Peptide vaccine for prevention and immunotherapy of dementia of the alzheimer's type

Abstract

The present disclosure is directed to individual Aβ peptide immunogen constructs, peptide compositions comprising these Aβ peptide immunogen constructs and mixtures thereof, pharmaceutical compositions including vaccine formulations comprising these Aβ peptide immunogen constructs, with the individual Aβ peptide immunogen constructs having the N-terminus of the Aβ peptide as the B cell (B) epitopes linked through spacer residue(s) to heterologous T helper cell (Th) epitopes derived from pathogen proteins that act together to stimulate the generation of highly specific antibodies directed against the N-terminus of the Aβ peptide offering protective immune responses to patients at risk for, or with, Alzheimer's Disease.

1 . An Aβ peptide immunogen construct comprising the following formula:
   (N-terminal fragment of Aβ 1-42 peptide)-(A) o -(Th)—X
 
 wherein (N-terminal fragment of Aβ 1-42  peptide) is a B cell epitope from Aβ comprising about 10 to about 14 amino acid residues selected from the group consisting of SEQ ID NOs: 4, 5, and 6; 
 each A is independently an amino acid or a linking group selected from the group consisting of an amino acid, Lys-, Gly-, Lys-Lys-Lys-, (α, ε-N)Lys, and ε-N-Lys-Lys-Lys-Lys (SEQ ID NOs: 32); 
 each Th comprises an amino acid sequence that constitutes a helper T cell epitope selected from the group consisting of SEQ ID NOs: 34, 37, 38, 40 to 47 and functional immunological analogues thereof; 
 X is an α-COOH or α-CONH2 of an amino acid; and 
 o is from 0 to about 4. 
 
     
     
         2 . The Aβ peptide immunogen construct of  claim 1 , wherein the (N-terminal fragment of Aβ 1-42  peptide) is Aβ 1-14  (SEQ ID NO: 4). 
     
     
         3 . The Aβ peptide immunogen construct of  claim 1 , wherein A is ε-N-Lys-Lys-Lys-Lys (SEQ ID NOs: 32). 
     
     
         4 . The Aβ peptide immunogen construct of  claim 1 , wherein the Th epitope is SEQ ID NOs: 45 or 46. 
     
     
         5 . The Aβ peptide immunogen construct of  claim 1 , comprising the amino acid sequence of SEQ ID NOs: 48-65. 
     
     
         6 . The Aβ peptide immunogen construct of  claim 1 , consisting essentially of the amino acid sequences of SEQ ID NOs: 62-65. 
     
     
         7 . The Aβ peptide immunogen construct of  claim 1  that is SEQ ID NOs: 62, 63, 64, and/or 65. 
     
     
         8 . A composition comprising the Aβ peptide immunogen construct of  claim 1 . 
     
     
         9 . A pharmaceutical composition comprising
 a. the Aβ peptide immunogen construct of  claim 1 ; and   b. a pharmaceutically acceptable delivery vehicle and/or adjuvant.   
     
     
         10 . An Alzheimer's Disease vaccine composition comprising
 a. the Aβ peptide immunogen construct of  claim 1 ; and   b. a pharmaceutically acceptable delivery vehicle and/or adjuvant.   
     
     
         11 . An Alzheimer's Disease vaccine composition comprising
 a. the Aβ peptide immunogen construct of  claim 7 ; and   b. a pharmaceutically acceptable delivery vehicle and/or adjuvant.   
     
     
         12 . The Alzheimer's Disease vaccine composition of  claim 10 , wherein the adjuvant in (b) is a mineral salt of Aluminum selected from the group consisting of alhydrogel (Al(OH) 3 ) or adjuphos (AlPO 4 ). 
     
     
         13 . The Alzheimer's Disease vaccine composition of  claim 10 , wherein the peptide antigen in (a) is mixed with an CpG oligodeoxynucleotide (ODN) to form a stabilized immunostimulatory complex. 
     
     
         14 . An isolated antibody or epitope-binding fragment thereof which binds to the (N-terminal fragment of Aβ 1-42  peptide) component of the Aβ peptide immunogen construct of  claim 1 . 
     
     
         15 . The isolated antibody or epitope-binding fragment thereof of  claim 14 , which specifically binds to Aβ 1-10  (SEQ ID NO: 6). 
     
     
         16 . The isolated antibody or epitope-binding fragment thereof of  claim 14 , bound to the Aβ peptide immunogen construct of  claim 1 . 
     
     
         17 . The isolated antibody or epitope-binding fragment thereof of  claim 15 , bound SEQ ID NO: 6. 
     
     
         18 . A composition comprising the isolated antibody or epitope-binding fragment thereof of  claim 14 . 
     
     
         19 . A method of reducing the severity or delaying onset of dementia in human patients comprising administering a vaccine formulation according to  claim 10 . 
     
     
         20 . The method of  claim 19 , wherein said vaccine formulation is administered in an aqueous solution comprising between 10 ug and 1000 ug per dose to patients at risk for, or with, AD.