Heterologous administration of tau vaccines

Patent metadata

Field	Value
Publication number	US-2020339643-A1
Application number	US-202016856400-A
Country	US
Kind code	A1
Filing date	Apr 23, 2020
Priority date	Apr 24, 2019
Publication date	Oct 29, 2020
Grant 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.

First claim

1 . A method of inducing antibodies against at least one of phosphorylated Tau and enriched paired helical filaments (ePHFs) in a subject in need thereof, the method comprising:
(i) administering to the subject a priming composition comprising an immunologically effective amount of a liposome comprising:
a. a first tau phosphopeptide;
b. a helper T-cell epitope;
c. a lipidated CpG oligonucleotide; and
d. an adjuvant containing a toll-like receptor 4 ligand;
 wherein the tau phosphopeptide is presented on the surface of the liposome, and the priming composition further comprises a pharmaceutically acceptable carrier; and (ii) administering to the subject 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, the conjugate having the structure of formula (I):

or having the structure of formula (II):

wherein
x is an integer of 0 to 10, preferably 2 to 6, most preferably 3;
n is an integer of 3 to 15, preferably 3 to 12;
Tau peptide represents the second tau phosphopeptide; and
Carrier represents the immunogenic carrier selected from the group consisting of keyhole limpet hemocyanin (KLH), tetanus toxoid, CRM197 and an outer membrane protein mixture from N. meningitidis (OMP), or a derivative thereof; and
the first boosting composition further comprises a pharmaceutically acceptable carrier;

wherein the first tau phosphopeptide and the second tau phosphopeptide each independently comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 1 to SEQ ID NO: 3 and SEQ ID NO: 5 to SEQ ID NO: 12.

2 . The method of claim 1 , wherein:
the liposome comprises:
a. the first tau phosphopeptide having an amino acid sequence selected from the group consisting of SEQ ID NO: 27 to SEQ ID NO: 29 and SEQ ID NO: 31 to SEQ ID NO: 38;
b. the helper T cell epitope having an amino acid sequence selected from the group consisting of SEQ ID NO: 39 to SEQ ID NO: 44, preferably, the helper T cell epitope consisting of an amino acid sequence selected from the group consisting of SEQ ID NO: 13 to SEQ ID NO: 17;
c. the lipidated CpG oligonucleotide having a nucleotide sequence selected from the group consisting of SEQ ID NO: 18 to SEQ ID NO: 22, wherein the CpG oligonucleotide comprises one or more phosphorothioate internucleotide linkages, and the CpG oligonucleotide is covalently linked to at least one cholesterol via a linker; and
d. monophosphoryl lipid A (MPLA); and
the conjugate comprises the second tau phosphopeptide having an amino acid sequence selected from the group consisting of SEQ ID NO: 1 to SEQ ID NO: 3 or SEQ ID NO: 5 to SEQ ID NO: 12 conjugated to CRM197 via the linker.

3 . The method of claim 1 , wherein the conjugate has the structure of:

wherein n is an integer of 3 to 7.

4 . A method for inducing antibodies against at least one of phosphorylated Tau and enriched paired helical filaments (ePHFs) in a subject in need thereof, the method comprising:
administering to the subject a priming composition comprising an immunologically effective amount of a liposome comprising:
a. a first tau phosphopeptide having an amino acid sequence selected from the group consisting of SEQ ID NO: 27 to SEQ ID NO: 29 or SEQ ID NO: 31 to SEQ ID NO: 38;
b. a helper T cell epitope having an amino acid sequence selected from the group consisting of SEQ ID NO: 39 to SEQ ID NO: 44, preferably, the helper T cell epitope consisting of an amino acid sequence selected from the group consisting of SEQ ID NO: 13 to SEQ ID NO: 17;
c. a lipidated CpG oligonucleotide having a nucleotide sequence selected from the group consisting of SEQ ID NO: 18 to SEQ ID NO: 22, wherein the CpG oligonucleotide comprises one or more phosphorothioate internucleotide linkages, and the CpG oligonucleotide is covalently linked to at least one cholesterol via a linker; and
d. monophosphoryl lipid A (MPLA);
 wherein the first tau phosphopeptide is presented on the surface of the liposome, and the priming composition further comprises a pharmaceutically acceptable carrier; and (ii) administering to the subject 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, the conjugate having the structure of:

wherein n is an integer of 3 to 7, and the first boosting composition further comprises a pharmaceutically acceptable carrier.

5 . A method for inducing antibodies against at least one of phosphorylated Tau and enriched paired helical filaments (ePHFs) in a subject in need thereof, the method comprising
(i) administering to the subject a priming composition comprising an immunologically effective amount of a liposome comprising:
(1) a first tau phosphopeptide having the amino acid sequence of SEQ ID NO:28;
(2) a toll-like receptor 4 agonist comprising monophosphoryl hexa-acyl Lipid A, 3-deacyl;
(3) a helper T-cell epitope comprising the amino acid sequence of SEQ ID NO: 39;
(4) a lipidated CpG oligonucleotide comprising the nucleotide sequence of SEQ ID NO:18; and
(5) at least one lipid selected from the group consisting of 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC), 1,2-dimyristoyl-sn-glycero-3-phosphoryl-3′-rac-glycerol (DMPG), and cholesterol,
 wherein the first tau phosphopeptide is presented on the surface of the liposome, and the priming composition further comprises a pharmaceutically acceptable carrier; and (ii) administering to the subject 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, the conjugate having the structure of:

wherein n is an integer of 3 to 7, and the first boosting composition further comprises a pharmaceutically acceptable carrier.

6 . The method of claim 1 , further comprising administering the first boosting composition to the subject at least once after the initial administration of the first boosting composition.

7 . The method of claim 1 , further comprising administering to the subject a second boosting composition comprising an immunologically effective amount of the liposome and a pharmaceutically acceptable carrier.

8 . The method of claim 7 , further comprising administering to the subject the second boosting composition at least once after the initial administration of the second boosting composition.

9 . A method for inducing antibodies against at least one of phosphorylated Tau and enriched paired helical filaments (ePHFs) in a subject in need thereof, the method comprising
(i) administering to the subject a priming composition comprising an immunologically effective amount of a liposome comprising:
(1) a first tau phosphopeptide having the amino acid sequence of SEQ ID NO:28;
(2) a toll-like receptor 4 agonist comprising monophosphoryl hexa-acyl Lipid A, 3-deacyl;
(3) a helper T-cell ep

Assignees

• Janssen Pharmaceuticals Inc
• Ac Immune Sa

Inventors

• Ramsburg Elizabeth Anne
• De Marco Donata
• Chakkumkal Anish
• Sadaka Charlotte
• Goudsmit Jaap
• Muhs Andreas
• Pihlgren Bosch Maria
• Vukicevic Verhille Marija
• Hickman David
• Piot Nicolas
• Ghimire Saroj Raj

Classifications

• A61K2039/627

  characterised by the linker · CPC title

• A61K2039/6068

  Other bacterial proteins, e.g. OMP · CPC title

• A61K2039/6018

  Lipids, e.g. in lipopeptides · CPC title

• A61K2039/575

  humoral response · CPC title

• A61K2039/55572

  Lipopolysaccharides; Lipid A; Monophosphoryl lipid A · CPC title