Wt1 antigen peptide conjugate vaccine

Abstract

A compound represented by the formula (1): wherein X a and Y a are each a single bond and the like, cancer antigen peptide A is an MHC class I-restricted WT1 peptide consisting of 7-30 amino acid residues, R 1 is a hydrogen atom, a group represented by the formula (2): wherein X b and Y b are each a single bond and the like, cancer antigen peptide B has a sequence different from that of the cancer antigen peptide A, and is an MHC class I-restricted WT1 peptide consisting of 7-30 amino acid residues, or cancer antigen peptide C, and cancer antigen peptide C has a sequence different from that of the cancer antigen peptide A, and is an MHC class I-restricted WT1 peptide or an MHC class II-restricted WT1 peptide, consisting of 7-30 amino acid residues containing one cysteine residue, or a salt thereof, and the like.

1 . A compound of formula (1): 
       
         
           
           
               
               
           
         
       
       wherein X a  and Y a  are each a single bond,
 cancer antigen peptide A is an MHC class I-restricted WT1 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 (1), 
 R 1  is a hydrogen atom, a group of formula (2), or cancer antigen peptide C: 
 
       
         
           
           
               
               
           
         
       
       wherein X b  and Y b  are each independently a single bond or a divalent peptide group consisting of 1-4 amino acid residues wherein X b  and Y b  together have 0-4 amino acid residues,
 cancer antigen peptide B has a sequence different from a sequence of the cancer antigen peptide A and is an MHC class I-restricted WT1 peptide consisting of 7-30 amino acid residues, 
 an amino group of an N-terminal amino acid of the cancer antigen peptide B binds to Y b  in the formula (2), and 
 a carbonyl group of a C-terminal amino acid of the cancer antigen peptide B binds to a hydroxyl group in the formula (2), and 
 a thioether group in the formula (2) binds to a thioether group in the formula (1), 
 cancer antigen peptide C is an MHC class I-restricted WT1 peptide different from the cancer antigen peptide A in the sequence and consisting of 7-30 amino acid residues containing one cysteine residue or an MHC class II-restricted WT1 peptide consisting of 7-30 amino acid residues containing one cysteine residue, wherein a thioether group of the cysteine residue of the cancer antigen peptide C binds to the thioether group in the formula (1), 
 
       or a pharmaceutically acceptable salt thereof, 
       provided when R 1  is a hydrogen atom, the sequence of the compound of the formula (1) is not the same as a partial sequence of a WT1 protein, 
       and the compound of the formula (1) is not a compound of formula (4) or formula (5) 
       
         
           
           
               
               
           
         
       
     
     
         2 . The compound according to  claim 1 , wherein the cancer antigen peptide A is
 a peptide comprising an amino acid sequence selected from the group consisting of:
 RMFPNAPYL (SEQ ID NO: 2), 
 CMTWNQMNL (SEQ ID NO: 3), 
 CYTWNQMNL (SEQ ID NO: 4), 
 ALLPAVPSL (SEQ ID NO: 5), 
 SLGEQQYSV (SEQ ID NO: 6) and 
 RVPGVAPTL (SEQ ID NO: 7), or 
   a peptide comprising an altered amino acid sequence, which is an amino acid sequence selected from the group consisting of SEQ ID NOs: 2, 3, 5, 6 and 7 but containing alteration of amino acid residue(s), and having a CTL induction activity, or a pharmaceutically acceptable salt thereof.   
     
     
         3 . The compound according to  claim 1 , wherein R 1  is a hydrogen atom,
 or a pharmaceutically acceptable salt thereof.   
     
     
         4 . The compound according to  claim 1 , wherein the compound of the formula (1) is a peptide consisting of an amino acid sequence selected from the group consisting of:
 CRMFPNAPYL (SEQ ID NO: 13),   CALLPAVPSL (SEQ ID NO: 16),   CSLGEQQYSV (SEQ ID NO: 17) and   CRVPGVAPTL (SEQ ID NO: 18),   
       or a pharmaceutically acceptable salt thereof. 
     
     
         5 . The compound according to  claim 1 , wherein R 1  is a group of the formula (2),
 or a pharmaceutically acceptable salt thereof.   
     
     
         6 . The compound according to  claim 5 , wherein X b  is a single bond, and Y b  is a single bond or an alanine residue, or a pharmaceutically acceptable salt thereof. 
     
     
         7 . The compound according to  claim 5 , wherein the cancer antigen peptide B is
 a peptide comprising an amino acid sequence selected from the group consisting of:
 RMFPNAPYL (SEQ ID NO: 2), 
 CMTWNQMNL (SEQ ID NO: 3), 
 CYTWNQMNL (SEQ ID NO: 4), 
 ALLPAVPSL (SEQ ID NO: 5), 
 SLGEQQYSV (SEQ ID NO: 6) and 
 RVPGVAPTL (SEQ ID NO: 7), or 
   a peptide comprising an altered amino acid sequence, which is an amino acid sequence selected from the group consisting of SEQ ID NOs: 2, 3, 5, 6 and 7 but containing alteration of amino acid residue(s), and having a CTL induction activity, or a pharmaceutically acceptable salt thereof.   
     
     
         8 . The compound according to  claim 1 , wherein the compound of the formula (1) is a compound of formula (3): 
       
         
           
           
               
               
           
         
       
       wherein the bond between C and C is a disulfide bond, or a pharmaceutically acceptable salt thereof. 
     
     
         9 . The compound according to  claim 1 , wherein, when the cancer antigen peptide B is an MHC class I-restricted WT1 peptide containing one cysteine residue, the thioether group in the cancer antigen peptide B is bonded to a thioether group in formula (16): 
       
         
           
           
               
               
           
         
       
       wherein X d  and Y d  are each a single bond,
 cancer antigen peptide D is an MHC class II-restricted WT1 peptide consisting of 7-30 amino acid residues, 
 an amino group of an N-terminal amino acid of the cancer antigen peptide D binds to Y d  in the formula (16), and 
 a carbonyl group of a C-terminal amino acid of the cancer antigen peptide D binds to a hydroxyl group in the formula (16), or to the thioether group of the cysteine residue of the cancer antigen peptide E, which is an MHC class II-restricted WT1 peptide consisting of 7-30 amino acid residues containing one cysteine residue, 
 
       or a pharmaceutically acceptable salt thereof. 
     
     
         10 . The compound according to  claim 9 , wherein the cancer antigen peptide B is a peptide consisting of:
 CYTWNQMNL (SEQ ID NO: 4),   or a pharmaceutically acceptable salt thereof.   
     
     
         11 . The compound according to  claim 9 , wherein the cancer antigen peptide D is a peptide consisting of:
 SGQARMFPNAPYLPSC (SEQ ID NO: 19),   SGQAYMFPNAPYLPSC (SEQ ID NO: 25),   SGQARMFPNAPYLPSCLES (SEQ ID NO: 11),   SGQAYMFPNAPYLPSCLES (SEQ ID NO: 12),   PGCNKRYFKLSHLQMHSRK (SEQ ID NO: 20),   PGCNKRYFKLSHLQMHSRKH (SEQ ID NO: 21),   PGCNKRYFKLSHLQMHSRKHTG (SEQ ID NO: 10),   CNKRYFKLSHLQMHSRK (SEQ ID NO: 22),   CNKRYFKLSHLQMHSRKH (SEQ ID NO: 23),   CNKRYFKLSHLQMHSRKHTG (SEQ ID NO: 24) or   WAPVLDFAPPGASAYGSL (SEQ ID NO: 244),   or a pharmaceutically acceptable salt thereof.   
     
     
         12 . The compound according to  claim 11 , wherein the cancer antigen peptide D is a peptide consisting of:
 WAPVLDFAPPGASAYGSL (SEQ ID NO: 244),   or a pharmaceutically acceptable salt thereof.   
     
     
         13 . The compound according to  claim 1 , wherein the compound of the formula (1) is a compound of formula (15): 
       
         
           
           
               
               
           
         
         wherein the bond between C and C is a disulfide bond, or a pharmaceutically acceptable salt thereof. 
       
     
     
         14 . The compound according to  claim 1 , wherein R 1  is cancer antigen peptide C,
 or a pharmaceutically acceptable salt thereof.   
     
     
         15 . The compound according to  claim 14 , wherein the cancer antigen peptide C is
 a peptide comprising an amino acid sequence selected from the group consisting of:
 CMTWNQMNL (SEQ ID NO: 3), 
 CYTWNQMNL (SEQ ID NO: 4), 
 SGQARMFPNAPYLPSC (SEQ ID NO: 19), 
 SGQAYMFPNAPYLPSC (SEQ ID NO: 25), 
 SGQARMFPNAPYLPSCLES (SEQ ID NO: 11), 
 SGQAYMFPNAPYLPSCLES (SEQ ID NO: 12), 
 PGCNKRYFKLSHLQMHSRK (SEQ ID NO: 20), 
 PGCNKRYFKLSHLQMHSRKH (SEQ ID NO: 21), 
 PGCNKRYFKLSHLQMHSRKHTG (SEQ ID NO: 10), 
 CNKRYFKLSHLQMHSRK (SEQ ID NO: 22), 
 CNKRYFKLSHLQMHSRKH (SEQ ID NO: 23) and 
 CNKRYFKLSHLQMHSRKHTG (SEQ ID NO: 24), or 
   a peptide comprising an altered amino acid sequence, which is an amino acid sequence selected from the group consisting of SEQ ID NOs: 10-11 and 19-24 but containing alteration of amino acid residue(s), and having a helper T cell induction activity,   
       or a pharmaceutically acceptable salt thereof. 
     
     
         16 . The compound according to  claim 15 , wherein the cancer antigen peptide C is a peptide consisting of:
 CYTWNQMNL (SEQ ID NO: 4),   or a pharmaceutically acceptable salt thereof.   
     
     
         17 . The compound according to  claim 14 , wherein, when the peptide consisting of 1-4 amino acid residues containing one cysteine residue is further bonded to the N-terminal of the cancer antigen peptide C, the thioether group of the cysteine residue of the peptide bonded to the N-terminal of the cancer antigen peptide C is bonded to a thioether group in formula (16): 
       
         
           
           
               
               
           
         
       
       wherein X d  and Y d  are each a single bond,
 cancer antigen peptide D is an MHC class II-restricted WT1 peptide consisting of 7-30 amino acid residues, 
 an amino group of an N-terminal amino acid of the cancer antigen peptide D binds to Y d  in the formula (16), and 
 a carbonyl group of a C-terminal amino acid of the cancer antigen peptide D binds to a hydroxyl group in the formula (16), or to the thioether group of the cysteine residue of the cancer antigen peptide E, which is an MHC class II-restricted WT1 peptide consisting of 7-30 amino acid residues containing one cysteine residue, 
 
       or a pharmaceutically acceptable salt thereof. 
     
     
         18 . The compound according to  claim 17 , wherein the peptide consisting of 1-4 amino acid residues containing one cysteine residue bonded to the N-terminal of the cancer antigen peptide C is a dipeptide consisting of CA,
 or a pharmaceutically acceptable salt thereof.   
     
     
         19 . The compound according to  claim 1 , wherein the compound of the formula (1) is a compound of formula (14): 
       
         
           
           
               
               
           
         
         wherein the bond between C and C is a disulfide bond, 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         20 . The compound according to  claim 9 , wherein the cancer antigen peptide E is a peptide consisting of an amino acid sequence selected from the group consisting of:
 SGQARMFPNAPYLPSC (SEQ ID NO: 19),   SGQAYMFPNAPYLPSC (SEQ ID NO: 25),   SGQARMFPNAPYLPSCLES (SEQ ID NO: 11),   SGQAYMFPNAPYLPSCLES (SEQ ID NO: 12),   PGCNKRYFKLSHLQMHSRK (SEQ ID NO: 20),   PGCNKRYFKLSHLQMHSRKH (SEQ ID NO: 21),   PGCNKRYFKLSHLQMHSRKHTG (SEQ ID NO: 10),   CNKRYFKLSHLQMHSRK (SEQ ID NO: 22),   CNKRYFKLSHLQMHSRKH (SEQ ID NO: 23) and   CNKRYFKLSHLQMHSRKHTG (SEQ ID NO: 24), or   a pharmaceutically acceptable salt thereof.   
     
     
         21 . The compound according to  claim 20 , wherein the cancer antigen peptide E is a peptide consisting of:
 CNKRYFKLSHLQMHSRK (SEQ ID NO: 22),   or a pharmaceutically acceptable salt thereof.   
     
     
         22 . The compound according to  claim 17 , wherein the cancer antigen peptide E is a peptide consisting of an amino acid sequence selected from the group consisting of:
 SGQARMFPNAPYLPSC (SEQ ID NO: 19),   s SGQAYMFPNAPYLPSC (SEQ ID NO: 25),   SGQARMFPNAPYLPSCLES (SEQ ID NO: 11),   SGQAYMFPNAPYLPSCLES (SEQ ID NO: 12),   PGCNKRYFKLSHLQMHSRK (SEQ ID NO: 20),   PGCNKRYFKLSHLQMHSRKH (SEQ ID NO: 21),   PGCNKRYFKLSHLQMHSRKHTG (SEQ ID NO: 10),   CNKRYFKLSHLQMHSRK (SEQ ID NO: 22),   CNKRYFKLSHLQMHSRKH (SEQ ID NO: 23) and   CNKRYFKLSHLQMHSRKHTG (SEQ ID NO: 24),   or a pharmaceutically acceptable salt thereof.   
     
     
         23 . The compound according to  claim 22 , wherein the cancer antigen peptide E is a peptide consisting of:
 CNKRYFKLSHLQMHSRK (SEQ ID NO: 22),   or a pharmaceutically acceptable salt thereof.   
     
     
         24 . The compound according to  claim 1 , wherein the compound of the formula (1) is a compound of formula (12): 
       
         
           
           
               
               
           
         
         wherein the bond between C and C is a disulfide bond, 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         25 . The compound according to  claim 1 , wherein the compound of the formula (1) is
 a compound of formula (6):   
       
         
           
           
               
               
           
         
         wherein the bond between C and C is a disulfide bond, a compound represented by the formula (7): 
       
       
         
           
           
               
               
           
         
         wherein the bond between C and C is a disulfide bond, a compound represented by the formula (8): 
       
       
         
           
           
               
               
           
         
         wherein the bond between C and C is a disulfide bond, or 
         a compound represented by the formula (9): 
       
       
         
           
           
               
               
           
         
         wherein the bond between C and C is a disulfide bond, or a pharmaceutically acceptable salt thereof. 
       
     
     
         26 . An altered form of an MHC class II-restricted WT1 peptide consisting of 7-30 amino acid residues. 
     
     
         27 . The altered form according to  claim 26 , which is an amino acid sequence consisting of:
 CWAPVLDFAPPGASAYGSL (SEQ ID NO: 242) or   WAPVLDFAPPGASAYGSLC (SEQ ID NO: 243).   
     
     
         28 . A compound of formula (10): 
       
         
           
           
               
               
           
         
         wherein the bond between C and C is a disulfide bond, 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         29 . A composition, comprising:
 a compound of formula (4) or formula (5):   
       
         
           
           
               
               
           
         
         wherein the bond between C and C in each of the formula (4) and the formula (5) is a disulfide bond; and 
         a peptide consisting of CNKRYFKLSHLQMHSRKH (SEQ ID NO: 23). 
       
     
     
         30 . A composition, comprising:
 a compound of formula (3):   
       
         
           
           
               
               
           
         
         wherein the bond between C and C is a disulfide bond; and 
         a peptide consisting of an amino acid sequence selected from the group consisting of:
 CNKRYFKLSHLQMHSRK (SEQ ID NO: 22), 
 CNKRYFKLSHLQMHSRKH (SEQ ID NO: 23), 
 CNKRYFKLSHLQMHSRKHTG (SEQ ID NO: 24), 
 WAPVLDFAPPGASAYGSL (SEQ ID NO: 244), 
 CWAPVLDFAPPGASAYGSL (SEQ ID NO: 242) and 
 WAPVLDFAPPGASAYGSLC (SEQ ID NO: 243). 
 
       
     
     
         31 . A pharmaceutical composition, comprising:
 pound according to  claim 1  or a pharmaceutically acceptable salt thereof; and   a pharmaceutically acceptable carrier.   
     
     
         32 . The pharmaceutical composition according to  claim 31 , which is a cancer vaccine. 
     
     
         33 . A pharmaceutical composition, comprising:
 the compound according to  claim 28  or a pharmaceutically acceptable salt thereof; and   a pharmaceutically acceptable carrier.   
     
     
         34 . The pharmaceutical composition according to  claim 33 , which is a cancer vaccine. 
     
     
         35 . A pharmaceutical composition, comprising:
 the composition according to  claim 29 ; and   a pharmaceutically acceptable carrier.   
     
     
         36 . The pharmaceutical composition according to  claim 35 , which is a cancer vaccine. 
     
     
         37 . A pharmaceutical composition, comprising:
 the composition according to  claim 30 ; and   a pharmaceutically acceptable carrier.   
     
     
         38 . The pharmaceutical composition according to  claim 37 , which is a cancer vaccine. 
     
     
         39 . A method for treating or preventing cancer, comprising:
 administering a therapeutically or prophylactically effective amount of the compound according to  claim 1  or a pharmaceutically acceptable salt thereof, to a WT1 positive cancer patient in need thereof.   
     
     
         40 . A method for treating or preventing cancer, comprising:
 administering a therapeutically or prophylactically effective amount of the compound according to  claim 28  or a pharmaceutically acceptable salt thereof, to a WT1 positive cancer patient in need thereof.   
     
     
         41 . A method for treating or preventing cancer, comprising:
 administering a therapeutically or prophylactically effective amount of the composition according to  claim 29  to a WT1 positive cancer patient in need thereof.   
     
     
         42 . A method for treating or preventing cancer, comprising:
 administering a therapeutically or prophylactically is effective amount of the composition according to  claim 30  to a WT1 positive cancer patient in need thereof.   
     
     
         43 . A method of obtaining two different MHC class I-restricted epitopes, or an MHC class I-restricted epitope and an MHC class II-restricted epitope, comprising:
 reacting the compound according to  claim 1  or a pharmaceutically acceptable salt thereof with ERAP1.   
     
     
         44 . A method of obtaining two different MHC class I-restricted epitopes, or an MHC class I-restricted epitope and an MHC class II-restricted epitope, comprising:
 reacting the compound according to  claim 28  or a pharmaceutically acceptable salt thereof with ERAP1.   
     
     
         45 . A method of synthesizing the compound according to  claim 1 , comprising:
 synthesizing, by reacting Fmoc-C(Mmt)A-SBn with the cancer antigen peptide C, a peptide (1) wherein a carbonyl group of the C-terminal amino acid of C(Mmt)A and the N-terminal amino group of the cancer antigen peptide C are bonded, wherein the antigen peptide C is an MHC class I-restricted WT1 peptide consisting of 7-30 amino acid residues containing one cysteine residue or an MHC class II-restricted WT1 peptide consisting of 7-30 amino acid residues containing one cysteine residue;   synthesizing, by reacting the peptide (1) with the cancer antigen peptide A wherein one cysteine residue protected by Npys group is bonded to the N-terminal, a peptide (2) wherein a thioether group of the cysteine residue of the cancer antigen peptide C in the peptide (1) and a thioether group of the cysteine residue bonded to the N-terminal of cancer antigen peptide A are bonded, wherein the cancer antigen peptide A is an MHC class I-restricted WT1 peptide consisting of 7-30 amino acid residues; and   synthesizing, by reacting the peptide (2) with cancer antigen peptide D containing a cysteine residue protected by Spy group, a peptide (3) wherein a thioether group of the cysteine residue bonded to the N-terminal of the cancer antigen peptide A in the peptide (2), and a thioether group of the cysteine residue of the cancer antigen peptide D are bonded, wherein the cancer antigen peptide D is an MHC class II-restricted WT1 peptide consisting of 7-30 amino acid residues containing one cysteine residue bonded to the N terminal or an MHC class II-restricted WT1 peptide consisting of 7-30 amino acid residues containing one cysteine residue.