Compositions and methods related to diseases associated with deposits of amyloid, tau, and alpha-synuclein
Disclosed are compositions, comprising one or more immunogens, wherein each immunogen comprises at least two regions, wherein one region comprises at least one amyloid-β (Aβ) B cell epitope or at least one Tau B cell epitope or at least one α-synuclein B cell epitope or combinations thereof, and a second region comprises at least one foreign T helper cell (Th) epitope, and usually multiple foreign Th epitopes. Methods of making and using the compositions are also disclosed.
1. A composition, comprising at least one immunogen, wherein each at least one immunogen comprises a region A coupled to a region B; wherein region A comprises:
(a) at least one AP B cell epitope in two or more copies, or
(b) at least one Tau B cell epitope in two or more copies, or
(c) at least one α-synuclein B cell epitope in two or more copies, or
(d) a combination of at least one amyloid-β (Aβ) B cell epitope in two or more copies and at least one Tau B cell epitope in two or more copies, or
(e) a combination of at least one amyloid-β (Aβ) B cell epitope in two or more copies and at least one α-synuclein B cell epitope in two or more copies, or
(f) a combination of at least one Tau B cell epitope in two or more copies and at least one α-synuclein B cell epitope in two or more copies, or
(g) a combination of at least one amyloid-β (Aβ)B cell epitope in two or more copies and at least one Tau B cell epitope in two or more copies and at least one α-synuclein B cell epitope in two or more copies, and
region B comprises an amino acid sequence that comprises a plurality of foreign T helper cell (Th) epitopes and comprises at least one amino acid sequence of PADRE (SEQ ID NO: 36), tetanus toxin P7 (SEQ ID NO: 32), tetanus toxin P17 (SEQ ID NO: 31), or tetanus toxin P28 (SEQ ID NO: 30).
2. The composition of claim 1 , wherein at least one immunogen comprises a linker domain coupling region A to region B.
3. The composition of claim 2 , wherein the linker domain is selected from the group consisting of the amino acid sequence GS, GSGSG (SEQ ID NO: 37), YNGK (SEQ ID NO: 38) and A(EAAAK)nA (SEQ ID NO: 39), where n is 2-5.
4. The composition of claim 1 , wherein region A is coupled to the N-terminus of region B or wherein region A is coupled to the C-terminus of region B.
5. The composition of claim 1 , wherein the at least one AP B cell epitope is located within SEQ ID NO:1.
6. The composition of claim 5 , wherein the AP B cell epitope comprises two or more copies of the amino acid sequence EFRH (SEQ ID NO: 41).
7. The composition of claim 1 , wherein the at least one Tau B cell epitope is located within SEQ ID NO: 2.
8. The composition of claim 7 , wherein the Tau B cell epitope comprises two or more copies of at least one amino acid sequence selected from the group consisting of:
(SEQ ID NO: 8)
AKAKTDHGAEIVYKSPVVSGDTSPRHLSNVSSTGSID,
(SEQ ID NO: 9)
RSGYSSPGSPGTPGSRSR,
(SEQ ID NO: 10)
NATRIPAKTPPAPKTPPSSGEPPKSGDRSGYSSPGS,
(SEQ ID NO: 11)
GEPPKSGDRSGYSSPGSPGTPGSRSRTPSLPTPPTREPKK,
(SEQ ID NO: 12)
KKVAVVRTPPKSPSS
and
(SEQ ID NO: 13)
AEPRQEFEVMEDHAGTY.
9. The composition of claim 1 , wherein the region B comprises the amino acid sequence
(SEQ ID NO: 45)
AKFVAAWTLKAAAGSVSIDKFRIFCKANPKGSLKFIIKRYTPNNEIDSGS
IREDNNITLKLDRCNNGSFNNFTVSFWLRVPKVSASHLEGSQYIKANSKF
IGITEGSPHHTALRQAILCWGELMTLAGSFFLLTRILTIPQSLDGSYSGP
LKAEIAQRLEDVGSNYSLDKIIVDYNLQSKITLPGSLINSTKIYSYFPSV
ISKVNQGSLEYIPEITLPVIAALSIAES.
10. A pharmaceutical composition comprising the composition of claim 1 and a pharmaceutically-acceptable excipient.
11. A composition comprising at least one nucleic acid molecule encoding an immunogen, wherein the immunogen comprises a region A coupled to a region B; wherein region A comprises:
(a) at least one Aβ B cell epitope in two or more copies, or
(b) at least one Tau B cell epitope in two or more copies or
(c) at least one α-synuclein B cell epitope in two or more copies, or
(d) a combination of at least one amyloid-β (Aβ) B cell epitope and at least one Tau B cell epitope, or
(e) a combination of at least one amyloid-β (Aβ) B cell epitope in two or more copies and at least one α-synuclein B cell epitope in two or more copies, or
(f) a combination of at least one Tau B cell epitope in two or more copies and at least one α-synuclein B cell epitope in two or more copies, or
(g) a combination of at least one amyloid-β (Aβ) B cell epitope in two or more copies and at least one Tau B cell epitope in two or more copies and at least one α-synuclein B cell epitope in two or more copies,
and region B comprises an amino acid sequence that comprises a plurality of foreign T helper cell (Th) epitopes and comprises at least one amino acid sequence of PADRE (SEQ ID NO: 36), tetanus toxin P7 (SEQ ID NO: 32), tetanus toxin P17 (SEQ ID NO: 31), or tetanus toxin P28 (SEQ ID NO: 30).
12. The composition of claim 11 , wherein the nucleic acid molecule encodes a Tau B cell epitope comprising two or more copies of a sequence located within SEQ ID NO:5.
13. The composition of claim 11 , wherein the nucleic acid molecule encodes an α-syn B cell epitope comprising two or more copies of a sequence located within SEQ ID NO:6.
14. A pharmaceutical composition comprising the composition of claim 11 and a pharmaceutically-acceptable excipient.
15. A method for generating an immune response in a subject against one or more of amyloid, tau or
α-syn, comprising administering the composition of claim 10 to the subject.
16. The method of claim 15 , wherein the subject is at risk of developing or has been diagnosed with Alzheimer's disease or one or more conditions associated with abnormal amyloid deposits, Tau deposits, and α-syn deposits.
17. A method for generating an immune response in a subject against one or more of amyloid, tau or α-syn, comprising administering the composition according to claim 14 to the subject.
18. The method of claim 17 , wherein the subject is at risk of developing or has been diagnosed with Alzheimer's disease or one or more conditions associated with abnormal amyloid deposits, Tau deposits, and α-syn deposits.
19. The composition of claim 11 , wherein the nucleic acid molecule encodes a Aβ B cell epitope comprising two or more copies of sequence EFRH (SEQ ID NO: 41).
20. The composition of claim 11 , in which the region B comprises the amino acid sequence
(SEQ ID NO: 45)
AKFVAAWTLKAAAGSVSIDKFRIFCKANPKGSLKFIIKRYTPNNEIDSGS
IREDNNITLKLDRCNNGSFNNFTVSFWLRVPKVSASHLEGSQYIKANSKF
IGITEGSPHHTALRQAILCWGELMTLAGSFFLLTRILTIPQSLDGSYSGP
LKAEIAQRLEDVGSNYSLDKIIVDYNLQSKITLPGSLINSTKIYSYFPSV
ISKVNQGSLEYIPEITLPVIAALSIAES.
21. A composition comprising at least one immunogen, wherein each at least one immunogen comprises a multi-TEP Th epitope that has the amino acid sequence
(SEQ ID NO: 45)
AKFVAAWTLKAAAGSVSIDKFRIFCKANPKGSLKFIIKRYTPNNEIDSGS
IREDNNITLKLDRCNNGSFNNFTVSFWLRVPKVSASHLEGSQYIKANSKF
IGITEGSPHHTALRQAILCWGELMTLAGSFFLLTRILTIPQSLDGSYSGP
LKAEIAQRLEDVGSNYSLDKIIVDYNLQSKITLPGSLINSTKIYSYFPSV
ISKVNQGSLEYIPEITLPVIAALSIAES.