Immunotherapeutic modulation of amyloidogenic disease using non-fibrillogenic, non-amyloidogenic polymerized proteins and peptides

Abstract

The present invention is directed to polymerized products and compositions useful for the treatment and prevention of amyloid disease in a subject. The invention further relates to isolated antibodies that recognize a common conformational epitope of amyloidogenic proteins or peptides that are useful for the diagnosis, treatment, and prevention of amyloid disease.

1 . A non-amyloidogenic, non-fibrillogenic polymerized product comprising two or more protein and/or peptide units, wherein each unit is independently selected from the group consisting of an amyloid-beta (Aβ) peptide, an α-synuclein protein or peptide, a tau protein or peptide, a TAR DNA-binding protein 43 (TDP-43) protein or peptide, an amylin protein or peptide, a prion protein (PrP) protein or peptide, and any combination thereof. 
     
     
         2 . The polymerized product of  claim 1 , wherein the Aβ peptide comprises an amino acid sequence selected from the group consisting of amino acid residues 1-16 of SEQ ID NO:1, amino acid residues 1-20 of SEQ ID NO: 1, amino acid residues 1-30 of SEQ ID NO:1, amino acid residues 1-40 of SEQ ID NO:1, amino acid residues 1-42 of SEQ ID NO:1, amino acid residues 10-30 of SEQ ID NO:1, amino acid residues 20-40 of SEQ ID NO:1, and amino acid residues 20-42 of SEQ ID NO:1. 
     
     
         3 . The polymerized product of  claim 2 , wherein the Aβ peptide comprises amino acid residues 1-42 of SEQ ID NO:1. 
     
     
         4 . The polymerized product of  claim 1 , wherein the Aβ peptide comprises an amino acid sequence selected from the group consisting of amino acid residues 1-30 of SEQ ID NO:2 (Aβ1-30K 18 K 19 ), amino acid residues 1-40 of SEQ ID NO:2 (Aβ1-40K 18 K 19 ), amino acid residues 1-42 of SEQ ID NO:2 (Aβ1-42K 18 K 19 ), amino acid residues 1-20 of SEQ ID NO:2 (Aβ1-20K 18 K 19 ), amino acid residues 10-30 of SEQ ID NO:2 (Aβ10-30K 18 K 19 ), amino acid residues 10-40 of SEQ ID NO:2 (Aβ10-40K 18 K 19 ), amino acid residues 10-42 of SEQ ID NO:2 (Aβ10-42K 18 K 19 ), amino acid residues 20-40 of SEQ ID NO:2 (Aβ20-40K 18 K 19 ), and amino acid residues 20-42 of SEQ ID NO:2 (Aβ20-42K 18 K 19 ). 
     
     
         5 . The polymerized product of  claim 4 , wherein the Aβ peptide comprises amino acid residues 1-30 of SEQ ID NO:2 (Aβ1-30K 18 K 19 ). 
     
     
         6 . The polymerized product of  claim 1 , wherein the α-synuclein protein or peptide comprises an amino acid sequence of SEQ ID NO:3 or a peptide derived from the amino acid sequence of SEQ ID NO:3. 
     
     
         7 . The polymerized product of  claim 1 , wherein the tau protein or peptide comprises an amino acid sequence of SEQ ID NO: 4 or a peptide derived from the amino acid sequence of SEQ ID NO:4. 
     
     
         8 . The polymerized product of  claim 1 , wherein the TDP-43 protein or peptide comprises an amino acid sequence of SEQ ID NO:5 or a peptide derived from the amino acid sequence of SEQ ID NO:5. 
     
     
         9 . polymerized product of  claim 1 , wherein the amylin protein or peptide comprises an amino acid sequence of SEQ ID NO:6 or a peptide derived from the amino acid sequence of SEQ ID NO:6. 
     
     
         10 . The polymerized product of  claim 1 , wherein the PrP protein or peptide comprising an amino acid sequence of SEQ ID NO:7 or a peptide derived from the amino acid sequence of SEQ ID NO:7. 
     
     
         11 . The polymerized product of  claim 1 , wherein the polymerized product is a co-polymer comprising one or more amyloid-beta (Aβ) peptides copolymerized with one or more α-synuclein proteins or peptides. 
     
     
         12 . The polymerized product of  claim 1 , wherein the polymerized product is a co-polymer comprising one or more amyloid-beta (Aβ) peptides co-polymerized with one or more tau peptides. 
     
     
         13 . The polymerized product of  claim 1 , wherein the polymerized product is a co-polymer comprising one or more TDP-43 peptides co-polymerized with one or more amyloid-beta (Aβ) peptides and/or one or more tau peptides. 
     
     
         14 . The polymerized product of  claim 1 , wherein an adjuvant polypeptide is linked in frame to one or more of the proteins or peptides of the polymerized product. 
     
     
         15 . The polymerized product of  claim 14 , wherein the adjuvant polypeptide is selected from the group consisting of cholera toxin B, flagellin, human papillomavirus L1 or L2 protein, herpes simplex glycoprotein D (gD), complement C4 binding protein, TL4 ligand, and IL-1β. 
     
     
         16 . (canceled) 
     
     
         17 . The polymerized product of  claim 1 , wherein an immunogenic carrier molecule is conjugated to the one or more proteins or peptides of the polymerized product. 
     
     
         18 . The polymerized product of  claim 17 , wherein the immunogenic carrier molecule is covalently or non-covalently bonded to the one or more proteins or peptides of the polymerized product. 
     
     
         19 . The polymerized product of  claim 17 , wherein the immunogenic carrier molecule is selected from the group consisting of bovine serum albumin, chicken egg ovalbumin, keyhole limpet hemocyanin, tetanus toxoid, diphtheria toxoid, thyroglobulin, a pneumococcal capsular polysaccharide, CRM 197, and a meningococcal outer membrane protein. 
     
     
         20 . A pharmaceutical composition comprising:
 the polymerized product of  claim 1  and   a pharmaceutically acceptable carrier.   
     
     
         21 . The pharmaceutical composition of  claim 20  further comprising:
 an adjuvant.