Conjugate vaccine using trimming function of erap1

Abstract

wherein Xc and Yc are each a single bond or the like, and cancer antigen peptide C is an MHC class II-restricted cancer antigen peptide; or cancer antigen peptide D, wherein the cancer antigen peptide D is an MHC class I or II-restricted cancer antigen peptide containing one cysteine residue, or a salt thereof, for example.

1 . A compound represented by formula (1): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, 
         wherein X a  and Y a  are each independently a single bond or a divalent peptide group consisting of 1-4 amino acid residues, and a total of the amino acid residue number for X a  and the amino acid residue number for Y a  is an integer of 0-4, 
         cancer antigen peptide A is an MHC class I-restricted cancer antigen peptide consisting of 7-30 amino acid residues, an amino group of an N-terminal amino acid of the cancer antigen peptide A binds to Y a  in the formula (1), and a carbonyl group of a C-terminal amino acid of the cancer antigen peptide A binds to a hydroxyl group in the formula (i), and 
         R 1  is a hydrogen atom; 
         a group represented by formula (3): 
       
       
         
           
           
               
               
           
         
         wherein X c  and Y c  are each independently a single bond or a divalent peptide group consisting of 1-4 amino acid residues, and a total of the amino acid residue number for X c  and the amino acid residue number for Y c  is an integer of 0-4, 
         cancer antigen peptide C is an MHC class II-restricted cancer antigen peptide consisting of 7-30 amino acid residues, a carbonyl group of a C-terminal amino acid of the cancer antigen peptide C binds to X c  in the formula (3), and an amino group of an N-terminal amino acid of the cancer antigen peptide C binds to a hydrogen atom in the formula (3), and 
         a thioether group in the formula (3) binds to a thioether group in the formula (1); 
         or cancer antigen peptide D, wherein the cancer antigen peptide D is an MHC class I-restricted cancer antigen peptide consisting of 7-30 amino acid residues containing one cysteine residue or an MHC class II-restricted cancer antigen peptide consisting of 7-30 amino acid residues containing one cysteine residue, and a thioether group of the cysteine residue of the cancer antigen peptide D binds to a thioether group in the formula (1), 
         provided when R 1  is a hydrogen atom, the sequence of the formula (1) is not identical to the partial sequence of a cancer antigen protein. 
       
     
     
         2 . The compound of  claim 1 , wherein X a  is a single bond, and Y a  is a single bond, an alanine residue, a leucine residue or a methionine residue,
 or a pharmaceutically acceptable salt thereof.   
     
     
         3 . The compound of  claim 1 , wherein X a  is a single bond, an alanine residue, a glycine residue, a serine residue or a tyrosine residue, and Y a  is a single bond,
 or a pharmaceutically acceptable salt thereof.   
     
     
         4 . The compound of  claim 1 , wherein X a  and Y a  are each a single bond,
 or a pharmaceutically acceptable salt thereof.   
     
     
         5 . The compound of  claim 1 , wherein the cancer antigen peptide A is a peptide consisting of an amino acid sequence selected from SEQ ID NOs: 1-85, 87 and 88,
 the cancer antigen peptide C is a peptide consisting of an amino acid sequence selected from SEQ ID NOs: 101 and 102, the cancer antigen peptide D is a peptide consisting of an amino acid sequence selected from SEQ ID NOs: 3, 26, 37, 39, 56, 69, 70, 72, 75, 83, 84, 87 and 88, or a peptide consisting of an amino acid sequence selected from SEQ ID NOs: 103, 104, 105, 106 and 107,   or a pharmaceutically acceptable salt thereof.   
     
     
         6 . The compound of  claim 1 , wherein the cancer antigen peptide A is a peptide consisting of an amino acid sequence selected from SEQ ID NOs: 3, 11, 13, 19, 26, 27, 29, 33, 40, 41, 43, 50, 53, 66, 83, 84, 85, 87 and 88,
 or a pharmaceutically acceptable salt thereof.   
     
     
         7 . The compound of  claim 1 , wherein the cancer antigen peptide A is a peptide consisting of an amino acid sequence selected from the following amino acid sequences: 
       
         
           
                 
                 
               
                     
                   (SEQ ID NO: 19) 
                 
                     
                   GLYDGMEHL, 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 43) 
                 
                     
                   VLQELNVTV and 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 53) 
                 
                     
                   KIFGSLAFL, 
                 
             
                
                
                
                
                
                
                
                
               
            
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         8 . The compound of  claim 1 , wherein R 1  is a hydrogen atom, or a pharmaceutically acceptable salt thereof. 
     
     
         9 . The compound of  claim 1 , wherein the compound is a peptide consisting of an amino acid sequence selected from SEQ ID NOs: 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 108, 111, 112, 114, 115, 116, 117, 119, 120, 121, 122 and 123,
 or a pharmaceutically acceptable salt thereof.   
     
     
         10 . The compound of  claim 1 , wherein R 1  is a group represented by the formula (3),
 or a pharmaceutically acceptable salt thereof.   
     
     
         11 . The compound of  claim 1 , wherein X c  and Y c  are each a single bond,
 or a pharmaceutically acceptable salt thereof.   
     
     
         12 . The compound of  claim 1 , wherein the cancer antigen peptide C is a peptide consisting of an amino acid sequence selected from the following amino acid sequences: 
       
         
           
                 
                 
               
                     
                   (SEQ ID NO: 101) 
                 
                     
                   AKFVAAWTLKAAA and 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 102) 
                 
                     
                   aKFVAAWTLKAAa, 
                 
             
                
                
                
                
                
               
            
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         13 . The compound of  claim 1 , wherein R 1  is cancer antigen peptide D,
 or a pharmaceutically acceptable salt thereof.   
     
     
         14 . The compound of  claim 1 , wherein the cancer antigen peptide D is a peptide consisting of an amino acid sequence selected from SEQ ID NOs: 3, 26, 37, 39, 56, 69, 70, 72, 75, 83, 84, 87 and 88, or a peptide consisting of an amino acid sequence selected from SEQ ID NOs: 103, 104, 105, 106 and 107,
 or a pharmaceutically acceptable salt thereof.   
     
     
         15 . The compound of  claim 1 , wherein the cancer antigen peptide D is a peptide consisting of an amino acid sequence selected from the following amino acid sequences: 
       
         
           
                 
                 
               
                     
                   (SEQ ID NO: 87) 
                 
                     
                   VYGFVRACL and 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 88) 
                 
                     
                   SLLMWITQC, 
                 
             
                
                
                
                
                
               
            
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         16 . The compound of  claim 1 , wherein the cancer antigen peptide D is a peptide consisting of the following amino acid sequence: 
       
         
           
                 
                 
               
                     
                   (SEQ ID NO: 103) 
                 
                     
                   aK-Cha-VAAWTLKAAa-Ahx-C, 
                 
             
                
                
               
            
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         17 . The compound of  claim 1 , wherein the cancer antigen peptide D is a peptide consisting of an amino acid sequence selected from the following amino acid sequences: 
       
         
           
                 
                 
               
                     
                   (SEQ ID NO: 104) 
                 
                     
                   AADHRQLQLSISSCLQQL, 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 105) 
                 
                     
                   RNGYRALMDKSLHVGTQCALTRR, 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 106) 
                 
                     
                   KKLQCVQLHVISM and 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 107) 
                 
                     
                   GSYVSRLLGICL, 
                 
             
                
                
                
                
                
                
                
                
                
                
                
               
            
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         18 . A pharmaceutical composition, comprising:
 the compound of  claim 1  or a pharmaceutically acceptable salt thereof; and   a pharmaceutically acceptable carrier.   
     
     
         19 . A method of treating or preventing cancer, comprising administering a therapeutically or prophylactically effective amount of the compound of  claim 1  or a pharmaceutically acceptable salt thereof to a cancer patient positive for a cancer antigen protein in need thereof.