Anti-tau antibody and use thereof

Abstract

This invention relates to anti-tau antibodies that specifically bind to tau protein and their uses. The anti-tau antibody of this invention specifically binds to tau protein, wherein the 280th lysine is acetylated, and inhibits the aggregation of abnormal tau protein. Furthermore, in the case of administering the anti-tau antibody of this invention to animal models of dementia, the anti-tau antibody can improve the motor and cognitive abilities of the animal models. Accordingly, the anti-tau antibody of this invention can be effectively used for the prevention or treatment of degenerative neurological diseases.

Description

[Technical Field] This invention relates to anti-tau antibodies that specifically bind to tau protein and their uses. [Previous Technology] Alzheimer's disease accounts for about 50% of all dementia cases. It is a degenerative cranial nerve disease, and its incidence rate has been on the rise since age 65. With the aging of the population, it is growing rapidly worldwide. It is believed that the pathogenesis of Alzheimer's disease is primarily attributed to the accumulation of β-amyloid protein caused by presenilin 1, hyperphosphorylation of tau protein, or increased production of β-amyloid protein. Among these, the neurotoxicity caused by β-amyloid protein accumulation is considered a major cause of Alzheimer's dementia (Hardy AJ et al., Science, 256, 184-185, 1992). However, the Phase III clinical trial of solanezumab, a candidate drug for Alzheimer's disease developed by Eli Lilly and Company, failed because the neurotoxicity caused by β-amyloid protein accumulation was not significant. Therefore, the focus has shifted to the idea that abnormal hyperphosphorylation of tau protein is the primary cause of Alzheimer's disease. Tau protein is a protein that stabilizes microtubules, which are proteins that transport cellular materials. Six isoforms of tau protein exist in the human body, and it is abundant in neurons of the central nervous system. Furthermore, in cases of tau protein mutation, hyperphosphorylation occurs, leading to an abnormal accumulation of neurofibrillary tangles (NFTs) in nerve cells, resulting in degenerative neurological diseases such as dementia and Parkinson's disease (Dong Hee Choie et al., Brain & NeuroRehabilitation, 4, 21-29, 2011). However, the human tau protein, composed of 441 amino acids, can undergo a wide range of post-translational modifications, making it difficult to identify target sites within the tau protein that could prevent or treat dementia. This variety of modifications also presents challenges in developing therapeutic agents. [Summary of the Invention] Technical issues Accordingly, the inventors researched and developed an effective therapeutic agent for degenerative neurological diseases. As a result, the inventors discovered an antibody that specifically binds to a fragment of tau protein, wherein the 280th lysine is acetylated to reduce tau protein aggregation. Furthermore, the inventors found that in animal models of dementia, the animal models administered the antibody exhibited improved motor and cognitive abilities, thus completing this invention. Questions and Answers To address the aforementioned problems, one embodiment of the present invention provides an anti-tau antibody or its antigen-binding fragment, comprising a heavy chain variable region (VH) including a heavy chain CDR1 having the amino acid sequence shown in SEQ ID NO: 1; a heavy chain CDR2 having the amino acid sequence shown in SEQ ID NO: 2; and a heavy chain CDR3 having the amino acid sequence shown in SEQ ID NO: 3; and a light chain variable region (VL) including a light chain CDR1 having the amino acid sequence shown in SEQ ID NO: 4; a light chain CDR2 having the amino acid sequence shown in SEQ ID NO: 5; and a light chain CDR3 having the amino acid sequence shown in SEQ ID NO: 6. In another embodiment of the invention, a polynucleotide is provided that encodes an anti-tau antibody or its antigen-binding fragment, or a heavy chain variable region and / or a light chain variable region of an anti-tau antibody. In another embodiment of the invention, an expression vector comprising polynucleotides is provided. In yet another embodiment of the invention, a host cell is provided in which an expression vector system is introduced. In yet another aspect of the invention, a method for generating anti-tau antibodies or antigen-binding fragments thereof is provided, comprising the step of culturing host cells. In yet another embodiment of the present invention, a fusion nodule with accession number KCTC 14155BP is provided. In yet another embodiment of the invention, a pharmaceutical composition for the prevention or treatment of degenerative neurological diseases is provided, comprising an anti-tau antibody or an antigen-binding fragment thereof as an active ingredient. In yet another aspect of the invention, a composition for diagnosing degenerative neurological diseases is provided, comprising an anti-tau antibody or an antigen-binding fragment thereof. In yet another embodiment of the invention, a kit for the prevention, treatment, or diagnosis of degenerative neurological diseases is provided, comprising an antibody or its antigen-binding fragment, a polynucleotide, an expression vector, or a host cell. Beneficial effects of the invention. The anti-tau antibody of this invention specifically binds to tau protein, wherein the 280th lysine is acetylated, and inhibits the aggregation of abnormal tau protein. Furthermore, in animal models of dementia induced by the anti-tau antibody of this invention, the anti-tau antibody can improve the motor and cognitive abilities of the animal models. Accordingly, the anti-tau antibody of this invention can be effectively used for the prevention or treatment of degenerative neurological diseases.

Implementation Method

Claims

1. An anti-tau antibody or an antigen-binding fragment thereof, comprising: a heavy chain variable region (VH) including a heavy chain CDR1 composed of an amino acid sequence shown in SEQ ID NO: 1; a heavy chain CDR2 composed of an amino acid sequence shown in SEQ ID NO: 2; and a heavy chain CDR3 composed of an amino acid sequence shown in SEQ ID NO: 3; and a light chain variable region (VL) including a light chain CDR1 composed of an amino acid sequence shown in SEQ ID NO: 4; a light chain CDR2 composed of an amino acid sequence shown in SEQ ID NO: 5; and a light chain CDR3 composed of an amino acid sequence shown in SEQ ID NO: 6, wherein the antibody or antigen-binding fragment thereof is selected from any of the following group: an anti-tau antibody or an antigen-binding fragment thereof comprising a heavy chain variable region having an amino acid sequence shown in SEQ ID NO: 7 and a light chain variable region having an amino acid sequence shown in SEQ ID NO: 12; The following are descriptions of anti-tau antibodies or antigen-binding fragments thereof: Anti-tau antibody comprising a heavy chain variable region having an amino acid sequence as shown in SEQ ID NO: 8 and a light chain variable region having an amino acid sequence as shown in SEQ ID NO: 13; Anti-tau antibody or antigen-binding fragment thereof comprising a heavy chain variable region having an amino acid sequence as shown in SEQ ID NO: 8 and a light chain variable region having an amino acid sequence as shown in SEQ ID NO: 14; Anti-tau antibody or antigen-binding fragment thereof comprising a heavy chain variable region having an amino acid sequence as shown in SEQ ID NO: 8 and a light chain variable region having an amino acid sequence as shown in SEQ ID NO: 15; Anti-tau antibody or antigen-binding fragment thereof comprising a heavy chain variable region having an amino acid sequence as shown in SEQ ID NO: 9 and a light chain variable region having an amino acid sequence as shown in SEQ ID NO: 13; Anti-tau antibody or antigen-binding fragment thereof comprising a heavy chain variable region having an amino acid sequence as shown in SEQ ID NO: 9 and a light chain variable region having an amino acid sequence as shown in SEQ ID NO: 13; An anti-tau antibody or antigen-binding fragment thereof comprising the light chain variable region of the amino acid sequence shown in SEQ ID NO: 9; an anti-tau antibody or antigen-binding fragment thereof comprising the heavy chain variable region of the amino acid sequence shown in SEQ ID NO: 10 and the light chain variable region of the amino acid sequence shown in SEQ ID NO: 15; an anti-tau antibody or antigen-binding fragment thereof comprising the heavy chain variable region of the amino acid sequence shown in SEQ ID NO: 10 and the light chain variable region of the amino acid sequence shown in SEQ ID NO: 15.The invention comprises an anti-tau antibody or an antigen-binding fragment thereof having a heavy chain variable region having an amino acid sequence as shown in SEQ ID NO: 11 and a light chain variable region having an amino acid sequence as shown in SEQ ID NO: 13; and an anti-tau antibody or an antigen-binding fragment thereof having a heavy chain variable region having an amino acid sequence as shown in SEQ ID NO: 11 and a light chain variable region having an amino acid sequence as shown in SEQ ID NO:

15.

2. The anti-tau antibody or its antigen-binding fragment as claimed in claim 1, wherein the fragment is selected from any of the group consisting of Fab, scFv, F(ab')2, and Fv.

3. A polynucleotide encoding an anti-tau antibody or an antigen-binding fragment thereof as claimed in claim 1.

4. An expression vector comprising: the polynucleotide of claim 3.

5. A host cell comprising: the expression vector as claimed in claim 4.

6. A method for generating an anti-tau antibody or an antigen-binding fragment thereof as claimed in claim 1, comprising: a step of culturing a host cell as claimed in claim 5.

7. A polynucleotide encoding a heavy or light chain of an antibody, the antibody comprising a heavy chain variable region and a light chain variable region as described in claim 1.

8. A pharmaceutical composition for the prevention or treatment of degenerative neurological diseases, comprising, as an active ingredient: an anti-tau antibody or an antigen-binding fragment thereof, as claimed in claim 1.

9. The pharmaceutical composition of claim 8, wherein the degenerative neurological disease is a tau protein-mediated neurological disease.

10. The pharmaceutical composition of claim 9, wherein the tau protein-mediated neurological disease is tauinopathy, primary age-related tauinopathy, chronic traumatic encephalopathy, progressive supranuclear palsy, corticobasal degeneration, frontotemporal dementia, Lytico-Bodig disease, Parkinson's disease, subacute sclerosing meningitis, lead encephalopathy, tuberous sclerosis, glioma, gangliocytoma, meningioangiomatosis, subacute sclerosing panencephalitis, Hallervorden-Spatz disease, or lipofuscinosis.

11. The pharmaceutical composition of claim 10, wherein the tau protein disease is Alzheimer's disease (AD), progressive supranuclear palsy (PSP), corticobasal ganglia degeneration (CBD), Pick's disease (PiD), a group of diseases collectively referred to as frontotemporal dementia linked to chromosome 17 with Parkinson's disease (FTDP-17), amyotrophic lateral sclerosis (ALS), Creutzfeld-Jakob disease (CJD), boxer's dementia (DP), Gerstmann-Sträussler-Scheinker disease (GSSD), Lewy body disease, chronic traumatic encephalopathy (CTE), or Huntington's disease.

12. The pharmaceutical composition of claim 8, wherein the pharmaceutical composition is administered via any route selected from the group consisting of intracerebral, ventricular, peritoneal, transcutaneous, intramuscular, dura mater, intravenous, subcutaneous, and nasal routes of administration.

13. A composition for diagnosing degenerative neurological diseases, comprising: an anti-tau antibody as claimed in claim 1 or an antigen-binding fragment thereof.

14. A kit for the prevention, treatment, or diagnosis of degenerative neurological diseases, comprising: an antibody or antigen-binding fragment thereof as claimed in claim 1, a polynucleotide as claimed in claim 3, an expression vector as claimed in claim 4, or a host cell as claimed in claim 5.

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