ANTI-N3pGlu AMYLOID BETA PEPTIDE ANTIBODIES AND USES THEREOF

Abstract

The invention is directed to a short term induction treatment with anti-N3pGlu A.beta. antibodies of a disease characterized by deposition of A.beta. in the brain, that include Alzheimer's disease (A.beta.), Down's syndrome, and cerebral amyloid angiopathy (CAA). In certain embodiments, patients are administered an induction dose of 10 to 60 mg/kg of an anti-N3pGlu A.beta. antibody for a period of 6 months or less.

Description

[0001] The present invention relates to treatment of a disease with anti-N3pGlu A.beta. antibodies, wherein the disease is characterized by deposition of Amyloid Beta (A.beta.) in a patient. More specifically, the present invention relates to a short term induction treatment with N3pGlu A.beta. antibodies of a disease characterized by deposition of A.beta. in the brain, including Alzheimer's disease (A.beta.). Down's syndrome, and cerebral amyloid angiopathy (CAA).

[0002] The deposits found in plaques of human patients are comprised of a heterogeneous mixture of A.beta. peptides. N3pGlu A.beta., also referred to as N3pE A.beta., AV pE3-42, or AN.sub.p3-42, is a truncated form of AV peptide and is found only in plaques. N3pGlu A.beta. lacks the first two amino acid residues at the N-terminus of human A.beta. and has a pyroglutamate which was derived from the glutamic acid at the third amino acid position. Although N3pGlu A.beta. peptide is a minor component of the deposited A.beta. in the brain, studies have demonstrated that N3pGlu A.beta. peptide has aggressive aggregation properties and accumulates early in the deposition cascade.

[0003] Antibodies to N3pGlu A.beta. are known in the art. For example, U.S. Pat. No. 8,679,498 discloses anti-N3pGlu A.beta. antibodies and methods of treating diseases such as Alzheimer's disease, with the antibodies. Passive immunization by long term chronic administration of antibodies against the A.beta., including N3pGlu A.beta., found in deposits has been shown to disrupt the A.beta. aggregates and promote the clearance of plaques in the brain in various animal models. However, in humans long term chronic administration of A.beta. antibodies has led to adverse events that include amyloid-related imaging abnormalities (ARIA), suggestive of vasogenic edema and sulcal effusions (ARIA-E), as well as microhaemorrhages and haemosiderin deposits (ARIA-H) as well as infusion site reactions and risk of 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.

[0004] The present invention overcomes the problems associated with long term chronic administration. Applicants found that short term induction treatment with relatively high doses of anti-N3pGlu A.beta. antibodies promotes significant clearance of plaques in the brain of patients with A.beta. deposits, and this clearance is surprisingly maintained for an extended period of time. The short term induction treatment can include a one-time dose of an anti-N3pGlu antibody, a biweekly dose of an anti-N3pGlu A.beta. antibody for a period of 6 months, or a monthly dose of an anti-N3pGlu A.beta. antibody for a period of 6 months or less. In addition to reducing the adverse events caused by long term chronic dosing of antibodies against A.beta., additional benefits of the short term induction treatment include improved patient compliance, reduced infusion site reactions and risk of immunogenicity, significant cost savings for treatment as well as reduced disruption to the patient and caregiver's lives.

[0005] As such, the present invention provides a method of treating a disease characterized by deposition of A.beta., comprising administering to a patient positive for amyloid deposits an induction dose of 10 to 60 mg/kg of an anti-N3pGlu A.beta. antibody for a period of 6 month or less. Particularly, the present invention provides a method of treating a disease characterized by deposition of A.beta., comprising administering to a patient positive for amyloid deposits an induction dose of 10 to 60 mg/kg of an anti-N3pGlu A.beta. antibody for a period of 6 month or less. More particularly, the present invention provides a method to treat a disease characterized by A.beta. deposits in the brain of a human patient comprising administering to the patient positive for amyloid deposits a one-time induction dose of 10 to 60 mg/kg of an anti-N3pGlu antibody. In another more particular embodiment, the present invention provides a method to treat a disease characterized by A.beta. deposits in the brain of a patient positive for amyloid deposits comprising administering to the patient an induction dose of 10 to 60 mg/kg every two weeks of an anti-N3pGlu A.beta. antibody for a period of 6 months or less. In another more particular embodiment, the present invention provides a method to treat a disease characterized by A.beta. deposits in the brain of a patient positive for amyloid deposits comprising administering to the patient a monthly induction dose of 10 to 60 mg/kg of an anti-N3pGlu A.beta. antibody for a period of 6 months or less. In a preferred embodiment of the present invention, the one-time induction dose administered to a patient is 10 mg/kg, 15 mg/kg, 20 mg/kg or 40 mg/kg. In a alternative preferred embodiment of the present invention, the biweekly and monthly induction dose administered to a 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 A.beta. antibody is selected from Table A.

[0006] Alternatively, the present invention provides a method of treating a disease characterized by deposition of A.beta., comprising administering to a patient positive for amyloid deposits a dose of 10 to 60 mg/kg of an anti-N3pGlu A.beta. antibody followed optionally by one or more dose of 10 to 60 mg/kg of an anti-N3pGlu A.beta. antibody for a period of 6 month or less Particularly, the present invention provides a method to treat a disease characterized by A.beta. deposits in the brain of a patient positive for amyloid deposits comprising administering to the patient 1-12 separate doses of 10 to 60 mg/kg of an anti-N3pGlu A.beta. antibody in a period of 6 months or less. In another more particular embodiment, the present invention provides a method to treat a disease characterized by A.beta. deposits in the brain of a patient positive for amyloid deposits comprising administering to the patient 6 separate doses of 10 to 60 mg/kg of an anti-N3pGlu A.beta. antibody for a period of 6 months or less. Alternatively, the present invention provides a method to treat a disease characterized by A.beta. deposits in the brain of a patient positive for amyloid deposits comprising administering to the patient 12 separate doses of 10 to 60 mg/kg of an anti-N3pGlu A.beta. antibody for a period of 6 months or less. In a preferred embodiment of the present invention, the 6 or 12 separate doses administered to a patient are 20 to 40 mg/kg or 15 to 30 mg/kg (e.g., 6 separate doses of 20 mg/kg administered to a patient over 6 months). In another preferred embodiment, the one-time, 6 or 12 separate doses administered to a patient is 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 by monthly interval and the 12 separate doses are separated by intervals of 2 weeks. In a preferred embodiment, the anti-N3pGlu A.beta. antibody is selected from Table A.

[0007] In an embodiment, the present invention provides a method of treating or preventing clinical or pre-clinical Alzheimer's disease, Down's syndrome, and clinical or pre-clinical CAA in a patient positive for amyloid deposits, comprising administering to a patient induction dose of 10 to 60 mg/kg of an anti-N3pGlu A.beta. antibody for a period of 6 month or less. Particularly, the present invention provides a method of treating or preventing clinical or pre-clinical Alzheimer's disease, Down's syndrome, and clinical or pre-clinical CAA in a patient positive for amyloid deposits, comprising administering to the patient a one-time induction dose of 10 to 60 mg/kg of an anti-N3pGlu A.beta. antibody. In another particular embodiment, the present invention provides a method of treating or preventing clinical or pre-clinical Alzheimer's disease, Down's syndrome, and clinical or pre-clinical CAA in a patient positive for amyloid deposits, administering to the an induction dose of 10 to 60 mg/kg every two weeks of an anti-N3pGlu A.beta. antibody for a period of 6 months or less. In another particular embodiment, the present invention provides a method of treating or preventing clinical or pre-clinical Alzheimer's disease, Down's syndrome, and clinical or pre-clinical CAA in a patient positive for amyloid deposits, administering to the patient a monthly induction dose of 10 to 60 mg/kg of an anti-N3pGlu A.beta. antibody for a period of 6 months or less. In a preferred embodiment of the invention for treating or preventing clinical or pre-clinical Alzheimer's disease, Down's syndrome, and clinical or pre-clinical CAA, the one-time, biweekly (every two weeks) and monthly induction dose administered to a patient is 20 to 40 mg/kg or 15 to 30 mg/kg. In a preferred embodiment of the present invention, the one-time induction dose administered to a patient is 10 mg/kg, 15 mg/kg, 20 mg/kg or 40 mg/kg. In a alternative preferred embodiment of the present invention, the biweekly and monthly induction dose administered to a 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 A.beta. antibody is selected from Table A. The anti-N3pGlu A.beta. antibody is preferably selected from Table A.

[0008] In another embodiment, the present invention provides a method of treating or preventing preclinical AD, prodromal AD (sometimes also referred to as A.beta.-related mild cognitive impairment. MCI or MCI due to AD), mild AD, moderate AD and severe AD in a patient positive for amyloid deposits, comprising administering to a patient an induction dose of an anti-N3pGlu A.beta. antibody for a period of 6 months or less. Particularly, the present invention provides a method of treating or preventing preclinical AD, prodromal AD, mild AD, moderate AD and severe AD in a patient positive for amyloid deposits, comprising administering to a patient an induction dose of 10 to 60 mg/kg of an anti-N3pGlu A.beta. antibody for a period of 6 month or less. More particularly, the present invention provides a method of treating or preventing preclinical AD, prodromal AD, mild AD, moderate AD and severe AD in a patient positive for amyloid deposits, comprising administering to the patient a one-time induction dose of 10 to 60 mg/kg of an anti-N3pGlu A.beta. antibody. In another more particular embodiment, the present invention provides a method of treating or preventing preclinical AD, prodromal AD, mild AD, moderate AD and severe AD in a patient positive for amyloid deposits, administering to the an induction dose of 10 to 60 mg/kg every two weeks of an anti-N3pGlu A.beta. antibody for a period of 6 months or less. In another more particular embodiment, the present invention provides a method of treating or preventing preclinical AD, prodromal AD, mild AD, moderate AD and severe AD in a patient positive for amyloid deposits, administering to the patient a monthly induction dose of 10 to 60 mg/kg of an anti-N3pGlu A.beta. antibody for a period of 6 months or less. In a preferred embodiment of the invention for treating or preventing preclinical AD, prodromal AD, mild AD, moderate AD and severe AD, the one-time, biweekly (every two weeks) and monthly induction dose administered to a patient is 20 to 40 mg/kg or 15 to 30 mg/kg. In a preferred embodiment of the present invention, the one-time induction dose administered to a 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 biweekly and monthly induction dose administered to a 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 A.beta. antibody is selected from Table A. The anti-N3pGlu A.beta. antibody is preferably selected from Table A.

[0009] In another embodiment, the present invention provides a method of slowing cognitive decline in a patient diagnosed with pre-clinical Alzheimer's disease or clinical Alzheimer's disease, comprising administering to a patient an induction dose of an anti-N3pGlu A.beta. antibody for a period of 6 months or less. Particularly, the present invention a method of slowing cognitive decline in a patient diagnosed with pre-clinical Alzheimer's disease or clinical Alzheimer's disease, comprising administering to a patient an induction dose of 10 to 60 mg/kg of an anti-N3pGlu A.beta. antibody for a period of 6 month or less. More particularly, the present invention provides a method of slowing cognitive decline in a patient diagnosed with pre-clinical Alzheimer's disease or clinical Alzheimer's disease, comprising administering to the patient a one-time induction dose of 10 to 60 mg/kg of an anti-N3pGlu A.beta. antibody. In another more particular embodiment, the present invention provides a method of slowing cognitive decline in a patient diagnosed with pre-clinical Alzheimer's disease or clinical Alzheimer's disease, administering to the patient an induction dose of 10 to 60 mg/kg every two weeks of an anti-N3pGlu A.beta. antibody for a period of 6 months or less. In another more particular embodiment, the present invention provides a method of slowing cognitive decline in a patient diagnosed with pre-clinical Alzheimer's disease or clinical Alzheimer's disease, administering to the patient a monthly induction dose of 10 to 60 mg/kg of an anti-N3pGlu A.beta. antibody for a period of 6 months or less. In a preferred embodiment of the invention for slowing cognitive decline in a patient diagnosed with pre-clinical Alzheimer's disease or clinical Alzheimer's disease, the one-time, biweekly and monthly induction dose administered to a patient is 20 to 40 mg/kg or 15 to 30 mg/kg. In a preferred embodiment of the present invention, the one-time induction dose administered to a 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 biweekly and monthly induction dose administered to a 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 A.beta. antibody is selected from Table A. The anti-N3pGlu A.beta. antibody is preferably selected from Table A.

[0010] In another embodiment, the present invention provides a method of slowing functional decline in a patient diagnosed with pre-clinical Alzheimer's disease or clinical Alzheimer's disease, comprising administering to a patient an induction dose of an anti-N3pGlu A.beta. antibody for a period of 6 months or less. Particularly, the present invention a method of slowing functional decline in a patient diagnosed with pre-clinical Alzheimer's disease or clinical Alzheimer's disease, comprising administering to a patient an induction dose of 10 to 60 mg/kg of an anti-N3pGlu A.beta. antibody for a period of 6 month or less. More particularly, the present invention provides a method of slowing functional decline in a patient diagnosed with pre-clinical Alzheimer's disease or clinical Alzheimer's disease, comprising administering to the patient a one-time induction dose of 10 to 60 mg/kg of an anti-N3pGlu A.beta. antibody. In another more particular embodiment, the present invention provides a method of slowing functional decline in a patient diagnosed with pre-clinical Alzheimer's disease or clinical Alzheimer's disease, administering to the patient an induction dose of 10 to 60 mg/kg every two weeks of an anti-N3pGlu A.beta. antibody for a period of 6 months or less. In another more particular embodiment, the present invention provides a method of slowing functional decline in a patient diagnosed with pre-clinical Alzheimer's disease or clinical Alzheimer's disease, administering to the patient a monthly induction dose of 10 to 60 mg/kg of an anti-N3pGlu A.beta. antibody for a period of 6 months or less. In a preferred embodiment of the invention for slowing functional decline in a patient diagnosed with pre-clinical Alzheimer's disease or clinical Alzheimer's disease, the one-time, biweekly and monthly induction dose administered to a patient is 20 to 40 mg/kg or 15 to 30 mg/kg. In a preferred embodiment of the present invention, the one-time induction dose administered to a 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 biweekly and monthly induction dose administered to a patient is 10 mg/kg, 15 mg/kg, 20 mg/kg or 40 mg/kg for a period of 6 months. The anti-N3pGlu A.beta. antibody is preferably selected from Table A.

[0011] In another embodiment the present invention provides a method of reducing brain A.beta. amyloid plaque load in a patient diagnosed with pre-clinical or clinical Alzheimer's disease, comprising administering to a patient an induction dose of an anti-N3pGlu A.beta. antibody for a period of 6 months or less. Particularly, the present invention provides a method of reducing brain A.beta. amyloid plaque load in a patient diagnosed with pre-clinical or clinical Alzheimer's disease, comprising administering to a patient an induction dose of 10 to 60 mg/kg of an anti-N3pGlu A.beta. antibody for a period of 6 month or less. More particularly, the present invention provides a method of reducing brain A.beta. amyloid plaque load in a patient diagnosed with pre-clinical or clinical Alzheimer's disease, comprising administering to the patient a one-time induction dose of 10 to 60 mg/kg of an anti-N3pGlu A.beta. antibody. In another more particular embodiment, the present invention provides a method of reducing brain A.beta. amyloid plaque load in a patient diagnosed with pre-clinical or clinical Alzheimer's disease, administering to the patient an induction dose of 10 to 60 mg/kg every two weeks of an anti-N3pGlu A.beta. antibody for a period of 6 months or less. In another more particular embodiment, the present invention provides a method of reducing brain A.beta. amyloid plaque load in a patient diagnosed with pre-clinical or clinical Alzheimer's disease, administering to the patient a monthly induction dose of 10 to 60 mg/kg of an anti-N3pGlu A.beta. antibody for a period of 6 months or less. In a preferred embodiment of the invention for a method of reducing brain A.beta. amyloid plaque load in a patient diagnosed with pre-clinical or clinical Alzheimer's disease, the one-time, biweekly and monthly induction dose administered to a patient is 20 to 40 mg/kg or 15 to 30 mg/kg. In a preferred embodiment of the present invention, the one-time induction dose administered to a 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 biweekly and monthly induction dose administered to a patient is 10 mg/kg, 15 mg/kg, 20 mg/kg or 40 mg/kg for a period of 6 months. The anti-N3pGlu A.beta. antibody is preferably selected from Table A.

[0012] In another embodiment the present invention provides a method of preventing memory loss or cognitive decline in clinically asymptomatic patients with low levels of A.beta.1-42 in the cerebrospinal fluid (CSF) and/or A.beta. deposits in the brain, comprising administering to a patient an induction dose of an anti-N3pGlu A.beta. antibody for a period of 6 months or less. Particularly, the present invention provides a method of preventing memory loss or cognitive decline in clinically asymptomatic patients with low levels of A.beta.1-42 in the cerebrospinal fluid (CSF) and/or A.beta. deposits in the brain, comprising administering to a patient an induction dose of 10 to 60 mg/kg of an anti-N3pGlu A.beta. antibody for a period of 6 month or less. More particularly, the invention provides a method of preventing memory loss or cognitive decline in clinically asymptomatic patients with low levels of A.beta.1-42 in the cerebrospinal fluid (CSF) and/or A.beta. deposits in the brain, comprising administering to the patient a one-time induction dose of 10 to 60 mg/kg of an anti-N3pGlu A.beta. antibody. In another more particular embodiment, the present invention provides a method of preventing memory loss or cognitive decline in clinically asymptomatic patients with low levels of A.beta.1-42 in the cerebrospinal fluid (CSF) and/or A.beta. deposits in the brain, comprising administering to the patient an induction dose of 10 to 60 mg/kg every two weeks of an anti-N3pGlu A.beta. antibody for a period of 6 months or less. In another more particular embodiment, the present invention provides a method of preventing memory loss or cognitive decline in clinically asymptomatic patients with low levels of A.beta.1-42 in the cerebrospinal fluid (CSF) and/or A.beta. deposits in the brain, administering to the patient a monthly induction dose of 10 to 60 mg/kg of an anti-N3pGlu A.beta. antibody for a period of 6 months or less.

[0013] In a preferred embodiment of the invention for a method of preventing memory loss or cognitive decline in clinically asymptomatic patients with low levels of A.beta.1-42 in the cerebrospinal fluid (CSF) and/or A.beta. deposits in the brain, the one-time, biweekly and monthly induction dose administered to a patient is 20 to 40 mg/kg or 15 to 30 mg/kg. In another preferred embodiment of the present invention, the one-time induction dose administered to a 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 biweekly and monthly induction dose administered to a patient is 10 mg/kg, 15 mg/kg, 20 mg/kg or 40 mg/kg for a period of 6 months. The anti-N3pGlu A.beta. antibody is preferably selected from Table A.

[0014] In another embodiment the present invention provides a method of treating clinically asymptomatic patients known to have an Alzheimer's disease-causing genetic mutation, comprising administering to a patient an induction dose of an anti-N3pGlu A.beta. antibody for a period of 6 months or less. Particularly, the present provides a method of treating clinically asymptomatic patients known to have an Alzheimer's disease-causing genetic mutation, comprising administering to a patient an induction dose of 10 to 60 mg/kg of an anti-N3pGlu A.beta. antibody for a period of 6 month or less. More particularly, the invention provides a method of treating clinically asymptomatic patients known to have an Alzheimer's disease-causing genetic mutation, comprising administering to the patient a one-time induction dose of 10 to 60 mg/kg of an anti-N3pGlu A.beta. antibody. In another more particular embodiment, the present invention provides a method of treating clinically asymptomatic patients known to have an Alzheimer's disease-causing genetic mutation, comprising administering to the patient an induction dose of 10 to 60 mg/kg every two weeks of an anti-N3pGlu A.beta. antibody for a period of 6 months or less. In another more particular embodiment, the present invention provides a method of treating clinically asymptomatic patients known to have an Alzheimer's disease-causing genetic mutation, administering to the patient a monthly induction dose of 10 to 60 mg/kg of an anti-N3pGlu A.beta. antibody for a period of 6 months or less. In the present invention "clinically asymptomatic patients known to have an Alzheimer's disease-causing genetic mutation", include patients known to have a PSEN1 E280A Alzheimer's disease-causing genetic mutation (Paisa mutation), a genetic mutation that causes autosomal-dominant Alzheimer's disease or are at higher risk for developing A.beta. by virtue of carrying one or two APOE e4 alleles comprising administering to the said patient a pharmaceutical composition of the present invention. In a preferred embodiment of the invention for a method of treating clinically asymptomatic patients known to have an Alzheimer's disease-causing genetic mutation, the one-time, biweekly and monthly induction dose administered to a patient is 20 to 40 mg/kg or 15 to 30 mg/kg. In another preferred embodiment of the present invention, the one-time induction dose administered to a 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 biweekly and monthly induction dose adminstered to a patient is 10 mg/kg, 15 mg/kg, 20 mg/kg or 40 mg/kg for a period of 6 months. The anti-N3pGlu A.beta. antibody is preferably selected from Table A.

[0015] In a further embodiment, the present invention provides a method of treating a disease characterized by deposition of A.beta. in the brain, comprising administering to a patient an induction dose of an anti-N3pGlu A.beta. antibody for a period of 6 months or less, wherein the A.beta. deposit in the brain of a human patient is reduced by 35-100% within 6 months post induction dose treatment. Particularly, the present invention provides a method of treating a disease characterized by deposition of A.beta., comprising administering to a patient an induction dose of 10 to 60 mg/kg of an anti-N3pGlu A.beta. antibody for a period of 6 month or less, wherein the A.beta. deposit in the brain of a human patient is reduced by 35-100% within 6 months post induction dose treatment. More particularly, the present invention provides a method to treat a disease characterized by A.beta. deposits in the brain of a human patient comprising administering to the patient a one-time induction dose of 10 to 60 mg/kg of an anti-N3pGlu A.beta. antibody, wherein the A.beta. deposit in the brain of a human patient is reduced by 35-100% within 6 months post induction dose treatment.

[0016] In another more particular embodiment, the present invention provides a method to treat a disease characterized by A.beta. deposits in the brain of a patient comprising administering to the patient an induction dose of 10 to 60 mg/kg every two weeks of an anti-N3pGlu A.beta. antibody for a period of 6 months or less, wherein the A.beta. deposit in the brain of a human patient is reduced by 35-100% within 6 months post induction dose treatment. In another more particular embodiment, the present invention provides a method to treat a disease characterized by A.beta. deposits in the brain of a patient comprising administering to the patient a monthly induction dose of 10 to 60 mg/kg of an anti-N3pGlu A.beta. antibody for a period of 6 months or less, wherein the A.beta. deposit in the brain of a human patient is reduced by 35-100% within 6 months post induction dose treatment. In a preferred embodiment of the present invention, the one-time induction dose administered to a 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 biweekly and monthly induction dose administered to a patient is 10 mg/kg, 15 mg/kg, 20 mg/kg or 40 mg/kg for a period of 6 months. The anti-N3pGlu A.beta. antibody is preferably selected from Table A.

[0017] In an embodiment, the present invention provides a method of treating clinical or pre-clinical Alzheimer's disease, Down's syndrome, and clinical or pre-clinical cerebral amyloid angiopathy, comprising administering to a patient an induction dose of an anti-N3pGlu A.beta. antibody for a period of 6 months or less, wherein the A.beta. deposit in the brain of a human patient is reduced by 35-100% within 6 months post induction dose treatment. Particularly, the present invention a method of treating clinical or pre-clinical Alzheimer's disease, Down's syndrome, and clinical or pre-clinical cerebral amyloid angiopathy, comprising administering to a patient an induction dose of 10 to 60 mg/kg of an anti-N3pGlu A.beta. antibody for a period of 6 month or less, wherein the A.beta. deposit in the brain of a human patient is reduced by 35-100% within 6 months post induction treatment. More particularly, the present invention provides a method of treating clinical or pre-clinical Alzheimer's disease. Down's syndrome, and clinical or pre-clinical cerebral amyloid angiopathy, comprising administering to the patient a one-time induction dose of 10 to 60 mg/kg of an anti-N3pGlu A.beta. antibody, wherein the A.beta. deposit in the brain of a human patient is reduced by 35-100% within 6 months post induction treatment. In another more particular embodiment, the present invention provides a method of treating clinical or pre-clinical Alzheimer's disease, Down's syndrome, and clinical or pre-clinical cerebral amyloid angiopathy, comprising administering to the patient an induction dose of 10 to 60 mg/kg every two weeks of an anti-N3pGlu A.beta. antibody for a period of 6 months or less, wherein the A.beta. deposit in the brain of a human patient is reduced by 35-100% within 6 months post induction treatment. In another more particular embodiment, the present invention provides a method of treating clinical or pre-clinical Alzheimer's disease, Down's syndrome, and clinical or pre-clinical cerebral amyloid angiopathy, comprising administering to the patient a monthly induction dose of 10 to 60 mg/kg of an anti-N3pGlu A.beta. antibody for a period of 6 months or less, wherein the A.beta. deposit in the brain of a human patient is reduced by 35-100% within 6 months post induction treatment. In an embodiment of the preferred invention, the anti-N3pGlu A.beta. antibody is selected from Table A.

[0018] In an embodiment, the present invention provides a method of slowing cognitive and/or functional decline in a patient diagnosed with pre-clinical Alzheimer's disease or clinical Alzheimer's disease, comprising administering to a patient an induction dose of an anti-N3pGlu A.beta. antibody for a period of 6 months or less, wherein the A.beta. deposit in the brain of a human patient is reduced by 35-100/6 within 6 months post induction dose treatment. Particularly, the present invention a method of slowing cognitive and/or functional decline in a patient diagnosed with pre-clinical Alzheimer's disease or clinical Alzheimer's disease, comprising administering to a patient an induction dose of 10 to 60 mg/kg of an anti-N3pGlu A.beta. antibody for a period of 6 month or less, wherein the A.beta. deposit in the brain of a human patient is reduced by 35-100% within 6 months post induction treatment. More particularly, the present invention provides a method of slowing cognitive and/or functional decline in a patient diagnosed with pre-clinical Alzheimer's disease or clinical Alzheimer's disease, comprising administering to the patient a one-time induction dose of 10 to 60 mg/kg of an anti-N3pGlu A.beta. antibody, wherein the A.beta. deposit in the brain of a human patient is reduced by 35-100% within 6 months post induction treatment. In another more particular embodiment, the present invention provides slowing cognitive and/or functional decline in a patient diagnosed with pre-clinical Alzheimer's disease or clinical Alzheimer's disease, comprising administering to the patient an induction dose of 10 to 60 mg/kg every two weeks of an anti-N3pGlu A.beta. antibody for a period of 6 months or less, wherein the A.beta. deposit in the brain of a human patient is reduced by 35-100% within 6 months post induction treatment. In another more particular embodiment, the present invention provides a method of slowing cognitive and/or functional decline in a patient diagnosed with pre-clinical Alzheimer's disease or clinical Alzheimer's disease, comprising administering to the patient a monthly induction dose of 10 to 60 mg/kg of an anti-N3pGlu A.beta. antibody for a period of 6 months or less, wherein the A.beta. deposit in the brain of a human patient is reduced by 35-100% within 6 months post induction treatment. In a preferred embodiment of the present invention, the one-time induction dose administered to a 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 biweekly and monthly induction dose administered to a patient is 10 mg/kg, 15 mg/kg, 20 mg/kg or 40 mg/kg for a period of 6 months. The anti-N3pGlu A.beta. antibody is preferably selected from Table A

[0019] In an embodiment, the present invention provides a method of treating clinical or pre-clinical Alzheimer's disease. Down's syndrome, and clinical or pre-clinical CAA with an anti-N3pGlu A.beta. antibody for a period of 6 months or less, wherein the A.beta. deposit in the brain of a human patient is reduced by 35-100% within 6 months post induction treatment and maintained in a reduced state for a period of 2-10 years post treatment. More preferably, for 2-5 years. Even more preferably, for 5-10 years. Particularly, the present invention provides a method of treating clinical or pre-clinical Alzheimer's disease, Down's syndrome, and clinical or pre-clinical cerebral amyloid angiopathy, comprising administering to a patient an induction dose of 10 to 60 mg/kg of an anti-N3pGlu A.beta. antibody for a period of 6 month or less, wherein the A.beta. deposit in the brain of a human patient is reduced by 35-100/6 within 6 months post induction treatment and maintained in a reduced state for a period of 2-10 years post treatment. More preferably, for 2-5 years. Even more preferably, for 5-10 years. More particularly, the present invention provides a method of treating clinical or pre-clinical Alzheimer's disease, Down's syndrome, and clinical or pre-clinical cerebral amyloid angiopathy, comprising administering to the patient a one-time induction dose of 10 to 60 mg/kg of an anti-N3pGlu A.beta. antibody, wherein the A.beta. deposit in the brain of a human patient is reduced by 35-100% within 6 months post induction treatment and maintained in a reduced state for a period of 1-10 years post treatment. More preferably, for 2-5 years. Even more preferably, for 5-10 years. In another more particular embodiment, the present invention provides a method of treating clinical or pre-clinical Alzheimer's disease, Down's syndrome, and clinical or pre-clinical cerebral amyloid angiopathy, comprising administering to the patient an induction dose of 10 to 60 mg/kg every two weeks of an anti-N3pGlu A.beta. antibody for a period of 6 months or less, wherein the A.beta. deposit in the brain of a human patient is reduced by 35-100% within 6 months post induction treatment and maintained in a reduced state for a period of 2-10 years post treatment. More preferably, for 2-5 years. Even more preferably, for 5-10 years. In another more particular embodiment, the present invention provides a method of treating clinical or pre-clinical Alzheimer's disease. Down's syndrome, and clinical or pre-clinical cerebral amyloid angiopathy, comprising administering to the patient a monthly induction dose of 10 to 60 mg/kg of an anti-N3pGlu A.beta. antibody for a period of 6 months or less, wherein the A.beta. deposit in the brain of a human patient is reduced by 35-100% within 6 months post induction treatment and maintained in a reduced state for a period of 2-10 years post treatment. More preferably, for 2-5 years. Even more preferably, for 5-10 years. In a preferred embodiment of the present invention, the one-time induction dose administered to a 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 biweekly and monthly induction dose administered to a patient is 10 mg/kg, 15 mg/kg, 20 mg/kg or 40 mg/kg for a period of 6 months. The anti-N3pGlu A.beta. antibody is preferably selected from Table A.

[0020] The present invention also provides a method of treating a disease characterized by deposition of A.beta. in the brain, comprising administering to a patient an induction dose of an anti-N3pGlu A.beta. antibody for a period of 6 months or less followed by a maintenance dose of an anti-N3pGlu A.beta. antibody every 12, 3, 5 or 10 years post completion of the induction treatment. Particularly, the present invention provides a method to treat a disease characterized by A.beta. deposits in the brain of a human patient comprising administering to the patient positive for amyloid deposits a one-time induction dose of 10 to 60 mg/kg of an anti-N3pGlu A.beta. antibody followed by a maintenance dose of an anti-N3pGlu A.beta. antibody every 1, 2, 3, 5 or 10 years post completion of the induction treatment. In another more particular embodiment, the present invention provides a method to treat a disease characterized by A.beta. deposits in the brain of a patient positive for amyloid deposits comprising administering to the patient an induction dose of 10 to 60 mg/kg every two weeks of an anti-N3pGlu A.beta. antibody for a period of 6 months or less followed by a maintenance dose of an anti-N3pGlu A.beta. antibody every 1, 2, 3, 5 or 10 years post completion of the induction treatment. In another more particular embodiment, the present invention provides a method to treat a disease characterized by A.beta. deposits in the brain of a patient positive for amyloid deposits comprising administering to the patient a monthly induction dose of 10 to 60 mg/kg of an anti-N3pGlu A.beta. antibody for a period of 6 months or less followed by a maintenance dose of an anti-N3pGlu A.beta. antibody every 1, 2, 3, 5 or 10 years post completion of the induction treatment. In one particular embodiment the maintenance dose of an A.beta. antibody is given every year. In another particular embodiment the maintenance dose of an A.beta. antibody is given every 2 years. In another particular embodiment the maintenance dose of an A.beta. antibody is given every 3 years. In another particular embodiment the maintenance dose of an A.beta. antibody is given every 5 years. In another particular embodiment the maintenance dose of an A.beta. antibody is given every 10 years. In another particular embodiment the maintenance dose of an AB antibody is given every 2 to 5 years. In another particular embodiment the maintenance dose of an A.beta. antibody is given every 5 to 10 years. In an embodiment of the present invention the same anti-N3pGlu A.beta. antibody is used for the induction and maintenance dose. In another embodiment of the present invention different anti-N3pGlu antibodies are used for the induction and maintenance doses. In an embodiment of the more particular invention, the anti-N3pGlu A.beta. antibody administered in the induction and maintenance dose is selected from Table A.

[0021] In an embodiment, the present invention also provides a method of treating a disease characterized by deposition of A.beta. in the brain, comprising administering to a patient an induction dose of an anti-N3pGlu A.beta. antibody for a period of 6 months or less in simultaneous, separate, or sequential combination with an effective amount of a BACE inhibitor. In a particular embodiment, the present invention provides a method of treating a disease characterized by deposition of A.beta. in the brain comprising administering to the patient a one-time induction dose of 10 to 60 mg/kg of an anti-N3pGlu A.beta. antibody in simultaneous, separate, or sequential combination with an effective amount of a BACE inhibitor. In another particular embodiment, the present invention provides a method of treating a disease characterized by deposition of A.beta. in the brain comprising administering to the patient an induction dose of 10 to 60 mg/kg every two weeks of an anti-N3pGlu A.beta. antibody for a period of 6 months or less in simultaneous, separate, or sequential combination with an effective amount of a BACE inhibitor. In another particular embodiment, the present invention provides a method of treating a disease characterized by deposition of A.beta. in the brain, comprising administering to the patient a monthly induction dose of 10 to 60 mg/kg of an anti-N3pGlu A.beta. antibody for a period of 6 months or less in simultaneous, separate, or sequential combination with an effective amount of a BACE inhibitor. In another preferred embodiment of the present invention, the one-time induction dose administered to a 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 biweekly and monthly induction dose administered to a patient is 10 mg/kg, 15 mg/kg, 20 mg/kg or 40 mg/kg for a period of 6 months.

[0022] In a more particular embodiment of the present invention, the anti-N3pGlu A.beta. antibody is preferably selected from Table A and the BACE inhibitor is selected from the group consisting of [0023] a) a compound of formula

[0023] ##STR00001## also referred to by the compound name N-[3-[(4aR,7aS)-2-amino-6-(5-fluoropyrimidin-2-yl)-4,4a,5,7-tetrahydropyr- rolo[3,4-d][1.3]thiazin-7a-yl]-4-fluoro-phenyl]-5-methoxy-pyrazine-2-carbo- xamide, or a pharmaceutically acceptable salt thereof; [0024] b) tosylate salt of N-[3-[(4aR,7aS)-2-amino-6-(5-fluoropyrimidin-2-yl)-4,4a,5,7-tetra- hydropyrrolo[3,4-d][1,3]thiazin-7a-yl]-4-fluoro-phenyl]-5-methoxy-pyrazine- -2-carboxamide; [0025] c) crystalline form of 2 N-[3-[(4aR,7aS)-2-amino-6-(5-fluoropyrimidin-2-yl)-4a,5,6,7-tetrahydropyr- rolo[3,4-d][1,3]thiazin-7a(4H)-yl]-4-fluoro-phenyl]-5-methoxy-pyrazine-2-c- arboxamide; and [0026] d) a compound of the formula

[0026] ##STR00002## also referred to by the compound name N-[3-[(5R)-3-Amino-5,6-dihydro-2,5-dimethyl-1,1-dioxido-2H-1,2,4-thiadiaz- in-5-yl]-4-fluorophenyl]-5-fluoro-2-pyridinecarboxamide or the generic name, verubecestat, or a pharmaceutically acceptable salt thereof.

[0027] In another more particular embodiment of the present invention, the anti-N3pGlu A.beta. antibody is preferably B12L and the BACE inhibitor is selected from the group consisting of [0028] a) a compound of formula

[0028] ##STR00003## also referred to by the compound name N-[3-[(4aR,7aS)-2-amino-6-(5-fluoropyrimidin-2-yl)-4,4a,5,7-tetrahydropyr- rolo[3,4-d][1.3]thiazin-7a-yl]-4-fluoro-phenyl]-5-methoxy-pyrazine-2-carbo- xamide, or a pharmaceutically acceptable salt thereof; [0029] b) tosylate salt of N-[3-[(4aR,7aS)-2-amino-6-(5-fluoropyrimidin-2-yl)-4,4a,5,7-tetra- hydropyrrolo[3,4-<d][1,3]thiazin-7a-yl]-4-fluoro-phenyl]-5-methoxy-pyra- zine-2-carboxamide; [0030] c) crystalline form of 2 N-[3-[(4aR,7aS)-2-amino-6-(5-fluoropyrimidin-2-yl)-4a,5,6,7-tetrahydropyr- rolo[3,4-d][1,3]thiazin-7a(4H)-yl]-4-fluoro-phenyl]-5-methoxy-pyrazine-2-c- arboxamide; and [0031] d) a compound of the formula

[0031] ##STR00004## also referred to by the compound name N-[3-[(5R)-3-Amino-5,6-dihydro-2,5-dimethyl-1,1-dioxido-2H-1,2,4-thiadiaz- in-5-yl]-4-fluorophenyl]-5-fluoro-2-pyridinecarboxamide or the generic name, verubecestat, or a pharmaceutically acceptable salt thereof.

[0032] In an embodiment, the present invention also provides a method of treating a disease characterized by deposition of A.beta. in the brain, comprising administering to a patient a one-time induction dose of an anti-N3pGlu A.beta. antibody for a period of 6 months or less in simultaneous, separate, or sequential combination with an effective amount of an A.beta. antibody. In a particular embodiment, the present invention also provides a method of treating a disease characterized by deposition of A.beta. in the brain, comprising administering to a patient a one-time, biweekly or monthly induction dose of 10 to 60 mg/kg of an anti-N3pGlu A.beta. antibody for a period of 6 months or less in simultaneous, separate, or sequential combination with an effective amount of an A.beta. antibody, wherein the A.beta. antibody comprises an amino acid light chain (LC) and an amino acid heavy chain (HC) selected from the group consisting of;

[0033] A) LC of SEQ ID NO: 65 and HC of SEQ ID NO:66 (solanezumab);

[0034] B) LC of SEQ ID NO: 61 and HC of SEQ ID NO: 62 (crenezumab):

[0035] C) LC of SEQ ID NO: 57 and HC of SEQ ID NO: 58 (aducunumab);

[0036] D) LC of SEQ ID NO: 63 and HC of SEQ ID NO: 64 (BAN2401) and;

[0037] E) LC of SEQ ID NO: 59 and HC of SEQ ID NO: 60 (gantenerunab).

[0038] In a preferred embodiment of the present invention, the one-time biweekly and monthly induction dose administered to a patient is 10 mg/kg, 15 mg/kg, 20 mg/kg or 40 mg/kg. The anti-N3pGlu A.beta. antibody is preferably selected from Table A.

[0039] In an embodiment, the present invention also provides a method of treating a disease characterized by deposition of A.beta. in the brain, comprising administering to a patient a one-time, biweekly or monthly induction dose of 10 to 60 mg/kg of an anti-N3pGlu A.beta. antibody for a period of 6 months or less in simultaneous, separate, or sequential combination with an effective amount of a 20 kD pegylated anti-A.beta. Fab antibody, wherein the anti-A.beta. Fab comprises an amino acid light chain variable region of SEQ ID NO: 55 and an amino acid heavy chain variable region of SEQ ID NO:56. In a preferred embodiment of the present invention, the one-time biweekly and monthly induction dose administered to a patient is 10 mg/kg, 15 mg/kg, 20 mg/kg or 40 mg/kg.

[0040] The anti-N3pGlu A.beta. antibody is preferably selected from Table A.

[0041] In another embodiment of the present invention also provides a method of treating a disease characterized by deposition of A.beta. in the brain, comprising administering to a patient a one-time, biweekly or monthly induction dose of 10 to 60 mg/kg of an anti-N3pGlu A.beta. antibody for a period of 6 months or less in simultaneous, separate, or sequential combination with an effective amount of a symptomatic agent to treat Alzheimer's disease. Symptomatic agents can be selected from cholinesterase inhibitors (ChEIs) and/or a partial N-methyl-D-aspartate (NMDA) antagonists. In a preferred embodiment the agent is a ChEI. In another preferred embodiment the agent is a NMDA antagonist or a combination agent comprising a ChEI and NMDA antagonist. In a more preferred embodiment of the present invention, the one-time induction dose administered to a 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 biweekly and monthly induction dose administered to a patient is 10 mg/kg, 15 mg/kg, 20 mg/kg or 40 mg/kg for a period of 6 months. The anti-N3pGlu A.beta. antibody is preferably selected from Table A.

[0042] In another embodiment the present invention provides an anti-N3pGlu A.beta. antibody for use in the treatment of clinical or pre-clinical Alzheimer's disease, Down's syndrome, and clinical or pre-clinical cerebral amyloid angiopathy, wherein the anti-N3pGlu A.beta. antibody is administered to a patient at a dose of 10 to 60 mg/kg for a period of 6 months or less. Particularly, the present invention provides an anti-N3pGlu A.beta. antibody for use in treatment of clinical or pre-clinical Alzheimer's disease. Down's syndrome, and clinical or pre-clinical cerebral amyloid angiopathy, wherein the anti-N3pGlu A.beta. antibody is administered to a patient as a one-time induction dose of 10 to 60 mg/kg of an anti-N3pGlu A.beta. antibody. In another more particular embodiment, the present invention provides an anti-N3pGlu A.beta. antibody for use in the treatment of clinical or pre-clinical Alzheimer's disease, Down's syndrome, and clinical or pre-clinical cerebral amyloid angiopathy, wherein the anti-N3pGlu A.beta. antibody is administered to a patient as an induction dose of 10 to 60 mg/kg every two weeks of an anti-N3pGlu A.beta. antibody for a period of 6 months or less. In another more particular embodiment, the present invention an anti-N3pGlu A.beta. antibody for use in the treatment of clinical or pre-clinical Alzheimer's disease, Down's syndrome, and clinical or pre-clinical cerebral amyloid angiopathy, wherein the anti-N3pGlu A.beta. antibody is administered to a patient as an induction dose of 10 to 60 mg/kg monthly for a period of 6 months or less. In a preferred embodiment of the invention for use in the treatment or preventing of clinical or pre-clinical Alzheimer's disease, Down's syndrome, and clinical or pre-clinical CAA, the one-time, biweekly and monthly induction dose administered to a patient is 20 to 40 mg/kg or 15 to 30 mg/kg. In a preferred embodiment of the present invention, the one-time induction dose administered to a 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 biweekly and monthly induction dose administered to a patient is 10 mg/kg, 15 mg/kg, 20 mg/kg or 40 mg/kg for a period of 6 months. Even more preferably, the anti-N3pGlu A.beta. antibody is selected from Table A.

[0043] In another embodiment the present invention provides an anti-N3pGlu A.beta. antibody for use in the treatment of prodromal AD, mild AD, moderate AD or severe AD, wherein the anti-N3pGlu A.beta. antibody is administered to a patient at a dose of 10 to 60 mg/kg for a period of 6 months or less. Particularly, the present invention provides an anti-N3pGlu A.beta. antibody for use in the treatment of prodromal AD, mild AD, moderate AD or severe AD, wherein the anti-N3pGlu A.beta. antibody is administered to a patient as a one-time induction dose of 10 to 60 mg/kg of an anti-N3pGlu A.beta. antibody. In another more particular embodiment, the present invention provides an anti-N3pGlu A.beta. antibody for use in the treatment of prodromal AD, mild AD, moderate AD or severe AD, wherein the anti-N3pGlu A.beta. antibody is administered to a patient as an induction dose of 10 to 60 mg/kg every two weeks of an anti-N3pGlu A.beta. antibody for a period of 6 months or less. In another more particular embodiment, the present invention an anti-N3pGlu A.beta. antibody for use in the treatment of prodromal AD, mild AD, moderate AD or severe AD, wherein the anti-N3pGlu A.beta. antibody is administered to a patient as an induction dose of 10 to 60 mg/kg monthly for a period of 6 months or less. In a preferred embodiment of the invention for use in the in the treatment of prodromal AD, mild AD, moderate AD or severe AD, the one-time, biweekly and monthly induction dose administered to a patient is 20 to 40 mg/kg or 15 to 30 mg/kg. In a preferred embodiment of the present invention, the one-time induction dose administered to a 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 biweekly and monthly induction dose administered to a patient is 10 mg/kg, 15 mg/kg, 20 mg/kg or 40 mg/kg for a period of 6 months. Even more preferably, the anti-N3pGlu A.beta. antibody is selected from Table A.

[0044] In another embodiment the present invention provides an anti-N3pGlu A.beta. antibody for use in preventing or slowing cognitive or functional decline in a patient diagnosed with a condition selected from clinical or pre-clinical Alzheimer's disease, Down's syndrome, and clinical or pre-clinical cerebral amyloid angiopathy, wherein the anti-N3pGlu A.beta. antibody is administered to a patient at a dose of 10 to 60 mg/kg for a period of 6 months or less. Particularly, the present invention provides an anti-N3pGlu A.beta. antibody for use in preventing or slowing cognitive decline in a patient diagnosed with a condition selected from clinical or pre-clinical Alzheimer's disease, Down's syndrome, and clinical or pre-clinical cerebral amyloid angiopathy, wherein the anti-N3pGlu A.beta. antibody is administered to a patient as a one-time induction dose of 10 to 60 mg/kg of an anti-N3pGlu A.beta. antibody. In another more particular embodiment, the present invention provides an anti-N3pGlu A.beta. antibody for use in preventing or slowing cognitive decline in a patient diagnosed with a condition selected from clinical or pre-clinical Alzheimer's disease, Down's syndrome, and clinical or pre-clinical cerebral amyloid angiopathy, moderate AD or severe AD, wherein the anti-N3pGlu A.beta. antibody is administered to a patient as an induction dose of 10 to 60 mg/kg every two weeks of an anti-N3pGlu A.beta. antibody for a period of 6 months or less. In another more particular embodiment, the present invention an anti-N3pGlu A.beta. antibody for use in preventing or slowing cognitive decline in a patient diagnosed with a condition selected from clinical or pre-clinical Alzheimer's disease, Down's syndrome, and clinical or pre-clinical cerebral amyloid angiopathy, wherein the anti-N3pGlu A.beta. antibody is administered to a patient as an induction dose of 10 to 60 mg/kg monthly for a period of 6 months or less. In a preferred embodiment of the invention for use in preventing or slowing cognitive decline in a patient diagnosed with a condition selected from clinical or pre-clinical Alzheimer's disease. Down's syndrome, and clinical or pre-clinical cerebral amyloid angiopathy, the one-time, biweekly and monthly induction dose administered to a patient is 20 to 40 mg/kg or 15 to 30 mg/kg. In a preferred embodiment of the present invention, the one-time induction dose administered to a 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 biweekly and monthly induction dose administered to a patient is 10 mg/kg, 15 mg/kg, 20 mg/kg or 40 mg/kg for a period of 6 months. Even more preferably, the anti-N3pGlu A.beta. antibody is selected from Table A.

[0045] In another embodiment the present invention provides an anti-N3pGlu A.beta. antibody for use in reducing A.beta. amyloid plaque load in the brain of a patient diagnosed with pre-clinical or clinical Alzheimer's disease, Down's syndrome, and clinical or pre-clinical cerebral amyloid angiopathy, wherein the anti-N3pGlu A.beta. antibody is administered to a patient at a dose of 10 to 60 mg/kg for a period of 6 months or less. Particularly, the present invention provides an anti-N3pGlu A.beta. antibody for use in reducing A.beta. amyloid plaque load in the brain of a patient diagnosed with pre-clinical or clinical Alzheimer's disease. Down's syndrome, and clinical or pre-clinical cerebral amyloid angiopathy, wherein the anti-N3pGlu A.beta. antibody is administered to a patient as a one-time induction dose of 10 to 60 mg/kg of an anti-N3pGlu A.beta. antibody. In another more particular embodiment, the present invention provides an anti-N3pGlu A.beta. antibody for use in reducing A.beta. amyloid plaque load in the brain of a patient diagnosed with pre-clinical or clinical Alzheimer's disease, Down's syndrome, and clinical or pre-clinical cerebral amyloid angiopathy, wherein the anti-N3pGlu A.beta. antibody is administered to a patient as an induction dose of 10 to 60 mg/kg every two weeks of an anti-N3pGlu A.beta. antibody for a period of 6 months or less. In another more particular embodiment, the present invention provides an anti-N3pGlu A.beta. antibody for use in reducing A.beta. amyloid plaque load in the brain of a patient diagnosed with pre-clinical or clinical Alzheimer's disease, Down's syndrome, and clinical or pre-clinical cerebral amyloid angiopathy, wherein the anti-N3pGlu A.beta. antibody is administered to a patient as an induction dose of 10 to 60 mg/kg monthly for a period of 6 months or less. In a preferred embodiment of the invention for use in reducing A.beta. amyloid plaque load in the brain of a patient diagnosed with pre-clinical or clinical Alzheimer's disease, Down's syndrome, and clinical or pre-clinical cerebral amyloid angiopathy, the one-time, biweekly and monthly induction dose administered to a patient is 20 to 40 mg/kg or 15 to 30 mg/kg. In another preferred embodiment of the present invention, the one-time induction dose administered to a 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 biweekly and monthly induction dose administered to a patient is 10 mg/kg, 15 mg/kg, 20 mg/kg or 40 mg/kg for a period of 6 months. Even more preferably, the anti-N3pGlu A.beta. antibody is selected from Table A.

[0046] In another embodiment the present invention provides an anti-N3pGlu A.beta. antibody for use in treating clinically asymptomatic patients known to have Alzheimer's disease causing genetic mutation, wherein the anti-N3pGlu A.beta. antibody is administered to a patient at a dose of 10 to 60 mg/kg for a period of 6 months or less. Particularly, the present invention provides an anti-N3pGlu A.beta. antibody for use in treating asymptomatic patients known to have Alzheimer's disease causing genetic mutation, wherein the anti-N3pGlu A.beta. antibody is administered to a patient as a one-time induction dose of 10 to 60 mg/kg of an anti-N3pGlu A.beta. antibody. In another more particular embodiment, the present invention provides an anti-N3pGlu A.beta. antibody for use in treating asymptomatic patients known to have Alzheimer's disease causing genetic mutation, wherein the anti-N3pGlu A.beta. antibody is administered to a patient as an induction dose of 10 to 60 mg/kg every two weeks of an anti-N3pGlu A.beta. antibody for a period of 6 months or less. In another more particular embodiment, the present invention provides an anti-N3pGlu A.beta. antibody for use in treating asymptomatic patients known to have Alzheimer's disease causing genetic mutation, wherein the anti-N3pGlu A.beta. antibody is administered to a patient as an induction dose of 10 to 60 mg/kg monthly for a period of 6 months or less. In a preferred embodiment of the invention for use in treating asymptomatic patients known to have Alzheimer's disease causing genetic mutation, the one-time, biweekly and monthly induction dose administered to a patient is 20 to 40 mg/kg or 15 to 30 mg/kg. In a preferred embodiment of the present invention, the one-time induction dose administered to a 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 biweekly and monthly induction dose administered to a patient is 10 mg/kg, 15 mg/kg, 20 mg/kg or 40 mg/kg for a period of 6 months. The anti-N3pGlu A.beta. antibody is selected from Table A.

[0047] In another embodiment the present invention provides for a use of an anti-N3pGlu A.beta. antibody for the manufacture of a medicament for the treatment of clinical or pre-clinical Alzheimer's disease, Down's syndrome, and clinical or pre-clinical cerebral amyloid angiopathy, wherein the medicament comprises an induction dose of 10 to 60 mg/kg of an anti-N3pGlu A.beta. antibody administered to a patient for a period of 6 months or less. Particularly, the present invention provides for a use of an anti-N3pGlu A.beta. antibody for the manufacture of a medicament for the treatment of clinical or pre-clinical Alzheimer's disease, Down's syndrome, and clinical or pre-clinical cerebral amyloid angiopathy, wherein the medicament comprises a one-time induction dose of 10 to 60 mg/kg of an anti-N3pGlu A.beta. antibody administered to a patient. In another more particular embodiment, the present invention provides for a use of an anti-N3pGlu A.beta. antibody for the manufacture of a medicament for the treatment of clinical or pre-clinical Alzheimer's disease. Down's syndrome, and clinical or pre-clinical cerebral amyloid angiopathy, wherein the medicament comprises an induction dose of 10 to 60 mg/kg of an anti-N3pGlu A.beta. antibody administered to a patient every two weeks for a period of 6 months or less. In another more particular embodiment, the present invention provides for a use of an anti-N3pGlu A.beta. antibody for the manufacture of a medicament for the treatment of clinical or pre-clinical Alzheimer's disease, Down's syndrome, and clinical or pre-clinical cerebral amyloid angiopathy, wherein the medicament comprises an induction dose of 10 to 60 mg/kg of an anti-N3pGlu A.beta. antibody administered to a patient every month for a period of 6 months or less. In a preferred embodiment of the invention the one-time, biweekly and monthly induction dose administered to a patient is 20 to 40 mg/kg or 15 to 30 mg/kg. In another preferred embodiment of the present invention, the one-time induction dose administered to a 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 biweekly and monthly induction dose administered to a patient is 10 mg/kg, 15 mg/kg, 20 mg/kg or 40 mg/kg for a period of 6 months. Even more preferably, the anti-N3pGlu A.beta. antibody is selected from Table A.

[0048] In another embodiment the present invention provides for a use of an anti-N3pGlu A.beta. antibody for the manufacture of a medicament for the treatment of prodromal AD, mild AD, moderate AD or severe AD, wherein the medicament comprises an induction dose of 10 to 60 mg % kg of an anti-N3pGlu A.beta. antibody administered to a patient for a period of 6 months or less. Particularly, the present invention provides for a use of an anti-N3pGlu A.beta. antibody for the manufacture of a medicament for the treatment of prodromal AD, mild AD, moderate AD or severe AD, wherein the medicament comprises a one-time induction dose of 10 to 60 mg/kg of an anti-N3pGlu A.beta. antibody administered to a patient for a period of 6 months or less. In another more particular embodiment, the present invention provides for a use of an anti-N3pGlu A.beta. antibody for the manufacture of a medicament for the treatment of prodromal AD, mild AD, moderate AD or severe AD, wherein the medicament comprises an induction dose of 10 to 60 mg/kg of an anti-N3pGlu A.beta. antibody administered to a patient every two weeks for a period of 6 months or less. In another more particular embodiment, the present invention provides for a use of an anti-N3pGlu A.beta. antibody for the manufacture of a medicament for the treatment of prodromal AD, mild AD, moderate AD or severe AD, wherein the medicament comprises an induction dose of 10 to 60 mg/kg of an anti-N3pGlu A.beta. antibody administered to a patient monthly for a period of 6 months or less. In a preferred embodiment of the invention the one-time, biweekly and monthly induction dose administered to a patient is 20 to 40 mg/kg or 15 to 30 mg/kg. In another preferred embodiment of the present invention, the one-time induction dose administered to a 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 biweekly and monthly induction dose administered to a patient is 10 mg/kg, 15 mg/kg, 20 mg/kg or 40 mg/kg for a period of 6 months. Even more preferably, the anti-N3pGlu A.beta. antibody is selected from Table A In another embodiment the present invention provides for a use of an anti-N3pGlu A.beta. antibody for the manufacture of a medicament for preventing or slowing cognitive or functional decline in a patient diagnosed with a condition selected from clinical or pre-clinical Alzheimer's disease. Down's syndrome, and clinical or pre-clinical cerebral amyloid angiopathy, wherein the medicament comprises an induction dose of 10 to 60 mg/kg of an anti-N3pGlu A.beta. antibody administered to a patient for a period of 6 months or less. Particularly, the present invention provides for a use of an anti-N3pGlu A.beta. antibody for the manufacture of a medicament for preventing or slowing cognitive decline in a patient diagnosed with a condition selected from clinical or pre-clinical Alzheimer's disease, Down's syndrome, and clinical or pre-clinical cerebral amyloid angiopathy, wherein the medicament comprises a one-time induction dose of 10 to 60 mg/kg of an anti-N3pGlu A.beta. antibody administered to a patient for a period of 6 months or less. In another more particular embodiment, the present invention provides for a use of an anti-N3pGlu A.beta. antibody for preventing or slowing cognitive decline in a patient diagnosed with a condition selected from clinical or pre-clinical Alzheimer's disease, Down's syndrome, and clinical or pre-clinical cerebral amyloid angiopathy, wherein the medicament comprises an induction dose of 10 to 60 mg/kg of an anti-N3pGlu A.beta. antibody administered every two weeks to a patient for a period of 6 months or less. In another more particular embodiment, the present invention provides for a use of an anti-N3pGlu A.beta. antibody for preventing or slowing cognitive decline in a patient diagnosed with a condition selected from clinical or pre-clinical Alzheimer's disease, Down's syndrome, and clinical or pre-clinical cerebral amyloid angiopathy, wherein the medicament comprises a one-time induction dose of 10 to 60 mg/kg of an anti-N3pGlu A.beta. antibody administered to a patient monthly for a period of 6 months or less. In a preferred embodiment of the invention the one-time, biweekly and monthly induction dose administered to a patient is 20 to 40 mg/kg or 15 to 30 mg/kg. In another preferred embodiment of the present invention, the one-time induction dose administered to a 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 biweekly and monthly induction dose administered to a patient is 10 mg/kg, 15 mg/kg, 20 mg/kg or 40 mg/kg for a period of 6 months. Even more preferably, the anti-N3pGlu A.beta. antibody is selected from Table A.

[0049] In another embodiment the present invention provides for a use of an anti-N3pGlu A.beta. antibody for the manufacture of a medicament for treating asymptomatic patients known to have an Alzheimer's disease causing genetic mutation, wherein the medicament is administered to a patient at a dosage of 10 to 60 mg/kg of the anti-N3pGlu A.beta. antibody for a period of 6 months or less. Particularly, the present invention provides for a use of an anti-N3pGlu A.beta. antibody for the manufacture of a medicament for treating asymptomatic patients known to have an Alzheimer's disease causing genetic mutation, wherein the medicament comprises a one-time induction dose of 10 to 60 mg/kg of an anti-N3pGlu A.beta. antibody administered to a patient for a period of 6 months or less. In another more particular embodiment, the present invention provides for a use of an anti-N3pGlu A.beta. antibody treating asymptomatic patients known to have an Alzheimer's disease causing genetic mutation, wherein the medicament comprises an induction dose of 10 to 60 mg/kg of an anti-N3pGlu A.beta. antibody administered to a patient every two weeks for a period of 6 months or less. In another more particular embodiment, the present invention provides for a use of an anti-N3pGlu A.beta. antibody treating asymptomatic patients known to have an Alzheimer's disease causing genetic mutation, wherein the medicament comprises an induction dose of 10 to 60 mg/kg of an anti-N3pGlu A.beta. antibody administered to a patient monthly for a period of 6 months or less. In a preferred embodiment of the invention the one-time, biweekly and monthly induction dose administered to a patient is 20 to 40 mg/kg or 15 to 30 mg/kg. In another preferred embodiment of the present invention, the one-time induction dose administered to a 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 biweekly and monthly induction dose administered to a patient is 10 mg/kg, 15 mg/kg, 20 mg/kg or 40 mg/kg for a period of 6 months. Even more preferably, the anti-N3pGlu A.beta. antibody is selected from Table A.

[0050] In another embodiment the present invention provides for a use of an anti-N3pGlu A.beta. antibody for the manufacture of a medicament for reducing A.beta. deposits in the brain of a patient, wherein the medicament comprises an induction dose of 10 to 60 mg/kg of an anti-N3pGlu A.beta. antibody administered to a patient for a period of 6 months or less, and wherein the A.beta. deposit in the brain of a patient is reduced by 35-100% within 6 months post induction dose treatment. Particularly the present invention provides for a use of an anti-N3pGlu A.beta. antibody for the manufacture of a medicament for reducing A.beta. deposits in the brain of a patient, wherein the medicament comprises a one-time induction dose of 10 to 60 mg/kg of an anti-N3pGlu A.beta. antibody administered to a patient for a period of 6 months or less, and wherein the A.beta. deposit in the brain of a patient is reduced by 35-100% within 6 months post induction dose treatment. In another more particular embodiment, the present invention provides for a use of an anti-N3pGlu A.beta. antibody for the manufacture of a medicament for reducing A.beta. deposits in the brain of a patient, wherein the medicament comprises an induction dose of 10 to 60 mg/kg of an anti-N3pGlu A.beta. antibody administered to a patient every two weeks for a period of 6 months or less, and wherein the A.beta. deposit in the brain of a patient is reduced by 35-100% within 6 months post induction dose treatment. In another more particular embodiment, the present invention provides for a use of an anti-N3pGlu A.beta. antibody for the manufacture of a medicament for reducing A.beta. deposits in the brain of a patient, wherein the medicament comprises an induction dose of 10 to 60 mg/kg of an anti-N3pGlu A.beta. antibody administered to a patient monthly for a period of 6 months or less, and wherein the A.beta. deposit in the brain of a patient is reduced by 35-100% within 6 months post induction dose treatment. In a preferred embodiment of the invention the one-time, biweekly and monthly induction dose administered to a patient is 20 to 40 mg/kg or 15 to 30 mg/kg. In another preferred embodiment of the present invention, the one-time induction dose administered to a 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 biweekly and monthly induction dose administered to a patient is 10 mg/kg, 15 mg/kg, 20 mg/kg or 40 mg/kg for a period of 6 months. Even more preferably, the anti-N3pGlu A.beta. antibody is selected from Table A.

[0051] As used herein, "anti-N3pglu A.beta. antibody" refers to an antibody that binds preferentially to N3pGlu A.beta. over A.beta..sub.1-40 or A.beta..sub.1-42. The sequence of N3pGlu A.beta. is the amino acid sequence of SEQ ID NO: 31. In particular embodiments, the anti-N3pGlu A.beta. antibodies comprise amino acid sequences listed in Table A. More specifically, the anti-N3pGlu A.beta. antibodies of the present invention comprises a light chain variable region (LCVR) and a heavy chain variable region (HCVR), wherein said LCVR comprises LCDR1, LCDR2 and LCDR3 and HCVR comprises HCDR1, HCDR2 and HCDR3 which are selected from the group consisting of: [0052] a) LCDR1 is SEQ ID. NO: 17, LCDR2 is SEQ ID. NO: 18. LCDR3 is SEQ ID. NO: 19, HCDR1 is SEQ ID. NO: 20, HCDR2 is SEQ ID: NO: 22, and HCDR3 is SEQ ID. NO: 23; and [0053] b) LCDR1 is SEQ ID. NO: 17, LCDR2 is SEQ ID. NO: 18, LCDR3 is SEQ ID. NO: 19, HCDR1 is SEQ ID. NO: 21. HCDR2 is SEQ ID. NO: 22, and HCDR3 is SEQ ID. NO: 24; [0054] c) LCDR1 is SEQ ID. NO: 17, LCDR2 is SEQ ID. NO: 18, LCDR3 is SEQ ID. NO: 19, HCDR1 is SEQ ID. NO: 36, HCDR2 is SEQ ID. NO: 22, and HCDR3 is SEQ ID. NO: 37; [0055] d) LCDR1 is SEQ ID. NO: 4. LCDR2 is SEQ ID. NO: 6. LCDR3 is SEQ ID. NO: 7, HCDR1 is SEQ ID. NO: 1. HCDR2 is SEQ ID. NO: 2, and HCDR3 is SEQ ID. NO: 3; and [0056] e) LCDR1 is SEQ ID. NO: 4, LCDR2 is SEQ ID. NO: 5, LCDR3 is SEQ ID. NO: 7, HCDR1 is SEQ ID. NO: 1, HCDR2 is SEQ ID. NO: 2, and HCDR3 is SEQ ID. NO: 3.

[0057] In other embodiments, the anti-N3pGlu A.beta. antibodies of the present invention comprise a light chain variable region (LCVR) and a heavy chain variable region (HCVR), wherein said LCVR and HCVR are selected from the group consisting of: [0058] a) LCVR of SEQ ID NO: 25 and HCVR of SEQ ID NO: 26; [0059] b) LCVR of SEQ ID NO: 25 and HCVR of SEQ ID NO: 27; [0060] c) LCVR of SEQ ID NO: 32 and HCVR of SEQ ID NO: 34; [0061] d) LCVR of SEQ ID NO: 9 and HCVR of SEQ ID NO: 8; and [0062] e) LCVR of SEQ ID NO: 10 and HCVR of SEQ ID NO: 8.

[0063] In further embodiments, the anti-N3pGlu A.beta. antibody comprises a light chain (LC) and a heavy chain (HC), wherein said LC and HC are selected from the group consisting of: [0064] a) LC of SEQ ID NO: 28 and HC of SEQ ID NO: 29; [0065] b) LC of SEQ ID NO: 28 and HC of SEQ ID NO: 30; [0066] c) LC of SEQ ID NO: 33 and HC of SEQ ID NO: 35; [0067] d) LC of SEQ ID NO: 12 and HC of SEQ ID NO: 11; and [0068] e) LC of SEQ ID NO: 13 and HC of SEQ ID NO: 11.

[0069] In other embodiments, the anti-N3pGlu A.beta. antibody comprises two light chains (LC) and two heavy chains (HC), wherein each LC and each HC are selected from the group consisting of [0070] a) LC of SEQ ID NO: 28 and HC of SEQ ID NO: 29; [0071] b) LC of SEQ ID NO: 28 and HC of SEQ ID NO: 30; [0072] c) LC of SEQ ID NO: 33 and HC of SEQ ID NO: 35; [0073] d) LC of SEQ ID NO: 12 and HC of SEQ ID NO: 11; and [0074] e) LC of SEQ ID NO: 13 and HC of SEQ ID NO: 11.

[0075] In some embodiments, the anti-N3pGlu A.beta. antibody comprises Antibody I, which has a light chain (LC) and a heavy chain (HC) of SEQ ID NOs: 12 and 11 respectively. Antibody I further has a light chain variable region (LCVR) and a heavy chain variable region (HCVR) of SEQ ID NOs: 9 and 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.

[0076] In some embodiments, the anti-N3pGlu A.beta. antibody comprises Antibody II, which has a light chain (LC) and a heavy chain (HC) of SEQ ID NOs: 13 and 11 respectively. Antibody II further has a light chain variable region (LCVR) and a heavy chain variable region (HCVR) of SEQ ID NOs: 10 and 8 respectively. The HCVR of Antibody IT 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.

[0077] In some embodiments, the anti-N3pGlu A.beta. antibody comprises B12L, which has a light chain (LC) and a heavy chain (HC) of SEQ ID NOs: 28 and 29 respectively. B12L further has a light chain variable region (LCVR) and a heavy chain variable region (HCVR) of SEQ ID NOs: 25 and 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.

[0078] In some embodiments, the anti-N3pGlu A.beta. antibody comprises R17L which has a light chain (LC) and a heavy chain (HC) of SEQ ID NOs: 28 and 30 respectively. R17L further has a light chain variable region (LCVR) and a heavy chain variable region (HCVR) of SEQ ID NOs: 25 and 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.

[0079] In some embodiments, the anti-N3pGlu Ali antibody comprises hE8L which has a light chain (LC) and a heavy chain (HC) of SEQ ID NOs: 33 and 35 respectively. hE8L further has a light chain variable region (LCVR) and a heavy chain variable region (HCVR) of in SEQ ID NOs: 32 and 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.

[0080] In some embodiments, the anti-N3pGlu Ali antibody comprises Antibody VI which has a light chain variable region (LCVR) and a heavy chain variable region (HCVR) of SEQ ID NOs: 39 and 40 respectively.

[0081] In some embodiments, the anti-N3pGlu A.beta. antibody comprises Antibody VII which has a light chain variable region (LCVR) and a heavy chain variable region (HCVR) of SEQ ID NOs: 41 and 42 respectively.

[0082] In some embodiments, the anti-N3pGlu A.beta. antibody comprises Antibody VIII which has a light chain variable region (LCVR) and a heavy chain variable region (HCVR) of SEQ ID NOs-43 and 44 respectively.

[0083] In some embodiments, the anti-N3pGlu A.beta. antibody comprises Antibody IX which has a light chain variable region (LCVR) and a heavy chain variable region (HCVR) of SEQ ID NOs: 45 and 46 respectively.

[0084] In some embodiments, the anti-N3pGlu A.beta. antibody comprises Antibody X which has a light chain variable region (LCVR) and a heavy chain variable region (HCVR) of SEQ ID NOs: 47 and 48 respectively.

[0085] In some embodiments, the anti-N3pGlu A.beta. antibody comprises Antibody XI which has a light chain variable region (LCVR) and a heavy chain variable region (HCVR) of SEQ ID NOs: 49 and 50 respectively.

[0086] In some embodiments, the anti-N3pGlu A.beta. antibody comprises Antibody XII which has a light chain variable region (LCVR) and a heavy chain variable region (HCVR) of SEQ ID NOs: 51 and 52 respectively.

[0087] In some embodiments, the anti-N3pGlu A.beta. antibody comprises Antibody XIII which has a light chain variable region (LCVR) and a heavy chain variable region (HCVR) of SEQ ID NOs: 53 and 54 respectively.

[0088] A person of skill in the art would recognize that an embodiment of the present invention provides a method of treating or preventing clinical or pre-clinical Alzheimer's disease. Down's syndrome, and clinical or pre-clinical CAA in a patient positive for amyloid deposits, comprising administering to a patient a one-time, biweekly or monthly induction dose of an anti-N3pGlu A.beta. antibody for a period of 6 months or less, wherein the anti-N3pGlu A.beta. antibody comprises a light chain variable region (LCVR) and a heavy chain variable region (HCVR), wherein said LCVR and HCVR are selected from the group consisting of: [0089] a) LCVR of SEQ ID NO: 25 and HCVR of SEQ ID NO: 26; [0090] b) LCVR of SEQ ID NO: 25 and HCVR of SEQ ID NO: 27; [0091] c) LCVR of SEQ ID NO: 32 and HCVR of SEQ ID NO: 34; [0092] d) LCVR of SEQ ID NO: 9 and HCVR of SEQ ID NO: 8; and [0093] e) LCVR of SEQ ID NO: 10 and HCVR of SEQ ID NO: 8.

[0094] Preferably the anti-N3pGlu A.beta. antibody comprises a LCVR of SEQ ID NO: 25 and HCVR of SEQ ID NO: 26. More preferably the anti-N3pGlu A.beta. antibody is administered one-time or biweekly. Even more preferably, the one-time or biweekly dose results in 35-100% reduction in A.beta. deposit m the brain of the patient within 6 months of administration of the induction dose.

[0095] In another particular embodiments, the present invention provides a method of treating or preventing clinical or pre-clinical Alzheimer's disease, Down's syndrome, and clinical or pre-clinical CAA in a patient positive for amyloid deposits, comprising administering to a patient a one-time, biweekly or monthly induction dose of an anti-N3pGlu A.beta. antibody for a period of 6 months or less, wherein the anti-N3pGlu A.beta. antibody comprises a light chain (LC) and a heavy chain (HC), wherein said LC and HC are selected from the group consisting of: [0096] a) LC of SEQ ID NO: 28 and HC of SEQ ID NO: 29; [0097] b) LC of SEQ ID NO: 28 and HC of SEQ ID NO: 30; [0098] c) LC of SEQ ID NO: 33 and HC of SEQ ID NO: 35; [0099] d) LC of SEQ ID NO: 12 and HC of SEQ ID NO: 11; and [0100] e) LC of SEQ ID NO: 13 and HC of SEQ ID NO: 11. Preferably the anti-N3pGlu A.beta. antibody comprises a LC of SEQ ID NO: 28 and HC of SEQ ID NO: 29. More preferably the anti-N3pGlu AB antibody is administered one-time or biweekly. Even more preferably, the one-time or biweekly dose results in 35-100% reduction in A.beta. deposit in the brain of the patient within 6 months of administration of the induction dose.

[0101] A further embodiment provides a method of treating or preventing clinical or pre-clinical Alzheimer's disease, Down's syndrome, and clinical or pre-clinical CAA in a patient positive for amyloid deposits, comprising administering to a patient a one-time, biweekly or monthly induction dose of an anti-N3pGlu A.beta. antibody for a period of 6 months or less, wherein the anti-N3pGlu A.beta. antibody comprises two light chains (LC's) and two heavy chains (HC's), wherein each LC and HC is selected from the group consisting of: [0102] a) LC of SEQ ID NO: 28 and HC of SEQ ID NO: 29; [0103] b) LC of SEQ ID NO: 28 and HC of SEQ ID NO: 30; [0104] c) LC of SEQ ID NO: 33 and HC of SEQ ID NO: 35; [0105] d) LC of SEQ ID NO: 12 and HC of SEQ ID NO: 11; and [0106] e) LC of SEQ ID NO: 13 and HC of SEQ ID NO: 11.

[0107] Preferably the anti-N3pGlu A.beta. antibody comprises a two LC's of SEQ ID NO: 28 and HC's of SEQ ID NO: 29. More preferably the anti-N3pGlu A.beta. antibody is administered one-time or biweekly. Even more preferably, the one-time or biweekly dose results in 35-100% reduction in A.beta. deposit in the brain of the patient within 6 months of administration of the induction dose.

[0108] The present invention also provides a method of treating or preventing clinical or pre-clinical Alzheimer's disease, Down's syndrome, and clinical or pre-clinical CAA in a patient positive for amyloid deposits, comprising administering to a patient a one-time, biweekly or monthly induction dose of 10 to 60 mg/kg of an anti-N3pGlu A.beta. antibody for a period of 6 month or less, wherein the anti-N3pGlu A.beta. antibody comprises a light chain variable region (LCVR) and a heavy chain variable region (HCVR), wherein said LCVR and HCVR are selected from the group consisting of: [0109] a) LCVR of SEQ ID NO: 25 and HCVR of SEQ ID NO: 26; [0110] b) LCVR of SEQ ID NO: 25 and HCVR of SEQ ID NO: 27; [0111] c) LCVR of SEQ ID NO: 32 and HCVR of SEQ ID NO: 34; [0112] d) LCVR of SEQ ID NO: 9 and HCVR of SEQ ID NO: 8; and [0113] e) LCVR of SEQ ID NO: 10 and HCVR of SEQ ID NO: 8.

[0114] Preferably the anti-N3pGlu A.beta. antibody comprises a LCVR of SEQ ID NO: 25 and HCVR of SEQ ID NO: 26. More preferably, the one-time, biweekly (every two weeks) and monthly induction dose administered to a patient is 10 mg/kg, 15 mg/kg, 20 mg/kg, 40 mg/kg, 20 to 40 mg/kg or 15 to 30 mg/kg. Even more preferably the induction dose of the anti-N3pGlu A.beta. antibody is administered one-time or biweekly. Even more preferably, the one-time or biweekly dose results in 35-100% reduction in A.beta. deposit in the brain of the patient within 6 months of administration of the induction dose.

[0115] In an embodiment, the present invention provides a method of treating or preventing clinical or pre-clinical Alzheimer's disease, Down's syndrome, and clinical or pre-clinical CAA in a patient positive for amyloid deposits, comprising administering to a patient a one-time, biweekly or monthly induction dose of 10 to 60 mg/kg of an anti-N3pGlu A.beta. antibody for a period of 6 month or less, wherein the anti-N3pGlu A.beta. antibody comprises a light chain (LC) and a heavy chain (HC), wherein said LC and HC are selected from the group consisting of: [0116] a) LC of SEQ ID NO: 28 and HC of SEQ ID NO: 29; [0117] b) LC of SEQ ID NO: 28 and HC of SEQ ID NO: 30; [0118] c) LC of SEQ ID NO: 33 and HC of SEQ ID NO: 35; [0119] d) LC of SEQ ID NO: 12 and HC of SEQ ID NO: 11; and [0120] e) LC of SEQ ID NO: 13 and HC of SEQ ID NO: 11.

[0121] Preferably the anti-N3pGlu A.beta. antibody comprises a LC of SEQ ID NO: 28 and a HC of SEQ ID NO: 29. More preferably, the one-time, biweekly (every two weeks) and monthly induction dose administered to a patient is 10 mg/kg, 15 mg/kg, 20 mg/kg, 40 mg/kg, 20 to 40 mg/kg or 15 to 30 mg/kg. Even more preferably the induction dose of the anti-N3pGlu A.beta. antibody is administered one-time or biweekly. Even more preferably, the one-time or biweekly dose results in 35-100% reduction in A.beta. deposit in the brain of the patient within 6 months of administration of the induction dose.

[0122] The present invention also provides a method of treating or preventing clinical or pre-clinical Alzheimer's disease, Down's syndrome, and clinical or pre-clinical CAA in a patient positive for amyloid deposits, comprising administering to a patient a one-time, biweekly or monthly induction dose of 10 to 60 mg/kg of an anti-N3pGlu A.beta. antibody for a period of 6 month or less, wherein the anti-N3pGlu A.beta. antibody comprises two light chains (LC) and two heavy chains (HC), wherein each LC and HC is selected from the group consisting of: [0123] a) LC of SEQ ID NO: 28 and HC of SEQ ID NO: 29; [0124] b) LC of SEQ ID NO: 28 and HC of SEQ ID NO: 30; [0125] c) LC of SEQ ID NO: 33 and HC of SEQ ID NO: 35; [0126] d) LC of SEQ ID NO: 12 and HC of SEQ ID NO: 11; and [0127] e) LC of SEQ ID NO: 13 and HC of SEQ ID NO: 11.

[0128] Preferably the anti-N3pGlu A.beta. antibody comprises two LC's of SEQ ID NO: 28 and two HC's of SEQ ID NO: 29. More preferably, the one-time, biweekly (every two weeks) and monthly induction dose administered to a patient is 10 mg/kg, 15 mg/kg, 20 mg/kg, 40 mg/kg, 20 to 40 mg/kg or 15 to 30 mg/kg. Even more preferably the induction dose of the anti-N3pGlu A.beta. antibody is administered one-time or biweekly. Even more preferably, the one-time or biweekly dose results in 35-100% reduction in A.beta. deposit in the brain of the patient within 6 months of administration of the induction dose.

[0129] One of ordinary skill in the art will appreciate and recognize that "anti-N3pGlu A.beta. antibody", and the specific antibodies, "hE8L", "B12L" and "R17L" are identified and disclosed along with methods for making and using said antibodies by one of ordinary skill in the art as set forth in U.S. Pat. No. 8,679,498 B2, entitled "Anti-N3pGlu Amyloid Beta Peptide Antibodies and Uses Thereof", issued Mar. 25, 2014 (U.S. Ser. No. 13/810,895). See for example Table I of U.S. Pat. No. 8,679,498 B2. Each of these three antibodies (e.g., "hE8L", "B12L" and "R17L") may be used as the anti-N3pGlu A.beta. antibody of the present invention. One of ordinary skill in the art will appreciate and recognize that "anti-N3pGlu A.beta. antibody", and the specific antibodies, "Antibody VI", "Antibody VI", "Antibody VIII", and "Antibody IX" are identified and disclosed along with methods for making and using said antibodies by one of ordinary skill in the art as set forth in WO2010/009987A2, entitled "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 A.beta. antibody of the present invention.

[0130] One of ordinary skill in the art will appreciate and recognize that "anti-N3pGlu A.beta. antibody", and the specific antibodies, "Antibody X" and "Antibody XI" are identified and disclosed along with methods for making and using said antibodies by one of ordinary skill in the art as set forth in WO 2011/151076 A2, entitled "Monoclonal Antibodies Targeting A.beta. Monoclonal Antibodies". Each of these two antibodies (e.g. "Antibody X" and "Antibody XI") may be used as the anti-N3pGlu A.beta. antibody of the present invention.

[0131] One of ordinary skill in the art will appreciate and recognize that "anti-N3pGlu A.beta. antibody", and the specific antibodies, "Antibody XII" and "Antibody XIII" are identified and disclosed along with methods for making and using said antibodies by one of ordinary skill in the art as set forth in WO 2012/136552A1, entitled "Antibodies Specific to Pyroglutamated A.beta.". Each of these two antibodies (e.g., "Antibody XII" and "Antibody XIII") may be used as the anti-N3pGlu A.beta. antibody of the present invention.

[0132] One of ordinary skill in the art will appreciate and recognize that "A.beta. antibody", and the specific antibody, "aducanumab" is identified and disclosed along with methods for making and using said antibody by one of ordinary skill in the art as set forth in WO14089500A1, entitled "A Method of Reducing Brain Amyloid Plaques Using Anti-Aft Antibodies", published Jun. 12, 2014. This may be used as the A.beta. antibody of the present invention.

[0133] One of ordinary skill in the art will appreciate and recognize that "A.beta. antibody", and the specific antibody, "gantenerumab" is identified and disclosed along with methods for making and using said antibody by one of ordinary skill in the art as set forth in WO2007068429, entitled "Antibodies Against Amyloid Beta 4 with Glycosylated in the Variable Region", published Jun. 21, 2007. This may be used as the A.beta. antibody of the present invention.

[0134] One of ordinary skill in the art will appreciate and recognize that "A.beta. antibody", and the specific antibody, "crenezumab" is identified and disclosed along with methods for making and using said antibody by one of ordinary skill in the art as set forth in 2015120280A1, entitled "Methods of treating alzheimer's disease", published Aug. 13, 2015. This may be used as the A.beta. antibody of the present invention.

[0135] One of ordinary skill in the art will appreciate and recognize that "A.beta. antibody", and the specific antibody, "BAN 2401" is identified and disclosed along with methods for making and using said antibody by one of ordinary skill in the art as set forth in U.S. Pat. No. 8,025,878 B2, entitled "Protofibril selective antibodies and the use thereof", issued Sep. 27, 2011. This may be used as the A.beta. antibody of the present invention.

[0136] One of ordinary skill in the art will appreciate and recognize that "A.beta. antibody", and the specific antibody, "solanezumab" is identified and disclosed along with methods for making and using said antibody by one of ordinary skill in the art as set forth in U.S. Pat. No. 7,195,761 B2, entitled "Humanized Antibodies that Sequester ABeta Peptide", issued Mar. 27, 2007. This may be used as the A.beta. antibody of the present invention.

[0137] One of ordinary skill in the art will appreciate and recognize that "A.beta. antibody", and the specific antibody. "Antibody XIV" is identified and disclosed along with methods for making and using said antibody by one of ordinary skill in the art as set forth in U.S. Pat. No. 8,066,999 B1, entitled "Pegylated A.beta. FAB", issued Nov. 29, 2011 (U.S. application Ser. No. 12/521,309). This may be used as the A.beta. antibody of the present invention.

[0138] The compound of formula:

##STR00005##

or a pharmaceutically acceptable salt thereof, is disclosed as a BACE inhibitor and can be prepared by one of ordinary skill in the art as set forth in U.S. Pat. No. 8,841,293 B1, entitled "Tetrahydropyrrolothiazine Compounds", issued Sep. 23, 2014 (U.S. application Ser. No. 14/195,897); see in particular, Example 4. N-[3-[(4aR,7aS)-2-amino-6-(5-fluoropyrimidin-2-yl)-4,4a,5,7-tetrahydropyr- rolo[3,4-d][1,3]thiazin-7a-yl]-4-fluoro-phenyl]-5-methoxy-pyrazine-2-carbo- xamide. The tosylate salt of N-[3-[(4aR,7aS)-2-amino-6-(5-fluoropyrimidin-2-yl)-4,4a,5,7-tetrahydropyr- rolo[3,4-d][1,3]thiazin-7a-yl]-4-fluoro-phenyl]-5-methoxy-pyrazine-2-carbo- xamide can be prepared by one of ordinary skill in the art as set forth in PCT/US2016/014423. The crystalline form of N-[3-[(4aR,7aS)-2-amino-6-(5-fluoropyrimidin-2-yl)-4,4a,5,7-tetrahydropyr- rolo[3,4-d][1,3]thiazin-7a-yl]-4-fluoro-phenyl]-5-methoxy-pyrazine-2-carbo- xamide can be prepared by one of ordinary skill in the art as set forth in WO 2016/043996, entitled "A Tetrahydropyrrolo[3,4-D][1,3] Thiazine-Derivative as BACE Inhibitor".

[0139] The compound of the formula:

##STR00006##

or a pharmaceutically acceptable salt thereof, is disclosed as a BACE inhibitor and can be prepared by one of ordinary skill in the art as set forth in U.S. Pat. No. 8,729,071 B1, entitled "Iminothiadiazine Dioxide Compounds As BACE Inhibitors. Compositions and Their Use" issued May 20, 2014. Crystalline forms and crystalline forms of the tosylate salt of N-[3-[(5R)-3-Amino-5,6-dihydro-2,5-dimethyl-1,1-dioxido-2H-1,2,4-thiadiaz- in-5-yl]-4-fluorophenyl]-5-fluoro-2-pyridinecarboxamide, verubecestat, are disclosed and can be prepared by one of ordinary skill in the art as set forth in WO2016/053767, entitled "Novel Crystalline forms of a BACE Inhibitor. Compositions, and their Use".

[0140] In addition, amino acid sequences for certain anti-N3pGlu A.beta. antibodies used in the present invention are provided below in Table A:

TABLE-US-00001 TABLE A Antibody Amino Acid Sequences Anti-N3pGlu Antibody LCVR HCVR LC HC Antibody I 9 8 12 11 Antibody II 10 8 13 11 Antibody III (B12L) 25 26 28 29 Antibody IV (R17L) 25 27 28 30 Antibody V(hE8L) 32 34 33 35 Antibody VI (5-5-6) 39 40 Antibody VII (6-1-6) 41 42 Antibody VIII (17-4-3) 43 44 Antibody IX (24-2-3) 45 46 Antibody X (9D5H6) 47 48 Antibody XI (8C4) 49 50 Antibody XII (5C9 (LuAb1h) 51 52 Antibody XIII (2E83 (LuAb2h) 53 54

[0141] With respect to "Antibody I", "Antibody 11", "Antibody III", "Antibody IV", and "Antibody V", additional amino acid sequences for such antibodies are provided in Table B:

TABLE-US-00002 TABLE B Antibody CDR Amino Acid Sequences Antibody SEQ ID NOs Antibody LCDR1 LCDR2 LCDR3 HCDR1 HCDR2 HCDR3 I 4 6 7 1 2 3 II 4 5 7 1 7 3 III (B12L) 17 18 19 20 22 23 IV (R17L) 17 18 19 21 22 24 V (hE8L) 17 18 19 36 22 37

[0142] As used herein, an "antibody" is an immunoglobulin molecule comprising two Heavy Chain (HC) and two Light Chain (LC) interconnected by disulfide bonds. The amino terminal portion of each LC and HC includes a variable region responsible for antigen recognition via the complementarity determining regions (CDRs) contained therein. The CDRs are interspersed with regions that are more conserved, termed framework regions. Assignment of amino acids to CDR domains within the LCVR and HCVR regions of the antibodies of the present invention is based on the following: Kabat numbering convention (Kabat, et al., Ann. NY Acad. Sci. 190:382-93 (1971); Kabat et al., Sequences of Proteins of Immunological Interest, Fifth Edition, U.S. Department of Health and Human Services. NIH Publication No. 91-3242 (1991)), and North numbering convention (North et al., A New Clustering of Antibody CDR Loop Conformations, Journal of Molecular Biology, 406:228-256 (2011)). Following the above method, the CDRs of the present invention were determined (Table B).

[0143] The anti-N3pGlu A.beta. antibodies of the present invention include kappa LC and IgG HC. In a particular embodiment, the anti-N3pglu A.beta. antibodies of the present invention are of the human IgG1 isotype.

[0144] The antibodies of the present invention are monoclonal antibodies ("mAbs"). Monoclonal antibodies can be produced, for example, by hybridoma technologies, recombinant technologies, phage display technologies, synthetic technologies, e.g., CDR-grafting, or combinations of such or other technologies known in the art. The monoclonal antibodies of the present invention are human or humanized. Humanized antibodies can be engineered to contain one or more human framework regions (or substantially human framework regions) surrounding CDRs derived from a non-human antibody. Human framework germline sequences can be obtained from ImunoGeneTics (INGT) via their website, http://imgt.cines.fr, or from The Immunoglobulin FactsBook by Marie-Paule Lefranc and Gerard Lefranc, Academic 25 Press, 2001. ISBN 012441351. Techniques for generating human or humanized antibodies are well known in the art.

[0145] In another embodiment of the present invention, the antibody, or the nucleic acid encoding the same, is provided in isolated form. As used herein, the term "isolated" refers to a protein, peptide or nucleic acid that is not found in nature and is free or substantially free from other macromolecular species found in a cellular environment. "Substantially free", as used herein, means the protein, peptide or nucleic acid of interest comprises more than 80% (on a molar basis) of the macromolecular species present, preferably more than 90% and more preferably more than 95%.

[0146] The anti-N3pGlu A.beta. antibody of the present invention is administered as a pharmaceutical composition. The pharmaceutical composition comprising an antibody of the present invention can be administered to a patient at risk for, or exhibiting, diseases or disorders as described herein by parental routes (e.g., subcutaneous, intravenous, intraperitoneal, intramuscular). Subcutaneous and intravenous routes are preferred.

[0147] The terms "treatment," "treating" or "to treat" and the like include restraining, slowing or stopping the progression or severity of an existing symptom, condition, disease, or disorder in a patient. The term "patient" refers to a human.

[0148] The term "prevention" means prophylactic administration of the antibody of the present invention to an asymptomatic patient or a patient with pre-clinical Alzheimer's disease to prevent onset or progression of the disease.

[0149] The terms "disease characterized by deposition of A.beta.' or a disease characterized by A.beta. deposits" are used interchangeably and refer to a disease that is pathologically characterized by A.beta. deposits in the brain or in brain vasculature. This includes diseases such as Alzheimer's disease. Down's syndrome, and cerebral amyloid angiopathy. A clinical diagnosis, staging or progression of Alzheimer's disease can be readily determined by the attending diagnostician or health care professional, as one skilled in the art, by using known techniques and by observing results. This generally includes some form of brain plaque imagining, mental or cognitive assessment (e.g. Clinical Dementia Rating-summary of boxes (CDR-SB), Mini-Mental State Exam (MMSE) or Alzheimer's Disease Assessment Scale-Cognitive (ADAS-Cog)) or functional assessment (e.g. Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL). The cognitive and functional assessment can be used to determine changes in a patients cognition (e.g. cognitive decline) and function (e.g. functional decline). "Clinical Alzheimer's disease" as used herein is a diagnosed stage of Alzheimer's disease. It includes conditions diagnosed as prodromal Alzheimer's disease, mild Alzheimer's disease, moderate Alzheimer's disease and severe Alzheimer's disease. The term "pre-clinical Alzheimer's disease" is a stage that precedes clinical Alzheimer's disease, where measurable changes in biomarkers (such as CSF A.beta.42 levels or deposited brain plaque by amyloid PET) indicate the earliest signs of a patient with Alzheimer's pathology, progressing to clinical Alzheimer's disease. This is usually before symptoms such as memory loss and confusion are noticeable. Pre-clinical Alzheimer's disease also includes pre-symptomatic autosomal dominant carriers, as well as patients with higher risk for developing A.beta. by virtue of carrying one or two APOE e4 alleles.

[0150] For patients undergoing brain plaque imaging, a patient is positive for amyloid deposits when amyloid is detected in the brain by methods such as amyloid imaging with radiolabeled PET compounds. An example of one such amyloid PET imaging compound is florbetapir F 18, which bind with high specificity to amyloid plaques. The chemical formula of florbetapir F 18 is C.sub.20H.sub.25.sup.18FN.sub.2O.sub.3. Amyloid imaging with radiolabeled PET compounds can be used to determine if A.beta. deposit in the brain of a human patient is reduced by 35-100% within 6 months post induction treatment. A person of skill in the art can correlate the standardized uptake value ratio (SUVR) values obtained from amyloid imaging (with radiolabeled PET compounds) to calculate the % reduction in A.beta. deposit in the brain of the patient before and after treatment. The SUVr values can be converted to standardized centiloid units, where 100 is average for A.beta. and 0 is average for young controls, allowing comparability amongst amyloid PET tracers, and calculation of reduction according to centiloid 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 time that is 6 months or less than 6 full consecutive calendar months, and wherein each month has 28-31 days. At the least this period includes a one-time induction dose given in a single administration.

[0151] A reduction or slowing of cognitive decline can be measured by cognitive assessments such as Clinical Dementia Rating-summary of boxes (CDR-SB). Mini-Mental State Exam (MMSE) or Alzheimer's Disease Assessment Scale-Cognitive (ADAS-Cog). A reduction or slowing of functional decline can be measured by functional assessments such as Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL).

[0152] An "induction dose" is a dose of an anti-N3pGlu A.beta. antibody that causes a sharp reduction in A.beta. deposit in the brain of a human patient within 6 months of treatment. A "one-time" dose is an induction dose that is administered once to a patient. A "one-time" dose can also be a dose that is administered to a patient once with a prolonged period of time, such as 2-10 years, between doses if such a dose is needed. Whether a patients needs more than one "one-time" induction dose can be determined by a diagnostician or health care professional by using known techniques and by observing results. A "biweekly" dose is a dose of that is administered to a patient every two weeks.

[0153] A "maintenance dose" is a dose administered to a patient after the induction dose treatment. A maintenance dose is an amount of antibody or drug administered to maintain the desired therapeutic response including reduced A.beta. deposit in the brain of a human patient. A maintenance dose can be dose that is the same or lower in amount of antibody or drug compared to the induction dose.

[0154] As used herein, "mg/kg" means an amount, in milligrams, of antibody or drug administered to a patient based on his or her bodyweight in kilograms. A dose is given at one time. For example, a 10 mg/kg dose of antibody for a patient weighing 70 kg would be a single 700 mg dose of antibody given in a single administration. Similarly, a 40 mg/kg dose of antibody for a patient weighing 80 kg would be a 3200 mg dose of antibody given at a single administration.

[0155] As used herein, the phrase "in combination with" refers to the administration of an anti-N3pGlu A.beta. antibody of the present invention, with another molecule (a "combination molecule", such as a BACE inhibitor, symptomatic agent or A.beta. antibody), simultaneously, or sequentially in any order, or any combination thereof. The two molecules may be administered either as part of the same pharmaceutical composition or in separate pharmaceutical compositions. The anti-N3pGlu A.beta. antibody can be administered prior to, at the same time as, or subsequent to administration of the combination molecule, or in some combination thereof. Where the combination molecule is administered at repeated intervals (e.g. during a standard course of treatment), the anti-N3pGlu A.beta. antibody can be administered prior to, at the same time as, or subsequent to, each administration of the combination molecule, or some combination thereof, or at different intervals in relation to therapy with the combination molecule, or in a single or series of dose(s) prior to, at any time during, or subsequent to the course of treatment with the combination molecule. One of ordinary skill in the art would recognize that a BACE inhibitor refers to a therapeutic agent, preferably a small molecule that inhibits the beta-secretase 1 enzyme, and can prevent the formation of amyloid plaque. Examples of BACE inhibitors are herein disclosed.

[0156] "Symptomatic agents," as used herein refer to therapeutic agents used to treat the cognitive manifestations of Alzheimer's symptomatically and have not shown to have any effect on Alzheimer disease progression. These include acetyl cholinesterase inhibitors and NMDA receptor antagonists. The cholinesterase inhibitors approved for the management of A.beta. symptoms include: donepezil (brand name Aricept.TM.), galantamine (Razadyne.TM.), and rivastigmine (branded as Exelon and Exelon.TM. Patch). Memantine (also known as NAMEDA.RTM.) is an approved NMDA receptor antagonist. NAMZARIC.RTM. is a combination agent comprising both an acetyl cholinesterase inhibitor and NMDA receptor antagonist.

[0157] The following Examples and assays demonstrate that the antibodies of the present invention are useful for treating a disease characterized by deposition of A.beta., such as of Alzheimer's disease. Down's syndrome, and CAA. It should be understood however, that the following Examples are set forth by way of illustration and not limitation, and that various modifications may be made by one of ordinary skill in the art.

EXAMPLES

Example 1: Single Dose Efficacy in Aged Transgenic Mice

[0158] Single dose longitudinal effects of the murine surrogate mE8c anti-N3pGlu antibody (IgG2a) (U.S. Pat. No. 8,679,498 B1) observed in aged PDAPP transgenic mice (18.5 to 20-months old). To mimic A.beta. deposition rates and conditions in humans with Alzheimer's disease, mice are placed on a chow diet containing a BACE inhibitor LY2811376 (0.015%) four days prior to receiving a single intraperitoneal injection of biotinylated mE8c antibody or biotinylated control antibody of the same isotype, and remain on this diet for the duration of the study. A prior 4-month study demonstrated in aged PDAPP mice treated with the BACE inhibitor in feed resulted in a level of BACE inhibition that led to no change in the deposited A.beta. over the 4-month interval (i.e. no further deposition and no clearance of deposited A.beta. occurred). Animals are sacrificed 4, 8, 12, or 16 weeks after the 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 sacrificed at study initiation (time zero cohort) and at 4, 8, 12, or 16 weeks (age matched control cohort). Hippocampus tissue is analyzed by acid urea gels to measure the A.beta.1-42 via denaturing conditions.

[0159] Following the procedure essentially as described above, there was no significant difference in the levels of A.beta.1-42 between the isotype control injected at 4, 8, 12, or 16-weeks (age matched control cohort) as compared to the time zero cohort. As such, the control animals were combined into one control group for comparison with animals injected with biotinylated mE8c antibody. Mice that received a single injection of 20 mg/kg biotinylated mE8c antibody had reduced levels of hippocampal A.beta.1-42 as compared to control animals at 4-weeks (-6%), 8-weeks (-32%; Dunnett's multiple comparison, p=0.0091), 12-weeks (-17%), and 16-weeks (-19%). The aged PDAPP mice that received a single injection of 100 mg/kg biotinylated mE8c antibody had reduced levels of hippocampal A.beta.1-42 as compared to control animals at 4-weeks (-23%), 8-weeks (-28%; Dunnett's multiple comparison, p=0.0252), 12-weeks (-14%), and 16-weeks (-17%).

Example 2: Single Dose Target Engagement in Aged Transgenic Mice

[0160] To determine in-vivo target engagement of deposited plaque after a single dose of N3pGlu antibody, frozen hemi-brains from the single dose antibody study described in Example 1 are analyzed histologically to determine the percent area of hippocampus demonstrating antibody bound to plaque at 0, 4, 8, 12, and 16 weeks after a single dose of antibody.

[0161] Brains are sectioned and immunohistochemistry is performed on sister sections with an anti-human antibody (to detect the bound N3pGlu antibody) and 3D6 (to detect the total amount of deposited target in the section). Percent area bound by the N3pGlu antibody is normalized against the total amount of deposited target in the section.

[0162] Following procedures essentially as described above, the total area covered by deposited A.beta. was not significantly different across all groups and the average hippocampal area covered by the stain varied from 27 to 39%. Little to no target engagement was observed for control animals. Significant target engagement was observed 4, 8, 12, and 16-weeks after the single dose of 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) of biotinylated mE8c antibody (as compared to controls). Dunn non-parametric analysis was used to determine p-values. The average area of target engagement in mE8c-injected animals was highest after 4-weeks of treatment and the average target engagement decreased longitudinally at the subsequent 8, 12, and 16-week time points (1.9%, 1.1%, 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 the high level of variability, significant differences were not observed between the 20 and 100 mg/kg mE8c single dose injected animals for the matched time points except for week 12 and 16 (p-value=0.0465, 0.0432 unadjusted Wilcoxon).

Example 3: Single-Dose and Multiple-Dose, Dose-Escalation Clinical Trial for Alzheimer's Disease

[0163] A phase I, double-blind, randomized, placebo-controlled, parallel-group, single-dose followed by multiple-dose, dose-escalation study in patients with MCI due to A.beta. or mild-to-moderate A.beta. was conducted to assess the safety, tolerability, and PK of single and multiple IV doses of LY3002813 (Antibody III). A.beta. patients were enrolled into the single-ascending dose (SAD) phase and were each administered a single intravenous (IV) dose of Antibody III (5 dosing cohorts 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 proceeded into the multiple-ascending dose (MAD) phase (5 cohorts) and were administered IV doses of Antibody III (0.3 mg/kg IV to 10 mg/kg IV) or placebo approximately once per month for up to 4 doses depending on the initial doses. This phase concluded with a 12-week follow-up period.

[0164] The results of the single-dose study, wherein the PK of Antibody III was assessed up to 84 days after a single dose, showed the mean terminal elimination half-life was approximately 4 days after single-dose administration from 0.1 mg/kg to 3.0 mg/kg, and was increased to approximately 10 days (243 hours) at the 10-mg/kg dose level. 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).

[0165] The results of the multiple-dose study, wherein patients entered the multiple-dose phase 12 weeks after receiving a single dose in the SAD phase, showed Antibody III concentrations were significantly lower following multiple doses of Antibody III than following the first single dose. In contrast to the 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 at dose levels 3 mg/kg had serum Antibody III concentrations below the limits of detection 28 days after dosing. Patients receiving 10 mg/kg had sustained quantifiable concentrations 28 days after dosing.

[0166] Greater than 90% of the patients with A.beta. had treatment-emergent antidrug antibodies (ADAs) 3 months after the first dose at all dose groups; titers tended to increase by the end of the MAD phase and persist 3 months after the last dose. The rapid decline of Antibody III concentrations after multiple-dose administration may be at least partly associated with the presence of ADAs. Treatment group also experienced increased infusion related reactions upon multiple dosing.

[0167] Florbetapir scans were performed at baseline and after the last MAD dose, separated by approximately 7 months. The change in whole grey matter standardized uptake value ratio (SUVr) with cerebellum as a reference region was compared across dose cohorts, and the SUVr values were converted to standardized centiloid (CL) units. There was a significant reduction in cerebral amyloid (as assessed by florbetapir PET imaging) in the 6 patients who received 3 to 5 doses of 10 mg/kg of Antibody III intravenously over 6 months, without cerebral vasogenic edema or microhemorrhage complications in this dose group. The mean reduction of 44 CL units corresponds to a mean 40-50/o reduction in brain amyloid.

[0168] Florbetapir scans in extended follow up from three subjects treated with 3-5 doses of 10 mg/kg IV of Antibody III (vs 2 placebo) demonstrated sustained amyloid removal 18 months after last dose. The data indicate that short term (and possibly single) dose of anti-N3pGlu A.beta. antibodies (such as Antibody III) is sufficient to result in a sustained removal of amyloid. Chronic dosing with anti-N3pGlu A.beta. antibodies is not required to maintain clearance of cerebral amyloid.

Example 4: Single-Dose and Multiple-Dose Clinical Trial for Alzheimer's Disease

[0169] As a result of the significant target engagement (amyloid reduction by florbetapir PET) that was identified after 3 to 5 doses of LY3002813 (Antibody III) 10 mg/kg intravenously over 6 months, a Phase 1b study is in progress to confirm that different dosing regimens (single-dose, short-term "induction" dosing with higher, more frequent dosing; and chronic dosing for maximal PD effect) can mitigate immunogenicity and immune safety issues, and produce sustained amyloid reduction. A phase Ib, double-blind, randomized within cohort, placebo-controlled, parallel-group, single- and multiple-dose study in patients with MCI due to A.beta. or mild-to-moderate A.beta. is being conducted to assess the safety, tolerability, and PK of single and multiple IV doses of Antibody III. The study will be conducted in at least seven cohorts, including single IV doses at 10 mg/kg, 20 mg/kg, or 40 mg/kg (cohorts 1, 2, and 3, respectively), IV doses every two weeks for 24 weeks at 10 mg/kg or 20 mg/kg (cohorts 4 and 5, respectively), and IV doses every four weeks for up to 72 weeks at 10 mg/kg or 20 mg/kg (cohorts 6 and 7, respectively).

[0170] The primary target engagement outcome is the reduction of cerebral amyloid as measured by quantitative amyloid PET imaging (florbetapir CL) assessed at baseline and at 12 weeks, 24 weeks, 36 weeks, 48 weeks, and 72 weeks after starting treatment.

[0171] The results demonstrate that 10 mg/kg, 20 mg/kg and 40 mg/kg single doses and 10 mg/kg multiple doses of Antibody III can reduce amyloid at 12 weeks (mean reductions in cohorts to date ranging from -12 to -39 CL by florbetapir PET). For the patients who have had additional scans beyond 12 weeks, the amyloid clearance is sustained in the single dose cohorts, and further amyloid clearance is observed with dosing in the multiple dose cohort.

Example 5: Expression and Purification of Engineered N3pGlu A.beta. Antibodies

[0172] Anti-N3pGlu A.beta. antibodies of the present invention can be expressed and purified essentially as follows. An appropriate host cell, such as HEK 293 EBNA or CHO, is either transiently or stably transfected with an expression system for secreting antibodies using an optimal predetermined HC:LC vector ratio or a single vector system encoding both HC and LC. Clarified media, into which the antibody has been secreted, is purified using any of many commonly-used techniques. For example, the medium may be conveniently applied to a Protein A or G Sepharose FF column that has been equilibrated with a compatible buffer, such as phosphate buffered saline (pH 7.4). The column is washed to remove nonspecific binding components. The bound antibody is eluted, for example, by pH gradient (such as 0.1 M sodium phosphate buffer pH 6.8 to 0.1 M sodium Citrate buffer (pH 2.5). Antibody fractions are detected, such as by SDS-PAGE, and then are pooled. Further purification is optional, depending on the intended use. The antibody may be concentrated and/or sterile filtered using common techniques. Soluble aggregate and multimers may be effectively removed by common techniques, including size exclusion, hydrophobic interaction, ion exchange, or hydroxyapatite chromatography. The purity of the antibody after these chromatography steps is greater than 99%. The product may be immediately frozen at -70.degree. C. or may be lyophilized. The amino acid sequences for the anti-N3pGlu A.beta. antibodies are provided in Table A.

Example 6: Binding Affinity and Kinetics

[0173] The binding affinity and kinetics of anti-N3pGlu A.beta. antibody of the present invention (Antibody I or Antibody 11) to pE3-42 A.beta. peptide or to A.beta.1-40 peptide is measured by surface plasmon resonance using BIACORE.RTM. 3000 (GE Healthcare). The binding affinity is measured by capturing the anti-N3pGlu A.beta. antibody via immobilized protein A on a BIACORE.RTM. CMS chip, and flowing pE3-42 A.beta. peptide or A.beta.1-40 peptide, starting from 100 nM in 2-fold serial dilution down to 3.125 nM. The experiments are carried out at 25.degree. C. in HBS-EP buffer (GE Healthcare BR100669; 10 mM HEPES, 150 mM NaCl, 3 mM EDTA, 0.05% surfactant P20, pH 7.4).

[0174] For each cycle, the antibody is captured with 5 .mu.L injection of antibody solution at a 10 .mu.g/mL concentration with 10 .mu.L/min. flow rate. The peptide is bound with 250 .mu.L injection at 50 .mu.L/min, and then dissociated for 10 minutes. The chip surface is regenerated with 5 .mu.L injection of glycine buffer at pH 1.5 at 10 .mu.L % mL flow rate. The data is fit to a 1:1 Langmuir binding model to derive k.sub.on, k.sub.off, and to calculate K.sub.D. Following procedures essentially as described above, the following parameters (shown in Table C) were observed.

TABLE-US-00003 TABLE C Binding affinity and kinetics. Antibody k.sub.on (.times.10.sup.51/MS) K.sub.off (.times.10.sup.-41/s) K.sub.D (nM) I 1.39 1.31 0.71 II 3.63 1.28 0.35 III 3.62 2.7 0.75 IV 4.03 3.72 0.92 V 5.78 3.21 0.55

No appreciable binding to A.beta.1-40 was detected, indicating that Antibodies 1-V bound preferentially to pE3-42 A.beta. peptide as compared to A.beta.1-40.

Example 7: Ex Vivo Target Engagement

[0175] To determine ex vivo target engagement on brain sections from a fixed PDAPP brain, immunohistochemical analysis is performed with an exogenously added anti-N3pGlu A.beta. antibodies of the present invention (hE8L, B12L, R17L, Antibody I or Antibody II). Cryostat serial coronal sections from aged PDAPP mice (25-month old) are incubated with 20 .mu.g/mL of an exemplified N3pGlu A.beta. antibody of the present invention. Secondary HRP reagents specific for human IgG are employed and the deposited plaques are visualized with DAB-Plus (DAKO). Biotinylated murine 3D6 antibody followed by Step-HRP secondary is used as a positive control. The positive control antibody (biotinylated 3D6) labeled significant quantities of deposited A.beta. in the PDAPP hippocampus, and the anti-N3pGlu A.beta. antibodies (hE8L, B12L, R17L, Antibody I or Antibody II) labeled a subset of deposits. These histological studies demonstrated that the anti-N3pGlu A.beta. antibodies of the present invention engaged deposited A.beta. target ex vivo.

Example 8: Synthesis of N-[3-[(4aR,7aS)-2-Amino-6-(5-fluoropyrimidin-2-yl)-4,4a,5,7-tetrahydropyr- rolo[3,4-d][1,3]thiazin-7a-yl]-4-fluoro-phenyl]-5-methoxy-pyrazine-2-carbo- xamide; toluenesulfonic Acid

##STR00007##

[0177] Crystalline Form 2 N-[3-[(4aR,7aS)-2-amino-6-(5-fluoropyrimidin-2-yl)-4,4a,5,7-tetrahydropyr- rolo[3,4-d][1,3]thiazin-7a-yl]-4-fluoro-phenyl]-5-methoxy-pyrazine-2-carbo- xamide hydrated (149.15 mg) is added to ethyl acetate (2 mL). The sample is stirred at 1000 rpm at a temperature of 80.degree. C. p-Toluenesulfonic acid (70 mg dissolved in ethyl acetate (1 mL)) is added to the stirring solution, and it is stirred overnight at 80.degree. C. to produce a slurry of a white solid which is isolated by vacuum filtration to provide the title compound.

Alternative Preparation A of N-[3-[(4aR,7aS)-2-Amino-6-(5-fluoropyrimidin-2-yl)-4,4a,5,7-tetrahydropyr- rolo[3,4-d][1,3]thiazin-7a-yl]-4-fluoro-phenyl]-5-methoxy-pyrazine-2-carbo- xamide; toluenesulfonic Acid

[0178] N-[3-[(4aR,7aS)-2-amino-6-(5-fluoropyrimidin-2-yl)-4,4a,5,7-tetrahy- dropyrrolo[3,4-d][1.3]thiazin-7a-yl]-4-fluoro-phenyl]-5-methoxy-pyrazine-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.degree. C. To the warm solution is added 2-propanol (200.0 mL) over approximately 3 hours. The mixture is seeded shortly after the start of the 2-propanol addition with a portion of the title compound (500 mg, 0.75 mmol). After the solvent addition is complete, the mixture is cooled to approximately 20.degree. C. over 1-3 hours. The mixture is heated from approximately 20.degree. C. to approximately 55.degree. C. over a target time of 2 hours. The temperature is held at 55.degree. C. for 1 hour and then cooled to about 20.degree. C. over approximately 4 hours. The slurry is stirred for at least 10 hours at approximately 20.degree. C. The slurry is filtered and the wet cake is washed with water (57 mL). The product is dried in vacuo at 45.degree. C. for at least 10 hours to give the title compound (10.4 g, 81%). ES/MS (m/z): 500 (M+H).

Alternative Preparation B of N-[3-[(4aR,7aS)-2-Amino-6-(5-fluoropyrimidin-2-yl)-4,4a,5,7-tetrahydropyr- rolo[3,4-d][1,3]thiazin-7a-yl]-4-fluoro-phenyl]-5-methoxy-pyrazine-2-carbo- xamide; toluenesulfonic Acid

[0179] N-[3-[(4aR,7aS)-2-amino-6-(5-fluoropyrimidin-2-yl)-4.4a,5,7-tetrahy- dropyrrolo[3,4-d][1,3]thiazin-7a-yl]-4-fluoro-phenyl]-5-methoxy-pyrazine-2- -carboxamide hydrated (20.7 g) is slurried at 170 rpm in 60:40 THF:H.sub.2O (85 mL) in a 500 mL 3-necked round bottomed flask equipped with a nitrogen bubbler. IKA.RTM. mechanical motor/agitator attached to a glass shaft having a TEFLON.RTM. banana blade, and a thermocouple connected to a programmable J-KEM.RTM. temperature controller. p-Toluenesulfonic acid monohydrate (7.6 g, 1.03 eq) is dissolved in a mixture of 60:40 THF:H.sub.2O (20 mL) and the solution added all at once to the stirring N-[3-[(4aR,7aS)-2-amino-6-(5-fluoropyrimidin-2-yl)-4,4a,5,7-tetrahydropyr- rolo[3,4-d][1,3]thiazin-7a-yl]-4-fluoro-phenyl]-5-methoxy-pyrazine-2-carbo- xamide slurry at 23.degree. C., leading almost immediately to a clear reddish tan solution. The agitation rate is then increased to 200 rpm as over 15 minutes, water (22 mL) is added to the solution, which is then seeded with N-[3-[(4aR,7aS)-2-amino-6-(5-fluoropyrimidin-2-yl)-4,4a,5,7-tetrahy dropyrrolo[3,4-d][1,3]thiazin-7a-yl]-4-fluoro-phenyl]-5-methoxy-pyrazine-- 2-carboxamide toluenesulfonic acid (750 mg, 3 wt % seed load) and is then stirred at 23.degree. C. for a further 15 minutes. Over 6 hours, water (226 mL, total solvent of 353 mL; or 13.6 vol., final solvent ratio of 17.5:82.5 THF:H.sub.2O) is added to the slurry, which is then stirred overnight (22 hours) at 23.degree. C. The slurry is filtered via vacuum, rinsed with 15:85 THF:H.sub.2O (2.times.20 mL), then left on vacuum for 20 minutes while cracks which form in the product wet cake are manually pressed closed. The wet solids are dried at 40.degree. C. under vacuum for about 72 hours to give the title compound as a white crystalline solid (24.07 g, 90.0 wt %).

[0180] The crystalline N-[3-[(4aR,7aS)-2-amino-6-(5-fluoropyrimidin-2-yl)-4,4a,5,7-tetrahydropyr- rolo[3,4-d][1,3]thiazin-7a-yl]-4-fluoro-phenyl]-5-methoxy-pyrazine-2-carbo- xamide; toluenesulfonic acid is characterized by an XRD pattern using CuKa radiation as having diffraction peaks (2-theta values) as described in Table D below, and in particular having peaks at diffraction angle 2-theta of 5.0.degree. in combination with one or more of the peaks selected from the group consisting of 19.6.degree., 13.8.degree., and 18.5.degree.; with a tolerance for the diffraction angles of 0.2 degrees.

TABLE-US-00004 TABLE D X-ray powder diffraction peaks of crystalline Example 8 Angle (2-Theta.degree.) +/- Relative Intensity (% of Peak 0.2.degree. most intense peak) 1 5.0 100.0 2 13.4 22.9 3 13.8 37.3 4 14.4 20.2 5 15.3 28.8 6 17.5 25.9 7 18.5 30.7 8 19.6 45.8 9 20.4 17.7 10 25.6 30.1

TABLE-US-00005 Sequences (HCDR1-Antibody I and Antibody II) <SEQ ID NO: 1; PRT1; Artificial> KASGYTFTDYYIN (HCDR2-Antibody I and Antibody II) <SEQ ID NO: 2; PRT1; Artificial> WINPGSGNTKYNEKFKG (HCDR3-Antibody I and Antibody II) <SEQ ID NO: 3; PRT1; Artificial> TREGETVY (LCDR1-Antibody I and Antibody II) <SEQ ID NO: 4; PRT1; Artificial> KSSQSLLYSRGKTYLN (LCDR2-Antibody II) <SEQ ID NO: 5; PRT1; Artificial> YAVSKLDS (LCDR2-Antibody I) <SEQ ID NO: 6; PRT1; Artificial> YDVSKLDS (LCDR3-Antibody I and Antibody II) <SEQ ID NO: 7; PRT1; Artificial> VQGTHYPET (HCVR-Antibody I and Antibody II) <SEQ ID NO: 8; PRT1; Artificial> QVQLVQSGAEVKKPGSSVKVSCKASGYTFTDYYINWVRQAPGQGLEWMGWINPGSGNT KYNEKFKGRVTITADESTSTAYMELSSLRSEDTAVYYCTREGETVYWGQGTLVTVSS (LCVR-Antibody I) <SEQ ID NO: 9; PRT1; Artificial> DVVMTQSPLSLPVTLGQPASISCKSSQSLLYSRGKTYLNWFQQRPGQSPRRLIYDVSKLDS GVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCVQGTHYPFTFGQGTKLEIK (LCVR-Antibody II) <SEQ ID NO: 10; PRT1; Artificial> DIQMTQSPSTLSASVGDRVTITCKSSQSLLYSRGKTYLNWLQQKPGKAPKLLIYAVSKLD SGVPSRFSGSGSGTEFTETISSURDDFATYYCVQGTHYPFTFGQGTKLEIK (HC-Antibody I and Antibody II) <SEQ ID NO: 11; PRT1; Artificial> QVQLVQSGAEVKKPGSSVKVSCKASGYTFTDYYINWVRQAPGQGLEWMGWINPGSGNT KYNEKFKGRVTITADESTSTAYMELSSLRSEDTAVYYCTREGETVYWGQGTLVTVSSAS TKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGL YSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSV FLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNST YRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELT KNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQ QGNVFSCSVMHEALHNHYTQKSLSLSPG (LC-Antibody I) <SEQ ID NO: 12; PRT1; Artificial> DVVMTQSPLSLPVTLGQPASISCKSSQSLLYSRGKTYLNWFQQRPGQSPRRLIYDVSKLDS GVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCVQGTHYPFTFGQGTKLEIKRTVAAPSVFI FPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLS STLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (LC-Antibody II) <SEQ ID NO: 13; PRT1; Artificial> DIQMTQSPSTLSASVGDRVTITCKSSQSLLYSRGKTYLNWLQQKPGKAPKLLIYAVSKLD SGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCVQGTHYPFTFGQGTKLEIKRTVAAPSVFI FPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLS STLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC <SEQ ID NO: 14; DNA; Artificial> Exemplified DNA fix Expressing Antibody Heavy Chain of SEQ ID NO: 11 CAGGTGCAGCTGGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTGGGTCCTCGGTGAAG GTCTCCTGCAAGGCTTCTGGATACACCTTCACCGACTATTATATCAACTGGGTGCGAC AGGCCCCTGGACAAGGGCTTGAGTGGATGGGATGGATCAACCCTGGCAGTGGTAATA CAAAGTACAATGAGAAGTTCAAGGGCAGAGTCACGATTACCGCGGACGAATCCACG AGCACAGCCTACATGGAGCTGAGCAGCCTGAGATCTGAGGACACGGCCGTGTATTAC TGTACAAGAGAAGGCGAGACGGTCTACTGGGGCCAGGGAACCCTGGTCACCGTCTCC TCAGCCTCCACCAAGGGCCCATCGGTCTTCCCGCTAGCACCCTCCTCCAAGAGCACCT CTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGAACTACTTCCCCGAACCGGTGA CGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCC TACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTT GGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGG ACAAGAAAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAG CACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACA CCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACG AAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCA AGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTC ACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAAC AAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGA GAACCACAGGTGTACACCCTGCCCCCATCCCGGGACGAGCTGACCAAGAACCAGGTC AGCCTGACCTGCCTGGTCAAAGGCTTcTATCCCAGCGACATCGCCGTGGAGTGGGAG AGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCCCCCGTGCTGGACTCCGA CGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGG GAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAA GAGCCTCTCCCTGTCTCCGGGT <SEQ ID NO: 15; DNA; Artificial> Exemplified DNA for Expressing Antibody Light Chain of SEQ ID NO: 12 GATGTTGTGATGACTCAGTCTCCACTCTCCCTGCCCGTCACCCTTGGACAGCCGGCCT CCATCTCCTGCAAGTCTAGTCAAAGCCTCCTGTACAGTCGCGGAAAAACCTACTTGA ATTGGTTTCAGCAGAGGCCAGGCCAATCTCCAAGGCGCCTAATTTATGATGTTTCTAA ACTGGACTCTCTGGGTCCCAGACAGATTCAGCGGCAGTGGGTCAGGCACTGATTTCAC ACTGAAAATCAGCAGGGTGGAGGCTGAGGATGTTGGGGTTTATTACTGCGTGCAAGG TACACACTACCCTTTCACTTTTGGCCAAGGGACCAAGCTGGAGATCAAACGGACCGT GGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACT GCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGG AAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGA CAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACT ACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCG TCACAAAGAGCTTCAACAGGGGAGAGTGC <SEQ ID NO: 16; DNA; Artificial> Exemplified DNA for Expressing Antibody Light Chain of SEO ID NO: 13 GACATCCAGATGACCCAGTCTCCTTCCACCCTGTCTGCATCTGTAGGAGACAGAGTCA CCATCACTTGCAAGTCCAGTCAGAGTCTCCTGTACAGTCGCGGAAAAACCTATTTGA ACTGGCTCCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGTCTCCA AACTGGACAGTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAATTCA CTCTCACCATCAGCAGCCTGCAGCCTGATGATTTTGCAACTTATTACTGCGTGCAGGG TACACATTATCCTTTCACTTTTGGCCAGGGGACCAAGCTGGAGATCAAACGGACCGT GGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACT GCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGG AAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGA CAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGACAAAGCAGACT ACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCG TCACAAAGAGCTTCAACAGGGGAGAGTCTC (LCDR1-B12L/R17L/hE8L) <SEQ ID NO: 17; PRT1: Artificial> KSSQSLLYSRGKTYLN (LCDR2-B12L/R17L/hE8L) <SEQ ID NO: 18; PRT1; Artificial> AVSKLDS (LCDR3-B12L/RI7L/hE8L) <SEQ ID NO: 19; PRT1; Artificial> VQGTHYPFT (HCDRI-B12L) <SEQ ID NO: 20; PRT1; Artificial> GYDFTRYYIN (HCDR1-R17L) <SEQ ID NO: 21; PRT1; Artificial> GYTFTRYYIN (HCDR2-B12L/R17L/hE8L) <SEQ ID NO: 22; PRT1; Artificial> WINPGSGNTKYNEKFKG (HCDR3-B12L) <SEQ ID NO: 23; PRT1; Artificial> EGITVY (HCDR3-R17L) <SEQ ID NO: 24; PRT1; ArtificiaL> EGTTVY (LCVR-B12L/R17L) <SEQ ID NO: 25; PRT1; Artificial> DIVMTQTPLSLSVTPGQPASISCKSSQSLLYSRGKTYLNWLLQKPGQSPQLLIYAVSKLDS GVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCVQGTHYPFTFGQGTKLEIK (HCVR-B12L) <SEQ ID NO: 26; PRT1; Artificial> QVOLVQSGAEVKKPGSSVKVSCKASGYDFTRYYINWVRQAPGQGLEWMGWINPGSGN TKYNEKFKGRVTITADESTSTAYMELSSLRSEDTAVYYCAREGITVYWGQGTTVTVSS (HCVR-R17L) <SEQ ID NO: 27; PRT1; Artificial> QVQLVQSGAEVKKPGSSVKVSCKASGYTFTRYYINWVRQAPGQGLEWMGWINPGSGNT KYNEKFKGRVTITADESTSTAYMELSSLRSEDTAVYYCAREGITVYWGQGTTVTVSS (LC-B12L/R17L) <SEQ ID NO: 28; PRT1; Artificial> DIVMTQTPLSLSVTPGQPASISCKSSQSLLYSRGKTYLNWLLQKPGQSPQLLIYAVSKLDS GVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCVQGTHYPFTFGQGTKLEIKRTVAAPSVFI FPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLS STLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

(HC-B12L) <SEQ ID NO: 29; PRT1; Artificial> QVQLVQSGAEVKKPGSSVKVSCKASGYDFTRYYINWVRQAPGQGLEWMGWINPGSGN TKYNEKFKGRVTITADESTSTAYMELSSLRSEDTAVYYCAREGITVYWGQGTTVTVSSAS TKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGL YSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSV FLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNST YRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELT KNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQ QGNVFSCSVMHEALHNHYTQKSLSLSPG (HC-RI7L) <SEQ ID NO: 30; PRT1; Artificial> QVOLVQSGAEVKKPGSSVKVSCKASGYTFTRYYINWVRQAPGQGLEWMGWINPGSGNT KYNEKEKGRVTITADESTSTAYMELSSLRSEDTAVYYCAREGITVYWGQGTTVTVSSAS TKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGL YSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELEGGPSV FLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNST YRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELT KNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQ QGNVFSCSVMHEALHNHYTQKSLSLSPG N3pGlu A.beta. (SEQ ID NO: 31) [pE]FRHDSGYEVHHQKLVFFAEDVGSNKGAIIGLMVGGVVIA (LCVR-hE8L) <SEQ ID NO, 32; PRT1; Artificial> DIVMTQTPLSLSVTPGQPASISCKSSQSLLYSRGKTYLNWLLQKPGQSPQLLIYAVSKLDS GVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCNTQGTFIYPETFGQGTKLEIK (LC-hE8L) <SEQ ID NO, 33; PRT1; Artificial> DIVMTQTPLSLSVTPGQPASISCKSSQSLLYSRGKTYLNWLLQKPGQSPQLLIYAVSKLDS GVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCVQGTHYPFTFGQGTKLEIKRTVAAPSVFI FPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLS STLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (HCVR-hE8L) <SEQ ID NO, 34; PRT1; Artificial> QVQLVQSGAEVKKPGSSVKVSCKASGYTFTDYYINWVRQAPGQGLEWMGWINPGSGNT KYNEKFKGRVTITADESTSTAYMELSSLRSEDTAVYYCAREGETVYWGQGTTVTVSS (HC-hE8L) <SEQ ID NO, 35; PRT1; Artificial> QVQLVQSGAEVKKPGSSVKVSCKASGYTFTDYYINWVRQAPGQGLEWMGWINPGSGNT KYNEKFKGRVTITADESTSTAYMELSSLRSEDTAVYYCAREGETVYWGQGTTVTVSSAS TKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGL YSLSSVVTVPSSSEGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELEGGPSV FLFPPKPKDTLMISRTPEVITCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNST YRVVSVETVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELT KNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQ QGNVESCSVMHEALHNHYTQKSLSLSPG (HCDR1-hE8L) <SEQ ID NO: 36; PRT1; Artificial> GYTFTDYYIN (HCDR3-hE8L) <SEQ ID NO: 37; FRT1: Artificial> EGETVY (A.beta. 1-42) <SEQ ID NO: 38; PRT1; Artificial> DAEFRHDSGYEVHHQKLVFFAEDVGSNKGAIIGLMVGGVVIA (LCVR-Antibody VI) <SEQ ID NO: 39; PRT1: Artificial> MVSSAQFLFLLVLWIQETNGDVVMTQTPLTLSVTIGQPASISCKSSQSLL YSDGKTYLNWLLQRPGQSPMRLIYLVSKLDSGVPDRFTGSGSGTDFTLK ISRVEAEDLGVYYCVQGTHFPFTFGSGTKLEIKRADAAPTVSIFPP (LCVR-Antibody VI) <SEQ ID NO: 40; PRT1; Artificial> MGWSGVFTFLLSGTAGVHSEVQLQQSGPELVKPGASMKISCKASGYSFTG YTMNWVKQSHGKNLEWIGLINPYSGVTRYNQKFKGKATLIVDKSSSTAYM ELLSLTSEDSAVYYCTREAKREWDETYWGQGTLVTVSAAKTTPPSV (LCVR-Antibody VII) <SEQ ID NO: 41; PRT1; Artificial> MVSTAQFLFLLVLWIQETNGDVVMTQTPLTLSVTIGQPASISCKSSQSLL YSDGKTYLNWLLQRPGQSPMRLIYLVSKLDSGVPDRFTGSGSGTDFTLK ISRVEAEDLGVYYCVQGTHFPFTFGSGTKLEIKRADAAPTVSIFPPS (LCVR-Antibody VII) <SEQ ID NO: 42; PRT1; Artificial> MGWSGVFIFLLSGTAGVHSEVQLQQSGPELVKPGASMKISCKASGYSFTG YTMNWVKQSHGKNLEWIGLINPYNGVTRYNQKFKGKATLIVDKSSSTAY MELLSLTSEDSAVYYCTREAKREWDETYWGQGTLVTVSAAKTTPPSVYPL (LCVR-Antibody VIII) <SEQ ID NO: 43; PRT1; Artificial> MKLPVRLLVLVFWIPVSSSDVVMTQTPLSLPVSLGDQASISCRSSQSLVH SDGNTYLHWYLQKPGQSPKLLIYKVSNRFSGVPDRFSGSGSGTDFTLKIS RVEAEDLGVYFCSQSTHVPPTEGGGTKLEIKRADAAPTVSIFPPSS (HCVR-Antibody VIII) <SEQ ID NO: 44; PRT1; Artificial> MDFGLSLLIFVLILKGVQCEVKLVESGGGLVQPGGSRKLSCAASGFTFSDY GMAWVRQAPGKGPEWVAFISNLAYSIYYADTVTGRFTISRENAKNTLYLEM SSLRSEDTAMYYCARYDYDNILDYVMDYWGQGTSVTVSSAKTTPPSVYPL (LCVR-Antibody IX) <SEQ ID NO: 45; PRT1; Artificial> MKLPVRLLVLWIQETKGDVVLTQTPLTLSVTIGQPASISCKSSQSLLYSN GKTYLNWLLQRPGQSPKRLIYVVSKLDSGVPDRFTGSGSGTDFTLKISRV EAEDLGVYYCVQGTHFPFTFGSGTKLEIKRADAAPTVSIFPPSS (HCVR-Antibody IX) <SEQ ID NO: 46; PRT1; Artifical> MGWSGVFLFLLSVTEGVHSQVQLQQSGAELVRPGSSVKISCKASGYIFNN YWINWVKQRPGQGLEWIGQIYPGDGDTNYNGKFKGKATLTADKSSSTAY MQLSSLTSEDSAVYFCAREGYIVYWGQGTLVTVSAAKTTPPSVYPL (HCVR-Antibody X) <SEQ ID NO: 47; PRT1; Artificial> DVVMTQTPLSLPVSLGDQASISCRSSQSLLHSNGNTYLHWYLQKPGQSPKLLI YKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDLGVYFCSQSTHVPLTFGAGT (HCVR-Antibody X) <SEQ ID NO: 48; PRT1; Artificial> QLQQSGAELMKPGASVKISCKATGYTFSSYWIEWVKQRPGHGLEWIGEILPGR GSTHYNEKFKGKATFTADTSSNTAYMQLSSLTSEDSAVYYCARSPITTSDYWG QGTTLTVSS (LCVR-Antibody XI) <SEQ ID NO: 49; PRT1; Artificial> SCRSSQSLVHSNGNTYLHWYLQKPGQSPKLLIYKVSNRFSGVPDRFSGSGSGT DFTLKISRVEAEDLGVYFCSQSTHVPLTFGAGT (HCVR-Antibody XI) <SEQ ID NO: 50; PRT1; Artificial> AELKKPGASVKISCKATGYTFRSYWIEWVKQRPGHLEWIGEILPGRGSTKY NEKFKGKATFTADTSSNTANMQLSSLTSEDSAVYYCARSPITTSDY (LCVR-Antibody XII) <SEQ ID NO: 51; PRT1; Artificial> DVVLTQTPFTLSVTIGQPASISCKSSQSLLHSNGESYLNWLFQRPGQSPKRLIY AVSKLDSGVPDRFTGSGSGTDFTLKISRVEAEDLGVYYCVQGTHFPFTFGGG TKLEIK (HCVR-Antibody XII) <SEQ ID NO: 52; PRT1; Artificial> QIQLQQSGPELVKPGAAVKISCKASGYTFTDYYLNWVKQKPGQGLEWIGWIY PGSGNVKYNEKFKGKATLTADTSSNTAHMQLSSLTSEDTAVYFCTREGLIVY WGQGTLVTVSA (HCVR-Antibody XIII) <SEQ ID NO: 53; PRT1; Artificial> DVVLTQTPLTLSVTIGQPASISCKSSQSLLYSNGKTYLNWLLQRPGQSPKRLIY VVSKLDSGVPDRFTGSGSGTDFTLKISRVEAEDLGVYYCVQGTHYPFTFGGGT KLEIK (HCVR-Antibody XIII) <SEQ ID NO: 54; PRT1; Artificial> QIQLQQSGPDLVKPGASVKISCKASGYTFTDYYINWVKQKPGQGLEWIGWLNP GSGNTKYNEKFKGKATMTVDTTSSTVYMQLSSLTSEDSAVYFCTREGPIDYWG RGTSVTVSS (LCVR-Antibody XIV) <SEQ ID NO: 55; PRT1; Artificial> DIVMTQTPLSLSVTPGQPASISCSSSQSLIYSDGNAYLHWYLQKP GQSPQLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVG VYYCTQSTHSPWTFGGGTKVEIK (HCVR-Antibody XIV) <SEQ ID NO: 56; PRT1; Artificial> EVQLVESGGGLVKPGGSLRLSCAASGYTFSRYSMSWVRQAPG KGLEWVGQINIRGCNTYYPDTVKGRFTISRDDSKNTLYLOMNS LKTEDTAVYYCTTGDFWGQGTLVTVSS (LC-Antibody XV) <SEQ ID NO: 57; PRT1; Artificial> DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYA ASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTPLTFGG GTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKV DNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQG LSSPVTKSFNRGEC (HC-Antibody XV) <SEQ ID NO: 58; PRT1; Artificial> QVQLVESGGGVVQPGRSLRLSCAASGFAFSSYGMHWVRQAPGKGLEWVAV IWFDGTKKYYTDSVKGRFTISRDNSKNTLYLQMNTLRAEDTAVYYCARDR GIGARRGPYYMDVWGKGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALG CLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSL

GTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLF PPKPKTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPRE EQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQP REPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKT TPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSL SPG (LC-Antibody XVI) <SEQ ID NO: 59; PRT1; Artificial> DIVLTQSPATLSLSPGERATLSCRASQSVSSSYLAWYQQKPGQAPRLLIYGASSRATGVPA RFSGSGSGTDFTLTISSLEPEDFATYYCLQIYNMPITFGQGTKVEIKRTVAAPSVFIFPPSDE QLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLS KADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (HC-Antibody XVI) <SEQ ID NO: 60; PRT1; Artificial> QVELVESGGGLVQPGGSLRLSCAASGFTESSYAMSWVRQAPGKGLEWVSAINAS GTRTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARGKGNTHKPYGYVRY FDVWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGAL TSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKT HTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVE VHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQ PREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDG SFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (LC-Antibody XVII) <SEQ ID NO: 61; P-RT1; Artificial> DIVMTQSPLSLPVTPCiEPASISCRSSQSLVYSNGDTYLHWYLQKPCQSPQLLIY KVSNRESGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCSQSTHVPWTFGQGT KVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQ SGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSF NRGEC (BC-Antibody XVII) <SEQ ID NO: 62; PRT1; Artificial> EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYGMSWVRQAPGKGLELVASIN SNGGSTYYPDSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCASGDYWG QGTTVTSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSG ALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKR VESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDP EVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKC KVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPS DIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLVDKSRWQEGNVFSCSVM HEALHNHYTQKSLSLSLG (LC-Antibody XVIII) <SEQ ID NO: 63; PRT1; Artificial> DVVMTQSPLSLPVTPGAPASISCRSSQSIVHSNGNTYLEWYLQKPGQSPK LLIYKVSNRFSGVPDRFSGSGSGTDFTLRISRVEAEDVGIYYCFQGSHVP PTFGPGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAK VQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACE VTHQGLSSPVTKSFNRGEC (HC-Antibody XVIII) <SEQ ID NO: 64; PRT1; Artificial> EVQLVESGGGLVQPGGSLRLSCSASGFTFSSFGMHWVRQAPGKGLEWVAY ISSGSSTIYYGDTVKGRFTISRDNAKNSLFLQMSSLRAEDTAVYYCAREG GYYYGRSYYTMDYTTVSSASTKGPSVFPLAPSSKSTSGGTAALG CLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSL GTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLF PPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPRE EQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTTISKAKGQP REPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKT TPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSL SPGK (LC-Antibody XIX) <SEQ ID NO: 65; PRT1; Artificial> DVVMTQSPLSLPVTLGQPASISCRSSQSLIYSDGNAYLHWFLQKPGQSPR LLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCSQSTHVP WTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNGFYPREA KVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYAC EVTHQGLSSPVTKSFNRGEC (HC-Antibody XIX) <SEQ ID NO: 66; PRT1; Artificial> EVQLVESGGGLVQPGGSLRLSCAASGFTFSRYSMSWVRQAPGKGLELVAQ INSVGNSTYYPDTVKGRFTISRDNAKNTLYLQMNSLRAEDTAVYYCASGD YWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVT VSWNSGALTSGVHTFPAVEQSSGLYSLSSVVTVPSSSLGTQTYICNVNHK PSNTKVDKKVEPKSCDKTHTCPPCPAPELEGGPSVFLFPPKPKDTLMISR TPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSV LTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSR DELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFF LYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

Sequence CWU 1

1

66113PRTArtificial SequenceSynthetic Construct 1Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr Tyr Ile Asn1 5 10217PRTArtificial SequenceSynthetic Construct 2Trp Ile Asn Pro Gly Ser Gly Asn Thr Lys Tyr Asn Glu Lys Phe Lys1 5 10 15Gly38PRTArtificial SequenceSynthetic Construct 3Thr Arg Glu Gly Glu Thr Val Tyr1 5416PRTArtificial SequenceSynthetic Construct 4Lys Ser Ser Gln Ser Leu Leu Tyr Ser Arg Gly Lys Thr Tyr Leu Asn1 5 10 1558PRTArtificial SequenceSynthetic Construct 5Tyr Ala Val Ser Lys Leu Asp Ser1 568PRTArtificial SequenceSynthetic Construct 6Tyr Asp Val Ser Lys Leu Asp Ser1 579PRTArtificial SequenceSynthetic Construct 7Val Gln Gly Thr His Tyr Pro Phe Thr1 58115PRTArtificial SequenceSynthetic Construct 8Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser1 5 10 15Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr 20 25 30Tyr Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45Gly Trp Ile Asn Pro Gly Ser Gly Asn Thr Lys Tyr Asn Glu Lys Phe 50 55 60Lys Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr65 70 75 80Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Thr Arg Glu Gly Glu Thr Val Tyr Trp Gly Gln Gly Thr Leu Val Thr 100 105 110Val Ser Ser 1159112PRTArtificial SequenceSynthetic Construct 9Asp Val Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Leu Gly1 5 10 15Gln Pro Ala Ser Ile Ser Cys Lys Ser Ser Gln Ser Leu Leu Tyr Ser 20 25 30Arg Gly Lys Thr Tyr Leu Asn Trp Phe Gln Gln Arg Pro Gly Gln Ser 35 40 45Pro Arg Arg Leu Ile Tyr Asp Val Ser Lys Leu Asp Ser Gly Val Pro 50 55 60Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile65 70 75 80Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Val Gln Gly 85 90 95Thr His Tyr Pro Phe Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 100 105 11010112PRTArtificial SequenceSynthetic Construct 10Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Lys Ser Ser Gln Ser Leu Leu Tyr Ser 20 25 30Arg Gly Lys Thr Tyr Leu Asn Trp Leu Gln Gln Lys Pro Gly Lys Ala 35 40 45Pro Lys Leu Leu Ile Tyr Ala Val Ser Lys Leu Asp Ser Gly Val Pro 50 55 60Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile65 70 75 80Ser Ser Leu Gln Pro Asp Asp Phe Ala Thr Tyr Tyr Cys Val Gln Gly 85 90 95Thr His Tyr Pro Phe Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 100 105 11011444PRTArtificial SequenceSynthetic Construct 11Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser1 5 10 15Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr 20 25 30Tyr Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45Gly Trp Ile Asn Pro Gly Ser Gly Asn Thr Lys Tyr Asn Glu Lys Phe 50 55 60Lys Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr65 70 75 80Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Thr Arg Glu Gly Glu Thr Val Tyr Trp Gly Gln Gly Thr Leu Val Thr 100 105 110Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro 115 120 125Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val 130 135 140Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala145 150 155 160Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly 165 170 175Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly 180 185 190Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys 195 200 205Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys 210 215 220Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu225 230 235 240Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu 245 250 255Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys 260 265 270Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys 275 280 285Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu 290 295 300Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys305 310 315 320Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys 325 330 335Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser 340 345 350Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys 355 360 365Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln 370 375 380Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly385 390 395 400Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln 405 410 415Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn 420 425 430His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 435 44012219PRTArtificial SequenceSynthetic Construct 12Asp Val Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Leu Gly1 5 10 15Gln Pro Ala Ser Ile Ser Cys Lys Ser Ser Gln Ser Leu Leu Tyr Ser 20 25 30Arg Gly Lys Thr Tyr Leu Asn Trp Phe Gln Gln Arg Pro Gly Gln Ser 35 40 45Pro Arg Arg Leu Ile Tyr Asp Val Ser Lys Leu Asp Ser Gly Val Pro 50 55 60Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile65 70 75 80Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Val Gln Gly 85 90 95Thr His Tyr Pro Phe Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 100 105 110Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu 115 120 125Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe 130 135 140Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln145 150 155 160Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser 165 170 175Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu 180 185 190Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser 195 200 205Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 210 21513219PRTArtificial SequenceSynthetic Construct 13Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Lys Ser Ser Gln Ser Leu Leu Tyr Ser 20 25 30Arg Gly Lys Thr Tyr Leu Asn Trp Leu Gln Gln Lys Pro Gly Lys Ala 35 40 45Pro Lys Leu Leu Ile Tyr Ala Val Ser Lys Leu Asp Ser Gly Val Pro 50 55 60Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile65 70 75 80Ser Ser Leu Gln Pro Asp Asp Phe Ala Thr Tyr Tyr Cys Val Gln Gly 85 90 95Thr His Tyr Pro Phe Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 100 105 110Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu 115 120 125Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe 130 135 140Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln145 150 155 160Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser 165 170 175Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu 180 185 190Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser 195 200 205Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 210 215141332DNAArtificial SequenceSynthetic Construct 14caggtgcagc tggtgcagtc tggggctgag gtgaagaagc ctgggtcctc ggtgaaggtc 60tcctgcaagg cttctggata caccttcacc gactattata tcaactgggt gcgacaggcc 120cctggacaag ggcttgagtg gatgggatgg atcaaccctg gcagtggtaa tacaaagtac 180aatgagaagt tcaagggcag agtcacgatt accgcggacg aatccacgag cacagcctac 240atggagctga gcagcctgag atctgaggac acggccgtgt attactgtac aagagaaggc 300gagacggtct actggggcca gggaaccctg gtcaccgtct cctcagcctc caccaagggc 360ccatcggtct tcccgctagc accctcctcc aagagcacct ctgggggcac agcggccctg 420ggctgcctgg tcaaggacta cttccccgaa ccggtgacgg tgtcgtggaa ctcaggcgcc 480ctgaccagcg gcgtgcacac cttcccggct gtcctacagt cctcaggact ctactccctc 540agcagcgtgg tgaccgtgcc ctccagcagc ttgggcaccc agacctacat ctgcaacgtg 600aatcacaagc ccagcaacac caaggtggac aagaaagttg agcccaaatc ttgtgacaaa 660actcacacat gcccaccgtg cccagcacct gaactcctgg ggggaccgtc agtcttcctc 720ttccccccaa aacccaagga caccctcatg atctcccgga cccctgaggt cacatgcgtg 780gtggtggacg tgagccacga agaccctgag gtcaagttca actggtacgt ggacggcgtg 840gaggtgcata atgccaagac aaagccgcgg gaggagcagt acaacagcac gtaccgtgtg 900gtcagcgtcc tcaccgtcct gcaccaggac tggctgaatg gcaaggagta caagtgcaag 960gtctccaaca aagccctccc agcccccatc gagaaaacca tctccaaagc caaagggcag 1020ccccgagaac cacaggtgta caccctgccc ccatcccggg acgagctgac caagaaccag 1080gtcagcctga cctgcctggt caaaggcttc tatcccagcg acatcgccgt ggagtgggag 1140agcaatgggc agccggagaa caactacaag accacgcccc ccgtgctgga ctccgacggc 1200tccttcttcc tctatagcaa gctcaccgtg gacaagagca ggtggcagca ggggaacgtc 1260ttctcatgct ccgtgatgca tgaggctctg cacaaccact acacgcagaa gagcctctcc 1320ctgtctccgg gt 133215657DNAArtificial SequenceSynthetic Construct 15gatgttgtga tgactcagtc tccactctcc ctgcccgtca cccttggaca gccggcctcc 60atctcctgca agtctagtca aagcctcctg tacagtcgcg gaaaaaccta cttgaattgg 120tttcagcaga ggccaggcca atctccaagg cgcctaattt atgatgtttc taaactggac 180tctggggtcc cagacagatt cagcggcagt gggtcaggca ctgatttcac actgaaaatc 240agcagggtgg aggctgagga tgttggggtt tattactgcg tgcaaggtac acactaccct 300ttcacttttg gccaagggac caagctggag atcaaacgga ccgtggctgc accatctgtc 360ttcatcttcc cgccatctga tgagcagttg aaatctggaa ctgcctctgt tgtgtgcctg 420ctgaataact tctatcccag agaggccaaa gtacagtgga aggtggataa cgccctccaa 480tcgggtaact cccaggagag tgtcacagag caggacagca aggacagcac ctacagcctc 540agcagcaccc tgacgctgag caaagcagac tacgagaaac acaaagtcta cgcctgcgaa 600gtcacccatc agggcctgag ctcgcccgtc acaaagagct tcaacagggg agagtgc 65716657DNAArtificial SequenceSynthetic Construct 16gacatccaga tgacccagtc tccttccacc ctgtctgcat ctgtaggaga cagagtcacc 60atcacttgca agtccagtca gagtctcctg tacagtcgcg gaaaaaccta tttgaactgg 120ctccagcaga aaccagggaa agcccctaag ctcctgatct atgctgtctc caaactggac 180agtggggtcc catcaaggtt cagcggcagt ggatctggga cagaattcac tctcaccatc 240agcagcctgc agcctgatga ttttgcaact tattactgcg tgcagggtac acattatcct 300ttcacttttg gccaggggac caagctggag atcaaacgga ccgtggctgc accatctgtc 360ttcatcttcc cgccatctga tgagcagttg aaatctggaa ctgcctctgt tgtgtgcctg 420ctgaataact tctatcccag agaggccaaa gtacagtgga aggtggataa cgccctccaa 480tcgggtaact cccaggagag tgtcacagag caggacagca aggacagcac ctacagcctc 540agcagcaccc tgacgctgag caaagcagac tacgagaaac acaaagtcta cgcctgcgaa 600gtcacccatc agggcctgag ctcgcccgtc acaaagagct tcaacagggg agagtgc 6571716PRTArtificial SequenceSynthetic Construct 17Lys Ser Ser Gln Ser Leu Leu Tyr Ser Arg Gly Lys Thr Tyr Leu Asn1 5 10 15187PRTArtificial SequenceSynthetic Construct 18Ala Val Ser Lys Leu Asp Ser1 5199PRTArtificial SequenceSynthetic Construct 19Val Gln Gly Thr His Tyr Pro Phe Thr1 52010PRTArtificial SequenceSynthetic Construct 20Gly Tyr Asp Phe Thr Arg Tyr Tyr Ile Asn1 5 102110PRTArtificial SequenceSynthetic Construct 21Gly Tyr Thr Phe Thr Arg Tyr Tyr Ile Asn1 5 102217PRTArtificial SequenceSynthetic Construct 22Trp Ile Asn Pro Gly Ser Gly Asn Thr Lys Tyr Asn Glu Lys Phe Lys1 5 10 15Gly236PRTArtificial SequenceSynthetic Construct 23Glu Gly Ile Thr Val Tyr1 5246PRTArtificial SequenceSynthetic Construct 24Glu Gly Thr Thr Val Tyr1 525112PRTArtificial SequenceSynthetic Construct 25Asp Ile Val Met Thr Gln Thr Pro Leu Ser Leu Ser Val Thr Pro Gly1 5 10 15Gln Pro Ala Ser Ile Ser Cys Lys Ser Ser Gln Ser Leu Leu Tyr Ser 20 25 30Arg Gly Lys Thr Tyr Leu Asn Trp Leu Leu Gln Lys Pro Gly Gln Ser 35 40 45Pro Gln Leu Leu Ile Tyr Ala Val Ser Lys Leu Asp Ser Gly Val Pro 50 55 60Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile65 70 75 80Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Val Gln Gly 85 90 95Thr His Tyr Pro Phe Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 100 105 11026115PRTArtificial SequenceSynthetic Construct 26Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser1 5 10 15Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Asp Phe Thr Arg Tyr 20 25 30Tyr Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45Gly Trp Ile Asn Pro Gly Ser Gly Asn Thr Lys Tyr Asn Glu Lys Phe 50 55 60Lys Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr65 70 75 80Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Glu Gly Ile Thr Val Tyr Trp Gly Gln Gly Thr Thr Val Thr 100 105 110Val Ser Ser 11527115PRTArtificial SequenceSynthetic Construct 27Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser1 5 10 15Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Arg Tyr 20 25 30Tyr Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45Gly Trp Ile Asn Pro Gly Ser Gly Asn Thr Lys Tyr Asn Glu Lys Phe 50 55 60Lys Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr65 70 75 80Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Glu Gly Thr Thr Val Tyr Trp Gly Gln Gly Thr Thr Val Thr 100 105 110Val Ser Ser 11528219PRTArtificial SequenceSynthetic Construct 28Asp Ile Val Met Thr Gln Thr Pro Leu Ser Leu Ser Val Thr Pro Gly1 5 10 15Gln Pro Ala Ser Ile Ser Cys Lys Ser Ser Gln Ser Leu Leu Tyr Ser 20 25 30Arg Gly Lys Thr Tyr Leu Asn Trp Leu Leu Gln Lys Pro Gly Gln Ser 35 40 45Pro Gln Leu Leu Ile Tyr Ala Val Ser Lys Leu Asp Ser Gly Val Pro 50 55 60Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile65 70 75 80Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Val Gln Gly 85 90 95Thr His Tyr Pro Phe Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 100 105 110Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu 115 120 125Gln Leu Lys Ser Gly Thr Ala

Ser Val Val Cys Leu Leu Asn Asn Phe 130 135 140Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln145 150 155 160Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser 165 170 175Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu 180 185 190Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser 195 200 205Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 210 21529444PRTArtificial SequenceSynthetic Construct 29Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser1 5 10 15Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Asp Phe Thr Arg Tyr 20 25 30Tyr Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45Gly Trp Ile Asn Pro Gly Ser Gly Asn Thr Lys Tyr Asn Glu Lys Phe 50 55 60Lys Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr65 70 75 80Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Glu Gly Ile Thr Val Tyr Trp Gly Gln Gly Thr Thr Val Thr 100 105 110Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro 115 120 125Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val 130 135 140Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala145 150 155 160Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly 165 170 175Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly 180 185 190Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys 195 200 205Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys 210 215 220Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu225 230 235 240Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu 245 250 255Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys 260 265 270Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys 275 280 285Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu 290 295 300Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys305 310 315 320Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys 325 330 335Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser 340 345 350Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys 355 360 365Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln 370 375 380Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly385 390 395 400Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln 405 410 415Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn 420 425 430His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 435 44030444PRTArtificial SequenceSynthetic Construct 30Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser1 5 10 15Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Arg Tyr 20 25 30Tyr Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45Gly Trp Ile Asn Pro Gly Ser Gly Asn Thr Lys Tyr Asn Glu Lys Phe 50 55 60Lys Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr65 70 75 80Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Glu Gly Thr Thr Val Tyr Trp Gly Gln Gly Thr Thr Val Thr 100 105 110Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro 115 120 125Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val 130 135 140Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala145 150 155 160Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly 165 170 175Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly 180 185 190Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys 195 200 205Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys 210 215 220Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu225 230 235 240Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu 245 250 255Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys 260 265 270Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys 275 280 285Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu 290 295 300Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys305 310 315 320Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys 325 330 335Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser 340 345 350Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys 355 360 365Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln 370 375 380Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly385 390 395 400Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln 405 410 415Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn 420 425 430His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 435 4403140PRTArtificial SequenceSynthetic ConstructMISC_FEATURE(1)..(1)Xaa at position 1 = pyroglutamic acid 31Xaa Phe Arg His Asp Ser Gly Tyr Glu Val His His Gln Lys Leu Val1 5 10 15Phe Phe Ala Glu Asp Val Gly Ser Asn Lys Gly Ala Ile Ile Gly Leu 20 25 30Met Val Gly Gly Val Val Ile Ala 35 4032112PRTArtificial SequenceSynthetic Construct 32Asp Ile Val Met Thr Gln Thr Pro Leu Ser Leu Ser Val Thr Pro Gly1 5 10 15Gln Pro Ala Ser Ile Ser Cys Lys Ser Ser Gln Ser Leu Leu Tyr Ser 20 25 30Arg Gly Lys Thr Tyr Leu Asn Trp Leu Leu Gln Lys Pro Gly Gln Ser 35 40 45Pro Gln Leu Leu Ile Tyr Ala Val Ser Lys Leu Asp Ser Gly Val Pro 50 55 60Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile65 70 75 80Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Val Gln Gly 85 90 95Thr His Tyr Pro Phe Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 100 105 11033219PRTArtificial SequenceSynthetic Construct 33Asp Ile Val Met Thr Gln Thr Pro Leu Ser Leu Ser Val Thr Pro Gly1 5 10 15Gln Pro Ala Ser Ile Ser Cys Lys Ser Ser Gln Ser Leu Leu Tyr Ser 20 25 30Arg Gly Lys Thr Tyr Leu Asn Trp Leu Leu Gln Lys Pro Gly Gln Ser 35 40 45Pro Gln Leu Leu Ile Tyr Ala Val Ser Lys Leu Asp Ser Gly Val Pro 50 55 60Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile65 70 75 80Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Val Gln Gly 85 90 95Thr His Tyr Pro Phe Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 100 105 110Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu 115 120 125Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe 130 135 140Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln145 150 155 160Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser 165 170 175Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu 180 185 190Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser 195 200 205Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 210 21534115PRTArtificial SequenceSynthetic Construct 34Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser1 5 10 15Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr 20 25 30Tyr Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45Gly Trp Ile Asn Pro Gly Ser Gly Asn Thr Lys Tyr Asn Glu Lys Phe 50 55 60Lys Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr65 70 75 80Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Glu Gly Glu Thr Val Tyr Trp Gly Gln Gly Thr Thr Val Thr 100 105 110Val Ser Ser 11535444PRTArtificial SequenceSynthetic Construct 35Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser1 5 10 15Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr 20 25 30Tyr Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45Gly Trp Ile Asn Pro Gly Ser Gly Asn Thr Lys Tyr Asn Glu Lys Phe 50 55 60Lys Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr65 70 75 80Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Glu Gly Glu Thr Val Tyr Trp Gly Gln Gly Thr Thr Val Thr 100 105 110Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro 115 120 125Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val 130 135 140Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala145 150 155 160Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly 165 170 175Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly 180 185 190Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys 195 200 205Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys 210 215 220Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu225 230 235 240Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu 245 250 255Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys 260 265 270Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys 275 280 285Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu 290 295 300Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys305 310 315 320Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys 325 330 335Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser 340 345 350Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys 355 360 365Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln 370 375 380Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly385 390 395 400Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln 405 410 415Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn 420 425 430His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 435 4403610PRTArtificial SequenceSynthetic Construct 36Gly Tyr Thr Phe Thr Asp Tyr Tyr Ile Asn1 5 10376PRTArtificial SequenceSynthetic Construct 37Glu Gly Glu Thr Val Tyr1 53842PRTArtificial SequenceSynthetic Construct 38Asp Ala Glu Phe Arg His Asp Ser Gly Tyr Glu Val His His Gln Lys1 5 10 15Leu Val Phe Phe Ala Glu Asp Val Gly Ser Asn Lys Gly Ala Ile Ile 20 25 30Gly Leu Met Val Gly Gly Val Val Ile Ala 35 4039145PRTArtificial SequenceSynthetic Construct 39Met Val Ser Ser Ala Gln Phe Leu Phe Leu Leu Val Leu Trp Ile Gln1 5 10 15Glu Thr Asn Gly Asp Val Val Met Thr Gln Thr Pro Leu Thr Leu Ser 20 25 30Val Thr Ile Gly Gln Pro Ala Ser Ile Ser Cys Lys Ser Ser Gln Ser 35 40 45Leu Leu Tyr Ser Asp Gly Lys Thr Tyr Leu Asn Trp Leu Leu Gln Arg 50 55 60Pro Gly Gln Ser Pro Met Arg Leu Ile Tyr Leu Val Ser Lys Leu Asp65 70 75 80Ser Gly Val Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe 85 90 95Thr Leu Lys Ile Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Tyr 100 105 110Cys Val Gln Gly Thr His Phe Pro Phe Thr Phe Gly Ser Gly Thr Lys 115 120 125Leu Glu Ile Lys Arg Ala Asp Ala Ala Pro Thr Val Ser Ile Phe Pro 130 135 140Pro14540146PRTArtificial SequenceSynthetic Construct 40Met Gly Trp Ser Gly Val Phe Leu Phe Leu Leu Ser Gly Thr Ala Gly1 5 10 15Val His Ser Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys 20 25 30Pro Gly Ala Ser Met Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ser Phe 35 40 45Thr Gly Tyr Thr Met Asn Trp Val Lys Gln Ser His Gly Lys Asn Leu 50 55 60Glu Trp Ile Gly Leu Ile Asn Pro Tyr Ser Gly Val Thr Arg Tyr Asn65 70 75 80Gln Lys Phe Lys Gly Lys Ala Thr Leu Ile Val Asp Lys Ser Ser Ser 85 90 95Thr Ala Tyr Met Glu Leu Leu Ser Leu Thr Ser Glu Asp Ser Ala Val 100 105 110Tyr Tyr Cys Thr Arg Glu Ala Lys Arg Glu Trp Asp Glu Thr Tyr Trp 115 120 125Gly Gln Gly Thr Leu Val Thr Val Ser Ala Ala Lys Thr Thr Pro Pro 130 135 140Ser Val14541146PRTArtificial SequenceSynthetic Construct 41Met Val Ser Thr Ala Gln Phe Leu Phe Leu Leu Val Leu Trp Ile Gln1 5 10 15Glu Thr Asn Gly Asp Val Val Met Thr Gln Thr Pro Leu Thr Leu Ser 20 25 30Val Thr Ile Gly Gln Pro Ala Ser Ile Ser Cys Lys Ser Ser Gln Ser 35 40 45Leu Leu Tyr Ser Asp Gly Lys Thr Tyr Leu Asn Trp Leu Leu Gln Arg 50 55 60Pro Gly Gln Ser Pro Met Arg Leu Ile Tyr Leu Val Ser Lys Leu Asp65 70 75 80Ser Gly Val Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe 85 90 95Thr Leu Lys Ile Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Tyr 100 105 110Cys Val Gln Gly Thr His Phe Pro Phe Thr Phe Gly Ser Gly Thr Lys 115 120 125Leu Glu Ile Lys Arg Ala Asp Ala Ala Pro Thr Val Ser Ile Phe Pro

130 135 140Pro Ser14542149PRTArtificial SequenceSynthetic Construct 42Met Gly Trp Ser Gly Val Phe Ile Phe Leu Leu Ser Gly Thr Ala Gly1 5 10 15Val His Ser Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys 20 25 30Pro Gly Ala Ser Met Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ser Phe 35 40 45Thr Gly Tyr Thr Met Asn Trp Val Lys Gln Ser His Gly Lys Asn Leu 50 55 60Glu Trp Ile Gly Leu Ile Asn Pro Tyr Asn Gly Val Thr Arg Tyr Asn65 70 75 80Gln Lys Phe Lys Gly Lys Ala Thr Leu Ile Val Asp Lys Ser Ser Ser 85 90 95Thr Ala Tyr Met Glu Leu Leu Ser Leu Thr Ser Glu Asp Ser Ala Val 100 105 110Tyr Tyr Cys Thr Arg Glu Ala Lys Arg Glu Trp Asp Glu Thr Tyr Trp 115 120 125Gly Gln Gly Thr Leu Val Thr Val Ser Ala Ala Lys Thr Thr Pro Pro 130 135 140Ser Val Tyr Pro Leu14543146PRTArtificial SequenceSynthetic Construct 43Met Lys Leu Pro Val Arg Leu Leu Val Leu Val Phe Trp Ile Pro Val1 5 10 15Ser Ser Ser Asp Val Val Met Thr Gln Thr Pro Leu Ser Leu Pro Val 20 25 30Ser Leu Gly Asp Gln Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu 35 40 45Val His Ser Asp Gly Asn Thr Tyr Leu His Trp Tyr Leu Gln Lys Pro 50 55 60Gly Gln Ser Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser65 70 75 80Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr 85 90 95Leu Lys Ile Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Phe Cys 100 105 110Ser Gln Ser Thr His Val Pro Pro Thr Phe Gly Gly Gly Thr Lys Leu 115 120 125Glu Ile Lys Arg Ala Asp Ala Ala Pro Thr Val Ser Ile Phe Pro Pro 130 135 140Ser Ser14544152PRTArtificial SequenceSynthetic Construct 44Met Asp Phe Gly Leu Ser Leu Leu Ile Phe Val Leu Ile Leu Lys Gly1 5 10 15Val Gln Cys Glu Val Lys Leu Val Glu Ser Gly Gly Gly Leu Val Gln 20 25 30Pro Gly Gly Ser Arg Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe 35 40 45Ser Asp Tyr Gly Met Ala Trp Val Arg Gln Ala Pro Gly Lys Gly Pro 50 55 60Glu Trp Val Ala Phe Ile Ser Asn Leu Ala Tyr Ser Ile Tyr Tyr Ala65 70 75 80Asp Thr Val Thr Gly Arg Phe Thr Ile Ser Arg Glu Asn Ala Lys Asn 85 90 95Thr Leu Tyr Leu Glu Met Ser Ser Leu Arg Ser Glu Asp Thr Ala Met 100 105 110Tyr Tyr Cys Ala Arg Tyr Asp Tyr Asp Asn Ile Leu Asp Tyr Val Met 115 120 125Asp Tyr Trp Gly Gln Gly Thr Ser Val Thr Val Ser Ser Ala Lys Thr 130 135 140Thr Pro Pro Ser Val Tyr Pro Leu145 15045144PRTArtificial SequenceSynthetic Construct 45Met Lys Leu Pro Val Arg Leu Leu Val Leu Trp Ile Gln Glu Thr Lys1 5 10 15Gly Asp Val Val Leu Thr Gln Thr Pro Leu Thr Leu Ser Val Thr Ile 20 25 30Gly Gln Pro Ala Ser Ile Ser Cys Lys Ser Ser Gln Ser Leu Leu Tyr 35 40 45Ser Asn Gly Lys Thr Tyr Leu Asn Trp Leu Leu Gln Arg Pro Gly Gln 50 55 60Ser Pro Lys Arg Leu Ile Tyr Val Val Ser Lys Leu Asp Ser Gly Val65 70 75 80Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys 85 90 95Ile Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Tyr Cys Val Gln 100 105 110Gly Thr His Phe Pro Phe Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile 115 120 125Lys Arg Ala Asp Ala Ala Pro Thr Val Ser Ile Phe Pro Pro Ser Ser 130 135 14046145PRTArtificial SequenceSynthetic Construct 46Met Gly Trp Ser Gly Val Phe Leu Phe Leu Leu Ser Val Thr Glu Gly1 5 10 15Val His Ser Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Val Arg 20 25 30Pro Gly Ser Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ile Phe 35 40 45Asn Asn Tyr Trp Ile Asn Trp Val Lys Gln Arg Pro Gly Gln Gly Leu 50 55 60Glu Trp Ile Gly Gln Ile Tyr Pro Gly Asp Gly Asp Thr Asn Tyr Asn65 70 75 80Gly Lys Phe Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser 85 90 95Thr Ala Tyr Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val 100 105 110Tyr Phe Cys Ala Arg Glu Gly Tyr Ile Val Tyr Trp Gly Gln Gly Thr 115 120 125Leu Val Thr Val Ser Ala Ala Lys Thr Thr Pro Pro Ser Val Tyr Pro 130 135 140Leu14547107PRTArtificial SequenceSynthetic Construct 47Asp Val Val Met Thr Gln Thr Pro Leu Ser Leu Pro Val Ser Leu Gly1 5 10 15Asp Gln Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Leu His Ser 20 25 30Asn Gly Asn Thr Tyr Leu His Trp Tyr Leu Gln Lys Pro Gly Gln Ser 35 40 45Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro 50 55 60Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile65 70 75 80Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Phe Cys Ser Gln Ser 85 90 95Thr His Val Pro Leu Thr Phe Gly Ala Gly Thr 100 10548115PRTArtificial SequenceSynthetic Construct 48Gln Leu Gln Gln Ser Gly Ala Glu Leu Met Lys Pro Gly Ala Ser Val1 5 10 15Lys Ile Ser Cys Lys Ala Thr Gly Tyr Thr Phe Ser Ser Tyr Trp Ile 20 25 30Glu Trp Val Lys Gln Arg Pro Gly His Gly Leu Glu Trp Ile Gly Glu 35 40 45Ile Leu Pro Gly Arg Gly Ser Thr His Tyr Asn Glu Lys Phe Lys Gly 50 55 60Lys Ala Thr Phe Thr Ala Asp Thr Ser Ser Asn Thr Ala Tyr Met Gln65 70 75 80Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys Ala Arg 85 90 95Ser Pro Ile Thr Thr Ser Asp Tyr Trp Gly Gln Gly Thr Thr Leu Thr 100 105 110Val Ser Ser 1154986PRTArtificial SequenceSynthetic Construct 49Ser Cys Arg Ser Ser Gln Ser Leu Val His Ser Asn Gly Asn Thr Tyr1 5 10 15Leu His Trp Tyr Leu Gln Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile 20 25 30Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro Asp Arg Phe Ser Gly 35 40 45Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile Ser Arg Val Glu Ala 50 55 60Glu Asp Leu Gly Val Tyr Phe Cys Ser Gln Ser Thr His Val Pro Leu65 70 75 80Thr Phe Gly Ala Gly Thr 855098PRTArtificial SequenceSynthetic Construct 50Ala Glu Leu Lys Lys Pro Gly Ala Ser Val Lys Ile Ser Cys Lys Ala1 5 10 15Thr Gly Tyr Thr Phe Arg Ser Tyr Trp Ile Glu Trp Val Lys Gln Arg 20 25 30Pro Gly His Gly Leu Glu Trp Ile Gly Glu Ile Leu Pro Gly Arg Gly 35 40 45Ser Thr Lys Tyr Asn Glu Lys Phe Lys Gly Lys Ala Thr Phe Thr Ala 50 55 60Asp Thr Ser Ser Asn Thr Ala Asn Met Gln Leu Ser Ser Leu Thr Ser65 70 75 80Glu Asp Ser Ala Val Tyr Tyr Cys Ala Arg Ser Pro Ile Thr Thr Ser 85 90 95Asp Tyr51112PRTArtificial SequenceSynthetic Construct 51Asp Val Val Leu Thr Gln Thr Pro Phe Thr Leu Ser Val Thr Ile Gly1 5 10 15Gln Pro Ala Ser Ile Ser Cys Lys Ser Ser Gln Ser Leu Leu His Ser 20 25 30Asn Gly Glu Ser Tyr Leu Asn Trp Leu Phe Gln Arg Pro Gly Gln Ser 35 40 45Pro Lys Arg Leu Ile Tyr Ala Val Ser Lys Leu Asp Ser Gly Val Pro 50 55 60Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile65 70 75 80Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Tyr Cys Val Gln Gly 85 90 95Thr His Phe Pro Phe Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 105 11052115PRTArtificial SequenceSynthetic Construct 52Gln Ile Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Ala1 5 10 15Ala Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr 20 25 30Tyr Leu Asn Trp Val Lys Gln Lys Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45Gly Trp Ile Tyr Pro Gly Ser Gly Asn Val Lys Tyr Asn Glu Lys Phe 50 55 60Lys Gly Lys Ala Thr Leu Thr Ala Asp Thr Ser Ser Asn Thr Ala His65 70 75 80Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Thr Ala Val Tyr Phe Cys 85 90 95Thr Arg Glu Gly Leu Ile Val Tyr Trp Gly Gln Gly Thr Leu Val Thr 100 105 110Val Ser Ala 11553112PRTArtificial SequenceSynthetic Construct 53Asp Val Val Leu Thr Gln Thr Pro Leu Thr Leu Ser Val Thr Ile Gly1 5 10 15Gln Pro Ala Ser Ile Ser Cys Lys Ser Ser Gln Ser Leu Leu Tyr Ser 20 25 30Asn Gly Lys Thr Tyr Leu Asn Trp Leu Leu Gln Arg Pro Gly Gln Ser 35 40 45Pro Lys Arg Leu Ile Tyr Val Val Ser Lys Leu Asp Ser Gly Val Pro 50 55 60Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile65 70 75 80Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Tyr Cys Val Gln Gly 85 90 95Thr His Tyr Pro Phe Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 105 11054115PRTArtificial SequenceSynthetic Construct 54Gln Ile Gln Leu Gln Gln Ser Gly Pro Asp Leu Val Lys Pro Gly Ala1 5 10 15Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr 20 25 30Tyr Ile Asn Trp Val Lys Gln Lys Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45Gly Trp Leu Asn Pro Gly Ser Gly Asn Thr Lys Tyr Asn Glu Lys Phe 50 55 60Lys Gly Lys Ala Thr Met Thr Val Asp Thr Thr Ser Ser Thr Val Tyr65 70 75 80Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys 85 90 95Thr Arg Glu Gly Pro Ile Asp Tyr Trp Gly Arg Gly Thr Ser Val Thr 100 105 110Val Ser Ser 11555112PRTArtificial SequenceSynthetic Construct 55Asp Ile Val Met Thr Gln Thr Pro Leu Ser Leu Ser Val Thr Pro Gly1 5 10 15Gln Pro Ala Ser Ile Ser Cys Ser Ser Ser Gln Ser Leu Ile Tyr Ser 20 25 30Asp Gly Asn Ala Tyr Leu His Trp Tyr Leu Gln Lys Pro Gly Gln Ser 35 40 45Pro Gln Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro 50 55 60Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile65 70 75 80Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Thr Gln Ser 85 90 95Thr His Ser Pro Trp Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 11056112PRTArtificial SequenceSynthetic Construct 56Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Thr Phe Ser Arg Tyr 20 25 30Ser Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Gly Gln Ile Asn Ile Arg Gly Cys Asn Thr Tyr Tyr Pro Asp Thr Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Thr Thr Gly Asp Phe Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 100 105 11057214PRTArtificial SequenceSynthetic Construct 57Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr 20 25 30Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro65 70 75 80Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ser Thr Pro Leu 85 90 95Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala 100 105 110Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln145 150 155 160Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205Phe Asn Arg Gly Glu Cys 21058453PRTArtificial SequenceSynthetic Construct 58Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ala Phe Ser Ser Tyr 20 25 30Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Val Ile Trp Phe Asp Gly Thr Lys Lys Tyr Tyr Thr Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asn Thr Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Asp Arg Gly Ile Gly Ala Arg Arg Gly Pro Tyr Tyr Met Asp 100 105 110Val Trp Gly Lys Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys 115 120 125Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly 130 135 140Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro145 150 155 160Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr 165 170 175Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val 180 185 190Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn 195 200 205Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro 210 215 220Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu225 230 235 240Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp 245 250 255Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp 260 265 270Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly 275 280 285Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn 290 295 300Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp305 310 315 320Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro 325 330 335Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala

Lys Gly Gln Pro Arg Glu 340 345 350Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn 355 360 365Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile 370 375 380Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr385 390 395 400Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys 405 410 415Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys 420 425 430Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu 435 440 445Ser Leu Ser Pro Gly 45059215PRTArtificial SequenceSynthetic Construct 59Asp Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly1 5 10 15Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser 20 25 30Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Val Pro Ala Arg Phe Ser 50 55 60Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu65 70 75 80Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln Ile Tyr Asn Met Pro 85 90 95Ile Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala 100 105 110Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser 115 120 125Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu 130 135 140Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser145 150 155 160Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu 165 170 175Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val 180 185 190Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys 195 200 205Ser Phe Asn Arg Gly Glu Cys 210 21560456PRTArtificial SequenceSynthetic Construct 60Gln Val Glu Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ser Ala Ile Asn Ala Ser Gly Thr Arg Thr Tyr Tyr Ala Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Gly Lys Gly Asn Thr His Lys Pro Tyr Gly Tyr Val Arg Tyr 100 105 110Phe Asp Val Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser 115 120 125Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr 130 135 140Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro145 150 155 160Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val 165 170 175His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser 180 185 190Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile 195 200 205Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val 210 215 220Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala225 230 235 240Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro 245 250 255Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val 260 265 270Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val 275 280 285Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln 290 295 300Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln305 310 315 320Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala 325 330 335Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro 340 345 350Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr 355 360 365Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser 370 375 380Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr385 390 395 400Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr 405 410 415Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe 420 425 430Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys 435 440 445Ser Leu Ser Leu Ser Pro Gly Lys 450 45561219PRTArtificial SequenceSynthetic Construct 61Asp Ile Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Pro Gly1 5 10 15Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Val Tyr Ser 20 25 30Asn Gly Asp Thr Tyr Leu His Trp Tyr Leu Gln Lys Pro Gly Gln Ser 35 40 45Pro Gln Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro 50 55 60Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile65 70 75 80Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Ser Gln Ser 85 90 95Thr His Val Pro Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 110Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu 115 120 125Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe 130 135 140Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln145 150 155 160Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser 165 170 175Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu 180 185 190Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser 195 200 205Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 210 21562438PRTArtificial SequenceSynthetic Construct 62Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Leu Val 35 40 45Ala Ser Ile Asn Ser Asn Gly Gly Ser Thr Tyr Tyr Pro Asp Ser Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Ser Gly Asp Tyr Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser 100 105 110Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg 115 120 125Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr 130 135 140Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser145 150 155 160Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser 165 170 175Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr 180 185 190Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys 195 200 205Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro 210 215 220Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys225 230 235 240Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val 245 250 255Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp 260 265 270Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe 275 280 285Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp 290 295 300Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu305 310 315 320Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg 325 330 335Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys 340 345 350Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp 355 360 365Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys 370 375 380Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser385 390 395 400Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser 405 410 415Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser 420 425 430Leu Ser Leu Ser Leu Gly 43563219PRTArtificial SequenceSynthetic Construct 63Asp Val Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Pro Gly1 5 10 15Ala Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Ile Val His Ser 20 25 30Asn Gly Asn Thr Tyr Leu Glu Trp Tyr Leu Gln Lys Pro Gly Gln Ser 35 40 45Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro 50 55 60Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Arg Ile65 70 75 80Ser Arg Val Glu Ala Glu Asp Val Gly Ile Tyr Tyr Cys Phe Gln Gly 85 90 95Ser His Val Pro Pro Thr Phe Gly Pro Gly Thr Lys Leu Glu Ile Lys 100 105 110Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu 115 120 125Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe 130 135 140Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln145 150 155 160Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser 165 170 175Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu 180 185 190Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser 195 200 205Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 210 21564454PRTArtificial SequenceSynthetic Construct 64Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ser Ala Ser Gly Phe Thr Phe Ser Ser Phe 20 25 30Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45Ala Tyr Ile Ser Ser Gly Ser Ser Thr Ile Tyr Tyr Gly Asp Thr Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Phe65 70 75 80Leu Gln Met Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Arg Glu Gly Gly Tyr Tyr Tyr Gly Arg Ser Tyr Tyr Thr Met Asp 100 105 110Tyr Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys 115 120 125Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly 130 135 140Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro145 150 155 160Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr 165 170 175Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val 180 185 190Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn 195 200 205Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro 210 215 220Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu225 230 235 240Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp 245 250 255Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp 260 265 270Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly 275 280 285Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn 290 295 300Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp305 310 315 320Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro 325 330 335Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu 340 345 350Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn 355 360 365Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile 370 375 380Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr385 390 395 400Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys 405 410 415Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys 420 425 430Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu 435 440 445Ser Leu Ser Pro Gly Lys 45065219PRTArtificial SequenceSynthetic Construct 65Asp Val Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Leu Gly1 5 10 15Gln Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Ile Tyr Ser 20 25 30Asp Gly Asn Ala Tyr Leu His Trp Phe Leu Gln Lys Pro Gly Gln Ser 35 40 45Pro Arg Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro 50 55 60Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile65 70 75 80Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Ser Gln Ser 85 90 95Thr His Val Pro Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 110Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu 115 120 125Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe 130 135 140Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln145 150 155 160Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser 165 170 175Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu 180 185 190Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser 195 200 205Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 210 21566442PRTArtificial SequenceSynthetic Construct 66Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly1 5 10 15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Arg Tyr 20 25 30Ser Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Leu Val 35 40 45Ala Gln Ile Asn Ser Val Gly Asn Ser Thr Tyr Tyr Pro Asp Thr Val 50 55 60Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Ser Gly Asp Tyr Trp Gly Gln Gly Thr

Leu Val Thr Val Ser Ser 100 105 110Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 115 120 125Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr 130 135 140Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser145 150 155 160Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser 165 170 175Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr 180 185 190Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys 195 200 205Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys 210 215 220Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro225 230 235 240Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys 245 250 255Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp 260 265 270Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu 275 280 285Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu 290 295 300His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn305 310 315 320Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly 325 330 335Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu 340 345 350Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr 355 360 365Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn 370 375 380Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe385 390 395 400Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn 405 410 415Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr 420 425 430Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 435 440

Claims

1-71. (canceled)

72. A method for treating Alzheimer's disease (A.beta.) in a human patient in need thereof comprising administering to the patient more than one 10 mg/kg dose of an anti-N3pGlu A.beta. antibody over a period of 6 months or less wherein the antibody has a light chain of SEQ ID NO: 28 and a heavy chain of SEQ ID NO: 29.

73. The method of claim 72, wherein the patient is suffering from preclinical AD, prodromal AD, mild AD, moderate A.beta., or severe AD.

74. The method of claim 73, wherein the patient is suffering from preclinical AD.

75. The method of claim 73, wherein the patient is suffering from prodromal AD.

76. The method of claim 72, wherein the patient carries one or two APOE e4 alleles.

77. The method of claim 72, wherein 3-5 doses of the anti-N3pGlu A.beta. antibody are administered to the patient over a period of 6 months or less.

78. The method of claim 77, wherein 3 doses of the anti-N3pGlu A.beta. antibody are administered to the patient.

79. The method of claim 77, wherein 4 doses of the anti-N3pGlu A.beta. antibody are administered to the patient.

80. The method of claim 77, wherein 5 doses of the anti-N3pGlu A.beta. antibody are administered to the patient.

81. The method of claim 72, wherein each 10 mg/kg dose of the anti-N3pGlu A.beta. antibody is administered once every month.

82. The method of claim 72, wherein each 10 mg/kg dose of the anti-N3pGlu A.beta. antibody is administered to the patient once every 4 weeks.

83. The method of claim 72, wherein each dose of the anti-N3pGlu A.beta. antibody is administered intravenously to the patient.

84. The method of claim 72, wherein administration of the anti-N3pGlu A.beta. antibody causes reduction in A.beta. deposits in the brain of the patient.

85. The method of claim 72, wherein administration of the anti-N3pGlu A.beta. antibody causes slowing of cognitive decline in the patient.

86. The method of claim 72, wherein the A.beta. deposits in the brain of the patient are reduced by 35-100% within 6 months post treatment.

87. The method of claim 72, wherein 40-50% mean reduction in A.beta. deposits in the brain of the patient is achieved over 6 months post treatment.

88. The method of claim 72, wherein the reduction of A.beta. deposits in the brain of the patient is sustained for a period of 2 to 10 years post treatment.

89. The method of claim 88, wherein the reduction of A.beta. deposits in the brain of the patient is sustained for a period of 3 to 5 years post treatment.

90. The method of claim 72, wherein the reduction of A.beta. deposits in the brain of the patient is sustained for a period of at least 18 months after the last dose of the anti-N3pGlu A.beta. antibody.

91. The method of claim 72, wherein the patients do not suffer from cerebral vasogenic edema or microhemorrhage upon administration of the anti-N3pGlu A.beta. antibody.