Amyloid beta1-6 antigen arrays

Abstract

The present invention is related to the fields of molecular biology, virology, immunology and medicine. The invention provides a composition comprising an ordered and repetitive antigen or antigenic determinant array, and in particular an Aβ1-6 peptide-VLP-composition. More specifically, the invention provides a composition comprising a virus-like particle and at least one Aβ1-6 peptide bound thereto. The invention also provides a process for producing the conjugates and the ordered and repetitive arrays, respectively. The compositions of the invention are useful in the production of vaccines for the treatment of Alzheimer's disease and as a pharmaccine to prevent or cure Alzheimer's disease and to efficiently induce immune responses, in particular antibody responses. Furthermore, the compositions of the invention are particularly useful to efficiently induce self-specific immune responses within the indicated context.

1 . (canceled) 
     
     
         2 . The vaccine composition of  claim 32 , wherein said core particle is selected from the group consisting of: i) a virus; ii) a virus-like particle; iii) a bacteriophage; iv) a virus-like particle of a RNA-phage; v) a bacterial pilus; vi) a viral capsid particle; and vii) a recombinant form of (i), (ii), (iii), (iv), (v) or (vi). 
     
     
         3 . The vaccine composition of  claim 2 , wherein said core particle comprises, preferably is, a virus-like particle, wherein preferably said virus-like particle is a recombinant virus-like particle. 
     
     
         4 . The vaccine composition of  claim 3 , wherein said virus-like particle comprises recombinant proteins, or fragments thereof, selected from the group consisting of: (a) recombinant proteins of Hepatitis B virus; (b) recombinant proteins of measles virus; (c) recombinant proteins of Sindbis virus; (d) recombinant proteins of Rotavirus; (e) recombinant proteins of Foot-and-Mouth-Disease virus; (f) recombinant proteins of Retrovirus; (g) recombinant proteins of Norwalk virus; (h) recombinant proteins of Alphavirus; (i) recombinant proteins of human Papilloma virus; (j) recombinant proteins of Polyoma virus; (k) recombinant proteins of bacteriophages; (1) recombinant proteins of RNA-phages; (m) recombinant proteins of Ty; (n) recombinant proteins of Qβ-phage; (o) recombinant proteins of GA-phage; (p) recombinant proteins of fr-phage; (q) recombinant proteins of AP205 phage; and (q) fragments of any of the recombinant proteins from (a) to (q). 
     
     
         5 . The vaccine composition of  claim 4 , wherein said virus-like particle is Hepatitis B virus core antigen. 
     
     
         6 . (canceled) 
     
     
         7 . The vaccine composition of  claim 35 , wherein said RNA-phage is selected from the group consisting of: (a) bacteriophage Qβ; (b) bacteriophage R 17; (c) bacteriophage fr; (d) bacteriophage GA; (e) bacteriophage SP; (f) bacteriophage MS2; (g) bacteriophage M11; (h) bacteriophage MX 1; (i) bacteriophage NL95; (k) bacteriophage f2; (1) bacteriophage PP7; and (m) bacteriophage AP205. 
     
     
         8 - 10 . (canceled) 
     
     
         11 . The vaccine composition of  claim 4 , wherein the recombinant proteins comprise, or alternatively consist essentially of, or alternatively consist of coat proteins of RNA phages. 
     
     
         12 . The vaccine composition of  claim 11 , wherein said coat, proteins of RNA phages having an amino acid are selected from the group consisting of: (a) SEQ ID NO: 4; (b) a mixture of SEQ ID NO: 4 and SEQ ID NO: 5; (c) SEQ ID NO: 6; (d) SEQ ID NO: 7; (e) SEQ ID NO: 8; (f) SEQ ID NO; 9; (g) a mixture of SEQ ID NO: 9 and SEQ ID NO: 1b; (h) SEQ ID NO: 11; (i) SEQ ID NO; 12′; (k) SEQ ID NO: 13; (l) SEQ ID NO: 14; (m) SEQ ID NO: 15; (n) SEQ ID NO: 16; and (o) SEQ ID NO:28. 
     
     
         13 . The vaccine composition of  claim 4 , wherein the recombinant proteins comprise, or alternatively consist essentially of, or alternatively consist of mutant coat proteins of RNA phages. 
     
     
         14 . The vaccine composition of  claim 13 , wherein said RNA-phage is selected from the group consisting of: (a) bacteriophage Qβ; (b) bacteriophage R 17; (c) bacteriophage fr; (d) bacteriophage GA; (e) bacteriophage SP; (f) bacteriophage MS2; (g) bacteriophage M 11; (h) bacteriophage MX 1; (i) bacteriophage NL95; (k) bacteriophage f2; (1) bacteriophage PP7; and (m) bacteriophage AP205. 
     
     
         15 . The vaccine composition of  claim 13 , wherein said mutant coat proteins of said RNA phage have been modified by removal of at least one lysine residue by way of substitution. 
     
     
         16 . The vaccine composition of  claim 13 , wherein said mutant coat proteins of said RNA phage have been modified by addition of at least one lysine residue by way of substitution. 
     
     
         17 . The vaccine composition of  claim 13 , wherein said mutant coat proteins of said RNA phage have been modified by deletion of at least one lysine residue. 
     
     
         18 . The vaccine composition of  claim 13 , wherein said mutant coat proteins of said RNA phage have been modified by addition of at least one lysine residue by way of insertion. 
     
     
         19 . The vaccine composition of  claim 32 , wherein said second attachment site is capable of association to said first attachment site through at least one covalent bond. 
     
     
         20 . The vaccine composition of  claim 32 , wherein said second attachment site is capable of association to said first attachment site through at least one non-peptide bond. 
     
     
         21 . The vaccine composition of  claim 32 , wherein said ABI-6 peptide is fused to said core particle. 
     
     
         22 . (canceled) 
     
     
         23 . The composition of  claim 39 , wherein said AβI-6 peptide has an amino acid sequence of SEQ ID NO: 75. 
     
     
         24 - 28 . (canceled) 
     
     
         29 . A pharmaceutical composition comprising: (a) the vaccine composition of  claim 32 ; and (b) an acceptable pharmaceutical carrier. 
     
     
         30 - 31 . (canceled) 
     
     
         32 . A vaccine composition comprising: (a) a core particle with at least one first attachment site; and (b) at least one antigen or antigenic determinant with at least one second attachment site, wherein said antigen or antigenic determinant is a Aβ 1-6 peptide, and wherein said second attachment site being selected from the group consisting of: (i) an attachment site not naturally occurring with said antigen or antigenic determinant; and (ii) an attachment site naturally occurring with said antigen or antigenic determinant wherein said second attachment site is capable of association to said first attachment site; and wherein said Aβ 1-6 peptide and said core particle interact through said association to form an ordered and repetitive antigen array. 
     
     
         33 . The vaccine composition of  claim 32 , further comprising an adjuvant. 
     
     
         34 . The vaccine composition of  claim 32 , wherein said vaccine composition is devoid of an adjuvant. 
     
     
         35 . The vaccine composition of  claim 4 , wherein said virus-like particle comprises recombinant proteins, or fragments thereof, of a RNA-phage. 
     
     
         36 . The vaccine composition of  claim 7 , wherein said virus-like particle comprises recombinant proteins or fragments thereof, of RNA-phage Qβ. 
     
     
         37 . The vaccine composition of  claim 7 , wherein said virus-like particle comprises recombinant proteins, or fragments thereof, of RNA-phage fr. 
     
     
         38 . The vaccine composition of  claim 7 , any one of  claims 32  to  35 , wherein said virus-like particle comprises recombinant proteins, or fragments thereof, of RNA-phage AP205. 
     
     
         39 . The vaccine composition of  claim 32 , wherein said AB 1-6 peptide is selected from the group consisting of: (a) human Aft 1-6 peptide having an amino acid sequence of SEQ ID NO: 75; (b) murine Aβ 1-6 peptide having an amino acid sequence of SEQ ID NO: 76; (b) primate AB 1-6 peptide having an amino acid sequence of SEQ ID NO: 84; (d) rabbit AG 1-6 peptide having an amino acid sequence of SEQ ID NO: 85; (e)  xenopus laevis  Aβ 1-6 peptide having an amino acid sequence of
 SEQ ID NO: 86; (f) rat AG 1-6 peptide having an amino acid sequence of SEQ ID NO: 87; and (g) guinea pig Aβ 1-6 peptide having an amino acid sequence of SEQ ID NO: 88.   
     
     
         40 . The vaccine composition of  claim 32  further comprising an amino acid linker, wherein said amino acid linker comprises, or alternatively consists of, said second attachment site. 
     
     
         41 . The vaccine composition of  claim 40 , wherein said amino acid linker with said second attachment site is bound to said Aβ 1-6 peptide at its C-terminus. 
     
     
         42 . The vaccine composition of  claim 40 , wherein said amino acid linker with said second attachment site is selected from the
 group consisting of: (a) GGC; (b) GGC-CONH2: (c) GC; (d) GC-CONH2; (e) C; and (f) C—CONH2.   
     
     
         43 . The vaccine composition of  claim 32 , wherein said antigen or antigenic determinant with said at least second attachment site is NH2-DAEFRHGGC-CONH2 (SEQ ID NO: 77). 
     
     
         44 . The vaccine composition of  claim 43 , wherein said virus-like particle is a virus-like particle of RNA-phage Q (3 coat protein. 
     
     
         45 . A process for producing a vaccine composition of  claim 32  comprising: (a) providing a core particle with at least one first attachment site; (b) providing at least one antigen or antigenic determinant with at least one second attachment site, wherein said antigen or antigenic determinant is a Aβ 1-6 peptide, and wherein said second attachment site being selected from, the group consisting of: (i) ah attachment site not naturally occurring with said antigen or antigenic determinant; and (ii) an attachment site naturally occurring with said antigen or antigenic determinant; and wherein said second attachment site is capable of association to said first attachment site; and (c) combining said core, particle and said at least one antigen or antigenic determinant, wherein said antigen or antigenic determinant and said core particle interact through said association to form an ordered and repetitive antigen array. 
     
     
         46 . A method of immunization comprising administering the composition of  claim 32  to an animal or human. 
     
     
         47 . The method of immunization of  claim 46 , wherein said antigen or antigenic determinant is a self-antigen. 
     
     
         48 . The method of immunization of  claim 46 , wherein said animal is a human. 
     
     
         49 . The method of immunization of  claim 46 , wherein said antigen or antigenic determinant is human Aβ 1-6 peptide. 
     
     
         50 - 51 . (canceled)