METHODS OF TREATING NEURODEGENERATIVE DISEASES

• US 20200131255A1
• Filed: 09/19/2019
• Published: 04/30/2020
• Est. Priority Date: 03/28/2017
• Status: Abandoned Application

• Current Assignee: Genentech, Inc. (Roche Holding AG)
• Original Assignee: Genentech, Inc. (Roche Holding AG)
• Inventors: Kerchner, Geoffrey, Teng, Edmond
• Application Number:
  US16/576,249
• Publication Number:
  US 20200131255A1
• Time in Patent Office: Days
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 2039/54 characterised by the route of administration
• CPC Class Codes: A61K 2039/545 characterised by the dose, timing or administration schedule
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 9/0019 Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner non-active ingredients are additionally classified in A61K47/00
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/28 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 Class Codes: C07K 16/18 against material from animals or humans
• CPC Class Codes: C07K 2317/24 containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
• CPC Class Codes: C07K 2317/567 Framework region [FR]
• CPC Class Codes: C07K 2317/76 Antagonist effect on antigen, e.g. neutralization or inhibition of binding
• CPC Class Codes: C07K 2317/92 Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value

Abstract

The invention provides methods of treating tauopathies with anti-Tau antibodies.

Claims

1. A method of treating a tauopathy comprising administering to an individual with a tauopathy a monoclonal antibody that binds human tau at a dose between 225 mg and 16800 mg, wherein the antibody comprises HVR-H1 comprising the amino acid sequence of SEQ ID NO:

20;

HVR-H2 comprising the amino acid sequence of SEQ ID NO;

21;

HVR-H3 comprising the amino acid sequence of SEQ ID NO;

22;

HVR-L1 comprising the amino acid sequence of SEQ ID NO;

23;

HVR-L2 comprising the amino acid sequence of SEQ ID NO;

24; and

HVR-L3 comprising the amino acid sequence of SEQ ID NO;

25.

2. The method of claim 1, wherein the method comprises administering the antibody at a dose of 225 mg, 675 mg, 1200 mg, 1500 mg, 2100 mg, 4200 mg, 4500 mg, 8100 mg, 8400 mg, or 16800 mg.

3. The method of claim 1, wherein the method comprises administering the antibody at a dose between 4000 mg and 16800 mg.

4. The method of claim 1, wherein the method comprises administering the antibody at a dose between 4000 mg and 8500 mg.

5. The method of claim 1, wherein the method comprises administering the antibody at a dose between 225 mg and 600 mg, 600 mg and 1000 mg, 1000 mg and 2000 mg, 2000 mg and 3000 mg, 3000 mg and 4000 mg, 4000 mg and 4500 mg, 4000 mg and 5000 mg, 4500 mg and 5000 mg, 5000 mg and 5500 mg, 5500 mg and 6000 mg, 6000 mg and 6500 mg, 6500 mg and 7000 mg, 7000 mg and 7500 mg, 7500 mg and 8000 mg, or 8000 mg and 8500 mg.

6. The method of claim 1, wherein the method comprises administering the antibody at a dose between 50 mg/kg and 240 mg/kg.

7. The method of claim 1, wherein the method comprises administering the antibody at a dose between 60 mg/kg and 120 mg/kg.

8. The method of claim 1, wherein the method comprises administering the antibody at a dose between 2.5 mg/kg and 5 mg/kg, 5 mg/kg and 10 mg/kg, 10 mg/kg and 15 mg/kg, 15 mg/kg and 20 mg/kg, 20 mg/kg and 30 mg/kg, 30 mg/kg and 40 mg/kg, 40 mg/kg and 50 mg/kg, 50 mg/kg and 60 mg/kg, 60 mg/kg and 70 mg/kg, 70 mg/kg and 80 mg/kg, 80 mg/kg and 90 mg/kg, 90 mg/kg and 100 mg/kg, 100 mg/kg and 110 mg/kg, or 110 mg/kg and 120 mg/kg.

9. The method of claim 1, wherein the method comprises administering the antibody once or twice every 1, 2, 4, 5, 6, 7, or 8 weeks.

11. The method of claim 1, wherein the method comprises administering the antibody subcutaneously or intravenously.

14. The method of claim 1, wherein the tauopathy is a neurodegenerative tauopathy.

15. The method of claim 1, wherein the tauopathy is selected from Alzheimer'"'"'s Disease, amyotrophic lateral sclerosis, Parkinson'"'"'s disease, Creutzfeldt-Jacob disease, Dementia pugilistica, Down'"'"'s Syndrome, Gerstmann-Straussler-Scheinker disease, inclusion-body myositis, prion protein cerebral amyloid angiopathy, traumatic brain injury, amyotrophic lateral sclerosis/parkinsonism-dementia complex of Guam, Non-Guamanian motor neuron disease with neurofibrillary tangles, argyrophilic grain dementia, corticobasal degeneration, diffuse neurofibrillary tangles with calcification, frontotemporal dementia, frontotemporal dementia with parkinsonism linked to chromosome 17, Hallervorden-Spatz disease, multiple system atrophy, Niemann-Pick disease type C, Pallido-ponto-nigral degeneration, Pick'"'"'s disease, progressive subcortical gliosis, progressive supranuclear palsy, Subacute sclerosing panencephalitis, Tangle only dementia, Postencephalitic Parkinsonism, and Myotonic dystrophy.

17. The method of claim 15, wherein the tauopathy is Alzheimer'"'"'s Disease (AD).

18. The method of claim 17, wherein the AD is early, prodromal, prodromal to mild, mild, mild to moderate or moderate.

19. The method of claim 1, wherein the treating comprises slowing memory loss or retaining or increasing memory capacity, memory function, or cognitive function in the individual.

20. The method of claim 19, wherein memory capacity, memory function, cognitive function, or memory loss is assessed using one or more of Clinical Dementia Rating-Sum of Boxes (CDR-SB), Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), and Alzheimer'"'"'s Disease Assessment Scale-Cognitive Subscale (ADAS-Cog).

21. The method of claim 20, wherein ADAS-Cog is ADAS-Cog 13.

22. The method of claim 20, wherein a decrease in CDR-SB score, or an increase in RBANS score, or a decrease in ADS-Cog score following administration of one or more doses of the antibody indicates one or more of increased memory capacity, memory function, or cognitive function in the individual.

23. The method of claim 20, wherein a stable CDR-SB score, RBANS score, or ADAS-Cog score, a slowing of the rate of increase of a CDR-SB score or ADAS-Cog score, or a slowing of the rate of decrease of a RBANS score following administration of one or more doses of the antibody indicates one or more of slowed memory loss or retained memory capacity, memory function, or cognitive function in the individual.

24. The method of claim 20, wherein the CDR-SB score, RBANS score, or ADAS-Cog score is compared to the respective score at baseline.

26. The method of claim 20, wherein the memory capacity, memory function, cognitive function, or memory loss is assessed at least 13 weeks, at least 24 weeks, at least 25 weeks, at least 37 weeks, at least 49 weeks, at least 61 weeks, at least 69 weeks, at least 73 weeks, at least 85 weeks, at least 97 weeks, at least 109 weeks, at least 121 weeks, at least 133 weeks, at least 145 weeks, at least 157 weeks, or at least 169 weeks after the beginning of treatment with the antibody.

54. The method of claim 1, wherein the method comprises administering at least one additional therapy.

55. The method of claim 54, wherein the additional therapy is selected from neurological drugs, corticosteroids, antibiotics, antiviral agents, anti-Tau antibodies, Tau inhibitors, anti-amyloid beta antibodies, beta-amyloid aggregation inhibitors, anti-BACE1 antibodies, and BACE1 inhibitors.

56. The method of claim 1, wherein the antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:

18 and a light chain variable region comprising the amino acid sequence of SEQ ID NO;

19.

57. The method of claim 1, wherein the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO:

26 or SEQ ID NO;

27 and a light chain comprising the amino acid sequence of SEQ ID NO;

28.

58. The method of claim 1, wherein the antibody comprises a heavy chain consisting of the amino acid sequence of SEQ ID NO:

26 or SEQ ID NO;

27 and a light chain consisting of the amino acid sequence of SEQ ID NO;

28.

59. The method of claim 56, wherein the antibody is an IgG1 or an IgG4 antibody.

60. The method of claim 59, wherein the antibody is an IgG4 antibody.

61. The method of claim 60, wherein the antibody comprises M252Y, S254T, and T256E mutations.

62. The method of claim 61, wherein the antibody comprises an S228P mutation.

63. The method of claim 1, wherein the antibody is an antibody fragment.

64. The method of claim 1, wherein the antibody binds each of monomeric Tau, phosphorylated Tau, non-phosphorylated Tau, and oligomeric Tau with a K_D of less than 100 nM, less than 75 nM, or less than 50 nM.

65. The method of claim 1, wherein the antibody binds cynomolgus monkey Tau (SEQ ID NO:

4).

10. (canceled)

12. (canceled)

13. (canceled)

16. (canceled)

25. (canceled)

27. A method of retaining or increasing one or more of memory capacity, memory function, or cognitive function or slowing memory loss in an individual, comprising administering to an individual with a tauopathy a monoclonal antibody that binds human tau at a dose between 225 mg and 16800 mg, wherein the antibody comprises HVR-H1 comprising the amino acid sequence of SEQ ID NO:

20;

HVR-H2 comprising the amino acid sequence of SEQ ID NO;

21;

HVR-H3 comprising the amino acid sequence of SEQ ID NO;

22;

HVR-L1 comprising the amino acid sequence of SEQ ID NO;

23;

HVR-L2 comprising the amino acid sequence of SEQ ID NO;

24; and

HVR-L3 comprising the amino acid sequence of SEQ ID NO;

25.

28-34. -34. (canceled)

35. A method of reducing the level of Tau protein, non-phosphorylated Tau protein, phosphorylated Tau protein, or hyperphosphorylated Tau protein in an individual, comprising administering to an individual with a tauopathy a monoclonal antibody that binds human tau at a dose between 225 mg and 16800 mg, wherein the antibody comprises HVR-H1 comprising the amino acid sequence of SEQ ID NO:

20;

HVR-H2 comprising the amino acid sequence of SEQ ID NO;

21;

HVR-H3 comprising the amino acid sequence of SEQ ID NO;

22;

HVR-L1 comprising the amino acid sequence of SEQ ID NO;

23;

HVR-L2 comprising the amino acid sequence of SEQ ID NO;

24; and

HVR-L3 comprising the amino acid sequence of SEQ ID NO;

25.

36-53. -53. (canceled)

66. (canceled)

67. (canceled)