Multiepitope vaccine for the treatment of ALZHEIMER'S disease
The disclosure provides peptide compositions and immunotherapy compositions comprising an amyloid-beta (Aβ, Abeta) peptide, a tau peptide, and an alpha-synuclein peptide. The disclosure also provides methods of treating or effecting prophylaxis of Alzheimer's disease or other diseases with beta-amyloid deposition in a subject, including methods of clearing deposits, inhibiting or reducing aggregation of Aβ and tau and an alpha-synuclein, blocking the uptake by neurons, clearing amyloid, and inhibiting propagation of tau seeds and an alpha-synuclein synucleinopathies in a subject having or at risk of developing Alzheimer's disease or other diseases containing tau and amyloid-beta and an alpha-synuclein accumulations. The methods include administering to such patients the compositions comprising an amyloid-beta (Aβ) peptide and a tau peptide and an alpha-synuclein peptide.
1 . A polypeptide comprising an amino acid sequence of:
DAEFRHDRRPDNEAYERRQIVYKPVKKC (SEQ ID NO:130);
DAEFRHDRRQIVYKPVRRPDNEAYEKKC (SEQ ID NO:131);
DAEFRHDRRPDNEAYERRNIKHVPGKKC (SEQ ID NO:132);
DAEFRHDRRNIKHVPGRRPDNEAYEKKC (SEQ ID NO: 133);
DAEFRHDRRQIVYKPVRRPDNEAYERRNIKHVPGGC (SEQ ID NO:134);
DAEFRHDRRDPDNEAYRRNIKHVPGRRQIVYKPVGGC (SEQ ID NO:135);
EFRHDSGRRQIVYKPVRRPDNEAYERRNIKHVPGGC (SEQ ID NO: 136);
EFRHDSGRRDPDNEAYRRNIKHVPGRRQIVYKPVGGC (SEQ ID NO:137);
DAEFRHDRRDPDNEAYERRENLKHQPGGGC (SEQ ID NO:1058);
DAEFRHDRRENLKHQPGRRDPDNEAYEGGC (SEQ ID NO:1059);
DAEFRHDRRPDNEAYERRENLKHOPGGGC (SEQ ID NO:1060);
DAEFRHDRRENLKHQPGRRPDNEAYEGGC (SEQ ID NO:1061);
DAEFRHDRRSKIGSKDNIKHRRDPDNEAYEGGC (SEQ ID NO:1062); or
DAEFRHDRRDPDNEAYERRSKIGSKDNIKHGGC (SEQ ID NO:1063).
2 . The polypeptide of claim 1 , wherein the polypeptide further comprises a blocked amine at the N-terminus.
3 . The polypeptide of claim 1 , wherein the polypeptide is EFRHDSGRRQIVYKPVRRPDNEAYERRNIKHVPGGC (SEQ ID NO:136), and further comprises a blocked amine at the N-terminus.
4 . The polypeptide of claim 1 , wherein the polypeptide is EFRHDSGRRDPDNEAYRRNIKHVPGRRQIVYKPVGGC (SEQ ID NO:137), and further comprising a blocked amine at the N-terminus.
5 . An immunotherapy composition, comprising the polypeptide of claim 1 , wherein the polypeptide is linked to a carrier.
6 . The immunotherapy composition of claim 5 , wherein the carrier comprises serum albumins, immunoglobulin molecules, thyroglobulin, ovalbumin, tetanus toxoid (TT), diphtheria toxoid (DT), a genetically modified cross-reacting material (CRM) of diphtheria toxin, CRM197, meningococcal outer membrane protein complex (OMPC) and H. influenzae protein D (HiD), rEPA ( Pseudomonas aeruginosa exotoxin A), KLH (keyhole limpet hemocyanin), and flagellin.
7 . The immunotherapy composition of claim 6 , wherein the carrier is CRM197.
8 . The immunotherapy composition of claim 6 , wherein the carrier is diphtheria toxoid.
9 . A pharmaceutical composition comprising the immunotherapy composition of claim 5 and an adjuvant.
10 . The pharmaceutical composition of claim 9 , wherein the adjuvant is selected from the group consisting of aluminum hydroxide, aluminum phosphate, aluminum sulfate, 3 De-O-acylated monophosphoryl lipid A (MPL), QS-21, TQL1055, QS-18, QS-17, QS-7, Complete Freund's Adjuvant (CFA), Incomplete Freund's Adjuvant (IFA), oil in water emulsions (such as squalene or peanut oil), CpG, polyglutamic acid, polylysine, AddaVax™, MF59®, and combinations thereof.
11 . The pharmaceutical composition of claim 10 , wherein the adjuvant is QS-21 or TQL1055.
12 . The pharmaceutical composition of claim 10 , wherein the adjuvant is MPL.
13 . The pharmaceutical composition of claim 10 , wherein the adjuvant is a combination of MPL and QS-21 or a combination of MPL and TQL1055.
14 . A method of treating or effecting prophylaxis of Alzheimer's disease in a subject, comprising administrating to the subject the immunotherapy composition of claim 5 .
15 . The method of claim 14 , further comprising repeating the administering at least a second time, at least a third time, at least a fourth time, at least a fifth time, or at least a sixth time.
16 . The method of claim 15 , further comprising repeating the administering at an interval of about 21 to about 28 days.
17 . A method of inhibiting or reducing aggregation of at least one of Aβ, tau, and alpha-synuclein in a subject having or at risk of developing Alzheimer's disease, comprising, administering to the subject the immunotherapy composition of claim 5 .
18 . A method of inducing an immune response in an animal, comprising administering to the animal the immunotherapy composition of claim 5 in a regimen effective to generate an immune response comprising antibodies that specifically bind to Aβ, tau, and/or alpha-synuclein.
19 . The method of claim 18 , wherein the immune response comprises antibodies that specifically bind to Aβ, antibodies that specifically bind to tau, and antibodies that specifically bind to alpha-synuclein.
20 . The method of claim 18 , wherein the inducing the immune response comprises antibodies that specifically bind to the N-terminal region of AB, the microtubule region of tau, and/or the C-terminal region of alpha-synuclein.
21 . An immunization kit comprising the immunotherapy composition of claim 5 .
22 . The kit of claim 21 , further comprising an adjuvant.
23 . The kit of claim 22 , wherein the immunotherapy composition is in a first container and the adjuvant is in a second container.
24 . A pharmaceutical formulation comprising (a) the polypeptide of claim 1 and (b) an adjuvant.
25 . The pharmaceutical formulation of claim 24 , wherein the adjuvant is selected from the group consisting of aluminum hydroxide, aluminum phosphate, aluminum sulfate, 3 De-O-acylated monophosphoryl lipid A (MPL), QS-21, TQL1055, QS-18, QS-17, QS-7, Complete Freund's Adjuvant (CFA), Incomplete Freund's Adjuvant (IFA), oil in water emulsions (such as squalene or peanut oil), CpG, polyglutamic acid, polylysine, AddaVax™, MF59®, and combinations thereof.
26 . The pharmaceutical formulation of claim 25 , wherein the adjuvant is QS-21 or TQL1055.
27 . The pharmaceutical formulation of claim 25 , wherein the adjuvant is MPL.
28 . The pharmaceutical formulation of claim 25 , wherein the adjuvant is a combination of MPL and QS-21 or a combination of MPL and TQL1055.
29 . The pharmaceutical formulation of claim 24 , wherein the adjuvant comprises a liposomal formulation.
30 . The pharmaceutical formulation of claim 24 , wherein the composition comprises at least one pharmaceutically acceptable diluent.
31 . The pharmaceutical formulation of claim 24 , comprising a multiple antigen presenting system (MAP).
32 . The pharmaceutical formulation of claim 31 , wherein the MAP comprises one or more of a Lys-based dendritic scaffold, helper T-cell epitopes, immune stimulating lipophilic moieties, cell penetrating peptides, radical induced polymerization, self-assembling nanoparticles as antigen-presenting platforms and gold nanoparticles.
33 . A nucleic acid comprising a nucleic acid sequence encoding a polypeptide of claim 1 .
34 . A nucleic acid immunotherapy composition comprising the nucleic acid of claim 33 and at least one adjuvant.
35 . A method of treating or effecting prophylaxis of Alzheimer's disease in a subject, comprising administrating to the subject the nucleic acid immunotherapy composition of claim 34 .
36 . A method of inhibiting or reducing aggregation of at least one of Aβ, tau, and alpha-synuclein in a subject having or at risk of developing Alzheimer's disease, comprising administering to the subject the nucleic acid immunotherapy composition of claim 34 .
37 . A kit comprising the nucleic acid immunotherapy composition of claim 34 .
38 . The kit of claim 37 , further comprising an adjuvant.
39 . The kit of claim 38 , wherein the nucleic acid is in a first container and the adjuvant is in a second container.