TAU AND AMYLOID BETA PEPTIDE IMMUNOGEN COMPOSITIONS AND RELATED METHODS
The present disclosure is directed to improved peptide immunogen constructs targeting portions of the Tau protein for the treatment and/or prevention of tauopathies. The present disclosure is also directed to improved peptide immunogen constructs targeting portions of the amyloid beta protein for the treatment and/or prevention of tauopathies. The present disclosure is also directed to compositions and kits containing the peptide immunogen constructs, in particular compositions and kits comprising combinations of various peptide immunogen constructs. Methods of making and using the peptide immunogen constructs, and antibodies produced by the peptide immunogen constructs, are also provided herein. In some aspects, the disclosure is directed to compositions comprising peptide immunogen constructs based on portions of the Tau protein and peptide immunogen constructs based on portions of the amyloid beta protein, and use of these peptide immunogen constructs and compositions in therapeutic methods.
1 . A composition or a kit comprising a first Tau peptide immunogen construct comprising a first Tau B cell epitope comprising or consisting of 6 to about 40 amino acid residues from the full-length Tau protein of SEQ ID NO: 60; and
(i) a second Tau peptide immunogen construct comprising a second Tau B cell epitope comprising or consisting of 6 to about 40 amino acid residues from the full-length Tau protein of SEQ ID NO: 60, wherein the second B cell epitope is not the same as the first B cell epitope, and/or
(ii) an amyloid beta (Aβ) peptide immunogen construct comprising an amyloid beta B cell epitope comprising or consisting of 6 to about 42 amino acid residues from the full-length amyloid beta protein of SEQ ID NO: 68.
2 . The composition or kit according to claim 1 , which comprises the second Tau peptide immunogen construct.
3 . The composition or kit according to claim 1 , which comprises the amyloid beta peptide immunogen construct.
4 . The composition or kit according to claim 1 , which comprises the second Tau peptide immunogen construct and the amyloid beta peptide immunogen construct.
5 . The composition or kit according to claim 1, 2 or 4 , wherein the first Tau B cell epitope comprises or consists of 6 to about 40 amino acid residues from N-terminal amino acids 1 to 44 of SEQ ID NO: 60, and the second Tau B cell epitope comprises or consists of 6 to about 40 amino acid residues from repeat domain amino acids 244 to 372 of SEQ ID NO: 60.
6 . The composition or kit according to claim 1, 3, 4 or 5 , wherein the amyloid beta B cell epitope comprises at least 6 amino acid residues from amino acids 1-16 of SEQ ID NO: 68.
7 . The composition or kit according to any one of claims 1-6 , wherein the first Tau B cell epitope, the second Tau B cell epitope, and the amyloid beta B cell epitope are each about 8 to 15 amino acids in length, or 10 to 14 amino acids in length.
8 . The composition or kit according to any one of claims 1-6 , wherein the first Tau B cell epitope and, if present, the second Tau B cell epitope are independently selected from SEQ ID NOs: 1-8, 17-30, 63-67, 72-76, 96, and 202.
9 . The composition or kit according to claim 8 , wherein the first Tau B cell epitope and, if present, the second Tau B cell epitope are independently selected from SEQ ID NOs: 2, 4, 7, and 72-76.
10 . The composition or kit according to any one of claims 1-6 , wherein the first Tau B cell epitope comprises or consists of SEQ ID NO: 2.
11 . The composition or kit according to any one of claims 1-6 , wherein the first Tau B cell epitope comprises or consists of SEQ ID NO: 7.
12 . The composition or kit according to any one of claims 1-6 , wherein the first Tau B cell epitope is selected from SEQ ID No: 1 or SEQ ID NO:2, and the second Tau B cell epitope is selected from SEQ ID NOs: 7 and 72-76.
13 . The composition or kit according to any one of claims 1-6 , wherein the first Tau B cell epitope comprises or consists of SEQ ID NO: 2, and the second Tau B cell epitope comprises or consists of SEQ ID NO: 7.
14 . The composition or kit according to any one of claims 1-13 , wherein the amyloid beta B cell epitope is selected from SEQ ID NOs: 69 and 82-88.
15 . The composition or kit according to any one of claims 1-13 , wherein the amyloid beta B cell epitope comprises or consists of SEQ ID NO: 69 or SEQ ID NO: 82.
16 . The composition or kit according to any one of claims 1-15 , wherein the first Tau peptide immunogen construct comprises a first heterologous T helper (Th) epitope, the second Tau peptide immunogen construct, if present, comprises a second heterologous Th epitope, and the amyloid beta peptide immunogen construct, if present, comprises a third heterologous Th epitope.
17 . The composition or kit according to claim 16 , wherein the first heterologous Th epitope, the second heterologous Th epitope and the third heterologous Th epitope is each independently selected from SEQ ID NOs: 31-59 and 97.
18 . The composition or kit according to claim 16 , wherein the first heterologous Th epitope, the second heterologous Th epitope and the third heterologous Th epitope is each independently selected from SEQ ID NOs: 42, 44, 45 and 97.
19 . The composition or kit according to claim 16 , wherein each of the first heterologous Th epitope, the second heterologous Th epitope and the third heterologous Th epitope has SEQ ID NO: 44.
20 . The composition or kit of any one of claims 1-19 , wherein the first heterologous Th epitope and the first Tau B cell epitope, the second heterologous Th epitope and the second Tau B cell epitope, and the third heterologous Th epitope and the amyloid beta B cell epitope, are each covalently linked directly or through a heterologous spacer.
21 . The composition or kit of claim 20 , which comprises the heterologous spacer linking the first heterologous Th epitope and the first Tau B cell epitope, the second heterologous Th epitope and the second Tau B cell epitope, and/or the third heterologous Th epitope and amyloid beta B cell epitope.
22 . The composition or kit of claim 21 , wherein the heterologous spacer comprises one or more amino acids.
23 . The composition or kit of claim 22 , wherein the one or more amino acids is Lys-, Gly-, Lys-Lys-Lys-, (α, ε-N)Lys, Lys-Lys-Lys-ε-Lys (SEQ ID NO: 95), or ε-Lys-Lys-Lys-Lys (SEQ ID NO: 62).
24 . The composition or kit of claim 22 , wherein the one or more amino acids is Lys-Lys-Lys-ε-Lys (SEQ ID NO: 95) or ε-N-Lys-Lys-Lys-Lys (SEQ ID NO: 62).
25 . The composition or kit according to any one of claims 1-24 , wherein the first Tau peptide immunogen construct and, if present, the second Tau peptide immunogen construct, is represented by the formulae:
wherein
Th is a heterologous T helper epitope;
A is a heterologous spacer;
(Tau fragment) is a B cell epitope having 6 to about 40 amino acid residues from the full-length Tau protein of SEQ ID NO: 60; optionally wherein the B cell epitope has about 10 to about 40 amino acid residues from the full-length Tau protein of SEQ ID NO: 60;
X is an α-COOH or α-CONH 2 of an amino acid;
m is from 1 to about 4; and
n is from 0 to about 10.
26 . The composition or kit according to any one of claims 1-25 , wherein the amyloid beta peptide immunogen construct is represented by the formulae:
wherein
Th is a heterologous T helper epitope;
A is a heterologous spacer;
(Aβ fragment) is a B cell epitope having 6 to about 42 amino acid residues from the full-length Aβ protein of SEQ ID NO: 68; optionally wherein the B cell epitope has about 10 to about 42 amino acid residues from the full-length Aβ protein of SEQ ID NO: 68;
X is an α-COOH or α-CONH 2 of an amino acid;
m is from 1 to about 4; and
n is from 0 to about 10.
27 . The composition or kit according to any one of claims 1-26 , wherein the first Tau peptide immunogen construct comprises the first heterologous Th epitope covalently linked to the carboxyl terminus of the first Tau B cell epitope, the second Tau peptide immunogen construct comprises the second heterologous Th epitope covalently linked to the amino terminus of the second Tau B cell epitope, and/or the amyloid beta peptide immunogen construct comprises the third heterologous Th epitope covalently linked to the carboxyl terminus of the amyloid beta B cell epitope.
28 . The composition or kit according to any one of claims 1-27 , wherein the first Tau peptide immunogen construct and the second Tau peptide immunogen construct are selected from SEQ ID NOs: 9-16 and 77-81, or a construct in which the positions of the peptide cell epitope and the Th epitope are reversed.
29 . The composition or kit according to any one of claims 1-28 , wherein the first Tau peptide immunogen construct comprises or consists of the amino acid sequence of SEQ ID NO: 10 or SEQ ID NO: 15.
30 . The composition or kit according to any one of claims 1-29 , wherein the first Tau peptide immunogen construct comprises or consists of the amino acid sequence of SEQ ID NO: 10, and the second Tau peptide immunogen construct comprises or consists of the amino acid sequence of SEQ ID NO: 15.
31 . The composition or kit according to any one of claims 1-28 , wherein the first Tau peptide immunogen construct and/or the second Tau peptide immunogen construct is selected from SEQ ID NOs: 77-81, optionally wherein the first Tau peptide immunogen construct has the amino acid sequence of SEQ ID NO: 10 and the second Tau peptide immunogen construct is selected from SEQ ID NOs: 77-81.
32 . The composition or kit according to any one of claims 1-31 , wherein the amyloid beta peptide immunogen construct is selected from SEQ ID Nos: 70, 71 and 89, or a construct in which the positions of the B cell epitope and the Th epitope are reversed.
33 . The composition or kit according to claim 32 , wherein the amyloid beta peptide immunogen construct comprises or consists of SEQ ID NO: 70.
34 . The composition or kit according to claim 32 , wherein the amyloid beta peptide immunogen construct comprises or consists of SEQ ID NO: 89.
35 . A Tau peptide immunogen construct comprising a B cell epitope comprising an amino acid sequence selected from any one of SEQ ID NOs: 72-76.
36 . The Tau peptide immunogen construct of claim 35 , which is represented by the formulae:
wherein
Th is a heterologous T helper epitope;
A is a heterologous spacer;
(the B cell epitope) comprises, essentially consists of, or consists of an amino acid sequence selected from any one of SEQ ID NOs: 72-76;
X is an α-COOH or α-CONH 2 of an amino acid;
m is from 1 to about 4; and
n is from 0 to about 10.
37 . The Tau peptide immunogen construct of claim 35 comprising an amino acid sequence selected from any one of SEQ ID NOs: 77-81.
38 . An amyloid beta peptide immunogen construct comprising a B cell epitope comprising, essentially consisting of, or consisting of an amino acid sequence of SEQ ID NO: 82.
39 . The amyloid beta peptide immunogen construct of claim 38 , which is represented by the formulae:
wherein
Th is a heterologous T helper epitope;
A is a heterologous spacer;
(the B cell epitope) comprises, essentially consists of, or consists of the amino acid sequence of SEQ ID NO: 82;
X is an α-COOH or α-CONH 2 of an amino acid;
m is from 1 to about 4; and
n is from 0 to about 10.
40 . The amyloid beta peptide immunogen construct of claim 38 comprising, essentially consisting of, or consisting of the amino acid sequence of SEQ ID NO: 89.
41 . A composition or kit comprising the Tau peptide immunogen construct according to any one of claims 35 to 37 .
42 . A composition or kit comprising the amyloid beta peptide immunogen construct according to any one of claims 38 to 40 .
43 . The composition or kit according to any one of claims 1-34, 41 and 42 , which is a single composition comprising the first Tau peptide immunogen construct, and at least one of: the second Tau peptide immunogen construct and the amyloid beta peptide immunogen construct.
44 . The composition or kit according to any one of claims 1-34, 41 and 42 , which is a kit comprising the first Tau peptide immunogen construct, and at least one of: the second Tau peptide immunogen construct and the amyloid beta peptide immunogen construct.
45 . The composition or kit according to claim 44 , wherein, prior to administration to a subject, the components of the kit are mixed to create a single composition comprising the first Tau peptide immunogen construct, and at least one of: the second Tau peptide immunogen construct and the amyloid beta peptide immunogen construct.
46 . The composition or kit according to claim 44 , wherein the components of the kit are used to create a first composition comprising the first Tau peptide immunogen construct, and a second composition comprising at least one of: the second Tau peptide immunogen construct and the amyloid beta peptide immunogen construct.
47 . A pharmaceutical composition comprising the composition according to any one of claims 43, 45 or 46 , and a pharmaceutically acceptable delivery vehicle and/or adjuvant.
48 . The pharmaceutical composition of claim 47 , wherein the first Tau peptide immunogen construct, the second Tau peptide immunogen construct and/or the amyloid beta peptide immunogen construct are mixed with an CpG oligodeoxynucleotide (ODN) to form a stabilized immunostimulatory complex.
49 . The pharmaceutical composition of claim 47 or 48 , which comprises 3 or 4 of Tau peptide immunogen constructs.
50 . The pharmaceutical composition of claim 47, 48 or 49 , which comprises more than one amyloid beta peptide immunogen constructs.
51 . An isolated antibody or epitope-binding fragment thereof that specifically binds to the B cell epitope of the Tau peptide immunogen construct or the amyloid beta peptide immunogen construct obtained by administering to a mammal the composition or the compositions according to any one of claims 43, 45, and 46-50 , or the peptide immunogen construct according to any one of claims 35 to 40 .
52 . The isolated antibody or epitope-binding fragment thereof according to claim 51 bound to the Tau peptide immunogen construct or the amyloid beta peptide immunogen construct.
53 . A composition comprising the isolated antibody or epitope-binding fragment thereof according to claim 51 or 52 .
54 . A method of preventing, inhibiting, reducing the severity of, delaying, or treating a tauopathy in a subject, the method comprising administering to the subject the Tau peptide immunogen construct, the amyloid beta peptide immunogen construct, the composition or the compositions according to any one of the preceding claims .
55 . The method of claim 54 , which comprises administering the composition wherein the first Tau peptide immunogen construct and at least one of the second Tau peptide immunogen construct and the amyloid beta peptide immunogen construct are comprised within a single composition.
56 . A method of preventing, inhibiting, reducing the severity of, delaying, or treating a tauopathy in a subject, the method comprising administering to the subject: a first Tau peptide immunogen construct comprising a first Tau B cell epitope comprising or consisting of 6 to about 40 amino acid residues from the full-length Tau protein of SEQ ID NO: 60; and
(i) a second Tau peptide immunogen construct comprising a second Tau B cell epitope comprising or consisting of 6 to about 40 amino acid residues from the full-length Tau protein of SEQ ID NO: 60, wherein the second B cell epitope is not the same as the first B cell epitope, and/or
(ii) an amyloid beta (Aβ) peptide immunogen construct comprising an amyloid beta B cell epitope comprising or consisting of 6 to about 42 amino acid residues from the full-length amyloid beta protein of SEQ ID NO: 68; and
wherein the first Tau peptide immunogen construct, and the second Tau peptide immunogen construct and/or the amyloid beta peptide immunogen construct, are comprised within separate compositions, which are administered separately.
57 . The method according to any one of claims 54-56 , 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.
58 . The method according to any one of claims 54-57 , wherein the tauopathy is Alzheimer's disease.
59 . The method of any one of claims 54-58 , wherein the subject is a human.