Anti-PHF-tau antibodies and uses thereof

Patent metadata

Field	Value
Publication number	US-10633435-B2
Application number	US-201916291303-A
Country	US
Kind code	B2
Filing date	Mar 4, 2019
Priority date	Mar 5, 2018
Publication date	Apr 28, 2020
Grant date	Apr 28, 2020

Abstract

Monoclonal anti-tau antibodies and antigen-binding fragments thereof are described. Also described are nucleic acids encoding the antibodies, compositions comprising the antibodies, methods of producing the antibodies and using the antibodies for treating or preventing conditions such as tauopathies. The antibodies of the invention may also be used to quantify tau in biological samples.

First claim

We claim:

1. An isolated antibody or antigen-binding fragment thereof that binds to paired helical filament-tau (PHF-tau) comprising a heavy chain variable region (VH) comprising a complementary determining region 1 (HCDR1), an HCDR2 and an HCDR3 and a light chain variable region (VL) comprising a complementary determining region 1 (LCDR1), an LCDR2 and an LCDR3, wherein:
(a) the antibody or antigen-binding fragment thereof comprises an HCDR1 of SEQ ID NO:1; an HCDR2 of SEQ ID NO:2 and an HCDR3 of SEQ ID NO:3 and an LCDR1 of SEQ ID NO:4; an LCDR2 of SEQ ID NO:5; and an LCDR3 of SEQ ID NO:6;
(b) the antibody or antigen-binding fragment thereof comprises an HCDR1 of SEQ ID NO:7; an HCDR2 of SEQ ID NO:8 and an HCDR3 of SEQ ID NO:3 and an LCDR1 of SEQ ID NO:9; an LCDR2 of SEQ ID NO:5; and an LCDR3 of SEQ ID NO:6;
(c) the antibody or antigen-binding fragment thereof comprises an HCDR1 of SEQ ID NO:7; an HCDR2 of SEQ ID NO:10 and an HCDR3 of SEQ ID NO:3 and an LCDR1 of SEQ ID NO:11; an LCDR2 of SEQ ID NO:5; and an LCDR3 of SEQ ID NO:6;
(d) the antibody or antigen-binding fragment thereof comprises an HCDR1 of SEQ ID NO:7; an HCDR2 of SEQ ID NO:12 and an HCDR3 of SEQ ID NO:3 and an LCDR1 of SEQ ID NO:11; an LCDR2 of SEQ ID NO:5; and an LCDR3 of SEQ ID NO:6;
(e) an HCDR1 of SEQ ID NO:7; an HCDR2 of SEQ ID NO:13 and an HCDR3 of SEQ ID NO:3 and an LCDR1 of SEQ ID NO:11; an LCDR2 of SEQ ID NO:5; and an LCDR3 of SEQ ID NO:6; or
(f) the antibody or antigen-binding fragment thereof comprises an HCDR1 of SEQ ID NO:7; an HCDR2 of SEQ ID NO:14 and an HCDR3 of SEQ ID NO:3 and an LCDR1 of SEQ ID NO:11; an LCDR2 of SEQ ID NO:5; and an LCDR3 of SEQ ID NO:6.

2. The isolated antibody or antigen-binding fragment of claim 1 comprising:
(a) a heavy chain variable region comprising a sequence at least 95% identical to SEQ ID NO:15 and a light chain variable region comprising a sequence at least 95% identical to SEQ ID NO:16;
(b) a heavy chain variable region comprising a sequence at least 95% identical to SEQ ID NO:17 and a light chain variable region comprising a sequence at least 95% identical to SEQ ID NO: 18;
(c) a heavy chain variable region comprising a sequence at least 95% identical to SEQ ID NO:19 and a light chain variable region comprising a sequence at least 95% identical to SEQ ID NO: 20;
(d) a heavy chain variable region comprising a sequence at least 95% identical to SEQ ID NO:21 and a light chain variable region comprising a sequence at least 95% identical to SEQ ID NO: 22;
(e) a heavy chain variable region comprising a sequence at least 95% identical to SEQ ID NO:23 and a light chain variable region comprising a sequence at least 95% identical to SEQ ID NO: 20; or
(f) a heavy chain variable region comprising a sequence at least 95% identical to SEQ ID NO:24 and a light chain variable region comprising a sequence at least 95% identical to SEQ ID NO: 25.

3. The isolated antibody or antigen-binding fragment of claim 1 comprising
(a) a heavy chain variable region SEQ ID NO:15 and a light chain variable region comprising SEQ ID NO: 16;
(b) a heavy chain variable region comprising SEQ ID NO:17 and a light chain variable region comprising SEQ ID NO: 18;
(c) a heavy chain variable region comprising SEQ ID NO:19 and a light chain variable region comprising SEQ ID NO: 20;
(d) a heavy chain variable region comprising SEQ ID NO:21 and a light chain variable region comprising SEQ ID NO: 22;
(e) a heavy chain variable region SEQ ID NO:23 and a light chain variable region comprising SEQ ID NO: 20; or
(f) a heavy chain variable region comprising SEQ ID NO:24 and a light chain variable region comprising SEQ ID NO: 25.

4. The isolated antibody or antigen-binding fragment of claim 1 that is humanized.

5. An isolated nucleic acid encoding the antibody or antigen-binding fragment of claim 1 .

6. A vector comprising the isolated nucleic acid of claim 5 .

7. A host cell comprising the nucleic acid of claim 6 .

8. A pharmaceutical composition comprising the isolated antibody or antigen-binding fragment of claim 1 and a pharmaceutically acceptable carrier.

9. A pharmaceutical composition comprising the isolated antibody or antigen-binding fragment of claim 4 and a pharmaceutically acceptable carrier.

10. A method of reducing pathological tau aggregation or spreading of tauopathy in a subject in need thereof, comprising administering to the subject the pharmaceutical composition of claim 8 .

11. A method of reducing pathological tau aggregation or spreading of tauopathy in a subject in need thereof, comprising administering to the subject the pharmaceutical composition of claim 9 .

12. A method of treating a tauopathy in a subject in need thereof, comprising administering to the subject the pharmaceutical composition of claim 8 .

13. A method of treating a tauopathy in a subject in need thereof, comprising administering to the subject the pharmaceutical composition of claim 9 .

14. A method of treating a tauopathy in a subject in need thereof, comprising administering to the subject the pharmaceutical composition of claim 8 , wherein the tauopathy is selected from the group consisting of Alzheimer's disease, frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17), progressive supranuclear palsy, corticobasal degeneration, Pick's disease, progressive subcortical gliosis, tangle only dementia, diffuse neurofibrillary tangles with calcification, argyrophilic grain dementia, amyotrophic lateral sclerosis parkinsonism-dementia complex, Down syndrome, Gerstmann-Straussler-Scheinker disease, Hallervorden-Spatz disease, inclusion body myositis, Creutzfeld-Jakob disease, multiple system atrophy, Niemann-Pick disease type C, prion protein cerebral amyloid angiopathy, subacute sclerosing panencephalitis, myotonic dystrophy, non-Guamanian motor neuron disease with neurofibrillary tangles, postencephalitic parkinsonism, chronic traumatic encephalopathy, and dementia pugulistica.

15. A method of treating a tauopathy in a subject in need thereof, comprising administering to the subject the pharmaceutical composition of claim 9 , wherein the tauopathy is selected from the group consisting of Alzheimer's disease, frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17), progressive supranuclear palsy, corticobasal degeneration, Pick's disease, progressive subcortical gliosis, tangle only dementia, diffuse neurofibrillary tangles with calcification, argyrophilic grain dementia, amyotrophic lateral sclerosis parkinsonism-dementia complex, Down syndrome, Gerstmann-Straussler-Scheinker disease, Hallervorden-Spatz disease, inclusion body myositis, Creutzfeld-Jakob disease, multiple system atrophy, Niemann-Pick disease type C, prion protein cerebral amyloid angiopathy, subacute sclerosing panencephalitis, myotonic dystrophy, non-Guamanian motor neuron disease with neurofibrillary tangles, postencephalitic parkinsonism, chronic traumatic encephalopathy, and dementia pugulistica.

16. A method of producing the antibody or antigen-binding fragment of claim 1 , comprising culturing a cell comprising a nucleic acid encoding the antibody or antigen-binding fragment under conditions to produce the antibody or antigen-binding fragment, and recovering the antibody or antigen-binding fragment from the cell or cell culture.

17. A method of producing a pharmaceutical composition comprising the humanized antibody or antigen-binding fragment of claim 1 , comprising combining the antibody or antigen-binding fragment with a pharmaceutically acceptable carrier to obtain the pharmaceutical compositio

Assignees

• Janssen Pharmaceutica Nv

Inventors

• Van Kolen Kristof
• Mercken Marc
• Barone Linda
• Lacy Eilyn R
• Nanjunda Rupesh
• Wheeler John
• Luo Jinquan

Classifications

• G01N33/6896

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

• A61P25/16 Primary

  Anti-Parkinson drugs · CPC title

• C07K16/18 Primary

  against material from animals or humans · CPC title

• C12N15/62

  DNA sequences coding for fusion proteins · CPC title