Human alzheimer's disease and traumatic brain injury associated tau variants as biomarkers and methods of use thereof

Patent metadata

Field	Value
Publication number	US-11549113-B2
Application number	US-201916712652-A
Country	US
Kind code	B2
Filing date	Dec 12, 2019
Priority date	Dec 11, 2015
Publication date	Jan 10, 2023
Grant date	Jan 10, 2023

Abstract

The present invention provides detection reagents and method for determining risk of traumatic brain injury (TBI) and/or susceptibility to neurodegenerative disease in a subject.

First claim

What is claimed is:

1. A binding molecule
wherein the binding molecule preferentially binds to human Alzheimer's Disease (AD)-associated tau and comprises an amino acid sequence at least 95% identical to:
(a) an antibody heavy chain variable domain and light chain variable domain of SEQ ID NO:2, SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, SEQ ID NO:18, SEQ ID NO:20, SEQ ID NO:22, SEQ ID NO:24, SEQ ID NO:26, SEQ ID NO:28, SEQ ID NO:30, SEQ ID NO:32, SEQ ID NO:34, SEQ ID NO:36, SEQ ID NO:38, or SEQ ID NO:40; or
(b) a DARPin of SEQ ID NO:8;
wherein differences from the heavy chain variable domain and light chain variable domain of (a) or the DARPin of (b) are conservative substitutions.

2. The binding molecule of claim 1 , wherein the antibody comprises a chimeric antibody, a single-chain antibody, a diabody, an Fab, or an scFv.

3. A nucleic acid that encodes the binding molecule of claim 1 .

4. A vector comprising the nucleic acid of claim 3 .

5. A phage comprising the vector of claim 4 .

6. A phage comprising the binding molecule of claim 1 .

7. A method of detecting Alzheimer's Disease (AD)-associated tau in a subject, the method comprising:
(a) incubating a sample from the subject with a binding molecule that preferentially recognizes AD-associated tau; and
(b) comparing the amount of AD-associated tau bound to the binding molecule with the amount of AD-associated tau bound to the binding molecule in a control sample;
wherein the binding molecule comprises an antibody or DARPin of claim 1 .

8. A method for detecting traumatic brain injury (TBI), neuronal damage, and/or susceptibility to neurodegenerative disease in a subject, the method comprising:
(a) detecting TBI-associated tau in a post-injury sample from the subject; and
(b) comparing the level of TBI-associated tau protein in the sample with TBI-associated tau protein level in a normal control;
wherein detecting TBI-associated tau comprises incubating the sample with a binding molecule of claim 1 that preferentially recognizes TBI-associated tau; and
wherein elevated TBI-associated tau protein in the post-injury sample indicates TBI, neuronal damage, and/or susceptibility to neurodegenerative disease.

9. The method of claim 8 , wherein the sample and the normal control comprise blood product samples or cerebrospinal fluid (CSF) samples.

10. A method for detecting Alzheimer's Disease (AD), neuronal damage, and/or susceptibility to neurodegenerative disease in a subject, the method comprising:
(a) detecting AD-associated tau in a post-injury sample from the subject; and
(b) comparing the level of AD-associated tau protein in the sample with AD-associated tau protein level in a normal control;
wherein detecting AD-associated tau comprises incubating the sample with a binding molecule of claim 1 that preferentially recognizes AD-associated tau; and
wherein elevated AD-associated tau protein in the post-injury sample indicates AD, neuronal damage, and/or susceptibility to neurodegenerative disease.

11. The method of claim 10 , wherein the sample and the normal control comprise blood product samples or cerebrospinal fluid (CSF) samples.

Assignees

• Univ Arizona State

Inventors

• Sierks Michael
• Venkataraman Lalitha
• Xin Wei

Classifications

• G01N2800/2821

  Alzheimer · CPC title

• C07K1/22

  Affinity chromatography or related techniques based upon selective absorption processes · CPC title

• G01N33/6896

  Neurological disorders, e.g. Alzheimer's disease · CPC title

• C12N15/62 Primary

  DNA sequences coding for fusion proteins · CPC title

• C07K16/18

  against material from animals or humans · CPC title