Expression system for modulating an immune response

Abstract

The present invention discloses methods and compositions for modulating the quality of an immune response to a target antigen in a mammal, which response results from the expression of a polynucleotide that encodes at least a portion of the target antigen, wherein the quality is modulated by replacing at least one codon of the polynucleotide with a synonymous codon that has a higher or lower preference of usage by the mammal to confer the immune response than the codon it replaces.

1 - 41 . (canceled) 
     
     
         42 . A chimeric construct comprising a synthetic polynucleotide that is operably connected to a regulatory polynucleotide, wherein the synthetic polynucleotide is distinguished from a parent polynucleotide that encodes a polypeptide that corresponds to at least a portion of a target antigen by the replacement of a first codon in the parent polynucleotide with a synonymous codon that has a higher immune response preference than the first codon, wherein the first and synonymous codons are selected according to TABLE 3: 
       
         
           
                 
                 
                 
               
                     
                   TABLE 3 
                 
                     
                     
                 
                     
                     
                   Synonymous 
                 
                     
                   First Codon 
                   Codon 
                 
                     
                     
                 
                     
                   Ala GCG   
                   Ala GCT   
                 
                     
                   Ala GCA   
                   Ala GCT   
                 
                     
                   Ala GCC   
                   Ala GCT   
                 
                     
                   Arg CGG   
                   Arg CGA   
                 
                     
                   Arg CGG   
                   Arg CGT   
                 
                     
                   Arg CGG   
                   Arg AGA   
                 
                     
                   Arg AGG   
                   Arg CGA   
                 
                     
                   Arg AGG   
                   Arg CGT   
                 
                     
                   Arg AGG   
                   Arg AGA   
                 
                     
                   Glu GAG   
                   Glu GAA   
                 
                     
                   Gly GGC   
                   Gly GGA   
                 
                     
                   Gly GGT   
                   Gly GGA   
                 
                     
                   Gly GGG   
                   Gly GGA   
                 
                     
                   Leu TTA   
                   Leu CTA   
                 
                     
                   Leu TTA   
                   Leu CTT   
                 
                     
                   Leu TTA   
                   Leu TTG   
                 
                     
                   Leu TTG   
                   Leu CTA   
                 
                     
                   Leu TTG   
                   Leu CTT   
                 
                     
                   phe TTC   
                   phe TTT   
                 
                     
                   pro CCG   
                   pro CCT   
                 
                     
                   pro CCA   
                   pro CCT   
                 
                     
                   Ser AGT   
                   Ser TCG   
                 
                     
                   Ser AGT   
                   Ser TCT   
                 
                     
                   Ser AGT   
                   Ser TCA   
                 
                     
                   Ser AGC   
                   Ser TCG   
                 
                     
                   Ser AGC   
                   Ser TCT   
                 
                     
                   Ser AGC   
                   Ser TCA   
                 
                     
                   Ser AGC   
                   Ser TCC   
                 
                     
                   Ser TCC   
                   Ser TCG   
                 
                     
                   Ser TCA   
                   Ser TCG   
                 
                     
                   Ser TCT   
                   Ser TCG   
                 
                     
                   Thr ACT   
                   Thr ACG   
                 
                     
                   Thr ACT   
                   Thr ACA   
                 
                     
                   Thr ACA   
                   Thr ACG   
                 
                     
                   Thr ACC   
                   Thr ACG   
                 
                     
                   Val GTA   
                   Val GTT   
                 
                     
                     
                 
             
                
                
                
                
                
               
               
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
               
            
           
         
       
     
     
         43 . The chimeric construct of  claim 42 , wherein at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% of the first codons of the parent polynucleotide are replaced with synonymous codons in accordance with TABLE 3. 
     
     
         44 . The chimeric construct of  claim 42 , wherein the target antigen is from a pathogenic organism. 
     
     
         45 . The chimeric construct of  claim 44 , wherein the pathogenic organism is selected from a virus, bacteria, fungi, parasite, algae, protozoa and amoebae. 
     
     
         46 . The chimeric construct of  claim 42 , wherein the target antigen is a herpes simplex virus antigen. 
     
     
         47 . The chimeric construct of  claim 42 , wherein the target antigen is a herpes simplex virus antigen glycoprotein D. 
     
     
         48 . The chimeric construct of  claim 47 , wherein the glycoprotein D is gD2. 
     
     
         49 . The chimeric construct of  claim 42 , wherein the target antigen is an HIV antigen (e.g., the gene products of the HIV gag, pol, or env genes, the Nef protein, and reverse transcriptase), hepatitis viral antigens (e.g., the S, M, and L proteins of hepatitis B virus, the pre-S antigen of hepatitis B virus, and other hepatitis viral components), influenza viral antigens (e.g., hemagglutinin, neuraminidase and other influenza viral components), a measles viral antigen (e.g., the measles virus fusion protein and other measles virus components), a rubella viral antigen (e.g., E1 and E2 proteins and other rubella virus components), a rotaviral antigen (e.g., VP7sc and other rotaviral components), a cytomegaloviral antigen (e.g., envelope glycoprotein B and other cytomegaloviral antigen components), a respiratory syncytial viral antigen (e.g., the RSV fusion protein, the M2 protein and other respiratory syncytial viral antigen components), a varicella zoster viral antigen (e.g., 9PI, gpII, and other varicella zoster viral antigen components), a Japanese encephalitis viral antigen (e.g., proteins E, M-E, M-E-NS 1, NS 1, NS 1-NS2A, and other Japanese encephalitis viral antigen components), a rabies viral antigen (e.g., rabies glycoprotein, rabies nucleoprotein and other rabies viral antigen components), a papillomavirus antigen (e.g., the L1 and L2 capsid proteins and the E6/E7 proteins). 
     
     
         50 . The chimeric construct of  claim 42 , wherein the target antigen is cancer or tumour antigen. 
     
     
         51 . The chimeric construct of  claim 42 , further comprising a coding sequence for an adjuvant. 
     
     
         52 . The chimeric construct of  claim 51 , wherein the adjuvant is a protein destabilizing element, which increased processing and presentation of the polypeptide that corresponds to at least a portion of the target antigen through the class I MHC pathway. 
     
     
         53 . The chimeric contrast of  claim 52 , wherein the protein-destabilizing element is an ubiquitin. 
     
     
         54 . A pharmaceutical composition that is useful for modulating an immune response to a target antigen in a mammal, which response is conferred by the expression of a parent polynucleotide that encodes a polypeptide corresponding to at least a portion of the target antigen, the composition comprising a chimeric construct and a pharmaceutically acceptable excipient and/or carrier, wherein the chimeric construct comprises a synthetic polynucleotide that is operably connected to a regulatory polynucleotide and that is distinguished from the parent polynucleotide by the replacement of a first codon in the parent polynucleotide with a synonymous codon that has a different immune response preference than the first codon and wherein the first and synonymous codons are selected according to any one of TABLE 3. 
     
     
         55 . The composition according to  claim 49 , further comprising an adjuvant that enhances the effectiveness of the immune response. 
     
     
         56 . The composition according to  claim 49 , which is formulated for transcutaneous administration. 
     
     
         57 . The composition according to  claim 49 , which is formulated for epidermal administration. 
     
     
         58 . The composition according to  claim 49 , which is formulated for dermal administration. 
     
     
         59 . The composition according to  claim 49 , which is formulated for intradermal administration. 
     
     
         60 . The composition according to  claim 49 , which is formulated for biolistic delivery. 
     
     
         61 . The composition according to  claim 49 , which is formulated for microneedle delivery. 
     
     
         62 . The composition according to  claim 49 , which is formulated for intradermal injection.