US-12624096-B2 - Anti-tau antibodies and methods of use thereof

US12624096B2US 12624096 B2US12624096 B2US 12624096B2US-12624096-B2

Abstract

Inventors

Charles Robert Harrington
Soumya PALLIYIL SOMAN
Andrew Justin Radcliffe Porter
Claude Michel Wischik
Mohammad Arastoo
Lewis Kirk PENNY
Richard LOFTHOUSE

Assignees

Gtinvent Limited

Dates

Publication Date: 20260512
Application Date: 20210709
Priority Date: 20200710

Claims (16)

1 . An anti-tau antibody or an antigen-binding fragment thereof that binds amino acids 337-355 of SEQ ID NO:1, wherein the anti-tau antibody or antigen-binding fragment thereof comprises a VH domain comprising the sequence of SEQ ID NO:443 and a VL domain comprising the sequence of SEQ ID NO:444.
2 . The anti-tau antibody or antigen-binding fragment thereof of claim 1 , wherein the anti-tau antibody is a humanized antibody and/or a monoclonal antibody, and/or the antigen-binding fragment thereof is a Fab or F(ab′)2 antibody fragment, or an scFv molecule.
3 . A composition comprising multiple anti-tau antibodies or antigen-binding fragments thereof according to claim 1 , wherein at least 90% of the anti-tau antibodies or antigen-binding fragments thereof in the composition bind an epitope comprising amino acids 337-355 of SEQ ID NO: 1 with a K D of less than 25 nM.
4 . A pharmaceutical composition comprising the anti-tau antibody or antigen-binding fragment according to claim 1 and one or more pharmaceutically acceptable diluents, carriers or excipients.
5 . A kit for detecting a tau protein or a fragment thereof that comprises amino acids 337-355 of SEQ ID NO:1 in a sample, comprising the anti-tau antibody according to claim 1 and reagents for detecting immunocomplexes of the anti-tau antibody with the tau protein or a fragment thereof in the sample by an immunoassay.
6 . An isolated nucleic acid molecule comprising a nucleic acid sequence encoding the anti-tau antibody or antigen-binding fragment thereof according to claim 1 .
7 . The nucleic acid molecule of claim 6 , wherein the nucleic acid sequence comprises the sequence of SEQ ID NO: 380.
8 . A construct comprising the nucleic acid molecule according to claim 6 .
9 . A vector comprising the construct of claim 8 .
10 . An isolated host cell comprising the construct of claim 8 .
11 . A method of preparing an anti-tau antibody comprising: i) introducing into an isolated host cell the nucleic acid molecule of claim 6 ; ii) expressing the nucleic acid molecule such that the anti-tau antibody is produced; and iii) purifying and collecting the anti-tau antibody.
12 . An anti-tau antibody obtained by the method according to claim 11 .
13 . An in vitro method of inhibiting aggregation of a tau protein or a fragment thereof, comprising i) incubating the tau protein or fragment thereof with dithiothreitol (DTT) to induce aggregation of the tau protein or fragment thereof; ii) contacting the aggregated tau protein or a fragment thereof with the anti-tau antibody or antigen-binding fragment thereof according to claim 1 or bovine serum albumin as a negative control; iii) detecting reduced levels of aggregation of the aggregated tau protein or fragment thereof treated with the anti-tau antibody or antigen-binding fragment thereof compared to the negative control using a Thioflavin T assay; and wherein the tau protein or fragment thereof comprises amino acids 297-391 of SEQ ID NO: 1.
14 . An in vitro method for detecting a tau protein or a fragment thereof that comprises amino acids 337-355 of SEQ ID NO:1 in a sample, comprising contacting the sample with the anti-tau antibody of claim 1 to form an immunocomplex and detecting the immunocomplex of the anti-tau antibody with the tau protein or fragment thereof by an immunoassay.
15 . The in vitro method for detecting a tau protein or a fragment thereof according to claim 14 , wherein: (i) the sample is a plasma sample; and/or (ii) the method further comprises a step of denaturing the tau protein or fragment thereof prior to contacting the sample with the anti-tau antibody.
16 . A diagnostic method comprising contacting a patient sample that comprises a tau protein or a fragment thereof comprising amino acids 337-355 of SEQ ID NO: 1 with the anti-tau antibody of claim 1 and determining whether the tau protein or the fragment thereof is present in the sample to form an immunocomplex, and detecting the immunocomplex of the anti-tau antibody with the tau protein or fragment thereof by an immunoassay.

Description

The invention relates to specific binding molecules, such as antibodies, directed to key epitopes of tau. The specific binding molecules of the invention find applications in diagnostics and therapeutics of tauopathies including Alzheimer's disease. Disorders related to tau are collectively referred to as neurodegenerative tauopathies. Alzheimer's disease (AD) is part of this group of neurodegenerative diseases. Conditions of dementia such as Alzheimer's disease (AD) are frequently characterised by a progressive accumulation of intracellular and/or extracellular deposits of proteinaceous structures such as β-amyloid plaques and neurofibrillary tangles (NFTs) composed of tau, in the brains of affected patients. The appearance of tau aggregation lesions largely correlates with pathological neurofibrillary degeneration and brain atrophy, as well as with cognitive impairment. In AD, tau protein self-assembles to form paired helical filaments (PHFs) and straight filaments that constitute the neurofibrillary tangles within neurons and dystrophic neurites in the brain. Protein misfolding to form amyloid fibrils is a hallmark of many different diseases collectively known as the amyloidoses, each of which is characterised by a specific precursor protein. The long history of research into the causes of AD and other protein conformational disorders has not led to the hoped-for major advances in diagnostics or therapeutics. One reason for the limited progress is thought to be a lack of high-affinity specific binding molecules targeted to key epitopes of tau. The present inventors address this shortcoming by the creation of the specific binding molecules disclosed herein. The disclosed specific binding molecules are derived from antibodies isolated from sheep immunised with full length tau protein and a truncated tau fragment from the core of the PHF. The use of sheep as a source of specific binding molecules is thought to have contributed to the high affinity of the specific binding molecules of the invention. SUMMARY OF THE INVENTION According to a first aspect, the invention provides a specific binding molecule that binds to an epitope within SEQ ID NO: 1 with a binding affinity greater than the binding affinity with which antibody mAb423 binds to an epitope within SEQ ID NO: 1. According to a second aspect, the invention provides a composition comprising a specific binding molecule according to the first aspect of the invention, wherein at least 90% of the specific binding molecules in the composition that bind an epitope within SEQ ID NO: 1 bind with a KD of less than 25 nM. According to a third aspect, the invention provides a nucleic acid molecule comprising a nucleic acid sequence encoding a specific binding molecule according to the first aspect of the invention. According to a fourth aspect, the invention provides a construct comprising a nucleic acid molecule of the third aspect of the invention. According to a fifth aspect, the invention provides a vector comprising a nucleic acid molecule of the third aspect of the invention or a construct of the fourth aspect of the invention. According to a sixth aspect, the invention provides a host cell comprising a nucleic acid molecule of the third aspect of the invention, a construct of the fourth aspect of the invention or a vector of the fifth aspect of the invention. According to a seventh aspect, the invention provides a method of preparing a specific binding molecule according to the first aspect of the invention comprising: i) introducing into a host cell a nucleic acid molecule of the third aspect of the invention, a construct of the fourth aspect of the invention or a vector of the fifth aspect of the invention;ii) expressing the nucleic acid molecule such that the specific binding molecule is produced; andiii) collecting the specific binding molecule, preferably by purification. According to an eighth aspect, the invention provides a specific binding molecule obtainable by a method according to the seventh aspect of the invention. According to a ninth aspect, the invention provides a pharmaceutical composition comprising a specific binding molecule according to the first aspect of the invention or a composition according to a second aspect of the invention and one or more pharmaceutically acceptable diluents, carriers or excipients. According to a tenth aspect, the invention provides a specific binding molecule according to the first aspect of the invention, a composition according to the second aspect of the invention or a pharmaceutical composition according to the ninth aspect of the invention for use in therapy. According to an eleventh aspect, the invention provides a specific binding molecule according to the first aspect of the invention, a composition according to the second aspect of the invention or a pharmaceutical composition according to the ninth aspect of the invention for use in treatment of a tauopathy. According to a twelfth aspect, the inv