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, non-fibrillogenic, heteropolymer product, said 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 and a prion protein (PrP) protein or peptide.
2. The heteropolymer product of claim 1 , wherein said product includes an Aβ 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 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 heteropolymer product of claim 2 , wherein the Aβ peptide comprises amino acid residues 1-42 of SEQ ID NO:1.
4. The heteropolymer product of claim 1 , wherein said product includes 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 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 heteropolymer 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 heteropolymer product of claim 1 , wherein said product includes 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 20 contiguous amino acid residues and having at least 80% homology to the amino acid sequence of SEQ ID NO:7.
7. The heteropolymer product of claim 1 further comprising: an adjuvant polypeptide linked in frame to one or more of the protein and/or peptide monomers of the heteropolymer product.
8. The heteropolymer product of claim 7 , 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.
9. The heteropolymer product of claim 7 , 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.
10. The heteropolymer product of claim 1 further comprising: an immunogenic carrier molecule conjugated to one or more of the protein and/or peptide monomers of the heteropolymer product.
11. The heteropolymer product of claim 10 , 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.
12. The heteropolymer product of claim 10 , 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.
13. A pharmaceutical composition comprising:
the heteropolymer product of claim 1 and
a pharmaceutically acceptable carrier.
14. The pharmaceutical composition of claim 13 further comprising:
an adjuvant.
15. The pharmaceutical composition of claim 14 , wherein the adjuvant is selected from the group consisting of an aluminum salt, flagellin, Freund's complete or incomplete adjuvant, lysolecithin, pluronic polyols, polyanions, an oil-water emulsion, dinitrophenol, iscomatrix, and liposome polycation DNA particles.
16. The pharmaceutical composition of claim 15 , wherein the adjuvant comprises aluminum salt.
17. The pharmaceutical composition according to claim 13 further comprising:
a delivery vehicle.
18. The pharmaceutical composition according to claim 17 , wherein the delivery vehicle is selected from the group consisting of biodegradable microspheres, microparticles, nanoparticles, liposomes, collagen minipellets, and cochleates.