Peptide analogues

Abstract

Some embodiments relate to analogs of peptides corresponding to class I MHC-restricted T cell epitopes and methods for their generation. These analogs can contain amino acid substitutions at residues that directly interact with MHC molecules, and can confer improved, modified or useful immunologic properties. Additionally, classes of analogs, in which the various substitutions comprise the non-standard residues norleucine and/or norvaline, are disclosed.

1 . An isolated peptide consisting essentially of P0-P1-P2-P3-P4-P5-P6-P7-P8-P9-P10, wherein P1-P2-P3-P4-P5-P6-P7-P8-P9 comprises a substitution in at least one position of the PRAME 425-433  sequence SLLQHLIGL (SEQ ID NO: 71), wherein the at least one position is at amino acid position P1, P2, P3, P6, P8, or P9, wherein the peptide has an affinity for a class I MHC binding cleft that is similar to or greater than the affinity of SLLQHLIGL (SEQ ID NO: 71) for said class I MHC binding cleft, wherein P0 is X, XX, or XXX, wherein X specifies any amino acid or no amino acid, and wherein P10 is X, XX, or XXX, wherein X specifies any amino acid or no amino acid. 
     
     
         2 . The isolated peptide of  claim 1  consisting essentially of the sequence: 
       
         
           
                 
               
                   (SEQ ID NO: 72) 
                 
                 
               
                   {K, F, Y, T, Orn, or Hse}LLQHLIGL; 
                 
                   or 
                 
                     
                 
                 
               
                   (SEQ ID NO: 73) 
                 
                 
               
                   S{V, M, l, Nva, Nle, or Abu}LQHLIGL; 
                 
                   or 
                 
                     
                 
                 
               
                   (SEQ ID NO: 74) 
                 
                 
               
                   SL{Nva, Nle or Abu}QHLIGL; 
                 
                   or 
                 
                     
                 
                 
               
                   (SEQ ID NO: 75) 
                 
                 
               
                   SLLQH{Nva, Nle or Abu}IGL; 
                 
                   or 
                 
                     
                 
                 
               
                   (SEQ ID NO: 76) 
                 
                 
               
                   SLLQHLI{A, S, or Sar}L; 
                 
                   or 
                 
                     
                 
                 
               
                   (SEQ ID NO: 77) 
                 
                 
               
                   SLLQHLIG{V, l, A, Nle, Nva, Abu, or L-NH 2 }; 
                 
                   or 
                 
                     
                 
                 
               
                   (SEQ ID NO: 78) 
                 
                 
               
                   {F, Y, T, Orn, or Hse}{Nva, Nle, M, or I}LQHLIGL; 
                 
                   or 
                 
                     
                 
                 
               
                   (SEQ ID NO: 79) 
                 
                 
               
                   S{Nva, Nle, or M}LQHLIG{Nva, Nle, or V}; 
                 
                   or 
                 
                     
                 
                 
               
                   (SEQ ID NO: 80) 
                 
                 
               
                   {K, F, Y, T, Orn, or Hse}LLQHLIGV; 
                 
                   or 
                 
                     
                 
                 
               
                   (SEQ ID NO: 81) 
                 
                 
               
                   {F or T}LLQHLIG{Nle}; 
                 
                   or 
                 
                     
                 
                 
               
                   (SEQ ID NO: 82) 
                 
                 
               
                   {F or T}{Nva or M}LQHLIG{Nle}. 
                 
             
                
               
            
             
                
                
                
               
            
             
                
               
            
             
                
                
                
               
            
             
                
               
            
             
                
                
                
               
            
             
                
               
            
             
                
                
                
               
            
             
                
               
            
             
                
                
                
               
            
             
                
               
            
             
                
                
                
               
            
             
                
               
            
             
                
                
                
               
            
             
                
               
            
             
                
                
                
               
            
             
                
               
            
             
                
                
                
               
            
             
                
               
            
             
                
                
                
               
            
             
                
               
            
             
                
               
            
           
         
       
     
     
         3 . The isolated peptide of  claim 2  consisting essentially of the sequence: 
       
         
           
                 
                 
               
                   {F, Y, T, Orn, or Hse}LLQHLIGL; 
                   (SEQ ID NO: 83) 
                 
                   or 
                 
                     
                 
                   S{Nva, Nle, or M}LQHLIGL; 
                   (SEQ ID NO: 84) 
                 
                   or 
                 
                     
                 
                   SLLQHLIG{Nle, Nva, or L-NH 2 }; 
                   (SEQ ID NO: 85) 
                 
                   or 
                 
                     
                 
                   SLLQH{Nva or Abu}IGL; 
                   (SEQ ID NO: 86) 
                 
                   or 
                 
                     
                 
                   S{Nva}LQHLIGL{Nle}; 
                   (SEQ ID NO: 87) 
                 
                   or 
                 
                     
                 
                   {F or T}{L or Nva}LQHLIG{Nle}. 
                   (SEQ ID NO: 88) 
                 
             
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
               
            
           
         
       
     
     
         4 . The isolated peptide of  claim 1 , wherein the class I MHC is HLA-A2. 
     
     
         5 . The isolated peptide of  claim 1 , wherein the halftime of dissociation is similar to or greater than the halftime of dissociation of SLLQHLIGL (SEQ ID NO: 71) from said class I MHC binding cleft. 
     
     
         6 . The isolated peptide of  claim 1 , that is recognized by T cells with specificity for the peptide SLLQHLIGL (SEQ ID NO: 71). 
     
     
         7 . The isolated peptide of  claim 1  complexed with a class I MHC molecule. 
     
     
         8 . The class I MHC-peptide complex of  claim 7 , that is cross-reactive with a TCR that recognizes a class I MHC/PRAME425-433 complex. 
     
     
         9 . The class I MHC-peptide complex of  claim 8 , wherein the class I MHC-complex is an HLA-A2/PRAME425-433 complex. 
     
     
         10 . A polypeptide comprising the peptide sequence of  claim 1 , embedded within a liberation sequence. 
     
     
         11 . An immunogenic composition comprising the peptide of  claim 1 . 
     
     
         12 . A nucleic acid means for expressing the peptide of  claim 1 . 
     
     
         13 . An immunogenic composition comprising the nucleic acid of  claim 12 . 
     
     
         14 . A method of inducing, maintaining, or entraining a CTL response comprising intranodal administration of the composition of  claim 13 . 
     
     
         15 . A method of inducing, maintaining, or amplifying a CTL response comprising intranodal administration of the composition of  claim 11 . 
     
     
         16 . The method of  claim 16 , further comprising intranodal administration of an immunopotentiating agent.