US2023183304A1PendingUtilityA1
Multi-Epitope Vaccine for the Treatment of Alzheimer's Disease
Est. expiryMay 19, 2040(~13.8 yrs left)· nominal 20-yr term from priority
A61K 2039/53A61K 2039/6037A61P 37/04A61K 39/0007A61K 39/39C07K 14/4711A61P 25/28A61K 9/127A61K 2039/55555A61K 2039/55516A61K 2039/55572A61K 47/26A61K 2039/55577C07K 2319/00A61K 2039/575A61K 2039/55544A61K 38/00A61K 2039/545
76
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Claims
Abstract
The disclosure provides peptide compositions and immunotherapy compositions comprising an amyloid-beta (Aβ) peptide and a fau. peptide. The disclosure also provides methods of treating or effecting prophylaxis of Alzheimer's disease or oilier diseases with beta-amyloid deposition in a subject, including methods of clearing deposits, inhibiting or reducing aggregation of Aβ and/or tan, blocking the uptake by neurons, clearing amyloid, and inhibiting propagation of tau seeds in a subject having or at risk of developing Alzheimer's disease or other diseases containing tau and/or amyloid-beta accumulations. The methods include administering to such patients the compositions comprising an amyloid-beta (Aβ) peptide and a tau peptide.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A polypeptide comprising a first peptide comprising 3-10 amino acids from residues 1-10 of SEQ ID NO:01 inked to a second peptide comprising 3-13 amino acids from residues 244-400 of SEQ ID NO:02.
2 . The polypeptide of claim 1 , wherein the second peptide is from the microtubule binding region (MTBR) of tau (residues 244-372 of SEQ ID NO:02).
3 . The polypeptide of claim 1 , wherein the first peptide is N-terminal to the second peptide.
4 . The polypeptide of claim 1 , wherein the first peptide is C-terminal to the second peptide.
5 . The polypeptide of any of claims 1 to 4 , wherein:
(a) the first peptide comprises an amino acid sequence selected from the group consisting of
(SEQ ID NO: 03)
DAEFRHDSGY,
(SEQ ID NO: 04)
DAEFRHDSG,
(SEQ ID NO: 05)
DAEFRHDS,
(SEQ ID NO: 06)
DAEFRHD,
(SEQ ID NO: 07)
DAEFRH,
(SEQ ID NO: 08)
DAEFR,
(SEQ ID NO: 09)
DAEF,
(SEQ ID NO: 10)
DAE,
(SEQ ID NO: 11)
AEFRHDSGY,
(SEQ ID NO: 12)
AEFRHDSG,
(SEQ ID NO: 13)
AEFRHDS,
(SEQ ID NO: 14)
AEFRHD,
(SEQ ID NO: 15)
AEFRH,
(SEQ ID NO: 16)
AEFR,
(SEQ ID NO: 17)
AEF,
(SEQ ID NO: 18)
EFRHDSGY,
(SEQ ID NO: 19)
EFRHDSG,
(SEQ ID NO: 20)
EFRHDS,
(SEQ ID NO: 21)
EFRHD,
(SEQ ID NO: 22)
EFRH,
(SEQ ID NO: 23)
EFR,
(SEQ ID NO: 24)
FRHDSGY,
(SEQ ID NO: 25)
FRHDSG,
(SEQ ID NO: 26)
FRHDS,
(SEQ ID NO: 27)
FRHD,
(SEQ ID NO: 28)
FRH,
(SEQ ID NO: 29)
RHDSGY,
(SEQ ID NO: 30)
RHDSG,
(SEQ ID NO: 31)
RHDS,
(SEQ ID NO: 32)
RHD,
(SEQ ID NO: 33)
HDSGY,
(SEQ ID NO: 34)
HDSG,
(SEQ ID NO: 35)
HDS,
(SEQ ID NO: 36)
DSGY,
(SEQ ID NO: 37)
DSG,
and
(SEQ ID NO: 38)
SGY;
and
(b) the second peptide comprises an amino acid sequence selected from the group consisting of
(SEQ ID NO: 39)
QIVYKPV,
(SEQ ID NO: 40)
QIVYKP,
(SEQ ID NO: 41)
QIVYKSV,
(SEQ ID NO: 42)
EIVYKSV,
(SEQ ID NO: 83)
QIVYKS,
(SEQ ID NO: 43)
EIVYKSP,
(SEQ ID NO: 84)
EIVYKS,
(SEQ ID NO: 44)
EIVYKPV,
(SEQ ID NO: 85)
EIVYKP,
(SEQ ID NO: 45)
IVYKSPV,
(SEQ ID NO: 46)
IVYK,
(SEQ ID NO: 86)
CNIKHVPG,
(SEQ ID NO: 47)
CNIKHVP,
(SEQ ID NO: 48)
NIKHVP,
(SEQ ID NO: 49)
HVPGGG,
(SEQ ID NO: 50)
HVPGG,
(SEQ ID NO: 51)
HKPGGG,
(SEQ ID NO: 52)
HKPGG,
(SEQ ID NO: 53)
KHVPGGG,
(SEQ ID NO: 54)
KHVPGG,
(SEQ ID NO: 55)
HQPGGG,
(SEQ ID NO: 56)
HQPGG,
(SEQ ID NO: 801)
VKSKIGST,
(SEQ ID NO: 817)
SKIGSTEN,
(SEQ ID NO: 695)
TENLKHQP,
(SEQ ID NO: 689)
ENLKHQPG,
(SEQ ID NO: 985)
SKIGSTDNIKH,
(SEQ ID NO: 986)
SKIGSKDNIKH,
(SEQ ID NO: 988)
SKIGSLDNIKH,
and
SEQ ID NO: 146-996.
6 . The polypeptide of any of claims 1 to 5 , wherein the first peptide and second peptide are linked by a cleavable linker.
7 . The polypeptide of claim 6 , wherein the cleavable linker comprises an amino acid sequence.
8 . The polypeptide of claim 7 , wherein the amino acid sequence comprises arginine-arginine (Arg-Arg), arginine-valine-arginine-arginine (Arg-Val-Arg-Arg (SEQ ID NO:69)), valine-citrulline valine-arginine (Val-Arg), valine-lysine (Val-Lys), valine-alanine (Val-Ala), phenylalanine-lysine (Phe-Lys), glycine-alanine-glycine-alanine (Glyn-Ala-Gly-Ala; SEQ ID NO:80), alanine-glycine-alanine-glycine (Ala-Gly-Ala-Gly; SEQ ID NO:81), or lysine-glycine-lysine-glycine (Lys-Gly-Lys-Gly; SEQ ID NO:82).
9 . The polypeptide of any of claims 1 to 8 , further comprising a linker to a carrier at either a C-terminal portion of the polypeptide, or a N-terminal portion of the polypeptide.
10 . The polypeptide of claim 9 , wherein the linker comprises an amino acid sequence selected from the group consisting of GG, GGG, AA, AAA, KK, KKK, SS, SSS, GAGA (SEQ ID NO:80), AGAG (SEQ ID NO:81), and KGKG (SEQ ID NO:82).
11 . The polypeptide of any of claims 1 to 10 , wherein the polypeptide or linker to the earner, if present, further comprises a C-terminal cysteine (C).
12 . The polypeptide of any of claims 1 to 11 , wherein the first peptide is DAEFRHD (SEQ ID NO:06).
13 . The polypeptide of any of claims 1 to 11 , wherein the first peptide is DAEFR (SEQ ID NO:08).
14 . The polypeptide of any of claims 1 to 11 , wherein the first peptide is EFRHD (SEQ ID NO:21).
15 . The polypeptide of any of claims 1 to 11 , wherein the second peptide comprises 5-10 amino acids.
16 . The polypeptide of any of claims 1 to 11 , wherein the second peptide comprises the amino acid sequence QIVYKPV (SEQ ID. NO:39).
17 . The polypeptide of any of claims 1 to 11 , wherein the second peptide comprises the amino acid sequence EIVYKSP (SEQ ID NO:43).
18 . The polypeptide of any of claims 1 to 11 , wherein the second peptide comprises the amino acid sequence NIKHVP (SEQ ID NO:48).
19 . The polypeptide of any of claims 1 to 11 , wherein the second peptide comprises the amino acid sequence VKSKIGST (SEQ ID NO:801).
20 . The polypeptide of any of claims 1 to 11 , wherein the second peptide comprises the amino acid sequence SKIGSTEN (SEQ ID NO:817).
21 . The polypeptide of any of claims 1 to 11 , wherein the second peptide comprises the amino acid sequence TENLKHQP (SEQ ID NO:803).
22 . The polypeptide of any of claims 1 to 11 , wherein the second peptide comprises the amino acid sequence ENLKHQPG (SEQ ID NO:689).
23 . The polypeptide of any of claims 1 to 11 , wherein the second peptide comprises the amino acid sequence SKIGSTDNIKH (SEQ ID NO:985).
24 . The polypeptide of any of claims 1 to 11 , wherein the second peptide comprises the amino acid sequence SKIGSKDNIKH (SEQ ID NO:986).
25 . The polypeptide of any of claims 1 to 11 , wherein the second peptide comprises the amino acid sequence SKIGSLDNIKH (SEQ ID NO:988).
26 . The polypeptide of claim 1 , comprising an amino acid sequence of
(SEQ ID NO: 57)
DAEFRHDRRQIVYKPV.
27 . The polypeptide of claim 1 , comprising an amino acid sequence of
(SEQ ID NO: 58)
DAEFRHDRREIVYKSV.
28 . The polypeptide of claim 1 , comprising an amino acid sequence of
(SEQ ID NO: 59)
DAEFRHDRRQIVYKPVGGC.
29 . The polypeptide of claim 1 , comprising an amino acid sequence of
(SEQ ID NO: 60)
DAEFRHDRRQIVYKPVC.
30 . The polypeptide of claim 1 , comprising an amino acid sequence of
(SEQ ID NO: 61)
DAEFRHDRRQIVYKPVAAC.
31 . The polypeptide of claim 1 , comprising an amino acid sequence of
(SEQ ID NO: 62)
DAEFRHDRRQIVYKPVKKC.
32 . The polypeptide of claim 1 , comprising an amino acid sequence of
(SEQ ID NO: 63)
DAEFRHDRREIVYKSPGGC.
33 . The polypeptide of claim 1 , comprising an amino acid sequence of
(SEQ ID NO: 64)
DAEFRHDRREIVYKSPAAC.
34 . The polypeptide of claim 1 , comprising an amino acid sequence of
(SEQ ID NO: 65)
DAEFRHDRREIVYKSPC.
35 . The polypeptide of claim 1 , comprising an amino acid sequence of
(SEQ ID NO: 66)
DAEFRHDRREIVYKSPKKC.
36 . The polypeptide of claim 1 , comprising an amino acid sequence of
(SEQ ID NO: 78)
DAEFRHDRRNIKHVPGGC.
37 . The polypeptide of claim 1 , comprising an amino acid sequence of
(SEQ ID NO: 997)
DAEFRHDRRVKSKIGSTGGC.
38 . The polypeptide of claim 1 , comprising an amino acid sequence of
(SEQ ID NO: 998)
DAEFRHDRRSKIGSTENGGC.
39 . The polypeptide of claim 1 , comprising an amino acid sequence of
(SEQ ID NO: 999)
DAEFRHDRRTENLKHQPGGC.
40 . The polypeptide of claim 1 , comprising an amino acid sequence of
(SEQ ID NO: 1000)
DAEFRHDRRENLKHQPGGGC.
41 . The polypeptide of claim 1 , comprising an amino acid sequence of
(SEQ ID NO: 1001)
DAEFRHDRRSKIGSKDNIKHGGC.
42 . The polypeptide of claim 1 , comprising the amino acid sequence of DAEFRHDRRQIVYKPVXXC (SEQ NO:70), wherein XX and C are independently optional and, if present, XX can be GG, AA, KK, SS, GAGA (SEQ ID NO:80), AGAG (SEQ ID NO:81), or KGKG (SEQ ID NO:82).
43 . An immunotherapy composition, comprising the polypeptide of any of claims 1 to 42 , wherein the polypeptide is linked to a carrier.
44 . The immunotherapy composition of claim 22 , 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 TEPA ( Pseudomonas aeruginosa exotoxin A), KLH (keyhole limpet hemocyanin), and flagellin.
45 . The immunotherapy composition of claim 23 , wherein the carrier is CRM197.
46 . The immunotherapy composition of claim 23 , wherein the carrier is diphtheria toxoid.
47 . A pharmaceutical formulation comprising (a) the polypeptide of any one of claims 1 to 42 or the immunotherapy composition of any of claims 43 to 46 and (b) at least one adjuvant.
48 . The pharmaceutical formulation of claim 47 , 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.
49 . The pharmaceutical formulation of claim 48 , wherein the adjuvant is QS-21 or TQL1055.
50 . The pharmaceutical formulation of claim 48 , wherein the adjuvant is MPL.
51 . The pharmaceutical formulation of claim 48 , wherein the adjuvant is a combination of MPL and QS-21 or a combination of MPL and TQL1055.
52 . The pharmaceutical formulation of any of claims 47 to 51 , wherein the adjuvant comprises a liposomal formulation.
53 . The pharmaceutical formulation of any of claims 47 to 52 , wherein the composition comprises at least one pharmaceutically acceptable diluent.
54 . The pharmaceutical formulation of any of claims 47 to 53 , comprising a multiple antigen presenting system (MAP).
55 . The pharmaceutical formulation of claim 54 , 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.
56 . An immunotherapy composition, comprising a first peptide sequence comprising 3-10 amino acid residues from the first ten N-terminal residues of SEQ ID NO:01 and a second peptide sequence comprising 3-13 amino acids from residues 244-400 of SEQ ID NO:02.
57 . The immunotherapy composition of claim 56 , wherein:
(a) the first peptide sequence comprises an amino acid sequence selected from the group consisting of
(SEQ ID NO: 03)
DAEFRHDSGY,
(SEQ ID NO: 04)
DAEFRHDSG,
(SEQ ID NO: 05)
DAEFRHDS,
(SEQ ID NO: 06)
DAEFRHD,
(SEQ ID NO: 07)
DAEFRH,
(SEQ ID NO: 08)
DAEFR,
(SEQ ID NO: 09)
DAEF,
(SEQ ID NO: 10)
DAE,
(SEQ ID NO: 11)
AEFRHDSGY,
(SEQ ID NO: 12)
AEFRHDSG,
(SEQ ID NO: 13)
AEFRHDS,
(SEQ ID NO: 14)
AEFRHD,
(SEQ ID NO: 15)
AEFRH,
(SEQ ID NO: 16)
AEFR,
(SEQ ID NO: 17)
AEF,
(SEQ ID NO: 18)
EFRHDSGY,
(SEQ ID NO: 19)
EFRHDSG,
(SEQ ID NO: 20)
EFRHDS,
(SEQ ID NO: 21)
EFRHD,
(SEQ ID NO: 22)
EFRH,
(SEQ ID NO: 23)
EFR,
(SEQ ID NO: 24)
FRHDSGY,
(SEQ ID NO: 25)
FRHDSG,
(SEQ ID NO: 26)
FRHDS,
(SEQ ID NO: 27)
FRHD,
(SEQ ID NO: 28)
FRH,
(SEQ ID NO: 29)
RHDSGY,
(SEQ ID NO: 30)
RHDSG,
(SEQ ID NO: 31)
RHDS,
(SEQ ID NO: 32)
RHD,
(SEQ ID NO: 33)
HDSGY,
(SEQ ID NO: 34)
HDSG,
(SEQ ID NO: 35)
HDS,
(SEQ ID NO: 36)
DSGY,
(SEQ ID NO: 37)
DSG,
and
(SEQ ID NO: 38)
SGY;
and
(b) the second peptide sequence comprises an amino acid sequence selected from the group consisting of
(SEQ ID NO: 39)
QIVYKPV,
(SEQ ID NO: 40)
QIVYKP,
(SEQ ID NO: 41)
QIVYKSV,
(SEQ ID NO: 83)
QIVYKS,
(SEQ ID NO: 43)
EIVYKSP,
(SEQ ID NO: 84)
EIVYKS,
(SEQ ID NO: 44)
EIVYKPV,
(SEQ ID NO: 85)
EIVYKP,
(SEQ ID NO: 45)
IVYKSPV,
(SEQ ID NO: 46)
IVYK,
(SEQ ID NO: 86)
CNIKHVPG,
(SEQ ID NO: 47)
CNIKHVP,
(SEQ ID NO: 48)
NIKHVP,
(SEQ ID NO: 49)
HVPGGG,
(SEQ ID NO: 50)
HVPGG,
(SEQ ID NO: 51)
HKPGGG,
(SEQ ID NO: 52)
HKPGG,
(SEQ ID NO: 53)
KHVPGGG,
(SEQ ID NO: 54)
KHVPGG,
(SEQ ID NO: 55)
HQPGGG,
(SEQ ID NO: 56)
HQPGG,
(SEQ ID NO: 801)
VKSKIGST,
(SEQ ID NO: 817)
SKIGSTEN,
(SEQ ID NO: 695)
TENLKHQP,
(SEQ ID NO: 689)
ENLKHQPG,
(SEQ ID NO: 985)
SKIGSTDNIKH,
(SEQ ID NO: 986)
SKIGSKDNIKH,
(SEQ ID NO: 988)
SKIGSLDNIKH,
and
SEQ ID NO: 146-996
wherein each of the first peptide sequence and the second peptide sequence may optionally comprise a C-terminal cysteine.
58 . The immunotherapy composition of any one of claims 56 to 57 , wherein the at least one of the first peptide and the second peptide further comprise a linker to a carrier at either a C-terminal portion of the polypeptide, or a N-terminal portion of the polypeptide.
59 . The immunotherapy composition of claim 58 , wherein the linker comprises an amino acid sequence selected from the group consisting of GG, GGG, AA, AAA, KK, KKK, SS, SSS, GAGA (SEQ ID NO:80), AGAG (SEQ ID NO:81), and KGKG (SEQ ID NO:82).
60 . The immunotherapy composition of claim 59 , wherein the linker to the carrier may optionally comprise a C-terminal cysteine (C).
61 . The immunotherapy composition of any one of claims 59 to 60 , 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 TEPA ( Pseudomonas aeruginosa exotoxin A), KLH (keyhole limpet hemocyanin), and flagellin.
62 . The immunotherapy composition of claim 61 , wherein the carrier is CRM197.
63 . The immunotherapy composition of claim 61 , wherein the carrier is diphtheria toxoid.
64 . The immunotherapy composition of any one of claims 56 to 63 , further comprising at least one pharmaceutically acceptable diluent.
65 . The immunotherapy composition of any one of claims 56 to 64 , further comprising a multiple antigen presenting system (MAP).
66 . The immunotherapy composition of claim 65 , 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.
67 . A pharmaceutical composition comprising the immunotherapy composition of any of claims 56 to 66 and at least one adjuvant.
68 . The pharmaceutical composition of claim 67 , 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 peanut oil), CpG, polyglutamic acid, polylysine, AddaVax™ MF59®, and combinations thereof.
69 . The pharmaceutical composition of claim 68 , wherein the adjuvant is QS-21 or TQL1055.
70 . The pharmaceutical composition of claim 68 , wherein the adjuvant is MPL.
71 . The pharmaceutical composition of claim 68 , wherein the adjuvant is a combination of MPL and QS-21 or a combination of MPL and TQL1055.
72 . A nucleic acid comprising a nucleic acid sequence encoding a polypeptide of any one of claims 1 to 42 of the immunotherapy composition of claims 56 to 60 .
73 . A nucleic acid immunotherapy composition comprising the nucleic acid of claim 72 and at least one adjuvant.
74 . A method of treating or effecting prophylaxis of Alzheimer's disease in a subject, comprising administrating to the subject the immunotherapy composition of any of claims 43 to 46 and 56 to 66 or the pharmaceutical formulations of any of claims 47 to 55 and 67 to 71 .
75 . A method of inhibiting or reducing aggregation of at least one of Aβ and tau in a subject having or at risk of developing Alzheimer's disease, comprising, administering to the subject the immunotherapy composition of any of claims 41 to 46 and 56 to 66 or the pharmaceutical formulations of any of claims 47 to 55 and 67 to 71 .
76 . 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 73 .
77 . A method of inhibiting, or reducing aggregation of at least one of Aβ and tau in a subject having or at risk of developing Alzheimer's disease, comprising administering to the subject the nucleic acid immunotherapy composition of claim 73 .
78 . The method of any of claims 74 to 77 , further comprising repeating the administering at least a second time, at least a third time, at least a fourth time, at least a fifth tune, or at least a sixth time.
79 . The method of claim 78 , further comprising repeating the administering at an interval of about 21 to about 28 days.
80 . A method of inducing an immune response in an animal, comprising administering to the animal any one of the polypeptide of claims 1 to 42 , the immunotherapy composition of claims 43 to 46 and 56 to 66 , the pharmaceutical formulations of claims 47 to 55 and 67 to 71 or the nucleic acid immunotherapy composition of claim 73 in a regimen effective to generate an immune response comprising antibodies that specifically bind to Aβ, tau, or both Aβ and tau.
81 . The method of claim 80 , wherein the immune response comprises antibodies that specifically bind to and antibodies that specifically bind to tau.
82 . The method of any of claims 80 to 81 , wherein the inducing the immune response comprises antibodies that specifically bind to the N-terminal region of Aβ and/or the microtubule region of tau.
83 . An immunization kit comprising the immunotherapy composition of any of claims 43 to 46 and 56 to 66 .
84 . The kit of claim 83 , further comprising an adjuvant.
85 . The kit of claim 84 , wherein the immunotherapy composition is in a first container and the adjuvant is in a second container.
86 . A kit comprising the nucleic acid immunotherapy composition of claim 73 .
87 . The kit of claim 86 , further comprising an adjuvant.
88 . The kit of claim 87 , wherein the nucleic acid is in a first container and the adjuvant is in a second container.Join the waitlist — get patent alerts
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