Nucleic acid-lipophilic conjugates

Abstract

The invention relates to a nucleic acid-lipophilic conjugates and methods for modulating an immune response using the conjugates. The lipophilic moiety associated with an immunostimulatory nucleic acid.

1 . A composition comprising;
   (N 1 PN 2 ).L   wherein N 1  and N 2  are independently nucleic acids of 0-100 nucleotides in length, P is a palindromic containing nucleic acid and comprising at least one YR dinucleotide, wherein Y is a cytosine or a modified cytosine and R is a guanine or a modified guanine, and wherein L is a lipophilic group.   
     
     
         2 . The composition of  claim 1 , wherein N 1 PN 2  is 3-14 nucleotides in length. 
     
     
         3 . The composition of  claim 1 , wherein L is linked to the nucleotide at the 3′ end of N 1 PN 2 . 
     
     
         4 . The composition of  claim 1 , wherein L is linked by a linker to a 2′-position of a nucleotide in N 1 PN 2 , to a heterocyclic base of a nucleotide in N 1 PN 2 , or a phosphodiester linkage in N 1 PN 2 . 
     
     
         5 . The composition of  claim 4 , wherein the nucleotide is selected from the group consisting of a nucleotide at the 3′ end of N 1 PN 2  and an internal nucleotide. 
     
     
         6 . The composition of  claim 1 , wherein L is selected from the group consisting of a cholesteryl, a modified cholesteryl, a cholesterol derivative, a reduced cholesterol, and a substituted cholesterol. 
     
     
         7 - 8 . (canceled) 
     
     
         9 . The composition of  claim 1 , wherein the formula comprises N 1 PN 2 -L-N 3 PN 4 , wherein N 3  and N 4  are independently nucleic acids of 0-100 nucleotides in length. 
     
     
         10 - 13 . (canceled) 
     
     
         14 . The composition of  claim 1 , wherein the formula comprises
   ([N 1 PN 2 ] n —(X 3 ) m ).(L) p      wherein X 3  is a linker, m is an integer from 0 to 20 (preferably from 1-10), n is an integer from 0 to 20 (preferably from 1-10), p is an integer from 1 to 10 (preferably 1), and wherein the oligonucleotide N 1 PN 2  has a length of 4 to 40 nucleotides.   
     
     
         15 . The composition of  claim 14 , wherein X 3  is a non-nucleotidic linker selected from the group consisting of abasic residues (dSpacer), oligoethyleneglycol, such as triethyleneglycol (spacer 9) or hexaethylenegylcol (spacer 18), and alkane-diol, such as butanediol. 
     
     
         16 . The composition of  claim 14 , wherein the linker is attached to the oligonucleotide through a linkage selected from the group consisting of phosphodiester, phosphorothioate, methylphosphonate, and amide linkages. 
     
     
         17 . The composition of  claim 14 , wherein n is greater than 1 and the multiple [N 1 PN 2 ] are linked through 3′-ends. 
     
     
         18 . The composition of  claim 14 , wherein N 1 PN 2  is a branched ODN and wherein N 1  includes at least one CG dinucleotide. 
     
     
         19 . The composition of  claim 14 , wherein L is attached to the 3′ end of the oligonucleotide [N 1 PN 2 ]. 
     
     
         20 . The composition of  claim 14 , wherein P is X 1 —Y—R—X 2 , wherein X 1  and X 2  are independently from 0 to 4 nucleotides. 
     
     
         21 - 24 . (canceled) 
     
     
         25 . The composition of  claim 20 , wherein X 2  is a palindrome or an inverted repeat. 
     
     
         26 . The composition of  claim 25 , wherein the palindrome or inverted repeat contains at least one unmethylated CpG motif. 
     
     
         27 - 47 . (canceled) 
     
     
         48 . The composition of  claim 1 , further comprising:
 a nucleic acid having at least one exposed 5′ end; comprising, at least one YR dinucleotide, wherein Y is a cytosine or a modified cytosine and R is a guanine or a modified guanine, at least one single stranded region, at least one double stranded region and wherein the nucleic acid is linked to at least one lipophilic group.   
     
     
         49 - 55 . (canceled) 
     
     
         56 . A method for modulating an immune response, comprising administering to a subject a composition of  claim 1 , in an effective amount to modulate an immune response. 
     
     
         57 - 72 . (canceled) 
     
     
         73 . A composition comprising;
   (N 1 YRN 2 ).L   wherein N 1  and N 2  are independently nucleic acids of 0-100 nucleotides in length, wherein Y is a cytosine or a modified cytosine and R is a guanine or a modified guanine, and N 1 YRN 2  is at least 10 nucleotides in length,   wherein L is a lipophilic group, and   wherein L is linked by a linker to a 2′-position of a nucleotide in N 1 YRN 2 , or to a heterocyclic base of a nucleotide in N 1 YRN 2 .   
     
     
         74 - 77 . (canceled) 
     
     
         78 . A composition comprising;
   (N 1 PN 2 ).L   wherein N 1  and N 2  are independently nucleic acids of 0-100 nucleotides in length, P is a palindromic containing nucleic acid and comprising at least one YR dinucleotide, wherein Y is a cytosine or a modified cytosine and R is a guanine or a modified guanine, and wherein L is cholesterol.   
     
     
         79 - 80 . (canceled)