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-2023220401-A1
Application number	US-202218085418-A
Country	US
Kind code	A1
Filing date	Dec 20, 2022
Priority date	Dec 11, 2015
Publication date	Jul 13, 2023
Grant date	—

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

1 - 31 . (canceled)

32 . A binding molecule,
wherein the binding molecule preferentially binds to human traumatic brain injury (TBI)-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:42, or
(b) a designed ankyrin repeat protein (DARPin) of SEQ ID NO:44, SEQ ID NO:48, SEQ ID NO:52, or SEQ ID NO:54;
wherein differences from the heavy chain variable domain and light chain variable domain of (a) or the DARPIN of (b) are conservative substitutions.

33 . The binding molecule of claim 32 , wherein the binding molecule comprises an antibody heavy chain variable domain and light chain variable domain of SEQ ID NO:42.

34 . The binding molecule of claim 33 , wherein the binding molecule comprises a chimeric antibody, a single-chain antibody, a diabody, an Fab, or an scFv.

35 . A nucleic acid that encodes the binding molecule of claim 32 .

36 . A vector comprising the nucleic acid of claim 35 .

37 . A phage comprising the vector of claim 36 .

38 . A phage comprising the binding molecule of claim 32 .

39 . A method of detecting traumatic brain injury (TBI)-associated tau in a subject, the method comprising:
(a) incubating a sample from the subject with a binding molecule that preferentially recognizes TBI-associated tau; and (b) comparing the amount of TBI-associated tau bound to the binding molecule with the amount of TBI-associated tau bound to the binding molecule in a control sample; wherein the binding molecule comprises an antibody or DARPin of claim 32 .

40 . The method of claim 39 , wherein the binding molecule comprises an antibody heavy chain variable domain and light chain variable domain of SEQ ID NO:42.

41 . The method of claim 40 , wherein the binding molecule comprises a chimeric antibody, a single-chain antibody, a diabody, an Fab, or an scFv.

42 . 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 32 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.

43 . The method of claim 42 , wherein the binding molecule comprises an antibody heavy chain variable domain and light chain variable domain of SEQ ID NO:42.

44 . The method of claim 43 , wherein the binding molecule comprises a chimeric antibody, a single-chain antibody, a diabody, an Fab, or an scFv.

45 . The method of claim 42 , 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

• G01N2333/4709

  Amyloid plaque core protein · CPC title

• G01N33/53

  Immunoassay; Biospecific binding assay; Materials therefor · CPC title

• G01N2800/2871

  Cerebrovascular disorders, e.g. stroke, cerebral infarct, cerebral haemorrhage, transient ischemic event · CPC title

• G01N33/50

  Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing (measuring or testing processes involving enzymes or microorganisms, compositions or test papers therefor; processes for forming such compositions, condition responsive control in microbiological or enzymological processes C12Q) · CPC title

• G01N2800/00

  Detection or diagnosis of diseases · CPC title