Pcsk9 vaccine

Abstract

The present invention relates to the provision of novel immunogens comprising an antigenic PCSK9 peptide linked to an immunogenic carrier for the prevention, treatment or alleviation of PCSK9-mediated disorders. The invention further relates to methods for production of these medicaments, immunogenic compositions and pharmaceutical compositing thereof and their use in medicine.

1 - 28 . (canceled) 
     
     
         29 . A method for alleviating a PCSK9-related disorder in an subject, comprising administering to the subject a therapeutically effective amount of an immunogen comprising at least one antigenic PCSK9 peptide linked to an immunogenic carrier, wherein the antigenic PCSK9 peptide consists of an amino acid sequence selected from the group consisting of SEQ ID NOs: 62-73, and wherein the PCSK9-related disorder is selected from the group consisting of an ateriosclerotic condition, a coronary artery disease, and a cardiovascular disease. 
     
     
         30 . The method according to  claim 29 , wherein the immunogenic carrier is Diphtheria Toxoid, CRM197, or a VLP. 
     
     
         31 . The method according to  claim 30 , wherein the antigenic PCSK9 peptide is selected from the group consisting of SEQ ID Nos. 67, 68, 69, 70, 71, 72, and 73. 
     
     
         32 . The method according to  claim 29 , wherein the immunogenic carrier is a VLP selected from HBcAg, HBsAg, Qbeta, PP7, PPV or Norwalk Virus VLP. 
     
     
         33 . The method according to  claim 31 , wherein the immunogen further comprises, between the antigenic peptide and carrier, either:
 at the C-terminus of the PCSK9 peptide a linker having the formula (G) n C, (G) n SC or (G) n K wherein n is 0, 1, 2, or 3; or   at the N-terminus of the PCSK9 peptide a linker having the formula C(G) n , CS(G) n  or K(G) n  wherein n is 0, 1, 2, or 3.   
     
     
         34 . The method according to  claim 31 , wherein the immunogen further comprises a cysteine between the C-terminus of the PCSK9 peptide and N-terminus of the carrier. 
     
     
         35 . The method according to  claim 31 , wherein the immunogen further comprises a CGG between the N-terminus of the PCSK9 peptide and C-terminus of the carrier. 
     
     
         36 . The method according to  claim 31 , wherein the immunogen further comprises a GGC between the N-terminus of the PCSK9 peptide and C-terminus of the carrier. 
     
     
         37 . The method according to  claim 31 , wherein the immunogen is cyclized and comprises a cysteine, a (G) n C, or a C(G) n  fragment between the antigenic PCSK9 peptide and immunogenic carrier, wherein n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. 
     
     
         38 . The immunogen according to  claim 29 , wherein the antigenic PCSK9 peptide is conformationally constrained. 
     
     
         39 . A method for alleviating a PCSK9-related disorder in an subject, comprising administering to the subject a therapeutically effective amount of an immunogen comprising at least one antigenic PCSK9 peptide linked to an immunogenic carrier, wherein the antigenic PCSK9 peptide is selected from the group consisting of SEQ ID Nos. 314, 318, and 319, and wherein the PCSK9-related disorder is selected from the group consisting of an ateriosclerotic condition, a coronary artery disease, and a cardiovascular disease. 
     
     
         40 . A method for alleviating a PCSK9-related disorder in an subject, comprising administering to the subject a therapeutically effective amount of a composition comprising at least two immunogens, wherein one of the two immunogens comprises at least one antigenic PCSK9 peptide linked to an immunogenic carrier, wherein the antigenic PCSK9 peptide consists of an amino acid sequence selected from the group consisting of SEQ ID NOs: 62-73, and wherein the PCSK9-related disorder is selected from the group consisting of an ateriosclerotic condition, a coronary artery disease, and a cardiovascular disease. 
     
     
         41 . The method according to  claim 29  further comprises administering to the subject a therapeutically effective amount of at least one adjuvant. 
     
     
         42 . The method according to  claim 41 , wherein the adjuvant is selected from alum, CpG ODN, and QS21. 
     
     
         43 . A method of preventing, alleviating, or treating a PCSK9-related disorder in an subject, comprising administering a therapeutically effective amount of a pharmaceutical composition comprising (i) the immunogen and (ii) a pharmaceutically acceptable excipient, wherein the immunogen comprises at least one antigenic PCSK9-peptide linked to an immunogenic carrier, wherein the antigenic PCSK9 peptide consists of an amino acid sequence selected form the group consisting of SEQ ID NOs: 62-73, and wherein the PCSK9-related disorder is selected from the group consisting of an ateriosclerotic condition, a coronary artery disease, and a cardiovascular disease. 
     
     
         44 . The method according to  claim 30 , wherein the antigenic PCSK9 peptide consists of the amino acid sequence of SEQ ID NO: 72. 
     
     
         45 . The method according to  claim 43 , wherein the antigenic PCSK9 peptide consists of the amino acid sequence of SEQ ID NO: 72 
     
     
         46 . A method for reducing plasma cholesterol levels in an subject, comprising administering to the subject a therapeutically effective amount of an immunogen, wherein the immunogen comprises an antigenic PCSK9 peptide linked to an immunogenic carrier, and wherein the antigenic PCSK9 peptide consists of an amino acid sequence selected from the group consisting of SEQ ID NOs: 67-73. 
     
     
         47 . The method according to  claim 46 , wherein the immunogenic carrier is selected form the group consisting of Diphtheria Toxoid, CRM197, and a VLP. 
     
     
         48 . The method according to  claim 46 , wherein the immunogenic carrier is a VLP selected from HBcAg, HBsAg, Qbeta, PP7, PPV or Norwalk Virus VLP. 
     
     
         49 . The method according to  claim 46 , wherein the immunogen further comprises, between the antigenic peptide and carrier, either:
 at the C-terminus of the PCSK9 peptide a linker having the formula (G) n C, (G) n SC or (G) n K wherein n is 0, 1, 2, or 3; or   at the N-terminus of the PCSK9 peptide a linker having the formula C(G) n , CS(G) n  or K(G) n  wherein n is 0, 1, 2, or 3.   
     
     
         50 . The method according to  claim 46 , wherein the immunogen further comprises a cysteine between the C-terminus of the PCSK9 peptide and N-terminus of the carrier. 
     
     
         51 . The method according to  claim 46 , wherein the immunogen further comprises a CGG between the N-terminus of the PCSK9 peptide and C-terminus of the carrier. 
     
     
         52 . The method according to  claim 46 , wherein the immunogen further comprises a GGC between the N-terminus of the PCSK9 peptide and C-terminus of the carrier. 
     
     
         53 . The method according to  claim 46 , wherein the immunogen is cyclized and comprises a cysteine, a (G) n C, or a C(G) n  fragment between the antigenic PCSK9 peptide and immunogenic carrier, wherein n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. 
     
     
         54 . The method according to  claim 46 , wherein the antigenic PCSK9 peptide is conformationally constrained. 
     
     
         55 . The method according to  claim 46 , wherein the antigenic PCSK9 peptide consists of the amino acid sequence of SEQ ID NO: 72. 
     
     
         56 . A method for reducing plasma cholesterol levels in an subject, comprising administering to the subject a therapeutically effective amount of an antigenic PCSK9 peptide consisting of an amino add sequence selected from the group consisting of SEQ ID NOs: 314, 318, 319. 
     
     
         57 . The method according to  claim 56 , wherein the antigenic PCSK9 peptide is linked to an immunogenic carrier selected from the group consisting of Diphtheria Toxoid, a VLP and CRM197. 
     
     
         58 . The method according to  claim 56 , wherein the immunogenic carrier is a VLP selected from HBcAg, HBsAg, Qbeta, PP7, PPV or Norwalk Virus VLP.