CN116981690A

CN116981690A - Anti-amyloid beta antibodies and uses thereof

Info

Publication number: CN116981690A
Application number: CN202280021042.6A
Authority: CN
Inventors: M·敏通; J·R·西姆斯二世
Original assignee: Eli Lilly and Co
Current assignee: Eli Lilly and Co
Priority date: 2021-03-12
Filing date: 2022-03-11
Publication date: 2023-10-31

Abstract

The present invention relates to methods of treating or preventing diseases characterized by the deposition of aβ in the brain using anti-aβ antibodies. Diseases that may be treated or prevented include, for example, alzheimer's disease, down's syndrome, and cerebral amyloid angiopathy. In some aspects, the invention also relates to selecting a human subject responsive to treatment or prevention of a disease characterized by deposition of aβ in the brain based on tau burden in the brain of the human subject, the treatment or prevention comprising administration of an anti-aβ antibody. The invention also relates to human subjects having one or both alleles of APOE 4.

Description

Anti-amyloid beta antibodies and uses thereof

In some aspects, the invention relates to methods of preventing or treating a disease with an anti-aβ antibody, wherein the disease is characterized by the deposition of amyloid β (aβ) in a human subject. Diseases that may be treated or prevented using the antibodies, dosing regimens, or methods disclosed herein include, for example, alzheimer's Disease (AD), down's syndrome, and Cerebral Amyloid Angiopathy (CAA). One aspect of the invention relates to the treatment or prevention of a disease characterized by aβ deposits in a human subject, wherein a human subject is selected for treatment or prevention based on its Tau levels/burden in the whole brain (e.g., overall Tau), in parts of the brain (e.g., in different lobes of the brain), and/or the presence of one or both alleles of ApoE 4 in the patient genome.

Healing of AD is one of the most important unmet needs of society. Accumulation of amyloid- β (aβ) peptides in the form of brain amyloid deposits is an early and fundamental event of Alzheimer's Disease (AD), leading to neurodegeneration and thus onset of clinical symptoms: cognitive and functional impairment (Selkoe, "The Origins of Alzheimer Disease: A is for Amyloid," JAMA 283:1615-7 (2000); hardy et al, "The Amyloid Hypothesis of Alzheimer's Disease: progress and Problems on the Road to Therapeutics," Science 297:353-6 (2002); masters et al, "Alzheimer's Disease," Nat. Rev. Dis. Primers 1:15056 (2015); and Selkoe et al, "The Amyloid Hypothesis ofAlzheimer's Disease at 25years," EMBO mol. Med.8:595-608 (2016)).

Amyloid beta (aβ) is formed by proteolytic cleavage of a larger glycoprotein called Amyloid Precursor Protein (APP). APP is an integral membrane protein expressed in many tissues, but particularly in neuronal synapses. APP is cleaved by gamma-secretase to release aβ peptides, which comprise a group of peptides ranging in size from 37 to 49 amino acid residues. Aβ monomers aggregate into various types of higher structures, including oligomers, fibrils, and amyloid fibrils. Amyloid oligomers are soluble and can be spread throughout the brain, while amyloid fibrils are larger and insoluble and can further aggregate to form amyloid deposits or plaques. Amyloid deposits found in human patients include heterogeneous mixtures of aβ peptides, some of which include N-terminal truncations, and may also include N-terminal modifications, such as N-terminal pyroglutamic acid residues (pGlu).

The role of amyloid deposits in driving disease progression was supported by studies of unusual genetic variants that increase or decrease aβ deposition (Fleisher et al, "Associations Between Biomarkers and Age in the Presenilin 1E280A Autosomal Dominant Alzheimer Disease Kindred:A Cross-sectional Study," JAMA Neurol 72:316-24 (2015); jonsson et al, "A Mutation in APP Protects Against Alzheimer's Disease and Age-related Cognitive Decline," Nature 488:96-9 (2012)). Furthermore, the presence of early Amyloid deposits in the disease increases the likelihood of Mild Cognitive Impairment (MCI) progressing to AD dementia (Doraiswamy et al, "Amyloid-. Beta. Assessed by Florbetapir F18PET and 18-month Cognitive Decline: A Multicenter Study," Neurology 79:1636-44 (2012)). Intervention aimed at removing aβ deposits (including amyloid plaques) is presumed to slow down the clinical progression of AD.

The second neuropathological marker of AD is the presence of intracellular neurofibrillary tangles containing hyperphosphorylated tau protein. Current disease models suggest that aβ triggers tau pathology in which more complex and synergistic interactions between aβ and tau manifest themselves later and drive disease progression (Busche et al, "Synergy Between Amyloid- β and Tau in Alzheimer's disease," Nature Neuroscience 23:1183-93 (2020)).

Antibodies to aβ and their use in methods of treating diseases (e.g., alzheimer's disease) are known in the art. (see, e.g., U.S. Pat. No.10,851,156;10,738,109, 10,662,239, 10,654,917, 10,647,759, 10,603,367, 10,519,223, 10,494,425, 10,464,976, 10,112,991, 10,112,987, 10,035,847, 9,944,696, 9,939,452, 9,895,429, 9,834,598, 9,738,712, 9,585,956, 9,573,994, 9,382,312, 9,329,189, 9,309,309, 9,309,307, 9,272,031, 9,181,332, 9,176,150, 9,175,094, 9,146,244, 9,133,267, 9,125,846, 9,062,102, 9,051,364, 9,051,363, 9,034,334, 8,916,999, 8,78, 8,178,178,178,8,178,178,906, 8,906, 8,906,906,906,906,8,906,906,906,8,906,906,8,906,8,906,8,906,8,906,8,906, 193, 8,636,981, 8,614,299, 8,591,894, 8,507,206, 8,491,903, 8,470,321, 8,425,905, 8,420,093, 8,414,893, 8,409,575, 8,404,459, 8,398,978, 8,383,113, 8,337,848, 8,333,967, 8,323,654, 8,303,954, 8,268,973, 8,268,593, 8,246,954, 8,227,576, 8,222,002, 8,221,750, 8,173,127, 8,128,930, 8,128,928, 8,353, 8,124,076, 8,106,164, 8,105,594, 8,105,593, 8,025,878, 7,955,812, 7,939,075,047,932, 7,7,175, 7,193,193,193,193, 7,193,193,193,320, 7,193,193,320, 7,193,193,320,175, 7,175, 7,175,175, 7,175,175,175, 7,175,175,175,175, 7,175,175, 7,175,175,175, 7,175,125, 7,125,125, 7,125, 7,7,7,set; and 6,750,324, which are incorporated by reference in their entirety).

In one example, U.S. patent No.8,679,498, which is incorporated herein by reference in its entirety, includes anti-N3 pGlu aβ antibodies disclosed therein, discloses anti-N3 pGlu aβ antibodies and methods of treating diseases such as alzheimer's disease with the antibodies. Passive immunization methods by chronic administration of antibodies directed against aβ found in deposits (including N3pGlu aβ) have been shown to disrupt aβ aggregates and promote plaque clearance in the brain in various animal models. Doramemumab (donanamab) (disclosed in U.S. patent No.8,679,498, called antibody B12L) is a pyroglutamic acid modified antibody directed against the third amino acid of the amyloid β (N3 pGlu aβ) epitope, which is present only in brain amyloid plaques. The mechanism of action of doramectin is to target and remove existing amyloid plaques, which are key pathological hallmarks of AD.

Therapeutic and prophylactic strategies for anti-aβ antibodies include targeting aβ populations in AD patients with early symptoms of existing brain amyloid burden. This rationale is based on the amyloid presumption of AD, which indicates that aβ production and deposition is an early and essential event in the pathogenesis of AD. See, e.g., selkoe, "The Origins of Alzheimer Disease: a is for amyoid, "JAMA 283:1615-1617 (2000). Clinical support for this presumption comes from the following demonstration: substantial aβ levels are elevated before AD symptoms appear and are supported by genetic variants of AD that overproduce brain aβ and genetic variants that prevent aβ production. See, e.g., jonsson et al, "A Mutation in APP Protects Against Alzheimer's Disease and Age-related Cognitive Decline," Nature 488 (7409): 96-99 (2012) and Fleisher et al, "Associations Between Biomarkers and Age in the Presenilin 1E2 80A Autosomal Dominant Alzheimer Disease Kindred: a Cross-section Study, "JAMMA neuron. 72:316-24 (2015).

Antibodies targeting amyloid plaques, such as antibodies targeting aβ, show promise as therapeutics for alzheimer's disease both in preclinical and clinical studies. Despite this hope, amyloid-targeting antibodies fail to meet the therapeutic endpoint in a number of clinical trials. The history of anti-amyloid clinical Trials spans over nearly twenty years and is largely questionable for the potential of this class of therapies to effectively treat AD (Aisen et al, "The Future of Anti-amyloid three," The Journal of Prevention of Alzheimer's Disease 7 146-151 (2020)). To date, only a few treatments for AD have been approved.

One of the challenges in treating alzheimer's disease is that it is still diagnosed and treated primarily based on symptoms such as mental disorders, rather than on brain pathology. Another challenge is the replication crisis faced during clinical trials, where reproducible results are often difficult to obtain even if the clinical trials are designed to be nearly identical. This is caused by two main factors. First, most trials set the recruitment criteria based on symptoms rather than pathology. Thus, they eventually recruit heterogeneous populations with widely varying levels of potential pathology, or more unfortunately patients with different potential diseases. Thus, these patients progress at very different rates, and intra-group variability, measured for example by standard deviation of the mean, is quite large in AD trials. Second, the population heterogeneity problem is compounded in the intra-subject noise in the outcome measurement.

Determining whether a subject with aβ deposits will respond to anti-aβ antibody therapy is a unique challenge. This is due in part to physiological and clinical heterogeneity in subjects with aβ deposits. For example, determining whether a patient with fine cognitive symptoms (e.g., memory decline) has pre-or preclinical Alzheimer's Disease (AD) and may progress to AD dementia in the near future remains a challenge for the clinician.

AD clinical trials placebo groups varied significantly on the trajectories of cognitive and functional decline (Veitch et al, "Understanding Disease Progression and Improving Alzheimer's Disease Clinical Trials: recent Highlights from the Alzheimer's Disease Neuroimaging Initiative," Alzheimer's & Dementia 15.1:106-152 (2019)), which was thought to be due to heterogeneity of the trial group (Devi et al, "Heterogeneity of Alzheimer's Disease: consequence for Drug Trials. Identifying and treating subjects who may benefit from a particular treatment continues to pose significant challenges. The task of correctly identifying whether a patient is likely to respond to anti-aβ antibody therapy is crucial for e.g. timely referral to memory clinics, correct and early AD diagnosis, onset of symptomatic therapy, future planning and onset of disease modifying therapy.

Historically, trial groups were selected by clinical features such as cognitive test scoring range and self-reported memory questions. Over the years of failure, experts in the field have claimed to test anti-amyloid Disease improvement therapy (DMT) in the early stages of Disease (Aisen, P.S. et al, "The future of anti-amyloid trials," The Journal of Prevention of Alzheimer's Disease 7.3 (2020): 146-151). However, although targeting patients in early alzheimer's disease, several clinical studies of anti-amyloid DMT failed to meet its endpoint. For example, a phase III clinical trial (Cread trial) of kerrimab (Crenezumab) recruited patients with pre-treatment to mild AD. The results of this study were only negative. No difference between the two endpoints-primary and secondary) was found between the treatment group and placebo group or within the precursor AD subgroup and the mild AD subgroup (NCT 03114657 at clinicaltrias.gov; therapeutic applications: crenezumab. Alzheimer. AC Immune SA, genntech, hoffmann-La Roche;2019[ 9.7.2020, cited ] from: alzforum. Org/therapeutics/crenzumab). Similarly, phase II/III clinical trials (5 Carlet RoAD trials) assessing efficacy and safety of more trelagrangab Abeta in prodromal AD patients were terminated because of the low probability of achieving efficacy for primary and secondary endpoints in the trial (Ostrowitzki et al, "A Phase III Randomized Trial of Gantenerumab in Prodromal Alzheimer's Disease," Alzheimer's research & therapy 9.1:1-15 (2017)).

Thus, there is a need for improved methods of appropriately identifying whether a subject will respond to an amyloid-targeted therapeutic.

One aspect of the invention is based on the following findings: alzheimer's disease patients with low or moderate tau respond to treatment with anti-Abeta antibodies and patients with high tau levels may not be effectively treated with anti-Abeta antibodies even if clinically classified as preclinical or early stage AD. Identifying the most susceptible subjects to anti-aβ antibody treatment solves the problem of finding clinically effective anti-amyloid treatment over 20 years old, thus reflecting significant advances in the art. Aspects of the invention relate to diagnosis and treatment of patients based on their brain pathology. The selection of patients based on their brain pathology not only provides a more homogenous population in clinical trials and reduced noise to ensure highly reproducible results, but also ensures correct identification of the AD stage and its progression. The correct identification of the AD stage also allows for e.g. timely referral to a memory clinic, correct and early AD diagnosis, initiation of symptomatic treatment, future planning and initiation of disease modifying treatment.

Some aspects of the invention relate to identifying the stage/progression of AD in a patient based on i) global or overall tau load in the brain of a human subject, ii) tau diffusion in the brain of the subject or a portion thereof, and/or iii) the presence of one or both alleles of epsilon-4 of apolipoprotein E in the genome of the subject (referred to herein as ApoE4 or ApoE 4).

In some embodiments, the patient may be stratified/identified/selected/treated based on the amount of tau present in the subject's brain (e.g., in the whole brain or in a portion of the brain) and/or the presence of one or both alleles of ApoE 4 in the subject's genome.

In other embodiments, the patient is stratified/identified/selected/treated based on the stage of AD progression (e.g., based on tau diffusion in the brain) and/or the presence of one or both alleles of ApoE 4 in the subject's genome. For example, during some phases tau load in AD patients is isolated to regions of the frontal or temporal lobes excluding the posterolateral temporal region (PLT). Another stage of AD is tau load limitation in AD patients to the posterolateral temporal region (PLT) or occipital region. Yet another stage of AD is when tau load in AD patients exists in the parietal or prefraxal or frontal region and tau load in PLT or occipital region. In some embodiments, AD patients have one or both alleles of ApoE 4 in the subject's genome and tau load isolated to frontal lobes or temporal lobe regions excluding the posterolateral temporal region (PLT). Another stage of AD is that AD patients have one or two alleles of ApoE 4 and tau burden is limited to the posterolateral temporal region (PLT) or occipital region. Another stage of AD is that AD patients have one or two alleles of ApoE 4 and tau load is present in the parietal or prefrontal or frontal region, and in the PLT or occipital region.

Patient stratification based on the amount of tau in the brain or the progression of AD in a portion of the brain may be used to determine, for example, whether a patient is responsive to anti-aβ antibody therapy. Layering/selecting patient populations based on the amount of tau in the brain or AD progression in portions of the brain also helps to address patient heterogeneity and repeatability issues faced during the design and execution of clinical trials. Identification of patients based on tau amount or AD progression also facilitates, for example, timely referral to memory clinics, correct and early diagnosis of AD. Initiate symptomatic treatment, future planning and initiate disease modifying treatments.

In addition, doody et al, "Phase 3Trials of Solanezumab for Mild-to-Moderate Alzheimer's Disease," NEJM,370;4,311-321 (2014) believes that a significant difference in efficacy is observed between APOE epsilon 4 carriers and non-carriers [ not ] ("[ n ] o clear differential treatment effects on efficacy measures were observed between APOE epsilon 4 carriers and noncarriers."). It has now been found that administration of an anti-N3 pGlu aβ antibody to a human subject having one or both alleles of ApoE 4 (e.g. a carrier of ApoE 4) provides unexpected and surprising efficacy when compared to a non-carrier of one or more of those alleles. Thus, some embodiments relate to the administration of doses of anti-N3 pGlu aβ antibodies to patients with such genes as a way to slow down cognitive decline in those patients. In particular, it has been found that there is a greater effect in the carrier of ApoE 4 than in the non-carrier when anti-N3 pGlu aβ antibodies are administered to a patient. This means that patients with ApoE 4 have less cognitive decline than non-carriers when using various clinical measurements and at various end-point measurements. Thus, patients may be stratified/identified/selected/treated based on the level of tau, the stage of AD progression (e.g., based on tau diffusion in the brain), and/or the presence of one or both alleles of ApoE 4 in the subject's genome.

One aspect of the invention provides a human subject responsive to treatment or prevention of a disease characterized by amyloid β (aβ) deposits in the brain of the human subject. In some embodiments of this aspect of the invention, the responsive human subject comprises a human subject having a low to medium tau load or a very low to medium tau load. In some embodiments of this aspect of the invention, the responsive human subject comprises a human subject having one or both alleles of low to medium tau load or very low to medium tau load and/or ApoE 4. In some embodiments of this aspect of the invention, the responsive human subjects do not include human subjects having a high tau load and a change in the Integrated Alzheimer's Disease Rating Scale (iADRS) of about-20 or greater after about 18 months have elapsed. In some embodiments, the anti-aβ antibodies of the invention are administered to a responsive human subject for the treatment or prevention of a disease characterized by amyloid β (aβ) deposits in the brain of the human subject.

One aspect of the invention relates to a method of treating or preventing a disease characterized by amyloid β (aβ) deposits in the brain of a human subject that has been determined to have a very low to moderate tau load or a low to moderate tau load, comprising administering to the subject one or more doses of an anti-aβ antibody. In some embodiments, the method comprises: i) Administering one or more first doses of anti-aβ antibody (e.g., one or more first doses of about 100mg to about 700mg of anti-aβ antibody) to the human subject, wherein each first dose is administered once for about 4 weeks, and ii) administering one or more second doses of anti-antibody (e.g., one or more second doses of greater than 700mg to about 1400mg of anti-aβ antibody) to the human subject about 4 weeks after administration of the one or more first doses, wherein each second dose is administered once for about 4 weeks. In some embodiments, the alzheimer's patient has one or both alleles of APOE 4.

Another aspect of the invention relates to a method of treating or preventing a disease characterized by amyloid β (aβ) deposits in the brain of a human subject that has been determined to have a very low to moderate tau load or a low to moderate tau load; and administering one or more doses of an anti-aβ antibody to the human subject if the human subject has a very low to moderate tau load or a low to moderate tau load. In some embodiments, the method comprises: i) Administering one or more first doses of about 100mg to about 700mg of anti-aβ antibody to a human subject, wherein each first dose is administered about once every 4 weeks, and ii) administering one or more second doses of anti-aβ antibody to a human subject about 4 weeks after administration of the one or more first doses, wherein each first dose is administered about once every 4 weeks; and ii) about 4 weeks after administration of the one or more first doses, administering one or more second doses of greater than 700mg to about 1400mg of the anti-aβ antibody to the human subject, wherein each second dose is administered about once every 4 weeks.

Another aspect of the invention relates to a method of treating or preventing a disease characterized by amyloid β (aβ) deposits in the brain of a human subject comprising: determining whether the human subject has one or both alleles of ApoE e4, a very low to moderate tau load and/or a low to moderate tau load; and administering one or more doses of the anti-aβ antibody to the human subject if the human subject has one or both alleles of ApoE 4, very low to moderate tau loading and/or low to moderate tau loading. In some embodiments, the method comprises i) administering to the human subject one or more first doses of about 100mg to about 700mg of the anti-aβ antibody, wherein each first dose is administered about once every 4 weeks, and ii) administering to the human subject one or more second doses of greater than 700mg to about 1400mg of the anti-aβ antibody, wherein each second dose is administered about once every 4 weeks, about 4 weeks after administration of the one or more first doses.

Another aspect of the invention relates to a method of treating or preventing a disease characterized by amyloid β (aβ) deposits in the brain of a human subject that has been determined to not have a high tau load, comprising administering an anti-aβ antibody to the human subject. In some embodiments, the method comprises: i) Administering one or more first doses of about 100mg to about 700mg of anti-aβ antibody to a human subject, wherein each first dose is administered about once every 4 weeks, and ii) administering one or more second doses of greater than 700mg to about 1400mg of anti-aβ antibody to a human subject about 4 weeks after administration of the one or more first doses, wherein each second dose is administered about once every 4 weeks. In some embodiments, the human subject has been determined to not have a high tau load and to have one or both alleles of ApoE 4.

Another aspect of the invention relates to a method of treating or preventing a disease characterized by amyloid β (aβ) deposits in the brain of a human subject comprising: determining whether the human subject has a high tau load; and administering one or more doses of an anti-aβ antibody to the human subject if the human subject does not have a high tau load. In some embodiments, the method comprises: i) Administering one or more first doses of about 100mg to about 700mg of anti-aβ antibody to a human subject, wherein each first dose is administered about once every 4 weeks, and ii) administering one or more second doses of greater than 700mg to about 1400mg of anti-aβ antibody to a human subject about 4 weeks after administration of the one or more first doses, wherein each second dose is administered about once every 4 weeks.

Another aspect of the invention relates to a method of treating or preventing a disease characterized by amyloid β (aβ) deposits in the brain of a human subject comprising: determining whether the human subject has a high tau load and has one or both alleles of ApoE e 4; and administering one or more doses of an anti-aβ antibody to the human subject if the human subject does not have a high tau load and has one or both alleles of ApoE e 4. In some embodiments, the method comprises: i) Administering one or more first doses of about 100mg to about 700mg of anti-aβ antibody to a human subject, wherein each first dose is administered about once every 4 weeks, and ii) administering one or more second doses of greater than 700mg to about 1400mg of anti-aβ antibody to the human subject about 4 weeks after administration of the one or more first doses, wherein each second dose is administered about once every 4 weeks.

Another aspect of the invention relates to a method of treating or preventing a disease characterized by amyloid β (aβ) deposits in the brain of a human subject, comprising administering to the human subject an effective amount of an anti-aβ antibody, wherein the human subject has been determined to have a very low to moderate tau load or a low to moderate tau load.

Another aspect of the invention relates to a method of treating or preventing a disease characterized by amyloid β (aβ) deposits in the brain of a human subject, comprising administering to the human subject an effective amount of an anti-aβ antibody, wherein the human subject has been determined to have one or two alleles of ApoE 4 and a very low to moderate tau load or a low to moderate tau load.

Another aspect of the invention relates to a method of treating or preventing a disease characterized by amyloid β (aβ) deposits in the brain of a human subject, comprising determining whether the human subject has a low to medium tau load or a very low to medium tau load; and if the human subject has a low to medium Tau load or a very low to medium Tau load: an effective amount of an anti-aβ antibody is administered to a human subject.

Another aspect of the invention relates to a method of treating or preventing a disease characterized by amyloid β (aβ) deposits in the brain of a human subject, comprising determining whether the human subject has one or two alleles of ApoE e4 and a low to medium tau load or a very low to medium tau load; and if the human subject has one or both alleles of ApoE e4 and a low to moderate tau load or a very low to moderate tau load: an effective amount of an anti-aβ antibody is administered to a human subject.

Another aspect of the invention relates to a method of treating or preventing a disease characterized by amyloid β (aβ) deposits in the brain of a human subject, comprising administering to the human subject an effective amount of an anti-aβ antibody, wherein the human subject has been determined to not have a high tau load and the human subject has not exhibited a reduction in the Integrated Alzheimer's Disease Rating Scale (iADRS) of greater than about-20 for about the past 18 months. In some embodiments, the human subject has one or both alleles of ApoE e 4.

Another aspect of the invention relates to a method of treating or preventing a disease characterized by amyloid β (aβ) deposits in the brain of a human subject, comprising determining whether the human subject has a high tau load; and if the human subject does not have a high tau load: an effective amount of an anti-aβ antibody is administered to a human subject.

Another aspect of the invention relates to a method of treating or preventing a disease characterized by amyloid β (aβ) deposits in the brain of a human subject, comprising determining whether the human subject has a high tau load and one or both alleles of ApoE 4; and if the human subject has one or both alleles of ApoE e4 and does not have a high tau load: an effective amount of an anti-aβ antibody is administered to a human subject.

In some aspects of the disclosed methods, anti-aβ antibodies can be used to reduce, prevent further increases or slows the rate of tau load/accumulation in different parts of the human brain (e.g., in different lobes of the human brain of a human subject). In some embodiments, the anti-aβ antibody is used to reduce, prevent further increases or slows the rate of tau load/accumulation in the frontal lobe of the human brain. In some embodiments, the anti-aβ antibody is used to reduce, prevent further increases or slows the rate of tau load/accumulation in the top lobe of the human brain. In some embodiments, the anti-aβ antibody is used to reduce, prevent further increases or slows the rate of tau load/accumulation in human brain occipital lobes. In some embodiments, the anti-aβ antibody is used to reduce, prevent further increases or slows the rate of tau load/accumulation in the temporal lobes of the human brain. In some embodiments, the anti-aβ antibody is used to reduce, prevent further increases or slows the rate of tau load/accumulation in the posterolateral temporal lobe. In some embodiments, i) one or more first doses of about 100mg to about 700mg of the anti-aβ antibody are administered to the human subject, wherein each first dose is administered about once every 4 weeks; and ii) about 4 weeks after administration of the one or more first doses, administering to the human subject one or more second doses of anti-aβ antibody greater than 700mg to about 1400mg, wherein each second dose is administered about once every 4 weeks.

Another aspect of the invention relates to a method of treating or preventing a disease characterized by amyloid β (aβ) deposits in the brain of a human subject that has been determined to have tau burden in occipital lobes of the brain, wherein the method comprises administering an anti-aβ antibody to the human subject. Another aspect of the invention relates to a method of treating or preventing a disease characterized by amyloid β (aβ) deposits in the brain of a human subject, the method comprising determining whether the human subject has tau burden in occipital lobes of the brain and administering an anti-aβ antibody to the human subject. In some embodiments, i) one or more first doses of about 100mg to about 700mg of the anti-aβ antibody are administered to the human subject, wherein each first dose is administered about once every 4 weeks; and ii) about 4 weeks after administration of the one or more first doses, administering to the human subject one or more second doses of anti-aβ antibody greater than 700mg to about 1400mg, wherein each second dose is administered about once every 4 weeks.

One aspect of the invention relates to a method of treating or preventing a disease characterized by amyloid β (aβ) deposits in the brain of a human subject that has been determined to have tau burden in the parietal lobe of the brain, wherein the method comprises administering an anti-aβ antibody to the human subject. Another aspect of the invention relates to a method of treating or preventing a disease characterized by amyloid β (aβ) deposits in the brain of a human subject, comprising determining whether the human subject has tau burden in the parietal lobe of the brain and administering an anti-aβ antibody to the human subject. In some embodiments, the human subject has tau load in the posterolateral temporal lobe. In some embodiments, i) one or more first doses of about 100mg to about 700mg of the anti-aβ antibody are administered to the human subject, wherein each first dose is administered about once every 4 weeks; and ii) about 4 weeks after administration of the one or more first doses, administering to the human subject one or more second doses of anti-aβ antibody greater than 700mg to about 1400mg, wherein each second dose is administered about once every 4 weeks. In some embodiments, the human subject has been determined to have one or both alleles of APOE 4.

Another aspect of the invention relates to a method of treating or preventing a disease characterized by amyloid β (aβ) deposits in the brain of a human subject that has been determined to have tau burden in the frontal lobe of the brain, wherein the method comprises administering an anti-aβ antibody to the human subject. Another aspect of the invention relates to a method of treating or preventing a disease characterized by amyloid β (aβ) deposits in the brain of a human subject, comprising determining whether the human subject has tau burden in the frontal lobe of the brain and administering an anti-aβ antibody to the human subject. In some embodiments, i) one or more first doses of about 100mg to about 700mg of the anti-aβ antibody are administered to the human subject, wherein each first dose is administered about once every 4 weeks; and ii) about 4 weeks after administration of the one or more first doses, administering to the human subject one or more second doses of anti-aβ antibody greater than 700mg to about 1400mg, wherein each second dose is administered about once every 4 weeks. In some embodiments, the human subject has been determined to have one or both alleles of APOE 4.

Another aspect of the invention relates to a method of treating or preventing a disease characterized by amyloid β deposits in the brain of a human subject who has been determined to have tau burden in the posterolateral temporal and/or occipital lobes of the brain, wherein the method comprises administering an anti-aβ antibody to the human subject. Another aspect of the invention relates to a method of treating or preventing a disease characterized by amyloid β (aβ) deposits in the brain of a human subject, comprising determining whether the human subject has tau burden in the posterolateral temporal lobe and/or occipital lobe of the brain and administering an anti-aβ antibody to the human subject. In some embodiments, i) one or more first doses of about 100mg to about 700mg of the anti-aβ antibody are administered to the human subject, wherein each first dose is administered about once every 4 weeks; and ii) about 4 weeks after administration of the one or more first doses, administering to the human subject one or more second doses of anti-aβ antibody greater than 700mg to about 1400mg, wherein each second dose is administered about once every 4 weeks. In some embodiments, the human subject has been substituted with one or both alleles of APOE 4.

Another aspect of the invention relates to a method of treating or preventing a disease characterized by amyloid β deposits in the brain of a human subject that has been determined to have tau burden in i) the parietal or prefeiral lobe region or ii) the frontal lobe of the brain and tau burden in the PLT or occipital lobe region of the brain, wherein the method comprises administering an anti-aβ antibody to the human subject. Another aspect of the invention relates to a method of treating or preventing a disease characterized by amyloid β deposits in the brain of a human subject, comprising determining whether the human subject has tau burden in i) the parietal or prefrontal regions or ii) the frontal and PLT or occipital regions of the brain, and administering an anti-aβ antibody to the human subject. In some embodiments, i) one or more first doses of about 100mg to about 700mg of the anti-aβ antibody are administered to the human subject, wherein each first dose is administered about once every 4 weeks; and ii) about 4 weeks after administration of the one or more first doses, administering to the human subject one or more second doses of anti-aβ antibody greater than 700mg to about 1400mg, wherein each second dose is administered about once every 4 weeks. In some embodiments, the human subject has been substituted with one or both alleles of APOE 4.

Another aspect of the invention relates to a method of treating or preventing a disease characterized by amyloid β deposits in the brain in a human subject that has been determined to have i) isolated to the frontal lobe or ii) tau burden in the temporal lobe region excluding the posterolateral temporal region (PLT) of the brain, wherein the method comprises administering an anti-aβ antibody to the human subject. Another aspect of the invention relates to a method of treating or preventing a disease characterized by amyloid β deposits, comprising determining whether a human subject has i) isolated to the frontal lobe or ii) tau burden in a temporal lobe region excluding the posterolateral temporal region (PLT) of the brain, and administering an anti-aβ antibody to the human subject. In some embodiments, i) one or more first doses of about 100mg to about 700mg of the anti-aβ antibody are administered to the human subject, wherein each first dose is administered about once every 4 weeks; and ii) about 4 weeks after administration of the one or more first doses, administering to the human subject one or more second doses of anti-aβ antibody greater than 700mg to about 1400mg, wherein each second dose is administered about once every 4 weeks. In some embodiments, the human subject has been substituted with one or both alleles of APOE 4.

In some aspects, the invention relates to methods of selecting a human subject for treating or preventing a disease characterized by amyloid β deposits in the brain of the human subject. In some embodiments, the human subject is selected based on the amount of integrated (total) tau in the brain of the human subject. For example, a human subject is selected for treatment or prevention of a disease characterized by amyloid β deposits in the brain, as the patient has very low to moderate tau in the brain. In another embodiment, the human subject is selected for treatment or prevention of a disease characterized by amyloid β deposits in the brain, because the patient has low to moderate tau (or moderate tau) in the brain. In another embodiment, the human subject is excluded from treatment or prevention of a disease characterized by amyloid β deposits in the brain, because the patient has high tau in the brain. In some embodiments, the human subject is selected based on the progression of AD in the brain of the human subject. For example, a human subject is selected for treatment or prevention of a disease characterized by amyloid β deposits in the brain, as the patient has tau burden in the frontal lobe of the brain. In another embodiment, the human subject is selected for treatment or prevention of a disease characterized by amyloid β deposits in the brain, because the patient has tau burden in the parietal lobe of the brain. In another embodiment, the human subject is selected for treatment or prevention of a disease characterized by amyloid β deposits in the brain, because the patient has tau burden in the occipital lobe of the brain. In another embodiment, the human subject is selected for treatment or prevention of a disease characterized by amyloid β deposits in the brain, because the patient has tau burden present in the temporal lobe of the brain. In some embodiments, the human subject is selected for treatment or prevention of a disease characterized by amyloid β deposits in the brain, because the patient has tau burden present in the posterolateral temporal lobe (PLT) and/or occipital lobe of the brain. In some embodiments, the human subject is selected for treatment or prevention of a disease characterized by amyloid β deposits in the brain, because the patient has Tau load present in i) the parietal or prefraxal region or ii) the frontal region of the brain and Tau load in the PLT or occipital region. In some embodiments, the human subject is selected for treatment or prevention of a disease characterized by amyloid β deposits in the brain because the patient has i) isolated to the frontal lobe or ii) tau load in temporal lobe areas excluding the posterolateral temporal area (PLT) of the brain. In some embodiments, i) one or more first doses of about 100mg to about 700mg of the anti-aβ antibody are administered to the human subject, wherein each first dose is administered about once every 4 weeks; and ii) about 4 weeks after administration of the one or more first doses, administering to the human subject one or more second doses of anti-aβ antibody greater than 700mg to about 1400mg, wherein each second dose is administered about once every 4 weeks. In some embodiments, the human subject has been substituted with one or both alleles of APOE 4.

In some embodiments, it has been determined that the subject described in the various aspects of the invention has a posterolateral temporal lobe tau load. In some embodiments, it has been determined that the subject described in the various aspects of the invention has a posterolateral temporal lobe and occipital lobe tau load. In some embodiments, it has been determined that the subject described in the various aspects of the invention has a posterolateral temporal lobe tau load, occipital lobe tau load, and/or parietal lobe tau load. In some embodiments, the subject described in the various aspects of the invention has been determined to have a posterolateral temporal lobe tau load, occipital lobe tau load, parietal lobe tau load. tau load and/or frontal lobe tau load. In some embodiments, it has been determined that the subject described in the various aspects of the invention has a posterolateral temporal lobe tau load, occipital lobe tau load, parietal lobe tau load, and/or frontal lobe tau load. In some embodiments, the subject described in the various aspects of the invention has been determined to have a posterolateral temporal lobe tau load, occipital lobe tau load, parietal lobe tau load, and/or frontal lobe tau load, which corresponds to a tau load of greater than 1.46SUVr based on PET imaging. In some embodiments, the human subject has been determined to have one or both alleles of ApoE e 4.

In some embodiments, tau load in a portion of the human brain (e.g., in a lobe of the brain) can be used to determine whether administration of an anti-aβ antibody should be discontinued. For example, a decrease, prevention of further increases, or slowing of the rate of tau load/accumulation in a portion of the brain may be used as a measure to determine the administration period of an anti-aβ antibody. In some embodiments, the anti-aβ antibody is administered to the subject until the rate of tau load/accumulation in the temporal, occipital, parietal or frontal lobe is reduced, prevented from further increasing or slowing that rate.

In some embodiments, tau load present in a portion of the brain of a human subject (e.g., in a defined lobe of the brain of a human subject) can be used to select an optimal treatment regimen or for administering a therapeutic regimen in combination with an anti-aβ antibody. For example, the presence of tau burden in the frontal lobe of the brain of an amyloid-positive human subject can be used as a metric to determine whether a human subject would benefit from administration of an anti-aβ antibody alone or in combination with an anti-tau antibody. In some embodiments, a combination of anti-aβ antibodies and anti-tau antibodies may be administered to a subject in order to reduce, prevent further increases or slow the rate of tau load/accumulation in different parts of the human brain (e.g., in different lobes of the human brain of a human subject). In some embodiments, tau load in different parts of the human brain (e.g., in different lobes of the human brain of a human subject) can be used i) to track the patient's response to treatment, or ii) to determine when a restart of therapy may be required.

In some embodiments, the antibodies, methods, or dosing regimens described in the different aspects of the invention result in: i) A reduction of aβ deposits in the brain of a human subject and/or ii) a reduction in cognition or function in a human subject. In some embodiments, an antibody, method, or dosing regimen described in the methods described herein results in a reduction of amyloid plaques.

In some embodiments, the anti-aβ antibodies described in the different aspects of the invention i) comprise anti-N3 pGlu aβ antibodies, ii) may be replaced with anti-N3 pGlu aβ antibodies, or iii) used with anti-N3 pGlu aβ antibodies, such as:

an anti-N3 pGlu aβ antibody comprising: having the SEq ID NO:5 (LCDR 1) having the amino acid sequence of SEQ ID NO:6, and a light chain complementarity determining region 2 (LCDR 2) having the amino acid sequence of SEQ ID NO:7 or an amino acid sequence identical to SEQ ID NO:5 (LCDR 1), an amino acid sequence having at least 95% homology with SEQ ID NO:6 (LCDR 2) and an amino acid sequence having at least 95% homology with SEQ ID NO:7 (LCDR 3) having an amino acid sequence that is at least 95% homologous to light chain complementarity determining region 3 (LCDR 3);

An anti-N3 pGlu aβ antibody comprising: has the sequence of SEQ ID NO:8 (HCDR 1) having the amino acid sequence of SEQ ID NO:9 (HCDR 2), and a heavy chain complementarity determining region 2 having the amino acid sequence of SEQ ID NO:10 or an amino acid sequence identical to SEQ ID NO:8 (HCDR 1), an amino acid sequence having at least 95% homology with SEQ ID NO:9 (HCDR 2) and an amino acid sequence having at least 95% homology with SEQ ID NO:10 (HCDR 3) having an amino acid sequence of at least 95% homology;

An anti-N3 pG1u A β antibody comprising: LCVR and HCVR, wherein the LCVR comprises: LCDR1, LCDR2, and LCDR3 and HCVR comprises HCDR1, HCDR2, and HCDR3 selected from the group consisting of: LCDR1 is SEQ ID NO:5, LCDR2 is SEQ ID NO:6, lcdr3 is SEQ ID NO:7, hcdr1 is SEQ ID NO:8, hcdr2 is SEQ ID NO:9, and HCDR3 is SEQ ID NO:10; or a LCVR and a HCVR, wherein the LCVR comprises LCDR1, LCDR2, and LCDR3 and the HCVR comprises HCDR1, HCDR2, and HCDR3 selected from the group consisting of: and SEQ ID NO:5, LCDR1 having at least 95% homology to SEQ ID NO:6 LCDR2 having at least 95% homology to SEQ ID NO:7 LCDR3 having at least 95% homology to SEQ ID NO:8, HCDR1 having at least 95% homology to SEQ ID NO:9 and HCDR2 having at least 95% homology to SEQ ID NO:10, HCDR3 having at least 95% homology.

An N3pGlu aβ antibody comprising a Light Chain (LC) comprising: SEQ ID NO:3 or an amino acid sequence identical to SEQ ID NO:3 having an amino acid sequence with at least 95% homology;

an N3pGlu aβ antibody comprising a Heavy Chain (HC) comprising: SEQ ID NO:4 or an amino acid sequence identical to SEQ ID NO:4 having an amino acid sequence with at least 95% homology;

An anti-N3 pGlu aβ antibody comprising LC and HC, wherein LC comprises the amino acid sequence of SEQ ID NO:3 and HC comprises the amino acid sequence of SEQ ID NO:4, or wherein LC comprises an amino acid sequence identical to SEQ ID NO:3 and HC comprises an amino acid sequence having at least 95% homology to SEQ ID NO:4 having an amino acid sequence with at least 95% homology;

an anti-N3 pGlu aβ antibody comprising two light chains and two heavy chains, wherein LC comprises the amino acid sequence of SEQ ID NO:3 or an amino acid sequence identical to SEQ ID NO:3, and HC comprises the amino acid sequence of SEQ ID NO:4 or an amino acid sequence identical to SEQ ID NO:4 having an amino acid sequence having at least 95% homology.

An N3pGlu aβ antibody comprising a polypeptide comprising the amino acid sequence of SEQ ID NO:1 or with SEQ ID NO:1 LCVR having an amino acid sequence with at least 95% homology;

an N3pGlu aβ antibody comprising a HCVR comprising the amino acid sequence of SEQ ID NO:2 or an amino acid sequence identical to SEQ ID NO:2 having an amino acid sequence with at least 95% homology.

An N3pGlu aβ antibody comprising a LCVR and a HCVR, wherein the LCVR comprises the amino acid sequence of SEQ ID NO:1 or an amino acid sequence identical to SEQ ID NO:1 having an amino acid sequence with at least 95% homology; and HCVR comprises SEQ ID NO:2 or an amino acid sequence identical to SEQ ID NO:2 having an amino acid sequence with at least 95% homology.

Anti-aβ antibodies described in the different aspects of the invention i) include anti-aβ antibodies disclosed in the art, ii) may be substituted with anti-aβ antibodies disclosed in the art, or iii) used therewith, such as the antibodies donepezil, soraman mab, pap mab, GSK933776, klebsituzumab, pomalituzumab, and BAN 2401. In some embodiments, the anti-aβ antibodies of the invention comprise κlc and IgG HC. In a specific embodiment, the anti-aβ antibodies of the invention have a human IgGl isotype.

In some embodiments of the disclosed methods, one or more first doses of about 100mg to about 700mg of an anti-aβ antibody as described herein are administered to a human subject. In some embodiments, one or more first doses are administered to the human subject such that each first dose is administered once every four weeks. In embodiments, the first dose is administered once to the subject. In some embodiments, the first dose is administered to the subject twice, wherein each first dose is administered once every four weeks. In some embodiments, the first dose is administered to the subject three times, wherein each first dose is administered once every four weeks.

In some embodiments, one, two, or three first doses of about 100mg to about 700mg are administered to the subject, wherein each first dose is administered about once every 4 weeks. In a specific embodiment, three first doses of about 700mg are administered to a human subject, wherein each first dose is administered about once every 4 weeks. In some embodiments, the first dose is administered to the human subject once, twice or three times before the second dose is administered.

In some embodiments, the subject is administered three first doses of about 700mg once every 4 weeks for a period of 12 weeks, followed by a second dose of about 1400 mg. In some embodiments, the subject is administered one or more first doses of about 700mg once every 4 weeks for a duration of about 3 months, followed by a second dose of about 1400 mg.

In some embodiments, the first dose is about 100mg, about 200mg, about 300mg, about 400mg, about 500mg, about 600mg, about 700mg. In some embodiments, the first dose is about 1mg/kg to about 10mg/kg of anti-aβ antibody. In particular embodiments, up to three first doses of about 1mg/kg to about 10mg/kg are administered to a subject. In some embodiments, one, two, or three first doses of about 1mg/kg to about 10mg/kg are administered to the subject. In a specific embodiment, three first doses of about 10mg/kg are administered to the subject, once every four weeks. In some embodiments, the first dose is about 1mg/kg, about 2mg/kg, about 3mg/kg, about 4mg/kg, about 5mg/kg, about 6mg/kg, about 7mg/kg, about 8mg/kg, about 9mg/kg, or about 10mg/kg.

In a specific embodiment, the first dose is administered once every 4 weeks or once a month. In one embodiment, three first doses of about 10mg/kg are administered to the subject, once every 4 weeks. In some embodiments, the first dose of anti-aβ antibody is administered to the subject for about one month, about two months, or about three months.

In some embodiments, one or more second doses of greater than 700mg to about 1400mg of anti-aβ antibody are administered to the subject. In some embodiments, one or more second doses of greater than 700mg to about 1400mg of anti-aβ antibody are administered to the subject, wherein each second dose is administered about once every 4 weeks. In some embodiments, the second dose is administered 4 weeks after the one or more first doses.

In embodiments, one or more second doses greater than 700mg are administered to the subject. In some embodiments, one or more second doses of about 1400mg are administered to the subject. In some embodiments, the second dose is greater than 700mg, about 800mg, about 900mg, about 1000mg, about 1100mg, about 1200mg, about 1300mg, or about 1400mg. In a specific embodiment, the second dose is administered once every 4 weeks. In one embodiment, one or more second doses greater than 700mg are administered to the subject once every 4 weeks. In one embodiment, one or more second doses of about 1400mg are administered to the subject once every 4 weeks.

MRI scans may be administered to human subjects to examine/evaluate any adverse effects resulting from administration of anti-aβ antibodies. In some embodiments, an MRI scan is administered to a human subject between doses of anti-aβ antibody administered. In some embodiments, the MRI scan is administered to the human subject prior to increasing the dose of anti-aβ antibody (e.g., from 700mg to 1400 mg). In some embodiments, an MRI scan is administered to a human subject. In some embodiments, an MRI scan is administered to a human subject prior to administration of the 1400mg dose. In some embodiments, an MRI scan is administered to a human subject prior to administration of a 20mg/kg dose. In some embodiments, the MRI scan is administered to the human subject after the final dose of 700mg dose. In some embodiments, the MRI scan is administered to the human subject after the last dose of 10mg/kg dose.

In some embodiments, one or more second doses of greater than 10mg/kg to about 20mg/kg of anti-aβ antibody are administered to the subject. In some embodiments, the second dose is greater than 10mg/kg, about 11mg/kg, about 12mg/kg, about 13mg/kg, about 14mg/kg, about 15mg/kg, about 16mg/kg, about 17mg/kg, about 18mg/kg, about 19mg/kg, or about 20mg/kg. In one embodiment, one or more second doses greater than 10mg/kg are administered to the subject. In one embodiment, one or more second doses of about 20mg/kg are administered to the subject. In one embodiment, the first dose is administered once a month. In one embodiment, one or more second doses greater than 10mg/kg are administered to the subject, wherein each second dose is administered once every 4 weeks or once a month. In one embodiment, one or more second doses of about 20mg/kg are administered to the subject, wherein each second dose is administered once every 4 weeks or once a month.

In some embodiments, a first dose of anti-aβ antibody is administered to a subject once, followed by one or more second doses, wherein the second dose is administered 4 weeks after the one or more first doses, and once every 4 weeks thereafter. In some embodiments, a first dose of anti-aβ antibody is administered to the subject twice (once every four weeks), followed by one or more second doses that are administered 4 weeks after the first dose and once every 4 weeks thereafter. In some embodiments, a first dose of anti-aβ antibody is administered to the subject three times (once every four weeks), followed by one or more second doses that are administered 4 weeks after the first dose and once every 4 weeks thereafter.

In some embodiments, the subject is treated with one or more first doses, one or more second doses of about 1400mg, followed by one or more second doses of greater than 700mg to about 1300 mg. In one embodiment, the subject is treated with one or more first doses of about 700mg, one or more second doses of about 1400mg, and then one or more doses of about 700 mg.

In some embodiments, the dosing regimen of the present invention comprises one or more additional doses (also referred to herein as third doses) following the one or more first doses of about 100mg to about 700mg and the one or more second doses of greater than 700mg to about 1400mg. In some embodiments, the third dose is administered to the subject to reduce deposition of aβ in the brain of the subject, prevent further cognitive decline, prevent memory loss, or prevent functional decline. The third dose may be about 100mg to about 1400mg. In some embodiments, different or the same antibodies are used for the first dose, the second dose, and the third dose. In some embodiments, a different aβ targeting antibody is administered in a third dose. For example, some embodiments of the invention include i) administering one or more first doses of about 100mg to about 700mg of an anti-aβ antibody to a human subject, wherein each first dose is administered about once every 4 weeks; ii) about 4 weeks after administration of the one or more first doses, administering to the human subject one or more second doses of the anti-aβ antibody of greater than 700mg to about 1400mg, wherein each second dose is administered about once every 4 weeks, and iii) subsequently administering one or more third doses of the anti-aβ antibody of about 100mg to about 1400mg. In some embodiments, one or more third doses of the anti-aβ antibodies of the invention may be administered to the subject every 2 or 4 weeks, monthly, every 1 year, every 2 years, every 3 years, every 4 years, every 5 years, or every 10 years. In some embodiments, the third dose is administered every 2 weeks. In some embodiments, the third dose is administered every 4 weeks. In some embodiments, the third dose is administered annually. In one embodiment, the third dose is administered every 2 years. In another embodiment, the third dose is administered every 3 years. In another embodiment, a third dose of antibody is administered every 5 years. In another embodiment, a third dose of antibody is administered every 10 years. In another embodiment, a third dose of antibody is administered every 2 to 5 years. In another embodiment, a third dose of antibody is administered every 5 to 10 years.

In some embodiments, the anti-aβ antibody is administered to the subject for a period of time sufficient to treat or prevent the disease. In some embodiments, the anti-aβ antibody (including the first dose of antibody and the second dose of antibody) is administered to the subject for up to about 72 weeks, optionally, once every 4 weeks or once a month. In some embodiments, the anti-aβ antibody (including the first dose of antibody and the second dose of antibody) is administered to the subject for up to about 98 weeks, optionally, once every 4 weeks or once a month. In some embodiments, the anti-aβ antibody (including the first dose of antibody and the second dose of antibody) is administered to the subject for up to about 124 weeks, optionally, once every 4 weeks or once a month. In some embodiments, the anti-aβ antibody (comprising a first dose of antibody and a second dose of antibody) is administered to a human subject until normal levels of amyloid are reached in the subject. In some embodiments, an anti-aβ antibody (including a first dose of antibody and a second dose of antibody) is administered to a human subject until the subject becomes amyloid negative (when the level of amyloid plaques in the brain of the subject is less than 24.1CL, the subject is considered amyloid negative). In some embodiments, the anti-aβ antibody (including the first dose of antibody and the second dose of antibody) is administered to the human subject until the subject's cerebral amyloid plaque level is within a normal range or cleared. The normal range of amyloid plaques is defined as a plaque level that exhibits 25 centella or less in two consecutive PET scans separated by at least 6 months, or less than 11 centella in a single PET scan. In the present disclosure, the term "normal range" of amyloid plaques in the brain is used interchangeably with "clearing" of brain amyloid plaques.

In some embodiments, the anti-aβ antibody (including the first dose of antibody and the second dose of antibody) is administered to the subject for a period of up to about 18 months, optionally, once every 4 weeks or once a month. In some embodiments, the anti-aβ antibody (including the first dose of antibody and the second dose of antibody) is administered to the subject for a period of up to about 24 months, optionally, once every 4 weeks or once a month. In some embodiments, the anti-aβ antibody (including the first dose of antibody and the second dose of antibody) is administered to the subject for a period of up to about 30 months, optionally, once every 4 weeks or once a month.

In one embodiment, three first doses of 700mg are administered to the subject once every four weeks, followed by a second dose of 1400mg once every four weeks for up to 72 weeks. In some embodiments, the anti-aβ antibody (including, e.g., a first dose of antibody and a second dose of antibody) is administered to the subject for a period of about 4 weeks, about 8 weeks, about 12 weeks, about 16 weeks, about 20 weeks, about 24 weeks, about 28 weeks, about 32 weeks, about 36 weeks, about 40 weeks, about 44 weeks, about 48 weeks, about 52 weeks, about 56 weeks, about 60 weeks, about 64 weeks, about 68 weeks, about 72 weeks, or about 76 weeks. In some embodiments, the anti-aβ antibody (including, e.g., the first dose of antibody and the second dose of antibody) is administered to the subject for a period of about 76% weeks, about 80 weeks, about 84 weeks, about 88 weeks, about 92 weeks, about 96 weeks, about 100 weeks, about 104 weeks, about 108 weeks, about 112 weeks, about 116 weeks, or about 120 weeks.

In a specific embodiment, the anti-aβ antibody is administered to the subject for a period of about 24 weeks. In a specific embodiment, the antibody is administered to the subject for a duration of about 28 weeks. In a specific embodiment, the antibody is administered to the subject for a period of about 52 weeks. In a specific embodiment, the antibody is administered to the subject for a period of about 72 weeks.

In some embodiments, the anti-aβ antibody (including, for example, a first dose of antibody and a second dose of antibody) is administered to the subject for a period of about 1 month to about 18 months. In some embodiments, the anti-aβ antibody is administered to the subject for a period of about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 12 months, about 13 months, about 14 months, about 15 months, about 16 months, about 17 months, or about 18 months. In some embodiments, the anti-aβ antibody is administered to the subject for a period of about 19 months, about 20 months, about 21 months, about 22 months, about 23 months, about 24 months, about 25 months, about 26 months, about 27 months, about 28 months, about 29 months, or about 30 months.

In some embodiments, the antibody is administered to the subject until the brain amyloid plaques reach normal range or are cleared.

In a specific embodiment, the antibody is administered to the subject for a period of about 3 months. In a specific embodiment, the antibody is administered to the subject for a period of about 6 months. In a specific embodiment, the antibody is administered to the subject for a period of about 12 months. In a specific embodiment, the antibody is administered to the subject for a period of about 18 months.

In some embodiments, the anti-aβ antibody is administered to the human subject for a period of time sufficient to treat or prevent a disease characterized by amyloid β (aβ) deposits in the brain of the human subject. In some embodiments, the anti-aβ antibody (including, e.g., the first dose and/or the second dose) is administered to the human subject for a period of time sufficient to bring amyloid plaques in the brain of the subject to a normal range. The normal range of amyloid plaques is defined as plaque levels that exhibit an amyloid plaque level of less than 11 centella for two consecutive PET scans separated by at least 6 months of time, 25 centella or less, or a single PET scan.

In some embodiments, the antibodies of the invention are administered to a subject until the amyloid plaque level in the subject is about 25 centoil or less. In some embodiments, the amyloid plaques are measured by PET imaging. In other embodiments, the antibodies of the invention are administered to a subject until the amyloid plaque level in the subject is about 25 centoil or less for two consecutive PET imaging scans. In some embodiments, two consecutive PET imaging scans are separated by at least 6 months. In some embodiments, the antibodies of the invention are administered to a subject until the amyloid plaque level in the subject is about 11 centoil or less, as measured by one PET imaging.

In a specific embodiment, three first doses of 700mg of the antibodies of the invention are administered to a subject, wherein each first dose is administered once every four weeks, followed by one or more second doses of 1400mg of antibody, wherein each second dose is administered once every four weeks until the amyloid plaque level in the patient is about 25 centwall or less.

In other embodiments, three first doses of 700mg of the antibodies of the invention are administered to a subject, wherein each first dose is administered once every four weeks, followed by a second dose of 1400mg of antibody, wherein each second dose is administered once every four weeks, until the amyloid plaque level in the patient is about 25centiloid or less for two consecutive PET imaging scans, or about 11centiloid or less for one PET imaging scan. In some embodiments, two consecutive PET imaging scans are separated by at least 6 months.

In some embodiments, the subject is not administered an anti-aβ antibody dose after amyloid plaque levels in the patient are about 25 centella asiatica or less for two consecutive PET imaging scans or about 11 centella asiatica or less for one PET imaging scan. In some embodiments, two consecutive PET imaging scans are separated by at least 6 months.

In some embodiments, one or more doses of 700mg of anti-aβ antibody may be administered to a subject after amyloid plaque levels in the patient of about 25 centwall or less for two consecutive PET imaging scans or about 11 centwall or less for one PET imaging scan.

In some embodiments, the antibodies of the invention are administered to a subject until amyloid plaques in the brain of the subject are reduced by about 25 to about 150 centoids. See, e.g., klenk et al, "The Centiloid Project: standardizing Quantitative Amyloid Plaque Estimation by PET, "Alzheimer's & Dementia 11.1: 1-15 (2015) and Navitsky et al, "Standardization of Amyloid Quantitation with Flortaucipir Standardized Uptake Value Ratios to the Centiloid Scale," Alzheimer's & Dementia 14.12:1565-1571 (2018), which is incorporated herein by reference in its entirety.

In some embodiments, the antibodies of the invention are administered to a subject until aβ deposits in the brain of the subject are reduced by about 50 to about 150 centoil. In some embodiments, the antibodies of the invention are administered to a subject until aβ deposits in the brain of the subject are reduced by about 25, about 30, about 40, about 50, about 60, about 70, about 80, about 90, about 100, about 110, about 120, about 130, about 140, or about 150 centileoid. In some embodiments, the antibodies of the invention are administered to a subject until aβ deposits in the brain of the subject are reduced by about 50 centoil. In some embodiments, the antibodies of the invention are administered to a subject until aβ deposits in the brain of the subject are reduced by about 60 centoil. In some embodiments, the antibodies of the invention are administered to a subject until aβ deposits in the brain of the subject are reduced by about 70 centoids. In some embodiments, the antibodies of the invention are administered to a subject until aβ deposits in the brain of the subject are reduced by about 80 centoid. In some embodiments, the antibodies of the invention are administered to a subject until aβ deposits in the brain of the subject are reduced by about 84 centoid. In some embodiments, the antibodies of the invention are administered to a subject until aβ deposits in the brain of the subject are reduced by about 90 centistokes. In some embodiments, the antibodies of the invention are administered to a subject until aβ deposits in the brain of the subject are reduced by about 100 centoil. In some embodiments, the antibodies of the invention are administered to a subject until aβ deposits in the brain of the subject are reduced by about 110 centoil. In some embodiments, the antibodies of the invention are administered to a subject until aβ deposits in the brain of the subject are reduced by about 120 centoil. In some embodiments, the antibodies of the invention are administered to a subject until aβ deposits in the brain of the subject are reduced by about 130 centoil. In some embodiments, the antibodies of the invention are administered to a subject until aβ deposits in the brain of the subject are reduced by about 140 centoil. In some embodiments, the antibodies of the invention are administered to a subject until aβ deposits in the brain of the subject are reduced by about 150 centoid.

In some embodiments, the antibodies of the invention are administered to a subject until the aβ deposits in the brain of the subject are reduced by an average of about 25 to about 100 centoil. In some embodiments, the antibodies of the invention are administered to a subject until the aβ deposits in the brain of the subject are reduced by an average of about 50 to about 100 centoil. In some embodiments, the antibodies of the invention are administered to a subject until the aβ deposits in the brain of the subject are reduced by an average of about 10, about 20, about 30, about 40, about 50, about 60, about 70, about 80, about 84, about 90, about 100 centileoids. In some embodiments, the antibodies of the invention are administered to a subject until the aβ deposits in the brain of the subject are reduced by about 50 centoil on average. In some embodiments, the antibodies of the invention are administered to a subject until the aβ deposits in the brain of the subject are reduced by about 60 centoil on average. In some embodiments, the antibodies of the invention are administered to a subject until the aβ deposits in the brain of the subject are reduced by about 70 centoil on average. In some embodiments, the antibodies of the invention are administered to a subject until the aβ deposits in the brain of the subject are reduced by about 80 centoil on average. In some embodiments, the antibodies of the invention are administered to a subject until the aβ deposits in the brain of the subject are reduced by about 84 centoil on average. In some embodiments, the antibodies of the invention are administered to a subject until the aβ deposits in the brain of the subject are reduced by about 90 centoil on average. In some embodiments, the antibodies of the invention are administered to a subject until the aβ deposits in the brain of the subject are reduced by about 100 centoil on average.

In some embodiments, a second dose of an antibody of the invention is administered to the subject until aβ deposits in the brain of the subject are reduced by about 25 to about 150 centoil. In some embodiments, a second dose of a compound of the invention is administered to the subject until aβ deposits in the brain of the subject are reduced by about 50 to about 150 centoil. In some embodiments, a second dose of an antibody of the invention is administered to the subject until aβ deposits in the brain of the subject are reduced by about 25, about 30, about 40, about 50, about 60, about 70, about 80, about 84, about 90, about 100, about 110, about 120, about 130, about 140, or about 150 centeoid. In some embodiments, a second dose of an antibody of the invention is administered to the subject until aβ deposits in the brain of the subject are reduced by about 50 centoil. In some embodiments, a second dose of an antibody of the invention is administered to the subject until aβ deposits in the brain of the subject are reduced by about 60 centoil. In some embodiments, a second dose of an antibody of the invention is administered to the subject until aβ deposits in the brain of the subject are reduced by about 70 centoil. In some embodiments, a second dose of an antibody of the invention is administered to the subject until aβ deposits in the brain of the subject are reduced by about 80 centoil. In some embodiments, a second dose of an antibody of the invention is administered to the subject until aβ deposits in the brain of the subject are reduced by about 84 centoil. In some embodiments, a second dose of an antibody of the invention is administered to the subject until aβ deposits in the brain of the subject are reduced by about 90 centoil. In some embodiments, a second dose of an antibody of the invention is administered to the subject until aβ deposits in the brain of the subject are reduced by about 100 centoil. In some embodiments, a second dose of an antibody of the invention is administered to the subject until aβ deposits in the brain of the subject are reduced by about 110 centoil. In some embodiments, a second dose of an antibody of the invention is administered to the subject until aβ deposits in the brain of the subject are reduced by about 120 centoil. In some embodiments, a second dose of an antibody of the invention is administered to the subject until aβ deposits in the brain of the subject are reduced by about 130 centoil. In some embodiments, a second dose of an antibody of the invention is administered to the subject until aβ deposits in the brain of the subject are reduced by about 140 centoil. In some embodiments, a second dose of an antibody of the invention is administered to the subject until aβ deposits in the brain of the subject are reduced by about 150 centoil.

In some embodiments, a second dose of an antibody of the invention is administered to the subject until the aβ deposits in the brain of the subject are reduced by an average of about 25 to about 100 centoil. In some embodiments, a second dose of a compound of the invention is administered to the subject until the aβ deposits in the brain of the subject are reduced by an average of about 50 to about 100 centoil. In some embodiments, a second dose of an antibody of the invention is administered to the subject until the aβ deposits in the brain of the subject are reduced by an average of about 25, about 30, about 40, about 50, about 60, about 70, about 80, about 84, about 90, about 100 centeoid. In some embodiments, a second dose of an antibody of the invention is administered to the subject until the aβ deposits in the brain of the subject are reduced by about 50 centoil on average. In some embodiments, a second dose of an antibody of the invention is administered to the subject until the aβ deposits in the brain of the subject are reduced by about 60 centoil on average. In some embodiments, a second dose of an antibody of the invention is administered to the subject until the aβ deposits in the brain of the subject are reduced by about 70 centoil on average. In some embodiments, a second dose of an antibody of the invention is administered to the subject until the aβ deposits in the brain of the subject are reduced by about 80 centoil on average. In some embodiments, a second dose of an antibody of the invention is administered to the subject until the aβ deposits in the brain of the subject are reduced by about 84 centoil on average. In some embodiments, a second dose of an antibody of the invention is administered to the subject until the aβ deposits in the brain of the subject are reduced by about 90 centoil on average. In some embodiments, a second dose of an antibody of the invention is administered to the subject until the aβ deposits in the brain of the subject are reduced by about 100 centoil on average.

In some embodiments, the antibodies, methods, dosing regimens and/or uses of the invention result in a decrease in aβ deposits in the brain of a human subject. In specific embodiments, aβ deposits are cleared or reduced by about 20 to 100% after treatment. In some embodiments, the antibodies of the invention are administered to a subject until the aβ deposits in the brain of the subject are reduced by about 20-100%. In some embodiments, the antibodies of the invention are administered to a subject until aβ deposits in the brain of the subject are reduced by about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 75%, or about 100%. In some embodiments, the antibodies of the invention are administered to a subject until the aβ deposits in the brain of the subject are reduced by about 20%. In some embodiments, the antibodies of the invention are administered to a subject until the aβ deposits in the brain of the subject are reduced by about 25%. In some embodiments, the antibodies of the invention are administered to a subject until the aβ deposits in the brain of the subject are reduced by about 30%. In some embodiments, the antibodies of the invention are administered to a subject until the aβ deposits in the brain of the subject are reduced by about 35%. In some embodiments, the antibodies of the invention are administered to a subject until the aβ deposits in the brain of the subject are reduced by about 40%. In some embodiments, the antibodies of the invention are administered to a subject until the aβ deposits in the brain of the subject are reduced by about 50%. In some embodiments, the antibodies of the invention are administered to a subject until the aβ deposits in the brain of the subject are reduced by about 75%. In some embodiments, the antibodies of the invention are administered to a subject until the aβ deposits in the brain of the subject are reduced by about 100%.

In some embodiments, the first dose and/or the second dose of the antibodies of the invention is administered to the subject until the aβ deposits in the brain of the subject are reduced by about 20-100%. In embodiments, a second dose of an antibody of the invention is administered to the subject until the aβ deposits in the brain of the subject are reduced by about 20-100%. In some embodiments, a second dose of an antibody of the invention is administered to the subject until aβ deposits in the brain of the subject are reduced by about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 75%, or about 100%. In some embodiments, the second dose is administered to the subject until the aβ deposits in the brain of the subject are reduced by about 20%. In some embodiments, the second dose is administered to the subject until the aβ deposits in the brain of the subject are reduced by about 25%. In some embodiments, the second dose is administered to the subject until the aβ deposits in the brain of the subject are reduced by about 30%. In some embodiments, the second dose is administered to the subject until the aβ deposits in the brain of the subject are reduced by about 35%. In some embodiments, the second dose is administered to the subject until the aβ deposits in the brain of the subject are reduced by about 40%. In some embodiments, the second dose is administered to the subject until the aβ deposits in the brain of the subject are reduced by about 50%. In some embodiments, the second dose is administered to the subject until the aβ deposits in the brain of the subject are reduced by about 75%. In some embodiments, the second dose is administered to the subject until the aβ deposits in the brain of the subject are reduced by about 100%.

In some embodiments, the percent reduction in aβ deposits in the brain of the subject is measured at about 4 weeks, about 8 weeks, about 12 weeks, about 16 weeks, about 20 weeks, about 24 weeks, about 28 weeks, about 32 weeks, about 36 weeks, about 40 weeks, about 44 weeks, about 48 weeks, about 52 weeks, about 56 weeks, about 60 weeks, about 64 weeks, about 68 weeks, or about 72 weeks.

In some embodiments, the central reduction in aβ deposits in the brain of the subject is measured at about 4 weeks, about 8 weeks, about 12 weeks, about 16 weeks, about 20 weeks, about 24 weeks, about 28 weeks, about 32 weeks, about 36 weeks, about 40 weeks, about 44 weeks, about 48 weeks, about 52 weeks, about 56 weeks, about 60 weeks, about 64 weeks, about 68 weeks, or about 72 weeks.

In some embodiments, the average centiloid reduction of aβ deposits in the brain of the subject is measured at about 4 weeks, about 8 weeks, about 12 weeks, about 16 weeks, about 20 weeks, about 24 weeks, about 28 weeks, about 32 weeks, about 36 weeks, about 40 weeks, about 44 weeks, about 48 weeks, about 52 weeks, about 56 weeks, about 60 weeks, about 64 weeks, about 68 weeks, or about 72 weeks.

In some embodiments, the invention results in a decrease in the cognitive-function complex endpoint from baseline of about 15% to about 45%. In some embodiments, the invention results in a reduction in the cognitive function complex endpoint from baseline of about 15% to about 45% over a period of about 4 weeks, about 8 weeks, about 12 weeks, about 16 weeks, about 20 weeks, about 24 weeks, about 28 weeks, about 32 weeks, about 36 weeks, about 40 weeks, about 44 weeks, about 48 weeks, about 52 weeks, about 56 weeks, about 60 weeks, about 64 weeks, about 68 weeks, about 72 weeks, or 76 weeks.

In some embodiments, the invention results in a decrease in the cognitive-function complex endpoint from baseline of about 15% to about 45% over a period of 76 weeks. In some embodiments, the slowing of the decline of the cognitive-functional complex endpoint from baseline is provided by an MMRM model or a bayesian Disease Progression Model (DPM). In some embodiments, the antibody of the invention is administered to a subject until it reaches a reduction in the cognitive-function complex endpoint from baseline of about 15% to about 45%. In some embodiments, the first dose or the second dose of the invention is administered to the subject until it reaches a reduction in the cognitive-functional complex endpoint from baseline of about 15% to about 45%.

In some embodiments, the invention results in a reduction in Integrated Alzheimer's Disease Rating Scale (iADRS) from baseline of about 15% to about 45%. In some embodiments, the invention results in a reduction in the integrated alzheimer's disease rating scale from baseline of about 15% to about 45% over a period of about 4 weeks, about 8 weeks, about 12 weeks, about 16 weeks, about 20 weeks, about 24 weeks, about 28 weeks, about 32 weeks, about 36 weeks, about 40 weeks, about 44 weeks, about 48 weeks, about 52 weeks, about 56 weeks, about 60 weeks, about 64 weeks, about 68 weeks, about 72 weeks, or 76 weeks.

In some embodiments, the invention results in a reduction in the integrated alzheimer's disease rating scale from baseline by about 20%, about 25%, about 30%, about 32%, about 35%, about 40%, or about 45%.

In some embodiments, the invention results in a reduction in the integrated alzheimer's disease rating scale from baseline of about 15% to about 45% over a period of 76 weeks. In a specific embodiment, the invention results in a reduction in the integrated Alzheimer's disease rating scale of about 32% from baseline over a period of 76 weeks. In some embodiments, the antibodies of the invention are administered to a subject until they reach a reduction in the integrated alzheimer's disease rating scale from baseline of about 15% to about 45%. In some embodiments, the first or second dose of the invention is administered to a subject until it slows from about 15% to about 45% from baseline decline on the integrated alzheimer's disease rating scale.

In some embodiments, the subject's cognitive function complex endpoint, including iADRS, is measured at about 4 weeks, about 8 weeks, about 12 weeks, about 16 weeks, about 20 weeks, about 24 weeks, about 28 weeks, about 32 weeks, about 36 weeks, about 40 weeks, about 44 weeks, about 48 weeks, about 52 weeks, about 56 weeks, about 60 weeks, about 64 weeks, about 68 weeks, or about 72 weeks.

In some embodiments, the antibodies of the invention may be administered simultaneously, separately or sequentially in combination with an effective amount of a symptomatic agent to treat alzheimer's disease. The symptomatic agent may be selected from cholinesterase inhibitors (CHEI)/or partial N-methyl-D-aspartate (NMDA) antagonists. In a preferred embodiment, the active agent is CHEI. In another preferred embodiment, the active agent is an NMDA antagonist or a combination comprising ChEI and an NMDA antagonist.

In some embodiments, the disease characterized by aβ deposits in the brain of the subject is selected from preclinical alzheimer's disease, clinical AD, prodromal AD, mild AD, moderate AD, severe AD, down's syndrome, clinical cerebral amyloid angiopathy, or preclinical cerebral amyloid angiopathy. In some embodiments, the subject is an early symptomatic AD patient. In some embodiments, the subject suffers from pre-AD and mild dementia caused by AD. In some embodiments, the subject suffers from mild cognitive impairment or mild dementia caused by AD.

The invention includes the use of biomarkers for diseases characterized by aβ deposits in the brain of a human subject, including alzheimer's disease. Such biomarkers include, for example, amyloid deposits, amyloid plaques, aβ in CSF, aβ in plasma, brain tau deposits, tau in plasma or tau in cerebrospinal fluid and their use in screening, diagnosis, treatment or prevention. Non-limiting potential uses for such biomarkers include: 1) Identifying a subject who is predisposed to being affected or in a "preclinical" stage of the disease; 2) Reducing disease heterogeneity in clinical trials or epidemiological studies; 3) Reflecting the natural history of the disease, including induction, latency and detection stages; and 4) a target subject for clinical trials or for the treatment/prevention of a disease.

In some embodiments, the biomarker can be used to assess whether a subject can be treated using the antibodies, dosing regimens, or methods described herein. In some embodiments, the biomarker can be used to assess whether the antibody, dosing regimen, or method described herein can be used to prevent a disease in a subject (as described herein). In some embodiments, the biomarker can be used to assess whether a subject is responsive to treating or preventing a disease (as described herein) using an antibody, dosing regimen or method described herein. In some embodiments, the biomarkers can be used to stratify or classify subjects into groups and identify which groups of subjects are responsive to treatment/prevention of a disease (as described herein) using the antibodies, dosing regimens or methods described herein. In some embodiments, the biomarker can be used to assess the disease status of a subject and/or the period of administration of an antibody or dose thereof as described herein to a subject.

In some embodiments, the subject has a genetic mutation that results in autosomal dominant alzheimer's disease or has a higher risk of developing AD due to carrying one or two ApoE 4 alleles. In embodiments, the subject carries one or two ApoE 4 alleles, i.e. the patient is heterozygous or homozygous.

In some embodiments, the subject has a low to medium tau load or has been determined to have a low to medium tau load. If brain imaging is performed by PET (using, for example, ¹⁸ f-flutoxipiride) at a normalized uptake value ratio (SUVr) of 1.10 or less to 1.46SUV, the subject can be characterized as having a low to medium tau load. In some embodiments, the subject has a low to moderate tau load or has been determined to have a low to moderate tau load and carries one or two ApoE 4 alleles.

In some embodiments, the subject has a very low tau load or has been determined to have a very low tau load. If brain imaging is performed by PET (using, for example, ¹⁸ f flutoxipiride) is below 1.10SUVr, the subject can be characterized as having a very low tau load. In some embodiments, the subject has a very low tau load or has been determined to have a very low tau load and carries one or two ApoE 4 alleles.

In some embodiments, having a very low to medium tau load or having been determined to have a very low to medium tau load. If brain imaging is performed by PET (using, for example, ¹⁸ F flutoxipiride) is less than or equal to 1.46SUVr, the subject can be characterized as having very low to medium tau loading. In some embodiments, the subject has a very low to moderate tau load or has been determined to have a very low to moderate tau load and carries one or two ApoE e4 alleles.

In some embodiments, the subject does not have a high tau load or has been determined to have no high tau load. In some embodiments, the brain is imaged (using, for example, ¹⁸ f flutoxipiride) measured tau load, then the human subject can be characterized as having a high tau load. In some embodiments, the non-target is of high tauIs administered with an antibody of the invention. In some embodiments, the subject does not have a high tau load or has been determined to have no high tau load and carries one or two ApoE 4 alleles.

In some embodiments of the disclosed methods, the subject has a high tau load. In some embodiments, the brain is imaged (using, for example, ¹⁸ f flutoxipiride) is greater than 1.46SUVr, the human subject can be characterized as having a high tau load. In some embodiments, the subject has a high tau load or has been determined to have a high tau load and carries one or two ApoE 4 alleles.

Subjects with high tau load may exhibit slow decline. Subjects exhibiting slow decline can be characterized as subjects that do not exhibit a decrease in the Integrated Alzheimer's Disease Rating Scale (iADRS) of greater than about-20 in about the last 18 months. IADRs are known in the art as a composite tool to combine scores from the AD assessment scale-cognition sub-scale (ADAS-Cog) and AD collaborative research-daily life instrumental activities (ADCS-IADL). iADRS can exhibit acceptable psychological test characteristics, and iADRS can be effective in capturing disease progression and separation of placebo and active drug effects. In some embodiments, an antibody of the invention is administered to a subject with high tau and slow descent. In other embodiments, the antibodies of the invention are not administered to subjects with high tau and rapid decline. Subjects exhibiting a rapid decline may be characterized as subjects exhibiting a decrease in the Integrated Alzheimer's Disease Rating Scale (iADRS) of greater than about-20 in about the last 18 months.

According to embodiments of the invention provided herein, a human subject has been determined to have a slow decline by one or more of ADAS-cog, IADL, CDR-SB, MMSE, apoE-4 genotyping and/or iADRS. In some embodiments, the human subject has been determined to have a slow decline by iADRS. In some embodiments, iADRS has decreased by less than 20. In some embodiments, iADRS drops below 20 over a 6 month period. In some embodiments, iADRS drops below 20 over a 12 month period. In some embodiments, iADRS decreases by less than 20 within 18 months. In some embodiments, iADRS drops below 20 within 24 months. In some embodiments, the human subject has been determined to have a slow decline by ApoE-4 genotyping. In some embodiments, the human subject has been determined to be ApoE-4 heterozygous. In some embodiments, the human subject has been determined to be ApoE-4 homozygous negative. In some embodiments, the human subject has been determined to have a slow decline by MMSE. In some embodiments, the human subject has been determined to have an MMSE above 27. In some embodiments, the MMSE drop is less than 3. In some embodiments, MMSE drops below 3 within 6 term months. In some embodiments, MMSE drops below 3 over a 12 month period. In some embodiments, MMSE drops below 3 over a period of 18 months. In some embodiments, MMSE drops below 3 over a 24 month period.

In some embodiments of the disclosed therapeutic and prophylactic methods, a human subject has a therapeutic effect as imaged by PET brain (using, for example, ¹⁸ f flutoxib) measured tau load. In some embodiments of the disclosed therapeutic and prophylactic methods, a human subject has a therapeutic effect as imaged by PET brain (using, for example, ¹⁸ f flutoxipiride) that is less than about 1.46SUVr, and may be administered to a subject. In other embodiments of the disclosed therapeutic and prophylactic methods, the human subject has a therapeutic effect as determined by PET brain imaging (using, for example, ¹⁸ f flutoxipiride) that is less than about 1.46SUVr and has one or both alleles of ApoE e4, and may be administered to a subject. In some embodiments of the disclosed therapeutic and prophylactic methods, a human subject has a therapeutic effect as imaged by PET brain (using, for example, ¹⁸ f flutoxipiride) that is less than about 1.27SUVr, and may be administered to a subject.

In some embodiments, the anti-aβ antibodies, dosing regimens or methods described herein are effective in human subjects with very low to medium tau. In some embodiments, the anti-aβ antibodies, dosing regimens or methods described herein are effective in human subjects with low to moderate tau. In some embodiments, the antibodies of the invention are most effective in human subjects having i) a tau level of less than or equal to about 1.14SUVr or ii) about 1.14SUVr to about 1.27 SUVr.

In some embodiments, the anti-aβ antibodies, dosing regimens or methods described herein are effective in human subjects having very low to medium tau and carrying one or two ApoE E4 alleles. In some embodiments, the anti-aβ antibodies, dosing regimens or methods described herein are effective in a human subject having low to moderate tau and carrying one or two ApoE 4 alleles. In some embodiments, the antibodies of the invention are most effective in human subjects carrying one or two ApoE E4 alleles and having i) a Tau level of less than or equal to about 1.14SUVr or ii) about 1.14SUVr to about 1.27 SUVr.

Tau levels in a human subject may be determined by a diagnostician or techniques and methods familiar to one of ordinary skill in the art. In some embodiments, a human subject suffering from a disease characterized by amyloid β (aβ) deposits is determined to have very low to moderate tau, or no high tau using techniques and methods familiar to a diagnostician or to one of ordinary skill in the art. In some embodiments, such methods may also be used to pre-screen, diagnose, assess an increase or decrease in brain tau load, and/or assess progression achieved in treating or preventing a disease described herein. In some embodiments, the methods can also be used to stratify subjects into groups and/or identify which groups of subjects are responsive to treatment/prevention of a disease (as described herein) using an antibody, dosing regimen, or method described herein. In some embodiments, methods or techniques for determining/detecting tau levels in a human subject can be used to pre-screen or screen subjects and determine which subjects are responsive to treatment/prevention of a disease (as described herein) using an antibody, dosing regimen or method described herein.

For the purposes of the present invention, tau levels in a human subject may be determined using techniques or methods such as detecting or quantifying i) brain tau deposition, ii) tau in plasma, or iii) tau in cerebrospinal fluid. In some embodiments, brain tau load, tau in plasma, or tau in cerebrospinal fluid may be used to stratify subjects into groups and identify which groups of subjects are responsive to treatment/prevention of a disease (described herein) using an antibody, dosing regimen, or method described herein.

Tau levels in the brain of a human subject may be determined, for example, using radiolabeled PET compounds (Leuzy et al, "Diagnostic Performance of RO 948F 18 Tau Positron Emission Tomography in the Differentiation of Alzheimer Disease from Other Neurodegenerative Disorders," JAMA Neurology 77.8:955-965 (2020); ossenkoppele et al, "Discriminative Accuracy of [ ¹⁸ F]Flortaucipir Positron Emission Tomography for Alzheimer Disease vs Other Neurodegenerative Disorders, "JAMA 320, 1151-1162, doi:10.1001/jama.2018.12917 (2018), which is incorporated herein by reference in its entirety.

In some embodiments, biomarkers as PET ligands [ ¹⁸ F]Fluoxel may be used for the purposes of the present invention. For example, PET tau images can be quantitatively evaluated by published methods to estimate SUVr (normalized uptake value ratio) (Pontecorevo et al, "A Multicentre Longitudinal Study of Flortaucipir (18F) in Normal Ageing, mild Cognitive Impairment and Alzheimer's Disease Dementia," Brain 142:1723-35 (2019); devous et al, "Test-Retest Reproducibility for the Tau PET Imaging Agent Flortaucipir F18," Journal of Nuclear Medicine 59:937-43 (2018); southekal et al, "Flortaucir F18 Quantitation Using Parametric Estimation of Reference signal integrity," J.Nucl. Med. 59:944-51 (2018), which is incorporated herein by reference in its entirety) and/or visually evaluate a patient, e.g., to determine whether the patient has an AD pattern (Fleisher et al, "Positron Emission Tomography Imaging With [ 35 ] ¹⁸ F]Flortaucipir and Postmortem Assessment of Alzheimer Disease Neuropathologic Changes, "JAMA Neurology 77:829-39 (2020), which is incorporated herein by reference in its entirety). A lower SUVr value indicates less tau load, while a higher SUVr value indicates higher tau load tau loading. In one embodiment, the quantitative evaluation with flutoxion is performed by, for example, southekal et al, "Flortaucipir F18 Quantitation Using Parametric Estimation of Reference Signal Intensity," j.nucleic.med.59: 944-951 (2018), which is incorporated herein by reference in its entirety. In some embodiments, counts within a particular target region of interest in the brain (e.g., multi-block barycentric discriminant analysis or MUBADA, see Devous et al, "Test-Retest Reproducibility for the Tau PET Imaging Agent Flortaucipir F," J.Nucl.Med..59:937-943 (2018), incorporated herein by reference in its entirety) are compared to a reference region, such as the whole cerebellum (whorlocere), cerebellum GM (cereCrus), map-based white matter (atlasWM), subject-specific WM (ssWM, e.g., parameter estimation using reference signal intensity (PERI), see Southekal et al, "Flortaucir F18 Quantitation Using Parametric Estimation of Reference Signal Intensity," J.Nucl.Med..59:944-951 (2018), incorporated herein by reference in its entirety).

The preferred method of determining tau load is quantitative analysis reported as a normalized uptake value ratio (SUVr), which represents a specific target region of interest in the brain when compared to a reference region (e.g., using PERSI).

In some embodiments, phosphorylated tau (P-tau; phosphorylated at threonine 181 or 217) may be used to measure tau load/burden for purposes of the present invention (Barthelemy et al, "Cerebrospinal Fluid Phospho-tau T217 Outperforms T181 as a Biomarker for the Differential Diagnosis of Alzheimer's Disease and PET Amyloid-positive Patient Identification," Alzheimer's Res. Ther.12, 26, doi:10.1186/s13195-020-00596-4 (2020); mattsson et al, "Abeta Deposition is Associated with Increases in Soluble and Phosphorylated Tau that Precede a Positive Tau PET in Alzheimer's Disease," Science Advances 6, eaaz2387 (2020), which is incorporated herein by reference in its entirety). In a specific embodiment, for the purposes of the present invention, antibodies directed to human tau phosphorylated at threonine at residue 217 may be used to measure tau load/burden in a subject (see international patent application publication No. WO 2020/242963, which is incorporated by reference in its entirety). In some embodiments, the invention includes the use of an anti-tau antibody disclosed in WO 2020/242963 to measure tau load in a subject. The anti-tau antibodies disclosed in WO 2020/242963 are directed against isoforms of human tau expressed in the CNS (e.g., recognize isoforms expressed in the CNS, but not isoforms of human tau expressed only outside the CNS). Such antibodies against isoforms of human tau expressed in the CNS may be used in a method of identifying/selecting patients as one or more of: (i) suffering from the diseases disclosed herein; (ii) at risk of having a disease disclosed herein; (iii) in need of treatment for the diseases disclosed herein; or (iv) a need for neuroimaging.

When amyloid is detected in the brain by, for example, amyloid imaging with a radiolabeled PET compound or using a diagnostic agent that detects aβ or a biomarker for aβ, the subject is positive for amyloid deposits. Exemplary methods that may be used in the present invention to measure cerebral amyloid load include, for example, fluroprolol Bei Ping (Carpenter et al, "The Use of the Exploratory IND in the Evaluation and Development of ¹⁸ F-PET Radiopharmaceuticals for Amyloid Imaging in the Brain: a Review of One Company's Experience, "The Quarterly Journal of Nuclear Medicine andMolecularImaging 53.4.4:387 (2009), incorporated herein by reference in its entirety); fluobetaban (Syed et al, "[ A ] ¹⁸ F]Florsetaben: areview in β -Amyloid PET Imaging in Cognitive Impairment, "CNS Drugs 29, 605-613 (2015), which is incorporated herein by reference in its entirety); and flumetanol (Heurling et al, "Imaging beta-amylase Using ] ¹⁸ F]Flutemetamol Positron Emission Tomography: from Dosimetry to Clinical Diagnosis, "European Journal of Nuclear Medicine and Molecular Imaging 43.2.2: 362-373 (2016), which are incorporated herein by reference in their entirety).

[ ¹⁸ F]Florol Bei Ping may provide a qualitative and quantitative measure of brain plaque burden in patients, including patients suffering from pre-or mild AD dementia. For example, seeApparently absent from the sense of reading ¹⁸ F]The flulobemide signal indicates that patients clinically exhibiting cognitive impairment have sparse to no amyloid plaques. As such [ ¹⁸ F]Florol Bei Ping also provides confirmation of amyloid pathology. [ ¹⁸ F]The fluoro Bei Ping PET also provides a quantitative assessment of fibrous amyloid plaques in the brain, and in some embodiments, can be used to assess that the antibodies of the invention reduce amyloid plaques from the brain.

Amyloid imaging with radiolabeled PET compounds can also be used to determine whether aβ deposits in the brain of a human patient are reduced or increased (e.g., calculating the percent reduction in aβ deposits after treatment or assessing the progression of AD). One skilled in the art can correlate normalized uptake value ratio (SUVr) values obtained from amyloid imaging (with radiolabeled PET compounds) to calculate% reduction of aβ deposits in the patient's brain before and after treatment. SUVr values can be converted to normalized centoid units, where 100 is the average of AD and 0 is the average of young controls, such that there is comparability between amyloid PET tracers, and the reduction is calculated from the centoid units (Klunk et al, "The Centiloid Project: standardizing QuantitatiVe Amyloid Plaque Estimation by PET," Alzheimer's) &Dementia 11.1:1-15 (2015) and Navitsky et al, "Standardization of Amyloid Quantitation with Flortaucipir Standardized Uptake Value Ratios to the Centiloid Scale," Alzheimer' s&Dementia 14.12: 1565-1571 (2018), incorporated herein by reference in its entirety). In some embodiments, the alteration in cerebral amyloid plaque deposition from baseline is passed by ¹⁸ F]Florol Bei Ping PET scan measurement.

For the purposes of the present invention, a cerebral spinal fluid or plasma based beta-amyloid assay may also be used to measure amyloid load. For example, abeta42 can be used to measure cerebral amyloid (Palmqvist, S.et al, "Accuracy of Brain Amyloid Detection in Clinical Practice Using Cerebrospinal Fluid Beta-amyoid 42: a Cross-validation Study Against Amyloid Positron Emission Tomonograph. JAMA neuron 71, 1282-1289 (2014), which is incorporated herein by reference in its entirety). In some embodiments, the ratio of Abeta42/Abeta40 or Abeta42/Abeta38 can be used as a biomarker for amyloid beta (Janelided et al, "CSF Abeta42/Abeta40 and Abeta42/Abeta38Ratios: better Diagnostic Markers of Alzheimer Disease," Ann Clin TranslNeurol, 154-165 (2016), which is incorporated herein by reference in its entirety).

In some embodiments, cerebral amyloid plaques or aβ deposited in CSF or plasma can be used to stratify subjects into groups and identify which groups of subjects are responsive to treatment/prevention of a disease (as described herein) using an antibody, dosing regimen or method described herein.

As used herein, an "anti-aβ antibody" refers to an antibody that binds to an epitope present on aβ. In some embodiments, the anti-aβ antibody binds to a soluble form of aβ. In other embodiments, the anti-aβ antibody binds to an insoluble form of aβ, such as aβ plaques. In some embodiments, the anti-Abeta antibody binds to an epitope present in Abeta 1-40 or Abeta 1-42. In other embodiments, the anti-aβ antibody binds to an epitope present in a truncated form of aβ1-40 or aβ1-42, e.g., a truncated form lacking 1-20N-terminal amino acids and/or lacking 1-20C-terminal amino acids and optionally comprising an N-terminal pyroglutamic acid residue (e.g., N3pGlu aβ). In other embodiments, the anti-Abeta antibody binds to an epitope present in Abeta 1-40 or Abeta 1-42 and having a length of about 5 to 20 amino acids and optionally comprising N-terminal pyroglutamic acid. Anti-aβ antibodies have been disclosed in the art. (see, e.g., U.S. Pat. No.10,851,156;10,738,109, 10,662,239, 10,654,917, 10,647,759, 10,603,367, 10,519,223, 10,494,425, 10,464,976, 10,112,991, 10,112,987, 10,035, 847, 9,944,696, 9,939,452, 9,895,429, 9,834,598, 9,738,712, 9,585,956, 9,573,594, 9,382,312, 9,329,189, 9,309,309,309,307, 9,272,031, 9,181,332, 9,176,150, 9,175,094, 9,146,244, 9,738,712, 9,585,955, 9,955,955, 9,051,364, 9,363, 8,916,165, 8,906,906,370,370, 8,193,906,367,981, 8,614,299, 8,591,894,894, 8,507,8,507, 8,jack, 8,support structure, 8,jack, jack, 7,support structure, 150,150, 9,175,175,175,175,7,175,146,146,244, 7,244,9,jack, 7,135,jack, 7,jack, jack, 7,135,jack, jack, 8,135, jack, 8,jack, jack, 8,jack, jack, 8, jack, 8,, 35,35,35,35,35, 8,8, 35, 8, 35, 8, 35, 8,8, 8, 35, 8, 35, 8, jack;);9);9,35, jack, support;);9 support, jack, support 5, support;support;support 5, support 5, support 5, support;support support;support 5, support;support 5, support 5, support;support, support support;support support and 6,750,324, which are incorporated by reference in their entirety). Anti-aβ antibodies may also include donaform, sorafen, bapidem, GSK933776, su Lanzhu, and rankanab, kleizumab, poiuzumab, and more tienomab.

In some embodiments, the disclosed antibodies target N3pGlu aβ (i.e., anti-N3 pGlu aβ antibodies). The disclosed antibodies can selectively bind to N3pGlu aβ peptides over other aβ peptides, such as those lacking N-terminal pyroglutamic acid or aβ (1-40) or aβ (1-42) peptides. Those of ordinary skill in the art will understand and appreciate that "anti-N3 pGlu aβ antibodies" and several specific antibodies, including "hE8L", "B12L" and "R17L" are identified and disclosed in U.S. patent No.8,679,498B2 (which is incorporated herein by reference in its entirety) (as well as methods of making and using such antibodies). See, for example, table 1 of U.S. Pat. No.8,679,498B 2. Each of the antibodies disclosed in U.S. Pat. No.8,679,498B2, including the "hE8L", "B12L" and "R17L" antibodies, may be used as an anti-N3 pGlu A beta antibody of the invention or in place of the anti-N3 pGlu A beta antibodies described in the various aspects of the invention. Other representative classes of anti-N3 pGlu aβ antibodies include, but are not limited to, U.S. patent No.8,961,972; U.S. Pat. No.10,647,759; U.S. Pat. No.9,944,696; WO 2010/009987 A2; WO 2011/151076 A2; the antibodies disclosed in WO 2012/136552 A1 and their equivalents are for example according to 35 u.s.c. 112 (f).

Those of ordinary skill in the art will understand and appreciate that "anti-N3 pGlu aβ antibodies" and several specific antibodies (methods of making and using such antibodies) are described in U.S. patent No.8,961,972 (incorporated herein by reference in its entirety); U.S. patent No.10,647,759 (incorporated herein by reference in its entirety); and U.S. patent No.9,944,696 (incorporated herein by reference in its entirety). U.S. Pat. No.8,961,972;9,944,696; and 10,647,759 can be used as the anti-N3 pGlu aβ antibody of the invention or in place of the anti-N3 pGlu aβ antibody described in the different aspects of the invention.

Those of ordinary skill in the art will understand and appreciate that "anti-N3 pGlu aβ antibodies" and several specific antibodies, including "antibody VI", "antibody VII", "antibody VIII" and "antibody IX" (and methods of making and using such antibodies) are identified and disclosed in WO2010/009987A2 (incorporated herein by reference in its entirety). Each of these four antibodies (e.g., "antibody VI", "antibody VII", "antibody VIII" and "antibody IX") may be used as an anti-N3 pGlu aβ antibody of the invention or in place of the anti-N3 pGlu aβ antibody described in the different aspects of the invention.

Those of ordinary skill in the art will understand and appreciate that "anti-N3 pGlu aβ antibodies" and several specific antibodies, including "antibody X" and "antibody XI" (and methods of making and using such antibodies) are identified and disclosed in WO 2011/151076 A2 (incorporated herein by reference in its entirety). Each of these two antibodies (e.g., "antibody X" and "antibody XI") may be used as an anti-N3 pGlu aβ antibody of the invention or in place of the anti-N3 pGlu aβ antibody described in the different aspects of the invention.

Those of ordinary skill in the art will understand and appreciate that "anti-N3 pGlu aβ antibodies" and several specific antibodies, including "antibody X" and "antibody XI" (and methods of making and using such antibodies) are identified and disclosed in WO 2011/151076 A2 (incorporated herein by reference in its entirety). Each of these two antibodies (e.g., "antibody XII" and "antibody XIII") can be used as an anti-N3 pGlu aβ antibody of the invention or in place of the anti-N3 pGlu aβ antibody described in the different aspects of the invention.

As used herein, an "antibody" is an immunoglobulin molecule comprising two HCs and two LCs interconnected by disulfide bonds. The amino-terminal portion of each LC and HC includes a variable region responsible for anti-pro recognition by the Complementarity Determining Regions (CDRs) contained therein. CDRs are interspersed with regions that are more conserved, called framework regions. The assignment of amino acids to CDR domains within the LCVR and HCVR regions of the antibodies of the invention is based on the following: kabat numbering convention (Kabat et al, ann.N.Y. Acad.Sci.190:382-93 (1971); kabat et al, sequences of Proteins of Immunological Interest, 5 th edition, U.S. device of Health and Human Services, NIH Publication No.91-3242 (1991)) and North numbering convention (North et al, A New Clustering of Antibody CDR Loop Conformations, journal of Molecular Biology,406:228-256 (2011)). The CDRs of the antibodies of the invention are determined as described above.

The antibodies of the invention are monoclonal antibodies ("mAbs"). Monoclonal antibodies can be produced, for example, by hybridoma technology, recombinant technology, phage display technology, synthetic technology (e.g., CDR grafting), or a combination of such or other technologies known in the art. The monoclonal antibodies of the invention are human or humanized. Humanized antibodies can be engineered to comprise one or more human framework regions (or substantially human framework regions) surrounding CDRs derived from a non-human antibody. Human framework germline sequences can be obtained from their website http:// i mgt.cines.fr or The Immunoglobulin FactsBook from Marie-Paule Lefranc and Gerard Lefranc, academic 25 Press,2001,ISBN 012441351. Techniques for generating human or humanized antibodies are well known in the art. In another embodiment of the invention, the antibody or nucleic acid encoding the same is provided in an isolated form. As used herein, the term "isolated" refers to a protein, peptide, or nucleic acid that is not found in nature and that is free or substantially free of other macromolecular species found in the cellular environment. As used herein, "substantially free" means that the protein, peptide or nucleic acid of interest comprises greater than 80% (by mole) of the macromolecular species present, preferably greater than 90%, and more preferably greater than 95%.

The anti-aβ antibodies of the invention are administered as a pharmaceutical composition. Pharmaceutical compositions comprising an antibody of the invention may be administered by parenteral routes (e.g., subcutaneous, intravenous, intraperitoneal, intramuscular) to subjects at risk of, or exhibiting, a disease or disorder as described herein. Subcutaneous and intravenous routes are preferred. In some embodiments, the anti-N3 pGlu aβ antibody is administered by intravenous infusion.

The term "treating" or the like includes inhibiting, slowing or stopping the progression or severity of an existing symptom, condition, disease or disorder in a subject. The term "subject" refers to a human.

The term "preventing" means that an asymptomatic subject or a subject suffering from preclinical alzheimer's disease is prophylactically administered an antibody of the invention to prevent the onset or progression of the disease.

The term "disease characterized by aβ deposition" or "disease characterized by aβ deposition" is used interchangeably and refers to a disease characterized pathologically by aβ deposition in the brain or cerebral vascular system. This includes diseases such as Alzheimer's disease, down's syndrome and cerebral amyloid angiopathy. As one of ordinary skill in the art, the attending diagnostician or health care professional can readily determine the clinical diagnosis, staging or progression of alzheimer's disease by using known techniques and by observing the results. This typically includes brain plaque imaging, mental or cognitive assessment (e.g., clinical dementia rating-box summary (CDR-SB), brief mental state examination (MMSE), or alzheimer's disease assessment scale-cognition (ADAS-Cog)) or functional assessment (e.g., alzheimer's disease collaborative research-activities of daily living (ADCS-ADL)). The cognitive and functional assessment may be used to determine changes in a patient's cognition (e.g., cognitive decline) and function (e.g., functional decline). As used herein, "clinical alzheimer's disease" is the diagnostic stage of alzheimer's disease. It includes conditions diagnosed as precursor Alzheimer's disease, mild Alzheimer's disease, moderate Alzheimer's disease and severe Alzheimer's disease. The term "preclinical alzheimer's disease" is a stage prior to clinical alzheimer's disease in which a measurable change in a biomarker (e.g., CSF aβ42 levels or brain plaques deposited by amyloid PET) is indicative of the earliest sign of a patient with alzheimer's disease pathology progressing to clinical alzheimer's disease. This usually occurs before symptoms such as memory loss and confusion are apparent. Preclinical alzheimer's disease also includes presymptomatic autosomal dominant carriers, as well as patients at higher risk of developing AD due to carrying one or two ApoE 4 alleles.

The reduction or alleviation of cognitive decline may be measured by cognitive assessment, such as clinical dementia ranking-box summaries, simple mental state examination or Alzheimer's disease assessment scale-cognition. The reduction or alleviation of the decrease in function may be measured by a function assessment such as ADCS-ADL.

As used herein, "mg/kg" means the amount (in milligrams) of antibody or drug administered to a subject based on his or her body weight (in kilograms). The dose is administered once. For example, for a subject weighing 70kg, the 10mg/kg dose of antibody may be a single 700mg dose of antibody administered in a single administration. Similarly, for a subject weighing 70kg, the 20mg/kg dose of antibody may be 1400mg dose of antibody administered at a single administration.

As used herein, if used is based on ¹⁸ Quantitative analysis of F-flutoxipiride tau load is less than 1.10SUVr (< 1.10 SUVr), then the human subject has a "very low tau" load, where quantitative analysis refers to calculation of SUVr and when compared to the reference region (parameter estimation of reference signal intensity or PERI, see Southekal et al, "flortakipir F18 Quantitation Using Parametric Estimation of Reference Signal Intensity," j.nucl.med.59:944-951 (2018)), SUVr represents counts within a specific target region of interest in the brain (multi-block centroid discriminant analysis or MUBADA, see devaus et al, "Test-Retest Reproducibility for the Tau PET Imaging Agent Flortaucipir F," j.nucl.med.59:937-943 (2018)).

As used herein, if used is based on ¹⁸ F-fluorotoxQuantitative analysis of cetylpyrate, tau load less than or equal to 1.46SUVr (i.e.,. Ltoreq.1.46 SUVr), then the human subject has a "very low tau to moderate tau" load, where quantitative analysis refers to calculation of SUVr, and when compared to a reference region (PERSI, see Southekal et al, "Flortaucipir F18 Quantitation Using Parametric Estimation of Reference Signal Intensity," J.Nucl.Med.59:944-951 (2018)), SUVr represents counts within a specific target region of interest in the brain (MUBADA, see Devous et al, "Test-Retest Reproducibility for the Tau PET Imaging Agent Flortaucipir F," J.Nucl. Med.59:937-943 (2018)).

As used herein, if used is based on ¹⁸ Quantitative analysis of F-flutoxipiride, tau load greater than or equal to 1.10 to less than or equal to 1.46 (i.e. 1.10SUVr to 1.46 SUVr), the human subject has a "very low tau" load. Based on ¹⁸ Quantitative analysis of F-flutoxipiride, wherein quantitative analysis refers to calculation of SUVr, and SUVr represents counts within a specific target region of interest in the brain when compared to a reference region (PERSI, see Southekal et al, "Flortaucir F18 Quantitation Using Parametric Estimation of Reference Signal Intensity," J.Nucl. Med.59:944-951 (2018)), see Devous et al, "Test-Retest Reproducibility for the Tau PET Imaging Agent Flortaucipir F," J.Nucl. Med.59:937-943 (2018)). The "low tau to moderate tau" load may also be referred to as the "intermediate" tau load.

As used herein, if used is based on ¹⁸ Quantitative analysis of F-Fluotoxipiride tau load is greater than 1.46SUVr (i.e. > 1.46 SUVr), then the human subject has a "high tau" load, where quantitative analysis refers to the calculation of SUVr and SUVr representing counts within a specific target region of interest in the brain (MUBADA, see Devous et al, "Test-Retest Reproducibility for the Tau PET Imaging Agent Flortaucipir F," J. Nucl. Med.59:937-943 (2018)) when compared to a reference region (PERCI, see Southekal et al, "Flortaupir F18Quantitation Using Parametric Estimation of Reference Signal Intensity," J. Nucl. Med. 59:944-951 (2018)).

As used herein, a human subject exhibits a slow decline if the human subject does not exhibit a decrease in Integrated Alzheimer's Disease Rating Scale (iADRS) of more than about-20 in about the last 18 months. If the human subject has shown a decrease in iADRS of more than about-20 within about the last 18 months, the human subject shows a rapid decrease.

As used herein, the term "about" means up to ±10%, unless the meaning of the term "about" differs from that meaning in view of the context in which it is used.

The terms "human subject" and "patient" are used interchangeably throughout this disclosure.

As used herein, "methods of treatment" are equally applicable to the use of a composition for treating a disease or disorder described herein and/or to the use of a composition and/or multiple uses for the preparation of a medicament for treating a disease or disorder described herein.

The following examples further illustrate the invention. However, it should be understood that these embodiments are set forth by way of example and not limitation, and that various modifications may be made by one of ordinary skill in the art.

Examples

Example 1: expression and purification of engineered N3pGlu A beta antibodies

An antibody to N3pGlu aβ was selected as an exemplary antibody for this example. Antibodies to N3pGlu aβ are known in the art. For example, U.S. Pat. No.8,679,498 and U.S. Pat. No.8,961,972, incorporated herein by reference in their entirety, disclose anti-N3 pGlu A beta antibodies, methods of making the antibodies, antibody formulations, and methods of treating diseases such as Alzheimer's disease with the antibodies.

Exemplary methods for expressing and purifying the anti-N3 pGlu aβ antibodies of the invention are as follows. Using the best predetermined HC: LC vector ratio or single vector system encoding both HC and LC, suitable host cells, e.g., HEK 293EBNA or CHO, are transiently or stably transfected with an expression system for secretion of antibodies. The clarified medium of secreted antibodies is purified using any of a number of common techniques. For example, the medium can be conveniently applied to a protein a or G sepharose FF column that has been equilibrated with a compatible buffer, such as phosphate buffered saline (ph 7.4). The column is washed to remove non-specific binding components. For example, bound antibody is eluted by a pH gradient, such as 0.1M sodium phosphate buffer pH6.8 to 0.1M sodium citrate buffer (pH 2.5). Antibody fractions are detected, for example, by SDS-PAGE, and pooled. Depending on the intended use, further purification is optional. The antibodies can be concentrated and/or sterile filtered using conventional techniques. Soluble aggregates and multimers can be effectively removed by conventional techniques, including size exclusion, hydrophobic interactions, ion exchange, or hydroxyapatite chromatography. After these chromatographic steps, the purity of the antibodies was greater than 99%. The product may be frozen immediately at-70 ℃ or it may be lyophilized.

Example 2: evaluation of safety, tolerability and efficacy of anti-N3 pGlu A beta antibodies

Donepezil-was chosen as an exemplary antibody for this example. Multicentric, randomized, double blind, placebo-controlled, phase 2 clinical studies (CT 03367403; clinicaltrias.gov) were designed to assess the safety and efficacy of the N3pGlu aβ antibody (also referred to herein as donazamab) in AD subjects with early symptomatic AD (prodromal AD and mild dementia caused by AD). This phase 2 study evaluates (among other things) whether removal of existing amyloid plaques can slow disease progression in up to 72 weeks of treatment, as determined by clinical measurements and biomarkers of disease pathology and neurodegeneration.

The study was a 133 week study and included a screening period of up to 9 weeks, a treatment period of up to 72 weeks, with final assessment after week 4 of week 76, and a 48 week immunogenicity and safety follow-up period.

Fig. 1 illustrates a study design of a clinical protocol.

Treatment combination period: about 1497 patients were screened and about 266 were randomly grouped. The patient received the following treatments (dosing) for up to 72 weeks:

donepezil antibody: intravenous donepezil (first 3 doses, 700mg q4wk, then 1400mg q4 wk) for up to 72 weeks; or (b)

Placebo: intravenous placebo Q4WK for up to 72 weeks.

Primary and secondary endpoints:

the main endpoints of this study were:

cognitive and functional changes as measured by the change in Integrated Alzheimer's Disease Rating Scale (iADRS) score from baseline to 18 months.

The secondary endpoints of this study were:

cognitive change from baseline to 18 months measured by: ADAS-Cog ₁₃ Changes in score, changes in the sum of the clinical dementia level scale boxes of scores (CDR-SB), changes in the simple mental state examination score (MMSE), and changes in the alzheimer's disease collaborative study-tool daily living activity scale (ADCS-IADL) score.

Such as pass through [ ¹⁸ F]Changes in cerebral amyloid plaque deposition from baseline to 18 months as measured by the flo Bei Ping PET scan.

Such as pass through [ ¹⁸ F]Changes in tau deposition measured by the florol Bei Ping PET scan from baseline to 18 months.

Change in volumetric MRI measurement from baseline to 18 months.

Safety endpoint:

the safety endpoint for this study was:

standard security assessment: spontaneously reported adverse reactions (AEs), clinical laboratory tests, vital sign and weight measurements, 12-lead Electrocardiography (ECG), physical and neurological examinations

MRI (amyloid-related imaging abnormalities [ ARIA ] and Emergency radiology findings)

Columbia suicide severity rating scale (C-SSRS)

Statistical analysis: unless otherwise indicated, all efficacy analyses will follow the Intent To Treat (ITT) principle. ITT analysis is an analysis of data from a group of subjects assigned by random assignment, however, subjects do not receive assigned treatment, do not receive the correct treatment, or else do not follow the regimen. All paired tests of therapeutic effect were performed at a 2-side alpha (α) level of 0.05, unless otherwise indicated; the 2-side Confidence Interval (CI) is shown at a 95% confidence level.

Efficacy: the main objective of this study was to test the following assumptions: intravenous infusion of donepezil in patients with early symptomatic AD slows cognitive and/or functional decline of AD compared to placebo, as measured by the multiplex measurement iADRS. Analysis of changes in iADRS from baseline scores at each predetermined post-baseline visit during the treatment period was performed using an MMRM model comprising: baseline scores, pooled investigators, treatments, visits, treatment-visit interactions, baseline-visit interactions, acetylcholinesterase inhibitors (AChEI) accompanying at baseline and/or memantine use (yes/no) and age at baseline. The main time point for treatment comparison was at the end of the double blind treatment period (week 76). For the treatment comparison of donazamab with placebo, the least squares mean progression and its associated p-value and 95% cl treatment group comparisons were calculated. Furthermore, bayesian posterior probabilities of at least the edge of interest (25% slower placebo progression) of the active ingredient treated group over placebo were calculated.

Analysis of secondary efficacy results (including ADAS-Cog ₁₃ ADCS-iADL, CDR-SB, and MMSE) from baseline at each predetermined post-baseline visit during the treatment period.

Safety: safety was assessed by generalizing and analyzing immunogenicity during AE, laboratory analytes, vital signs, MRI scans, ECG, double blind treatment periods.

Pharmacokinetics/pharmacodynamics: pharmacokinetic or pharmacodynamic (PK/PD) relationships between plasma donepezil concentration and SUVr, cognitive endpoints, ARIA morbidity or other markers of PD activity were explored graphically. The relationship between the presence of the donepezil antibody and PK, PD, safety and/or efficacy can be assessed graphically. Additional assays may be explored to assess potential interactions of anti-drug antibodies, PD and other endpoints (PET scan, ARIA-E, etc.) if necessary. Additional modeling may be performed based on the results of the graphical analysis.

Dosing and dose escalation: donepezil was administered every 4 weeks with an IV infusion of about 140mL in a minimum of 30 minutesMonoclonal antibodies (700 mg or 1400 mg). Based on current preclinical pharmacological and toxicological data, and clinical PK, PD and safety data, a dose of donepezil of 700mg and 1400mg was selected for intravenous administration once every 4 weeks. Previous and ongoing exposures include 0.1mg/kg, 0.3mg/kg, 1mg/kg, 3mg/kg, 10mg/kg, 20mg/kg and 40mg/kg in single and/or multi-dose dosing regimens. Data from study ACC (NCT 01837641, clinicaltrias.gov) suggest that the PK of donepezil is linear when the dose is not less than 10 mg/kg. The average half-life was about 9-11 days at doses ≡10mg/kg, so minimal accumulation in plasma PK was predicted for 700mg and 1400mg of Q4 week IV administration. High levels of amounts were observed with a single dose of 20mg/kg [ ¹⁸ F]Florol Bei Ping PET was reduced and was observed with 10mg/kg Q2 weeks at 3 months [ ¹⁸ F]-fluroro Bei Ping PET signal decreases by little. Based on this and the reduced patient load and comparable safety per 4 week dosing regimen compared to the every 2 week dosing regimen, 1400mg of week Q4 dosing was chosen as the highest dosing regimen to stabilize amyloid plaque reduction. The lowest ratio of ARIA-E was observed with 10mg/kg monthly dosing. For this reason, an incremental schedule (first 3 doses 700mg Q4 weeks, then 1400mg Q4 weeks) was proposed to reduce the incidence of ARIA while allowing patients to achieve high PD effects. Furthermore, dose reduction rules have been established for sporadic ARIA-E.

Selection criteria: patients between 60 and 85 years of age (including men and women) were eligible for participation in the study upon informed consent. The patient may exhibit a gradual and progressive change in memory function of ≡6 months reported by the patient or by the study partner (informative). In some cases, the patient may have a history of 20 to 28 (inclusive) at visit 1 or acceptable within 6 months prior to visit 1 [ ¹⁸ F]MMSE score of the cetuximab PET scan, meeting the center reading criteria. The patient can also meet [ [ ¹⁸ F]Standard of cetuximab scanning (center number) and/or [ ¹⁸ F]Florol Bei Ping scan (center number) standard.

Elimination standard: patients were excluded from study enrollment if they met any of the following criteria: improved Hachinski ischemia scale with no less than 4(MHIS; hachinski et al 1975) score; researchers consider that there is a lack of sufficient pre-illness read-write capability, sufficient vision, or sufficient hearing to complete the required psychological measurement test; significant neurological diseases affecting the Central Nervous System (CNS) other than AD, which may affect the cognition or ability to complete the study, include, but are not limited to, other dementias, severe brain infections, parkinson's disease, multiple concussions or seizures or recurrent seizures (other than febrile pediatric seizures); diseases that are currently severe or unstable, including cardiovascular, liver, kidney, gastrointestinal, respiratory, endocrine, neurological (except AD), psychiatric, immune, or hematological diseases, and other conditions that researchers consider likely to interfere with the analysis in this study; or life expectancy < 24 months; a history of cancer in the past 5 years, non-metastatic basal cell carcinoma and/or squamous cell carcinoma of the outer skin, cervical cancer in situ, non-progressive prostate cancer, or other cancers with low risk of recurrence or spread; patients with any current primary psychiatric diagnosis other than AD if, at the discretion of the researcher, a mental disorder or symptom may confuse the explanation of the drug action, affect cognitive assessment, or affect the ability of the patient to complete the study; patients with schizophrenia or other chronic history of psychosis; has a history of long QT syndrome; researchers are clinically judged to be at serious suicidal risk through medical history, examination or C-SSRS evaluation; a history of alcohol or drug use disorder (except tobacco use disorder) within 2 years prior to screening visit; has a clinically significant history of multiple or severe drug allergies, or severe post-treatment hypersensitivity reactions (including but not limited to heavy erythema multiforme, linear immunoglobulin a skin disease, toxic epidermonecrobiosis and/or exfoliative dermatitis); or have a known positive serological finding for Human Immunodeficiency Virus (HIV) antibodies. Local laws and regulations may be applicable to whether testing is required; any clinically significant abnormalities in screening, as determined by the researcher in physical or neurological examinations, vital signs, ECG or clinical laboratory test results, which may be harmful to the patient, may harm the study, or show evidence of other etiologies of dementia; screening MRI, which shows evidence of significant abnormalities, would suggest progressive dementia Another potential cause of fool or clinically significant findings that may affect the ability of a patient to safely participate in the study; there are any MRI contraindications, including claustrophobia or metallic (ferromagnetic) implants/cardiac pacemakers where contraindications exist; center read MRI with a central readout showing the presence of ARJA-E, > 4 brain microhemorrhages, more than 1 surface iron deposition area, any major hemorrhages or severe white matter disease; average (triplicate ECG) corrected QT (QTcF) interval measurement > 450msec (male) or > 470msec (female) at screening (measured at study site; patients with prior history of hepatitis B should be tested for HBsAg at screening and excluded if HBsAg is positive; patients with prior history of hepatitis C should be tested for HCV RNA PCR at screening and excluded if HCV RNA PCR is positive; calculated creatinine clearance < 30mL/min (Cockcroft-Gault formula; cockcroft and Gault 1976) at screening; alanine Aminotransferase (ALT) gtoreq 2X is laboratory normal Upper Limit (ULN), aspartate Aminotransferase (AST) gtoreq 2 XULN, total Bilirubin Level (TBL) gtoreq 1.5 XULN, or alkaline phosphatase (ALP) gtoreq 1.5 XULN; stable doses of ACI and/or gold have been received prior to randomization, calculated creatinine clearance < 30mL/min (Cockcroft-Gault formula; cockcroft and Gault 1976) at screening, potential for a significant change in the anti-drug half-life of any drug-life (e.g., 1) at least one of the same group of time as those of the prior art, and prior to a significant change in the anti-drug therapy (1-tumor therapy) at least by a significant part of the time of the drug-delay of drug-release, epinephrine or methylprednisolone allergy; couple [ ¹⁸ F]-fluroro Bei Ping or [ ¹⁸ F]-flutoxib sensitivity; contraindicated for MRI; contraindicated for PET; the current or planned exposure to ionizing radiation in combination with the planned administration of the study PET ligand can result in cumulative exposure exceeding locally recommended exposure limits.

Dose-escalation of ARIA-E: in the following examples depicted in Table A, the donepezil dose adjustments were adjusted for the occurrence of ARIA-E. If a dose reduction is required, the donepezil dose is reduced to the next lower dose (from 1400mg to 700mg or from 700mg to placebo).

Table a: dose adjustment of ARIA-E first bleeding donazamab

^a Researchers may choose to temporarily stop the donepezil after discussion with sponsors.

^b If the patient has a second ARIA-E onset and has previously reduced the dose or temporarily stopped taking the donepezil, the donepezil is permanently discontinued.

All ARIA-E cases require an unscheduled MRI scan every 4-6 weeks until ARIA-E regresses.

Discontinuing study treatment: possible causes leading to permanent discontinuation of study treatment: subject decision (subject or designated personnel of subject; e.g., legal guardian requires discontinuation of study product) or discontinuation due to liver event or liver test abnormality. Subjects who discontinue the study product due to liver events or liver test abnormalities should have additional liver safety data acquired via CRF/electronic data input.

The study product was considered stopped for abnormal liver testing when the subject met one of the following conditions: alanine Aminotransferase (ALT) or aspartate Aminotransferase (AST) > 8x upper normal limit (ULN); ALT or AST > 5XULN for more than 2 weeks; ALT or AST > 3 XULN and Total Bilirubin Level (TBL) > 2 XULN or International Normalized Ratio (INR) > 1.5; ALT or AST > 3 XULN, manifested by fatigue, nausea, vomiting, pain or tenderness in the upper right quadrant, fever, rash, and/or eosinophilia (> 5%); alkaline phosphatase (ALP) > 3 XULN; ALP > 2.5 XULN and TBL > 2 XULN; or ALP > 2.5 XULN, manifested as fatigue, nausea, vomiting, right quadrant pain or tenderness, fever, rash and/or eosinophilia (> 5%).

Furthermore, subjects stopped the study product in the following cases:

permanent discontinuation of treatment with donepezil in patients with:

the second occurrence of ARJA-E following prior dose reduction or temporary withdrawal of donepezil;

any increase in omicron ARJA-H is accompanied by clinically significant symptoms;

a new microhemorrhage at > 4, > a new area of superficial iron deposition or significant exacerbation of pre-existing superficial iron deposition at 1, or any major hemorrhage, regardless of symptoms; or (b)

The omicron was reported as an ARJA-E event of a Significant Adverse Event (SAE), regardless of the severity of the symptoms or MRI findings.

Treatment with donanadomab will also be permanently discontinued in patients with:

prolonged acute infusion response (i.e., no response to drugs such as antihistamines, non-steroidal anti-inflammatory drugs, and/or anesthetics and/or short-term discontinuation of infusion); or (b)

Adverse or clinically significant laboratory values, ECG results, physical examination findings, MRI findings (e.g. symptomatic ischemic stroke),

treatment by ARIA-E temporary suspension of donazamab study

If ARJA-E meets the criteria for suspension shown in Table A, ARJA-E is allowed to suspend treatment with donepezil. Where the regimen indicates continued administration or dose reduction rather than temporary interruption, the administration of the donepezil may be temporarily interrupted.

If complete regression of symptoms and radiology is found, for example, due to temporary discontinuation of administration of ARIA-E and within 16 weeks after temporary drug discontinuation, the resumption of doranemab may be performed after the first occurrence of ARIA-E. If the ARIA-E symptoms and radiology found not to completely regress within 16 weeks, the patient permanently stopped the treatment with donazamab.

Study medication may be restarted with 700mg or placebo, double blind, depending on the original study group of patients randomized. An unscheduled safe MRI scan is required 4-6 weeks after dose restart.

Efficacy evaluation: cognition and functional testing was performed using eDOA tablets. Audio voice recordings of the grader questions and responses of patients and study partners will also be collected during performance of cognitive and functional tests by the ECOA panel for central monitoring by the grader scale. The cognitive and functional tests of each patient should be performed at about the same time each day that the test occurs to reduce potential variability. Note that ADAS-Cog and MMSE must be managed by a different grader than ADCs-ADL and CDRs. The 2 graders should continue to conduct the same scale on the same patient throughout the study. Each evaluation of a given patient should be made by the same grader at each visit, if possible. The Primary Investigator (PI) is responsible for selecting the graders that will manage the instrument on site, provided that these graders have met all of the training requirements.

When administered, cognitive and functional testing should first be performed prior to medical procedures that may stress the patient (e.g., drawing blood). Note that some operations (MRI, [ ¹⁸ F]-flutoxipirtine PET imaging [ ¹⁸ F]Florol Bei Ping PET amyloid imaging) may be performed on other days within the access window.

Main efficacy evaluation:

alzheimer's disease comprehensive rating scale (iADRS; wessels et al, "A Combined Measure of Cognition and Function for Clinical Trials: the Integrated Alzheimer's Disease Rating Scale (iADRS)," J Prev Alzheimers Dis.2 (4): 227-241 (2015), incorporated herein by reference in its entirety). iADRS represents a complex developed using a theory driven approach (combining measurements of both cognition and function) and a data mining approach (identifying the most sensitive scale combination by analyzing data from the alzheimer's neuroimaging initiative). iADRS is a widely accepted measure of ADAS-Cog from 2 well-accepted, treatment-sensitive, widely accepted measures in AD ₁₃ And a simple linear combination of scoring of ADCs-IADL, thereby measuring the core domain of AD. All of the items comprising these 2 scales without additional weighting of the items, thereby producing surface effects and composite phasesEase of explanation for its components. The iADRS score was derived from ADAS-Cog ₁₃ And ADCS-iADL, and is the primary efficacy measure. ADAS-Cog ₁₃ And ADCS-iADL is the actual scale administered to the patient.

Secondary efficacy assessment: in the evaluation of ADAS-Cog ₁₃ Additional clinical outcome measures should be taken at each visit in the same order. To minimize missing data, the rater should include orally recording each measurement with the patient or study partner (as specified in the description) and appropriately recording the response. The same study partner should be used as the notifier in all visits.

Alzheimer's disease assessment scale-cognition sub-scale A: ADAS-Cog ₁₃ Is a tool of rater management aimed at assessing the severity of cognitive and non-cognitive behavioral dysfunction in AD patients (Rosen et al, "A New Rating Scale for Alzheimer's Disease," Am J Psychiary.141 (11): 1356-1364 (1984), incorporated herein by reference in its entirety). ADAS-Cog ₁₃ The same rater should manage at each visit to reduce potential variability. ADAS cognition sub-Scale ADAS-Cog ₁₃ Consisting of 13 projects, which evaluate the most common areas of impaired cognitive function in AD: orientation, speech memory, language, practice, delayed free recall, digital cancellation, and maze completion measurements (Mohs et al, "Development of Cognitive Instruments for Use in Clinical Trials of Antidementia Drugs: additions to The Alzheimer ' S Disease Assessment Scale that Broaden its Scope," The Alzheimer ' S S Disease Cooperative student. Alzheimer ' S Disassoc Disord.11 (Suppl 2): S13-S21 (1997), incorporated herein by reference in its entirety). ADAS-Cog compared to ADAS-Cog11 ₁₃ Allowing better differentiation between mild patients and inclusion as a secondary outcome. ADAS-Cog ₁₃ The scale ranges from 0 to 85, with higher scores indicating greater severity of the disease.

Alzheimer's disease partnership study-daily activities of living scale: ADCS-ADL is a 23-item scale developed for The rater, a questionnaire managed by The rater, which is answered by The patient ' S study partner (Galasko et al, "An Inventory to Assess Activities of Daily LiVing for Clinical Trials in Alzheimer ' S Disease," The Alzheimer ' S Disease Cooperative study. Alzheimer ' S Disease Assoc Disease 1997;11 (journal 2): S33-S39; galasko et al, "Galantamine Maintains Ability to Perform Activities of Daily Living in Patients with Alzheimer ' S Disease," J Am Geriat Soc.52 (7): 1070-1076 (2004), which is incorporated herein by reference in its entirety). ADCS-ADL should be managed by the same grader at each visit to reduce potential variability. The subset of ADCS-ADL items (items 7 through 23) of daily life tool activity (ADCS-iADL) was used as a secondary efficacy measure. The focus of early symptomatic AD populations is on the Instrumental Activities of Daily Living (iADL) rather than the basic activities of daily living (bADL), which are thought to be affected in the more severe stages of the disease. The iADL score ranged from 0 to 56, with lower scores indicating higher disease severity. For each particular project, study partner patients were first asked if they tried ADL within the last 4 weeks. If the patient does try ADL, the study partner is asked to score the patient's performance level according to a set of performance descriptions. The score for each item and the overall score for the tool are calculated. The total score for ADCS-ADL ranged from 0 to 78, with higher scores indicating greater levels of damage. Individual scores for the bADL (0 to 22) were also calculated.

Clinical dementia rating scale: the CDRs are semi-structured interviews with patients and research partners (informative) that provide an index of overall function (Berg et al, "Mild Senile Dementia of the Alzheimer's type.4.Evaluation of interaction," Ann neuron.31 (3): 242-249 (1992), incorporated herein by reference in its entirety). CDRs should be managed by the same grader from visit to reduce potential variability. Inquiring about the memory, orientation, judgment and problem solving of the information person patient, community business, family and hobbies, and personal care. The patient's ability to memorize, orient, judge and solve the problem is assessed. A higher score indicates a greater severity of the disease. By assigning a severity score to each of the 6 regions, a total score, called the sum of the boxes-hence the abbreviation CDR-SB, is obtained. CDR-SB ranged from 0 to 18, with higher values indicating greater damage.

Simple mental state examination: MMSE is a simple tool for assessing cognitive function in patients (Folstein et al, "Mini-Mental State". A Practical Method for Grading the Cognitive State of Patients for the Clinician, "J Psychiatr Res.12 (13): 189-198 (1975), incorporated herein by reference in its entirety). MMSE should be managed from visit to visit by the same grader to reduce potential variability. The instrument was divided into 2 parts. The first part measures orientation, memory and attention. The maximum score of the first part is 21. The second section tests the patient for the ability to name objects, follow verbal and written commands, write sentences, and replicate graphics. The maximum score of the second part is 9. The total MMSE score ranged from 0 to 30, with lower scores indicating higher levels of injury.

Biomarker efficacy measurement (double blind stage) [ ¹⁸ F]Florol Bei Ping PET scan: alterations in amyloid burden (e.g., by [ through ] ¹⁸ F]Evaluation of the fluroxypyr Bei Ping PET signal) and in patients treated with donepezil and placebo, for at baseline, week 52 [ visit 15]And week 76 [ visit 21]Or experience when early aborting a visit (ED) ¹⁸ F]Those patients scanned with florol Bei Ping PET were compared.

[ ¹⁸ F]-flutoxion PET scan: comparison between baseline and endpoint experienced in patients treated with donanazumab and placebo (visit 21[ week 76 ]]Or ED) [ ¹⁸ F]Tau burden changes in those patients scanned for flutoxion (e.g., by [ through ] ¹⁸ F]-evaluation of the flutoxion PET signal).

Volumetric MRI: magnetic resonance assessment and comparative imaging of the brain can be performed during visit 2-14. The effects of donepezil and placebo treatment on volumetric MRI were used to assess the brain volume loss that occurred in AD patients.

Removal of amyloid deposits: at baseline, visit 8 (week 24), visit 15 (week 52) and end point visit 21 (week 76) or ED [ ¹⁸ F]Amyloid deposition in patients compared to placebo-treated patients of the florasulam Bei Ping PET scanRemoval of objects (e.g. by ¹⁸ F]-flurorol Bei Ping PET signal evaluation).

Deposition of Tau deposits: comparison of patients undergoing baseline and endpoint visits 21 weeks or ED in Duonanemab and placebo treated patients ¹⁸ F]The extent of tau PHF deposit accumulation upon PET scanning and summing of flutoxion (e.g. by [ ¹⁸ F]-evaluation of the flutoxion PET signal).

Biomarkers: biomarker studies were performed to address issues related to drug treatment, target participation, PD, mechanism of action, variability (including safety) of patient response, and clinical outcome. Sample collection is incorporated into clinical studies to enable examination of these problems by measuring biomolecules including deoxyribonucleic acid (DNA), ribonucleic acid (RNA), proteins, lipids, and other cellular elements. Serum, plasma and whole blood RNA samples for biomarker studies were collected during visit 2-14, as allowed by local regulations.

Example 3: results from safety, tolerability and efficacy studies

Donepezil was chosen as an exemplary antibody for this example. This example provides results obtained from the safety, adverse effects and efficacy of donepezil in participants with early symptomatic AD. Registration was based on a fluroxypyr-meptyl Positron Emission Tomography (PET) scan of fluroxypyr Bei Pinghe to show tau and amyloid plaque pathology, respectively. The participants received intravenous placebo or donepezil (doses 1-3 were 700mg, and thereafter 1400 mg) every 4 weeks for up to 72 weeks. The primary outcome measure was the change from baseline in the integrated AD rating scale (iADRS; range 0 to 144, lower indicating greater cognitive deficits and impaired daily life activity) at 76 weeks. Secondary outcome measures included the sum of clinical dementia rating scale boxes (CDR-SB; range 0 to 18, higher indicated larger lesions), AD assessment scale-cognition (ADAS-Cog ₁₃ The method comprises the steps of carrying out a first treatment on the surface of the Ranging from 0 to 85, higher indicating greater disease severity), AD collaborative research-tool activities of daily living (ADCS-iADL; ranges 0 to 59, lower indicates larger lesions), simple mental state examination (MMSE; ranging from 0 to 30, lower indicating larger lesions), respectivelyPerfluorolol Bei Ping [ ¹⁸ F]Tau burden and volumetric magnetic resonance imaging MRI (vMRI) of the flutoxion PET evaluation.

Patient population and study design: the study was a multicenter, randomized, double-blind, placebo-controlled study to evaluate the onset of donepezil in early symptomatic AD (prodromal AD, symptomatic pre-dementia stage of AD in which MCI is apparent [ MCI-AD ] at an age of 60-85 years]And mild AD dementia [ symptomatically severe enough to meet dementia and AD diagnostic criteria ]]The combination of (a) in the above) the safety, adverse reactions and efficacy in the participants (Dubois et al, "Research Criteria for the Diagnosis of Alzheimer's Disease: revising the NINCDS-ADRDA criterion, "The Lancet Neurology: 734-46 (2007) are incorporated herein by reference in their entirety). Screening methods include simple mental state examination (MMSE; range 0 to 30, lower indicating larger lesions, folstein et al, "Mini-portal state A Practical Method for Grading the Cognitive State of Patients for the Clinician," J.Psychiatr.Res.12:189-98 (1975), incorporated herein by reference in its entirety)) ¹⁸ F]-Fluoxelpine PET scan, magnetic Resonance Imaging (MRI) and [ ¹⁸ F]Florol Bei Ping PET scan. Fluoxelpine [ sic ] ¹⁸ F]The fluroro Bei Ping PET scan is reviewed by a centralized PET imaging device to assess patient eligibility. All eligible patients require evidence of pathological tau on PET scans and quantify tau levels below a certain upper threshold. The latter criterion addresses the problem of limited efficacy of anti-amyloid treatment in advanced disease, as indicated by the broad range of tau pathology. The Tau images were quantitatively assessed by published methods to estimate SUVr (normalized uptake value ratio) (Pontecorevo et al, "A Multicentre Longitudinal Study of Flortaucipir (18F) in Normal imaging, mild Cognitive Impairment and Alzheimer's Disease Dementia," Brain 142:1723-35 (2019); devous et al, "Test-Retest Reproducibility for the Tau PET Imaging Agent Flortaucipir F," Journal of Nuclear Medicine 59:937-43 (2018); southekal et al, "Flortaucir F18 Quantitation Using Parametric Estimation of Reference Signal Intensity, J.Nucl. Med.59:944-51 (2018),which is incorporated herein by reference in its entirety) and visually assessed (Fleisher et al, "Positron Emission Tomography Imaging With ] ¹⁸ F]Flortaucipir and Postmortem Assessment of Alzheimer Disease Neuropathologic Changes, "JAMA Neurology 77:829-39 (2020), incorporated herein by reference in its entirety) to determine if they have AD mode.

Any image with SUVr > 1.46 is excluded as having high tau. For those images that are not excluded as having high tau, images with a SUVr value < Chuan 0 or images that are visually read as having negative AD mode are excluded due to having insufficient tau level, but this is still included if the excluded image is visually read as having high tau AD mode but with a SUVr value < 1.10. In addition to MRI, each patient is required to be screened ¹⁸ F]Florol Bei Ping PET pre-scan met all other visit qualification criteria 1.

Participants who met the entry criteria were followed by 1:1 randomized group, intravenous (IV) received donepezil (700 mg for the first 3 doses, 1400mg thereafter) every 4 weeks or placebo every 4 weeks for up to 72 weeks. For inter-group comparability of site factors, participants are randomly grouped and layered by survey site. There is no layering through the entry criteria. Among the participants treated with donepezil, the dose was either down-regulated to 700mg if the amyloid removal in Centoil (CL) measured by the fluroxypyr Bei Ping scan (24 and 52 weeks) was ≡11 and < 25, or converted to placebo if either measured ≡11 < 11 or two consecutive scans > 11 and < 25. If Amyloid-related imaging abnormalities-edema/exudation (ARIA-E; high signal intensity in fluid attenuation reversal recovery imaging sequences on MRI due to substantial fluid accumulation or groove fluid exudation; sperling et al, "Amyloid-related Imaging Abnormalities in Amyloid-Modifying Therapeutic Trials: recommendations from the Alzheimer's Association Research Roundtable Workgroup" Alzheimer's & Dementia 7:367-85 (2011), incorporated herein by reference in its entirety) occurs during the first three doses of 700mg up-ramp, the dose is not expanded. Final endpoint measurements and safety assessments were made at week 76, 4 weeks after the last infusion.

Clinical and biomarker outcome measurement: the primary outcome measure is the change in iADRS from baseline to 76 weeks compared to placebo (range 0 to 144, lower indicating greater cognitive impairment and impairment of daily life; wessels et al, "A Combined Measure of Cognition and Function for Clinical Trials: the Integrated Alzheimer's Disease Rating Scale (iADRS)," j.prev. Alzheimer's ' dis.2:227-41 (2015), incorporated herein by reference in its entirety). iADRS is a linear combination of its individual components, AD assessment scale-cognition (ADAS-Cog ₁₃ The method comprises the steps of carrying out a first treatment on the surface of the Ranges from 0 to 85, higher indicating greater disease severity; mohs et al, "Development of Cognitive Instruments for use in Clinical Trials of Antidementia Drugs: additions to the Alzheimer's Disease Assessment Scale that Broaden its scope. The Alzheimer's Disease Cooperative Study, "Alzheimer Dis Assoc Disord 11 criminal 2: s13-21 (1997), incorporated herein by reference in its entirety) and AD collaborative learning daily life tool activities (ADCS-iADL; ranging from 0 to 59, lower indicating greater damage; galasko et al, "An Inventory to Assess Activities of Daily Living for Clinical Trials in Alzheimer's disease," Alzheimer Diseaseand Associated Disorders 11: S33-S9 (1997) and Galasko et al, "Galantamine Maintains Ability to Perform Activities of Daily Living in Patients with Alzheimer' S Disease," Journal of the American Geriatrics Society: 1070-6 (2004), incorporated herein by reference in its entirety).

iADRS was developed using a theoretical structure aimed at measuring the core disease process, and clinical trial data was used to identify the item/scale that performed best for that structure. Comprising ADAS-Cog ₁₃ All items of the total score and ADCS-iADL score were not weighted to yield surface efficacy and ease of interpretation of both the complex and its components. iADRS allows for overall measurement of AD lesions (overall score) and individual sub-scores (cognitive and functional). Verification of iADRS has been established and statistical properties of composite performance have been described.

For secondary structure measurement,Clinical dementia rating scale block sum (CDR-SB; ranges 0 to 18, higher for larger lesions; morris, "The Clinical Dementia Rating (CDR)," Current Version and Scoring Rules 43:2412-a (1993), incorporated herein by reference in its entirety), ADAS-Cog ₁₃ ADCS-iADL, MMSE, e.g. by fluroro Bei Ping and [ respectively ] ¹⁸ F]The method of amyloid and tau burden and volumetric MRI assessed by cetuximab PET is detailed in the protocol. Using Tau ^IQ The algorithm evaluates the overall tau load (Whittington et al, "TauIQ-A Canonical Image Based Algorithm to Quantify Tau PET Scans," J.of Nuclear Medicine (2021), incorporated herein by reference in its entirety), thereby explaining the spatiotemporal distribution of tau.

Determination and statistical analysis of sample size: recruitment of 250 participants randomly allocated 1:1 to two treatment groups (where 200 participants were expected to complete treatment) was determined to provide about 84% efficacy to demonstrate that the active treatment group had a posterior probability of iADRS progression of ≡0.6 slowed by at least 25% relative to placebo. The assumption for efficacy calculations was that the average level of progression in the placebo and donepezil groups was approximately 12 and 6 points (50% slowing) respectively within 18 months, with a common standard deviation of 17. Efficacy analysis was performed based on modified intent-to-treat guidelines (unless otherwise indicated), where the participants had a baseline and at least one post-baseline iADRS measurement. All paired tests of treatment effect were performed at a double sided alpha level of 0.05, unless otherwise indicated.

Baseline characteristics were summarized by treatment and global groups, with descriptive statistics on continuous and categorical measurements. The primary results were analyzed using a Mixed Model Repeat Measurement (MMRM) analysis, in which the change in iADRS score from baseline at each predetermined post-baseline time point was taken as the amount of strain. The model of the fixed effect includes the following: baseline scores, investigators, treatments, visits, treatment-visit interactions, baseline-visit interactions, acetylcholinesterase inhibitors accompanying at baseline and/or memantine use (yes/no) and age at baseline. The visit is considered a classification variable. Secondary efficacy results were assessed using MMRM analysis. Bretz graphic method (Bretz et al, "A Graphical Approach to S) equentially Rejective Multiple Test Procedures, "Statistics in Medicine,28 (4): 586-604 (2009), incorporated herein by reference in its entirety) for providing control of study mode type I error rates for primary and key secondary hypotheses with alpha levels of 0.05. Assuming the primary analysis is significant, then for CDR-SB, ADAS-Cog ₁₃ MMRM analysis described for the primary analysis was performed, ADCS-iADL and MMSE scores, and significance was determined based on the hypothesized multiple plots. Longitudinal clinical results provide point estimates and error bars. For post-baseline classification data, fisher's exact test was used for treatment group comparison. For continuous data after baseline collected at endpoint, analysis of covariance (ANCOVA) was used, with independent factors of treatment and age. Each primary field investigator is responsible for selecting a rater that meets the training requirements to manage the tool in the field. The evaluator was blinded to the treatment assignment.

A bayesian Disease Progression Model (DPM) was used to evaluate the rate of decline of iADRS between the donepezil and placebo groups in the 76 week study, as pre-specified in the protocol. The model assumes a proportional therapeutic effect relative to placebo and includes a diffusion prior. A similar model was previously used, except that in the current model the a priori distribution of the parameters representing placebo descent is not forced to be monotonic. This analysis produced a posterior probability distribution of the Disease Progression Ratio (DPR), defined as a proportional decrease in the donepezil group relative to placebo. DPR less than 1 favors donepezil. Posterior averages of 95% confidence intervals and disease progression ratios are presented. The posterior probability of slowing disease progression by at least 25% relative to placebo is pre-specified and calculated according to DPM. DPM model for evaluation of CDR-SB, ADAS-Cog ₁₃ Drop rates for ADCS-iADL and MMSE. The DPM model is not included as part of the multiple test strategy for our pre-specified secondary endpoint.

Descriptive statistics of continuous variables and frequencies and percentages of categorical variables are used to summarize safety parameters (AE, laboratory analytes, vital signs, electrocardiography and MRI) during treatment.

Missing data of the MMRM model is processed using a likelihood-based mixed effect model for repeated measurements. Model parameters are estimated simultaneously using constraint probability estimates that combine all observed data. The estimate has been shown to be unbiased when missing data is missing randomly and when there is negligible non-random missing data. Repeated measurement analysis uses only the accessed data from the predetermined collection of data. Efficacy or safety data measurements may have been made when participants stopped the study early, when no visit to the acquisition variables was scheduled. This data was used for all other analyses.

Crowd and baseline characteristics: baseline demographics for placebo and donepezil monotherapy groups were: average ages were 75.4 years and 75.0 years, female sexes were 51.6% and 51.9%, caucasians were 96.0% and 93.1%, and ApoE4 carriers were 74.2% and 72.5% (table B).

Table B: characterization of baseline test participants

* Note that: including multi-ethnic and american indians or alaska original residents.Including participants in the combination group. ^# The number of participants with non-missing data acting as denominators, ^a donanazumab monotherapy n=130, ^b the total n=271 is calculated as, ^c placebo n=121 and, ^d donanazumab monotherapy n=126, ^e total n=261 of the total number, ^f placebo n=124, ^g donanazumab monotherapy n=130, ^h total n=269. Apo4 = apolipoprotein E allele 4; AChEI = acetylcholinesterase inhibitor; ADAS-Cog ₁₃ =ad assessment scale-cognitive 13 sub-scale;ADCS-ADL = alzheimer's disease collaborative research activity daily life scale; ADCS-iADL = alzheimer's disease collaborative research tool activity daily life scale; iADRS = alzheimer's disease integrated rating scale; MMSE = simple mental state check; CDR-SB = clinical dementia rating block sum; PET = positron emission tomography; N/N = number of participants; sd=standard deviation.

At the beginning of the experiment, the study consisted of three groups, including a combination group of donepezil and BACE 1 inhibitor. The group was discontinued early in the trial and 15 participants were randomly assigned to the group. Of the 1955 participants screened, 126 were randomized to placebo and 131 to donazamab in the modified intent-to-treat population. The average baseline score for iADRS was 105.9 for placebo and 106.2 for donepezil; MMSE was 23.7 and 23.6, respectively; CDR-SB is 3.4 and 3.6; [ ¹⁸ F]The overall tau load of cetuximab PE was 0.46 and 0.47; amyloid PET values were 101.1 and 107.6 (table B).

The main results are: the donepezil showed a significantly slower decline in the combined measure of cognitive and daily function in early symptomatic alzheimer's patients compared to placebo. In the Integrated Alzheimer's Disease Rating Scale (iADRS), the majority of the endpoints of the change from baseline to 76 weeks were met by donepezil, which slowed the decline by 32% relative to placebo (FIG. 2A), which was statistically significant. iADRS is a combined cognitive measurement ADAS-Cog ₁₃ And a clinical compounding tool for functional measurement of ADCS-IADL, two commonly used measures in alzheimer's disease. Variation of iADRS from baseline at 76 weeks was-10.06 for placebo and-6.86 for donazamab-treated patients (treatment differences: 3.20, 95% confidence interval [ CI ]]:0.12,6.27; p=0.04) (fig. 2A and table C).

FIGS. 2A-F illustrate primary iADRS and secondary CDR-SB, ADAS-Cog ₁₃ Clinical outcome of ADCS-iADL and MMSE. Fig. 2A shows the results of the primary results, i.e., the IADRS score for MMRM analysis, varied from baseline to LS mean over 76 weeks. FIG. 2B shows the estimated percent slow down from the MMRM model at the end of 18 months, and from Bayesian DP throughout the 18 month study The percent slow down estimate of the M model. Showing a 95% confidence interval. FIGS. 2C-F show the results of secondary results, namely CDR-SB (FIG. 2C), ADAS-Cog, analyzed by MMRM ₁₃ (fig. 2D), ADCS-iADL (fig. 2E) and MMSE scores (LS mean change from baseline to 76 weeks in fig. 2F. In fig. 2A-F, delta = difference; W = weeks; iADRS = integrated alzheimer's disease rating scale; ADAS-Cog ₁₃ =alzheimer's disease assessment scale-cognitive sub-scale; ADCS-iADL = alzheimer's disease collaborative study-daily life tool activity scale; CDR-SB = clinical dementia rating scale box sum; MMSE = simple mental state check; MMRM = hybrid model of repeated measurements; DPM = disease progression model; ls=least squares method; CI = confidence interval; n = number of participants; SE = standard error.

Table C: primary iADRS and secondary CDR-SB, ADAS-Cog ₁₃ ADCS-iADL and MMSE clinical outcome

The average of primary iADRS and secondary ADAS-Cog13, ADCSiADL, CDR-SB and MMSE clinical results analyzed with MMRM changed results from baseline. iADRS = alzheimer's disease integrated rating scale; ADAS-Cog ₁₃ =alzheimer's disease assessment scale-cognitive sub-scale; ADCS iADL = alzheimer's disease collaborative research tool daily life activity scale; CDR-SB = clinical dementia rating scale box sum; MMSE = simple mental state check; MMRM = hybrid model of repetition metrics; ls=least squares method; CI = confidence interval; SE = mean change from baseline of standard error clinical results. iADRS = alzheimer's disease integrated rating scale; ADAS-Cog13 = alr Cognitive subscale for the Alzheimer's disease assessment scale; ADCS iADL = alzheimer's disease collaborative research tool daily life activity scale; CDR-SB = clinical dementia rating scale box sum; MMSE = mini mental state examination; MMRM = hybrid model of repetition metrics; ls=least squares method; CI = confidence interval; SE = standard error

The percent reduction in disease progression relative to placebo estimated from MMRM model at the 18 month endpoint and bayesian DPM throughout 18 months showed a reduction in iADRS using both methods (fig. 2B). According to bayesian DPM, the posterior probability of slowing down disease progression by at least 25% on iADRS relative to placebo is calculated to be 0.78.

Secondary results: the donepezil also showed consistent improvement in all pre-specified secondary endpoints of measured cognition and function compared to placebo, but did not reach nominal statistical significance at each secondary endpoint. In the donepezil group, the differential CDR-SB observed at 76 weeks for baseline changes compared to placebo was-0.36 (95% CI: -0.83 to 0.12), ADAS-Cog ₁₃ Is-1.86 (95% CI: -3.63 to-0.09), ADCS-IADL is 1.21 (95% CI: -0.77 to 3.20), MMSE is 0.64 (95% CI: -0.40 to 1.67) (FIGS. 2C-F and Table D).

Table D: primary iADRS and secondary CDR-SB, ADAS-Cog ₁₃ ADCS-iADL and MMSE clinical outcome

The average of primary iADRS and secondary ADAS-Cog13, ADCSiADL, CDR-SB and MMSE clinical results analyzed with MMRM changed results from baseline. iADRS = alzheimer's disease overall evaluationA quantitative table; ADAS-Cog ₁₃ =alzheimer's disease assessment scale-cognitive sub-scale; ADCS-iADL = alzheimer's disease collaborative research tool daily life activity scale; CDR-SB = clinical dementia rating scale box sum; MMSE = simple mental state check; MMRM = hybrid model of repetition metrics; ls=least squares method; CI = confidence interval; SE = standard error

Biomarkers: by targeting N3pGlu aβ, it has been shown that donaform treatment rapidly results in high levels of amyloid plaque clearance as measured by amyloid imaging. For PET amyloid, the participants treated with donepezil showed 85CL amyloid plaque reduction at 76 weeks compared to placebo (placebo = 0.93, donepezil = -84.13) (fig. 3A). The separation of the 68CL decrease from the donepezil group to 24 weeks was evident compared to placebo (placebo = -1.82, donepezil- = -69.64; 65% decrease from baseline in the donepezil group). In the donepezil group, the percentage of "amyloid negative" participants as defined by < 24.1CL amyloid plaques was 40.0%, 59.8% and 67.8% at 24, 52 and 76 weeks, respectively (fig. 3A). About 27% and 55% of the donepezil participants dosed at week 28 and week 56, respectively, achieved sufficient amyloid reduction to reduce placebo infusion. In this study, once the patient's amyloid plaque level was below 25centiloid in two consecutive measurements or below 11centiloid in any one measurement, the patient stopped receiving donepezil and was converted to placebo.

Evaluation is passed [ ¹⁸ F]Total tau load assessed by cetuximab PET revealed no difference from baseline to 76 weeks. However, fig. 3B (ii) shows that tau slows down significantly for the overall measurement of the MUBADA/cerebellar foot ref region. Effect of donepezil on progression of total tau protein (neurofibrillary tangles measured by flutoxib PET) in the whole brain. The Mubada region represents a global region of the entire brain, which corresponds to a typical region with accumulation of neurofibrillary tangles consistent with Alzheimer's disease. Treatment with danamycin had a statistically significant effect on slowing down the progression of neurofibrillary tangles throughout the brain. In fig. 3B (II), "x" indicates p < 0.05, bl=baseline; ls=least squares; MUBADA = multi-block centroid discriminant analysis; n = number of participants; SE = standard error; SUVR = normalized uptake value ratio. The figure illustrates the effect of donepezil on the progression of total tau (neurofibrillary tangles as determined by cetuximab PET) throughout the brain, as opposed to other assays focused on individual leaves or regions. The MUBADA region represents a total region of the entire brain that corresponds to a typical region of neurofibrillary tangle stacks consistent with Alzheimer's disease. Treatment with donepezil has a statistically significant effect on slowing down the progression of neurofibrillary tangles throughout the brain. In fig. 3B (ii), "x" indicates p < 0.05, bl=baseline; ls=least squares method; MUBADA = multi-block centroid discriminant analysis; n = number of participants; SE = standard error; SUVr = normalized uptake value ratio.

Hippocampal volume changes assessed with vMRI showed no differences between groups (fig. 3E). There was a greater whole brain volume decrease and a greater ventricle volume increase in the participants treated with donepezil at age 52 compared to placebo (fig. 3C and 3D).

Figures 3A-E show the results for the secondary biomarkers. FIG. 3A shows secondary results of cerebral amyloid plaque deposition (change from baseline to 76 weeks), as measured by Centeioid (CL) ¹⁸ F]Florol Bei Ping measured in PET scans. 'amyloid negative e'/< 24.1CL = average CL level for other healthy individuals of similar age. Figures 3C-E show vMRI of whole brain (figure 3C), ventricles (figure 3D) and hippocampus (figure 3E). In fig. 3A-E, a = difference; w = week; ls=least squares method; CI = confidence interval; cl=centiloid; n = number of participants; SE = standard error.

Adverse reaction: there was no difference in the incidence of death or Severe Adverse Effects (SAE) between the donepezil and placebo groups. A total of 113 out of 125 participants (90.4%) in the placebo group and 119 out of 131 out of the donepezil group (90.8%) had at least one Treatment Emergent Adverse Effect (TEAE) during the double blind period in the safety population. The incidence of ARJA-E was significantly higher in the donepezil group (27%) compared to the placebo group (0.8%). Compared to 0.8% in the placebo group, 6.1% of all participants in the donepezil group (22% of the participants had ARIA-E) reported symptomatic ARIA-E. Most cases of ARJA-E occur at week 12 of the beginning of the administration. Severe symptomatic ARJA-E in need of hospitalization occurred in 2 participants (1.5%) treated with donepezil. Both participants had symptoms of confusion and one report had difficulty expressing themselves, all of which resolved completely. ARIA-E resolved completely in both cases with an average ARIA-E resolution time of 18 weeks. The incidence of superficial iron deposition, an ARIA (ARIA-H) with central nervous system bleeding, nausea and infusion-related reactions (IRR), was significantly higher in the donepezil group compared to placebo. Treatment interruption due to ARIA-E occurred in 7 participants (5.3%) in the donepezil group; 2 (1.5%) were discontinued due to ARIA-E. No cerebral hemorrhage was observed in either group. IRR was reported in 7.6% of the participants using donepezil and 0% of the participants using placebo. Severe IRR or hypersensitivity reactions occurred in 3 participants (2.3%) treated with donepezil. The incidence of treatment with emergent anti-drug antibodies (TE-ADA) was about 90% among the participants treated with donanazumab.

These results indicate that amyloid clearance in the donepezil mab group is accompanied by a slowing of disease progression in amyloid plaque specific intervention in patients with early symptomatic AD compared to placebo. This 3.20 treatment difference on the iADRS scale at 76 weeks should be interpreted not only in the context of the scoring range (0 to 144) of the whole disease spectrum, but importantly in the context of the dynamic range (26 points) of iADRS and the decline (-10.06) of the placebo group in the participant population.

The results provided herein are unexpected and surprising in several respects. The dosing regimen of donepezil provided a large amount of amyloid removal early in the trial, with almost 60% of the participants having an "amyloid negative" scan by 52 weeks. This is to screen all of the possession [ ¹⁸ F]The first study of the PET scan of cetuximab may reduce the range of potential pathologies, which in turn may beCan reduce the variance of clinical decline.

Tau PET screening of patients precluded subjects with high tau. Patients with high tau respond less to anti-amyloid treatment or suffer from diseases that are more resistant to anti-amyloid treatment.

iADRS, ADAS-Cog, as proposed by the european dementia prevention program, using relatively new disease progression models ₁₃ Treatment variance analysis of ADCS-iADL, CDR-SB and MMSE scores. In view of the better sensitivity of detecting therapeutic effects (Solomon et al, "European Prevention of Alzheimer's Dementia Longitudinal Cohort Study (EPAD LCS): study Protocol," BMJ Open 8: e021017 (2018), incorporated herein by reference in its entirety), this model may allow for a significant increase in statistical efficacy (Wang et al, "A Novel Cognitive Disease Progression Model for Clinical Trials in Autosomal-dominant Alzheimer's disease," Statistics in Medicine: 3047-55 (2018), incorporated herein by reference in its entirety), and in this experiment reveal a disease reduction estimate similar to that of the MMRM model single point estimate.

Regarding the observed lack of therapeutic effect on total tau load, it is conceivable that tau changes of PET were significantly delayed relative to amyloid changes and that the 18 month time period was too short to detect imaging changes. Modeling in autosomal dominant subjects suggests a 10-20 year lag from the first detectable PET amyloid change and the first detectable tau PET change (Barth lemy et al, "A Soluble Phosphorylated Tau Signature Links Tau, amyloid and the Evolution of Stages of Dominantly Inherited Alzheimer's Disease," nat. Med.26:398-407 (2020), incorporated herein by reference in its entirety). The effect on overall tau deficiency may raise issues as to whether targeted amyloid-beta reduction affects biological disease progression. However, in the donepezil group, additional pre-defined analysis of brain regions suggests reduced tau accumulation in frontal and temporal lobe regions compared to placebo (fig. 4A-E).

Robust reduced or further increased prevention of tau accumulation is observed in e.g. frontal lobes of the brain. It is important to note that no statistical significance was observed in the occipital lobes of the brain. The leaf has some highest baseline signal and thus may provide an upper-limit effect on the ability to display a decrease in increased tau load.

Figures 4A-E show a regional SUVr analysis of tau accumulation with cerebellar gray reference. In symptomatic early AD subjects, frontal lobe tau load measured using the cerebellar reference region, as by flutoxion, correlates with iADRS and CDR-SB changes over the following 76 weeks. In fig. 4A-E, ls=least squares method; SE = standard error; AAL area a postcerebellum gray reference area was used. Tau accumulation slows down in the amount She Xianshi 59.1.1% (P value: 0.0020); the top leaf showed a slow tau accumulation of 44.6% (P value: 0.0024); occipital lobe showed a slow tau accumulation of 21.0% (P value: 0.2036); and the lateral temporal lobe showed a slow tau accumulation of 31.8% (P value: 0.0328).

Fig. 5A-B show the change in placebo group relative to baseline frontal tau SUVr at 76 weeks, and lower frontal tau load correlates with less decline in patient. High leaf tau burden is associated with rapid decline in patients. In other words, patients with low leaf tau loading experience a slower decline (as measured by iADRS or CDR-SB) compared to patients with high leaf tau loading.

This measurement reflects the overall change in tau load, and further exploration may show sub-regions that may be more sensitive to changes. The best method for quantifying tau changes and regional selection and analysis of response to treatment remains in its infancy.

There was no significant change in hippocampal volume compared to the recently BACE inhibitor study that showed significant volume changes (Wessels et al, "Efficacy and safety of lanA beta ecestat for treatment of early and mild Alzheimer disease: the amaranth and daybreak-alz randomized clinical trials," JAMA Neurology 77:199-209 (2020), which is incorporated herein by reference in its entirety). A larger decrease in total brain volume and a larger increase in ventricle volume were observed with the treatment with donepezil compared to placebo, which can be explained in the context of protein removal rather than atrophy. The overall volumetric MRI changes are typically due to atrophy in the natural history study of AD, but it is still unclear whether they represent true atrophy in the context of rapid structural removal of protein aggregates, as observed in this study and in another anti-amyloid therapy study (Sur et al, "BACE Inhibition Causes Rapid, regional, and Non-progressiVe Volume Reduction in Alzheimer's Disease Brain," Brain 143:3816-26 (2020), incorporated herein by reference in its entirety).

ARIA-E and ARIA-H are associated with Amyloid plaque removal therapy (Sperling et al, "Amyloid-related imaging abnormalities in Amyloid-modifying therapeutic trials: recommendations from the Alzheimer's Association Research Roundtable Workgroup," Alzheimer's & Dementia 7:367-85 (2011); sevigny et al, "The Antibody Aducanumab Reduces A beta Plaques in Alzheimer's Disease," Nature 537:50-6 (2016); ostrowitzki et al, "Mechanism of Amyloid Removal in Patients With Alzheimer Disease Treated With Gantenerumab," Archives of Neurology 69:198-207 (2012); salloway et al, "Two Phase 3Trials of Bapineuzumab in Mild-to-Moderate Alzheimer's Disease," New England Journal of Medicine 370:322-33 (2014); salloway et al, "A Phase 2 Multiple Ascending Dose Trial of Bapineuzumab in Mild to Moderate Alzheimer Disease," Neurology 73:2061-70 (2009); and Sperling et al, "Amyloid-related Imaging Abnormalities in Patients with Alzheimer's Disease Treated with Bapineuzumab: A Retrospective Analysis," Lancet neurol.11:241-9 (2012), which is incorporated herein by reference in its entirety).

In phase 1b studies, the incidence of ARIA-E was 26.1% among the participants treated with donepezil, with 2 participants reporting symptomatic ARIA-E (4.3%). In this study, similar incidence of ARIA-E was found in the donepezil mab group (27%), with 6.1% reporting symptomatic ARIA-E. The incidence of ARIA-E is more common in ApoE4 carriers, as observed in other experiments with plaque-targeting antibodies (Sevigny et al, "The Antibody Aducanumab Reduces A beta Plaques in Alzheimer's Disease," Nature 2016;537:50-6; ostrowitzki et al, "Mechanism of Amyloid Removal in Patients With Alzheimer Disease Treated With Gantenerumab," Archives of Neurology: 198-207; salloway et al, "Two Phase 3 Trials of Bapineuzumab in Mild-to-Moderate Alzheimer's Disease," NEJM 2014;370:322-33 (2014); and Sperling et al, "Amyloid-related Imaging Abnormalities in Patients with Alzheimer's Disease Treated withBapineuzumab: A Retrospective Analysis," Lancet neurol.11:241-9 (2012), herein incorporated by reference in its entirety). The incidence of TE-ADA (about 90%) among the participants treated with donepezil antibody was similar to the findings of phase 1 (> 85%).

Taken together, these results demonstrate that treatment with donepezil resulted in amyloid plaque clearance, as well as a reduced cognitive and functional decline as measured by the iADRS scale, in participants with early symptomatic AD.

Example 4: efficacy associated with stratification of baseline Tau PET patients

Donepezil was chosen as an exemplary antibody for this example. The anti-N3 pGlu aβ antibody, donepezil, was found to be most effective in subjects with the lowest baseline flutoxib level. The antibody may be less effective in subjects with high tau (> 1.46 SUVr). In other words, subjects with high tau (> 1.46 SUVr) may respond less to aβ therapy.

Based on an initial visual assessment of the flutoxion scan, quantitative analysis is then performed to determine Tau levels (e.g., for stratification purposes in human subjects with AD). Visual assessment relies on a 3-layer reading based on the presence of tracer uptake in specific areas of the neocortex (tAD-, tAD +, tAD ++). Quantitative analysis refers to the calculation of SUVr, which represents counts within a specific target region of interest in the brain (e.g., multi-block barycentric discriminant analysis or MUBADA) when compared to a reference region (reference signal intensity or parameter estimate). A lower SUVr value indicates less tau load, while a higher SUVr value indicates greater tau load.

As shown in table E, scans in the low to medium tau group (e.g., SUVr with ∈1.10 to ∈1.46) are eligible for administration of anti-N3 pGlu aβ antibodies.

Visual assessment: methods for visual assessment of human subjects are described in Fleisher et al, "Positron Emission Tomography Imaging With [ Positron Emission Tomography Imaging With ] ¹⁸ F]flortaucipir and Postmortem Assessment of Alzheimer Disease Neuropathologic Changes, "JAMA neuron 77 (7): 829-839 (2020), which is incorporated herein by reference in its entirety. Briefly, if there is no increased neocortical tracer activity in any region of the brain, the fluoxestrip scan is negative (tAD-), or the activity is sequestered to regions of the frontal or temporal lobe that do not include the posterolateral temporal (PLT) region. Positive scans fall into two categories based on areas of increased neocortical tracer activity. Fluoxel scans with neocortical tracer activity limited to the posterolateral temporal (PLT) or occipital region were classified as tAD +.

Finally, fluoropyridine scans were classified as tAD ++ if they showed an increase in tracer activity in the parietal or pre-wedge region, or the presence of activity in the frontal region and activity in the PLT or occipital region. All tAD + and tAD ++ scans were analyzed quantitatively.

Quantitative analysis: quantitative analysis is accomplished by an automated image processing pipeline. The previously developed neocortical target volume of interest (MUBADA, see Devous et al, "Test-Retest Reproducibility for the Tau PET Imaging Agent Flortaucipir F," J.Nucl. Med.2018;59:937-943 (2018), incorporated herein by reference in its entirety) was applied to each scan and the derived counts were calibrated to a patient-specific reference region (PERI). Other target and reference regions are also extracted through the pipeline. The Persi reference region is a subject-specific, data-driven technique that recognizes voxels with nonspecific fluoxepini uptake within the white matter region defined by the atlas (see, e.g., southekal et al, "Flortaucir F18 Quantitation Using Parametric Estimation of Reference Signal Intensity," J.Nucl. Med.59:944-951 (2018), incorporated herein by reference in its entirety)). The MUBADA target region was developed using statistical methods to maximize the separation of diagnostic groups based on image characteristics (see Devous et al, "Test-Retest Reproducibility for the Tau PET Imaging Agent Flortaucipir F," J.Nucl. Med.59:937-943 (2018), incorporated herein by reference in its entirety). This analysis resulted in 2 dimensions (also known as factors) when applied to flutoxib images from 202 subjects (55aβ -elderly cognitively normal, 43aβ -MCI, 24aβ+mci, 16aβ -AD and 34aβ+ad). The first dimension (which accounts for 95% of variance) provides the greatest group separation by diagnosis and amyloid status and is converted to a VOI, currently known as a MUBADA VOI (see, e.g., devaus et al, "Test-Retest Reproducibility for the Tau PET Imaging Agent Flortaucipir F18," j.nucleic. Med.2018;59:937-943 (2018), incorporated herein by reference in its entirety)).

The MUBADA VOI, proportional to the PERSI reference region, was then applied to 204 subjects and the resulting values were divided into 4 tau load quartiles: 1) Very low; 2) Low; 3) Medium; and 4) high. The cut-off SUVr value for very low and low separation is 1.10; low and medium 1.23; medium and high 1.46. These values were used to screen subjects according to the algorithm described above.

anti-N3 pGlu aβ antibodies were not administered to subjects with SUVr > 1.46 tAD + and tAD ++ scans, based on the assumption that cognitive decline in patients with high tau is driven primarily by their tauopathies and therefore does not respond to anti-amyloid therapies.

Table E: tau evaluation criteria

As shown in fig. 6A-C, the anti-N3 pGlu aβ antibody, donazamab, was found to be most effective in the treatment subgroup with the lowest baseline flutoxib signal. Based on this trend, it can be assumed that patients with high tau (> 1.46 SUVr) are unlikely to respond to therapy.

The data demonstrate that the anti-N3 pGlu aβ antibody, donafanizumab, was most effective in human subjects with tau levels of less than or equal to about 1.14SUVr or less than or equal to about 1.27SUVr (fig. 6A and 6B). In the rightmost panels, the change in scale scores for the donepezil-treated group compared to placebo was statistically insignificant, defined by a baseline tau PET SUVr value greater than 1.274SUVr (fig. 6C). Fig. 6A-C show the iADRS-based baseline tau subgroup analysis (FTP = flutuxeprane).

Example 5: comparison of neural Tau load with cognitive changes

In contrast to cognitive changes, assessment of neural tau burden (both overall and frontal lobes) was measured substantially as follows. Neural tau burden in both the population and frontal lobes of subjects was assessed at baseline by flutoxion as described herein. In addition, at baseline, subjects were subjected to cognitive assessment in iADRS or CDR-SB, as known in the art. At a given point in time thereafter, e.g., at 26 weeks, 52 weeks, 78 weeks, or 104 weeks, the subject may be subjected to cognitive reevaluation, e.g., in iADRS or CDR-SB. Changes in cognitive assessment relative to neurological tau burden can be plotted as shown in figures 5, 7 and 8. Fig. 7 shows the overall tau load at baseline versus the change in iADRS over 18 months. Fig. 8 shows changes in frontal lobe tau load at baseline versus iADRS over 18 months.

Figures 5, 7 and 8 demonstrate lower cognitive decline associated with lower tau load at baseline. In addition, fig. 5, 7, and 8 demonstrate heterogeneity of cognitive decline in patients determined to have higher tau loads (e.g., SUVR greater than about 1.4) at baseline.

Example 6: treatment of subjects identified as having high Tau load

According to the methods described herein, including PET imaging, including using flutoxion, and human pTau217 assessment, subjects can be determined to have high tau burden at baseline. Tau load can be assessed overall, or based on regional lung lobe load (based on brain lobes), such as posterolateral temporal lobes, occipital lobes, parietal lobes, and/or frontal lobes. Patients identified as having a high tau burden may be treated with an anti-aβ antibody described herein and according to a dosage regimen as described herein.

In addition, subjects at baseline can be subjected to cognitive assessment by means as described herein, including by one or more of ADAS-cog, IADL, CDR-SB, MMSE, apoE-4 genotyping and/or iADRS. After treatment with anti-aβaβ as described herein and according to a dosage regimen as described herein, the subject may be subjected to cognitive reevaluation, e.g. at 26 weeks, 52 weeks, 78 weeks or 104 weeks. Patients exhibiting slow or non-rapid cognitive decline, including those determined to have a high tau load, may continue to be treated with the anti-aβ antibodies described herein.

Example 7: efficacy and safety associated with carriers of allelic apolipoprotein e4 (ApoE 4)

The phase-II clinical trial (NCT 03367403; clinicalTrials. Gov-) disclosed above in examples 2, 3, 4 and 5 also included examining the efficacy and safety of an anti-N3 pGlu A beta antibody (donanalizumab) in a subset of participants with one or both alleles of ApoE e 4.

The phase II clinical trial was a randomized, placebo-controlled, double-blind, multicenter phase 2 study to evaluate the safety, tolerability and efficacy of donepezil in early symptomatic AD patients. All enrolled patients with moderate tau pathology levels were evaluated for clinical changes from baseline to 76 weeks using a comprehensive AD rating scale (iADR; primary endpoint), a composite tool for measuring cognitive and daily functions, and a clinical dementia rating scale-block sum (CDR-SB; secondary endpoint). Baseline characteristics showed that 72.5% and 74.2% of patients treated with donepezil or placebo, respectively, were ApoE4 carriers. Additional analysis of iADRS and key secondary endpoints focused on this subset of population.

Results: at 76 weeks, in ApoE4 carriers, donanel single treatment resulted in a 49% decrease in cognitive decline (p=0.004) (fig. 9A), and a 36% decrease in cognitive decline in CDR-SB (p=0.038) (fig. 9C), as measured with iADRS, compared to placebo.

The difference in treatment with donepezil between carrier and non-carrier was significantly greater for the carrier (IADR: p=0.001, fig. 9A-B; CDR-SB: p=0.046, fig. 9C-D). The additional key secondary endpoint showed consistent and strong efficacy of donepezil in ApoE4 carriers compared to placebo. See tables F and G below.

Table F: secondary endpoint for APOE4 carrier

Table G: secondary endpoint for APOE4 non-carriers

The safety profile of ApoE4 carriers was consistent with the total donepezil treatment population. The slowing of the increase in tau PET by donepezil was numerically greater in ApoE4 carriers dosed with donepezil than in non-carriers.

Amyloid-associated imaging abnormalities (ARIA) with edema or exudation (most asymptomatic) are more common in ApoE4 carriers (33.7%) than in non-carriers (8.3%). ARIA with iron-containing hemoxanthin-containing deposits (e.g. micro-bleeding) occurred in 34.5% of ApoE4 carriers receiving donepezil. The carrier subjects with ARIA were examined for no significance of changing placebo treatment differences for iahrs (p=0.020) and CDR-SB (p=0.050).

Analysis of the study population showed that donepezil had higher efficacy in ApoE4 carriers than in non-carriers, with significantly slower disease progression measured in both iADRS and CDR-SB.

Figures 9A-B show that donepezil shows higher efficacy in ApoE e4 carriers than in non-carriers. Fig. 9A shows that donepezil showed higher efficacy in ApoE e4 carriers than in non-carriers on the iADR5 scale. Fig. 9B shows that donepezil showed higher efficacy in ApoE e4 carriers than in non-carriers on the CDR-SB scale. Fig. 9E shows amyloid changes (centoil) in ApoE4 status in patients in the dosing and placebo groups. Fig. 9F shows a change in tau PET SUVR by ApoE e4 status in a patient. The left panel shows frontal lobe data for a carrier of ApoE E4 (referred to as the E4 carrier in fig. 9F) and a non-carrier (referred to as the E4 non-carrier in fig. 9F). The right panel shows temporal lobe data for a carrier of ApoE E4 (referred to as the E4 carrier in the figure) and a non-carrier (referred to as the E4 non-carrier in the figure). Figures 9G-I show iADRS-based baseline tau subgroup analysis of ApoE e4 carriers in the donepezil-treated and placebo groups. The lower third shows baseline cetuximab (FTP) SUVR ∈ 1.144 patients in placebo and donanel single groups. The middle third shows patients with a baseline FTP SUVR of 1.144 to 1.268 for placebo and donazamab groups. The upper third shows patients with baseline FTP SUVR > 1.268 for placebo and donepezil groups.

Sequence (underlined concentration section represents CDR)

SEQ ID NO:1, a step of; light Chain Variable Region (LCVR)

SEQ ID NO:2; heavy Chain Variable Region (HCVR)

SEQ IS NO:3, a step of; light Chain (LC)

SEQ IS NO:4, a step of; heavy Chain (HC)

SEQ ID NO:5, a step of; light chain complementarity determining region 1 (LCDR 1)

SEQ ID NO:6, preparing a base material; light chain complementarity determining region 2 (LCDR 2)

SEQ ID NO:7, preparing a base material; light chain complementarity determining region 3 (LCDR 3)

SEQ ID NO:8, 8; heavy chain complementarity determining region 1 (HCDR 1)

SEQ ID NO:9, a step of performing the process; heavy chain complementarity determining region 2 (HCDR 2)

SEQ ID NO:10; heavy chain complementarity determining region 3 (HCDR 3)

SEQ ID NO:11; SEQ ID NO:1, a nucleotide sequence of 1; light Chain Variable Region (LCVR)

SEQ ID NO.12; SEQ ID NO:2, a nucleotide sequence of seq id no; heavy Chain Variable Region (HCVR)

SEQ ID NO.13; SEQ ID NO:3, a nucleotide sequence of 3; light Chain (LC)

SEQ ID NO.14; SEQ ID NO:4, a nucleotide sequence of seq id no; heavy Chain (HC)

Sequence listing

<110> Eli Lilly and Company

<120> anti-N3 pGlu amyloid beta antibodies and uses thereof

<130> X23016

<150> 63/160642

<151> 2021-03-12

<150> 63/192271

<151> 2021-05-24

<160> 14

<170> PatentIn version 3.5

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Pro Gln Leu Leu Ile Tyr Ala Val Ser Lys Leu Asp Ser Gly Val Pro

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Gly Trp Ile Asn Pro Gly Ser Gly Asn Thr Lys Tyr Asn Glu Lys Phe

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Ala Arg Glu Gly Ile Thr Val Tyr Trp Gly Gln Gly Thr Thr Val Thr

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<212> DNA

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gatattgtga tgactcagac tccactctcc ctgtccgtca cccctggaca gccggcctcc 60

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<210> 12

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cctggacaag ggcttgagtg gatgggatgg attaatcctg gaagcggtaa tactaagtac 180

aatgagaaat tcaagggcag agtcaccatt accgcggacg aatccacgag cacagcctac 240

atggagctga gcagcctgag atctgaggac acggccgtgt attactgtgc gagagaaggc 300

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<210> 13

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<220>

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cctggacaag ggcttgagtg gatgggatgg attaatcctg gaagcggtaa tactaagtac 180

aatgagaaat tcaagggcag agtcaccatt accgcggacg aatccacgag cacagcctac 240

atggagctga gcagcctgag atctgaggac acggccgtgt attactgtgc gagagaaggc 300

atcacggtct actggggcca agggaccacg gtcaccgtct cctcagcctc caccaagggc 360

ccatcggtct tcccgctagc accctcctcc aagagcacct ctgggggcac agcggccctg 420

ggctgcctgg tcaaggacta cttccccgaa ccggtgacgg tgtcgtggaa ctcaggcgcc 480

ctgaccagcg gcgtgcacac cttcccggct gtcctacagt cctcaggact ctactccctc 540

agcagcgtgg tgaccgtgcc ctccagcagc ttgggcaccc agacctacat ctgcaacgtg 600

aatcacaagc ccagcaacac caaggtggac aagaaagttg agcccaaatc ttgtgacaaa 660

actcacacat gcccaccgtg cccagcacct gaactcctgg ggggaccgtc agtcttcctc 720

ttccccccaa aacccaagga caccctcatg atctcccgga cccctgaggt cacatgcgtg 780

gtggtggacg tgagccacga agaccctgag gtcaagttca actggtacgt ggacggcgtg 840

gaggtgcata atgccaagac aaagccgcgg gaggagcagt acaacagcac gtaccgtgtg 900

gtcagcgtcc tcaccgtcct gcaccaggac tggctgaatg gcaaggagta caagtgcaag 960

gtctccaaca aagccctccc agcccccatc gagaaaacca tctccaaagc caaagggcag 1020

ccccgagaac cacaggtgta caccctgccc ccatcccggg acgagctgac caagaaccag 1080

gtcagcctga cctgcctggt caaaggcttc tatcccagcg acatcgccgt ggagtgggag 1140

agcaatgggc agccggagaa caactacaag accacgcccc ccgtgctgga ctccgacggc 1200

tccttcttcc tctatagcaa gctcaccgtg gacaagagca ggtggcagca ggggaacgtc 1260

ttctcatgct ccgtgatgca tgaggctctg cacaaccact acacgcagaa gagcctctcc 1320

ctgtctccgg gt 1332

Claims

1. A method of treating or preventing a disease characterized by amyloid β (aβ) deposits in the brain of a human subject, the method comprising:

administering an effective amount of an anti-aβ antibody to the human subject, wherein the human subject has been determined to have a low to moderate tau load or very low to moderate tau load, or to have a low to moderate tau load or very low to moderate tau load and one or both alleles of ApoE 4.

2. A method of treating or preventing a disease characterized by amyloid β (aβ) deposits in the brain of a human subject, the method comprising:

administering an effective amount of an anti-aβ antibody to the human subject, wherein the human subject has been determined to have i) a high tau load or ii) one or both alleles of high tau load and ApoE e 4; and the human subject has been determined to exhibit a slow decline.

3. A method of treating or preventing a disease characterized by amyloid β (aβ) deposits in the brain of a human subject, the method comprising:

i) Determining whether the human subject has a low to medium tau load or a very low to medium tau load; and if the human subject has a low to moderate tau load or a very low to moderate tau load, or

ii) determining whether the human subject has one or both alleles of ApoE e4 and a low to medium tau load or a very low to medium tau load; and if the human subject has one or both alleles of ApoE e4 and a low to medium tau load or a very low to medium tau load:

administering an effective amount of an anti-aβ antibody to the human subject.

4. A method of treating or preventing a disease characterized by amyloid β (aβ) deposits in the brain of a human subject, the method comprising:

i) Determining whether the human subject has a high tau load; and if the human subject has a high tau load, further determining if the human subject has exhibited a slow decline; and if the human subject has exhibited a slow decline, or

ii) determining whether the human subject has a high tau load and one or both alleles of ApoE e 4; and if the human subject has a high tau load and one or both alleles of ApoE 4, further determining if the human subject has exhibited a slow decline; and if the human subject has exhibited a slow decline:

Administering an effective amount of an anti-aβ antibody to the human subject.

5. A method of treating or preventing a disease characterized by amyloid β (aβ) deposits in the brain of a human subject, the method comprising:

administering an effective amount of an anti-aβ antibody to the human subject, wherein the human subject has been determined to be i) not having a high tau load or ii) having one or both alleles of ApoE e4 and not having a high tau load.

6. A method of treating or preventing a disease characterized by amyloid β (aβ) deposits in the brain of a human subject, the method comprising:

administering an effective amount of an anti-aβ antibody to the human subject, wherein the human subject has been determined to have a high tau load; and the human subject has been determined to exhibit a slow decline, or

Administering an effective amount of an anti-aβ antibody to the human subject, wherein the human subject has been determined to have a high tau load and one or both alleles of ApoE 4; and the human subject has been determined to exhibit a slow decline.

7. The method of any one of claims 1-6, wherein the anti-aβ antibody is administered to the human subject for a duration sufficient to treat or prevent the disease.

8. The method of any one of claims 1-7, wherein treatment or prevention of the disease results in i) a reduction of aβ deposits in the brain of the human subject and/or ii) a slowing of cognitive or functional decline in the human subject.

9. The method of claim 8, wherein the reduction of aβ deposits in the brain of the human subject is determined by amyloid PET brain imaging or diagnosis of biomarkers that detect aβ.

10. The method of claim 8 or 9, wherein an effective dose of the anti-aβ antibody is administered to the human subject until aβ deposits in the brain of the human subject are reduced by about 20-100%.

11. The method of claim 10, wherein aβ deposits in the brain of the human subject are reduced by about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 75%, or about 100%.

12. The method of any one of claims 1-11, wherein an effective dose of anti-aβ antibody is administered to the human subject until aβ deposits in the brain of the human subject are reduced by i) about 25 centoil to about 100 centoil, ii) about 50 centoil to about 100 centoil, iii) about 100 centoil, or iv) about 84 centoil.

13. The method of any one of claims 1-12, wherein the disease characterized by aβ deposits in the brain of the human subject is selected from preclinical Alzheimer's Disease (AD), clinical AD, prodromal AD, mild AD, moderate AD, severe AD, down's syndrome, clinical cerebral amyloid angiopathy, or preclinical cerebral amyloid angiopathy.

14. The method of any one of claims 1-13, wherein the human subject is an early symptomatic AD patient.

15. The method of claim 14, wherein the human subject has pre-acquired AD and mild dementia caused by AD.

16. A method according to claim 1 or 3, wherein: i) If tau load is ∈1.46SUVr as measured by PET brain imaging, the human subject has very low to medium tau load; and ii) if the tau load as measured by PET brain imaging is 1.10 to 1.46SUVr, the human subject has a low to medium tau load.

17. The method of claim 2, 4, 5 or 6, wherein the human subject has a high tau load if the tau load as measured by PET brain imaging is higher than 1.46 SUVr.

18. The method of claim 2, 4 or 6, wherein the human subject has been determined to exhibit a slow decline, wherein the human subject does not exhibit an iADRS decline of greater than about-20 for about the last 18 months.

19. The method of any one of claims 1-6, wherein the tau burden of the human subject is determined using PET brain imaging or diagnosis of biomarkers to detect tau.

20. The method of any one of claims 1-19, wherein the anti-aβ antibody is an anti-N3 pGlu aβ antibody.

21. The method of any one of claims 1-20, wherein administering comprises: (i) Administering to the human subject one or more first doses of about 100mg to about 700mg of anti-aβ antibody, wherein each first dose is administered about once every 4 weeks; and (ii) administering to the subject one or more second doses of greater than about 700mg to about 1400mg of the anti-aβ antibody about 4 weeks after administering the one or more first doses, wherein each second dose is administered about once every 4 weeks.

22. A method for testing the efficacy of anti-aβ antibody therapy for treating or preventing a disease characterized by amyloid β (aβ) deposits in the brain of a human subject, the method comprising:

(a) Administering an effective amount of an anti-aβ antibody to the human subject, wherein the human subject has been determined to have a low to medium tau load or a very low to medium tau load; and is also provided with

(b) Determining whether the disease has been treated or prevented.

23. The method of claim 22, wherein determining whether the disease has been treated or prevented comprises: i) Determining a decrease in aβ deposits in the brain of the human subject and/or ii) determining a decrease in cognitive or functional decline in the human subject, optionally wherein a decrease in aβ deposits in the brain of the human subject is determined by amyloid PET brain imaging or diagnosis of biomarkers that detect aβ.

24. The method of claim 22 or 23, comprising determining 20-100% reduction of aβ deposits in the brain of the human subject.

25. The method of claim 22 or 23, comprising determining a reduction of aβ deposits in the brain of the human subject of about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 75%, or about 100%.

26. The method of any one of claims 22-25, comprising determining a decrease in aβ deposits in the brain of the human subject: i) An approximate average of about 25 to about 100 cents of oil, ii) an approximate average of about 50 to about 100 cents of oil, iii) about 100 cents of oil, or iv) about 84 cents of oil.

27. The method of any one of claims 22-26, wherein the disease characterized by aβ deposits in the brain of the human subject is selected from preclinical Alzheimer's Disease (AD), clinical AD, prodromal AD, mild AD, moderate AD, severe AD, down's syndrome, clinical cerebral amyloid angiopathy, or preclinical cerebral amyloid angiopathy.

28. The method of any one of claims 22-27, wherein the human subject is an early symptomatic AD patient.

29. The method of claim 28, wherein the human subject has pre-acquired AD and mild dementia caused by AD.

30. The method of any one of claims 22-29, wherein: i) If tau load is ∈1.46SUVr as measured by PET brain imaging, the human subject has very low to medium tau load; and ii) if the tau load as measured by PET brain imaging is 1.10 to 1.46SUVr, the human subject has a low to medium tau load.

31. The method of any one of claims 22-30, wherein the anti-aβ antibody is an anti-N3 pgluaβ antibody.

32. A method for reducing, preventing further increases, and/or slowing the rate of tau load/accumulation in one or more parts of the human brain of a human subject, the method comprising administering to the subject an effective amount of an anti-aβ antibody.

33. The method of claim 32, wherein the portion of the human brain is the frontal lobe.

34. The method of claim 32, wherein the portion of the human brain is the parietal lobe.

35. The method of claim 32, wherein the portion of the human brain is occipital lobe.

36. The method of claim 32, wherein the portion of the human brain is the temporal lobe.

37. The method of claim 32, wherein the portion of the human brain is the posterolateral temporal lobe.

38. A method of treating or preventing a disease characterized by amyloid β (aβ) deposits in the brain of a human subject that has been determined to have a tau burden in the temporal lobe of the brain, the method comprising administering an anti-aβ antibody to the human subject.

39. A method of treating or preventing a disease characterized by amyloid β (aβ) deposits in the brain of a human subject, the method comprising: (a) Determining whether the human subject has tau load in temporal lobes of the brain; and (b) administering an anti-aβ antibody to the human subject.

40. A method of treating or preventing a disease characterized by amyloid β (aβ) deposits in the brain of a human subject that has been determined to have tau burden in the posterolateral temporal lobe of the brain, comprising administering an anti-aβ antibody to the human subject.

41. A method of treating or preventing a disease characterized by amyloid β (aβ) deposits in the brain of a human subject, the method comprising: (a) Determining whether the human subject has tau load in the posterolateral temporal lobe of the brain; and (b) administering an anti-aβ antibody to the human subject.

42. A method of treating or preventing a disease characterized by amyloid β (aβ) deposits in the brain of a human subject that has been determined to have tau burden in occipital lobes of the brain, the method comprising administering an anti-aβ antibody to the human subject.

43. A method of treating or preventing a disease characterized by amyloid β (aβ) deposits in the brain of a human subject, the method comprising: (a) Determining whether the human subject has tau load in occipital lobes of the brain; and (b) administering an anti-aβ antibody to the human subject.

44. A method of treating or preventing a disease characterized by amyloid β (aβ) deposits in the brain of a human subject that has been determined to have a tau burden in the parietal lobe of the brain, comprising administering to the human subject an anti-aβ antibody.

45. A method of treating or preventing a disease characterized by amyloid β (aβ) deposits in the brain of a human subject, the method comprising: (a) Determining whether the human subject has tau load in the parietal lobe of the brain; and (b) administering an anti-aβ antibody to the human subject.

46. A method of treating or preventing a disease characterized by amyloid β (aβ) deposits in the brain of a human subject that has been determined to have tau burden in the frontal lobe of the brain, the method comprising administering an anti-aβ antibody to the human subject.

47. A method of treating or preventing a disease characterized by amyloid β (aβ) deposits in the brain of a human subject, the method comprising: (a) Determining whether the human subject has tau load in frontal lobes of the brain; and (b) administering an anti-aβ antibody to the human subject.

48. A method of treating or preventing a disease characterized by amyloid β (aβ) deposits in the brain of a human subject who has been determined to have tau burden in the posterolateral temporal and/or occipital lobes of the brain, the method comprising administering an anti-aβ antibody to the human subject.

49. A method of treating or preventing a disease characterized by amyloid β (aβ) deposits in the brain of a human subject, the method comprising: (a) Determining whether the human subject has tau load in the posterolateral temporal lobe and/or occipital lobe of the brain; and (b) administering an anti-aβ antibody to the human subject.

50. A method of treating or preventing a disease characterized by amyloid β (aβ) deposits in the brain of a human subject who has been identified as being in the (i) parietal or anterior wedge regions of the brain; and/or (ii) tau load in frontal and posterolateral temporal lobes or occipital lobes, the method comprising administering an anti-aβ antibody to the human subject.

51. A method of treating or preventing a disease characterized by amyloid β (aβ) deposits in the brain of a human subject, the method comprising: (a) Determining whether the human subject is in (i) the parietal or anterior wedge region of the brain; and/or (ii) tau load in frontal and posterolateral temporal or occipital lobes; and (b) administering an anti-aβ antibody to the human subject.

52. A method of treating or preventing a disease characterized by amyloid β (aβ) deposits in the brain of a human subject that has been determined to have: (i) tau load isolated to frontal lobe; and/or (ii) tau load in temporal lobe regions of the posterolateral temporal lobe excluding the brain, the method comprising administering an anti-aβ antibody to the human subject.

53. A method of treating or preventing a disease characterized by amyloid β (aβ) deposits in the brain of a human subject, the method comprising: (a) Determining whether the human subject has (i) tau load isolated to frontal lobe; and/or (ii) tau load in temporal lobe regions of the posterolateral temporal lobe excluding the brain; and (b) administering an anti-aβ antibody to the human subject.

54. The method of any one of claims 22-53, wherein administering comprises: (i) Administering to the human subject one or more first doses of about 100mg to about 700mg of anti-aβ antibody, wherein each first dose is administered about once every 4 weeks; and (ii) administering to the subject one or more second doses of greater than about 700mg to about 1400mg of the anti-aβ antibody about 4 weeks after administering the one or more first doses, wherein each second dose is administered about once every 4 weeks.

55. The method of any one of claims 38-54, wherein the disease characterized by aβ deposits in the brain of the human subject is selected from preclinical Alzheimer's Disease (AD), clinical AD, prodromal AD, mild AD, moderate AD, severe AD, down's syndrome, clinical cerebral amyloid angiopathy, or preclinical cerebral amyloid angiopathy.

56. A method of selecting a human subject for treating or preventing a disease characterized by amyloid β deposits in the brain of the human subject, the method comprising selecting the human subject based on the amount of integrated (total) tau in the brain of the human subject.

57. The method of claim 56, wherein the human subject is selected for treatment or prevention of a disease characterized by amyloid β deposits in the brain because the human subject has very low to medium tau in the brain.

58. The method of claim 56, wherein the human subject is selected for treatment or prevention of a disease characterized by amyloid β deposits in the brain because the human subject has very low to moderate tau (or moderate tau) in the brain.

59. The method of claim 56, wherein the human subject is excluded from treatment or prevention of a disease characterized by amyloid β deposits in the brain because the human subject has high tau in the brain.

60. The method of claim 56, wherein the human subject is selected based on the progression of AD and optionally tau burden in the brain of the human subject.

61. The method of claim 56, wherein the human subject is selected because the human subject has tau load present in frontal lobes of the brain.

62. The method of claim 56, wherein the human subject is selected because the human subject has tau load present in the parietal lobe of the brain.

63. The method of claim 56, wherein the human subject is selected because the human subject has tau load present in occipital lobes of the brain.

64. The method of claim 56, wherein the human subject is selected because the human subject has tau load present in temporal lobes of the brain.

65. The method of claim 56, wherein the human subject is selected because the human subject has tau load present in the posterolateral temporal lobe and/or occipital lobe of the brain.

66. The method of claim 56, wherein the human subject is selected because the human subject has tau load present in i) the parietal or anterior wedge lobe region or ii) the frontal lobe region, and tau load in the posterolateral temporal lobe or occipital lobe region of the brain.

67. The method of claim 56, wherein said human subject is selected because the human subject has: i) Tau load isolated to frontal lobe or ii) tau load in temporal lobe region excluding posterolateral temporal lobe region (PLT) of brain.

68. The method of any of claims 34-67, wherein the tau load is greater than about 1.46SUVr based on PET imaging.

69. A method for determining whether to discontinue administration of an anti-aβ antibody to a human subject undergoing therapy with an anti-aβ antibody, the method comprising determining tau load/accumulation in a portion of the brain of the human subject.

70. The method of claim 69, wherein determining tau load/accumulation comprises determining a decrease in the rate of tau load/accumulation in a portion of the brain, preventing further increase or slowing thereof.

71. The method of claim 69 or 70, wherein the portion of the brain is selected from the group consisting of temporal lobe, occipital lobe, parietal lobe, frontal lobe, or any combination thereof.

72. The method of any one of claims 22-71, wherein the human subject has one or both alleles of ApoE e 4.