GGGG (SEQ ID NO:29) wherein R1 and R2 are a ribonucleoside, a deoxyribonucleoside, a spacer, or a non-nucleotidic linker, U is Uridine or a derivative thereof, G is guanosine, wherein n=0-20, wherein m=0-20.
An RNA oligonucleotide (ORN) of 10-100 ribonucleotides in length comprising:
- GG(R1)n (U)5-20(R2)m GGGG (SEQ ID NO:30) wherein R1 and R2 are a ribonucleoside, a deoxyribonucleoside, a spacer, or a non-nucleotidic linker, U is Uridine or a derivative thereof, G is guanosine, wherein n=0-20, wherein m=0-20.
An RNA oligonucleotide (ORN) of 10-100 ribonucleotides in length comprising:
- GG(R1)n (U)4(R2)m GGGG (SEQ ID NO:31) wherein R1 and R2 are a ribonucleoside, a deoxyribonucleoside, a spacer, or a non-nucleotidic linker, U is Uridine or a derivative thereof, G is guanosine, wherein n=0-20, wherein m=0-20 and wherein when (R1)n is GG (R2)m is not G or m is not=0.
An RNA oligonucleotide (ORN) of 10-100 ribonucleotides in length comprising:
- GG(R1)n (U)4-20(R2)m GGGG (SEQ ID NO:29) wherein R1 and R2 are a ribonucleoside, a deoxyribonucleoside, a spacer, or a non-nucleotidic linker, U is Uridine or a derivative thereof, G is guanosine, wherein n=0-20, wherein m=0-20, and wherein the ORN does not include a modified phosphate linkage selected from the group consisting of:
- wherein
- R1 is hydrogen (H), COOR, OH, C1-C18 alkyl, C6H5, or (CH2)m-NH—R2, wherein R is H or methyl, butyl, methoxyethyl, pivaloyl oxymethyl, pivaloyl oxybenzyl, or S-pivaloyl thioethyl;
- R2 is H, C1-C18 alkyl, or C2-C18 acyl;
- and m is 1 to 17;
- X is oxygen (O) or sulfur (S);
- and
- each of Nu and Nu′ independently is a nucleoside or nucleoside analog;
- with the proviso that if R1 is H, then X is S;
- wherein
- X is O or S;
- X1 is OH, SH, BH3, OR3, or NHR3, wherein R3 is C1-C18 alkyl;
- each of X2 and X3 independently is O, S, CH2, or CF2;
- and
- each of Nu and Nu′ independently is a nucleoside or nucleoside analog;
- with the proviso that
- (a) at least one of X, X2, and X3 is not O or X1 is not OH,
- (b) if X1 is SH, then at least one of X, X2, and X3 is not O,
- (c) if X and X2 are O and if X1 is OH, then X3 is not S and Nu is 3′Nu and Nu′ is 5′Nu′, and
- (d) if X1 is BH3, then at least one of X, X2, or X3 is S;
- and
- (iii) any combination of (i) and (ii)
- or at least one nucleotide analog provided as Formula IIIA or Formula IIIB
- wherein
- R4 is H or OR, wherein R is H or C1-C18 acyl;
- B is a nucleobase, a modified nucleobase, or H;
- each of X and X5 independently is O or S;
- and
- X4 is OH, SH, methyl, or NHR5, wherein R5 is C1-C1-8 alkyl;
- and
- each dashed line independently represents an optional bond to an adjacent unit, hydrogen, or an organic radical;
- with the proviso that at least one of X and X5 is not O or X4 is not OH.
An ORN comprising rG*rG*rG*rG*rU*rU*rU*rU*rU*rU*rU*rU*rU*rU*rG*rG*rG*rG*rG*rG*rG (SEQ ID NO:4).
An ORN comprising rG*rG*rG*rG*rU*rU*rG*rU*rU*rG*rU*rU*rG*rU*rG*rG*rG*rG*rG*rG*rG (SEQ ID NO:5).
An ORN comprising rG*rG*rG*rG*rU*rU*rA*rU*rU*rA*rU*rU*rA*rU*rG*rG*rG*rG*rG*rG*rG (SEQ ID NO:6).
An ORN comprising rG*rG*rG*rG-rU-rU-rU-rU-rU-rU-rU-rU-rU-rU-rG*rG*rG*rG*rG*rG*rG (SEQ ID NO:8).
An ORN comprising rG*rU*rU*rG*rU*rG*rU*dG*dG*dG*dG*dG (SEQ ID NO:10).
An immunostimulatory RNA oligonucleotide (ORN) of 8-100 ribonucleotides in length comprising:
- an immunostimulatory ORN motif linked to a poly-G motif, wherein the poly-G motif is 3′ to the immunostimulatory ORN motif and the poly-G motif comprises at least 4 Gs, wherein G is guanosine.
A method for stimulating production of IFN-α, comprising:
- contacting a TLR7 expressing cell with an RNA oligonucleotide (ORN) comprising:
- an immunostimulatory ORN motif linked to a poly-G motif, wherein the poly-G motif is 3′ to the immunostimulatory ORN motif and the poly-G motif comprises at least 4 Gs, wherein G is guanosine, in an effective amount to stimulate IFN-α production and wherein IFN-γ or IL-12 production in response to the ORN is not induced significantly relative to background.
Dependencies are inferred from the claim text.