Treatment of tauopathies with TAU-binding antibodies

Abstract

The present invention provides a tau-binding antibody or antigen-binding fragment thereof for use in a method of treating a tauopathy in a human subject in need thereof, the method comprising administering to the human subject at least one dose of 30 mg / kg to 120 mg / kg of the tau-binding antibody or binding fragment thereof, wherein the tau-binding antibody or binding fragment thereof comprises: a light chain variable region comprising a CDR1 selected from SEQ ID No.: 1, a CDR2 selected from SEQ ID No.: 2, and a CDR3 selected from SEQ ID No.: 3; and a heavy chain variable region comprising a CDR1 selected from SEQ ID No.: 4, a CDR2 selected from SEQ ID No.: 5, and a CDR3 selected from SEQ ID No.: 6. In various embodiments, the human subject has a low tau burden or is not an APOE4 carrier.

Description

[0001] TREATMENT OF TAUOPATHIES WITH TAU-BINDING ANTIBODIES

[0002] FIELD OF THE INVENTION

[0003] The present invention relates to the treatment of tauopathies, in particular the treatment of tauopathies such as Progressive Supranuclear Palsy (PSP) and / or Alzheimer’s Disease (AD) with a tau-binding antibody or antigen-binding fragment thereof. Amongst other things the present invention relates to particular dosages of antibody or antigen-binding fragment thereof to be employed.

[0004] BACKGROUND OF THE INVENTION

[0005] Pathologically, tau has been shown to contribute to the development of the group of neurodegenerative diseases which are classed as tauopathies. Tauopathies occur as a result of misfolding and aggregation of the tau protein, which then affects normal neuronal function (Zhang et al., Mol Neuro, 2022). Tau is coded for by the microtubule-associated protein tau gene (MAPT), that is widely distributed in neurons and also expressed in glial cells. In its nonpathological state, tau is a highly soluble protein, which occurs in the central nervous system in 6 main isoforms due to alternative MAPT gene splicing, ranging from 352 to 441 amino acids in length. These isoforms can have 0, 1, or 2 N-terminal inserts (ON, IN, or 2N), and either 3 or 4 C-terminal “repeat” sequences (3R or 4R). These 30 to 32 amino acid C-terminal repeat sequences, Rl, R2, R3, and R4, together constitute the tau MTBR (microtubule binding region).

[0006] In physiological conditions, tau exists in equal balance between 3R and 4R isoforms (Irwin, Parkinsonism Relat Disord. 2016;22 Suppl 1: S29-33), is mainly concentrated in the distal part of axons, and is natively unfolded (Huang et al, Cell Mol Life Sci. 2016;73(l): l-21). Depending on the relative abundance of different tau isoforms in the pathological inclusions found in brain specimens of patients, tauopathies are usually classified as 3R tauopathies (i.e., Pick’s disease), 3R / 4R tauopathies (i.e., Alzheimer’s disease (AD)), and 4R tauopathies (i.e., progressive supranuclear palsy (PS), corticobasal degeneration (CBD), argyrophilic grain disease, and globular glial tauopathies) (Irwin, Parkinsonism Relat Disord. 2016;22 Suppl 1: S29-33).

[0007] PSP is a rare and fatal tauopathy, whose pathology begins with the accumulation of tau in the subcortical and brain stem nuclei, as well as regions related to symptoms such as sleeping disorders, motor dysfunction and Parkinsonism (Coughlin et al., Parkinsonism Relat Disord 2020 Apr;73: 105-116). The progression of PSP results in the reduction of quality of life (QoL) and autonomy of people living with the disease, as they experience worsening dysarthria, cognitive difficulties, and physical disability (Agarwal and Gilbert, StatPearls Publishing 2023), which in turn affects the quality of life of their caregivers and families. Currently, PSP is thought to have a global prevalence of approximately 5-6 per 100 000 (CurePSP Handbook, 2020), with an average time from onset of symptoms to death of 7 years (Hoglinger et al., Mov Dis, 2017; 32: 853-64; Agarwal and Gilbert, StatPearls Publishing 2023). There are currently no approved diseasemodifying treatments to slow down the progression of tauopathies such as PSP or CBD, nor their underlying causes; current treatments only serve to reduce the symptoms of people living with these conditions (Cummings et al., Alzheimer’s Dement. 2023; 9: el2385; Yiannopoulou et al., Biomedicines, 2019 Dec 9;7(4):97). The relentless progression of PSP, short time from symptom onset to death, as well as challenges with accurate and timely diagnosis therefore highlight the high unmet need for disease-modifying treatments.

[0008] In Alzheimer’s disease, the hyperphosphorylation of tau contributes to the amyloid cascade which is responsible for the development of the disease (Yiannopoulou et al., Biomedicines, 2019 Dec 9;7(4):97). In the case of AD aducanumab and lecanemab, two beta-amyloid targeting antibodies, have been approved by the FDA after having demonstrated a slowing of disease progression in clinical trials. Alzheimer’s disease (AD) pathology is characterised by formation of both neuronal tau fibrils and extracellular amyloid plaques. The behavioral symptoms of AD correlate with the accumulation of plaques and tangles, and they are a direct consequence of the damage and destruction of synapses that mediate memory and cognition. These treatments will nonetheless address only one of the two agents that are believed to be directly related to the pathology.

[0009] WO 2017 / 005734 describes tau-binding antibodies with a specificity to the central region of human tau. In a tau seeding experiment, these antibodies blocked the seeding of both human AD and PSP tau. Based on these results, targeting the central region of tau blocked the seeding of human tau, whereas targeting the N-terminal region did not.

[0010] Emerging data on the biology of human tau suggests that the efficacy of passive antibody treatment is likely to be influenced by the fragmentation pattern of the tau molecule and the antibody epitope (Hoglinger et al. Lancet Neurology 2021). Previous studies have investigated antibodies that targeted the N-terminal region of human tau. Examples of those studies were Phase 2 clinical trials, which assessed the safety and efficacy of gosuranemab (NCT03068468, N=486) and tilavonemab (NCT02985879, N=377) in people with PSP. These antibodies however, failed to demonstrate clinical efficacy. Similarly, both antibodies also failed in Phase 2 clinical trials in people with Alzheimer’s disease. An additional N-terminal targeting anti-tau antibody, semorinemab (NCT03289143, N=457; and NCT03828747, N=272) was also assessed in Phase 2 trials in patients with prodromal to mild Alzheimer’s disease and moderate Alzheimer’s disease, respectively. Neither trial reached its primary endpoint and development of semorinemab was terminated.

[0011] Thus, the need for effective antibody treatments to target human tau and hence tauopathies such as Alzheimer’s disease and PSP remains.

[0012] SUMMARY OF THE INVENTION

[0013] The present invention provides in one embodiment a tau-binding antibody or antigenbinding fragment thereof for use in a method of treating a tauopathy in a human subject in need thereof, wherein the method comprising determining which of the three weight bands of <60 kg, 60kg to 90kg, and >90 kg the subject falls in, then administering the antibody or antigen-binding fragment at a dose or doses of:

[0014] (i) 3.5g to 4.5g if the body weight of the subject is <60 kg;

[0015] (ii) 5.5g to 6.5 g if the body weight of the subject is 60 kg to 90 kg; or

[0016] (iii) 7.5g to 8.5 g if the body weight of the subject is >90 kg, wherein the tau-binding antibody or antigen-binding fragment thereof binds to an epitope comprising the amino acid residues of S238, A239, S241, T245, A246, of SEQ ID No.: 11, optionally wherein the epitope further comprises one or more residues selected from S235, S237, K240, R242, L243, Q244, V248, and M250 of SEQ ID No.: 11.

[0017] The present invention further provides a tau-binding antibody or antigen-binding fragment thereof for use in a method of treating Alzheimer’s disease (AD) in a human subject in need thereof, the method comprising administering to the human subject a tau-binding antibody or antigen-binding fragment thereof, wherein the tau-binding antibody or antigen-binding fragment thereof binds to an epitope comprising the amino acid residues of S238, A239, S241, T245, A246, of SEQ ID No. : 11, optionally wherein the epitope further comprises one or more residues selected from S235, S237, K240, R242, L243, Q244, V248, and M250 of SEQ ID No.: 11, wherein the human subject has a low tau burden or is not an APOE4 carrier.

[0018] The present invention also provides a tau-binding antibody or antigen-binding fragment thereof for use in a method of treating Alzheimer’s Disease in a human subject in need thereof, the method comprising administering to the human subject at least one dose of 85 mg / kg to 95 mg / kg of the tau-binding antibody or antigen-binding fragment thereof, wherein the tau-binding antibody or antigen-binding fragment thereof comprises: a light chain variable region comprising a CDR1 selected from SEQ ID No.: 1, a CDR2 selected from SEQ ID No.: 2, and a CDR3 selected from SEQ ID No.: 3; and a heavy chain variable region comprising a CDR1 selected from SEQ ID No.: 4, a CDR2 selected from SEQ ID No.: 5, and a CDR3 selected from SEQ ID No.: 6.

[0019] The present invention further provides a method of treating a tauopathy in a human subject in need thereof, wherein the method comprises determining which of the three weight bands of <60 kg, 60kg to 90kg, and >90 kg the subject falls in, then administering a tau-binding antibody or antigen-binding fragment thereof at a dose or doses of:

[0020] (i) 3.5g to 4.5g if the body weight of the subject is <60 kg;

[0021] (ii) 5.5g to 6.5 g if the body weight of the subject is 60 kg to 90 kg; or

[0022] (iii) 7.5g to 8.5 g if the body weight of the subject is >90 kg, wherein the tau-binding antibody or antigen-binding fragment thereof binds to an epitope comprising the amino acid residues of S238, A239, S241, T245, A246, of SEQ ID No.: 11, optionally wherein the epitope further comprises one or more residues selected from S235, S237, K240, R242, L243, Q244, V248, and M250 of SEQ ID No.: 11.

[0023] The present invention further provides a method of treating Alzheimer’s disease (AD) in a human subject in need thereof, the method comprising administering to the human subject a tau- binding antibody or antigen-binding fragment thereof, wherein the tau-binding antibody or antigen-binding fragment thereof binds to an epitope comprising the amino acid residues of S238, A239, S241, T245, A246, of SEQ ID No.: 11, optionally wherein the epitope further comprises one or more residues selected from S235, S237, K240, R242, L243, Q244, V248, and M250 of SEQ ID No.: 11, wherein the human subject has a low tau burden or is not an APOE4 carrier.

[0024] The present invention further provides a method of treating Alzheimer’s Disease in a human subject in need thereof, the method comprising administering to the human subject at least one dose of 85 mg / kg to 95 mg / kg of a tau-binding antibody or antigen-binding fragment thereof, wherein the tau-binding antibody or antigen-binding fragment thereof comprises: a light chain variable region comprising a CDR1 selected from SEQ ID No.: 1, a CDR2 selected from SEQ ID No.: 2, and a CDR3 selected from SEQ ID No.: 3; and a heavy chain variable region comprising a CDR1 selected from SEQ ID No.: 4, a CDR2 selected from SEQ ID No.: 5, and a CDR3 selected from SEQ ID No.: 6.

[0025] In a further embodiment, the invention provides a tau-binding antibody or antigen-binding fragment thereof for use in a method of treating a tauopathy in a human subject (also referred to herein as “a patient”, “the patient”, “sufferer” or “patients” (where more than one human subject is discussed) in need thereof, the method comprising administering to the human subject at least one dose of 30 mg / kg to 120 mg / kg of the tau-binding antibody or antigen-binding fragment thereof, wherein the tau-binding antibody or antigen-binding fragment thereof comprises: a light chain variable region comprising a CDR1 selected from SEQ ID No.: 1, a CDR2 selected from SEQ ID No.: 2, and a CDR3 selected from SEQ ID No.: 3; and a heavy chain variable region comprising a CDR1 selected from SEQ ID No.: 4, a CDR2 selected from SEQ ID No.: 5, and a CDR3 selected from SEQ ID No.: 6.

[0026] BRIEF DESCRIPTION OF THE FIGURES

[0027] Figure 1. UP0047 - Dose proportionality of bepranemab exposure in serum (PK- PPS). (A) Cmax; (B) AUC. AUC=area under the concentration-time curve from time 0 to infinity; AUC(O-t) = area under the concentration-time curve from time 0 to time t; CI = confidence interval; Cmax = maximum observed concentration; PK-PPS = Pharmacokinetic-Per Protocol Set. Note: Regression line formula for AUC (original values - linear scale) was y=l l 874.95*x+21800.79. Note: Regression line formula for AUC(O-t) (original values - linear scale) was y=11433.58*x+22368.11. Note: Regression line formula for Cmax (original values - linear scale) was y = 26.376*x-21.074.

[0028] Figure 2. UP0065 - Dose proportionality of bepranemab exposure in serum (PK-PPS). (A) Cmax; (B) AUC. AUC = area under the concentration-time curve from time 0 to infinity; AUC(O-t) = area under the concentration-time curve from time 0 to time t; CI=confidence interval; Cmax = maximum observed concentration; PK PPS=Pharmacokinetic-Per Protocol Set. The slight deviation from dose proportionality in the exposure (AUC) is due to the variability between participants, as this analysis was based on a limited sample size (6 subjects per arm).

[0029] Figure 3. Schedule of activities and endpoint recording for PSP003.

[0030] Figure 4. Overview of incidence of TEAEs in PSP003.

[0031] Figure 5. Most frequent TEAEs by SOC and PT.

[0032] Figure 6. Free tau species targeted by bepranemab levels in CSF - % change from baseline to week 1: all participants. Due to technical & biological considerations, study sample data were reported as a percentage of baseline data, and not as concentration data (neat sample analysis only). Data should be viewed as qualitative rather than quantitative.

[0033] Figure 7. CSF free tau inhibition in placebo versus 90 mg / kg bepranemab groups CSF=cerebrospinal fluid.

[0034] Figure 8. Individual values of CSF free tau over time, showing the decrease of free tau in CSF over time in 90mg / kg treated groups versus placebo.

[0035] Figure 9. Tau accumulation across the full AH0003 population in (A) Whole Cortical Grey Region and (B) Jack Temporal Meta Region, showing the difference in tau accumulation from week 56 to week 80, for patients having received 45 mg / kg bepranemab or 90 mg / kg bepranemab compared to placebo. Y-axis is showing adjusted scores for change from baseline (CFB) calculated with a confidence interval (CI) of 95%.

[0036] Figure 10. Tau accumulation in the Whole Cortical Grey Region in (A) patients with low tau burden at baseline or non APOE4 carriers and (B) patients with high tau burden at baseline and are APOE4 carriers, showing bepranemab slows tau accumulation in patients who are either non-APOE4 carriers or had low tau burden at baseline. Y-axis is showing adjusted scores for change from baseline (CFB) calculated with a confidence interval (CI) of 95%.

[0037] Figure 11. Tau accumulation in the Jack Temporal Meta Region in (A) patients with low tau burden at baseline or non APOE4 carriers and (B) patients with high tau burden at baseline and are APOE4 carriers, showing bepranemab slows tau accumulation in patients who are either non-APOE4 carriers or had low tau burden at baseline. Y-axis is showing adjusted scores for change from baseline (CFB) calculated with a confidence interval (CI) of 95%.

[0038] Figure 12. Overview of efficacy results for the full AH0003 population, showing a statistically significant reduction in the rates of tau burden accumulation and cognitive decline as measured by ADAS-Cogl4. In this figure(1)means statistically significant efficacy,(2)means positive efficacy trend,(3)means null effect,(4)means trend favours placebo and(5)means statistically significant favours placebo. The threshold for efficacy was set at a 2-sided p-value of <0.2.

[0039] Figure 13. Overview of subpopulation efficacy results for patients having received 45 mg / kg of bepranemab, showing that in a subpopulation with either low tau burden at baseline (L- Tau) or who are APOE4 non-carriers (s4-) bepranemab treatment results in a statistically significant lower tau accumulation, and in cognitive decline as measured in ADAS-Cogl4 and MMSE. In this figure(1)means statistically significant efficacy,(2)means positive efficacy trend,(3)means null effect,(4)means trend favours placebo and(5)means statistically significant favours placebo. H-Tau means high tau burden at baseline and s4+ means APOE4 carrier. Threshold for efficacy was set at a 2-sided p-value of <0.2.

[0040] Figure 14. Overview of subpopulation efficacy results for patients having received 90 mg / kg of bepranemab, showing that in a subpopulation with either low tau burden at baseline (L- Tau) or who are APOE4 non-carriers (s4-) bepranemab treatment resulted in slower cognitive and functional decline as measured by CDR-SB with a statistically significant mean reduction of 28.7% relative to placebo, reduced the rate of tau accumulation by 67-69%, and slowed cognitive and functional decline in all secondary clinical endpoints including activities of daily living. In this figure(1)means statistically significant efficacy,(2)means positive efficacy trend,(3)means null effect,(4)means trend favours placebo and(5)means statistically significant favours placebo. H-Tau means high tau burden at baseline and s4+ means APOE4 carrier. Threshold for efficacy was set at a 2-sided p-value of <0.2.

[0041] Figure 15. Simulated average (Cave), predose (Ctrough) and maximal (Cmax) bepranemab concentrations shown respectively in panels A, B, and C for varying body weight (bw)-based (mg / kg) and fixed (mg) bepranemab doses, per bodyweight band. In each group of plots results are shown going left to right for 45 mg / kg, a fixed dose of 3200 mg, 60 mg / kg, a fixed dose of 4300 mg, 90 mg / kg, and a fixed dose of 6400 mg.

[0042] Figure 16. Simulated average (Cave), predose (Ctrough) and maximal (Cmax) bepranemab concentrations shown respectively in panels A, B, and C at varying fixed doses and 90 mg / kg for body weights of 80-130 kg. In each group of plots results are shown going left to right for 90 mg / kg, then for fixed doses of 6400 mg, 7200 mg, 8100 mg, 9000mg, 9900 mg and 10,800 mg. Figure 17. Histograms of mg bepranemab doses assuming 90 mg / kg dosing for all

[0043] AH0003 study participants. Vertical lines represent fixed doses of 4300, 6400, 8000 and 9000 mg.

[0044] Figure 18. Simulated average (Cave) and maximal (Cmax) bepranemab concentrations for varying bodyweight-based (mg / kg) and fixed (mg) bepranemab doses, per body weight bands. In the key for each panel the dosages shown going from top to bottom correspond to those going from left to right in the graph itself.

[0045] Figure 19. Histograms of mg bepranemab doses assuming 60 mg / kg dosing for all AH0003 study participants. Vertical lines represent fixed doses of 3000, 4000 and 5000 mg.

[0046] Figure 20. Simulated relative change from baseline and placebo in CDR-SB and ADAS-Cogl4 following 80 weeks of bepranemab dosing every 4 weeks for fixed vs 90 mg / kg dosing. Going from left to right in each panel results are shown for 90 mg / kg, as well as for fixed doses of 4300 mg, 6400 mg, 8000 mg, and 9000 mg.

[0047] Figure 21. Simulated relative change from baseline and placebo in CDR-SB, ADAS- Cogl4 and A-iADL, per low or high GTP1 tau burden at baseline, following 80 weeks of bepranemab dosing every 4 weeks for fixed doses vs 60 mg / kg or 90 mg / kg. In each panel going from left to right results are shown for 60 mg / kg, a fixed dose of 3000 mg for subjects <60 kg, a fixed dose of 4000 mg for subjects 60 kg to <90 kg, a fixed dose of 5000 mg for subjects >90kg, 90 mg / kg, a fixed dose of 4000 mg for subjects <60 kg, a fixed dose of 6000 mg for subjects 60 kg to <90 kg, and 8000 mg for subjects >90 kg.

[0048] DETAILED DESCRIPTION OF THE INVENTION

[0049] This invention pertains to methods of treating a tauopathy in which the administration of a tau-binding antibody is beneficial. The present invention pertains to particularly effective doses and dosing regimens for treating tauopathies. The invention also pertains to specific patient groups. The present invention provides the methods themselves. The present invention also provides tau binding antibodies and antigen-binding fragments thereof for use in such methods. It also provides use of tau binding antibodies and antigen-binding fragments thereof for the manufacture of a medicament for treating tauopathies. Hence, for instance, wherever a method of treatment is set out herein, the present invention also provides for use in the manufacture of a medicament of what is set out as well as a tau binding antibody or antigen-binding fragment thereof for use in such a method of treatment, as well as vice versa. Although, the present invention is applicable to tauopathies in general, particular tauopathies of interest are Progressive Supranuclear Palsy (PSP) and Alzheimer’s Disease (AD). In one embodiment, the tauopathy is Alzheimer’s Disease (AD).

[0050] Tau binding antibodies and antigen-binding fragments thereof

[0051] The present application is based in part on the identification of particularly effective dose and dosing schedules for tau-binding antibodies or binding fragments thereof in the treatment of tauopathies. The present section sets out examples of particular tau-binding antibodies and antigenbinding fragments thereof that may be used in the present invention. As is customary in the field, Tau residue numbering in this text refers to Tau isoform 2 of SEQ ID No. : 11 (NCBI reference sequence: NP_005901.2).

[0052] In one embodiment, the tau binding antibody or antigen-binding fragment thereof binds to the central region of the human tau protein. Optionally the antibody or antigen-binding fragment thereof employed in the invention recognizes an epitope comprising at least the amino acids residues of S238, A239, S241, T245, A246 of SEQ ID No.: 11. This region is just before the first MTBR repeat region present in all 6 isoforms of Tau that may be found in the central nervous system. In a further particular embodiment, the tau-binding antibody or binding fragment thereof binds to an epitope comprising the amino acid residues of S238, A239, S241, T245, A246, and one or more residues selected from S235, S237, K240, R242, L243, Q244, V248, and M250 of SEQ ID No.: 11. In a further particular embodiment, the epitope bound by the tau-binding antibody or binding fragment thereof is determined by heteronuclear single quantum coherence nuclear magnetic resonance (HSQC NMR).

[0053] In one embodiment, the antibody or antigen-binding fragment thereof is a monoclonal antibody or antigen-binding fragment thereof. In one particular embodiment the antibody or antigen-binding fragment thereof is a humanized monoclonal Tau-binding antibody or antigenbinding fragment thereof.

[0054] In another embodiment, the tau-binding antibody or binding fragment thereof binds to both soluble human and paired helical filaments (PHF) of human tau.

[0055] Examples of antibodies and antigen-binding fragments thereof which may be employed in the present invention are described in WO 2017 / 005734. WO 2017 / 005734 is incorporated by reference in its entirety. It is also incorporated by reference in relation to the tau binding antibodies and antigen-binding fragments thereof described.

[0056] Table 1 below sets out particular antibody sequences to be employed in the present invention as well as providing the amino acid sequence of human tau protein.

[0057] Table 1

[0058] In one particular embodiment, the tau-binding antibody or binding fragment thereof comprises a light chain variable region comprising a CDR1 selected from SEQ ID No.: 1, a CDR2 selected from SEQ ID No. : 2, and a CDR3 selected from SEQ ID No. : 3; and a heavy chain variable region comprising a CDR1 selected from SEQ ID No.: 4, a CDR2 selected from SEQ ID No.: 5, and a CDR3 selected from SEQ ID No.: 6. Thus, in any of the embodiments set out herein such an antibody or antigen-binding fragment thereof may be employed.

[0059] In a further embodiment, the tau-binding antibody or binding fragment thereof comprises a light chain variable region comprising SEQ ID No.: 7, and a heavy chain variable region comprising SEQ ID No.: 8. Thus, in any of the embodiments set out herein such an antibody or antigen-binding fragment thereof may be employed.

[0060] In another embodiment of the present invention, the tau-binding antibody or binding fragment thereof comprises a light chain comprising SEQ ID No. : 9, and a heavy chain comprising SEQ ID No.: 10. Thus, in any of the embodiments set out herein such an antibody or antigenbinding fragment thereof may be employed. In a further optional embodiment, the antibody comprises two such heavy chains and two such light chains. Thus, in any of the embodiments set out herein such an antibody or antigen-binding fragment thereof may be employed.

[0061] An antibody or antigen-binding fragment of the present invention may be provided in any suitable format. In one particular embodiment, an antibody or antigen-binding fragment thereof of the present invention may be an IgG class antibody or fragment thereof. In one embodiment, it may be an IgGl, IgG2, IgG3, or IgG4 isotype antibody and in particular IgGl. In another embodiment, an antibody of antigen-binding fragment thereof of the invention may be an IgA, IgE, IgD, or IgM class antibody. In a particular alternative embodiment, the antibody is a monoclonal IgG4 antibody.

[0062] In another alternative embodiment, the antibody employed is bepranemab. Hence, for any of the embodiments set out herein bepranemab may be employed. Bioequivalents of bepranemab may also be employed. Antibodies or antigen-binding fragments thereof that are able to crossblock any of the antibodies set out herein may be employed. In one embodiment, an antibody that is able to cross-block bepranemab is employed. In one embodiment, an antibody that is able to bind to substantially the same epitope of bepranemab is employed. It should be noted that another name for bepranemab is UCB0107, and therefore these terms may be used interchangeably.

[0063] The present disclosure refers to antibodies and antibody fragments. Wherever mention is made of an antibody an antibody fragment which is an antigen-binding fragment may be employed unless specifically stated otherwise. Hence, antibodies of the present invention may comprise a complete antibody having full length heavy and light chains or be an antigen-binding fragment, for instance, a Fab, modified Fab, Fab’, modified Fab’, F(ab’)2, Fv, single domain antibody (e.g. VH or VL or VHH), scFv, bi, tri or tetra-valent antibody, Bis-scFv, diabody, triabody, tetrabody or epitope-binding fragments of any of the above (see for example Holliger and Hudson, 2005, Nature Biotech. 23(9): 1126-1136; Adair and Lawson, 2005, Drug Design Reviews - Online 2(3), 209-217). The methods for creating and manufacturing antibody fragments are well known in the art (see for example Verma et al., 1998, Journal of Immunological Methods, 216, 165-181). Other antibody fragments for use in the present invention include the Fab and Fab’ fragments described in International patent applications W02005 / 003169, W02005 / 003170 and W02005 / 003171. Multi-valent antibodies may comprise multiple specificities, e.g. bispecific or may be monospecific (see for example WO 92 / 22853, WO05 / 113605, W02009 / 040562 and WO2010 / 035012). Examples of possible antibody formats are known in the art, for example as disclosed in the review “The coming of Age of Engineered Multivalent Antibodies”, Nunez-Prado et al Drug Discovery Today Vol 20 Number 5 Mar 2015, page 588-594, D. Holmes, Nature Rev Drug Disc Nov 2011 : 10; 798, Chan and Carter, Nature Reviews Immunology vol. 10, May 2010, 301 incorporated herein by reference. In one embodiment an antibody, not an antigen-binding fragment, is employed.

[0064] Doses

[0065] In one embodiment, the present invention is based on the identification of particularly effective doses of tau-binding antibody or antigen-binding fragment thereof for treating a tauopathy. The doses are particularly effective for tau-binding antibodies or antigen-binding fragments thereof that bind the central region of tau protein, such as any of the antibodies and antigen-binding-fragments thereof disclosed in WO 2017 / 005732. In one embodiment a dose is 30 mg / kg to 120 mg / kg of antibody or antigen-binding fragment thereof.

[0066] In one embodiment, the dose is 30 mg / kg, 45 mg / kg, 60 mg / kg, 90 mg / kg or 120 mg / kg of antibody or antigen-binding fragment thereof. In one embodiment a dose is 45 mg / kg to 90 mg / kg. In a particular alternative embodiment of the invention a dose or doses of about 45 mg / kg or about 90 mg / kg of the tau-binding antibody or antigen-binding fragment thereof are employed. In an alternative embodiment of the invention a dose or doses of 45 mg / kg or 90 mg / kg of the tau- binding or antigen-binding fragment thereof are employed.

[0067] In one embodiment, it is 40 mg / kg to 50 mg / kg. In another alternative embodiment, the dose is about 45 mg / kg. Such doses may be administered to a patient with a tauopathy, such as any of those set out herein. In a particular embodiment, the patient has a low tau burden or is not an APOE4 carrier. In one embodiment, such doses are administered to a sufferer with AD and the patient has a low tau burden or is not an APOE4 carrier. In another doses are administered to a sufferer with PSP and the patient has a low tau burden or is not an APOE4 carrier.

[0068] In another alternative embodiment, the dose is 85 mg / kg to 95 mg / kg. In another alternative embodiment, the dose is about 90 mg / kg. Such doses may be administered to a patient with a tauopathy, such as any of those set out herein. In a particular embodiment, the patient has a low tau burden or is not an APOE4 carrier. In one embodiment, such doses are administered to a sufferer with AD and the patient has a low tau burden or is not an APOE4 carrier. In another the doses are administered to a sufferer with PSP and the patient has a low tau burden or is not an APOE4 carrier.

[0069] Fixed dosing

[0070] In one embodiment, rather than administering doses based on a value of mg of the drug to be administered per kg body weight of a subject, fixed dosing is used where a set overall amount is administered to the subject. One advantage is that fixed dosing may avoid the need to calculate a specific dosage for each patient based on mg / kg. That may help simplify manufacturing and administration.

[0071] In one embodiment a fixed dose of 3 g to 10g of antibody or antigen-binding fragment thereof is administered. In one embodiment, a fixed dose of 3 g to 9g of antibody or antigen-binding fragment thereof is administered. In one embodiment, a fixed dose of from 4g to 8g of antibody or antigen-binding fragment thereof is administered.

[0072] In one embodiment, fixed dosing is employed, but rather than employ a single fixed dose for all, patients are allocated to bands based on their body weight, wherein the band a patient falls- into will determine which specific fixed dose that the patient is given. Any of the methods set out herein may, in one embodiment, may comprise as a step determining which of the particular weight bands the subject falls into in order to determine the dosage to be administered.

[0073] In one embodiment, patients are allocated to three bands corresponding to the lower weight band, the mid-weight, and the higher weight band and given a fixed dose defined by which of the three weight bands that they fall in. In one embodiment, the patients in the lower weight band are given a fixed dose of 2.5g to 4.5g of antibody or antigen-binding fragment thereof, those in the mid-weight band are given a fixed dose of 3.5g to 6.5g of antibody or antigen-binding fragment thereof, and those in the higher weight band are given a fixed dose of 4.5g to 8.5g of antibody or antigen-binding fragment thereof. In one embodiment, the patients in the lower weight band are given a fixed dose of 3.5g to 4.5g of antibody or antigen-binding fragment thereof, those in the midweight band are given a fixed dose of 5.5g to 6.5g of antibody or antigen-binding fragment thereof and those in the higher weight category are given a fixed dose of 7.5g to 8.5g of antibody or antigen-binding fragment thereof. Alternatively, in another embodiment, the patients in the lower weight band are given a fixed dose of 2.5g to 3.5g of antibody or antigen-binding fragment thereof, those in the midweight band are given a fixed dose of 3.5g to 4.5g or antigen-binding fragment thereof and those in the higher weight category are given a fixed dose of 4.5g to 5.5g of antibody or antigen-binding fragment thereof.

[0074] In one embodiment, the three bands used to allocated fixed doses are: (i) a first band with patients with a body weight <60 kg; (ii) a second band with patients with a body weight of >60 kg to <90 kg; and (iii) a third band with patients with a body weight of >90 kg. Hence, unless otherwise stated, in any of the fixed dose embodiments set out herein, in one embodiment will comprise determining which of those three weight bands the subject falls into.

[0075] In any of the embodiments where weight banding is employed, in one specific embodiment the weight of a subject may be measured prior to each antibody administration to check if their weight has changed and, if needed, the subject assigned to a different fixed dose if the subject falls within a different weight band.

[0076] In one embodiment, the present invention provides a tau-binding antibody or antigenbinding fragment thereof for use in a method of treating a tauopathy in a human subject in need thereof, wherein the antibody or antigen-binding fragment thereof is administered at a dose or doses of:

[0077] (i) 2.5g to 4.5g if the body weight of the subject is < 60 kg;

[0078] (ii) 3.5g to 6.5g if the body weight of the subject is 60 kg to 90 kg; or

[0079] (iii) 4.5g to 8.5g if the body weight of the subject is > 90 kg, wherein the tau-binding antibody or antigen-binding fragment thereof binds to an epitope comprising the amino acid residues of S238, A239, S241, T245, A246, of SEQ ID No.: 11, optionally wherein the epitope further comprises one or more residues selected from S235, S237, K240, R242, L243, Q244, V248, and M250 of SEQ ID No.: 11. In one such embodiment, the tau- binding antibody or antigen-binding fragment thereof comprises: a light chain variable region comprising a CDR1 selected from SEQ ID No.: 1, a CDR2 selected from SEQ ID No.: 2, and a CDR3 selected from SEQ ID No.: 3; and a heavy chain variable region comprising a CDR1 selected from SEQ ID No.: 4, a CDR2 selected from SEQ ID No.: 5, and a CDR3 selected from SEQ ID No.: 6. In one embodiment, it comprises a light chain variable region comprising SEQ ID No.: 7, and a heavy chain variable region comprising SEQ ID No.: 8. In one such embodiment, it comprises a light chain comprising SEQ ID No.: 9, and a heavy chain comprising SEQ ID No.: 10. In one such embodiment, the human subject has a low tau burden or is not an APOE4 carrier. In one embodiment the tauopathy is Alzheimer’s disease. In one embodiment the doses are administered at about 4 weekly or about monthly intervals. In one embodiment, at least 12 doses are administered where the doses are administered at about 4 weekly or about monthly intervals. In one embodiment, at least 12 doses are administered where the doses are administered at about 4 weekly or about monthly intervals, wherein the doses are administered via intravenous administration. In one embodiment the intravenous administration is intravenous infusion.

[0080] In one embodiment, the present invention provides a tau-binding antibody or antigenbinding fragment thereof for use in a method of treating a tauopathy in a human subject in need thereof, wherein the antibody or antigen-binding fragment thereof is administered at a dose or doses of:

[0081] (i) 3.0g to 4.0g if the body weight of the subject is < 60 kg;

[0082] (ii) 4.0g to 6.0g if the body weight of the subject is 60 kg to 90 kg; or

[0083] (iii) 5.0g to 8.0g if the body weight of the subject is > 90 kg, wherein the tau-binding antibody or antigen-binding fragment thereof binds to an epitope comprising the amino acid residues of S238, A239, S241, T245, A246, of SEQ ID No.: 11, optionally wherein the epitope further comprises one or more residues selected from S235, S237, K240, R242, L243, Q244, V248, and M250 of SEQ ID No.: 11. In one such embodiment, the tau- binding antibody or antigen-binding fragment thereof comprises: a light chain variable region comprising a CDR1 selected from SEQ ID No.: 1, a CDR2 selected from SEQ ID No.: 2, and a CDR3 selected from SEQ ID No.: 3; and a heavy chain variable region comprising a CDR1 selected from SEQ ID No.: 4, a CDR2 selected from SEQ ID No.: 5, and a CDR3 selected from SEQ ID No.: 6. In one embodiment, it comprises a light chain variable region comprising SEQ ID No.: 7, and a heavy chain variable region comprising SEQ ID No.: 8. In one such embodiment, it comprises a light chain comprising SEQ ID No.: 9, and a heavy chain comprising SEQ ID No.: 10. In one such embodiment, the human subject has a low tau burden or is not an APOE4 carrier. In one embodiment the tauopathy is Alzheimer’s disease. In one embodiment the doses are administered at about 4 weekly or about monthly intervals. In one embodiment, at least 12 doses are administered where the doses are administered at about 4 weekly or about monthly intervals. In one embodiment, at least 12 doses are administered where the doses are administered at about 4 weekly or about monthly intervals, wherein the doses are administered via intravenous administration. In one embodiment the intravenous administration is intravenous infusion.

[0084] In one embodiment, the present invention provides a tau-binding antibody or antigenbinding fragment thereof for use in a method of treating a tauopathy in a human subject in need thereof, wherein the antibody or antigen-binding fragment thereof is administered at a dose or doses of:

[0085] (i) about 3g or about 4g if the body weight of the subject is < 60 kg;

[0086] (ii) about 4g or about 6g if the body weight of the subject is 60 kg to 90 kg; or

[0087] (iii) about 5g or about 8g if the body weight of the subject is > 90 kg, wherein the tau-binding antibody or antigen-binding fragment thereof binds to an epitope comprising the amino acid residues of S238, A239, S241, T245, A246, of SEQ ID No.: 11, optionally wherein the epitope further comprises one or more residues selected from S235, S237, K240, R242, L243, Q244, V248, and M250 of SEQ ID No.: 11. In one such embodiment, the tau- binding antibody or antigen-binding fragment thereof comprises: a light chain variable region comprising a CDR1 selected from SEQ ID No.: 1, a CDR2 selected from SEQ ID No.: 2, and a CDR3 selected from SEQ ID No.: 3; and a heavy chain variable region comprising a CDR1 selected from SEQ ID No.: 4, a CDR2 selected from SEQ ID No.: 5, and a CDR3 selected from SEQ ID No.: 6. In one embodiment, it comprises a light chain variable region comprising SEQ ID No.: 7, and a heavy chain variable region comprising SEQ ID No.: 8. In one such embodiment, it comprises a light chain comprising SEQ ID No.: 9, and a heavy chain comprising SEQ ID No.: 10. In one such embodiment, the human subject has a low tau burden or is not an APOE4 carrier. In one embodiment the tauopathy is Alzheimer’s disease. In one embodiment the doses are administered at about 4 weekly or about monthly intervals. In one embodiment, at least 12 doses are administered where the doses are administered at about 4 weekly or about monthly intervals. In one embodiment, at least 12 doses are administered where the doses are administered at about 4 weekly or about monthly intervals, wherein the doses are administered via intravenous administration. In one embodiment the intravenous administration is intravenous infusion.

[0088] Banded higher fixed doses

[0089] As discussed in the Examples, initially three body weight-based doses were assessed, namely 45 mg / kg, 60 mg / kg, and 90 mg / kg, before analysis was performed to determine possible fixed doses and in particular fixed doses based on allocating patients to one of three body weight bands. In one embodiment, the fixed doses are based on approximating a body weight-based dose of 90 mg / kg. In one such embodiment, patients are allocated a particular fixed dose based on which of three weight bands that they fall in, namely a lower, middle and higher weight band. In

[0090] Y1 one embodiment, the three weight bands are: (i) <60 kg; (ii) >60-<90 kg; and (iii) >90 kg

[0091] In one embodiment a fixed dose of about 4g of antibody or antigen binding fragment thereof is administered for the lower weight band and in particular for the <60 kg weight band. For example, in one embodiment, a fixed dose of 3.5g to 4.5g of antibody or antigen binding fragment thereof is administered. In one embodiment, a fixed dose of 3.8 g to 4.2g of antibody or antigen binding fragment thereof is administered. In one embodiment, a fixed dose of 3.9g to 4.1g of antibody is administered. In one embodiment, a fixed dose of about 4.0g of antibody or antigen binding fragment thereof is administered to patients who have a body weight <60 kg.

[0092] In one embodiment a fixed dose of about 6g is administered for the middle weight band and in particular for the >60-<90kg weight band. For example, in one embodiment, a fixed dose of 5.5g to 6.5g of antibody or antigen binding fragment thereof is administered. In one embodiment, a fixed dose of 5.8g to 6.2g of antibody or antigen binding fragment thereof is administered. In one embodiment, a fixed dose of 5.9g to 6.1g of antibody or antigen binding fragment thereof is administered. In one embodiment, a fixed dose of about 6.0g of antibody is administered to patients who have a body weight of 60 kg to 90 kg.

[0093] In one embodiment, a fixed dose of about 8g is administered for the higher weight band and in particular for the >90 kg weight band. For example, in one embodiment, a fixed dose of 7.5g to 8.5 g of antibody or antigen binding fragment thereof is administered. In one embodiment, a fixed dose of 7.8 g to 8.2 g of antibody or antigen binding fragment thereof is administered. In one embodiment, a fixed dose of 7.9 g to 8.1 g of antibody or antigen binding fragment thereof is administered. In one embodiment, a fixed dose of about 8.0g of antibody or antigen binding fragment thereof is administered to patients who have a body weight of >90 kg.

[0094] In one embodiment, the present invention provides a tau-binding antibody or antigenbinding fragment thereof for use in a method of treating a tauopathy in a human subject in need thereof, wherein the antibody or antigen-binding fragment thereof is administered at a dose or doses of:

[0095] (i) 3.5 g to 4.5 g if the body weight of the subject is < 60 kg;

[0096] (ii) 5.5 g to 6.5 g if the body weight of the subject is 60 kg to 90 kg; or

[0097] (iii) 7.5 g to 8.5 g if the body weight of the subject is > 90 kg, wherein the tau-binding antibody or antigen-binding fragment thereof binds to an epitope comprising the amino acid residues of S238, A239, S241, T245, A246, of SEQ ID No.: 11, optionally wherein the epitope further comprises one or more residues selected from S235, S237, K240, R242, L243, Q244, V248, and M250 of SEQ ID No.: 11. In one such embodiment, the tau- binding antibody or antigen-binding fragment thereof comprises: a light chain variable region comprising a CDR1 selected from SEQ ID No.: 1, a CDR2 selected from SEQ ID No.: 2, and a CDR3 selected from SEQ ID No.: 3; and a heavy chain variable region comprising a CDR1 selected from SEQ ID No.: 4, a CDR2 selected from SEQ ID No.: 5, and a CDR3 selected from SEQ ID No.: 6. In one embodiment, it comprises a light chain variable region comprising SEQ ID No.: 7, and a heavy chain variable region comprising SEQ ID No.: 8. In one such embodiment, it comprises a light chain comprising SEQ ID No.: 9, and a heavy chain comprising SEQ ID No.: 10. In one such embodiment, the human subject has a low tau burden or is not an APOE4 carrier. In one embodiment the tauopathy is Alzheimer’s disease. In one embodiment the doses are administered at about 4 weekly or about monthly intervals. In one embodiment, at least 12 doses are administered where the doses are administered at about 4 weekly or about monthly intervals. In one embodiment, at least 12 doses are administered where the doses are administered at about 4 weekly or about monthly intervals, wherein the doses are administered via intravenous administration. In one embodiment the intravenous administration is intravenous infusion.

[0098] In one embodiment, the antibody or antigen-binding fragment thereof is administered at a dose or doses of: (i) 3.8 g to 4.2 g if the body weight of the subject is < 60 kg; (ii) 5.8g to 6.2g if the body weight of the subject is 60 kg to 90 kg; or (iii) 7.8g to 8.2g if the body weight of the subject is > 90 kg. In one embodiment, the tau-binding antibody or antigen-binding fragment thereof binds to an epitope, wherein the antibody or antigen-binding fragment thereof comprises a light chain comprising SEQ ID No.: 9, and a heavy chain comprising SEQ ID No.: 10, and wherein the tauopathy is Alzheimer’s disease (AD). In one such embodiment, the doses are administered at about 4-week or monthly intervals. In one embodiment, the doses are administered intravenously. Hence, in one embodiment, they are administered intravenously at about 4-week intervals. In one embodiment, at least 12 such doses are administered. In one embodiment, the human subject has: (i) a low tau burden and is not an APOE4 carrier, (ii) a low tau burden and is an APOE4 carrier, or (iii) a high tau burden and is not an APOE4 carrier. In one embodiment the doses are administered at about 4 weekly or about monthly intervals. In one embodiment, at least 12 doses are administered where the doses are administered at about 4 weekly or about monthly intervals. In one embodiment, at least 12 doses are administered where the doses are administered at about 4 weekly or about monthly intervals, wherein the doses are administered via intravenous administration. In

[0099] In one embodiment, the antibody or antigen-binding fragment thereof is administered at a dose or doses of: (i) 3.9g to 4.1g if the body weight of the subject is < 60 kg; (ii) 5.9g to 6.1g if the body weight of the subject is 60 kg to 90 kg; or (iii) 7.9g to 8.1g if the body weight of the subject is > 90 kg. In one embodiment, the tau-binding antibody or antigen-binding fragment thereof binds to an epitope, wherein the antibody or antigen-binding fragment thereof comprises a light chain comprising SEQ ID No.: 9, and a heavy chain comprising SEQ ID No.: 10, and wherein the tauopathy is Alzheimer’s disease (AD). In one such embodiment, the doses are administered at about 4-week or monthly intervals. In one embodiment, the doses are administered intravenously. Hence, in one embodiment, they are administered intravenously at about 4-week intervals. In one embodiment, at least 12 such doses are administered. In one embodiment, the human subject has: (i) a low tau burden and is not an APOE4 carrier, (ii) a low tau burden and is an APOE4 carrier, or (iii) a high tau burden and is not an APOE4 carrier. In one embodiment the doses are administered at about 4 weekly or about monthly intervals. In one embodiment, at least 12 doses are administered where the doses are administered at about 4 weekly or about monthly intervals. In one embodiment, at least 12 doses are administered where the doses are administered at about 4 weekly or about monthly intervals, wherein the doses are administered via intravenous administration. In one embodiment, the intravenous administration is intravenous infusion.

[0100] In one embodiment, the antibody or antigen-binding fragment thereof is administered at a dose or doses of: (i) 4g if the body weight of the subject is < 60 kg; (ii) 6g if the body weight of the subject is 60 kg to 90 kg; or (iii) 8g if the body weight of the subject is > 90 kg. In one embodiment, the tau-binding antibody or antigen-binding fragment thereof binds to an epitope, wherein the antibody or antigen-binding fragment thereof comprises a light chain comprising SEQ ID No.: 9, and a heavy chain comprising SEQ ID No.: 10, and wherein the tauopathy is Alzheimer’s disease (AD). In one such embodiment, the doses are administered at about 4-week or monthly intervals. In one embodiment, the doses are administered intravenously. Hence, in one embodiment, they are administered intravenously at about 4-week intervals. In one embodiment, at least 12 such doses are administered. In one embodiment, the human subject has: (i) a low tau burden and is not an APOE4 carrier, (ii) a low tau burden and is an APOE4 carrier, or (iii) a high tau burden and is not an APOE4 carrier. In one embodiment the doses are administered at about 4 weekly or about monthly intervals. In one embodiment, at least 12 doses are administered where the doses are administered at about 4 weekly or about monthly intervals. In one embodiment, at least 12 doses are administered where the doses are administered at about 4 weekly or about monthly intervals, wherein the doses are administered via intravenous administration. In one embodiment, the intravenous administration is intravenous infusion.

[0101] In one embodiment, the present invention provides a tau-binding antibody or antigenbinding fragment thereof for use in a method of treating a tauopathy in a human subject in need thereof, wherein the antibody or antigen-binding fragment thereof is administered at a dose or doses of: (i) 4g if the body weight of the subject is < 60 kg; (ii) 6g if the body weight of the subject is 60 kg to 90 kg; or (iii) 8g if the body weight of the subject is > 90 kg, wherein the tau-binding antibody or antigen-binding fragment thereof binds to an epitope, wherein the antibody or antigenbinding fragment thereof comprises a light chain comprising SEQ ID No.: 9, and a heavy chain comprising SEQ ID No.: 10, and wherein the tauopathy is Alzheimer’s disease (AD). In one such embodiment, the doses are administered at about 4-week or monthly intervals. In one embodiment, the doses are administered intravenously. Hence, in one embodiment, they are administered intravenously at about 4-week intervals. In one embodiment, at least 12 such doses are administered. In one embodiment, the human subject has: (i) a low tau burden and is not an APOE4 carrier, (ii) a low tau burden and is an APOE4 carrier, or (iii) a high tau burden and is not an APOE4 carrier. In one embodiment the doses are administered at about 4 weekly or about monthly intervals. In one embodiment, at least 12 doses are administered where the doses are administered at about 4 weekly or about monthly intervals. In one embodiment, at least 12 doses are administered where the doses are administered at about 4 weekly or about monthly intervals, wherein the doses are administered via intravenous administration. In one embodiment the intravenous administration is intravenous infusion.

[0102] Banded mid fixed doses

[0103] In an alternative embodiment, the fixed doses are based on the analysis to approximate a body weight-based dose of 60 mg / kg. In one such embodiment, patients are allocated a particular fixed dose based on which of three weight bands that they fall in, namely a lower, middle and higher weight band, in one embodiment, the three weight bands are: (i) <60 kg; (ii) >60-<90 kg; and (iii) >90 kg In one embodiment a fixed dose of about 3g of antibody is administered for the lower weight band and in particular for the <60 kg weight band. For example, in one embodiment, a fixed dose of 2.5g to 3.5g of antibody or antigen-binding fragment thereof is administered. In one embodiment, a fixed dose of 2.8g to 3.2 g of antibody or antigen-binding fragment thereof is administered. In one embodiment, a fixed dose of 2.9g to 3.1g of antibody or antigen-binding fragment thereof is administered. In one embodiment, a fixed dose of about 3.0g of antibody is administered.

[0104] In one embodiment a fixed dose of about 4g is administered for the middle weight band and in particular for the >60-<90kg weight band. For example, in one embodiment, a fixed dose of 3.5g to 4.5g of antibody or antigen-binding fragment thereof is administered. In one embodiment, a fixed dose of 3.8g to 4.2g of antibody or antigen-binding fragment thereof is administered. In one embodiment, a fixed dose of 3.9g to 4.1g of antibody or antigen-binding fragment thereof is administered. In one embodiment, a fixed dose of about 4.0g of antibody is administered.

[0105] In one embodiment, a fixed dose of about 5 g is administered for the higher weight band and in particular for the >90 kg weight band. For example, in one embodiment, a fixed dose of 4.5g to 5.5g of antibody or antigen-binding fragment thereof is administered. In one embodiment, a fixed dose of 4.8g to 5.2g of antibody or antigen-binding fragment thereof is administered. In one embodiment, a fixed dose of 4.9g to 5.1g of antibody or antigen-binding fragment thereof is administered. In one embodiment, a fixed dose of 5.0g of antibody is administered.

[0106] In one embodiment, the present invention provides a tau-binding antibody or antigenbinding fragment thereof for use in a method of treating a tauopathy in a human subject in need thereof, wherein the antibody or antigen-binding fragment thereof is administered at a dose or doses of:

[0107] (i) 2.5 g to 3.5 g if the body weight of the subject is < 60 kg;

[0108] (ii) 3.5 g to 4.5 g if the body weight of the subject is 60 kg to 90 kg; or

[0109] (iii) 4.5 g to 5.5 g if the body weight of the subject is > 90 kg, wherein the tau-binding antibody or antigen-binding fragment thereof binds to an epitope comprising the amino acid residues of S238, A239, S241, T245, A246, of SEQ ID No.: 11, optionally wherein the epitope further comprises one or more residues selected from S235, S237, K240, R242, L243, Q244, V248, and M250 of SEQ ID No.: 11. In one such embodiment, the tau- binding antibody or antigen-binding fragment thereof comprises: a light chain variable region comprising a CDR1 selected from SEQ ID No.: 1, a CDR2 selected from SEQ ID No.: 2, and a CDR3 selected from SEQ ID No.: 3; and a heavy chain variable region comprising a CDR1 selected from SEQ ID No.: 4, a CDR2 selected from SEQ ID No.: 5, and a CDR3 selected from SEQ ID No.: 6. In one embodiment, it comprises a light chain variable region comprising SEQ ID No.: 7, and a heavy chain variable region comprising SEQ ID No.: 8. In one such embodiment, it comprises a light chain comprising SEQ ID No.: 9, and a heavy chain comprising SEQ ID No.: 10. In one such embodiment, the human subject has a low tau burden or is not an APOE4 carrier. In one embodiment the tauopathy is Alzheimer’s disease. In one embodiment, the antibody may be, for instance, administered by intravenous infusion. In one embodiment the antibody is given about every 4 weeks or about monthly by intravenous infusion. In one embodiment the antibody is given about every 4 weeks or about monthly with at least 12 doses being given by intravenous infusion.

[0110] In one embodiment, the present invention provides a tau-binding antibody or antigenbinding fragment thereof for use in a method of treating a tauopathy in a human subject in need thereof, wherein the antibody or antigen-binding fragment thereof is administered at a dose or doses of:

[0111] (i) 2.8g to 3.2g if the body weight of the subject is < 60 kg;

[0112] (ii) 3.8g to 4.2g if the body weight of the subject is 60 kg to 90 kg; or

[0113] (iii) 4.8g to 5.2g if the body weight of the subject is > 90 kg, wherein the tau-binding antibody or antigen-binding fragment thereof binds to an epitope comprising the amino acid residues of S238, A239, S241, T245, A246, of SEQ ID No.: 11, optionally wherein the epitope further comprises one or more residues selected from S235, S237, K240, R242, L243, Q244, V248, and M250 of SEQ ID No.: 11. In one such embodiment, the tau- binding antibody or antigen-binding fragment thereof comprises: a light chain variable region comprising a CDR1 selected from SEQ ID No.: 1, a CDR2 selected from SEQ ID No.: 2, and a CDR3 selected from SEQ ID No.: 3; and a heavy chain variable region comprising a CDR1 selected from SEQ ID No.: 4, a CDR2 selected from SEQ ID No.: 5, and a CDR3 selected from SEQ ID No.: 6. In one embodiment, it comprises a light chain variable region comprising SEQ ID No.: 7, and a heavy chain variable region comprising SEQ ID No.: 8. In one such embodiment, it comprises a light chain comprising SEQ ID No.: 9, and a heavy chain comprising SEQ ID No.: 10. In one such embodiment, the human subject has a low tau burden or is not an APOE4 carrier. In one embodiment the tauopathy is Alzheimer’s disease. In one embodiment, the antibody may be, for instance, administered by intravenous infusion. In one embodiment, the antibody may be, for instance, administered by intravenous infusion. In one embodiment the antibody is given about every 4 weeks or about monthly by intravenous infusion. In one embodiment the antibody is given about every 4 weeks or about monthly with at least 12 doses being given by intravenous infusion.

[0114] In one embodiment, the present invention provides a tau-binding antibody or antigenbinding fragment thereof for use in a method of treating a tauopathy in a human subject in need thereof, wherein the antibody or antigen-binding fragment thereof is administered at a dose or doses of:

[0115] (i) about 3g if the body weight of the subject is < 60 kg;

[0116] (ii) about 4g if the body weight of the subject is 60 kg to 90 kg; or

[0117] (iii) about 5 g if the body weight of the subject is > 90 kg, wherein the tau-binding antibody or antigen-binding fragment thereof binds to an epitope comprising the amino acid residues of S238, A239, S241, T245, A246, of SEQ ID No.: 11, optionally wherein the epitope further comprises one or more residues selected from S235, S237, K240, R242, L243, Q244, V248, and M250 of SEQ ID No.: 11. In one such embodiment, the tau- binding antibody or antigen-binding fragment thereof comprises: a light chain variable region comprising a CDR1 selected from SEQ ID No.: 1, a CDR2 selected from SEQ ID No.: 2, and a CDR3 selected from SEQ ID No.: 3; and a heavy chain variable region comprising a CDR1 selected from SEQ ID No.: 4, a CDR2 selected from SEQ ID No.: 5, and a CDR3 selected from SEQ ID No.: 6. In one embodiment, it comprises a light chain variable region comprising SEQ ID No.: 7, and a heavy chain variable region comprising SEQ ID No.: 8. In one such embodiment, it comprises a light chain comprising SEQ ID No.: 9, and a heavy chain comprising SEQ ID No.: 10. In one such embodiment, the human subject has a low tau burden or is not an APOE4 carrier. In one embodiment the tauopathy is Alzheimer’s disease. In one embodiment, the antibody may be, for instance, administered by intravenous infusion. In one embodiment the antibody is given about every 4 weeks or about monthly by intravenous infusion. In one embodiment the antibody is given about every 4 weeks or about monthly with at least 12 doses being given by intravenous infusion. Number and timing of doses

[0118] In one embodiment, a plurality of doses will be administered, for example at least 4 doses. In one alternative embodiment, at least 12 doses are administered. In a further embodiment, at least 20 doses are administered. In one embodiment at least 24 doses are administered. In one embodiment from 4 to 30 doses are administered. In one embodiment, dosing is continued indefinitely.

[0119] As with treatment of any disease, clinical judgement must be exercised when considering the length of treatment. However given that tauopathies are neurodegenerative diseases of relatively slow progression, and the method of treating them according to the current invention is preferably able to slow progression of the symptoms, it is considered that a method according to the current invention will include administering the tau-binding antibody or binding fragment thereof to the human subject in need thereof for, at least 12 weeks, at least 24 weeks, at least 52 weeks, at least 68 weeks or at least 80 weeks, or until no longer clinically relevant. In one embodiment the antibody or antigen-binding fragment thereof the antibody will be administered for at least a year. Given the nature of these diseases there is a potential requirement for life-time administration.

[0120] As typically more than one dose of antibody or antigen-binding fragment thereof is administered there will be an interval between each pair of doses. A skilled person would understand that dosing intervals in the clinical setting are expressed as a function of time, and these timing intervals may be typically expressed in days, weeks or months. In one particular embodiment, doses are administered at regular intervals, so that the intervals are the same or approximately the same each time. In one embodiment, doses are administered at intervals of 3 to 5 weeks. In another embodiment, doses are administered about monthly. In another optional embodiment, doses may be administered about every 4 weeks. In a further particular embodiment, the tau-binding antibody is administered once every 4 + / - 1 weeks, or alternatively once every 21 to 35 days. In one embodiment, at least 12 doses will be administered at intervals of about 4 weeks or about a month. In one embodiment, at least 12 doses will be administered at intervals of about 4 weeks or about a month wherein the doses are given via intravenous administration. Routes of administration

[0121] The tau-binding antibody or antigen-binding fragment thereof may be administered by any suitable route to the patient. Examples of optional routes include intravenous, subcutaneous or intramuscular administration of the tau-binding antibody or antibody fragment to the individual in need thereof.

[0122] In another embodiment, the route of administration is intravenous. In one particular embodiment, the administration is via intravenous injection. In one embodiment, the administration is via intravenous infusion. In one embodiment, administration is via intravenous infusion from an IV bag. In one embodiment, administration is via intravenous infusion using an IV pump.

[0123] In one embodiment, the administration is subcutaneous. Subcutaneous administration is advantageous because the patient may self-administer a therapeutic substance, e.g., a tau-binding antibody or antibody fragment thereof, which is convenient for both the patient and the health care provider.

[0124] Illustrative optional regimens

[0125] In one embodiment, the present invention provides a tau-binding antibody or antigenbinding fragment thereof for use in a method of treating a tauopathy in a human subject in need thereof, the method comprising administering to the human subject at least one dose of 30 mg / kg to 120 mg / kg of the tau-binding antibody or binding fragment thereof. In a further embodiment, the human subject has a low tau burden or is not an APOE4 carrier. In one particular embodiment, the tauopathy is AD and the patient has a low tau burden or is not an APOE4 carrier. In another particular embodiment it is PSP and the patient has a low tau burden or is not an APOE4 carrier.

[0126] In one embodiment, the present invention provides a tau-binding antibody or antigenbinding fragment thereof for use in a method of treating a tauopathy in a human subject in need thereof, the method comprising administering to the human subject at least one dose of 30 mg / kg to 120 mg / kg of the tau-binding antibody or binding fragment thereof, wherein the antibody or antigen-binding fragment thereof comprises: a light chain variable region comprising a CDR1 selected from SEQ ID No.: 1, a CDR2 selected from SEQ ID No.: 2, and a CDR3 selected from SEQ ID No. : 3; and a heavy chain variable region comprising a CDR1 selected from SEQ ID No. : 4, a CDR2 selected from SEQ ID No.: 5, and a CDR3 selected from SEQ ID No.: 6. In one alternative embodiment, the antibody is bepranemab. In a further embodiment, the human subject has a low tau burden or is not an APOE4 carrier. In one particular embodiment, the tauopathy is AD and the patient has a low tau burden or is not an APOE4 carrier. In another particular embodiment it is PSP and the patient has a low tau burden or is not an APOE4 carrier.

[0127] In one embodiment, the present invention provides a tau-binding antibody or antigenbinding fragment thereof for use in a method of treating a tauopathy in a human subject in need thereof, the method comprising administering to the human subject a plurality of doses of 30 mg / kg to 120 mg / kg of the tau-binding antibody or binding fragment thereof, wherein the doses are administered 3 weeks to 5 weeks apart. In one particular embodiment, the antibody or antigenbinding fragment thereof comprises: a light chain variable region comprising a CDR1 selected from SEQ ID No.: 1, a CDR2 selected from SEQ ID No.: 2, and a CDR3 selected from SEQ ID No.: 3; and a heavy chain variable region comprising a CDR1 selected from SEQ ID No.: 4, a CDR2 selected from SEQ ID No.: 5, and a CDR3 selected from SEQ ID No.: 6. In one alternative embodiment, the antibody is bepranemab. In a further embodiment, the human subject has a low tau burden or is not an APOE4 carrier. In one particular embodiment, the tauopathy is AD and the patient has a low tau burden or is not an APOE4 carrier. In one particular embodiment, it is PSP and the patient has a low tau burden or is not an APOE4 carrier.

[0128] In one embodiment, the present invention provides a tau-binding antibody or antigenbinding fragment thereof for use in a method of treating a tauopathy in a human subject in need thereof, the method comprising administering to the human subject a plurality of doses of 40 mg / kg to 50 mg / kg of the tau-binding antibody or binding fragment thereof, wherein the doses are administered 3 weeks to 5 weeks apart. In one particular embodiment, the doses are 4 weeks apart. In a preferred embodiment, the dose is about 45 mg / kg. In one particular embodiment, the antibody or antigen-binding fragment thereof comprises: a light chain variable region comprising a CDR1 selected from SEQ ID No.: 1, a CDR2 selected from SEQ ID No.: 2, and a CDR3 selected from SEQ ID No. : 3; and a heavy chain variable region comprising a CDR1 selected from SEQ ID No. : 4, a CDR2 selected from SEQ ID No.: 5, and a CDR3 selected from SEQ ID No.: 6. In one alternative embodiment, the antibody is bepranemab. In a further embodiment, the human subject has a low tau burden or is not an APOE4 carrier. In one particular embodiment, the tauopathy is AD and the patient has a low tau burden or is not an APOE4 carrier. In one particular embodiment, it is PSP and the patient has a low tau burden or is not an APOE4 carrier. In one embodiment, the present invention provides a tau-binding antibody or antigenbinding fragment thereof for use in a method of treating a tauopathy in a human subject in need thereof, the method comprising administering to the human subject a plurality of doses of 85 mg / kg to 95 mg / kg of the tau-binding antibody or binding fragment thereof, wherein the doses are administered 3 weeks to 5 weeks apart. In one embodiment, they are 4 weeks apart. In a particular embodiment, the dose is about 90 mg / kg. In one particular embodiment, the antibody or antigenbinding fragment thereof comprises: a light chain variable region comprising a CDR1 selected from SEQ ID No.: 1, a CDR2 selected from SEQ ID No.: 2, and a CDR3 selected from SEQ ID No.: 3; and a heavy chain variable region comprising a CDR1 selected from SEQ ID No.: 4, a CDR2 selected from SEQ ID No.: 5, and a CDR3 selected from SEQ ID No.: 6. In one alternative embodiment, the antibody is bepranemab. In a further embodiment, the human subject has a low tau burden or is not an APOE4 carrier. In one particular embodiment, the tauopathy is AD and the patient has a low tau burden or is not an APOE4 carrier. In one particular embodiment, it is PSP and the patient has a low tau burden or is not an APOE4 carrier.

[0129] In one embodiment, the present invention provides a tau-binding antibody or antigenbinding fragment thereof for use in a method of treating PSP in a human subject in need thereof, the method comprising administering to the human subject a plurality of doses of 85 mg / kg to 95 mg / kg of the tau-binding antibody or binding fragment thereof, wherein the doses are administered 3 weeks to 5 weeks apart. In a particular embodiment, the dose is about 90 mg / kg. In one particular embodiment, the antibody or antigen-binding fragment thereof comprises: a light chain variable region comprising a CDR1 selected from SEQ ID No.: 1, a CDR2 selected from SEQ ID No.: 2, and a CDR3 selected from SEQ ID No.: 3; and a heavy chain variable region comprising a CDR1 selected from SEQ ID No.: 4, a CDR2 selected from SEQ ID No.: 5, and a CDR3 selected from SEQ ID No.: 6. In one alternative embodiment, the antibody is bepranemab. In a further embodiment, the human subject has a low tau burden or is not an APOE4 carrier.

[0130] In one embodiment, the present invention provides a tau-binding antibody or antigenbinding fragment thereof for use in a method of treating AD in a human subject in need thereof, the method comprising administering to the human subject a plurality of doses of 40 mg / kg to 50 mg / kg of the tau-binding antibody or binding fragment thereof, wherein the doses are administered 3 weeks to 5 weeks apart. In a particular embodiment, the dose is about 45 mg / kg. In one particular embodiment, the antibody or antigen-binding fragment thereof comprises: a light chain variable region comprising a CDR1 selected from SEQ ID No.: 1, a CDR2 selected from SEQ ID No.: 2, and a CDR3 selected from SEQ ID No.: 3; and a heavy chain variable region comprising a CDR1 selected from SEQ ID No.: 4, a CDR2 selected from SEQ ID No.: 5, and a CDR3 selected from SEQ ID No.: 6. In one alternative embodiment, the antibody is bepranemab. In a particular embodiment, the human subject has a low tau burden or is not an APOE4 carrier. In one embodiment, at least 10 doses are administered. In another embodiment, at least 20 doses are administered.

[0131] In one embodiment, the present invention provides a tau-binding antibody or antigenbinding fragment thereof for use in a method of treating AD in a human subject in need thereof, the method comprising administering to the human subject a plurality of doses of 85 mg / kg to 95 mg / kg of the tau-binding antibody or antigen-binding fragment thereof, wherein the doses are administered 3 to 5 weeks apart. In a particular embodiment, the dose is about 90 mg / kg. In one particular embodiment, the antibody or antigen-binding fragment thereof comprises: a light chain variable region comprising a CDR1 selected from SEQ ID No.: 1, a CDR2 selected from SEQ ID No.: 2, and a CDR3 selected from SEQ ID No.: 3; and a heavy chain variable region comprising a CDR1 selected from SEQ ID No.: 4, a CDR2 selected from SEQ ID No.: 5, and a CDR3 selected from SEQ ID No.: 6. In one alternative embodiment, the antibody is bepranemab. In a particular embodiment, the human subject has a low tau burden or is not an APOE4 carrier. In one embodiment, at least 10 doses are administered. In another embodiment, at least 20 doses are administered.

[0132] In an optional embodiment, in any of the embodiments set out above, the administration is intravenous. In one more particular embodiment, it is via intravenous infusion. In another, it is via subcutaneous injection.

[0133] In one optional embodiment, in any of the embodiments set out above the doses are administered about once a month or once every 4 weeks.

[0134] Illustrative optional fixed dosage regimens

[0135] In one embodiment, the present invention provides a tau-binding antibody or antigenbinding fragment thereof for use in a method of treating a tauopathy in a human subject in need thereof, the antibody or antigen-binding fragment thereof is administered at a dose or doses of: (i) about 4g if the body weight of the subject is < 60 kg; (ii) about 6g if the body weight of the subject is 60 kg to 90 kg; or about 8 g if the body weight of the subject is > 90 kg. In one embodiment, the tauopathy is AD. In one embodiment, the tauopathy is early AD. In one particular embodiment, the tauopathy is AD and the patient has a low tau burden or is not an APOE4 carrier. In one embodiment with such dosages, the subject: (i) has AD; and (ii) has a low tau burden or is not an APOE4 carrier, wherein at least 12 doses of the antibody or antigen-binding fragment thereof are administered at intervals at about 4 weeks or about monthly, wherein the administration is via intravenous infusion.

[0136] In one embodiment, the present invention provides a tau-binding antibody or antigenbinding fragment thereof for use in a method of treating a tauopathy in a human subject in need thereof, the method comprising administering to the human subject a tau-binding antibody or antigen-binding fragment thereof, wherein: the tau-binding antibody or antigen-binding fragment thereof binds to an epitope comprising the amino acid residues of S238, A239, S241, T245, A246, of SEQ ID No.: 11, optionally wherein the epitope further comprises one or more residues selected from S235, S237, K240, R242, L243, Q244, V248, and M250 of SEQ ID No.: 11; and the antibody or antigen-binding fragment thereof is administered at a dose or doses of: (i) about 4 g if the body weight of the subject is < 60 kg; (ii) about 6 g if the body weight of the subject is 60 kg to 90 kg; or about 8 g if the body weight of the subject is > 90 kg. In one embodiment, the tauopathy is AD. In one embodiment, the tauopathy is early AD. In one particular embodiment, the tauopathy is AD and the patient has a low tau burden or is not an APOE4 carrier. In one embodiment with such dosages, the subject: (i) has AD; and (ii) has a low tau burden or is not an APOE4 carrier, wherein at least 12 doses of the antibody or antigen-binding fragment thereof are administered at intervals at about 4 weeks or about monthly, wherein the administration is via intravenous infusion.

[0137] In one embodiment, the present invention provides a tau-binding antibody or antigenbinding fragment thereof for use in a method of treating a tauopathy in a human subject in need thereof, wherein the antibody or antigen-binding fragment thereof comprises: a light chain variable region comprising a CDR1 selected from SEQ ID No.: 1, a CDR2 selected from SEQ ID No.: 2, and a CDR3 selected from SEQ ID No.: 3; and a heavy chain variable region comprising a CDR1 selected from SEQ ID No.: 4, a CDR2 selected from SEQ ID No.: 5, and a CDR3 selected from SEQ ID No. : 6, wherein the antibody or antigen-binding fragment thereof is administered at a dose or doses of: (i) about 4g if the body weight of the subject is < 60 kg; (ii) about 6g if the body weight of the subject is 60 kg to 90 kg; or about 8 g if the body weight of the subject is > 90 kg. In one embodiment, the tauopathy is AD. In one embodiment, the tauopathy is early AD. In one particular embodiment, the tauopathy is AD and the patient has a low tau burden or is not an APOE4 carrier.

[0138] In one embodiment, in any of the embodiments discussed in this section at least 10 doses are administered. In another embodiment, at least 20 doses are administered. In one embodiment at least 12 doses are administered.

[0139] In an optional embodiment, in any of the embodiments set out above, the administration is intravenous. In one more particular embodiment, it is via intravenous infusion. In another, it is via subcutaneous injection.

[0140] In one optional embodiment, in any of the embodiments set out above the doses are administered about once a month or once every 4 weeks.

[0141] In one optional embodiment, in any of the embodiments set out above the doses are administered about once a month or once every 4 weeks and the antibody is bepranemab.

[0142] In one embodiment at least 12 doses are administered via intravenous infusion wherein the interval between each dose is about 4 weeks or about monthly. In one such embodiment the subject has AD.

[0143] Illustrative intravenous administration based regimens

[0144] In any of the embodiments set out herein it may be that administration is via intravenous administration. In any of the embodiments set out herein, unless otherwise stated, it may be that administration is via intravenous infusion. In any of the embodiments set out herein, unless otherwise stated, it may be that the antibody is administered from an IV bag or a loaded IV pump to the subject. Hence, the present invention also provides a IV bag containing an antibody as set out herein for use in treating a tauopathy via intravenous administration, wherein the antibody is administered at a dosage as set out herein. Similarly, the present invention also provides an IV pump loaded with an antibody as set out herein for use in treating a tauopathy via intravenous administration, wherein the antibody is administered at a dosage as set out herein.

[0145] In one embodiment, a method of treatment as set out herein may first comprise preparing a solution of the antibody for instance in saline. In one embodiment, the antibody is initially provided in a vial and a solution is then prepared for an infusion pump or IV bag. Thus, the present invention also provides such a vial for use in the methods set out therein.

[0146] In one embodiment the dilution of the antibody to allow it to be administered intravenously is performed no more than about 4 hours before administration. In one embodiment, the dilution is performed no more than about 3 hours prior to administration.

[0147] In one embodiment, the antibody will be administered via intravenous infusion over a time of from 1 to 4 hours. In one embodiment, the infusion time is 1 to 3 hours. In one embodiment, the infusion time is about 2 hours.

[0148] In one embodiment, the rate of infusion of the antibody or antigen-binding fragment thereof is 0.5 mg / kg / min to 1.0 mg / kg / min. In one embodiment, the rate of infusion of the antibody or antigen-binding fragment thereof is 0.6 mg / kg / min to 0.8 mg / kg / min. In one embodiment, the rate of infusion of the antibody or antigen-binding fragment thereof is about 0.75 mg / kg / min to 0.8 mg / kg / min.

[0149] Illustrative body weight-based regimens

[0150] In some embodiments, rather than a fixed dose, the dose of antibody will be calculated in terms of mg / kg based on the body weight of the subject.

[0151] In one embodiment, the present invention provides a tau-binding antibody or antigenbinding fragment thereof for use in a method of treating a tauopathy in a human subject in need thereof, the method comprising administering to the human subject at least one dose of 45 mg / kg to 90 mg / kg of the tau-binding antibody or antigen-binding fragment thereof, wherein the tau- binding antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising a CDR1 selected from SEQ ID No.: 1, a CDR2 selected from SEQ ID No.: 2, and a CDR3 selected from SEQ ID No.: 3; and (ii) a heavy chain variable region comprising a CDR1 selected from SEQ ID No.: 4, a CDR2 selected from SEQ ID No.: 5, and a CDR3 selected from SEQ ID No. : 6. In one such embodiment, the antibody or antigen-binding fragment thereof will be administered via intravenous infusion from an IV bag. In one embodiment, the dose of antibody or antigen-binding fragment thereof is 85 mg / kg to 95 mg / kg. In one embodiment, the dose of antibody or antigen-binding fragment thereof is about 90 mg / kg. In one embodiment, the doses are administered at about 4 week or about monthly intervals. In one embodiment, at least 12 doses are administered at about 4 week or about monthly intervals. In one particular embodiment, the tauopathy is AD and the patient has a low tau burden or is not an APOE4 carrier. In an alternative embodiment, the subject is not limited to whether they have low tau burden and whether they are an APOE4 carrier.

[0152] In one embodiment, the present invention further provides an IV bag comprising pharmaceutical formulation of a tau-binding antibody or antigen-binding fragment thereof for use in a method of treating a tauopathy in a human subject in need thereof, the method comprising administering to the human subject at least one dose of 45 mg / kg to 90 mg / kg of the tau-binding antibody or antigen-binding fragment thereof via intravenous infusion from the IV bag, wherein the tau-binding antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising a CDR1 selected from SEQ ID No.: 1, a CDR2 selected from SEQ ID No.: 2, and a CDR3 selected from SEQ ID No.: 3; and (ii) a heavy chain variable region comprising a CDR1 selected from SEQ ID No.: 4, a CDR2 selected from SEQ ID No.: 5, and a CDR3 selected from SEQ ID No. : 6. In one embodiment, the dose of antibody or antigen-binding fragment thereof is 85 mg / kg to 95 mg / kg. In one embodiment, the dose of antibody or antigen-binding fragment thereof is about 90 mg / kg. In one embodiment, the doses are administered at about 4 week or about monthly intervals. In one embodiment, at least 12 doses are administered at about 4 week or about monthly intervals. In one particular embodiment, the tauopathy is AD and the patient has a low tau burden or is not an APOE4 carrier. In an alternative embodiment, the subject is not limited to whether they have low tau burden and whether they are an APOE4 carrier.

[0153] In one embodiment, the present invention further provides a vial containing a pharmaceutical formulation of a tau-binding antibody or antigen-binding fragment thereof for use in a method of treating a tauopathy in a human subject in need thereof, the method comprising preparing a pharmaceutical formulation comprising the antibody or antigen-binding fragment thereof which is suitable for intravenous infusion and administering to the human subject at least one dose of 45 mg / kg to 90 mg / kg of the tau-binding antibody or antigen-binding fragment thereof via intravenous infusion, wherein the tau-binding antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising a CDR1 selected from SEQ ID No.: 1, a CDR2 selected from SEQ ID No.: 2, and a CDR3 selected from SEQ ID No.: 3; and (ii) a heavy chain variable region comprising a CDR1 selected from SEQ ID No.: 4, a CDR2 selected from SEQ ID No.: 5, and a CDR3 selected from SEQ ID No.: 6. In one embodiment, the dose of antibody or antigen-binding fragment thereof is 85 mg / kg to 95 mg / kg. In one embodiment, the dose of antibody or antigen-binding fragment thereof is about 90 mg / kg. In one embodiment, the method comprises a step of preparing an IV bag comprising a pharmaceutical formulation comprising the antibody or antigen-binding fragment thereof from the vial. In one embodiment, the doses are administered at about 4 week or about monthly intervals. In one embodiment, at least 12 doses are administered at about 4 week or about monthly intervals. In one particular embodiment, the tauopathy is AD and the patient has a low tau burden or is not an APOE4 carrier. In an alternative embodiment, the subject is not limited to whether they have low tau burden and whether they are an APOE4 carrier.

[0154] In one embodiment, the present invention provides a tau-binding antibody or antigenbinding fragment thereof for use in a method of treating a tauopathy in a human subject in need thereof, the method comprising administering to the human subject at least one dose of 55 mg / kg to 65 mg / kg of the tau-binding antibody or antigen-binding fragment thereof, wherein the tau- binding antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising a CDR1 selected from SEQ ID No.: 1, a CDR2 selected from SEQ ID No.: 2, and a CDR3 selected from SEQ ID No.: 3; and (ii) a heavy chain variable region comprising a CDR1 selected from SEQ ID No.: 4, a CDR2 selected from SEQ ID No.: 5, and a CDR3 selected from SEQ ID No. : 6. In one such embodiment, the antibody or antigen-binding fragment thereof will be administered via intravenous infusion from an IV bag. In one embodiment, the dose of antibody or antigen-binding fragment thereof is about 60 mg / kg. In one embodiment, the doses are administered at about 4 week or about monthly intervals. In one embodiment, at least 12 doses are administered at about 4 week or about monthly intervals. In one particular embodiment, the tauopathy is AD and the patient has a low tau burden or is not an APOE4 carrier. In an alternative embodiment, the subject is not limited to whether they have low tau burden and whether they are an APOE4 carrier.

[0155] In one embodiment, the present invention further provides an IV bag comprising pharmaceutical formulation of a tau-binding antibody or antigen-binding fragment thereof for use in a method of treating a tauopathy in a human subject in need thereof, the method comprising administering to the human subject at least one dose of 55 mg / kg to 65 mg / kg of the tau-binding antibody or antigen-binding fragment thereof via intravenous infusion from the IV bag, wherein the tau-binding antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising a CDR1 selected from SEQ ID No.: 1, a CDR2 selected from SEQ ID No.: 2, and a CDR3 selected from SEQ ID No.: 3; and (ii) a heavy chain variable region comprising a CDR1 selected from SEQ ID No.: 4, a CDR2 selected from SEQ ID No.: 5, and a CDR3 selected from SEQ ID No. : 6. In one embodiment, the dose of antibody or antigen-binding fragment thereof is about 60 mg / kg. In one embodiment, the doses are administered at about 4 week or about monthly intervals. In one embodiment, at least 12 doses are administered at about 4 week or about monthly intervals. In one particular embodiment, the tauopathy is AD and the patient has a low tau burden or is not an APOE4 carrier. In an alternative embodiment, the subject is not limited to whether they have low tau burden and whether they are an APOE4 carrier.

[0156] In one embodiment, the present invention further provides a vial containing a pharmaceutical formulation of a tau-binding antibody or antigen-binding fragment thereof for use in a method of treating a tauopathy in a human subject in need thereof, the method comprising preparing a pharmaceutical formulation comprising the antibody or antigen-binding fragment thereof which is suitable for intravenous infusion and administering to the human subject at least one dose of 55 mg / kg to 65 mg / kg of the tau-binding antibody or antigen-binding fragment thereof via intravenous infusion, wherein the tau-binding antibody or antigen-binding fragment thereof comprises: (i) a light chain variable region comprising a CDR1 selected from SEQ ID No.: 1, a CDR2 selected from SEQ ID No.: 2, and a CDR3 selected from SEQ ID No.: 3; and (ii) a heavy chain variable region comprising a CDR1 selected from SEQ ID No.: 4, a CDR2 selected from SEQ ID No.: 5, and a CDR3 selected from SEQ ID No.: 6. In one embodiment, the dose of antibody or antigen-binding fragment thereof is about 60 mg / kg. In one embodiment, the method comprises a step of preparing an IV bag comprising a pharmaceutical formulation comprising the antibody or antigen-binding fragment thereof from the vial. In one embodiment, the doses are administered at about 4 week or about monthly intervals. In one embodiment, at least 12 doses are administered at about 4 week or about monthly intervals. In one particular embodiment, the tauopathy is AD and the patient has a low tau burden or is not an APOE4 carrier. In an alternative embodiment, the subject is not limited to whether they have low tau burden and whether they are an APOE4 carrier.

[0157] In any of the embodiments set out in this section, it may be that the antibody or antigen binding fragment thereof is administered via intravenous infusion, for instance, for an infusion time of about 1 hour to about 4 hours. In one embodiment, the administration time via intravenous infusion is no more than 4 hours in length. Methods of treatment and manufacture of medicaments

[0158] The present disclosure sets out a tau-binding antibody or antigen-binding fragment thereof for use in various methods of treatment. The present invention also provides the methods themselves. It also provides for the use of a tau-binding antibody or antigen-binding fragment thereof in the manufacture of a medicament for treating a tauopathy as set out. Hence, where a tau- binding antibody or antigen-binding fragment thereof for use, a method of treatment, or use in the manufacture of a medicament is set out, the equivalent other format is also provided.

[0159] Pharmaceutical compositions and formulation

[0160] The tau-binding antibody or antibody fragment of the invention can be incorporated into pharmaceutical composition. Thus, where reference herein is made to an antibody or antigenbinding fragment thereof a pharmaceutical composition comprising the antibody or antigenbinding fragment thereof may be provided or employed. Typically, the pharmaceutical composition comprises the tau-binding antibody or antibody fragment of the invention and / or a pharmaceutically acceptable carrier and / or other active ingredient such as galantamine, rivastigmine, or donepezil.

[0161] As used herein, "pharmaceutically acceptable carrier" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like that are physiologically compatible and are suitable for administration to a subject for the methods described herein. Examples of pharmaceutically acceptable carriers include one or more of water, saline, phosphate buffered saline, dextrose, glycerol, ethanol and the like, as well as combinations thereof. In many cases, it will be preferable to include isotonic agents, for example, sugars, polyalcohols such as mannitol, sorbitol, or sodium chloride in the composition. Pharmaceutically acceptable carriers may further comprise minor amounts of auxiliary substances such as wetting or emulsifying agents, preservatives or buffers, which enhance the shelf life or effectiveness of the antibody or antibody portion. The compositions of this invention may be in a variety of forms. These include, for example, liquid solutions (e.g., injectable and infusible solutions), dispersions or suspensions, powders and liposomes. The preferred form depends on the intended mode of administration and therapeutic application. Typical preferred compositions are in the form of injectable or infusible solutions, such as compositions similar to those used for passive immunization of humans with other antibodies.

[0162] In one embodiment, the formulation is specific for one of the administration routes set out herein, for instance compositions suitable for administration to a subject intravenously, subcutaneously or intramuscularly may be provided. Hence, in another embodiment of the invention is a pharmaceutical composition comprising the tau-binding antibody or antigen-binding fragment according to any of the embodiments of the invention and a pharmaceutically acceptable carrier wherein the composition is prepared for intravenous, subcutaneous or intramuscular administration to the individual in need thereof.

[0163] In another embodiment the composition is part of a kit with instructions for use, including instructions and optionally a device for intravenous, subcutaneous or intramuscular administration to the individual in need thereof. In one embodiment, the instructions set out a dosage and / or regimen as disclosed herein.

[0164] In one embodiment, the antibody or antigen-binding fragment thereof is provided in a pharmaceutical composition that is subsequently diluted to give the final composition for administration. In one embodiment, the antibody or antigen-binding fragment thereof is provided in a pharmaceutical composition is provided in a vial with the pharmaceutical composition being diluted with saline in an IV bag before administration.

[0165] Tauopathies and patient assessment

[0166] The present invention may be used to treat tauopathies in general. Examples of particular tauopathies to be treated are Progressive Supranuclear Palsy (PSP), Corti cobasal Degeneration and Alzheimer’s disease (AD). In an alternative embodiment the tauopathy is PSP or AD. In any of the embodiments set out herein the tauopathy may be AD unless otherwise stated.

[0167] Progressive supranuclear palsy (PSP) is characterised by the misfolding and aggregation of pathological tau which spreads through the brain, causing neurodegeneration and resultant brain atrophy (Cohn et al Acta Neuropathol 2020; 139: 3-25; Gong et al. Curr Med Chem 2008; 15: 2321-8; Orr et al Trends Pharmacol Sci 2017; 38: 637-48). Pathology in PSP begins with tau accumulation in subcortical and brainstem nuclei, the globus pallidus and striatum, regions associated with symptoms such as postural instability, sleep disorders, ocular motor dysfunction, and Parkinsonism. This is followed by tau accumulation in cortical areas including the frontal, parietal, and temporal lobes, which are associated with symptoms such as cognitive impairment and behavioural alterations, apraxia, and impaired language function, respectively (Coughlin et al. Parkinsonism Relat Disord 2020; 73: 105-16). There are a number of clinical phenotypes of PSP, characterised by different combinations of these symptoms: Richardson syndrome (PSP RS), PSP predominant parkinsonism (PSP P) and PSP progressive gait freezing (PSP PGF), among others (Hoglinger et al Mov Disord 2017; 32: 853-64). In one particular embodiment of the invention, the tauopathy is selected from PSP RS, PSP P and PSP PGF.

[0168] Initial symptoms of PSP RS typically develop in patients aged approximately 65 years and include gait difficulties and falls. As the disease progresses, patients may experience worsening parkinsonism, dysarthria, dysphagia, frontal cognitive difficulties, and supranuclear ophthalmoplegia. Disease progression is rapid and relentless, with increased physical disability; on average, PSP RS advances from symptom onset to death in 7 years, with a dependency on care developing within 3-4 years from presentation (Williams et al Brain 2005; 128: 1247-58; Hoglinger et al Mov Disord 2017; 32: 853-64). The average age at death in people with PSP-RS is earlier at 72.1 years, compared with 75.5 years in people with PSP P.

[0169] There are currently no approved treatments to target the underlying cause of PSP, or to slow down disease progression.

[0170] In one alternative embodiment, a treatment of the invention results in a slowing of disease progression as measured by adequate rating tools recommended by the regulatory agencies. One such currently available tool is the PSP Rating Scale. The PSP Rating Scale (PSPRS) is a prospectively validated physician-rated measure of disease severity for PSP, measured by 28 items within 6 categories: daily activities, mentation, bulbar, ocular motor, limb motor, and gait / midline exam. The rater assigns 0-2 or 0-4 points for each item, yielding a total PSPRS score from 0-100. Higher PSPRS scores indicate higher degrees of disease severity, with higher functional impairment. Previous studies that utilized the PSPRS as a primary endpoint indicate annual increases in the total PSPRS score between 10 and 12. A reduction of progression in PSP by -40% is considered clinically meaningful (Donker Kaat et al. Parkinsonism Relat Disord 2018; 56: 98- 101).

[0171] In a particular embodiment, the present invention results in a slowing of disease progression as measured by the PSP-Rating Scale, wherein said reduction of disease progression is obtained for at least one of the indices selected from the PSP-Rating Scale. In a further particular embodiment, said reduction of disease progression is at least 20%, at least 25%, at least 30%, at least 35% or at least 40% according to the PSP-Rating Scale.

[0172] Alternatively, the Combined Assessment of Function and Survival (CAFS), which is based on the Joint Rank Test, and originally developed for the analysis of function adjusted for mortality in amyotrophic lateral sclerosis (ALS), may be a further useful tool to measure disease progression in PSP. In the current setting, CAFS would rank patient clinical outcomes based on survival time and change in the PSP-Rating Scale. Consequently, in a further embodiment the subject treated achieves a reduction in disease progression according to the Combined Assessment of Function and Survival with respect to PSP.

[0173] The Schwab and England ADL (Activities of Daily Living) scale (also known as SEADL scale) is a method of assessing the capabilities of people with impaired mobility. The scale uses percentages to represent how much effort and dependence on other people need to complete daily chores. The rating may be given by a professional or by the person being tested. In a further particular embodiment wherein PSP is treated the subject treated achieves a slowing of disease progression as measured by the SEADL scale.

[0174] As described above, one of the features of PSP is progressive brain atrophy. Therefore, in a further alternative embodiment, the subject treated achieves a reduction in the progression of brain atrophy. Measurement of brain atrophy is performed routinely by a person of ordinary skill in the art with available techniques in a neurology unit, such as for example by Volumetric MRI or Computed Tomography (CT) scan. In a further alternative embodiment, the subject treated achieves a reduction in the progression of brain atrophy as measured by Volumetric MRI. Alternatively, in another particular embodiment the treated subject achieved a reduction in the progression of brain atrophy as measured by CT scan.

[0175] In another particular embodiment of the invention the tauopathy is Alzheimer’s Disease (AD). Typically, three stages of Alzheimer’s disease are recognized: early stage or mild AD, middle stage or moderate AD and late stage or severe AD, according to the severity of symptoms. Therefore, in a particular embodiment of the method of the invention the tauopathy is early AD (prodromal and mild). In another it is moderate AD. In another it is severe AD. In one embodiment, the invention slows or stops progression from one of those forms of AD to a more severe form.

[0176] Alzheimer’s disease is considered a secondary tauopathy, where the degree of tau accumulation in the brain appears to correlate with cognitive decline, highlighting the relevance of tau in this disease. Therefore, in a particular embodiment of the invention the subject treated has a low tau burden. Alternatively, in another particular embodiment of the invention the subject treated has a high tau burden.

[0177] Tau burden in the brain is typically measured using positron emission tomography (PET). Multiple PET imaging tracers targeting aggregated tau in the brain have been developed to detect tau accumulation and monitor its progression to facilitate the diagnosis and prognosis of AD (see for example O’Connor et al, 2023, Alzheimer’s Research & Therapy vol 15, article 99). Examples of Tau PET tracers include18F-MK6240, [18F] GTP1, [18F]RO-948), [18F]PI2620,18F-AV-1451 or [18F] JNJ-311.

[0178] Therefore in a further particular embodiment of the method of the invention the subject treated has a low tau burden as determined by PET imaging, optionally using one of the above exemplified tracers. In another embodiment, the subject treated has a high tau burden as determined by PET imaging, optionally using one of the above exemplified tracers.

[0179] As is known to the skilled artisan the temporal meta-ROI or temporal meta region of interest, is the temporal region of the brain where AD typically begins, where AD pathology is first seen and where memory and cognition are controlled. For the purposes of the current disclosure the terms “temporal meta” and “Jack temporal meta” regions are used interchangeably. SUV or Standardized Uptake Value measures how much of a radioactive tracer (a substance used to highlight areas of interest in the body) is taken up by a specific region of the body. The SUVR, or SUV Ratio compares the SUV of one region to another, often a reference region that is expected to have normal uptake, in AD trials this reference region is typically the cerebellum. In summary, the SUVR allows physicians to determine the relative absorption of a PET tracer of one particular area or target region of the body as compared to a control area.

[0180] Tools are available that allow for standardization of SUVR measurements from different Tau PET tracers. One such tool is the CenTauR scale (see Villemagne et al. Diagnosis, Assessment & Disease Monitoring vol 15, issue 3, el 2454). For example, a value of 1.3 SUVR for [18F] GTPlin the temporal meta ROI would correspond to a value of 1.38 on the CenTauR scale, which in turn would allow the skilled person to calculate a corresponding SUVR value of 1.28 for18F- MK6240.

[0181] As used herein “low tau burden” means subjects with a temporal meta-ROI SUVR value below about 1.3, below about 1.29 or below about 1.28. Alternatively, “low tau burden” means subj ects with a temporal meta-ROI CenTauR value below about 1.38. In a particular embodiment, “low tau burden” means subjects with a temporal meta-ROI SUVR value below 1.3, 1.29 or 1.28 or a temporal meta-ROI CenTauR value below 1.38.

[0182] Conversely as used herein “high tau burden” means subjects with a temporal meta-ROI SUVR value equal to or above about 1.3, above about 1.29 or above about 1.28. Alternatively, “high tau burden” means subjects with a temporal meta-ROI CenTauR value equal to or above about 1.38. In a particular embodiment, “high tau burden” means subjects with a temporal meta- ROI SUVR value equal to or above 1.3, 1.29 or 1.28 or a temporal meta-ROI CenTauR value equal to or above 1.38.

[0183] A major genetic risk factor for Alzheimer’s disease is the presence of the s4 allele of apolipoprotein E (APOE4). Although the underlying mechanism for this increased risk remains unknown, there is evidence suggesting differential effects of the apoE isoforms on beta-amyloid aggregation and clearance, and more recent observations indicate a different tau deposition pattern in individuals who are APOE4 carriers.

[0184] In another particular embodiment of the method of the invention, the subject to be treated is not an APOE4 carrier. Alternatively, the subject to be treated is an APOE4 carrier. In a further particular embodiment a subject who is an APOE4 carrier, may be a heterozygote carrier (i.e. the subject has only one allele that is APOE4) or a homozygote carrier (i.e. both alleles are APOE4).

[0185] As used herein the terms “not an APOE4 carrier”, “APOE4 non-carrier”, “does not carry APOE4”, “non APOE4 carrier”, or “s4-” are interchangeable and used to refer to individuals who do not have an APOE4 allele.

[0186] In an alternative embodiment of the method of the invention the subject to be treated has a low tau burden and is not an APOE4 carrier. In another embodiment, the subject to be treated has a low tau burden and is an APOE4 carrier. In another embodiment, the subject to be treated has a high tau burden and is not an APOE4 carrier. In another embodiment, the subject to be treated has a high tau burden and is an APOE4 carrier.

[0187] In a further particular embodiment, the subject to be treated has a low tau burden or is not an APOE4 carrier. For the avoidance of doubt, this group includes patients who are:

[0188] Low tau burden and non APOE4 carrier,

[0189] Low tau burden and APOE4 carrier (either homozygote or heterozygote), and High tau burden and non APOE4 carrier. Cognitive decline in Alzheimer’s disease may be determined according to a number of established rating tools including the Clinical Dementia Rating, Alzheimer’s disease assessment scale-cognitive subscale, Amsterdam-Instrument Activities of Daily Living Questionnaire, Repeatable Battery for the Assessment of Neuropsychological Status, Alzheimer’s disease Cooperative Study- Activities of Daily Living, Mini-Mental State Examination, Alzheimer’s disease Composite Score, or Integrated Alzheimer’s disease Rating Scale. Accordingly, in one embodiment, the invention results in a slowing of disease progression according to any one of the above tools. These tools are used to both help diagnose the disease but also to monitor disease progression.

[0190] The CDR (Clinical Dementia Rating) scale is a clinician-rated dementia staging system that tracks the progression of cognitive impairment in 6 categories (memory, orientation judgment and problem solving, community affairs, home and hobbies, and personal care). Each category is scored on a 5-point scale in which None = 0, Questionable = 0.5, Mild = 1, Moderate = 2, and Severe = 3. The global CDR score is established by clinical scoring rules and has values of 0 (no dementia), 0.5, (questionable dementia), 1 (mild dementia), 2 (moderate dementia), and 3 (severe dementia). The CDR-SB (CDR Sum of Boxes) is obtained by adding the ratings in each of the 6 categories and ranges from 0 to 18 with higher scores indicative of greater impairment; it typically provides more information in cases of mild dementia than the global CDR score. The CDR / CDR- SB is administered to the patient and informant separately by a trained rater and takes approximately 40 to 75 minutes.

[0191] The Alzheimer’s Disease Assessment Scale-Cognitive Subscale or ADAS-Cogl4 is a composite scale (neuropsychological test battery and clinician reported outcome) that evaluates memory, orientation, attention, reasoning, language, and constructional praxis. Higher scores indicate greater impairment, with a minimum of 0 and a maximum of 90. The ADAS Cogl4 is administered to the patient by a trained rater and takes approximately 30-45 minutes.

[0192] The Amsterdam-Instrumental Activities of Daily Living Questionnaire or A-iADL, is an adaptive and computerized observer-reported outcome measure designed to assess impairments in instrumental activities of daily living (iADL) in early dementia. The questionnaire is administered to an informant such as a relative or friend, with every effort made to use the same informant for a particular study participant throughout the study. The questionnaire consists of 70 items in 7 categories, which takes approximately 20 to 25 minutes to complete. The A-iADL assesses impairments in a broad range of daily activities including household activities, household appliances, finances, work, computer, appliances, leisure activities. The scoring range is 20 to 80 using an item response theory algorithm, with higher scores indicating better functioning. The A- iADL will be administered by a trained rater.

[0193] The Repeatable Battery for the Assessment of Neuropsychological Status or RBANS is a neuropsychological test battery that was developed for screening dementia.

[0194] The RBANS consists of 12 subtests, which give 5 Index scores, one for each of the five domains tested, and a Total Scale Score:

[0195] • Immediate memory (range: 40 to 152);

[0196] • Visuospatial / constructional (range: 50 to 136);

[0197] • Language (range: 40 to 137);

[0198] • Attention (range: 40 to 154);

[0199] • Delayed memory (range: 40 to 137); AND

[0200] • Total Scale Score (range: 40 to 160).

[0201] Index scores have a mean of 100 and a standard deviation (SD) of 15, all of which are corrected for age and education.

[0202] RBANS is administered to the patient by a trained rater and takes approximately 30 to 45 minutes to administer.

[0203] The Alzheimer’s Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) is an observer (informant) -reported outcome measure that assesses impairments in basic activities of daily living (bADLs) and iADLs. The ADCS ADL is a 23 -item scale that includes 6 bADL items and 17 iADL items (the 17 items used in Integrated Alzheimer’s Disease Rating Scale [iADRS]) that score from 0 to 78, with a lower score indicating greater severity. The ADCS-ADL is administered by a trained rater and takes approximately 30 to 45 minutes to complete.

[0204] The Mini -Mental State Examination or MMSE is an 11 -item neuropsychological test that is used to assess cognitive status in adults, and can be used to screen for cognitive impairment and to estimate severity of cognitive impairment. It assesses orientation, memory, attention, ability to name, ability to follow verbal and written commands, ability to write a sentence and to copy a drawing. The MMSE is administered by a trained rater and takes approximately 10 to 15 minutes to complete. The score ranges from 0 to 30. Lower scores are indicative of poorer cognitive performance. The Alzheimer’s Disease Composite Score (ADCOMS) was developed for patients with amnestic MCI due to AD and mild AD. The ADCOMS is a composite score that includes 2 MMSE items, 6 CDR-SB items, and 4 ADAS Cogl4 subscales and is considered to be more sensitive to change and treatment effects than individual study instruments. There is no action for the site / Investigator to perform to achieve collection of the ADCOMS.

[0205] The ADAS-Cogl4 may be combined with the ADCS-ADL score to form the iADRS or Integrated Alzheimer’s Disease Rating Scale. The iADRS is a linear combination of the ADAS- Cogl4 and the instrumental items of the ADCS-ADL. iADRS = [-1(ADAS-Cogl4) + 90] + 1ADL

[0206] The total range of the iADRS is 0 to 146, with lower scores indicating worse performance. The iADRS has been shown to be composed of 2 principal components, cognition, and instrumental function. It has been shown to be more responsive to disease progression in MCI and AD than previous versions of the ADAS-Cog, or the ADAS Cog 14 alone. There is no action for the site / Investigator to perform to achieve collection of the iADRS.

[0207] Mitochondrial impairment can also be a feature of taupoathies. In one embodiment, treatment with an antibody or antigen-binding fragment thereof of the present invention may help restore mitochondrial function in a tauopathy. For example, in such tauopathies mitochondrial membrane potential may be affected, and treatment with an antibody or antigen-binding fragment thereof may help restore mitochondrial membrane potential to, or towards, normal levels. In one embodiment, the subject to be treated is one that displays mitochondrial dysfunction. In one embodiment, the subject may be one who displays altered mitochondrial membrane potential. In one embodiment, the subject displays lowered membrane potential. In a particular embodiment, the subject displays raised membrane potential and in particular displays such raised membrane potential and has a 10+16 MAPT mutation. In one embodiment, such a subject may display excess 4Rtau protein isoforms. In another embodiment, the subject has a P301L mutation and in particular may display hyperpolarised mitochondrial membranes. In one embodiment, employing the invention may mean that mitochondrial membrane potential may return, or at least be closer to, normal.

[0208] Any suitable tauopathy sufferer may be treated using the invention provided. In one embodiment though the subject has Alzheimer’s Disease (AD). Hence, in any of the embodiments set out herein, unless otherwise stated, the subject to be treated may have AD. As discussed herein in one embodiment patients may be characterized by whether they have low or high tau burden. In another embodiment, patients may be characterized as to whether or not they are ApoE carriers. In one embodiment, they are characterized as to both, i.e. whether they have low or high tau burden and also whether they are ApoE carriers. Hence, in one embodiment, the AD subject to be treated has: (i) a low tau burden and is not an APOE4 carrier; (ii) a low tau burden and is an APOE4 carrier; or (iii) a high tau burden and is not an APOE4 carrier. However, in another embodiment though it may be that the AD patient to be treated is not selected based on their tau burden and APOE4 carrier status.

[0209] In a further embodiment, the AD patient to be treated may have a particular age. In one embodiment, the subject with AD may be at least 50 years of age. For instance, in any of the embodiments set out herein, unless otherwise stated, it may be that a subject with AD being treated is at least 60 years of age. In another embodiment, the subject may be at least 65 years of age. In another embodiment, the subject may be at least 70 years of age.

[0210] Definitions

[0211] In order that the present invention may be more readily understood, certain terms are defined below. In the absence of a definition, terms may be construed as they would be by the skilled person working in the present technical field.

[0212] Where the term “comprising” is used in the present description and claims, it does not exclude other elements. For the purposes of the present disclosure, the term “consisting of’ is considered to be a preferred embodiment of the term “comprising of’. If hereinafter a group is defined to comprise at least a certain number of embodiments, this is also to be understood to disclose a group which preferably consists only of these embodiments. Also provided are embodiments, consisting essentially of what is set out.

[0213] For the purposes of the present disclosure, the term “obtained” is considered to be a preferred embodiment of the term “obtainable”. If hereinafter e.g. an antibody is defined to be obtainable from a specific source, this is also to be understood to disclose an antibody which is obtained from this source.

[0214] Where an indefinite or definite article is used when referring to a singular noun, e.g. “a”, “an” or “the”, this includes a plural of that noun unless something else is specifically stated. The terms “about” or “approximately” denote an interval of accuracy that the person skilled in the art will understand to still ensure the technical effect of the feature in question. The term typically indicates deviation from the indicated numerical value of ±10%, and preferably of ±5%. Where the term “about” is used, also disclosed is exactly what is set out, so, for instance, where about 4 g is referred to, also disclosed is 4 g itself.

[0215] As used herein, the terms “treatment”, “treating” and the like, refer to obtaining a desired pharmacologic and / or physiologic effect. The effect may be prophylactic in terms of completely or partially preventing a disease or symptom thereof and / or may be therapeutic in terms of slowing the progression or, obtaining a partial or complete cure for a disease and / or adverse effect attributable to the disease. Treatment thus covers any treatment of a disease in a human subject, and includes: (a) preventing the disease from occurring in a subject which may be predisposed to the disease but has not yet been diagnosed as having it; (b) inhibiting the disease, i.e., arresting its development; and (c) relieving the disease, i.e., causing regression of the disease. The present disclosure sets out various approaches for assessing tauopathy patients, including in particular for assessing PSP and AD.

[0216] Priority

[0217] The present application claims priority from US 63 / 694,307 filed 13 September 2024 and EP 24204948.4 filed 7 October 2024 both of which are incorporated in their entirety.

[0218] With respect to these various aspects and embodiments which have been described herein, the present disclosure contemplates inter alia:

[0219] 1. A tau-binding antibody or antigen-binding fragment thereof for use in a method of treating a tauopathy in a human subject in need thereof, the method comprising administering to the human subject at least one dose of 30 mg / kg to 120 mg / kg of the tau-binding antibody or antigen-binding fragment thereof, wherein the tau-binding antibody or antigen-binding fragment thereof comprises: a light chain variable region comprising a CDR1 selected from SEQ ID No.: 1, a CDR2 selected from SEQ ID No.: 2, and a CDR3 selected from SEQ ID No.: 3; and a heavy chain variable region comprising a CDR1 selected from SEQ ID No.: 4, a CDR2 selected from SEQ ID No.: 5, and a CDR3 selected from SEQ ID No.: 6. 2. The tau-binding antibody or antigen-binding fragment thereof for use according to embodiment 1, wherein the dose or doses are each 45 mg / kg to 90 mg / kg of the tau-binding antibody or antigen binding fragment thereof.

[0220] 3. The tau-binding antibody or antigen-binding fragment thereof for use according to embodiment 1 or 2, wherein the dose or doses are each 40 mg / kg to 50 mg / kg of the tau-binding antibody or antigen-binding fragment thereof and are optionally about 45 mg / kg of the antibody or antigen-binding fragment thereof.

[0221] 4. The tau-binding antibody or antigen-binding fragment thereof for the use according to any preceding embodiments, wherein the dose or doses are each 85 mg / kg to 95 mg / kg of the tau- binding antibody or antigen- binding fragment thereof and are optionally about 90 mg / kg of the antibody or antigen-binding fragment thereof.

[0222] 5. The tau-binding antibody or binding fragment thereof for use according to any one of the preceding embodiments, wherein a plurality of doses of the tau-binding antibody or antigenbinding fragment are administered wherein the interval between each pair of doses is 3 to 5 weeks.

[0223] 5. The tau-binding antibody or antigen-binding fragment thereof for use according to any one of the preceding embodiments, wherein a plurality of doses of the tau-binding antibody or antigenbinding fragment are administered wherein the interval between each pair of doses is 4 weeks.

[0224] 6. The tau-binding antibody or antigen-binding fragment thereof for use according to any one of the preceding embodiments, wherein the tau-binding antibody or antigen-binding fragment thereof is administered to the human subject in need thereof for at least 12 weeks, at least 24 weeks, at least 52 weeks, at least 68 weeks or at least 80 weeks.

[0225] 7. The tau-binding antibody or antigen-binding fragment thereof according to any one of the preceding embodiments, wherein the tau-binding antibody or antigen-binding fragment thereof binds to an epitope comprising the amino acid residues of S238, A239, S241, T245, A246, of SEQ ID No.: 11, optionally wherein the epitope further comprises one or more residues selected from S235, S237, K240, R242, L243, Q244, V248, and M250 of SEQ ID No.: 11.

[0226] 8. The tau-binding antibody or antigen-binding fragment thereof for use according to any one of the preceding embodiments, wherein the tau-binding antibody or antigen-binding fragment thereof binds to both soluble human and paired helical filaments (PHF) of human tau. 9. The tau-binding antibody or antigen-binding fragment thereof for use according to any one of the preceding embodiments, wherein the tau-binding antibody or antigen-binding fragment thereof comprises a light chain variable region comprising SEQ ID No. : 7, and a heavy chain variable region comprising SEQ ID No.: 8.

[0227] 10. The tau-binding antibody or antigen-binding fragment thereof for use according to any one of the preceding embodiments, wherein the tau-binding antibody or antigen-binding fragment thereof comprises a light chain comprising SEQ ID No.: 9, and a heavy chain comprising SEQ ID No.: 10.

[0228] 11. The tau-binding antibody or antigen-binding fragment thereof for use according to any one of the preceding embodiments, wherein the tau-binding antibody or antigen-binding fragment thereof is a monoclonal humanized antibody.

[0229] 12. The tau-binding antibody or antigen-binding fragment thereof for use according to any one of the preceding embodiments, wherein the tau-binding antibody or antigen-binding fragment thereof is administered intravenously.

[0230] 13. The tau-binding antibody or antigen-binding fragment thereof for use according to any one of the preceding embodiments, wherein the tauopathy is selected from progressive supranuclear palsy (PSP), corti cobasal degeneration and Alzheimer’s disease (AD).

[0231] 14. The tau-binding antibody or antigen-binding fragment thereof for use according to any one of the preceding embodiments, wherein the tauopathy is Alzheimer’s disease (AD), optionally wherein the subject treated achieves a slowing of disease progression as measured by Clinical Dementia Rating score, Clinical Dementia Rating Memory Box, the delayed recall domain of the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), or mini-mental state examination (MMSE).

[0232] 15. The tau-binding antibody or antigen-binding fragment thereof for use according to any one of the preceding embodiments, wherein the tauopathy is Alzheimer’s disease (AD), optionally wherein the subject treated achieves a slowing of disease progression as measured by Clinical Dementia Rating score Sum of Boxes (CDR-SB), the Alzheimer’s Disease Assessment Scale- Cognitive Subscale (ADAS-Cogl4), the Amsterdam-Instrumental Activities of Daily Living Questionnaire (A-iADL-Q), the mini-mental state examination (MMSE) and / or the Alzheimer’s Disease Cooperative Study- Activities of Daily Living (ADCS-ADL).

[0233] 16. The tau-binding antibody or antigen-binding fragment thereof for use according to any one of the preceding embodiments, wherein the tauopathy is progressive supranuclear palsy (PSP), optionally wherein the method achieves a slowing of disease progression as measured by the PSP- Rating Scale.

[0234] 17. Use of a tau-binding antibody or antigen-binding fragment thereof in the manufacture of a medicament for the treatment of a tauopathy, wherein at least one dose of 30 mg / kg to 120 mg / kg of the tau-binding antibody or binding fragment thereof is administered to a human subject in need thereof, wherein the tau-binding antibody or binding fragment thereof comprises: a light chain variable region comprising a CDR1 selected from SEQ ID No.: 1, a CDR2 selected from SEQ ID No.: 2, and a CDR3 selected from SEQ ID No.: 3; and a heavy chain variable region comprising a CDR1 selected from SEQ ID No.: 4, a CDR2 selected from SEQ ID No.: 5, and a CDR3 selected from SEQ ID No.: 6.

[0235] The present invention also contemplates the following further numbered embodiments inter alia'.

[0236]

[0001] A tau-binding antibody or antigen-binding fragment thereof for use in a method of treating Alzheimer’s disease (AD) in a human subject in need thereof, the method comprising administering to the human subject a tau-binding antibody or antigen-binding fragment thereof, wherein the tau-binding antibody or antigen-binding fragment thereof binds to an epitope comprising the amino acid residues of S238, A239, S241, T245, A246, of SEQ ID No.: 11, optionally wherein the epitope further comprises one or more residues selected from S235, S237, K240, R242, L243, Q244, V248, and M250 of SEQ ID No.: 11, wherein the human subject has a low tau burden or is not an APOE4 carrier.

[0237] [2] A tau-binding antibody or antigen-binding fragment thereof for use in a method of treating Alzheimer’s disease (AD) in a human subject in need thereof, the method comprising administering to the human subject a tau-binding antibody or antigen-binding fragment thereof, wherein the tau-binding antibody or antigen-binding fragment thereof comprises: a light chain variable region comprising a CDR1 selected from SEQ ID No.: 1, a CDR2 selected from SEQ ID No.: 2, and a CDR3 selected from SEQ ID No.: 3; and a heavy chain variable region comprising a CDR1 selected from SEQ ID No.: 4, a CDR2 selected from SEQ ID No.: 5, and a CDR3 selected from SEQ ID No.: 6; wherein the human subject has a low tau burden or is not an APOE4 carrier.

[0238] [3] The tau-binding antibody or antigen-binding fragment thereof for use according to [1] or [2] wherein the human subject has:

[0239] - a low tau burden and is not an APOE4 carrier,

[0240] - a low tau burden and is an APOE4 carrier, or

[0241] - a high tau burden and is not an APOE4 carrier

[0242] [4] The tau-binding antibody or antigen-binding fragment thereof for use according to [1] or [2] or [3], the method comprising administering to the human subject at least one dose of 30 mg / kg to 120 mg / kg.

[0243] [5] The tau-binding antibody or antigen-binding fragment thereof for use according to any preceding claim, wherein the dose or doses are each 45 mg / kg to 90 mg / kg of the tau-binding antibody or antigen binding fragment thereof.

[0244] [6] The tau-binding antibody or antigen-binding fragment thereof for use according to any one of [1] to [5], wherein the dose or doses are each 40 mg / kg to 50 mg / kg of the tau-binding antibody or antigen-binding fragment thereof and are optionally about 45 mg / kg of the antibody or antigenbinding fragment thereof.

[0245] [7] The tau-binding antibody or antigen-binding fragment thereof for the use according to any one of [1] to [6], wherein the dose or doses are each 85 mg / kg to 95 mg / kg of the tau-binding antibody or antigen- binding fragment thereof and are optionally about 90 mg / kg of the antibody or antigen-binding fragment thereof.

[0246] The tau-binding antibody or antigen-binding fragment thereof for the use according to any one of [1] to [6], wherein the dose or doses are each 55 mg / kg to 65 mg / kg of the tau-binding antibody or antigen- binding fragment thereof and are optionally about 60 mg / kg of the antibody or antigen-binding fragment thereof. [8] The tau-binding antibody or binding fragment thereof for use according to any one of [1] to [7], wherein a plurality of doses of the tau-binding antibody or antigen-binding fragment are administered wherein the interval between each pair of doses is 3 to 5 weeks.

[0247] [9] The tau-binding antibody or antigen-binding fragment thereof for use according to any one of [1] to [8], wherein a plurality of doses of the tau-binding antibody or antigen-binding fragment are administered wherein the interval between each pair of doses is 4 weeks.

[0248]

[0010] The tau-binding antibody or antigen-binding fragment thereof for use according to any one of [1] to [9], wherein the tau-binding antibody or antigen-binding fragment thereof is administered to the human subject in need thereof for at least 12 weeks, at least 24 weeks, at least 52 weeks, at least 68 weeks or at least 80 weeks.

[0249]

[0011] The tau-binding antibody or antigen-binding fragment thereof for use according to any one of [1] to

[0010] , wherein the tau-binding antibody or antigen-binding fragment thereof binds to an epitope comprising the amino acid residues of S238, A239, S241, T245, A246, of SEQ ID No.: 11, optionally wherein the epitope further comprises one or more residues selected from S235, S237, K240, R242, L243, Q244, V248, and M250 of SEQ ID No.: 11.

[0250]

[0012] The tau-binding antibody or antigen-binding fragment thereof for use according to any one of [1] to

[0011] , wherein the tau-binding antibody or antigen-binding fragment thereof binds to both soluble human and paired helical filaments (PHF) of human tau.

[0251]

[0013] The tau-binding antibody or antigen-binding fragment thereof for use according to any one of [1] to

[0012] , wherein the tau-binding antibody or antigen-binding fragment thereof comprises a light chain variable region comprising SEQ ID No. : 7, and a heavy chain variable region comprising SEQ ID No.: 8.

[0252]

[0014] The tau-binding antibody or antigen-binding fragment thereof for use according to any one of [1] to

[0013] , wherein the tau-binding antibody or antigen-binding fragment thereof comprises a light chain comprising SEQ ID No.: 9, and a heavy chain comprising SEQ ID No.: 10.

[0253]

[0015] The tau-binding antibody or antigen-binding fragment thereof for use according to any one of [1] to

[0014] , wherein the tau-binding antibody or antigen-binding fragment thereof is a monoclonal humanized antibody.

[0016] The tau-binding antibody or antigen-binding fragment thereof for use according to any one of [1] to

[0015] , wherein the tau-binding antibody or antigen-binding fragment thereof is administered intravenously.

[0254]

[0017] The tau-binding antibody or antigen-binding fragment thereof for use according to any one of [1] to

[0016] , wherein the subject treated achieves a slowing of disease progression as measured by Clinical Dementia Rating score Sum of Boxes (CDR-SB), the Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-Cogl4), the Amsterdam-Instrumental Activities of Daily Living Questionnaire (A-iADL-Q), the mini-mental state examination (MMSE) and / or the Alzheimer’s Disease Cooperative Study- Activities of Daily Living (ADCS-ADL).

[0255]

[0018] Use of a tau-binding antibody or antigen-binding fragment thereof in the manufacture of a medicament for the treatment of Alzheimer’s disease, wherein at least one dose of 30 mg / kg to 120 mg / kg of the tau-binding antibody or binding fragment thereof is administered to a human subject in need thereof, wherein the tau-binding antibody or binding fragment thereof comprises: a light chain variable region comprising a CDR1 selected from SEQ ID No.: 1, a CDR2 selected from SEQ ID No.: 2, and a CDR3 selected from SEQ ID No.: 3; and a heavy chain variable region comprising a CDR1 selected from SEQ ID No.: 4, a CDR2 selected from SEQ ID No.: 5, and a CDR3 selected from SEQ ID No.: 6; wherein the human subject has a low tau burden or is not an APOE4 carrier.

[0256]

[0019] A method of treating Alzheimer’s disease (AD) in a human subject in need thereof, the method comprising administering to the human subject a tau-binding antibody or antigen-binding fragment thereof, wherein the tau-binding antibody or antigen-binding fragment thereof binds to an epitope comprising the amino acid residues of S238, A239, S241, T245, A246, of SEQ ID No.: 11, optionally wherein the epitope further comprises one or more residues selected from S235, S237, K240, R242, L243, Q244, V248, and M250 of SEQ ID No.: 11, wherein the human subject has a low tau burden or is not an APOE4 carrier.

[0257]

[0020] A method of treating Alzheimer’s disease (AD) in a human subject in need thereof, the method comprising administering to the human subject a tau-binding antibody or antigen-binding fragment thereof, wherein the tau-binding antibody or antigen-binding fragment thereof comprises: a light chain variable region comprising a CDR1 selected from SEQ ID No.: 1, a CDR2 selected from SEQ ID No.: 2, and a CDR3 selected from SEQ ID No.: 3; and a heavy chain variable region comprising a CDR1 selected from SEQ ID No.: 4, a CDR2 selected from SEQ ID No.: 5, and a CDR3 selected from SEQ ID No.: 6; wherein the human subject has a low tau burden or is not an APOE4 carrier.

[0258]

[0021] The method according to

[0019] or

[0020] wherein the human subject has:

[0259] - a low tau burden and is not an APOE4 carrier,

[0260] - a low tau burden and is an APOE4 carrier, or

[0261] - a high tau burden and is not an APOE4 carrier

[0262]

[0022] The method according to any one of

[0019] -

[0021] , the method comprising administering to the human subject at least one dose of 30 mg / kg to 120 mg / kg.

[0263]

[0023] The method according to any one of

[0019] -

[0022] , wherein the dose or doses are each 45 mg / kg to 90 mg / kg of the tau-binding antibody or antigen binding fragment thereof.

[0264]

[0024] The method according to any one of

[0019] -

[0023] , wherein the dose or doses are each 40 mg / kg to 50 mg / kg of the tau-binding antibody or antigen-binding fragment thereof and are optionally about 45 mg / kg of the antibody or antigen-binding fragment thereof.

[0265]

[0025] The method according to any one of

[0019] -

[0024] , wherein the dose or doses are each 85 mg / kg to 95 mg / kg of the tau-binding antibody or antigen- binding fragment thereof and are optionally about 90 mg / kg of the antibody or antigen-binding fragment thereof.

[0266]

[0026] The method according to any one of

[0019] -

[0025] , wherein a plurality of doses of the tau- binding antibody or antigen-binding fragment are administered wherein the interval between each pair of doses is 3 to 5 weeks.

[0267]

[0027] The method according to any one of

[0019] -

[0026] , wherein a plurality of doses of the tau- binding antibody or antigen-binding fragment are administered wherein the interval between each pair of doses is 4 weeks.

[0268]

[0028] The method according to any one of

[0019] -

[0027] , wherein the tau-binding antibody or antigen-binding fragment thereof is administered to the human subject in need thereof for at least 12 weeks, at least 24 weeks, at least 52 weeks, at least 68 weeks or at least 80 weeks.

[0269]

[0029] The method according to any one of

[0019] -

[0028] , wherein the tau-binding antibody or antigen-binding fragment thereof binds to an epitope comprising the amino acid residues of S238, A239, S241, T245, A246, of SEQ ID No.: 11, optionally wherein the epitope further comprises one or more residues selected from S235, S237, K240, R242, L243, Q244, V248, and M250 of SEQ ID No.: 11.

[0030] The method according to any one of

[0019] -

[0029] , wherein the tau-binding antibody or antigen-binding fragment thereof binds to both soluble human and paired helical filaments (PHF) of human tau.

[0270]

[0031] The method according to any one of

[0019] -

[0030] , wherein the tau-binding antibody or antigen-binding fragment thereof comprises a light chain variable region comprising SEQ ID No. : 7, and a heavy chain variable region comprising SEQ ID No.: 8.

[0271]

[0032] The method according to any one of

[0019] -

[0031] , wherein the tau-binding antibody or antigen-binding fragment thereof comprises a light chain comprising SEQ ID No.: 9, and a heavy chain comprising SEQ ID No.: 10.

[0272]

[0033] The method according to any one of

[0019] -

[0032] , wherein the tau-binding antibody or antigen-binding fragment thereof is a monoclonal humanized antibody.

[0273]

[0034] The method according to any one of

[0019] -

[0033] , wherein the tau-binding antibody or antigen-binding fragment thereof is administered intravenously.

[0274]

[0035] The method according to any one of

[0019] -

[0034] , wherein the subject treated achieves a slowing of disease progression as measured by Clinical Dementia Rating score Sum of Boxes (CDR-SB), the Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-Cogl4), the Amsterdam-Instrumental Activities of Daily Living Questionnaire (A-iADL-Q), the mini-mental state examination (MMSE) and / or the Alzheimer’s Disease Cooperative Study- Activities of Daily Living (ADCS-ADL).

[0275] EXAMPLES

[0276] EXAMPLE 1 : Studies in healthy volunteers

[0277] UP0047 was a Phase 1, first-in-human, placebo-controlled, participant- blind, investigator blind, single-dose, dose-escalation study of intravenous (iv) bepranemab in healthy participants (NCT03464227). The study was conducted in Germany. The present Example describes a further study in healthy patients, UP0065. The primary objective of UP0065 was to assess the safety, tolerability and serum PK of a single-dose of bepranemab in healthy Japanese study participants, in order to determine whether these differed from the safety, tolerability and PK assessments in Caucasian participants in UP0047. An exploratory objective of the study was to assess the incidence and emergence of AD As in serum (immunogenicity).

[0278] In the UP0047 study, a total of 258 participants were screened, and of these, 52 participants were randomized to either receive bepranemab or placebo (bepranemab 0.3mg / kg: N=2; Img / kg: N=6; 3mg / kg: N=6; lOmg / kg: N=6; 30mg / kg: N=6, 60mg / kg; 120mg / kg: N=6 and placebo: N=14; Figure la). The main reason for screen failure was ineligibility (139 participants [53.9%]), and all 52 participants completed the study.

[0279] In the UP0065 study, a total of 49 participants were screened, and 24 of these participants were randomized to receive either bepranemab or placebo (bepranemab 30mg / kg: N=6; 60mg / kg: N=6; 120mg / kg: N=6; placebo N=6; Figure lb). The main reason for screen failure was ineligibility (15 participants [30.6%]), and all 24 participants completed the study.

[0280] Dose proportionality was observed for both Cmax and AUC across the dose range 30-120 mg / kg in both studies.

[0281] EXAMPLE 2: Studies in PSP patients

[0282] Introduction & Methods

[0283] PSP003 is a randomised, double-blind, placebo-controlled, phase lb study designed to primarily assess the safety and tolerability of bepranemab in 25 study participants with PSP (NCT04185415). The study was conducted in a hospital setting across 13 centres in Belgium, Spain, Germany, and the UK. Study participants received either intravenous (iv) 90 mg / kg bepranemab or a matching volume of placebo at each infusion time point, once every four weeks over a 52- week treatment period, for a maximum of 13 infusions per study participant.

[0284] Blood and CSF samples were collected to measure concentrations of bepranemab, antidrug antibodies and for biomarker research (Figure 3). Lumbar punctures were performed before dosing. CSF sampling was carried out at baseline and day 7 (with a 14-day window in between); each CSF sample was split into aliquots for PK analyses, biomarker analyses, quality control, and biorepository samples (if consent was provided). Blood samples for coagulation parameters and platelets counts were taken and the results were evaluated before the lumbar puncture. Blood draws were performed via venipuncture and the sample divided into two aliquots for PK analyses. Postdose PK samples were only collected for the first two infusions; for all subsequent infusions only trough samples were taken. The Progressive Supranuclear Palsy rating scale (PSPRS) was used to measure clinical disability and disease severity of study participants at timepoints specified in Figure 3. PSPRS was an exploratory endpoint and the study was not powered to determine differences between treatment groups.

[0285] Serial structure brain MRIs were performed to detect eventual emergent alterations in brain structure at timepoints specified in Figure 3. At any time during the study, additional brain MRIs or MRI sequences may have been performed in any study participant if deemed appropriate by the Investigator / local radiologist.

[0286] Safety and tolerability of bepranemab in study participants with PSP

[0287] Overall, most Adverse Events were non-serious, mild or moderate in intensity. All Serious Adverse Events were assessed as non-related to bepranemab. No consistent or clinically relevant treatment-related patterns were observed in this study for any hematology, clinical chemistry, vital signs, ECG (electrocardiogram) or C-SSRS (Columbia-suicide severity rating scale) findings. There has been no evidence of neuroinflammatory findings on safety MRI (magnetic resonance imaging). Overall, no new safety signals were identified.

[0288] Figures 4 and 5 summarise the treatment-emergent adverse events (TEAEs) from baseline to last visit and most frequent TEAEs observed in PSP003.

[0289] Serum concentrations of bepranemab (PK)

[0290] For participants who received at least 5 consecutive doses of bepranemab, steady state was achieved by approximately Week 12.

[0291] Free tau species targeted by bepranemab in the CSF

[0292] In this assay, the term “bepranemab-tau” refers to those species of tau present in the CSF containing the epitopes for both bepranemab and the detection antibody.

[0293] The baseline (pre-dose) value of free bepranemab-tau species was taken as the 100% value, and this was used to assess the reduction of measured tau species. In other words, the term ‘free’ indicates tau species that have not been bound by bepranemab and are still detectable in the assay. Hence, before bepranemab treatment, all bepranemab-tau species are free and after treatment, only a proportion will remain free, depending on the administered dose of bepranemab. The percentage of change in free bepranemab-tau from baseline to week 1 was measured for all participants (Figure 7).

[0294] In the bepranemab group, the concentrations of free bepranemab-tau in CSF changed from baseline to week 1 as follows: four participants (26.7%) had 25-100% of baseline free tau, nine participants (60.0%) had 10-25% of baseline free tau, and two participants (13.3%) had 0-10% of baseline free tau.

[0295] In the bepranemab group, the mean (SD) percent change from baseline of free bepranemab- tau levels in CSF was -80.41% (12-14) compared with -8.42% (19-97) in the placebo group (figure 6). The approximate 80% reduction of mean free bepranemab-tau levels in CSF was observed in the bepranemab group, suggesting high bepranemab target occupancy in CSF.

[0296] This determination of free bepranemab-tau was derived on an individual subject basis and is shown in Figure 8.

[0297] PSP-Rating Scale

[0298] As mentioned above, the study was not powered to determine differences between treatment groups. However, there is a difference in the bulbar domain rating (relating to speech and swallowing) between study arms, that appears consistently across different analysis approaches. See table:

[0299] Table 2

[0300] *CZ is based on the assumption that the data is normally distributed.

[0301] Hence, despite the small sample size it appears that bepranemab has achieved a statistically significant change in decline rate at the 10% significance level in at least one of the PSP-Rating Scale’s indices. No adjustment for multiplicity was performed. Example 3: Studies in patients with Alzheimer’s disease

[0302] AH0003 (NCT04867616) is a global, multicenter, patient-blind, investigator-blind, placebo-controlled, parallel-group study, investigating the efficacy, safety, and tolerability of bepranemab (administered intravenously, every 4 weeks) versus placebo in patients with prodromal (40%) or mild (60%) AD over an 80-week treatment period, followed by an optional 48- week open-label extension (OLE). The primary objective is the change from baseline to Week 80 in the Clinical Dementia Rating (CDR) Scale Sum of Boxes total score. Secondary objectives include: pharmacokinetics (PK); safety and tolerability; the effect of bepranemab on tau positron emission tomography (PET) imaging at Weeks 56 and 80; and the changes from baseline in the 14-item Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-Cogl4), Amsterdam- Instrumental Activities of Daily Living, and Mini-Mental State Examination (MMSE) at Weeks 56 and 80. The OLE will assess the long-term safety and tolerability of bepranemab. Approximately 150 patients per arm were enrolled across 3 study arms (45 mg / kg and 90 mg / kg bepranemab, and placebo; randomized 1: 1: 1). Eligible patients met the National Institute of Aging- Alzheimer’s Association (NIA-AA) 2018 Stage 3 or 4 definitions of prodromal or mild AD, respectively. Patients had a global CDR score indicative of prodromal AD (0.5) or mild AD (0.5 or 1.0) and a CDR-Memory Box score >0.5 at screening and baseline. Patients had a score of <85 for the delayed recall domain of the Repeatable Battery for the Assessment of Neuropsychological Status, MMSE >20 at screening and had to meet the NIA-AA 2018 definition of cerebral betaamyloid (A0) accumulation, by either a positive centrally read PET scan or a positive cerebrospinal fluid pTaul81 / Api-42 ratio.

[0303] Once eligible, patients were enrolled and stratified by disease stage at baseline (prodromal or mild AD), baseline use symptomatic AD treatments (yes or no), and APOE4 genotype (carrier or non-carrier). [18F] GTP1 PET imaging was used to assess baseline levels of insoluble intracellular tau burden, where participants having a temporal meta-ROI SUVR > 1.3 were considered to be “high tau burden” and “low tau burden” included participants with temporal meta- ROI SUVR < 1.3.

[0304] AH0003 did not meet the primary objective of change from baseline to Week 80 in the Clinical Dementia Rating (CDR) Scale Sum of Boxes total score. However, bepranemab reduced the rate of tau accumulation as assessed by PET and reduced the rate of cognitive decline as measured by ADAS-Cogl4. Bepranemab was well tolerated with an acceptable safety profile and no evidence of imaging abnormalities were observed. No treatment effects on function (e.g. daily living) were observed, and no evidence of a dose response was seen when comparing the results for 45 and 90 mg / kg groups.

[0305] The results of the different measurements obtained for the full population of AH0003 is shown in Figure 12.

[0306] Because the primary endpoint did not meet significance favoring bepranemab, all other pre-planned endpoints and analyses are considered exploratory. However, in a Post-Hoc analysis, evidence of a consistent treatment benefit was observed in primary and all secondary endpoints in the pre-defined subgroups with low tau burden at baseline, and for APOE4 non-carriers. The results of the different measurements obtained in the two subgroups (low tau at baseline or noncarriers of APOE4 vs high tau at baseline and APOE4 carriers) treated with 45 mg / kg or 90 mg / kg bepranemab are shown in Figures 13 and 14, respectively.

[0307] The results showed that for patients who were either low tau burden at baseline or APOE4 non-carriers (47% of the trial population), treatment with 90 mg / kg bepranemab:

[0308] • Slowed disease progression as measured by CDR-SB (primary endpoint) with a, statistically significant, mean reduction of 28.7% relative to placebo.

[0309] • Reduced the rate of tau accumulation (as measured by PET) by 67-69%.

[0310] • Slowed disease progression in all secondary clinical endpoints, including measures of activities of daily living.

[0311] The treatment effects were dose-dependent in CDR-SB, A-iADL-Q, ADCS-ADL and MMSE scales, whereby statistically significant benefit was only observed with 90mg / kg of bepranemab.

[0312] In the high tau and APOE4 carrier subpopulation (53% of the trial population), treatment didn’t show an advantage over placebo in CDR-SB and ADL Scales. However, treatment did reduce the rate of tau accumulation as assessed by PET and reduced the rate of cognitive decline as measured by ADAS-Cogl4. EXAMPLE 4: Overview of fixed dose conversion for bepranemab

[0313] Overview

[0314] The use of fixed dosing approaches for antibody dosing is often much more convenient, for instance, as it helps avoid the need to perform a new dosage calculation for every new patient and specifically preparing doses for that patient. Bepranemab dosing in studies UP0047, UP0065, PSP002, PSP003 and AH0003 was individualized based on total body weight (bw); i.e., mg / kg, rather than on fixed dosing. In order to simplify dosing in the future clinical use of bepranemab, a conversion to bw-tiered fixed dosing was undertaken following the AH0003 trial described in Example 3. Determination of fixed doses occurred in the following steps:

[0315] 1. Determination of bw bands (tiers) to cover the wide range of bws observed in an early

[0316] AD study population

[0317] 2. Derivation of theoretical fixed bepranemab doses, equating to 45, 60 & 90 mg / kg, based on bws in study AH0003

[0318] 3. Pharmacokinetic simulations to assess systemic bepranemab exposures of various fixed doses compared with exposures for bw-based dosing

[0319] 4. Selection of bw tier-based fixed doses

[0320] 5. Exposure-response (E-R) simulations for selected fixed doses to predict key efficacy and biomarker outcomes.

[0321] Simulations were conducted using models established for the AH0003 biomarker-defined subgroup (low tau burden at Baseline or APOs4 noncarrier genotype status) identified in Example 3 as having achieved positive outcomes (vs placebo) in favour of bepranemab.

[0322] All dose regimens evaluated involved a dosing frequency of every 4 weeks.

[0323] Ultimately, three fixed doses were arrived at, rather than a single fixed dose for all patients, to replace 90 mg / kg body weight-based dosing. The three fixed doses determined were: (i) a fixed dose of about 4g of bepranemab for subjects with a body weight of less than 60kg; (ii) a fixed dose of about 6g of bepranemab for subjects with a body weight of 60 kg to 90 kg; and (iii) a fixed dose of about 8g of bepranemab for subjects with a body weight greater than 90 kg. Three fixed doses, rather than a single fixed dose, were also determined for replacing 60 mg / kg body weight-based dosing. The three fixed doses determined were: (i) a fixed dose of about 3g of bepranemab for subjects with a body weight of less than 60kg; (ii) a fixed dose of about 4g of bepranemab for subjects with a body weight of 60 kg to 90 kg; and (iii) a fixed dose of about 5g of bepranemab for subjects with a body weight greater than 90 kg.

[0324] Determination of starting theoretical fixed doses

[0325] As a starting point, initial fixed doses were calculated based on median and mean body weights (bws) in modelling dataset (70.6 kg and 72.3 kg, respectively), with that resulting in doses of 3177-3253 mg for bw-based dose of 45 mg / kg, 4236-4338 mg for 60 mg / kg and 6354- 6507 mg for 90 mg / kg. Based on this, fixed doses of 3200, 4300 and 6400 mg were calculated as replacement doses for 45, 60 and 90 mg / kg, respectively. However, since population PK modelling of bepranemab (see below) identified bw as the most influential descriptor (covariate) of bepranemab PK, it was recognised that a single fixed (mg) dose bepranemab in place of previous mg / kg-based dosing, would result in an undesirably wide range of systemic bepranemab exposures across a clinical study population in early AD (the observed bw range in study AH0003 was 36.8-130.6 kg). Thus, the following three bw bands (tiers) were selected in order to reduce inter-individual variability in PK exposures with fixed dosing: <60 kg, >60-<80 or 90kg, and >80 or 90 kg. These bw tiers were applied to each fixed dose derivation; i.e., three different fixed doses (for the three aforementioned bw bands) would be derived for each mg / kg target dose assessed.

[0326] Simulations based on E-R models established from AH0003 indicated that relative reduction in change from Baseline to Week 80 with bepranemab compared to placebo increased with increasing bepranemab doses of 45, 60 or 90mg / kg Q4W. Thus, in a maximally-acceptable bepranemab dose range of up to 90mg / kg, a bepranemab dose of 90mg / kg was determined to be that associated with the highest possible clinical benefit in terms of slowing disease progression. Consequently, targeting a dose of 90 mg / kg, as well as 60 mg / kg as an alternative, were the focus of fixed dose predictions. Pharmacokinetic simulations

[0327] A two-compartment Pop PK model to characterize the PK of bepranemab in healthy volunteers and patients with PSP or AD dosed with intravenous (i.v.) bepranemab was established. This Pop PK model was used to simulate systemic bepranemab exposures for a 90 mg / kg dose, together with exposures for replacement fixed doses, as follows.

[0328] - One thousand individuals and weights were sampled with replacement from the AH0003 E-R analysis data set;

[0329] - Bepranemab concentrations were simulated for each subject using the Pop PK model (including inter-individual, but no residual, variabiltiy and no uncertainty);

[0330] - Average (Cave), predose (Ctrough) and maximal (Cmax) bepranemab concentrations were derived for each individual and dose.

[0331] PK simulations indicated that to achieve comparable systemic exposures associated with (a) 90 mg / kg confirmed a bw band for 60-80 kg, (b) 4300 mg and 6400 mg are acceptable fixed doses for bw bands of <60 kg and 60-80 kg, respectively, and (c) a fixed dose >6400 mg was required for bws >80 kg (Fig.15). In further PK simulations conducted for bws of 80-130 kg, fixed doses ranging from 6400 to 10800 mg were assessed relative to 90 mg / kg (Fig. 16). These latter simulations for higher bws indicated that a fixed bepranemab dose of 8000 mg or 9000 mg would achieve comparable systenic exposures as that for 90 mg / kg for a bw band of 80-130 kg.

[0332] The fixed doses of 4300 mg, 6400 mg and 8000 or 9000 mg for bw bands of <60 kg, >60- <90 kg, and >90 kg, respectively, relative to the histogram distributions of 90 mg / kg doses based on observed bws in AH0003 (Fig. 17) confirmed the appropriateness of the derived fixed doses. The 4300 and 6400 mg fixed doses were then rounded to 4000 and 6000 mg, respectively.

[0333] In order to provide a lower bepranemab dosing regimen for clinical consideration, the PK simulations outlined above were also conducted for fixed dose alternatives to 60 mg / kg. These PK simulations indicated that fixed bepranemab doses of 3000, 4000 and 5000 mg for bw bands of <60 kg, >60-<90 kg, and >90 kg, respectively, were viable replacements for a 60 mg / kg dose (Figs. 18 & 19). Exposure-response simulations

[0334] E-R models, accounting for linear progression of placebo and drug response over 80 weeks as well as Baseline clinical and demographic characteristics, were established for various measures (clinical endpoints and tau PET) in AH0003. In determining the adequacy of the calculated fixed doses as replacements for 60 & 90 mg / kg, selected key clinical endpoints were predicted, via E-R simulations, using the established AH0003 E-R models The E-R simulations were conducted for the following fixed doses using the bw bands of <60 kg, >60-<90 kg, and >90 kg, respectively: 3 g, 4 g and 5 g for 60 mg / kg and 4 g, 6 g and 8 g or 9 g for 90 mg / kg. The methodological steps undertaken were:

[0335] - One thousand individuals and weights were sampled with replacement from the AH0003 E-R analysis data set;

[0336] - Bepranemab concentrations were simulated for each subject using the Pop PK model (including inter-individual, but no residual, variabiltiy and no uncertainty);

[0337] - Two hundred vectors of population parameters for the respective E-R model (thetas and omegas) were sampled from the variance-covariance matrix;

[0338] - Individual endpoint parameters were simulated for the 1000 subjects for each of the 200 parameter vectors;

[0339] - Individual differences in each endpoint from placebo was calculated for each subject and summarized for each of the 200 replicates. Medians (and 90% CI) of differences were calculated.

[0340] The initial E-R simulations of CDR-SB and ADAS-Cogl4 at Week 80 indicated that, for the highest bw band (>90 kg) relative to a dose of 90 mg / kg, there was minimal difference in predicted clinical endpoint outcomes between a fixed dose of 8 g and 9 g (Fig. 20). Thus, a dose of 8 g was applied for bws >90 kg.

[0341] E-R simulations were conducted for the finalised fixed dose replacements of 60 mg / kg and 90 mg / kg (Table 3). Table 3. Bepranemab fixed doses as replacements for body weight-based doses

[0342] Simulated relative change from baseline and placebo in CDR-SB, ADAS-Cogl4 and A- iADL, per low or high GTP1 tau burden at baseline, for fixed doses vs 60 mg / kg or 90 mg / kg (Fig. 21) demonstrated comparability in clinical endpoint outcomes for the calculated fixed doses to that for bw-based bepranemab dosing.

[0343] Conclusion

[0344] For bw bands of <60 kg, >60-<90 kg, and >90 kg, respectively, fixed bepranemab doses of 3 g, 4 g and 5 g were determined to be viable replacements for a 60 mg / kg dose, and 4g, 6g, and 8g were determined to be viable replacements for a 90 mg / kg dose.

Claims

CLAIMS1. A tau-binding antibody or antigen-binding fragment thereof for use in a method of treating a tauopathy in a human subject in need thereof, wherein the method comprising determining which of the three weight bands of <60 kg, 60kg to 90kg, and >90 kg the subject falls in, then administering the antibody or antigen-binding fragment at a dose or doses of:(i) 3.5g to 4.5g if the body weight of the subject is <60 kg;(ii) 5.5g to 6.5 g if the body weight of the subject is 60 kg to 90 kg; or(iii) 7.5g to 8.5 g if the body weight of the subject is >90 kg, wherein the tau-binding antibody or antigen-binding fragment thereof binds to an epitope comprising the amino acid residues of S238, A239, S241, T245, A246, of SEQ ID No.: 11, optionally wherein the epitope further comprises one or more residues selected from S235, S237, K240, R242, L243, Q244, V248, and M250 of SEQ ID No.: 11.

2. The tau-binding antibody or antigen-binding fragment thereof for use according to claim 1, wherein the antibody or antigen-binding fragment thereof is administered at a dose or doses of:(i) about 4g if the body weight of the subject is < 60 kg;(ii) about 6g if the body weight of the subject is 60 kg to 90 kg; or(iii) about 8g if the body weight of the subject is > 90 kg,3. The tau-binding antibody or antigen-binding fragment thereof for use according to claim 1 or 2, wherein the human subject has a low tau burden and / or is not an APOE4 carrier.

4. The tau-binding antibody or antigen-binding fragment thereof for use according to claim 3, wherein the human subject has: a low tau burden and is not an APOE4 carrier, a low tau burden and is an APOE4 carrier, or a high tau burden and is not an APOE4 carrier.

5. The tau-binding antibody or antigen-binding fragment thereof for use according to any one of the preceding claims, wherein the tauopathy is Alzheimer’s Disease (AD).

6. A tau-binding antibody or antigen-binding fragment thereof for use in a method of treating Alzheimer’s disease (AD) in a human subject in need thereof, the method comprising administering to the human subject a tau-binding antibody or antigen-binding fragment thereof, wherein the tau-binding antibody or antigen-binding fragment thereof binds to an epitope comprising the amino acid residues of S238, A239, S241, T245, A246, of SEQ ID No.: 11, optionally wherein the epitope further comprises one or more residues selected from S235, S237, K240, R242, L243, Q244, V248, and M250 of SEQ ID No.: 11, wherein the human subject has a low tau burden or is not an AP0E4 carrier.

7. The tau-binding antibody or antigen-binding fragment thereof for use according to claim 6, wherein the human subject has: a low tau burden and is not an AP0E4 carrier, a low tau burden and is an AP0E4 carrier, or a high tau burden and is not an AP0E4 carrier.

8. The tau-binding antibody or antigen-binding fragment thereof for use according to claim 6 or 7, wherein the method comprises determining which of the three weight bands of <60 kg, 60kg to 90kg, and >90 kg the subject falls in, then administering the antibody or antigen-binding fragment at a dose or doses of:(i) 3.5g to 4.5g if the body weight of the subject is <60 kg;(ii) 5.5g to 6.5 g if the body weight of the subject is 60 kg to 90 kg; or(iii) 7.5g to 8.5 g if the body weight of the subject is >90 kg, wherein the tau-binding antibody or antigen-binding fragment thereof binds to an epitope comprising the amino acid residues of S238, A239, S241, T245, A246, of SEQ ID No.: 11, optionally wherein the epitope further comprises one or more residues selected from S235, S237, K240, R242, L243, Q244, V248, and M250 of SEQ ID No.: 11.

9. The tau-binding antibody or antigen-binding fragment thereof for use according to any one of claims 6 to 8, wherein the antibody or antigen-binding fragment thereof is administered at a dose or doses of:66(i) about 4g if the body weight of the subject is < 60 kg;(ii) about 6g if the body weight of the subject is 60 kg to 90 kg; or(iii) about 8g if the body weight of the subject is > 90 kg.

10. The tau-binding antibody or antigen-binding fragment thereof for the use according to claim 6 or 7, wherein the antibody or antigen-binding fragment thereof is administered in a dose or doses that are each 85 mg / kg to 95 mg / kg of the tau-binding antibody or antigen- binding fragment thereof.

11. The tau-binding antibody or antigen-binding fragment thereof for the use according to claim 10, wherein the dose or doses are each about 90 mg / kg of the antibody or antigen-binding fragment thereof.

12. The tau-binding antibody or antigen-binding fragment thereof for the use according to any one of the preceding claims, wherein the tau-binding antibody or antigen-binding fragment thereof comprises: a light chain variable region comprising a CDR1 selected from SEQ ID No.: 1, a CDR2 selected from SEQ ID No.: 2, and a CDR3 selected from SEQ ID No.: 3; and a heavy chain variable region comprising a CDR1 selected from SEQ ID No.: 4, a CDR2 selected from SEQ ID No.: 5, and a CDR3 selected from SEQ ID No.: 6.

13. A tau-binding antibody or antigen-binding fragment thereof for use in a method of treating Alzheimer’s Disease in a human subject in need thereof, the method comprising administering to the human subject at least one dose of 85 mg / kg to 95 mg / kg of the tau-binding antibody or antigenbinding fragment thereof, wherein the tau-binding antibody or antigen-binding fragment thereof comprises: a light chain variable region comprising a CDR1 selected from SEQ ID No.: 1, a CDR2 selected from SEQ ID No.: 2, and a CDR3 selected from SEQ ID No.: 3; and a heavy chain variable region comprising a CDR1 selected from SEQ ID No.: 4, a CDR2 selected from SEQ ID No.: 5, and a CDR3 selected from SEQ ID No.: 6.6714. The tau-binding antibody or antigen-binding fragment thereof for use according to claim13, wherein the human subject has a low tau burden and / or is not an AP0E4 carrier.

15. The tau-binding antibody or antigen-binding fragment thereof for use according to claim 14, wherein the human subject has: a low tau burden and is not an AP0E4 carrier, a low tau burden and is an AP0E4 carrier, or a high tau burden and is not an AP0E4 carrier.

16. The tau-binding antibody or binding fragment thereof for use according to any one of the preceding claims, wherein a plurality of doses of the tau-binding antibody or antigen-binding fragment are administered wherein the interval between each pair of doses is 3 to 5 weeks.

17. The tau-binding antibody or antigen-binding fragment thereof for use according to any one of the preceding claims, wherein a plurality of doses of the tau-binding antibody or antigen-binding fragment are administered wherein the interval between each pair of doses is about 4 weeks or about monthly.

18. The tau-binding antibody or antigen-binding fragment thereof for use according to any one of the preceding claims, wherein the tau-binding antibody or antigen-binding fragment thereof is administered to the human subject in need thereof for at least 12 weeks, at least 24 weeks, at least 52 weeks, at least 68 weeks or at least 80 weeks.

19. The tau-binding antibody or antigen-binding fragment thereof for use according to any one of the preceding claims, wherein the antibody or antigen binding fragment thereof is administered to the subject from an IV bag.

20. The tau-binding antibody or antigen-binding fragment thereof for use according to any one of the preceding claims, wherein the antibody or antigen binding fragment thereof is administered to the subject using an IV pump.6821. The tau-binding antibody or antigen-binding fragment thereof for use according to any one of the preceding claims, wherein the antibody or antigen binding fragment thereof is administered to the subject via intravenous infusion for an infusion time of 1 hour to 4 hours.

22. The tau-binding antibody or antigen-binding fragment thereof for use according to any one of the preceding claims, wherein the antibody or antigen binding fragment thereof is present in a vial and then prepared for IV administration before intravenous administration to the subject.

23. The tau-binding antibody or antigen-binding fragment thereof for use according to claim 22, wherein the antibody or antigen-binding fragment thereof is present in the vial in a formulation comprising 100 mg / ml of the antibody or antigen-binding fragment thereof, 50 mM L-histidine, 150 mM L arginine, and 0.02% polysorbate 80 at H 6.0.

24. The tau-binding antibody or antigen-binding fragment thereof for use according to claim 22 or 23, wherein the formulation for IV intravenous administration is prepared from the vial comprising the antibody or antigen-binding fragment thereof no more than 4 hours prior to the planned intravenous infusion start time.

25. The tau-binding antibody or antigen-binding fragment thereof for use according to any one of the preceding claims, wherein the tau-binding antibody or antigen-binding fragment thereof binds to both soluble human and paired helical filaments (PHF) of human tau.

26. The tau-binding antibody or antigen-binding fragment thereof for use according to any one of the preceding claims, wherein the tau-binding antibody or antigen-binding fragment thereof comprises a light chain variable region comprising SEQ ID No.: 7, and a heavy chain variable region comprising SEQ ID No.: 8.

27. The tau-binding antibody or antigen-binding fragment thereof for use according to any one of the preceding claims, wherein the tau-binding antibody or antigen-binding fragment thereof comprises:69a light chain comprising SEQ ID No.: 9, and a heavy chain comprising SEQ ID No.: 10.

28. The tau-binding antibody or antigen-binding fragment thereof for use according to any one of the preceding claims, wherein the tau-binding antibody or antigen-binding fragment thereof is a monoclonal humanized antibody.

29. The tau-binding antibody or antigen-binding fragment thereof for use according to any one of the preceding claims, wherein the subject treated achieves a slowing of disease progression as measured by Clinical Dementia Rating score Sum of Boxes (CDR-SB), the Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-Cogl4), the Amsterdam-Instrumental Activities of Daily Living Questionnaire (A-iADL-Q), the mini-mental state examination (MMSE) and / or the Alzheimer’s Disease Cooperative Study- Activities of Daily Living (ADCS-ADL).

30. A method of treating a tauopathy in a human subject in need thereof, wherein the method comprises determining which of the three weight bands of <60 kg, 60kg to 90kg, and >90 kg the subject falls in, then administering a tau-binding antibody or antigen-binding fragment thereof at a dose or doses of:(i) 3.5g to 4.5g if the body weight of the subject is <60 kg;(ii) 5.5g to 6.5 g if the body weight of the subject is 60 kg to 90 kg; or(iii) 7.5g to 8.5 g if the body weight of the subject is >90 kg, wherein the tau-binding antibody or antigen-binding fragment thereof binds to an epitope comprising the amino acid residues of S238, A239, S241, T245, A246, of SEQ ID No.: 11, optionally wherein the epitope further comprises one or more residues selected from S235, S237, K240, R242, L243, Q244, V248, and M250 of SEQ ID No.: 11.

31. The method of claim 30, wherein the method comprises administering the antibody or antigen-binding fragment thereof at a dose or doses of:(i) about 4g if the body weight of the subject is < 60 kg;(ii) about 6g if the body weight of the subject is 60 kg to 90 kg; or(iii) about 8g if the body weight of the subject is > 90 kg,7032. The method of claim 30 or 31, wherein the human subject has a low tau burden and / or is not an APOE4 carrier.

33. The method of claim 32, wherein the human subject has: a low tau burden and is not an APOE4 carrier, a low tau burden and is an APOE4 carrier, or a high tau burden and is not an APOE4 carrier.

34. The method of any one of claims 30 to 33, wherein the tauopathy is Alzheimer’s Disease (AD).

35. A method of treating Alzheimer’s disease (AD) in a human subject in need thereof, the method comprising administering to the human subject a tau-binding antibody or antigen-binding fragment thereof, wherein the tau-binding antibody or antigen-binding fragment thereof binds to an epitope comprising the amino acid residues of S238, A239, S241, T245, A246, of SEQ ID No.: 11, optionally wherein the epitope further comprises one or more residues selected from S235, S237, K240, R242, L243, Q244, V248, and M250 of SEQ ID No.: 11, wherein the human subject has a low tau burden or is not an APOE4 carrier.

36. The method according to claim 35, wherein the human subject has: a low tau burden and is not an APOE4 carrier, a low tau burden and is an APOE4 carrier, or a high tau burden and is not an APOE4 carrier.

37. The method according to claim 35 or 36, wherein the method comprises determining which of the three weight bands of <60 kg, 60kg to 90kg, and >90 kg the subject falls in, then administering the antibody or antigen-binding fragment at a dose or doses of:(i) 3.5g to 4.5g if the body weight of the subject is <60 kg;(ii) 5.5g to 6.5 g if the body weight of the subject is 60 kg to 90 kg; or(iii) 7.5g to 8.5 g if the body weight of the subject is >90 kg,wherein the tau-binding antibody or antigen-binding fragment thereof binds to an epitope comprising the amino acid residues of S238, A239, S241, T245, A246, of SEQ ID No.: 11, optionally wherein the epitope further comprises one or more residues selected from S235, S237, K240, R242, L243, Q244, V248, and M250 of SEQ ID No.: 11.

38. The method according to any one of claims 35 to 37, wherein the method comprises administering the antibody or antigen-binding fragment thereof at a dose or doses of:(i) about 4g if the body weight of the subject is < 60 kg;(ii) about 6g if the body weight of the subject is 60 kg to 90 kg; or(iii) about 8g if the body weight of the subject is > 90 kg.

39. The method according to claim 35 or 36, wherein the method comprises administering the antibody or antigen-binding fragment in a dose or doses that are each 85 mg / kg to 95 mg / kg of the tau-binding antibody or antigen- binding fragment thereof.

40. The method according to claim 39, wherein the dose or doses are each about 90 mg / kg of the antibody or antigen-binding fragment thereof.

41. The method according to any one of claims 30 to 30, wherein the tau-binding antibody or antigen-binding fragment thereof comprises: a light chain variable region comprising a CDR1 selected from SEQ ID No.: 1, a CDR2 selected from SEQ ID No.: 2, and a CDR3 selected from SEQ ID No.: 3; and a heavy chain variable region comprising a CDR1 selected from SEQ ID No.: 4, a CDR2 selected from SEQ ID No.: 5, and a CDR3 selected from SEQ ID No.: 6.

42. A method of treating Alzheimer’s Disease in a human subject in need thereof, the method comprising administering to the human subject at least one dose of 85 mg / kg to 95 mg / kg of a tau- binding antibody or antigen-binding fragment thereof, wherein the tau-binding antibody or antigen-binding fragment thereof comprises: a light chain variable region comprising a CDR1 selected from SEQ ID No.: 1, a CDR2 selected from SEQ ID No.: 2, and a CDR3 selected from SEQ ID No.: 3; anda heavy chain variable region comprising a CDR1 selected from SEQ ID No.: 4, a CDR2 selected from SEQ ID No.: 5, and a CDR3 selected from SEQ ID No.: 6.

43. The method according to claim 42, wherein the human subject has a low tau burden and / or is not an APOE4 carrier.

44. The method according to claim 43, wherein the human subject has: a low tau burden and is not an APOE4 carrier, a low tau burden and is an APOE4 carrier, or a high tau burden and is not an APOE4 carrier.

45. The method according to any one of claims 30 to 44, wherein a plurality of doses of the tau-binding antibody or antigen-binding fragment are administered wherein the interval between each pair of doses is 3 to 5 weeks.

46. The method according to any one of claims 30 to 45, wherein a plurality of doses of the tau-binding antibody or antigen-binding fragment are administered wherein the interval between each pair of doses is about 4 weeks or about monthly.

47. The method according to any one of claims 30 to 46, wherein the method comprises administering the tau-binding antibody or antigen-binding fragment thereof to the human subject in need thereof for at least 12 weeks, at least 24 weeks, at least 52 weeks, at least 68 weeks or at least 80 weeks.

48. The method according to any one of claims 30 to 47, wherein the method comprises administering the antibody or antigen binding fragment thereof from an IV bag.

49. The method according to any one of claims 30 to 48, wherein the method comprises administering the antibody or antigen binding fragment thereof to the subject using an IV pump.7350. The method according to any one of claims 30 to 49, wherein the method comprises administering the antibody or antigen binding fragment thereof to the subject via intravenous infusion for an infusion time of 1 hour to 4 hours.

51. The method according to any one of claims 30 to 50, wherein antibody or antigen-binding fragment thereof is present in a vial, with the method comprises preparing an IV bag for IV administration of the antibody or antigen binding fragment thereof using the contents of the vial, before then administering the intravenous administration to the subject.

52. The method according to claim 51, wherein the antibody or antigen-binding fragment thereof is present in the vial in a formulation comprising 100 mg / ml of the antibody or antigenbinding fragment thereof, 50 mM L-histidine, 150 mM L arginine, and 0.02% polysorbate 80 at H 6.0.

53. The method according to claim 51 or 52, wherein the formulation for IV intravenous administration is prepared from the vial comprising the antibody or antigen-binding fragment thereof no more than 4 hours prior to the planned intravenous infusion start time.

54. The method according to any one of claims 30 to 53, wherein the tau-binding antibody or antigen-binding fragment thereof binds to both soluble human and paired helical filaments (PHF) of human tau.

55. The method according to any one of claims 30 to 54, wherein the tau-binding antibody or antigen-binding fragment thereof comprises a light chain variable region comprising SEQ ID No.: 7, and a heavy chain variable region comprising SEQ ID No.: 8.

56. The method according to any one of claims 30 to 55, wherein the tau-binding antibody or antigen-binding fragment thereof comprises: a light chain comprising SEQ ID No.: 9, and a heavy chain comprising SEQ ID No.: 10.7457. The method according to any one of claims 30 to 56, wherein the tau-binding antibody or antigen-binding fragment thereof is a monoclonal humanized antibody.

58. The method according to any one of claims 30 to 57, wherein the subject treated achieves a slowing of disease progression as measured by Clinical Dementia Rating score Sum of Boxes (CDR-SB), the Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-Cogl4), the Amsterdam-Instrumental Activities of Daily Living Questionnaire (A-iADL-Q), the mini-mental state examination (MMSE) and / or the Alzheimer’s Disease Cooperative Study- Activities of Daily Living (ADCS-ADL).

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