TAU PEPTIDE IMMUNOGEN CONSTRUCTS
The present disclosure is directed to individual peptide immunogen constructs targeting portions of the Tau protein for the treatment and/or prevention of tauopathies. The present disclosure is also directed to compositions containing the peptide immunogen constructs, methods of making and using the peptide immunogen constructs, and antibodies produced by the peptide immunogen constructs.
1 - 23 . (canceled)
24 . A Tau peptide immunogen construct comprising:
a B cell epitope comprising SEQ ID NO: 2 or a functional analogue thereof; and
a heterologous T helper cell epitope selected from SEQ ID NOs: 138-166;
wherein the B cell epitope is covalently linked to the heterologous T helper cell epitope directly or through a heterologous spacer.
25 . The Tau peptide immunogen construct of claim 24 , which is represented by the formulae:
wherein
(Th) is the heterologous T helper cell epitope;
(A) is the heterologous spacer;
(Tau fragment) is the B cell epitope;
X is an α-COOH or α-CONH 2 of an amino acid;
m is from 1 to 4; and
n is from 0 to 10.
26 . The Tau peptide immunogen construct of claim 24 , wherein the B cell epitope is of the amino acid sequence of SEQ ID NO: 2.
27 . The Tau peptide immunogen construct of claim 24 , wherein the T helper cell epitope is selected from SEQ ID NOs: 149 and 151-152.
28 . The Tau peptide immunogen construct of claim 24 , wherein the T helper cell epitope is of the amino acid sequence of SEQ ID NO: 151.
29 . The Tau peptide immunogen construct of claim 24 , wherein the T helper cell epitope is of the amino acid sequence of SEQ ID NO: 151 and the B cell epitope is of the amino acid sequence of SEQ ID NO: 2.
30 . The Tau peptide immunogen construct of claim 24 , wherein the Tau peptide immunogen construct comprises the heterologous spacer, and the heterologous spacer is selected from an amino acid, Lys-, Gly-, Lys-Lys-Lys-, (α, ε-N) Lys, Lys-Lys-Lys-ε-N-Lys-, and ε-N-Lys-Lys-Lys-Lys-.
31 . The Tau peptide immunogen construct of claim 24 , wherein the Tau peptide immunogen construct comprises the heterologous spacer, and the heterologous spacer is Lys-Lys-Lys-ε-N-Lys-, or ε-N-Lys-Lys-Lys-Lys-.
32 . The Tau peptide immunogen construct of claim 29 , wherein the Tau peptide immunogen construct comprises the heterologous spacer, and the heterologous spacer is Lys-Lys-Lys-ε-N-Lys-, or ε-N-Lys-Lys-Lys-Lys-.
33 . The Tau peptide immunogen construct of claim 24 , wherein the Tau peptide immunogen construct comprises or is of the amino acid sequence of SEQ ID NO: 10, or comprises or is of the amino acid sequence of a construct in which the positions of the B cell epitope and the T helper cell epitope according to SEQ ID NO: 10 are reversed.
34 . The Tau peptide immunogen construct of claim 24 , wherein the Tau peptide immunogen construct is of the amino acid sequence of SEQ ID NO: 10.
35 . A pharmaceutical composition comprising the Tau peptide immunogen construct of claim 24 and a pharmaceutically acceptable delivery vehicle and/or adjuvant.
36 . The pharmaceutical composition of claim 35 , wherein the Tau peptide immunogen construct is mixed with an CpG oligonucleotide (ODN) to form a stabilized immunostimulatory complex, optionally wherein the CpG ODN is CpG1, CpG2, or CpG3.
37 . The pharmaceutical composition of claim 35 , wherein the pharmaceutically acceptable delivery vehicle and/or adjuvant comprises an aluminum-based adjuvant, optionally wherein the aluminum-based adjuvant is aluminum phosphate or aluminum hydroxide.
38 . A pharmaceutical composition comprising the Tau peptide immunogen construct of claim 33 and a pharmaceutically acceptable delivery vehicle and/or adjuvant.
39 . The pharmaceutical composition of claim 38 , wherein the Tau peptide immunogen construct is mixed with an CpG oligonucleotide (ODN) to form a stabilized immunostimulatory complex, optionally wherein the CpG ODN is CpG1, CpG2, or CpG3.
40 . The pharmaceutical composition of claim 39 , wherein the pharmaceutically acceptable delivery vehicle and/or adjuvant comprises an aluminum-based adjuvant, optionally wherein the aluminum-based adjuvant is aluminum phosphate or aluminum hydroxide.
41 . An isolated antibody or epitope-binding fragment thereof elicited by the Tau peptide immunogen construct of claim 24 .
42 . A method of preventing, inhibiting, reducing the severity of, delaying, or treating a tauopathy in a subject, the method comprising administering the Tau peptide immunogen construct of claim 24 to the subject, optionally wherein the tauopathy is selected from Alzheimer's disease, Lewy body disease, frontotemporal dementia, parkinsonism linked to chromosome 17 (FTDP-17), progressive supranuclear palsy, corticobasal degeneration, Pick's disease, progressive subcortical gliosis, tangle only dementia, diffuse neurofibrillary tangles with calcification, argyrophilic grain dementia, amyotrophic lateral sclerosis parkinsonism-dementia complex, dementia pugilistica, Down syndrome, Gerstmann-Straussler-Scheinker disease, Hallerworden-Spatz disease, inclusion body myositis, Creutzfeld-Jakob disease, multiple system atropy, Niemann-Pick disease type C, prion protein cerebral amyloid angiopathy, subacute sclerosing panencephalitis, myotonic dystrophy, non-guanamian motor neuron disease with neurofibrillary tangles, postencephalitic parkinsonism, and chronic traumatic encephalopathy.
43 . The method of claim 42 , wherein the tauopathy is Alzheimer's disease.
44 . A method of
(a) inhibiting Tau aggregation in a subject;
(b) inducing disaggregate of preformed Tau aggregates in a subject;
(c) reducing neurodegeneration triggered by exogenous Tau aggregates in a subject;
(d) reducing neurodegeneration in Tau overexpressing cells;
(e) reducing serum Tau levels in a subject;
(f) reducing oligomeric Tau level in the brain of a subject; or
(g) reducing neuropathology and recovery of motor activities in a subject;
the method comprising administering the Tau peptide immunogen construct of claim 24 to the subject.
45 . A method of preventing, inhibiting, reducing the severity of, delaying, or treating a tauopathy in a subject, the method comprising administering the Tau peptide immunogen construct of claim 33 to the subject, optionally wherein the tauopathy is selected from Alzheimer's disease, Lewy body disease, frontotemporal dementia, parkinsonism linked to chromosome 17 (FTDP-17), progressive supranuclear palsy, corticobasal degeneration, Pick's disease, progressive subcortical gliosis, tangle only dementia, diffuse neurofibrillary tangles with calcification, argyrophilic grain dementia, amyotrophic lateral sclerosis parkinsonism-dementia complex, dementia pugilistica, Down syndrome, Gerstmann-Straussler-Scheinker disease, Hallerworden-Spatz disease, inclusion body myositis, Creutzfeld-Jakob disease, multiple system atropy, Niemann-Pick disease type C, prion protein cerebral amyloid angiopathy, subacute sclerosing panencephalitis, myotonic dystrophy, non-guanamian motor neuron disease with neurofibrillary tangles, postencephalitic parkinsonism, and chronic traumatic encephalopathy.
46 . The method of claim 45 , wherein the tauopathy is Alzheimer's disease.
47 . A method of
(a) inhibiting Tau aggregation in a subject;
(b) inducing disaggregate of preformed Tau aggregates in a subject;
(c) reducing neurodegeneration triggered by exogenous Tau aggregates in a subject;
(d) reducing neurodegeneration in Tau overexpressing cells;
(e) reducing serum Tau levels in a subject;
(f) reducing oligomeric Tau level in the brain of a subject; or
(g) reducing neuropathology and recovery of motor activities in a subject;
the method comprising administering the Tau peptide immunogen construct of claim 33 to the subject.