JPWO2020163730A5

JPWO2020163730A5 -

Info

Publication number: JPWO2020163730A5
Application number: JP2021546263A
Authority: JP
Publication date: 2023-02-15

Description

Listed below are the inventions originally claimed in this application.
[Invention 1]
A method of inducing anti-phospho-tau antibodies in a human subject in need thereof without inducing severe adverse events comprising a toll-like receptor 4 agonist and SEQ ID NOs: 1-3 and 5 to said subject an effective amount of a liposome comprising a tau phosphopeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 12, wherein said tau phosphopeptide is in an amount of about 25 nmole to about 750 nmole per dose. and wherein said tau phosphopeptide is presented on the surface of said liposome.
[Invention 2]
The invention, wherein the tau phosphopeptide consists of 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, preferably the tau phosphopeptide consists of the amino acid sequence of SEQ ID NO:28. 1. The method according to 1.
[Invention 3]
wherein said effective amount of liposomes comprises 100 μg to 2500 μg of said tau phosphopeptide per dose, preferably 300 μg to 2400 μg per dose, 300 μg to 1800 μg per dose, or 300 μg to 900 μg of said tau phosphopeptide per dose; The method according to invention 1 or 2.
[Invention 4]
4. The method of invention 3, wherein said effective amount of liposomes comprises 300 μg per dose, 900 μg per dose, 1800 μg per dose, or 2400 μg per dose of said tau phosphopeptide.
[Invention 5]
5. The method of any one of inventions 1-4, wherein said liposomes are administered subcutaneously.
[Invention 6]
5. The method of any one of inventions 1-4, wherein said liposomes are administered intramuscularly.
[Invention 7]
7. The method of any one of inventions 1-6, further comprising administering a second dose of said effective amount of liposomes to said subject 1-24 weeks after the initial administration.
[Invention 8]
8. The method of any one of inventions 1-7, wherein said liposome further comprises a helper T cell epitope and a lipidated CpG oligonucleotide.
[Invention 9]
said lipidated CpG oligonucleotide has a nucleotide sequence selected from the group consisting of SEQ ID NO: 18-SEQ ID NO: 22, said CpG oligonucleotide has one or more phosphorothioate internucleotide linkages, said CpG oligonucleotide comprises A method according to invention 8, wherein the at least one lipophilic group is covalently linked, optionally via a PEG linker.
[Invention 10]
10. The method of claim 9, wherein said CpG oligonucleotide is covalently linked to at least one lipophilic group via a PEG linker.
[Invention 11]
The liposomes are composed of 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC), 1,2-dimyristoyl-sn-glycero-3-phosphoryl-3'-rac-glycerol (DMPG), and cholesterol. 11. The method according to any one of inventions 1 to 10, further comprising one or more lipids selected from the group consisting of:
[Invention 12]
Inventions 8-11, wherein said helper T cell epitope comprises at least one amino acid sequence selected from the group consisting of SEQ ID NOs: 13-17, SEQ ID NOs: 23-26, and SEQ ID NOs: 39-44 The method according to any one of
[Invention 13]
13. The method of any one of inventions 8-12, wherein said effective amount of liposomes comprises an amount of said helper T cell epitope from about 2 nmole to about 110 nmole per dose.
[Invention 14]
Said effective amount of liposomes is SEQ ID NO: 13-SEQ ID NO: 17, SEQ ID NO: 23-SEQ ID NO: 26, and SEQ ID NO: 39-44 in an amount of 25 μg to 620 μg per dose, preferably 75 μg to 450 μg per dose. any of inventions 8 to 13, wherein said helper T cell epitope has an amino acid sequence selected from the group consisting of, preferably said helper T cell epitope is a T50 helper T cell epitope consisting of the amino acid sequence of SEQ ID NO: 13 The method described in one.
[Invention 15]
Said effective amount of liposomes comprises said toll-like receptor 4 agonist in an amount of 30 μg to 900 μg per dose, preferably 100 μg to 585 μg per dose, preferably said toll-like receptor 4 agonist is monophosphoryl hexaacyl lipid A, The method according to any one of Inventions 1 to 14, which is 3-deacylation.
[Invention 16]
said lipidated CpG oligonucleotide having a nucleotide sequence selected from the group consisting of SEQ ID NO: 18 to SEQ ID NO: 22, wherein said effective amount of liposomes is in an amount of 50 μg to 1250 μg per dose, preferably 150 μg to 800 μg per dose. and preferably said lipidated CpG oligonucleotide consists of the nucleotide sequence of SEQ ID NO:18.
[Invention 17]
The liposome is
(1) the tau phosphopeptide having the amino acid sequence of SEQ ID NO: 28;
(2) monophosphoryl hexaacyl lipid A, said toll-like receptor 4 agonist comprising 3-deacylated;
(3) the helper T cell epitope comprising the amino acid sequence of SEQ ID NO:39;
(4) said lipidated CpG oligonucleotide comprising the nucleotide sequence of SEQ ID NO: 18, and
(5) consisting of 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC), 1,2-dimyristoyl-sn-glycero-3-phosphoryl-3′-rac-glycerol (DMPG), and cholesterol at least one lipid selected from the group
17. The method according to any one of inventions 1 to 16, comprising
[Invention 18]
according to any one of inventions 1 to 17, wherein said subject is in need of treatment for Alzheimer's disease, preferably early Alzheimer's disease, mild cognitive impairment (MCI) due to Alzheimer's disease, or mild to moderate Alzheimer's disease described method.

Claims

A liposome for use in a method of inducing anti-phospho-tau antibodies in a human subject in need thereof without inducing severe adverse events, said method comprising: a toll-like receptor 4 agonist; administering to the subject an effective amount of the liposome comprising a tau phosphopeptide comprising an amino acid sequence selected from the group consisting of: Nos. 1 to 3 and 5 to 12; is administered in an amount of about 25 nmole to about 750 nmole per dose, and said tau phosphopeptide is presented on the surface of said liposome .

wherein said tau phosphopeptide consists of an amino acid sequence selected from the group consisting of SEQ ID NO:27-SEQ ID NO:29 and SEQ ID NO:31-38, preferably said tau phosphopeptide consists of the amino acid sequence of SEQ ID NO:28; Item 1. The liposome according to item 1.

wherein said effective amount of liposomes comprises 100 μg to 2500 μg of said tau phosphopeptide per dose, preferably 300 μg to 2400 μg per dose, 300 μg to 1800 μg per dose, or 300 μg to 900 μg of said tau phosphopeptide per dose; A liposome according to claim 1 or 2.

4. The liposome of claim 3, wherein said effective amount of liposomes comprises 300 μg per dose, 900 μg per dose, 1800 μg per dose, or 2400 μg per dose of said tau phosphopeptide.

5. The liposome of any one of claims 1-4, wherein said liposome is administered subcutaneously.

5. A liposome according to any one of claims 1-4, wherein said liposome is administered intramuscularly.

7. The liposome of any one of claims 1-6, further comprising administering a second dose of said effective amount of liposomes to said subject 1 to 24 weeks after the initial administration.

8. The liposome of any one of claims 1-7, wherein said liposome further comprises a helper T-cell epitope and a lipidated CpG oligonucleotide.

said lipidated CpG oligonucleotide has a nucleotide sequence selected from the group consisting of SEQ ID NO: 18-SEQ ID NO: 22, said CpG oligonucleotide has one or more phosphorothioate internucleotide linkages, said CpG oligonucleotide comprises 9. A liposome according to claim 8, covalently linked to at least one lipophilic group, optionally via a PEG linker.

10. The liposome of claim 9, wherein said CpG oligonucleotide is covalently linked to at least one lipophilic group via a PEG linker.

The liposomes are composed of 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC), 1,2-dimyristoyl-sn-glycero-3-phosphoryl-3'-rac-glycerol (DMPG), and cholesterol. 11. The liposome of any one of claims 1-10, further comprising one or more lipids selected from the group consisting of:

9. from claim 8, wherein said helper T cell epitope comprises at least one amino acid sequence selected from the group consisting of SEQ ID NOs: 13-17, SEQ ID NOs: 23-26, and SEQ ID NOs: 39-44 12. Liposome according to any one of 11.

13. The liposome of any one of claims 8-12, wherein said effective amount of liposomes comprises an amount of said helper T cell epitope per dose of about 2 nmole to about 110 nmole.

Said effective amount of liposomes is SEQ ID NO: 13-SEQ ID NO: 17, SEQ ID NO: 23-SEQ ID NO: 26, and SEQ ID NO: 39-44 in an amount of 25 μg to 620 μg per dose, preferably 75 μg to 450 μg per dose. 14. Any of claims 8 to 13, comprising said helper T cell epitope having an amino acid sequence selected from the group consisting of: or the liposome according to claim 1.

Said effective amount of liposomes comprises said toll-like receptor 4 agonist in an amount of 30 μg to 900 μg per dose, preferably 100 μg to 585 μg per dose, preferably said toll-like receptor 4 agonist is monophosphoryl hexaacyl lipid A liposome according to any one of claims 1 to 14, which is A,3-deacylated.

said lipidated CpG oligonucleotide having a nucleotide sequence selected from the group consisting of SEQ ID NO: 18 to SEQ ID NO: 22, wherein said effective amount of liposomes is in an amount of 50 μg to 1250 μg per dose, preferably 150 μg to 800 μg per dose. and preferably said lipidated CpG oligonucleotide consists of the nucleotide sequence of SEQ ID NO:18.

The liposome is
(1) the tau phosphopeptide having the amino acid sequence of SEQ ID NO: 28;
(2) monophosphoryl hexaacyl lipid A, said toll-like receptor 4 agonist comprising 3-deacylated;
(3) the helper T cell epitope comprising the amino acid sequence of SEQ ID NO:39;
(4) said lipidated CpG oligonucleotide comprising the nucleotide sequence of SEQ ID NO: 18, and (5) 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC), 1,2-dimyristoyl-sn-glycero -3-phosphoryl-3'-rac-glycerol (DMPG), and at least one lipid selected from the group consisting of cholesterol.

18. Any one of claims 1 to 17, wherein the subject is in need of treatment for Alzheimer's disease, preferably early Alzheimer's disease, mild cognitive impairment (MCI) due to Alzheimer's disease, or mild to moderate Alzheimer's disease. Liposomes according to.