Anti-N3pGlu amyloid beta antibodies, dosages, and uses thereof

Abstract

Treatment or prevention of diseases characterized by the deposition of amyloid beta (Aβ) plaques in the brain of a human subject, particularly intravenous and subcutaneous doses and dosing regimens of anti-N3pG antibodies.

Description

[Technical Field]

[0001] (Reference to sequence listing) This application contains a Sequence Listing that has been submitted electronically in ST.26XML format and is incorporated herein by reference in its entirety. The ST.26XML Sequence Listing was created on October 23, 2023, is named 30394.xml, and is 15,353 bytes in size.

[0002] FIELD OF THE INVENTION The present invention relates to anti-N3pGlu Aβ antibodies, their dosages, their dosing regimens, and methods of using such antibodies, including use for the treatment or prevention of diseases characterized by Aβ deposition in the brain of a subject. Diseases that can be treated or prevented using the antibodies, dosing regimens, or methods disclosed herein include, for example, Alzheimer's disease (AD), Down's syndrome, and cerebral amyloid angiopathy (CAA). [Background technology]

[0003] Alzheimer's disease (AD) is an age-related neurodegenerative disorder characterized by a progressive decline in cognitive function and the ability to perform activities of daily living, which may ultimately lead to death due to complications of the disease. Pathological hallmarks of AD identified at autopsy include the presence of neuritic Aβ plaques, neurofibrillary tangles (Selkoe, "The Molecular Pathology of Alzheimer's Disease," Neuron 6(4):487-498 (1991); Hyman et al., "National Institute on Aging-Alzheimer's Association Guidelines on Neuropathologic Assessment of Alzheimer's Disease," Alzheimers Dement. 8(1):1-13 (2012)), and neuronal loss in cognitively important brain regions such as the hippocampus and temporal cortex (Padurariu et al., "Hippocampal Neuronal Loss in the CA1 and CA3 Areas of Alzheimer's Disease Patients," Psychiatr Danub. 24(2):152-158 (2012)).

[0004] The amyloid hypothesis of AD states that the production and deposition of Aβ is an early and necessary event in the pathogenesis of AD (Hardy and Selkoe, "The Amyloid Hypothesis of Alzheimer's Disease: Progress and Problems on the Road to Therapeutics," Science 297(5580):353-356 (2002)). Amyloid beta is formed by proteolytic cleavage of a larger glycoprotein called amyloid precursor protein (APP). APP is an integral membrane protein expressed in many tissues, but particularly in neuronal synapses. APP is cleaved by γ-secretase to release Aβ peptides, which comprise a group of peptides ranging in size from 37 to 49 amino acid residues. Aβ monomers aggregate into various types of higher-order structures, including oligomers, protofibrils, and amyloid fibrils. While amyloid oligomers are soluble and can spread throughout the brain, amyloid fibrils are larger and insoluble and can further aggregate to form amyloid plaques. Amyloid plaques found in human patients contain a heterogeneous mixture of Aβ peptides, some of which contain N-terminal truncations and may further contain N-terminal modifications such as N-terminal pyroglutamate (pGlu) residues.

[0005] The role of amyloid plaques in driving disease progression is supported by studies of rare genetic variants that increase or decrease Aβ deposition (Fleisher et al., "Associations Between Biomarkers and Age in the Presenilin 1 E280A Autosomal Dominant Alzheimer Disease Kindred: A Cross-sectional Study," JAMA Neurol 72:316-24 (2015); Jonsson et al., "A Mutation in APP Protects Against Alzheimer's Disease and Age-related Cognitive Decline," Nature 488:96-9 (2012)). Additionally, the presence of amyloid plaques early in the disease increases the likelihood of progression from mild cognitive impairment (MCI) to AD-type dementia (Doraiswamy et al., "Amyloid-β Assessed by Florbetapir F18 PET and 18-Month Cognitive Decline: A Multicenter Study," Neurology 79:1636-44 (2012)). Another hallmark neuropathological lesion of AD consists of intraneuronal neurofibrillary tangles composed of tau protein, which spread throughout the brain and characterize disease progression (Braak and Braak, "Evolution of the Neuropathology of Alzheimer's Disease," Acta Neurol Scand Suppl. 165:3-12 (1996)). The presence of both is required for a definitive AD diagnosis, but scientific understanding of the relationship between these two pathologies is still evolving.

[0006] Interventions or therapies aimed at clearing Aβ plaques are hypothesized to slow the clinical progression of AD. Antibodies targeting Aβ have shown promise as therapeutics for Alzheimer's disease in both preclinical and clinical studies. Despite this promise, many amyloid-targeting antibodies have failed to meet therapeutic endpoints in multiple clinical trials. The history of anti-amyloid clinical trials spans nearly two decades, with most casting doubt on the potential of such therapies to effectively treat AD (Aisen et al., "The Future of Anti-amyloid Trials," The Journal of Prevention of Alzheimer's Disease 7:146-151 (2020); Budd et al., "Clinical Development of Aducanumab, an Anti-Aβ Human Monoclonal Antibody Being Investigated for the Treatment of Early Alzheimer's Disease," The Journal of Prevention of Alzheimer's Disease 4(4):255-263 (2017); and Klein et al., "Gantenerumab Reduces Amyloid-β Plaques in Patients with Prodromal to Moderate Alzheimer's Disease: A PET Substudy Interim Analysis," Alzheimer's Research & Therapy 11.1:1-12 (2019)).

[0007] Furthermore, some anti-amyloid monoclonal antibodies carry significant safety risks: Administration of Aβ antibodies has been linked to adverse events in humans, including amyloid-related imaging abnormalities (ARIA), those suggestive of vasogenic edema and crevicular effusion (ARIA-E), microhemorrhages and hemosiderin deposits (ARIA-H), injection site reactions, and the risk of immunogenicity. For example, Piazza and Winblad, “Amyloid-Related Imaging Abnormalities (ARIA) in Immunotherapy Trials for Alzheimer's Disease:Need for Prognostic Biomarkers?” Journal of Alzheimer's Disease, 52:417-420 (2016), Sperling, et al., “Amyloid-related Imaging Abnormalities in Patients with Alzheimer's Disease Treated with Bapineuzumab: A Retrospective Analysis,” The Lancet Neurology 11.3:241-249(2012), Brashear et al., “Clinical Evaluation of Amyloid-related Imaging Abnormalities in Bapineuzumab Phase III Studies,” J. of Alzheimer's Disease 66.4:1409-1424(2018), Budd et al., “Clinical Development of Aducanumab, an Anti-Aβ See “Human Monoclonal Antibody Being Investigated for the Treatment of Early Alzheimer's Disease,” The Journal of Prevention of Alzheimer's Disease 4.4:255 (2017). ARIA is the most common side effect of this class of medications.ARIA is usually asymptomatic and can be detected using brain MRI. ARIA can lead to symptoms such as headache, confusion, dizziness, visual disturbances, nausea, and seizures. The relationship between the stage of Alzheimer's disease progression, the target population of Alzheimer's disease patients, the rate of amyloid plaque removal by anti-amyloid antibody treatment, and the incidence of ARIA upon treatment is not well understood.

[0008] Some therapeutic amyloid-targeting antibodies have shown a dose-response-related increase in ARIA-E. See, e.g., Brashear et al., "Clinical Evaluation of Amyloid-Related Imaging Abnormalities in Bapineuzumab Phase III Studies," J. of Alzheimer's Disease 66.4:1409-1424 (2018); Budd et al., "Clinical Development of Aducanumab, an Anti-Aβ Human Monoclonal Antibody Being Investigated for the Treatment of Early Alzheimer's Disease," The Journal of Prevention of Alzheimer's Disease 4.4:255 (2017). In some cases, there is a higher incidence of ARIA-E in patients carrying the epsilon 4 allele of apolipoprotein E (referred to herein as APOE4, apoE4, or ApoE-e4).

[0009] To reduce the adverse event rate of ARIA-E while maintaining plaque clearance, some antibody treatment programs implement a dose escalation scheme involving multiple dose escalations (3–4 steps) over a period of approximately 6 months before reaching an effective dose level. See, for example, Budd et al., “Clinical Development of Aducanumab, an Anti-Aβ Human Monoclonal Antibody Being Investigated for the Treatment of Early Alzheimer's Disease,” The Journal of Prevention of Alzheimer's Disease 4.4:255 (2017), and Klein et al., “Gantenerumab Reduces Amyloid-β Plaques in Patients with Prodromal to Moderate Alzheimer's Disease: a PET Substudy Interim Analysis,” Alzheimer's Research & Therapy 11.1:101 (2019). Such treatment regimens may not completely clear amyloid plaques or may delay plaque clearance.

[0010] Thus, there is a need for improved doses, dosing regimens, or methods that adequately treat subjects without causing or increasing problematic adverse events. Summary of the Invention

[0011] The present disclosure relates to anti-N3pGlu Aβ antibodies that exhibit surprisingly rapid amyloid clearance rates upon administration to human subjects in need of amyloid clearance without causing or increasing problematic adverse events. In one embodiment, the anti-N3pGlu Aβ antibody of the present disclosure is remternetug (LY3372993). Remternetug is an IgG1 antibody that targets the pyroglutamic acid modification of the third amino acid of the amyloid beta peptide (N3pG Aβ), which is present exclusively in brain amyloid plaques. The mechanism of action of remternetug is to target and remove deposited amyloid plaques, a key pathological feature of AD, via microglia-mediated phagocytosis.

[0012] Lemterneg has a relatively long half-life, reduced risk of immunogenicity, and robust amyloid plaque clearance, allowing flexibility in dosing regimens. Such flexibility is not achievable with other anti-amyloid antibodies, such as donanemab. Lemterneg can be given less frequently (longer time frames between doses) while achieving robust and rapid amyloid plaque clearance. In some embodiments, Lemterneg can be administered intravenously (IV) at dosing intervals of 8 weeks (Q8W) to 12 weeks (Q12W). Such intervals allow time for adverse events, such as asymptomatic ARIA, to resolve without interrupting dosing. In some embodiments, Lemterneg can be administered subcutaneously (SC). SC doses can be administered weekly (Q1W), once every two weeks (Q2W), or every other month. Collectively, these dosing regimens provide rapid and robust amyloid clearance, reduce the risk of adverse events, and reduce participant burden by allowing for less frequent dosing regimens and / or a reduced number of doses. Because lemternex can be administered intravenously or subcutaneously, dosing regimens can be selected based on patient preferences or requirements, potentially increasing compliance and adherence to therapy. SC dosing may also reduce the potential risk of ARIA due to the lower Cmax observed with the medication. Another advantage of lemternex is that it can be administered at a lower dose and / or less frequently to achieve rapid and complete amyloid plaque clearance. High-dose lemternex can achieve population amyloid plaque clearance levels of over 90%, representing a best-in-class treatment option. Both lemternex and donanemab target epitopes of amyloid peptides present only in brain amyloid plaques and can achieve robust removal of amyloid plaques from the brain. Amyloid plaques can be cleared by both of these antibodies, thereby fixing the dosing regimen and thereby positively impacting compliance and adherence to the dosing regimen compared to treatments administered for the patient's lifetime.Given the robust amyloid plaque clearance of lemternex, lower doses of lemternex can be given compared to other amyloid plaque-lowering therapies currently being explored in clinical trial development.

[0013] In some embodiments, the disease characterized by Aβ plaques in the brain of the human subject is preclinical Alzheimer's disease (AD), clinical AD, prodromal AD, mild AD, moderate AD, severe AD, Down's syndrome, clinical cerebral amyloid angiopathy, or preclinical cerebral amyloid angiopathy. In one embodiment, the disease is preclinical AD. In some embodiments, the disease is prodromal AD. In some embodiments, the disease is mild dementia due to AD.

[0014] In some embodiments, the antibodies, methods, or dosing regimens identified in this disclosure result in the treatment or prevention of Alzheimer's disease. In some embodiments, the antibodies, methods, or dosing regimens identified in this disclosure cause i) a reduction in Aβ plaques in the brain of a human subject, ii) a slowing of cognitive decline in a human subject, or iii) a slowing of functional decline in a human subject.

[0015] The anti-N3pGlu Aβ antibodies described in various embodiments of the present disclosure include: an anti-N3pGlu Aβ antibody comprising a light chain complementarity determining region 1 (LCDR1) having the amino acid sequence of SEQ ID NO: 4, a light chain complementarity determining region 2 (LCDR2) having the amino acid sequence of SEQ ID NO: 5, and a light chain complementarity determining region 3 (LCDR3) having the amino acid sequence of SEQ ID NO: 6, or an amino acid sequence having at least 95% identity to LCDR1 of SEQ ID NO: 4, an amino acid sequence having at least 95% identity to LCDR2 of SEQ ID NO: 5, and an amino acid sequence having at least 95% identity to LCDR3 of SEQ ID NO: 6; an anti-N3pGlu Aβ antibody comprising a heavy chain complementarity determining region 1 (HCDR1) having the amino acid sequence of SEQ ID NO: 1, a heavy chain complementarity determining region 2 (HCDR2) having the amino acid sequence of SEQ ID NO: 2, and a heavy chain complementarity determining region 3 (HCDR3) having the amino acid sequence of SEQ ID NO: 3, or an amino acid sequence having at least 95% identity with HCDR1 of SEQ ID NO: 1, an amino acid sequence having at least 95% identity with HCDR2 of SEQ ID NO: 2, and an amino acid sequence having at least 95% identity with HCDR3 of SEQ ID NO: 3; an anti-N3pGlu Aβ antibody comprising an LCDR1 having the amino acid sequence of SEQ ID NO: 4, an LCDR2 having the amino acid sequence of SEQ ID NO: 5, an LCDR3 having the amino acid sequence of SEQ ID NO: 6, an HCDR1 having the amino acid sequence of SEQ ID NO: 1, an HCDR2 having the amino acid sequence of SEQ ID NO: 2, and an HCDR3 having the amino acid sequence of SEQ ID NO: 3, or an amino acid sequence having at least 95% identity with LCDR1 of SEQ ID NO: 4, an amino acid sequence having at least 95% identity with LCDR2 of SEQ ID NO: 5, an amino acid sequence having at least 95% identity with LCDR3 of SEQ ID NO: 7, an amino acid sequence having at least 95% identity with HCDR1 of SEQ ID NO: 8, an amino acid sequence having at least 95% identity with HCDR2 of SEQ ID NO: 9, and an amino acid sequence having at least 95% identity with HCDR3 of SEQ ID NO: 10; an LCVR and an HCVR, wherein the LCVR comprises LCDR1, LCDR2, and LCDR3, and the HCVR comprises HCDR1, HCDR2, and HCDR3, selected from the group consisting of LCDR1 being SEQ ID NO: 4, LCDR2 being SEQ ID NO: 5, LCDR3 being SEQ ID NO: 6, HCDR1 being SEQ ID NO: 1, HCDR2 being SEQ ID NO: 2, and HCDR3 being SEQ ID NO: 3; an HCVR comprising HCDR1, HCDR2, and HCDR3 selected from the group consisting of: LCDR1 having at least 95% homology to SEQ ID NO:4; LCDR2 having at least 95% homology to SEQ ID NO:5; LCDR3 having at least 95% homology to SEQ ID NO:6; HCDR1 having at least 95% homology to SEQ ID NO:1; HCDR2 having at least 95% homology to SEQ ID NO:2; and HCDR3 having at least 95% homology to SEQ ID NO:3. an N3pGlu Aβ antibody comprising a light chain (LC) comprising the amino acid sequence of SEQ ID NO: 10 or an amino acid sequence having at least 95% homology to SEQ ID NO: 10; an N3pGlu Aβ antibody comprising a heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 9 or an amino acid sequence having at least 95% homology to SEQ ID NO: 9; an anti-N3pGlu Aβ antibody comprising an LC and an HC, wherein the LC comprises the amino acid sequence of SEQ ID NO: 10 and the HC comprises the amino acid sequence of SEQ ID NO: 9, or the LC comprises an amino acid sequence having at least 95% homology with SEQ ID NO: 10 and the HC comprises an amino acid sequence having at least 95% homology with SEQ ID NO: 9; an anti-N3pGlu Aβ antibody comprising two light chains and two heavy chains, wherein the LC comprises the amino acid sequence of SEQ ID NO: 10, or an amino acid sequence having at least 95% identity to SEQ ID NO: 10, and the HC comprises the amino acid sequence of SEQ ID NO: 9, or an amino acid sequence having at least 95% identity to SEQ ID NO: 9. an N3pGlu Aβ antibody comprising an LCVR comprising the amino acid sequence of SEQ ID NO: 8, or an amino acid sequence having at least 95% homology to SEQ ID NO: 8; An N3pGlu Aβ antibody comprising an HCVR, the antibody comprising the amino acid sequence of SEQ ID NO:7, or an amino acid sequence having at least 95% homology to SEQ ID NO:7. The present invention also includes an anti-N3pGlu Aβ antibody comprising an LCVR and an HCVR, wherein the LCVR comprises the amino acid sequence of SEQ ID NO: 8 or an amino acid sequence having at least 95% homology to SEQ ID NO: 8, and the HCVR comprises the amino acid sequence of SEQ ID NO: 7 or an amino acid sequence having at least 95% homology to SEQ ID NO: 7.

[0016] In some embodiments, the anti-N3pGlu Aβ antibodies of the present disclosure comprise a kappa LC and an IgG HC. In certain embodiments, the anti-N3pGlu Aβ antibodies of the present disclosure are of the human IgG1 isotype.

[0017] In embodiments, the anti-N3pGlu Aβ antibody of the present disclosure is Lemterneg. Lemterneg is a monoclonal antibody directed against N3pG Aβ, which is present only in deposited amyloid plaques. Lemterneg comprises two light chains and two heavy chains, where the LC comprises the amino acid sequence of SEQ ID NO: 10 and the HC comprises the amino acid sequence of SEQ ID NO: 9. Lemterneg is an IgG1 monoclonal antibody consisting of two identical light chain polypeptides, each consisting of 214 amino acids, and two identical heavy chain polypeptides, each consisting of 451 amino acids. Each heavy chain contains a single N-linked glycosylation site at Asn302. Lemterneg specifically binds to aggregated N3pG Aβ peptides with high affinity (apparent dissociation constant of approximately 45.7 nM). Lemternetsug has been engineered to selectively target deposited plaques in the AD brain and maximize potent effector functions, including target engagement and microglia-mediated phagocytosis of plaques.

[0018] In some embodiments, a dose of an antibody of the present disclosure is administered to a subject for a duration sufficient to treat or prevent a disease. In some embodiments, an antibody dose is administered to a subject until Aβ plaques are cleared in the human subject's brain. In some embodiments, the antibody is administered until at least one of the following occurs: i) Aβ plaques in the human subject's brain are 24.1 centiloids or less as measured by two consecutive amyloid PET imaging scans, the two consecutive amyloid PET imaging scans being at least six months apart, or ii) Aβ plaques in the human subject's brain are 11 centiloids or less as measured by a single amyloid PET imaging scan. In some embodiments, the antibody is administered to a subject until the subject becomes amyloid negative. In some embodiments, the antibody is administered to a subject until an Aβ plaque level of <24.1 C1 is reached as measured by an amyloid PET imaging scan.

[0019] In some embodiments, a human subject of the present disclosure is administered one or more intravenous doses of about 200 mg to about 3000 mg of an anti-N3pGlu Aβ antibody described herein. In some embodiments, a human subject is administered one or more intravenous doses of at least 200 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, 1050 mg, 1100 mg, 1150 mg, 1200 mg, 1250 mg, 1300 mg, 1350 mg, 1400 mg, 1450 mg, 1500 mg, 1550 mg, 1600 mg, 1650 mg In one embodiment, the patient is administered a dose of an anti-N3pGlu Aβ antibody described herein of 1 mg, 1700 mg, 1750 mg, 1800 mg, 1850 mg, 1900 mg, 1950 mg, 2000 mg, 2050 mg, 2100 mg, 2150 mg, 2200 mg, 2250 mg, 2300 mg, 2350 mg, 2400 mg, 2450 mg, 2500 mg, 2550 mg, 2600 mg, 2650 mg, 2700 mg, 2750 mg, 2800 mg, 2850 mg, 2900 mg, 2950 mg, or 3000 mg.

[0020] In some embodiments, an intravenous dose of an anti-N3pGlu Aβ antibody is administered to a human subject once per week, once per 2 weeks, once per 4 weeks, once per 6 weeks, once per 8 weeks, once per 12 weeks, or once per 16 weeks. In some embodiments, an intravenous dose is administered once per 12 weeks. In some embodiments, an intravenous dose is administered once per 8 weeks. In some embodiments, an intravenous dose is administered once per 4 weeks. In some embodiments, an intravenous dose is administered once per 2 weeks.

[0021] In some embodiments, about 1 to about 20 intravenous doses of an anti-N3pGlu Aβ antibody are administered to a human subject. In some embodiments, about 1 to about 10 intravenous doses are administered to a human subject. In some embodiments, about 1 to about 5 intravenous doses are administered to a human subject. In some embodiments, at least one intravenous dose of an anti-N3pGlu Aβ antibody is administered to a subject. In some embodiments, 2 doses, 3 doses, 4 doses, 5 doses, 6 doses, 7 doses, 8 doses, 9 doses, 10 doses, 11 doses, 12 doses, 13 doses, 14 doses, 15 doses, 16 doses, 17 doses, 18 doses, 19 doses, or 20 doses of an anti-N3pGlu Aβ antibody are administered to a human subject.

[0022] In some embodiments, the human subject has early symptomatic AD and is administered i) about 1 to about 20 intravenous doses, ii) about 1 to about 10 intravenous doses, or iii) about 1 to about 5 intravenous doses of 2300 mg of an anti-N3pGlu Aβ antibody of the disclosure once every 12 weeks (Q12W). In some embodiments, the human subject has early symptomatic AD and is administered about 3 intravenous doses of 2300 mg of an anti-N3pGlu Aβ antibody of the disclosure once every 12 weeks (Q12W).

[0023] In some embodiments, the human subject has early symptomatic AD and is administered i) about 1 to about 20 intravenous doses, ii) about 1 to about 10 intravenous doses, or iii) about 1 to about 5 intravenous doses of 1500 mg of an anti-N3pGlu Aβ antibody of the disclosure once every 12 weeks (Q12W). In some embodiments, the human subject has early symptomatic AD and is administered about 4 intravenous doses of 1500 mg of an anti-N3pGlu Aβ antibody of the disclosure once every 12 weeks (Q12W).

[0024] In some embodiments, the human subject has early symptomatic AD and is administered i) about 1 to about 20 intravenous doses, ii) about 1 to about 10 intravenous doses, or iii) about 1 to about 5 intravenous doses of 800 mg of an anti-N3pGlu Aβ antibody of the disclosure once every eight weeks (Q8W). In some embodiments, the human subject has early symptomatic AD and is administered about 7 intravenous doses of 800 mg of an anti-N3pGlu Aβ antibody of the disclosure once every eight weeks (Q8W).

[0025] In some embodiments, the human subject has early symptomatic AD and is administered i) about 1 to about 20 intravenous doses, ii) about 1 to about 10 intravenous doses, or iii) about 1 to about 5 intravenous doses of 800 mg of an anti-N3pGlu Aβ antibody of the disclosure every four weeks (Q4W). In some embodiments, the human subject has early symptomatic AD and is administered about 7 intravenous doses of 800 mg of an anti-N3pGlu Aβ antibody of the disclosure every four weeks (Q4W).

[0026] In some embodiments, the human subject is suffering from early symptomatic AD and is administered about three intravenous doses of 2300 mg of an anti-N3pGlu Aβ antibody of the present disclosure every twelve weeks (Q12W). In some embodiments, the human subject is suffering from early symptomatic AD and is administered about four intravenous doses of 1500 mg of an anti-N3pGlu Aβ antibody of the present disclosure every twelve weeks (Q12W). In some embodiments, the human subject is suffering from early symptomatic AD and is administered about seven intravenous doses of 800 mg of an anti-N3pGlu Aβ antibody of the present disclosure every eight weeks (Q8W). In some embodiments, the human subject is suffering from early symptomatic AD and is administered about seven intravenous doses of 800 mg of an anti-N3pGlu Aβ antibody of the present disclosure every four weeks (Q4W). In some embodiments, the human subject has early symptomatic AD and is administered about 12 intravenous doses of 400 mg of an anti-N3pGlu Aβ antibody of the present disclosure once every four weeks (Q4W). In some embodiments, the human subject has early symptomatic AD and is administered about 19 intravenous doses of 400 mg of an anti-N3pGlu Aβ antibody of the present disclosure once every four weeks (Q4W).

[0027] In some embodiments, the human subject is suffering from early symptomatic AD and is administered about 36 subcutaneous doses of 400 mg of an anti-N3pGlu Aβ antibody of the present disclosure once per week (Q1W). In some embodiments, the human subject is suffering from early symptomatic AD and is administered about 52 subcutaneous doses of 400 mg of an anti-N3pGlu Aβ antibody of the present disclosure once per week (Q1W). In some embodiments, the human subject is suffering from early symptomatic AD and is administered about 76 subcutaneous doses of 400 mg of an anti-N3pGlu Aβ antibody of the present disclosure once per week (Q1W). In some embodiments, the human subject is suffering from early symptomatic AD and is administered about 36 subcutaneous doses of 400 mg of an anti-N3pGlu Aβ antibody of the present disclosure once every two weeks (Q2W). In some embodiments, a human subject has early symptomatic AD and is administered about 52 subcutaneous doses of 400 mg of an anti-N3pGlu Aβ antibody of the present disclosure every two weeks (Q2W). In some embodiments, a human subject has early symptomatic AD and is administered about 76 subcutaneous doses of 400 mg of an anti-N3pGlu Aβ antibody of the present disclosure every two weeks (Q2W). In some embodiments, a human subject has early symptomatic AD and is administered about 9 subcutaneous doses of 800 mg (or 2 x 400 mg, e.g., two injections of 400 mg) of an anti-N3pGlu Aβ antibody of the present disclosure every four weeks (Q4W). In some embodiments, a human subject has early symptomatic AD and is administered about 12 subcutaneous doses of 800 mg (or 2 x 400 mg, e.g., two injections of 400 mg) of an anti-N3pGlu Aβ antibody of the disclosure once every four weeks (Q4W).

[0028] In some embodiments, the human subject has preclinical AD and is administered i) about 1 to about 20 intravenous doses, ii) about 1 to about 10 intravenous doses, or iii) about 1 to about 5 intravenous doses of 2300 mg of an anti-N3pGlu Aβ antibody of the disclosure once every 12 weeks (Q12W). In some embodiments, the human subject has preclinical AD and is administered about 2 intravenous doses of 2300 mg of an anti-N3pGlu Aβ antibody of the disclosure once every 12 weeks (Q12W).

[0029] In some embodiments, the human subject has preclinical AD and is administered i) about 1 to about 20 intravenous doses, ii) about 1 to about 10 intravenous doses, or iii) about 1 to about 5 intravenous doses of 1500 mg of an anti-N3pGlu Aβ antibody of the disclosure once every 12 weeks (Q12W). In some embodiments, the human subject has preclinical AD and is administered about 3 intravenous doses of 1500 mg of an anti-N3pGlu Aβ antibody of the disclosure once every 12 weeks (Q12W).

[0030] In some embodiments, the human subject has preclinical AD and is administered i) about 1 to about 20 intravenous doses, ii) about 1 to about 10 intravenous doses, or iii) about 1 to about 5 intravenous doses of 800 mg of an anti-N3pGlu Aβ antibody of the disclosure once every eight weeks (Q8W). In some embodiments, the human subject has preclinical AD and is administered about 5 or about 6 intravenous doses of 800 mg of an anti-N3pGlu Aβ antibody of the disclosure once every eight weeks (Q8W).

[0031] In some embodiments, the human subject has preclinical AD and is administered i) about 1 to about 20 intravenous doses, ii) about 1 to about 10 intravenous doses, or iii) about 1 to about 5 intravenous doses of an 800 mg anti-N3pGlu Aβ antibody of the disclosure once every four weeks (Q4W). In some embodiments, the human subject has preclinical AD and is administered about 5 or about 6 intravenous doses of an 800 mg anti-N3pGlu Aβ antibody of the disclosure once every four weeks (Q8W).

[0032] In some embodiments, a human subject of the present disclosure is administered one or more subcutaneous doses of about 20 mg to about 1000 mg of an anti-N3pGlu Aβ antibody described herein. In some embodiments, a human subject of the present disclosure is administered one or more subcutaneous doses of about 250 mg to about 500 mg of an anti-N3pGlu Aβ antibody described herein. In some embodiments, a human subject is administered one or more subcutaneous doses of 20 mg, 40 mg, 60 mg, 80 mg, 100 mg, 120 mg, 140 mg, 160 mg, 180 mg, 200 mg, 220 mg, 240 mg, 260 mg, 280 mg, 300 mg, 320 mg, 340 mg, 360 mg, 380 mg, 400 mg, 420 mg, 440 mg, 460 mg, 480 mg, 500 mg, 520 mg, 540 mg, 560 mg, 580 mg, 590 mg, 600 mg, 610 mg, 620 mg, 630 mg, 640 mg, 650 mg, 660 mg, 670 mg, 680 mg, 690 mg, 700 mg, 710 mg, 720 mg, 730 mg, 740 mg, 750 mg, 760 mg, 770 mg, 780 mg, 790 mg, 800 mg, 810 mg, 820 mg, 830 mg, 840 mg, 850 mg, 860 mg, 870 mg, 880 mg, 890 mg, 900 mg, 910 mg, 920 mg, 930 mg, 940 mg, 950 mg, 960 mg, g, 540 mg, 560 mg, 580 mg, 600 mg, 620 mg, 640 mg, 660 mg, 680 mg, 700 mg, 720 mg, 740 mg, 760 mg, 780 mg, 800 mg, 820 mg, 840 mg, 860 mg, 880 mg, 900 mg, 920 mg, 940 mg, 960 mg, 980 mg, or 1000 mg is administered.

[0033] In some embodiments, a subcutaneous dose of an anti-N3pGlu Aβ antibody is administered to a human subject once per week, once per 2 weeks, once per 4 weeks, once per 6 weeks, once per 8 weeks, or once per 12 weeks. In some embodiments, a subcutaneous dose is administered once per week. In some embodiments, a subcutaneous dose is administered once per 2 weeks. In some embodiments, a subcutaneous dose is administered once per 4 weeks. In some embodiments, a subcutaneous dose is administered once per 6 weeks. In some embodiments, a subcutaneous dose is administered once per 8 weeks.

[0034] In some embodiments, about 1 to about 100 subcutaneous doses of an anti-N3pGlu Aβ antibody are administered to a human subject. In some embodiments, about 1 to about 90 subcutaneous doses are administered to a human subject. In some embodiments, about 1 to about 80 subcutaneous doses are administered to a human subject. In some embodiments, about 1 to about 70 subcutaneous doses are administered to a human subject. In some embodiments, about 1 to about 60 subcutaneous doses are administered to a human subject. In some embodiments, about 1 to about 50 subcutaneous doses are administered to a human subject. In some embodiments, about 1 to about 40 subcutaneous doses are administered to a human subject. In some embodiments, about 1 to about 30 subcutaneous doses are administered to a human subject. In some embodiments, about 1 to about 20 subcutaneous doses are administered to a human subject. In some embodiments, about 1 to about 10 subcutaneous doses are administered to a human subject. In some embodiments, at least one subcutaneous dose of an anti-N3pGlu Aβ antibody is administered to a subject. In some embodiments, 10 doses, 20 doses, 30 doses, 40 doses, 50 doses, 60 doses, 70 doses, 80 doses, 90 doses, or 100 doses of an anti-N3pGlu Aβ antibody are administered to a human subject. In some embodiments, about 24 subcutaneous doses are administered to a human subject. In some embodiments, about 36 subcutaneous doses are administered to a human subject. In some embodiments, about 52 subcutaneous doses are administered to a human subject. In some embodiments, about 76 subcutaneous doses are administered to a human subject.

[0035] In some embodiments, the human subject has early symptomatic AD and is administered i) about 1 to about 90 subcutaneous doses, ii) about 1 to about 60 subcutaneous doses, or iii) about 1 to about 30 subcutaneous doses of 400 mg of an anti-N3pGlu Aβ antibody of the disclosure once per week (Q1W). In some embodiments, the human subject has early symptomatic AD and is administered about 36 subcutaneous doses of 1500 mg of an anti-N3pGlu Aβ antibody of the disclosure once per week (Q1W).

[0036] In some embodiments, a human subject has early symptomatic AD and is administered i) about 1 to about 90 subcutaneous doses, ii) about 1 to about 60 subcutaneous doses, or iii) about 1 to about 30 subcutaneous doses of 400 mg of an anti-N3pGlu Aβ antibody of the present disclosure every two weeks (Q2W). In some embodiments, a human subject has early symptomatic AD and is administered about 52 subcutaneous doses of 400 mg of an anti-N3pGlu Aβ antibody of the present disclosure every two weeks (Q2W). In some embodiments, a human subject has early symptomatic AD and is administered about 76 subcutaneous doses of 400 mg of an anti-N3pGlu Aβ antibody of the present disclosure every two weeks (Q2W).

[0037] In some embodiments, the human subject has preclinical AD and is administered about two intravenous doses of 2300 mg of an anti-N3pGlu Aβ antibody of the present disclosure every twelve weeks (Q12W). In some embodiments, the human subject has preclinical AD and is administered about three intravenous doses of 1500 mg of an anti-N3pGlu Aβ antibody of the present disclosure every twelve weeks (Q12W). In some embodiments, the human subject has preclinical AD and is administered about five intravenous doses of 800 mg of an anti-N3pGlu Aβ antibody of the present disclosure every eight weeks (Q8W). In some embodiments, the human subject has preclinical AD and is administered about six intravenous doses of 800 mg of an anti-N3pGlu Aβ antibody of the present disclosure every eight weeks (Q8W). In some embodiments, the human subject has preclinical AD and is administered about 5 intravenous doses of 800 mg of an anti-N3pGlu Aβ antibody of the present disclosure once every four weeks (Q4W). In some embodiments, the human subject has preclinical AD and is administered about 6 intravenous doses of 800 mg of an anti-N3pGlu Aβ antibody of the present disclosure once every four weeks (Q4W).

[0038] In some embodiments, a human subject suffers from preclinical AD and is administered i) about 1 to about 60 subcutaneous doses, ii) about 1 to about 30 subcutaneous doses, or iii) about 1 to about 10 subcutaneous doses of 400 mg of an anti-N3pGlu Aβ antibody of the present disclosure once per week (Q1W). In some embodiments, a human subject suffers from preclinical AD and is administered about 24 subcutaneous doses of 400 mg of an anti-N3pGlu Aβ antibody of the present disclosure once per week (Q1W). In some embodiments, a human subject suffers from preclinical AD and is administered about 36 subcutaneous doses of 400 mg of an anti-N3pGlu Aβ antibody of the present disclosure once per week (Q1W). In some embodiments, a human subject suffers from preclinical AD and is administered about 52 subcutaneous doses of 400 mg of an anti-N3pGlu Aβ antibody of the present disclosure once per week (Q1W). In some embodiments, the human subject is suffering from preclinical AD and is administered about 24 subcutaneous doses of 400 mg of an anti-N3pGlu Aβ antibody of the present disclosure once per week (Q1W). In some embodiments, the human subject is suffering from preclinical AD and is administered about 12 subcutaneous doses of 400 mg of an anti-N3pGlu Aβ antibody of the present disclosure once every two weeks (Q2W). In some embodiments, the human subject is suffering from preclinical AD and is administered about 18 subcutaneous doses of 400 mg of an anti-N3pGlu Aβ antibody of the present disclosure once per two weeks (Q2W). In some embodiments, the human subject is suffering from preclinical AD and is administered about 26 subcutaneous doses of 400 mg of an anti-N3pGlu Aβ antibody of the present disclosure once per two weeks (Q2W). In some embodiments, the human subject has preclinical AD and is administered about 6 subcutaneous doses of 800 mg (or 2 x 400 mg, e.g., 2 injections of 400 mg) of an anti-N3pGlu Aβ antibody of the present disclosure once every 4 weeks (Q4W). In some embodiments, the human subject has preclinical AD and is administered about 8 subcutaneous doses of 800 mg (or 2 x 400 mg, e.g., 2 injections of 400 mg) of an anti-N3pGlu Aβ antibody of the present disclosure once every 4 weeks (Q4W). In some embodiments, the human subject has preclinical AD and is administered about 9 subcutaneous doses of 800 mg (or 2 x 400 mg, e.g., 2 injections of 400 mg) of an anti-N3pGlu Aβ antibody of the present disclosure once every 4 weeks (Q4W).In some embodiments, a human subject has preclinical AD and is administered about 12 subcutaneous doses of 800 mg (or 2 x 400 mg, e.g., two injections of 400 mg) of an anti-N3pGlu Aβ antibody of the disclosure once every four weeks (Q4W).

[0039] In some embodiments, a human subject suffers from preclinical AD and is administered i) about 1 to about 60 subcutaneous doses, ii) about 1 to about 30 subcutaneous doses, or iii) about 1 to about 10 subcutaneous doses of 400 mg of an anti-N3pGlu Aβ antibody of the present disclosure every two weeks (Q2W). In some embodiments, a human subject suffers from preclinical AD and is administered about 24 subcutaneous doses of 400 mg of an anti-N3pGlu Aβ antibody of the present disclosure every two weeks (Q2W). In some embodiments, a human subject suffers from preclinical AD and is administered about 36 subcutaneous doses of 400 mg of an anti-N3pGlu Aβ antibody of the present disclosure every two weeks (Q2W). In some embodiments, a human subject suffers from preclinical AD and is administered about 52 subcutaneous doses of 400 mg of an anti-N3pGlu Aβ antibody of the present disclosure every two weeks (Q2W).

[0040] In some embodiments, the dosing regimens of the present disclosure include one or more additional doses (also referred to as maintenance doses) that may be administered after completion of the IV or subcutaneous dosing regimen described herein (e.g., after the subject's amyloid beta has been cleared). For example, in some embodiments, a subject may be administered one or more maintenance doses to reduce Aβ deposition in the subject's brain, prevent further Aβ deposition in the subject's brain, prevent further cognitive decline, prevent further memory loss, or prevent further functional decline. The intravenous maintenance dose may be about 250 mg to about 3000 mg of an anti-N3pGlu Aβ antibody. In some embodiments, the subcutaneous maintenance dose may be about 20 mg to about 1000 mg of an anti-N3pGlu Aβ antibody.

[0041] Some embodiments of the present disclosure include a method of treating or preventing a disease characterized by the deposition of amyloid beta (Aβ) plaques in the brain in a human subject in need thereof, comprising administering one or more intravenous (IV) doses of about 250 mg to about 3000 mg of an anti-N3pG Aβ antibody i) about once every 12 weeks (Q12W), ii) about once every 8 weeks (Q8W), or iii) about once every 4 weeks (Q4W), followed by one or more maintenance doses of about 250 mg to about 3000 mg of an anti-N3pGlu Aβ antibody, wherein the anti-N3pGlu Aβ antibody comprises a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO:8 and a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO:7.

[0042] In some embodiments, the disclosure includes a method of treating or preventing a disease characterized by the deposition of amyloid beta (Aβ) plaques in the brain in a human subject in need thereof, comprising administering to the subject one or more subcutaneous doses of about 20 mg to about 1000 mg of an anti-N3pG Aβ antibody about once a week, about once every two weeks, or about once every four weeks, followed by one or more maintenance doses of about 20 mg to about 1000 mg of an anti-N3pGlu Aβ antibody, wherein the anti-N3pGlu Aβ antibody comprises a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO:8 and a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO:7.

[0043] In some embodiments, one or more maintenance doses of an anti-N3pGlu Aβ antibody of the present disclosure can be administered to a subject every 2 weeks, 4 weeks, 8 weeks, 12 weeks, monthly, yearly, 2 years, 3 years, 4 years, 5 years, or 10 years. In some embodiments, the maintenance dose is given annually. In some embodiments, the maintenance dose is given every 2 years. In other embodiments, the maintenance dose is given every 3 years. In other embodiments, the maintenance dose of the antibody is given every 5 years. In other embodiments, the maintenance dose of the antibody is given every 10 years. In other embodiments, the maintenance dose of the antibody is given every 2-5 years. In other embodiments, the maintenance dose of the antibody is given every 5-10 years.

[0044] In some aspects, the present disclosure relates to a method of treating or preventing a disease characterized by the deposition of amyloid beta (Aβ) plaques in the brain of a human subject, comprising: i) administering to the subject one or more doses of an anti-N3pGlu Aβ antibody disclosed herein; and ii) evaluating a magnetic resonance image (MRI) scan of the subject's brain after administration of a dose of the antibody and before administration of a subsequent dose for amyloid-related imaging abnormalities (ARIA), wherein if symptoms consistent with ARIA occur, administration of the subsequent dose is temporarily withheld; and the anti-N3pGlu Aβ antibody comprises a light chain variable region (LCVR) and a heavy chain variable region (HCVR), wherein the LCVR consists of the amino acid sequence of SEQ ID NO: 8 and the HCVR consists of the amino acid sequence of SEQ ID NO: 7. In some embodiments, administration of the subsequent dose (as well as other subsequent doses specified herein) is resumed after resolution of ARIA symptoms or stabilization of MRI radiographic images. In some embodiments, the subsequent dose is withheld and a corticosteroid is administered to the subject. In some embodiments, the disease characterized by the deposition of amyloid beta (Aβ) plaques in the brain of a human subject is Alzheimer's disease. In some embodiments, the antibody is lemternative.

[0045] In some aspects, the present disclosure relates to a method of treating or preventing a disease characterized by the deposition of amyloid beta (Aβ) plaques in the brain in a human subject in need thereof, the method comprising: i) administering to the subject one or more doses of an anti-N3pGlu Aβ antibody disclosed herein; and ii) evaluating a magnetic resonance imaging (MRI) scan of the subject's brain for ARIA after administration of the dose and before administration of any subsequent doses; wherein administration of the subsequent doses is discontinued if symptoms consistent with severe or symptomatic ARIA occur; and wherein the anti-N3pGlu Aβ antibody comprises a light chain variable region (LCVR) and a heavy chain variable region (HCVR), wherein the LCVR consists of the amino acid sequence of SEQ ID NO: 8 and the HCVR consists of the amino acid sequence of SEQ ID NO: 7. In some embodiments, administration of the one or more subsequent doses is discontinued and a corticosteroid is administered to the subject. In some embodiments, the disease characterized by the deposition of amyloid beta (Aβ) plaques in the brain of the human subject is Alzheimer's disease. In some embodiments, the antibody is lemternex.

[0046] In some embodiments, the present disclosure relates to a method of treating or preventing a disease characterized by the deposition of amyloid beta (Aβ) plaques in a subject until symptoms consistent with ARIA-E occur, the method comprising: i) administering to the subject one or more doses of an anti-N3pGlu Aβ antibody disclosed herein, wherein the anti-N3pGlu Aβ antibody comprises a light chain variable region (LCVR) and a heavy chain variable region (HCVR), wherein the LCVR consists of the amino acid sequence of SEQ ID NO: 8 and the HCVR consists of the amino acid sequence of SEQ ID NO: 7. In some embodiments, symptoms of ARIA are detected by MRI or present in the subject. In some embodiments, the disease characterized by the deposition of amyloid beta (Aβ) plaques in the brain of a human subject is Alzheimer's disease. In some embodiments, the antibody is lemternex.

[0047] In some embodiments, the present disclosure provides a method for treating a subject suffering from Alzheimer's disease with lemterneg, comprising: a) administering lemterneg to the subject; and b) determining whether the subject has symptoms of ARIA-E by i) performing or having performed an MRI, or ii) if clinical symptoms consistent with ARIA-E occur. c) if the patient has moderate symptoms of ARIA-E, temporarily discontinuing treatment with lemterneg. d) if the patient does not have symptoms of ARIA-E, administering lemterneg to the patient until cerebral amyloid is cleared, negative, or <24.1 CL. In some embodiments, subsequent doses are withheld and a corticosteroid is administered to the subject. In some embodiments, the disease characterized by the deposition of amyloid beta (Aβ) plaques in the brain of a human subject is Alzheimer's disease. In some embodiments, the antibody is lemterneg.

[0048] In some embodiments, the present disclosure relates to an improved method for treating a subject suffering from Alzheimer's disease with lemterneg, the method comprising: a) administering lemterneg to the subject; and b) determining whether the subject has symptoms of ARIA-E by i) performing or having performed an MRI, or ii) if clinical symptoms consistent with ARIA-E occur. c) if the patient has moderate symptoms of ARIA-E, temporarily discontinuing treatment with lemterneg. d) if the patient does not have symptoms of ARIA-E, administering lemterneg to the subject until cerebral amyloid is cleared, negative, or <24.1 CL. In some embodiments, subsequent doses are withheld and a corticosteroid is administered to the subject. In some embodiments, the disease characterized by the deposition of amyloid beta (Aβ) plaques in the brain of a human subject is Alzheimer's disease. In some embodiments, the antibody is lemterneg.

[0049] In some embodiments, the present disclosure relates to an improved method for treating a subject suffering from Alzheimer's disease with lemterneg, the method comprising: a) administering lemterneg to the subject; and b) determining whether the subject has symptoms of ARIA-E by i) performing or having performed an MRI, or ii) if clinical symptoms consistent with ARIA-E occur. c) if the patient has moderate symptoms of ARIA-E, temporarily discontinuing treatment with lemterneg. d) if the patient does not have symptoms of ARIA-E, administering lemterneg to the subject until cerebral amyloid is cleared, negative, or <24.1 CL. In some embodiments, subsequent doses are withheld and a corticosteroid is administered to the subject. In some embodiments, the disease characterized by the deposition of amyloid beta (Aβ) plaques in the brain of a human subject is Alzheimer's disease. In some embodiments, the antibody is lemterneg.

[0050] In some embodiments, the present disclosure relates to an improved method for treating a subject suffering from Alzheimer's disease with lemterneg, the method comprising: a) administering or having administered lemterneg to the subject; b) determining whether the patient has symptoms of ARIA-E by i) performing or having performed an MRI, or ii) if clinical symptoms consistent with ARIA-E occur; and c) if the patient does not have symptoms of ARIA-E, further administering lemterneg to the patient. In some embodiments, subsequent doses are withheld and a corticosteroid is administered to the subject. In some embodiments, the disease characterized by the deposition of amyloid beta (Aβ) plaques in the brain of a human subject is Alzheimer's disease. In some embodiments, the antibody is lemterneg.

[0051] In some embodiments, the present disclosure relates to an improved method for treating a subject suffering from Alzheimer's disease with lemternex, the method comprising: a) administering or having administered lemternex to the subject; b) discontinuing treatment if the patient has moderate symptoms of ARIA-E; and c) continuing treatment upon resolution of ARIA-E by administering lemternex until cerebral amyloid is cleared, negative, <24.1 CL, or ARIA-E symptoms reappear. In some embodiments, symptoms of ARIA-E are confirmed or determined by an MRI scan.

[0052] In some embodiments, treatment with lemterneg is withheld or discontinued due to or upon the onset of severe or symptomatic ARIA-E. In some embodiments, upon the onset of mild or moderate asymptomatic ARIA-E in a subject, treatment with lemterneg may be temporarily withheld or interrupted. In some embodiments, upon the onset of mild or moderate asymptomatic ARIA-E in a subject, the dose of lemterneg may be temporarily reduced. In some embodiments, upon the onset of ARIA-E, supportive care including corticosteroids may be administered to the patient. In some embodiments, treatment with lemterneg may be resumed after resolution of symptoms or stabilization of abnormal brain MRI radiographs.

[0053] If symptoms of ARIA-H occur, they are often in the presence of ARIA-E and are managed accordingly for ARIA-E. In some embodiments, a brain MRI of the patient is obtained before administering lemterneg or if symptoms consistent with ARIA-H occur. In some embodiments, treatment with lemterneg is withheld or discontinued due to or upon the onset of ARIA-H. In some embodiments, treatment with lemterneg may be temporarily interrupted upon the onset of ARIA-H in a patient, for example, when ARIA-H symptoms are mild or moderate. In some embodiments, upon the onset of mild or moderate asymptomatic ARIA-H in a patient, the dose of lemterneg may be temporarily reduced. In some embodiments, upon the onset of ARIA-H, supportive care including corticosteroids may be administered to the patient. In some embodiments, treatment with lemterneg may be temporarily discontinued until symptoms of ARIA-E or ARIA-H improve.

[0054] Some aspects of the present disclosure relate to identifying, monitoring, or evaluating a human subject for amyloid-related imaging abnormalities (ARIA) before or after the subject is administered an anti-N3pGlu Aβ antibody of the present disclosure. In some embodiments, the present disclosure relates to identifying, monitoring, or evaluating a human subject for ARIA while the subject is being treated with an anti-N3pGlu Aβ antibody of the present disclosure. In some embodiments, ARIA includes both ARIA-E and ARIA-H. ARIA-E refers to cerebral edema, which involves the breakdown of tight endothelial junctions of the blood-brain barrier and the subsequent accumulation of fluid. ARIA-H refers to cerebral microhemorrhage (mH), which is a small bleeding in the brain, often accompanied by hemosiderosis.

[0055] In some embodiments, a brain MRI scan can be performed on a human subject to diagnose / assess / monitor adverse events caused by administration of an anti-N3pGlu Aβ antibody. For example, a brain magnetic resonance imaging (MRI) scan can be performed on a human subject to identify, monitor, or evaluate the human subject for ARIA, including, for example, ARIA-E or ARIA-H.

[0056] In some embodiments, the methods of the disclosure include excluding a subject from treatment with an anti-N3pGlu Aβ antibody if the subject is identified as having ARIA at screening (i.e., prior to treatment with the antibody).

[0057] In some embodiments, a baseline brain MRI is obtained or assessed before initiating treatment with an anti-N3pGlu Aβ antibody. The human subject may undergo a brain MRI scan between administration of doses of the anti-N3pGlu Aβ antibody (e.g., once per week, once per two weeks, once per four weeks, or once per twelve weeks). In some embodiments, the human subject undergoes a brain MRI scan before administering an intravenous or subcutaneous dose of the anti-N3pGlu Aβ antibody. In some embodiments, the human subject undergoes a brain MRI scan after the first dose of the anti-N3pGlu Aβ antibody is administered to the patient. In some embodiments, the human subject undergoes a brain MRI scan after two or three doses of the anti-N3pGlu Aβ antibody are administered.

[0058] In some embodiments, the human subject undergoes a brain MRI scan after the first week or first four weeks of treatment. In some embodiments, the human subject undergoes a brain MRI scan after the first 12 weeks of initiation of treatment. In some embodiments, the human subject undergoes a brain MRI scan after the last dose. In some embodiments, the human subject undergoes a brain MRI scan and is evaluated for ARIA upon physician recommendation or upon suspicion of ARIA. In some embodiments, if a centrally read MRI shows the presence of ARIA-E, more than four cerebral microhemorrhages, more than one area of ​​superficial hemosiderosis, any macrohemorrhage, or severe white matter disease at screening prior to initiation of treatment, the subject will not be administered an antibody of the present disclosure.

[0059] In some embodiments, the anti-N3pGlu Aβ antibody of the present disclosure can be administered in simultaneous, separate, or sequential combination with an effective amount of a drug for treating Alzheimer's disease. The symptomatic treatment agent can be selected from a cholinesterase inhibitor (ChEI) and / or a partial N-methyl-D-aspartate (NMDA) antagonist. In a preferred embodiment, the drug is a ChEI. In another preferred embodiment, the drug is an NMDA antagonist, or a combination drug comprising a ChEI and an NMDA antagonist. In some embodiments, the anti-N3pGlu Aβ antibody of the present disclosure can be administered in simultaneous, separate, or sequential combination with another anti-Aβ antibody or another anti-N3pGlu Aβ antibody. In some embodiments, the anti-N3pGlu Aβ of the present disclosure is administered in combination with donanemab, solanezumab, aducanumab, lecanemab, or gantenerumab.

[0060] As used herein, the terms "anti-N3pGlu Aβ antibody," "anti-N3pG antibody," or "anti-N3pE antibody," which are used interchangeably, refer to an antibody that preferentially binds to N3pGluAβ over Aβ1-40 or Aβ1-42. As used herein, an "antibody" is an immunoglobulin molecule comprising two HCs and two LCs interconnected by disulfide bonds. The amino-terminal portions of each LC and HC comprise variable regions involved in antigen recognition via the complementarity-determining regions (CDRs) contained therein. The CDRs are interspersed with more conserved regions called framework regions. The assignment of amino acids to the CDR domains within the LCVR and HCVR regions of the antibodies of the present disclosure is based on the Kabat numbering convention (Kabat, et al., Ann. NY Acad. Sci., 190:382-93 (1971); Kabat et al., Sequences of Proteins of Immunological Interest, Fifth Edition, USDapartment of Health and Human Services, NIH Publication No. 91-3242 (1991)) and the North numbering convention (North et al., A New Clustering of Antibody CDR Loop Conformations, Journal of Molecular Biology, 406:228-256 (2011)). The CDRs of the antibodies of the present disclosure were determined according to the above method.

[0061] The antibodies of the present invention are monoclonal antibodies ("mAbs"). Monoclonal antibodies can be produced, for example, by hybridoma technology, recombinant technology, phage display technology, synthetic technology, e.g., CDR grafting, or a combination of such techniques or other techniques known in the art. The monoclonal antibodies of the present disclosure are human or humanized. Humanized antibodies can be engineered to contain one or more human framework regions (or substantially human framework regions) surrounding CDRs derived from a non-human antibody. Human framework germline sequences can be obtained from ImmunoGeneTics (INGT) via their website http: / / imgt.cines.fr or from The Immunoglobulin FactsBook by Marie-Paule Lefranc and Gerard Lefranc, Academic 25 Press, 2001, ISBN 012441351. Techniques for generating human or humanized antibodies are well known in the art. The present disclosure includes antibodies or nucleic acids encoding antibodies. In some embodiments, the antibody or nucleic acid is provided in isolated form. As used herein, the term "isolated" refers to a protein, peptide, or nucleic acid that is not found in nature and is free or substantially free from other macromolecular species found in a cellular environment. "Substantially free," as used herein, means that the protein, peptide, or nucleic acid of interest contains more than 80% (on a molar basis), preferably more than 90%, and more preferably more than 95% of the macromolecular species present.

[0062] The anti-N3pGlu Aβ antibodies of the present disclosure can be administered as pharmaceutical compositions. Pharmaceutical compositions comprising the antibodies of the present disclosure can be administered to subjects at risk for or exhibiting a disease or disorder described herein by parenteral routes (e.g., subcutaneous, intravenous). Subcutaneous and intravenous routes are preferred. In some embodiments, the anti-N3pGlu Aβ antibodies are administered by intravenous infusion. In some embodiments, the anti-N3pGlu Aβ antibodies are administered by subcutaneous infusion. [Brief explanation of the drawings]

[0063] [Figure 1] Graph illustrating least squares mean change in brain amyloid plaques from baseline to day 169 represented by dosing group, where LY=LY3372993 / lemternetug, MMRM=mixed model for repeated measures, Q4W=q4w, QW=qw, SC=subcutaneous, SD=single dose, TRT=treatment. [Figure 2] Amyloid PET scan images from LAKB participants in Cohort 12 who received a single dose of 2800 mg of lemternex, showing representative amyloid reduction by Day 85. The X-axis is the standardized uptake value (SUV), which indicates amyloid reduction of 144 CL at Day 85. Brain regions are labeled "A" for anterior, "P" for posterior, "L" for left, and "R" for right. [Figure 3] A representation of the study summary for Addendum 1 of LAKC described in Example 5 is provided, where IV = intravenous, Q12W = every 12 weeks, V = visit, and V1 occurs up to 49 days before V2 (represented as "a"). [Figure 4] A representation of the study summary for Addendum 3 of LAKC described in Example 5 is provided, where IV = intravenous, Q4W = every 4 weeks, Q8W = every 8 weeks, V = visit, and V1 occurs up to 49 days prior to the start of study intervention at V2 (represented as "a"). [Figure 5] A representation of the study summary for Addendum 4 of LAKC described in Example 5 is provided, where SC = subcutaneous, QW = weekly, Q4W = every 4 weeks, and V1 occurs up to 49 days before V2 (denoted as "a"). [Figure 6] A representation of the study outline for Addendum 4 of LAKC described in Example 5 is provided, where SC = subcutaneous, and Visit 1 occurs 49 days prior to the start of study intervention at Visit 2 (represented as "a"). Visit 801 occurs 20 weeks after the last dose (represented as "b"). [Figure 7]A representation of the study summary for the main protocol of Study LAKC described in Example 5 is provided, where V601 occurs up to 30 days before V1 (denoted as "a"), V1 occurs up to 49 days before V2 (denoted as "a"), and participants in the 400 mg QW SC cohort are titrated to 800 mg SC Q4W or placebo after a minimum of 4 weeks off treatment (denoted as "b"). [Figure 8] A representation of the study summary for the study LAKD described in Example 6 is provided, where SC = subcutaneous, V601 occurs up to 30 days before V1 (represented as "a"), and V1 occurs up to 63 days before V2 (represented as "a"). [Figure 9] 1 provides a representation of the study summary of Study LAKE described in Example 7. [Figure 10] A representation of the study summary for Study LAKE described in Example 8 is provided, where IV = intravenous, V601 occurs up to 30 days before V1 (represented as "a"), and V1 occurs up to 63 days before V2 (represented as "a"). [Figure 11] FIG. 10 provides a schematic diagram of tau stratification for LAKD and LAKF of Example 9. DETAILED DESCRIPTION OF THE INVENTION

[0064] The terms "treatment," "treating," or "treat" as used herein include inhibiting, slowing, or halting the progression or severity of an existing symptom, condition, disease, or disorder in a subject.

[0065] The term "subject" refers to a human.

[0066] The term "prevention" refers to the prophylactic administration of an antibody of the present disclosure to an asymptomatic subject or a subject with preclinical Alzheimer's disease to prevent the onset or progression of the disease.

[0067] The terms "disease characterized by Aβ deposition" or "disease characterized by Aβ plaques" are used interchangeably and refer to diseases pathologically characterized by Aβ plaques in the brain or cerebral vasculature. This includes diseases such as Alzheimer's disease, Down's syndrome, and cerebral amyloid angiopathy. The clinical diagnosis, staging, or progression of Alzheimer's disease can be easily determined by the attending diagnostician or medical professional as skilled in the art by using known techniques and by observing the results. This generally involves imaging of brain plaques, psychiatric or cognitive assessments (e.g., Clinical Dementia Rating-summary of boxes (CDR-SB), Mini-Mental State Exam (MMSE), or Alzheimer's Disease Assessment Scale-Cognitive (ADAS-Cog)), or functional assessments (e.g., Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADAS-Cog)). Cognitive and functional assessments can be used to determine changes in a patient's cognition (e.g., cognitive decline) and function (e.g., functional decline). As used herein, "clinical Alzheimer's disease" refers to a diagnosed stage of Alzheimer's disease. This includes conditions diagnosed as prodromal Alzheimer's disease, mild Alzheimer's disease, moderate Alzheimer's disease, and severe Alzheimer's disease. The term "preclinical Alzheimer's disease" refers to a stage preceding clinical Alzheimer's disease, in which measurable changes in biomarkers (such as CSF Aβ42 levels or deposited brain plaques by amyloid PET) indicate the earliest signs of a patient with Alzheimer's pathology that will progress to clinical Alzheimer's disease. This is usually before symptoms such as memory loss and confusion become noticeable. Preclinical Alzheimer's disease also includes presymptomatic autosomal dominant carriers and patients at higher risk of developing AD due to having one or two APOE4 alleles.

[0068] A reduction or slowing of cognitive decline can be measured by a cognitive assessment such as the Clinical Dementia Assessment-Summary of Boxes, Mini-Mental State Examination, or Alzheimer's Disease Assessment Scale-Cognition. A reduction or slowing of functional decline can be measured by a functional assessment such as the ADCS-ADL.

[0069] In some embodiments, the subjects / patients of the present disclosure have very low tau burden. 18 Using F-flortaucipir-based quantitative analysis, a human subject has a "very low tau" burden if the tau burden is less than 1.10 SUVr (<1.10 SUVr, standardized uptake value ratio), where quantitative analysis refers to the calculation of SUVr, which represents counts within a specific target region of interest in the brain compared to a reference region (multiblock barycentric discriminant analysis or MUBADA, see Devous et al., "Test-Retest Reproducibility for the Tau PET Imaging Agent Flortaucipir F18," J. Nucl. Med. 59:937-943 (2018)) (parametric estimate of reference signal intensity or PERSI, Southekal et al., "Flortaucipir F 18 Quantitation Using Parametric Estimation of Reference Signal Intensity"). Intensity,” J. Nucl. Med. 59:944-951 (2018).

[0070] In some embodiments, subjects / patients of the present disclosure have very low to moderate tau load. As used herein, a human subject has a "very low to moderate tau" load if the tau load is 1.46 SUVr or less (i.e., ≦1.46 SUVr) using 18F-flortaucipir-based quantitative analysis, where quantitative analysis refers to the calculation of SUVr, which represents counts within a specific target region of interest in the brain compared to a reference region (see MUBADA, Devous et al., "Test-Retest Reproducibility for the Tau PET Imaging Agent Flortaucipir F18," J. Nucl. Med. 59:937-943 (2018)) (PERSI, see Southekal et al., "Flortaucipir F 18 Quantitation Using Parametric Estimation of Reference Signal Intensity," J. Nucl. Med. 59:944-951 (2018)).

[0071] In some embodiments, subjects / patients of the present disclosure have low to moderate tau burden. 18Using F-flortaucipir-based quantitative analysis, a human subject has a "low to moderate tau" burden if the tau load is between 1.10 and 1.46 (i.e., ≥1.10 SUVr and ≤1.46 SUVr), and quantitative analysis refers to the calculation of SUVr, which represents counts within a specific target region of interest in the brain compared to a reference region (see MUBADA, Devous et al., "Test-Retest Reproducibility for the Tau PET Imaging Agent Flortaucipir F18," J. Nucl. Med. 59:937-943 (2018)) (PERSI, see Southekal et al., "Flortaucipir F18 Quantitation Using Parametric Estimation of Reference Signal Intensity," J. Nucl. Med. 59:944-951 (2018)). "Low to moderate tau" load can also be referred to as "intermediate" tau load.

[0072] In some embodiments, a subject / patient of the present disclosure has a high tau burden. 18 Using F-flortaucipir-based quantitative analysis, a human subject has a "high tau" burden if the tau burden is greater than 1.46 SUVr (i.e., >1.46 SUVr), and quantitative analysis refers to the calculation of SUVr, which represents counts within a specific target region of interest in the brain compared to a reference region (see MUBADA, Devous et al., "Test-Retest Reproducibility for the Tau PET Imaging Agent Flortaucipir F18," J. Nucl. Med. 59:937-943 (2018)) (see PERSI, Southekal et al., "Flortaucipir F 18 Quantitation Using Parametric Estimation of Reference Signal Intensity," J. Nucl. Med. 59:944-951 (2018)).

[0073] The antibodies, doses, dosing regimens, or methods disclosed herein can be used to treat or prevent early-symptomatic Alzheimer's disease. As used herein, early-symptomatic Alzheimer's disease encompasses the mild cognitive impairment stage of AD (also known as prodromal AD) and the mild dementia stage of AD. The National Institute on Aging and Alzheimer's Association (NIA-AA) has developed a framework to help define Alzheimer's disease (see Jack et al., "NIA-AA Research Framework: Toward a Biological Definition of Alzheimer's Disease," Alzheimer's & Dementia: The Journal of the Alzheimer's Association 14(4)535-562 (2018), which is incorporated herein by reference in its entirety).

[0074] The term "with chronic administration" means throughout the life of the subject.

[0075] As used herein, mild cognitive impairment is defined as cognitive performance below the range expected for that individual based on all available information. This may be based on clinical judgment and / or cognitive test performance. Cognitive performance is usually within the reduced / abnormal range based on population norms, but this is not required as long as performance is below the range expected for that individual. In addition to evidence of cognitive impairment, there must also be evidence of a decline in cognitive performance from baseline. This can be reported by the individual or by an observer, or observed by changes in longitudinal cognitive tests / behavioral assessments, or a combination of these. At this stage, individuals independently perform activities of daily living, but cognitive difficulties may result in detectable but mild functional impacts on more complex activities of daily living, either self-reported or confirmed by a research partner.

[0076] As used herein, mild dementia is defined as substantial progressive cognitive impairment and / or neurobehavioral impairment affecting several areas. This is documented by personal report, by observer (e.g., research partner) report, or by changes in longitudinal cognitive testing. This stage involves a clear functional impact on daily life, mainly affecting instrumental activities, and the individual is no longer fully independent / requires occasional assistance with daily living activities. When AD has worsened to the point where a) widespread functional impact on daily life, with impairment of basic activities, and b) no longer independent and requiring frequent assistance with daily living activities, the individual is no longer considered to have mild AD dementia.

[0077] As used herein, the term "about" means up to ±10%.

[0078] The terms "subject" and "patient" are used interchangeably in this disclosure.

[0079] The phrases "slowing decline" and "slowing disease progression" are used interchangeably in this disclosure.

[0080] As used herein, "method of treatment" is equally applicable to the use of a composition to treat a disease or disorder described herein and / or the use of and / or the composition for use in the manufacture of a medicament for treating a disease or disorder described herein. [Example]

[0081] The following examples further illustrate the present disclosure, however, it should be understood that the examples are given for purposes of illustration and not limitation, and that various modifications may occur to those skilled in the art.

[0082] The following table provides some examples of dosing regimens for lemternex provided by the present disclosure.

[0083] [Table 1] "A" treatment or prevention also results in i) a reduction in Aβ plaques in the brain of a human subject, ii) a slowing of cognitive decline in a human subject, or iii) a slowing of functional decline in a human subject. "b" Treatment or prevention also results in i) a reduction in Aβ plaques in the brain of a human subject, ii) a slowing of cognitive decline in a human subject, or iii) a slowing of functional decline in a human subject. "c" indicates that a total of three doses of 400 mg are delivered to the patient at a frequency of one dose every four weeks (Q4W), followed by a total of five doses of 800 mg, each delivered at a frequency of one dose every eight weeks (Q8W). "d" indicates that a total of three doses of 400 mg are delivered to the patient at a frequency of one dose every four weeks (Q4W), followed by a total of ten doses of 800 mg, each delivered at a frequency of one dose every four weeks (Q4W). "e" indicates that a total of three doses of 400 mg are delivered to the patient at a frequency of one dose every four weeks (Q4W), followed by a total of three doses of 800 mg, each delivered at a frequency of one dose every eight weeks (Q8W). "f" indicates that a total of three doses of 400 mg are delivered to the patient at a frequency of one dose every four weeks (Q4W), followed by a total of four doses of 800 mg, each delivered at a frequency of one dose every eight weeks (Q8W). "g" indicates that a total of three doses of 400 mg are delivered to the patient at a frequency of one dose every four weeks (Q4W), followed by a total of eight doses of 800 mg, each delivered at a frequency of one dose every four weeks (Q4W).

[0084] Example 1: Non-clinical studies. Nonclinical ADME: The nonclinical pharmacokinetics (PK) of lemterneg were characterized after a single intravenous (IV) or subcutaneous (SC) dose in cynomolgus monkeys. Multiple-dose toxicokinetics were characterized in cynomolgus monkeys after two weekly IV doses over a 6-week period. Serum concentrations of lemterneg were determined by a validated ELISA employing the immobilized ligand N3pG Aβ to capture lemterneg.

[0085] The PK of Lemternetug in monkeys showed low CL, small Vss, and a terminal elimination time of 329-390 hours (approximately 14-16 days). 1 / 2 reported. Subcutaneous bioavailability in monkeys was approximately 74%. After twice-weekly IV dosing in cynomolgus monkeys for 6 weeks, exposure to lemternex increased approximately dose-proportionally with increasing doses from 20 to 200 mg / kg. Approximately a 3- to 4-fold accumulation in exposure was observed. No anti-drug antibodies were detected after administration of lemternex in single- or multiple-dose studies.

[0086] Single-Dose Pharmacokinetics: The serum PK of lemternex in cynomolgus monkeys was characterized after a single bolus dose of 1 mg / kg (IV) or 40 mg / kg (IV and SC), as shown in Table 1.

[0087] [Table 2] Abbreviation: AUC 0~∞ = area under the concentration-time curve from time 0 to infinity, C0 = estimated serum concentration at time 0, CL = clearance, CL / F = relative clearance, C max = maximum observed serum concentration, %F = percent bioavailability, IV = intravenous, SC = subcutaneous, N3pG Aβ = pyroglutamic acid modification of the third amino acid of the amyloid beta peptide, N = number of determinations, NA = not applicable, ND = not determined, t 1 / 2 = terminal half-life, T max = time to maximum serum concentration, V ss = steady-state volume of distribution. Parameters were calculated based on concentrations determined by aN3pG Aβ antigen capture enzyme-linked immunosorbent assay. Values ​​are presented as mean (n=2) or mean + / - standard deviation (n=3). bThe first time point collected was 6 hours post-dose.

[0088] Serum concentrations of lemterneg were determined by ELISA employing the immobilized ligand N3pG Aβ to capture lemterneg. For each time point, samples were collected from two or three animals. lemterneg PK showed low CL and small Vss, consistent with reported blood volumes in cynomolgus monkeys, indicating that lemterneg is widely distributed within the vasculature. Mean elimination t 1 / 2 The mean onset of nausea and vomiting ranged from 329 to 390 hours (approximately 14 to 16 days). Comparing IV doses of 1 and 40 mg / kg, Cmax and AUC were dose-proportional, and bioavailability after SC administration was 74%. There were no injection site reactions (clinical observation of the injection site and microscopic evaluation of skin biopsies).

[0089] Multiple-Dose Toxicokinetics: Toxicology studies were conducted in cynomolgus monkeys with twice-weekly dosing over six weeks. Repeated-dose serum toxicity of lemterneg was determined as part of a GLP toxicology study. Lemterneg was administered at 20 or 200 mg / kg to six animals per group. Serum concentrations of lemterneg were determined by a validated ELISA employing immobilized ligand N3pG Aβ to capture lemterneg and detection via horseradish peroxidase-labeled anti-human IgG. Serum toxicokinetics in cynomolgus monkeys are described in Table 2.

[0090] [Table 3] Abbreviation: AUC 0~96 = area under the curve during the dosing interval, C0 = back-extrapolated concentration at time 0, Cmax = maximum observed concentration, F = female, M = male, MF = male and female combined, N = number of animals, SD = standard deviation, Tmax = time of maximum observed concentration.

[0091] Samples from all experimental animals were tested for the presence of ADAs, and after 6 weeks of administration of Lemterneg, no ADAs were detected that developed after the start of treatment.

[0092] Exposure to lemternex, as assessed by the area under the curve during the dosing interval (AUC), the back-extrapolated concentration at time 0 (C), and C, increased with increasing dose on all days assessed and was approximately dose-proportional from 20 to 200 mg / kg. C and AUC 0~96 The values ​​were approximately 3-4 times higher on day 39 than on day 1, indicating accumulation of lemternative in monkey serum after multiple doses. Pre-dose and 1 hour post-dose concentrations on day 22 were comparable to those on day 39 for corresponding groups and time points. Anti-drug antibodies were not detected in any samples.

[0093] Nonclinical Safety Pharmacology and Toxicology: The safety of lemternex was evaluated in a 6-week toxicity study in cynomolgus monkeys using pharmacological and toxicological evaluations. No adverse or significant drug-related findings were found.

[0094] The overall nonclinical safety profile of lemternex is supportive of human clinical studies (see Tables 3 and 4).

[0095] [Table 4] Abbreviations: AUC = area under the serum concentration versus time curve, AUC 0~96h = AUC from time 0 to 96 hours post-dose, AUC 0~∞ = area under the concentration versus time curve from 0 to infinity, C max = maximum serum concentration, NOAEL = no adverse effect level. aThe dose multiple is the NOAEL dose in monkeys (200 mg / kg) / human dose (assuming a subject weight of 70 kg) on ​​a mg / kg basis. For biologics with a molecular weight >100,000 Da administered intravenously, scaling the dose on a mg / kg basis is the preferred approach (FDA 2005). b Exposure folds are calculated AUCs in animals after 6 weeks of treatment (day 36) from study LAKB (NCT04451408, clinicaltrials.gov) 0~96h (or C max / AUC in humans after a single dose 0~∞ (or C max ) c NOAEL determined in a 6-week repeated dose toxicity study in cynomolgus monkeys.

[0096] [Table 5] Abbreviation:C av,ss = mean steady-state serum concentration, C max = maximum serum concentration, C max,ss = maximum observed drug concentration at steady state, NA = not applicable, NOAEL = no observed adverse effect level, PK = pharmacokinetics, Q4W = once every 4 weeks, Q12W = once every 12 weeks, SC = subcutaneous. a The dose multiple is the total weekly dose at the NOAEL in monkeys (200 mg / kg twice weekly for a total of 400 mg / week) divided by the weekly drug dose in humans on a mg / kg basis (assuming a subject weight of 70 kg and dividing the human dose by the weeks in the dosing interval). b Cynomolgus C av,ss is the mean toxicity study AUC at day 39 0~96 was calculated by dividing by 96 hours. max is the mean C observed on day 39 max Human C values ​​for SC and IV dosing av,ss and C max Values ​​were derived from a population PK model, with a data cutoff of May 30, 2022. c C av,ss or C max The exposure factor was the number of monkeys in the 36th day. av,ss or C max Model predictions for human C av,ss (or C max,ss ) is divided by d NOAEL determined in a 6-week repeated dose toxicity study in cynomolgus monkeys. e IV escalation of doses of 200 mg Q8W x 2, 400 mg Q8W x 2, and 800 mg Q8W x 3. f Maximum administered clinical dose (2800 mg given intravenously Q4W).

[0097] Tissue cross-reactivity studies using human and cynomolgus monkey tissues were also performed. Lemterneg produced immunoreactivity in plaques in the cerebellum or cerebrum, extracellular material in the walls of small blood vessels, and glial cells in the human brain. Additionally, binding to Lemterneg was observed in several epithelial cell types and spermatogonia in the human testis. In cynomolgus monkey tissue, binding to Lemterneg was present only in epithelial cells in the skin and interstitial cells in the decidual lamina of the placenta. The immunoreactivity observed with Lemterneg in plaques in the human brain was expected based on the known diagnosis of AD in one donor and the age (86 years) of the other donor, despite the absence of an AD diagnosis. Plaques were not expected to be present in the cynomolgus monkey brain samples because these samples were obtained from young adults. All other immunoreactivity observed with Lemterneg in human and cynomolgus monkey tissue panels was unexpected because the target epitope is specific to AD plaques and has not been reported to be expressed in normal tissues or physiological fluids. However, all cell binding in the human and cynomolgus monkey tissue panels in the current study was cytoplasmic in nature. Monoclonal antibodies that bind to cytoplasmic sites are generally considered to be of little or no toxicological significance because cytoplasmic / cytoplasmic structures are considered inaccessible to monoclonal antibodies in vivo.

[0098] Example 2: Clinical study. Dosage Considerations for Participants with Early Symptomatic AD and / or Pre-symptomatic AD (Preclinical AD) Selecting a dose for administration to a human participant seeks to address one or both of the following: (i) achieving robust amyloid plaque clearance in participants, i.e., achieving amyloid plaque clearance (<24.1 centiloids) in approximately 80-90% of participants (i.e., within 52 or 72 weeks of treatment or less), and (ii) reducing the risk of ARIA development while maintaining robust plaque clearance. Dosing at 4-, 8-, and 12-week intervals, or combinations thereof, is contemplated herein, allowing time for any asymptomatic ARIA to resolve without interrupting dosing and also seeking to reduce the risk of ARIA exacerbations. Titration schemes are also contemplated herein to reduce the incidence and severity of observed ARIA (Salloway et al. 2022).

[0099] Subcutaneous dosing is contemplated herein to allow for a slower increase in serum concentration with a lower Cmax compared to IV administration. It is hypothesized that a lower Cmax and slower increase in serum concentration may reduce the risk of ARIA (Hayato et al. 2020, Salloway et al. 2022). Dosing intervals of 4, 8, and 12 weeks, or combinations thereof, are contemplated herein to allow time for any asymptomatic ARIA to resolve without interrupting dosing and potentially reduce the risk of ARIA exacerbations. Titration schemes are also contemplated herein for subcutaneous dosing to reduce the incidence and severity of observed ARIA.

[0100] The intravenous and subcutaneous dosing regimens also seek to provide acceptable preparation and convenience for patients. The dosing regimens provided herein take into account Lemterneg's relatively long half-life, reduced risk of immunogenicity, and robust amyloid plaque clearance, attributes not applicable to other anti-N3pGlu Aβ antibodies. Such attributes seek to achieve robust amyloid plaque clearance with less frequent dosing (e.g., dosing intervals of 4, 8, and 12 weeks, or a combination thereof, for either IV or SC dosing), dosing intervals to allow any asymptomatic ARIA to resolve without interrupting dosing, and SC dosing, which may reduce the potential risk of ARIA due to the lower Cmax observed with the dose, as well as reduce participant burden.

[0101] Lemterneg targets amyloid beta peptide, where the peptide is modified with pyroglutamic acid at the third position. Pyroglutamic acid-modified Aβ is present only in cerebral amyloid plaques. Lemterneg can achieve strong removal of amyloid plaques from the brain. The dosing regimen provided herein can be of fixed duration, which has a positive effect on compliance and adherence to the dosing regimen compared to treatment administered throughout a patient's life.

[0102] Example 3: A single-dose, dose-escalation study to evaluate the safety, tolerability, and pharmacokinetics of lemternex in healthy participants. Study LAKA (NCT03720548, clinicaltrials.gov) was the first-in-human administration of lemternex. This completed single-ascending dose (SAD) Phase 1 study was conducted in healthy participants to evaluate the safety, tolerability, pharmacokinetics (PK), and immunogenicity of lemternex. Study LAKA was designed as a single- and multiple-ascending dose study, but only the SAD portion was conducted.

[0103] Study Design Overview: Participants received a single dose of lemternative or placebo and were monitored for approximately 12 weeks after dosing for safety assessments and collection of PK and immunogenicity samples. Four dose levels were evaluated (i.e., 20, 75, 250, and 700 mg).

[0104] Primary Objective: The primary objective of Study LAKA was to evaluate the safety and tolerability of lemternex in healthy participants and patients with Alzheimer's disease (AD).

[0105] Secondary Objectives: The secondary objectives of Study LAKA were i) to evaluate the serum PK of lemternex following a single intravenous (IV) infusion in healthy participants and multiple IV infusions in patients with AD, and ii) to evaluate the effect of lemternex on brain amyloid burden in patients with AD.

[0106] Patient population: Study LAKA consisted of healthy men and women aged 18-45 years with a body mass index (BMI) of 18.0-32.0 kg / m². Participants were excluded if they had evidence of cognitive impairment (Mini-Mental State Examination [MMSE] total score less than 29), brain magnetic resonance imaging (MRI) scans that showed clinically significant findings, or a family history of early-onset AD.

[0107] Safety and tolerability results: There were no deaths or other serious adverse events (SAEs), and no participants discontinued due to adverse events (AEs). Twelve (33.3%) participants reported a total of 15 adverse events, with no clear treatment-related trends. All reported AEs were mild in intensity. Only one AE (dizziness after administration of 700 mg of lemternex) was considered related to study treatment. No infusion-related reactions or hypersensitivity events were observed.

[0108] Immunogenicity Results: None of the patients developed anti-drug antibodies (treatment-induced or treatment-enhanced) after the start of treatment following administration of Lemterneg.

[0109] Pharmacokinetic (PK) Results: The PK of lemternex was evaluated up to 12 weeks after a single IV dose in healthy participants at doses ranging from 20 to 700 mg in Study LAKA. The PK parameters of lemternex are presented in Table 5 below.

[0110] [Table 6] Abbreviation: AUC (0~∞) = area under the concentration versus time curve from time 0 to infinity, C max = maximum observed drug concentration, CV = coefficient of variation, CL = total body clearance of drug calculated after IV administration, IV = intravenous, N = number of participants, t 1 / 2 = half-life associated with the terminal phase rate constant.

[0111] Pharmacodynamic Results: Study LAKA was designed with a multiple-ascending dose (MAD) portion to investigate pharmacodynamic (PD) outcomes, but only the SAD portion was conducted. Therefore, PD results were not available for this study.

[0112] Conclusions: Single IV doses of up to 700 mg of lemternex were safe and well tolerated after administration to healthy participants. Participants did not develop anti-drug antibodies that emerged after treatment initiation up to 12 weeks after a single dose of lemternex. The PK of lemternex was generally linear, with the long t 1 / 2 showed.

[0113] Example 4: Study to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of lemternex in participants with Alzheimer's disease and healthy participants. Study LAKB (NCT04451408, clinicaltrials.gov) is an ongoing Phase 1 study consisting of two parts. Part A of the study is being conducted to investigate the safety and tolerability of lemternex following single and multiple doses (IV or subcutaneous (SC)) in participants with AD, including participants of Japanese descent, and to investigate the effect of lemternex on brain amyloid plaque levels.

[0114] Part B of the study is being conducted in healthy participants, including those of Japanese descent, to evaluate the safety, tolerability, and PK of up to 2800 mg of lemternex following both IV and SC administration, and to explore any immunogenicity risk. Table 6 below depicts the cohorts in Study LAKB.

[0115] [Table 7] Abbreviations: AD = Alzheimer's disease, IV = intravenous, PBO = placebo, Q4W = once every 4 weeks, SC = subcutaneous. a The Lemternex to placebo randomization ratio for all cohorts in Part A was 5:1. b Cohort 7 was two doses of 700 mg IV Q4W followed by an escalation cohort of 1400 mg IV Q4W.

[0116] As shown herein, lemternex demonstrated rapid and robust amyloid plaque clearance in patients with AD, with acceptable safety and tolerability.

[0117] Part A Study Design Overview: Part A will consist of cohorts, each with a 5:1 lemternative to placebo randomization ratio. The decision for dose escalation will be made after at least six participants within a particular cohort have been dosed and safety data through Day 29 have been evaluated from at least four participants who have received the study intervention. Additional participants may be added to existing cohorts based on review of safety, tolerability, PK, and PD data. All potential participants in Part A will undergo screening procedures, including the MMSE, a screening magnetic resonance imaging (MRI), and a screening florbetapir positron emission tomography (PET) scan.

[0118] Participants in cohorts 1-4, 7, and 12 received the first dose of the study intervention as an IV infusion on day 1 of the treatment period and were placed under overnight observation as inpatients after the first dose. Participants were monitored as outpatients and underwent repeat neurological examinations and MRIs approximately 4 weeks after the first dose of the study intervention. The remaining doses of the study intervention were administered IV approximately once every 4 weeks (Q4W) on an outpatient basis, except for participants randomized to cohort 12, who received only a single 2800 mg dose.

[0119] Participants in Cohort 14 received the first dose of the study intervention as an SC injection on Day 1 of the treatment period. Participants were under observation for approximately 6 hours after completing each of the first four doses and for at least 2 hours after completing all subsequent dosing visits. Participants were monitored as outpatients and underwent repeat neurological examinations and MRIs after the first administration of the study intervention.

[0120] All participants in Part A will be monitored for safety, particularly amyloid-related imaging abnormalities (ARIA) and hypersensitivity reactions, for at least 12 weeks after the last dose of study intervention with regular outpatient visits.

[0121] Part B Study Design Overview: Part B is a SAD study conducted in healthy participants receiving either IV or SC administration of Lemterneg. Participants will receive a single dose of Lemterneg or placebo and will be monitored for approximately 12 weeks post-dose for safety assessments and collection of PK and immunogenicity samples.

[0122] Primary Objective: The primary objective of Part B of Study LAKB is to evaluate the safety and tolerability of lemternex in participants with AD, including participants of Japanese descent, and healthy participants after IV or SC administration.

[0123] Secondary Objectives: The secondary objectives of Part B of Study LAKB are i) to evaluate the serum PK of lemternex in participants with AD, including participants of Japanese descent, after single or multiple IV infusions, or administered SC in healthy patients, including participants of Japanese descent, after a single dose IV infusion and a single dose SC, and ii) to evaluate the effect of lemternex on brain amyloid plaque levels in participants with AD, including participants of Japanese descent.

[0124] Patient Population: Part A of Study LAKB included men and women aged 55 to 85 years with a clinical diagnosis of mild cognitive impairment due to AD or AD dementia and gradual and progressive changes in memory function. Participants also had evidence of amyloid brain pathology as determined by amyloid PET scan and an MMSE score of 16 or higher. Participants must have a study partner to participate. Participants with serious illnesses (other than AD) that could interfere with study analysis or affect the participant's ability to complete the study were excluded. Participants with a centrally read MRI showing ARIA-E, more than four cerebral microbleeds, more than one area of ​​superficial hemosiderosis, any large hemorrhage, or the presence of severe white matter disease were excluded.

[0125] Part B of the LAKB study included healthy men and women aged 18 to 45 years with a BMI between 18.0 and 32.0 kg / m². Participants were excluded if they had a brain magnetic resonance imaging scan that showed clinically significant findings or a family history of early-onset AD.

[0126] Safety and tolerability results for participants with Alzheimer's disease: As of August 2023, a total of 75 participants with AD had received at least one dose of Lemterneg or placebo.

[0127] Forty participants (53.3%) with AD reported at least one treatment-emergent adverse event (TEAE), most of which were mild or moderate in severity. ARIA-E (n=16, 21.3%) was the most frequently reported TEAE. The incidence of ARIA-E appeared to be dose-dependent with intravenous administration. ARIA-H was reported in 12 participants (16.0%). No major bleeding events were observed. Three cases of ARIA-E (out of 16 identified cases) were symptomatic. All but six patients who experienced ARIA were managed with temporary discontinuation (six patients were discontinued from the study). Follow-up MRI after temporary discontinuation of the study intervention showed partial or complete resolution of ARIA-E.

[0128] Participants with AD experienced no injection site pain, pruritus, or edema. Two infusion-related reactions and one contact dermatitis hypersensitivity event were observed; all three events were considered mild.

[0129] Safety and tolerability results in healthy participants: As of May 2022, a total of 64 healthy participants, 20 of Japanese descent, have received a single dose of lemternex or placebo.

[0130] No deaths, SAEs, or early discontinuations due to AEs were observed. Twelve (18.8%) healthy participants reported at least one TEAE. The TEAE reported by at least two participants was COVID-19 infection. The overall incidence of TEAEs was similar between Japanese and non-Japanese participants. No TEAEs were considered related to study treatment by the investigators.

[0131] Injection site reactions were prospectively evaluated after a single SC injection in 34 participants. Preliminary analysis showed mild injection site reactions. Findings included mild injection site erythema and induration in approximately 50% of healthy participants, mild injection site pain in two participants, and / or pruritus and edema in one participant each. The majority of injection site reactions persisted for up to 4 hours after administration.

[0132] Immunogenicity Results: In this ongoing study, none of the participants had anti-drug antibodies (treatment-induced or treatment-enhanced) that developed after treatment initiation following single or multiple doses of lemternex as of August 2023.

[0133] Pharmacokinetic Results: PK after a single dose of 2800 mg IV and 400 mg SC in healthy participants was evaluated up to 56 days after administration in Study LAKB. Bioavailability after SC administration was observed to be 61%, which is consistent with the geometric mean observed AUC 0.01 after a single dose of 2800 mg IV or 400 mg SC in healthy volunteers. 0~∞ The PK results are shown in Table 7 below.

[0134] [Table 8] Abbreviation: AUC (0~672) = 672 hours between doses (1st month), AUC (0~1344) = 672 hours between doses = 2nd month, AUC (0~∞) = area under the concentration versus time curve from time 0 to infinity, bioavailability = (dose-normalized geometric mean AUCτ SC / dose-normalized geometric mean AUCτ IV) * 100, C max = maximum observed drug concentration, CL = total body clearance after intravenous administration, CV = coefficient of variation, IV = intravenous, N = number of participants, SC = subcutaneous, tmax = time of maximum observed drug concentration, V z = apparent volume of distribution during the terminal phase. a Median (range).

[0135] PK data for participants with AD from ongoing Studies LAKB and LAKC (detailed in Examples 4 and 5) are reported below as of the data cutoff date of March 24, 2023. Both Cmax,ss and AUCτ,ss increased with dose. In Study LAKB, there was accumulation with repeated monthly administration of lemternex, with accumulation ratios of approximately 1.6, 1.3, 1.0, and 1.9 after Q4W IV doses of 250 mg, 700 mg, 1400 mg, and 2800 mg, respectively. A preliminary population PK analysis was performed using all observed LAKB and LAKC data (n = 451 participants). The intravenous and subcutaneous PK data were best described by a first-order absorption, two-compartment model with clearance and volume terms scaled for patient weight using fixed exponents of 0.8 and 1, respectively (based on allometric principles). Age of the Phase 1 (20 mg / mL) drug product was identified as a significant covariate during exposure. Age of material in the Phase 1 study at the start of treatment (time, day = 0) varied from 182 to 621 days. Exposure (LAKB) decreased linearly with age of material over a range of 180 to 423 days. Examination of the effect of age of material indicated that increased oxidation associated with age contributed to PK changes. The formulation of the Phase 3 drug product incorporated modifications, including increased lemborexant concentration and inclusion of methionine, to stabilize it against oxidation.

[0136] Based on LAKC PK data, no change in serum exposure was observed with age of Phase 3 material. Based on a preliminary population PK model, bioavailability was estimated to be 60%, and the mean absorption rate of lemternex after subcutaneous administration was estimated to be 0.008 h-1. The maximum concentration (Cmax) was achieved at the end of IV infusion (30 minutes to 3 hours) or approximately 7 days after IV or SC administration, respectively. The central volume of distribution was 2.74 L with an inter-individual variability of 38%, while the peripheral volume of distribution was 2.73 L with an inter-individual variability of 28%. Serum clearance was 0.0053 L / h with an inter-participant variability of 54%.

[0137] The PK of lemternex is dose-proportional within the dose range of 250 mg to 2800 mg IV, with a dose-dependent increase in serum exposure following SC dosing of 400 mg and 800 mg (limited data available).

[0138] Pharmacodynamic results: In study LAKB, 18 F-florbetapir PET scans were performed prior to, and approximately 12 and 24 weeks after, IV administration of Lemterneg or placebo every 4 weeks, or single dose or Lemterneg or placebo. For SC administration of Lemterneg, 18 F-florbetapir PET scans were performed 4, 12, and 24 weeks after initiation of weekly dosing with Lemternex or placebo.

[0139] Florbetapir images of the available cohort were prepared essentially as described herein. A composite SUVr was calculated using six target cortical regions and the entire cerebellum as a reference region (Clark et al. 2011). This composite SUVr, measuring brain Aβ plaques, was converted to centiloid units via the following formula: centiloid units = 183.07 * SUVr -177.26 (Navitsky et al. 2018). As previously reported (Navitsky et al. 2018), a threshold of 24.1 centiloid units (CL) distinguishes between absent or sparse neuropathologically verified plaques versus moderate to frequent plaques in autopsy-confirmed data. A threshold of 0 CL represents the mean value in "high certainty" amyloid-negative subjects, i.e., young (≤45 years) controls (Klunk et al. 2015).

[0140] Figure 1 illustrates the change in brain amyloid plaques from baseline to Day 169 by individual participant and time point. For both the IV and SC cohorts, time- and dose / concentration-dependent amyloid plaque reduction was observed. Amyloid plaque levels <24.1 CL were used to define amyloid clearance (Navitsky et al. 2018, Mintun et al. 2021). The proportion of participants achieving amyloid clearance increased with lemternative dose and time. Similar trends were observed when amyloid plaque levels <0 CL were used as the threshold (see Tables 8a and 8b).

[0141] [Table 9]

[0142] [Table 10] Abbreviations: LY = Lemternetug, N = number of randomized subjects, n = subjects with florbetapir F18 PET levels meeting criteria, s = number of florbetapir F18 PET scans available, Q4W = once every 4 weeks, SD = single dose, SC = subcutaneous, QW = once weekly.

[0143] Amyloid clearance was rapid and robust in some participants. An example of amyloid clearance is depicted in Figure 2 as a representative example from Study LAKB in a participant who received a single 2800 mg dose and achieved amyloid clearance at the Day 85 visit. The X-axis of Figure 2 provides the standardized uptake value (SUV), and Figure 2 reflects that the participant experienced an amyloid reduction of 144 centiloids (CL) at Day 85.

[0144] Pharmacokinetics / Pharmacodynamics:( 18A PK / PD analysis of the relationship between serum lemternative concentrations (measured using F-florbetapir PET) and amyloid plaque levels found that a linear model best described the treatment effect on amyloid plaque level reduction over time. The time to achieve amyloid plaque clearance (levels <24.1CL) depended on dose and baseline amyloid plaque levels. An exposure-response model was used to fit the amyloid plaque data over time. The model was parameterized in terms of the natural degradation half-life of amyloid plaques, treatment effect, and baseline. The lemternative PK effect was described using a linear model that simulated the degradation rate of plaque clearance. The treatment effect, represented by the slope, was also found to correlate with baseline amyloid plaque levels. The exposure-amyloid plaque model: It was suggested that there was a proportional increase in the rate of plaque clearance with increasing exposure. Although the data at the time of filing did not allow for estimation of the relative serum concentrations required for maximal and half-maximal responses, it was clear from observations that 2800 mg IV Q4W achieved the highest plaque clearance within the dose range studied. The time to achieve amyloid plaque (<24.1 CL units) clearance depended on baseline amyloid plaque levels: the higher the baseline value, the more time was required to achieve amyloid plaque clearance. ApoE4 carrier status (limited data) was examined as a potential covariate at both baseline and slope but was not identified as a significant covariate in this preliminary exposure-amyloid plaque model.

[0145] Example 5: Evaluation of safety and efficacy as measured by amyloid reduction of lemternex in early symptomatic Alzheimer's disease Study LAKC (NCT04451408, clinicaltrials.gov) is an ongoing Phase 3 study consisting of an open-label addendum and a double-blind, placebo-controlled, randomized clinical trial (i.e., the primary protocol). The open-label addendum is collecting open-label safety data in participants with early symptomatic AD with evidence of amyloid pathology who receive either IV or SC Remternez-1 dosing regimens. The primary protocol is evaluating IV and SC Remternez-1 compared to placebo to measure amyloid plaque clearance in participants with early symptomatic AD.

[0146] Open-Label Addendum Study Design Overview: The purpose of these addendums is to evaluate the open-label safety in participants receiving Lemterneg IV or SC; no placebo doses will be administered in these addendums.

[0147] Addendums 1, 3, and 4, listed below, have been initiated. Participants: Lemternetug 2300 mg IV every 12 weeks in three doses; Lemternetug 1500 mg IV every 12 weeks in 4 doses; Lemternetug 800 mg IV every 8 weeks in 7 doses; Lemternex 400 mg IV every 4 weeks in 3 doses given at weeks 0, 4, and 8, and 800 mg IV every 8 weeks in 5 doses given at weeks 16, 24, 32, 40, and 48; 400 mg IV every 8 weeks in two doses given at weeks 0 and 8, and 800 mg IV every 8 weeks in five doses given at weeks 16, 24, 32, 40, and 48; 200 mg IV every 8 weeks in two doses administered at weeks 0 and 8, 400 mg IV every 8 weeks in two doses administered at weeks 16 and 24, and 800 mg IV every 8 weeks in three doses administered at weeks 32, 40, and 48; 400 mg SC weekly in 36 doses, or assigned to 400 mg SC every 4 weeks in 13 doses.

[0148] A study summary for Supplement 1 is provided in Figure 3, a study summary for Supplement 3 is provided in Figure 4, and a study summary for Supplement 4 is provided in Figure 5.

[0149] Evaluation of the SC treatment group may also be conducted substantially as provided herein and according to Appendix 5 (study summary provided in Figure 6). Thus, participants will be randomized (1:1:1) to one of the three following open-label subcutaneous dosing regimens: Treatment Arm 1 (13 doses total) 100mg Q8W in two doses, followed by 400mg Q8W in two doses, followed by 800mg Q8W in two doses, followed by 800mg Q4W in up to 7 doses. Treatment Arm 2 (15 doses total) 200mg Q8W in a single dose, followed by 400mg Q8W in two doses, followed by 800mg Q8W in a single dose, followed by 800mg Q4W in up to 11 doses. Treatment Arm 3 (16 doses total) 400mg Q8W in two doses, followed by 800mg Q8W in a single dose, followed by 800mg Q4W for a maximum of 13 doses. Additionally, Arm 4 (14 doses total) may also be initiated substantially as described below: 400 mg every 12 weeks in two doses, followed by 800mg Q8W in a single dose, followed by 800mg Q4W in up to 11 doses.

[0150] Summary statistics and statistical analyses will be provided for the safety and exposure data collected in the addendum as defined in the statistical analysis plan. Analyses in the addendum will generally follow those described in the statistical analysis plan for the main protocol, except that there will be no testing of the lemternex or placebo groups during the double-blind treatment phase.

[0151] Objectives of the Open-Label Addendum: The primary objective of the addendum is to describe the safety of Lemterneg. Secondary objectives of the addendum are to evaluate peripheral PK and the presence of anti-Lemterneg antibodies. Additionally, secondary objectives of Addendum 4 are to evaluate the proportion of participants achieving cerebral amyloid clearance and the mean absolute change from baseline in cerebral amyloid plaques on amyloid PET scans.

[0152] Open-Label Addendum Patient Population: In general, individuals may participate in the Open-Label Addendum if they: are between 60 and 85 years old, have gradual and progressive changes in cognitive function, have an MMSE score of 20-28 (Appendix 1, 3, and 4) or an MMSE score of 22-30 (Appendix 5), and Have amyloid PET scan results consistent with the presence of cerebral amyloid pathology (e.g., have greater than 24 cL of Aβ plaques in the brain).

[0153] Under LAKC Addendum 5, participants must also have a CDR-GS of 0.5 or 1 to be enrolled.

[0154] In general, individuals should not participate in research if they: have a significant neurological or psychiatric diagnosis other than AD that may interfere with their ability to complete the analysis or study; have any clinically significant abnormality at screening that may be harmful to the participant, may compromise the study, or may show evidence of other etiologies of dementia; have a current serious or unstable illness or condition that may interfere with the study's analysis, and / or A woman of childbearing potential.

[0155] Study LAKC (Main Protocol) Study Design Overview: Study LAKC is an ongoing, multicenter, randomized, double-blind, placebo-controlled Phase 3 study of lemternex in participants with early symptomatic AD. Participants who meet the inclusion criteria will be enrolled in one of the SC QW, SC Q4W, or IV cohorts, each randomly assigned in a 3:1 ratio to lemternex vs. placebo. IV cohort (N = approximately 200) Lemternetug 800 mg IV every 8 weeks for up to 7 doses, or Placebo IV SC QW cohort (N = approximately 200) * Lemternetug 400 mg SC weekly in 36 doses, or Placebo SC SC Q4W cohort (N = approximately 200) Lemternetug 800 mg SC Q4W in 13 doses, or Placebo SC

[0156] Participants were previously enrolled and randomized to the SC QW cohort, with dosing adjusted to 800 mg SC Q4W or placebo after a minimum of 4 weeks off treatment. A study summary of the main protocol is provided in Figure 7.

[0157] Each cohort will be randomized to receive Lemternex in a 3:1 ratio to placebo. Analysis of the primary and key secondary endpoints will be performed for each cohort. The primary endpoint will be the superiority of each dosing regimen over placebo in the proportion of participants achieving plaque clearance at week 52.

[0158] Study Objectives of Study LAKC (Main Protocol): The primary objective of this study is to test the hypothesis that at least one dosing regimen of lemternag (SC or IV) is superior to placebo in clearing brain amyloid plaques in participants with early symptomatic AD. Secondary objectives of this study are: i) to test the hypothesis that at least one dosing regimen of lemternag (SC or IV) is superior to placebo in terms of the degree of brain amyloid plaque reduction; ii) to test the hypothesis that at least one dosing regimen of lemternag (SC or IV) is superior to placebo in terms of the degree of brain amyloid plaque reduction in participants with early symptomatic AD; and iii) to test the hypothesis that at least one dosing regimen of lemternag (SC or IV) is superior to placebo in terms of the degree of brain amyloid plaque reduction. Other secondary objectives of this study include: i) to describe the safety of lemternag, and ii) to evaluate peripheral PK and the presence of anti-lemternag antibodies.

[0159] Study LAKC (Main Protocol) Patient Population: In general, individuals may participate in Study LAKC (Main Protocol) if they are: 60-85 years of age, have gradual and progressive changes in cognitive function, have an MMSE score of 20-28, have P-tau results consistent with the presence of cerebral amyloid pathology, and have amyloid PET scan results consistent with the presence of cerebral amyloid pathology.

[0160] In general, individuals should not participate in the study if they: have a serious neurological disease or psychiatric diagnosis other than AD that may affect cognition and interfere with study analyses or ability to complete the study; have any clinically significant abnormality at screening that may be harmful to the participant, compromise the study, or show evidence of other etiologies of dementia; have a current serious or unstable illness or condition that may interfere with study analyses; and / or are female of childbearing potential.

[0161] Justification for Study LAKC Dose: The dose was selected considering the following factors: safety and tolerability data from Phase 1 development in participants with early symptomatic AD, safety data from the open-label addendum of LAKC in participants with early symptomatic AD, observed bioavailability of the SC drug product in healthy volunteers, and PK exposure and amyloid plaque analysis of all available data across a wide dose range.

[0162] The inventors of the present disclosure provided herein propose the following: Lemternetuzug 800 mg administered intravenously once every 8 weeks, given over seven infusions (weeks 0, 8, 16, 24, 32, 40, and 48), is expected to result in ≥ 80% of participants achieving amyloid plaque clearance at week 52 from the start of dosing, while still allowing for built-in pauses to mitigate ARIA risk. A 2300 mg dose of Lemternetuzug given over three infusions (weeks 0, 12, and 24) administered once every 12 weeks is expected to result in approximately 90% of participants achieving amyloid plaque clearance 52 weeks after starting the medication. A 1500mg dose of Lemternetuzug given over three infusions (weeks 0, 12, 24, and 36) administered once every 12 weeks is expected to result in approximately 90% of participants achieving amyloid plaque clearance 52 weeks after starting the medication. An escalating regimen of 400 mg of lemternex administered intravenously once every 4 weeks for three infusions (weeks 0, 4, and 8), followed by 800 mg of lemternex administered intravenously once every 8 weeks for five infusions (weeks 16, 24, 32, 40, and 48), is expected to result in ≥80% of participants achieving amyloid plaque clearance at week 52 from the start of dosing, while still allowing for a built-in pause at the higher dose (i.e., 800 mg) to reduce ARIA risk. An escalating regimen of 400 mg of lemternex administered intravenously once every four weeks for two infusions (weeks 0 and 8), followed by 800 mg of lemternex administered intravenously once every eight weeks for five infusions (weeks 16, 24, 32, 40, and 48), is expected to result in ≥80% of participants achieving amyloid plaque clearance at week 52 from the start of dosing, while still allowing for a built-in pause to mitigate ARIA risk. An escalating regimen of 200 mg of lemternex administered intravenously every 4 weeks for two infusions (weeks 0 and 8), followed by 400 mg of lemternex administered intravenously every 8 weeks for two infusions (weeks 16 and 24), followed by 800 mg of lemternex administered intravenously every 8 weeks for three infusions (weeks 32, 40, and 48) is expected to result in ≥60% of participants achieving amyloid plaque clearance at week 52. An alternative scheme is 200 mg and 400 mg infusions followed by 800 mg of lemternex administered intravenously every 8 weeks for six infusions (weeks 32, 40, 48, 56, 64, and 72); this dosing regimen is expected to result in ≥90% of participants achieving amyloid plaque clearance at week 76 from the start of dosing, while still allowing for built-in pauses to mitigate ARIA risk. The fixed IV dosing regimens include a built-in dosing break (2-3 months between infusions). These IV dosing regimens are also expected to result in robust plaque clearance, with breaks between doses helping to minimize ARIA risk. The expected exposure range will be within the range previously explored in Phase 1. It is hypothesized that an 8-12 week dosing interval may allow time for potential asymptomatic ARIA to resolve, reducing the risk of ARIA exacerbations (Salloway et al. 2022). The titration-based IV dosing regimen includes a built-in dose break (2 months between infusions). It is hypothesized that the 8-week dose break helps minimize the ARIA risk associated with dose escalation, while the titration scheme may reduce the severity of observed ARIA. An alternative IV dosing regimen of 400 mg of Lemternezug administered intravenously once every 4 weeks, given over 13 infusions (weeks 0, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, and 48), is also being considered, with the expectation that ≥80% of participants will achieve amyloid plaque clearance at week 52 from the start of dosing. A SC dosing regimen of 400 mg administered weekly for 36 doses or 800 mg administered once every four weeks for 13 doses is expected to result in approximately 80-90% of participants achieving amyloid plaque clearance at 52 weeks from the start of dosing. The SC dosing regimen resulted in a lower C compared with that achieved after IV administration. max It is hypothesized that the serum concentration will increase more slowly with a C at steady state after subcutaneous administration. max is achieved after approximately 4 months for both SC dosing regimens, providing a slower increase in serum concentrations similar to that of the titration scheme. max It is hypothesized that a slower increase in serum concentrations of BAN2401 and ARIA-E may reduce ARIA risk (Hayato et al., "OC14:BAN2401 and ARIA-E in Early Alzheimer's Disease: Pharmacokinetic / pharmacodynamic Time-to-event Analysis from the Phase 2 Study in Early Alzheimer's Disease," J. Prev. Alzheimer's Dis. 7(Suppl 1):2-54 (2020); Salloway et al., "Amyloid-related Imaging Abnormalities in 2 Phase 3 Studies Evaluating Aducanumab in Patients with Early Alzheimer's Disease," JAMA Neurol. 79(1):13-21 (2022), which are incorporated herein by reference in their entireties). Both SC dosing regimens are predicted to achieve monthly serum exposures within the range of steady-state exposures observed after 700 and 1400 mg IV Q4W from the Phase 1 study, with once-every-4-week and weekly SC dosing approaching the lower and higher exposure ranges, respectively. C max If ARIA is not a dominant factor in the development of ARIA, titration-based SC dosing regimens with built-in breaks have been evaluated. While titration schemes may reduce the severity of observed ARIA, an initial 8-12 week dosing break helps minimize the ARIA risk associated with dose escalation. The following titration-based dosing regimens may be evaluated: Lemternex in two doses of 400 mg SC every 8 weeks administered at weeks 0 and 8, with escalation to a maximum of 800 mg Lemternex SC in one dose administered at week 16, and 800 mg Lemternex SC every 4 weeks in 13 doses administered at weeks 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, and 72. Lemternex in two doses of 400 mg SC every 12 weeks administered at weeks 0 and 12, with escalation to a maximum of 800 mg Lemternex SC in one dose administered at week 24, and 800 mg Lemternex SC every 4 weeks in 11 doses administered at weeks 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, and 72. Lemterneg in a single dose of 200 mg SC administered at week 0, with escalation to a maximum of 400 mg Lemterneg SC every 8 weeks in two doses administered at weeks 8 and 16, with escalation to a maximum of 800 mg Lemterneg SC in a single dose administered at week 24, and 800 mg Lemterneg SC every 4 weeks in 11 doses administered at weeks 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, and 72. Lemterneg at 100 mg SC in two doses administered at weeks 0 and 8, with escalation to a maximum of 400 mg Lemterneg SC every 8 weeks in two doses administered at weeks 16 and 24; Lemterneg at 800 mg SC in two doses every 8 weeks in weeks 32 and 40; and Lemterneg at 800 mg SC every 4 weeks in seven doses administered at weeks 48, 52, 56, 60, 64, 68, and 72. Lemternex 400 mg SC every 8 weeks in three doses administered at weeks 0, 8, and 16, with escalation to a maximum of 800 mg Lemternex SC in three doses administered at weeks 24, 32, and 40, and 800 mg Lemternex SC every 4 weeks in seven doses administered at weeks 48, 52, 56, 60, 64, 68, and 72.

[0163] Safety results from the ongoing Phase 3 LAKC study: To date, 53.4% ​​of participants have reported at least one treatment-emergent adverse event (TEAE). Among TEAEs, ARIA-E and ARIA-H occurred in more than 10 of 100 participants. Other observed TEAEs (occurring in 1-9 of 100 participants) included, but were not limited to, headache, COVID-19, falls, upper respiratory tract infection, dizziness, urinary tract infection, diarrhea, and confusional state. Symptomatic ARIA-E occurred in 1-9 of 100 participants. Headache occurred in approximately half of symptomatic cases. ARIA has been associated with serious adverse events (SAEs) and death in participants receiving lemternatives. The incidence of ARIA-related SAEs was higher in participants with pre-existing superficial cerebral hemosiderosis. Studies LAKB and LAKC were amended to exclude additional participants with baseline superficial siderosis for enrollment, and all randomized participants with baseline superficial siderosis were discontinued from further study treatment.

[0164] In participants receiving study treatment, ARIA-E, if it occurred, generally occurred within the first 12 weeks of dosing. While the incidence of ARIA-E was higher in cohorts testing higher doses of intravenously administered lemternex, the incidence was lower in participants receiving less frequent subcutaneous dosing (e.g., 800 mg Q4W compared with 400 mg QW), but the initial dose was higher in the Q4W dosing regimen. The incidence of ARIA-E was higher in participants who were APOE ε4 / ε4 compared with heterozygotes or non-carriers of the APOE ε4 allele. Major bleeding events were observed in participants taking lemternex, but such events were uncommon (<1 in 100).

[0165] Hypersensitivity events occurred in fewer than 1 in 100 participants. One report of an infusion-related reaction has been reported. No anaphylaxis has been observed. In participants receiving SC Remternez or placebo, injection site reactions occurred in 1 to 9 in 100 participants. Injection site reactions were mild to moderate in severity, with erythema being the predominant sign and symptom.

[0166] Pharmacodynamic Results: In a subset of study participants, florbetapir F18 PET scans were performed prior to and 24 weeks after initiation of open-label IV administration of lemternex. As of September 22, 2023, the following raw mean changes from baseline at week 24 were observed: 81.9 CL for participants (n=12) receiving lemternative 2300 mg IV Q12W 66.3 CL for participants receiving 1500 mg IV Q12W of lemternex (n=7), 53.4 CL for participants (n=14) receiving lemternative 800 mg IV Q8W Florbetapir F18 PET scans were performed prior to and 8 weeks after initiation of open-label SC administration of Lemternex. As of September 22, 2023, the following raw mean changes from baseline at Week 8 were observed: 26.5 CL for participants receiving 400 mg SC QW of lemternex (n=25), and -22.3 CL for participants (n=23) receiving lemternative 800 mg SC Q4W

[0167] Example 6: Evaluation of the safety and efficacy of subcutaneous lemternex in early symptomatic Alzheimer's disease. Study LAKD (EU Study Number: 2022-501473-38-00) is an upcoming multicenter, randomized, double-blind, placebo-controlled Phase 3 study to evaluate the safety and efficacy of lemternex in participants with early symptomatic AD with evidence of cerebral amyloid and tau pathology. The primary objective of Study LAKD is to evaluate whether treatment with lemternex administered SC can slow disease progression as assessed by cognitive and functional clinical outcomes over 76 weeks of double-blind observation.

[0168] Study LAKD Study Design Overview: Study LAKD is a multicenter, randomized, double-blind, placebo-controlled Phase 3 study of lemternex in participants with early symptomatic AD. The study overview is depicted in Figure 8. Participants who meet the inclusion criteria will be randomly assigned 1:1 to receive lemternex 400 mg SC weekly or placebo SC for 36 doses each.

[0169] The primary objective of this study is to test the hypothesis that treatment with Lemternetsug SC will slow the progression of AD, as measured by the change from baseline in iADRS score through week 76 compared to placebo, which is the primary endpoint. Based on previous studies, approximately two-thirds of randomized participants are expected to be in the intermediate tau population. It is contemplated that some aspects of the study design, such as the primary analysis population (intermediate tau vs. intermediate and high tau, APOE ε4 carriers only vs. carriers and non-carriers), sample size, and other aspects of the design, such as the randomization ratio, may be modified.

[0170] Study Objectives of Study LAKD (Main Protocol): The primary objective of this study is to test the hypothesis that Lemtelnetsug SC is superior to placebo in slowing clinical progression (as measured by the iADRS) in participants with early symptomatic AD. An important secondary objective of this study is to test the hypothesis that Lemtelnetsug SC is superior to placebo in slowing clinical progression as measured using the Clinical Dementia Rating-Summary of Boxes (CDR-SB), the ADAS-Cog13 (13-item Alzheimer's Disease Assessment Scale-Cognitive Subscale), the ADCS-iADL (Alzheimer's Disease Cooperative Study-Activities of Daily Living Scale), and / or the Mini-Mental State Examination (MMSE). Another secondary objective is to describe the safety of Lemtelnetsug.

[0171] Study LAKD (Main Protocol) Patient Population: In general, individuals may participate in Study LAKD if they are: 60-85 years of age, have gradual and progressive changes in cognitive function, have an MMSE score of 20-28, have biomarkers consistent with the presence of cerebral amyloid pathology, if available, and have tau positron emission tomography scan results consistent with the presence of tau pathology.

[0172] In general, individuals should not participate in the study if they: have a serious neurological disease or psychiatric diagnosis other than AD that may affect cognition and interfere with study analyses or ability to complete the study; have any clinically significant abnormality at screening that may be harmful to the participant, compromise the study, or show evidence of other etiologies of dementia; have a current serious or unstable illness or condition that may interfere with study analyses; and / or are female of childbearing potential.

[0173] Study LAKD Amyloid and Tau Substudy: The purpose of this substudy is to collect additional amyloid and tau PET scans in participants enrolled in Study LAKD. These additional PET scans will provide data on the effect of lemternex on brain amyloid plaque and tau pathology over time, informing lemternex's PD efficacy. Approximately 250 participants are planned to participate over the course of the study. Justification for study LAKD dose: A dose of 400 mg administered SC once weekly for 36 doses was selected considering the following factors: Safety and tolerability data from Phase 1 development in participants with early symptomatic AD. Observed bioavailability of SC drug products in healthy volunteers. PK / PD (amyloid plaque) analysis of all available data across a wide dose range. The inventors of the present disclosure provided herein propose that an SC dosing regimen administered weekly in 36 doses results in a lower C compared to that achieved after IV administration. max This is expected to result in approximately 90% of participants achieving amyloid plaque clearance, while allowing for a slower increase in serum concentrations with SC administration. max is achieved after approximately 4 months of weekly dosing, providing a slower increase in serum concentration similar to that of the titration scheme. maxIt is hypothesized that a slower increase in serum concentrations of BAN2401 and ARIA-E may reduce ARIA risk. (Hayato et al., "OC14:BAN2401 and ARIA-E in Early Alzheimer's Disease: Pharmacokinetic / pharmacodynamic Time-to-event Analysis from the Phase 2 Study in Early Alzheimer's Disease," J. Prev. Alzheimer's Dis. 7(Suppl. 1):2-54 (2020); Salloway et al., "Amyloid-related Imaging Abnormalities in 2 Phase 3 Studies Evaluating Aducanumab in Patients with Early Alzheimer's Disease," JAMA Neurol. 79(1):13-21 (2022), which are incorporated herein by reference in their entireties.) Weekly SC dosing of lemternex is predicted to achieve monthly serum exposures within the range of steady-state exposures observed after 700 and 1400 mg IV Q4W from the Phase 1 study. Additionally, Lemternex may be administered at a dose of 800 mg SC every 4 weeks for 13 doses administered at weeks 0, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, and 48. The 800 mg SC dosing regimen administered once every 4 weeks for 13 doses is expected to result in approximately 90% of participants achieving amyloid plaque clearance at week 52 from the start of dosing. C max If ARIA is not a dominant factor in the development of ARIA, a titration-based SC dosing regimen with a built-in break is being evaluated in a study of LAKC. While a titration scheme may reduce the severity of observed ARIA, an initial 8-12 week dose break helps minimize the ARIA risk associated with dose escalation. Therefore, based on ongoing results from LAKC, one of the following alternative dosing regimens may be evaluated: Escalating doses of lemternex of 400 mg SC every 8 weeks in two doses administered at weeks 0 and 8, with escalating doses of lemternex of 800 mg SC in one dose administered at week 16, and 13 doses of lemternex of 800 mg SC every 4 weeks administered at weeks 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, and 72. Lemternex in two doses of 400 mg SC every 12 weeks administered at weeks 0 and 12, with escalation to a maximum of 800 mg Lemternex SC in one dose administered at week 24, and 800 mg Lemternex SC every 4 weeks in 11 doses administered at weeks 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, and 72. Lemterneg in a single dose of 200 mg SC administered at week 0, with escalation to a maximum of 400 mg Lemterneg SC every 8 weeks in two doses administered at weeks 8 and 16, with escalation to a maximum of 800 mg Lemterneg SC in a single dose administered at week 24, and 800 mg Lemterneg SC every 4 weeks in 11 doses administered at weeks 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, and 72. Escalating doses of lemternex of 100 mg SC given every 8 weeks in two doses administered at weeks 0 and 8, with escalating doses of lemternex of up to 400 mg SC every 8 weeks in two doses administered at weeks 16 and 24, escalating doses of lemternex of up to 800 mg SC given in two doses every 8 weeks at weeks 32 and 40, and 800 mg SC every 4 weeks in seven doses administered at weeks 48, 52, 56, 60, 64, 68, and 72.

[0174] Example 7: A study to investigate the safety, tolerability, and pharmacokinetics of a single dose of lemternex in healthy Chinese participants. Study LAKE is an upcoming single-center, randomized, participant- and investigator-blinded, placebo-controlled, parallel-group, single-dose Phase 1 study. Study LAKE will investigate the safety, tolerability, and PK of a single dose of lemternative IV or SC administration in healthy Chinese participants. To date, lemternative has not been evaluated in the native Chinese population. This study will support future clinical development and registration of lemternative in China.

[0175] Study LAKE Study Design Overview: The purpose of this study is to evaluate the safety, tolerability, and PK of lemternex compared to placebo after a single IV or SC dose in healthy Chinese participants. The study includes three cohorts in which participants were randomized to lemternex or placebo in a 5:1 ratio. A study overview is provided in Figure 9.

[0176] Approximately 36 participants will be enrolled in the study. The primary objective of the study is to evaluate the safety and tolerability of lemternex in healthy Chinese participants after a single-dose IV or SC administration.

[0177] Study LAKE Objectives: The primary objective of Study LAKE is to evaluate the safety and tolerability of lemternex in healthy Chinese participants after a single-dose IV or SC administration. A secondary objective is to evaluate the serum PK of lemternex in healthy Chinese participants after a single-dose IV infusion or a single-dose SC administration.

[0178] Study LAKE Patient Population: This study will include healthy men and women of Chinese origin, aged 18-28 years, with a body mass index (BMI) of 18.0-32.0 kg / m². Participants with evidence of cognitive impairment, clinically significant brain magnetic resonance imaging scans, or a family history of early-onset AD will be excluded.

[0179] Example 8: Evaluation of the safety and efficacy of intravenous lemternex in early symptomatic Alzheimer's disease. Study LAKF (EU Study Number: 2022-501886-38-00) is an upcoming multicenter, randomized, double-blind, placebo-controlled Phase 3 study to evaluate the safety and efficacy of lemternex in participants with early symptomatic AD with evidence of cerebral amyloid and tau pathology. The primary objective of Study LAKF is to evaluate whether treatment with IV lemternex can slow disease progression as assessed by cognitive and functional clinical outcomes over 76 weeks of double-blind observation.

[0180] Study LAKF Study Design Overview: Study LAKF is a multicenter, randomized, double-blind, placebo-controlled Phase 3 study of lemternex in participants with early symptomatic AD. A study overview is provided in Figure 10. Participants who meet the inclusion criteria will be randomly assigned 1:1 to receive lemternex 2300 mg IV Q12W (approximately N=1300) or placebo IV (approximately N=1300) in three doses each.

[0181] The primary objective of this study is to test the hypothesis that treatment with Lemternex IV will slow the progression of AD, as measured by the change from baseline in iADRS score through week 76, compared with placebo, as the primary endpoint. Approximately two-thirds of randomized participants are expected to be in the intermediate tau population.

[0182] It is contemplated that some aspects of the study design, such as the primary analysis population (intermediate tau vs. intermediate and high tau, APOE ε4 carriers only vs. carriers and non-carriers), sample size, and other aspects of the design, such as the randomization ratio, may be varied.

[0183] Study Objectives of Study LAKF (Main Protocol): The primary objective of this study is to test the hypothesis that Lemternetug IV is superior to placebo in slowing clinical progression (as measured by the iADRS) in participants with early symptomatic AD. An important secondary objective of this study is to test the hypothesis that Lemternetug IV is superior to placebo in slowing clinical progression as measured using the rating scales defined above: CDR-SB, ADAS-Cog13, ADCS-iADL, and / or MMSE.

[0184] Another secondary objective of this study is to describe the safety of lemternex.

[0185] Study LAKF (Main Protocol) Patient Population: In general, individuals may participate in Study LAKF if they are: 60-85 years of age, have gradual and progressive changes in cognitive function, have an MMSE score of 20-28, have biomarkers consistent with the presence of cerebral amyloid pathology, if available, or have tau positron emission tomography scan results consistent with the presence of tau pathology.

[0186] In general, individuals should not participate in the study if they: have a serious neurological disease or psychiatric diagnosis other than AD that may affect cognition and interfere with study analyses or ability to complete the study; have any clinically significant abnormality at screening that may be harmful to the participant, compromise the study, or show evidence of other etiologies of dementia; have a current serious or unstable illness or condition that may interfere with study analyses; and / or are female of childbearing potential.

[0187] Study LAKF Amyloid and Tau Substudy: The purpose of this substudy is to collect additional amyloid and tau PET scans in participants enrolled in Study LAKF. These additional PET scans will provide data on the effect of lemternative on brain amyloid plaque and tau pathology over time to inform lemternative's efficacy in PD.

[0188] Justification for study LAKF dose: A dose of 2300 mg administered IV once every 12 weeks in three doses was selected considering the following factors: Safety and tolerability data from Phase 1 development in participants with early symptomatic AD, Observed bioavailability of SC drug products in healthy volunteers, PK exposure and amyloid plaque analysis of all available data across a wide dose range. The inventors of the present disclosure provided herein propose that 2300 mg of lemternex given over three infusions (weeks 0, 12, and 24) administered once every 12 weeks is expected to result in approximately 90% of participants achieving amyloid plaque clearance at week 52 from the start of dosing; and / or The IV dosing regimen includes a built-in dosing break (3 months between infusions). This IV dosing regimen is also expected to result in robust plaque clearance, with a break between doses that helps minimize ARIA risk. The expected exposure range will be within the range previously explored in Phase 1. It is hypothesized that a 12-week dosing interval may allow time for potential asymptomatic ARIA to resolve and reduce the risk of ARIA exacerbation (Salloway et al., "Amyloid-related Imaging Abnormalities in 2 Phase 3 Studies Evaluating Aducanumab in Patients with Early Alzheimer's Disease," JAMA Neurol. 79(1):13-21 (2022), which is incorporated herein by reference in its entirety).

[0189] One or more of the following alternative dosing schedules and escalating dosing schedules with built-in breaks may be implemented as protocol addenda to minimize ARIA risk while expecting >80% of participants to achieve amyloid plaque clearance upon completion of the full dosing regimen. 800 mg IV every 8 weeks for 7 doses administered at weeks 0, 8, 16, 24, 32, 40, and 48. 400 mg IV every 4 weeks for 13 doses administered at weeks 0, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, and 48. 400 mg IV every 4 weeks for 3 doses given at weeks 0, 4, and 8, and 800 mg IV every 8 weeks for 5 doses given at weeks 16, 24, 32, 40, and 48. 400 mg IV every 4 weeks for 3 doses given at weeks 0, 4, and 8, and 800 mg IV every 8 weeks for 5 doses given at weeks 12, 20, 28, 36, and 44. 400 mg IV every 8 weeks in two doses given at weeks 0 and 8, and 800 mg IV every 8 weeks in five doses given at weeks 16, 24, 32, 40, and 48. 200 mg IV every 8 weeks in two doses given at weeks 0 and 8, with escalation to a maximum of 400 mg IV every 8 weeks in two doses given at weeks 16 and 24, and escalation to a maximum of 800 mg IV every 8 weeks in six doses given at weeks 32, 40, 48, 56, 64, and 72.

[0190] Example 9: Use of baseline tau in participant screening. Participants' tau baselines can be screened substantially as described herein. For stratification in the study LAKD and LAKF, tau levels can be determined based on an initial visual assessment of the flortaucipir scan, followed by quantitative analysis. An example is shown in FIG. 11. As illustrated in FIG. 11, visual assessment can be stratified according to (AD-, AD+, AD++) based on the presence of tracer uptake in specific regions of the neocortex. Quantitative analysis can be determined based on calculation of SUVr, which represents the counts within specific target regions of interest (e.g., multiblock centroid discriminant analysis or MUBADA) compared to a reference region (parametric estimate of reference signal intensity or PERSI). Participants can be stratified based on screening substantially as described herein, for example, as illustrated in FIG. 11.

[0191] Example 10: Management of ARIA. The development of ARIA-E (cerebral edema / effusion) and / or ARIA-H (cerebral microhemorrhage [MCH], cortical superficial siderosis [cSS], or large cerebral hemorrhage) is an expected event with amyloid plaque-clearing antibodies such as Lemterneg.

[0192] MCH is known to occur during aging and in individuals with AD, and the presence of MCH may or may not be an ARIA-H finding associated with lemmatization (Goos et al., 2010; Carlson et al., 2016; Sperling et al., 2012; Poels et al., 2011). Risk factors for increased risk of ARIA during treatment with amyloid plaque-clearing antibodies include APOE ε4 status and MCH / cSS / white matter disease (WMD) observed at baseline (Arrighi et al., 2016).

[0193] MRI-identified ARIA-E and ARIA-H have been associated with the administration of Lemternex. The incidence of ARIA-E was higher in participants who were APOE ε4 / ε4 compared with heterozygotes or noncarriers of the APOE ε4 allele. The incidence of ARIA-associated SAEs was higher in participants with pre-existing superficial hemosiderosis. The ongoing study excluded additional participants with baseline superficial hemosiderosis for enrollment in the currently studied dosing regimen.

[0194] ARIA was observed in both fixed-dose and escalation cohorts and was generally asymptomatic and resolved with treatment cessation. ARIA was generally observed with the initial dose of lemternative (e.g., the first 3 months of treatment).

[0195] IV dosing regimens for lemternex include built-in dose breaks (2 or 3 months between infusions). Due to the relatively long half-life of lemternex, these IV dosing regimens not only result in robust plaque clearance, but the breaks between doses also help minimize the risk of ARIA. The breaks may also allow MRI-identified ARIA observed between doses to resolve and / or stabilize before the next dose. The incidence of ARIA-E is generally higher in cohorts testing higher doses of intravenously administered lemternex; therefore, a dosing regimen using a titration scheme may reduce the incidence and severity of ARIA observed at lower starting doses, leading to robust amyloid plaque clearance at later higher doses in the titration scheme.

[0196] Fixed-dose SC dosing regimens are expected to reach steady-state Cmax after approximately 4 months of dosing. SC dosing regimens provide a slower increase in serum concentrations compared to IV dosing regimens, similar to those with titration schemes. It has been hypothesized that a lower Cmax and slower increase in serum concentrations may reduce the risk of ARIA (Hayato et al. 2020, Salloway et al. 2022). However, the incidence of ARIA-E was lower in participants receiving less frequent subcutaneous dosing (800 mg Q4W compared to 400 mg QW), although the initial dose was higher in the Q4W dosing regimen. Therefore, titration-based dosing schemes using subcutaneous dosing are also being investigated. It is hypothesized that a dosing regimen using a titration scheme may initially reduce the incidence and severity of observed ARIA with a lower starting dose and less frequent dosing, and later lead to robust amyloid plaque clearance with higher doses and more frequent dosing in a titration scheme.

[0197] Example 11: MRI schedule for a Phase 3 clinical trial of early symptomatic AD participants. In all clinical trials investigating lemternex, scheduled MRI brain scans will be performed to routinely monitor for ARIA. In addition, unscheduled MRI should be performed upon investigator suspicion of ARIA.

[0198] All participants must undergo MRI during screening to be eligible for enrollment. Considering potential risk factors for ARIA, participants with a centrally read MRI showing the presence of ARIA-E, major hemorrhage, more than four MCH, cortico-superficial hemosiderosis, or severe white matter disease (WMD) at screening will be excluded.

[0199] MRI scans will be read locally and sent to a centralized MRI vendor for analysis. Scan-specific analyses will be interpreted by the centralized MRI vendor for data analysis and reporting. Results of the centrally read MRIs related to participant care and safety will be reported back to the investigator.

[0200] Study LAKC Open-Blind Addendum: The MRI schedules for Study LAKC (Addendum 1), Study LAKC (Addendum 3), Study LAKC (Addendum 4), and Study LAKC (Addendum 5) are listed below (Tables 9, 10, 11, and 12).

[0201] [Table 11] ED = early discontinuation, V801 is a follow-up visit Scheduled MRIs at dosing visits must be performed and analyzed prior to dosing.

[0202] [Table 12] ED = early discontinuation, V801 is a follow-up visit. IV Titration 1 = 400mg Q4W x 2, 400mg Q8W x 1, 800mg Q8W x 5 IV titration 2 = 400 mg Q8W x 2, 800 mg Q8W x 5 IV Titration 3 = 200mg Q8W x 2, 400mg Q8W x 2, 800mg Q8W x 3 Scheduled MRIs at dosing visits must be performed and analyzed prior to dosing.

[0203] [Table 13] ED = Early Discontinuation, V801 is a follow-up visit. Scheduled MRIs at visits with scheduled on-site dosing must be performed and analyzed prior to dosing.

[0204] [Table 14] ED = Early Discontinuation, V801 is a follow-up visit. Scheduled MRIs at visits with on-site dosing must be performed and analyzed prior to dosing.

[0205] The open-label supplemental MRI schedule for Study LAKC is designed to monitor participants for potential ARIA for safety and inform dose selection for IV and SC dosing. MRIs performed at visits during the first 12 weeks of dosing will provide information about the potential onset of ARIA shortly after study drug administration and the impact on starting dose. These early analyses will also inform whether a built-in dosing break allows time for asymptomatic ARIA to resolve and / or stabilize before subsequent doses in the schedule.

[0206] For titration-based dosing regimens, MRIs will be performed at visits before and after dose escalation or increased frequency of dosing. These MRIs serve a dual purpose: (1) to monitor for potential ARIA before dosing and inform the eventual dosing decision as described in the ARIA Management Plan (next section), and (2) to investigate the impact of dose escalation or increased frequency of the titration-based dosing schedule. Investigators will be permitted to perform unscheduled MRIs under suspicion of ARIA.

[0207] Study LAKC (Main Protocol): The MRI schedule for Study LAKC (Main Protocol) is listed below (Tables 13a and 13b).

[0208] [Table 15] Scheduled MRIs at dosing visits must be performed and analyzed prior to dosing.

[0209] [Table 16] Scheduled MRIs at dosing visits must be performed and analyzed prior to dosing.

[0210] The MRI schedule for Study LAKC was designed to safely monitor participants for potential ARIA for both IV and SC dosing regimens. The effect of dose and dosing frequency on ARIA occurrence has been previously described in connection with the open-label safety addendum.

[0211] MRIs after the first dosing visit will monitor for potential ARIA before dosing and ultimately inform dosing decisions as described in the ARIA Management Plan (next section). These MRIs will also serve to continue monitoring those receiving the SC dosing regimen. An MRI at week 52 will inform current ARIA status before crossover dosing at week 52 of the second study.

[0212] There will be no scheduled MRIs after Visit 18 (Week 78, 24 weeks after crossover). As demonstrated in Studies LAKB and LAKC described herein, the potential ARIA risk resides primarily in the first few months of medication. Investigators will still be permitted to perform unscheduled MRIs under suspicion of ARIA.

[0213] Study LAKD (Subcutaneous Dosing): The MRI schedule for study LAKD is listed below (Table 14).

[0214] [Table 17]

[0215] The study LAKD MRI schedule is designed to safely monitor participants for potential ARIA on the SC dosing regimen. The week 76 MRI will inform current ARIA status prior to crossover dosing in the second 52 weeks of the study.

[0216] There are no scheduled MRIs after Visit 19 (Week 102, 24 weeks after crossover). As described in Studies LAKB and LAKC, the risk of ARIA is primarily due to medication use during the first few months. Investigators are still permitted to perform unscheduled MRIs under suspicion of ARIA.

[0217] Study LAKF (intravenous dosing): The MRI schedule for study LAKF is listed below (Table 15).

[0218] [Table 18] MRIs at Visits 5, 7, 18, and 20 must be performed and analyzed prior to dosing.

[0219] The study LAKF MRI schedule is designed to monitor participants for potential ARIA for safety with the IV dosing regimen. MRIs should be performed before participants' second and third doses. These MRIs will monitor for potential ARIA before dosing and ultimately inform dosing decisions, as described in the ARIA Management Plan (next section). The Week 76 MRI will inform current ARIA status before crossover dosing at Week 52 of the second part of the study.

[0220] There will be no scheduled MRIs after Visit 20 (Week 102, 24 weeks after crossover). As demonstrated in Studies LAKB and LAKC, the potential ARIA risk is primarily due to medication use during the first few months. Investigators will still be permitted to perform unscheduled MRIs under suspicion of ARIA.

[0221] Example 12: ARIA management plan for studies LAKD and LAKF. The development of ARIA-E and / or ARIA-H is an expected event and occurred in some participants treated with lemternex (as observed in Studies LAKB and LAKC). ARIA monitoring (detailed in the previous section) is determined, in part, by scheduled MRI. A single symptom suggestive of ARIA may warrant an unscheduled MRI, at the investigator's discretion. If a participant simultaneously develops more than one symptom suggestive of ARIA, an unscheduled MRI should be performed.

[0222] Treatment must be permanently discontinued in participants with an SAE associated with ARIA-E and / or ARIA-H that occurs after treatment initiation and in participants who develop one or more major bleeding events.

[0223] Treatment with the study intervention may be permanently discontinued in participants with ARIA-E and / or ARIA-H that develop after initiation of treatment, at the investigator's discretion and based on the severity of clinical and radiological findings.

[0224] Management of ARIA is fully detailed in the Manual of Operations for each clinical trial. Management of ARIA may be modified in light of additional clinical trial data and / or changes in standard of care. Changes will be reflected in updates to the Manual of Operations and / or amendments to the clinical trial protocol. The ARIA management plan for ARIA-E is detailed in Table 16 below.

[0225] [Table 19]

[0226] Complete resolution of ARIA-E (Table 14) is determined by the first MRI scan indicating the absence of ARIA-E. For participants receiving an SC dosing regimen, injections should be resumed upon ARIA-E resolution and continued until the end of the study period. For participants receiving an IV dosing regimen, investigators should consult with Lilly personnel regarding the timing of resuming IV dosing. Infusions should occur no more than 4 to 12 weeks apart, depending on the dosing regimen, and all infusions must be completed by the end of the study period. An unscheduled clinic visit may be necessary to administer any missed infusions. The ARIA management plan for ARIA-H is detailed in Table 17 below.

[0227] [Table 20] NOTE: Participants who develop superficial cerebral hemosiderosis after the initiation of any treatment during the primary study period will be excluded from participation in the extension period.

[0228] Stabilization of ARIA-H and / or major hemorrhage (Table 15) was defined as the first MRI scan noting no new cSS or increase in size, no more than one new MCH, and / or no increase in size of major hemorrhage.

[0229] For mild to moderate symptoms associated with ARIA-E, oral or IV steroids can be considered on an outpatient basis. For severe symptoms associated with ARIA-E, it is recommended that participants be hospitalized for close observation and that IV steroids, such as high-dose dexamethasone, methylprednisolone, or similar agents, be considered (which can be switched to oral steroids on an outpatient basis). The choice of steroids below is based on their high anti-inflammatory activity and lack of mineralocorticoid activity. The final treatment decision is ultimately at the discretion of the investigator or treating physician.

[0230] Example 13: Evaluation of the safety, efficacy, and tolerability of lemternex in preclinical Alzheimer's disease. Lemternetuzumab will be investigated in participants with preclinical Alzheimer's disease either as an addendum to Study AACM or as a stand-alone Phase 3 clinical trial. Study AACM (NCT05026866, clinicaltrials.gov, TRAILBLAZER-3) is an ongoing multicenter, randomized, double-blind, placebo-controlled Phase 3 study evaluating the safety, tolerability, and efficacy of donanemab in participants with preclinical AD.

[0231] The primary objective will be to evaluate whether treatment with lemternex can slow clinical progression in participants with preclinical AD. Clinical progression will be assessed by a slowing of progression from normal cognition to mild cognitive impairment (MCI) / dementia, as measured by the Clinical Dementia Rating Global Score (CDR-GS) and using time-to-event analysis. The primary outcome event will be time to clinical progression, as measured by an increase in CDR-GS from baseline (conversion) over two consecutive visits. Participants will be followed until a pre-specified number of participants experience the primary outcome event of clinical progression; therefore, the total duration of study participation will vary for each participant and will depend on the overall conversion rate.

[0232] Study Design Overview: The clinical trial is a multicenter, randomized, double-blind, placebo-controlled Phase 3 study of Lemterneg in participants with preclinical AD. Participants who meet the inclusion criteria will be randomly assigned 1:1 to Lemterneg or placebo.

[0233] Participants will be medicated in the double-blind treatment period until completion of the medication. Participants will then enter a double-blind observation phase with visits every 26 weeks for a total of not more than 150 weeks.

[0234] Study Objectives: The primary objective of this study is to test the hypothesis that lemternative is superior to placebo at slowing the time to clinical progression (as measured by the CDR-GS) in participants with preclinical AD. Key secondary objectives include describing the safety of lemternative and testing the hypothesis that lemternative is superior to placebo at slowing clinical progression, as measured using the following scale: SAP (statistical analysis plan), ISLT (International Shopping List Test), CPAL (Continuous Paired Associate Learning), iDSSTm (International Daily Symbol Substitution Test-Medicines), Category fluency, FNAME (Face Name Association Test), BPS-O (Behavioral Pattern Separation-Object test), CBB (Cogstate Brief Battery), CDR-SB (Clinical Dementia Rating-Sum of Boxes), CFI (Cognitive Function Index), and / or MoCA score (Montreal Cognitive Assessment).

[0235] Patient Population: In general, individuals may participate in a study if they: are between 55 and 80 years old, TICS-M score, reflecting intact cognitive function; have biomarkers consistent with the presence of cerebral amyloid pathology, and / or Have a reliable research partner.

[0236] In general, individuals should not participate in research if they: have mild impairment, dementia, or other CNS disorders that affect cognition, Have any clinically significant abnormality at screening that may be harmful to the participant or may compromise the study; and / or Have a current serious or unstable illness or condition that may interfere with the study's analysis.

[0237] Dose justification: The dosing regimen for Lemternezug is selected taking into account the following factors: safety and tolerability data from Phase 1 and 3 development; PK exposure and amyloid plaque analysis of all available data across a wide dose range, and / or A fixed or escalating dosing regimen expected to result in approximately 80-90% of participants achieving amyloid plaque clearance over the duration of treatment.

[0238] One of the following dosing regimens of lemternative may be administered as part of a clinical trial: 2300 mg IV every 12 weeks in two doses administered at weeks 0 and 12. 1500 mg IV every 12 weeks in three doses administered at weeks 0, 12, and 24. 800 mg IV every 8 weeks in 5 doses administered at weeks 0, 8, 16, 24, and 32. 400 mg IV every 4 weeks in 3 doses given at weeks 0, 4, and 8, with escalation to a maximum of 800 mg IV every 8 weeks in 3 or 4 doses given at weeks 16, 24, 32, and / or 40. 400 mg IV every 8 weeks in two doses given at weeks 0 and 8, with escalation to a maximum of 800 mg IV every 8 weeks in three or four doses given at weeks 16, 24, 32, and / or 40. 400 mg IV every 4 weeks for 10 doses administered at weeks 0, 4, 8, 12, 16, 20, 24, 28, 32, and 36. 200 mg IV every 8 weeks in two doses given at weeks 0 and 8, with escalation to a maximum of 400 mg IV every 8 weeks in two doses given at weeks 16 and 24, and with escalation to a maximum of 800 mg IV every 8 weeks in three or four doses given at weeks 32, 40, 48, and / or 56. 100 mg SC every 8 weeks for two doses given at weeks 0 and 8, then 400 mg SC every 8 weeks for two doses given at weeks 16 and 24, then 800 mg SC every 8 weeks for two doses given at weeks 32 and 40, then 800 mg SC every 4 weeks for up to seven doses (e.g., doses given at weeks 44, 48, 52, 56, 60, 64, 68, and 72). 200 mg SC every 8 weeks in one dose given at week 0, then 400 mg SC every 8 weeks in two doses given at weeks 8 and 16, then 800 mg SC every 8 weeks in one dose given at week 24, then 800 mg SC every 4 weeks for 9 to 11 doses (e.g., doses given at weeks 28, 31, 36, 40, etc. up to at least week 64 or as long as week 72). 400 mg SC every 8 weeks for two doses administered at weeks 0 and 8, then 800 mg SC every 8 weeks for one dose administered at week 16, then 800 mg SC every 4 weeks for 8 to 13 doses (e.g., doses administered at weeks 20, 24, 28, 32, 36, 40, etc., up to at least 48 weeks or as long as 72 weeks). 400 mg SC every 12 weeks for 21 doses given at weeks 0 and 8, then 800 mg SC every 12 weeks for one dose given at week 20, then 800 mg SC every 4 weeks for 9 to 11 doses (e.g., doses given at weeks 24, 28, 32, 36, 40, etc. up to at least week 64 or as long as week 72). 400 mg SC weekly for 25 doses administered at weeks 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, and 24. 800 mg SC every 4 weeks for 10 doses administered at weeks 0, 4, 8, 12, 16, 20, 24, 28, 32, and 36. 400 mg SC every 4 weeks for 3 doses given at weeks 0, 4, and 8, with escalation to a maximum of 800 mg SC every 4 weeks for 8 doses given at weeks 12, 16, 20, 24, 28, 32, 36, and 40.

[0239] In the trial design for Remternex in preclinical AD, an MRI schedule could be designed to safely monitor participants for potential ARIA for either the IV or SC dosing regimen. Investigators could perform unscheduled MRIs to check for ARIA at any time throughout the study or if ARIA is suspected.

[0240] Example 14. Use of lemternex to prevent or delay the onset of Alzheimer's disease. Lemterneg can be used to prevent or delay the onset or progression of Alzheimer's disease, substantially as described herein. According to some embodiments, such patients may be at risk for AD. For example, the patient may have a family history of AD and / or be at risk as identified by biomarkers of AD pathology. In addition, Lemterneg can be used to prevent or delay the onset or progression of Alzheimer's disease, substantially as described herein, in patients who are homozygous or heterozygous APOE ε4 and / or in patients with a dominant inheritance (also known as autosomal dominant) genetic profile for AD. In addition, Lemterneg can be used as a maintenance therapy to prevent or delay the progression of AD after treatment with an Aβ-reducing / Aβ-clearing disease-modifying therapy, such as after treatment with donanemab, Lemterneg, Leqembi® (lecanemab), or Aduhelm® (aducanumab). For example, in patients with overtly inherited AD, patients with a family history of AD, other at-risk populations with identified biomarkers of AD pathology, following any Aβ-lowering / Aβ-clearing disease-modifying therapy, and / or where the patient has been previously treated with an Aβ-lowering / Aβ-clearing disease-modifying therapy and has cleared Aβ plaques below a specific level (e.g., 24 centiloids), in embodiments, Lemterneg may be administered as follows: Chronic administration (e.g., up to 72 or 76 weeks) of about 200 mg or about 400 mg via subcutaneous injection every 12 weeks; about 200 mg or about 400 mg via subcutaneous injection every 12 weeks in five doses, followed by chronic administration (e.g., up to 72 or 76 weeks) of about 400 mg via subcutaneous injection every 8 weeks; About 200 mg or about 400 mg via subcutaneous injection every 12 weeks for five doses, followed by about 400 mg and / or about 800 mg via subcutaneous injection every 8 or 12 weeks with chronic administration (e.g., up to 72 or 76 weeks).

[0241] Additional embodiments may include use for the primary prevention of AD in subject populations with known homozygous or heterozygous APOE ε4 genetic profiles and / or other at-risk populations with identified biomarkers of AD pathology, where Lemterneg may be administered as follows: Chronic administration (e.g., up to 72 or 76 weeks) of approximately 200 mg via subcutaneous injection every 26 weeks; Chronic administration (e.g., up to 72 or 76 weeks) of approximately 200 mg via subcutaneous injection every 52 weeks; Chronic administration (e.g., up to 72 or 76 weeks) of approximately 400 mg via subcutaneous injection every 26 weeks; Chronic administration (e.g., up to 72 or 76 weeks) of approximately 400 mg via subcutaneous injection every 52 weeks; Chronic administration (e.g., up to 72 or 76 weeks) of approximately 600 mg via subcutaneous injection every 26 weeks; or Chronic administration (e.g., up to 72 or 76 weeks) of approximately 600 mg via subcutaneous injection every 52 weeks.

[0242] Additional embodiments may include use as maintenance therapy following treatment with an Aβ-lowering / Aβ-clearing disease-modifying therapy, thereby preventing progression of Aβ pathology. According to such embodiments, lemternex may be administered according to the dosing regimen described in Example 14 provided herein.

[0243] References (each of which is incorporated herein by reference in its entirety): Arrighi H, Barakos J, Barkhof F, et al.Amyloid-related imaging abnormalities-haemosiderin(ARIA-H)in patients with Alzheimer's disease treated with bapineuzumab: a historical, prospective secondary analysis.J Neurol Neurosurg Psychiatry 2016;8 7:106-112 Bretz F,Maurer W,Brannath W,Posch M.A graphical approach to sequentially rejective multiple test procedures.Stat Med.2009;28(4):586-604 Bretz F,Posch M,Glimm E,et al.Graphical approaches for multiple comparison procedures using weighted Bonferroni,Simes,or parametric tests.Biom J.2011;53(6):894-913 Carlson,C,Siemers,E,Hake,A et al.Amyloid-related imaging abnormalities from trials of solanezumab for Alzheimer’s disease.Alzheimer’s & Dementia 2016;2(2):75-85 Clark CM,Schneider JA,Bedell BJ,et al.Use of florbetapir-PET for imaging beta-amyloid pathology.JAMA.2011;305(3):275-83 Devous,M.,Joshi,A.,Navitsky,M et al.Test-retest reproducibility for the Tau PET imaging agent flortaucipir F18.J Nucl Med.2018;59(6):937-943 Goos JD,Henneman,W,Sluimer,J et al.Incidence of cerebral microbleeds:a longitudinal study in a memory clinic population.Neurology 2010;74:1954-60 Hayato S, Reyderman L, Zhang Y, et al. OC14: BAN2401 and ARIA-E in early Alzheimer’s disease: pharmacokinetic / pharmacodynamic time-to-event analysis from the phase 2 study in early Alzheimer’s disease. J. Prev. Alzheimer’s Dis. 2020;7(Suppl 1):2-54 Klunk WE, Koeppe RA, Price JC, et al. The Centiloid Project: standardizing quantitative amyloid plaque estimation by PET. Alzheimer’s Dement. 2015 Jan;11(1):1-15.e1-4 Fleisher, A., Pontecorvo, M., Devous, M et al., 「Positron Emission Tomography Imaging With [18F]flortaucipir and Postmortem Assessment of Alzheimer Disease Neuropathologic Changes,」 JAMA Neurol. 2020;77(7):829-839 [FDA] United States Food and Drug Administration. Estimating the maximum safe starting dose in initial clinical trials for therapeutics in adult healthy volunteers. July 2005. Accessed July 1, 2022. https: / / www.fda.gov / regulatory-information / search-fda-guidance-documents / estimating-maximum-safe-starting-dose-initial-clinical-trials-therapeutics-adult-healthy-volunteers. Mintun MA,Lo AC,Evans CD,et al.Donanemab in early Alzheimer’s disease.N Eng J Med.2021;384(18):1691-1704 Navitsky M,Joshi AD.,Kennedy I.Standardization of amyloid quantitation with florbetapir standardized uptake value ratios to the Centiloid scale.Alzheimer’s Dementia:J.Alzheimer’s Assoc.2018;14(12):1565-1571 Poels M,Ikram,M,Lugt,A et al.Incidence of cerebral microbleeds in the general population:the Rotterdam Scan Study Stroke 2011 42(3):656-61 Salloway S,Chalkias S,Barkhof F,et al.Amyloid-related imaging abnormalities in 2 phase 3 studies evaluating aducanumab in patients with early Alzheimer disease.JAMA Neurol.2022;79(1):13-21 Sperling R,Salloway,S,Broos,D et al.Amyloid-related imaging abnormalities in patients with Alzheimer’s disease treated with bapineuzumab:a retrospective analysis.Lancet Neurol 2012;11:241-9 A Study of LY3372993 in Participants With Alzheimer's Disease(AD)and Healthy Participants(Clinical Trial No.:NCT04451408)https: / / clinicaltrials.gov / ct2 / show / NCT04451408?term=LY3372993&draw=2&rank=1 A Study of LY3372993 in Healthy Participants and Participants With Alzheimer's Disease(AD)(Clinical Trial No.:NCT03720548)https: / / clinicaltrials.gov / ct2 / show / NCT04451408?term=LY3372993&draw=2&rank=1 A Study of Remternetug(LY3372993)in Participants With Alzheimer's Disease(TRAILRUNNER-ALZ 1)(Clinical Trial No.:NCT05463731)https: / / clinicaltrials.gov / ct2 / show / NCT05463731?term=LY3372993&draw=2&rank=3 U.S. Patent No. 8,679,498 U.S. Patent No. 8,961,972 U.S. Patent No. 11,312,763 U.S. Patent No. 10,647,759 U.S. Patent No. 11,078,261 U.S. Patent Application No. 17 / 711,099 International Application No. US2022 / 011894 U.S. Patent Application No. 17 / 391,821

[0244] Illustrative Embodiments 1. A method for treating or preventing a disease characterized by the deposition of amyloid beta (Aβ) plaques in the brain in a human subject in need thereof, comprising: The subject receives one or more intravenous (IV) doses of about 20 mg to about 3000 mg of an anti-N3pG Aβ antibody. i) Approximately once every 12 weeks (Q12W), ii) approximately once every 8 weeks (Q8W), or iii) administration at a frequency of about once every four weeks (Q4W); The method, wherein the anti-N3pGlu Aβ antibody comprises a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO:8 and a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO:7. 2. The method of embodiment 1, wherein the subject is administered one or more doses of the antibody for a duration sufficient to treat or prevent the disease. 3. The method of embodiment 1 or 2, wherein the antibody is administered until Aβ plaques are cleared in the brain of the human subject. 4. The antibody is administered until at least one of the following occurs: i) Aβ plaques in the brain of the human subject are 24.1 centiloids or less as measured by two consecutive amyloid PET imaging scans, the two consecutive amyloid PET imaging scans being at least six months apart; or ii) The method of embodiment 1, wherein the human subject has Aβ plaques in the brain of 11 centiloids or less as measured by a single amyloid PET imaging scan. 5. The method of embodiment 1 or 2, wherein the antibody is administered until the subject is amyloid-negative. 6. The method of embodiment 1 or 2, wherein the antibody is administered until an Aβ plaque level of ≦24.1 centiloids is reached, as measured by amyloid PET imaging scan. 7. The method of embodiment 1, wherein the subject is administered about 1 dose to about 20 doses of the antibody, or about 1 dose to about 10 doses of the antibody. 8. The method of embodiment 1, wherein the subject is administered about 3 doses to about 7 doses. 9. The method of embodiment 1, wherein the subject is administered the antibody at a dose of about 250 mg to about 2800 mg. 10. The method of embodiment 1, wherein the subject is administered at least two doses of about 2300 mg of the antibody at a frequency of about once every 12 weeks (Q12W). 11. The method of embodiment 10, wherein the subject is administered two doses of about 2300 mg of the antibody approximately once every 12 weeks. 12. The method of embodiment 11, wherein the subject has preclinical AD. 13. The method of embodiment 11, wherein the subject is administered three doses of about 2300 mg of the antibody approximately once every 12 weeks. 14. The method of embodiment 13, wherein the subject has early symptomatic AD. 15. The method of embodiment 1, wherein the subject is administered at least two doses of about 1500 mg of the antibody at a frequency of about once every 12 weeks (Q12W). 16. The method of embodiment 15, wherein the subject is administered three doses of about 1500 mg of the antibody approximately once every 12 weeks. 17. The method of embodiment 16, wherein the subject has preclinical AD. 18. The method of embodiment 15, wherein the subject is administered four doses of about 1500 mg of the antibody at a frequency of about once every 12 weeks. 19. The method of embodiment 18, wherein the subject has early symptomatic AD. 20. The method of embodiment 1, wherein the subject is administered at least two doses of about 800 mg of the antibody at a frequency of about once every eight weeks (Q8W). 21. The method of embodiment 20, wherein the subject is administered about 5 to about 7 doses of about 800 mg of the antibody at a frequency of about once every 8 weeks. 22. The method of embodiment 21, wherein the subject is administered about 5 doses, about 6 doses, or about 7 doses of the antibody. 23. The method of embodiment 1, wherein the subject is administered at least two doses of about 800 mg of the antibody at a frequency of about once every four weeks (Q4W). 24. The method of embodiment 23, wherein the subject is administered about 5 to about 7 doses of about 800 mg of the antibody at a frequency of about once every 4 weeks. 25. The method of embodiment 24, wherein the subject is administered about 5 doses, about 6 doses, or about 7 doses. 26. The method of any one of embodiments 1 to 25, wherein the disease characterized by Aβ plaques in the brain of a human subject is selected from preclinical Alzheimer's disease (AD), clinical AD, prodromal AD, mild AD, moderate AD, severe AD, Down's syndrome, clinical cerebral amyloid angiopathy, or preclinical cerebral amyloid angiopathy. 27. The method of embodiment 1, wherein the disease is preclinical AD. 28. The method of embodiment 1, wherein the disease is early symptomatic AD, prodromal AD, or mild dementia due to AD. 29. The method of any one of the above embodiments, wherein treating or preventing the disease results in i) a reduction in Aβ plaques in the brain of the human subject, ii) a slowing of cognitive decline in the human subject, or iii) a slowing of functional decline in the human subject. 30. The method of embodiment 29, wherein the reduction of Aβ plaques in the brain of the human subject is determined by amyloid PET brain imaging or a diagnostic that detects Aβ or a biomarker of Aβ. 31. The method of any one of the above embodiments, wherein administration of the antibody does not result in an amyloid-related imaging abnormality (ARIA) event in the subject. 32. The method of any one of the above embodiments, wherein administration of the antibody does not result in a symptomatic ARIA event in the subject. 33. The method of embodiment 1, further comprising the step of evaluating a magnetic resonance imaging (MRI) scan of the subject's brain for ARIA after administration of at least one dose of the antibody, and modifying the administration step until the ARIA resolves. 34. The method of embodiment 33, wherein administration of the antibody is temporarily withheld or discontinued if symptoms consistent with ARIA occur. 35. The method of embodiment 33, wherein administration of the antibody is temporarily withheld if symptoms consistent with mild to moderate ARIA occur. 36. The method of embodiment 33, wherein administration of the anti-N3pGlu Aβ antibody is discontinued if symptoms consistent with severe or symptomatic ARIA occur. 37. The method of any one of the above embodiments, wherein the anti-N3pGlu antibody comprises an LC and an HC, wherein the LC comprises the amino acid sequence of SEQ ID NO: 10, and the HC comprises the amino acid sequence of SEQ ID NO: 9. 38. The method of any one of the previous embodiments, wherein the anti-N3pGlu antibody comprises two light chains and two heavy chains, wherein LC comprises the amino acid sequence of SEQ ID NO: 10, and HC comprises the amino acid sequence of SEQ ID NO: 9. 39. The method of embodiment 1, wherein the subject has a brain tau level with a standardized uptake value ratio (SUVr) of less than 1.46 before administering the antibody, and the brain tau level is measured by a tau PET imaging scan. 40. The method of embodiment 1, wherein the subject has a brain tau level greater than 1.10 SUVr and less than 1.46 SUVr before administering the antibody, and the brain tau level is measured by a tau PET imaging scan. 41. Brain tau levels are 18 The method of embodiment 39 or 40, wherein F-flortaucipir is measured by PET imaging. 42. The method of embodiment 1, wherein the subject has at least one APOE4 allele. 43. The method of any one of the above embodiments, wherein the dose of antibody is administered to the human subject until Aβ plaques in the brain of the human subject are reduced by i) approximately an average of about 25 centiloids to about 100 centiloids, ii) approximately an average of about 50 centiloids to about 100 centiloids, or iii) about 100 centiloids, or iv) about 84 centiloids. 44. The method of any one of the above embodiments, wherein the dose of antibody is administered to the human subject until Aβ plaques in the brain of the human subject are reduced by i) about 25 centiloids to about 100 centiloids, or ii) about 50 centiloids to about 100 centiloids. 45. A method for treating or preventing a disease characterized by the deposition of amyloid beta plaques in the brain in a human subject in need thereof, comprising: The subject receives one or more subcutaneous doses of about 20 mg to about 1000 mg of an anti-N3pG Aβ antibody. i) Approximately once a week (Q1W), ii) approximately once every two weeks (Q2W), or iii) administration at a frequency of about once every four weeks (Q4W); The method, wherein the anti-N3pGlu Aβ antibody comprises a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO:8 and a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO:7. 46. ​​The method of embodiment 45, wherein the subject is administered one or more doses of the antibody for a duration sufficient to treat or prevent the disease. 47. The method of embodiment 45 or 46, wherein the antibody is administered until Aβ plaques are cleared in the brain of the human subject. 48. The antibody is administered until at least one of the following occurs: i) Aβ plaques in the brain of the human subject are 24.1 centiloids or less as measured by two consecutive amyloid PET imaging scans, the two consecutive amyloid PET imaging scans being at least six months apart; or ii) The method of embodiment 45, wherein the Aβ plaques in the brain of the human subject are 11 centiloids or less as measured by a single amyloid PET imaging scan. 49. The method of embodiment 45 or 46, wherein the antibody is administered until the subject is amyloid negative. 50. The method of embodiment 45 or 46, wherein the antibody is administered until an Aβ plaque level of ≦24.1 centiloids is reached, as measured by amyloid PET imaging scan. 51. The method of embodiment 45, wherein the subject is administered about 1 dose to about 100 doses of the antibody. 52. The method of embodiment 45, wherein the subject is administered 24 doses. 53. The method of embodiment 45, wherein the subject is administered 36 doses. 54. The method of embodiment 45, wherein the subject is administered 52 doses. 55. The method of embodiment 45, wherein the subject is administered 76 doses. 56. The method of embodiment 45, wherein the subject is administered the antibody at a dose of about 250 mg to about 500 mg. 57. The method of embodiment 45, wherein 400 mg of the antibody is administered to the subject approximately once a week (Q1W) for 24 weeks or once a week for 36 weeks. 58. The method of embodiment 45, wherein 400 mg of the antibody is administered to the subject about once every two weeks (Q2W) for 36 weeks, 52 weeks, or 76 weeks. 59. The method of any one of embodiments 45 to 58, wherein the disease characterized by Aβ plaques in the brain of a human subject is selected from preclinical AD, clinical AD, prodromal AD, mild AD, moderate AD, severe AD, Down's syndrome, clinical cerebral amyloid angiopathy, or preclinical cerebral amyloid angiopathy. 60. The method of embodiment 45, wherein the disease is preclinical AD. 61. The method of embodiment 60, wherein the subject is administered about 1 to about 24 doses of about 400 mg of the antibody once a week. 62. The method of embodiment 60, wherein the subject is administered about 1 to about 26 doses of about 400 mg of the antibody once every two weeks. 63. The method of embodiment 62, wherein the subject is administered 18 doses or 26 doses of the antibody. 64. The method of embodiment 45, wherein the disease is early symptomatic AD, prodromal AD, or mild dementia due to AD. 65. The method of embodiment 45, wherein the disease is early symptomatic AD. 66. The method of embodiment 65, wherein the subject is administered about 1 to about 36 doses of about 400 mg of the antibody once a week. 67. The method of embodiment 65, wherein the subject is administered about 1 to about 38 doses of about 400 mg of the antibody once every two weeks. 68. The method of embodiment 67, wherein the subject is administered 26 doses or 38 doses of the antibody. 69. The method of any one of the above embodiments, wherein administration of the antibody does not result in an amyloid-related imaging abnormality (ARIA) event in the subject. 70. The method of any one of the above embodiments, wherein administration of the antibody does not result in a symptomatic ARIA event in the subject. 71. The method of embodiment 45, further comprising the step of evaluating a magnetic resonance imaging (MRI) scan of the subject's brain for ARIA after administration of at least one dose of the antibody, and modifying the administration step until the ARIA resolves. 72. The method of embodiment 71, wherein administration of the antibody is temporarily withheld or discontinued if symptoms consistent with ARIA occur. 73. The method of embodiment 72, wherein administration of the antibody is temporarily withheld if symptoms consistent with mild to moderate ARIA occur. 74. The method of embodiment 72, wherein administration of the anti-N3pGlu Aβ antibody is discontinued if symptoms consistent with severe or symptomatic ARIA occur. 75. The method of any one of the above embodiments, wherein the anti-N3pGlu antibody comprises an LC and a HC, wherein the LC comprises the amino acid sequence of SEQ ID NO: 10, and the HC comprises the amino acid sequence of SEQ ID NO: 9. 76. The method of any one of the above embodiments, wherein the anti-N3pGlu antibody comprises two light chains and two heavy chains, wherein LC comprises the amino acid sequence of SEQ ID NO: 10, and HC comprises the amino acid sequence of SEQ ID NO: 9. 77. The method of any one of the above embodiments, wherein treating or preventing the disease results in i) a reduction in Aβ plaques in the brain of the human subject, ii) a slowing of cognitive decline in the human subject, or iii) a slowing of functional decline in the human subject. 78. The method of embodiment 77, wherein the reduction of Aβ plaques in the brain of the human subject is determined by amyloid PET brain imaging or a diagnosis that detects Aβ or a biomarker of Aβ. 79. The method of embodiment 45, wherein the subject has a brain tau level with a standardized uptake value ratio (SUVr) of less than 1.46 before administering the antibody, and the brain tau level is measured by a tau PET imaging scan. 80. The method of embodiment 45, wherein the subject has a brain tau level greater than 1.10 SUVr and less than 1.46 SUVr before administering the antibody, and the brain tau level is measured by a tau PET imaging scan. 81. Brain tau levels are 18 The method of embodiment 79 or 80, wherein F-flortaucipir is measured by PET imaging. 82. The method of embodiment 45, wherein the subject has at least one APOE4 allele. 83. The method of any one of the above embodiments, wherein the dose of antibody is administered to the human subject until Aβ plaques in the brain of the human subject are reduced by i) approximately an average of about 25 centiloids to about 100 centiloids, ii) approximately an average of about 50 centiloids to about 100 centiloids, or iii) about 100 centiloids, or iv) about 84 centiloids. 84. The method of any one of the above embodiments, wherein the dose of antibody is administered to the human subject until Aβ plaques in the brain of the human subject are reduced by i) about 25 centiloids to about 100 centiloids, or ii) about 50 centiloids to about 100 centiloids. 85. A method for reducing amyloid beta plaques in the brain of a human subject in need thereof, comprising: The subject receives one or more intravenous doses of about 20 mg to about 3000 mg of an anti-N3pG Aβ antibody. i) approximately once every 12 weeks, ii) approximately once every 8 weeks, or iii) administration at a frequency of about once every four weeks; The method, wherein the anti-N3pGlu Aβ antibody comprises a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO:8 and a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO:7. 86. A method for reducing amyloid beta plaques in the brain of a human subject in need thereof, comprising: The subject receives one or more subcutaneous doses of about 20 mg to about 1000 mg of an anti-N3pG Aβ antibody. i) Approximately once a week, ii) approximately once every two weeks, or iii) administration at a frequency of about once every four weeks; The method, wherein the anti-N3pGlu Aβ antibody comprises a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO:8 and a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO:7. 87. A method for slowing the disease progression of Alzheimer's disease (AD) in a human subject in need thereof, comprising: The subject receives one or more intravenous doses of about 20 mg to about 3000 mg of an anti-N3pG Aβ antibody. i) approximately once every 12 weeks, ii) approximately once every 8 weeks, or iii) administration at a frequency of about once every four weeks; The method, wherein the anti-N3pGlu Aβ antibody comprises a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO:8 and a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO:7. 88. A method for slowing the disease progression of Alzheimer's disease (AD) in a human subject in need thereof, comprising: The subject receives one or more subcutaneous doses of about 20 mg to about 1000 mg of an anti-N3pG Aβ antibody. i) Approximately once a week, ii) approximately once every two weeks, or iii) administration at a frequency of about once every four weeks; The method, wherein the anti-N3pGlu Aβ antibody comprises a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO:8 and a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO:7. 89. An improved method for reducing amyloid beta in the brain of a human subject in need thereof, comprising: i) administering to the subject one to three IV doses of 2300 mg of an anti-N3pGlu Aβ antibody once every 12 weeks (Q12W); ii) administering to the subject one to four IV doses of 1500 mg of an anti-N3pGlu Aβ antibody once every 12 weeks (Q12W); or iii) administering to the subject 1 to 7 IV doses of 800 mg of an anti-N3pGlu Aβ antibody once every 8 weeks (Q8W); The improved method, wherein the anti-N3pGlu Aβ antibody comprises a light chain variable region (LCVR) and a heavy chain variable region (HCVR), wherein the LCVR consists of the amino acid sequence of SEQ ID NO: 8 and the HCVR consists of the amino acid sequence of SEQ ID NO: 7. 90. An improved method for reducing amyloid beta in the brain of a human AD subject in need thereof, comprising: i) administering to the subject 1 to 36 SC doses of 400 mg of an anti-N3pGlu Aβ antibody once weekly (Q1W); ii) administering to the subject 1 to 26 SC doses of 400 mg of an anti-N3pGlu Aβ antibody once every two weeks (Q2W); or iii) administering to the subject 1 to 38 SC doses of 400 mg of an anti-N3pGlu Aβ antibody once every two weeks (Q2W); The improved method, wherein the anti-N3pGlu Aβ antibody comprises a light chain variable region (LCVR) and a heavy chain variable region (HCVR), wherein the LCVR consists of the amino acid sequence of SEQ ID NO: XX, and the HCVR consists of the amino acid sequence of SEQ ID NO: XX. 91. The method of any one of embodiments 85-90, further comprising, after administration of the dose of the anti-N3pGlu Aβ antibody, evaluating a magnetic resonance imaging (MRI) scan of the subject's brain for amyloid-related imaging abnormalities (ARIA), and wherein further administration of the dose is temporarily withheld if symptoms consistent with ARIA occur. 92. The method of embodiment 91, wherein administration of further doses is resumed after resolution of ARIA symptoms or radiographic stabilization on MRI. 93. The method of embodiment 91, wherein further doses are withheld and a corticosteroid is administered to the subject. 94. The method of any one of embodiments 85 to 90, further comprising a step of evaluating a magnetic resonance imaging (MRI) scan of the subject's brain for amyloid-related imaging abnormalities (ARIA) after administration of the dose, wherein further administration of the dose is temporarily discontinued if symptoms consistent with severe or symptomatic ARIA occur. 95. The method of embodiment 94, wherein administration of further doses is resumed after resolution of ARIA symptoms or radiographic stabilization on MRI. 96. The method of embodiment 94, wherein further doses are withheld, and optionally, a corticosteroid is administered to the subject. 97. The method of embodiment 94, wherein further administration of the dose is discontinued and, optionally, a corticosteroid is administered to the subject. 98. A method of treating Alzheimer's disease in a subject in need thereof until symptoms consistent with ARIA-E occur, comprising: i) administering to the subject one or more intravenous doses of about 20 mg to about 3000 mg of an anti-N3pG Aβ antibody at a frequency of about once every 12 weeks, about once every 8 weeks, or about once every 4 weeks; or ii) administering to the subject one or more intravenous doses of about 20 mg to about 1000 mg of an anti-N3pG Aβ antibody about once a week, about once every two weeks, or about once every four weeks; The method, wherein the anti-N3pGlu Aβ antibody comprises a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO:8 and a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO:7. 99. The method of embodiment 98, wherein symptoms of ARIA are detected by MRI or are present in the subject. 100. A method for treating a patient with lemternex, wherein the patient is suffering from Alzheimer's disease; a) administering to a subject: i) one or more intravenous doses of about 20 mg to about 3000 mg of an anti-N3pG Aβ antibody about once every 12 weeks, about once every 8 weeks, or about once every 4 weeks; or ii) one or more subcutaneous doses of about 20 mg to about 1000 mg of an anti-N3pG Aβ antibody about once every week, about once every 2 weeks, or about once every 4 weeks; b) determining whether the patient has symptoms of ARIA-E by i) performing or having performed an MRI after administration of the antibody, or ii) if clinical symptoms consistent with ARIA-E occur; c) temporarily discontinuing treatment with lemternex if the patient has moderate symptoms of ARIA-E; d) if the patient does not have symptomatic ARIA-E, administering lemternex to the patient until brain amyloid is cleared, amyloid negative, or <24.1 centimeters. 101. An improved method for treating a patient with lemternex, wherein the patient is suffering from Alzheimer's disease and the improvement is: a) administering to a subject (or having administered to a subject): i) one or more intravenous doses of about 20 mg to about 3000 mg of an anti-N3pG Aβ antibody about once every 12 weeks, about once every 8 weeks, or about once every 4 weeks; or ii) one or more subcutaneous doses of about 20 mg to about 1000 mg of an anti-N3pG Aβ antibody about once every week, about once every 2 weeks, or about once every 4 weeks; b) determining whether the patient has symptoms of ARIA-E by i) performing or having performed an MRI after administration of the antibody, or ii) if clinical symptoms consistent with ARIA-E occur; c) If the patient has moderate symptoms of ARIA-E, temporarily discontinue treatment with lemternex; d) if the patient does not have symptomatic ARIA-E, administering lemternex to the patient until cerebral amyloid is cleared, amyloid negative, or <24.1 centimeters. 102. A method for treating a patient with lemternex, wherein the patient is suffering from Alzheimer's disease; a) administering to the subject: i) one or more intravenous doses of about 20 mg to about 3000 mg of an anti-N3pG Aβ antibody about once every 12 weeks, about once every 8 weeks, or about once every 4 weeks; or ii) one or more subcutaneous doses of about 20 mg to about 1000 mg of an anti-N3pG Aβ antibody about once every week, about once every 2 weeks, or about once every 4 weeks; b) discontinuing treatment if the patient has moderate symptoms of ARIA-E; c) continuing treatment once ARIA-E has resolved by administering lemternex to the patient until cerebral amyloid is cleared, negative, <24.1CL, or ARIA-E symptoms reappear. 103. The method of embodiment 102, wherein the symptoms or ARIA-E are confirmed or determined by an MRI scan. 104. A method for treating a patient with lemternex, wherein the patient is suffering from Alzheimer's disease; a) administering to the subject: i) one or more intravenous doses of about 20 mg to about 3000 mg of an anti-N3pG Aβ antibody about once every 12 weeks, about once every 8 weeks, or about once every 4 weeks; or ii) one or more subcutaneous doses of about 20 mg to about 1000 mg of an anti-N3pG Aβ antibody about once every week, about once every 2 weeks, or about once every 4 weeks; b) unless the patient has symptomatic ARIA-E, continuing treatment with lemternex until cerebral amyloid is cleared, negative, or <24.1CL. 105. The method of embodiment 104, wherein the symptoms or ARIA-E are confirmed or determined by an MRI scan. 106. A method of treating or preventing early-symptomatic Alzheimer's disease in a human subject in need thereof, comprising: a. administering to the subject three doses of 2300 mg of an anti-N3pGlu Aβ antibody once every 12 weeks (Q12W); b. administering four doses of 1500 mg of antibody to subjects at a frequency of one dose every 12 weeks (Q12W); c. administering to the subject seven doses of 800 mg of antibody at a frequency of one dose every eight weeks (Q8W); d. administering to a subject three doses of 400 mg of antibody given once every four weeks (Q4W), followed by five doses of 800 mg of antibody given once every eight weeks (Q8W); or e. administering to a subject 13 doses of 400 mg of the antibody at a frequency of one dose every eight weeks (Q8W); the anti-N3pGlu Aβ antibody comprises a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 8 and a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 7, and each dose is administered intravenously. 107. A method of treating or preventing early-symptomatic Alzheimer's disease in a human subject in need thereof, comprising: a. administering to the subject 36 doses of 400 mg of an anti-N3pGlu Aβ antibody at a frequency of once weekly (Q1W); b. administering 13 doses of 800 mg of antibody to the subject at a frequency of one dose every four weeks (Q4W); or c. administering to a subject three doses of 400 mg of the antibody once every four weeks (Q4W), followed by ten doses of 800 mg of the antibody once every four weeks (Q4W); The method, wherein the anti-N3pGlu Aβ antibody comprises a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 8 and a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 7, and each dose is administered subcutaneously. 108. A method of treating or preventing preclinical Alzheimer's disease in a human subject in need thereof, comprising: a. administering to the subject two doses of 2300 mg of an anti-N3pGlu Aβ antibody once every 12 weeks (Q12W); b. administering to the subject three doses of 1500 mg of antibody at a frequency of one dose every 12 weeks (Q12W); c. administering to the subject five doses of 800 mg of antibody at a frequency of one dose every eight weeks (Q8W); d. administering to the subject three doses of 400 mg of the antibody once every four weeks (Q4W), followed by three doses of 800 mg of the antibody once every eight weeks (Q8W); e. administering to a subject three doses of 400 mg of antibody given once every four weeks (Q4W), followed by four doses of 800 mg of antibody given once every eight weeks (Q8W); or f. administering to a subject 10 doses of 400 mg of the antibody at a frequency of one dose every 8 weeks (Q8W); the anti-N3pGlu Aβ antibody comprises a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 8 and a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 7, and each dose is administered intravenously. 109. A method of treating or preventing preclinical Alzheimer's disease in a human subject in need thereof, comprising: a. administering to the subject 25 doses of 400 mg of an anti-N3pGlu Aβ antibody at a frequency of one dose per week (Q1W); b. administering 10 doses of 800 mg of antibody to a subject at a frequency of one dose every four weeks (Q4W); or c. administering to the subject three doses of 400 mg of the antibody given once every four weeks (Q4W), followed by eight doses of 800 mg of the antibody given once every four weeks (Q4W); The method, wherein the anti-N3pGlu Aβ antibody comprises a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 8 and a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 7, and each dose is administered subcutaneously. 110. At least one of the following occurs upon completion of administration: a. Aβ plaques in the brain of a human subject are 24.1 centiloids or less as measured by two consecutive amyloid PET imaging scans, the two consecutive amyloid PET imaging scans being at least six months apart; b. the subject is amyloid negative; c. The method of any one of embodiments 106 to 109, wherein the Aβ plaques in the brain of the human subject are 11 centiloids or less as measured by a single amyloid PET imaging scan. 111. A method according to any one of embodiments 106 to 109, wherein treating or preventing a disease results in i) a reduction in Aβ plaques in the brain of a human subject, ii) a slowing of cognitive decline in a human subject, or iii) a slowing of functional decline in a human subject. 112. The method of embodiment 111, wherein the reduction of Aβ plaques in the brain of the human subject is determined by amyloid PET brain imaging or a diagnosis that detects Aβ or a biomarker of Aβ. 113. The method of any one of embodiments 106-112, wherein administration of the antibody does not result in an amyloid-related imaging abnormality (ARIA) event in the subject. 114. The method of any one of embodiments 106 to 113, wherein administration of the antibody does not result in symptomatic ARIA events in the subject. 115. The method of any one of embodiments 106 to 109, further comprising the step of evaluating a magnetic resonance imaging (MRI) scan of the subject's brain for ARIA after administration of at least one dose of the antibody, and modifying the administration step until the ARIA resolves. 116. The method of embodiment 115, wherein administration of the antibody is temporarily withheld or discontinued if symptoms consistent with ARIA occur. 117. The method of embodiment 115, wherein administration of the antibody is temporarily withheld if symptoms consistent with mild to moderate ARIA occur. 118. The method of embodiment 115, wherein administration of the anti-N3pGlu Aβ antibody is discontinued if symptoms consistent with severe or symptomatic ARIA occur. 119. The method of any one of embodiments 106 to 118, wherein the anti-N3pGlu antibody comprises an LC and an HC, wherein the LC comprises the amino acid sequence of SEQ ID NO: 10, and the HC comprises the amino acid sequence of SEQ ID NO: 9. 120. The method of any one of embodiments 106 to 119, wherein the anti-N3pGlu antibody comprises two light chains and two heavy chains, wherein the LC comprises the amino acid sequence of SEQ ID NO: 10, and the HC comprises the amino acid sequence of SEQ ID NO: 9. 121. The method of any one of embodiments 106 to 109, wherein the subject has a brain tau level with a standardized uptake value ratio (SUVr) of less than 1.46 before administering the antibody, and the brain tau level is measured by a tau PET imaging scan. 122. The method of any one of embodiments 106 to 109, wherein the subject has a brain tau level greater than 1.10 SUVr and less than 1.46 SUVr before administering the antibody, and the brain tau level is measured by a tau PET imaging scan. 123. Brain tau levels are 18 The method of embodiment 121 or 122, wherein F-flortaucipir is measured by PET imaging. 124. The method of any one of embodiments 106 to 109, wherein the subject has at least one APOE4 allele. 125. The method of any one of embodiments 106 to 124, wherein the patient does not have baseline superficial cerebral hemosiderosis.

[0245] array Antibody 1 (Lemternetug), HCDR1 (SEQ ID NO: 1) AASGFTFSSYPMS Antibody 1, HCDR2 (SEQ ID NO: 2) AISGSGGSTYYADSVKG Antibody 1, HCDR3 (SEQ ID NO: 3) AREGGSGSYYNGFDY Antibody 1, LCDR1 (SEQ ID NO: 4) RASQSLGNWLA Antibody 1, LCDR2 (SEQ ID NO: 5) YQASTLES Antibody 1, LCDR3 (SEQ ID NO: 6) QHYKGSFWT Antibody 1, HCVR (SEQ ID NO: 7) EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYPMSWVRQAPGKGLEWVSAISGSGGSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREGGSGSYYNGFDYWGQGTLVTVSS Antibody 1, LCVR (SEQ ID NO: 8) DIQMTQSPSTLSASVGDRVTITCRASQSLGNWLAWYQQKPGKAPKLLIYQASTLESGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQHYKGSFWTFGQGTKVEIK Antibody 1, heavy chain (SEQ ID NO: 9) EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYPMSWVRQAPGKGLEWVSAISGSGGSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREGGSGSYYNGFDYW GQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIE KTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG Antibody 1, light chain (SEQ ID NO: 10) DIQMTQSPSTLSASVGDRVTITCRASQSLGNWLAWYQQKPGKAPKLLIYQASTLESGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQHYKGSFWTFGQGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC Exemplary DNA for expressing Antibody 1 heavy chain (SEQ ID NO: 11) gaggtgcagctgttggagtctgggggaggcttggtacagcctggggggtccctgagactctcctgtgcagcctctggattcacctttagcagctatcctatgagctgggtccgccaggctccagggaaggggctggagtgggtctca gctattagtggtagtggtggtagcacatactacgcagactccgtgaagggccggttcaccatctccagagacaattccaagaacacgctgtatctgcaaatgaacagcctgagagccgaggacacggccgtatattactgtgcgaga gaggggggctcagggagttattataacggctttgattattggggccagggaaccctggtcaccgtctcctcagcctccaccaagggcccatcggtcttcccgctagcaccctcctccaagagcacctctgggggcacagcggccctg ggctgcctggtcaaggactacttccccgaaccggtgacggtgtcgtggaactcaggcgccctgaccagcggcgtgcacaccttcccggctgtcctacagtcctcaggactctactccctcagcagcgtggtgaccgtgccctccagc agcttgggcacccagacctacatctgcaacgtgaatcacaagcccagcaacaccaaggtggacaagaaagttgagcccaaatcttgtgacaaaactcacacatgcccaccgtgcccagcacctgaactcctggggggaccgtcagtcttcctcttccccccaaaacccaaggacaccctcatgatctcccggacccctgaggtcacatgcgtggtggtggacgtgagccacgaagaccctgaggtcaagttcaactggtacgtggacggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacaacagcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggctgaatggcaaggagtacaagtgcaaggtctccaacaaagccctcccagcccccatcgagaaaaccatctccaaagccaaagggcagccccgagaaccacaggtgtacaccctgcccccatcccgggacgagctgaccaagaaccaggtcagcctgacctgcctggtcaaaggcttctatcccagcgacatcgccgtggagtgggagagcaatgggcagccggagaacaactacaagaccacgccccccgtgctggactccgacggctccttcttcctctatagcaagctcaccgtggacaagagcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgaggctctgcacaaccactacacgcagaagagcctctccctgtctccgggt Exemplified DNA for expressing antibody 1 light chain (SEQ ID NO: 12) gacatccagatgacccagtctccttccaccctgtctgcatctgtaggagacagagtcaccatcacttgccgggccagtcagagtcttggtaactggttggcctggtatcagcagaaaccagggaaagcccctaaactcctgatctatcaggcgtctactttagaatctggggtcccatcaagattcagcggcagtggatctgggacagagttcactctcaccatcagcagcctgcagcctgatgattttgcaacttattactgccaacattataaaggttctttttggacgttcggccaagggaccaaggtggaaatcaaacggaccgtggctgcaccatctgtcttcatcttcccgccatctgatgagcagttgaaatctggaactgcctctgttgtgtgcctgctgaataacttctatcccagagaggccaaagtacagtggaaggtggataacgccctccaatcgggtaactcccaggagagtgtcacagagcaggacagcaaggacagcacctacagcctcagcagcaccctgacgctgagcaaagcagactacgagaaacacaaagtctacgcctgcgaagtcacccatcagggcctgagctcgcccgtcacaaagagcttcaacaggggagagtgc N3pGlu Aβ(SEQ ID NO: 13) [pE]FRHDSGYEVHHQKLVFFAEDVGSNKGAIIGLMVGGVVIA

Claims

1. 1. A method of reducing amyloid beta (Aβ) plaques in the brain in a human subject in need of reduction of Aβ plaques, treating a disease characterized by the deposition of Aβ plaques in the brain in a human subject in need of treatment, preventing a disease characterized by the deposition of Aβ plaques in the brain in a human subject in need of prevention of the disease, or delaying the onset of a disease characterized by the deposition of Aβ plaques in the brain in a human subject in need of prevention of the disease, comprising: administering to the subject one or more intravenous (IV) doses of about 20 mg to about 3000 mg of an anti-N3pG Aβ antibody about once every 12 weeks (Q12W), about once every 8 weeks (Q8W), about once every 4 weeks (Q4W), or a combination thereof; The method, wherein the anti-N3pGlu Aβ antibody comprises a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 8 and a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO:

7.

2. 10. The method of claim 1, wherein the one or more IV doses are selected from one of about 200 mg, about 400 mg, about 700 mg, about 800 mg, about 1400 mg, about 1500 mg, about 2300 mg, about 2800 mg, or a combination thereof.

3. the one or more IV doses i. about 200 mg administered about once every four weeks (Q4W); ii. about 400 mg administered about once every four weeks (Q4W); iii. about 700 mg administered about once every four weeks (Q4W); iv. about 800 mg administered about once every four weeks (Q4W); v. about 200 mg administered about once every 8 weeks (Q8W); vi. about 400 mg administered about once every eight weeks (Q8W); vii. about 800 mg administered about once every eight weeks (Q8W); viii. about 1500 mg administered about once every 12 weeks (Q12W); or ix. about 2300 mg administered at a frequency of about once every 12 weeks (Q12W).

4. the administering step comprising: administering to the subject an intravenous dose of about 2300 mg of the anti-N3pG Aβ antibody about once every 12 weeks (Q12W) for a period of at least 24 weeks; administering to the subject an intravenous dose of about 1500 mg of the anti-N3pG Aβ antibody about once every 12 weeks (Q12W) for a period of at least 36 weeks; administering to the subject an intravenous dose of about 800 mg of the anti-N3pG Aβ antibody about once every 8 weeks (Q8W) for a period of at least 48 weeks; administering to the subject an intravenous dose of about 400 mg of the anti-N3pG Aβ antibody about once every four weeks (Q4W) for a period of 8 weeks, followed by an intravenous dose of about 800 mg of the anti-N3pG Aβ antibody about once every eight weeks (Q8W) for a period of at least 32 weeks; or 4. The method of claim 1, comprising one of administering to the subject an intravenous dose of about 400 mg of the anti-N3pG Aβ antibody about once every eight weeks (Q8W) for a period of eight weeks, followed by administering to the subject an intravenous dose of about 800 mg of the anti-N3pG Aβ antibody about once every eight weeks (Q8W) for a period of at least 32 weeks.

5. 1. A method of reducing amyloid beta (Aβ) plaques in the brain in a human subject in need of reduction of Aβ plaques, treating a disease characterized by the deposition of Aβ plaques in the brain in a human subject in need of treatment, preventing a disease characterized by the deposition of Aβ plaques in the brain in a human subject in need of prevention of the disease, or delaying the onset of a disease characterized by the deposition of Aβ plaques in the brain in a human subject in need of prevention of the disease, comprising: administering to the subject an intravenous dose of about 200 mg of an anti-N3pG Aβ antibody about once every eight weeks (Q8W), wherein the about 200 mg doses are administered at weeks 0 and 8; thereafter, administering to the subject an intravenous dose of about 400 mg of the anti-N3pG Aβ antibody about once every eight weeks (Q8W), wherein the doses of about 400 mg are administered at weeks 16 and 24; thereafter, administering to the subject an intravenous dose of about 800 mg of the anti-N3pG Aβ antibody about once every eight weeks (Q8W), wherein the about 800 mg doses are administered at weeks 32, 40, 48, 56, 64, and 72; The method, wherein the anti-N3pGlu Aβ antibody comprises a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 8 and a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO:

7.

6. 1. A method of reducing amyloid beta (Aβ) plaques in the brain in a human subject in need thereof, treating a disease characterized by the deposition of Aβ plaques in the brain in a human subject in need thereof, or preventing a disease characterized by the deposition of Aβ plaques in the brain in a human subject in need thereof, comprising: administering to the subject one or more subcutaneous doses of about 100 mg to about 1000 mg of an anti-N3pG Aβ antibody about once every two weeks (Q2W), about once every four weeks (Q4W), about once every eight weeks (Q8W), about once every twelve weeks (Q12W), or a combination thereof; The method, wherein the anti-N3pGlu Aβ antibody comprises a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 8 and a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO:

7.

7. 7. The method of claim 6, wherein the one or more subcutaneous doses are selected from one of about 100 mg, about 200 mg, about 400 mg, about 800 mg, or about 1000 mg.

8. the one or more subcutaneous doses i. about 100 mg administered about once every 8 weeks (Q8W); ii. about 100 mg administered about once every 12 weeks (Q12W); iii. about 200 mg administered about once every eight weeks (Q8W); iv. about 200 mg administered about once every 12 weeks (Q12W); v. about 200 mg administered about once every 16 weeks (Q16W); vi. about 400 mg administered about once a week (Q1W); vii. about 400 mg administered about once every two weeks (Q2W); viii. about 400 mg administered about once every four weeks (Q4W); ix. about 400 mg administered about once every eight weeks (Q8W); x. about 400 mg administered approximately once every 12 weeks (Q12W); xi. about 400 mg administered approximately once every 16 weeks (Q16W); xii. about 600 mg administered about once every eight weeks (Q8W); xiii. about 600 mg administered about once every 12 weeks (Q12W); xiv. about 600 mg administered about once every 16 weeks (Q16W); xv. about 800 mg administered about once every two weeks (Q2W); xvi. about 800 mg administered about once every four weeks (Q4W); xvii. about 800 mg administered about once every eight weeks (Q8W); or xviii. The method of claim 5 or 6, wherein the dose is selected from one of about 800 mg administered at a frequency of about once every 12 weeks (Q12W).

9. the administering step comprising: administering to the subject a subcutaneous dose of about 400 mg of the anti-N3pG Aβ antibody about once a week (Q1W) for a period of at least 35 weeks; administering to the subject a subcutaneous dose of about 800 mg of the anti-N3pG Aβ antibody about once every four weeks (Q4W) for a period of at least 48 weeks; administering to the subject a subcutaneous dose of about 400 mg of the anti-N3pG Aβ antibody about once every eight weeks (Q8W) for a period of at least eight weeks, followed by a subcutaneous dose of about 800 mg of the anti-N3pG Aβ antibody, followed after eight weeks by a subcutaneous dose of about 800 mg of the anti-N3pG Aβ antibody about once every four weeks (Q4W) for a period of at least several weeks for a period of at least 24 weeks to about 48 weeks; administering to the subject a subcutaneous dose of about 200 mg of the anti-N3pG Aβ antibody, followed 8 weeks later by administering to the subject a subcutaneous dose of about 400 mg of the anti-N3pG Aβ antibody about once every 8 weeks (Q8W) for a period of 8 weeks, followed by administering to the subject a subcutaneous dose of about 800 mg of the anti-N3pG Aβ antibody, followed 8 weeks later by administering to the subject a subcutaneous dose of about 800 mg of the anti-N3pG Aβ antibody about once every 4 weeks (Q4W) for a period of at least 32 weeks to about 40 weeks; or administering to the subject subcutaneous doses of about 100 mg of the anti-N3pG Aβ antibody about once every eight weeks (Q8W) for a period of eight weeks, followed by subcutaneous doses of about 400 mg of the anti-N3pG Aβ antibody about once every eight weeks (Q8W) for a period of eight weeks, followed by subcutaneous doses of about 800 mg of the anti-N3pG Aβ antibody about once every eight weeks (Q8W) for a period of eight weeks, followed by subcutaneous doses of about 800 mg of the anti-N3pG Aβ antibody about once every four weeks (Q4W) for a period of at least 24 weeks to about 28 weeks; or 9. The method of claim 6, comprising one of administering to the subject a subcutaneous dose of about 400 mg of the anti-N3pG Aβ antibody about once every 12 weeks (Q12W) for a period of 12 weeks, followed by administering to the subject a subcutaneous dose of about 800 mg of the anti-N3pG Aβ antibody, followed 8 weeks later by administering to the subject a subcutaneous dose of about 800 mg of the anti-N3pG Aβ antibody about once every four weeks (Q4W) for a period of at least 32 weeks to about 40 weeks.

10. 10. The method of any one of claims 1 to 9, wherein the human subject has one of MCI, preclinical AD, or early symptomatic Alzheimer's disease.

11. 11. The method of any one of claims 1-10, wherein the antibody is administered until the Aβ plaques in the brain of the human subject are 24.1 centiloids or less as measured by an amyloid PET imaging scan.

12. 12. The method of any one of claims 1-11, wherein the step of administering results in at least one of: (i.) a reduction in Aβ plaques in the brain as determined by an amyloid PET imaging scan; (ii.) a slowing of cognitive decline; or (iii.) a slowing of functional decline.

13. The method of any one of claims 1 to 12, wherein the subject has at least one APOE4 allele.

14. 1. A method of preventing the progression of AD, delaying the onset of AD, or preventing the progression of Aβ pathology in a human subject in need thereof, comprising administering to the subject subcutaneous doses of about 100 mg to about 800 mg of an anti-N3pG Aβ antibody about once every 8 weeks (Q8W), about once every 12 weeks (Q12W), about once every 26 weeks (Q26W), or about once every 52 weeks (Q52W); The method, wherein the anti-N3pGlu Aβ antibody comprises a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 8 and a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO:

7.

15. 1. A method of preventing the progression of AD, delaying the onset of AD, or preventing the progression of Aβ pathology in a human subject in need thereof, comprising administering to said subject a subcutaneous dose of an anti-N3pG Aβ antibody: i. about 200 mg once every 26 weeks (Q26W) for a period of up to 52 weeks; ii. about 200 mg once every 52 weeks (Q52W) for a period of up to 52 weeks; iii. about 400 mg once every 12 weeks (Q12W) for a period of up to 72 weeks; iv. about 400 mg once every 26 weeks (Q26W) for a period of up to 52 weeks; v. about 400 mg once every 52 weeks (Q52W) for a period of up to 52 weeks; vi. about 600 mg once every 26 weeks (Q26W) for a period of up to 52 weeks; vii. about 600 mg once every 52 weeks (Q52W) for a period of up to 52 weeks; viii. about 400 mg about once every 12 weeks (Q12W) for about 48 weeks, then about 400 mg about once every 8 weeks (Q8W); ix. about 400 mg about once every 12 weeks (Q12W) for about 48 weeks, then about 800 mg about once every 12 weeks (Q12W); or x. administering at a dose and frequency of about 400 mg about once every 8 weeks (Q8W) for about 16 weeks, then about 800 mg about once every 8 weeks (Q8W) for about 16 weeks, then about 800 mg about once every 4 weeks (Q4W); The method, wherein the anti-N3pGlu Aβ antibody comprises a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 8 and a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO:

7.

16. 16. The method of claim 14 or 15, wherein the human subject has a family history of AD, has a biomarker of AD pathology, has the APOe4 allele, is homozygous for APOe4, has a dominant inherited genetic profile for AD, or has been previously treated for AD with an anti-N3pG Aβ antibody.

17. The method of any one of claims 1 to 16, wherein the anti-N3pGlu Aβ antibody comprises a light chain (LC) comprising the amino acid sequence of SEQ ID NO: 10 and a heavy chain (HC) comprising the amino acid sequence of SEQ ID NO:

9.

18. 18. The method of any one of claims 1-17, wherein said administering step does not result in symptomatic amyloid-related imaging abnormalities (ARIA) in said human subject.

19. 19. The method of any one of claims 1-18, wherein after administration of one or more doses of the anti-N3pGlu Aβ antibody, the human subject experiences symptoms consistent with mild to moderate ARIA.

20. 20. The method of claim 19, further comprising administering a corticosteroid to the human subject.

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