Immunotherapeutic modulation of amyloidogenic disease using non-fibrillogenic, non-amyloidogenic polymerized proteins and peptides
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 and non-fibrillogenic heteropolymer product formed from two or more different protein and/or peptide monomers, wherein each protein and/or peptide monomer forming said product is covalently linked to one or more other protein and/or peptide monomers forming said product by one or more glutaraldehyde molecules, and wherein each of the two or more different protein and/or peptide monomers is independently selected from the group consisting of amyloid-beta (Aβ) peptide, an u-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, and a priori protein (PrP) protein or peptide.
2. The heteropolymer product of claim 1 , wherein one of the two or more different protein and/or peptide monomers is an A13 peptide comprising the 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 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 heteropolymer product of claim 2 , wherein the A13 peptide comprises amino acid residues 1-42 of SEQ ID NO:1.
4. The heteropolymer product of claim 1 , wherein one of the two or more different protein and/or peptide monomers is an Aβ peptide comprising the 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 NO:2 (Aβ1-40K 18 K 19 ), amino acid residues 1-42 of SEQ ID N0:2 (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 1( 19 ), amino acid residues 10-42 of SEQ ID NO:2 (Aβ10-40K 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 heteropolymer product of claim 4 , wherein the Aja peptide comprises amino acid residues 1-30 of SEQ ID NO:2 (Aβ1-30K 18 K 19 .
6. The heteropolymer product of claim 1 , wherein one of the two or more different protein and/or peptide monomers is an α-synuclein protein comprising the amino acid sequence of SEQ NO:3, or a peptide derived from the amino acid sequence of SEQ NO:3, said peptide comprising at least 10 contiguous amino acid residues and having at least 80% homology to the amino acid sequence of SEQ ID NO: 3.
7. The heteropolymer product of claim 1 , wherein one of the two or more different protein and/or peptide monomers is a mu protein comprising the amino acid sequence of SEQ ID NO: 4, or a peptide derived from the amino acid sequence of SEQ ID NO:4, said peptide comprising at least 10 contiguous amino acid residues and having at least 80% homology to the amino acid sequence of SEQ ID NO: 4.
8. The heteropolymer product of claim 1 , wherein one of the two or more different protein and/or peptide monomers is a TDP-43 protein comprising the amino acid sequence of SEQ ID NO: 5, or a peptide derived from the amino acid sequence of SEQ ID NO: 5, said peptide comprising at least 10 contiguous amino acid residues and having at least 80% homology to the amino acid sequence of SEQ ID NO: 5.
9. The heteropolymer product of claim 1 , wherein one of the two or more different protein and/or peptide monomers is an amylin protein comprising the amino acid sequence of SEQ ID NO:6, or a peptide derived from the amino acid sequence of SEQ ID NO:6, said peptide comprising at least 10 contiguous amino acid residues and having at least 80% homology to the amino acid sequence of SEQ ID NO: 6.
10. The heteropolymer product of claim 1 , wherein one of the two or more different protein and/or peptide monomers is a PrP protein or peptide comprising the amino acid sequence of SEQ ID NO:7, or a peptide derived thereof, said peptide comprising at least 10 contiguous amino acid residues and having at least 80% homology to the amino acid sequence of SEQ ID NO:7.
11. The heteropolymer product of claim 1 , wherein the heteropolymer product comprises one or more amyloid-beta (Aβ) peptides covalently linked to one or more α-synuclein proteins or peptides.
12. The heteropolymer product of claim 1 , wherein the heteropolymer product comprises one or more amyloid-beta (Aβ) peptides covalently linked to one or more tau peptides.
13. The heteropolymer product of claim 1 , wherein the heteropolymer product comprises one or more TDP-43 peptides covalently linked to one or more amyloid-beta (Aβ) peptides and/or one or more tau peptides.
14. The heteropolymer product of claim 1 , wherein said product is non-amyloidogenic and non-fibrillogenic.
15. The heteropolymer product of claim 1 , wherein an adjuvant polypeptide is linked in frame to one or more of the protein and/or peptide monomers of the heteropolymer product.
16. The heteropolymer product of claim 15 , 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.
17. The heteropolymer product of claim 15 , wherein the one or more protein and/or peptide monomers of the heteropolymer product further comprise a linker sequence connecting the protein or peptide monomer and the adjuvant polypeptide.
18. The heteropolymer product of claim 1 , wherein an immunogenic carrier molecule is conjugated to one or more of the protein and/or peptide monomers of the heteropolymer product.
19. The heteropolymer product of claim 18 , wherein the immunogenic carrier molecule is covalently or non-covalently bonded to the one or more protein and/or peptide monomers of the heteropolymer product.
20. The heteropolymer product of claim 18 , 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.
21. A pharmaceutical composition comprising:
the heteropolymer product of claim 1 and
a pharmaceutically acceptable carrier.
22. The pharmaceutical composition of claim 21 further comprising:
an adjuvant.
23. A non-amyloidogenic and non-fibrillogenic heteropolymer product formed from two or more different protein and/or peptide monomers, Wherein each protein and/or peptide monomer forming said product is covalently linked by a controlled glutaraldehyde reaction to one or more other protein and/or peptide monomers forming said product, and wherein each of the two or more different protein and/or peptide monomers 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, and a prion protein (PrP) protein or peptide.