Antibodies that bind to human tau and assay for quantifying human tau using the antibodies

Patent metadata

Field	Value
Publication number	US-2016356794-A1
Application number	US-201515117677-A
Country	US
Kind code	A1
Filing date	Feb 9, 2015
Priority date	Feb 10, 2014
Publication date	Dec 8, 2016
Grant date	—

Abstract

The present invention provides novel antibodies that bind to human Tau and assays for quantifying human Tau using these antibodies.

First claim

1 . An isolated antibody or antigen binding fragment thereof that specifically binds an epitope on human Tau consisting of amino acids 220 to 224.

2 . An isolated antibody or antigen binding fragment of claim 1 , which comprises three light chain CDRs of SEQ ID NO: 20 (CDRL1), SEQ ID NO: 21 (CDRL2) and SEQ ID NO: 22 (CDRL3) and three heavy chain CDRs of SEQ ID NO: 26 (CDRH1), SEQ ID NO: 27 (CDRH2) and SEQ ID NO: 28 (CDRH3).

3 . The isolated antibody or antigen binding fragment of claim 1 , which comprises a light chain variable region of SEQ ID NO: 24 and a heavy chain variable region of SEQ ID NO: 30.

4 . The isolated antibody or antigen binding fragment of claim 1 , which is the monoclonal antibody 10H8 or antigen binding fragment thereof.

5 . (canceled)

6 . (canceled)

7 . (canceled)

8 . An isolated antibody or antigen binding fragment thereof that specifically binds an epitope on human Tau consisting of amino acids 189 to 194.

9 . The isolated antibody or antigen binding fragment of claim 8 , which comprises three light chain CDRs of SEQ ID NO: 32 (CDRL1), SEQ ID NO: 33 (CDRL2) and SEQ ID NO: 34 (CDRL3) and three heavy chain CDRs of SEQ ID NO: 38 (CDRH1), SEQ ID NO: 39 (CDRH2) and SEQ ID NO: 40 (CDRH3).

10 . The isolated antibody or antigen binding fragment of claim 8 , which comprises a light chain variable domain of SEQ ID NO: 36 and a heavy chain variable domain of SEQ ID NO: 42.

11 . The isolated antibody or antigen binding fragment of claim 8 , which is the monoclonal antibody 19G10 or antigen binding fragment thereof.

12 . (canceled)

13 . (canceled)

14 . (canceled)

15 . (canceled)

16 . (canceled)

17 . (canceled)

18 . (canceled)

19 . A method of quantitating human Tau in a biological sample, the method comprising:
(a) contacting the biological sample with an antibody or antigen binding fragment of claim 1 under conditions allowing formation of an immune complex between human Tau and the antibody or antigen binding fragment thereof; and (b) detecting the immune complex formed.

20 . The method of claim 19 , wherein the antibody is monoclonal antibody 10H8 or an antigen binding fragment thereof.

21 . A method of quantitating human Tau in a biological sample, the method comprising:
(a) contacting the biological sample with the antibody of antigen binding fragment of claim 8 under conditions allowing formation of an immune complex between human Tau and the antibody or antigen binding fragment thereof; and (b) detecting the immune complex formed.

22 . The method of claim 21 , wherein the antibody is monoclonal antibody 19G10 or an antigen binding fragment thereof.

23 . A method for quantitating human Tau in a cerebrospinal fluid sample, the method comprising:
(a) capturing human Tau from the sample by contacting the sample with the antibody or antigen binding fragment thereof of claim 1 under conditions allowing formation of a capture antibody/Tau complex, wherein the antibody or antigen binding fragment is immobilized onto a solid support; and (b) detecting the captured Tau by contacting the capture antibody/Tau complex with a detectably labeled antibody or antibody fragment thereof of claim 8 under conditions allowing formation of a capture antibody/Tau/detectable labeled antibody complex.

24 . The method of claim 23 , wherein the capture antibody is monoclonal antibody 10H8 or antigen binding fragment thereof and the detectably labeled antibody is monoclonal antibody 19G10 or an antigen binding fragment thereof.

25 . The method of claim 23 , wherein the solid support is selected from the group consisting of magnetic particles, microspheres, magnetic microspheres, beads, membranes, plastic tubes, microtiter wells.

26 . The method of claim 25 , wherein the solid support is a magnetic microsphere.

27 . The method of claim 23 , wherein the detectably labeled antibody is labeled with a reagent selected from the group consisting of a radioactive isotope, an enzyme, a biotin, dye, fluorescent label and chemiluminescent label.

28 . The method of claim 27 , wherein the reagent is biotin.

29 . The method of claim 28 , wherein the biotin is attached to a streptavidin-phycoerythrin conjugate.

30 . A method for diagnosing Alzheimer's disease in a patient suspected of having this disease, the method comprising:
(a) quantifying the amount of human Tau in a cerebrospinal fluid sample of the patient using the method of claim 23 ; and (b) determining the concentration of human Tau in step (a), wherein a value greater than 184 pg/mL indicates a diagnosis of AD in the patient.

31 . The method of claim 30 , further comprising
(a) quantifying the amount of Aβ 1-42 in the cerebrospinal fluid sample of the patient; and (b) determining the ratio of human Tau/Aβ 1-42 in the sample of the patient, wherein a ratio value greater than 0.215 indicates a diagnosis of AD in the patient.

32 . The method of claim 31 , wherein in step (c) the amount of Aβ 1-42 is quantified utilizing at least one monoclonal antibody selected from the group consisting of 6E10, 12F4, 1-11-3, G2-11 and 4G8, or an antigen binding fragment of any of these antibodies.

33 . The method of claim 31 , wherein in step (c) the amount of Aβ 1-42 in the cerebrospinal fluid sample is quantified by:
(i) capturing Aβ 1-42 from the sample by contacting the sample with an antibody or antigen binding fragment thereof specifically binding to an epitope on the C-terminal end of Aβ 1-42 under conditions allowing formation of a capture antibody/Aβ 1-42 complex, wherein the antibody or antigen binding fragment thereof is immobilized onto a solid support; and
(ii) detecting the captured Aβ 1-42 by contacting the capture antibody/Aβ 1-42 complex with a detectably labeled antibody or antigen binding fragment thereof specifically binding to an epitope on the N-terminal end of Aβ 1-42 under conditions allowing formation of a detectably labeled antibody/Aβ 1-42 /capture antibody complex.

34 . The method of claim 33 , wherein the antibody used in step (c)(i) is monoclonal antibody 1-11-3 and the antibody used in step (c)(ii) is monoclonal antibody 6E10.

35 . A method for treating Alzheimer's disease in a patient in need thereof, the method comprising:
(a) selecting a patient in need of treatment by
(i) quantifying the amount of human Tau in a cerebrospinal fluid sample of the patient using the method of claim 23 ; and
(ii) determining the concentration of human Tau in step (i), wherein a value greater than 184 pg/mL indicates a diagnosis of AD in the patient; and
(b) administering to the patient a therapeutically effective amount of an AD therapeutic agent.

36 . The method of claim 35 , wherein the AD therapeutic agent is a BACE-1 inhibitor.

37 . The method of claim 36 , wherein the BACE-1 inhibitor is a compound selected from the group consisting of

or a tautomer thereof, or pharmaceutically acceptable salt of the compound or tautomer.

38 . The method o

Assignees

• Merck Sharp & Dohme

Inventors

• Laterza Omar
• Tanen Michael
• Wong Oitak

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P25/28

  for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia · CPC title

• C07K14/4711

  Alzheimer's disease; Amyloid plaque core protein · CPC title

• C07K2317/56

  variable (Fv) region, i.e. VH and/or VL · CPC title

• A61K31/549

  having two or more nitrogen atoms in the same ring, e.g. hydrochlorothiazide · CPC title