Nucleoside-Modified RNA For Inducing an Adaptive Immune Response

Abstract

The present invention relates to compositions and methods for inducing an adaptive immune response in a subject. In certain embodiments, the present invention provides a composition comprising a nucleoside-modified nucleic acid molecule encoding an antigen, adjuvant, or a combination thereof. For example, in certain embodiments, the composition comprises a vaccine comprising a nucleoside-modified nucleic acid molecule encoding an antigen, adjuvant, or a combination thereof.

1 . A composition for inducing an adaptive immune response in a subject, the composition comprising at least one nucleoside-modified RNA encoding at least one antigen. 
     
     
         2 . The composition of  claim 1 , wherein the at least one isolated nucleoside-modified RNA comprises at least one selected from the group consisting of pseudouridine and 1-methyl-pseudouridine. 
     
     
         3 . (canceled) 
     
     
         4 . The composition of  claim 1 , wherein the at least one antigen comprises at least one selected from the group consisting of a viral antigen, a bacterial antigen, a fungal antigen, a parasitic antigen, a tumor-associated antigen, and a tumor-specific antigen 
     
     
         5 . The composition of  claim 1 , wherein the at least one antigen comprises an antigen selected from the group consisting of an HIV antigen and an influenza antigen. 
     
     
         6 . The composition of  claim 5 , wherein the antigen comprises an antigen selected from the group consisting of HIV envelope (Env) and influenza hemagglutinin (HA). 
     
     
         7 - 8 . (canceled) 
     
     
         9 . The composition of  claim 1 , wherein the composition further comprises an adjuvant. 
     
     
         10 . The composition of  claim 1 , wherein the at least one nucleoside-modified RNA further encodes at least one adjuvant. 
     
     
         11 . The composition of  claim 1 , further comprising a lipid nanoparticle (LNP). 
     
     
         12 . The composition of  claim 11 , wherein the at least one nucleoside-modified RNA is encapsulated within the LNP. 
     
     
         13 . The composition of  claim 1 , wherein the composition is a vaccine. 
     
     
         14 . The composition of  claim 11 , wherein the LNP comprises a compound having a structure of Formula (I): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, tautomer, prodrug or stereoisomer thereof, wherein:
 L 1  and L 2  are each independently —O(C═O)—, —(C═O)O— or a carbon-carbon double bond; 
 R 1a  and R 1b  are, at each occurrence, independently either (a) H or C 1 -C 12  alkyl, or (b) R 1a  is H or C 1 -C 12  alkyl, and R 1b  together with the carbon atom to which it is bound is taken together with an adjacent R 1b  and the carbon atom to which it is bound to form a carbon-carbon double bond; 
 R 2a  and R 2b  are, at each occurrence, independently either (a) H or C 1 -C 12  alkyl, or (b) R 2a  is H or C 1 -C 12  alkyl, and R 2b  together with the carbon atom to which it is bound is taken together with an adjacent R 2b  and the carbon atom to which it is bound to form a carbon-carbon double bond; 
 R 3a  and R 3b  are, at each occurrence, independently either (a) H or C 1 -C 12  alkyl, or (b) R 3a  is H or C 1 -C 12  alkyl, and R 3b  together with the carbon atom to which it is bound is taken together with an adjacent R 3b  and the carbon atom to which it is bound to form a carbon-carbon double bond; 
 R 4a  and R 4b  are, at each occurrence, independently either (a) H or C 1 -C 12  alkyl, or (b) R 4a  is H or C 1 -C 12  alkyl, and R 4b  together with the carbon atom to which it is bound is taken together with an adjacent R 4b  and the carbon atom to which it is bound to form a carbon-carbon double bond; 
 R 5  and R 6  are each independently methyl or cycloalkyl; 
 R 7  is, at each occurrence, independently H or C 1 -C 12  alkyl; 
 R 8  and R 9  are each independently unsubstituted C 1 -C 12  alkyl; or R 8  and R 9 , together with the nitrogen atom to which they are attached, form a 5, 6 or 7-membered heterocyclic ring comprising one nitrogen atom; 
 a and d are each independently an integer from 0 to 24; 
 b and c are each independently an integer from 1 to 24; and 
 e is 1 or 2. 
 
     
     
         15 . The composition of  claim 11 , wherein the LNP comprises a compound having a structure of Formula (II): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, tautomer, prodrug or stereoisomer thereof, wherein:
 L 1  and L 2  are each independently —O(C═O)—, —(C═O)O—, —C(═O)—, —O—, —S(O) x —, —S—S—, —C(═O)S—, —SC(═O)—, —NR a C(═O)—, —C(═O)NR a —, —NR a C(═O)NR a , —OC(═O)NR a —, —NR a C(═O)O—, or a direct bond; 
 G 1  is C 1 -C 2  alkylene, —(C═O)—, —O(C═O)—, —SC(═O)—, —NR a C(═O)— or a direct bond; 
 G 2  is —C(═O)—, —(C═O)O—, —C(═O)S—, —C(═O)NR a  or a direct bond; 
 G 3  is C 1 -C 6  alkylene; 
 R a  is H or C 1 -C 12  alkyl; 
 R 1a  and R 1b  are, at each occurrence, independently either: (a) H or C 1 -C 12  alkyl; or (b) R 1a  is H or C 1 -C 12  alkyl, and R 1b  together with the carbon atom to which it is bound is taken together with an adjacent R 1b  and the carbon atom to which it is bound to form a carbon-carbon double bond; 
 R 2a  and R 2b  are, at each occurrence, independently either: (a) H or C 1 -C 12  alkyl; or (b) R 2a  is H or C 1 -C 12  alkyl, and R 2b  together with the carbon atom to which it is bound is taken together with an adjacent R 2b  and the carbon atom to which it is bound to form a carbon-carbon double bond; 
 R 3a  and R 3b  are, at each occurrence, independently either: (a) H or C 1 -C 12  alkyl; or (b) R 3a  is H or C 1 -C 12  alkyl, and R 3b  together with the carbon atom to which it is bound is taken together with an adjacent R 3b  and the carbon atom to which it is bound to form a carbon-carbon double bond; 
 R 4a  and R 4b  are, at each occurrence, independently either: (a) H or C 1 -C 12  alkyl; or (b) R 4a  is H or C 1 -C 12  alkyl, and R 4b  together with the carbon atom to which it is bound is taken together with an adjacent R 4b  and the carbon atom to which it is bound to form a carbon-carbon double bond; 
 R 5  and R 6  are each independently H or methyl; 
 R 7  is C 4 -C 20  alkyl; 
 R 8  and R 9  are each independently C 1 -C 12  alkyl; or R 8  and R 9 , together with the nitrogen atom to which they are attached, form a 5, 6 or 7-membered heterocyclic ring; 
 a, b, c and d are each independently an integer from 1 to 24; and 
 x is 0, 1 or 2. 
 
     
     
         16 . The composition of  claim 11 , wherein the LNP comprises a compound having a structure of Formula (III): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, tautomer, prodrug or stereoisomer thereof, wherein:
 one of L 1  or L 2  is —O(C═O)—, —(C═O)O—, —C(═O)—, —O—, —S(O) x —, —S—S—, —C(═O)S—, SC(═O)—, —NR a C(═O)—, —C(═O)NR a —, NR a C(═O)NR a —, —OC(═O)NR a — or —NR a C(═O)O—, and the other of L 1  or L 2  is —O(C═O)—, —(C═O)O—, —C(═O)—, —O—, —S(O) x —, —S—S—, —C(═O)S—, SC(═O)—, —NR a C(═O)—, —C(═O)NR a —, NR a C(═O)NR a —, —OC(═O)NR a — or —NR a C(═O)O— or a direct bond; 
 G 1  and G 2  are each independently unsubstituted C 1 -C 12  alkylene or C 1 -C 12  alkenylene; 
 G 3  is C 1 -C 24  alkylene, C 1 -C 24  alkenylene, C 3 -C 8  cycloalkylene, C 3 -C 8  cycloalkenylene; 
 R a  is H or C 1 -C 12  alkyl; 
 R 1  and R 2  are each independently C 6 -C 24  alkyl or C 6 -C 24  alkenyl; 
 R 3  is H, OR 5 , CN, —C(═O)OR 4 , —OC(═O)R 4  or —NR 5 C(═O)R 4 ; 
 R 4  is C 1 -C 12  alkyl; 
 R 5  is H or C 1 -C 6  alkyl; and 
 x is 0, 1 or 2. 
 
     
     
         17 . The composition of  claim 11 , wherein the LNP comprises a compound having one of the following structures: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         18 . The composition of  claim 11 , wherein the LNP comprises a pegylated lipid having the following structure (IV): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein:
 R 10  and R 11  are each independently a straight or branched, saturated or unsaturated alkyl chain containing from 10 to 30 carbon atoms, wherein the alkyl chain is optionally interrupted by one or more ester bonds; and 
 z has a mean value ranging from 30 to 60. 
 
     
     
         19 . The composition of  claim 18 , wherein the pegylated lipid has the following structure (IVa): 
       
         
           
           
               
               
           
         
         wherein n is an integer selected such that the average molecular weight of the pegylated lipid is about 2500 g/mol. 
       
     
     
         20 - 44 . (canceled)