Anti-N3pGlu amyloid-beta peptide antibody and its use

Abstract

To provide a method of treating or preventing a disease characterized by deposition of Aβ in a brain, including Alzheimer's disease (AD), Down's syndrome, and cerebral amyloid angiopathy (CAA).SOLUTION: A method of treating or preventing a disease characterized by amyloid beta (Aβ) deposits in the brain of a patient comprises administering to the patient an induction dose of 10 to 60 mg / kg of an anti-N3pGlu Aβ antibody for a period of 6 months or less.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to the treatment of diseases with anti-N3pGlu Aβ antibodies, which are characterized by the deposition of amyloid beta (Aβ) in patients. More specifically, the present invention relates to short-term induction therapy with anti-N3pGlu Aβ antibodies for diseases characterized by Aβ deposition in the brain, including Alzheimer's disease (AD), Down syndrome, and cerebral amyloid angiopathy (CAA).

[0002] The deposits observed in plaques from human patients consist of a heterogeneous mixture of Aβ peptides: N3pE Aβ, Aβ pE3-42, or Aβ P3-42 N3pGlu Aβ, also known as N3pGlu Aβ, is a cleavage form of the Aβ peptide and is found only in plaques. N3pGlu Aβ lacks the first two amino acid residues at the N-terminus of human Aβ and has a pyroglutamate derived from glutamic acid at the third amino acid position. Although the N3pGlu Aβ peptide is a trace component of Aβ deposited in the brain, studies have demonstrated that the N3pGlu Aβ peptide has invasive aggregation properties and accumulates early in the deposition cascade.

[0003] Antibodies against N3pGlu Aβ are known in the art. For example, U.S. Patent No. 8,679,498 discloses an anti-N3pGlu Aβ antibody and a method of treating diseases such as Alzheimer's disease with the antibody. Passive immunization by long-term chronic administration of antibodies against Aβ, including N3pGlu Aβ found in deposits, has been shown to disrupt Aβ aggregates and promote plaque clearance in the brain in various animal models. However, in humans, long-term chronic administration of Aβ antibodies has caused adverse events including angiogenic edema and sulcal exudate (ARIA-E), as well as microhemorrhages and hemosiderin deposits (ARIA-H), and amyloid-related imaging abnormalities (ARIA) suggesting a risk of injection site reactions and immunogenicity. See 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(2016) 417-420. [Overview of the Initiative]

[0004] This invention overcomes the problems associated with long-term chronic administration. The applicants have found that short-term induction therapy with relatively high doses of anti-N3pGlu Aβ antibody promotes significant clearance of plaques in the brains of patients with Aβ deposits, and this clearance is remarkably maintained for a long period. Short-term induction therapy may include a single dose of anti-N3pGlu antibody, a bi-weekly dose of anti-N3pGlu Aβ antibody for a period of 6 months, or a monthly dose of anti-N3pGlu Aβ antibody for a period of 6 months or less. In addition to reducing adverse events caused by long-term chronic administration of antibodies against Aβ, additional benefits of short-term induction therapy include improved patient compliance, reduced risk of injection site reactions and immunogenicity, significant reduction in treatment costs, and reduced disruption to the lives of patients and caregivers.

[0005] As such, the present invention provides a method for treating a disease characterized by Aβ deposition, comprising administering an induction dose of 10-60 mg / kg of anti-N3pGlu Aβ antibody to a patient positive for amyloid deposits for a period of 6 months or less. More specifically, the present invention provides a method for treating a disease characterized by Aβ deposition, comprising administering an induction dose of 10-60 mg / kg of anti-N3pGlu Aβ antibody to a patient positive for amyloid deposits for a period of 6 months or less. More specifically, the present invention provides a method for treating a disease characterized by Aβ deposition in the brain of a human patient, comprising administering a single induction dose of 10-60 mg / kg of anti-N3pGlu Aβ antibody to a patient positive for amyloid deposits. In another, more specific embodiment, the present invention provides a method for treating a disease characterized by Aβ deposition in the brain of a patient who is positive for amyloid deposits, comprising administering an induction dose of anti-N3pGlu Aβ antibody at 10–60 mg / kg every two weeks for a period of six months or less. In another, more specific embodiment, the present invention provides a method for treating a disease characterized by Aβ deposition in the brain of a patient who is positive for amyloid deposits, comprising administering an induction dose of anti-N3pGlu Aβ antibody at 10–60 mg / kg once a month for a period of six months or less. In a preferred embodiment of the present invention, the single induction dose administered to the patient is 10 mg / kg, 15 mg / kg, 20 mg / kg, or 40 mg / kg. In an alternative, preferred embodiment of the present invention, the bi-weekly and monthly induction doses administered to the patient are 10 mg / kg, 15 mg / kg, 20 mg / kg, or 40 mg / kg for a period of six months. In another, more preferred embodiment, the anti-N3pGlu Aβ antibody is selected from Table 1.

[0006] Alternatively, the present invention provides a method for treating a disease characterized by Aβ deposition, comprising administering to a patient positive for amyloid deposits a dose of 10-60 mg / kg of anti-N3pGlu Aβ antibody, followed optionally by one or more doses of 10-60 mg / kg of anti-N3pGlu Aβ antibody for a period of six months or less. Specifically, the present invention provides a method for treating a disease characterized by Aβ deposition in the brain of a patient positive for amyloid deposits, comprising administering to the patient one to twelve separate doses of 10-60 mg / kg of anti-N3pGlu Aβ antibody for a period of six months or less. In another, more specific embodiment, the present invention provides a method for treating a disease characterized by Aβ deposition in the brain of a patient positive for amyloid deposits, comprising administering to the patient six separate doses of 10-60 mg / kg of anti-N3pGlu Aβ antibody for a period of six months or less. Alternatively, the present invention provides a method for treating a disease characterized by Aβ deposition in the brain of a patient who is positive for amyloid deposits, comprising administering to the patient 12 separate doses of anti-N3pGlu Aβ antibody at 10–60 mg / kg over a period of 6 months or less. In a preferred embodiment of the present invention, the 6 or 12 separate doses administered to the patient are 20–40 mg / kg or 15–30 mg / kg (for example, 6 separate doses of 20 mg / kg administered to the patient over 6 months). In another preferred embodiment, the 1, 6 or 12 separate doses administered to the patient are 10 mg / kg, 15 mg / kg, 20 mg / kg, or 40 mg / kg per dose. In another preferred embodiment, the 6 separate doses are separated at 1-month intervals, and the 12 separate doses are separated at 2-week intervals. In a preferred embodiment, the anti-N3pGlu Aβ antibody is selected from Table 1.

[0007] In one embodiment, the present invention provides a method for treating or preventing clinical or preclinical Alzheimer's disease, Down syndrome, and clinical or preclinical CAA in a patient positive for amyloid deposits, comprising administering an induction dose of 10-60 mg / kg of anti-N3pGlu Aβ antibody to the patient for a period of six months or less. Specifically, the present invention provides a method for treating or preventing clinical or preclinical Alzheimer's disease, Down syndrome, and clinical or preclinical CAA in a patient positive for amyloid deposits, comprising administering a single induction dose of 10-60 mg / kg of anti-N3pGlu Aβ antibody to the patient. In another specific embodiment, the present invention provides a method for treating or preventing clinical or preclinical Alzheimer's disease, Down syndrome, and clinical or preclinical CAA in a patient positive for amyloid deposits, comprising administering an induction dose of 10-60 mg / kg of anti-N3pGlu Aβ antibody every two weeks for a period of six months or less. In another specific embodiment, the present invention provides a method for treating or preventing clinical or preclinical Alzheimer's disease, Down syndrome, and clinical or preclinical CAA in a patient positive for amyloid deposits, comprising administering an anti-N3pGlu Aβ antibody in a monthly induction dose of 10–60 mg / kg for a period of six months or less. In a preferred embodiment of the present invention for treating or preventing clinical or preclinical Alzheimer's disease, Down syndrome, and clinical or preclinical CAA, the single, bi-weekly (every two weeks), and monthly induction doses administered to the patient are 20–40 mg / kg or 15–30 mg / kg. In a preferred embodiment of the present invention, the single induction dose administered to the patient is 10 mg / kg, 15 mg / kg, 20 mg / kg, or 40 mg / kg. In an alternative preferred embodiment of the present invention, the bi-weekly and monthly induction doses administered to the patient are 10 mg / kg, 15 mg / kg, 20 mg / kg, or 40 mg / kg for a period of six months. In another, more preferred embodiment, the anti-N3pGlu Aβ antibody is selected from Table 1. The anti-N3pGlu Aβ antibody is preferably selected from Table 1.

[0008] In another embodiment, the present invention provides a method for treating or preventing preclinical AD, prodromal AD (sometimes called Aβ-related mild cognitive impairment, MCI, or AD-induced MCI), mild AD, moderate AD, and severe AD in patients who are positive for amyloid deposits, comprising administering an induction dose of anti-N3pGlu Aβ antibody to the patient for a period of six months or less. Specifically, the present invention provides a method for treating or preventing preclinical AD, prodromal AD, mild AD, moderate AD, and severe AD in patients who are positive for amyloid deposits, comprising administering an induction dose of anti-N3pGlu Aβ antibody at 10-60 mg / kg for a period of six months or less. More specifically, the present invention provides a method for treating or preventing preclinical AD, prodromal AD, mild AD, moderate AD, and severe AD in patients positive for amyloid deposits, comprising administering to the patient a single induction dose of anti-N3pGlu Aβ antibody at 10-60 mg / kg. In another more specific embodiment, the present invention provides a method for treating or preventing preclinical AD, prodromal AD, mild AD, moderate AD, and severe AD in patients positive for amyloid deposits, comprising administering to the patient an induction dose of anti-N3pGlu Aβ antibody at 10-60 mg / kg every two weeks for a period of six months or less. In yet another more specific embodiment, the present invention provides a method for treating or preventing preclinical AD, prodromal AD, mild AD, moderate AD, and severe AD in patients positive for amyloid deposits, comprising administering to the patient an induction dose of anti-N3pGlu Aβ antibody once a month at 10-60 mg / kg for a period of six months or less. In preferred embodiments of the present invention for treating or preventing preclinical AD, prodromal AD, mild AD, moderate AD, and severe AD, the single, bi-weekly (every two weeks), and monthly induction doses administered to the patient are 20-40 mg / kg or 15-30 mg / kg. In preferred embodiments of the present invention, the single induction dose administered to the patient is 10 mg / kg, 15 mg / kg, 20 mg / kg, or 40 mg / kg.In an alternative preferred embodiment of the present invention, the bi-weekly and monthly induction dose administered to the patient is 10 mg / kg, 15 mg / kg, 20 mg / kg, or 40 mg / kg for a period of 6 months. In another more preferred embodiment, the anti-N3pGlu Aβ antibody is selected from Table 1. The anti-N3pGlu Aβ antibody is preferably selected from Table 1.

[0009] In another embodiment, the present invention provides a method for delaying cognitive decline in a patient diagnosed with preclinical or clinical Alzheimer's disease, comprising administering an induction dose of anti-N3pGlu Aβ antibody to the patient for a period of six months or less. More specifically, the present invention provides a method for delaying cognitive decline in a patient diagnosed with preclinical or clinical Alzheimer's disease, comprising administering an induction dose of anti-N3pGlu Aβ antibody of 10-60 mg / kg to the patient for a period of six months or less. More specifically, the present invention provides a method for delaying cognitive decline in a patient diagnosed with preclinical or clinical Alzheimer's disease, comprising administering a single induction dose of anti-N3pGlu Aβ antibody of 10-60 mg / kg to the patient. In another, more specific embodiment, the present invention provides a method for delaying cognitive decline in a patient diagnosed with preclinical or clinical Alzheimer's disease, comprising administering an induction dose of 10-60 mg / kg of anti-N3pGlu Aβ antibody to the patient every two weeks for a period of six months or less. In another, more specific embodiment, the present invention provides a method for delaying cognitive decline in a patient diagnosed with preclinical or clinical Alzheimer's disease, comprising administering an induction dose of 10-60 mg / kg of anti-N3pGlu Aβ antibody to the patient for a period of six months or less. In a preferred embodiment of the present invention for delaying cognitive decline in a patient diagnosed with preclinical or clinical Alzheimer's disease, the single, bi-weekly, and monthly induction doses administered to the patient are 20-40 mg / kg or 15-30 mg / kg. In a preferred embodiment of the present invention, the single induction dose administered to the patient is 10 mg / kg, 15 mg / kg, 20 mg / kg, or 40 mg / kg. In an alternative preferred embodiment of the present invention, the bi-weekly and monthly induction dose administered to the patient is 10 mg / kg, 15 mg / kg, 20 mg / kg, or 40 mg / kg for a period of 6 months. In another more preferred embodiment, the anti-N3pGlu Aβ antibody is selected from Table 1. The anti-N3pGlu Aβ antibody is preferably selected from Table 1.

[0010] In another embodiment, the present invention provides a method for delaying functional decline in a patient diagnosed with preclinical or clinical Alzheimer's disease, comprising administering an induction dose of anti-N3pGlu Aβ antibody to the patient for a period of six months or less. More specifically, the present invention provides a method for delaying functional decline in a patient diagnosed with preclinical or clinical Alzheimer's disease, comprising administering an induction dose of anti-N3pGlu Aβ antibody of 10-60 mg / kg to the patient for a period of six months or less. More specifically, the present invention provides a method for delaying functional decline in a patient diagnosed with preclinical or clinical Alzheimer's disease, comprising administering a single induction dose of anti-N3pGlu Aβ antibody of 10-60 mg / kg to the patient. In another, more specific embodiment, the present invention provides a method for delaying functional decline in a patient diagnosed with preclinical or clinical Alzheimer's disease, comprising administering an induction dose of 10-60 mg / kg of anti-N3pGlu Aβ antibody to the patient every two weeks for a period of six months or less. In another, more specific embodiment, the present invention provides a method for delaying functional decline in a patient diagnosed with preclinical or clinical Alzheimer's disease, comprising administering an induction dose of 10-60 mg / kg of anti-N3pGlu Aβ antibody once a month for a period of six months or less. In preferred embodiments of the present invention for delaying functional decline in a patient diagnosed with preclinical or clinical Alzheimer's disease, the single, bi-weekly, and monthly induction doses administered to the patient are 20-40 mg / kg or 15-30 mg / kg. In a preferred embodiment of the present invention, the single induction dose administered to the patient is 10 mg / kg, 15 mg / kg, 20 mg / kg, or 40 mg / kg. In an alternative preferred embodiment of the present invention, the bi-weekly and monthly induction dose administered to the patient is 10 mg / kg, 15 mg / kg, 20 mg / kg, or 40 mg / kg over a period of 6 months. The anti-N3pGlu Aβ antibody is preferably selected from Table 1.

[0011] In another embodiment, the present invention provides a method for reducing the cerebral Aβ amyloid plaque load in a patient diagnosed with preclinical or clinical Alzheimer's disease, comprising administering an induction dose of anti-N3pGlu Aβ antibody to the patient for a period of six months or less. More specifically, the present invention provides a method for reducing the cerebral Aβ amyloid plaque load in a patient diagnosed with preclinical or clinical Alzheimer's disease, comprising administering an induction dose of anti-N3pGlu Aβ antibody of 10-60 mg / kg to the patient for a period of six months or less. More specifically, the present invention provides a method for reducing the cerebral Aβ amyloid plaque load in a patient diagnosed with preclinical or clinical Alzheimer's disease, comprising administering a single induction dose of anti-N3pGlu Aβ antibody of 10-60 mg / kg to the patient. In another, more specific embodiment, the present invention provides a method for reducing the cerebral Aβ amyloid plaque load in a patient diagnosed with preclinical or clinical Alzheimer's disease, comprising administering an induction dose of anti-N3pGlu Aβ antibody at 10-60 mg / kg every two weeks for a period of six months or less. In another, more specific embodiment, the present invention provides a method for reducing the cerebral Aβ amyloid plaque load in a patient diagnosed with preclinical or clinical Alzheimer's disease, comprising administering an induction dose of anti-N3pGlu Aβ antibody at 10-60 mg / kg once monthly for a period of six months or less. In a preferred embodiment of the present invention for a method for reducing the cerebral Aβ amyloid plaque load in a patient diagnosed with preclinical or clinical Alzheimer's disease, the single, bi-weekly, and monthly induction doses administered to the patient are 20-40 mg / kg or 15-30 mg / kg. In a preferred embodiment of the present invention, the single induction dose administered to the patient is 10 mg / kg, 15 mg / kg, 20 mg / kg, or 40 mg / kg. In alternative preferred embodiments of the present invention, the bi-weekly and monthly induction dose administered to the patient is 10 mg / kg, 15 mg / kg, 20 mg / kg, or 40 mg / kg for a period of 6 months. The anti-N3pGlu Aβ antibody is preferably selected from Table 1.

[0012] In another embodiment, the present invention provides a method for preventing memory loss or cognitive impairment in clinically asymptomatic patients having low levels of Aβ1-42 in cerebrospinal fluid (CSF) and / or Aβ deposits in the brain, comprising administering an induction dose of anti-N3pGlu Aβ antibody to the patient for a period of six months or less. More specifically, the present invention provides a method for preventing memory loss or cognitive impairment in clinically asymptomatic patients having low levels of Aβ1-42 in cerebrospinal fluid (CSF) and / or Aβ deposits in the brain, comprising administering an induction dose of anti-N3pGlu Aβ antibody of 10-60 mg / kg to the patient for a period of six months or less. More specifically, the present invention provides a method for preventing memory loss or cognitive impairment in clinically asymptomatic patients having low levels of Aβ1-42 in cerebrospinal fluid (CSF) and / or Aβ deposits in the brain, comprising administering a single induction dose of anti-N3pGlu Aβ antibody of 10-60 mg / kg to the patient. In another, more specific embodiment, the present invention provides a method for preventing memory loss or cognitive impairment in clinically asymptomatic patients having low levels of Aβ1-42 in cerebrospinal fluid (CSF) and / or Aβ deposits in the brain, comprising administering an induction dose of anti-N3pGlu Aβ antibody at 10-60 mg / kg every two weeks for a period of six months or less. In another, more specific embodiment, the present invention provides a method for preventing memory loss or cognitive impairment in clinically asymptomatic patients having low levels of Aβ1-42 in cerebrospinal fluid (CSF) and / or Aβ deposits in the brain, comprising administering an induction dose of anti-N3pGlu Aβ antibody at 10-60 mg / kg once monthly for a period of six months or less. In a preferred embodiment of the present invention for a method of preventing memory loss or cognitive decline in clinically asymptomatic patients having low levels of cerebrospinal fluid (CSF) Aβ1-42 and / or brain Aβ deposits, the single, bi-weekly, and monthly induction dose administered to the patient is 20-40 mg / kg or 15-30 mg / kg. In another preferred embodiment of the present invention, the single induction dose administered to the patient is 10 mg / kg, 15 mg / kg, 20 mg / kg, or 40 mg / kg.In alternative preferred embodiments of the present invention, the bi-weekly and monthly induction dose administered to the patient is 10 mg / kg, 15 mg / kg, 20 mg / kg, or 40 mg / kg for a period of 6 months. The anti-N3pGlu Aβ antibody is preferably selected from Table 1.

[0013] In another embodiment, the present invention provides a method for treating a clinically asymptomatic patient known to have a gene mutation that causes Alzheimer's disease, comprising administering an induction dose of anti-N3pGlu Aβ antibody to the patient for a period of six months or less. Specifically, the present invention provides a method for treating a clinically asymptomatic patient known to have a gene mutation that causes Alzheimer's disease, comprising administering an induction dose of anti-N3pGlu Aβ antibody of 10-60 mg / kg to the patient for a period of six months or less. More specifically, the present invention provides a method for treating a clinically asymptomatic patient known to have a gene mutation that causes Alzheimer's disease, comprising administering a single induction dose of anti-N3pGlu Aβ antibody of 10-60 mg / kg to the patient. In yet another, more specific embodiment, the present invention provides a method for treating a clinically asymptomatic patient known to have a gene mutation that causes Alzheimer's disease, comprising administering an induction dose of anti-N3pGlu Aβ antibody of 10-60 mg / kg to the patient every two weeks for a period of six months or less. In another, more specific embodiment, the present invention provides a method for treating clinically asymptomatic patients known to have a gene mutation that causes Alzheimer's disease, comprising administering an anti-N3pGlu Aβ antibody to the patient in a monthly induction dose of 10-60 mg / kg for a period of six months or less. In the present invention, “clinically asymptomatic patients known to have a gene mutation that causes Alzheimer's disease” includes patients known to have a gene mutation that causes autosomal dominant Alzheimer's disease, or patients who are at higher risk of developing AD by possessing one or two APOE e4 alleles, including administering the pharmaceutical composition of the present invention to the above patients. In preferred embodiments of the present invention for a method for treating clinically asymptomatic patients known to have a gene mutation that causes Alzheimer's disease, the single, bi-weekly, and monthly induction doses administered to the patient are 20-40 mg / kg or 15-30 mg / kg.In another preferred embodiment of the present invention, the single induction dose administered to the patient is 10 mg / kg, 15 mg / kg, 20 mg / kg, or 40 mg / kg. In an alternative preferred embodiment of the present invention, the bi-weekly and monthly induction dose administered to the patient is 10 mg / kg, 15 mg / kg, 20 mg / kg, or 40 mg / kg over a period of 6 months. The anti-N3pGlu Aβ antibody is preferably selected from Table 1.

[0014] In further embodiments, the present invention provides a method for treating a disease characterized by Aβ deposition in the brain, comprising administering an induction dose of anti-N3pGlu Aβ antibody to a patient for a period of six months or less, wherein the Aβ deposits in the brain of a human patient are reduced by 35-100% within six months after induction dose treatment. More specifically, the present invention provides a method for treating a disease characterized by Aβ deposition, comprising administering an induction dose of anti-N3pGlu Aβ antibody of 10-60 mg / kg to a patient for a period of six months or less, wherein the Aβ deposits in the brain of a human patient are reduced by 35-100% within six months after induction dose treatment. More specifically, the present invention provides a method for treating a disease characterized by Aβ deposition in the brain of a human patient, comprising administering a single induction dose of anti-N3pGlu Aβ antibody of 10-60 mg / kg to a patient, wherein the Aβ deposits in the brain of a human patient are reduced by 35-100% within six months after induction dose treatment. In another, more specific embodiment, the present invention provides a method for treating a disease characterized by Aβ deposition in a patient's brain, comprising administering an induction dose of 10-60 mg / kg of anti-N3pGlu Aβ antibody to the patient every two weeks for a period of six months or less, wherein the Aβ deposition in the brain of a human patient is reduced by 35-100% within six months after induction dose treatment. In another, more specific embodiment, the present invention provides a method for treating a disease characterized by Aβ deposition in a patient's brain, comprising administering an induction dose of 10-60 mg / kg of anti-N3pGlu Aβ antibody once a month for a period of six months or less, wherein the Aβ deposition in the brain of a human patient is reduced by 35-100% within six months after induction dose treatment. In a preferred embodiment of the present invention, the single induction dose administered to the patient is 10 mg / kg, 15 mg / kg, 20 mg / kg, or 40 mg / kg. In alternative preferred embodiments of the present invention, the bi-weekly and monthly induction dose administered to the patient is 10 mg / kg, 15 mg / kg, 20 mg / kg, or 40 mg / kg for a period of 6 months. The anti-N3pGlu Aβ antibody is preferably selected from Table 1.

[0015] In one embodiment, the present invention provides a method for treating clinical or preclinical Alzheimer's disease, Down syndrome, and clinical or preclinical cerebral amyloid angiopathy, comprising administering an induction dose of anti-N3pGlu Aβ antibody to a patient for a period of six months or less, wherein Aβ deposits in the brain of a human patient are reduced by 35-100% within six months after induction dose treatment. Specifically, the present invention provides a method for treating clinical or preclinical Alzheimer's disease, Down syndrome, and clinical or preclinical cerebral amyloid angiopathy, comprising administering an induction dose of anti-N3pGlu Aβ antibody at 10-60 mg / kg to a patient for a period of six months or less, wherein Aβ deposits in the brain of a human patient are reduced by 35-100% within six months after induction treatment. More specifically, the present invention provides a method for treating clinical or preclinical Alzheimer's disease, Down syndrome, and clinical or preclinical cerebral amyloid angiopathy, comprising administering a patient a single induction dose of 10-60 mg / kg of anti-N3pGlu Aβ antibody, wherein Aβ deposits in the brain of a human patient are reduced by 35-100% within 6 months after induction treatment. In another more specific embodiment, the present invention provides a method for treating clinical or preclinical Alzheimer's disease, Down syndrome, and clinical or preclinical cerebral amyloid angiopathy, comprising administering a patient an induction dose of 10-60 mg / kg of anti-N3pGlu Aβ antibody every two weeks for a period of 6 months or less, wherein Aβ deposits in the brain of a human patient are reduced by 35-100% within 6 months after induction treatment. In another, more specific embodiment, the present invention provides a method for treating clinical or preclinical Alzheimer's disease, Down syndrome, and clinical or preclinical cerebral amyloid angiopathy, comprising administering an induction dose of 10-60 mg / kg of anti-N3pGlu Aβ antibody once monthly to a patient for a period of six months or less, wherein Aβ deposits in the brain of a human patient are reduced by 35-100% within six months after induction treatment. In a preferred embodiment of the present invention, the anti-N3pGlu Aβ antibody is selected from Table 1.

[0016] In one embodiment, the present invention provides a method for delaying cognitive and / or functional decline in patients diagnosed with preclinical or clinical Alzheimer's disease, comprising administering an induction dose of anti-N3pGlu Aβ antibody to the patient for a period of six months or less, wherein Aβ deposits in the brain of the human patient are reduced by 35-100% within six months after induction dose treatment. Specifically, the present invention provides a method for delaying cognitive and / or functional decline in patients diagnosed with preclinical or clinical Alzheimer's disease, comprising administering an induction dose of anti-N3pGlu Aβ antibody at 10-60 mg / kg to the patient for a period of six months or less, wherein Aβ deposits in the brain of the human patient are reduced by 35-100% within six months after induction treatment. More specifically, the present invention provides a method for delaying cognitive and / or functional decline in a patient diagnosed with preclinical or clinical Alzheimer's disease, comprising administering a single induction dose of 10-60 mg / kg of anti-N3pGlu Aβ antibody to the patient, wherein Aβ deposits in the brain of the human patient are reduced by 35-100% within 6 months after induction treatment. In another more specific embodiment, the present invention provides a method for delaying cognitive and / or functional decline in a patient diagnosed with preclinical or clinical Alzheimer's disease, comprising administering an induction dose of 10-60 mg / kg of anti-N3pGlu Aβ antibody to the patient every two weeks for a period of 6 months or less, wherein Aβ deposits in the brain of the human patient are reduced by 35-100% within 6 months after induction treatment. In another, more specific embodiment, the present invention provides a method for delaying cognitive and / or functional decline in a patient diagnosed with preclinical or clinical Alzheimer's disease, comprising administering an induction dose of 10–60 mg / kg of anti-N3pGlu Aβ antibody once monthly to the patient for a period of six months or less, wherein Aβ deposits in the brain of the human patient are reduced by 35–100% within six months after induction treatment. In a preferred embodiment of the present invention, the single induction dose administered to the patient is 10 mg / kg, 15 mg / kg, 20 mg / kg, or 40 mg / kg.In alternative preferred embodiments of the present invention, the bi-weekly and monthly induction dose administered to the patient is 10 mg / kg, 15 mg / kg, 20 mg / kg, or 40 mg / kg for a period of 6 months. The anti-N3pGlu Aβ antibody is preferably selected from Table 1.

[0017] In one embodiment, the present invention provides a method for treating clinical or preclinical Alzheimer's disease, Down syndrome, and clinical or preclinical CAA with an anti-N3pGlu Aβ antibody for a period of 6 months or less, wherein Aβ deposits in the brain of a human patient are reduced by 35-100% within 6 months after induction treatment and maintained in a reduced state for a period of 2-10 years after treatment. More preferably, 2-5 years. Even more preferably, 5-10 years. Specifically, the present invention provides a method for treating clinical or preclinical Alzheimer's disease, Down syndrome, and clinical or preclinical cerebral amyloid angiopathy, comprising administering an induction dose of 10-60 mg / kg of anti-N3pGlu Aβ antibody to a patient for a period of 6 months or less, wherein Aβ deposits in the brain of a human patient are reduced by 35-100% within 6 months after induction treatment and maintained in a reduced state for a period of 2-10 years after treatment. More preferably, 2-5 years. Even more preferably, 5-10 years. More specifically, the present invention provides a method for treating clinical or preclinical Alzheimer's disease, Down syndrome, and clinical or preclinical cerebral amyloid angiopathy, comprising administering a patient a single induction dose of 10-60 mg / kg of anti-N3pGlu Aβ antibody, wherein Aβ deposits in the brain of a human patient are reduced by 35-100% within 6 months after induction treatment, and the reduced state is maintained for a period of 1-10 years after treatment. More preferably, for 2-5 years. Even more preferably, for 5-10 years. In another more specific embodiment, the present invention provides a method for treating clinical or preclinical Alzheimer's disease, Down syndrome, and clinical or preclinical cerebral amyloid angiopathy, comprising administering a patient a single induction dose of 10-60 mg / kg of anti-N3pGlu Aβ antibody every two weeks for a period of 6 months or less, wherein Aβ deposits in the brain of a human patient are reduced by 35-100% within 6 months after induction treatment, and the reduced state is maintained for a period of 2-10 years after treatment. More preferably, for 2-5 years. Even more preferably, 5 to 10 years.In another, more specific embodiment, the present invention provides a method for treating clinical or preclinical Alzheimer's disease, Down syndrome, and clinical or preclinical cerebral amyloid angiopathy, comprising administering an anti-N3pGlu Aβ antibody to a patient in a monthly induction dose of 10-60 mg / kg for a period of 6 months or less, wherein Aβ deposits in the brain of a human patient are reduced by 35-100% within 6 months after induction treatment and maintained in a reduced state for a period of 2-10 years after treatment, more preferably 2-5 years, and even more preferably 5-10 years. In a preferred embodiment of the present invention, the single induction dose administered to the patient is 10 mg / kg, 15 mg / kg, 20 mg / kg, or 40 mg / kg. In an alternative preferred embodiment of the present invention, the bi-weekly and monthly induction doses administered to the patient are 10 mg / kg, 15 mg / kg, 20 mg / kg, or 40 mg / kg for a period of 6 months. The anti-N3pGlu Aβ antibody is preferably selected from Table 1.

[0018] The present invention also provides a method for treating a disease characterized by Aβ deposition in the brain, comprising administering an induction dose of anti-N3pGlu Aβ antibody to a patient for a period of six months or less, followed by maintenance doses of anti-N3pGlu Aβ antibody every 12, 3, 5, or 10 years after the completion of induction therapy. Specifically, the present invention provides a method for treating a disease characterized by Aβ deposition in the brain of a human patient, comprising administering a single induction dose of anti-N3pGlu Aβ antibody of 10-60 mg / kg to a patient positive for amyloid deposition, followed by maintenance doses of anti-N3pGlu Aβ antibody every 1, 2, 3, 5, or 10 years after the completion of induction therapy. In another, more specific embodiment, the present invention provides a method for treating a disease characterized by Aβ deposition in the brain of a patient who is positive for amyloid deposits, comprising administering an induction dose of 10-60 mg / kg of anti-N3pGlu Aβ antibody to the patient every two weeks for a period of six months or less, followed by maintenance doses of anti-N3pGlu Aβ antibody every 1, 2, 3, 5, or 10 years after the completion of induction therapy. In another, more specific embodiment, the present invention provides a method for treating a disease characterized by Aβ deposition in the brain of a patient who is positive for amyloid deposits, comprising administering a single induction dose of 10-60 mg / kg of anti-N3pGlu Aβ antibody to the patient for a period of six months or less, followed by maintenance doses of anti-N3pGlu Aβ antibody every 1, 2, 3, 5, or 10 years after the completion of induction therapy. In one particular embodiment, the maintenance dose of Aβ antibody is given annually. In another particular embodiment, the maintenance dose of Aβ antibody is given every two years. In another specific embodiment, a maintenance dose of Aβ antibody is administered every 3 years. In another specific embodiment, a maintenance dose of Aβ antibody is administered every 5 years. In another specific embodiment, a maintenance dose of Aβ antibody is administered every 10 years. In another specific embodiment, a maintenance dose of Aβ antibody is administered every 2 to 5 years. In another specific embodiment, a maintenance dose of Aβ antibody is administered every 5 to 10 years. In one embodiment of the present invention, the same anti-N3pGlu Aβ antibody is used for both the induction and maintenance doses. In another embodiment of the present invention, different anti-N3pGlu antibodies are used for both the induction and maintenance doses.In a more specific embodiment of the invention, the anti-N3pGlu Aβ antibody administered in induction and maintenance doses is selected from Table 1.

[0019] In one embodiment, the present invention also provides a method for treating a disease characterized by Aβ deposition in the brain, comprising administering to a patient an induction dose of anti-N3pGlu Aβ antibody concurrently, separately, or in succession with an effective amount of a BACE inhibitor for a period of six months or less. In a specific embodiment, the present invention provides a method for treating a disease characterized by Aβ deposition in the brain, comprising administering to a patient a single induction dose of 10-60 mg / kg of anti-N3pGlu Aβ antibody concurrently, separately, or in succession with an effective amount of a BACE inhibitor. In another specific embodiment, the present invention provides a method for treating a disease characterized by Aβ deposition in the brain, comprising administering to a patient an induction dose of 10-60 mg / kg of anti-N3pGlu Aβ antibody every two weeks for a period of six months or less concurrently, separately, or in succession with an effective amount of a BACE inhibitor. In another specific embodiment, the present invention provides a method for treating a disease characterized by Aβ deposition in the brain, comprising administering to a patient an induction dose of 10–60 mg / kg of anti-N3pGlu Aβ antibody once monthly for a period of six months or less, concurrently, separately, or in sequential combination with an effective amount of a BACE inhibitor. In another preferred embodiment of the present invention, the single induction dose administered to the patient is 10 mg / kg, 15 mg / kg, 20 mg / kg, or 40 mg / kg. In an alternative preferred embodiment of the present invention, the bi-weekly and once monthly induction doses administered to the patient are 10 mg / kg, 15 mg / kg, 20 mg / kg, or 40 mg / kg for a period of six months.

[0020] In a more specific embodiment of the present invention, the anti-N3pGlu Aβ antibody is preferably selected from Table 1, and the BACE inhibitor is a) Formula [ka] A compound of, A compound also known as N-[3-[(4aR,7aS)-2-amino-6-(5-fluoropyrimidin-2-yl)-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiadiazin-7a-yl]-4-fluorophenyl]-5-methoxypyrazine-2-carboxamide, or a pharmaceutically acceptable salt thereof, b) N-[3-[(4aR,7aS)-2-amino-6-(5-fluoropyrimidin-2-yl)-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiadiazin-7a-yl]-4-fluorophenyl]-5-methoxypyrazine-2-carboxamide, c) 2 N-[3-[(4aR,7aS)-2-amino-6-(5-fluoropyrimidin-2-yl)-4a,5,6,7-tetrahydropyrrolo[3,4-d][1,3]thiadiazin-7a(4H)-yl]-4-fluorophenyl]-5-methoxypyrazine-2-carboxamide, and d) A compound of the formula

Chemical formula

[0021] In another more specific embodiment of the present invention, the anti-N3pGlu Aβ antibody is preferably B12L, and the BACE inhibitor is a) A compound of the formula

Chemical formula

[0022] In one embodiment, the present invention also provides a method for treating a disease characterized by Aβ deposition in the brain, comprising administering to a patient a single induction dose of anti-N3pGlu Aβ antibody for a period of six months or less, concurrently, separately, or in sequential combination with an effective amount of Aβ antibody. In a specific embodiment, the present invention also provides a method for treating a disease characterized by Aβ deposition in the brain, comprising administering to a patient a single, bi-weekly, or monthly induction dose of anti-N3pGlu Aβ antibody at a dose of 10-60 mg / kg for a period of six months or less, concurrently, separately, or in sequential combination with an effective amount of Aβ antibody, A) LC (Sequence ID 65) and HC (Sequence ID 66) (solanezumab), B) LC of SEQ ID NO: 61 and HC of SEQ ID NO: 62 (crenezumab), C) LC (aducanumab) of sequence number 57 and HC (aducanumab) of sequence number 58, D) LC of sequence number 63 and HC of sequence number 64 (BAN2401), and E) A method is provided comprising an amino acid light chain (LC) and an amino acid heavy chain (HC) selected from the group consisting of LC of SEQ ID NO: 59 and HC of SEQ ID NO: 60 (gantenerumab).

[0023] In preferred embodiments of the present invention, the single, bi-weekly, and monthly induction doses administered to the patient are 10 mg / kg, 15 mg / kg, 20 mg / kg, or 40 mg / kg. The anti-N3pGlu Aβ antibody is preferably selected from Table 1.

[0024] In one embodiment, the present invention also provides a method for treating a disease characterized by Aβ deposition in the brain, comprising administering to a patient an induction dose of 10-60 mg / kg of anti-N3pGlu Aβ antibody at a single, bi-weekly, or monthly dose for a period of six months or less, concurrently, separately, or in sequential combination with an effective amount of 20kD pegylated anti-Aβ Fab antibody, wherein the anti-Aβ Fab comprises the amino acid light chain variable region of SEQ ID NO: 55 and the amino acid heavy chain variable region of SEQ ID NO: 56. In a preferred embodiment of the present invention, the single, bi-weekly, and monthly induction doses administered to the patient are 10 mg / kg, 15 mg / kg, 20 mg / kg, or 40 mg / kg. The anti-N3pGlu Aβ antibody is preferably selected from Table 1.

[0025] In another embodiment, the present invention also provides a method for treating a disease characterized by Aβ deposition in the brain, comprising administering to a patient an induction dose of 10-60 mg / kg of anti-N3pGlu Aβ antibody, either concurrently, separately, or in succession, with an effective amount of a symptomatic treatment agent for treating Alzheimer's disease for a period of six months or less. The symptomatic treatment agent can be selected from cholinesterase inhibitors (ChEIs) and / or partial N-methyl-D-aspartate (NMDA) antagonists. In a preferred embodiment, the agent is a ChEI. In another preferred embodiment, the agent is an NMDA antagonist or a combination agent comprising a ChEI and an NMDA antagonist. In a more preferred embodiment of the present invention, the single induction dose administered to the patient is 10 mg / kg, 15 mg / kg, 20 mg / kg, or 40 mg / kg. In an alternative, more preferred embodiment of the present invention, the bi-weekly and monthly induction dose administered to the patient is 10 mg / kg, 15 mg / kg, 20 mg / kg, or 40 mg / kg for a period of 6 months. The anti-N3pGlu Aβ antibody is preferably selected from Table 1.

[0026] In another embodiment, the present invention provides an anti-N3pGlu Aβ antibody for use in the treatment of clinical or preclinical Alzheimer's disease, Down syndrome, and clinical or preclinical cerebral amyloid angiopathy, which is administered to a patient at a dose of 10-60 mg / kg for a period of 6 months or less. Specifically, the present invention provides an anti-N3pGlu Aβ antibody for use in the treatment of clinical or preclinical Alzheimer's disease, Down syndrome, and clinical or preclinical cerebral amyloid angiopathy, which is administered to a patient as a single induction dose of 10-60 mg / kg of anti-N3pGlu Aβ antibody. In yet another, more specific embodiment, the present invention provides an anti-N3pGlu Aβ antibody for use in the treatment of clinical or preclinical Alzheimer's disease, Down syndrome, and clinical or preclinical cerebral amyloid angiopathy, which is administered to a patient as an induction dose of 10-60 mg / kg of anti-N3pGlu Aβ antibody every two weeks for a period of 6 months or less. In another, more specific embodiment, the present invention provides an anti-N3pGlu Aβ antibody for use in the treatment of clinical or preclinical Alzheimer's disease, Down syndrome, and clinical or preclinical cerebral amyloid angiopathy, which is administered to a patient as an induction dose of 10-60 mg / kg once a month for a period of six months or less. In a preferred embodiment of the present invention for use in the treatment or prevention of clinical or preclinical Alzheimer's disease, Down syndrome, and clinical or preclinical CAA, the single, bi-weekly, and monthly induction doses administered to the patient are 20-40 mg / kg or 15-30 mg / kg. In a preferred embodiment of the present invention, the single induction dose administered to the patient is 10 mg / kg, 15 mg / kg, 20 mg / kg, or 40 mg / kg. In an alternative preferred embodiment of the present invention, the bi-weekly and monthly induction doses administered to the patient are 10 mg / kg, 15 mg / kg, 20 mg / kg, or 40 mg / kg for a period of six months. More preferably, the anti-N3pGlu Aβ antibody is selected from Table 1.

[0027] In another embodiment, the present invention provides an anti-N3pGlu Aβ antibody for use in the treatment of prodromal AD, mild AD, moderate AD, or severe AD, which is administered to the patient at a dose of 10-60 mg / kg for a period of 6 months or less. Specifically, the present invention provides an anti-N3pGlu Aβ antibody for use in the treatment of prodromal AD, mild AD, moderate AD, or severe AD, which is administered to the patient as a single induction dose of 10-60 mg / kg of anti-N3pGlu Aβ antibody. In yet another, more specific embodiment, the present invention provides an anti-N3pGlu Aβ antibody for use in the treatment of prodromal AD, mild AD, moderate AD, or severe AD, which is administered to the patient as an induction dose of 10-60 mg / kg of anti-N3pGlu Aβ antibody every two weeks for a period of 6 months or less. In another, more specific embodiment, the present invention provides an anti-N3pGlu Aβ antibody for use in the treatment of prodromal AD, mild AD, moderate AD, or severe AD, which is administered to a patient as an induction dose of 10-60 mg / kg once a month for a period of six months or less. In a preferred embodiment of the present invention for use in the treatment of prodromal AD, mild AD, moderate AD, or severe AD, the single, bi-weekly, and monthly induction doses administered to the patient are 20-40 mg / kg or 15-30 mg / kg. In a preferred embodiment of the present invention, the single induction dose administered to the patient is 10 mg / kg, 15 mg / kg, 20 mg / kg, or 40 mg / kg. In an alternative preferred embodiment of the present invention, the bi-weekly and monthly induction doses administered to the patient are 10 mg / kg, 15 mg / kg, 20 mg / kg, or 40 mg / kg for a period of six months. More preferably, the anti-N3pGlu Aβ antibody is selected from Table 1.

[0028] In another embodiment, the present invention provides an anti-N3pGlu Aβ antibody for use in the prevention or delay of cognitive or functional decline in patients diagnosed with a condition selected from clinical or preclinical Alzheimer's disease, Down syndrome, and clinical or preclinical cerebral amyloid angiopathy, wherein the patient is administered an anti-N3pGlu Aβ antibody at a dose of 10-60 mg / kg for a period of 6 months or less. Specifically, the present invention provides an anti-N3pGlu Aβ antibody for use in the prevention or delay of cognitive decline in patients diagnosed with a condition selected from clinical or preclinical Alzheimer's disease, Down syndrome, and clinical or preclinical cerebral amyloid angiopathy, wherein the patient is administered an anti-N3pGlu Aβ antibody as a single induction dose of 10-60 mg / kg. In another, more specific embodiment, the present invention provides an anti-N3pGlu Aβ antibody for use in the prevention or delay of cognitive decline in patients diagnosed with a condition selected from clinical or preclinical Alzheimer's disease, Down syndrome, and clinical or preclinical cerebral amyloid angiopathy, moderate AD, or severe AD, wherein the patient is administered an induction dose of 10-60 mg / kg of anti-N3pGlu Aβ antibody every two weeks for a period of six months or less. In another, more specific embodiment, the present invention provides an anti-N3pGlu Aβ antibody for use in the prevention or delay of cognitive decline in patients diagnosed with a condition selected from clinical or preclinical Alzheimer's disease, Down syndrome, and clinical or preclinical cerebral amyloid angiopathy, wherein the patient is administered an induction dose of 10-60 mg / kg every month for a period of six months or less. In preferred embodiments of the present invention for use in the prevention or delay of cognitive decline in patients diagnosed with a condition selected from clinical or preclinical Alzheimer's disease, Down syndrome, and clinical or preclinical cerebral amyloid angiopathy, the single, bi-weekly, and monthly induction dose administered to the patient is 20-40 mg / kg or 15-30 mg / kg. In preferred embodiments of the present invention, the single induction dose administered to the patient is 10 mg / kg, 15 mg / kg, 20 mg / kg, or 40 mg / kg.In alternative preferred embodiments of the present invention, the bi-weekly and monthly induction dose administered to the patient is 10 mg / kg, 15 mg / kg, 20 mg / kg, or 40 mg / kg for a period of 6 months. More preferably, the anti-N3pGlu Aβ antibody is selected from Table 1.

[0029] In another embodiment, the present invention provides an anti-N3pGlu Aβ antibody for use in reducing the Aβ amyloid plaque load in the brains of patients diagnosed with preclinical or clinical Alzheimer's disease, Down syndrome, and clinical or preclinical cerebral amyloid angiopathy, which is administered to the patient at a dose of 10-60 mg / kg for a period of 6 months or less. Specifically, the present invention provides an anti-N3pGlu Aβ antibody for use in reducing the Aβ amyloid plaque load in the brains of patients diagnosed with preclinical or clinical Alzheimer's disease, Down syndrome, and clinical or preclinical cerebral amyloid angiopathy, which is administered to the patient as a single induction dose of 10-60 mg / kg of anti-N3pGlu Aβ antibody. In another, more specific embodiment, the present invention provides an anti-N3pGlu Aβ antibody for use in reducing the Aβ amyloid plaque load in the brains of patients diagnosed with preclinical or clinical Alzheimer's disease, Down syndrome, and clinical or preclinical cerebral amyloid angiopathy, wherein the patient is administered an introduction dose of 10-60 mg / kg of anti-N3pGlu Aβ antibody every two weeks for a period of six months or less. In another, more specific embodiment, the present invention provides an anti-N3pGlu Aβ antibody for use in reducing the Aβ amyloid plaque load in the brains of patients diagnosed with preclinical or clinical Alzheimer's disease, Down syndrome, and clinical or preclinical cerebral amyloid angiopathy, wherein the patient is administered an introduction dose of 10-60 mg / kg every month for a period of six months or less. In a preferred embodiment of the present invention for use in reducing the Aβ amyloid plaque load in the brains of patients diagnosed with preclinical or clinical Alzheimer's disease, Down syndrome, and clinical or preclinical cerebral amyloid angiopathy, the single, bi-weekly, and monthly induction dose administered to the patient is 20–40 mg / kg or 15–30 mg / kg. In another preferred embodiment of the present invention, the single induction dose administered to the patient is 10 mg / kg, 15 mg / kg, 20 mg / kg, or 40 mg / kg.In alternative preferred embodiments of the present invention, the bi-weekly and monthly induction dose administered to the patient is 10 mg / kg, 15 mg / kg, 20 mg / kg, or 40 mg / kg for a period of 6 months. More preferably, the anti-N3pGlu Aβ antibody is selected from Table 1.

[0030] In another embodiment, the present invention provides an anti-N3pGlu Aβ antibody for use in the treatment of clinically asymptomatic patients known to have a gene mutation that causes Alzheimer's disease, which is administered to the patient at a dose of 10-60 mg / kg for a period of 6 months or less. Specifically, the present invention provides an anti-N3pGlu Aβ antibody for use in the treatment of asymptomatic patients known to have a gene mutation that causes Alzheimer's disease, which is administered to the patient as a single induction dose of 10-60 mg / kg of anti-N3pGlu Aβ antibody. In yet another, more specific embodiment, the present invention provides an anti-N3pGlu Aβ antibody for use in the treatment of asymptomatic patients known to have a gene mutation that causes Alzheimer's disease, which is administered to the patient as an induction dose of 10-60 mg / kg of anti-N3pGlu Aβ antibody every two weeks for a period of 6 months or less. In another, more specific embodiment, the present invention provides an anti-N3pGlu Aβ antibody for use in the treatment of asymptomatic patients known to have a gene mutation that causes Alzheimer's disease, which is administered to the patient as an induction dose of 10-60 mg / kg once a month for a period of six months or less. In a preferred embodiment of the present invention for use in the treatment of asymptomatic patients known to have a gene mutation that causes Alzheimer's disease, the single, bi-weekly, and monthly induction doses administered to the patient are 20-40 mg / kg or 15-30 mg / kg. In a preferred embodiment of the present invention, the single induction dose administered to the patient is 10 mg / kg, 15 mg / kg, 20 mg / kg, or 40 mg / kg. In an alternative preferred embodiment of the present invention, the bi-weekly and monthly induction doses administered to the patient are 10 mg / kg, 15 mg / kg, 20 mg / kg, or 40 mg / kg for a period of six months. The anti-N3pGlu Aβ antibody is selected from Table 1.

[0031] In another embodiment, the present invention provides the use of an anti-N3pGlu Aβ antibody for the manufacture of a drug for the treatment of clinical or preclinical Alzheimer's disease, Down syndrome, and clinical or preclinical cerebral amyloid angiopathy, wherein the drug comprises an induction dose of 10-60 mg / kg of anti-N3pGlu Aβ antibody administered to a patient for a period of six months or less. Specifically, the present invention provides the use of an anti-N3pGlu Aβ antibody for the manufacture of a drug for the treatment of clinical or preclinical Alzheimer's disease, Down syndrome, and clinical or preclinical cerebral amyloid angiopathy, wherein the drug comprises a single induction dose of 10-60 mg / kg of anti-N3pGlu Aβ antibody administered to a patient. In another, more specific embodiment, the present invention provides the use of an anti-N3pGlu Aβ antibody for the manufacture of a drug for the treatment of clinical or preclinical Alzheimer's disease, Down syndrome, and clinical or preclinical cerebral amyloid angiopathy, wherein the drug comprises an induction dose of 10-60 mg / kg of anti-N3pGlu Aβ antibody administered to a patient every two weeks for a period of six months or less. In another, more specific embodiment, the present invention provides the use of an anti-N3pGlu Aβ antibody for the manufacture of a drug for the treatment of clinical or preclinical Alzheimer's disease, Down syndrome, and clinical or preclinical cerebral amyloid angiopathy, wherein the drug comprises an induction dose of 10-60 mg / kg of anti-N3pGlu Aβ antibody administered to a patient monthly for a period of six months or less. In a preferred embodiment of the present invention, the single, bi-weekly, and monthly induction doses administered to the patient are 20-40 mg / kg or 15-30 mg / kg. In another preferred embodiment of the present invention, the single induction dose administered to the patient is 10 mg / kg, 15 mg / kg, 20 mg / kg, or 40 mg / kg. In an alternative preferred embodiment of the present invention, the bi-weekly and monthly induction doses administered to the patient are 10 mg / kg, 15 mg / kg, 20 mg / kg, or 40 mg / kg for a period of six months. More preferably, the anti-N3pGlu Aβ antibody is selected from Table 1.

[0032] In another embodiment, the present invention provides the use of an anti-N3pGlu Aβ antibody for the manufacture of a drug for the treatment of progenitor AD, mild AD, moderate AD, or severe AD, wherein the drug comprises an induction dose of 10-60 mg / kg of anti-N3pGlu Aβ antibody administered to a patient for a period of six months or less. Specifically, the present invention provides the use of an anti-N3pGlu Aβ antibody for the manufacture of a drug for the treatment of progenitor AD, mild AD, moderate AD, or severe AD, wherein the drug comprises a single induction dose of 10-60 mg / kg of anti-N3pGlu Aβ antibody administered to a patient for a period of six months or less. In yet another, more specific embodiment, the present invention provides the use of an anti-N3pGlu Aβ antibody for the manufacture of a drug for the treatment of progenitor AD, mild AD, moderate AD, or severe AD, wherein the drug comprises an induction dose of 10-60 mg / kg of anti-N3pGlu Aβ antibody administered to a patient every two weeks for a period of six months or less. In another, more specific embodiment, the present invention provides the use of an anti-N3pGlu Aβ antibody for the manufacture of a drug for the treatment of prodromal AD, mild AD, moderate AD, or severe AD, wherein the drug comprises an induction dose of 10-60 mg / kg of anti-N3pGlu Aβ antibody administered to a patient monthly for a period of up to 6 months. In a preferred embodiment of the present invention, the single, bi-weekly, and monthly induction doses administered to the patient are 20-40 mg / kg or 15-30 mg / kg. In another preferred embodiment of the present invention, the single induction dose administered to the patient is 10 mg / kg, 15 mg / kg, 20 mg / kg, or 40 mg / kg. In an alternative preferred embodiment of the present invention, the bi-weekly and monthly induction doses administered to the patient are 10 mg / kg, 15 mg / kg, 20 mg / kg, or 40 mg / kg for a period of 6 months. More preferably, the anti-N3pGlu Aβ antibody is selected from Table 1.

[0033] In another embodiment, the present invention provides the use of an anti-N3pGlu Aβ antibody for the manufacture of a drug for the prevention or delay of cognitive or functional decline in patients diagnosed with a condition selected from clinical or preclinical Alzheimer's disease, Down syndrome, and clinical or preclinical cerebral amyloid angiopathy, wherein the drug comprises an induction dose of 10-60 mg / kg of anti-N3pGlu Aβ antibody administered to the patient for a period of six months or less. Specifically, the present invention provides the use of an anti-N3pGlu Aβ antibody for the manufacture of a drug for the prevention or delay of cognitive decline in patients diagnosed with a condition selected from clinical or preclinical Alzheimer's disease, Down syndrome, and clinical or preclinical cerebral amyloid angiopathy, wherein the drug comprises a single induction dose of 10-60 mg / kg of anti-N3pGlu Aβ antibody administered to the patient for a period of six months or less. In another, more specific embodiment, the present invention provides the use of an anti-N3pGlu Aβ antibody for the prevention or delay of cognitive decline in patients diagnosed with a condition selected from clinical or preclinical Alzheimer's disease, Down syndrome, and clinical or preclinical cerebral amyloid angiopathy, wherein the agent comprises an induction dose of 10-60 mg / kg of anti-N3pGlu Aβ antibody administered to the patient every two weeks for a period of six months or less. In another, more specific embodiment, the present invention provides the use of an anti-N3pGlu Aβ antibody for the prevention or delay of cognitive decline in patients diagnosed with a condition selected from clinical or preclinical Alzheimer's disease, Down syndrome, and clinical or preclinical cerebral amyloid angiopathy, wherein the agent comprises a single induction dose of 10-60 mg / kg of anti-N3pGlu Aβ antibody administered to the patient every month for a period of six months or less. In a preferred embodiment of the present invention, the single, bi-weekly, and monthly induction doses administered to the patient are 20-40 mg / kg or 15-30 mg / kg. In another preferred embodiment of the present invention, the single induction dose administered to the patient is 10 mg / kg, 15 mg / kg, 20 mg / kg, or 40 mg / kg. In an alternative preferred embodiment of the present invention, the bi-weekly and monthly induction dose administered to the patient is 10 mg / kg, 15 mg / kg, 20 mg / kg, or 40 mg / kg over a period of 6 months.More preferably, the anti-N3pGlu Aβ antibody is selected from Table 1.

[0034] In another embodiment, the present invention provides the use of an anti-N3pGlu Aβ antibody for the manufacture of a drug for treating asymptomatic patients known to have a gene mutation that causes Alzheimer's disease, wherein the drug is administered to the patient at a dose of 10-60 mg / kg of anti-N3pGlu Aβ antibody for a period of six months or less. Specifically, the present invention provides the use of an anti-N3pGlu Aβ antibody for the manufacture of a drug for treating asymptomatic patients known to have a gene mutation that causes Alzheimer's disease, wherein the drug comprises a single induction dose of 10-60 mg / kg of anti-N3pGlu Aβ antibody administered to the patient for a period of six months or less. In yet another, more specific embodiment, the present invention provides the use of an anti-N3pGlu Aβ antibody for treating asymptomatic patients known to have a gene mutation that causes Alzheimer's disease, wherein the drug comprises an induction dose of 10-60 mg / kg of anti-N3pGlu Aβ antibody administered to the patient every two weeks for a period of six months or less. In another, more specific embodiment, the present invention provides the use of an anti-N3pGlu Aβ antibody for treating asymptomatic patients known to have a gene mutation causing Alzheimer's disease, wherein the agent comprises an induction dose of 10-60 mg / kg of anti-N3pGlu Aβ antibody administered to the patient monthly for a period of up to six months. In a preferred embodiment of the present invention, the single, bi-weekly, and monthly induction doses administered to the patient are 20-40 mg / kg or 15-30 mg / kg. In another preferred embodiment of the present invention, the single induction dose administered to the patient is 10 mg / kg, 15 mg / kg, 20 mg / kg, or 40 mg / kg. In an alternative preferred embodiment of the present invention, the bi-weekly and monthly induction doses administered to the patient are 10 mg / kg, 15 mg / kg, 20 mg / kg, or 40 mg / kg for a period of six months. More preferably, the anti-N3pGlu Aβ antibody is selected from Table 1.

[0035] In another embodiment, the present invention provides the use of an anti-N3pGlu Aβ antibody for the manufacture of a drug for reducing Aβ deposits in a patient's brain, wherein the drug comprises an induction dose of 10-60 mg / kg of anti-N3pGlu Aβ antibody administered to the patient for a period of 6 months or less, and the Aβ deposits in the patient's brain are reduced by 35-100% within 6 months after induction dose treatment. Specifically, the present invention provides the use of an anti-N3pGlu Aβ antibody for the manufacture of a drug for reducing Aβ deposits in a patient's brain, wherein the drug comprises a single induction dose of 10-60 mg / kg of anti-N3pGlu Aβ antibody administered to the patient for a period of 6 months or less, and the Aβ deposits in the patient's brain are reduced by 35-100% within 6 months after induction dose treatment. In another, more specific embodiment, the present invention provides the use of an anti-N3pGlu Aβ antibody for the manufacture of a drug for reducing Aβ deposits in a patient's brain, wherein the drug comprises an induction dose of 10-60 mg / kg of anti-N3pGlu Aβ antibody administered to the patient every two weeks for a period of up to six months, and the Aβ deposits in the patient's brain are reduced by 35-100% within six months after induction dose treatment. In another, more specific embodiment, the present invention provides the use of an anti-N3pGlu Aβ antibody for the manufacture of a drug for reducing Aβ deposits in a patient's brain, wherein the drug comprises an induction dose of 10-60 mg / kg of anti-N3pGlu Aβ antibody administered to the patient every month for a period of up to six months, and the Aβ deposits in the patient's brain are reduced by 35-100% within six months after induction dose treatment. In a preferred embodiment of the present invention, the single, bi-weekly, and monthly induction doses administered to the patient are 20-40 mg / kg or 15-30 mg / kg. In another preferred embodiment of the present invention, the single induction dose administered to the patient is 10 mg / kg, 15 mg / kg, 20 mg / kg, or 40 mg / kg. In an alternative preferred embodiment of the present invention, the bi-weekly and monthly induction dose administered to the patient is 10 mg / kg, 15 mg / kg, 20 mg / kg, or 40 mg / kg over a period of 6 months. More preferably, the anti-N3pGlu Aβ antibody is selected from Table 1.

[0036] As used herein, "anti-N3pglu Aβ antibody" refers to Aβ 1-40 or Aβ 1-42 This refers to an antibody that preferentially binds to N3pGlu Aβ. The sequence of N3pGlu Aβ is the amino acid sequence of SEQ ID NO: 31. In certain embodiments, the anti-N3pGlu Aβ antibody includes the amino acid sequences listed in Table 1. More specifically, the anti-N3pGlu Aβ antibody of the present invention includes a light chain variable region (LCVR) and a heavy chain variable region (HCVR), wherein the LCVR includes LCDR1, LCDR2, and LCDR3, and the HCVR includes HCDR1, HCDR2, and HCDR3, which are selected from the group consisting of the following: a) LCDR1 is sequence number 17, LCDR2 is sequence number 18, LCDR3 is sequence number 19, HCDR1 is sequence number 20, HCDR2 is sequence number 22, HCDR3 is sequence number 23, b) LCDR1 is sequence number 17, LCDR2 is sequence number 18, LCDR3 is sequence number 19, HCDR1 is sequence number 21, HCDR2 is sequence number 22, HCDR3 is sequence number 24, c) LCDR1 is sequence number 17, LCDR2 is sequence number 18, LCDR3 is sequence number 19, HCDR1 is sequence number 36, HCDR2 is sequence number 22, HCDR3 is sequence number 37, d) LCDR1 is sequence number 4, LCDR2 is sequence number 6, LCDR3 is sequence number 7, HCDR1 is sequence number 1, HCDR2 is sequence number 2, HCDR3 is sequence number 3, e) LCDR1 is sequence number 4, LCDR2 is sequence number 5, LCDR3 is sequence number 7, HCDR1 is sequence number 1, HCDR2 is sequence number 2, and HCDR3 is sequence number 3.

[0037] In other embodiments, the anti-N3pGlu Aβ antibody of the present invention comprises a light chain variable region (LCVR) and a heavy chain variable region (HCVR), wherein the LCVR and HCVR are a) LCVR of sequence number 25 and HCVR of sequence number 26, b) LCVR of sequence number 25 and HCVR of sequence number 27, c) LCVR of SEQ ID NO: 32 and HCVR of SEQ ID NO: 34 d) LCVR of SEQ ID NO: 9 and HCVR of SEQ ID NO: 8, and e) Selected from the group consisting of LCVR of sequence number 10 and HCVR of sequence number 8.

[0038] In further embodiments, the anti-N3pGlu Aβ antibody comprises a light chain (LC) and a heavy chain (HC), wherein the LC and HC are a) LC of SEQ ID NO: 28 and HC of SEQ ID NO: 29, b) LC of SEQ ID NO: 28 and HC of SEQ ID NO: 30 c) LC of SEQ ID NO: 33 and HC of SEQ ID NO: 35 d) LC of SEQ ID NO: 12 and HC of SEQ ID NO: 11, and e) Selected from the group consisting of LC of sequence number 13 and HC of sequence number 11.

[0039] In other embodiments, the anti-N3pGlu Aβ antibody comprises two light chains (LCs) and two heavy chains (HCs), where each LC and each HC is a) LC of SEQ ID NO: 28 and HC of SEQ ID NO: 29, b) LC of SEQ ID NO: 28 and HC of SEQ ID NO: 30 c) LC of SEQ ID NO: 33 and HC of SEQ ID NO: 35 d) LC of SEQ ID NO: 12 and HC of SEQ ID NO: 11, and e) Selected from the group consisting of LC of sequence number 13 and HC of sequence number 11.

[0040] In some embodiments, the anti-N3pGlu Aβ antibody comprises antibody I having a light chain (LC) and a heavy chain (HC) of SEQ ID NO: 12 and SEQ ID NO: 11, respectively. Antibody I further comprises a light chain variable region (LCVR) and a heavy chain variable region (HCVR) of SEQ ID NO: 9 and SEQ ID NO: 8, respectively. The HCVR of antibody I further comprises HCDR1 of SEQ ID NO: 1, HCDR2 of SEQ ID NO: 2, and HCDR3 of SEQ ID NO: 3. The LCVR of antibody I further comprises LCDR1 of SEQ ID NO: 4, LCDR2 of SEQ ID NO: 6, and LCDR3 of SEQ ID NO: 7, respectively.

[0041] In some embodiments, the anti-N3pGlu Aβ antibody comprises antibody II having a light chain (LC) and a heavy chain (HC) of SEQ ID NO: 13 and SEQ ID NO: 11, respectively. Antibody II further comprises a light chain variable region (LCVR) and a heavy chain variable region (HCVR) of SEQ ID NO: 10 and SEQ ID NO: 8, respectively. The HCVR of antibody II further comprises HCDR1 of SEQ ID NO: 1, HCDR2 of SEQ ID NO: 2, and HCDR3 of SEQ ID NO: 3. The LCVR of antibody II further comprises LCDR1 of SEQ ID NO: 4, LCDR2 of SEQ ID NO: 5, and LCDR3 of SEQ ID NO: 7, respectively.

[0042] In some embodiments, the anti-N3pGlu Aβ antibody comprises B12L having a light chain (LC) and a heavy chain (HC) of SEQ ID NO: 28 and SEQ ID NO: 29, respectively. B12L further comprises a light chain variable region (LCVR) and a heavy chain variable region (HCVR) of SEQ ID NO: 25 and SEQ ID NO: 26, respectively. The HCVR of B12L further comprises HCDR1 of SEQ ID NO: 20, HCDR2 of SEQ ID NO: 22, and HCDR3 of SEQ ID NO: 23. The LCVR of B12L further comprises LCDR1 of SEQ ID NO: 17, LCDR2 of SEQ ID NO: 18, and LCDR3 of SEQ ID NO: 19, respectively.

[0043] In some embodiments, the anti-N3pGlu Aβ antibody comprises R17L having a light chain (LC) and a heavy chain (HC) of SEQ ID NO: 28 and SEQ ID NO: 30, respectively. R17L further comprises a light chain variable region (LCVR) and a heavy chain variable region (HCVR) of SEQ ID NO: 25 and SEQ ID NO: 27, respectively. The HCVR of R17L further comprises HCDR1 of SEQ ID NO: 21, HCDR2 of SEQ ID NO: 22, and HCDR3 of SEQ ID NO: 24. The LCVR of R17L further comprises LCDR1 of SEQ ID NO: 17, LCDR2 of SEQ ID NO: 18, and LCDR3 of SEQ ID NO: 19, respectively.

[0044] In some embodiments, the anti-N3pGlu Aβ antibody comprises hE8L having a light chain (LC) and a heavy chain (HC) of SEQ ID NO: 33 and SEQ ID NO: 35, respectively. hE8L further comprises a light chain variable region (LCVR) and a heavy chain variable region (HCVR) of SEQ ID NO: 32 and SEQ ID NO: 34, respectively. The HCVR of hE8L further comprises HCDR1 of SEQ ID NO: 36, HCDR2 of SEQ ID NO: 22, and HCDR3 of SEQ ID NO: 37. The LCVR of hE8L further comprises LCDR1 of SEQ ID NO: 17, LCDR2 of SEQ ID NO: 18, and LCDR3 of SEQ ID NO: 19, respectively.

[0045] In some embodiments, the anti-N3pGlu Aβ antibody comprises antibody VI having light chain variable regions (LCVR) and heavy chain variable regions (HCVR) of SEQ ID NOs. 39 and 40, respectively.

[0046] In some embodiments, the anti-N3pGlu Aβ antibody comprises antibody VII having light chain variable regions (LCVR) and heavy chain variable regions (HCVR) of sequence numbers 41 and 42, respectively.

[0047] In some embodiments, the anti-N3pGlu Aβ antibody comprises antibody VIII having light chain variable regions (LCVR) and heavy chain variable regions (HCVR) of SEQ ID NOs. 43 and 44, respectively.

[0048] In some embodiments, the anti-N3pGlu Aβ antibody comprises antibody IX having light chain variable regions (LCVR) and heavy chain variable regions (HCVR) of SEQ ID NOs. 45 and 46, respectively.

[0049] In some embodiments, the anti-N3pGlu Aβ antibody comprises antibody X having light chain variable regions (LCVR) and heavy chain variable regions (HCVR) of sequence numbers 47 and 48, respectively.

[0050] In some embodiments, the anti-N3pGlu Aβ antibody comprises antibody XI having light chain variable regions (LCVR) and heavy chain variable regions (HCVR) of SEQ ID NOs. 49 and 50, respectively.

[0051] In some embodiments, the anti-N3pGlu Aβ antibody comprises antibody XII having light chain variable regions (LCVR) and heavy chain variable regions (HCVR) of sequence numbers 51 and 52, respectively.

[0052] In some embodiments, the anti-N3pGlu Aβ antibody comprises antibody XIII having light chain variable regions (LCVR) and heavy chain variable regions (HCVR) of SEQ ID NOs. 53 and 54, respectively.

[0053] Those skilled in the art will know that one embodiment of the present invention is a method for treating or preventing clinical or preclinical Alzheimer's disease, Down syndrome, and clinical or preclinical CAA in a patient positive for amyloid deposits, comprising administering an induction dose of anti-N3pGlu Aβ antibody to the patient once, every other week, or once a month for a period of six months or less, wherein the anti-N3pGlu Aβ antibody comprises a light chain variable region (LCVR) and a heavy chain variable region (HCVR), and the LCVR and HCVR are a) LCVR of sequence number 25 and HCVR of sequence number 26, b) LCVR of sequence number 25 and HCVR of sequence number 27, c) LCVR of SEQ ID NO: 32 and HCVR of SEQ ID NO: 34 d) LCVR of SEQ ID NO: 9 and HCVR of SEQ ID NO: 8, and e) It will be recognized that a method is provided which is selected from the group consisting of LCVR of SEQ ID NO: 10 and HCVR of SEQ ID NO: 8.

[0054] Preferably, the anti-N3pGlu Aβ antibody comprises LCVR of SEQ ID NO: 25 and HCVR of SEQ ID NO: 26. More preferably, the anti-N3pGlu Aβ antibody is administered once or every other week. Even more preferably, the once or every other week dose results in a 35-100% reduction in Aβ deposits in the patient's brain within 6 months of administration of the induction dose.

[0055] In another specific embodiment, the present invention relates to a method for treating or preventing clinical or preclinical Alzheimer's disease, Down syndrome, and clinical or preclinical CAA in a patient positive for amyloid deposits, comprising administering an induction dose of anti-N3pGlu Aβ antibody to the patient once, every other week, or once a month for a period of six months or less, wherein the anti-N3pGlu Aβ antibody comprises a light chain (LC) and a heavy chain (HC), and the LC and HC are a) LC of SEQ ID NO: 28 and HC of SEQ ID NO: 29, b) LC of SEQ ID NO: 28 and HC of SEQ ID NO: 30 c) LC of SEQ ID NO: 33 and HC of SEQ ID NO: 35 d) LC of SEQ ID NO: 12 and HC of SEQ ID NO: 11, and e) Provide a method selected from the group consisting of LC of SEQ ID NO: 13 and HC of SEQ ID NO: 11.

[0056] Preferably, the anti-N3pGlu Aβ antibody comprises LC of SEQ ID NO: 28 and HC of SEQ ID NO: 29. More preferably, the anti-N3pGlu Aβ antibody is administered once or every other week. Even more preferably, the once or every other week dose results in a 35-100% reduction in Aβ deposits in the patient's brain within 6 months of administration of the induction dose.

[0057] Further embodiments include a method for treating or preventing clinical or preclinical Alzheimer's disease, Down syndrome, and clinical or preclinical CAA in a patient positive for amyloid deposits, comprising administering an induction dose of anti-N3pGlu Aβ antibody to the patient once, every other week, or once a month for a period of six months or less, wherein the anti-N3pGlu Aβ antibody comprises two light chains (LCs) and two heavy chains (HCs), each LC and HC being a) LC of SEQ ID NO: 28 and HC of SEQ ID NO: 29, b) LC of SEQ ID NO: 28 and HC of SEQ ID NO: 30 c) LC of SEQ ID NO: 33 and HC of SEQ ID NO: 35 d) LC of SEQ ID NO: 12 and HC of SEQ ID NO: 11, and e) Provide a method selected from the group consisting of LC of SEQ ID NO: 13 and HC of SEQ ID NO: 11.

[0058] Preferably, the anti-N3pGlu Aβ antibody contains two LCs of SEQ ID NO: 28 and one HC of SEQ ID NO: 29. More preferably, the anti-N3pGlu Aβ antibody is administered once or every other week. Even more preferably, the once or every other week dose results in a 35-100% reduction in Aβ deposits in the patient's brain within 6 months of administration of the induction dose.

[0059] The present invention also provides a method for treating or preventing clinical or preclinical Alzheimer's disease, Down syndrome, and clinical or preclinical CAA in patients who are positive for amyloid deposits, comprising administering an induction dose of 10-60 mg / kg of anti-N3pGlu Aβ antibody to the patient once, every other week, or once a month for a period of 6 months or less, wherein the anti-N3pGlu Aβ antibody comprises a light chain variable region (LCVR) and a heavy chain variable region (HCVR), and the LCVR and HCVR are a) LCVR of sequence number 25 and HCVR of sequence number 26, b) LCVR of sequence number 25 and HCVR of sequence number 27, c) LCVR of SEQ ID NO: 32 and HCVR of SEQ ID NO: 34 d) LCVR of SEQ ID NO: 9 and HCVR of SEQ ID NO: 8, and e) Provide a method selected from the group consisting of LCVR of SEQ ID NO: 10 and HCVR of SEQ ID NO: 8.

[0060] Preferably, the anti-N3pGlu Aβ antibody comprises LCVR of SEQ ID NO: 25 and HCVR of SEQ ID NO: 26. More preferably, the single, bi-weekly (every two weeks), and monthly induction dose administered to the patient is 10 mg / kg, 15 mg / kg, 20 mg / kg, 40 mg / kg, 20-40 mg / kg, or 15-30 mg / kg. Even more preferably, the induction dose of anti-N3pGlu Aβ antibody is administered once or every two weeks. Even more preferably, the single or bi-weekly dose results in a 35-100% reduction in Aβ deposits in the patient's brain within 6 months of administration of the induction dose.

[0061] In one embodiment, the present invention provides a method for treating or preventing clinical or preclinical Alzheimer's disease, Down syndrome, and clinical or preclinical CAA in a patient positive for amyloid deposits, comprising administering an induction dose of 10-60 mg / kg of anti-N3pGlu Aβ antibody to the patient once, every other week, or once a month for a period of 6 months or less, wherein the anti-N3pGlu Aβ antibody comprises a light chain (LC) and a heavy chain (HC), and the LC and HC are a) LC of SEQ ID NO: 28 and HC of SEQ ID NO: 29, b) LC of SEQ ID NO: 28 and HC of SEQ ID NO: 30 c) LC of SEQ ID NO: 33 and HC of SEQ ID NO: 35 d) LC of SEQ ID NO: 12 and HC of SEQ ID NO: 11, and e) Provide a method selected from the group consisting of LC of SEQ ID NO: 13 and HC of SEQ ID NO: 11.

[0062] Preferably, the anti-N3pGlu Aβ antibody comprises LC of SEQ ID NO: 28 and HC of SEQ ID NO: 29. More preferably, the single, bi-weekly (every two weeks), and monthly induction dose administered to the patient is 10 mg / kg, 15 mg / kg, 20 mg / kg, 40 mg / kg, 20-40 mg / kg, or 15-30 mg / kg. Even more preferably, the induction dose of anti-N3pGlu Aβ antibody is administered once or every two weeks. Even more preferably, the single or bi-weekly dose results in a 35-100% reduction in Aβ deposits in the patient's brain within 6 months of administration of the induction dose.

[0063] The present invention also relates to a method for treating or preventing clinical or preclinical Alzheimer's disease, Down syndrome, and clinical or preclinical CAA in patients positive for amyloid deposits, comprising administering an induction dose of 10-60 mg / kg of anti-N3pGlu Aβ antibody to the patient for a period of 6 months or less, wherein the anti-N3pGlu Aβ antibody comprises two light chains (LCs) and two heavy chains (HCs), and each LC and HC is a) LC of SEQ ID NO: 28 and HC of SEQ ID NO: 29, b) LC of SEQ ID NO: 28 and HC of SEQ ID NO: 30 c) LC of SEQ ID NO: 33 and HC of SEQ ID NO: 35 d) LC of SEQ ID NO: 12 and HC of SEQ ID NO: 11, and e) Provide a method selected from the group consisting of LC of SEQ ID NO: 13 and HC of SEQ ID NO: 11.

[0064] Preferably, the anti-N3pGlu Aβ antibody contains two LCs of SEQ ID NO: 28 and two HCs of SEQ ID NO: 29. More preferably, the single, bi-weekly (every two weeks), and monthly induction dose administered to the patient is 10 mg / kg, 15 mg / kg, 20 mg / kg, 40 mg / kg, 20-40 mg / kg, or 15-30 mg / kg. Even more preferably, the induction dose of anti-N3pGlu Aβ antibody is administered once or every two weeks. Even more preferably, the single or bi-weekly dose results in a 35-100% reduction in Aβ deposits in the patient's brain within 6 months of administration of the induction dose.

[0065] Those skilled in the art will understand and recognize that the “anti-N3pGlu Aβ antibody,” as well as the specific antibodies “hE8L,” “B12L,” and “R17L,” are identified and disclosed, along with methods for producing and using them, by those skilled in the art, as described in U.S. Patent Application No. 13 / 810,895, issued March 25, 2014, titled “Anti-N3pGlu Amyloid Beta Peptide Antibodies and Uses Thereof.” See, for example, Table 1 of U.S. Patent No. 8,679,498B2. Each of these three antibodies (e.g., “hE8L,” “B12L,” and “R17L”) may be used as the anti-N3pGlu Aβ antibody of the present invention. Those skilled in the art will understand and recognize that the “anti-N3pGlu Aβ antibody,” as well as the specific antibodies “Antibody VI,” “Antibody VII,” “Antibody VIII,” and “Antibody IX,” are identified and disclosed, along with methods for producing and using these antibodies, as described in WO2010 / 009987A2, titled “Diagnosed Antibody Assay.” Each of these four antibodies (e.g., “Antibody VI,” “Antibody VII,” “Antibody VIII,” and “Antibody IX”) may be used as the anti-N3pGlu Aβ antibody of the present invention.

[0066] Those skilled in the art will understand and recognize that the “anti-N3pGlu Aβ antibody,” as well as the specific antibodies “Antibody X” and “Antibody XI,” are identified and disclosed by those skilled in the art, along with methods for producing and using these antibodies, as described in WO2011 / 151076A2, titled “Monoclonal Antibodies Targeting Aβ Monoclonal Antibodies.” Each of these two antibodies (e.g., “Antibody X” and “Antibody XI”) may be used as the anti-N3pGlu Aβ antibody of the present invention.

[0067] Those skilled in the art will understand and recognize that the “anti-N3pGlu Aβ antibody,” as well as the specific antibodies “Antibodies XII” and “Antibodies XIII,” are identified and disclosed by those skilled in the art, along with methods for producing and using them, as described in WO2012 / 136552A1, titled “Antibodies Specific to Pyroglutamated Aβ.” Each of these two antibodies (e.g., “Antibodies XII” and “Antibodies XIII”) may be used as the anti-N3pGlu Aβ antibody of the present invention.

[0068] Those skilled in the art will understand and recognize that the “Aβ antibody” and the specific antibody “aducanumab” are identified and disclosed, along with methods for producing and using the antibody, as described in WO14089500A1, titled “A Method of Reducing Brain Amyloid Plaques Using Anti-Aβ Antibodies,” published on June 12, 2014. This can be used as the Aβ antibody of the present invention.

[0069] Those skilled in the art will understand and recognize that the “Aβ antibody” and the specific antibody “gantenerumab” are identified and disclosed by those skilled in the art, along with methods for producing and using the antibody, as described in WO2007 / 068429, titled “Antibodies Against Amyloid Beta 4 with Glycosylated in the Variable Region,” published on June 21, 2007. This can be used as the Aβ antibody of the present invention.

[0070] Those skilled in the art will understand and recognize that the “Aβ antibody” and the specific antibody “crenezumab” are identified and disclosed by those skilled in the art, along with methods for producing and using the antibody, as described in 2015 / 120280A1, titled “Methods of treating alzheimer’s disease,” published on August 13, 2015. This may be used as the Aβ antibody of the present invention.

[0071] Those skilled in the art will understand and recognize that the “Aβ antibody” and the specific antibody “BAN 2401” are identified and disclosed by those skilled in the art, along with methods for producing and using the antibody, as described in US8025878B2, published September 27, 2011, titled “Protofibril selective antibodies and the use thereof.” This may be used as the Aβ antibody of the present invention.

[0072] Those skilled in the art will understand and recognize that the “Aβ antibody” and the specific antibody “solanezumab” are identified and disclosed, along with methods for producing and using the antibody, as described in U.S. Patent No. 7,195,761B2, titled “Humanized Antibodies that Sequester ABeta Peptide,” issued on March 27, 2007. This can be used as the Aβ antibody of the present invention.

[0073] Those skilled in the art will understand and recognize that “Aβ antibody” and the specific antibody “Antibody XIV” are identified and disclosed, along with methods for producing and using the antibody, as described in U.S. Patent Application No. 8,066,999B1, titled “Pegylated Aβ FAB,” issued on November 29, 2011 (U.S. Patent Application No. 12 / 521,309). This may be used as the Aβ antibody of the present invention.

[0074] formula: [ka] Compounds thereof, or pharmaceutically acceptable salts thereof, are disclosed as BACE inhibitors and can be prepared by those skilled in the art, as described in U.S. Patent Application No. 14 / 195,897, issued September 23, 2014, titled "Tetrahydropyrrolothiazine Compounds," particularly Example 4, N-[3-[(4aR,7aS)-2-amino-6-(5-fluoropyrimidine-2-yl)-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiazin-7a-yl]-4-fluorophenyl]-5-methoxypyrazine-2-carboxamide. The tosylate salt of N-[3-[(4aR,7aS)-2-amino-6-(5-fluoropyrimidine-2-yl)-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiadin-7a-yl]-4-fluorophenyl]-5-methoxypyrazine-2-carboxamide can be prepared by those skilled in the art, as described in PCT / US2016 / 014423. The crystalline form of N-[3-[(4aR,7aS)-2-amino-6-(5-fluoropyrimidine-2-yl)-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiazine-7a-yl]-4-fluorophenyl]-5-methoxypyrazine-2-carboxamide can be prepared by those skilled in the art, as described in WO2016 / 043996, titled "A Tetrahydropyrrolo[3,4-D][1,3]Thiazine-Derivative as BACE Inhibitor".

[0075] formula: [ka] Compounds of or pharmaceutically acceptable salts thereof are disclosed as BACE inhibitors and can be prepared by those skilled in the art as described in U.S. Patent No. 8,729,071B1, issued May 20, 2014, titled "Iminothiadiazine Dioxide Compounds As BACE Inhibitors, Compositions and Their Use". The crystalline forms of N-[3-[(5R)-3-amino-5,6-dihydro-2,5-dimethyl-1,1-dioxide-2H-1,2,4-thiadin-5-yl]-4-fluorophenyl]-5-fluoro-2-pyridinecarboxamide and the crystalline forms of its tosylate salt, verbecestat, are disclosed and can be prepared by those skilled in the art as described in WO2016 / 053767, titled "Novel Crystalline forms of a BACE Inhibitor, Compositions, and their Use".

[0076] In addition, the amino acid sequences of specific anti-N3pGlu Aβ antibodies used in the present invention are provided in Table 1 below.

[0077] [Table 1]

[0078] Table 2 provides additional amino acid sequences for "Antibody I," "Antibody II," "Antibody III," "Antibody IV," and "Antibody V."

[0079] [Table 2]

[0080] As used herein, “antibody” is an immunoglobulin molecule comprising two heavy chains (HC) and two light chains (LC) linked together by disulfide bonds. The amino-terminus of each LC and HC contains a variable region that gives rise to antigen recognition via a complementation-determining region (CDR) contained therein. The CDR contains interspersed, more conserved regions called framework regions. The assignment of amino acids to the CDR domains within the LCVR and HCVR regions of the antibody of the present invention is based on the following: Kabat numbering rules (Kabat, et al., Ann. NY Acad. Sci. 190:382-93 (1971), Kabat et al., Sequences of Proteins of Immunological Interest, Fifth Edition, USD Department of Health and Human Services, NIH Publication No. 91-3242 (1991)), and North numbering rules (North et al., A New Clustering of Antibody CDR Loop Conformations, Journal of Molecular Biology, 406:228-256 (2011)). The CDR of the present invention was determined according to the above method (Table 2).

[0081] The anti-N3pGlu Aβ antibody of the present invention comprises κLC and IgG HC. In certain embodiments, the anti-N3pGlu Aβ antibody of the present invention is of the human IgG1 isotype.

[0082] The antibodies of the present invention are monoclonal antibodies ("mAb"). Monoclonal antibodies can be produced, for example, by hybridoma technology, recombinant technology, phage display technology, synthesis technology, such as CDR grafting, or a combination of these or other technologies known in the art. The monoclonal antibodies of the present invention are human or humanized. Humanized antibodies can be manipulated to contain one or more human framework regions (or substantially human framework regions) surrounding a CDR derived from a non-human antibody. Human framework germline sequences can be obtained from ImunoGeneTics (INGT) via its website http: / / imgt.cines.fr or from The Immunoglobulin FactsBook, Academic 25 Press, 2001, ISBN 012441351 by Marie-Paule Lefranc and Gerard Lefranc. Techniques for producing human or humanized antibodies are well known in the art. In another embodiment of the present invention, the antibody, or nucleic acid encoding the antibody, is provided in an isolated form. As used herein, the term “isolated” means a protein, peptide, or nucleic acid that is not found in nature and does not contain, or substantially contains, other macromolecular species found in the cellular environment. “Substantially contained” as used herein means that the protein, peptide, or nucleic acid of interest contains more than 80% (molar basis), preferably more than 90%, and more preferably more than 95% of the macromolecular species present.

[0083] The anti-N3pGlu Aβ antibody of the present invention is administered as a pharmaceutical composition. A pharmaceutical composition containing the antibody of the present invention may be administered by parenteral routes (e.g., subcutaneous, intravenous, intraperitoneal, intramuscular) to patients who are at risk of or exhibiting any of the diseases or disorders described herein. Subcutaneous and intravenous routes are preferred.

[0084] The terms “treatment,” “treating,” or “to treat” and related terms include the suppression, delay, or cessation of the progression or severity of a pre-existing symptom, condition, disease, or disability in a patient. The term “patient” refers to a human being.

[0085] The term "prevention" means the prophylactic administration of the antibodies of the present invention to asymptomatic patients or patients with preclinical Alzheimer's disease in order to prevent the onset or progression of the disease.

[0086] The terms “diseases characterized by Aβ deposition” or “diseases characterized by Aβ deposits” are used interchangeably and refer to diseases pathologically characterized by Aβ deposits in the brain or cerebrovascular system. This includes diseases such as Alzheimer’s disease, Down syndrome, and cerebral amyloid angiopathy. The clinical diagnosis, staging, or progression of Alzheimer’s disease can be readily determined by a diagnostician or healthcare professional skilled in the art using known techniques and by observing the results. This generally includes certain forms of brain plaque imaging, mental or cognitive assessments (e.g., Clinical Dementia Assessment Scale (CDR-SB), Mini-Mental State Examination (MMSE), or Alzheimer's Disease Assessment Scale - Cognitive Assessment (ADAS-Cog)), or functional assessments (e.g., Alzheimer's Disease Collaborative Study - Activities of Daily Living (ADCS-ADL). Cognitive and functional assessments can be used to determine changes in patient cognition (e.g., cognitive decline) and function (e.g., functional decline). As used herein, “clinical Alzheimer’s disease” refers to the 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 and is associated with biomarkers (CSF). Measurable changes (such as Aβ42 levels or amyloid plaques on amyloid PET) indicate the earliest signs of Alzheimer's pathology progressing to clinical Alzheimer's disease. This is usually before symptoms such as memory loss and confusion become prominent. Preclinical Alzheimer's disease also includes pre-symptomatic autosomal dominant carriers and patients who are at higher risk of developing AD due to carrying one or two APOE e4 alleles.

[0087] In patients undergoing plaque imaging, a patient is positive for amyloid deposits if amyloid is detected in the brain by methods such as amyloid imaging with radiolabeled PET compounds. One example of such an amyloid PET imaging compound is florbetapyr F18, which binds to amyloid plaques with high specificity. The chemical formula for florbetapyr F18 is C 20 H 25 18 The compound is FN2O3. Using amyloid imaging with radiolabeled PET compounds, it is possible to determine whether Aβ deposits in the brains of human patients decrease by 35–100% within 6 months after induction treatment. Those skilled in the art can calculate the percentage reduction in Aβ deposits in the brains of patients before and after treatment by correlating the standardized uptake ratio (SUVR) values ​​obtained from amyloid imaging (with radiolabeled PET compounds). The SUVr value can be converted to standard centroid units, where 100 is the mean for AD and 0 is the mean for young controls, providing comparability between amyloid PET tracers and enabling the calculation of reduction in centroid units (Klunk et al., Alzheimers Dement, 2015;11:1-15). As used herein, “a period of 6 months or less” refers to a period of 6 months or less in full consecutive calendar months, where each month has 28–31 days. This period includes at least one induction dose given in a single dose.

[0088] The reduction or slowing of cognitive decline can be measured by cognitive assessments such as the Clinical Dementia Assessment Scale (CDR-SB), the Mini-Mental State Examination (MMSE), or the Alzheimer's Disease Assessment Scale - Cognitive Assessment (ADAS-Cog). The reduction or slowing of functional decline can be measured by functional assessments such as the Alzheimer's Disease Collaborative Study - Activities of Daily Living (ADCS-ADL).

[0089] The "induction dose" is the dose of anti-N3pGlu Aβ antibody that causes a rapid reduction in Aβ deposits in the brain of a human patient within six months of treatment. The "single dose" is the induction dose administered to the patient once. The "single dose" may also be a dose administered to the patient once over a long period, such as 2 to 10 years, between doses, if such a dose is required. Whether a patient requires more than one "single dose" induction dose can be determined by a diagnostician or healthcare professional by using known techniques and observing the results. The "bi-weekly" dose is a dose administered to the patient every two weeks.

[0090] The "maintenance dose" is the dose administered to a patient after induction dose therapy. The maintenance dose is the amount of antibody or drug administered to maintain the desired therapeutic response, including a reduction in Aβ deposits in the brain of a human patient. The maintenance dose may be the same as or lower than the induction dose of antibody or drug.

[0091] As used herein, "mg / kg" means the amount in milligrams of antibody or drug administered to a patient based on their body weight in kilograms. 1 The dosage is administered in a single dose. For example, a 10 mg / kg dose of antibody for a patient weighing 70 kg would be a single 700 mg dose of antibody administered in one dose. Similarly, a 40 mg / kg dose of antibody for a patient weighing 80 kg would be a single 3200 mg dose of antibody administered in one dose.

[0092] As used herein, the phrase “in combination with” refers to the administration of the anti-N3pGlu Aβ antibody of the present invention simultaneously, sequentially in any order, or in any combination thereof, with another molecule (a “combination molecule” such as a BACE inhibitor, a symptomatic treatment agent, or an Aβ antibody). The two molecules may be administered either as part of the same pharmaceutically active ingredient or as separate pharmaceutically active ingredients. The anti-N3pGlu Aβ antibody may be administered before, simultaneously with, or after the administration of the combination molecule, or in any combination thereof. If the combination molecule is administered at repeated intervals (e.g., during a standard course of treatment), the anti-N3pGlu Aβ antibody may be administered before, simultaneously with, or after each administration of the combination molecule, or in any combination thereof, or at different intervals with respect to the therapy with the combination molecule, or at any point in between before, during, or after the course of treatment with the combination molecule, in a single or series of doses. Those skilled in the art will recognize that a BACE inhibitor refers to a small molecule that can inhibit a therapeutic agent, preferably the β-secretase 1 enzyme, and prevent the formation of amyloid plaques. Examples of BACE inhibitors are disclosed herein.

[0093] As used herein, “symptomatic agents” refers to agents used to symptomatically treat cognitive symptoms of Alzheimer’s disease and does not imply any effect on the progression of Alzheimer’s disease. These include acetylcholinesterase inhibitors and NMDA receptor antagonists. Cholinesterase inhibitors approved for the management of AD symptoms include donepezil (trade name Aricept®), galantamine (trade name Razadyne®), and rivastigmine (trade names Exelon and Exelon® Patch). Memantine (also known as NAMEDA®) is an approved NMDA receptor antagonist. NAMZARIC® is a combination agent containing both an acetylcholinesterase inhibitor and an NMDA receptor antagonist.

[0094] The following examples and assays demonstrate that the antibodies of the present invention are useful for treating diseases characterized by Aβ deposition, such as Alzheimer's disease, Down syndrome, and CAA. However, it should be understood that the following examples are provided as illustrations and not limitations, and that various modifications can be made by those skilled in the art. [Examples]

[0095] Example 1: Single-dose efficacy in aged transgenic mice Longitudinal effects of a single dose of mouse surrogate mE8c anti-N3pGlu antibody (IgG2a) (US Patent No. 8,679,498B1) observed in aged PDAPP transgenic mice (18.5–20 months old). To mimic the Aβ deposition rate and conditions in humans with Alzheimer's disease, mice were fed a grain diet containing the BACE inhibitor LY2811376 (0.015%) starting 4 days prior to receiving a single intraperitoneal injection of a biotinylated mE8c antibody or a biotinylated control antibody of the same isotype, and remained on this diet throughout the study period. A preceding 4-month study demonstrated in aged PDAPP mice treated with the BACE inhibitor in the diet resulted in BACE inhibition at a level that did not alter the deposited Aβ over the 4-month period (i.e., no further deposition or clearance of deposited Aβ occurred). Animals are euthanized 4, 8, 12, or 16 weeks after a single injection of biotinylated mE8c antibody (20 mg / kg or 100 mg / kg) or biotinylated control antibody (100 mg / kg). An additional control group of transgenic mice is euthanized at the start of the study (time zero cohort) and at 4, 8, 12, or 16 weeks (age-matched control cohort). Hippocampal tissue is analyzed by acid urea gel, and Aβ1-42 is measured under denatured conditions.

[0096] Essentially, after the procedure described above, there were no significant differences in Aβ1-42 levels among isotype controls (age-matched control cohort) injected at 4, 8, 12, or 16 weeks compared to the time-zero cohort. For comparison with animals injected with biotinylated mE8c antibody, the control animals were combined into a single control group. Mice that received a single injection of 20 mg / kg of biotinylated mE8c antibody showed reduced hippocampal Aβ1-42 levels at 4 weeks (-6%), 8 weeks (-32%, Dunnett's multiple comparison, p=0.0091), 12 weeks (-17%), and 16 weeks (-19%) compared to the control animals. Aged PDAPP mice that received a single injection of 100 mg / kg of biotinylated mE8c antibody showed reduced levels of hippocampal Aβ1-42 at 4 weeks (-23%), 8 weeks (-28%, Dunnett's multiple comparison, p=0.0252), 12 weeks (-14%), and 16 weeks (-17%) compared to control animals.

[0097] Example 2: Single-dose target binding in aged transgenic mice To determine in vivo target binding of deposition plaques after single-dose N3pGlu antibody, frozen cerebral hemispheres from the single-dose antibody test described in Example 1 were histologically analyzed to determine the hippocampal area percentage showing antibody binding to plaques after 0, 4, 8, 12, and 16 weeks of single-dose antibody treatment.

[0098] Brain sections are sectioned, and immunohistochemistry is performed on sister sections containing anti-human antibodies (to detect bound N3pGlu antibodies) and 3D6 (to detect the total amount of deposited targets in the section). The area percentage bound by N3pGlu antibodies is normalized to the total amount of deposited targets in the section.

[0099] Essentially, after the procedure described above, the total area covered by deposited Aβ did not differ significantly across all groups, and the mean hippocampal area covered by staining varied between 27% and 39%. In control animals, little to no target binding was observed. Significant target binding was observed at 4, 8, 12, and 16 weeks of single dose biotinylated mE8c antibody at 20 mg / kg (2.8% (p<0.0001), 1.9% (p<0.0001), 1.1% (p=0.003), 0.6% (p=0.0323), respectively) or 100 mg / kg (5.5% (p<0.0001), 4.0% (p<0.0001), 2.6% (p<0.0001), 1.5% (p=0.0002), respectively). p-values ​​were determined using Dunn nonparametric analysis. The mean area of ​​target binding in mE8c-injected animals was: Mean target binding was highest 4 weeks after treatment and decreased longitudinally at subsequent weeks 8, 12, and 16 (1.9%, 1.1%, and 0.6%, respectively, for the 20 mg / kg mE8c group, and 4.0%, 2.6%, and 1.5%, respectively, for the 100 mg / kg mE8c group). Due to high levels of variability, no significant differences were observed between animals injected with a single dose of 20 and 100 mg / kg mE8c at matched time points, excluding weeks 12 and 16 (p = 0.0465, 0.0432 unadjusted Wilcoxon).

[0100] Example 3: Single-dose and multi-dose, dose-escalation clinical trials for Alzheimer's disease The safety, tolerability, and pharmacokinetics (PK) of single and multiple IV doses of LY3002813 (Antibody III) were evaluated in a Phase I, double-blind, randomized, placebo-controlled, parallel-group, single-dose followed by multiple-dose dose escalation study in patients with Alzheimer's disease (AD) or mild to moderate AD-related mild cognitive impairment (MCI). AD patients were enrolled in the Single Elevation Dose (SAD) phase, receiving either a single intravenous (IV) dose of Antibody III (five dosing cohorts ranging from 0.1 mg / kg IV to 10 mg / kg IV) or placebo, followed by a 12-week follow-up period for each dose level. After the follow-up period, the same patients progressed to the Multiple Elevation Dose (MAD) phase (five cohorts), receiving IV doses of Antibody III (0.3 mg / kg IV to 10 mg / kg IV) or placebo, approximately once per month depending on the initial dose, up to four doses. This phase concluded with a 12-week follow-up period.

[0101] Results from a single-dose study evaluating the pharmacokinetics (PK) of antibody III up to 84 days after single-dose administration showed that the mean terminal elimination half-life was approximately 4 days after single-dose administration of 0.1 mg / kg to 3.0 mg / kg, and increased to approximately 10 days (243 hours) at a dose level of 10 mg / kg. The mean clearance values ​​at each dose level ranged from 26.3 mL / hour (10 mg / kg) to 35.6 mL / hour (1.0 mg / kg).

[0102] Results from multi-dose studies in which patients entered the multi-dose phase 12 weeks after receiving a single dose in the SAD phase showed that antibody III concentrations were significantly lower after multi-dose antibody III than after the initial single dose. In contrast to other dose levels, at the 10 mg / kg dose level, antibody III concentrations were generally similar to those observed after single-dose administration. Most patients had serum antibody III concentrations below the detection limit 28 days after administration at dose levels ≤3 mg / kg. Patients receiving 10 mg / kg maintained quantifiable concentrations 28 days after administration.

[0103] Over 90% of patients with AD had treatment-induced anti-drug antibodies (ADAs) 3 months after the first dose in all dose groups, and titers tended to increase by the end of the MAD phase and persist for 3 months after the last dose. The rapid decline in antibody III concentrations after multiple doses may be at least partially associated with the presence of ADAs. The treatment groups also experienced an increase in infusion-related responses with multiple doses.

[0104] Florbetapir scans were performed at baseline and after the last MAD dose, separated by approximately 7 months. Changes in the standardized ultraviolet uptake ratio (SUVr) of all gray matter with respect to the cerebellum as a reference region were compared across dose cohorts, and SUVr values ​​were converted to standard centroid (CL) units. In this dose group, six patients who received 3–5 doses of 10 mg / kg antibody III intravenously over 6 months showed a significant reduction in cerebral amyloid (assessed by florbetapir PET imaging) without complications of cerebral vasoembolic edema or microbleeding. A mean reduction of 44 CL units corresponds to a mean reduction of 40–50% in cerebral amyloid.

[0105] A florbetapil scan in extended follow-up from three subjects treated with 3-5 doses of 10 mg / kg IV antibody III (vs. 2 placebo) showed sustained amyloid clearance 18 months after the last dose. The data indicate that short-term (and possibly single) doses of anti-N3pGlu Aβ antibodies (such as antibody III) are sufficient to produce sustained amyloid clearance. Long-term administration of anti-N3pGlu Aβ antibodies is not necessary to maintain cerebral amyloid clearance.

[0106] Example 4: Single-dose and multi-dose clinical trials for Alzheimer's disease A Phase Ib trial is underway to confirm that different dosing regimens (single dose with higher, more frequent dosing, short "induction" dosing, and long-term dosing for maximum PD effect) can mitigate immunogenicity and immunosafety issues and lead to sustained amyloid reduction, as a result of significant target binding (amyloid reduction by florbetapir PET) identified after 3–5 intravenous doses of LY3002813 (Antibody III) 10 mg / kg over 6 months. A Phase Ib, double-blind, cohort-in-randomized, placebo-controlled, parallel-group, single and multiple-dose trial will be conducted in patients with AD or MCI resulting from mild to moderate AD to evaluate the safety, tolerability, and PK of single and multiple IV doses of Antibody III. This trial will evaluate single IV doses of 10 mg / kg, 20 mg / kg, or 40 mg / kg (cohorts 1, 2, and 3, respectively), and 24 doses of 10 mg / kg or 20 mg / kg. week The study will be conducted in at least seven cohorts, including IV doses every two weeks for up to 72 weeks (Cohorts 4 and 5, respectively), and IV doses every four weeks for up to 72 weeks (Cohorts 6 and 7, respectively) of 10 mg / kg or 20 mg / kg.

[0107] The primary target binding outcome is a reduction in brain amyloid, as measured by quantitative amyloid PET imaging (florbetapir CL), evaluated at baseline and at 12, 24, 36, 48, and 72 weeks after the start of treatment.

[0108] The results demonstrate that single doses of 10 mg / kg, 20 mg / kg, and 40 mg / kg, as well as multiple doses of 10 mg / kg of antibody III, can reduce amyloid levels over 12 weeks (mean reduction in the cohort to date, ranging from -12 to -39 CL, as measured by florbetapir PET). In patients who underwent additional scanning beyond 12 weeks, amyloid clearance was sustained in the single-dose cohort, while further amyloid clearance was observed with medication in the multi-dose cohort.

[0109] Example 5: Expression and purification of manipulated N3pGlu Aβ antibody The anti-N3pGlu Aβ antibody of the present invention can be expressed and purified essentially as follows: Suitable host cells, such as HEK293EBNA or CHO, are transfected transiently or stably in an expression system for antibody secretion using an optimal predetermined HC:LC vector ratio or a single vector system encoding both HC and LC. The clarified medium from which the antibody has been secreted is purified using one of many commonly used techniques. For example, the medium can be conveniently applied to a Protein A or G Sepharose FF column equilibrated with a suitable buffer such as phosphate-buffered saline (pH 7.4). The column is washed to remove nonspecific binding components. The bound antibody is eluted, for example, by a pH gradient (e.g., 0.1M sodium phosphate buffer pH 6.8 to 0.1M sodium citrate buffer pH 2.5). The antibody fraction is detected by SDS-PAGE or the like and then pooled. Further purification is optional, depending on the intended use. The antibody can be concentrated and / or filtered using common techniques. Soluble aggregates and polymers can be efficiently removed by common techniques, including size exclusion, hydrophobic interactions, ion exchange, or hydroxyapatite chromatography. The purity of the antibody after these chromatographic steps exceeds 99%. The product may be immediately frozen at -70°C or lyophilized. The amino acid sequence of the anti-N3pGlu Aβ antibody is provided in Table 1.

[0110] Example 6: Binding affinity and rate The binding affinity and kinetics of the anti-N3pGlu Aβ antibodies (Antibody I or Antibody II) of the present invention for the pE3-42 Aβ peptide or Aβ1-40 peptide are measured by surface plasmon resonance using BIACORE® 3000 (GE Healthcare). The binding affinity is measured by capturing the anti-N3pGlu Aβ antibody via Protein A immobilized on a BIACORE® CMS chip and flowing the pE3-42 Aβ peptide or Aβ1-40 peptide from 100 nM to 3.125 nM in 2-fold serial dilutions. These experiments are conducted at 25 °C in HBS-EP buffer (GE Healthcare BR100669, 10 mM HEPES, 150 mM NaCl, 3 mM EDTA, 0.05% surfactant P20, pH 7.4).

[0111] For each cycle, the antibody is captured by injecting 5 μL of an antibody solution at a concentration of 10 μg / mL at a flow rate of 10 μL / min. The peptide is bound by injecting 250 μL at 50 μL / min and then dissociated for 10 minutes. The chip surface is regenerated by injecting 5 μL of a glycine buffer at pH 1.5 at a flow rate of 10 μL / mL. The data is fitted to a 1:1 Langmuir binding model to derive k on 、k off and calculate K D After essentially the above procedure, the following parameters (shown in Table 3) were observed.

[0112]

Table 3

[0113] Example 7: Ex vivo target binding To determine ex vivo target binding in brain sections derived from immobilized PDAPP brains, immunohistochemical analysis is performed using exogenously added anti-N3pGlu Aβ antibodies of the present invention (hE8L, B12L, R17L, antibody I, or antibody II). Cryostat serial coronal sections from aged PDAPP mice (25 months old) are incubated with 20 μg / mL of an exemplary N3pGlu Aβ antibody of the present invention. Deposition plaques are visualized using DAB-Plus (DAKO) with a human IgG-specific secondary HRP reagent. Biotinylated mouse 3D6 antibody, followed by Step-HRP secondary, is used as a positive control. The positive control antibody (biotinylated 3D6) labeled a significant amount of deposited Aβ in the PDAPP hippocampus, while the anti-N3pGlu Aβ antibodies (hE8L, B12L, R17L, antibody I, or antibody II) labeled a subset of the deposits. These histological studies demonstrated that the anti-N3pGlu Aβ antibody of the present invention bound to the deposited Aβ target ex vivo.

[0114] Example 8: Synthesis of N-[3-[(4aR,7aS)-2-amino-6-(5-fluoropyrimidine-2-yl)-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiadin-7a-yl]-4-fluorophenyl]-5-methoxypyrazine-2-carboxamide and toluenesulfonic acid [ka] 149.15 mg of crystalline form 2 N-[3-[(4aR,7aS)-2-amino-6-(5-fluoropyrimidine-2-yl)-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiadin-7a-yl]-4-fluorophenyl]-5-methoxypyrazine-2-carboxamide hydrate is added to ethyl acetate (2 mL). The sample is stirred at 1000 rpm at 80°C. 70 mg of p-toluenesulfonic acid (dissolved in ethyl acetate (1 mL)) is added to the stirred solution, and the mixture is stirred overnight at 80°C to produce a white solid slurry, which is isolated by vacuum filtration to provide the title compound.

[0115] N-[3-[(4aR,7aS)-2-amino-6-(5-fluoropyrimidine-2-yl)-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiadin-7a-yl]-4-fluorophenyl]-5-methoxypyrazine-2-carboxamide, alternative preparation A of toluenesulfonic acid N-[3-[(4aR,7aS)-2-amino-6-(5-fluoropyrimidine-2-yl)-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiadin-7a-yl]-4-fluorophenyl]-5-methoxypyrazine-2-carboxamide (9.5 g, 19 mmol) and p-toluenesulfonic acid (3.80 g, 19.8 mmol) are added to tetrahydrofuran (31 mL), water (7.9 mL), and 2-propanol (8.6 mL). The solution is heated to 40°C. 200.0 mL of 2-propanol is added to the warm solution over approximately 3 hours. Immediately after the start of 2-propanol addition, a portion of the title compound (500 mg, 0.75 mmol) is seeded into the mixture. After the addition of the solvent is complete, the mixture is cooled to approximately 20°C over 1–3 hours. The mixture is heated from approximately 20°C to approximately 55°C over a target time of 2 hours. The temperature is maintained at 55°C for 1 hour, then cooled to approximately 20°C over approximately 4 hours. The slurry is stirred at approximately 20°C for at least 10 hours. The slurry is filtered, and the wet cake is washed with water (57 mL). The product is vacuum-dried at 45°C for at least 10 hours to obtain the title compound (10.4 g, 81%). ES / MS (m / z): 500 (M+H).

[0116] N-[3-[(4aR,7aS)-2-amino-6-(5-fluoropyrimidine-2-yl)-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiadin-7a-yl]-4-fluorophenyl]-5-methoxypyrazine-2-carboxamide, alternative preparation B of toluenesulfonic acid N-[3-[(4aR,7aS)-2-amino-6-(5-fluoropyrimidine-2-yl)-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiadin-7a-yl]-4-fluorophenyl]-5-methoxypyrazine-2-carboxamide hydrate (20.7 g) is slurryed at 170 rpm in 60:40 THF:H2O (85 mL) in a 500 mL three-necked round-bottom flask equipped with a nitrogen bubbler, an IKA® mechanical motor / agitator mounted on a glass shaft with TEFLON® banana blades, and a thermocouple connected to a programmable J-KEM® temperature controller. Dissolve p-toluenesulfonic acid monohydrate (7.6 g, 1.03 equivalents) in a 60:40 THF:H2O (20 mL) mixture, and add the solution entirely at once to a stirred N-[3-[(4aR,7aS)-2-amino-6-(5-fluoropyrimidine-2-yl)-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiadin-7a-yl]-4-fluorophenyl]-5-methoxypyrazine-2-carboxamide slurry at 23°C, yielding a clear reddish-yellowish-brown solution almost immediately. Next, the stirring speed is increased to 200 rpm over 15 minutes, water (22 mL) is added to the solution, followed by the inoculation of N-[3-[(4aR,7aS)-2-amino-6-(5-fluoropyrimidine-2-yl)-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiadin-7a-yl]-4-fluorophenyl]-5-methoxypyrazine-2-carboxamidetoluenesulfonic acid (750 mg, 3 wt% seed load), and the mixture is then stirred at 23°C for another 15 minutes. Over 6 hours, water (226 mL, 353 mL of total solvent, or 13.6 volumes of THF:H2O with a final solvent ratio of 17.5:82.5) is added to the slurry, and the mixture is then stirred at 23°C overnight (22 hours). The slurry was filtered under vacuum, rinsed with 15:85 THF:H2O (2 × 20 mL), and then placed under vacuum for 20 minutes while manually closing any cracks formed in the wet cake of the product. The wet solid was dried under vacuum at 40°C for approximately 72 hours to obtain the title compound as a white crystalline solid (24.07 g, 90.0 wt%).

[0117] Crystalline N-[3-[(4aR,7aS)-2-amino-6-(5-fluoropyrimidine-2-yl)-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiadin-7a-yl]-4-fluorophenyl]-5-methoxypyrazine-2-carboxamide and toluenesulfonic acid are characterized by having diffraction peaks (2-θ values) as shown in Table 4 below, based on XRD patterns obtained using CuKa irradiation, and in particular by having a peak at a diffraction angle 2-θ of 5.0° in combination with one or more peaks selected from the group consisting of 19.6°, 13.8°, and 18.5°, with a tolerance of 0.2 degrees for the diffraction angle.

[0118] [Table 4]

[0119] array <Sequence ID 1, PRT1, Artificial> (HCDR1-Antibody I and Antibody II) KASGYTFTDYYIN <Sequence ID 2, PRT1, Artificial> (HCDR2-Antibody I and Antibody II) WINPGSGNTKYNEKFKG <Sequence ID 3, PRT1, Artificial> (HCDR3-Antibody I and Antibody II) TREGETVY <Sequence ID 4, PRT1, Artificial> (LCDR1-Antibody I and Antibody II) KSSQSLLYSRGKTYLN <Sequence ID 5, PRT1, Artificial> (LCDR2-Antibody II) YAVSKLDS <Sequence ID 6, PRT1, Artificial> (LCDR2-Antibody I) YDVSKLDS <Sequence ID 7, PRT1, Artificial> (LCDR3-Antibody I and Antibody II) VQGTHYPFT <Sequence ID 8, PRT1, Artificial> (HCVR-Antibody I and Antibody II)QVQLVQSGAEVKKPGSSVKVSCKASGYTFTDYYINWVRQAPGQGLEWMGWINPGSGNTKYNEKFKGRVTITADESTSTAYMELSSLRSEDTAVYYCTREGETVYWGQGTLVTVSS <Sequence ID 9, PRT1, Artificial> (LCVR-Antibody I)DVVMTQSPLSLPVTLGQPASISCKSSQSLLYSRGKTYLNWFQQRPGQSPRRLIYDVSKLDSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCVQGTHYPFTFGQGTKLEIK <Sequence ID 10, PRT1, Artificial> (LCVR-Antibody II) DIQMTQSPSTLSASVGDRVTITCKSSQSLLYSRGKTYLNWLQQKPGKAPKLLIYAVSKLDSGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCVQGTHYPFTFGQGTKLEIK <Sequence ID 11, PRT1, Artificial> (HC-Antibody I and Antibody II) QVQLVQSGAEVKKPGSSVKVSCKASGYTFTDYYINWVRQAPGQGLEWMGWINPGSGNTKYNEKFKGRVTITADESTSTAYMELSSLRSEDTAVYYCTREGETVYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG <SEQ ID NO: 12, PRT1, artificial> (LC - Antibody I) DVVMTQSPLSLPVTLGQPASISCKSSQSLLYSRGKTYLNWFQQRPGQSPRRLIYDVSKLDSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCVQGTHYPFTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC <SEQ ID NO: 13, PRT1, artificial> (LC - Antibody II) DIQMTQSPSTLSASVGDRVTITCKSSQSLLYSRGKTYLNWLQQKPGKAPKLLIYAVSKLDSGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCVQGTHYPFTFGQGTKL EIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC <SEQ ID NO: 14, DNA, Artificial> Exemplary DNA for expressing the antibody heavy chain of SEQ ID NO: 11 <SEQ ID NO: 15, DNA, Artificial> Exemplary DNA for expressing the antibody light chain of SEQ ID NO: 12 GATGTTGTGATGACTCAGTCTCCACTCTCCCTGCCCGTCACCCTTGACAGCCGGCCTCCATCTCCTGCAAGTCTAGTCAAAGCCTCCTGTACAGTCGCGGAAAAACCTACTTGAATTGGTTTCAGCAGAGGCCAGGCCAATCTCCAAGGCGCCTAATTTATGA TGTTTCTAAACTGGACTCTGGGGTCCCAGACAGATTCAGCGGCAGTGGGTCAGGCACTGATTTCACACTGAAAATCAGCAGGGTGGAGGGCTGAGGATGTTGGGGTTTATTACTGCGTGCAAGGTACACACTACCCTTTCACTTTTGGCCAAGGGACCAAGCTGG AGATCAAACGGACCGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCC CAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGC <SEQ ID NO: 16, DNA, Artificial> Exemplary DNA for expressing the antibody light chain of SEQ ID NO: 13 GACATCCAGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCAAGTCCAGTCAGAGTCTCCTGTACAGTCGCGGAAAAACCTATTTGAACTGGCTCCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGTCTCCAAACTGGACAGTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAATTCACTCTCACCATCAGCAGCCTGCAGCCTGATGATTTTGCAACTTATTACTGCGTGCAGGGTACACATTATCCTTTCACTTTTGGCCAGGGGACCAAGCTGGAGATCAAACGGACCGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGC <SEQ ID NO: 17, PRT1, artificial> (LCDR1 - B12L / R17L / hE8L) KSSQSLLYSRGKTYLN <SEQ ID NO: 18, PRT1, artificial> (LCDR2 - B12L / R17L / hE8L) AVSKLDS <SEQ ID NO: 19, PRT1, artificial> (LCDR3 - B12L / R17L / hE8L) VQGTHYPFT <SEQ ID NO: 20, PRT1, artificial> (HCDR1 - B12L) GYDFTRYYIN <SEQ ID No. 21, PRT1, Artificial>(HCDR1-R17L) GYTFTRYYIN <SEQ ID No. 22, PRT1, Artificial>(HCDR2-B12L / R17L / hE8L) WINPGSGNTKYNEKFKG <SEQ ID No. 23, PRT1, Artificial>(HCDR3-B12L) EGITVY <SEQ ID No. 24, PRT1, Artificial>(HCDR3-R17L) EGTTVY <SEQ ID No. 25, PRT1, Artificial>(LCVR-B12L / R17L) DIVMTQTPLSLSVTPGQPASISC KSSQSLLYSRGKTYLN WLLQKPGQSPQLLIY AVSKLDS GVPDRFSGSGSGTDFTLKISRVEAEDVGVYYC VQGTHYPFT FGQGTKLEIK <SEQ ID No. 26, PRT1, Artificial>(HCVR-B12L) QVQLVQSGAEVKKPGSSVKVSCKAS GYDFTRYYIN WVRQAPGQGLEWMG WINPGSGNTKYNEKFKG RVTITADESTSTAYMELSSLRSEDTAVYYCAR EGITVY WGQGTTVTVSS <SEQ ID No. 27, PRT1, Artificial>(HCVR-R17L) QVQLVQSGAEVKKPGSSVKVSCKAS GYTFTRYYIN WVRQAPGQGLEWMG WINPGSGNTKYNEKFKG RVTITADESTSTAYMELSSLRSEDTAVYYCAR EGTTVY WGQGTTVTVSS <SEQ ID No. 28, PRT1, Artificial>(LC-B12L / R17L) DIVMTQTPLSLSVTPGQPASISC KSSQSLLYSRGKTYLN WLLQKPGQSPQLLIY AVSKLDS GVPDRFSGSGSGTDFTLKISRVEAEDVGVYYC VQGTHYPFT FGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC <SEQ ID NO: 29, PRT1, artificial> (HC-B12L) QVQLVQSGAEVKKPGSSVKVSCKAS GYDFTRYYIN WVRQAPGQGLEWMG WINPGSGNTKYNEKFKG RVTITADESTSTAYMELSSLRSEDTAVYYCAR EGITVY WGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG <SEQ ID NO: 30, PRT1, artificial> (HC-R17L) QVQLVQSGAEVKKPGSSVKVSCKAS GYTFTRYYIN WVRQAPGQGLEWMG WINPGSGNTKYNEKFKG RVTITADESTSTAYMELSSLRSEDTAVYYCAR EGTTVYWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG N3pGlu Aβ(SEQ ID NO: 31) [pE]FRHDSGYEVHHQKLVFFAEDVGSNKGAIIGLMVGGVVIA <SEQ ID NO: 32, PRT1, artificial>(LCVR-hE8L) DIVMTQTPLSLSVTPGQPASISC KSSQSLLYSRGKTYLN WLLQKPGQSPQLLIY AVSKLDS GVPDRFSGSGSGTDFTLKISRVEAEDVGVYYC VQGTHYPFT FGQGTKLEIK <SEQ ID NO: 33, PRT1, artificial>(LC-hE8L) DIVMTQTPLSLSVTPGQPASISC KSSQSLLYSRGKTYLN WLLQKPGQSPQLLIY AVSKLDS GVPDRFSGSGSGTDFTLKISRVEAEDVGVYYC VQGTHYPFT FGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC <SEQ ID NO: 34, PRT1, artificial>(HCVR-hE8L) QVQLVQSGAEVKKPGSSVKVSCKAS GYTFTDYYIN WVRQAPGQGLEWMG WINPGSGNTKYNEKFKG RVTITADESTSTAYMELSSLRSEDTAVYYCAR EGETVY WGQGTTVTVSS <SEQ ID NO: 35, PRT1, artificial>(HC-hE8L) QVQLVQSGAEVKKPGSSVKVSCKAS GYTFTDYYIN WVRQAPGQGLEWMG WINPGSGNTKYNEKFKG RVTITADESTSTAYMELSSLRSEDTAVYYCAR EGETVY WGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG <SEQ ID NO: 36, PRT1, artificial>(HCDR1-hE8L) GYTFTDYYIN <SEQ ID NO: 37, PRT1, artificial>(HCDR3-hE8L) EGETVY <SEQ ID NO: 38, PRT1, artificial>(Aβ1-42) DAEFRHDSGYEVHHQKLVFFAEDVGSNKGAIIGLMVGGVVIA <SEQ ID NO: 39, PRT1, artificial>(LCVR-antibody VI) MVSSAQFLFLLVLWIQETNGDVVMTQTPLTLSVTIGQPASISCKSSQSLL YSDGKTYLNWLLQRPGQSPMRLIYLVSKLDSGVPDRFTGSGSGTDFTLK ISRVEAEDLGVYYCVQGTHFPFTFGSGTKLEIKRADAAPTVSIFPP <SEQ ID NO:40, PRT1, artificial>(HCVR - antibody VI) MGWSGVFLFLLSGTAGVHSEVQLQQSGPELVKPGASMKISCKASGYSFTG YTMNWVKQSHGKNLEWIGLINPYSGVTRYNQKFKGKATLIVDKSSSTAYM ELLSLTSEDSAVYYCTREAKREWDETYWGQGTLVTVSAAKTTPPSV <SEQ ID NO:41, PRT1, artificial>(LCVR - antibody VII) MVSTAQFLFLLVLWIQETNGDVVMTQTPLTLSVTIGQPASISCKSSQSLL YSDGKTYLNWLLQRPGQSPMRLIYLVSKLDSGVPDRFTGSGSGTDFTLK ISRVEAEDLGVYYCVQGTHFPFTFGSGTKLEIKRADAAPTVSIFPPS <SEQ ID NO:42, PRT1, artificial>(HCVR - antibody VII) MGWSGVFIFLLSGTAGVHSEVQLQQSGPELVKPGASMKISCKASGYSFTG YTMNWVKQSHGKNLEWIGLINPYNGVTRYNQKFKGKATLIVDKSSSTAY MELLSLTSEDSAVYYCTREAKREWDETYWGQGTLVTVSAAKTTPPSVYPL <SEQ ID NO:43, PRT1, artificial>(LCVR - antibody VIII)[[ID=�5]] MKLPVRLLVLVFWIPVSSSDVVMTQTPLSLPVSLGDQASISCRSSQSLVH SDGNTYLHWYLQKPGQSPKLLIYKVSNRFSGVPDRFSGSGSGTDFTLKIS RVEAEDLGVYFCSQSTHVPPTFGGGTKLEIKRADAAPTVSIFPPSS <SEQ ID NO: 44, PRT1, artificial> (HCVR - antibody VIII) MDFGLSLLIFVLILKGVQCEVKLVESGGGLVQPGGSRKLSCAASGFTFSDY GMAWVRQAPGKGPEWVAFISNLAYSIYYADTVTGRFTISRENAKNTLYLEM SSLRSEDTAMYYCARYDYDNILDYVMDYWGQGTSVTVSSAKTTPPSVYPL <SEQ ID NO: 45, PRT1, artificial> (LCVR - antibody IX) MKLPVRLLVLWIQETKGDVVLTQTPLTLSVTIGQPASISCKSSQSLLYSN GKTYLNWLLQRPGQSPKRLIYVVSKLDSGVPDRFTGSGSGTDFTLKISRV EAEDLGVYYCVQGTHFPFTFGSGTKLEIKRADAAPTVSIFPPSS <SEQ ID NO: 46, PRT1, artificial> (HCVR - antibody IX) MGWSGVFLFLLSVTEGVHSQVQLQQSGAELVRPGSSVKISCKASGYIFNN YWINWVKQRPGQGLEWIGQIYPGDGDTNYNGKFKGKATLTADKSSSTAY MQLSSLTSEDSAVYFCAREGYIVYWGQGTLVTVSAAKTTPPSVYPL <SEQ ID NO: 47, PRT1, artificial> (LCVR - antibody X) DVVMTQTPLSLPVSLGDQASISCRSSQSLLHSNGNTYLHWYLQKPGQSPKLLI YKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDLGVYFCSQSTHVPLTFGAGT <SEQ ID NO:48, PRT1, Artificial>(HCVR - Antibody X) QLQQSGAELMKPGASVKISCKATGYTFSSYWIEWVKQRPGHGLEWIGEILPGR GSTHYNEKFKGKATFTADTSSNTAYMQLSSLTSEDSAVYYCARSPITTSDYWG QGTTLTVSS <SEQ ID NO:49, PRT1, Artificial>(LCVR - Antibody XI) SCRSSQSLVHSNGNTYLHWYLQKPGQSPKLLIYKVSNRFSGVPDRFSGSGSGT DFTLKISRVEAEDLGVYFCSQSTHVPLTFGAGT <SEQ ID NO:50, PRT1, Artificial>(HCVR - Antibody XI) AELKKPGASVKISCKATGYTFRSYWIEWVKQRPGHGLEWIGEILPGRGSTKY NEKFKGKATFTADTSSNTANMQLSSLTSEDSAVYYCARSPITTSDY <SEQ ID NO:51, PRT1, Artificial>(LCVR - Antibody XII) DVVLTQTPFTLSVTIGQPASISCKSSQSLLHSNGESYLNWLFQRPGQSPKRLIY AVSKLDSGVPDRFTGSGSGTDFTLKISRVEAEDLGVYYCVQGTHFPFTFGGG TKLEIK <SEQ ID NO:52, PRT1, Artificial>(HCVR - Antibody XII) QIQLQQSGPELVKPGAAVKISCKASGYTFTDYYLNWVKQKPGQGLEWIGWIY PGSGNVKYNEKFKGKATLTADTSSNTAHMQLSSLTSEDTAVYFCTREGLIVY WGQGTLVTVSA <SEQ ID NO:53, PRT1, artificial>(LCVR - antibody XIII) DVVLTQTPLTLSVTIGQPASISCKSSQSLLYSNGKTYLNWLLQRPGQSPKRLIY VVSKLDSGVPDRFTGSGSGTDFTLKISRVEAEDLGVYYCVQGTHYPFTFGGGT KLEIK <SEQ ID NO:54, PRT1, artificial>(HCVR - antibody XIII) QIQLQQSGPDLVKPGASVKISCKASGYTFTDYYINWVKQKPGQGLEWIGWLNP GSGNTKYNEKFKGKATMTVDTTSSTVYMQLSSLTSEDSAVYFCTREGPIDYWG RGTSVTVSS <SEQ ID NO:55, PRT1, artificial>(LCVR - antibody XIV) DIVMTQTPLSLSVTPGQPASISCSSSQSLIYSDGNAYLHWYLQKP GQSPQLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVG VYYCTQSTHSPWTFGGGTKVEIK <SEQ ID NO:56, PRT1, artificial>(HCVR - antibody XIV) EVQLVESGGGLVKPGGSLRLSCAASGYTFSRYSMSWVRQAPG KGLEWVGQINIRGCNTYYPDTVKGRFTISRDDSKNTLYLQMNS LKTEDTAVYYCTTGDFWGQGTLVTVSS <SEQ ID NO:57, PRT1, artificial>(LC - antibody XV) DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYA ASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPLTFGG GTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKV DNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQG LSSPVTKSFNRGEC <SEQ ID NO: 58, PRT1, artificial> (HC - antibody XV) QVQLVESGGGVVQPGRSLRLSCAASGFAFSSYGMHWVRQAPGKGLEWVAV IWFDGTKKYYTDSVKGRFTISRDNSKNTLYLQMNTLRAEDTAVYYCARDR GIGARRGPYYMDVWGKGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALG CLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSL GTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLF PPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPRE EQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQP REPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKT TPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSL SPG <SEQ ID NO: 59, PRT1, artificial> (LC - antibody XVI) DIVLTQSPATLSLSPGERATLSCRASQSVSSSYLAWYQQKPGQAPRLLIYGASSRATGVPARFSGSGSGTDFTLTISSLEPEDFATYYCLQIYNMPITFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC <SEQ ID NO: 60, PRT1, Artificial> (HC - Antibody XVI) QVELVESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSAINAS GTRTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARGKGNTHKPYGYVRYFDVWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK <SEQ ID NO: 61, PRT1, Artificial> (LC - Antibody XVII) DIVMTQSPLSLPVTPGEPASISCRSSQSLVYSNGDTYLHWYLQKPGQSPQLLIY KVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCSQSTHVPWTFGQGT KVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQ SGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSF NRGEC <SEQ ID NO: 62, PRT1, artificial> (HC - antibody XVII) EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYGMSWVRQAPGKGLELVASIN SNGGSTYYPDSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCASGDYWG QGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSG ALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKR VESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDP EVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKC KVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPS DIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLG <SEQ ID NO: 63, PRT1, artificial> (LC - antibody XVIII) DVVMTQSPLSLPVTPGAPASISCRSSQSIVHSNGNTYLEWYLQKPGQSPK LLIYKVSNRFSGVPDRFSGSGSGTDFTLRISRVEAEDVGIYYCFQGSHVP PTFGPGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAK VQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACE VTHQGLSSPVTKSFNRGEC <SEQ ID NO: 64, PRT1, artificial>(HC - antibody XVIII) EVQLVESGGGLVQPGGSLRLSCSASGFTFSSFGMHWVRQAPGKGLEWVAY ISSGSSTIYYGDTVKGRFTISRDNAKNSLFLQMSSLRAEDTAVYYCAREG GYYYGRSYYTMDYWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALG CLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSL GTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLF PPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPRE EQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQP REPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKT TPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSL SPGK <SEQ ID NO: 65, PRT1, artificial>(LC - antibody XIX) DVVMTQSPLSLPVTLGQPASISCRSSQSLIYSDGNAYLHWFLQKPGQSPRLLIY KVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCSQSTHVPWTFGQGT KVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQ SGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSF NRGEC <SEQ ID NO: 66, PRT1, artificial>(HC - antibody XIX) EVQLVESGGGLVQPGGSLRLSCAASGFTFSRYSMSWVRQAPGKGLELVAQINS VGNSTYYPDTVKGRFTISRDNAKNTLYLQMNSLRAEDTAVYYCASGDYWGQG TLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTS GVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFN WYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKAL PAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESN GQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

Claims

1. A pharmaceutical product for the treatment of Alzheimer's disease (AD) in human patients requiring treatment for Alzheimer's disease (AD), wherein the pharmaceutical product contains an anti-N3pGlu Aβ antibody up to four doses of 10 mg / kg, administered intravenously to the patient once a month, and the anti-N3pGlu Aβ antibody in the pharmaceutical product has a light chain of SEQ ID NO: 28 and a heavy chain of SEQ ID NO:

29.

2. The pharmaceutical product according to claim 1, wherein the patient is suffering from preclinical AD, prodromal AD, mild AD, moderate AD, or severe AD.

3. The pharmaceutical product according to claim 2, wherein the patient is suffering from preclinical AD.

4. The pharmaceutical product according to claim 2, wherein the patient is suffering from prodromal AD.

5. The pharmaceutical product according to claim 1, wherein the patient possesses one or two APOE e4 alleles.

6. The pharmaceutical product according to claim 1, comprising a 700 mg dose of anti-N3pGlu Aβ antibody for a patient weighing 70 kg.

7. The pharmaceutical agent according to claim 1, wherein administration of an anti-N3pGlu Aβ antibody causes a reduction in Aβ deposits in the patient's brain.

8. The pharmaceutical agent according to claim 1, wherein administration of an anti-N3pGlu Aβ antibody causes a delay in cognitive decline in a patient.

9. The pharmacopoeia according to claim 1, wherein the reduction in Aβ deposits in the patient's brain is maintained for at least 18 months after the last dose of the anti-N3pGlu Aβ antibody.

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