Heterologous administration of tau vaccines
Inventors
Ramsburg, Elizabeth Anne • De Marco, Donata • Anish, Chakkumkal • Sadaka, Charlotte • Goudsmit, Jaap • Muhs, Andreas • Pihlgren Bosch, Maria • Vukicevic Verhille, Marija • Hickman, David • Piot, Nicolas • Ghimire, Saroj Raj
Assignees
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Publication Number
US-11591377-B2
Publication Date
2023-02-28
Expiration Date
Abstract
Methods for inducing an immune response against tau protein in a subject suffering from a neurodegenerative disease, disorder or condition, such as Alzheimer's Disease, are described. The methods include administering a liposomal priming composition containing tau peptides, preferably phosphorylated tau peptides, and a conjugate boosting composition containing tau peptides, preferably phosphorylated tau peptides, conjugated to an immunogenic carrier.
Core Innovation
The invention relates to inducing antibodies against phosphorylated Tau and enriched paired helical filaments (ePHFs) in a subject in need thereof. It includes administering a priming composition comprising a liposome that presents a first tau phosphopeptide on the surface together with a helper T-cell epitope, a lipidated CpG oligonucleotide, and an adjuvant containing a toll-like receptor 4 ligand, with a pharmaceutically acceptable carrier.
Following priming, the invention includes administering a first boosting composition comprising a conjugate of a second tau phosphopeptide and an immunogenic carrier conjugated thereto via a linker. The immunogenic carrier is selected from KLH, tetanus toxoid, CRM197, or an outer membrane protein mixture from N. meningitidis (OMP) or a derivative thereof, and the boosting composition further comprises a pharmaceutically acceptable carrier.
The first tau phosphopeptide and the second tau phosphopeptide each independently comprise amino acid sequences selected from specified SEQ ID NO ranges, including SEQ ID NO: 1 to SEQ ID NO: 3, SEQ ID NO: 5 to SEQ ID NO: 12, and other defined groups of SEQ ID NO ranges. The regimen is directed to phosphorylated Tau, including ePHFs, and is associated with neurodegenerative diseases and tauopathies including neurofibrillary lesions, Alzheimer’s disease, and mild AD/MCI in specified contexts.
Claims Coverage
The provided dataset includes four independent claims. The claims center on a two-stage immunization regimen with a liposome-based priming composition followed by a conjugate-based boosting composition, with sequence selections and boosting schedule variants.
Liposome priming with surface-presented phospho-tau plus T-cell epitope, lipidated CpG, and TLR4 ligand adjuvant
Administering a priming composition comprising an immunologically effective amount of a liposome that includes a first tau phosphopeptide presented on the surface, a helper T-cell epitope, a lipidated CpG oligonucleotide, and an adjuvant containing a toll-like receptor 4 ligand, with a pharmaceutically acceptable carrier.
Conjugate boosting with second phospho-tau linked to an immunogenic carrier via a linker
Administering a first boosting composition comprising an immunologically effective amount of a conjugate comprising a second tau phosphopeptide and an immunogenic carrier conjugated thereto via a linker, where the carrier is selected from KLH, tetanus toxoid, CRM197, or an outer membrane protein mixture from N. meningitidis (OMP) or a derivative thereof, with a pharmaceutically acceptable carrier.
Defined phospho-tau and epitope sequence selections for priming and boosting
The method where the first tau phosphopeptide and the second tau phosphopeptide each independently comprise an amino acid sequence selected from SEQ ID NO: 1 to SEQ ID NO: 3 and SEQ ID NO: 5 to SEQ ID NO: 12; and in other embodiments includes a first tau phosphopeptide selected from SEQ ID NO: 27 to SEQ ID NO: 29 or SEQ ID NO: 31 to SEQ ID NO: 38, a helper T cell epitope selected from SEQ ID NO: 39 to SEQ ID NO: 44, and a boosting conjugate in which n is an integer of 3 to 7 and VYKS(p)PVVSGDTS(p)PRHL-CONH2 comprises the phospho-tau peptide of SEQ ID NO: 2.
Boosting schedule including additional boosting administrations
Administering the first boosting composition or a second boosting composition comprising an immunologically effective amount of the liposome and a pharmaceutically acceptable carrier, including embodiments specifying repeated administration of the first boosting composition and/or the second boosting composition.
The independent claims collectively cover a surface-presenting liposome priming composition followed by boosting with a conjugate of a second tau phosphopeptide linked to an immunogenic carrier via a linker, together with sequence selections and boosting schedule variants.
Stated Advantages
Increased epitope coverage and stronger immune responses than homologous regimens.
Documented Applications
Inducing antibodies in a subject against phosphorylated Tau and enriched paired helical filaments (ePHFs).
Use in a subject having a neurodegenerative disease or disorder associated with neurofibrillary lesions.
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