RU2789485C2 - Methods for treatment of neurodegenerative diseases - Google Patents

Abstract

FIELD: medicine; immunotherapy.

SUBSTANCE: group of inventions relates to immunotherapy with antibodies binding tau protein. A method for the treatment of Alzheimer’s disease (hereinafter – AD) from a light to moderate degree of severity and a method for preservation or increase in one or more of a memory volume, a memory function, or a cognitive function, or slowing down of memory loss in an individual with AD from a light to moderate degree of severity are proposed. Methods provide intravenous injection to an individual, once every 4 weeks, of an antibody, which binds human tau protein, at a dose of 4500 mg. The antibody contains HVR-H1 with SEQ ID NO: 20, HVR-H2 with SEQ ID NO: 21, HVR-H3 with SEQ ID NO: 22, HVR-L1 with SEQ ID NO: 23, HVR-L2 with SEQ ID NO: 24, and HVR-L3 with SEQ ID NO: 25.

EFFECT: inventions provide safe and tolerated, at injection in high doses, treatment of patients suffering from AD and preservation or increase in a memory volume, a memory function, or a cognitive function, or slowing down of memory loss.

34 cl, 7 dwg, 3 tbl, 2 ex

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority under US Provisional Application No. 62/477,535, filed March 28, 2017; U.S. Provisional Application No. 62/532,696, filed July 14, 2017; U.S. Provisional Application No. 62/577,559, filed October 26, 2017; and U.S. Provisional Application No. 62/580359, filed November 1, 2017, each of which is hereby incorporated by reference in its entirety for all purposes.

FIELD OF TECHNOLOGY

[0002] The present invention relates to methods for treating neurodegenerative diseases with anti-tau antibodies.

BACKGROUND OF THE INVENTION

[0003] Neurofibrillary tangles and neuropil filaments (NT) are the main neuropathological features of Alzheimer's disease (AD). NTs consist of a microtubule-associated tau protein that has undergone post-translational modifications, including phosphorylation, and results from the aggregation of hyperphosphorylated tau conformers. This pathology is common to AD and many neurodegenerative taupathies, in particular some types of frontotemporal dementia (FTD). Tau appears to be a key factor in cognitive decline in AD and related neurodegenerative taupathies.

[0004] Therapeutic approaches that target tau are few and include primarily kinase inhibitors, which are believed to increase tau phosphorylation to pathological levels, and compounds that block cytoplasmic aggregation of hyperphosphorylated tau. These approaches have various disadvantages in terms of specificity and efficiency. There is a need for additional therapeutic agents that target abnormal protein conformers known or suspected to cause neurodegenerative disorders.

[0005] An additional problem in finding suitable therapeutic agents is the need for a therapeutic agent that can access neurofibrillary tangles and other neuropathological forms of tau that are located in the brain. If the therapeutic agent is a protein, only a very small proportion of the peripherally administered therapeutic agent is able to cross the blood-brain barrier and reach the intended location of the protein's pathological conformers to which the agent is intended to target. Thus, there is a need for treatment regimens capable of delivering therapeutically effective amounts of an agent without any deleterious effect.

[0006] One of the particular problems that arises in relation to the methods of treating AD is the appearance of visual processing disorders, which are believed to indicate cerebral vasogenic edema and microbleeding. These disorders have been reported in connection with research use of immunotherapy targeting beta-amyloid peptide, possibly by interacting with beta-amyloid peptide deposited in or around blood vessels and stimulating an immune response. These disturbances were found to be dose dependent and more likely to occur with higher doses of the antibody. See, for example, Sevigny et al., 2016, Nature. 537:50-6. Symptoms, when present in association with such visual processing disorders, have been reported to include headache, cognitive decline, altered consciousness, seizures, unsteadiness, and vomiting (Salloway et al. 2009, Neurology 73:2061-70; Sperling et al 2011, Alzheimers Dement 7:367-85). Tau pathology appears mainly intracellularly in the cytoplasm of affected neurons (Braak et al. 2006), and soluble extracellular tau is found in the cerebrospinal fluid (Blennow and Zetterberg 2009). Unlike Aβ, there is no evidence that tau is deposited in vascular structures, however, it is not known whether targeting tau in the human brain can cause the types of dose-dependent side effects observed with any immunotherapy directed against beta-amyloid, in particular, by administering high doses of an anti-tau immunotherapeutic agent.

SHORT DESCRIPTION

[0007] The present invention provides methods for treating neurodegenerative diseases with anti-tau antibodies. As described herein, the present inventors have found that tau-binding antibody immunotherapy is safe and tolerable, even when administered at high doses, to both healthy volunteers and AD patients.

[0008] According to some embodiments of the present invention, a method of treating a neurodegenerative disease comprises administering an isolated antibody that binds to human tau, said antibody binding to monomeric tau, oligomeric tau, unphosphorylated tau, and phosphorylated tau. In some embodiments, the antibody binds an epitope within amino acids 2 to 24 of mature human tau. In some embodiments, the antibody is a monoclonal antibody. In some embodiments, the antibody is a human, humanized, or chimeric antibody. In some embodiments, the antibody is an antibody fragment that binds human tau. In some embodiments of the present invention, the human tau comprises the sequence of SEQ ID NO: 2.

[0009] According to some embodiments of the present invention, the antibody comprises an HVR-H1 heavy chain hypervariable region comprising the amino acid sequence of SEQ ID NO: 20; HVR-H2 containing the amino acid sequence of SEQ ID NO: 21; HVR-H3 containing the amino acid sequence of SEQ ID NO: 22; hypervariable region of the light chain -HVR-L1 containing the amino acid sequence of SEQ ID NO: 23; HVR-L2 containing the amino acid sequence of SEQ ID NO: 24; and HVR-L3 containing the amino acid sequence of SEQ ID NO: 25.

[00010] According to some embodiments of the present invention, the antibody comprises an HVR-H1 containing the amino acid sequence of SEQ ID NO: 20; HVR-H2 containing the amino acid sequence of SEQ ID NO: 21; HVR-H3 containing the amino acid sequence of SEQ ID NO: 22; HVR-L1 containing the amino acid sequence of SEQ ID NO: 23; HVR-L2 containing the amino acid sequence of SEQ ID NO: 24; and HVR-L3 containing the amino acid sequence of SEQ ID NO: 25.

[00011] In some embodiments, 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.

[00012] According to some embodiments of the present invention, the antibody comprises a heavy chain containing the amino acid sequence of SEQ ID NO: 26 or SEQ ID NO: 27, and a light chain containing the amino acid sequence of SEQ ID NO: 28. In some embodiments of the present invention, the hMTAU antibody described herein contains a heavy chain containing the amino acid sequence of SEQ ID NO: 27 and a light chain containing the amino acid sequence of SEQ ID NO: 28.

[00013] In some embodiments, the invention provides an isolated antibody that binds to human tau, said antibody comprising 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. In some embodiments, the present invention provides an isolated antibody that binds to human tau, said antibody comprising a heavy chain comprising the amino acid sequence of SEQ ID NO: 26 and a light chain comprising the amino acid sequence of SEQ ID NO: 28. According to Some embodiments of the present invention provide an isolated antibody that binds to human tau, said antibody comprising a heavy chain comprising the amino acid sequence of SEQ ID NO: 27 and a light chain comprising the amino acid sequence of SEQ ID NO: 28. According to some Embodiments of the present invention provide an isolated antibody that binds to human tau, said antibody comprising 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. In some embodiments, the present invention provides an isolated antibody that binds to human tau, said antibody comprising a heavy chain consisting of the amino acid sequence of SEQ ID NO: 26 and a light chain consisting of the amino acid sequence of SEQ ID NO: 28. According to some embodiments of the present invention provide an isolated antibody that binds to human tau, said antibody comprising a heavy chain consisting of the amino acid sequence of SEQ ID NO: 27 and a light chain consisting of the amino acid sequence of SEQ ID NO: 28. The isolated antibodies described are herein, can be used in methods of treating diseases associated with tau protein. The isolated antibodies described herein can be used in methods of slowing down memory loss or maintaining or increasing memory capacity, memory function, or cognitive function in an individual. The isolated antibodies described herein can be used in methods for reducing tau levels.

[00014] In any of the embodiments described herein, the antibody may be an IgG1 or IgG4 antibody. In any of the embodiments described herein, the antibody may be an IgG4 antibody. In some such embodiments, the antibody contains the M252Y, S254T, and T256E mutations. According to any of the embodiments described herein, the antibody may contain the S228P mutation. According to any of the embodiments described herein, the antibody may contain mutations S228P, M252Y, S254T and T256E. In any of the embodiments described herein, the antibody may be an IgG4 antibody containing the S228P, M252Y, S254T, and T256E mutations. In some embodiments of the present invention, the antibody is an antibody fragment. In any of the embodiments described herein, the antibody may be an IgG4 antibody containing the S228P, M252Y, S254T, and T256E mutations and lacking the C-terminal lysine of the heavy chain constant region. The C-terminal lysine of the heavy chain constant region can be removed, for example, during purification of the antibody or by recombinantly constructing the nucleic acid encoding the antibody such that the C-terminal lysine is not encoded.

[00015] According to some embodiments of the present invention, an isolated antibody is provided that binds to human tau, wherein said 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 . In some embodiments, the antibody binds to cynomolgus macaque tau (SEQ ID NO: 4).

[00016] According to some embodiments of the present invention, there is provided a method of treating a tau-associated disease, comprising administering to an individual having a tau-associated disease an antibody described herein or a pharmaceutical composition comprising an antibody described herein. . In some embodiments of the present invention, the disease associated with the tau protein is tauopathy. In some embodiments of the present invention, the tauopathy is neurodegenerative tauopathy. In some embodiments of the present invention, taupopathy is selected from Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease, Creutzfeldt-Jakob disease, Boxer's dementia, Down's syndrome, Gerstmann-Straussler-Scheinker's disease, inclusion body myositis, cerebral amyloid angiopathy caused by prion proteins, traumatic brain injury, amyotrophic lateral sclerosis/parkinsonism-dementia complex (Guam disease), non-Guam motor neuron disease with neurofibrillary tangles, dementia with argyrophilic granules, corticobasal degeneration, diffuse neurofibrillary tangles with calcification, frontotemporal dementia, frontotemporal dementia with parkinsonism associated with chromosome 17, Hallevorden-Spatz disease, multiple system atrophy, Niemann-Pick type C disease, pallido-ponto-nigral degeneration, Pick's disease, progressive subcortical gliosis, progressive supranuclear palsy, subacute sclerosing panencephalitis, dementia with a predominance of neurofibrillary tangles, postencephalitic parkinsonism and myotonic dystrophy. In some embodiments, the tauopathy is Alzheimer's disease (AD) or progressive supranuclear palsy. In some embodiments, AD is early, prodromal, prodromal to mild, mild to moderate, or moderate.

[00017] According to some embodiments of the present invention, the treatment of a disease associated with a tau protein includes slowing down memory loss or maintaining or increasing memory capacity, memory function, or cognitive function in an individual.

[00018] According to some embodiments of the present invention, a method is provided for slowing down memory loss, or maintaining or increasing memory capacity, memory function, or cognitive function in an individual, comprising administering an antibody described herein, or a pharmaceutical composition containing an antibody described herein.

[00019] According to some embodiments of the present invention, memory capacity, memory function, cognitive function, or memory loss is assessed using one or more of the Cell Sum of Clinical Dementia Rating Scale (CDR-SB), the Repetitive Neuropsychological Status Test Battery (RBANS). ) and the Alzheimer's Disease Assessment Scale with Complementary Cognitive Scale (ADAS-Cog). In some embodiments of the present invention, the ADAS-Cog is ADAS-Cog 13.

[00020] According to some embodiments of the present invention, a decrease in CDR-SB score or an increase in RBANS score, or a decrease in ADAS-Cog score after administration of one or more doses of an antibody indicates an increase in cognitive memory in an individual. In some embodiments of the present invention, a stable CDR-SB score, RBANS score, or ADAS-Cog score following administration of one or more doses of an antibody is indicative of preserved memory capacity, memory function, cognitive function, or delayed memory loss in an individual. According to some embodiments of the present invention, slowing the rate of increase in the CDR-SB score or ADAS-Cog score or slowing the rate of decline in the RBANS score is indicative of saved memory capacity, memory function, cognitive function, or delayed memory loss in an individual.

[00021] According to some embodiments of the present invention, the CDR-SB score, the RBANS score, or the ADS-Cog score is compared with the corresponding score under initial conditions. According to some variants of implementation of the present invention, the initial conditions precede the introduction of antibodies. According to some embodiments of the present invention, memory capacity, memory function, cognitive function, or memory loss is assessed after 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 start of antibody treatment.

[00022] According to some embodiments of the present invention, a method is provided for reducing the level of tau protein, non-phosphorylated tau protein, phosphorylated tau protein, or hyperphosphorylated tau protein in an individual, comprising administering an antibody described herein, or a pharmaceutical composition containing an antibody, described in this document.

[00023] In some embodiments, the isolated antibody described herein is for use as a drug. In some embodiments, the isolated antibody described herein is for use in the treatment of tauopathy in an individual. In some embodiments of the present invention, the tauopathy is neurodegenerative tauopathy. In some embodiments of the present invention, taupopathy is selected from Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease, Creutzfeldt-Jakob disease, Boxer's dementia, Down's syndrome, Gerstmann-Straussler-Scheinker's disease, inclusion body myositis, cerebral amyloid angiopathy caused by prion proteins, traumatic brain injury, amyotrophic lateral sclerosis/parkinsonism-dementia complex (Guam disease), non-Guam motor neuron disease with neurofibrillary tangles, dementia with argyrophilic granules, corticobasal degeneration, diffuse neurofibrillary tangles with calcification, frontotemporal dementia, frontotemporal dementia with parkinsonism associated with chromosome 17, Hallevorden-Spatz disease, multiple system atrophy, Niemann-Pick type C disease, pallido-ponto-nigral degeneration, Pick's disease, progressive subcortical gliosis, progressive supranuclear palsy, subacute sclerosing panencephalitis, dementia with a predominance of neurofibrillary tangles, postencephalitic parkinsonism and myotonic dystrophy. In some embodiments, the tauopathy is Alzheimer's disease (AD) or progressive supranuclear palsy. In some embodiments, AD is early, prodromal, prodromal to mild, mild to moderate, or moderate.

[00024] According to some embodiments of the present invention, the isolated antibody described herein is provided for use in slowing memory loss or maintaining or increasing memory capacity, memory function, or cognitive function in an individual. In some embodiments, the isolated antibody described herein is provided for use in reducing the level of tau, phosphorylated tau, unphosphorylated tau, or hyperphosphorylated tau in an individual.

[00025] In some embodiments, the present invention provides the use of an antibody described herein for the manufacture of a medicament for the treatment of a disease associated with a tau protein in an individual. In some embodiments of the present invention, the disease associated with the tau protein is tauopathy. In some embodiments of the present invention, the tauopathy is neurodegenerative tauopathy. In some embodiments of the present invention, taupopathy is selected from Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease, Creutzfeldt-Jakob disease, Boxer's dementia, Down's syndrome, Gerstmann-Straussler-Scheinker's disease, inclusion body myositis, cerebral amyloid angiopathy caused by prion proteins, traumatic brain injury, amyotrophic lateral sclerosis/parkinsonism-dementia complex (Guam disease), non-Guam motor neuron disease with neurofibrillary tangles, dementia with argyrophilic granules, corticobasal degeneration, diffuse neurofibrillary tangles with calcification, frontotemporal dementia, frontotemporal dementia with parkinsonism associated with chromosome 17, Hallevorden-Spatz disease, multiple system atrophy, Niemann-Pick type C disease, pallido-ponto-nigral degeneration, Pick's disease, progressive subcortical gliosis, progressive supranuclear palsy, subacute sclerosing panencephalitis, dementia with a predominance of neurofibrillary tangles, postencephalitic parkinsonism and myotonic dystrophy. In some embodiments of the present invention, the tauopathy is Alzheimer's disease or progressive supranuclear palsy. In some embodiments, AD is early, prodromal, prodromal to mild, mild to moderate, or moderate.

[00026] According to some embodiments of the present invention, the use of an antibody described herein for the manufacture of a medicament for slowing memory loss or maintaining or increasing memory capacity, memory function, or cognitive function in an individual is provided.

[00027] In some embodiments, the invention provides a method for detecting neurofibrillary tangles, neuropil filaments, or dystrophic neuritis, comprising contacting a sample with an antibody described herein. In some embodiments of the present invention, the sample is a brain sample, a cerebrospinal fluid sample, or a blood sample.

[00028] According to any of the embodiments described herein, the method or use may include administering an antibody described herein in combination with at least one additional therapeutic agent. Non-limiting examples of types of additional therapeutic agents include neurological drugs, corticosteroids, antibiotics, antiviral agents, and other therapeutic agents. Such other therapeutic agents include, but are not limited to, other anti-tau antibodies, anti-amyloid-beta antibodies, anti-beta secretase ("BACE") antibodies, such as anti-beta secretase 1 ("BACE1") antibodies, or anti-beta secretase antibodies. -secretase 2 ("BACE 2"), and beta-secretase inhibitors such as beta-secretase 1 inhibitors or beta-secretase 2 inhibitors.

[00029] According to some embodiments of the present invention, the antibody is administered 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. In some embodiments of the present invention, the antibody is administered at a dose of 225 mg to 1000 mg. In some embodiments of the present invention, the antibody is administered at a dose of 225 mg to 600 mg. In some embodiments of the present invention, the antibody is administered at a dose of 600 mg to 1000 mg. In some embodiments of the present invention, the antibody is administered at a dose of 1000 mg to 2000 mg. In some embodiments of the present invention, the antibody is administered at a dose of 2000 mg to 3000 mg. In some embodiments of the present invention, the antibody is administered at a dose of 3000 mg to 4000 mg. In some embodiments of the present invention, the antibody is administered at a dose of 4000 mg to 16800 mg. In some cases, the antibody can be administered at a dose of 4000 mg to 8500 mg. In some embodiments, the antibody is administered at a dose of 4000 mg to 4500 mg, 4000 mg to 5000 mg, 4500 mg to 5000 mg, 5000 mg to 5500 mg, 5500 mg to 6000 mg, 6000 mg to 6500 mg. mg, 6500 mg to 7000 mg, 7000 mg to 7500 mg, 7500 mg to 8000 mg, or 8000 mg to 8500 mg.

[00030] According to some embodiments of the present invention, the antibody is administered at a dose of 2.5 mg/kg to 5 mg/kg, 5 mg/kg to 10 mg/kg, 10 mg/kg to 15 mg/kg, 15 mg/kg to 20 mg/kg, 20 mg/kg to 30 mg/kg, 30 mg/kg to 40 mg/kg, 40 mg/kg to 50 mg/kg, 50 mg/kg to 60 mg /kg, from 50 mg/kg to 240 mg/kg. In some cases, the antibody is administered at a dose of 60 mg/kg to 120 mg/kg. In some embodiments of the present invention, the antibody is administered at a dose of 60 mg/kg to 70 mg/kg, 70 mg/kg to 80 mg/kg, 80 mg/kg to 90 mg/kg, 90 mg/kg to 100 mg/kg, 100 mg/kg to 110 mg/kg, or 110 mg/kg to 120 mg/kg.

[00031] According to some embodiments of the present invention, the methods and uses described herein include administering the antibody once every 2, 4, 5, 6, 7, or 8 weeks. In some cases, the antibody is administered twice every 2, 4, 5, 6, 7 or 8 weeks.

[00032] According to some embodiments of the present invention, the methods and uses described herein include subcutaneous administration of the antibody. In some instances, the methods and uses include intravenous administration of the antibody.

BRIEF DESCRIPTION OF THE DRAWINGS

[00033] FIG. 1 shows the overall design of the study, including the single dose escalation step and the multiple dose step of the clinical study in Example 1. The abbreviations used in the figure are as follows: ADN, dose-limiting adverse event; HH, healthy volunteers; AD, Alzheimer's disease; in / in, intravenously; s / c, subcutaneously; CSF, cerebrospinal fluid.

[00034] FIG. 2 shows mean (±SD) serum hMTAU concentration versus time profiles after i.v. or s.c. administration.

[00035] FIG. 3 shows mean (±SD) hMTAU concentration versus time profiles in the CSF after i.v. administration of a single dose of 2100 mg and 8400 mg.

[00036] FIG. 4 shows mean (±SD) serum hMTAU concentration versus time profiles after i.v. or s.c. single dose or multiple doses.

[00037] FIG. 5 shows mean (±SD) hMTAU concentration versus time profiles in the CSF after i.v. administration of a single dose of 2100 mg and 8400 mg or i.v. administration of multiple doses of 8400 mg.

[00038] FIG. 6 shows mean (±SD) serum hMTAU concentration versus time profiles (left axis) and mean (±SD) plasma tau concentration versus time profiles (right axis) following iv administration of four weekly doses hMTAU 8400 mg. Concentration-time profiles are shown for PK (pharmacokinetics) and PD (pharmacodynamics). AD = patients with Alzheimer's disease; HH=healthy volunteers.

[00039] FIG. 7 shows a design of a clinical study of hMTAU in patients with prodromal or mild Alzheimer's disease.

DETAILED DESCRIPTION OF EMBODIMENTS

I. DEFINITIONS

[00040] "Human acceptor framework" for the purposes of this document is a framework containing the amino acid sequence of a light chain variable (VL) framework or a heavy chain variable domain (VH) framework that is derived from a human immunoglobulin framework or a human consensus framework, as defined below. A human acceptor framework "derived from" a human immunoglobulin framework or a human consensus framework may contain the same amino acid sequence or may contain alterations in the amino acid sequence. In some embodiments of the present invention, the number of amino acid substitutions is 10 or less, 9 or less, 8 or less, 7 or less, 6 or less, 5 or less, 4 or less, 3 or less, or 2 or less. In some embodiments of the present invention, the sequence of the human VL acceptor framework is identical to that of the human immunoglobulin VL framework or the human consensus framework sequence.

[00041] "Affinity" refers to the strength of all non-covalent interactions between a single binding site of a molecule (eg, an antibody) and its binding partner (eg, an antigen). Unless otherwise indicated, as used herein, "binding affinity" refers to intrinsic binding affinity, which reflects a 1:1 interaction between members of a binding pair (eg, antibody and antigen). The affinity of a molecule X for its partner Y can usually be represented by a dissociation constant (K _D ). Affinity can be measured using conventional methods known in the art, including those described herein. Specific illustrative and exemplary embodiments for measuring binding affinity are described below.

[00042] "Affinity matured antibody" refers to an antibody with one or more changes in one or more hypervariable regions (HVR) compared to the parent antibody that does not contain such changes, such changes resulting in an improvement in the affinity of the antibody for the antigen. .

[00043] The terms "anti-tau antibody" (anti-tau antibody) and "antibody that binds to tau" refer to an antibody that is capable of binding tau with sufficient affinity such that the antibody can be used as a diagnostic and/or therapeutic agent. when targeting the tau. In some embodiments of the present invention, the degree of binding of an anti-tau antibody to an unrelated protein other than tau is less than about 10% of the binding of the antibody to tau as measured, for example, by radioimmunoassay (RIA). According to some embodiments of the present invention, an antibody that binds to tau has a dissociation constant (K _D ) ≤1 μM, ≤100 nM, ≤10 nM, ≤1 nM, ≤0.1 nM, ≤0.01 nM, or ≤0.001 nM (eg 10 ^-8 M or less, eg 10 ^-8 M to 10 ^-13 M, eg 10 ^-9 M to 10 ^-13 M). In certain embodiments of the present invention, an anti-tau antibody binds to a tau epitope that is conserved across tau from different species. As used herein, the terms "anti-tau antibody" and "antibody that binds to tau" refer to an antibody that binds monomeric tau, oligomeric tau, and/or phosphorylated tau, unless specifically stated otherwise. In some such embodiments, the anti-tau antibody binds to monomeric tau, oligomeric tau, unphosphorylated tau, and phosphorylated tau with comparable affinities, such as affinities that differ by no more than 50-fold from each other. In some embodiments of the present invention, an antibody that binds monomeric tau, oligomeric tau, non-phosphorylated tau, and phosphorylated tau is referred to as a "pan-tau antibody".

[00044] As used herein, the term "antibody" is used in its broadest sense and encompasses various antibody structures, including, but not limited to, monoclonal antibodies, polyclonal antibodies, polyspecific antibodies (e.g., bispecific antibodies), and antibody fragments, provided that they exhibit the desired antigen binding specificity.

[00045] "Antibody fragment" refers to a molecule, other than an intact antibody, that contains a portion of the intact antibody that binds the antigen to which the intact antibody binds. Examples of antibody fragments include, but are not limited to, Fv, Fab, Fab', Fab'-SH, F(ab') ₂ ; diabody; linear antibodies; single chain antibody molecules (eg scFv); and polyspecific antibodies formed from antibody fragments.

[00046] "An antibody that binds to the same epitope" as a reference antibody (comparison antibody) refers to an antibody that blocks the binding of a reference antibody to its antigen by 50% or more in a competitive assay, and vice versa, a reference antibody blocks the binding of an antibody to its antigen by 50% or more in a competitive assay. An exemplary competitive quantitative study is presented in this document.

[00047] The term "chimeric" antibody refers to an antibody in which part of the heavy and/or light chain is from a particular source or species, while the remainder of the heavy and/or light chain is from a different source or species.

[00048] The "class" of an antibody refers to the type of constant domain or constant region that its heavy chain contains. There are five main classes of antibodies: IgA, IgD, IgE, IgG and IgM, and some of these can be further divided into subclasses (isotypes), such as IgG ₁ , IgG ₂ , IgG ₃ , IgG ₄ , IgA ₁ and IgA ₂ . Heavy chain constant domains that correspond to different classes of immunoglobulins are called α, δ, ε, γ, and μ, respectively.

[00049] As used herein, the term "cytotoxic agent" refers to a substance that inhibits or prevents cellular function and/or causes cell death or destruction. Cytotoxic agents include, but are not limited to, radioactive isotopes (eg, ²¹¹ At, ¹³¹ I, ¹²⁵ I, ⁹⁰ Y, ¹⁸⁶ Re, ¹⁸⁸ Re, ¹⁵³ Sm, ²¹² Bi, ³² P, ²¹² Pb and Lu radioactive isotopes); chemotherapeutic agents or drugs (eg methotrexate, adriamycin, vinca alkaloids (vincristine, vinblastine, etoposide), doxorubicin, melphalan, mitomycin C, chlorambucil, daunorubicin or other intercalating agents); growth inhibitory agents; enzymes and fragments thereof, such as nucleolytic enzymes; antibiotics; toxins such as low molecular weight toxins or enzymatically active toxins of bacterial, fungal, plant or animal origin, including fragments and/or variants thereof; and various antitumor or anticancer agents described below.

[00050] "Effector functions" refers to those biological activities characteristic of the Fc region of an antibody that vary depending on the isotype of the antibody. Examples of antibody effector functions include: C1q binding and complement dependent cytotoxicity (CDC); binding to the Fc receptor; antibody-dependent cellular cytotoxicity (ADCC); phagocytosis; downregulation of cell surface receptors (eg B-cell receptor); and activation of B cells.

[00051] An "effective amount" of an agent, such as a pharmaceutical formulation, refers to an amount effective at dosages and for periods of time necessary to achieve the desired therapeutic or prophylactic result.

[00052] As used herein, the term "Fc region" is used to refer to the C-terminal region of an immunoglobulin heavy chain that contains at least a portion of a constant region. The term includes native sequence Fc regions and variants of Fc regions. In some embodiments, the Fc region of the human IgG heavy chain extends from Cys226 or Pro230 to the carboxyl terminus of the heavy chain. However, the C-terminal lysine (Lys447) of the Fc region may or may not be present. Unless otherwise indicated, the numbering of amino acid residues in the Fc region or constant region follows the EC numbering system, also referred to as the EC index, as described in Kabat et al. , Sequences of Proteins of Immunological Interest , ^5th Ed., Public Health Service, National Institutes of Health, Bethesda, MD, 1991.

[00053] "Framework" or "FR" refers to variable domain residues other than hypervariable region (HVR) residues. The variable domain FR typically consists of four FR domains: FR1, FR2, FR3, and FR4. Accordingly, the HVR and FR sequences typically occur in the VH (or VL) in the following order: FR1-H1(L1)-FR2-H2(L2)-FR3-H3(L3)-FR4.

[00054] As used herein, the terms "full-length antibody", "intact antibody", and "whole antibody" are used interchangeably to refer to an antibody having a structure substantially similar to that of a native antibody, or having heavy chains that contain an Fc region as defined in this document.

[00055] The terms "host cell", "host cell line" and "host cell culture" are used interchangeably and refer to cells into which exogenous nucleic acid has been introduced, including the progeny of such cells. Host cells include "transformants" and "transformed cells", which include the primary transformed cell and its progeny, regardless of the number of passages. The offspring may not be completely identical in nucleic acid content to the parent cell and may contain mutations. The term includes mutant progeny that have the same function or biological activity as identified by screening or selected in the original transformed cell.

[00056] A "human antibody" is an antibody that contains an amino acid sequence that corresponds to that of an antibody produced by a human or a human cell, or derived from a non-human source that uses the human antibody repertoire or other sequences encoding human antibodies. This definition of a human antibody specifically excludes a humanized antibody containing antigen-binding residues from a non-human species.

[00057] The term "variable region" or "variable domain" refers to the heavy or light chain domain of an antibody that is involved in the binding of an antibody to an antigen. The heavy chain and light chain variable domains (VH and VL, respectively) of a native antibody typically have similar structures, with each domain containing four conserved framework regions (FRs) and three hypervariable regions (HVRs). (See, for example, Kindt et al. Kuby Immunology , ^6th Ed., WH Freeman and Co., page 91 (2007)). A single VH or VL domain may be sufficient to confer antigen-binding specificity. In addition, antibodies that bind a particular antigen can be isolated using the VH or VL domain from an antibody that binds the antigen to screen for a library of complementary VL or VH domains, respectively. See, for example, Portolano et al., J. Immunol. 150:880-887 (1993); Clarkson et al., Nature 352:624-628 (1991).

[00058] A "human consensus framework" is a framework that represents the most frequently occurring amino acid residues in a group of human immunoglobulin VL or VH framework sequences. Typically, a group of human immunoglobulin VL or VH sequences is derived from a subset of variable domain sequences. Generally, a subset of sequences is a subset as in Kabat et al., Sequences of Proteins of Immunological Interest , Fifth Edition, NIH Publication 91-3242, Bethesda MD (1991), vols. 1-3. In some embodiments of the present invention, for VL, the subgroup is a kappa I subgroup, as in Kabat et al., supra. In some embodiments, for VH, the subgroup is subgroup III, as in Kabat et al., supra.

[00059] A "humanized" antibody refers to a chimeric antibody containing amino acid residues from a non-human HVR and amino acid residues from a human FR. In some embodiments of the present invention, a humanized antibody will comprise substantially all of at least one, and typically two, variable domains, wherein all or substantially all of the HVRs (e.g., CDRs) correspond to those of an antibody from a non-human species, and all or substantially all of the FRs correspond to those of a human antibody. A humanized antibody may optionally contain at least a portion of an antibody constant region derived from a human antibody. A "humanized form" of an antibody, such as an antibody from a non-human species, refers to an antibody that has been humanized.

[00060] As used herein, the term "hypervariable region" or "HVR" refers to each of the antibody variable domain regions whose sequences are hypervariable ("complementarity determining regions" or "CDRs") and/or form structurally defined loops ("hypervariable loops") and/or contain antigen-binding residues ("antigenic contacts"). Typically, antibodies contain six HVRs: three in VH (H1, H2, H3) and three in VL (L1, L2, L3). Typical HVRs in this document include:

(a) hypervariable loops present at amino acid residues 26-32 (L1), 50-52 (L2), 91-96 (L3), 26-32 (H1), 53-55 (H2) and 96-101 (H3 ) (Chothia and Lesk, J. Mol. Biol. 196:901-917 (1987));

(b) CDRs present at amino acid residues 24-34 (L1), 50-56 (L2), 89-97 (L3), 31-35b (H1), 50-65 (H2) and 95-102 (H3) (Kabat et al. , Sequences of Proteins of Immunological Interest , ^5th Ed., Public Health Service, National Institutes of Health, Bethesda, MD (1991));

(c) antigenic contacts present at amino acid residues 27c-36 (L1), 46-55 (L2), 89-96 (L3), 30-35b (H1), 47-58 (H2) and 93-101 (H3 ) (MacCallum et al. J. Mol. Biol. 262: 732-745 (1996)); And

(d) combinations of (a), (b) and/or (c) including HVR amino acid residues 46-56 (L2), 47-56 (L2), 48-56 (L2), 49-56 (L2), 26-35 (H1), 26-35b (H1), 49-65 (H2), 93-102 (H3) and 94-102 (H3).

[00061] Unless otherwise indicated, HVR residues and other residues in the variable domain (eg, FR residues) are numbered herein in accordance with Kabat et al., supra.

[00062] An "immunoconjugate" is an antibody conjugated to one or more heterologous molecules, including, but not limited to, a cytotoxic agent.

[00063] "Individual", "subject" or "patient" is a mammal. Mammals include, but are not limited to, domesticated animals (e.g., cows, sheep, cats, dogs, and horses), primates (e.g., humans and non-human primates such as monkeys), rabbits, and rodents (e.g., mice and rats). ). In certain embodiments of the present invention, the individual or subject is a human.

[00064] An "isolated" antibody is an antibody that has been separated from a component of its natural environment. In some embodiments of the present invention, the antibody is purified to greater than 95% or 99% purity as determined by, for example, electrophoretic (e.g., SDS-PAGE, IEF, capillary electrophoresis) or chromatographic (e.g., ion exchange chromatography or reverse phase HPLC) methods. For a review of methods for assessing the purity of antibodies, see, for example, Flatman et al., J. Chromatogr. B 848:79-87 (2007).

[00065] An "isolated" nucleic acid refers to a nucleic acid molecule that has been separated from a component of its natural environment. An isolated nucleic acid includes a nucleic acid molecule contained in cells that normally contain the nucleic acid molecule, but the nucleic acid molecule is present extrachromosomally or at a chromosomal location that differs from its natural chromosomal location.

[00066] "An isolated nucleic acid encoding an anti-tau antibody" refers to one or more nucleic acid molecules encoding the antibody heavy and light chains (or fragments thereof), including such nucleic acid molecule(s) in one vector or individual vectors, and such nucleic acid(s) molecule(s) present(s) at one or more locations in the host cell.

[00067] As used herein, the term "monoclonal antibody" refers to an antibody derived from a population of substantially homogeneous antibodies, i. the individual antibodies that make up the population are identical and/or bind the same epitope, with the exception of possible variants of antibodies, for example, containing natural mutations or mutations that occur during the preparation of a monoclonal antibody preparation, such variants are usually present in small quantities. Unlike polyclonal antibody preparations, which typically include different antibodies directed against different determinants (epitopes), each monoclonal antibody of a monoclonal antibody preparation is directed against a single determinant on the antigen. Thus, the circumstance "monoclonal" indicates the nature of the antibody as derived from a substantially homogeneous population of antibodies, and should not be construed as requiring the production of the antibody by any particular method. For example, monoclonal antibodies for use in accordance with the present invention can be obtained using various methods, including, but not limited to, the hybridoma method, recombinant DNA methods, phage display methods, and methods using transgenic animals containing all or part of the human immunoglobulin loci. , such methods, and other exemplary methods for producing monoclonal antibodies are described herein.

[00068] "Naked antibody" refers to an antibody that is not conjugated to a heterologous moiety (eg, a cytotoxic moiety) or a radioactive label. The naked antibody may be present in a pharmaceutical formulation.

[00069] "Native antibodies" refers to natural immunoglobulin molecules with different structures. For example, native IgG antibodies are heterotetrameric glycoproteins of approximately 150,000 daltons, consisting of two identical light chains and two identical heavy chains that are linked by a disulfide bond. In the N-terminal to C-terminal direction, each heavy chain has a variable region (VH), also called a heavy chain variable domain or a heavy chain variable domain, followed by three constant domains (CH1, CH2 and CH3). Similarly, from the N-terminus to the C-terminus, each light chain has a variable region (VL), also referred to as a variable light domain or a light chain variable domain, followed by a constant light domain (CL). An antibody light chain can be assigned to one of two types, called kappa (κ) and lambda (λ), based on the amino acid sequence of its constant domain.

[00070] The term "package insert" is used to refer to instructions commonly included in commercial packages of therapeutic products that contain information about the indications, use, dosage, administration, combination therapy, contraindications, and/or warnings regarding the use of such therapeutic products.

[00071] "Percent (%) Amino Acid Sequence Identity" relative to a reference polypeptide sequence is defined as the percentage of amino acid residues in a candidate sequence that are identical to amino acid residues in the reference polypeptide sequence after sequence alignment and gaps, if necessary, to achieve the maximum percent sequence identity and not considering any conservative substitutions as part of the sequence identity. Alignment for purposes of determining percent amino acid sequence identity can be achieved by a variety of methods known in the art, for example using publicly available computer software such as BLAST, BLAST-2, ALIGN or Megalign (DNASTAR) software. Suitable parameters for sequence alignment can be determined by those skilled in the art, including any algorithms necessary to achieve maximum alignment over the entire length of the compared sequences. However, for the purposes of this disclosure, percent (%) amino acid sequence identity values are obtained using the ALIGN-2 sequence comparison computer program. The ALIGN-2 sequence comparison computer program was created by Genentech, Inc. and the source code was filed with the user documentation to the US Copyright Office, Washington, DC 20559, where it is registered under US copyright registration number TXU510087. The ALIGN-2 program is publicly available from Genentech, Inc., South San Francisco, CA or may be compiled from source code. The ALIGN-2 program must be compiled for use on a UNIX operating system, including Digital UNIX V4.0D. All sequence comparison parameters are set by the ALIGN-2 program and do not change.

[00072] In situations where ALIGN-2 is used for amino acid sequence comparisons, the percentage (%) identity of a particular amino acid sequence A to, or in comparison with, a particular amino acid sequence B (which may alternatively be formulated as a particular amino acid sequence A that shares or shares a certain % amino acid sequence identity with, or in comparison to, a specific amino acid sequence of B) is calculated as follows:

Share X/Y×100,

where X is the number of amino acid residues judged to be identical matches by the ALIGN-2 sequence alignment program when A and B are aligned by that program, and where Y is the total number of amino acid residues in B. It should be understood that if the amino acid length sequence A is not equal to the length of amino acid sequence B, the % amino acid sequence identity of A with B will not be equal to the % amino acid sequence identity of B with A. Unless specifically stated otherwise, all percentages (%) of amino acid sequence identity used herein are obtained, as described in the immediately preceding paragraph using the ALIGN-2 computer program.

[00073] The term "pharmaceutical formulation" refers to a formulation that is in a form that provides the biological activity of the active ingredient contained therein, and that does not contain additional components that are unacceptably toxic to the subject to whom the formulation will be administered.

[00074] A "pharmaceutically acceptable carrier" refers to an ingredient in a pharmaceutical composition, other than the active ingredient, that is non-toxic to the subject. A pharmaceutically acceptable carrier includes, but is not limited to, a buffer, excipient, stabilizer, or preservative.

[00075] As used herein, the term "tau" refers to any native tau protein from any vertebrate animal, including mammals such as primates (eg, humans) and rodents (eg, mice and rats), unless otherwise indicated. The term encompasses "full length" unprocessed tau as well as any form of tau resulting from cellular processing. The term also encompasses naturally occurring tau variants, such as splice variants or allelic variants.

[00076] As used herein, the term "pTau" refers to a tau in which a serine, threonine, or tyrosine residue is phosphorylated by a protein kinase by the addition of a covalently linked phosphate group. In some embodiments of the present invention, pTau is phosphorylated at a serine or threonine residue. In some embodiments, pTau is phosphorylated at serine at position 409 and/or serine at position 404. In some embodiments, pTau is phosphorylated at serine at position 409.

[00077] As used herein, the terms "soluble tau" or "soluble tau protein" refer to proteins consisting of both fully solubilized tau protein/peptide monomers and tau-like peptides/proteins, or modified or truncated peptides/ tau proteins or from other derivatives of tau peptide/protein monomers and tau protein oligomers. "Soluble tau" specifically excludes neurofibrillary tangles (NFTs).

[00078] As used herein, the term "insoluble tau" refers to a plurality of aggregated monomers of tau peptides or proteins, or tau-like peptides/proteins, or modified or truncated tau peptides/proteins, or other derivatives of tau peptides/proteins, forming oligomeric or polymeric structures. , which are insoluble both under in vitro conditions in an aquatic environment and under in vivo conditions in a mammalian or human body, more specifically in the brain, and in particular to a variety of aggregated tau monomers or modified or truncated tau peptides/proteins or their derivatives , which are insoluble in the mammalian or human body, more specifically in the brain, respectively. "Insoluble tau" specifically includes neurofibrillary tangles (NFTs).

[00079] As used herein, the terms "monomeric tau" or "monomer tau" refer to fully solubilized tau proteins without aggregated complexes in an aqueous medium.

[00080] As used herein, the terms "aggregated tau", "oligomeric tau", and "oligomer tau" refer to a plurality of aggregated monomers of tau peptides or proteins, or tau-like peptides/proteins, or modified or truncated tau peptides/proteins, or other tau peptide/protein derivatives forming oligomeric or polymeric structures that are insoluble or soluble both under in vitro conditions in an aquatic environment and under in vivo conditions in a mammalian or human body, more specifically in the brain, and, in particular, to a variety of aggregated tau monomers or modified or truncated tau peptides/proteins or derivatives thereof, which are insoluble or soluble in a mammalian or human body, more specifically in the brain, respectively.

[00081] As used herein, the terms "pTau PHF", "PHF", and "paired helical filaments" are used interchangeably and refer to pairs of filaments wound in a spiral at 160 nm intervals that are visible under electron microscopy. The width varies from 10 to 22 nm. PHF are the predominant structures in neurofibrillary tangles in Alzheimer's disease (AD) and neuropil filaments. PHF can also be seen in some, but not all, dystrophic neuritis associated with neuritic plaques. The main component of PHF is a hyperphosphorylated form of the microtubule-associated tau protein. PHF may partially consist of disulfide-linked antiparallel hyperphosphorylated tau proteins. PHF tau can be truncated at its 20 C-terminal amino acid residues. The mechanisms underlying the formation of PHF have not been determined, but hyperphosphorylation of tau can separate it from microtubules, increasing the soluble pool of tau from which PHF can form within neurons.

[00082] As used herein, the term "treatment" (and its grammatical variants such as "treat" or "treating") refers to a clinical intervention to alter the natural course of the disease of the individual being treated, and can be carried out both for prevention and during clinical pathology. Desirable effects of treatment include, but are not limited to, preventing the onset or recurrence of a disease, ameliorating symptoms, reducing any direct or indirect pathological consequences of a disease, preventing the formation of metastases, reducing the rate of disease progression, improving or alleviating the disease state, and remission or improving prognosis. In some embodiments, the antibodies of the present invention are used to delay the development of a disease or to slow the progression of a disease.

[00083] A "fixed" or "fixed" dose of a therapeutic agent refers to the dose that is administered to a human patient without regard to the weight (WT) or body surface area (BSA) of the patient. Accordingly, the fixed or constant dose is not provided as a mg/kg dose or mg/m ² dose, but as an absolute amount of the therapeutic agent.

[00084] As used herein, the term "early Alzheimer's disease" or "early AD" (e.g., "patient diagnosed with early AD" or "patient suffering from early AD") includes patients with mild cognitive impairment, for example, memory deficits associated with AD and patients with biomarkers for AD, such as amyloid-positive patients, patients with a positive PET scan for florbetapir, or patients with a positive tau PET scan.

[00085] The term "MMSE" refers to a short mental status scale that gives a score from 1 to 30. See Folstein, et al., 1975, J. Psychiatr. Res. 12:189-98. Ratings of 26 and below are generally considered to be indicative of a deficit. The lower the MMSE score, the greater the deficiency or impairment in the study patient compared to another individual with a lower score. An increase in the MMSE score may be indicative of an improvement in the patient's condition, while a decrease in the MMSE score may indicate a deterioration in the patient's condition.

[00086] The term "CDR-SB" refers to a clinical dementia rating scale based on the sum of the cells, which gives a score from 0 to 18. See, for example. O'Bryant et al., 2008, Arch Neurol 65: 1091-1095. The CDR-SB score is based on semi-structured interviews of patients and caregivers completing the questionnaire and provides five degrees of performance impairment for each of six cognitive function categories: memory, orientation, judgment and problem solving, social engagement, home and hobbies, and personal care. Each category is scored from 0 to 3 (the five grades are 0, 0.5, 1, 2 and 3). The sum of the scores in the six categories is the CDR-SB score. A decrease in the CDR-SB score may be indicative of an improvement in the patient's condition, while an increase in the CDR-SB score may be indicative of a deterioration in the patient's condition. According to some embodiments of the present invention, a stable CDR-SB score may be indicative of slowing, delaying, or stopping the progression of AD, or the absence of new clinical, functional, or cognitive symptoms or impairments, or general stabilization of disease activity.

[00087] The term "RBANS" refers to a battery of multiple neuropsychological assessment tests that consists of twelve subtests that are combined to produce five indices, one for each of the five domains tested (short-term memory, visuospatial design, language, attention and long term memory). See, for example, Randolph et al., 1998, J Clin Exp Neuropsychol 20: 310-319. Comprehensive guideline values are given in the testing manuals. An increase in the RBANS score may be indicative of an improvement in the patient's condition, while a decrease in the RBANS score may be indicative of a deterioration in the patient's condition. According to some embodiments of the present invention, a stable RBANS score may be indicative of slowing, delaying, or stopping the progression of AD, or reducing clinical or cognitive deterioration.

[00088] The term "ADAS-Cog 13" refers to a version of the Alzheimer's disease score with an additional cognitive scale that includes 13 items. See, for example, Rosen et al., 1984, Amer. J. Psych . 141: 1356-1364; Mohs et al., 1997, Alzheimer's Disease Assoc. Disorders , 11(2): S13-S21. ADAS-Cog 13 is a multi-part cognitive assessment that assesses multiple cognitive domains including memory, name test, word search, conscious perception, praxis, attention, orientation, and spontaneous speech. ADAS-Cog 13 builds on ADAS-Cog and additionally includes a word delay and a strikeout test. ADAS-Cog 13 gives scores up to 85 points. A decrease in the ADAS-Cog 13 score may be indicative of an improvement in the patient's condition, while an increase in the ADAS-Cog 13 score may be indicative of a deterioration in the patient's condition. According to some embodiments of the present invention, a stable ADAS-Cog 13 score may be indicative of slowing, delaying, or stopping the progression of AD, or reducing clinical or cognitive deterioration.

[00089] As used herein, the term "vector" refers to a nucleic acid molecule capable of propagating another nucleic acid to which it is linked. The term includes a vector as a self-replicating nucleic acid structure, as well as a vector inserted into the genome of the host cell into which it has been introduced. Certain vectors are capable of directing the expression of the nucleic acids to which they are operably linked. Such vectors are referred to herein as "expression vectors".

II. COMPOSITIONS AND METHODS

[00090] The present invention provides methods for treating taupathies with tau-binding antibodies. In particular, methods for treating taupathies with tau-binding antibodies have been found to be safe and tolerable even when administered at high doses. Thus, the present invention provides methods for the treatment of taupathies using antibodies that bind tau at doses ranging from 225 mg to 16800 mg. In some embodiments, the antibody binds monomeric tau, oligomeric tau, non-phosphorylated tau, and phosphorylated tau. In some embodiments, the antibody binds to an epitope within amino acids 2 to 24 of mature human tau. In some embodiments, the antibody binds to an epitope within amino acids 2 to 24 of tau and binds monomeric tau, oligomeric tau, unphosphorylated tau, and phosphorylated tau. In some embodiments, the antibody binds to a human tau epitope having or consisting of the sequence AEPRQEFEVMEDHAGTYGLGDRK (SEQ ID NO: 2). In some embodiments, the antibody binds to a cynomolgus monkey tau epitope having or consisting of the sequence AEPRQEFDVMEDHAGTYGLGDRK (SEQ ID NO: 4).

A. Exemplary anti-tau antibodies

[00091] In some embodiments, the anti-tau antibody comprises (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 20; (b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 21; and (c) an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 22. In some embodiments, the anti-tau antibody comprises at least one, two, or three HVRs selected from (a) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 20; (b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 21; and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 22. In some embodiments, the anti-tau antibody comprises (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 20; (b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 21; (c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 22; (d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 23; (e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 24; and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 25.

[00092] In some embodiments, the anti-tau antibody comprises (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 12; (b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 13; and (c) an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 14. In some embodiments, the anti-tau antibody comprises at least one, two, or three HVRs selected from (a) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 12; (b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 13; and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 14. In some embodiments, the anti-tau antibody comprises (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 12; (b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 13; (c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 14; (d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 15; (e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 16; and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 17.

[00093] In some embodiments, the anti-tau antibody is humanized. In some embodiments, the anti-tau antibody comprises an HVR as in the above embodiment and further comprises a human acceptor framework, eg, a human immunoglobulin framework or a human consensus framework.

[00094] According to some embodiments of the present invention, the antibody comprises the VH and VL sequences shown in SEQ ID NO: 18 and SEQ ID NO: 19, respectively, including post-translational modifications of these sequences, if any.

[00095] According to some embodiments of the present invention, the antibody comprises the VH and VL sequences shown in SEQ ID NO: 10 and SEQ ID NO: 11, respectively, including post-translational modifications of these sequences, if any.

[00096] In some embodiments, an anti-tau antibody is provided, wherein said 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. According to Some embodiments of the present invention provide an anti-tau antibody, the antibody comprising 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. In some embodiments, implementation of the present invention proposed an antibody to tau, and the specified antibody contains a heavy chain containing the amino acid sequence of SEQ ID NO: 27, and a light chain containing the amino acid sequence of SEQ ID NO: 28. an antibody is made up of strands a white chain comprising the amino acid sequence of SEQ ID NO: 27; and a light chain consisting of the amino acid sequence of SEQ ID NO: 28. In some embodiments, an anti-tau antibody is provided, wherein said antibody consists of a heavy chain comprising the amino acid sequence of SEQ ID NO: 26, and a light chain consisting of the amino acid sequence of SEQ ID NO: 27. According to a further aspect of the present invention, an anti-tau antibody according to any of the above embodiments is a monoclonal antibody, including a chimeric, humanized, or human antibody. In one embodiment, the anti-tau antibody is an antibody fragment, eg, a Fv, Fab, Fab', scFv, diabody, or F(ab') ₂ fragment. According to another embodiment of the present invention, the antibody is a full-length antibody, for example, an intact IgG1 or IgG4 antibody, or another antibody class or isotype as defined herein.

[00097] According to a further aspect of the present invention, an anti-tau antibody according to any of the above embodiments may include any of the features, singly or in combination, described in sections 1-5 below:

1. Antibody affinity

[00098] According to some embodiments of the present invention, an antibody of the present invention has a dissociation constant (K _D ) ≤1 μM, ≤100 nM, ≤10 nM, ≤1 nM, ≤0.1 nM, ≤0.01 nM, or ≤0.001 nM (eg 10 ^-8 M or less, eg 10 ^-8 M to 10 ^-13 M, eg 10 ^-9 M to 10 ^-13 M).

[00099] According to some variants of implementation of the present invention, K _D is measured using a quantitative analysis of the binding of an antigen containing a radioactive label (RIA). In some embodiments of the present invention, RIA is performed with the Fab variant of the antibody of interest and its antigen. For example, the binding affinity of a Fab to an antigen in solution is measured by equilibrating a Fab with a minimum concentration of ( ¹²⁵ I)-labeled antigen in the presence of a series of titrating concentrations of unlabeled antigen, followed by capturing the bound antigen on an anti-Fab antibody coated plate (see, e.g., Chen et al., J. Mol Biol 293:865-881 (1999)). To establish conditions for quantitation, ^MICROTITER® multiwell plates (Thermo Scientific) are coated overnight with 5 μg/ml of capturing anti-Fab antibody (Cappel Labs) in 50 mM sodium carbonate (pH=9.6) and then blocked with 2% (wt. ./vol.) with bovine serum albumin in phosphate-buffered saline (PBS) for two to five hours at room temperature (approximately 23°C). In a non-absorbent plate (Nunc #269620), 100 pM or 26 pM [ ¹²⁵ I] antigen are mixed with serial dilutions of the Fab of interest (e.g., as assessed by the anti-VEGF antibody, Fab-12, in Presta et al., Cancer Res. 57:4593-4599 (1997)). The Fab of interest is then incubated overnight; however, incubation may be continued for a longer period (eg, about 65 hours) to reach equilibrium. The mixtures are then transferred to a capture plate for incubation at room temperature (eg, one hour). The solution is then removed and the plate is washed eight times with 0.1% polysorbate 20 (TWEEN- ^20® ) in PBS. After the plates are dry, 150 μl/well of scintillator (MICROSCINT-20™; Packard) is added and the signal in the plates is counted on a TOPCOUNT™ gamma counter (Packard) for ten minutes. Concentrations of each Fab that give 20% or less of maximum binding are selected for use in competitive binding assays.

[000100] According to another implementation variant, K _D was quantitatively measured using surface plasmon resonance BIACORE ^® . For example, a quantification using ^BIACORE® -2000 or ^BIACORE® -3000 (BIAcore, Inc., Piscataway, NJ, USA) was performed at 25° C. using CM5 antigen immobilized chips at ~10 resonance units (RU). In some embodiments of the present invention, carboxymethylated dextran biosensor chips (CM5, BIACORE, Inc.) are activated with N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC) and N-hydroxysuccinimide (NHS) according to the supplier's instructions. The antigen was diluted with 10 mM sodium acetate, pH=4.8, to 5 μg/ml (~0.2 μM) prior to injection at a flow rate of 5 μl/minute to achieve approximately 10 resonance units (RU) of bound protein. After injection of the antigen, 1 M ethanolamine was injected to block unreacted groups. For kinetic measurements, two-fold serial dilutions of Fab (from 0.78 nM to 500 nM) in PBS with 0.05% polysorbate 20 surfactant (TWEEN-20™) (PBST) were injected at 25° C. at a flow rate of approximately 25 μl/min. Association rate (k _on ) and dissociation rate (k _off ) values were calculated using a simple 1:1 Langmuir binding model ( ^BIACORE® evaluation software version 3.2) by simultaneously fitting association and dissociation sensorgrams. The equilibrium dissociation constant (K _D ) was calculated as the ratio k _off /k _on . See, for example, Chen et al., J. Mol. Biol. 293:865-881 (1999). If the association rate exceeds 10 ⁶ M ^-1 s ^-1 as measured by the quantitative surface plasmon resonance assay described above, then the association rate can be determined using a fluorescence quenching technique that measures the increase or decrease in fluorescence intensity (excitation=295 nm ; emission=340 nm, bandwidth 16 nm) 20 nM anti-antigen antibody (Fab form) in PBS, pH=7.2 at 25° C., in the presence of increasing concentrations of antigen measured in a spectrometer such as a spectrophotometer equipped to stop flow rate (Aviv Instruments), or an SLM-AMINCO™ 8000 series spectrophotometer (ThermoSpectronic) equipped with a stirred cuvette.

2. Antibody fragments

[000101] In certain embodiments, an antibody of the present invention is an antibody fragment. Antibody fragments include, but are not limited to, Fab, Fab', Fab'-SH, F(ab') ₂ , Fv and scFv fragments and other fragments described below. For a review of some antibody fragments, see Hudson et al. Nat. Med. 9:129-134 (2003). For a review of scFv fragments, see, for example, Pluckthün, in The Pharmacology of Monoclonal Antibodies , vol. 113, Rosenburg and Moore eds., (Springer-Verlag, New York), pp. 269-315 (1994); see also WO 93/16185; U.S. Patent Nos. 5,571,894 and 5,587,458. For a discussion of Fab and F(ab') ₂ fragments containing reutilization receptor binding epitope residues and having an increased in vivo half-life, see U.S. Patent No. 5,869,046.

[000102] Diabodies are antibody fragments with two antigen-binding sites, which can be divalent or bispecific. See, for example, EP 404,097; WO 1993/01161; Hudson et al., Nat. Med. 9:129-134 (2003); and Hollinger et al., Proc. Natl. Acad. sci. USA 90: 6444-6448 (1993). Tribodies and tetrabodies are also described in Hudson et al., Nat. Med. 9:129-134 (2003).

[000103] Single domain antibodies are antibody fragments containing all or part of the heavy chain variable domain, or all or part of the light chain variable domain of an antibody. In some embodiments, the single domain antibody is a human single domain antibody (Domantis, Inc., Waltham, Massachusetts, USA; see, for example, US Pat. No. 6,248,516 B1).

[000104] Antibody fragments can be generated using a variety of techniques, including, but not limited to, proteolytic cleavage of intact antibodies, as well as production by recombinant host cells (eg, E. coli or phage), as described herein.

3. Chimeric and humanized antibodies

[000105] According to certain embodiments of the present invention, the antibody of the present invention is a chimeric antibody. Some chimeric antibodies are described, for example, in US patent No. 4816567; and Morrison et al. , Proc. Natl. Acad. sci. USA 81:6851-6855 (1984)). In one example, a chimeric antibody comprises a variable region from a non-human species (eg, a variable region derived from a mouse, rat, hamster, rabbit, or non-human primate such as a monkey) and a human constant region. In a further example, a chimeric antibody is a "class-switched" antibody in which the class or subclass has been changed from the parent antibody. Chimeric antibodies include their antigen-binding fragments.

[000106] According to certain embodiments of the present invention, the chimeric antibody is a humanized antibody. Typically, a non-human antibody is humanized to reduce immunogenicity in humans while retaining the specificity and affinity of the parent non-human antibody. Typically, a humanized antibody contains one or more variable domains in which the HVRs, e.g., the CDRs (or portions thereof), are derived from an antibody from a non-human species, and the FRs (or portions thereof) are derived from human antibody sequences. The humanized antibody will optionally also contain at least a portion of the human constant region. In some embodiments of the present invention, some FR residues in a humanized antibody are replaced with corresponding residues from a non-human antibody (e.g., an antibody from which HVR residues are derived), e.g., to restore or improve the specificity or affinity of the antibody.

[000107] Humanized antibodies and methods for their preparation are discussed, for example, in Almagro and Fransson, Front. biosci. 13:1619-1633 (2008), and are further described in, for example, Riechmann et al., Nature 332:323-329 (1988); Queen et al., Proc. Nat'l Acad. sci. USA 86:10029-10033 (1989); U.S. Patent Nos. 5,821,337, 7,527,791, 6,982,321, and 7,087,409; Kashmiri et al ., Methods 36:25-34 (2005) (which describes grafting a specificity determining region (SDR)); Padlan, Mol. Immunol. 28:489-498 (1991) (which describes "surface change");Dall'Acqua et al., Methods 36:43-60 (2005) (which describes "FR permutation"); and Osbourn et al., Methods 36:61-68 (2005) and Klimka et al., Br. J. Cancer , 83:252-260 (2000) (description of the "guided selection" approach to FR permutation).

[000108] Human framework regions that can be used for humanization include, but are not limited to: framework regions selected using the "best fit" method (see, for example, Sims et al. J. Immunol. 151:2296 (1993 )); framework regions derived from the consensus sequence of human antibodies from a defined subgroup of light or heavy chain variable regions (see, e.g., Carter et al. Proc. Natl. Acad. Sci. USA, 89:4285 (1992); and Presta et al. J. Immunol., 151:2623 (1993)); mature human framework regions (somatically mutated) or human germline framework regions (see, for example, Almagro and Fransson, Front. Biosci. 13:1619-1633 (2008)); and framework regions resulting from screening of FR libraries (see, for example, Baca et al., J. Biol. Chem. 272:10678-10684 (1997) and Rosok et al., J. Biol. Chem. 271:22611 -22618 (1996)).

4. Polyspecific antibodies

[000109] According to certain embodiments of the present invention, the antibody of the present invention is a polyspecific antibody, eg, a bispecific antibody. Multispecific antibodies are monoclonal antibodies that have binding specificities for at least two different sites. In certain embodiments of the present invention, one of the binding specificities is for tau and the other is for any other antigen. In some embodiments of the present invention, one of the binding specificities is for tau and the other is for beta-amyloid. In certain embodiments of the present invention, the bispecific antibodies can bind to two different tau epitopes. Bispecific antibodies can also be used to localize cytotoxic agents in cells that express tau. Bispecific antibodies can be prepared as full length antibodies or antibody fragments.

[000110] Techniques for producing multispecific antibodies include, but are not limited to, recombinant co-expression of two immunoglobulin heavy chain and light chain pairs having different specificities (see Milstein and Cuello,Nature 305: 537 (1983)), WO 93/08829, and Traunecker et al.,EMBO J. 10: 3655 (1991)), and lip-to-bottom design (see, for example, US Pat. No. 5,731,168). Multispecific antibodies can also be obtained by design using the effect of electrostatic interaction to obtain Fc-heterodimeric antibody molecules (WO 2009/089004A1); cross-linking of two or more antibodies or fragments (see, for example, US patent No. 4676980, and Brennan et al., Science, 229: 81 (1985)); using leucine zippers to obtain bispecific antibodies (see, for example, Kostelny et al.,J. Immunol., 148(5):1547-1553 (1992)); using "diabody" technology to generate bispecific antibody fragments (see, e.g., Hollinger et al., Proc. Natl. Acad. sci. USA90:6444-6448 (1993)); and using single chain Fv (sFv) dimers (see, for example, Gruber et al., J. Immunol., 152:5368 (1994)); and obtaining trispecific antibodies, as described, for example, in Tutt et al.J. Immunol. 147:60 (1991).

[000111] Engineered antibodies with three or more functional antigen-binding sites, including "octopus antibodies", are also included within the scope of the present invention (see, for example, US 2006/0025576A1).

[000112] An antibody or fragment of the present invention also includes "dual activity FAbs" or "DAFs" containing an antigen-binding site that binds to tau as well as another antigen (see, for example, US 2008/0069820).

5. Antibody variants

[000113] In certain embodiments of the present invention, amino acid sequence variants of the antibodies of the present invention are provided. For example, it may be desirable to improve the binding affinity and/or other biological properties of an antibody. Variants of the amino acid sequence of an antibody can be obtained by introducing appropriate modifications to the nucleotide sequence encoding the antibody, or by peptide synthesis. Such modifications include, for example, deletions from and/or insertions into and/or substitutions of residues in the amino acid sequences of the antibodies. Any combination of deletion, insertion, and substitution can be made to produce a finished construct, provided that the finished construct has the desired characteristics, such as antigen binding.

a) Variants with substitution, insertion and deletion

[000114] According to certain embodiments of the present invention, antibody variants having one or more amino acid substitutions are provided. Sites of interest for substitutional mutagenesis include HVR and FR. Conservative substitutions are presented in Table 1 under the heading "preferred substitutions". More significant changes are presented in Table 1 under the heading "exemplary substitutions" and as further described below with reference to amino acid side chain classes. Amino acid substitutions can be introduced into the antibody of interest and the products can be screened for desired activity, eg, preserved/improved antigen binding, reduced immunogenicity, or improved ADCC or CDC.

TABLE 1

original balance Exemplary substitutions Preferred Substitutions Ala (A) Val; Leu; ile Val Arg(R) Lys; gln; Asn Lys Asn(N) gln; His; Asp, Lys; Arg Gln Asp(D) Glu; Asn Glu Cys(C) Ser; Ala Ser Gln(Q) asn; Glu Asn Glu(E) asp; Gln asp Gly (G) Ala Ala His(H) asn; gln; Lys; Arg Arg Ile (I) Leu; Val; met; Ala; Ph; norleucine Leu Leu (L) Norleucine; Ile; Val; met; Ala; Phe ile Lys (K) Arg; gln; Asn Arg Met(M) Leu; Ph; ile Leu Phe(F) trp; Leu; Val; Ile; Ala; Tyr Tyr Pro (P) Ala Ala Ser(S) Thr Thr Thr(T) Val; Ser Ser TRP(W) Tyr; Phe Tyr Tyr (Y) trp; Ph; Thr; Ser Phe Val(V) Ile; Leu; met; Ph; Ala; norleucine Leu

Amino acids can be grouped according to common side chain properties:

(1) hydrophobic: norleucine, Met, Ala, Val, Leu, Ile;

(2) neutral hydrophilic: Cys, Ser, Thr, Asn, Gln;

(3) acidic: Asp, Glu;

(4) main: His, Lys, Arg;

(5) residues that affect chain orientation: Gly, Pro;

(6) aromatic: Trp, Tyr, Phe.

[000115] Non-conservative substitutions will entail replacing a member of one of these classes with another class.

[000116] One type of substitution variant involves replacing one or more hypervariable region residues of the parent antibody (eg, a humanized or human antibody). Typically, the resulting variant(s) selected for further study will (will) have modifications (e.g., improvements) in certain biological properties (e.g., increased affinity, reduced immunogenicity) compared to the parent antibody and/or will (will) substantially retain certain biological properties of the parent antibody. An exemplary substitution variant is an affinity matured antibody that can be easily generated, for example, using phage display based affinity maturation techniques such as those described herein. In general terms, one or more HVR residues are mutated and antibody variants are displayed on phage and screened for specific biological activity (eg, binding affinity).

[000117] Changes (eg, substitutions) can be made to the HVR, eg, to improve the affinity of the antibody. Such changes can be made in HVR hotspots, i.e. in residues encoded by codons that mutate at high frequency during the somatic maturation process (see, for example, Chowdhury, Methods Mol. Biol. 207:179-196 (2008)), and/or in residues that come into contact with antigen while testing the binding affinity of the resulting VH or VL variant. Affinity maturation by design and reselection from secondary libraries has been described, for example, in Hoogenboom et al. in Methods in Molecular Biology 178:1-37 (O'Brien et al., ed., Human Press, Totowa, NJ, (2001). In some embodiments of affinity maturation, diversity is introduced into the variable genes selected for maturation, with using any of a variety of methods (e.g., error-prone PCR, strand shuffling, or oligonucleotide directed mutagenesis. A secondary library is then created. The library is then screened for any antibody variants with the desired affinity. Another method for introducing diversity includes HVR-targeted approaches, in which multiple HVR residues are randomized (e.g. 4-6 residues at a time. HVR residues involved in antigen binding can be specifically identified, for example, using alanine scanning mutagenesis or modeling. In particular, targets are often CDR-H3 and CDR-L3.

[000118] According to certain embodiments of the present invention, substitutions, insertions, or deletions may occur within one or more HVRs, provided that such changes do not substantially reduce the ability of an antibody to bind to an antigen. For example, conservative changes (eg, conservative substitutions as provided herein) can be made to the HVR that do not substantially reduce binding affinity. Such changes may, for example, be outside the antigen-contacting residues in the HVR. In certain embodiments of the VH and VL sequences presented above, each HVR either remains unchanged or contains no more than one, two, or three amino acid substitutions.

[000119] A suitable method for identifying antibody residues or regions that can be the target of mutagenesis is called "alanine scanning mutagenesis" described by Cunningham and Wells (1989) Science , 244:1081-1085. In this method, a residue or group of target residues (e.g., charged residues such as Arg, Asp, His, Lys, and Glu) are identified and replaced with a neutral or negatively charged amino acid (e.g., alanine or polyalanine) to determine if this had an effect on interaction of an antibody with an antigen. Additional substitutions may be made at amino acid positions that demonstrate functional sensitivity to the initial substitutions. Alternatively or additionally, the crystal structure of the antigen-antibody complex can be used to identify points of contact between an antibody and an antigen. Such contact residues and adjacent residues may be targeted or may be removed as candidates for replacement. Variants can be screened to determine if they have the desired properties.

[000120] Amino acid sequence insertions include amino and/or carboxy terminal fusions ranging in length from one residue to polypeptides containing one hundred or more residues, as well as insertions of one or more amino acid residues within the sequence. Examples of end inserts include an antibody with an N-terminal methionyl residue. Other insertion variants of an antibody molecule include fusion of the N- or C-terminus of the antibody with an enzyme (eg, for ADEPT) or a polypeptide that increases the serum half-life of the antibody.

b) Glycosylation variants

[000121] According to certain embodiments of the present invention, the antibody of the present invention is modified to increase or decrease the degree of glycosylation of the antibody. The addition or removal of glycosylation sites to an antibody can conveniently be accomplished by altering the amino acid sequence so as to create or remove one or more glycosylation sites.

[000122] If the antibody contains an Fc region, then the carbohydrate attached to it can be changed. Native antibodies produced by mammalian cells typically contain a branched bianthenary oligosaccharide that is typically N-linked to Asn297 of the CH2 domain of the Fc region. See, for example, Wright et al. TIBTECH 15:26-32 (1997). The oligosaccharide may include various carbohydrates, such as mannose, N-acetylglucosamine (GlcNAc), galactose and sialic acid, as well as fucose attached to GlcNAc in the stem of the bianthenary oligosaccharide structure. In some embodiments of the invention, modifications can be made to the oligosaccharide in an antibody of the invention to create antibody variants with certain improved properties.

[000123] In some embodiments, the invention provides antibody variants having a carbohydrate structure lacking fucose attached (directly or indirectly) to an Fc region. For example, the amount of fucose in such an antibody may be 1% to 80%, 1% to 65%, 5% to 65%, or 20% to 40%. The amount of fucose is determined by calculating the average amount of fucose in the sugar chain in Asn297 relative to the sum of all glycostructures attached to Asn 297 (for example, complex, hybrid and high-mannose structures), as measured by MALDI-TOF mass spectrometry, for example, as described in WO 2008/077546. Asn297 refers to an asparagine residue located approximately at position 297 in the Fc region (Fc region residues are numbered according to the EU system); however, Asn297 can also be located approximately ±3 amino acids to the left or right of position 297, ie. between positions 294 and 300, due to minor sequence changes in the antibodies. Such fucosylation variants may have improved ADCC function. See, for example, US Patent Publications No. US 2003/0157108 (Presta, L.); US 2004/0093621 (Kyowa Hakko Kogyo Co., Ltd). Examples of publications relating to "defucosylated" or "fucose-deficient" antibody variants include: US 2003/0157108; WO2000/61739; WO 2001/29246; US 2003/0115614; US 2002/0164328; US 2004/0093621; US 2004/0132140; US 2004/0110704; US 2004/0110282; US 2004/0109865; WO2003/085119; WO2003/084570; WO2005/035586; W02005/035778; WO2005/053742; WO2002/031140; Okazaki et al. J. Mol. Biol. 336:1239-1249 (2004); Yamane-Ohnuki et al. Biotech. Bioeng. 87:614 (2004). Examples of cell lines capable of producing defucosylated antibodies include Lec13 CHO cells deficient in protein fucosylation (Ripka et al. Arch. Biochem. Biophys. 249:533-545 (1986); US patent application US 2003/0157108 A1, Presta, L; and WO 2004/056312 A1, Adams et al ., in particular in example 11), and cell lines with genes knocked out, such as the gene for alpha-1,6-fucosyltransferase, FUT8, CHO cell lines with genes knocked out (see ., for example, Yamane-Ohnuki et al Biotech Bioeng 87:614 (2004), Kanda, Y et al Biotechnol Bioeng 94(4):680-688 (2006) and WO2003/085107 ).

[000124] According to the present invention, variants of antibodies with bifurcated oligosaccharides, for example, in which the bianthenary oligosaccharide attached to the Fc region of the antibody is bifurcated by GlcNAc are provided. Such antibody variants may have reduced fucosylation and/or improved ADCC function. Examples of such antibody variants are described, for example, in WO 2003/011878 (Jean-Mairet et al.); US patent No. 6602684 (Umana et al.); and US 2005/0123546 (Umana et al .). The present invention also provides antibody variants with at least one galactose residue in the oligosaccharide attached to the Fc region. Such antibody variants may have improved CSC function. Such antibody variants are described, for example, in WO 1997/30087 (Patel et al.); WO 1998/58964 (Raju, S.); and WO 1999/22764 (Raju, S.).

c) Fc region options

[000125] According to certain embodiments of the present invention, one or more amino acid modifications can be introduced into the Fc region of an antibody of the present invention to produce a variant Fc region. A variant Fc region may comprise a human Fc region sequence (eg, a human IgG1, IgG2, IgG3, or IgG4 Fc region) containing an amino acid modification (eg, substitution) at one or more amino acid positions.

[000126] According to some embodiments of the present invention, a variant of an antibody is provided that has some, but not all, effector functions, making it a desirable candidate for applications in which the half-life of the antibody in vivo is important, but certain effector functions ( such as CSC and ADCC) are unnecessary or harmful. In vitro and/or in vivo quantitative cytotoxicity studies can be performed to confirm the decline/depletion of CDC and/or ADCC activity. For example, quantitative Fc receptor (FcR) binding assays can be performed to verify that an antibody is not capable of FcγR binding (hence likely not having ADCC activity) but retains the ability to bind FcRn. The primary cells mediating ADCC, NK cells, only express FcγRIII, while monocytes express FcγRI, FcγRII, and FcγRIII. FcR expression on hematopoietic cells is summarized in Table 3 on page 464 of Ravetch and Kinet, Annu. Rev. Immunol. 9:457-492 (1991). Non-limiting examples of in vitro quantitative assays to evaluate ADCC activity of a molecule of interest are described in US Pat. 7063 (1986)) and Hellstrom, I et al., Proc. Nat'l Acad. sci. USA 82:1499-1502 (1985); 5821337 (see Bruggemann, M. et al., J. Exp. Med. 166:1351-1361 (1987)). Alternatively, non-radioactive assay methods can be used (see, for example, ACTI™ non-radioactive cytotoxicity assay for flow cytometry (CellTechnology, Inc., Mountain View, CA, USA; and CytoTox ^96® non-radioactive cytotoxicity assay (Promega, Madison). , Wisconsin, USA).Effector cells suitable for such assays include peripheral blood mononuclear cells (PBMCs) and natural killer (NK) cells.Alternatively or additionally, the ADCC activity of a molecule of interest can be assessed in vivo , for example, in an animal model such as that disclosed in Clynes et al Proc Nat'l Acad Sci USA 95:652-656 (1998) C1q binding assays can also be quantified to confirm that the antibody is not capable of binding C1q and therefore has no CSC activity See, for example, ELISA for binding C1q and C3c in WO 2006/02 9879 and WO 2005/100402. To evaluate complement activation, a quantitative study of CSC can be performed (see, e.g., Gazzano-Santoro et al ., J. Immunol. Methods 202:163 (1996); Cragg, MS et al., Blood 101:1045-1052 (2003) ; and Cragg, MS and MJ Glennie, Blood 103:2738-2743 (2004)). FcRn binding and in vivo clearance/half-life determinations can also be made using methods known in the art (see, for example, Petkova, SB et al., Int'l. Immunol. 18(12):1759-1769 (2006)).

[000127] Antibodies with reduced effector function include antibodies with the replacement of one or more residues of the Fc region 238, 265, 269, 270, 297, 327 and 329 (US patent No. 6737056). Such Fc mutants include Fc mutants with substitutions at two or more amino acid positions 265, 269, 270, 297, and 327, including the so-called "DANA" Fc mutant with alanine substitutions at residues 265 and 297 (US Pat. No. 7,332,581).

[000128] Certain antibody variants with improved or reduced FcR binding have been described (see, for example, US Pat. No. 6,737,056; WO 2004/056312, and Shields et al. , J. Biol. Chem. 9(2): 6591-6604 (2001)).

[000129] In certain embodiments, the antibody variant comprises an Fc region with one or more amino acid substitutions that improve ADCC, such as substitutions at positions 298, 333, and/or 334 of the Fc region (residue numbering according to the EU system).

[000130] According to some embodiments of the present invention, changes are made to the Fc region that result in altered (i.e., either improved or reduced) C1q binding and/or complement dependent cytotoxicity (CDC), for example, as described in US patent No. 6194551 , WO 99/51642, and Idusogie et al. J. Immunol. 164: 4178-4184 (2000).

[000131] Antibodies with extended half-life and improved binding to the neonatal Fc receptor (FcRn), which is responsible for the transfer of maternal IgG to the fetus (Guyer et al., J. Immunol. 117:587 (1976) and Kim et al., J. Immunol 24:249 (1994)), described in US2005/0014934A1 (Hinton et al.). These antibodies contain an Fc region with one or more substitutions that improve the binding of the Fc region to FcRn. Such Fc variants include those with substitutions at one or more Fc region residues: 238, 252, 254, 256, 265, 272, 286, 303, 305, 307, 311, 312, 317, 340, 356, 360, 362, 376 , 378, 380, 382, 413, 424, or 434, eg, substitution of residue 434 for the Fc region (eg, US Pat. No. 7,371,826).

[000132] See also Duncan & Winter, Nature 322:738-40 (1988); US patent No. 5648260; US patent No. 5624821; and WO 94/29351 for other examples of Fc region variants.

d) Cysteine-modified antibody variants

[000133] According to some embodiments of the present invention, it may be desirable to create antibodies modified with cysteine, for example, "thioMAT", in which one or more antibody residues are replaced by cysteine residues. In specific embodiments, the substituted residues occur at accessible sites on the antibody. By replacing these residues with cysteine, the reactive thiol groups are thus located at accessible sites on the antibody and can be used to conjugate the antibody to other moieties, such as drug moieties or linker-drug moieties, to create the immunoconjugate described hereinafter. According to certain embodiments of the present invention, any one or more of the following residues may be replaced by cysteine: V205 (Kabat numbering) light chain; A118 (EU numbering) heavy chain; and S400 (EC numbering) of the heavy chain Fc region. Cysteine-modified antibodies can be prepared as described, for example, in US Pat. No. 7,521,541.

e) Antibody derivatives

[000134] According to certain embodiments of the present invention, an antibody of the present invention may be further modified to include additional non-protein fragments that are known in the art and readily available. Fragments suitable for antibody derivatization include, but are not limited to, water-soluble polymers. Non-limiting examples of water-soluble polymers include, but are not limited to, polyethylene glycol (PEG), ethylene glycol/propylene glycol copolymers, carboxymethylcellulose, dextran, polyvinyl alcohol, polyvinylpyrrolidone, poly-1,3-dioxolane, poly-1,3,6-trioxane, ethylene copolymer /maleic anhydride, polyamino acids (both homopolymers and random copolymers) and dextran or poly(n-vinylpyrrolidone) polyethylene glycol, propylene glycol homopolymers, prolypropylene oxide/ethylene oxide copolymers, polyoxyethylated polyols (eg glycerol), polyvinyl alcohol and mixtures thereof. Polyethylene glycol propionaldehyde may have manufacturing advantages due to its stability in water. The polymer may be of any molecular weight and may be branched or unbranched. The number of polymers attached to an antibody may vary, and if more than one polymer is attached, they may be the same or different molecules. In general, the amount and/or type of polymers used for derivatization can be determined based on considerations that include, but are not limited to, the specific properties or functions of the antibody that is being improved, whether or not the antibody derivative is to be used in therapy under certain conditions. conditions, etc.

[000135] In another embodiment, the present invention provides antibody-non-protein fragment conjugates that can be selectively heated by irradiation. In some embodiments of the present invention, the non-protein fragment is a carbon nanotube (Kam et al., Proc. Natl. Acad. Sci. USA 102: 11600-11605 (2005)). The radiation may be of any wavelength and includes, but is not limited to, wavelengths that do not harm normal cells but that heat the non-protein fragment to a temperature that kills cells located proximal to the antibody-non-protein fragment conjugate.

B. Recombinant Methods and Compositions

[000136] Antibodies can be made using recombinant methods and compositions, for example, as described in US Pat. No. 4,816,567. In some embodiments, the present invention provides an isolated nucleic acid encoding an anti-tau antibody described herein. Such a nucleic acid may encode an amino acid sequence containing VL and/or an amino acid sequence containing VH, antibodies (eg light and/or heavy chains of an antibody). In a further embodiment, the present invention provides one or more vectors (eg, expression vectors) containing such a nucleic acid. According to an additional implementation variant of the present invention, a host cell containing such a nucleic acid is provided. In one such embodiment, the host cell contains (e.g., has been transformed): (1) a vector containing a nucleic acid that encodes an amino acid sequence containing an antibody VL and an amino acid sequence containing an antibody VH, or (2) a first vector containing a nucleic acid that encodes an amino acid sequence containing the VL of the antibody, and a second vector containing a nucleic acid that encodes an amino acid sequence containing the VH of the antibody. In some embodiments of the present invention, the host cell is eukaryotic, such as a Chinese Hamster Ovary (CHO) cell or a lymphoid cell (eg, a Y0, NS0, Sp20 cell). According to some embodiments of the present invention, a method for producing an anti-tau antibody is provided, said method comprising culturing a host cell containing a nucleic acid encoding an antibody as described above under conditions suitable for expression of the antibody, and optionally isolating the antibody from the host cell ( or culture medium of the host cell).

[000137] For recombinant production of an anti-tau antibody, a nucleic acid encoding an antibody, such as described above, is isolated and inserted into one or more vectors for further cloning and/or expression in a host cell. Such nucleic acid can be easily isolated and sequenced using conventional procedures (eg, using oligonucleotide probes that are capable of specifically binding to genes encoding antibody heavy and light chains).

[000138] Suitable host cells for cloning or expression of antibody-encoding vectors include prokaryotic or eukaryotic cells as described herein. For example, antibodies can be produced in bacteria, in particular if glycosylation and Fc effector function are not required. For the expression of antibody fragments and polypeptides in bacteria, see, for example, U.S. Patent Nos. 5,648,237 , 5,789,199, and 5,840,523. ), pp. 245-254, which describes the expression of antibody fragments in E. coli ). After expression, the antibody can be isolated from the bacterial cell paste in a soluble fraction and can then be purified.

[000139] In addition to prokaryotes, eukaryotic microbes such as filamentous fungi or yeasts are suitable hosts for cloning or expressing vectors encoding antibodies, including fungi and yeast strains whose glycosylation pathways have been "humanized" resulting in antibody formation with partial or a fully human glycosylation profile. See Gerngross, Nat. Biotech. 22:1409-1414 (2004) and Li et al., Nat. Biotech. 24:210-215 (2006).

[000140] Host cells suitable for expression of the glycosylated antibody also originate from multicellular organisms (invertebrates and vertebrates). Examples of invertebrate cells include plant and insect cells. Numerous baculovirus strains have been identified that can be used in conjunction with insect cells, in particular for transfection of Spodoptera frugiperda cells.

[000141] Plant cell cultures can also be used as hosts. See, for example, US Pat. Nos. 5,959,177; 6,040,498; 6,420,548;

[000142] Vertebrate cells can also be used as hosts. For example, mammalian cell lines that are adapted for propagation in suspension may be suitable. Other examples of suitable mammalian host cell lines are the CV1 monkey kidney cell line transformed with SV40 (COS-7); human embryonic kidney cell line (293 or 293 cells as described, for example, in Graham et al. , J. Gen Virol. 36:59 (1977)); newborn hamster kidney (BHK) cells; mouse Sertoli cells (TM4 cells as described, for example, in Mather, Biol. Reprod. 23:243-251 (1980)); monkey kidney cells (CV1); African green monkey kidney cells (VERO-76); human cervical carcinoma (HELA) cells; dog kidney cells (MDCK; buffalo liver cells (BRL 3A); human lung cells (W138); human liver cells (Hep G2); mouse mammary tumor cells (MMT 060562); TRI cells as described, for example, in Mather et al. , Annals NY Acad. Sci . 383:44-68 (1982), MRC 5 cells as well as FS4 cells Other suitable mammalian host cell lines include Chinese Hamster Ovary (CHO) cells, including ^DHFR CHO cells (Urlaub et al. , Proc. Natl. Acad. Sci. USA 77:4216 (1980)), and myeloma cell lines such as Y0, NS0, and Sp2/0. For a review of some mammalian host cell lines suitable for generating antibodies, see ., for example, Yazaki and Wu, Methods in Molecular Biology, Vol.248 (BKC Lo, ed., Humana Press, Totowa, NJ), pp. 255-268 (2003).

C. Quantitative research

[000143] Anti-tau antibodies of the present invention can be identified, screened, or characterized for their physical/chemical properties and/or biological activities using various assays known in the art.

1. Quantitative binding studies and other quantitative studies

[000144] In one aspect, the antigen-binding activity of an antibody of the present invention is tested, for example, by known methods such as ELISA, Western blot, etc.

[000145] According to another aspect, competitive assays can be used to identify an antibody that competes with the antibody described herein for binding to tau. In certain embodiments of the present invention, such a competing antibody binds to the same epitope (eg, a linear or conformational epitope) that is bound by MTAU or hMTAU. Detailed exemplary methods for mapping an epitope to which an antibody binds are provided in Morris (1996) "Epitope Mapping Protocols" in Methods in Molecular Biology vol. 66 (Humana Press, Totowa, NJ).

[000146] In an exemplary competitive assay, immobilized tau (such as monomeric tau) is incubated in a solution containing a first labeled antibody that binds to tau (eg, any antibody described herein, such as MTAU or hMTAU) and a second unlabeled an antibody whose ability to compete with the first antibody for tau binding is tested. The second antibody may be present in the hybridoma supernatant. As a control, the immobilized tau is incubated in a solution containing the first labeled antibody but not the second unlabeled antibody. After incubation under conditions that ensure the binding of the first antibody to tau, the excess of unbound antibody is removed and the amount of label associated with immobilized tau is measured. If the amount of label associated with immobilized tau is significantly reduced in the test sample compared to the control sample, this indicates that the second antibody is competing with the first antibody for binding to tau. See Harlow and Lane (1988) Antibodies: A Laboratory Manual ch.14 (Cold Spring Harbor Laboratory, Cold Spring Harbor, NY).

2. Quantitative activity studies

[000147] In one aspect, quantitative assay methods are provided for identifying anti-tau antibodies (eg, pan-tau) that have biological activity. Biological activity may include, for example, the binding of such antibodies to several forms of tau (e.g., monomeric tau, oligomeric tau, unphosphorylated tau, and phosphorylated tau) and reduction of tau protein (e.g., total tau, total soluble tau, soluble unphosphorylated tau, soluble phosphorylated tau, total insoluble tau, insoluble unphosphorylated tau, insoluble phosphorylated tau, hyperphosphorylated tau, or paired helical filaments containing hyperphosphorylated tau in the brain, e.g., in the cerebral cortex and/or hippocampus). The present invention also provides antibodies having such biological activity under in vivo and/or in vitro conditions.

[000148] According to certain embodiments of the present invention, an antibody of the present invention is tested to determine such biological activity. For example, an animal model of taupathy, such as tau transgenic mice (eg, P301L), can be used to detect the binding of tau antibodies to brain sections and, for example, neurofibrillary tangles in the brains of transgenic mice. In addition, an animal model of tauopathy, such as a tau transgenic mouse (e.g., P301L), can be treated with anti-tau antibodies, and experimental techniques known in the art can be used to evaluate whether such treatment reduces tau levels (e.g., P301L). , total soluble tau, soluble phosphorylated tau, soluble unphosphorylated tau, total insoluble tau, insoluble phosphorylated tau, insoluble unphosphorylated tau, hyperphosphorylated tau, or paired helical filaments containing hyperphosphorylated tau) in the mouse brain (e.g., in the cerebral cortex and /or hippocampus).

D. Immunoconjugates

[000149] The present invention also provides immunoconjugates comprising an anti-tau antibody conjugated to one or more other therapeutic agents or radioactive isotopes.

[000150] According to another embodiment of the present invention, the immunoconjugate comprises an antibody described herein conjugated to a radioactive atom to form a radioconjugate. Various radioactive isotopes are available for the production of radioconjugates. Examples include²¹¹At,¹³¹I¹²⁵I⁹⁰Y,¹⁸⁶Re,¹⁸⁸Re,¹⁵³sm,²¹²bi,³²P,²¹²Pb and radioactive isotopes Lu. If the radioconjugate is used for detection, it may contain a radioactive atom for scintigraphy, such as tc99m or I123, or a spin label for nuclear magnetic resonance (NMR) (also known as magnetic resonance imaging, MRI), such as iodine-123, iodine-131, indium-111, fluorine-19, carbon-13, nitrogen-15, oxygen-17, gadolinium, manganese or iron.

[000151] Antibody conjugates can be prepared using various bifunctional protein binding agents such as N-succinimidyl-3-(2-pyridyldithio)propionate (SPDP), succinimidyl-4-(N-maleimidomethyl)cyclohexane-1-carboxylate (SMCC ), iminothiolane (IT), difunctional imidoester derivatives (such as dimethyl adipimidate HCl), active esters (such as disuccinimidyl suberate), aldehydes (such as glutaraldehyde), bis-azido compounds (such as bis-(p-azidobenzoyl)hexanediamine, bis -diazonium (such as bis-(p-diazoniumbenzoyl)ethylenediamine), diisocyanates (such as toluene-2,6-diisocyanate), and bis-active fluorine compounds (such as 1,5-difluoro-2,4-dinitrobenzene). , the ricin immunotoxin can be prepared as described in Vitetta et al., Science 238:1098 (1987) Carbon-14 labeled 1-isothiocyanatobenzyl-3-methyldiethylenetriaminopentaacetic acid (MX-DTPA) is a typical chelating agent for conjugating a radionuclide to an antibody See WO94/11026 . The linker may be a "cleavable linker" to facilitate the release of the cytotoxic drug into the cell. For example, an acid-labile linker, a peptidase-sensitive linker, a photolabile linker, a dimethyl linker, or a disulfide-containing linker can be used (Chari et al., Cancer Res. 52:127-131 (1992); US Pat. No. 5,208,020).

[000152] Immunoconjugates or ADCs are expressly provided in the present invention, but are not limited to such conjugates made with cross-linking reagents including, but not limited to, BMPS, EMCS, GMBS, HBVS, LC-SMCC, MBS, MPBH, SBAP, SIA, SIAB, SMCC, SMPB, SMPH, sulfo-EMCS, sulfo-GMBS, sulfo-KMUS, sulfo-MBS, sulfo-SIAB, sulfo-SMCC and sulfo-SMPB, and SVSB (succinimidyl-(4-vinylsulfone)benzoate ) that are commercially available (eg, from Pierce Biotechnology, Inc., Rockford, IL, USA).

E. Pharmaceutical formulations

[000153] Pharmaceutical formulations of an anti-tau antibody described herein are prepared by mixing such an antibody having the desired purity with one or more optional pharmaceutically acceptable carriers, diluents, and/or excipients ( Remington 's Pharmaceutical Sciences 16th ed., Osol, A. Ed. (1980)), in the form of lyophilized formulations or aqueous solutions. Pharmaceutically acceptable carriers, diluents, and excipients are generally non-toxic to recipients at the dosages and concentrations employed and include, but are not limited to: sterile water; buffers such as phosphate, citrate, and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride; benzethonium chloride; phenol, butyl or benzyl alcohol; alkyl parabens such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecular weight (less than about 10 residues) polypeptides; proteins such as serum albumin, gelatin or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine or lysine; monosaccharides, disaccharides and other carbohydrates, including glucose, mannose or dextrins; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose or sorbitol; salt-forming counterions such as sodium; metal complexes (eg Zn-protein complexes); and/or non-ionic surfactants such as polyethylene glycol (PEG). Exemplary pharmaceutically acceptable carriers of the present invention further include interstitial drug dispersing agents, such as soluble neutrally active hyaluronidase glycoproteins (sHASEGP), for example, soluble human hyaluronidase PH-20 glycoproteins, such as rHuPH20 ( ^HYLENEX® , Baxter International, Inc. ). Some exemplary sHASEGPs and methods of using them, including rHuPH20, are described in US Patent Publication Nos. 2005/0260186 and 2006/0104968. In one aspect, sHASEGP is combined with one or more additional glycosaminoglycanases, such as chondroitinases.

[000154] Exemplary lyophilized antibody formulations are described in US Pat. No. 6,267,958. Aqueous antibody formulations include those described in US Pat. No. 6,171,586 and WO2006/044908, the latter formulations including a histidine acetate buffer.

[000155] The composition according to the present invention may also contain more than one active ingredient, if necessary for the particular indication being treated, preferably those that have complementary activities and do not adversely affect each other. Such active ingredients are suitably present in combination in amounts that are effective for the intended purpose.

[000156] The active ingredients may also be microencapsulated, for example, by coacervation or interfacial polymerization techniques, e.g. albumin microspheres, microemulsions, nanoparticles and nanocapsules) or in macroemulsions. Such techniques are described in Remington 's Pharmaceutical Sciences , ^16th Ed., Osol, A. Ed. (1980).

[000157] Sustained release formulations can be obtained. Suitable examples of sustained release formulations include semipermeable matrices of solid hydrophobic polymers containing the antibody, the matrices being in the form of molded articles such as films or microcapsules.

[000158] Formulations that will be used for in vivo administration are typically sterile. Sterility can be easily achieved, for example, by filtration through sterile filter membranes.

F. Therapeutic Methods and Compositions

[000159] Any tau antibody of the present invention can be used in therapeutic methods.

[000160] In one aspect, an anti-tau antibody is provided for use as a drug. In additional aspects, an anti-tau antibody is provided for use in the treatment of a disease or disorder associated with a tau protein. In some embodiments, the present invention provides an anti-tau antibody for use in the treatment of diseases or disorders caused by or associated with the formation of neurofibrillary tangles or neuropil filaments. Specific embodiments of the present invention provide an anti-tau antibody for use in the treatment of tauopathy, such as neurodegenerative tauopathy. Exemplary tau-related diseases or disorders that can be treated with tau antibodies include, but are not limited to, Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease, Creutzfeldt-Jakob disease, Boxer's dementia, Down's syndrome, Gerstmann-Streussler's disease -Scheinker, inclusion body myositis, prion protein-induced cerebral amyloid angiopathy, traumatic brain injury, amyotrophic lateral sclerosis/parkinsonism-dementia complex (Guam disease), non-Guam motor neuron disease with neurofibrillary tangles, dementia with argyrophilic granules, corticobasal degeneration, diffuse neurofibrillary tangles with calcification, frontotemporal dementia, frontotemporal dementia with chromosome 17-related parkinsonism, Hallevorden-Spatz disease, multiple system atrophy, Niemann-Pick type C disease, pallido-ponto-nigral degeneration, Pick's disease, progressive subcortical gliosis, progressive general supranuclear palsy, subacute sclerosing panencephalitis, dementia with a predominance of neurofibrillary tangles, postencephalitic parkinsonism, and myotonic dystrophy. In some embodiments of the present invention, the tauopathy is Alzheimer's disease (AD). In some embodiments, the anti-tau antibody is for use in the treatment of moderate AD, mild or moderate AD, mild AD, early stage AD, prodromal or mild AD, or prodromal AD. stages. In addition, tau-associated diseases or disorders that can be treated with anti-tau antibody include diseases or disorders that manifest as impairment or loss of cognitive function such as reasoning, situational judgment, memory capacity, learning, and/or specialized navigation. . In certain embodiments, the present invention provides an anti-tau antibody for use in a method of treatment. In certain embodiments, the present invention provides an anti-tau antibody for use in a method of treating a subject having any one of the diseases or disorders associated with tau described above, comprising administering to the subject an effective amount of the anti-tau antibody. In one such embodiment, the method further comprises administering to the individual an effective amount of at least one additional therapeutic agent, such as those described below.

[000161] According to some embodiments of the present invention, an antibody of the present invention is used to treat an individual having an MMSE score of 16 to 28, 16 to 18, 16 to 20, 20 to 30, 20 to 26, 24 to 30 , 21 to 26, 22 to 26, 22 to 28, 23 to 26, 24 to 26, or 25 to 26. According to some embodiments of the present invention, the patient has an MMSE score of 22 to 26. In this document the MMSE estimate between two numbers includes the numbers at each end of the range. For example, an MMSE score of 22 to 26 includes MMSE scores of 22 and 26.

[000162] According to some embodiments of the present invention, an antibody of the present invention is used to treat an individual who is "tau positive", e.g., a patient having deposits of tau in the brain that are typical of tau-related disorders, e.g., a patient with a positive positron emission tomography (PET) tau scan.

[000163] In further embodiments, the present invention provides an anti-tau antibody for use in reducing an individual's levels of tau protein (e.g., total tau, total soluble tau, soluble phosphorylated tau, total insoluble tau, aggregated tau, insoluble phosphorylated tau, hyperphosphorylated tau or paired helical filaments containing hyperphosphorylated tau). In some embodiments, an anti-tau antibody is provided for use in reducing an individual's levels of tau protein (e.g., total tau, total soluble tau, soluble phosphorylated tau, total insoluble tau, aggregated tau, insoluble phosphorylated tau, hyperphosphorylated tau, or paired helical filaments containing hyperphosphorylated tau) as measured by PET tau. For example, such a decrease may occur in the brain (eg, in the cerebral cortex and/or the hippocampus). In some embodiments, the present invention provides an anti-tau antibody for use in reducing levels of phosphorylated tau, including soluble phosphorylated tau. In some embodiments, the present invention provides an anti-tau antibody for use in reducing levels of aggregated tau. In some embodiments, the present invention provides an anti-tau antibody for use in reducing levels of insoluble tau (eg, insoluble phosphorylated tau). In some embodiments, the present invention provides an anti-tau antibody for use in reducing levels of hyperphosphorylated tau. In some embodiments, the present invention provides an anti-tau antibody for use in reducing levels of paired helical filaments (eg, paired helical filaments containing hyperphosphorylated tau) in brain tissue (eg, in the cerebral cortex and/or hippocampus). In some embodiments, an anti-tau antibody is provided for use in a method for reducing an individual's levels of tau protein (e.g., total tau, total soluble tau, soluble phosphorylated tau, total insoluble tau, insoluble phosphorylated tau, hyperphosphorylated tau, or paired helical filaments, containing hyperphosphorylated tau) in the brain (eg, in the cerebral cortex and/or hippocampus), comprising administering to the subject an effective amount of an anti-tau antibody to reduce levels of tau protein. An "individual" according to any of the above embodiments is a mammal, preferably a human. According to some variants of implementation of the present invention, the decrease in the level of tau protein is determined by measuring the density and/or degree of tauopathy and/or aggregated tau. Accordingly, a decrease in the density or degree of taupathy and/or aggregated tau (measured, for example, by positron emission tomography) is considered to be indicative of a decrease in tau. Tau, unphosphorylated tau, phosphorylated tau, or hyperphosphorylated tau can be measured by positron emission tomography (PET) or by analysis of cerebrospinal fluid, such as cerebrospinal fluid obtained by lumbar puncture. According to some variants of implementation of the present invention, the decrease in the level of tau protein is determined by measuring the level of the tau fragment.

[000164] In some embodiments, an anti-tau antibody is provided for use in modulating tau protein levels (e.g., total tau, total soluble tau, soluble phosphorylated tau, total insoluble tau, aggregated tau, insoluble phosphorylated tau, hyperphosphorylated tau, or paired helical filaments containing hyperphosphorylated tau), for example, in the brain (eg, in the cerebral cortex and/or hippocampus) of an individual.

[000165] According to a further aspect of the present invention, the use of an anti-tau antibody in the manufacture or preparation of a medicament is provided. According to some variants of implementation of the present invention, the medicinal product is intended for the treatment of a disease or disorder associated with the tau protein. A tau-related disease or disorder can be a disease or disorder caused by or associated with the formation of neurofibrillary tangles or neuropil filaments. In some embodiments of the present invention, the medicament is for the treatment of tauopathy, such as neurodegenerative tauopathy. According to specific embodiments of the present invention, the medicinal product is intended for the treatment of diseases or disorders selected from the group consisting of: Alzheimer's disease (AD), Creutzfeldt-Jakob disease, Boxer's dementia, Down's syndrome, Gerstmann-Straussler-Scheinker's disease, myositis with inclusion bodies , cerebral amyloid angiopathy caused by prion proteins, traumatic brain injury, amyotrophic lateral sclerosis/parkinsonism-dementia complex (Guam disease), non-Guam motor neuron disease with neurofibrillary tangles, dementia with argyrophilic granules, corticobasal degeneration, diffuse neurofibrillary tangles with calcification, frontal temporal dementia, frontotemporal dementia with chromosome 17 parkinsonism, Hallevorden-Spatz disease, multiple system atrophy, Niemann-Pick type C disease, pallido-ponto-nigral degeneration, Pick's disease, progressive subcortical gliosis, progressive dementia with a predominance of neurofibrillary tangles, postencephalitic parkinsonism and myotonic dystrophy. According to some embodiments of the present invention, the drug is for the treatment of AD. According to some embodiments of the present invention, the drug is for the treatment of a disease or disorder associated with tau, which manifests itself as an impairment or loss of cognitive function, such as reasoning, situational judgment, memory capacity, learning, or specialized navigation. According to a further embodiment of the present invention, the medicament is for use in a method of treating one of the diseases listed above (eg, tauopathy, such as AD), comprising administering to an individual having such a disease an effective amount of the medicament. In one such embodiment, the method further comprises administering to the individual an effective amount of at least one additional therapeutic agent, such as those described below.

[000166] In a further embodiment of the present invention, the drug is for reducing levels of tau protein (e.g., total tau, total soluble tau, soluble unphosphorylated tau, soluble phosphorylated tau, total insoluble tau, aggregated tau, insoluble phosphorylated tau, insoluble unphosphorylated tau , hyperphosphorylated tau, or paired helical filaments containing hyperphosphorylated tau). For example, such a decrease in tau protein can be observed in the brain (eg, in the cerebral cortex and/or hippocampus) or in the cerebrospinal fluid of an individual. According to some variants of implementation of the present invention, the drug is designed to reduce the levels of paired helical filaments. According to a further embodiment of the present invention, the drug is for use in a method for reducing an individual's levels of tau protein (e.g., total tau, total soluble tau, soluble phosphorylated tau, total insoluble tau, aggregated tau, insoluble phosphorylated tau, hyperphosphorylated tau, or paired helical filaments containing hyperphosphorylated tau), comprising administering to the subject an effective amount of a drug to reduce the level of tau protein. An "individual" according to any of the above embodiments is a mammal, preferably a human.

[000167] According to a further aspect of the present invention, there is provided a method for treating a disease or disorder associated with a tau protein. A tau-associated disease or disorder that can be treated in accordance with the methods of the present invention includes diseases or disorders caused by or associated with the formation of neurofibrillary tangles or neuropil filaments. In specific embodiments, the present invention provides a method for treating tauopathy, such as neurodegenerative tauopathy. According to specific embodiments, the present invention provides a method for treating a disease or disorder selected from the group consisting of: Alzheimer's disease, Creutzfeldt-Jakob disease, Boxer's dementia, Down's syndrome, Gerstmann-Streussler-Scheinker's disease, inclusion body myositis, cerebral amyloid angiopathy, prion protein-induced traumatic brain injury, amyotrophic lateral sclerosis/parkinsonism-dementia complex (Guam disease), non-Guam motor neuron disease with neurofibrillary tangles, dementia with argyrophilic granules, corticobasal degeneration, diffuse neurofibrillary tangles with calcification, frontotemporal dementia, frontotemporal dementia, temporal dementia with chromosome 17 parkinsonism, Hallevorden-Spatz disease, multiple system atrophy, Niemann-Pick type C disease, pallido-ponto-nigral degeneration, Pick's disease, progressive subcortical gliosis, progressive supranuclear palsy , subacute sclerosing panencephalitis, dementia with a predominance of neurofibrillary tangles, postencephalitic parkinsonism and myotonic dystrophy. In some embodiments, the present invention provides a method for treating Alzheimer's disease (AD). In specific embodiments, the present invention provides a method of treating a tau-associated disease or disorder that manifests as impairment or loss of cognitive function such as reasoning, situational judgment, memory capacity, learning, or specialized navigation. In some embodiments of the present invention, the method comprises administering to an individual having any of the diseases or disorders described above an effective amount of an anti-tau antibody. In one such embodiment, the method further comprises administering to the individual an effective amount of at least one additional therapeutic agent, such as those described below. In some embodiments, the method includes administering to an individual having one of the diseases described herein an effective amount of an anti-tau antibody. In one such embodiment, the method further comprises administering to the individual an effective amount of at least one additional therapeutic agent, described below. An "individual" in accordance with any of the above embodiments may be a human.

[000168] According to a further aspect of the present invention, there is provided a method for reducing an individual's levels of tau protein (e.g., total tau, total soluble tau, soluble phosphorylated tau, total insoluble tau, aggregated tau, insoluble phosphorylated tau, hyperphosphorylated tau, or paired helical filaments containing hyperphosphorylated tau). For example, such a decrease in tau protein levels can be observed in the brain (eg, in the cerebral cortex and/or hippocampus) or cerebrospinal fluid of an individual. In some embodiments, the present invention provides a method for reducing levels of paired helical filaments. In some embodiments of the present invention, the method comprises administering to an individual an effective amount of an anti-tau antibody to reduce tau levels. An "individual" in accordance with any of the above embodiments may be a human.

[000169] According to some aspects of the present invention provides a method of alleviating one or more symptoms of a disease or disorder associated with tau protein; or an anti-tau antibody or a drug containing an anti-tau antibody to alleviate one or more symptoms of a disease or disorder associated with tau protein (such as any of the diseases or disorders described herein, eg, AD). According to some aspects of the present invention, there is provided a method for reducing the number of symptoms or the severity of one or more symptoms of a disease or disorder associated with a tau protein; or an anti-tau antibody or a drug containing an anti-tau antibody to reduce the number of symptoms or the severity of one or more symptoms of a disease or disorder associated with tau protein (for example, any of the diseases or disorders described herein, for example, AD ). According to a specific embodiment of the present invention, the symptom of a tau-associated disease or disorder is a cognitive impairment. According to a specific embodiment of the present invention, the symptom of a tau-associated disease or disorder is a learning and/or memory impairment. According to a specific embodiment of the present invention, the symptom of a disease or disorder associated with tau protein is a loss of long-term memory. According to a specific embodiment of the present invention, the symptom of a tau-associated disease or disorder is dementia. In some embodiments of the present invention, the symptom of a tau disease or disorder is confusion, irritability, aggression, mood swings, or speech disturbance. In some embodiments of the present invention, a symptom of a tau-associated disease or disorder is impairment or loss of one or more cognitive functions, such as reasoning, situational judgment, memory capacity, and/or learning. The methods of the present invention include administering an amount (eg, a therapeutically effective amount) of an anti-tau antibody to an individual (eg, who is exhibiting one or more symptoms of memory loss or memory loss).

[000170] According to specific aspects of the present invention, there is provided a method of maintaining or enhancing memory capacity, memory function, or cognitive function, or slowing down memory loss associated with a tau-related disease or disorder; or an anti-tau antibody or a drug containing an anti-tau antibody to preserve or enhance memory capacity, memory function or cognitive function, or to slow down memory loss associated with a tau-related disease or disorder (such as any of the diseases or disorders described in this document, such as AD). The methods of the present invention include administering an amount (eg, a therapeutically effective amount) of an anti-tau antibody to an individual (eg, who is exhibiting one or more symptoms of memory loss or memory loss).

[000171] According to some aspects of the present invention provides a method of reducing the rate of progression of a disease or disorder associated with tau protein; or an anti-tau antibody or a drug containing an anti-tau antibody to reduce the rate of progression of a disease or disorder associated with tau protein (such as any of the diseases or disorders described herein, eg, AD). The methods of the present invention include administering an amount (eg, a therapeutically effective amount) of an anti-tau antibody to an individual (eg, who is exhibiting one or more symptoms of a tau-associated disease or disorder).

[000172] According to some aspects of the present invention provides a method of preventing the development of a disease or disorder associated with tau protein; or an anti-tau antibody or a drug containing an anti-tau antibody to prevent the development of a tau-associated disease or disorder (such as any of the diseases or disorders described herein, eg, AD). The methods of the present invention include administering an amount (eg, a therapeutically effective amount) of an anti-tau antibody to an individual (eg, who is at risk for a tau-associated disease or disorder).

[000173] According to some aspects of the present invention provides a method of delaying the development of a disease or disorder associated with tau protein; or an anti-tau antibody or a drug containing an anti-tau antibody to delay the development of a disease or disorder associated with tau protein (such as any of the diseases or disorders described herein, eg, AD). The methods of the present invention include administering an amount (eg, a therapeutically effective amount) of an anti-tau antibody to an individual (eg, who is exhibiting one or more symptoms of a tau-associated disease or disorder).

[000174] According to a further aspect of the present invention, pharmaceutical compositions are provided comprising any anti-tau antibody of the present invention, for example, for use in any of the above therapeutic methods. In some embodiments of the present invention, the pharmaceutical composition comprises any of the anti-tau antibodies of the present invention and a pharmaceutically acceptable carrier. According to another embodiment of the present invention, the pharmaceutical composition comprises any of the anti-tau antibodies of the present invention and at least one additional therapeutic agent, for example, as described below.

[000175] The antibodies of the present invention can be used either alone or in combination with other agents in therapy. For example, an antibody of the present invention can be co-administered with at least one additional therapeutic agent.

[000176] For example, a composition in accordance with the present invention can be administered in combination with other compositions containing an additional therapeutic agent, such as a biologically active substance or compound, such as, for example, a known compound used in the treatment of taupathies and/or amyloidosis, group diseases and disorders associated with amyloid or amyloid-like protein, such as the beta-amyloid protein involved in Alzheimer's disease.

[000177] Typically, the other biologically active compound may include neurotransmission enhancers, psychotherapeutic drugs, acetylcholinesterase inhibitors, calcium channel blockers, biogenic amines, benzodiazepine tranquilizers, acetylcholine synthesis, storage, or release enhancers, postsynaptic acetylcholine receptor agonists, monoamine oxidase A or B inhibitors, antagonists NMDA-type glutamate receptors (N-methyl-D-aspartate), non-steroidal anti-inflammatory drugs, antioxidants, serotonergic receptor antagonists, or other therapeutic agents. In particular, the biologically active agent or compound may contain at least one compound selected from compounds against oxidative stress, anti-apoptotic compounds, metal chelators, DNA repair inhibitors such as pirenzepine and metabolites, 3-amino-1-propanesulfonic acid (3APS) , 1,3-propane disulfonate (1,3PDS), secretase activators, beta- and gamma-secretase inhibitors, tau proteins, anti-tau antibodies (including but not limited to the antibodies described in WO2012049570, WO2014028777, WO2014165271, WO2014100600, WO2015200806, US8980270 and US8980271), a neurotransmitter, beta pattern disruptors, anti-inflammatory molecules, "atypical antipsychotics" such as, for example, clozapine, ziprasidone, risperidone, aripiprazole or olanzapine, or cholinesterase inhibitors (ChEIs) such as tacrine, rivastigmine, donepezil and/or galantamine, and other drugs and nutritional supplements such as, for example, vitamin B 12, cysteine, a precursor of acetylcholine, cytin, choline, ginkgo biloba, acetyl-L-carnitine, idebenone, propentofylline or a xanthine derivative together with a binding peptide according to the present invention, including antibodies, in particular monoclonal antibodies and active fragments thereof, and optionally a pharmaceutically acceptable carrier and/or diluent and / or excipient and instructions for the treatment of diseases.

[000178] In some embodiments, an antibody of the present invention may be administered in combination with a neurological drug. Such neurological drugs include, but are not limited to, an antibody or other binding molecule (including, but not limited to, a small molecule, peptide, aptamer, or other protein-binding molecule) that specifically binds to a target selected from: beta-secretase, presenilin, amyloid precursor protein or part thereof, beta-amyloid peptide or oligomers or fibrils thereof, death receptor 6 (DR6), glycosylation end products receptor (RAGE), parkin and huntingtin; an NMDA receptor antagonist (ie memantine), a monoamine depleter (ie tetrabenazine); ergoloid mesylate; an anticholinergic agent against parkinsonism (ie, procyclidine, diphenhydramine, trihexylphenidyl, benzotropine, biperidene, and trihexyphenidyl); a dopaminergic anti-parkinsonian agent (ie, entacapone, selegiline, pramipexole, bromocriptine, rotigotine, selegiline, ropinirole, rasagiline, apomorphine, carbidopa, levodopa, pergolide, tolcapone, and amantadine); tetrabenazine; anti-inflammatory agent (including, but not limited to, non-steroidal anti-inflammatory drug (eg, indomethicin and other compounds listed above), hormone (i.e., estrogen, progesterone, and leuprolide), vitamin (i.e., folate and nicotinamide) dimebolin , homotaurine (i.e., 3-aminopropanesulfonic acid; 3APS), a serotonin receptor activity modulator (i.e., haliproden), interferon, and a glucocorticoid or corticosteroid. The term "corticosteroid" includes, but is not limited to, fluticasone (including fluticasone propionate ( FP)), beclomethasone, budesonide, ciclesonide, mometasone, flunisolide, betamethasone, and triamcinolone. "Inhaled corticosteroid" means a corticosteroid that is suitable for delivery by inhalation. Examples of inhaled corticosteroids include fluticasone, beclomethasone dipropionate, budenoside, mometasone furoate, ciclesonide, flunisolide, and triamcinolone acetonide.

[000179] According to some embodiments of the present invention, one or more anti-amyloid beta (anti-Aβ) antibodies may be administered with an anti-tau antibody of the present invention. Non-limiting examples of such anti-Aβ antibodies include crenezumab, solanezumab, bapineuzumab, adukanumab, gantenerumab, and BAN-2401 (Biogen, Eisai Co., Ltd.). In some embodiments of the present invention, one or more inhibitors of beta-amyloid aggregation may be administered with an anti-tau antibody of the present invention. Non-limiting exemplary beta-amyloid aggregation inhibitors include ELND-005 (also referred to as AZD-103 or scillo-inositol), tramiprosate, and PTI-80 (exebryl- ^1® ; ProteoTech). In some embodiments of the present invention, one or more BACE inhibitors may be administered with an anti-tau antibody of the present invention. Non-limiting examples of such BACE inhibitors include E-2609 (Biogen, Eisai Co., Ltd.), AZD3293 (also known as LY3314814; AstraZeneca, Eli Lilly & Co.), MK-8931 (verubecestat), and JNJ-54861911 (Janssen, Shionogi pharmaceutical). In some embodiments of the present invention, one or more tau inhibitors may be administered with an anti-tau antibody of the present invention. Non-limiting examples of such tau inhibitors include methylthioninium, LMTX (also known as leuco-methylthioninium or Trx-0237; TauRx Therapeutics Ltd.), Rember™ (methylene blue or methylthioninium chloride [MTC]; Trx-0014; TauRx Therapeutics Ltd), PBT2 ( Prana Biotechnology) and PTI-51-CH3 (TauPro™; ProteoTech). In some embodiments of the present invention, one or more other anti-tau antibodies may be administered with the anti-tau antibody of the present invention. Non-limiting examples of such other anti-tau antibodies include BIIB092 or BMS-986168 (Biogen, Bristol-Myers Squibb) and ABBV-8E12 or C2N-8E12 (AbbVie, C2N Diagnostics, LLC). In some embodiments of the present invention, a common misfolding inhibitor such as NPT088 (NeuroPhage Pharmaceuticals) may be administered with an anti-tau antibody of the present invention.

[000180] According to some embodiments of the present invention, the composition in accordance with the present invention may contain niacin or memantine together with a chimeric antibody or a humanized antibody in accordance with the present invention, including antibodies, in particular, monoclonal antibodies and active fragments thereof, and optionally pharmaceutically acceptable carrier and/or diluent and/or excipient.

[000181] According to some embodiments of the present invention, compositions are provided that contain "atypical antipsychotics", such as, for example, clozapine, ziprasidone, risperidone, aripiprazole, or olanzapine, for the treatment of positive and negative psychotic symptoms, including hallucinations, delusions, disturbances in thought processes (manifested in significant inconsistency, slippage, tangentiality) and bizarre or disorganized behavior, as well as anhedonia, affective dullness, apathy, and social withdrawal, together with a chimeric antibody or a humanized antibody of the present invention or active fragments thereof, and optionally a pharmaceutically acceptable carrier and/or diluent and/or excipient.

[000182] Other compounds that may be suitably used in compositions in addition to the chimeric antibody or humanized antibody of the present invention include those disclosed in, for example, WO 2004/058258 (see, in particular, pages 16 and 17), including therapeutic drug targets (pp. 36-39), alkanesulfonic acids and alkanolsulfonic acids (pp. 39-51), cholinesterase inhibitors (pp. 51-56), NMDA receptor antagonists (pp. 56-58), estrogens (pp. 58-59), nonsteroidal anti-inflammatory drugs (pp. 60-61), antioxidants (pp. 61-62), peroxisome proliferator-activated receptor (PPAR) agonists (pp. 63-67), cholesterol-lowering agents (pp. .68-75); amyloid inhibitors (pp. 75-77), inhibitors of amyloid formation (pp. 77-78), metal chelators (pp. 78-79), antipsychotics and antidepressants (pp. 80-82), dietary supplements (pp. 83-89) ) and compounds that increase the availability of biologically active substances in the brain (see pages 89-93), as well as prodrugs (pp. 93 and 94), and the specified document is incorporated into this application by reference, and, in particular, the compounds mentioned on the pages above.

[000183] Such combination therapies noted above encompass combined administration (in which two or more therapeutic agents are included in the same or separate formulations) and separate administration, in which case administration of an antibody of the present invention may occur before, simultaneously and/or after administration of an additional therapeutic agent or agents. In some embodiments of the present invention, the administration of the anti-tau antibody and the administration of the additional therapeutic agent occur approximately one month apart, or approximately one, two, or three weeks apart, or approximately one, two, three, four, five, or six days apart.

[000184] The antibody of the present invention (and any additional therapeutic agent) can be administered by any suitable route, including parenteral, intrapulmonary and intranasal, and, if necessary for topical treatment, intralesional administration. Parenteral infusions include intramuscular, intravenous, intra-arterial, intraperitoneal or subcutaneous administration. Dosing may be by any suitable route, for example by injection, such as intravenous or subcutaneous injection, depending on whether the administration is short term or long term. Various dosing regimens are contemplated according to the present invention, including, but not limited to, single or multiple administration at different time points, bolus administration, and pulsed infusion.

[000185] According to some embodiments of the present invention, a dose of MTAU or hMTAU is administered. In some embodiments of the present invention, the dose of MTAU or hMTAU administered is between 225 mg and 16800 mg. In some embodiments of the present invention, the dose of MTAU or hMTAU administered is 225 mg, 675 mg, 1200 mg, 1500 mg, 2100 mg, 4200 mg, 4500 mg, 8100 mg, 8400 mg, or 16800 mg.

4000 mg , 5200 mg 5300 mg 5400 mg 5500 mg 5600 mg 5700 mg 5800 mg 5900 mg 6000 mg 6100 mg 6200 mg 6300 mg 6400 mg 6500 mg mg, 6900 mg, 7000 mg, 7100 mg, 7200 mg, 7300 mg, 7400 mg, 7500 mg, 7600 mg, 7700 mg, 7800 mg, 7900 mg, 8000 mg, 8100 mg, 8200 mg, 8300 mg, 8400 mg or 8500 mg.

[000187] According to some embodiments of the present invention, the administered dose of MTAU or hMTAU is 200 mg, 700 mg, 1200 mg, 1500 mg, 1700 mg, 2200 mg, 2700 mg, 3200 mg, 3700 mg, 9000 mg, 9500 mg, 10000 mg .

[000188] According to some embodiments of the present invention, the administered dose of MTAU or hMTAU is 225 mg, 725 mg, 1225 mg, 1725 mg, 2225 mg, 2725 mg, 3225 mg, 3725 mg, 4225 mg, 4725 mg, 5225 mg, 5725 mg , 6225 mg 6725 mg 7225 mg 7725 mg 8225 mg 8725 mg 9225 mg 9725 mg 10225 mg mg, 14725 mg, 15225 mg, 15725 mg, 16225 mg or 16725 mg.

[000189] According to some embodiments of the present invention, the dose of MTAU or hMTAU administered is between 1000 mg and 2000 mg. In some embodiments of the present invention, the dose of MTAU or hMTAU administered is between 4000 mg and 16800 mg. In some embodiments of the present invention, the dose of MTAU or hMTAU administered is between 4000 mg and 5000 mg. In some embodiments of the present invention, the dose of MTAU or hMTAU administered is between 4000 mg and 4500 mg. In some embodiments of the present invention, the dose of MTAU or hMTAU administered is between 4500 mg and 5000 mg. In some embodiments of the present invention, the dose of MTAU or hMTAU administered is between 5000 mg and 5500 mg. In some embodiments of the present invention, the dose of MTAU or hMTAU administered is between 5500 mg and 6000 mg. In some embodiments of the present invention, the dose of MTAU or hMTAU administered is between 6000 mg and 6500 mg. In some embodiments of the present invention, the dose of MTAU or hMTAU administered is between 6500 mg and 7000 mg. In some embodiments of the present invention, the dose of MTAU or hMTAU administered is between 7000 mg and 7500 mg. In some embodiments of the present invention, the dose of MTAU or hMTAU administered is between 7500 mg and 8000 mg. In some embodiments of the present invention, the dose of MTAU or hMTAU administered is between 8000 mg and 8500 mg. In some embodiments of the present invention, the dose of MTAU or hMTAU administered is between 8500 mg and 9000 mg. In some embodiments of the present invention, the dose of MTAU or hMTAU administered is between 9000 mg and 9500 mg. In some embodiments of the present invention, the dose of MTAU or hMTAU administered is between 9500 mg and 10000 mg. In some embodiments of the present invention, the dose of MTAU or hMTAU administered is between 10,000 mg and 10,500 mg. In some embodiments of the present invention, the dose of MTAU or hMTAU administered is between 10,500 mg and 11,000 mg. In some embodiments of the present invention, the dose of MTAU or hMTAU administered is between 11,000 mg and 11,500 mg. In some embodiments of the present invention, the dose of MTAU or hMTAU administered is between 11,500 mg and 12,000 mg. In some embodiments of the present invention, the dose of MTAU or hMTAU administered is between 12,000 mg and 12,500 mg. In some embodiments of the present invention, the dose of MTAU or hMTAU administered is between 12,500 mg and 13,000 mg. In some embodiments of the present invention, the dose of MTAU or hMTAU administered is between 13,000 mg and 13,500 mg. In some embodiments of the present invention, the dose of MTAU or hMTAU administered is between 13,500 mg and 14,000 mg. In some embodiments of the present invention, the dose of MTAU or hMTAU administered is between 14,000 mg and 14,500 mg. In some embodiments of the present invention, the dose of MTAU or hMTAU administered is between 14,500 mg and 15,000 mg. In some embodiments of the present invention, the dose of MTAU or hMTAU administered is between 15,000 mg and 15,500 mg. In some embodiments of the present invention, the dose of MTAU or hMTAU administered is between 15,500 mg and 16,000 mg. In some embodiments of the present invention, the dose of MTAU or hMTAU administered is between 16,000 mg and 16,500 mg. In some embodiments of the present invention, the dose of MTAU or hMTAU administered is between 16,500 mg and 17,000 mg.

[000190] According to some embodiments of the present invention, the administered dose of hMTAU is from 50 mg/kg to 240 mg/kg. In some embodiments of the present invention, the administered dose of hMTAU is between 60 mg/kg and 120 mg/kg. In some embodiments of the present invention, the administered dose of hMTAU is between 60 mg/kg and 70 mg/kg. In some embodiments of the present invention, the administered dose of hMTAU is between 70 mg/kg and 80 mg/kg. In some embodiments of the present invention, the administered dose of hMTAU is between 80 mg/kg and 90 mg/kg. In some embodiments of the present invention, the administered dose of hMTAU is between 90 mg/kg and 100 mg/kg. In some embodiments of the present invention, the administered dose of hMTAU is between 100 mg/kg and 110 mg/kg. In some embodiments of the present invention, the administered dose of hMTAU is between 110 mg/kg and 120 mg/kg. According to some embodiments of the present invention, the administered dose of hMTAU is 2.5 mg/kg to 5 mg/kg, 5 mg/kg to 10 mg/kg, 10 mg/kg to 15 mg/kg, 15 mg/kg up to 20 mg/kg, 20 mg/kg to 30 mg/kg, 30 mg/kg to 40 mg/kg, 40 mg/kg to 50 mg/kg, or 50 mg/kg to 60 mg/kg.

[000191] According to some embodiments of the present invention, the administered dose of hMTAU is 60 mg/kg, 70 mg/kg, 80 mg/kg, 90 mg/kg, 100 mg/kg, 110 mg/kg, 120 mg/kg, 130 mg /kg, 140 mg/kg, 150 mg/kg, 160 mg/kg, 170 mg/kg or 180 mg/kg. In some embodiments of the present invention, the administered dose of hMTAU is 150 mg/kg. In some embodiments of the present invention, the administered dose of hMTAU is 180 mg/kg.

[000192] The antibodies of the present invention will be manufactured, dosed, and administered in a manner consistent with Good Medical Practice. Factors to be considered herein include the particular disorder being treated, the particular mammal being treated, the clinical condition of the individual patient, the cause of the disorder, site of delivery of the agent, route of administration, schedule of administration, and other factors known to physicians. As used herein, the term "split dose" is the division of a single unit dose or total daily dose into two or more doses, eg, two or more administrations of a single unit dose. The antibody can be administered as a "split dose".

[000193] The antibody is optionally made with one or more agents currently used to prevent or treat the disorder in question, however this is not required. The effective amount of such other agents depends on the amount of antibody present in the formulation, the type of disorder or treatment, and other factors discussed above. Other agents are generally used at the same dosages and administered via the routes described herein, or from about 1% to about 99% of the dosages described herein, or at any dosage and route empirically/clinically determined to be appropriate. In some embodiments of the present invention, the antibody is provided in an immediate release formulation and the other agent is provided in a sustained release form, or vice versa.

[000194] The antibody is appropriately administered to the patient at one time or over a series of treatments. In some embodiments of the present invention, hMTAU is administered once every 4 weeks. In some embodiments of the present invention, hMTAU is administered once every 1, 2, 4, 5, 6, 7, or 8 weeks. In some embodiments of the present invention, hMTAU is administered 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 times every 1, 2, 4, 5, 6, 7, or 8 weeks.

[000195] According to some embodiments of the present invention, hMTAU is administered intravenously. In some embodiments of the present invention, hMTAU is administered subcutaneously. In some embodiments of the present invention, hMTAU is administered subcutaneously at a dose of 1200 mg. In some embodiments of the present invention, hMTAU is administered intravenously at a dose of 225 mg, 675 mg, 1500 mg, 2100 mg, 4200 mg, 4500 mg, 8100 mg, 8400 mg, or 16800 mg.

G. Monitoring/assessment of response to therapeutic treatment

[000196] According to some embodiments of the present invention, a patient being treated with an antibody described herein is monitored or evaluated to determine if the patient is benefiting from the treatment. According to some embodiments of the present invention, the therapeutic benefit is slowing, delaying, or stopping the progression of AD, or reducing clinical, functional, or cognitive deterioration. For example, benefits may include, but are not limited to, (1) inhibition, to some extent, of the progression of the disease, including slowing the progression and stopping it completely; (2) reduction in plaque or reduction in brain amyloid accumulation and/or reduction in neurofibrillary tangles and/or reduction in brain tau accumulation; (3) improvement in one or more score matrices, including but not limited to CDR-SB, RBANS, and/or ADAS-Cog 13 scores; (4) improving the daily functioning of the patient; (5) a decrease in a biomarker indicative of AD, such as Aβ or tau, in cerebrospinal fluid; and (6) an increase in a biomarker indicating improvement in AD. Patients can be assessed using any indicator that may reveal a benefit to the patient.

[000197] According to some embodiments of the present invention, the cognitive abilities and/or daily functioning of the patient is assessed before, during and/or after the course of antibody therapy described herein. Various cognitive and functional assessment tools are known in the art that can be used to assess, diagnose, and/or determine a measure of mental function, cognitive and/or neurological deficits. Examples of tools include, but are not limited to, ADAS-Cog (including ADAS-Cog 12, ADAS-Cog 13, and ADAS-Cog 14), CDR-SB, MMSE, Useful Daily Life (iADL), activities in Alzheimer's disease of the Alzheimer's Disease Cooperative Research Group (ADCS-ADL) and RBANS.

[000198] According to some embodiments of the present invention, a patient who has been treated with an antibody described herein has an improvement (i.e., a decrease) in that patient's CDR-SB score compared to baseline (e.g., before treatment or at an earlier time during treatment). According to some embodiments of the present invention, the patient's CDR-SB score is reduced by at least 15%, or at least 20%, or at least 25%, or at least 30%, or at least 35%, or at least 40%, or at least 45%, or at least 50%. In some embodiments of the present invention, a patient treated with an antibody described herein exhibits a slowdown in the rate of increase in their CDR-SB score of at least 15%, or at least 20%, or at least 25%, or at least 30%, or at least 35%, or at least 40%, or at least 45%, or at least 50%. According to some embodiments of the present invention, a stable CDR-SB score from baseline (e.g., before treatment or earlier during treatment) may indicate a slowing, delay, or cessation of AD progression, or the absence of new clinical, functional, or cognitive symptoms. or disturbances, or general stabilization of disease activity.

[000199] According to some embodiments of the present invention, a patient who has been treated with an antibody described herein demonstrates an improvement (i.e., an increase) in that patient's RBANS score from baseline (e.g., before treatment or at an earlier time during treatment). According to some embodiments of the present invention, a patient's RBANS score is increased by at least 15%, or 20%, or at least 25%, or at least 30%, or at least 35%, or at least 40%, or at least 45% or at least 50%. In some embodiments, a patient treated with an antibody described herein exhibits a slowdown in the rate of decrease in their RBANS score of at least 15%, at least 20%, or at least 25%, or at least by 30%, or at least 35%, or at least 40%, or at least 45%, or at least 50%. According to some embodiments of the present invention, a stable RBANS score from baseline (e.g., before treatment or earlier during treatment) may be indicative of slowing, delaying, or stopping progression of AD, or reducing clinical or cognitive deterioration.

[000200] According to some embodiments of the present invention, a patient who has been treated with an antibody described herein demonstrates an improvement (i.e., decrease) in that patient's ADAS-Cog score (such as ADAS-Cog 13) from baseline (e.g., , before treatment or at an earlier point during treatment). According to some embodiments of the present invention, a patient's ADAS-Cog score is reduced by at least 15%, or at least 20%, or at least 25%, or at least 30%, or at least 35%, or at least 40%, or at least 45%, or at least 50%. According to some embodiments of the present invention, a patient treated with an antibody described herein exhibits a slowdown in the rate of increase in ADAS-Cog 13 score of at least 15%, or at least 20%, or at least 25%, or at least 30%, or at least 35%, or at least 40%, or at least 45%, or at least 50%. According to some embodiments of the present invention, a stable ADAS-Cog 13 score from baseline (e.g., before treatment or earlier during treatment) may be indicative of slowing, delaying, or halting progression of AD or reducing clinical or cognitive deterioration.

[000201] According to various embodiments of the present invention, the patient is evaluated after 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 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 start of treatment with the antibody described herein. In various embodiments of the present invention, the baseline score is obtained prior to initiation of treatment according to the present invention. As used herein, "before treatment" means at any point in time from the diagnosis of a disease (such as AD) to the administration of the drug of the present invention. According to some embodiments of the present invention, pre-treatment means within 12 months, 6 months, 3 months, 2 months, 1 month, 3 weeks, 2 weeks, or 1 week prior to treatment. According to some embodiments of the present invention, the baseline corresponds to an earlier point during the treatment according to the present invention. According to some embodiments of the present invention, the interval between the baseline assessment and the time point during which the therapeutic benefit to the patient is assessed is 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.

H. Finished product

[000202] According to another aspect of the present invention, a finished product is provided containing materials that can be used to treat, prevent and/or diagnose the disorders described above. The finished product contains a container and a label or package insert on or associated with the container. Suitable containers include, for example, bottles, vials, syringes, intravenous solution bags, etc. The containers can be made from various materials such as glass or plastic. The container contains a composition that, alone or in combination with another composition, is effective in treating, preventing, and/or diagnosing a condition, and may have a sterile entry port (for example, the container may be an intravenous solution bag or vial with a stopper pierceable by a needle for subcutaneous injection). At least one active agent in the composition is an antibody according to the present invention. The label or package insert indicates that the composition is used to treat the selected condition. In addition, the finished product may contain (a) the first container containing the composition, and the specified composition contains the antibody according to the present invention; and (b) a second container containing a composition, said composition containing an additional cytotoxic or other therapeutic agent. The finished product in this embodiment of the present invention may further comprise a package insert indicating that the compositions can be used to treat a particular condition. Alternatively or additionally, the finished product may further comprise a second (or third) container containing a pharmaceutically acceptable buffer such as bacteriostatic water for injection (BWFI), phosphate buffered saline, Ringer's solution, and dextrose solution. In addition, it may contain other materials desirable from a commercial and user point of view, including other buffers, diluents, filters, needles and syringes.

[000203] It should be understood that any of the above finished articles may contain the immunoconjugate of the present invention in place of or in addition to the anti-tau antibody.

III. EXAMPLES

[000204] The following are examples of methods and compositions according to the present invention. It should be understood that various other embodiments may be practiced given the general description above.

Example 1 Clinical Study to Evaluate the Safety and Tolerability of a Humanized Anti-tau Monoclonal Antibody in Healthy Volunteers and Patients with Mild to Moderate Alzheimer's Disease

[000205] A randomized, placebo-controlled, double-blind, phase I study was designed to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of a humanized tau monoclonal antibody (hMTAU) in healthy volunteers and patients diagnosed with mild to moderate Alzheimer's disease (AD). Healthy volunteers were aged 18-80 years and without symptomatic cognitive decline. The AD patients were aged 50-80 years and had a diagnosis of probable AD (by NIA-AA criteria) with a Mini Mental Status Assessment (MMSE) score of 16-28; Folstein et al., 1975, J Psychiatr. Res. 12 :189-98), an overall score of 0.5, 1, or 2 on the Clinical Dementia Rating Scale (CDR; Morris, 1993, Neurology 43:2412-4), and an ¹⁸ F-florbetapyr PET scan that was positive for cerebral amyloid according to the visual definition.

[000206] The study included a single dose escalation (SD) step in healthy volunteers followed by a multiple dose (MD) step in healthy volunteers and AD patients. The study included approximately seven cohorts of SD in healthy volunteers who were given hMTAU, either intravenously (IV) or subcutaneously (SC), one or more MD cohorts in healthy volunteers who were given hMTAU every week (Q1W) x 4 , and one or more MD cohorts in participants with AD who received hMTAU intravenously with Q1W×4. In a single dose escalation study, healthy volunteers received single doses of hMTAU either intravenously (IV; doses ranged from 225 mg to 16800 mg) or subcutaneously (SC; 1200 mg). Each IV SD cohort included 6 healthy volunteers receiving active hMTAU and 2 participants receiving matched placebo at the single dose level. The s.c. SD cohort was designed to evaluate s.c. bioavailability and tolerability. The s.c. SD cohort included 12 healthy volunteers treated with active hMTAU; no placebo group. The SD stage design is depicted in FIG. 1.

[000207] Approximately 10 healthy volunteers were included in the MD (intravenous administration) cohorts, and approximately 10 participants with AD were included in the MD (intravenous administration) cohorts. The MD cohorts consisted of healthy volunteers or participants with AD. Each IV MD cohort included 8 participants receiving active hMTAU and 2 participants receiving a matched placebo. MD cohorts in healthy volunteers and participants with AD were included in the study in a rolling, parallel manner. Table 2 provides details of the treatment cohorts.

[000208] Table 2

Cohort A
225 mg IV ×1 Cohort B 675 mg IV ×1 Cohort C 2100 mg IV ×1 Cohort D 4200 mg IV ×1 Cohort E 8400 mg IV ×1 Cohort H 16800 mg IV ×1 Cohort G 1200 mg s.c. ×1 Cohort F 8400 mg IV QW ×4 BA cohort 8400 mg
I/O QW ×4 N
(active agent: placebo) 3 (2:1) 8 (6:2) 8 (6:2) 8 (6:2) 8 (6:2) 8 (6:2) 12 (12:0) 10 (8:2) 10 (8:2)

[000209] Evaluations were performed as follows. Clinical and safety assessments at screening and at predetermined time points during the study included: vital signs, physical and neurological examinations, laboratory tests, ECG, serum and (in some cohorts) cerebrospinal fluid (CSF) pharmacokinetics, levels tau in plasma and (in some cohorts) in CSF. The Safety Monitoring Committee reviewed safety data on an ongoing basis and made dose escalation decisions in accordance with study stoppage rules and dose-limiting adverse events defined in the protocol. For an event to be considered a dose-limiting adverse event (ADR), it must have occurred within the ADR window, have no well-defined cause other than the investigational drug, and be at least one of the following: serious; 3 degrees or higher; 2 degrees in the neurological category; or grade 2 and associated with infusion/injection.

[000210] Fifty-five (55) healthy volunteers were included in single dose cohorts. At the single dose escalation stage, preliminary data from early evaluations indicated that the most commonly reported adverse events (AEs), regardless of causation, were headache (n=6), nausea (n=3), and infusion site bruising ( n=2) and hematoma (n=1), as well as urinary tract infection (n=3). AEs related to study treatment were injection site reactions (injection site bruising (n=2) and injection site pain (n=1). Additional associated AEs were reported in one patient (ALT/AST increase; nausea; malaise; fatigue; headache; diarrhea; arthralgia. When evaluating single-dose cohorts with additional time points, data showed that adverse events occurred in >1 participant, including headache (n=6), injection/infusion site reaction ( n=6), upper respiratory tract infection (n=3), nausea (n=3), vomiting (n=2), and gastrointestinal viral infection (n=2). >1 participant included vascular puncture site complications (n=2) and postural dizziness (n=2) Nine (12%) participants (all in single dose cohorts) experienced an adverse event reported as being related to study drug: reaction in injection site grade 1 was single significant associated adverse event in >1 participant (n=3, including 2 subjects reporting bruising and 1 subject reporting injection site pain; all three resolved without treatment). At the time of data evaluation, 32 (43%) participants had experienced an adverse event, regardless of causality: 23/55 (42%) in single dose cohorts; 9/20 (45%) in multiple dose cohorts (40% of DA and 50% of AD patients).

[000211] Overall, the study showed that hMTAU was well tolerated. At pre-study evaluation, AEs were non-serious Grade 1-2; no AE ≥3 severity was noted. There were no dose-limiting adverse events (ADARs) or AEs leading to treatment discontinuation, dose modifications, or dosing interruptions. One patient in cohort D (4200 mg IV) withdrew from the study on study day 57 by personal decision. There were no reports of serious AEs or deaths in the study, even at the highest dose tested. In conclusion, preliminary data indicated that single intravenous and subcutaneous doses of hMTAU up to 16800 mg were safe and well tolerated in healthy volunteers.

[000212] hMTAU exhibited dose-proportional and two-compartment serum pharmacokinetics over the entire dose range studied (225 mg - 16800 mg). The terminal half-life of hMTAU was ~30 days: the median terminal t1/2 hMTAU was 32.3 days (range 23-46 days; after a single intravenous injection). FIG. 4. The bioavailability estimate for the subcutaneous formulation (1200 mg) was ~70%. hMTAU was detectable in CSF and had a % CSF/serum of 0.15-0.2%. FIG. 2-5 show the mean concentration of hMTAU in serum (FIG. 2 and FIG. 4) and CSF (FIG. 3 and FIG. 5) following single dose administration at the indicated doses and via the indicated routes. Overall, the pharmacokinetic properties of hMTAU showed a dose-proportional relationship, with no evidence of target-mediated drug distribution. In addition, hMTAU was detectable in the CSF, indicating an effect of the antibody on the CNS.

[000213] Accordingly, hMTAU was safe and well tolerated at single doses up to 16800 mg IV in human volunteers and at multiple doses of 8400 mg Q1Wx4 in human volunteers and AD patients. hMTAU showed dose-proportional FA and a median t _1/2 of 32.3 days, as well as an SC bioavailability of approximately 70%. hMTAU was detectable in the CSF, indicating an effect on the CNS.

[000214] Pharmacokinetic (PK) and pharmacodynamic (PD) profiles were assessed in eight (8) Alzheimer's disease (AD) patients and seven (7) healthy volunteers (HD) following intravenous administration of four weekly doses of hMTAU 8400 mg. One healthy volunteer was incorrectly dosed with 4200 mg hMTAU and excluded from exposure analysis. As shown in FIG. 6, preliminary results showed that, despite similar exposure to hMTAU, a more pronounced PD response was observed in patients with Alzheimer's disease (AD) compared with healthy volunteers (HD). In AD patients, plasma levels of tau after hMTAU administration were twice as high as those in ZD. The FC response was the same in patients with AD and DD. Preliminary studies have shown that baseline plasma tau levels were higher in patients with AD (mean=26.3536 pg/mL; median=24.806 pg/mL) compared with TD (mean=16.4181 pg/mL; median= 15.0045 pg/ml).

Example 2 Clinical Study to Evaluate Three Different Doses of a Humanized Anti-tau Monoclonal Antibody in Patients with Prodromal or Mild Alzheimer's Disease

[000215] Figure 7 shows a design of a clinical study evaluating three different doses of a humanized anti-tau monoclonal antibody (hMTAU) in patients with prodromal, mild Alzheimer's disease. The study included 360 patients with the following selection criteria: one or more of (1) a score of 20-30 on the Mini Mental Status Assessment (MMSE); (2) an overall score of 0.5 or 1 on the Clinical Dementia Rating Scale (CDR-GS); (3) a delayed recall score of ≤85 according to a multiple-choice neuropsychological status battery (RBANS); and/or (4) a positive PET result for amyloid or a positive CSF Aβ result. hMTAU was administered at 1, 3 and 5 weeks and then approximately every 4 weeks. During the study, patients were subjected to one or more of MRI, [ ¹⁸ F]GTP1 PET scans for tau, MMSE, CDR-GS, RBANS, and CSF Aβ screening.

[000216] While the present invention has been described in detail above by way of illustration and example for purposes of clarity of understanding, the descriptions and examples should not be construed as limiting the scope of the present invention. Unless explicitly stated otherwise, all ranges described herein (eg, "4000 mg to 16800 mg") cover the end points of the range. Disclosures of all patents and scientific literature cited herein are incorporated by reference in their entirety.

Sequence table

SEQID NO Description Subsequence 2 Human tau epitope (2-24) AEPRQEFEVMEDHAGTYGLGDRK 4 Epitope of tau cynomolgus macaque (2-24) AEPRQEFDVMEDHAGTYGLGDRK 10 Heavy chain variable region MTAU (VH) EVQLVESGGD LAKPGGSLKL SCTASGLIFR SYGMSWVRQT PDKRLEWVAT INSGGTYTYY PDSVKGRFTI SRDNAKNTLY LQMSSLKSED TAMYYCANSY SGAMDYWGQG TSVTVSS eleven Light chain variable region MTAU (VL) DDLLTQTPLS LPVSLGDPAS ISCRSSQSIV HSNGNTYFEW YLQKPGQSPK LLIYKVSNRF SGVPDRFSGS GSGTDFTLKI SRVEAEDLGV YYCFQGSLVP WTFGGGTKLE IK 12 MTAU HVR-H1 SYGMS 13 MTAU HVR-H2 TINSGGTYTYYPDSVKG 14 MTAU HVR-H3 SYSGAMDY 15 MTAU HVR-L1 RSSQSIVHSNGNTYFE 16 MTAU HVR-L2 KVSNRFS 17 MTAU HVR-L3 FQGSLVVPWT 18 hMTAU heavy chain variable region (VH) EVQLVESGGG LVQPGGSLRL SCAASGLIFR SYGMSWVRQA PGKGLEWVAT INSGGTYTYY PDSVKGRFTI SRDNSKNTLY LQMNSLRAED TAVYYCANSY SGAMDYWGQG TLVTVSS 19 hMTAU light chain variable region (VL) DDVLTQTPLS LPVTPGQPAS ISCRSSQSIV HSNGNTYLEW YLQKPGQSPQ LLIYKVSNRF SGVPDRFSGS GSGTDFTLKI SRVEAEDVGV YYCFQGSLVP WTFGQGTKVE IK 20 hMTAU HVR-H1 SYGMS 21 hMTAU HVR-H2 TINSGGTYTYYPDSVKG 22 hMTAU HVR-H3 SYSGAMDY 23 hMTAU HVR-L1 RSSQSIVHSNGNTYLE 24 hMTAU HVR-L2 KVSNRFS 25 hMTAU HVR-L3 FQGSLVVPWT 26 Heavy chain variant hMTAU 1 EVQLVESGGG LVQPGGSLRL SCAASGLIFR SYGMSWVRQA PGKGLEWVAT INSGGTYTYY PDSVKGRFTI SRDNSKNTLY LQMNSLRAED TAVYYCANSY SGAMDYWGQG TLVTVSSAST KGPSVFPLAP CSRSTSESTA ALGCLVKDYF PEPVTVSWNS GALTSGVHTF PAVLQSSGLY SLSSVVTVPS SSLGTKTYTC NVDHKPSNTK VDKRVESKYG PPCPPCPAPE FLGGPSVFLF PPKPKDTLYI TREPEVTCVV VDVSQEDPEV QFNWYVDGVE VHNAKTKPRE EQFNSTYRVV SVLTVLHQDW LNGKEYKCKV SNKGLPSSIE KTISKAKGQP REPQVYTLPP SQEEMTKNQV SLTCLVKGFY PSDIAVEWES NGQPENNYKT TPPVLDSDGS FFLYSRLTVD KSRWQEGNVF SCSVMHEALH NHYTQKSLSL SLGK 27 Heavy chain variant hMTAU 2 EVQLVESGGG LVQPGGSLRL SCAASGLIFR SYGMSWVRQA PGKGLEWVAT INSGGTYTYY PDSVKGRFTI SRDNSKNTLY LQMNSLRAED TAVYYCANSY SGAMDYWGQG TLVTVSSAST KGPSVFPLAP CSRSTSESTA ALGCLVKDYF PEPVTVSWNS GALTSGVHTF PAVLQSSGLY SLSSVVTVPS SSLGTKTYTC NVDHKPSNTK VDKRVESKYG PPCPPCPAPE FLGGPSVFLF PPKPKDTLYI TREPEVTCVV VDVSQEDPEV QFNWYVDGVE VHNAKTKPRE EQFNSTYRVV SVLTVLHQDW LNGKEYKCKV SNKGLPSSIE KTISKAKGQP REPQVYTLPP SQEEMTKNQV SLTCLVKGFY PSDIAVEWES NGQPENNYKT TPPVLDSDGS FFLYSRLTVD KSRWQEGNVF SCSVMHEALH NHYTQKSLSL SLG 28 Light chain hMTAU DDVLTQTPLS LPVTPGQPAS ISCRSSQSIV HSNGNTYLEW YLQKPGQSPQ LLIYKVSNRF SGVPDRFSGS GSGTDFTLKI SRVEAEDVGV YYCFQGSLVP WTFGQGTKVE IKRTVAAPSV FIFPPSDEQL KSGTASVVCL LNNFYPREAK VQWKVDNALQ SGNSQESVTE QDSKDSTYSL SSTLTLSKAD YEKHKVYACE VTHQGLSSPV TKSFNRGEC

--->

Sequence listing

<110> GENENTECH, INC.

<120> Methods for the treatment of neurodegenerative diseases

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<150> US 62/477,535

<151> 2017-03-28

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<151> 2017-07-14

<150> US 62/577,559

<151> 2017-10-26

<150> US 62/580,359

<151> 2017-11-01

<160> 28

<170> PatentIn version 3.5

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<400> 3

000

<210> 4

<211> 23

<212> PRT

<213> Macaca fascicularis

<400> 4

Ala Glu Pro Arg Gln Glu Phe Asp Val Met Glu Asp His Ala Gly Thr

1 5 10 15

Tyr Gly Leu Gly Asp Arg Lys

20

<210> 5

<400> 5

000

<210> 6

<400> 6

000

<210> 7

<400> 7

000

<210> 8

<400> 8

000

<210> 9

<400> 9

000

<210> 10

<211> 117

<212> PRT

<213> Unknown

<220>

<223> Species of mice

<400> 10

Glu Val Gln Leu Val Glu Ser Gly Gly Asp Leu Ala Lys Pro Gly Gly

1 5 10 15

Ser Leu Lys Leu Ser Cys Thr Ala Ser Gly Leu Ile Phe Arg Ser Tyr

20 25 30

Gly Met Ser Trp Val Arg Gln Thr Pro Asp Lys Arg Leu Glu Trp Val

35 40 45

Ala Thr Ile Asn Ser Gly Gly Thr Tyr Thr Tyr Tyr Pro Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Ser Ser Leu Lys Ser Glu Asp Thr Ala Met Tyr Tyr Cys

85 90 95

Ala Asn Ser Tyr Ser Gly Ala Met Asp Tyr Trp Gly Gln Gly Thr Ser

100 105 110

Val Thr Val Ser Ser

115

<210> 11

<211> 112

<212> PRT

<213> Unknown

<220>

<223> Species of mice

<400> 11

Asp Asp Leu Leu Thr Gln Thr Pro Leu Ser Leu Pro Val Ser Leu Gly

1 5 10 15

Asp Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Ile Val His Ser

20 25 30

Asn Gly Asn Thr Tyr Phe Glu Trp Tyr Leu Gln Lys Pro Gly Gln Ser

35 40 45

Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro

50 55 60

Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile

65 70 75 80

Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Tyr Cys Phe Gln Gly

85 90 95

Ser Leu Val Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys

100 105 110

<210> 12

<211> 5

<212> PRT

<213> Unknown

<220>

<223> Species of mice

<400> 12

Ser Tyr Gly Met Ser

15

<210> 13

<211> 17

<212> PRT

<213> Unknown

<220>

<223> Species of mice

<400> 13

Thr Ile Asn Ser Gly Gly Thr Tyr Thr Tyr Tyr Pro Asp Ser Val Lys

1 5 10 15

gly

<210> 14

<211> 8

<212> PRT

<213> Unknown

<220>

<223> Species of mice

<400> 14

Ser Tyr Ser Gly Ala Met Asp Tyr

15

<210> 15

<211> 16

<212> PRT

<213> Unknown

<220>

<223> Species of mice

<400> 15

Arg Ser Ser Gln Ser Ile Val His Ser Asn Gly Asn Thr Tyr Phe Glu

1 5 10 15

<210> 16

<211> 7

<212> PRT

<213> Unknown

<220>

<223> Species of mice

<400> 16

Lys Val Ser Asn Arg Phe Ser

15

<210> 17

<211> 9

<212> PRT

<213> Unknown

<220>

<223> Species of mice

<400> 17

Phe Gln Gly Ser Leu Val Pro Trp Thr

15

<210> 18

<211> 117

<212> PRT

<213> Artificial sequence

<220>

<223> Heavy chain variable region (VH) hMTAU

<400> 18

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Leu Ile Phe Arg Ser Tyr

20 25 30

Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ala Thr Ile Asn Ser Gly Gly Thr Tyr Thr Tyr Tyr Pro Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Asn Ser Tyr Ser Gly Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu

100 105 110

Val Thr Val Ser Ser

115

<210> 19

<211> 112

<212> PRT

<213> Artificial sequence

<220>

<223> Light chain variable region (VL) hMTAU

<400> 19

Asp Asp Val Leu Thr Gln Thr Pro Leu Ser Leu Pro Val Thr Pro Gly

1 5 10 15

Gln Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Ile Val His Ser

20 25 30

Asn Gly Asn Thr Tyr Leu Glu Trp Tyr Leu Gln Lys Pro Gly Gln Ser

35 40 45

Pro Gln Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro

50 55 60

Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile

65 70 75 80

Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Phe Gln Gly

85 90 95

Ser Leu Val Pro Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105 110

<210> 20

<211> 5

<212> PRT

<213> Artificial sequence

<220>

<223> hMTAU HVR-H1

<400> 20

Ser Tyr Gly Met Ser

15

<210> 21

<211> 17

<212> PRT

<213> Artificial sequence

<220>

<223> hMTAU HVR-H2

<400> 21

Thr Ile Asn Ser Gly Gly Thr Tyr Thr Tyr Tyr Pro Asp Ser Val Lys

1 5 10 15

gly

<210> 22

<211> 8

<212> PRT

<213> Artificial sequence

<220>

<223> hMTAU HVR-H3

<400> 22

Ser Tyr Ser Gly Ala Met Asp Tyr

15

<210> 23

<211> 16

<212> PRT

<213> Artificial sequence

<220>

<223> hMTAU HVR-L1

<400> 23

Arg Ser Ser Gln Ser Ile Val His Ser Asn Gly Asn Thr Tyr Leu Glu

1 5 10 15

<210> 24

<211> 7

<212> PRT

<213> Artificial sequence

<220>

<223> hMTAU HVR-L2

<400> 24

Lys Val Ser Asn Arg Phe Ser

15

<210> 25

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> hMTAU HVR-L3

<400> 25

Phe Gln Gly Ser Leu Val Pro Trp Thr

15

<210> 26

<211> 444

<212> PRT

<213> Artificial sequence

<220>

<223> hMTAU heavy chain variant 1

<400> 26

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Leu Ile Phe Arg Ser Tyr

20 25 30

Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ala Thr Ile Asn Ser Gly Gly Thr Tyr Thr Tyr Tyr Pro Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Asn Ser Tyr Ser Gly Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu

100 105 110

Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu

115 120 125

Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys

130 135 140

Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser

145 150 155 160

Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser

165 170 175

Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser

180 185 190

Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn

195 200 205

Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro

210 215 220

Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe

225 230 235 240

Pro Pro Lys Pro Lys Asp Thr Leu Tyr Ile Thr Arg Glu Pro Glu Val

245 250 255

Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe

260 265 270

Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro

275 280 285

Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr

290 295 300

Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val

305 310 315 320

Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala

325 330 335

Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln

340 345 350

Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly

355 360 365

Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro

370 375 380

Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser

385 390 395 400

Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu

405 410 415

Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His

420 425 430

Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys

435 440

<210> 27

<211> 443

<212> PRT

<213> Artificial sequence

<220>

<223> hMTAU 2 heavy chain variant

<400> 27

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Leu Ile Phe Arg Ser Tyr

20 25 30

Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ala Thr Ile Asn Ser Gly Gly Thr Tyr Thr Tyr Tyr Pro Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Asn Ser Tyr Ser Gly Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu

100 105 110

Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu

115 120 125

Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys

130 135 140

Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser

145 150 155 160

Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser

165 170 175

Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser

180 185 190

Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn

195 200 205

Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro

210 215 220

Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe

225 230 235 240

Pro Pro Lys Pro Lys Asp Thr Leu Tyr Ile Thr Arg Glu Pro Glu Val

245 250 255

Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe

260 265 270

Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro

275 280 285

Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr

290 295 300

Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val

305 310 315 320

Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala

325 330 335

Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln

340 345 350

Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly

355 360 365

Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro

370 375 380

Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser

385 390 395 400

Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu

405 410 415

Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His

420 425 430

Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly

435 440

<210> 28

<211> 219

<212> PRT

<213> Artificial sequence

<220>

<223> hMTAU light chain

<400> 28

Asp Asp Val Leu Thr Gln Thr Pro Leu Ser Leu Pro Val Thr Pro Gly

1 5 10 15

Gln Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Ile Val His Ser

20 25 30

Asn Gly Asn Thr Tyr Leu Glu Trp Tyr Leu Gln Lys Pro Gly Gln Ser

35 40 45

Pro Gln Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro

50 55 60

Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile

65 70 75 80

Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Phe Gln Gly

85 90 95

Ser Leu Val Pro Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105 110

Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu

115 120 125

Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe

130 135 140

Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln

145 150 155 160

Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser

165 170 175

Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu

180 185 190

Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser

195 200 205

Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys

210 215

<---

Claims (34)

1. A method of treating mild to moderate Alzheimer's disease (AD) comprising administering to an individual with mild to moderate AD a monoclonal antibody that binds human tau protein at a dose of 4500 mg, said antibody comprising HVR-H1, containing the amino acid sequence of SEQ ID NO: 20; HVR-H2 containing the amino acid sequence of SEQ ID NO: 21; HVR-H3 containing the amino acid sequence of SEQ ID NO: 22; HVR-L1 containing the amino acid sequence of SEQ ID NO: 23; HVR-L2 containing the amino acid sequence of SEQ ID NO: 24; and HVR-L3 containing the amino acid sequence of SEQ ID NO: 25, and wherein said antibody is administered intravenously once every 4 weeks. 2. The method of claim 1, wherein the individual has a Mini Mental Status Assessment (MMSE) score of 16 to 20. 3. The method according to any one of the preceding claims, characterized in that said treatment comprises slowing down memory loss or maintaining or increasing memory capacity, memory function or cognitive function in an individual. 4. The method of claim. 3, characterized in that the memory capacity, memory function, cognitive function or memory loss is assessed using one or more of the clinical manifestations of dementia rating scale by cell sum (CDR-SB), a battery of multiple tests to determine neuropsychological status (RBANS) and the Alzheimer's Disease Assessment Scale with Complementary Cognitive Scale (ADAS-Cog). 5. The method of claim 3, wherein memory capacity, memory function, cognitive function, or memory loss is assessed using ADAS-Cog. 6. The method according to claim 5, characterized in that the ADAS-Cog is ADAS-Cog 13. 7. The method according to any one of paragraphs. 3-6, characterized in that a decrease in the CDR-SB score or an increase in the RBANS score, or a decrease in the ADS-Cog score after administration of one or more doses of the antibody indicates one or more of an increase in memory capacity, memory function, or cognitive function in the individual. 8. The method according to any one of paragraphs. 3-7, characterized in that a stable CDR-SB score, RBANS score, or ADAS-Cog score, a slowdown in the rate of increase in the CDR-SB score or ADAS-Cog score, or a slowdown in the rate of decrease in the RBANS score after administration of one or more doses of antibody indicates one or more of delayed memory loss or retained memory capacity, memory function, or cognitive function in an individual. 9. The method according to any one of paragraphs. 3-8, characterized in that said CDR-SB score, RBANS score, or ADAS-Cog score is compared with the corresponding score at baseline. 10. The method according to p. 9, characterized in that the initial level precedes the introduction of the antibody. 11. The method according to any one of paragraphs. 3-10, characterized in that said memory capacity, memory function, cognitive function or memory loss is assessed after 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 start of antibody treatment. 12. A method of maintaining or increasing one or more of memory capacity, memory function, or cognitive function, or slowing down memory loss in an individual, comprising administering to an individual with mild to moderate Alzheimer's disease (AD) a monoclonal antibody that binds human tau protein, at a dose of 4500 mg, and the specified antibody contains HVR-H1 containing the amino acid sequence of SEQ ID NO: 20; HVR-H2 containing the amino acid sequence of SEQ ID NO: 21; HVR-H3 containing the amino acid sequence of SEQ ID NO: 22; HVR-L1 containing the amino acid sequence of SEQ ID NO: 23; HVR-L2 containing the amino acid sequence of SEQ ID NO: 24; and HVR-L3 containing the amino acid sequence of SEQ ID NO: 25, and wherein said antibody is administered intravenously once every 4 weeks. 13. The method of claim 12, wherein memory capacity, memory function, cognitive function, or memory loss is assessed using one or more of the Cell Sum Dementia Clinical Rating Scale (CDR-SB), a neuropsychological multiplex battery. status (RBANS) and the Alzheimer's Disease Assessment Scale with Complementary Cognitive Scale (ADAS-Cog). 14. The method of claim. 13, characterized in that the memory capacity, memory function, cognitive function or memory loss is assessed using ADAS-Cog. 15. The method of claim 14 wherein the ADAS-Cog is ADAS-Cog 13. 16. The method according to any one of paragraphs. 13-15, characterized in that a decrease in the CDR-SB score or an increase in the RBANS score, or a decrease in the ADS-Cog score after administration of one or more doses of the antibody indicates increased memory capacity, memory function, or cognitive function in the individual. 17. The method according to any one of paragraphs. 13-16, characterized in that a stable CDR-SB score, RBANS score, or ADS-Cog score, a slowdown in the rate of increase in the CDR-SB score or ADAS-Cog score, or a slowdown in the rate of decrease in the RBANS score after administration of one or more doses of antibody indicates one or more of delayed memory loss or retained memory capacity, memory function, or cognitive function in an individual. 18. The method according to any one of paragraphs. 13-17, characterized in that said CDR-SB score, RBANS score, or ADS-Cog score is compared with the corresponding score at baseline. 19. The method of claim 18, characterized in that the baseline precedes the administration of the antibody. 20. The method according to any one of paragraphs. 13-19, characterized in that said memory capacity, memory function, cognitive function or memory loss is assessed after 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 start of antibody treatment. 21. A method according to any one of the preceding claims, characterized in that said method comprises administering at least one additional therapeutic agent. 22. The method according to claim 21, characterized in that said additional therapeutic agent is selected from neurological drugs, corticosteroids, antibiotics, antiviral agents, tau antibodies, tau inhibitors, antibodies to beta-amyloid, inhibitors of beta-amyloid aggregation, antibodies to BACE1, BACE1 inhibitors, cholinesterase inhibitors, N-methyl-D-aspartate (NMDA) receptor antagonists and dietary supplements. 23. The method of claim 22 wherein the cholinesterase inhibitor is galantamine, rivastigmine, or donepezil. 24. The method of claim 22 wherein the NMDA receptor antagonist is memantine. 25. The method according to any of the preceding claims, characterized in that said 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. 26. The method according to any of the preceding paragraphs, characterized in that the specified antibody contains a heavy chain containing the amino acid sequence of SEQ ID NO: 26 or SEQ ID NO: 27, and a light chain containing the amino acid sequence of SEQ ID NO: 28. 27. The method according to any of the preceding claims, characterized in that said antibody contains 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. 28. The method according to any one of paragraphs. 1-27, characterized in that said antibody is an IgG1 or IgG4 antibody. 29. The method of claim 28, wherein said antibody is an IgG4 antibody. 30. The method according to p. 29, characterized in that the specified antibody contains mutations M252Y, S254T and T256E in accordance with the EU index. 31. The method according to claim 29 or 30, characterized in that said antibody contains the S228P mutation according to the EU index. 32. The method according to any one of paragraphs. 1-31, characterized in that said antibody is an antibody fragment. 33. The method according to any of the preceding claims, characterized in that said antibody binds each of monomeric tau, phosphorylated tau, non-phosphorylated tau, and oligomeric tau with a KD of less than 100 nM, less than 75 nM, or less than 50 nM. 34. The method according to any one of the preceding claims, characterized in that said antibody binds the cynomolgus monkey tau protein of SEQ ID NO: 4.

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