Methods for treating alzheimer's disease

Abstract

To provide methods for treating Alzheimer's disease.SOLUTION: The disclosure provides a method for treating Alzheimer's disease (AD) in a human subject in need thereof when the subject develops amyloid-related image abnormality (ARIA) during a therapeutic regimen comprising plural dose administration of an anti-beta amyloid antibodies (e.g., BIIB037) to the human subject. The disclosure satisfies the demand in the art for a method that reduces the ARIA occurrence rate in Alzheimer's disease patient at the AD treatment protocols.SELECTED DRAWING: Figure 10

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority to U.S. Provisional Application No. 62 / 346,818, filed June 7, 2016, and U.S. Provisional Application No. 62 / 435,531, filed December 16, 2016, the contents of both of which are incorporated herein by reference in their entireties.

[0002] The present disclosure relates generally to methods of treating Alzheimer's disease. [Background technology]

[0003] Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized clinically by cognitive impairment, behavioral abnormalities, psychiatric symptoms, and impairment in activities of daily living. These clinical manifestations constitute AD dementia.

[0004] AD International estimates that the number of people living with dementia worldwide will increase from the current 35.6 million to 115.4 million by 2050. AD is the most common cause of dementia, accounting for 60-80% of dementia cases. In the United States, it is estimated that 5.3 million Americans have dementia due to AD, and the prevalence will double or triple by 2050 unless an effective treatment is found.

[0005] Clinical research criteria for dementia due to AD have been recently revised, creating a diagnostic framework that encompasses pre-dementia stages of AD (e.g., prodromal AD) in line with current concepts of the disease. The primary neuropathological hallmarks of the disease are (i) extracellular senile plaques (senile / neuritic plaques) containing aggregated β-amyloid (Aβ) peptides and (ii) intracellular neurofibrillary tangles (NFTs) composed of abnormal hyperphosphorylated tau protein. While the pathogenesis of these plaques and tangles and the mechanisms by which they contribute to the clinical syndrome remain incompletely understood, the prevailing hypothesis, the "amyloid cascade," proposes that the driving force behind the disease process is Aβ accumulation resulting from an imbalance between Aβ production and Aβ clearance in the brain.

[0006] Aβ is a peptide produced by the metabolism of amyloid precursor protein. Several Aβ peptide alloforms exist (e.g., Aβ40, Aβ42). These monomeric peptides tend to vary and aggregate into higher-order dimers and oligomers. During fibril formation, soluble oligomers can transition into insoluble deposits with a β-pleated sheet structure. These deposits, also known as amyloid plaques, are primarily composed of fibrillar amyloid. Both soluble and fibrillar forms of Aβ are thought to contribute to the disease process.

[0007] Biomarker, clinicopathological, and cohort studies support that the disease process begins 10 to 20 years before clinical symptoms appear, and some of the early pathological findings include the deposition of neocortical senile plaques and mesial temporal NFTs, followed several years later by neocortical NFTs.

[0008] Currently, there are no treatments that modify the course of Alzheimer's disease. Currently approved treatments provide only modest symptomatic benefit and do not attenuate the disease process. Several promising disease-modifying drug candidates are currently in testing. These candidates include small molecules and immunotherapies (active and passive) that target the Aβ pathway and aim to reduce soluble or insoluble forms of Aβ in the brain and cerebrospinal fluid (CSF) to provide therapeutic benefit.

[0009] In response to guidance issued by the US Food and Drug Administration (FDA) to various sponsors conducting clinical trials of amyloid-modifying agents for the treatment of AD, a Workgroup was formed in July 2010 by the Alzheimer's Association Research Roundtable. The Workgroup was composed of representatives from academia and industry, identified based on their expertise and interest in the area. It was tasked with providing expert advice on FDA concerns related to magnetic resonance imaging (MRI) abnormalities, including signal changes thought to represent vasogenic edema (VE) and microhemorrhages (mH). MRI signal changes were first observed in clinical trials of monoclonal antibodies against β-amyloid and have since been associated with other amyloid-modifying therapeutic agents.

[0010] Although the exact pathophysiological mechanisms of these MRI abnormalities have not been determined, VE and mH are typically detected on different MRI sequences. They appear to represent a spectrum of imaging abnormalities that may share some common underlying pathophysiological mechanisms in both the natural history of AD and amyloid-modifying therapies. The Workgroup proposed to call this spectrum amyloid-related imaging abnormalities (ARIA).

[0011] Although underlying mechanisms may be shared, it may be more useful to describe specific phenomena. Therefore, the Workgroup further refined the terminology: ARIA-E refers to MR signal changes thought to represent VE and related fluid leakage phenomena. ARIA-H refers to MR signal changes due to mH and hemosiderosis.

[0012] ARIA-E manifests most frequently as high MR signal intensity on FLAIR or other T2-weighted sequences in the parenchyma and / or pia mater of the parietal, occipital, and frontal lobes, but has also been observed in the cerebellum and brainstem. The presence of the ε4 allele of apolipoprotein E, ApoE ε4, has been found to be a significant risk factor for the development of ARIA-E.

[0013] Currently, there are very limited publicly available data regarding the clinical course associated with ARIA-E occurring in clinical trials of amyloid-modifying therapies. The Workgroup reviewed data from trials of bapineuzumab and found that it was unclear whether ARIA observed with other amyloid-modifying therapies would follow a similar clinical course. In any event, the pathophysiological mechanisms underlying vasogenic edema remain unclear.

[0014] mH is generally due to one of two etiologies: small-vessel angiopathy and cerebral amyloid angiopathy (CAA). The prevalence of mH is significantly higher in elderly individuals with cardiovascular risk factors and / or evidence of a previous cerebrovascular event. In AD, mH and superficial hemosiderosis result from leakage of blood from CAA vessels. CAA is thought to weaken blood vessel walls, increasing the risk of blood microleakage into the adjacent brain and forming mH. Furthermore, there is limited publicly available data on the development of mH in ARIA-E associated with amyloid-modifying therapy.

[0015] Preliminary reports of ARIA expression in therapeutic strategies aimed at reducing the production of specific Aβ peptides suggest that reducing Aβ1-42 or altering the ratio of various Aβ species may alter the kinetics of amyloid production and clearance leading to ARIA. Direct removal of amyloid from the vessel wall may compromise vascular integrity. Alternatively, amyloid-associated endothelial cell dysfunction may increase vascular permeability, which could explain the similarity with high permeability. It is also possible that there is a focal inflammatory component leading to both ARIA-E and ARIA-H, as suggested by pathology reports from CAA patients. Normal CSF has also been reported in inflammatory CAA, suggesting that focal amyloid-associated vascular inflammation may play a role in some cases of ARIA. It remains unclear whether different forms of immunotherapy or specific antibodies may differentially contribute to ARIA.

[0016] The incidence of ARIA in patients being treated for Alzheimer's disease remains a persistent problem, and although there are many likely target mechanisms of action, no solution to the problem has been found.

[0017] Thus, there is a need in the art for methods to reduce the incidence of ARIA in susceptible Alzheimer's disease patients during AD treatment protocols. Summary of the Invention [Means for solving the problem]

[0018] The present disclosure fulfills the need in the art for methods of reducing the incidence of ARIA in Alzheimer's disease (AD) patients during AD treatment protocols.

[0019] In one aspect, the disclosure features a method of treating AD in a human subject in need thereof, comprising administering multiple doses of an anti-beta amyloid antibody to the human subject, wherein the subject develops amyloid-related imaging abnormalities (ARIA) during treatment with the anti-beta amyloid antibody. ARIA may be, for example, (i) ARIA-E, which is moderate or severe and is not associated with clinical symptoms; (ii) ARIA-E, which is mild, moderate, or severe and is accompanied by mild, moderate, or severe clinical symptoms, or clinical symptoms that meet the "other medically significant" severity classification criteria; (iii) ARIA-H, which has 5 to 9 cumulative microbleeds and is not associated with clinical symptoms; (iv) ARIA-H, which has 1 to 9 cumulative microbleeds and is accompanied by mild, moderate, or severe clinical symptoms, or clinical symptoms that meet the "other medically significant" severity classification criteria; (v) ARIA-H, which has two cumulative areas of superficial hemosiderosis and is not associated with clinical symptoms; or (vi) ARIA-H, which has 1 or 2 cumulative areas of superficial hemosiderosis and is accompanied by mild, moderate, or severe clinical symptoms, or clinical symptoms that meet the "other medically significant" severity classification criteria. After the subject develops ARIA, administration of the anti-beta amyloid antibody to the subject is discontinued until the ARIA has resolved (and, if clinical symptoms are present, until the symptoms have resolved). The method further includes resuming administration of the anti-beta amyloid antibody to the subject at the same dose administered to the subject immediately prior to the onset of ARIA.

[0020] In some embodiments, the multiple doses of anti-beta amyloid antibody are the same dose. In certain cases, the multiple doses are each 1 mg / kg of subject body weight. In certain cases, the multiple doses are each 3 mg / kg of subject body weight. In certain cases, the multiple doses are each 6 mg / kg of subject body weight. In certain cases, the multiple doses are each 10 mg / kg of subject body weight. In certain cases, the multiple doses are each 12 mg / kg of subject body weight. In certain cases, the multiple doses are each 15 mg / kg of subject body weight. In certain cases, the multiple doses are each 18 mg / kg of subject body weight. In certain cases, the multiple doses are each 20 mg / kg of subject body weight. In certain cases, the multiple doses are each 24 mg / kg of subject body weight. In certain cases, the multiple doses are each 30 mg / kg of subject body weight.

[0021] In other embodiments, the multiple doses of anti-beta amyloid antibody comprise different dose amounts. In certain instances, the multiple doses comprise 1 mg / kg and 3 mg / kg of subject body weight. In certain instances, the multiple doses comprise 1 mg / kg, 3 mg / kg, and 6 mg / kg of subject body weight. In certain instances, the multiple doses comprise 3 mg / kg and 6 mg / kg of subject body weight. In certain instances, the multiple doses comprise 1 mg / kg, 3 mg / kg, 6 mg / kg, and 10 mg / kg of subject body weight. In certain instances, the multiple doses comprise 3 mg / kg, 6 mg / kg, and 10 mg / kg of subject body weight. In certain instances, the multiple doses comprise 3 mg / kg, 6 mg / kg, 10 mg / kg, and 12 mg / kg of subject body weight. In certain instances, the multiple doses comprise 3 mg / kg, 6 mg / kg, 10 mg / kg, and 15 mg / kg of subject body weight.

[0022] In some embodiments, where the subject is an ApoE4 carrier, the multiple doses include two or more of 1 mg / kg, 3 mg / kg, 6 mg / kg, or 10 mg / kg of the subject's body weight. In some embodiments, where the subject is an ApoE4 non-carrier, the multiple doses include two or more of 1 mg / kg, 3 mg / kg, 6 mg / kg, 10 mg / kg, 15 mg / kg, or 30 mg / kg of the subject's body weight.

[0023] In certain embodiments, the method further comprises administering a subsequent administration of an anti-beta amyloid antibody at a higher dose than the dose administered when administration is resumed after resolution of the ARIA.

[0024] In some embodiments, multiple doses are administered at 4 week intervals.

[0025] In some embodiments, the number of multiple doses administered to a subject prior to ARIA onset is 2 to 14 doses (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 doses). In other embodiments, the number of multiple doses administered to a subject prior to ARIA onset is 2 to 5 doses. In one embodiment, the number of multiple doses administered to a subject prior to ARIA onset is 2 doses. In one embodiment, the number of multiple doses administered to a subject prior to ARIA onset is 3 doses. In one embodiment, the number of multiple doses administered to a subject prior to ARIA onset is 4 doses. In one embodiment, the number of multiple doses administered to a subject prior to ARIA onset is 5 doses.

[0026] In one embodiment, administering multiple doses of an anti-beta amyloid antibody to a human subject includes, prior to the onset of ARIA, performing two or more of the following administration steps, in order, beginning with step (a): (a) administering to a subject an anti-beta amyloid antibody in an amount of 1 mg / kg of the subject's body weight; (b) 4 weeks after step (a), administering the antibody to the subject in an amount of 1 mg / kg of the subject's body weight; (c) 4 weeks after step (b), administering the antibody to the subject in an amount of 3 mg / kg of the subject's body weight; (d) 4 weeks after step (c), administering the antibody to the subject in an amount of 3 mg / kg of the subject's body weight; (e) 4 weeks after step (d), administering the antibody to the subject in an amount of 3 mg / kg of the subject's body weight; (f) 4 weeks after step (e), administering the antibody to the subject in an amount of 3 mg / kg of the subject's body weight; (g) 4 weeks after step (f), administering the antibody to the subject in an amount of 6 mg / kg of the subject's body weight; and (h) After step (g), at subsequent 4 week intervals, administering the antibody to the subject in an amount of 6 mg / kg of the subject's body weight.

[0027] In one embodiment, the method comprises, after resolution of ARIA (and resolution of clinical symptoms), administering the following steps, in order, that were not administered prior to the onset of ARIA: (a) administering to a subject an anti-beta amyloid antibody in an amount of 1 mg / kg of the subject's body weight; (b) 4 weeks after step (a), administering the antibody to the subject in an amount of 1 mg / kg of the subject's body weight; (c) 4 weeks after step (b), administering the antibody to the subject in an amount of 3 mg / kg of the subject's body weight; (d) 4 weeks after step (c), administering the antibody to the subject in an amount of 3 mg / kg of the subject's body weight; (e) 4 weeks after step (d), administering the antibody to the subject in an amount of 3 mg / kg of the subject's body weight; (f) 4 weeks after step (e), administering the antibody to the subject in an amount of 3 mg / kg of the subject's body weight; (g) 4 weeks after step (f), administering the antibody to the subject in an amount of 6 mg / kg of the subject's body weight; and (h) After step (g), at subsequent 4 week intervals, administering the antibody to the subject in an amount of 6 mg / kg of the subject's body weight.

[0028] In one embodiment, the method involves administering multiple doses of an anti-beta amyloid antibody to a human subject (the subject being an ApoE4 non-carrier or an ApoE4 carrier) prior to the onset of ARIA by performing two or more of the following administration steps, in sequence, starting with step (a): (a) administering to a subject an anti-beta amyloid antibody in an amount of 1 mg / kg of the subject's body weight; (b) 4 weeks after step (a), administering the antibody to the subject in an amount of 1 mg / kg of the subject's body weight; (c) 4 weeks after step (b), administering the antibody to the subject in an amount of 3 mg / kg of the subject's body weight; (d) 4 weeks after step (c), administering the antibody to the subject in an amount of 3 mg / kg of the subject's body weight; (e) 4 weeks after step (d), administering the antibody to the subject in an amount of 6 mg / kg of the subject's body weight; (f) 4 weeks after step (e), administering the antibody to the subject in an amount of 6 mg / kg of the subject's body weight; and (g) After step (f), at subsequent 4 week intervals, administering the antibody to the subject in an amount of 10 mg / kg of the subject's body weight.

[0029] In one embodiment, the method comprises, after resolution of ARIA, administering the following steps, in order, if any, that were not administered prior to onset of ARIA: (a) administering to a subject an anti-beta amyloid antibody in an amount of 1 mg / kg of the subject's body weight; (b) 4 weeks after step (a), administering the antibody to the subject in an amount of 1 mg / kg of the subject's body weight; (c) 4 weeks after step (b), administering the antibody to the subject in an amount of 3 mg / kg of the subject's body weight; (d) 4 weeks after step (c), administering the antibody to the subject in an amount of 3 mg / kg of the subject's body weight; (e) 4 weeks after step (d), administering the antibody to the subject in an amount of 6 mg / kg of the subject's body weight; (f) 4 weeks after step (e), administering the antibody to the subject in an amount of 6 mg / kg of the subject's body weight; and (g) After step (f), at subsequent 4 week intervals, administering the antibody to the subject in an amount of 10 mg / kg of the subject's body weight.

[0030] In one embodiment, the administration of multiple doses of an anti-beta amyloid antibody to a human subject (wherein the subject is an ApoE4 carrier) comprises: (a) administering to a subject an anti-beta amyloid antibody in an amount of 1 mg / kg of the subject's body weight; (b) 4 weeks after step (a), administering the antibody to the subject in an amount of 1 mg / kg of body weight of the subject; and (c) after step (b), at subsequent 4 week intervals, administering the antibody to the subject in an amount of 3 mg / kg of the subject's body weight.

[0031] In some embodiments, after reinstating administration of the anti-beta amyloid antibody, the human subject develops a second ARIA. The second ARIA may be, for example, (i) ARIA-E that is moderate or severe and is not associated with clinical symptoms; (ii) ARIA-E that is mild, moderate, or severe and is accompanied by mild, moderate, or severe clinical symptoms, or clinical symptoms that meet the "other medically significant" severity classification criteria; (iii) ARIA-H that has 5 to 9 cumulative microbleeds and is not associated with clinical symptoms; (iv) ARIA-H that has 1 to 9 cumulative microbleeds and is accompanied by mild, moderate, or severe clinical symptoms, or clinical symptoms that meet the "other medically significant" severity classification criteria; (v) ARIA-H that has two cumulative areas of superficial hemosiderosis and is not associated with clinical symptoms; or (vi) ARIA-H that has 1 or 2 cumulative areas of superficial hemosiderosis and is accompanied by mild, moderate, or severe clinical symptoms, or clinical symptoms that meet the "other medically significant" severity classification criteria. The method further includes discontinuing administration of the anti-beta amyloid antibody to the subject until the second ARIA has resolved (and until clinical symptoms, if present, have resolved). The method further includes resuming administration of the anti-beta amyloid antibody to the subject at a dose lower than the dose administered to the subject immediately prior to the subject developing the second ARIA.

[0032] In some embodiments, ARIA is not associated with clinical symptoms. In other embodiments, ARIA is associated with mild clinical symptoms. In yet other embodiments, ARIA is associated with moderate clinical symptoms. In yet other embodiments, ARIA is associated with clinical symptoms that meet the "other medically significant" severity classification criteria.

[0033] In another aspect, the disclosure features a method of treating AD in a human subject in need thereof. The method comprises administering multiple doses of an anti-beta amyloid antibody (e.g., aducanumab) to the human subject (the subject being an ApoE4 carrier or an ApoE4 non-carrier). The method includes: (a) administering to a subject an anti-beta amyloid antibody in an amount of 1 mg / kg of the subject's body weight; (b) 4 weeks after step (a), administering the antibody to the subject in an amount of 1 mg / kg of the subject's body weight; (c) 4 weeks after step (b), administering the antibody to the subject in an amount of 3 mg / kg of the subject's body weight; (d) 4 weeks after step (c), administering the antibody to the subject in an amount of 3 mg / kg of the subject's body weight; (e) 4 weeks after step (d), administering the antibody to the subject in an amount of 3 mg / kg of body weight of the subject; (f) 4 weeks after step (e), administering the antibody to the subject in an amount of 3 mg / kg of the subject's body weight; (g) 4 weeks after step (f), administering the antibody to the subject in an amount of 6 mg / kg of the subject's body weight; (h) 4 weeks after step (g), administering the antibody to the subject in an amount of 6 mg / kg of subject body weight; (i) 4 weeks after step (h), administering the antibody to the subject in an amount of 6 mg / kg of body weight of the subject; (j) 4 weeks after step (i), administering the antibody to the subject in an amount of 6 mg / kg of body weight of the subject; (k) 4 weeks after step (j), administering the antibody to the subject in an amount of 6 mg / kg of body weight of the subject; and (l) after step (k), in subsequent four-week intervals, administering the antibody to the subject in an amount of 10 mg / kg of the subject's body weight. In certain embodiments, the subject receives at least two, three, four, five, six, seven, or eight consecutive doses of the antibody in an amount of 10 mg / kg of the subject's body weight at four-week intervals.

[0034] In another aspect, the disclosure features a method of treating AD in a human subject in need thereof. The method comprises administering multiple doses of an anti-beta amyloid antibody (e.g., aducanumab) to the human subject (the subject being an ApoE4 carrier or an ApoE4 non-carrier). The method includes: (a) administering to the subject an anti-beta amyloid antibody in an amount of 3 mg / kg of the subject's body weight; (b) 4 weeks after step (a), administering the antibody to the subject in an amount of 3 mg / kg of the subject's body weight; (c) 4 weeks after step (b), administering the antibody to the subject in an amount of 3 mg / kg of the subject's body weight; (d) 4 weeks after step (c), administering the antibody to the subject in an amount of 3 mg / kg of the subject's body weight; (e) 4 weeks after step (d), administering the antibody to the subject in an amount of 6 mg / kg of the subject's body weight; (f) 4 weeks after step (e), administering the antibody to the subject in an amount of 6 mg / kg of the subject's body weight; (g) 4 weeks after step (f), administering the antibody to the subject in an amount of 6 mg / kg of the subject's body weight; (h) 4 weeks after step (g), administering the antibody to the subject in an amount of 6 mg / kg of subject body weight; (i) 4 weeks after step (h), administering the antibody to the subject in an amount of 6 mg / kg of body weight of the subject; and (j) after step (i), administering the antibody to the subject in an amount of 10 mg / kg of subject body weight at subsequent 4-week intervals. In certain embodiments, the subject receives at least 2, 3, 4, 5, 6, 7, or 8 consecutive doses of the antibody in an amount of 10 mg / kg of subject body weight at 4-week intervals.

[0035] In another aspect, the disclosure features a method of treating AD in a human subject in need thereof. The method comprises administering multiple doses of an anti-beta amyloid antibody (e.g., aducanumab) to the human subject (the subject being an ApoE4 carrier or an ApoE4 non-carrier). The method includes: (a) administering to a subject an anti-beta amyloid antibody in an amount of 1 mg / kg of the subject's body weight; (b) 4 weeks after step (a), administering the antibody to the subject in an amount of 1 mg / kg of the subject's body weight; (c) 4 weeks after step (b), administering the antibody to the subject in an amount of 3 mg / kg of the subject's body weight; (d) 4 weeks after step (c), administering the antibody to the subject in an amount of 3 mg / kg of the subject's body weight; (e) 4 weeks after step (d), administering the antibody to the subject in an amount of 6 mg / kg of the subject's body weight; (f) 4 weeks after step (e), administering the antibody to the subject in an amount of 6 mg / kg of body weight of the subject; and (g) after step (f), administering the antibody to the subject in an amount of 10 mg / kg of subject body weight at subsequent 4-week intervals. In certain embodiments, the subject receives at least 2, 3, 4, 5, 6, 7, or 8 consecutive doses of the antibody in an amount of 10 mg / kg of subject body weight at 4-week intervals.

[0036] In another aspect, the disclosure features a method of treating AD in a human subject in need thereof. The method comprises administering multiple doses of an anti-beta amyloid antibody (e.g., aducanumab) to the human subject (the subject being an ApoE4 carrier or an ApoE4 non-carrier). The method includes: (a) administering to the subject an anti-beta amyloid antibody in an amount of 3 mg / kg of the subject's body weight; (b) 4 weeks after step (a), administering the antibody to the subject in an amount of 3 mg / kg of the subject's body weight; (c) 4 weeks after step (b), administering the antibody to the subject in an amount of 6 mg / kg of the subject's body weight; (d) 4 weeks after step (c), administering the antibody to the subject in an amount of 6 mg / kg of body weight of the subject; and (e) after step (d), administering the antibody to the subject in an amount of 10 mg / kg of subject body weight at subsequent 4-week intervals. In certain embodiments, the subject receives at least 2, 3, 4, 5, 6, 7, or 8 consecutive doses of the antibody in an amount of 10 mg / kg of subject body weight at 4-week intervals.

[0037] The following embodiments apply to all of the above aspects.

[0038] In some embodiments, the anti-beta amyloid antibody is administered intravenously to a human subject.

[0039] In some embodiments, the anti-beta amyloid antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises a first complementarity determining region (VHCDR1) having the amino acid sequence of SEQ ID NO: 3, a VHCDR2 having the amino acid sequence of SEQ ID NO: 4, and a VHCDR3 having the amino acid sequence of SEQ ID NO: 5, and the VL comprises a VLCDR1 having the amino acid sequence of SEQ ID NO: 6, a VLCDR2 having the amino acid sequence of SEQ ID NO: 7, and a VLCDR3 having the amino acid sequence of SEQ ID NO: 8. In certain cases, the antibody comprises a human IgG1 constant region.

[0040] In some embodiments, the anti-beta amyloid antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH consists of SEQ ID NO: 1 and the VL consists of SEQ ID NO: 2. In certain cases, the antibody comprises a human IgG1 constant region.

[0041] In one embodiment, the anti-beta amyloid antibody comprises a heavy chain and a light chain, wherein the heavy chain consists of SEQ ID NO:10 and the light chain consists of SEQ ID NO:11.

[0042] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present application, including definitions, will control. The materials, methods, and examples are illustrative only and are intended to be non-limiting.

[0043] Other features and advantages of the invention will become apparent from the following detailed description and claims. [Brief explanation of the drawings]

[0044] [Figure 1] 1 shows the mean positron emission tomography (PET) composite standard uptake value ratio (SUVR) by time point, as determined by PET scan, in a study of subjects treated with antibody BIIB037. [Figure 2] 1 shows the adjusted mean change from baseline PET composite SUVR for subjects by baseline clinical stage, i.e., prodromal or mild AD. [Figure 3] The adjusted mean change from baseline PET composite SUVR by subject's baseline ApoE4 status is shown. [Figure 4] We report the estimated incidence of ARIA-E and / or ARIA-H in studies of AD subjects treated with antibody BIIB037. [Figure 5] The adjusted mean change from baseline in Clinical Dementia Rating Scale-Sum of Boxes (CDR-SB) score is shown for patients receiving placebo or 1 mg / kg, 3 mg / kg, or 10 mg / kg of antibody BIIB037 every 4 weeks for 54 weeks. [Figure 6] The adjusted mean change from baseline Minute Mental Status Examination (MMSE) + standard error (SE) is shown for patients receiving placebo or 1 mg / kg, 3 mg / kg, or 10 mg / kg of antibody BIIB037 every 4 weeks for 54 weeks. [Figure 7A] Figure 1 shows amyloid plaque reduction with aducanumab. Figure 2 shows the mean composite SUVR over time for the PD analysis population. The dashed line indicates the SUVR cutpoint for florbetapir. [Figure 7B] Figure 1 shows amyloid plaque reduction with aducanumab. Figure 2 shows the adjusted mean (±SE) change from baseline in composite SUVR at weeks 26 and 54 for the entire PD analysis population. [Figure 7C] Figure 1 shows amyloid plaque reduction with aducanumab. Adjusted mean (±SE) change from baseline in composite SUVR at weeks 26 and 54 in ApoE ε4 carriers. [Figure 7D] Figure 1 shows amyloid plaque reduction with aducanumab. Figure 2 shows the adjusted mean (±SE) change from baseline in composite SUVR at weeks 26 and 54 in ApoE ε4 non-carriers. [Figure 7E] Figure 1 shows amyloid plaque reduction with aducanumab. Figure 2 shows the adjusted mean (±SE) change from baseline in composite SUVR at weeks 26 and 54 in patients with prodromal AD. [Figure 7F] Figure 1 shows amyloid plaque reduction with aducanumab. Figure 2 shows the adjusted mean (±SE) change from baseline in composite SUVR at weeks 26 and 54 in patients with mild AD. [Figure 8] The effect of aducanumab on MMSE is shown. [Figure 9] 1 shows the effect of aducanumab on CDR-SB. [Figure 10] Selected dosing schedules for ApoE4 carriers and ApoE4 non-carriers are shown. [Figure 11] Demonstrating aducanumab's ability to reduce amyloid plaques. [Figure 12]Shows slowing of decline in CDR-SB with aducanumab. [Figure 13] Showing slowing of MMSE decline with aducanumab. [Figure 14] The study design for PRIME, a multicenter, randomized, double-blind, placebo-controlled, multiple-dose trial, shows that patients (planned enrollment, N=188) were randomized in a 3:1 active-to-placebo ratio to one of nine treatment arms (target enrollment, n=30 per active treatment arm) using a staggered dose-escalation design. [Figure 15] The primary and secondary endpoints of the PRIME study are shown below. [Figure 16] The PRIME evaluation schedule is provided. Data were analyzed through week 54 for the 1 mg / kg, 3 mg / kg, and 10 mg / kg groups, and through week 30 for the 6 mg / kg group. [Figure 17] The patient profile for the PRIME trial is as follows: 165 of 166 randomized patients received treatment; 107 (65%) were ApoE ε4 carriers and 68 (41%) had prodromal AD. [Figure 18] Baseline demographic and disease characteristics of the PRIME trial are shown. [Figure 19] To provide an overview of ARIA findings and patient demographics after the onset of ARIA-E. DETAILED DESCRIPTION OF THE INVENTION

[0045] Alzheimer's disease Alzheimer's disease, abbreviated herein as AD, is a dementia primarily identified by clinical diagnosis and confirmed by disease markers.

[0046] AD is a continuum with specifically operationally defined stages of disease progression. AD pathology begins before the onset of clinical symptoms. For example, amyloid plaques, one marker of AD pathology, form 10 to 20 years before AD dementia manifests. Currently recognized stages of AD include preclinical, prodromal, mild, moderate, and severe. These stages can be further subdivided into subcategories based on the severity of symptoms and the AD progression scale.

[0047] Because AD does not occur in discrete stages, those skilled in the art will recognize that differences between patient groups may not be apparent in certain clinical settings. Nevertheless, clinical disease stages can be characterized by measures and their changes over time, such as Aβ accumulation (CSF / PET), synaptic dysfunction (FDG-PET / fMRI), tau-mediated neuronal damage (CSF), brain structure (volumetric MRI), cognitive, and clinical function. (Jack CR, et al. Hypothetical model of dynamic biomarkers of the Alzheimer's disease. pathological cascade. Lancet Neurol.,2010;9(1):119-28).

[0048] The current major clinical diagnostic criteria for dementia are known as the NINCDS-ADRDA diagnostic criteria (McKhann GM, V. Diagnosis of dementia due to Alzheimer's disease: Recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimer's & Dementia, 7 (2011) 263-269), which are known in the art and can be incorporated into the practice of the present invention. These include cognitive or behavioral impairments, including impaired ability to acquire and retain new information, impaired reasoning and complex task performance, impaired visuospatial abilities, impaired language function (speech, reading, writing), and changes in personality, behavior, or demeanor. Alzheimer's disease is diagnosed using the current major diagnostic criteria and is typically characterized by symptoms that develop gradually over months to years and develop slowly (insidious onset) over hours or days. Reports or observations of subjects with Alzheimer's disease usually indicate a significant prior deterioration in cognitive function.

[0049] Other diagnostic classification systems have become available that have evolved as new information about AD is gained. These systems include the International Working Group (IWG) New Research Criteria for Diagnosis of AD (Dubois B et al., Lancet Neurol., 2007;6(8):734-736), the IWG Research Criteria (Dubois et al., Lancet Neurol., 2010;9(11):1118-27), the NIA / AA Diagnostic Criteria (Jack CR et al. Alzheimer's Dement., 2011;7(3):257-62), and the DSM-5 Diagnostic Criteria (American Psychiatric Association, DSM-5, 2013). These classification systems can also be used to diagnose AD subjects for treatment according to the methods of the present disclosure.

[0050] patient The term "patient" is intended to include any human subject for whom diagnosis, prognosis, prevention, or treatment of Alzheimer's disease is desired, including a human subject in need of treatment. Human subjects in need of treatment include those already suffering from AD, as well as those susceptible to AD or in whom AD symptoms are to be prevented. A typical patient will be male or female between the ages of 40 and 90 (e.g., 45-90, 50-90, 55-90, 60-90). In one embodiment, the present disclosure provides a method of treating AD patients (including, but not limited to, patients suffering from preclinical, prodromal, mild, moderate, or severe AD). In a further embodiment, the patient has amyloid pathology as determined, for example, by positron emission tomography (PET) imaging.

[0051] AD patients requiring treatment range from subjects with amyloid pathology and early neuronal degeneration, to subjects with widespread neurodegeneration and irreversible neuronal loss accompanied by progressive cognitive and functional impairment, to subjects with dementia.

[0052] Patients with preclinical AD can be identified by a subclinical phase with or without the onset of memory complaints and impairments in event memory and executive function. This stage is typically characterized by the absence of in vivo expression of AD molecular biomarkers and clinical symptoms.

[0053] Prodromal AD patients are primarily characterized by cognitive impairment and the development of functional impairment as the disease progresses. Patients with prodromal AD typically have a Minor Mental State Examination (MMSE) score of 24-30 (inclusive), spontaneous memory complaints, objective memory loss defined as a free recall score of <27 on the Free and Cued Selective Recall Test (FCCSRT), a Clinical Dementia Scale (CDR) total score of 0.5, no significant levels of impairment in other cognitive domains, basic preservation of activities of daily living, and no evidence of dementia.

[0054] Patients with mild AD typically have an MMSE score of 20-26 (inclusive), an overall CDR of 0.5 or 1.0, and meet the National Institute on Aging-Alzheimer's Association's key clinical diagnostic criteria for probable AD (see Section 22).

[0055] In a clinical diagnosis of AD, patients with mild AD will exhibit eye-catching behavior at work, amnesia, mood swings, and attention disorders. Patients with moderate AD will exhibit cognitive impairment, limitations in daily activities, disorientation, apraxia, agnosia, aphasia, and behavioral abnormalities. Patients with severe AD are characterized by loss of independence, memory and speech decline, and incontinence.

[0056] In one embodiment, the treatment is for early-stage patients who are amyloid-positive as assessed by PET scan with 18F-AV-45. ​​Patients may be asymptomatic or only experience transient symptoms such as headache, confusion, difficulty walking, or visual disturbances. Patients may or may not be ApoE4 carriers as determined by ApoE genotyping.

[0057] In other embodiments, the treatment is treatment of patients with any disease or neurological condition (other than AD) that may be a contributing factor to the subject's cognitive impairment, such as stroke or other cerebrovascular condition, other neurodegenerative disease, a history of clinically significant psychiatric illness, acute or subacute microhemorrhage or macrohemorrhage, a history of macrohemorrhage, or superficial hemosiderosis, etc. These patients may be treated after screening and selection by a clinician.

[0058] treatment As used herein, the term "treating" or "treatment" generally refers to obtaining a desired pharmacological and / or physiological effect. The effect may be prophylactic, in that it completely or partially prevents AD or its symptoms, and / or may be therapeutic, in that it partially or completely cures AD and / or one or more adverse effects caused by AD. Thus, as used herein, the term "treatment" includes (a) preventing AD from developing in a subject who is predisposed to, but has not yet been diagnosed with, AD; (b) inhibiting AD, e.g., halting its development; (c) alleviating AD, e.g., causing it to regress; or (d) prolonging survival beyond the expected survival time in the absence of treatment.

[0059] In one embodiment, the treatment is a prophylactic treatment that completely or partially prevents AD or symptoms thereof in the patient, or the treatment is a therapeutic treatment that partially or completely cures AD or symptoms caused by AD in the patient.

[0060] In another embodiment, the treatment has a disease-modifying effect, meaning that the treatment slows or delays the course of the underlying pathological or pathophysiological disease and improves the clinical signs and symptoms of AD relative to placebo.

[0061] In further embodiments, treatment results in symptomatic improvement, which may consist of improved cognition, increased autonomy, and / or improvement in neuropsychiatric and behavioral dysfunction, even if only for a short period of time.

[0062] It will be understood that while the goal of any treatment is to prevent or cure the disease, the present disclosure contemplates clinical decline or slowing of progression of the disease, or alleviation of symptoms. Clinical decline or slowing of disease progression directly impacts patients and caregivers, thereby slowing disability, maintaining independence, and enabling patients to lead normal lives for a longer period of time. Relieving symptoms to the best extent possible can result in gradual improvements in cognitive, functional, and behavioral symptoms, as well as mood.

[0063] In a method for treating AD according to the present disclosure, an anti-beta amyloid antibody is administered to a human patient. In one embodiment, the anti-beta amyloid antibody is a monoclonal antibody. In another embodiment, the anti-beta amyloid antibody is a fully human antibody. In a further embodiment, the anti-beta amyloid antibody is a recombinant antibody. In another embodiment, the anti-beta amyloid antibody is a recombinant, fully human, monoclonal antibody. In one embodiment, the anti-beta amyloid antibody is selective for soluble Aβ oligomers and fibril binding, and does not substantially bind to monomers. These properties improve pharmacokinetics (PK), reduce antibody sink, and minimize off-target cross-reactivity with APP-expressing tissues. An exemplary monoclonal antibody that meets these diagnostic criteria is antibody BIIB037.

[0064] The antibody BIIB037, also known as aducanumab, is a biological treatment for Alzheimer's disease. It is an anti-Aβ antibody that recognizes aggregated forms of Aβ, including plaques. BIIB037 contains human kappa light chains. BIIB037 consists of two heavy chains and two human kappa light chains, which are linked by interchain disulfide bonds. "BIIB037" or "aducanumab" refers to an anti-Aβ antibody comprising the amino acid sequences set forth in SEQ ID NOs: 10 and 11.

[0065] In vitro characterization studies have confirmed that antibody BIIB037 recognizes a conformational epitope present in Aβ aggregates, the accumulation of which is thought to underlie the development and progression of AD.

[0066] In vivo pharmacological studies have shown that a mouse IgG2a chimeric form of the antibody (ch12F6A), with similar properties, significantly reduces amyloid plaque burden in the brain of aged Tg2576 mice, a mouse model of AD. The parenchymal amyloid reduction was not accompanied by changes in vascular amyloid, as has been reported for certain anti-Aβ antibodies (Wilcock OM, Colton CA. Immunotherapy, vascular pathology, and microhemorrhages in transgenic mice. CNS & Neurological Disorders Drug Targets, 2009 Mar;8(1):50-64).

[0067] The VH and VL of antibody BIIB037 have amino acid sequences identical to those of antibody NI-101.12F6A described in U.S. Patent No. 8,906,367 (see Tables 2-4, which are incorporated herein by reference in their entirety). Specifically, antibody BIIB037 has an antigen-binding domain comprising the VH and VL variable regions shown in Table 1 (VH) and Table 2 (VL), the corresponding complementarity-determining regions (CDRs) shown in Table 3, and the heavy and light chains shown in Table 4(H) and Table 5(L). [Table 1] [Table 2] [Table 3]

[0068] The amino acid sequence of the mature heavy chain of BIIB037 is set forth in Table 4 below. [Table 4]

[0069] The amino acid sequence of the mature light chain of BIIB037 is set forth in Table 5 below. [Table 5-1] [Table 5-2]

[0070] In addition to antibody BIIB037, the present disclosure contemplates the use of other anti-beta amyloid antibodies, such as antibodies comprising a VH region comprising or consisting of SEQ ID NO: 1 or a VL region comprising or consisting of SEQ ID NO: 2, or antibodies comprising a VH region comprising or consisting of SEQ ID NO: 1 and a VL region comprising or consisting of SEQ ID NO: 2, wherein the VH and / or VL regions have one or more substitutions, deletions, and / or insertions. In some embodiments, these VH and VL regions may have up to 25, up to 20, up to 15, up to 10, up to 5, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 amino acid substitutions and still bind beta-amyloid. In specific embodiments, these amino acid substitutions occur only within the framework regions. In some embodiments, the amino acid substitution(s) are conservative amino acid substitutions. In some embodiments, the VH and VL regions may include 1 to 5 (1, 2, 3, 4, 5) amino acid deletions and / or amino acid additions and still bind beta-amyloid. In some embodiments, these deletions and / or additions are made at the N-terminus and / or C-terminus of the VH and / or VL regions. In one embodiment, a single amino acid deletion and / or addition is made at the N-terminus and / or C-terminus of the VH region. In one embodiment, a single amino acid deletion and / or addition is made at the N-terminus and / or C-terminus of the VL region.

[0071] Other antibodies contemplated for use in the present disclosure include antibodies comprising the variable heavy chain (VH) CDRs and variable light chain (VL) CDRs of Table 3. Thus, anti-beta amyloid antibodies comprise CDRs comprising or consisting of the amino acid sequences of SEQ ID NOs: 3-8. In one embodiment, an anti-beta amyloid antibody comprises CDRs comprising or consisting of the amino acid sequences of SEQ ID NOs: 4-8, and includes an amino acid sequence comprising or consisting of GFAFSSYGMH (SEQ ID NO: 9) as the VH CDR1. In some cases, the present disclosure encompasses anti-beta amyloid antibodies comprising the VH and VL CDRs of BIIB037 based on any CDR definition (e.g., Kabat, Chothia, enhanced Chothia, AbM, or contact definition). See, for example, http: / / www.bioinf.org.uk / abs / index.html. In one embodiment, the present disclosure encompasses anti-beta amyloid antibodies comprising the VH and VL CDRs of BIIB037 based on the Chothia definition. In one embodiment, the disclosure encompasses anti-beta amyloid antibodies comprising the VH and VL CDRs of BIIB037 according to the enhanced Chothia definition. In another embodiment, the disclosure encompasses anti-beta amyloid antibodies comprising the VH and VL CDRs of BIIB037 according to the AbM definition. In yet another embodiment, the disclosure encompasses anti-beta amyloid antibodies comprising the VH and VL CDRs of BIIB037 according to the contact definition. The present invention encompasses anti-beta amyloid antibodies comprising the VL CDR and the VL CDR.

[0072] Antibody BIIB037, and other antibodies used in the present invention, can be prepared using known methods. In some embodiments, the antibodies are expressed in Chinese hamster ovary (CHO) cell lines.

[0073] The patient's response to treatment according to the present invention is generally dose-dependent. One embodiment of the present invention comprises administering to the patient at least one dose of an anti-Aβ antibody at a dose less than the minimum therapeutic dose required to treat AD patients. Following this administration, the patient is administered at least one dose of an anti-Aβ antibody at approximately the minimum therapeutic dose required to treat AD patients. Thereafter, the patient is administered at least one dose of an anti-Aβ antibody at an effective dose greater than the minimum therapeutic dose but less than the maximum tolerated dose required to treat AD patients. In a preferred embodiment, the patient's brain amyloid burden is reduced. In a further preferred embodiment, the patient's susceptibility to ARIA is reduced.

[0074] A therapeutically effective amount refers to an amount of anti-Aβ antibody that is sufficient to improve symptoms or pathology associated with Alzheimer's disease.The therapeutic efficacy and toxicity of anti-Aβ antibody can be determined by standard pharmaceutical procedures.Ideally, the anti-Aβ antibody is used in an amount sufficient to restore normal behavior and / or cognitive characteristics in Alzheimer's disease, or at least slow or prevent the progression of AD in patients.

[0075] In Tg2576 mice, a dose-dependent reduction in brain amyloid was observed after chronic administration of the monoclonal antibody BIIB037 (0.3 mg / kg to 30 mg / kg). Significant amyloid reduction was observed at 3 mg / kg, which was determined to be the minimum therapeutic dose of antibody BIIB037 in this animal model.

[0076] An effective amount of an anti-Aβ antibody is an amount of antibody that produces a clinically significant response in the treatment of Alzheimer's disease. Effective doses of about 1 to 30 mg / kg per month (e.g., 1 mg / kg, 3 mg / kg, 6 mg / kg, 10 mg / kg, 12 mg / kg, 15 mg / kg, 18 mg / kg, 20 mg / kg, 24 mg / kg, 25 mg / kg, 28 mg / kg, 30 mg / kg) can be used. Efficacy of antibody BIIB037, consistent with safety, can plateau at effective doses of about 10 mg / kg to about 30 mg / kg of patient body weight. In one embodiment, an effective dose of about 3 mg / kg to about 10 mg / kg of patient body weight is contemplated. In other embodiments, effective doses are about 3 mg / kg, about 6 mg / kg, and about 10 mg / kg of patient body weight.

[0077] The maximum tolerated dose of an anti-Aβ antibody is the amount of antibody that produces a clinically significant response in the treatment of Alzheimer's disease, consistent with safety. A major safety concern in treating patients according to the methods of the invention is the development of ARIA, particularly ARIA-E or ARIA-H. The methods of the invention allow for the use of higher doses of antibody BIIB037 in the treatment of AD patients than were feasible using previously known protocols.

[0078] It will be understood that dosage adjustment can be carried out during the treatment protocol.For example, for reasons of safety or efficacy, the dosage can be increased so that the effect of anti-Aβ antibody on AD can be enhanced, or the dosage can be decreased so that the rate and severity of ARIA can be reduced.If one dose is missed, preferably, the patient should receive the missed dose and resume administration, and then continue according to the described regimen.

[0079] In one embodiment, the anti-Aβ antibody is diluted in saline and then administered to the patient by intravenous infusion. Using this method of administration, each infusion step in the titration regimen of the present invention will typically take about 1 hour.

[0080] The dose ranges and other numerical values ​​herein include amounts that are equivalent in effect to the numerical amounts indicated for treating Alzheimer's disease in a patient, and that reduce the incidence or susceptibility of a patient to ARIA when compared to individuals not treated with the methods of the invention. At a minimum, each numerical parameter should be construed to include significant digits by applying ordinary rounding techniques. Moreover, any numerical value inherently includes error from the standard deviation of its measurement, and such values ​​are within the scope of the invention.

[0081] composition The anti-Aβ antibodies described herein (e.g., BIIB037) can be formulated as pharmaceutical compositions. Pharmaceutical compositions for use in the present invention can be formulated according to methods well known in the art, for example, as described in Remington: The Science and See Practice of Pharmacy (2000) by the University of Sciences in Philadelphia, ISBN 683-306472. The composition may further comprise a pharmacologically acceptable carrier. Examples of suitable pharmaceutical carriers are well known in the art and include phosphate buffered saline, water, emulsions such as oil / water emulsions, various wetting agents, sterile solutions, and the like.

[0082] Furthermore, the pharmaceutical composition may contain an additional agent. For example, when used in the treatment of Alzheimer's disease, the additional agent can be selected from the group consisting of an organic small molecule, another anti-Aβ antibody, an anti-tau antibody, and a combination thereof. Non-limiting examples of anti-Aβ antibodies can be found in U.S. Patent No. 8,906,367. Non-limiting examples of anti-tau antibodies can be found in U.S. Patent No. 8,940,272 and U.S. Patent Application Publication No. US2015 / 0344553.

[0083] The administration of the composition can be carried out in different ways, for example, intravenously, intraperitoneally, subcutaneously, intramuscularly, topically, or intradermally.

[0084] standard dose In one treatment for Alzheimer's disease, an anti-beta amyloid antibody (e.g., BIIB037) is administered to a human patient in multiple doses (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12) of the same dose of antibody (i.e., a standard dose) over a period of time.

[0085] For example, a human patient may receive multiple doses of 3 mg / kg of patient body weight of anti-beta amyloid antibody over a period of time.

[0086] In another example, a human patient may receive multiple doses of anti-beta amyloid antibody at 6 mg / kg of patient body weight over a period of time.

[0087] In another example, a human patient may receive multiple doses of anti-beta amyloid antibody at 10 mg / kg of patient body weight over a period of time.

[0088] In yet another example, a human patient may receive multiple doses of anti-beta amyloid antibody at 15 mg / kg of patient body weight over a period of time.

[0089] In a further example, a human patient may receive multiple doses of anti-beta amyloid antibody at 20 mg / kg of patient body weight over a period of time.

[0090] In another example, a human patient may receive multiple doses of anti-beta amyloid antibody at 30 mg / kg of patient body weight over a period of time.

[0091] The duration of each of these methods can be, for example, once every 1, 2, 3, 4, 5, 6, 7, or 8 weeks. Treatment can proceed for as long as deemed beneficial by a medical professional.

[0092] In certain embodiments, the anti-Aβ antibody is diluted in saline and administered to the patient by intravenous infusion.

[0093] In any of the above embodiments, the anti-Aβ antibody may comprise a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises a first complementarity-determining region (VHCDR1) having the amino acid sequence of SEQ ID NO: 3 or SEQ ID NO: 9, a VHCDR2 having the amino acid sequence of SEQ ID NO: 4, and a VHCDR3 having the amino acid sequence of SEQ ID NO: 5, and the VL comprises a VLCDR1 having the amino acid sequence of SEQ ID NO: 6, a VLCDR2 having the amino acid sequence of SEQ ID NO: 7, and a VLCDR3 having the amino acid sequence of SEQ ID NO: 8.

[0094] In some embodiments, the anti-Aβ antibody comprises a VH and a VL, wherein the VH comprises a VH CDR1, a VH CDR2, and a VH CDR3 of SEQ ID NO: 1, and the VL comprises a VL CDR1, a VL CDR2, and a VL CDR3 of SEQ ID NO: 2, wherein the CDRs are defined according to the Chothia, enhanced Chothia, AbM, or contact definition.

[0095] In some embodiments, the anti-Aβ antibody comprises a VH and a VL, wherein the VH comprises or consists of SEQ ID NO:1 and the VL comprises or consists of SEQ ID NO:2.

[0096] In certain embodiments, the anti-Aβ antibody further comprises a human IgG1 constant region.

[0097] In certain embodiments, the anti-Aβ antibody comprises a heavy chain that comprises or consists of SEQ ID NO:10 and a light chain that comprises or consists of SEQ ID NO:11.

[0098] Dose adjustment (sequential dose escalation) The occurrence of ARIA in AD patients treated with anti-beta amyloid antibodies (e.g., BIIB037) is dose-dependent. ARIA has been observed after the third and fifth doses in patients receiving 1 mg / kg and 3 mg / kg of antibody. ARIA has been observed after the second dose at doses of 6 mg / kg and 10 mg / kg of body weight. The methods of the present disclosure include treatment regimens selected to reduce the incidence of ARIA.

[0099] One method of treating Alzheimer's disease involves administering increasing amounts of an anti-beta amyloid antibody to a human patient over a period of time. This approach of sequentially administering the antibody to a patient is referred to herein as "dose titration," since a standardized drug of known concentration is administered in carefully measured amounts until completion of the approach is confirmed by specific endpoints. In the present invention, endpoints include the effect of treatment on patients' Alzheimer's disease and on reducing the incidence of ARIA, particularly ARIA-E or ARIA-H, in a treated patient population.

[0100] One advantage of the dose titration regimen of the present invention is that it allows for the administration of high doses of monoclonal antibodies to AD patients, particularly apolipoprotein E4 (ApoE4) carriers, without incurring the same degree of ARIA as observed with standard dose regimens. In one embodiment, the high dose comprises a dose(s) of 10 mg / kg of anti-Aβ antibody per subject's body weight. Without intending to be limited to any particular mechanism, it is believed that dose titration results in lower initial amyloid clearance and slower clearance throughout the treatment period.

[0101] The dose of anti-Aβ antibody (e.g., BIIB037) is adjusted in multiple doses. For example, two doses of the antibody can be administered to the patient at a dose less than the minimum therapeutic dose per dose, followed by four doses of the antibody at a dose approximately equal to the minimum therapeutic dose per dose. This regimen can then be followed by multiple doses at a dose greater than the minimum therapeutic dose but less than the maximum tolerated dose per dose until an acceptable change in the patient's AD is observed. For example, doses can be administered at intervals of about 4 weeks for about 52 weeks (a total of 14 doses). Periodic evaluations can be performed to monitor progress.

[0102] One protocol of the present disclosure, identified as Protocol (1), is: (A) administering to a patient an anti-beta amyloid antibody in an amount of 1 mg / kg of the patient's body weight; (B) 4 weeks after step (A), administering the antibody to the patient in an amount of 1 mg / kg of body weight of the patient; (C) 4 weeks after step (B), administering the antibody to the patient in an amount of 3 mg / kg of the patient's body weight; (D) 4 weeks after step (C), administering the antibody to the patient in an amount of 3 mg / kg of the patient's body weight; (E) 4 weeks after step (D), administering the antibody to the patient in an amount of 3 mg / kg of body weight of the patient; (F) 4 weeks after step (E), administering the antibody to the patient in an amount of 3 mg / kg of the patient's body weight; (G) 4 weeks after step (F), administering the antibody to the patient in an amount of 6 mg / kg of the patient's body weight; and (H) after step (G), at consecutive intervals of 4 weeks, administering the antibody to the patient in an amount of 6 mg / kg of the patient's body weight.

[0103] In other words, protocol (1) involves administering an initial dose of an anti-beta amyloid antibody to a patient in an amount of 1 mg / kg of the patient's body weight, followed by a second dose at 1 mg / kg of body weight four weeks after the initial dose. After the second dose, at four-week intervals, doses 3, 4, 5, and 6 of the antibody are administered to the patient in an amount of 3 mg / kg of body weight. Then, after administration of dose 6, at four-week intervals, doses 7 and 8 of the antibody are administered to the patient in an amount of 6 mg / kg of body weight.

[0104] Protocol (1) comprises a total of 14 doses administered at about 4-week intervals for about 52 weeks, with optional continued dose administration about every 4 weeks thereafter, thereby treating AD with a low ARIA predisposition in patients. In other words, 4 weeks after administration of dose 8, doses 9-14 may be administered to the patient at 6 mg / kg body weight every 4 weeks. In some embodiments, the antibody continues to be administered to the patient at 6 mg / kg body weight every 4 weeks until at least week 76. In other words, in some embodiments, the method comprises administering doses 9-20 at 6 mg / kg body weight every 4 weeks after dose 8 to the patient. In some embodiments, after dose 8, the antibody is administered to the patient at 6 mg / kg body weight every 4 weeks indefinitely. In some embodiments, the amount of antibody administered to the patient at 12-week intervals after the final dose of 6 mg / kg body weight is 3 mg / kg body weight. In some embodiments, the patient is first administered this reduced dose 12 weeks after week 52 (i.e., 12 weeks after dose 14), and in other embodiments, the patient is first administered this reduced dose 12 weeks after week 76 (i.e., 12 weeks after dose 20). In some embodiments, the amount of antibody administered to the patient at 4-week intervals after the final dose of 6 mg / kg body weight is 1 mg / kg body weight. In some embodiments, the patient is first administered this reduced dose 4 weeks after week 52 (i.e., 4 weeks after dose 14), and in other embodiments, the patient is first administered this reduced dose 4 weeks after week 76 (i.e., 4 weeks after dose 20).

[0105] Protocol (1) may be used with patients who are ApoE4 carriers or ApoE4 non-carriers as determined by ApoE genotyping. In any of the alternative embodiments of Protocol (1), the anti-Aβ antibody may comprise a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises a first complementarity-determining region (VHCDR1) having the amino acid sequence of SEQ ID NO:3 or SEQ ID NO:9, a VHCDR2 having the amino acid sequence of SEQ ID NO:4, and a VHCDR3 having the amino acid sequence of SEQ ID NO:5, and the VL comprises a VLCDR1 having the amino acid sequence of SEQ ID NO:6, a VLCDR2 having the amino acid sequence of SEQ ID NO:7, and a VLCDR3 having the amino acid sequence of SEQ ID NO:8. In some embodiments of Protocol (1), the anti-Aβ antibody comprises a VH and a VL, wherein the VH comprises VH CDR1, VH CDR2, and VH CDR3 of SEQ ID NO: 1, and the VL comprises VL CDR1, VL CDR2, and VL CDR3 of SEQ ID NO: 2, where the CDRs are defined according to the Chothia, enhanced Chothia, AbM, or contact definition. In some embodiments of Protocol (1), the anti-Aβ antibody comprises a VH and a VL, wherein the VH comprises or consists of SEQ ID NO: 1, and the VL comprises or consists of SEQ ID NO: 2. In certain embodiments of Protocol (1), the anti-Aβ antibody comprises a human IgG1 constant region. In certain embodiments, the anti-Aβ antibody comprises a heavy chain comprising or consisting of SEQ ID NO: 10, and a light chain comprising or consisting of SEQ ID NO: 11.

[0106] Another protocol according to the present disclosure, designated Protocol (2), is: (A) administering to a patient an anti-beta amyloid antibody in an amount of 1 mg / kg of the patient's body weight; (B) 4 weeks after step (A), administering the antibody to the patient in an amount of 1 mg / kg of body weight of the patient; (C) 4 weeks after step (B), administering the antibody to the patient in an amount of 3 mg / kg of the patient's body weight; (D) 4 weeks after step (C), administering the antibody to the patient in an amount of 3 mg / kg of the patient's body weight; (E) 4 weeks after step (D), administering the antibody to the patient in an amount of 6 mg / kg of body weight of the patient; (F) 4 weeks after step (E), administering the antibody to the patient in an amount of 6 mg / kg of the patient's body weight; and (G) after step (F), at consecutive intervals of 4 weeks, administering the antibody to the patient in an amount of 10 mg / kg of the patient's body weight.

[0107] In other words, protocol (2) involves administering an initial dose of an anti-beta amyloid antibody to a patient in an amount of 1 mg / kg of the patient's body weight, followed by a second dose at 1 mg / kg of body weight four weeks after the initial dose. After the second dose, at four-week intervals, doses 3 and 4 of the antibody are administered to the patient in an amount of 3 mg / kg of body weight. At four-week intervals after administration of dose 4, doses 5 and 6 of the antibody are administered to the patient in an amount of 6 mg / kg of body weight. Then, four weeks after administration of dose 6, dose 7 of the antibody is administered to the patient in an amount of 10 mg / kg of body weight.

[0108] Protocol (2) includes a total of 14 doses administered at approximately 4-week intervals over approximately 52 weeks, with optional dose administration continuing approximately every 4 weeks thereafter, thereby treating AD with a low patient predisposition to ARIA. In other words, 4 weeks after administration of Dose 7, Dose 8-14 may be administered to the patient at 10 mg / kg body weight every 4 weeks. In some embodiments, the anti-Aβ antibody continues to be administered to the patient at 10 mg / kg body weight every 4 weeks until at least Week 76. In other words, in some embodiments, the method includes administering Dose 8-20 at 10 mg / kg body weight every 4 weeks after Dose 7. In some embodiments, after Dose 7, the anti-Aβ antibody is administered to the patient at 10 mg / kg body weight every 4 weeks indefinitely. In some embodiments, after the final dose of 10 mg / kg body weight, the amount of anti-Aβ antibody is reduced to 3 mg / kg body weight and administered to the patient at 12-week intervals. In some embodiments, the patient is first administered this reduced dose 12 weeks after week 52 (i.e., 12 weeks after dose 14), and in other embodiments, the patient is first administered this reduced dose 12 weeks after week 76 (i.e., 12 weeks after dose 20). In some embodiments, 4 weeks after the last dose of 10 mg / kg body weight, the amount of antibody administered to the patient is reduced to 1 mg / kg body weight every 4 weeks. In some embodiments, the reduced dose begins 4 weeks after week 52 (i.e., 4 weeks after dose 14), and in other embodiments, the reduced dose begins 4 weeks after week 76 (i.e., 4 weeks after dose 20).

[0109] Protocol (2) can be used to treat both ApoE4 carriers and ApoE4 non-carriers. In any of the alternative embodiments of Protocol (2), the anti-Aβ antibody may comprise a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises a first complementarity-determining region (VHCDR1) having the amino acid sequence of SEQ ID NO: 3 or SEQ ID NO: 9, a VHCDR2 having the amino acid sequence of SEQ ID NO: 4, and a VHCDR3 having the amino acid sequence of SEQ ID NO: 5, and the VL comprises a VLCDR1 having the amino acid sequence of SEQ ID NO: 6, a VLCDR2 having the amino acid sequence of SEQ ID NO: 7, and a VLCDR3 having the amino acid sequence of SEQ ID NO: 8. In some embodiments of Protocol (2), the anti-Aβ antibody comprises a VH and a VL, where the VH comprises VH CDR1, VH CDR2, and VH CDR3 of SEQ ID NO: 1, and the VL comprises VL CDR1, VL CDR2, and VL CDR3 of SEQ ID NO: 2, where the CDRs are defined based on the Chothia, enhanced Chothia, AbM, or contact definition. In certain embodiments of Protocol (2), the anti-Aβ antibody may comprise a heavy chain variable region (VH) and a light chain variable region (VL), where the VH comprises or consists of SEQ ID NO: 1, and the VL comprises or consists of SEQ ID NO: 2. In some embodiments of Protocol (2), the anti-Aβ antibody comprises a human IgG1 constant region. In certain embodiments, the anti-Aβ antibody comprises a heavy chain comprising or consisting of SEQ ID NO: 10, and a light chain comprising or consisting of SEQ ID NO: 11.

[0110] The present disclosure provides another protocol, Protocol (3), for treating ApoE4 carriers. This embodiment comprises: (A) administering to a patient an anti-beta amyloid antibody in an amount of 1 mg / kg of the patient's body weight; (B) 4 weeks after step (A), administering the antibody to the patient in an amount of 1 mg / kg of the patient's body weight; and (C) after step (B), at consecutive intervals of 4 weeks, administering the antibody to the patient in an amount of 3 mg / kg of the patient's body weight.

[0111] In other words, protocol (3) involves administering to a patient an initial dose of an anti-beta amyloid antibody in an amount of 1 mg / kg of the patient's body weight. Four weeks after the initial dose, a second dose of the antibody is administered to the patient in an amount of 1 mg / kg of body weight. Then, four weeks after the second dose, dose 3 of the antibody is administered to the patient in an amount of 3 mg / kg of body weight.

[0112] Protocol (3) includes a total of 14 doses administered at approximately 4-week intervals over approximately 52 weeks, with optional continued dose administration approximately every 4 weeks thereafter, thereby treating AD with a low ARIA predisposition in patients. In other words, 4 weeks after administration of Dose 3, Dose 4-14 may be administered to the patient at 3 mg / kg body weight every 4 weeks. In some embodiments, the antibody continues to be administered to the patient at 3 mg / kg body weight every 4 weeks until at least Week 76. In other words, in some embodiments, the method includes administering Dose 3, followed by Dose 4-20 at 3 mg / kg body weight every 4 weeks. In some embodiments, after Dose 3, the antibody is administered to the patient every 4 weeks indefinitely at 3 mg / kg body weight. In some embodiments, after the prescribed period, the amount of antibody administered to the patient may be reduced to 3 mg / kg body weight every 12 weeks. In some embodiments, the 12-weekly dosing begins after week 52 (i.e., after dose 14), and in other embodiments, the 12-weekly dosing begins after week 76 (i.e., after dose 20). In some embodiments, after the prescription period, the amount of antibody administered to the patient may be reduced to 1 mg / kg body weight every 4 weeks. In some embodiments, this reduced dose begins 4 weeks after week 52 (i.e., 4 weeks after dose 14), and in other embodiments, this reduced dose begins 4 weeks after week 76 (i.e., 4 weeks after dose 20).

[0113] Protocol (3) may be used in ApoE4 carriers as determined by ApoE genotyping. In any of the alternative embodiments of Protocol (3), the anti-Aβ antibody may comprise a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises a first complementarity determining region (VHCDR1) having the amino acid sequence of SEQ ID NO: 3 or SEQ ID NO: 9, a VHCDR2 having the amino acid sequence of SEQ ID NO: 4, and a VHCDR3 having the amino acid sequence of SEQ ID NO: 5, and the VL comprises a VLCDR1 having the amino acid sequence of SEQ ID NO: 6, a VLCDR2 having the amino acid sequence of SEQ ID NO: 7, and a VLCDR3 having the amino acid sequence of SEQ ID NO: 8. In some embodiments of Protocol (3), the anti-Aβ antibody comprises a VH and a VL, wherein the VH comprises VH CDR1, VH CDR2, and VH CDR3 of SEQ ID NO: 1, and the VL comprises VL CDR1, VL CDR2, and VL CDR3 of SEQ ID NO: 2, where the CDRs are defined according to the Chothia, enhanced Chothia, AbM, or contact definition. In some embodiments of Protocol (3), the anti-Aβ antibody comprises a VH and a VL, wherein the VH comprises or consists of SEQ ID NO: 1, and the VL comprises or consists of SEQ ID NO: 2. In certain embodiments of Protocol (3), the anti-Aβ antibody comprises a human IgG1 constant region. In certain embodiments, the anti-Aβ antibody comprises a heavy chain comprising or consisting of SEQ ID NO: 10, and a light chain comprising or consisting of SEQ ID NO: 11.

[0114] Another protocol of the present disclosure, identified as Protocol (4), comprises: (A) administering to a patient an anti-beta amyloid antibody in an amount of 1 mg / kg of the patient's body weight; (B) 4 weeks after step (A), administering the antibody to the patient in an amount of 1 mg / kg of body weight of the patient; (C) 4 weeks after step (B), administering the antibody to the patient in an amount of 3 mg / kg of the patient's body weight; (D) 4 weeks after step (C), administering the antibody to the patient in an amount of 3 mg / kg of the patient's body weight; and (E) 4 weeks after step (D), administering the antibody to the patient in an amount of 6 mg / kg of the patient's body weight.

[0115] In other words, protocol (4) involves administering an initial dose of anti-beta amyloid antibody to a patient in an amount of 1 mg / kg of the patient's body weight, followed by a first dose at 1 mg / kg of body weight four weeks after the first dose. After the second dose, doses 3 and 4 are administered to the patient at four-week intervals in amounts of 3 mg / kg of body weight. Then, four weeks after administration of dose 4, dose 5 of the antibody is administered to the patient in an amount of 6 mg / kg of body weight.

[0116] Protocol (4) comprises a total of 14 doses administered at about 4-week intervals over about 52 weeks, with optional continued dose administration about every 4 weeks thereafter, thereby treating AD with a low ARIA predisposition in the patient. In other words, 4 weeks after administration of Dose 5, Dose 6-14 may be administered to the patient at 6 mg / kg body weight every 4 weeks. In some embodiments, the antibody continues to be administered to the patient at 6 mg / kg body weight every 4 weeks until at least Week 76. In other words, in some embodiments, the method comprises administering Dose 6-20 to the patient at 6 mg / kg body weight every 4 weeks after Dose 5. In some embodiments, after Dose 5, the antibody is administered to the patient at 6 mg / kg body weight every 4 weeks indefinitely. In some embodiments, after the final dose of 6 mg / kg body weight, the amount of antibody administered to the patient is reduced to 3 mg / kg body weight every 12 weeks. In some embodiments, the patient is first administered this reduced dose 12 weeks after week 52 (i.e., 12 weeks after dose 14), and in other embodiments, the patient is first administered this reduced dose 12 weeks after week 76 (i.e., 12 weeks after dose 20). In some embodiments, after the final dose of 10 mg / kg body weight, the amount of antibody administered to the patient is reduced to 1 mg / kg body weight every 4 weeks. In some embodiments, the reduced dose begins 4 weeks after week 52 (i.e., 4 weeks after dose 14), and in other embodiments, the reduced dose begins 4 weeks after week 76 (i.e., 4 weeks after dose 20).

[0117] In any of the alternative embodiments of Protocol (4), the anti-Aβ antibody may comprise a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises a first complementarity determining region (VH CDR1) having the amino acid sequence of SEQ ID NO: 3 or SEQ ID NO: 9, a VH CDR2 having the amino acid sequence of SEQ ID NO: 4, and a VH CDR3 having the amino acid sequence of SEQ ID NO: 5, and the VL comprises a VL CDR1 having the amino acid sequence of SEQ ID NO: 6, a VL CDR2 having the amino acid sequence of SEQ ID NO: 7, and a VL CDR3 having the amino acid sequence of SEQ ID NO: 8. In some embodiments of Protocol (4), the anti-Aβ antibody comprises a VH and a VL, wherein the VH comprises a VH CDR1, a VH CDR2, and a VH CDR3 of SEQ ID NO: 1, and the VL comprises a VL CDR1, a VL CDR2, and a VL CDR3 of SEQ ID NO: 2, wherein the CDRs are defined based on the Chothia, enhanced Chothia, AbM, or contact definition. In some embodiments of Protocol (4), the anti-Aβ antibody comprises a VH and a VL, where the VH comprises or consists of SEQ ID NO: 1 and the VL comprises or consists of SEQ ID NO: 2. In certain embodiments of Protocol (4), the anti-Aβ antibody comprises a human IgG1 constant region. In particular embodiments, the anti-Aβ antibody comprises a heavy chain that comprises or consists of SEQ ID NO: 10 and a light chain that comprises or consists of SEQ ID NO: 11.

[0118] Yet another protocol of the present disclosure, identified as protocol (5), comprises: (A) administering to a patient an anti-beta amyloid antibody in an amount of 1 mg / kg of the patient's body weight; (B) 4 weeks after step (A), administering the antibody to the patient in an amount of 1 mg / kg of body weight of the patient; (C) 4 weeks after step (B), administering the antibody to the patient in an amount of 3 mg / kg of the patient's body weight; (D) 4 weeks after step (C), administering the antibody to the patient in an amount of 3 mg / kg of the patient's body weight; (E) 4 weeks after step (D), administering the antibody to the patient in an amount of 3 mg / kg of body weight of the patient; (F) 4 weeks after step (E), administering the antibody to the patient in an amount of 3 mg / kg of the patient's body weight; (G) after step (F), at consecutive intervals of 4 weeks, administering the antibody to the patient in an amount of 6 mg / kg of body weight of the patient; (H) after step (G), at consecutive four-week intervals, administering the antibody to the patient in an amount of 6 mg / kg of the patient's body weight; (I) after step (H), at consecutive four-week intervals, administering the antibody to the patient in an amount of 6 mg / kg of the patient's body weight; (J) after step (I), at consecutive intervals of 4 weeks, administering the antibody to the patient in an amount of 6 mg / kg of body weight of the patient; (K) after step (J), in consecutive four-week intervals, administering the antibody to the patient in an amount of 6 mg / kg of the patient's body weight; and (L) after step (K), at consecutive intervals of 4 weeks, administering the antibody to the patient in an amount of 10 mg / kg of the patient's body weight.

[0119] In other words, protocol (5) involves administering an initial dose of an anti-beta amyloid antibody to a patient in an amount of 1 mg / kg of the patient's body weight, followed by a second dose at 1 mg / kg of body weight four weeks after the initial dose. After the second dose, at four-week intervals, doses 3, 4, 5, and 6 of the antibody are administered to the patient in an amount of 3 mg / kg of body weight. At four-week intervals after administration of dose 6, doses 7, 8, 9, 10, and 11 are administered to the patient in an amount of 6 mg / kg of body weight. Then, four weeks after administration of dose 11, dose 12 of the antibody is administered to the patient in an amount of 10 mg / kg of body weight.

[0120] Protocol (5) includes a total of 14 doses administered at approximately 4-week intervals over approximately 52 weeks, with optional continued dose administration approximately every 4 weeks thereafter, thereby treating AD in patients with a low ARIA predisposition. In other words, 4 weeks after administration of dose 12, doses 13-14 may be administered to the patient at 10 mg / kg body weight every 4 weeks. In some embodiments, the antibody continues to be administered to the patient at 10 mg / kg body weight every 4 weeks until at least week 76. In other words, in some embodiments, the method includes administering doses 13-20 at 6 mg / kg body weight every 4 weeks after dose 12 to the patient. In some embodiments, after dose 12, the antibody is administered to the patient at 10 mg / kg body weight every 4 weeks indefinitely. In some embodiments, after the final dose of 10 mg / kg body weight, the amount of antibody administered to the patient is reduced to 3 mg / kg body weight every 12 weeks. In some embodiments, the patient is initially administered this reduced dose 12 weeks after Week 52 (i.e., 12 weeks after Dose 14), and in other embodiments, the patient is initially administered this reduced dose 12 weeks after Week 76 (i.e., 12 weeks after Dose 20). In some embodiments, after the final dose of 10 mg / kg body weight, the amount of antibody administered to the patient is reduced to 1 mg / kg body weight every 4 weeks. In some embodiments, the reduced dose begins 4 weeks after Week 52 (i.e., 4 weeks after Dose 14), and in other embodiments, the reduced dose begins 4 weeks after Week 76 (i.e., 4 weeks after Dose 20). In one embodiment, the subject administered in Protocol (5) is an ApoE4 carrier. High doses (e.g., 10 mg / kg) of aducanumab can be administered in a dose-adjusted regimen to ApoE4 carriers without incurring ARIA to the same extent as observed with fixed-dose regimens. In another embodiment, subjects treated under Protocol (5) are ApoE4 non-carriers.

[0121] In any of the alternative embodiments of Protocol (5), the anti-Aβ antibody may comprise a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises a first complementarity determining region (VH CDR1) having the amino acid sequence of SEQ ID NO: 3 or SEQ ID NO: 9, a VH CDR2 having the amino acid sequence of SEQ ID NO: 4, and a VH CDR3 having the amino acid sequence of SEQ ID NO: 5, and the VL comprises a VL CDR1 having the amino acid sequence of SEQ ID NO: 6, a VL CDR2 having the amino acid sequence of SEQ ID NO: 7, and a VL CDR3 having the amino acid sequence of SEQ ID NO: 8. In some embodiments of Protocol (5), the anti-Aβ antibody comprises a VH and a VL, wherein the VH comprises a VH CDR1, a VH CDR2, and a VH CDR3 of SEQ ID NO: 1, and the VL comprises a VL CDR1, a VL CDR2, and a VL CDR3 of SEQ ID NO: 2, wherein the CDRs are defined based on the Chothia, enhanced Chothia, AbM, or contact definition. In some embodiments of Protocol (5), the anti-Aβ antibody comprises a VH and a VL, where the VH comprises or consists of SEQ ID NO: 1 and the VL comprises or consists of SEQ ID NO: 2. In certain embodiments of Protocol (5), the anti-Aβ antibody comprises a human IgG1 constant region. In particular embodiments, the anti-Aβ antibody comprises a heavy chain that comprises or consists of SEQ ID NO: 10 and a light chain that comprises or consists of SEQ ID NO: 11.

[0122] Exemplary dosing schemes for ApoE4 carriers and ApoE4 non-carriers are set forth in Table 6 below. [Table 6]

[0123] The foregoing exemplary protocols optimize efficacy while meeting safety requirements. In certain embodiments of the invention, a patient's susceptibility to vasogenic edema (VE) is reduced, or a patient's susceptibility to cerebral microhemorrhages (mH) is reduced, or a patient's VE and mH are reduced.

[0124] Variations of these preferred protocols are also possible. A dosing scheme can be used in which multiple doses of an anti-Aβ antibody are administered at 1 mg / kg per patient's body weight with regular dose intervals, followed by multiple doses at 3 mg / kg per patient's body weight with regular dose intervals. For example, a dosing scheme can include two doses at 1 mg / kg per patient's body weight with a 4-week dose interval, followed by four doses at 3 mg / kg per patient's body weight with a 4-week dose interval. Another example of this dosing scheme includes two doses at 1 mg / kg per patient's body weight with a 4-week dose interval, followed by multiple doses at 3 mg / kg per patient's body weight with a 4-week dose interval until treatment is complete. Another example of this dosing scheme includes four doses at 1 mg / kg per patient's body weight with a 4-week dose interval, followed by multiple doses at 3 mg / kg per patient's body weight with a 4-week dose interval until treatment is complete. Given that ARIA typically occurs between doses 2 and 5, this simplified protocol can provide an additional safety margin. Thus, patients may not need to continue titrating to 6 mg / kg; rather, dose escalation can be discontinued at approximately 3 mg / kg per patient's body weight.

[0125] Another variation of these preferred protocols involves a dosing scheme of multiple doses of anti-Aβ antibody at 1 mg / kg patient body weight with regular dose intervals, followed by multiple doses of 3 mg / kg with regular dose intervals, and finally multiple doses of 6 mg / kg patient body weight with regular dose intervals until the end of treatment. An example of this dosing scheme involves two doses of 1 mg / kg patient body weight with four week dose intervals, followed by four doses of 3 mg / kg with four week dose intervals, and finally multiple doses of 6 mg / kg patient body weight until the end of treatment.

[0126] In another embodiment, an exemplary dosing scheme begins with administration of 3 mg / kg of patient body weight with 4-week intervals between doses (e.g., 2, 4, 5, or 5 doses), followed by multiple doses of 6 mg / kg of patient body weight with 4-week intervals between doses (e.g., 2, 4, 5, 6, 10 doses), followed by multiple doses of 10 mg / kg of patient body weight with 4-week intervals between doses (e.g., 2, 4, 5, 6, 10, 15, 20 doses) until the end of treatment. Optionally, an optional dose of 1 mg / kg of patient body weight may be administered at 4-week intervals (e.g., 2, 4, 5, or 5 doses) prior to the 3 mg / kg dose. The subject may be an ApoE4 carrier or non-ApoE4 carrier.

[0127] In a further embodiment of the present invention, if a patient shows an appropriate response without the dose adjustment step, the dose adjustment of the monoclonal antibody tailored to the patient can be omitted. In this case, for example, an ApoE4 carrier can be administered with a dose of 1 mg / kg, 3 mg / kg, 6 mg / kg, or 10 mg / kg of anti-Aβ antibody per patient's body weight, and an ApoE4 non-carrier can be administered with a dose of 3 mg / kg, 6 mg / kg, 10 mg / kg, 15 mg / kg, 20 mg / kg, 25 mg / kg, or 30 mg / kg of anti-Aβ antibody per patient's body weight. A total of 14 doses can be administered at intervals of about 4 weeks for about 52 weeks, and optionally, the dose administration can be continued about every 4 weeks thereafter, thereby treating AD with a patient with a low susceptibility to ARIA.

[0128] Management of ARIA during treatment with anti-Aβ antibodies Despite the above methods of preventing or reducing the likelihood of ARIA, patients may still develop ARIA (ARIA-E and / or ARIA-H). The present disclosure also provides methods of modifying treatment for such patients. Such methods can include discontinuing and / or adjusting the dose and / or terminating treatment with an anti-Aβ antibody.

[0129] (1) Breakdown of ARIA-E cases Table 7 below provides a projected breakdown of ARIA-E cases that may occur during the above treatment regimen. [Table 7-1] [Table 7-2]

[0130] The severity of clinical symptoms is defined as follows:

[0131] Mild: Symptom(s) are barely noticeable or cause the subject discomfort; symptoms do not affect performance or function; prescription medications are not usually required to alleviate symptom(s) but may be given for personality reasons.

[0132] Moderate: Symptom(s) of sufficient severity to cause discomfort to the subject; impact on performance of daily activities; subject is able to continue in the study; treatment of symptom(s) may be required.

[0133] Severe: The symptom(s) cause significant discomfort; the symptoms impair or significantly affect the subject's daily activities; the severity may result in discontinuation of study treatment; the symptom(s) may be treated and / or the subject may be hospitalized.

[0134] The severity of ARIA-E is defined as follows:

[0135] Mild ARIA-E: Mild fluid-attenuated inversion recovery (FLAIR) hyperintensities are confined to the sulci and / or cortical or subcortical white matter (with or without gyral swelling and sulcal obliteration), affecting a single area less than 5 cm in greatest dimension. Only one area of ​​lesion is detected.

[0136] Moderate ARIA-E: Moderately sever- ated lesions with a single FLAIR hyperintense area measuring 5-10 cm in its largest diameter, or two or more lesions each measuring less than 10 cm in its largest diameter.

[0137] Severe ARIA-E: Severe lesions (FLAIR hyperintense area measuring >10 cm in single largest dimension), often with prominent subcortical white matter and / or sulcal involvement (with associated gyral swelling and sulcal loss). One or more distinct / independent lesion sites may be present.

[0138] Per Table 7, patients who develop mild ARIA-E by MRI reading without clinical symptoms at any time during treatment with an anti-Aβ antibody (e.g., BIIB037) may continue treatment with the anti-Aβ antibody at their current dose. Patients should undergo MRI approximately every 4 weeks until ARIA-E is resolved by MRI reading. Patients should also undergo MMSE at every scheduled visit until ARIA-E is resolved. Healthcare professionals may discontinue treatment or request that patients continue treatment at a lower dose based on their evaluation of safety and MRI data.

[0139] Patients who develop moderate or severe ARIA-E by MRI reading at any time during treatment with an anti-Aβ antibody and who are asymptomatic should temporarily discontinue treatment, but should complete all scheduled evaluations and undergo unscheduled MRIs approximately every 4 weeks until the ARIA-E resolves. These patients should also undergo MMSE at each scheduled visit until the ARIA-E resolves. If the ARIA-E resolves and the subject remains asymptomatic, the patient may resume treatment at the same dose of the anti-Aβ antibody. If the patient has a history of ARIA-E or ARIA-H and required dose discontinuation, the patient should resume treatment at the next lower dose of the anti-Aβ antibody.

[0140] Patients who develop mild, moderate, or severe ARIA-E by MRI reading accompanied by mild, moderate, severe, or critical ("other medically significant events" only) clinical symptoms at any time during treatment with an anti-Aβ antibody should temporarily discontinue treatment, but should complete all scheduled evaluations and additionally undergo unscheduled MRI visits approximately every 4 weeks until ARIA-E by MRI resolves. Patients should also undergo MMSE at every scheduled visit until ARIA-E resolves. If ARIA-E resolves and clinical symptoms resolve, patients may resume treatment at the same dose of anti-Aβ antibody. If patients have a previous history of ARIA-E or ARIA-H that required dose discontinuation, patients will be resumed at the next lower dose of anti-Aβ antibody.

[0141] Patients who develop mild, moderate, or severe ARIA-E by MRI reading accompanied by serious clinical symptoms (other than "other medically significant events") at any time during treatment with anti-Aβ antibodies should discontinue treatment with anti-Aβ antibodies. Patients should complete all scheduled visits for evaluation and should also undergo unscheduled MRI visits approximately every 4 weeks until ARIA-E resolves, according to central MRI reading. Patients will also undergo MMSE at every scheduled visit until ARIA-E resolves.

[0142] If a patient has a third episode of ARIA requiring dose discontinuation, the patient will discontinue treatment with the anti-Aβ antibody.

[0143] (2) Breakdown of ARIA-H (microbleeding) cases Table 8 below provides a breakdown of ARIA-H (microhemorrhage) cases that may occur during the above treatment regimen. [Table 8-1] [Table 8-2]

[0144] The severity of clinical symptoms is defined as follows:

[0145] Mild: Symptom(s) are barely noticeable or cause the subject discomfort; symptoms do not affect performance or function; prescription medications are not usually required to alleviate symptom(s) but may be given for personality reasons.

[0146] Moderate: Symptom(s) of sufficient severity to cause discomfort to the subject; impact on performance of daily activities; subject is able to continue in the study; treatment of symptom(s) may be required.

[0147] Severe: The symptom(s) cause significant discomfort; the symptoms impair or significantly affect the subject's daily activities; the severity may result in discontinuation of study treatment; the symptom(s) may be treated and / or the subject may be hospitalized.

[0148] The severity of ARIA-H (microhemorrhage) is defined as follows: Mild: 1-4 microbleeds Moderate: 5-9 microbleeds Severe: 10 or more microbleeds

[0149] Patients who develop at least one but no more than four cumulative microbleed(s) without clinical symptoms during treatment with an anti-Aβ antibody may continue treatment at their current dose but should undergo unscheduled MRI visits approximately every 2 weeks until MRI confirms stability of the microbleeds. Microbleeds are considered stable if there is no change between two consecutive MRIs, including the initial detection MRI and one performed 2 weeks later. Patients should also undergo MMSE at every scheduled visit until ARIA-H is stable.

[0150] Patients who develop five or more but not more than nine cumulative microbleeds without clinical symptoms during treatment with an anti-Aβ antibody should temporarily discontinue treatment, but should complete all scheduled visits for evaluation and undergo unscheduled MRIs approximately every two weeks until the MRI confirms stability of the microbleeds. Microbleeds are considered stable if there is no change between two consecutive MRIs, including the initial detection MRI and one performed two weeks later. Patients will also undergo MMSE at each scheduled visit until ARIA-H is stable. Once microbleeds are deemed stable, patients may resume treatment at the same dose. If the subject has a previous history of ARIA-E or ARIA-H and required dose discontinuation, the subject will resume treatment at the next lower dose.

[0151] Patients who develop 9 or fewer cumulative microbleed(s) and mild, moderate, severe, or critical ("other medically significant events") clinical symptoms should temporarily discontinue treatment with anti-Aβ antibodies, but should complete all scheduled evaluation visits and additionally undergo unscheduled MRIs approximately every 2 weeks until MRI confirms stability of the microbleed(s). Microbleeds are considered stable if there is no change between two consecutive MRIs, including the initial detection MRI and one performed 2 weeks later. Patients should also undergo MMSE at every scheduled visit until ARIA-H is stable. Once the microbleed(s) are deemed stable and clinical symptoms have resolved, patients may resume treatment with the same dose of anti-Aβ antibodies. If the subject has a history of ARIA-E or ARIA-H and required dose discontinuation, the patient will be resumed at the next lower dose of anti-Aβ antibodies.

[0152] Patients who experience serious clinical symptoms (other than "other medically significant events") related to the microbleed(s) should discontinue treatment but should complete all scheduled visits for evaluation, as well as undergo unscheduled MRIs approximately every 2 weeks until the MRI confirms stability of the microbleed(s). Patients will also undergo an MMSE at every scheduled visit until the ARIA-H is stable.

[0153] Patients who develop 10 or more cumulative microbleeds during treatment with anti-Aβ antibodies should discontinue treatment, regardless of symptom severity. Patients should complete all scheduled visits for evaluation and should also undergo unscheduled MRIs approximately every 2 weeks until the MRIs deem the microbleeds stable. Patients will also undergo MMSE at every scheduled visit until the ARIA-H is stable.

[0154] If a patient has a third episode of ARIA requiring dose discontinuation, the subject will discontinue treatment.

[0155] (3) Breakdown of ARIA-H (superficial cerebral hemosiderosis) cases Table 9 below provides a projected breakdown of ARIA-H (superficial cerebral hemosiderosis) cases that may occur during the above treatment regimen.

[0156] The severity of clinical symptoms is defined as follows:

[0157] Mild: Symptom(s) are barely noticeable or cause the subject discomfort; symptoms do not affect performance or function; prescription medications are not usually required to alleviate symptom(s) but may be given for personality reasons.

[0158] Moderate: Symptom(s) of sufficient severity to cause discomfort to the subject; impact on performance of daily activities; subject is able to continue in the study; treatment of symptom(s) may be required.

[0159] Severe: The symptom(s) cause significant discomfort; the symptoms impair or significantly affect the subject's daily activities; the severity may result in discontinuation of study treatment; the symptom(s) may be treated and / or the subject may be hospitalized.

[0160] The severity of ARIA-H (superficial cerebral hemosiderosis-H) is defined as follows: Mild superficial hemosiderosis: A new focal area Moderate superficial hemosiderosis: Two new focal areas Severe superficial hemosiderosis: >2 new focal areas. [Table 9-1] [Table 9-2]

[0161] Patients who develop a single, focal area of ​​superficial hemosiderosis without clinical symptoms may continue treatment with anti-Aβ antibodies at their current dose but must undergo unscheduled MRI visits approximately every 2 weeks until central MRI review confirms stability of superficial hemosiderosis. Superficial hemosiderosis is considered stable if there is no change between two consecutive MRIs, including the initial detection MRI and one performed 2 weeks later. Patients will also undergo MMSE at every scheduled visit until ARIA-H is stable.

[0162] Patients who develop two cumulative focal superficial hemosiderosis areas without clinical symptoms during treatment with an anti-Aβ antibody should temporarily discontinue treatment, but should complete all scheduled evaluation visits and undergo unscheduled MRI scans approximately every 2 weeks until MRI confirms stability of superficial hemosiderosis. Superficial hemosiderosis is considered stable if there is no change between two consecutive MRI scans, including the initial detection MRI and one performed 2 weeks later. Patients should also undergo MMSE at each scheduled visit until ARIA-H is stable. Once superficial hemosiderosis is deemed stable, patients may resume treatment at the same dose. If a patient has a history of ARIA-E or ARIA-H and required dose discontinuation, the subject will resume treatment at the next lower dose.

[0163] Patients with two or fewer cumulative focal superficial hemosiderosis areas and who develop mild, moderate, severe, or critical ("other medically significant events" only) clinical symptoms should temporarily discontinue treatment with anti-Aβ antibodies, but should complete all scheduled evaluation visits and undergo unscheduled MRIs approximately every 2 weeks until central MRI review confirms stability of superficial hemosiderosis. Superficial hemosiderosis is considered stable if there is no change between two consecutive MRIs, including the initial detection MRI and one performed 2 weeks later. Patients will also undergo MMSE at every scheduled visit until ARIA-H is stable. Once superficial hemosiderosis is considered stable and clinical symptoms have resolved, patients may resume treatment at the same dose. If a patient has a previous history of ARIA-E or ARIA-H that required dose discontinuation, the patient should be restarted at the next lower dose of anti-Aβ antibody.

[0164] Patients who experience serious clinical symptoms (other than "other medically significant events") related to superficial siderosis will discontinue treatment with anti-Aβ antibodies but should complete all scheduled evaluation visits and should also undergo unscheduled MRIs approximately every 2 weeks until MRI confirms stability of superficial siderosis. Patients should also undergo MMSE at every scheduled visit until ARIA-H is stable.

[0165] Patients who develop more than two cumulative focal superficial hemosiderosis areas should discontinue treatment with anti-Aβ antibodies regardless of clinical severity, but should complete all scheduled evaluation visits and undergo unscheduled MRIs approximately every 2 weeks until central MRI interpretation confirms stability of superficial hemosiderosis. Patients should also undergo MMSE at every scheduled visit until ARIA-H is stable.

[0166] If a patient has a third episode of ARIA requiring dose discontinuation, the patient will discontinue treatment.

[0167] (4) Breakdown of cases in which ARIA-H occurred simultaneously with ARIA-E Patients who develop both ARIA-H and ARIA-E at any time during treatment with an anti-Aβ antibody should follow the most restrictive of the aforementioned guidelines: ARIA-E must resolve, ARIA-H must be considered stable, and the subject must be asymptomatic, if applicable, before resuming treatment.

[0168] (5) Breakdown of ARIA-H (major bleeding) cases During the study, patients who experience incident major bleeding, regardless of symptom severity, should discontinue treatment with anti-Aβ antibodies but should complete all scheduled visits for evaluation and should also undergo unscheduled MRI visits approximately every 2 weeks until the MRI confirms stability of the major bleeding. Patients should also undergo MMSE at every scheduled visit until the major bleeding stabilizes.

[0169] The severity of ARIA-H (major bleeding) is defined as follows: Mild: 1-2 cm in maximum diameter Moderate: 2-4 cm in maximum diameter Severe: >4 cm in greatest dimension

[0170] (6) Exemplary Treatment Methods for Patients Who Develop ARIA on Standard Dosage Regimen If a patient receiving a standard dose of an anti-Aβ antibody develops moderate or severe ARIA-E without clinical symptoms, the dose should be discontinued until the ARIA-E resolves. At the time of ARIA-E resolution, the patient can be administered the same dose that the patient was receiving immediately before the onset of moderate or severe ARIA-E. If the patient has a history of ARIA-E or ARIA-H and has required dose discontinuation, the patient should be administered a lower dose of anti-Aβ antibody than the dose that the patient was receiving immediately before the most recent moderate or severe ARIA-E. For example, if a patient receiving a standard dose of 6 mg / kg of anti-Aβ antibody develops moderate or severe ARIA-E without clinical symptoms, the patient's treatment with the anti-Aβ antibody should be discontinued until the ARIA-E resolves. After the ARIA-E resolves, the patient can continue treatment with the 6 mg / kg anti-Aβ antibody. However, if the patient has previously experienced ARIA-E or ARIA-H, which required discontinuation of the dose, the patient should be given a lower dose of anti-Aβ antibody (e.g., 1 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, or 5 mg / kg) once the ARIA has resolved.

[0171] If a patient on a standard dose of anti-Aβ antibody develops mild, moderate, or severe ARIA-E with mild, moderate, severe, or severe clinical symptoms, the dose should be discontinued until the ARIA-E resolves. At the time the ARIA-E resolves and clinical symptoms resolve, the patient can be administered the same dose that the patient was administered immediately before the onset of moderate or severe ARIA-E. If the patient has a history of ARIA-E or ARIA-H that required dose discontinuation, the patient should be administered a lower dose of anti-Aβ antibody than the dose that the patient was administered immediately before the onset of the most recent moderate or severe ARIA-E with mild, moderate, severe, or severe clinical symptoms. For example, if a patient receiving a standard dose of 6 mg / kg of an anti-Aβ antibody develops mild, moderate, or severe ARIA-E with mild, moderate, severe, or severe clinical symptoms, treatment of the patient with the anti-Aβ antibody should be discontinued until the ARIA-E and clinical symptoms resolve, after which the patient can continue treatment with the 6 mg / kg anti-Aβ antibody. However, if the patient has previously developed ARIA-E or ARIA-H and required dose discontinuation, the patient should be administered a lower dose (e.g., 1 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, or 5 mg / kg) of the anti-Aβ antibody after the ARIA and clinical symptoms resolve.

[0172] If a patient on a standard dose of anti-Aβ antibody develops 5 to 9 cumulative microbleeds without clinical symptoms, the dose should be discontinued until ARIA-H is stabilized. At this point, the patient can be administered the same dose that the patient was receiving immediately before the onset of 5 to 9 cumulative microbleeds. If the patient has a history of ARIA-E or ARIA-H and has required dose discontinuation, the patient should be administered a lower dose of anti-Aβ antibody than the dose that the patient was receiving immediately before the onset of 5 to 9 cumulative microbleeds. For example, if a patient receiving a standard dose of 6 mg / kg anti-Aβ antibody develops 5 to 9 cumulative microbleeds without clinical symptoms, the patient's treatment with the anti-Aβ antibody should be discontinued until ARIA-H is stabilized. After stabilization, the patient can continue treatment with the 6 mg / kg anti-Aβ antibody. However, if the patient has previously experienced ARIA-E or ARIA-H, which required discontinuation of the dose, the patient should be given a lower dose (e.g., 1 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, or 5 mg / kg) of anti-Aβ antibody once the ARIA-H has stabilized.

[0173] If a patient on a standard dose of anti-Aβ antibody develops 1 to 9 cumulative microbleeds with mild, moderate, severe, or severe clinical symptoms, the dose should be discontinued until ARIA-H is stabilized. At this point, the patient can be administered the same dose as the patient was administered immediately before the onset of 1 to 9 cumulative microbleeds. If the patient has a history of ARIA-E or ARIA-H that required dose discontinuation, the patient should be administered a lower dose of anti-Aβ antibody than the dose administered immediately before the patient developed 1 to 9 cumulative microbleeds with mild, moderate, severe, or severe clinical symptoms. For example, if a patient receiving a standard dose of 6 mg / kg of anti-Aβ antibody develops 1-9 cumulative microbleeds with mild, moderate, severe, or critical clinical symptoms, treatment with the anti-Aβ antibody should be discontinued until ARIA-H stabilizes and clinical symptoms resolve. After that, the patient can continue treatment with the 6 mg / kg anti-Aβ antibody. However, if the patient has previously experienced ARIA-E or ARIA-H, which required discontinuation of the dose, the patient should be administered a lower dose (e.g., 1 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, or 5 mg / kg) of anti-Aβ antibody once ARIA-H stabilizes and clinical symptoms resolve.

[0174] If a patient receiving a standard dose of anti-Aβ antibody develops two cumulative superficial hemosiderosis zones without clinical symptoms, the dose should be discontinued until ARIA-H stabilizes. At this point, the patient can be administered the same dose that the patient was receiving immediately before the development of the two cumulative superficial hemosiderosis zones. If the patient has a history of ARIA-E or ARIA-H and has required dose discontinuation, the patient should be administered a lower dose of anti-Aβ antibody than the dose that the patient was receiving immediately before the development of the two cumulative superficial hemosiderosis zones. For example, if a patient receiving a standard dose of 6 mg / kg anti-Aβ antibody develops two cumulative superficial hemosiderosis zones without clinical symptoms, the patient's treatment with the anti-Aβ antibody should be discontinued until ARIA-H stabilizes. After stabilization, the patient can continue treatment with the 6 mg / kg anti-Aβ antibody. However, if the patient has previously experienced ARIA-E or ARIA-H, which required discontinuation of the dose, the patient should be given a lower dose (e.g., 1 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, or 5 mg / kg) of anti-Aβ antibody once the ARIA-H has stabilized.

[0175] If a patient on a standard dose of anti-Aβ antibody develops one or two cumulative superficial hemosiderosis zones accompanied by mild, moderate, severe, or profound clinical symptoms, the dose should be discontinued until ARIA-H stabilizes and clinical symptoms resolve. At this point, the patient can be administered the same dose that the patient was receiving immediately before the development of two cumulative superficial hemosiderosis zones. If the patient has a history of ARIA-E or ARIA-H that required dose discontinuation, the patient should be administered a lower dose of anti-Aβ antibody than the dose that the patient was receiving immediately before the development of one or two cumulative superficial hemosiderosis zones. For example, if a patient receiving a standard dose of 6 mg / kg of an anti-Aβ antibody develops one or two cumulative superficial hemosiderosis lesions with mild, moderate, severe, or profound clinical symptoms, treatment with the anti-Aβ antibody should be discontinued until ARIA-H stabilizes and clinical symptoms resolve, after which the patient can continue treatment with the 6 mg / kg anti-Aβ antibody. However, if the patient has previously developed ARIA-E or ARIA-H, which required discontinuation of the dose, the patient should be administered a lower dose (e.g., 1 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, or 5 mg / kg) of the anti-Aβ antibody once ARIA-H stabilizes and clinical symptoms resolve.

[0176] (7) Exemplary Treatment Methods for Patients Who Develop ARIA During a Dose-Adjusted Regimen If a patient receiving a dose-adjusted regimen of an anti-Aβ antibody develops asymptomatic moderate or severe ARIA-E, the dose should be discontinued until the ARIA-E resolves. At the time of ARIA-E resolution, the patient can be administered the same dose that was administered to the patient immediately prior to the onset of moderate or severe ARIA-E. If the patient has a history of ARIA-E or ARIA-H that required dose discontinuation, the patient should be administered a lower dose of the anti-Aβ antibody than the dose administered to the patient immediately prior to the most recent ARIA that required dose discontinuation. For example, if a patient is receiving the regimen described in protocol (5) above and develops asymptomatic moderate or severe ARIA-E after step (C), treatment with the anti-Aβ antibody should be discontinued until the ARIA-E resolves. At the time of ARIA-E resolution, the patient can be administered the same dose that was administered to the patient immediately prior to the onset of moderate or severe ARIA-E (i.e., 3 mg / kg of patient body weight). If treatment with an anti-Aβ antibody is restarted after dose discontinuation, the patient must receive at least two doses of the restart dose (i.e., at least two doses of 3 mg / kg). MRI should be performed after the second restart dose and after the second dose of any escalating dose. The patient may then continue with the remaining steps of Protocol (5) (i.e., steps (D) through (L)).

[0177] However, if a patient receiving treatment according to the regimen in Protocol (5) develops asymptomatic moderate or severe ARIA-E after step (C), but has a history of ARIA-E or ARIA-H that required dose discontinuation, treatment with the anti-Aβ antibody should be discontinued until ARIA-E resolves. At that time, the patient should be administered a lower dose of the anti-Aβ antibody (in this case, 1 mg / kg of the patient's body weight) than the dose of the anti-Aβ antibody administered to the patient immediately prior to the most recent moderate or severe ARIA that required dose discontinuation. If treatment with the anti-Aβ antibody is resumed after dose discontinuation, the patient must receive at least two doses of the restart dose (i.e., at least two doses of 1 mg / kg). MRI should be performed after the second restart dose and after the second dose of any subsequent dose escalation. The patient may then continue with the remaining steps of Protocol (5) (i.e., steps (D) through (L)).

[0178] If a patient receiving a dose-adjusted regimen of an anti-Aβ antibody develops mild, moderate, or severe ARIA-E with mild, moderate, or severe clinical symptoms, or clinical symptoms that meet the "other medically significant" severity classification criteria, dose discontinuation is required until the ARIA-E resolves. At the time of resolution of the ARIA-E and resolution of clinical symptoms, the patient can be administered the same dose that the patient was receiving immediately before the onset of mild, moderate, or severe ARIA-E. If the patient has a history of ARIA-E or ARIA-H that required dose discontinuation, the patient should be administered a lower dose of the anti-Aβ antibody than the dose that the patient was receiving immediately before the most recent ARIA that required dose discontinuation. For example, if a patient undergoing the above-mentioned protocol (5) regimen develops mild, moderate, or severe ARIA-E after step (E), with mild, moderate, or severe clinical symptoms, or clinical symptoms that meet the "other medically significant" severity classification criteria, treatment with the anti-Aβ antibody should be discontinued until the ARIA-E resolves and the clinical symptoms resolve. At the time of resolution of the ARIA-E and clinical symptoms, the patient can be administered the same dose (i.e., 3 mg / kg of the patient's body weight) that was administered to the patient immediately prior to the onset of moderate or severe ARIA-E. If treatment with the anti-Aβ antibody is resumed after dose discontinuation, the patient must receive at least two doses of the restart dose (i.e., at least two doses of 3 mg / kg). MRI should be performed after the second restart dose and after the second dose of each dose escalation. The patient can then continue with the remaining steps of protocol (5) (i.e., steps (F) through (L)).

[0179] However, if a patient undergoing treatment according to the regimen in Protocol (5) develops mild, moderate, or severe ARIA-E after Step (E), with mild, moderate, or severe clinical symptoms, or clinical symptoms that meet the "other medically significant" severity classification criteria, and has a history of ARIA-E or ARIA-H that required dose discontinuation, treatment with the anti-Aβ antibody should be discontinued until resolution of ARIA-E and / or stabilization of ARIA-H and resolution of clinical symptoms. At that time, the patient should be administered a lower dose of the anti-Aβ antibody (in this case, 1 mg / kg of body weight) than the dose of the anti-Aβ antibody administered to the patient immediately prior to the onset of the most severe ARIA. If treatment with an anti-Aβ antibody is resumed after dose discontinuation, the patient must receive at least two doses of the restart dose (i.e., at least two doses of 1 mg / kg). MRI should be performed after the second restart dose and after the second dose of each dose escalation. The patient may then continue with the remaining steps of protocol (5) (i.e., steps (F) through (L)).

[0180] For example, if a patient undergoing the above-described protocol (5) regimen develops mild, moderate, or severe ARIA-E after step (G) with clinical symptoms meeting the mild, moderate, severe, or "other medically significant" severity classification criteria, treatment with the anti-Aβ antibody should be discontinued until the ARIA-E resolves and the clinical symptoms resolve. Once the ARIA-E and clinical symptoms have resolved, the patient can be administered the same dose (i.e., 6 mg / kg of the patient's body weight) that was administered to the patient immediately prior to the onset of moderate or severe ARIA-E. If treatment with the anti-Aβ antibody is resumed after dose discontinuation, the patient must receive at least two doses of the restart dose (i.e., at least two doses of 6 mg / kg). MRI should be performed after the second restart dose and after the second dose of any dose escalation. The patient can then continue with the remaining steps of protocol (5) (i.e., steps (H) through (L)). However, if a patient receiving treatment according to the regimen in Protocol (5) develops mild, moderate, severe, or severe ARIA-E after Step (G) with mild, moderate, severe, or critical clinical symptoms, and has a history of ARIA-E or ARIA-H that required dose discontinuation, treatment with the anti-Aβ antibody should be discontinued until the ARIA-E and clinical symptoms resolve, at which point the patient should be administered a lower dose of the anti-Aβ antibody (in this case, 3 mg / kg of body weight) than the dose of the anti-Aβ antibody administered to the patient immediately prior to the most recent moderate or severe ARIA-E episode. If treatment with the anti-Aβ antibody is resumed after dose discontinuation, the patient must receive at least two doses of the restart dose (i.e., at least two doses of 3 mg / kg). MRI should be performed after the second restart dose and after the second dose of each dose escalation. The patient may then continue with the remaining steps of protocol (5) (i.e., steps (F) through (L)).

[0181] If a patient undergoing a dose-adjusted regimen of an anti-Aβ antibody develops 5 to 9 cumulative microbleeds without clinical symptoms, the dose should be discontinued until ARIA-H is stabilized. At this point, the patient can be administered the same dose as the patient was receiving immediately before the onset of 5 to 9 cumulative microbleeds. If the patient has a history of ARIA-E or ARIA-H and has required dose discontinuation, the patient should be administered a lower dose of anti-Aβ antibody than the anti-Aβ antibody dose administered immediately before the onset of 5 to 9 cumulative microbleeds. For example, if a patient undergoing an anti-Aβ antibody protocol (5) treatment regimen develops 5 to 9 cumulative microbleeds without clinical symptoms after step (D), the patient's treatment with the anti-Aβ antibody should be discontinued until ARIA-H is stabilized. After stabilization, the patient can continue treatment with the same dose of anti-Aβ antibody as in step (D) (i.e., 3 mg / kg of patient body weight). If treatment with an anti-Aβ antibody is restarted after dose discontinuation, the patient must receive at least two doses of the restart dose (i.e., at least two doses of 3 mg / kg), after which the patient may continue with the remaining steps of Protocol (5) (i.e., steps (E) through (L)).

[0182] However, if the patient has previously experienced ARIA-E or ARIA-H, requiring discontinuation of the dose, the patient should be administered a lower dose (i.e., 1 mg / kg of patient body weight) of the anti-Aβ antibody of Protocol (5) once ARIA-H has stabilized. The patient should be administered two or more doses of the anti-Aβ antibody at 1 mg / kg of patient body weight. Thereafter, the patient may continue with the remaining steps of Protocol (5) (i.e., steps (E) through (L)).

[0183] If a patient receiving a dose-adjusted regimen of an anti-Aβ antibody develops 1 to 9 cumulative microbleeds with mild, moderate, severe, or critical clinical symptoms, dose discontinuation is required until ARIA-H stabilizes and clinical symptoms resolve. At this point, the patient can be administered the same dose as the patient was administered immediately before the onset of 1 to 9 cumulative microbleeds. If the patient has a history of ARIA-E or ARIA-H that required dose discontinuation, the patient should be administered a lower dose of anti-Aβ antibody than the anti-Aβ antibody dose administered immediately before the onset of 1 to 9 cumulative microbleeds with mild, moderate, or severe clinical symptoms, or clinical symptoms that meet the "other medically significant" severity classification criteria. For example, if a patient undergoing Protocol (5) develops 1 to 9 cumulative microbleeds with mild, moderate, severe, or critical clinical symptoms after Step (E), the patient's treatment with the anti-Aβ antibody should be discontinued until ARIA-H stabilizes and clinical symptoms disappear, after which the patient may continue treatment with the same dose of anti-Aβ antibody used in Step (E) (i.e., 3 mg / kg of patient body weight). If treatment with the anti-Aβ antibody is resumed after dose discontinuation, the patient must receive at least two doses of the restarted dose (i.e., at least two doses of 3 mg / kg). Thereafter, the patient may continue with the remaining steps of Protocol (5) (i.e., Steps (F) through (L)).

[0184] However, if the patient has previously experienced ARIA-E or ARIA-H, requiring discontinuation of the dose, the patient should be administered a low dose (i.e., 1 mg / kg of patient body weight) of anti-Aβ antibody once ARIA-H has stabilized and clinical symptoms have resolved. The patient should be administered two or more doses of 1 mg / kg of patient body weight of anti-Aβ antibody. Thereafter, the patient may continue with the remaining steps of Protocol (5) (i.e., steps (F) through (L)).

[0185] If a patient undergoing a dose-adjusted regimen of an anti-Aβ antibody develops two cumulative superficial hemosiderosis zones without clinical symptoms, the dose should be discontinued until ARIA-H is stabilized. At this point, the patient can be administered the same dose as was administered immediately before the patient developed two cumulative superficial hemosiderosis zones. If the patient has a history of ARIA-E or ARIA-H and has required dose discontinuation, the patient should be administered a lower dose of the anti-Aβ antibody than was administered immediately before the patient developed two cumulative superficial hemosiderosis zones. For example, if a patient undergoing protocol (5) develops two cumulative superficial hemosiderosis zones without clinical symptoms after step (E), treatment with the anti-Aβ antibody should be discontinued until ARIA-H is stabilized. After stabilization, the patient can continue treatment with the same amount of antibody as in step (E) (i.e., 3 mg / kg of patient body weight). The patient is administered two or more doses of 3 mg / kg of patient body weight of an anti-Aβ antibody, after which the patient can continue with the remaining steps of Protocol (5) (i.e., steps (F) through (L)).

[0186] However, if the patient has previously experienced ARIA-E or ARIA-H, requiring discontinuation of the dose, the patient should receive two or more doses of the next lower dose of anti-Aβ antibody in the protocol (i.e., 1 mg / kg of patient body weight) once ARIA-H has stabilized. Thereafter, the patient may continue with the remaining steps of Protocol (5) (i.e., steps (F) through (L)).

[0187] If a patient receiving a dose-adjusted regimen of an anti-Aβ antibody develops one or two cumulative superficial cerebral hemosiderosis zones accompanied by mild, moderate, or severe clinical symptoms, or clinical symptoms that meet the "other medically significant" severity classification criteria, dose discontinuation is required until ARIA-H stabilizes and clinical symptoms resolve. At this point, the patient can be administered the same dose that the patient was receiving immediately before the development of two cumulative superficial cerebral hemosiderosis zones. If the patient has a history of ARIA-E or ARIA-H that required dose discontinuation, the patient should be administered a lower dose of anti-Aβ antibody than the dose that the patient was receiving immediately before the development of one or two cumulative superficial cerebral hemosiderosis zones. For example, if a patient undergoing Protocol (5) develops one or two cumulative superficial hemosiderosis areas with mild, moderate, severe, or critical clinical symptoms after step (C), treatment of the patient with the anti-Aβ antibody should be discontinued until ARIA-H stabilizes and clinical symptoms disappear, after which the patient may continue treatment with two or more doses of the anti-Aβ antibody (i.e., 3 mg / kg of patient body weight) in the same amount as in step (C) of Protocol (5). Thereafter, the patient may continue with the remaining steps of Protocol (5) (i.e., steps (D) through (L)).

[0188] However, if the patient has previously experienced ARIA-E or ARIA-H, requiring dose discontinuation, the patient should receive two or more doses of the next lower dose of anti-Aβ antibody (i.e., 1 mg / kg of patient body weight) in Protocol (5) once ARIA-H has stabilized and clinical symptoms have resolved. Thereafter, the patient may continue with the remaining steps of Protocol (5) (i.e., steps (D) through (L)).

[0189] (8) Resumption of treatment after discontinuation due to ARIA In either case, if treatment with an anti-Aβ antibody (e.g., BIIB037) is restarted after dose discontinuation, the patient should receive at least two doses of the restart dose. MRI should be performed after the second restart dose and after the second dose of any escalating dose.

[0190] Measuring and reducing symptoms of AD Measurement of the risk, presence, severity, and progression of AD can be determined by clinical diagnosis over time; assessment of the patient's overall level of functioning; evaluation of daily living abilities or behavioral impairment; volumetric analysis of brain structure; in vivo measurements of pathological deposits of abnormal proteins in the brain (e.g., PET beta-amyloid imaging) or biochemical variables of body fluids (e.g., tau protein or Aβ peptide); and comparison with the natural history / history of the disease.

[0191] The following clinical assessments can be used to stage AD in patients: CDR, FCSRT, Neuropsychiatric Symptom Assessment Questionnaire (NPI-Q), and a neuropsychological test battery including the Reay Auditory Verbal Learning Test (RA VLT) immediate and delayed recall, the Wechsler Memory Scale (WMS) Verbal Paired Associate Learning Test immediate and delayed recall, the Delis-Kaplan Executive Function Test Verbal Fluency Items 1 and 2, and the Wechsler Adult Intelligence Scale-Fourth Edition Symbol Search and Signing subtests; and the Cognitive Drug Research computerized test battery.

[0192] In one embodiment, the diagnostic method comprises determining the change from baseline in the Clinical Dementia Rating (CDR) scale, neuropsychological test battery, Dementia Drug Research Computerized Test Battery, Free and Cued Selective Recall Test (FCSRT), Short Mental State Examination (MMSE), Columbia-Suicide Severity Rating Scale (C-SSRS), and Neuropsychiatric Imaging Questionnaire (NPI-Q).

[0193] Biomarkers are emerging as essential for defining AD and staging the disease along the disease spectrum. Biomarker phenotypes can bridge the gap between clinical and neuropathological phenotypes, such as amyloid plaques, neurofibrillary tangles, inflammation, and neurodegeneration. AD biomarkers include ApoE isotype, CSF Aβ42, amyloid PET, CSF tau, and hippocampal volumetric (HCV) MRI.

[0194] Amyloid plaque burden in specific brain regions can be measured using 18F-AV-45 PET imaging. 18F-AV-45 is an amyloid ligand developed by Avid Radiopharmaceuticals (Philadelphia, Pennsylvania). It binds to fibrillar Aβ with high affinity (Kd = 3.1 nM). 18F-AV-45 PET imaging results demonstrate that in AD patients, the tracer selectively accumulates in cortical regions thought to be rich in amyloid deposits, whereas in healthy controls, it rapidly disappears from these regions, with minimal tracer accumulation in the cortex. Significant differences in mean 18F-AV-45 uptake were observed between AD subjects and age-matched controls. Test-retest variance in 18F-AV-45 PET imaging is low (<5%) in both AD patients and cognitively healthy controls. Visual assessment of 18F-AV-45 PET images and mean quantitative estimates of cortical uptake correlate with the presence and amount of amyloid pathology at autopsy, as measured by immunohistochemistry and silver-stained senile plaque scores (Clark CM, et al. Use of florbetapir-PET for imaging β-amyloid pathology. JAMA,2011 Jan;305(3):275-283).

[0195] The radiation dosimetry of 18F-AV-45 is within the range of typical PET ligands. The average human whole-body effective dose is estimated to be 0.019 mSv / MBq. A dose of 370 MBq per injection has also been shown to produce good imaging results.

[0196] Patients with AD have characteristically reduced regional glucose metabolism as measured by FDG PET, which is associated with progressive cognitive impairment (Landau SM, et al. Associations between cognitive, functional, and FDG-PET measures of decline in AD and MCI. Neurobiol Aging, 2011 Jul;32(7):1207-18; Mielke R, et al. HMPAO SPET and FDG PET in Alzheimer's disease and vascular dementia: comparison of perfusion and metabolic pattern. Eur J Nucl Med., 1994 Oct;21(10):1052-60). The effect of anti-Aβ antibodies in preventing the progression of impaired glucose metabolism is due to the FDG It can be routinely assessed using PET measurements. FDG radiation dosimetry is within the range of typical PET ligands. The average human whole-body effective dose is estimated to be 0.019 mSv / MBq. Standard FDG imaging protocols use a dose of 185 MBq per injection. Patients can typically receive up to 185 MBq per scan.

[0197] Measurement of Aβ1-42 and T-tau or P-tau levels in CSF is gaining acceptance as predictive biomarkers for AD. Evidence supports that tau aggregation pathology is a very early event in the pathogenesis (Duyckaerts (2011) Lancet Neurol. 10, 774-775, and Braak et al., (2013), Acta Neuropath., 126:631-41).

[0198] AD-related biomarkers can also be used, including, but not limited to, pyroglutamylated-Aβ, Aβ40, and Aβ42 in the blood, and total tau, phosphorylated-tau, pyroglutamylated-Aβ, Aβ40, and Aβ42 in the CSF.

[0199] MRI morphometry is also useful in assessing AD. These include whole brain volume, hippocampal volume, ventricular volume, and cortical gray matter volume. Assessment protocols can include cerebral blood flow measured by ASL-MRI and functional connectivity measured by tf-fMRI.

[0200] Use of an anti-Aβ antibody (e.g., BIIB037) in the treatment of AD patients in accordance with the present disclosure results in improvement in one or more of these parameters relative to baseline measurements, or at least prevents or slows the progression of AD from one stage to the next.

[0201] Measuring ARIA AD patients generally respond to anti-Aβ antibodies (e.g., BIIB037) in a dose-dependent manner. Therefore, it is advantageous to use a high dose to achieve maximum efficacy. However, increasing the dose of anti-Aβ antibodies may increase the incidence or occurrence of ARIA in certain patient populations. The present disclosure makes it possible to reduce the incidence of ARIA in susceptible patients undergoing treatment for Alzheimer's disease, particularly those receiving high-dose anti-Aβ antibodies, as well as ApoE4 carriers. In particular, the present disclosure makes it possible to reduce the incidence of amyloid-related imaging abnormalities - edema (ARIA-E), or amyloid-related imaging abnormalities - hemorrhage or hemosiderosis (ARIA-H), or to reduce both ARIA-E and ARIA-H.

[0202] ARIA, including edema (ARIA-E) and microhemorrhage or hemosiderosis (ARIA-H), is diagnosed by MRI (i.e., fluid-suppressed inversion recovery (FLAIR / T2 for ARIA-E and T2 for ARIA-H)). *It can be easily detected by T2 / gradient echo (Sperling R, et al. Amyloid-related imaging abnormalities in patients with Alzheimer's disease treated with bapineuzumab: a retrospective analysis. Lancet Neurol., 2012;11(3):241-9). * Susceptibility-weighted imaging (SWI), an MRI technique that is much more sensitive than gradient echo imaging (Sperling RA, et al. Amyloid-related imaging abnormalities in amyloid-modifying therapeutic trials: Recommendations from the Alzheimer's Association Research Roundtable Workgroup. Alzheimer's and Dementia, 2011;7(4):367-85), can also be used.

[0203] Signs of vasogenic edema include T2-weighted hyperintensity and FLAIR sequences, commonly confined to the white matter and often associated with swelling of the gyri. Symptoms of vasogenic edema, if present, include headache, cognitive deterioration, altered consciousness, seizures, unsteadiness, and vomiting.

[0204] ARIA-H is visible on MRI and is considered an imaging finding without clinical correlation (i.e., patients are asymptomatic) (Sperling RA, et al. Amyloid-related imaging abnormalities in amyloid-modifying therapeutic trials: Recommendations from the Alzheimer's Association Research Roundtable Workgroup. Alzheimer's and Dementia, 2011;7(4):367-85). Specifically, hemorrhages can be detected using gradient-echo, T1-weighted, T2-weighted, and FLAIR MRI sequences. Microhemorrhages are usually asymptomatic, whereas large hemorrhages typically have nonspecific symptoms, including focal signs and symptoms reflecting the affected area of ​​the brain and symptoms in cases of vasogenic edema. The frequency of MRI acquisition depends on safety monitoring needs.

[0205] The following are examples of the present invention, which should not be construed as limiting the scope of the invention in any way. [Example]

[0206] Example 1: In vivo toxicity testing of BIIB037 Toxicity evaluation of BIIB037 was performed using Tg2576 mice and cynomolgus monkeys, which are considered the first pharmacologically relevant species because amyloid plaques accumulate in the brain parenchyma and vasculature of the two species.

[0207] In addition to standard histopathological evaluation in mice, Perls staining for hemosiderin (a breakdown product of hemoglobin) was performed to quantify microhemorrhages. Microhemorrhages are a background finding in transgenic AD mouse models (Winkler DT, et al. Spontaneous hemorrhagic stroke in a mouse model of cerebral amyloid angiopathy. J. Neurosci., 2001 Mar 1;21(5):1619-27), including Tg2576 mice (Kumar-Singh S, et al. Dense-core plaques in Tg2576 and PSAPP mouse models of Alzheimer's disease are centered on vessel walls. American Journal of Pathology, 2005 Aug;167(2):527-43), and a drug-related finding in some transgenic mice treated with anti-Aβ antibodies (Pfeifer M, et al. Cerebral hemorrhage after passive anti-Aβ antibodies). immunotherapy. Science 2002 Nov 15;298(5597):1379;Racke MM,et al. Exacerbation of cerebral amyloid angiopathy- associated microhemorrhage in amyloid precursor protein transgenic mice by immunotherapy is dependent on antibody recognition of deposited forms of amyloid beta. J Neurosci.,2005 Jan 19;25(3):629-36.; Wilcock OM, Colton CA. Immunotherapy, vascular pathology, and microhemorrhages in transgenic mice. CNS & Neurological Disorders Drug Targets,2009 Mar;8(1):50-64.

[0208] Example 2: Short-term testing of BIIB037 in vivo In a 13-week study, Tg2576 mice received weekly IV doses of 10 mg / kg or 70 mg / kg ch12F6A, or 500 mg / kg ch12F6A or BIIB037. Minimal to mild acute hemorrhage, as assessed by standard histopathological staining, was observed in two mice dosed above 70 mg / kg / week. Additional findings included a slightly increased incidence and / or severity of meningeal vascular inflammation in mice treated above 70 mg / kg / week compared with control animals, and thrombosis in two animals dosed at 500 mg / kg / week. At the end of the 6-week recovery period, the incidence and severity of findings observed in ch12F6A- and BIIB037-treated mice were within the range observed in the control group throughout the study.

[0209] In addition to standard brain histopathology, the presence of microhemorrhages was assessed by Perls staining, and no significant differences in microhemorrhages were observed between the ch12F6A / BIIB037-treated and control groups after 13 weeks of treatment.

[0210] The increased incidence and / or severity of meningeal vascular inflammation and acute hemorrhage observed at 70 mg / kg / week and above contributed to the determination of a no-observed-adverse-effect level (NOAEL) of 10 mg / kg / week.

[0211] Example 3: Long-term study of BIIB037 in vivo In a 6-month study, Tg2576 mice received weekly IV doses of 10 mg / kg or 40 mg / kg ch12F6A, or 250 mg / kg ch12F6A or BIIB037. There were no treatment-related changes in any of the parameters assessed during the study or recovery period, except for a slightly higher incidence and / or severity of combined meningeal / cerebral vascular inflammation and vascular thickening in the brains of primary and early-death animals treated with chimeric 12F6A containing a mouse constant domain (ch12F6A) at doses greater than 40 mg / kg, and increased areas of microhemorrhage in a subset of animals treated with 250 mg / kg ch12F6A.

[0212] In Tg2576 mice receiving weekly intravenous injections of 250 mg / kg BIIB037, there were no treatment-related findings, no increase in the incidence and / or severity of meningeal / cerebral vascular inflammation and / or vascular thickening, and no statistically significant differences in the number and / or area percentage of microhemorrhage foci in the brain of ch12F6A- or BIIB037-treated animals.

[0213] After a 6-week recovery period, the incidence and / or severity of vascular inflammation or thickening were similar in treated and control groups. Although the possibility of a treatment-related exacerbation of these changes cannot be completely ruled out, the cerebral vascular inflammation, thickening, and possible worsening microhemorrhages were considered to be of uncertain relationship to treatment and likely to be age-related degenerative changes solely intrinsic to the disease model. Therefore, the NOAEL in this study is 250 mg / kg / week.

[0214] Treatment-related findings were observed in a 4-week monkey study, with a NOAEL of 300 mg / kg / week.

[0215] In summary, the toxicity assessment of BIIB037 identified a toxicity profile consistent with antibody binding to deposited Aβ.

[0216] Example 4: Reduction of amyloid beta in vivo In Tg2576 mice, a dose-dependent reduction in brain amyloid was observed after chronic administration of ch12F6A (0.3 mg / kg to 30 mg / kg). Significant amyloid reduction was observed at the minimally effective dose of 3 mg / kg, and efficacy appeared to plateau between 10 mg / kg and 30 mg / kg. The no-observed-adverse-effect level (NOAEL) obtained from a 13-week toxicity study in Tg2576 mice (10 mg / kg / week) was used to determine the safety margin.

[0217] Steady-state average exposure (AUC) of BIIB037 in humans at 1 mg / kg and 3 mg / kg 0~4wk ) was calculated based on the exposure (AUC 0~4wk The steady-state average exposure of BIIB037 after the 10 mg / kg dose is planned to be approximately one-twelfth and one-quarter of the NOAEL dose. The steady-state average exposure of BIIB037 after the 10 mg / kg dose is planned to be similar to that at the NOAEL dose. The highest dose, 30 mg / kg, is planned to achieve a steady-state average exposure that is two to three times the NOAEL exposure and one-third of the exposure at the 70 mg / kg dose, where a slight increase in the severity of meningeal vascular inflammation and the incidence of cerebral hemorrhage was observed.

[0218] Example 5: Clinical Experience with BIIB037 The first clinical trial was a Phase 1, randomized, blinded, placebo-controlled, single-ascending-dose (SAD) study evaluating the safety, tolerability, and pharmacokinetics (PK) of BIIB037 in subjects with mild to moderate AD. 53 subjects were enrolled in the SAD study.

[0219] The starting dose of BIIB037 was 0.3 mg / kg, followed by 500 mg / kg (AUCTAU = 402,000 μg * The dose was titrated up to 60 mg / kg, a dose predicted to provide an average exposure (AUC) not exceeding that in Tg2576 mice given 24 h / mL. Doses up to 30 mg / kg (0.3 mg / kg, 1 mg / kg, 3 mg / kg, 10 mg / kg, 20 mg / kg, and 30 mg / kg) were generally well tolerated.

[0220] Two symptomatic amyloid-related imaging abnormalities-edema (ARIA-E) serious adverse events (SAEs) and one asymptomatic ARIA-E adverse event (AE) were reported in the 60 mg / kg cohort. Per study protocol, further enrollment in the 60 mg / kg cohort was halted. No deaths or discontinuations due to AEs were reported in the SAD study. Serum exposure to BIIB037 was linear up to a dose of 30 mg / kg.

[0221] Example 6: Clinical Trials of BIIB037 A. Phase 1b Clinical Trial of BIIB037 in Human AD Subjects A Phase 1b clinical trial was conducted. The trial was a randomized, blinded, placebo-controlled, dose-escalation study of BIIB037 in subjects with prodromal to mild AD and those with amyloid scan-positive disease. The primary endpoint of the trial was safety. Secondary endpoints included evaluation of the effect on cerebral amyloid plaque content as measured by 18F-AV-45 PET imaging. Changes from baseline in 18F-AV-45 PET signal in specific brain regions were assessed. Exploratory endpoints assessed subjects' cognitive function. Subjects received 1 mg / kg, 3 mg / kg, 6 mg / kg, or 10 mg / kg BIB037, based on patient weight, or placebo.

[0222] B. Pre-specified Interim Analysis #1 Pre-specified interim analysis #1 provided 26-week data for the 1 mg / kg, 3 mg / kg, and 10 mg / kg groups and the placebo group.

[0223] AD subjects were randomized into four groups: placebo, BIIB037 at 1 mg / kg of patient body weight, BIIB037 at 3 mg / kg of body weight, and BIIB037 at 10 mg / kg of body weight. There were approximately 31 subjects in each group. The mean age of subjects was approximately 72 years (mean). ApoE4 carriers comprised 63%, 61%, 66%, and 63% of the groups, respectively.

[0224] The subjects were assessed for clinical stage of AD. Subjects with prodromal AD comprised 47%, 32%, 44%, and 41% of each group, respectively. Subjects with mild AD comprised 53%, 68%, 56%, and 59% of each group, respectively.

[0225] A static PET imaging protocol was used: each subject was injected with a tracer and underwent a single scan. The tracer was AV45, a PET ligand that targets fibrous Aβ plaques.

[0226] Results of the amyloid PET imaging protocol were expressed as normalized uptake ratios, which are a measure of the uptake of the β-amyloid ligand used for PET imaging and correspond to the amount of β-amyloid present. Normalized uptake ratios normalize the PET signal by taking the ratio of the region of interest to the reference region. In the region of interest, specific binding and binding signal changes reflect pharmacological modulation induced by treatment. In the reference region, nonspecific binding indicates no therapeutic effect.

[0227] Dose-dependent reductions in amyloid were observed. There were statistically significant reductions observed at 3 mg / kg and 10 mg / kg at week 26. These effects appeared to continue through week 54 based on a small subset of subjects. There was no clear ApoE modification associated with the observed effects. Greater effects were observed in subjects with higher baseline normalized uptake ratios.

[0228] Safety and tolerability of treatment were assessed. Adverse events were generally mild or moderate. The most common adverse event was headache, which appeared to be dose-related. There were no significant changes in chemistry, hematology, urinalysis, ECG, or vital signs. Twenty-seven subjects experienced ARIA-E or ARIA-E / H.

[0229] Higher incidence of ARIA was observed with higher BIIB037 doses and ApoE4 carriers. Homozygous and heterozygous E4 carriers appeared to be at similar risk for ARIA.

[0230] ARIA-E occurred early in the course of treatment in most cases. ARIA-E occurred after 3 to 5 doses (week 18 or week 10) at the 1 mg / kg and 3 mg / kg doses. No cases were detected after the fifth dose. ARIA-E occurred after 2 doses (week 6) and week 30 at the 6 mg / kg and 10 mg / kg doses. Imaging findings resolved in most cases within 4 to 12 weeks, indicating that ARIA-E is reversible.

[0231] All subjects with an ARIA-H event also had an ARIA-E event. The incidence of ARIA-E was higher than the incidence of ARIA-H in the 3 mg / kg and 10 mg / kg treatment groups. The incidence of each event was the same in the 1 mg / kg dose group.

[0232] C. Pre-specified Interim Analysis #2 Pre-specified interim analysis #2 provided 54 weeks of data for the 1 mg / kg, 3 mg / kg, and 10 mg / kg groups and the placebo group, and 26 weeks of data for the 6 mg / kg group.

[0233] Figure 1 shows the mean PET complex standardized uptake value ratio (SUVR) by measurement time point based on observed data for each treatment group. Figure 1 shows that there was a reduction in amyloid burden from baseline to week 26 in each treatment group receiving antibody BIIB037. There was further amyloid burden reduction from week 26 to week 54 in each treatment group receiving BIIB037. The placebo group did not show a corresponding reduction in amyloid burden.

[0234] Figure 1 also shows that amyloid reduction with BIIB037 was dose-dependent. Higher doses of BIIB037 were associated with greater reductions in brain amyloid, as measured by amyloid scan. Similar effects were not observed in the placebo group.

[0235] Figure 2 shows the adjusted mean change from baseline PET composite SUVR at week 26 by baseline clinical stage, i.e., prodromal or mild AD. Figure 2 is based on observational data. Figure 2 shows that amyloid reduction was dose-dependent on amyloid scans.

[0236] Figure 3 shows the amyloid burden reduction by subject ApoE4 status. Both carrier and non-carrier groups showed amyloid burden reduction compared to the placebo group. The reduction was dose-dependent in each case.

[0237] The incidence of ARIA-E and / or ARIA-H during the study was estimated. The results are shown in Figure 4. The incidence of ARIA in ApoE4 carriers and non-carriers is also reported in Figure 4. The incidence was dose-dependent and, at 6 mg / kg and 10 mg / kg, ApoE4 carrier status-dependent. ARIA-E occurred early in the treatment course in most cases. ARIA-E was generally reversible. ARIA-H was stable. Imaging findings resolved in most cases within 4 to 12 weeks.

[0238] D. Clinical assessment of the patient's cognition Clinical assessments were used to measure changes in Alzheimer's disease symptoms in treated patients. Specifically, the Clinical Dementia Rating Scale (CDR) and the Minute Mental Status Examination (MMSE) were used to measure change from baseline. The results of these assessments based on observational data are summarized in Figures 5 and 6.

[0239] Figure 5 shows the adjusted mean change from baseline in CDR-SB comparing patients receiving placebo with patient populations receiving 1 mg / kg, 3 mg / kg, or 10 mg / kg of antibody BIIB037. Measurements were taken at week 54 of treatment at the specified doses.

[0240] Figure 6 shows the adjusted mean change from baseline in MMSE comparing patients receiving placebo with patient populations receiving 1 mg / kg, 3 mg / kg, or 10 mg / kg of antibody BIIB037, measured at week 54 of treatment at the specified doses.

[0241] Example 7: Randomized, Double-Blind, Placebo-Controlled Phase 1b Study of the Anti-Aβ Monoclonal Antibody Aducanumab (BIIB037) in Patients with Prodromal or Mild Alzheimer's Disease: Interim Results by Disease Stage and ApoE ε4 Status Aducanumab (BIIB037) is a human monoclonal antibody selective for aggregated forms of beta-amyloid (Aβ) peptide, including soluble oligomers and insoluble fibrils. A single-dose escalation study of aducanumab demonstrated acceptable safety and efficacy in patients with mild to moderate AD at doses up to 30 mg / kg. This Phase 1b study evaluated the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics of aducanumab in patients with prodromal or mild AD.

[0242] The objective was to present interim results of safety and Aβ clearance (changes in positron emission tomography [PET] results with florbetapir [18-AV-45]) with aducanumab according to disease stage and ApoE ε4 status.

[0243] Study design PRIME is a multicenter, randomized, double-blind, placebo-controlled, multiple-dose trial [NCT01677572].

[0244] Patients were aged 50 to 90 years, taking a stable dose of concomitant medication, had a Minor Mental Status Examination (MMSE) score of 20 or higher, and met the following clinical and radiological diagnostic criteria. Prodromal AD: spontaneous memory complaints with an MMSE score of 24-30; combined free recall score of 27 or less on free and cued selective recall tests; Clinical Dementia Scale (CDR) total score of 0.5; no significant impairment in other cognitive domains; essentially preserved activities of daily living and no dementia; positive florbetapir PET scan with visual assessment. Mild AD: MMSE score of 20-26; composite CDR of 0.5 or 1.0; met the National Institute on Aging and Alzheimer's Association's key clinical diagnostic criteria for probable AD; and had a positive florbetapir PET scan with visual assessment.

[0245] The PRIME study design is shown in Figure 14. Patients (planned enrollment, N=188) were randomized in a 3:1 active-to-placebo ratio to one of nine treatment arms (target enrollment: n=30 per active treatment arm) in a staggered dose-escalation design. Primary and secondary endpoints are listed in Figure 15. The PRIME evaluation schedule is shown in Figure 16. PRIME is currently ongoing. For interim analyses, data were analyzed through week 54 for the 1 mg / kg, 3 mg / kg, and 10 mg / kg arms and through week 30 for the 6 mg / kg arm.

[0246] patient Of 166 randomized patients, 165 received treatment: 107 (65%) were ApoE ε4 carriers and 68 (41%) had prodromal AD. Patient demographics are shown in Figure 17. Baseline demographic and disease characteristics were generally very similar across treatment groups, as shown in Figure 18.

[0247] safety Adverse events (AEs) were reported in 84% to 98% of patients across all treatment groups. The most common AE and serious AE (SAE) was amyloid-related imaging abnormality (ARIA; MRI-based) (Table 9), with other AEs / SAEs consistent with the patient population. Figure 19 provides an overview of ARIA findings and patient disposition following ARIA-E.

[0248] Three deaths were reported (two in the placebo group and one in the aducanumab 10 mg / kg group); none were considered treatment-related (two occurred after study discontinuation).

[0249] The incidence of isolated ARIA-edema (ARIA-E) was dose- and ApoE ε4-status-dependent (FIG. 19): The overall incidence of ARIA-E in ApoE ε4 carriers was 5%, 5%, 43%, and 55% for 1 mg / kg, 3 mg / kg, 6 mg / kg, and 10 mg / kg aducanumab, respectively, compared with 0% for placebo. • The corresponding incidence rates in ApoE ε4 non-carriers were 0%, 9%, 11%, and 17% vs. 0%. The incidence of ARIA-microhemorrhage / hemosiderosis (ARIA-H) alone was similar across doses and ApoE ε4 status (data not shown).

[0250] Based on the small sample size, there was no apparent difference in the incidence of ARIA-E between subjects with prodromal or mild AD when considering ApoE ε4 status (Figure 19). Most (92%) ARIA-E events were observed within the first 5 doses, and 65% of ARIA-E events were asymptomatic. If symptoms were present, they typically disappeared within four weeks. • MRI findings typically resolved within 4 to 12 weeks.

[0251] Most patients (54%) who developed ARIA-E continued treatment (93% of those who continued treatment continued at a reduced dose), and no patients experienced recurrence of ARIA-E. Treatment discontinuation in patients with ARIA-E was consistent across mild and prodromal subgroups (data not shown).

[0252] There were no significant changes in chemistry, hematology, urinalysis, electrocardiogram, or vital signs.

[0253] Reduction of brain Aβ plaques Cerebral Aβ plaque reduction was assessed by a composite SUVR derived from the volumes of six regions: frontal, parietal, lateral temporal, sensorimotor, anterior cingulate, and posterior cingulate.

[0254] The dose- and time-dependent reductions in brain Aβ plaques (evidenced by reduced SUVR) at weeks 26 and 54 were generally consistent across mild and prodromal AD subgroups and across ApoE ε4 carriers and non-carriers within the doses tested, as shown in Figure 7.

[0255] Clinical endpoints There was a statistically significant dose-dependent slowing of decline in exploratory endpoints, namely MMSE (Figure 8) and CDR-sb (Figure 9) at 1 year.

[0256] conclusion Compared to placebo, there was a significant dose- and time-dependent reduction in brain Aβ plaques as measured by PET imaging, an effect that was evident at 6 months and 1 year of treatment.

[0257] The pattern of effect of aducanumab versus placebo on reducing Aβ plaques was mostly consistent across disease stage and ApoE ε4 status.

[0258] A statistically significant dose-dependent slowing of decline in MMSE and CDR-sb at 1 year was observed.

[0259] Aducanumab demonstrated an acceptable safety profile over 54 weeks. The primary safety and tolerability finding was ARIA, which was monitored and managed. The incidence of ARIA was dose- and ApoE-ε4-status-dependent. ARIA was mostly observed early in the treatment course and was mild, transient, or asymptomatic.

[0260] Interim Analysis #3 Interim analysis #3 includes data for the 6 mg / kg group and the corresponding placebo group (which will be combined into a pooled placebo population for analysis) through week 54.

[0261] Reduction of brain Aβ plaques Brain Aβ plaque reduction was assessed by a composite SUVR derived from volumes of six regions: frontal, parietal, lateral temporal, sensorimotor, anterior cingulate, and posterior cingulate. As shown in Figure 11, there was a dose-dependent reduction in brain Aβ plaques (evidenced by a decrease in SUVR) at 54 weeks.

[0262] Clinical endpoints There was a statistically significant dose-dependent slowing of decline in exploratory endpoints, namely MMSE (Figure 13) and CDR-sb (Figure 12) at 1 year.

[0263] Other embodiments While the present invention has been described in conjunction with its detailed description, the foregoing description is intended to be illustrative, not limiting, of the scope of the invention, which is defined by the scope of the appended claims. Other aspects, advantages, and modifications are within the scope of the following claims. The present invention provides, for example, the following items. (Item 1) 1. A method of treating Alzheimer's disease (AD) in a human subject in need thereof, comprising: The human subject is administered multiple doses of an anti-beta amyloid antibody, wherein the subject develops amyloid-related imaging abnormalities (ARIA) during treatment with the anti-beta amyloid antibody, wherein the ARIA is selected from the group consisting of: (i) ARIA-E without clinical symptoms that is moderate or severe; (ii) ARIA-E that is mild, moderate, or severe and is associated with mild, moderate, severe, or severe clinical symptoms; (iii) cumulative minimal ARIA-E; (iv) ARIA-H with 5 to 9 hemorrhages and no clinical symptoms; (v) ARIA-H with 2 cumulative areas of superficial hemosiderosis and no clinical symptoms; or (vi) ARIA-H with 1 or 2 cumulative areas of superficial hemosiderosis and no clinical symptoms and no clinical symptoms; After the onset of the ARIA, discontinuing administration of the anti-beta amyloid antibody to the subject until the ARIA resolves; resuming administration of an anti-beta amyloid antibody to the subject at the same dose as that administered immediately prior to the subject developing the ARIA; wherein the anti-beta amyloid antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises a first complementarity determining region (VHCDR1) having the amino acid sequence of SEQ ID NO: 3, a VHCDR2 having the amino acid sequence of SEQ ID NO: 4, and a VHCDR3 having the amino acid sequence of SEQ ID NO: 5; The VL comprises a VLCDR1 having the amino acid sequence of SEQ ID NO:6, a VLCDR2 having the amino acid sequence of SEQ ID NO:7, and a VLCDR3 having the amino acid sequence of SEQ ID NO:8. The method comprising: (Item 2) 2. The method of claim 1, wherein the multiple doses of the anti-beta amyloid antibody are equal doses. (Item 3) 2. The method of claim 1, wherein the multiple doses of the anti-beta amyloid antibody comprise doses of different amounts. (Item 4) 3. The method of claim 2, wherein the multiple dose is 1 mg / kg of the subject's body weight. (Item 5) 3. The method of claim 2, wherein the multiple dose is 3 mg / kg of the subject's body weight. (Item 6) 3. The method of claim 2, wherein the multiple dose is 6 mg / kg of the subject's body weight. (Item 7) 3. The method of claim 2, wherein the multiple dose is 10 mg / kg of the subject's body weight. (Item 8) 3. The method of claim 2, wherein the multiple dose is 15 mg / kg of the subject's body weight. (Item 9) 3. The method of claim 2, wherein the multiple dose is 30 mg / kg of the subject's body weight. (Item 10) 4. The method of claim 3, wherein the multiple doses include 1 mg / kg and 3 mg / kg of the subject's body weight. (Item 11) 4. The method of claim 3, wherein the multiple doses include 1 mg / kg, 3 mg / kg, and 6 mg / kg of the subject's body weight. (Item 12) 4. The method of claim 3, wherein the multiple doses include 1 mg / kg, 3 mg / kg, 6 mg / kg, and 10 mg / kg of the subject's body weight. (Item 13) 4. The method of claim 3, wherein the subject is an ApoE4 carrier and the multiple doses include two or more doses of 1 mg / kg, 3 mg / kg, or 6 mg / kg of the subject's body weight. (Item 14) 4. The method of item 3, wherein the subject is an ApoE4 non-carrier and the multiple doses include two or more doses of 1 mg / kg, 3 mg / kg, 6 mg / kg, 10 mg / kg, 15 mg / kg, or 30 mg / kg of the subject's body weight. (Item 15) 15. The method of any one of items 1, 3, or 10 to 14, further comprising subsequent administration of a higher dose of an anti-beta amyloid antibody than the dose administered upon resumption of administration after the disappearance of the ARIA. (Item 16) 16. The method of any one of items 1 to 15, wherein the multiple doses are administered at 4 week intervals. (Item 17) 17. The method of any one of items 1 to 16, wherein the number of multiple doses administered to the subject prior to the onset of ARIA is 2 to 14 doses. (Item 18) 15. The method of any one of items 1 to 14, wherein the number of multiple doses administered to the subject prior to the onset of ARIA is 2 to 5 doses. (Item 19) Administration of multiple doses of the anti-beta amyloid antibody to the human subject begins at step (a) prior to the onset of ARIA and includes the following administration steps: (a) administering the anti-beta amyloid antibody to the subject in an amount of 1 mg / kg of body weight of the subject; (b) 4 weeks after step (a), administering the antibody to the subject in an amount of 1 mg / kg of body weight of the subject; (c) 4 weeks after step (b), administering the antibody to the subject in an amount of 3 mg / kg of body weight of the subject; (d) 4 weeks after step (c), administering the antibody to the subject in an amount of 3 mg / kg of body weight of the subject; (e) 4 weeks after step (d), administering the antibody to the subject in an amount of 3 mg / kg of body weight of the subject; (f) 4 weeks after step (e), administering the antibody to the subject in an amount of 3 mg / kg of body weight of the subject; (g) 4 weeks after step (f), administering the antibody to the subject in an amount of 6 mg / kg of body weight of the subject; and (h) following step (g), at subsequent 4 week intervals, administering the antibody to the subject in an amount of 6 mg / kg of body weight of the subject. Item 1. The method according to item 1, comprising sequentially performing two or more of the following steps: (Item 20) The method further comprises, after the ARIA has disappeared, administering: (a) administering the anti-beta amyloid antibody to the subject in an amount of 1 mg / kg of body weight of the subject; (b) 4 weeks after step (a), administering the antibody to the subject in an amount of 1 mg / kg of body weight of the subject; (c) 4 weeks after step (b), administering the antibody to the subject in an amount of 3 mg / kg of body weight of the subject; (d) 4 weeks after step (c), administering the antibody to the subject in an amount of 3 mg / kg of body weight of the subject; (e) 4 weeks after step (d), administering the antibody to the subject in an amount of 3 mg / kg of body weight of the subject; (f) 4 weeks after step (e), administering the antibody to the subject in an amount of 3 mg / kg of body weight of the subject; (g) 4 weeks after step (f), administering the antibody to the subject in an amount of 6 mg / kg of body weight of the subject; and (h) following step (g), at subsequent 4 week intervals, administering the antibody to the subject in an amount of 6 mg / kg of body weight of the subject. 20. The method of claim 19, further comprising sequentially performing the steps of: (Item 21) Administration of multiple doses of the anti-beta amyloid antibody to the human subject begins at step (a) prior to the onset of ARIA and includes the following administration steps: (a) administering the anti-beta amyloid antibody to the subject in an amount of 1 mg / kg of body weight of the subject; (b) 4 weeks after step (a), administering the antibody to the subject in an amount of 1 mg / kg of body weight of the subject; (c) 4 weeks after step (b), administering the antibody to the subject in an amount of 3 mg / kg of body weight of the subject; (d) 4 weeks after step (c), administering the antibody to the subject in an amount of 3 mg / kg of body weight of the subject; (e) 4 weeks after step (d), administering the antibody to the subject in an amount of 6 mg / kg of body weight of the subject; (f) 4 weeks after step (e), administering the antibody to the subject in an amount of 6 mg / kg of body weight of the subject; and (g) following step (f), at subsequent 4 week intervals, administering the antibody to the subject in an amount of 10 mg / kg of body weight of the subject. Two or more of these steps are carried out in order, Item 10. The method according to item 1, wherein the subject is an ApoE4 non-carrier. (Item 22) The method further comprises, after the ARIA has disappeared, administering: (a) administering the anti-beta amyloid antibody to the subject in an amount of 1 mg / kg of body weight of the subject; (b) 4 weeks after step (a), administering the antibody to the subject in an amount of 1 mg / kg of body weight of the subject; (c) 4 weeks after step (b), administering the antibody to the subject in an amount of 3 mg / kg of body weight of the subject; (d) 4 weeks after step (c), administering the antibody to the subject in an amount of 3 mg / kg of body weight of the subject; (e) 4 weeks after step (d), administering the antibody to the subject in an amount of 6 mg / kg of body weight of the subject; (f) 4 weeks after step (e), administering the antibody to the subject in an amount of 6 mg / kg of body weight of the subject; and (g) following step (f), at subsequent 4 week intervals, administering the antibody to the subject in an amount of 10 mg / kg of body weight of the subject. 22. The method according to item 21, comprising sequentially performing the steps of: (Item 23) administering multiple doses of the anti-beta amyloid antibody to the human subject (a) administering the anti-beta amyloid antibody to the subject in an amount of 1 mg / kg of body weight of the subject; (b) 4 weeks after step (a), administering the antibody to the subject in an amount of 1 mg / kg of body weight of the subject; and (c) following step (b), at subsequent 4 week intervals, administering the antibody to the subject in an amount of 3 mg / kg of body weight of the subject; Item 10. The method according to item 1, wherein the subject is an ApoE4 carrier. (Item 24) After resuming administration of the anti-beta amyloid antibody, the human subject develops a second ARIA: (i) ARIA-E that is moderate or severe and is asymptomatic; (ii) ARIA-E that is mild, moderate, or severe and is associated with mild, moderate, severe, or severe clinical symptoms; (iii) ARIA-H that has 5 to 9 cumulative microhemorrhages and is asymptomatic; (iv) ARIA-H that has 1 to 9 cumulative microhemorrhages and is associated with mild, moderate, severe, or severe clinical symptoms; (v) ARIA-H that has 2 cumulative areas of superficial hemosiderosis and is asymptomatic; or (vi) ARIA-H that has 1 or 2 cumulative areas of superficial hemosiderosis and is associated with mild, moderate, severe, or severe clinical symptoms; discontinuing administration of the anti-beta amyloid antibody to the subject until the second ARIA resolves; and 24. The method of any one of items 1 to 23, further comprising resuming administration of the anti-beta amyloid antibody to the subject at a dose lower than the dose administered to the subject immediately before the subject developed the second ARIA. (Item 25) 25. The method of any one of items 1 to 24, wherein the ARIA is not accompanied by clinical symptoms. (Item 26) 25. The method of any one of items 1 to 24, wherein the ARIA is accompanied by mild clinical symptoms. (Item 27) 25. The method of any one of items 1 to 24, wherein the ARIA is accompanied by moderate clinical symptoms. (Item 28) 25. The method of any one of items 1 to 24, wherein the ARIA is accompanied by severe clinical symptoms. (Item 29) 29. The method according to any one of items 1 to 28, wherein the administration is performed intravenously. (Item 30) the VH consists of SEQ ID NO: 1, and 30. The method according to any one of items 1 to 29, wherein the VL consists of SEQ ID NO: 2. (Item 31) 31. The method according to any one of items 1 to 30, wherein the antibody comprises a human IgG1 constant region. (Item 32) The antibody comprises a heavy chain and a light chain, wherein: the heavy chain consists of SEQ ID NO: 10, and 30. The method according to any one of items 1 to 29, wherein the light chain consists of SEQ ID NO: 11. (Item 33) 1. A method of treating Alzheimer's disease in a human subject in need thereof, comprising administering to said human subject multiple doses of an anti-beta amyloid antibody, said multiple doses comprising: (a) administering the anti-beta amyloid antibody to the subject in an amount of 1 mg / kg of body weight of the subject; (b) 4 weeks after step (a), administering the antibody to the subject in an amount of 1 mg / kg of body weight of the subject; (c) 4 weeks after step (b), administering the antibody to the subject in an amount of 3 mg / kg of body weight of the subject; (d) 4 weeks after step (c), administering the antibody to the subject in an amount of 3 mg / kg of body weight of the subject; (e) 4 weeks after step (d), administering the antibody to the subject in an amount of 3 mg / kg of body weight of the subject; (f) 4 weeks after step (e), administering the antibody to the subject in an amount of 3 mg / kg of body weight of the subject; (g) 4 weeks after step (f), administering the antibody to the subject in an amount of 6 mg / kg of body weight of the subject; (h) 4 weeks after step (g), administering the antibody to the subject in an amount of 6 mg / kg of body weight of the subject; (i) 4 weeks after step (h), administering the antibody to the subject in an amount of 6 mg / kg of body weight of the subject; (j) 4 weeks after step (i), administering the antibody to the subject in an amount of 6 mg / kg of body weight of the subject; (k) 4 weeks after step (j), administering the antibody to the subject in an amount of 6 mg / kg of body weight of the subject; and (l) after step (k), at subsequent 4 week intervals, administering the antibody to the subject in an amount of 10 mg / kg of body weight of the subject. The method comprises administering the compound as follows: (Item 34) 1. A method of treating Alzheimer's disease in a human subject in need thereof, comprising administering to said human subject multiple doses of an anti-beta amyloid antibody, said multiple doses comprising: (a) administering the anti-beta amyloid antibody to the subject in an amount of 3 mg / kg of body weight of the subject; (b) 4 weeks after step (a), administering the antibody to the subject in an amount of 3 mg / kg of body weight of the subject; (c) 4 weeks after step (b), administering the antibody to the subject in an amount of 3 mg / kg of body weight of the subject; (d) 4 weeks after step (c), administering the antibody to the subject in an amount of 3 mg / kg of body weight of the subject; (e) 4 weeks after step (d), administering the antibody to the subject in an amount of 6 mg / kg of body weight of the subject; (f) 4 weeks after step (e), administering the antibody to the subject in an amount of 6 mg / kg of body weight of the subject; (g) 4 weeks after step (f), administering the antibody to the subject in an amount of 6 mg / kg of body weight of the subject; (h) 4 weeks after step (g), administering the antibody to the subject in an amount of 6 mg / kg of body weight of the subject; (i) 4 weeks after step (h), administering the antibody to the subject in an amount of 6 mg / kg of body weight of the subject; and (j) following step (i), at subsequent 4 week intervals, administering the antibody to the subject in an amount of 10 mg / kg of body weight of the subject. The method comprises administering the compound as follows: (Item 35) 1. A method of treating Alzheimer's disease in a human subject in need thereof, comprising administering to said human subject multiple doses of an anti-beta amyloid antibody, said multiple doses comprising: (a) administering the anti-beta amyloid antibody to the subject in an amount of 1 mg / kg of body weight of the subject; (b) 4 weeks after step (a), administering the antibody to the subject in an amount of 1 mg / kg of body weight of the subject; (c) 4 weeks after step (b), administering the antibody to the subject in an amount of 3 mg / kg of body weight of the subject; (d) 4 weeks after step (c), administering the antibody to the subject in an amount of 3 mg / kg of body weight of the subject; (e) 4 weeks after step (d), administering the antibody to the subject in an amount of 6 mg / kg of body weight of the subject; (f) 4 weeks after step (e), administering the antibody to the subject in an amount of 6 mg / kg of body weight of the subject; and (g) following step (f), at subsequent 4 week intervals, administering the antibody to the subject in an amount of 10 mg / kg of body weight of the subject. The method comprises administering the compound as follows: (Item 36) 1. A method of treating Alzheimer's disease in a human subject in need thereof, comprising administering to said human subject multiple doses of an anti-beta amyloid antibody, said multiple doses comprising: (a) administering the anti-beta amyloid antibody to the subject in an amount of 3 mg / kg of body weight of the subject; (b) 4 weeks after step (a), administering the antibody to the subject in an amount of 3 mg / kg of body weight of the subject; (c) 4 weeks after step (b), administering the antibody to the subject in an amount of 6 mg / kg of body weight of the subject; (d) 4 weeks after step (c), administering the antibody to the subject in an amount of 6 mg / kg of body weight of the subject; and (e) following step (d), at subsequent 4 week intervals, administering the antibody to the subject in an amount of 10 mg / kg of body weight of the subject. The method comprises administering the compound as follows: (Item 37) 37. The method of any one of items 33 to 36, wherein the human subject is an ApoE4 carrier. (Item 38) 38. The method according to any one of items 1 to 37, wherein the administration is performed intravenously. (Item 39) The anti-beta amyloid antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein: the VH consists of SEQ ID NO: 1, and 39. The method according to any one of items 1 to 38, wherein the VL consists of SEQ ID NO: 2. (Item 40) 40. The method according to any one of items 1 to 39, wherein the antibody comprises a human IgG1 constant region. (Item 41) The anti-beta amyloid antibody comprises a heavy chain and a light chain, wherein: the heavy chain consists of SEQ ID NO: 10, and 39. The method according to any one of items 1 to 38, wherein the light chain consists of SEQ ID NO: 11.

Claims

[Claim 1] The invention as described in the drawings.

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