Treatment method for neurological disorders using anti-Aβ antibodies

Abstract

An antibody that binds to human β-amyloid peptide, a method for detecting, measuring, and treating amyloid disorders using such antibody, a pharmaceutical composition comprising such antibody, and a method for manufacturing the same are provided.

Description

Technology Field

[0001] Cross-reference regarding the application

[0002] This application claims priority to U.S. provisional application No. 63 / 618,054 filed on January 5, 2024, the entirety of which is incorporated herein by reference.

[0003] Sequence list

[0004] A computer-readable form of the sequence list is submitted with the present application by electronic submission, and the entirety thereof is incorporated herein by reference. The sequence list is contained in a file named "20-1030-WO3_SEQLIST.xml" with a size of 21 kb, created on December 27, 2024.

[0005] Technology field

[0006] The present invention relates to an anti-amyloid beta (Aβ) antibody, a composition, and a method of using the same. Background Technology

[0007] Alzheimer's disease (AD) is a progressive disease leading to senile dementia. The disease is generally classified into a late-onset type, which occurs in old age (65 years or older), and an early-onset type, which occurs before old age, specifically between 35 and 60 years. While the pathology of the disease appears to be the same in these two types, abnormalities tend to be more severe and widespread in cases where it develops at an earlier age. The disease is characterized by at least two types of lesions in the brain: neurofibrillary tangles and amyloid plaques. Neurofibrillary tangles are intracellular deposition of microtubule-associated tau protein, consisting of two filaments twisted together. Amyloid plaques (i.e., amyloid plaques) are regions of disordered neural networks up to 150 μm in diameter, containing a central extracellular amyloid deposit, which can be seen in microscopic analysis of brain tissue fragments.

[0008] The primary component of plaques is a peptide referred to as amyloid beta (Aβ or Abeta) or β-amyloid peptide. The Aβ peptide is a 4-kDa internal fragment consisting of 39–43 amino acids from a larger transmembrane glycoprotein referred to as amyloid precursor protein (APP). As a result of APP being proteolytically degraded by various secretase enzymes, Aβ is primarily found in two forms: a short form 40 amino acids long and a long form ranging from 42 to 43 amino acids. The hydrophobic transmembrane domain of APP is found at the carboxyl terminus of Aβ, which may explain the aggregation forces that cause Aβ to aggregate into plaques, particularly in the long form. The accumulation of amyloid plaques in the brain ultimately leads to the death of neuronal cells. Physical symptoms associated with this type of neurological deterioration are characteristic of Alzheimer's disease.

[0009] Monoclonal antibodies (mAbs) targeting amyloid beta have been clinically proven to reduce the burden of amyloid plaques in patients. The FDA granted accelerated approval for the anti-amyloid β antibodies aducanumab and lecanemab. FDA approval for these antibodies was based on proven evidence that the antibodies reduced amyloid beta in PET imaging, a surrogate endpoint deemed to reasonably predict clinical benefit. Indeed, clinical trials of anti-amyloid β antibodies, including aducanumab and lecanemab, have shown that a reduction in plaque burden is associated with a slowing of cognitive decline in Alzheimer's disease. However, these treatments suffer from limited efficacy and / or treatment-related side effects. Furthermore, these antibodies require intravenous administration and / or frequent high-dose subcutaneous administration, placing a burden on patients and caregivers. Therefore, there is still a need for effective and safe anti-amyloid β antibodies to treat Alzheimer's disease, particularly antibodies effective when administered subcutaneously as part of a relatively rare administration regimen.

[0010] The present invention relates to antibodies (and antibody fragments) that specifically bind to Aβ, methods for producing such antibodies and antibody fragments and related nucleic acids, methods for treating patients with Aβ-related neurological disorders, e.g., amyloidogenic disease, to treat, reduce the risk of, or delay the onset of amyloidogenic disease, to prevent, reduce, or inhibit markers of amyloidogenic disease, e.g., amyloid plaques, and to improve cognition, pharmaceutical formulations and compositions of antibodies exhibiting high affinity binding to Aβ for prophylactic and / or therapeutic uses. The present invention also relates to methods for detecting amyloid plaques and methods for measuring therapeutic efficacy in patients treated for amyloidogenic disease. The present invention is based, at least in part, on identifying and characterizing monoclonal antibodies that specifically bind to Aβ peptides and are effective in neutralizing soluble Aβ species associated with amyloidogenic disorders and reducing plaque burden.

[0011] In one aspect, the present invention provides a method for treating Alzheimer's disease in an individual, comprising administering to the individual about 205 mg to about 400 mg of an anti-amyloid β antibody or an antigen-binding fragment thereof once every about 3 to 5 weeks. In another aspect, the present invention provides a method for reducing brain amyloid beta plaques in an individual, comprising administering to the individual about 205 mg to about 400 mg of an anti-amyloid β antibody or an antigen-binding fragment thereof once every about 3 to 5 weeks. In another aspect, the present invention provides a method for converting an individual from amyloid-positive to amyloid-negative, comprising administering to the individual about 205 mg to about 400 mg of an anti-amyloid β antibody or an antigen-binding fragment thereof once every about 3 to 5 weeks.

[0012] In some embodiments, the method comprises administering about 300 mg to about 400 mg of an anti-amyloid β antibody or its antigen-binding fragment. In some embodiments, the method comprises administering about 350 mg to about 400 mg of an anti-amyloid β antibody or its antigen-binding fragment. In some embodiments, the method comprises administering about 250 mg of an anti-amyloid β antibody or its antigen-binding fragment. In some embodiments, the method comprises administering about 300 mg of an anti-amyloid β antibody or its antigen-binding fragment. In some embodiments, the method comprises administering 350 mg of an anti-amyloid β antibody or its antigen-binding fragment. In some embodiments, the method comprises administering about 400 mg of an anti-amyloid β antibody or its antigen-binding fragment. In some embodiments, the anti-amyloid β antibody is administered once every about 4 weeks.

[0013] In another aspect, the present invention provides a method for treating Alzheimer's disease in an individual, comprising administering to the individual about 45 mg to about 200 mg of an anti-amyloid β antibody or an antigen-binding fragment thereof twice every 3 to 5 weeks. In another aspect, the present invention provides a method for treating Alzheimer's disease in an individual, comprising administering to the individual about 100 mg to about 200 mg of an anti-amyloid β antibody or an antigen-binding fragment thereof twice every 3 to 5 weeks. In another aspect, the present invention provides a method for reducing brain amyloid beta plaques in an individual, comprising administering to the individual about 100 mg to about 200 mg of an anti-amyloid β antibody or an antigen-binding fragment thereof twice every 3 to 5 weeks. In another aspect, the present invention provides a method for converting an individual from amyloid-positive to amyloid-negative, comprising administering to the individual about 100 mg to about 200 mg of an anti-amyloid β antibody or an antigen-binding fragment thereof twice every about 3 to 5 weeks.

[0014] In another aspect, the present invention provides a method for treating Alzheimer's disease in an individual, comprising administering to the individual about 45 mg to about 200 mg of an anti-amyloid β antibody or an antigen-binding fragment thereof once every about 2 weeks. In another aspect, the present invention provides a method for treating Alzheimer's disease in an individual, comprising administering to the individual about 100 mg to about 200 mg of an anti-amyloid β antibody or an antigen-binding fragment thereof once every about 2 weeks. In another aspect, the present invention provides a method for reducing brain amyloid beta plaques in an individual, comprising administering to the individual about 100 mg to about 200 mg of an anti-amyloid β antibody or an antigen-binding fragment thereof once every about 2 weeks. In another aspect, the present invention provides a method for converting an individual from amyloid-positive to amyloid-negative, comprising administering to the individual about 100 mg to about 200 mg of an anti-amyloid β antibody or an antigen-binding fragment thereof once every about 2 weeks.

[0015] In some embodiments, the method comprises administering about 45 mg to about 100 mg of an anti-amyloid β antibody or its antigen-binding fragment once every about 2 weeks. In some embodiments, the method comprises administering about 150 mg to about 200 mg of an anti-amyloid β antibody or its antigen-binding fragment once every about 2 weeks. In some embodiments, the method comprises administering about 200 mg of an anti-amyloid β antibody or its antigen-binding fragment once every about 2 weeks.

[0016] In some embodiments, the anti-amyloid β antibody or its antigen-binding fragment is administered in the form of a composition comprising a pharmaceutically acceptable diluent. In some embodiments, administration is intravenous or subcutaneous. In some embodiments, administration is subcutaneous.

[0017] In some embodiments, the anti-amyloid β antibody or its antigen-binding fragment binds to an epitope located at the N-terminus of an Aβ peptide, and the epitope comprises one or more amino acids selected from amino acids 1-10 of the Aβ peptide. In some embodiments, the anti-amyloid β antibody or its antigen-binding fragment binds to an epitope comprising one or more amino acids selected from amino acids 1-7 of the Aβ peptide. In some embodiments, the anti-amyloid β antibody or its antigen-binding fragment binds to amyloid β with an apparent KD of about 5 nM or less 1-42 It binds to protofibril. In some embodiments, an anti-amyloid β antibody or its antigen-binding fragment binds to amyloid β at an apparent KD of about 1 nM or less. 1-42 It binds to protopibrill. In some embodiments, an anti-amyloid β antibody or its antigen-binding fragment binds to amyloid β at an apparent KD of about 10 nM or less. 1-28 It binds to the monomer.

[0018] In some embodiments, the anti-amyloid β antibody or its antigen-binding fragment is administered as a pharmaceutical composition comprising the anti-amyloid β antibody or its antigen-binding fragment and a pharmaceutically acceptable diluent. In some embodiments, administration is performed intravenously or subcutaneously. In some embodiments, administration is performed subcutaneously.

[0019] In some embodiments, the anti-amyloid β antibody or its antigen-binding fragment comprises a heavy chain variable region comprising heavy chains CDR1, CDR2, and CDR3 and a light chain variable region comprising light chains CDR1, CDR2, and CDR3, wherein

[0020] Heavy chain CDR1 comprises the amino acid sequence of SEQ ID NO. 3, and

[0021] Heavy chain CDR2 comprises the amino acid sequence of SEQ ID NO. 4, and

[0022] Heavy chain CDR3 comprises the amino acid sequence of SEQ ID NO. 5, and

[0023] Light chain CDR1 comprises the amino acid sequence of SEQ ID NO. 6, and

[0024] Light chain CDR2 comprises the amino acid sequence of SEQ ID NO. 7, and

[0025] The light chain CDR3 contains the amino acid sequence of SEQ ID NO. 8.

[0026] In some embodiments, the heavy chain variable region excluding the CDR is at least 95% identical to the amino acid sequence of SEQ ID NO. 1, and the light chain variable region excluding the CDR is at least 95% identical to the amino acid sequence of SEQ ID NO. 2. In some embodiments, the heavy chain variable region excluding the CDR is at least 98% identical to the amino acid sequence of SEQ ID NO. 1, and the light chain variable region excluding the CDR is at least 98% identical to the amino acid sequence of SEQ ID NO. 2. In some embodiments, the heavy chain variable region comprises the amino acid sequence of SEQ ID NO. 1, and the light chain variable region comprises the amino acid sequence of SEQ ID NO. 2. In some embodiments, the heavy chain variable region is composed of SEQ ID NO. 1, and the light chain variable region is composed of the amino acid sequence of SEQ ID NO. 2.

[0027] In some embodiments, the anti-amyloid β antibody is humanized IgG1. In some embodiments, the anti-amyloid β antibody is a whole antibody, a chimeric antibody, a CDR-transplant antibody, or a recombinant antibody.

[0028] In some embodiments, the anti-amyloid β antibody or its antigen-binding fragment further comprises a heavy chain constant region comprising an amino acid sequence at least 95% identical to SEQ ID NO. 9 and / or a light chain constant region comprising an amino acid sequence at least 95% identical to SEQ ID NO. 10. In some embodiments, the anti-amyloid β antibody or its antigen-binding fragment further comprises a heavy chain constant region comprising an amino acid sequence at least 98% identical to SEQ ID NO. 9 and / or a light chain constant region comprising an amino acid sequence at least 98% identical to SEQ ID NO. 10. In some embodiments, the anti-amyloid β antibody comprises a heavy chain constant region comprising an amino acid sequence of SEQ ID NO. 9 with or without C-terminal lysine and a light chain constant region comprising an amino acid sequence of SEQ ID NO. 10. In some embodiments, the anti-amyloid β antibody comprises a heavy chain constant region essentially composed of the amino acid sequence of SEQ ID NO. 9, with or without C-terminal lysine, and a light chain constant region essentially composed of the amino acid sequence of SEQ ID NO. 10.

[0029] In some embodiments, the anti-amyloid β antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO. 11, with or without C-terminal lysine, and a light chain comprising the amino acid sequence of SEQ ID NO. 12. In some embodiments, the anti-amyloid β antibody comprises a heavy chain essentially composed of the amino acid sequence of SEQ ID NO. 11, with or without C-terminal lysine, and a light chain essentially composed of the amino acid sequence of SEQ ID NO. 12. In some embodiments, the anti-amyloid β antibody comprises a heavy chain of SEQ ID NO. 11 and a light chain of SEQ ID NO. 12, with or without C-terminal lysine. In some embodiments, the anti-amyloid β antibody is h2731.

[0030] In another aspect, the present invention provides a method for treating Alzheimer's disease in an individual, comprising administering about 250 mg of an anti-amyloid β antibody to the individual subcutaneously once every about 4 weeks; wherein the anti-amyloid β antibody comprises a heavy chain of SEQ ID NO. 11 and a light chain of SEQ ID NO. 12, with or without C-terminal lysine.

[0031] In another aspect, the present invention provides a method for treating Alzheimer's disease in an individual, comprising administering about 300 mg of an anti-amyloid β antibody to the individual subcutaneously once every about 4 weeks; wherein the anti-amyloid β antibody comprises a heavy chain of SEQ ID NO. 11 and a light chain of SEQ ID NO. 12, with or without C-terminal lysine.

[0032] In another aspect, the present invention provides a method for treating Alzheimer's disease in an individual, comprising administering about 350 mg of an anti-amyloid β antibody to the individual subcutaneously once every about 4 weeks; wherein the anti-amyloid β antibody comprises a heavy chain of SEQ ID NO. 11 and a light chain of SEQ ID NO. 12, with or without C-terminal lysine.

[0033] In another aspect, the present invention provides a method for treating Alzheimer's disease in an individual, comprising administering about 400 mg of an anti-amyloid β antibody subcutaneously to an individual once every about 4 weeks; wherein the anti-amyloid β antibody comprises a heavy chain of SEQ ID NO. 11 and a light chain of SEQ ID NO. 12, with or without C-terminal lysine. In another aspect, the present invention provides a method for treating Alzheimer's disease in an individual, comprising administering about 200 mg of an anti-amyloid β antibody subcutaneously to an individual once every about 2 weeks; wherein the anti-amyloid β antibody comprises a heavy chain of SEQ ID NO. 11 and a light chain of SEQ ID NO. 12, with or without C-terminal lysine. In another aspect, the present invention comprises administering about 300 mg of an anti-amyloid β antibody subcutaneously to an individual once every about 4 weeks; A method for reducing amyloid plaques in an individual is provided, wherein an anti-amyloid β antibody comprises the heavy chain of SEQ ID NO. 11 and the light chain of SEQ ID NO. 12, with or without C-terminal lysine.

[0034] In another aspect, the present invention provides a method for reducing amyloid plaques in an individual, comprising administering about 250 mg of an anti-amyloid β antibody subcutaneously to an individual once every about 4 weeks; wherein the anti-amyloid β antibody comprises a heavy chain of SEQ ID NO. 11 and a light chain of SEQ ID NO. 12 with or without C-terminal lysine. In another aspect, the present invention provides a method for reducing amyloid plaques in an individual, comprising administering about 300 mg of an anti-amyloid β antibody subcutaneously to an individual once every about 4 weeks; wherein the anti-amyloid β antibody comprises a heavy chain of SEQ ID NO. 11 and a light chain of SEQ ID NO. 12 with or without C-terminal lysine. In another aspect, the present invention comprises administering about 400 mg of an anti-amyloid β antibody subcutaneously to an individual once every about 4 weeks; The present invention provides a method for reducing amyloid plaques in an individual, wherein the anti-amyloid β antibody comprises the heavy chain of SEQ ID NO. 11 and the light chain of SEQ ID NO. 12, with or without C-terminal lysine. In another aspect, the present invention provides a method for reducing amyloid plaques in an individual, comprising administering about 200 mg of an anti-amyloid β antibody subcutaneously to an individual once every about 2 weeks; wherein the anti-amyloid β antibody comprises the heavy chain of SEQ ID NO. 11 and the light chain of SEQ ID NO. 12, with or without C-terminal lysine.

[0035] In another aspect, the present invention is C ave The present invention provides a method for treating Alzheimer's disease in an individual, comprising subcutaneously administering an anti-Aβ antibody to an individual at a dose sufficient to achieve an AUC of about 20 µg / ml to about 40 µg / ml, wherein the anti-Aβ antibody comprises a heavy chain of SEQ ID NO. 11 and a light chain of SEQ ID NO. 12 with or without C-terminal lysine. In another aspect, the present invention provides an AUC 0-tauA method for treating Alzheimer's disease in an individual is provided, comprising administering an anti-Aβ antibody subcutaneously to an individual in a dose sufficient to achieve a value of about 15,000 hr*µg / ml to about 30,000 hr*µg / ml, wherein the anti-Aβ antibody comprises a heavy chain of SEQ ID NO. 11 and a light chain of SEQ ID NO. 12, with or without C-terminal lysine.

[0036] In some embodiments, the maximum concentration of the anti-amyloid β antibody or its antigen-binding fragment in an individual during the administration interval (C max ) is about 30 µg / ml to about 60 µg / ml. In some embodiments, C of the anti-amyloid β antibody or its antigen-binding fragment in the individual max The value is about 50 µg / ml to about 60 µg / ml. In some embodiments, C of the anti-amyloid β antibody or its antigen-binding fragment in an individual max The value does not exceed about 60 µg / ml. In some embodiments, C max The value is serum C max It is a value. In some implementations, C max The value is plasma C max It is a value.

[0037] In some embodiments, the average concentration of the anti-amyloid β antibody or its antigen-binding fragment in an individual during the administration interval (C ave The value) is about 20 µg / ml to about 40 µg / ml. In some embodiments, C of the anti-amyloid β antibody or its antigen-binding fragment in an individual ave The value is about 30 µg / ml to about 40 µg / ml. In some embodiments, C of the anti-amyloid β antibody or its antigen-binding fragment in an individual ave The value does not exceed about 40 µg / ml. In some embodiments, C ave The value is serum C ave It is a value. In some implementations, C ave The value is plasma C ave It is a value.

[0038] In some embodiments, the area under the concentration-time curve (AUC) during the administration interval of the anti-amyloid β antibody or its antigen-binding fragment in an individual 0-tau The value is about 15,000 hr*µg / ml to about 30,000 hr*µg / ml. In some embodiments, the AUC of the anti-amyloid β antibody or its antigen-binding fragment in an individual 0-tau The value is about 20,000 hr*µg / ml to about 30,000 hr*µg / ml. In some embodiments, the AUC of the anti-amyloid β antibody or its antigen-binding fragment in an individual 0-tau The value does not exceed approximately 30,000 hr*µg / ml. In some embodiments, AUC 0-tau The value is serum AUC 0-tau It is a value. In some implementations, AUC 0-tau The value is plasma AUC 0-tau It is a value.

[0039] In some embodiments, brain amyloid β plaques are reduced in an individual. In some embodiments, the reduction of brain amyloid β plaques comprises a reduction of at least about 30 centiloids to about 70 centiloids. In some embodiments, the reduction of brain amyloid β plaques comprises a reduction of about 45 centiloids to about 80 centiloids. In some embodiments, the reduction of brain amyloid β plaques comprises a reduction of about 50 centiloids to about 85 centiloids. In some embodiments, the reduction of brain amyloid β plaques comprises a reduction of at least about 40% to about 90%. In some embodiments, the reduction of brain amyloid β plaques comprises a reduction of about 60% to about 100%.

[0040] In some embodiments, the reduction in brain amyloid β plaques is a reduction relative to baseline (value before initiation of treatment using the method of the present invention). In some embodiments, the reduction in brain amyloid β plaques is a reduction compared to the individual before administration of the anti-amyloid β antibody.

[0041] In some embodiments, a reduction in brain amyloid β plaques is achieved after 6 months of treatment. In some embodiments, a reduction in brain amyloid β plaques is achieved after approximately 12 months of treatment. In some embodiments, a reduction in brain amyloid β plaques is achieved after approximately 18 months of treatment. In some embodiments, a reduction in brain amyloid β plaques is evaluated by positron emission tomography (PET).

[0042] In some embodiments, the object is switched from amyloid-positive to amyloid-negative.

[0043] In some embodiments, the treatment includes increasing the likelihood of the individual transitioning from amyloid-positive to amyloid-negative. In some embodiments, the treatment includes increasing the likelihood of the individual transitioning from amyloid-positive to amyloid-negative by about 10% to about 40%. In some embodiments, the treatment includes increasing the likelihood of the individual transitioning from amyloid-positive to amyloid-negative by about 30% to about 60%. In some embodiments, the treatment includes increasing the likelihood of the individual transitioning from amyloid-positive to amyloid-negative by about 40% to about 80%. In some embodiments, the likelihood of the individual transitioning from amyloid-positive to amyloid-negative is the likelihood after about 6 months of treatment. In some embodiments, the likelihood of the individual transitioning from amyloid-positive to amyloid-negative is the likelihood after about 12 months of treatment. In some embodiments, the likelihood of the individual transitioning from amyloid-positive to amyloid-negative is the likelihood after about 18 months of treatment.

[0044] In some embodiments, treatment includes slowing, stopping, or reversing the decline of cognitive function. In some embodiments, treatment includes slowing the decline of cognitive function. In some embodiments, cognitive function is measured by one or more of CRD-SB, ADAS-Cog14, ADCOMS, and ADCS MCI-ADL. In some embodiments, cognitive function is measured by ADCOMS.

[0045] In another aspect, the present invention provides a method for controlling a biomarker in an individual, comprising administering about 205 mg to about 400 mg of an anti-amyloid β antibody to an individual once every about 3 to 5 weeks, wherein the anti-amyloid β antibody comprises a heavy chain of SEQ ID NO. 11 and a light chain of SEQ ID NO. 12 with or without C-terminal lysine. In another aspect, the present invention provides a method for controlling a biomarker in an individual, comprising administering about 100 mg to about 200 mg of an anti-amyloid β antibody to an individual twice every about 3 to 5 weeks, wherein the anti-amyloid β antibody comprises a heavy chain of SEQ ID NO. 11 and a light chain of SEQ ID NO. 12 with or without C-terminal lysine.

[0046] In another aspect, the present invention provides a method for increasing the Aβ 42 / 40 ratio in an individual, comprising administering about 205 mg to about 400 mg of an anti-amyloid β antibody once every about 3-5 weeks to an individual, wherein the anti-amyloid β antibody comprises a heavy chain of SEQ ID NO. 11 and a light chain of SEQ ID NO. 12 with or without C-terminal lysine. In another aspect, the present invention provides a method for increasing the Aβ 42 / 40 ratio in an individual, comprising administering about 100 mg to about 200 mg of an anti-amyloid β antibody twice every about 3-5 weeks to an individual, wherein the anti-amyloid β antibody comprises a heavy chain of SEQ ID NO. 11 and a light chain of SEQ ID NO. 12 with or without C-terminal lysine.

[0047] In another aspect, the present invention provides a method for reducing the amount of phospho-tau in an individual, comprising administering about 205 mg to about 400 mg of an anti-amyloid β antibody to an individual once every about 3 to 5 weeks, wherein the anti-amyloid β antibody comprises a heavy chain of SEQ ID NO. 11 and a light chain of SEQ ID NO. 12 with or without C-terminal lysine. In another aspect, the present invention provides a method for reducing the amount of phospho-tau in an individual, comprising administering about 100 mg to about 200 mg of an anti-amyloid β antibody to an individual twice every about 3 to 5 weeks, wherein the anti-amyloid β antibody comprises a heavy chain of SEQ ID NO. 11 and a light chain of SEQ ID NO. 12 with or without C-terminal lysine.

[0048] In some embodiments, administration involves a single subcutaneous injection. In some embodiments, a biomarker is adjusted in an individual. In some embodiments, a biomarker is adjusted in an individual relative to a baseline. In some embodiments, the method further comprises detecting a biomarker in a sample collected from an individual. In some embodiments, the method further comprises quantifying a biomarker in a sample collected from an individual.

[0049] In some embodiments, the biomarker includes an Aβ 42 / 40 ratio in the individual. In some embodiments, the Aβ 42 / 40 ratio in the individual increases by at least 25%. In some embodiments, the Aβ 42 / 40 ratio in the individual increases by at least 50%. In some embodiments, the Aβ 42 / 40 ratio in the individual increases by about 25% to about 100%. In some embodiments, the Aβ 42 / 40 ratio in the individual increases by about 50% to about 100%.

[0050] In some embodiments, the biomarker includes a phospho-tau value. In some embodiments, the phospho-tau value includes at least one of the following: a p181-tau value, a p212-tau value, a p217-tau value, a p231-tau value, and a p235-tau value. In some embodiments, the phospho-tau value includes a p181-tau value. In some embodiments, the phospho-tau value includes a p212-tau value. In some embodiments, the phospho-tau value includes a p217-tau value. In some embodiments, the phospho-tau value includes a p231-tau value. In some embodiments, the phospho-tau value includes a p235-tau value. In some embodiments, the phospho-tau value is reduced. The phospho-tau value is reduced by at least about 10%. In some embodiments, the phospho-tau value is reduced by about 10% to about 30%. In some embodiments, the phospho-tau value is reduced by about 20% to about 30%.

[0051] In some embodiments, the sample comprises blood or a portion thereof collected from an individual. In some embodiments, the sample comprises plasma collected from an individual. In some embodiments, the sample comprises serum collected from an individual. In some embodiments, the sample comprises cerebrospinal fluid (“CSF”) collected from an individual.

[0052] In some embodiments, the method contains an ARIA-E risk of less than about 45%. In some embodiments, the method contains an ARIA-E risk of about 25% to about 45%. In some embodiments, the method contains an ARIA-E risk of less than about 75%. In some embodiments, the method contains an ARIA-E risk of about 50% to about 75%. In some embodiments, the method contains a symptomatic ARIA-E risk of less than about 15%. In some embodiments, the method contains a symptomatic ARIA-E risk of less than about 30%. In some embodiments, the ARIA-E risk is a severe ARIA-E risk.

[0053] In some embodiments, the risk of ARIA-E is after approximately 6 months of treatment. In some embodiments, the risk of ARIA-E is after approximately 12 months of treatment. In some embodiments, the risk of ARIA-E is after approximately 18 months of treatment. In some embodiments, the individual does not experience symptomatic ARIA-E during treatment.

[0054] In some embodiments, the method contains an ARIA-H risk of less than about 35%, or the method contains an ARIA-H risk of about 10% to about 35%, or the ARIA-H risk is a severe ARIA-H risk. In some embodiments, the ARIA-H risk is a risk after about 6 months of treatment. In some embodiments, the ARIA-H risk is a risk after about 12 months of treatment. In some embodiments, the ARIA-H risk is a risk after about 18 months of treatment. In some embodiments, the individual does not experience symptomatic ARIA-H during treatment.

[0055] In some embodiments, ARIA-E and / or ARIA-H are evaluated by magnetic resonance imaging ("MRI").

[0056] In some embodiments, the individual is an APOE4 homozygous individual. In some embodiments, the individual is an APOE4 heterozygous individual or an APOE4 non-possessing individual. In some embodiments, the method further comprises determining the individual's APOE4 status prior to administration.

[0057] In some embodiments, the treatment period is at least 6 months. In some embodiments, the treatment period is at least 12 months. In some embodiments, the treatment period is at least 18 months.

[0058] In some embodiments, administration is performed using a syringe. In some embodiments, administration is performed using an auto-injector.

[0059] In some embodiments, the individual is a mammal. In some embodiments, the individual is a human. Brief explanation of the drawing

[0060] Fig. 1 This is a diagram outlining the clinical trial plan for a single dose escalation study of h2731 in healthy volunteers and subjects with Alzheimer's disease. It describes specific inclusion criteria, dosages, and specific evaluation schedules. Fig. 2 This is a diagram outlining the clinical trial plan for a multiple dose escalation study of h2731 in subjects with Alzheimer's disease. It describes specific inclusion criteria, dosages, and specific evaluation schedules. Fig. 3 This describes the details of the h2731 open-label extension study on some subjects with Alzheimer's disease enrolled in the single dose escalation study of Example 2 or the multiple dose escalation study of Example 3. It describes specific dosages and specific evaluation schedules. Specific details for implementing the invention

[0061] Monoclonal antibodies (mAbs) targeting the N-terminus of amyloid β (Aβ) have been clinically proven to reduce the amyloid plaque burden, and at least two antibodies, aducanumab and recanemab, have been shown to be associated with a significant reduction in plaque burden and a slowing of cognitive decline in Alzheimer's disease (AD). Furthermore, in preclinical studies, monoclonal antibodies (mAbs) targeting the N-terminus epitope of Aβ have been shown to induce antibody-dependent microglia-mediated Aβ-plaque clearing and neutralize soluble toxic Aβ oligomers in vitro and in vivo. It is hypothesized that the administration of mAbs targeting the Aβ N-terminus slows disease progression in AD patients by clearing Aβ plaques and neutralizing soluble Aβ aggregation. The present invention provides a method for treating Alzheimer's disease and / or reducing amyloid plaques by administering an mAb targeting N-terminal Aβ intravenously or subcutaneously.

[0062] Before describing specific aspects of the present invention in more detail, various terms are defined.

[0063] definition

[0064] The term "antibody" includes intact antibodies and their binding fragments. Typically, the fragment competes with the intact antibody from which it originated for specific binding to a target. Fragments include isolated heavy chains, light chains Fab, Fab', F(ab')2, F(ab)c, Fv, and single-domain antibodies. A single (variable) domain antibody contains a VH region isolated from its VL partner in a conventional antibody (or vice versa) (Ward et al., 1989, Nature 341: 544-546), as well as a VH region derived from species such as camelid or cartilaginous fish (e.g., bearded sharks) (sometimes known as VHH), in which the VH region is not bound to the VL region (see, e.g., WO 9404678). Single-domain antibodies in which a single chain is separated from its original partner are sometimes referred to as Dabs, and single-domain antibodies derived from camelid or cartilaginous fish are sometimes known as nanobodies. Single-domain antibodies may or may not contain a constant region or part of a constant region. For example, a natural single-variable region antibody derived from camelid includes a VHH variable region and CH2 and CH3 constant regions. Single-domain antibodies may be targets for humanization in a manner similar to conventional antibodies. Dab types of antibodies are typically derived from antibodies of human origin. Nanobody types of antibodies are of camelid or shark origin and may be humanized. Fragments can be prepared by recombinant DNA techniques or through enzymatic or chemical separation from intact immunoglobulins. The term "antibody" also includes bispecific antibodies. Bispecific antibodies or bifunctional antibodies are artificial hybrid antibodies having two different heavy / light chain pairs and two different binding sites (e.g., Songsivilai and Lachmann, Clin. Exp. Immunol., 79:315-321 (1990); see Kostelny et al., J. Immunol., 148:1547-53 (1992)).

[0065] The variable region of the immunoglobulin light or heavy chain (sometimes referred to herein as the “light chain variable domain” (“VL domain”) or “heavy chain variable domain” (“VH domain”)), respectively) consists of a “framework” region in which three “complementary determination regions” or “CDRs” exist. The framework region serves to align the CDRs to bind specifically to an antigen epitope. The CDRs contain amino acid residues responsible for the antibody’s binding primarily to the antigen. Both the VL and VH domains contain framework (FR) and CDR regions in the amino-terminal to carboxy-terminal direction as follows: FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4. CDRs 1, 2, and 3 of the VL domain are sometimes referred to herein as CDR-L1, CDR-L2, and CDR-L3, respectively; CDR 1, 2, and 3 of the VH domain are sometimes referred to herein as CDR-H1, CDR-H2, and CDR-H3, respectively. Where a VL sequence having R as a C-terminal residue is mentioned in this application, R may alternatively be considered as an N-terminal residue of the light chain invariant region. Accordingly, the present invention should be understood to refer to a VL sequence without a C-terminal R.

[0066] Assigning amino acids to each VL and VH domain is done according to any conventional CDR definition. Conventional definitions include the Kabat definition (Kabat, Sequences of Proteins of Immunological Interest (National Institutes of Health, Bethesda, MD, 1987 and 1991), the Chothia definition (Chothia & Lesk, J. Mol. Biol. 196:901-917, 1987; Chothia et al., Nature 342:878-883, 1989); the Chothia-Kabat CDR composite, in which CDR-H1 synthesizes the Chothia CDR and Kabat CDR; the AbM definition applied in Oxford Molecular's antibody modeling software; and the contact definition by Martin et al. (bioinfo.org.uk / abs) (see Table A). Kabat provides a widely used numbering convention (Kabat numbering) that assigns the same number to corresponding residues among multiple heavy chains or among multiple light chains. Where an antibody is referred to as containing a CDR according to a specific CDR definition (e.g., Kabat), The definition specifies the minimum CDR residues present in the antibody (i.e., Kabat CDRs). This also does not exclude the presence of other residues that are included in other conventional definitions of CDR but are not included in the specified definition. For example, antibodies containing a CDR defined according to Kabat include, among other possibilities, antibodies in which the CDR contains Kabat CDR residues and does not contain other CDR residues, and antibodies in which CDR H1 is Chothia-Kabat composite CDR H1 and other CDRs contain Kabat CDR residues but do not contain additional CDR residues according to other definitions.

[0067]

[0068] In some embodiments, the CDRs of the humanized antibodies of the present invention are defined as selected from the group consisting of Kabat, Chothia, Kabat / Chothia composite, AbM, and Contact.

[0069] One or several amino acids at the amino or carboxyl terminus of the light and / or heavy chains, for example, the C-terminal lysine of the heavy chain may be omitted or derivatized in all or some of the molecules. Substitutions may be made in the invariant region to increase or decrease operator functions such as complement-mediated cytotoxicity or ADCC (e.g., see Winter et al., U.S. Patent 5,624,821; Tso et al., U.S. Patent 5,834,597; and Lazar et al., Proc. Natl. Acad. Sci. USA 103:4005, 2006), or to extend the half-life in humans (e.g., see Hinton et al., J. Biol. Chem. 279:6213, 2004). Examples of substitutions include Gln at position 250 and / or Leu at position 428 to extend the antibody's half-life (EU numbering applies to paragraphs regarding this invariant region). Substitutions at any or all of positions 234, 235, 236, and / or 237 reduce affinity for Fcγ receptors, particularly FcγRI receptors (e.g., US 6,624,821). Alanine substitutions may be applied to positions 234, 235, and 237 of human IgG1 to reduce operator function. Some antibodies have alanine substitutions at positions 234, 235, and 237 of human IgG1 to reduce operator function. Optionally, positions 234, 236, and / or 237 of human IgG2 are substituted with alanine, and position 235 is substituted with glutamine (e.g., see US 5,624,821). For some antibodies, mutations are applied to one or more of the positions 241, 264, 265, 270, 296, 297, 322, 329, and 331 according to the EU numbering of human IgG1. For some antibodies, mutations are applied to one or more of the positions 318, 320, and 322 according to the EU numbering of human IgG1.For some antibodies, positions 234 and / or 235 are substituted with alanine and / or position 329 is substituted with glycine. For some antibodies, positions 234 and 235 are substituted with alanine. For some antibodies, the isoform is human IgG2 or IgG4. For example, C-terminal lysine in SEQ ID NO. 11 (heavy chain) or SEQ ID NO. 9 (heavy chain constant region) is optional, so that C-terminal lysine may be present or absent in SEQ ID NO. 11 and SEQ ID NO. 9.

[0070] The term “humanized immunoglobulin” or “humanized antibody” refers to an immunoglobulin or antibody having one or more humanized immunoglobulin or antibody chains (i.e., one or more humanized light chains or heavy chains). The term “humanized immunoglobulin chain” or “humanized antibody chain” (i.e., “humanized immunoglobulin light chain” or “humanized immunoglobulin heavy chain”) refers to an immunoglobulin or antibody chain (i.e., light chain or heavy chain, respectively) having a variable region containing a variable framework region substantially derived from a human immunoglobulin or antibody and a complementarity determining region (CDR) substantially derived from a non-human immunoglobulin or antibody (e.g., one or more CDRs, preferably two types of CDRs, more preferably three types of CDRs), and additionally includes a constant region (e.g., one or more constant regions in the case of a light chain, or preferably three types of constant regions in the case of a heavy chain). The term “humanized variable region” (e.g., “humanized light chain variable region” or “humanized heavy chain variable region”) refers to a variable region containing a variable framework region substantially derived from a human immunoglobulin or antibody and a complementarity determining region (CDR) substantially derived from a non-human immunoglobulin or antibody. As used herein, “excluding CDR” means a portion of the antibody that does not contain amino acids of the CDR, e.g., the framework region and the antibody constant region.

[0071] Accordingly, a region or residue of the humanized immunoglobulin or antibody, or a region or residue of the humanized immunoglobulin or antibody chain, is substantially identical to a corresponding region or residue in one or more original human immunoglobulin sequences, possibly excluding the CDR. The terms “corresponding region” or “corresponding residue” refer to a region or residue in a second amino acid or nucleotide sequence that is located at the same (equivalent) position as a region or residue in a first amino acid or nucleotide sequence when optimally aligned to compare the first sequence and the second sequence.

[0072] The term "epitope" or "antigenic determinant" refers to a region of an antigen to which an antibody binds. An epitope can be formed from adjacent amino acids or from non-adjacent amino acids juxtaposed by the tertiary folding of one or more proteins. Epitopes formed from adjacent amino acids are typically retained when exposed to a denaturing solvent, whereas epitopes formed by tertiary folding are typically dissolved when treated with a denaturing solvent. An epitope typically contains at least three amino acids, more typically at least five or eight to ten, in a unique spatial conformation. If an epitope is referred to as a specific range of amino acid residues within a protein (e.g., residues 1–6 of Aβ), that range includes residues that define both boundaries. Certain residues within that range may contribute to the epitope, while others may not. The residues forming the epitope may or may not be adjacent to each other. Similarly, when an antibody binds to an epitope found within a specific amino acid range, the antibody does not come into contact with all amino acid residues present in that range, and the epitope residues in contact with the antibody may or may not be adjacent to each other. Methods for determining the spatial structure of an epitope include, for example, X-ray crystallography and two-dimensional nuclear magnetic resonance. For example, see Epitope Mapping Protocols, in Methods in Molecular Biology, Vol. 66, Glenn E. Morris, Ed. (1996).

[0073] Antibodies that recognize the same epitope can be identified by a simple immunoassay, namely a competitive binding assay, which confirms the ability of an antibody to compete with or block other antibodies from binding to a target antigen. Competitive binding is confirmed by an assay in which a test immunoglobulin inhibits the specific binding of a reference antigen to a common antigen, such as Aβ. Various types of competitive binding assays exist, e.g., solid-phase direct or indirect radioimmunoassay (RIA), solid-phase direct or indirect enzyme immunoassay (EIA), sandwich competitive assay (Stahli et al., Methods in Enzymology 9:242 (1983)); solid-phase direct biotin-avidin EIA (Kirkland et al., J. Immunol. 137:3614 (1986)); solid-phase direct labeling assay, solid-phase direct labeling sandwich assay (Harlow and Lane, Antibodies: A Laboratory Manual, Cold Spring Harbor Press (1988)); Solid-phase direct labeled RIA using I-125 labeling (Morel et al., Mol. Immunol. 25(1):7 (1988)); solid-phase direct biotin-avidin EIA (Cheung et al., Virology 176:546 (1990)); and direct labeled RIA (Moldenhauer et al., Scand. J. Immunol. 32:77 (1990)) are known. Typically, these analyses involve the use of cells possessing either unlabeled test immunoglobulin or labeled reference immunoglobulin, or purified antigens bound to a solid surface. Competitive inhibition is measured by determining the amount of labeling material bound to the solid surface or cell in the presence of test immunoglobulin. Typically, test immunoglobulin is provided in excess.Typically, when a competitive antibody is present in excess, the competitive antibody will inhibit the specific binding of the reference antibody to the common antigen by at least 50-55%, 55-60%, 60-65%, 65-70%, 70-75% or more.

[0074] Competition among antibodies is determined by an assay in which the test antibody inhibits the specific binding of a reference antibody (e.g., 3D6, aducanumab, bapineuzumab) to a common antigen (e.g., Junghans et al., Cancer Res. 50:1495, 1990). If, when measured by a competitive binding assay, an excess amount (e.g., at least 2x, 5x, 10x, 20x, or 100x) of the test antibody inhibits the binding of the reference antibody by at least 50%, preferably 75%, 90%, or 99%, the test antibody is competing with the reference antibody. Antibodies identified by the competitive assay (competitive antibodies) include antibodies that bind to the same epitope as the reference antibody, and antibodies that bind to a proximate epitope sufficiently adjacent to the epitope to which the reference antibody binds to cause steric interference.

[0075] The epitopes of antibodies can also be determined through X-ray crystallography of antibodies bound to their own antigens to identify contact residues. Alternatively, if all amino acid mutations within an antigen that lower or clear the binding affinity of one antibody also lower or clear the binding affinity of another antibody, then these two antibodies have the same epitope. If some amino acid mutations that lower or clear the binding affinity of one antibody also lower or clear the binding affinity of another antibody, then these two antibodies have overlapping epitopes.

[0076] Epitopes are also recognized by immune cells, for example, B cells and / or T cells. Cellular recognition of epitopes is 3It can be confirmed through in vitro assays measuring antigen-dependent proliferation, such as those measured by H-thymidine conjugation, cytokine secretion, antibody secretion, or antigen-dependent killing (cytotoxic T lymphocyte assay).

[0077] Exemplary epitopes or epitopes may be found in human amyloid precursor protein (APP), but preferably in the Aβ peptide of APP. Various isoforms of APP, e.g., APP 695 , APP 751 and APP 770 This exists. The amino acids within APP are APP 770 Numbers are assigned according to the sequence of the isoform (e.g., see GenBank entry number P05067).

[0078] Aβ peptides (also referred to herein as beta-amyloid peptides and A-beta) are internal fragments of about 4-kDa consisting of amino acids 39–43 of APP (Aβ39, Aβ40, Aβ41, Aβ42, and Aβ43). Aβ40 consists of, for example, residues 672–711 of APP, and Aβ42 consists of residues 673–713 of APP. Aβ is found in two forms: a short form of 40 amino acids and a long form ranging from 42 to 43 amino acids, as a result of APP undergoing proteolysis in vivo or in situ by various secretase enzymes. As described herein, a preferred epitope or epitope determinant is located at the N-terminus of an Aβ peptide and comprises a residue within amino acids 1-10 of Aβ, preferably a residue derived from residues 1-3, 1-4, 1-5, 1-6, 1-7, or 3-7 of Aβ 42. An additionally referenced epitope or epitope determinant comprises residues 2-4, 5, 6, 7, or 8 of Aβ, or residues 3-5, 6, 7, 8, or 9 of Aβ, or residues 4-7, 8, 9, or 10 of Aβ 42.

[0079] "Soluble" or "dissociated" Aβ refers to Aβ species in monomeric, aggregated, or oligomeric forms that remain in the solution (supernatant) when centrifuged at 100,000 xg, whether or not they are associated with other proteins and lipids. "Insoluble" Aβ refers to aggregated Aβ species that do not remain in the solution when centrifuged at 100,000 xg, whether they are amyloid (beta-sheets) or not, where, for example, Aβs are bound to each other by non-covalent bonds. Aβ (e.g., Aβ42) appears to aggregate, at least partially, due to hydrophobic residues located at the C-terminus of the peptide (part of the transmembrane domain of APP). One method for preparing soluble Aβ is to dissolve lyophilized peptides by sonication in clean DMSO. The solution obtained in this way is centrifuged to remove any insoluble particulates.

[0080] "Specific binding" of an antibody means that the antibody exhibits substantial affinity for an antigen or a preferred epitope, and preferably does not exhibit significant cross-reactivity. "Substantial" or preferred binding is at least 10 6 , 10 7 , 10 8 , 10 9 M -1 or 10 10 M -1 Includes binding through affinity. 10 7 M -1 Higher than, preferably 10 8 M -1 Higher affinity is more desirable. Intermediate values ​​of the values ​​described herein are also intended to be included within the scope of the invention, and the preferred bonding affinity is a range of affinities, for example, 10 6 to 10 10 M -1 , preferably 10 7 to 10 10 M -1, more preferably 10 8 to 10 10 M -1 It may also be referred to as such. An antibody that does not exhibit "significant cross-reactivity" is one that does not bind to an inappropriate entity (e.g., an inappropriate protein entity) to a significant degree. For example, an antibody that specifically binds to Aβ will bind to Aβ to a significant degree but will not react to non-Aβ proteins or peptides (e.g., non-Aβ proteins or peptides contained in plaques) to a significant degree. An antibody specific to a desired epitope will not significantly cross-react with, for example, a distal epitope on the same protein or peptide. Specific binding can be verified through any means recognized in the art to confirm such binding. Preferably, specific binding is verified according to scatchard analysis and / or competitive binding analysis.

[0081] Binding fragments are prepared by recombinant DNA techniques or through enzymatic or chemical cleavage of intact immunoglobulins. Binding fragments include Fab, Fab', F(ab')2, Fabc, Fv, short-chain and short-chain antibodies.

[0082] As used in the present invention, the term “peripheral administration” includes, for example, intravenous, intra-arterial, intraperitoneal, intramuscular, subcutaneous, intranasal, intraocular / vitreous, rectal, or vaginal administration. While it is evident that all such forms of administration are within the scope of the present invention, an example of a form of administration would be a solution for injection, particularly for subcutaneous, intravenous, or intra-arterial injection or drip. Pharmaceutical compositions suitable for injection may include buffers, surfactants, optionally stabilizers, etc. Preparations for peripheral administration include sterile aqueous or non-aqueous solutions, suspensions, and emulsions. Preservatives and other additives, such as antimicrobial agents, antioxidants, chelating agents, and inert gases, may also be present, for example.

[0083] The term "patient" includes human and other mammalian individuals receiving preventive or therapeutic treatment. In some embodiments, the term "individual" is used interchangeably with "patient."

[0084] The term "entity" includes human and other entities receiving preventive or therapeutic treatment, and includes, but is not limited to, the "patient" described herein.

[0085] The terms "effective dose" or "effective dosage" are defined as an amount sufficient to achieve the desired effect, or at least partially achieve it. The term "therapeutic effective dose" is defined as an amount sufficient to cure the disease and its complications, or at least partially stop them, in patients already suffering from the disease. The effective dose for such use will be determined based on the overall condition of the patient's own immune system and the severity of the infection.

[0086] As used herein, the term “treatment” is defined as the application or administration of a therapeutic substance to a patient having a disease, symptoms of a disease, or predisposition to a disease, for the purpose of curing, healing, alleviating, reducing, modifying, treating, improving, enhancing, or affecting a disease, symptoms of a disease, or predisposition to a disease, or the application or administration of a therapeutic substance to a tissue or cell line isolated from a patient.

[0087] The term "amyloid-producing disease" encompasses any disease associated with (or caused by) the formation or deposition of insoluble amyloid fibrils or amyloid plaques. Examples of amyloid-producing diseases include, but are not limited to, systemic amyloidosis, Alzheimer's disease, mature-onset diabetes mellitus, Parkinson's disease, Huntington's disease, frontotemporal dementia, Down syndrome, mild cognitive impairment, and prion-associated transmissible spongiform encephalopathy (in humans, kuru and Creutzfeldt-Jakob disease; in sheep and cattle, scrapie and BSE), etc. Various amyloid-producing diseases are defined or specified according to the characteristics of the polypeptide components of the deposited fibrils. For example, in individuals or patients with Alzheimer's disease, β-amyloid protein (e.g., wild-type, variant, or truncated β-amyloid protein) is the characteristic polypeptide component of amyloid deposits. That is, Alzheimer's disease is, for example, an example of a "disease characterized by Aβ deposition" or a "disease associated with Aβ deposition" in the brain of an individual or patient. The terms "β-amyloid protein," "β-amyloid peptide," "β-amyloid," "Aβ," and "Aβ peptide" are used interchangeably herein.

[0088] If an individual has one or more known risk factors (e.g., genetic, biochemical, family history, situational exposure) and is placed in a situation where the risk of developing the disease is statistically significantly higher than that of an individual without risk factors, then that individual is in a state of increased risk of the disease.

[0089] The term "symptom" refers to subjective evidence of a disease, such as gait deformities perceived by the patient. "Sign" refers to objective evidence of a disease observed by a physician.

[0090] Statistical significance means p<0.05.

[0091] "Half-life (t1 / 2)" refers to the time required for the concentration of an antigen-binding polypeptide to be reduced to half of its original value. The serum half-life of a protein can be measured through pharmacokinetic studies according to the method described in Kim et al. (Eur. J. of Immuno. 24: 542, 1994). According to this method, a radiolabeled protein is intravenously injected into mice, and its plasma concentration is measured periodically as a function of time after injection, for example, from about 3 minutes to about 72 hours after injection. Other methods for pharmacokinetic analysis and half-life determination for molecules will also be familiar to those skilled in the art. Details can be found in Kenneth, A et al.: Chemical Stability of Pharmaceuticals: A Handbook for Pharmacists and in Peters et al., Pharmacokinetic analysis: A Practical Approach (1996).

[0092] "Clearing (CL)" refers to the volume of irreversible protein removal from plasma per unit time. Clearing is calculated as dose / AUC (AUC: area under the curve or area under the plasma drug concentration-time curve). Clearing can also be calculated by dividing the drug clearance rate by the plasma concentration of the drug (Clearing rate = CL * concentration).

[0093] "Mean Retention Time (MRT)" is the average time an antigen-binding polypeptide remains in the body before being irreversibly removed. It is calculated as MRT = AUMC / AUC.

[0094] "Steady-state concentration" (Css) is the concentration achieved when the drug clearance rate is equal to the drug administration rate as a result of continuous drug administration. Css fluctuates between a peak and a trough level and is measured in μg / ml.

[0095] As used herein, "baseline" is a parameter value before or at the time of administration of the pharmaceutical composition of the present invention, which includes, for example, a value of a predetermined biomarker or the condition of an individual before the first administration of the antibody of the present invention.

[0096] "Amyloid negative" means that there are no brain amyloid β plaques observable using positron emission tomography ("PET") in the individual, and includes, but is not limited to, individuals with a centilloid value of 0.

[0097] "Amyloid positive" means the presence of brain amyloid β plaques that can be observed using PET in an individual.

[0098] As used herein, “risk of ARIA” or “risk of ARIA” means the likelihood that an individual will develop an amyloid-related imaging abnormality observable by MRI. Total risk of ARIA includes the risk of developing observable ARIA-E and / or observable ARIA-H. In contrast, “risk of ARIA-E” means only the likelihood that an individual will develop an observable ARIA-E regardless of whether there is a likelihood of developing an observable ARIA-H, and “risk of ARIA-H” means only the likelihood that an individual will develop an observable ARIA-E regardless of whether there is a likelihood of developing an observable ARIA-E. Risk of ARIA may be evaluated at baseline (before administration of the anti-amyloid β antibody of the present invention) or alternatively during or after treatment.

[0099] Therapeutic usage

[0100] Prophylactic use: The pharmaceutical composition or medicine is administered to a patient who is predisposed to or at risk of developing Alzheimer's disease or other amyloid-producing diseases in an amount sufficient to eliminate or reduce the risk of the disease, including biochemical, histological, and / or behavioral symptoms of the intermediate pathological phenotype appearing during disease progression, as well as its complications and intermediate pathological phenotypes. Patient susceptibility to or risk of developing amyloid-producing diseases may be determined, for example, by genetic markers, biochemical markers, nonspecific genetic risk, or other means. For therapeutic use, the composition or medicine is administered to a patient who is suspected of having or already has such diseases in an amount sufficient to cure or at least partially stop the symptoms (biochemical, histological, and / or behavioral) of the disease, including its complications and intermediate pathological phenotypes during disease progression.

[0101] In some embodiments, administration of the substance alleviates or eliminates cognitive impairment in patients in whom the cognitive pathology of characteristic Alzheimer's or other amyloid-producing diseases has not yet developed. An amount sufficient to achieve therapeutic or prophylactic treatment is defined as the therapeutic or prophylactic effective amount. In both prophylactic and therapeutic administrations, the substance is generally administered in multiple doses until a sufficient immune response is achieved, wherein the “immune response” or “immunological response” includes the manifestation of a humoral (antibody-mediated) and / or cellular (antigen-specific T cells or their secretions) response to the antigen in the recipient. Such a response may be an active response, i.e., a response triggered by the administration of an immunogen, or a passive response, i.e., a response triggered by the administration of immunoglobulins or antibodies or sensitized T cells.

[0102] In some embodiments, the antibody is administered several times. The interval between single doses may be weekly, monthly, or annually. In some embodiments, the single dose may be administered about once or twice a week, about once or twice every two weeks, about once or twice every three weeks, about once or twice every four weeks, about once or twice every five weeks, or about once or twice every six weeks. In one specific embodiment, the antibody is administered intravenously or subcutaneously once every four weeks. In another embodiment, the antibody is administered intravenously or subcutaneously once every two weeks.

[0103] The interval may also be irregular, as specified by measuring blood antibody levels against Aβ in the patient. For some methods, the dosage is adjusted to reach plasma antibody concentrations of 1–1000 µg / mL, and for others, to reach 25–300 µg / mL. Alternatively, antibodies can be administered as sustained-release formulations, in which case the administration frequency is less frequent. The dosage and frequency depend on the antibody half-life in the patient. Generally, human antibodies have the longest half-life, followed by humanized antibodies, chimeric antibodies, and non-human antibodies.

[0104] In some embodiments, patients with Alzheimer's disease who receive an anti-Aβ antibody (or an antigen-binding fragment thereof) in a pharmaceutically effective amount as described herein are treated by a reduction in the burden of amyloid plaques as measured by PET imaging.

[0105] In another embodiment, the antibody may be administered in a fixed amount at each administration. For example, a fixed amount of about 200 mg, about 250 mg, about 300 mg, about 350 mg, or about 400 mg may be administered to the individual at once. In one specific embodiment, about 250 mg of the antibody is administered subcutaneously once every about 4 weeks. In one specific embodiment, about 300 mg of the antibody is administered subcutaneously once every about 4 weeks. In one specific embodiment, about 350 mg of the antibody is administered subcutaneously once every about 4 weeks. In one specific embodiment, about 400 mg of the antibody is administered subcutaneously once every about 4 weeks. In one specific embodiment, about 200 mg of the antibody is administered subcutaneously once every about 4 weeks. In one specific embodiment, 200 mg of the antibody is administered subcutaneously once every about 2 weeks.

[0106] In another specific embodiment, approximately 250 mg of h2731 is administered subcutaneously once every approximately 4 weeks. In another specific embodiment, approximately 300 mg of h2731 is administered subcutaneously once every approximately 4 weeks. In another specific embodiment, approximately 350 mg of h2731 is administered subcutaneously once every approximately 4 weeks. In another specific embodiment, approximately 400 mg of h2731 is administered subcutaneously once every approximately 4 weeks. In another specific embodiment, approximately 200 mg of h2731 is administered subcutaneously twice every approximately 4 weeks. In another specific embodiment, approximately 200 mg of h2731 is administered subcutaneously once every approximately 2 weeks.

[0107] The dosage and frequency of administration may vary depending on whether the treatment is prophylactic or therapeutic. For prophylactic use, the composition containing the antibody or cocktail thereof of the present invention is administered to patients who are not yet suffering from the disease to enhance the patient's resistance. This amount is defined as the "prophylactic effective dose." In such applications, the precise amount is again determined based on the patient's health status and overall immunity. Relatively low doses are administered at relatively infrequent intervals over a long period. Some patients continue to receive the treatment for the rest of their lives.

[0108] For therapeutic use, relatively high doses may sometimes be required for relatively short intervals until disease progression is alleviated or terminated, and in some cases, until the patient shows partial or complete improvement in disease symptoms. Subsequently, prophylactic administration may be administered to the patient.

[0109] Administration: Therapeutic substances may be administered by parenteral, topical, intravenous, oral, subcutaneous, intra-arterial, intracranial, intraperitoneal, intranasal, intramuscular, or intramuscular means for prophylactic and / or therapeutic treatment. Intramuscular injection is most typically performed in the muscles of the arm or leg. In some methods, the substance is injected directly into specific tissues where deposits have accumulated, for example, by intracranial injection. Intramuscular injection or intravenous infusion is preferred when administering antibodies. In some methods, specific therapeutic antibodies are injected directly into the skull. In some methods, antibodies are administered as a sustained-release composition or via a device. In some embodiments, antibodies are administered subcutaneously using an auto-injector device.

[0110] Administration

[0111] The present invention provides a method for treating a neurological disorder (e.g., Alzheimer's disease) comprising administering a composition comprising an anti-amyloid β antibody. For example, in some embodiments, the present invention provides a method for treating Alzheimer's disease in an individual comprising administering about 205 mg to about 400 mg of an anti-amyloid β antibody or an antigen-binding fragment thereof to the individual once every about 3 to 5 weeks.

[0112] The present invention also provides a method for reducing amyloid plaques in an individual. For example, in some embodiments, the present invention provides a method for reducing amyloid plaques in an individual comprising administering about 205 mg to about 400 mg of an anti-amyloid β antibody or an antigen-binding fragment thereof to an individual once every about 3 to 5 weeks.

[0113] The present invention further provides a method for converting an individual from amyloid-positive to amyloid-negative. For example, in some embodiments, the present invention provides a method for converting an individual from amyloid-positive to amyloid-negative, comprising administering to the individual about 205 mg to about 400 mg of an anti-amyloid β antibody or an antigen-binding fragment thereof once every about 3 to 5 weeks.

[0114] In some embodiments, the method comprises administering to an individual about 205 mg to about 400 mg of an anti-amyloid β antibody or its antigen-binding fragment (e.g., about 250 mg to about 400 mg, about 300 mg to about 400 mg, or about 350 mg to about 400 mg) once every about 3 to 5 weeks. In some embodiments, the method comprises administering to an individual about 205 mg to about 400 mg of an anti-amyloid β antibody or its antigen-binding fragment (e.g., about 250 mg to about 400 mg, about 300 mg to about 400 mg, or about 350 mg to about 400 mg) once every about 4 weeks.

[0115] In an exemplary embodiment, the method comprises administering to an individual about 295 mg to about 305 mg of an anti-amyloid β antibody or its antigen-binding fragment once every about 3 to 5 weeks. In an exemplary embodiment, the method comprises administering to an individual about 345 mg to about 355 mg of an anti-amyloid β antibody or its antigen-binding fragment once every about 3 to 5 weeks. In an exemplary embodiment, the method comprises administering to an individual about 395 mg to about 405 mg of an anti-amyloid β antibody or its antigen-binding fragment once every about 3 to 5 weeks.

[0116] In some embodiments, the present method provides an individual with about 205 mg, about 210 mg, about 215 mg, about 220 mg, about 225 mg, about 230 mg, about 235 mg, about 240 mg, about 245 mg, about 250 mg, about 255 mg, about 260 mg, about 265 mg, about 270 mg, about 275 mg, about 280 mg, about 285 mg, about 290 mg, about 295 mg, about 300 mg, about 305 mg, about 310 mg, about 315 mg, about 320 mg, about 325 mg, about 330 mg, about 335 mg, about 340 mg, about 345 mg, about 350 mg, about 355 mg, about 360 It includes administering about 365 mg, about 370 mg, about 375 mg, about 380 mg, about 385 mg, about 390 mg, about 395 mg, or about 400 mg once every 3 to 5 weeks. In some embodiments, the method comprises administering about 300 mg, about 350 mg, or about 400 mg of an anti-amyloid β antibody or its antigen-binding fragment to an individual once every about 3 to 5 weeks (e.g., once every about 4 weeks).

[0117] In an exemplary embodiment, the method comprises administering about 250 mg of an anti-amyloid β antibody or its antigen-binding fragment to an individual once every about 3 to 5 weeks. In an exemplary embodiment, the method comprises administering about 300 mg of an anti-amyloid β antibody or its antigen-binding fragment to an individual once every about 3 to 5 weeks. In an exemplary embodiment, the method comprises administering about 350 mg of an anti-amyloid β antibody or its antigen-binding fragment to an individual once every about 3 to 5 weeks. In an exemplary embodiment, the method comprises administering about 400 mg of an anti-amyloid β antibody or its antigen-binding fragment to an individual once every about 3 to 5 weeks.

[0118] In an exemplary embodiment, the method comprises administering about 250 mg of an anti-amyloid β antibody or its antigen-binding fragment to an individual once every about 4 weeks. In an exemplary embodiment, the method comprises administering about 300 mg of an anti-amyloid β antibody or its antigen-binding fragment to an individual once every about 4 weeks. In an exemplary embodiment, the method comprises administering about 350 mg of an anti-amyloid β antibody or its antigen-binding fragment to an individual once every about 4 weeks. In an exemplary embodiment, the method comprises administering about 400 mg of an anti-amyloid β antibody or its antigen-binding fragment to an individual once every about 4 weeks.

[0119] In some embodiments, the method comprises administering an anti-amyloid β antibody or its antigen-binding fragment once every approximately 4 weeks. In some embodiments, the method comprises administering an anti-amyloid β antibody or its antigen-binding fragment once every approximately 1 month. In some embodiments, the method comprises administering an anti-amyloid β antibody or its antigen-binding fragment once every approximately 28 days.

[0120] In some embodiments, the method comprises administering an anti-amyloid β antibody or its antigen-binding fragment as a single dose (e.g., a single subcutaneous injection) once every 3 to 5 weeks. In some embodiments, the method comprises administering an anti-amyloid β antibody or its antigen-binding fragment as a single dose once every 4 weeks. In some embodiments, the method comprises administering an anti-amyloid β antibody or its antigen-binding fragment as a single dose once every 4 weeks. In some embodiments, the method comprises administering an anti-amyloid β antibody or its antigen-binding fragment as a single dose once every 1 month. In some embodiments, the method comprises administering an anti-amyloid β antibody or its antigen-binding fragment as a single dose once every 28 days.

[0121] In some embodiments, the present invention provides a method for treating Alzheimer's disease in an individual, comprising administering to the individual about 45 mg to about 200 mg of an anti-amyloid β antibody or an antigen-binding fragment thereof twice every about 3 to 5 weeks (e.g., once every about 2 weeks). In some embodiments, the present invention provides a method for treating Alzheimer's disease in an individual, comprising administering to the individual about 100 mg to about 200 mg of an anti-amyloid β antibody or an antigen-binding fragment thereof twice every about 3 to 5 weeks (e.g., once every about 2 weeks).

[0122] In some embodiments, the present invention provides a method for reducing amyloid plaques in an individual, comprising administering to the individual about 45 mg to about 200 mg of an anti-amyloid β antibody or an antigen-binding fragment thereof twice every about 3 to 5 weeks (e.g., once every about 2 weeks). In some embodiments, the present invention provides a method for reducing amyloid plaques in an individual, comprising administering to the individual about 100 mg to about 200 mg of an anti-amyloid β antibody or an antigen-binding fragment thereof twice every about 3 to 5 weeks (e.g., once every about 2 weeks).

[0123] In some embodiments, the present invention provides a method for converting an individual from amyloid-positive to amyloid-negative, comprising administering to the individual about 45 mg to about 200 mg of an anti-amyloid β antibody or an antigen-binding fragment thereof twice every about 3 to 5 weeks (e.g., once every about 2 weeks). In some embodiments, the present invention provides a method for converting an individual from amyloid-positive to amyloid-negative, comprising administering to the individual about 100 mg to about 200 mg of an anti-amyloid β antibody or an antigen-binding fragment thereof twice every about 3 to 5 weeks (e.g., once every about 2 weeks).

[0124] In some embodiments, the method comprises administering to an individual about 70 mg, about 100 mg to about 200 mg (e.g., about 125 mg to about 200 mg, about 150 mg to about 200 mg, or about 175 mg to about 200 mg) of an anti-amyloid β antibody or its antigen-binding fragment twice every about 3 to 5 weeks (e.g., once every about 2 weeks).

[0125] In an exemplary embodiment, the method comprises administering about 65 mg to about 75 mg of an anti-amyloid β antibody or its antigen-binding fragment to an individual. In an exemplary embodiment, the method comprises administering about 145 mg to about 155 mg of an anti-amyloid β antibody or its antigen-binding fragment to an individual. In an exemplary embodiment, the method comprises administering about 195 mg to about 205 mg of an anti-amyloid β antibody or its antigen-binding fragment to an individual twice every about 3 to 5 weeks (e.g., once every about 2 weeks).

[0126] In some embodiments, the present method comprises administering to an individual about 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, about 150 mg, about 155 mg, about 160 mg, about 165 mg, about 170 mg, about 175 mg, about 180 mg, about 185 mg, about 190 mg, about 195 mg, or about 200 mg of an anti-amyloid β antibody or its antigen-binding fragment about 3 to 5 weeks twice (e.g., every 2 weeks). 1) includes administering. In some embodiments, the method comprises administering about 150 mg or about 200 mg of an anti-amyloid β antibody or its antigen-binding fragment to an individual twice every about 3-5 weeks (e.g., once every about 2 weeks).

[0127] In an exemplary embodiment, the method comprises administering about 70 mg of an anti-amyloid β antibody or its antigen-binding fragment to an individual twice every about 3 to 5 weeks. In an exemplary embodiment, the method comprises administering about 70 mg of an anti-amyloid β antibody or its antigen-binding fragment to an individual once every about 2 weeks.

[0128] In an exemplary embodiment, the method comprises administering about 100 mg of an anti-amyloid β antibody or its antigen-binding fragment to an individual twice every about 3 to 5 weeks. In an exemplary embodiment, the method comprises administering about 100 mg of an anti-amyloid β antibody or its antigen-binding fragment to an individual once every about 2 weeks.

[0129] In an exemplary embodiment, the method comprises administering about 200 mg of an anti-amyloid β antibody or its antigen-binding fragment to an individual twice every about 3 to 5 weeks. In an exemplary embodiment, the method comprises administering about 200 mg of an anti-amyloid β antibody or its antigen-binding fragment to an individual once every about 2 weeks.

[0130] In some embodiments, the method comprises administering an anti-amyloid β antibody or its antigen-binding fragment twice every four weeks. In some embodiments, the method comprises administering an anti-amyloid β antibody or its antigen-binding fragment twice every month. In some embodiments, the method comprises administering an anti-amyloid β antibody or its antigen-binding fragment twice every 28 days.

[0131] In some embodiments, the method comprises administering an anti-amyloid β antibody or its antigen-binding fragment as a single dose (e.g., a single subcutaneous injection) once every approximately 1 to 3 weeks. In some embodiments, the method comprises administering an anti-amyloid β antibody or its antigen-binding fragment as a single dose once every approximately 2 weeks. In some embodiments, the method comprises administering an anti-amyloid β antibody or its antigen-binding fragment as a single dose once every 2 weeks. In some embodiments, the method comprises administering an anti-amyloid β antibody or its antigen-binding fragment as a single dose once every approximately 14 days.

[0132] In some embodiments, the method comprises administering an anti-amyloid β antibody or its antigen-binding fragment by injection. In some embodiments, the method comprises administering an anti-amyloid β antibody or its antigen-binding fragment by parenteral injection. In some embodiments, the method comprises administering an anti-amyloid β antibody or its antigen-binding fragment by intravenous injection or subcutaneous injection. In an exemplary embodiment, the method comprises administering an anti-amyloid β antibody or its antigen-binding fragment by subcutaneous injection. In some embodiments, the method comprises administering an anti-amyloid β antibody or its antigen-binding fragment using an auto-injector.

[0133] Anti-Aβ antibodies

[0134] The present invention provides a method for using an antibody or a fragment thereof that specifically binds to an Aβ peptide. In some aspects, the present invention utilizes an anti-amyloid β antibody or a fragment thereof to achieve therapeutic efficacy by monthly subcutaneous administration. The present invention further describes the selection and design of an anti-amyloid β antibody or a fragment thereof suitable for monthly subcutaneous administration.

[0135] In some embodiments, the monoclonal antibody for use in the present invention may bind to an epitope within residues 1-6 of Aβ (the first N-terminal residue of natural Aβ is designated as 1). Some monoclonal antibodies bind to an epitope within amino acids 1-6, some bind to an epitope within amino acids 1-5, and some bind to an epitope within amino acids 1-4. Some antibodies bind to epitopes within amino acids 1-3, 2-5, 3-5, 2-4, 2-5, 2-6, 3-5, or 3-6. Where an antibody is described as binding to an epitope within specified residues, such as, for example, Aβ 1-6, this means that the antibody specifically binds to a polypeptide containing one or more of the specified residues (i.e., for example, one or more amino acids derived from Aβ amino acids 1-6); These antibodies do not necessarily come into contact with all residues within Aβ 1-6. In some embodiments, the antibody binds to an epitope containing one or more amino acids derived from amino acids 1-10 of the Aβ peptide. In other aspects, the antibody binds to an epitope containing one or more amino acids derived from amino acids 1-7 of the Aβ peptide. Additional amino acids of the epitope may be located outside the amino acid 1-10 or amino acid 1-7 regions.

[0136] The antibody used in this method may be a humanized, human antibody or a fragment thereof (e.g., an antigen-binding fragment), and may be monoclonal or polyclonal as described herein. In another aspect, the present invention is characterized by administering an antibody prepared from a human immunized with an Aβ peptide, wherein the human may be a patient to be treated with the antibody.

[0137] In some embodiments, the anti-amyloid β antibody or fragment comprises a heavy chain variable region having heavy chains CDR1, CDR2, and CDR3 derived from the compositions shown in Table 1, and a light chain variable region having light chains CDR1, CDR2, and CDR3.

[0138] Table 1

[0139]

[0140] In some embodiments, the anti-amyloid β antibody or fragment of the present invention comprises a heavy chain variable region (VH) as listed for any one of the compositions in Table 1. In some embodiments, the anti-amyloid β antibody or fragment also comprises a light chain variable region (VL) as listed for one of the compositions in Table 1.

[0141] In some embodiments, the anti-amyloid β antibody or its antigen-binding fragment comprises a heavy chain variable region comprising heavy chains CDR1, CDR2, and CDR3 and a light chain variable region comprising light chains CDR1, CDR2, and CDR3, wherein

[0142] Heavy chain CDR1 comprises the amino acid sequence of SEQ ID NO. 3, and

[0143] Heavy chain CDR2 comprises the amino acid sequence of SEQ ID NO. 4, and

[0144] Heavy chain CDR3 comprises the amino acid sequence of SEQ ID NO. 5, and

[0145] Light chain CDR1 comprises the amino acid sequence of SEQ ID NO. 6, and

[0146] Light chain CDR2 comprises the amino acid sequence of SEQ ID NO. 7, and

[0147] The light chain CDR3 contains the amino acid sequence of SEQ ID NO. 8.

[0148] In some embodiments, for example, an anti-amyloid β antibody or a fragment thereof for use in the method of the present invention comprises a heavy chain variable region that is at least 90% (e.g., at least 95%, at least 98%, or 100%) identical to SEQ ID NO. 1 and a light chain variable region, excluding the CDR, that is at least 90% (e.g., at least 95%, at least 98%, or 100%) identical to SEQ ID NO. 2.

[0149] In some embodiments, the heavy chain variable region excluding the CDR is at least 95% identical to the amino acid sequence of SEQ ID NO. 1, and the light chain variable region excluding the CDR is at least 95% identical to the amino acid sequence of SEQ ID NO. 2. In some embodiments, the heavy chain variable region excluding the CDR is at least 98% identical to the amino acid sequence of SEQ ID NO. 1, and the light chain variable region excluding the CDR is at least 98% identical to the amino acid sequence of SEQ ID NO. 2. In some embodiments, the heavy chain variable region comprises the amino acid sequence of SEQ ID NO. 1, and the light chain variable region comprises the amino acid sequence of SEQ ID NO. 2. In some embodiments, the heavy chain variable region is composed of SEQ ID NO. 1, and the light chain variable region is composed of the amino acid sequence of SEQ ID NO. 2.

[0150] In some embodiments, the anti-amyloid β antibody is a complete antibody, a chimeric antibody, a CDR-transplant antibody, or a recombinant antibody. In some embodiments, the anti-amyloid β antibody is humanized IgG. In some embodiments, the anti-amyloid β antibody is humanized IgG1.

[0151] In some embodiments, the anti-amyloid β antibody or fragment thereof for use in the method of the present invention also comprises a heavy chain constant region that is at least 75% identical to SEQ ID NO. 9. For example, the heavy chain constant region may be 75% identical, 80% identical, 85% identical, 90% identical, 95% identical, 96% identical, 97% identical, 98% identical, 99% identical, or 100% identical to SEQ ID NO. 9.

[0152] In some embodiments, the anti-amyloid β antibody or fragment thereof for use in the method of the present invention also comprises a light chain constant region that is at least 75% identical to SEQ ID NO. 10. For example, the light chain constant region may be 75% identical, 80% identical, 85% identical, 90% identical, 95% identical, 96% identical, 97% identical, 98% identical, 99% identical, or 100% identical to SEQ ID NO. 10.

[0153] In some embodiments, the anti-amyloid β antibody or its antigen-binding fragment further comprises a heavy chain constant region comprising an amino acid sequence at least 95% identical to SEQ ID NO. 9 and / or a light chain constant region comprising an amino acid sequence at least 95% identical to SEQ ID NO. 10. In some embodiments, the anti-amyloid β antibody or its antigen-binding fragment further comprises a heavy chain constant region comprising an amino acid sequence at least 98% identical to SEQ ID NO. 9 and / or a light chain constant region comprising an amino acid sequence at least 98% identical to SEQ ID NO. 10. In some embodiments, the anti-amyloid β antibody comprises a heavy chain constant region comprising an amino acid sequence of SEQ ID NO. 9 with or without C-terminal lysine and a light chain constant region comprising an amino acid sequence of SEQ ID NO. 10. In some embodiments, the anti-amyloid β antibody comprises a heavy chain constant region essentially composed of the amino acid sequence of SEQ ID NO. 9, with or without C-terminal lysine, and a light chain constant region essentially composed of the amino acid sequence of SEQ ID NO. 10.

[0154] In some embodiments, the anti-amyloid β antibody or its antigen-binding fragment further comprises a heavy chain having an amino acid sequence at least 95% identical to SEQ ID NO. 11 and / or a light chain having an amino acid sequence at least 95% identical to SEQ ID NO. 12. In some embodiments, the anti-amyloid β antibody or its antigen-binding fragment further comprises a heavy chain having an amino acid sequence at least 98% identical to SEQ ID NO. 11 and / or a light chain having an amino acid sequence at least 98% identical to SEQ ID NO. 12. In an exemplary embodiment, the anti-amyloid β antibody comprises a heavy chain having an amino acid sequence of SEQ ID NO. 11 with or without C-terminal lysine and a light chain having an amino acid sequence of SEQ ID NO. 12. In an exemplary embodiment, the anti-amyloid β antibody comprises a heavy chain constant region essentially composed of an amino acid sequence of SEQ ID NO. 11 with or without C-terminal lysine and a light chain constant region essentially composed of an amino acid sequence of SEQ ID NO. 12. In an exemplary embodiment, the anti-amyloid β antibody comprises a heavy chain constant region consisting of the amino acid sequence of SEQ ID NO. 11, with or without C-terminal lysine, and a light chain constant region consisting of the amino acid sequence of SEQ ID NO. 12. In an exemplary embodiment, the anti-amyloid β antibody is h2731.

[0155] A variant antibody or fragment that is less than 100% identical to the sequence (+ any invariant region) mentioned in Table 1A may differ from the anti-Aβ antibody of Table 1 by only 1-15, 1-10, e.g. 6-10, or just 5, 4, 3, 2, or even 1 amino acid residue. "Conservative amino acid substitution" is the substitution of an amino acid residue with an amino acid residue having a side chain with similar charge. Series of amino acid residues with similar charge side chains are defined in the art. These series include amino acids with basic side chains (e.g., lysine, arginine, histidine), amino acids with acidic side chains (e.g., aspartic acid, glutamic acid), amino acids with non-charged polar side chains (e.g., glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine), amino acids with non-polar residues (e.g., alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, tryptophan), amino acids with beta-branched side chains (e.g., threonine, valine, isoleucine), and amino acids with aromatic side chains (e.g., tyrosine, phenylalanine, tryptophan, histidine). Alternatively, random mutations can be introduced into all or part of the coding sequence, such as by saturated mutagenesis, and the constructed mutants can be selected by biological activity (e.g., Aβ polypeptide binding affinity) to identify mutants possessing activity.

[0156] For example, it is possible to introduce mutations only in the framework region of the antibody molecule (i.e., region(s) excluding the CDR). The introduced mutation may be a silent or neutral missense mutation, meaning it has no or minimal effect on the antigen-binding affinity of the antibody. This type of mutation may be useful for optimizing codon usage or improving antibody production in hybridomas. Alternatively, non-neutral missense mutations may alter the antigen-binding affinity of the antibody. A person skilled in the art would be able to design and test mutant molecules with desired characteristics, such as non-variation in antigen-binding activity or variation in binding activity (e.g., improvement in antigen-binding activity or alteration in antibody specificity). After mutagenesis, the encoded protein may be routinely expressed, and the functional and / or biological activity of the encoded protein (e.g., ability to immune-specifically bind to one or more epitopes of the Aβ polypeptide) may be determined by routinely modifying techniques known in the art or by using the techniques described herein.

[0157] In each of the embodiments described above, the antibody or fragment of the present invention may be a humanized antibody as described herein. For example, the antibody may be a human IgG1 antibody. Additionally, the antibody may be a complete antibody, a chimeric antibody, a CDR-transplant antibody, or a recombinant antibody. The fragment of the antibody may be Fab, Fab', F(ab')2, Fabc, or Fv. The fragment is prepared by recombinant DNA techniques or by enzymatic or chemical separation of intact immunoglobulin.

[0158] The antibody h2731 has several physicochemical properties that make it suitable for use in the method of the present invention, including, for example, the properties mentioned in Tables 2 and 3. Additional properties, such as pharmacokinetic parameters, are discussed herein.

[0159] Table 2

[0160] IC 50 Ratio(h2731:hBP)Aβ 1-42 raw fiber IC 50 (µg / ml h2731)Aβ aggregates EC 50 (ng / ㎖ h2731)Aβ 1-42 raw fiber EC 50 (h2731 ng / ㎖)Aβ pE3-42 raw fiber 0.61 5.024 36.71 > 100

[0161] Table 2 is Aβ 1-42 fibrils, Aβ 1-42 Aggregates and Aβ pE3-42 IC of h2731 binding to various amyloid β species, such as fibrils 50 and / or EC 50 Provides value data. For example, refer to U.S. Patent 11,440,953.

[0162] IC of h2731 using an analysis based on binding competition (inhibition) of labeled antibodies against antigen-coated plates 50 was decided. Then, IC 50 IC of bapineuzumab (hBP) 50 Divided by, the ratio that is 50% of the maximum inhibitory concentration listed in the first column of Table 2 (IC 50 ) was calculated. This ratio of 0.61 is that h2731 is Aβ 1-42 This means that it performs better than hBP in binding to fibrils. Using a similar competitive analysis, h2731 IC 50 It was confirmed that the value was 5.024 µg / ml (2nd column of Table 2), which corresponds to the IC5 observed in hBP. 50 It is several times lower than the value.

[0163] Aβ 1-42 and Aβ pE3-42 The direct binding of h2731 to fibrils was also investigated by ELISA (Columns 3 and 4 of Table 2), and Aβ 1-42 EC of h2731 for fibrils 50 The value was 36.71 ng / mL. h2731 exhibited high affinity for fibrils and significantly higher antigen-antibody binding affinity than aducanumab. Furthermore, it showed a threefold increase in the assay signal (OD490) and a 15–20-fold lower estimated EC10. 50This means that h2731 increased overall binding to fibril Aβ and relative antigen-antibody binding affinity compared to aducanumab.

[0164] However, h2731 binds with apparent affinity to the N-terminus of full-length Aβ, but pyroglutamate-modified Aβ (Aβ pE3-42 It does not specifically bind to ). h2731 is an N-terminally undeformed fibril Aβ species (Aβ 1-42 ) at a 1 / 2-maximum effective concentration (EC) of 8.1 ng / ㎖ (54 pM) 50 It was bound as ). h2731 was bound to Aβ up to a maximum of 100 ng / mL. pE3-42 Detectable binding for was not observed.

[0165] Table 3

[0166] 1:1 combined ka (1 / Ms) kd (1 / s) Apparent KD (M) Rmax (RU) Aβ 1-42 raw fiber 3.72e+5 2.62e-5 7.04e-11 50.7 Aβ 1-28 1.19e+5 5.95e-4 5.01e-9 78.3 Aβ: Amyloid β, Aβ; ka: Binding rate constant; kd: Dissociation rate constant; KD: Apparent equilibrium dissociation constant; mAb: Monoclonal antibody; R max : Maximum response; SPR: Surface plasmon resonance.

[0167] Table 3 is recombinant Aβ 1-42 fibrils and Aβ 1-28 We present additional amyloid β binding data for h2731, including binding kinetics data for h2731 to monomers. As shown in column 2 of Table 3, h2731 binds to Aβ 1-42 fibrils and Aβ 1-28 Binding constants for monomers are 3.72 x 10⁻⁶, respectively. 5 M -1 s -1 and 1.19 x 10 5 M -1 s -1 It binds. Although aducanumab binds to Aβ fibrils with a faster binding rate (ka), the dissociation rate (kd) of h2731 of the present invention is much slower, so the measured antigen-antibody binding affinity was higher than that of aducanumab (i.e., lower KD*).

[0168] Dissociation-rate data (kd) for h2731 are presented in column 3 of Table 3, and Aβ 1-42 fibrils and Aβ 1-28The kd values ​​of h2731 for the monomer are 2.62 x 10, respectively. -5 s -1 and 5.95 x 10 -4 s -1 The relative enhancement of the antigen-antibody binding affinity of h2731 of the present invention toward fibrilated Aβ observed by ELISA was verified by SPR equilibrium binding kinetics (Column 4 of Table 3), which Aβ 1-28 This means that the antigen-antibody binding strength (apparent KD) is 5 to 11 times higher than that of aducanumab, including a binding affinity of 4-7 nM for monomers.

[0169] In additional embodiments, the method of the present invention may utilize one or more of various types of anti-amyloid β antibodies or fragments thereof. Specifically, antibodies suitable for use in the method of the present invention have the physicochemical and pharmacological properties discussed herein that enable the administration of a therapeutically effective dose via subcutaneous administration once a month and / or twice a month. Additional exemplary anti-amyloid β antibodies suitable for use in the method of the present invention include those described in U.S. Patent 11,440,953, the entirety of which is incorporated into the present invention by reference.

[0170] In some embodiments, the anti-amyloid β antibody or binding fragment, variant, or derivative has a dissociation rate (k(off)) of 5X10 -2 sec -1 , 10 -2 sec -1 , 5Х10 -3 sec -1 or 10 -3 sec -1 It binds to Aβ (or a fragment or variant thereof) below. In certain embodiments, the anti-amyloid β antibody or binding fragment, variant, or derivative has a dissociation rate (k(off)) of 5×10 4 sec -1 , 10 -4 sec -1 , 5Х10-5 sec -1 , or 10 -5 sec -1 , 5Х10 -6 sec -1 , 10 -6 sec -1 , 5Х10 -7 sec -1 or 10 -7 sec -1 It binds to Aβ (or a fragment or variant thereof) below.

[0171] In some embodiments, the anti-amyloid β antibody or binding fragment, variant, or derivative has a binding rate (k(on)) of 10 3 M -1 sec -1 , 5x10 3 M -1 sec -1 , 10 4 M -1 sec -1 or 5x10 4 M -1 sec -1 It binds to Aβ (or a fragment or variant thereof) above. In certain embodiments, the anti-amyloid β antibody or binding fragment, variant, or derivative has a binding rate (k(on)) of 10 5 M -1 sec -1 , 5x10 5 M -1 sec -1 , 10 6 M -1 sec -1 , 5x10 6 M -1 sec -1 or 10 7 M -1 sec -1 It binds to Aβ (or its fragments or variants) above.

[0172] As described herein, anti-Aβ antibodies or their antigen-binding fragments, variants, or derivatives may be described or specified in terms of their Aβ binding affinity. Binding affinity is defined as a dissociation constant or Kd of 5x10 -2　 M, 10 -2　 M, 5x10 -3　 M, 10 -3　 M, 5x10 -4　 M, 10 -4　 M, 5x10 -5　 M, 10 -5　 M, 5x10 -6　 M, 10 -6　 M, 5x10 -7　 M, 10 -7　 M, 5x10 -8　 M, 10 -8　 M, 5x10 -9　 M, 10 -9　 M, 5x10 -10　 M, 10 -10　 M, 5x10 -11　 M, 10 -11　 M, 5x10 -12　 M, 10 -12　 M, 5x10 -13　 M, 10 -13　 M, 5x10 -14　 M, 10 -14　 M, 5x10 -15　 M or 10 -15　 It may include things less than M.

[0173] The present invention will be more fully explained by the following non-limiting examples.

[0174] Sequence No. 1 h2731_VH (variable heavy chain) amino acid sequence

[0175] EVQLLESGGGLVQPGGSLRLSCAASGFTFSNYGMSWVRQAPGKGLEWVASIRSGSGRTYYSDNVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCVRYDHYSGSSDYWGQGTLVTVSS

[0176] Sequence No. 2 h2731_VL (variable light chain) amino acid sequence

[0177] DVVMTQSPLSLPVT L GEPASISCKSSQSLLDYDGKTYLNWLLQKPGQSPQRLIYRVTNRDTGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCWQGTHFPRSFGQGTKVEIK

[0178] Sequence No. 3: VH CDR1 GFTFSNYGMS

[0179] Sequence No. 4: VH CDR2 SIRSGSGRTYYSDNVKG

[0180] Sequence No. 5: VH CDR3 YDHYSGSSDY

[0181] Sequence No. 6: VL CDR1 KSSQSLLDYDGKTYLN

[0182] Sequence No. 7: VL CDR2 RVTNRDT

[0183] Sequence No. 8: VL CDR3 WQGTHFPRS

[0184] Sequence No. 9: huIgG1 Invariant Amino Acid Sequence

[0185] ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGV EVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

[0186] SEQ ID NO. 10: huKappa invariant amino acid sequence

[0187] RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0188] Sequence No. 11: h2731 Complete heavy chain amino acid sequence

[0189] EVQLLESGGGLVQPGGSLRLSCAASGFTFSNYGMSWVRQAPGKGLEWVASIRSGSGRTYYSDNVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCVRYDHYSGSSDYWGQG TLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDK THTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEK TISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

[0190] Sequence No. 12: h2731 Complete light chain amino acid sequence

[0191] DVVMTQSPLSLPVTLGEPASISCKSSQSLLDYDGKTYLNWLLQKPGQSPQRLIYRVTNRDTGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCWQGTHFPRSFGQGTKV EIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0192] Sequence No. 13: h2731_VH (variable heavy chain) nucleotide sequence

[0193] GAAGTGCAGCTTCTGGAGAGCGGGGGCGGCCTGGTGCAGCCGGGCGGATCCCTGAGACTGTCCTGTGCCGCGTCCGGTTTTACCTTCTCCAACTACGGAATGTCATGGGTCCGCCAAGCACCCGGAAAGGGATTGGAATGGGTGGCTTCGATCCGGTCCGGCTCGGGACGGACCTACTACTCCGATAACGTCAAGGGCAGATTCACTATTAGCCGGGACAACAGCAAGAATACCCTGTACCTCCAAATGAACTCCCTGAGGGCCGAGGACACCGCCGTGTATTACTGCGTGCGCTACGACCACTACTCGGGTTCCTCTGATTACTGGGGACAGGGGACCCTCGTGACTGTGTCAAGC

[0194] 서열번호 14: h2731_VL (가변성 경쇄) 뉴클레오티드 서열

[0195] GATGTCGTGATGACTCAGTCACCTCTGTCCCTGCCTGTGACCCTTGGGGAACCCGCCTCGATCTCGTGCAAGAGCTCCCAGAGCCTGCTCGACTATGATGGAAAGACCTACCTGAACTGGTTGCTCCAAAAGCCGGGCCAGAGCCCCCAGAGGCTGATCTACCGCGTGACCAACCGCGACACCGGGGTGCCGGACCGGTTCTCCGGATCCGGCAGCGGCACTGACTTCACCCTGAAAATTTCCAGAGTGGAAGCCGAGGACGTGGGAGTGTACTACTGTTGGCAGGGTACTCACTTTCCACGGTCCTTCGGTCAAGGAACCAAGGTCGAGATCAAG

[0196] 서열번호 15: huIgG1 불변 뉴클레오티드 서열

[0197] GCCAGCACTAAGGGGCCTAGCGTCTTTCCGCTGGCCCCGTCCTCCAAGTCCACTTCGGGTGGAACCGCGGCACTGGGGTGCCTCGTGAAGGACTACTTCCCCGAGCCGGTCACCGTGTCCTGGAACTCGGGAGCCCTGACCTCCGGAGTGCATACTTTCCCTGCGGTGCTGCAGTCCTCCGGGCTCTACTCGCTGTCAAGCGTGGTCACCGTCCCGAGCTCATCCCTGGGTACTCAGACCTACATTTGCAACGTGAACCACAAACCTTCCAACACCAAGGTCGACAAGAAAGTGGAGCCTAAGAGCTGCGACAAGACCCACACCTGTCCCCCGTGTCCCGCCCCTGAGCTGCTGGGCGGCCCCAGCGTGTTCCTCTTCCCGCCTAAGCCGAAGGACACTCTGATGATCTCGAGAACCCCTGAAGTGACCTGTGTGGTGGTGGATGTGTCCCACGAGGATCCGGAAGTGAAGTTCAATTGGTACGTGGACGGAGTGGAAGTCCATAACGCCAAGACCAAGCCCCGCGAGGAACAGTACAACTCAACTTACCGGGTGGTGTCAGTGCTGACCGTGCTGCACCAAGATTGGCTGAACGGGAAGGAGTACAAGTGCAAAGTCTCCAACAAGGCGCTGCCGGCCCCCATTGAAAAGACCATCAGCAAGGCTAAGGGCCAGCCCCGGGAACCACAGGTCTACACCTTGCCCCCTTCCCGGGAGGAAATGACCAAGAACCAAGTGTCGCTGACGTGCCTGGTCAAGGGCTTTTATCCATCTGACATCGCCGTGGAGTGGGAAAGCAACGGCCAGCCGGAAAACAACTACAAGACTACCCCGCCTGTGCTGGACTCCGACGGCTCGTTCTTCCTGTATTCCAAGCTCACCGTGGATAAGTCCAGATGGCAGCAGGGCAATGTGTTCAGCTGCAGCGTGATGCATGAGGCCCTGCACAACCACTACACTCAGAAATCACTGTCCCTTTCCCCCGGAAAGTAA

[0198] SEQ ID NO. 16: huKappa invariant nucleotide sequence

[0199] CGAACTGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAG AGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGTTAA

[0200] Sequence No. 17: h2731 complete heavy chain nucleotide sequence

[0201]

[0202] 서열번호 18: h2731 완전 경쇄 뉴클레오티드 서열

[0203] GATGTTGTGATGACCCAGTCCCCACTCTCTTTGCCCGTTACCCTTGGAGAACCTGCCTCCATCTCTTGCAAGTCAAGTCAGAGCCTCTTAGATTACGATGGAAAGACATATTTGAATTGGTTGCTGCAGAAGCCAGGCCAGTCTCCACAGCGCCTAATCTATCGGGTGACCAACCGGGACACTGGAGTCCCTGACAGGTTCAGTGGCAGTGGATCAGGGACAGATTTCACACTGAAAATCAGCAGAGTGGAGGCTGAGGATGTGGGAGTTTATTATTGCTGGCAAGGCACACATTTTCCGCGCTCTTTCGGACAGGGGACCAAGGTGGAAATAAAACGAACTGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGCTTAAGTCCGGAACTGCTAGCGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGAAACTCCCAGGAGAGCGTCACAGAGCAGGACAGCAAAGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT

[0204] Pharmaceutical composition

[0205] In some embodiments, an anti-Aβ antibody or a fragment thereof is administered as part of a pharmaceutical composition. Several methods are known for preparing a composition comprising an anti-Aβ antibody or its antigen-binding fragment, variant, or derivative for individuals requiring this. In some embodiments, the anti-Aβ antibody or its antigen-binding fragment is formulated for parenteral administration. In an exemplary embodiment, the anti-Aβ antibody or its antigen-binding fragment is formulated for subcutaneous injection.

[0206] For the purposes of the present invention, a pharmaceutically effective amount of an anti-Aβ antibody or its antigen-binding fragment, variant, or derivative means an amount sufficient to effectively bind to a target to achieve benefits, for example, to reduce brain amyloid plaques without affecting vascular amyloid, or to minimize the occurrence of microhemorrhage during long-term administration of the anti-Aβ antibody or its antigen-binding fragment. In some embodiments, the anti-Aβ antibody or its antigen-binding fragment, variant, or derivative crosses the blood-brain barrier in an effective amount to reduce brain amyloid plaques.

[0207] The amount of anti-Aβ antibody, or its fragments, variants, or derivatives combined with a carrier material to form a single dosing formulation will vary depending on the individual being treated and the specific method of administration. The dosage regimen may also be adjusted to provide the optimal desired response (e.g., therapeutic or prophylactic response).

[0208] The present invention provides an anti-Aβ antibody or an antigen-binding fragment thereof in several pharmaceutically effective amounts (e.g., about 205 mg to about 400 mg and additional amounts and / or ranges disclosed herein). Accordingly, the present invention provides for the use of a pharmaceutical composition comprising these amounts in the methods disclosed herein. These pharmaceutically effective amounts may be administered as a single dose, as multiple doses, or through infusions over a set period. In an exemplary embodiment, such a pharmaceutical composition is administered as a single dose. In an exemplary embodiment, such a pharmaceutical composition is administered by a single subcutaneous injection.

[0209] For example, in some aspects, the present invention provides a method for treating Alzheimer's disease in an individual, comprising administering to the individual once every 3 to 5 weeks a pharmaceutical composition comprising about 205 mg to about 400 mg of an anti-amyloid β antibody or an antigen-binding fragment thereof.

[0210] In some aspects, the present invention provides a method for reducing amyloid plaques in an individual, comprising administering to the individual once every 3 to 5 weeks a pharmaceutical composition comprising about 205 mg to about 400 mg of an anti-amyloid β antibody or an antigen-binding fragment thereof.

[0211] In some aspects, the present invention provides a method for converting an individual from amyloid-positive to amyloid-negative, comprising administering to the individual a pharmaceutical composition containing about 205 mg to about 400 mg of an anti-amyloid β antibody or an antigen-binding fragment thereof once every about 3 to 5 weeks (e.g., once every about 4 weeks).

[0212] For example, in some aspects, the present invention provides a method for treating Alzheimer's disease in an individual, comprising administering to the individual a pharmaceutical composition containing about 45 mg to about 200 mg of an anti-amyloid β antibody or an antigen-binding fragment thereof twice every about 3 to 5 weeks. In some aspects, the present invention provides a method for treating Alzheimer's disease in an individual, comprising administering to the individual a pharmaceutical composition containing about 100 mg to about 200 mg of an anti-amyloid β antibody or an antigen-binding fragment thereof twice every about 3 to 5 weeks.

[0213] For example, in some aspects, the present invention provides a method for treating Alzheimer's disease in an individual, comprising administering to the individual a pharmaceutical composition containing about 45 mg to about 200 mg of an anti-amyloid β antibody or an antigen-binding fragment thereof once every about 2 weeks. In some aspects, the present invention provides a method for treating Alzheimer's disease in an individual, comprising administering to the individual a pharmaceutical composition containing about 100 mg to about 200 mg of an anti-amyloid β antibody or an antigen-binding fragment thereof once every about 2 weeks.

[0214] In some aspects, the present invention provides a method for reducing amyloid plaques in an individual, comprising administering to the individual a pharmaceutical composition comprising about 45 mg to about 200 mg of an anti-amyloid β antibody or an antigen-binding fragment thereof twice every about 3 to 5 weeks. In some aspects, the present invention provides a method for reducing amyloid plaques in an individual, comprising administering to the individual a pharmaceutical composition comprising about 100 mg to about 200 mg of an anti-amyloid β antibody or an antigen-binding fragment thereof twice every about 3 to 5 weeks.

[0215] In some aspects, the present invention provides a method for converting an individual from amyloid-positive to amyloid-negative, comprising administering to the individual a pharmaceutical composition comprising about 45 mg to about 200 mg of an anti-amyloid β antibody or an antigen-binding fragment thereof twice every about 3 to 5 weeks. In some aspects, the present invention provides a method for converting an individual from amyloid-positive to amyloid-negative, comprising administering to the individual a pharmaceutical composition comprising about 100 mg to about 200 mg of an anti-amyloid β antibody or an antigen-binding fragment thereof twice every about 3 to 5 weeks.

[0216] In some embodiments, the method comprises administering to an individual a pharmaceutical composition comprising about 295 mg to about 305 mg of an anti-amyloid β antibody or its antigen-binding fragment once every about 3 to 5 weeks. In some embodiments, the method comprises administering to an individual a pharmaceutical composition comprising about 345 mg to about 355 mg of an anti-amyloid β antibody or its antigen-binding fragment once every about 3 to 5 weeks. In an exemplary embodiment, the method comprises administering to an individual a pharmaceutical composition comprising about 395 mg to about 405 mg of an anti-amyloid β antibody or its antigen-binding fragment once every about 3 to 5 weeks. In an exemplary embodiment, the method comprises administering to an individual a pharmaceutical composition comprising about 195 mg to about 205 mg of an anti-amyloid β antibody or its antigen-binding fragment twice every about 3 to 5 weeks.

[0217] In an exemplary embodiment, the method comprises administering to an individual a pharmaceutical composition comprising about 250 mg of an anti-amyloid β antibody or its antigen-binding fragment once every about 3 to 5 weeks. In an exemplary embodiment, the method comprises administering to an individual a pharmaceutical composition comprising about 300 mg of an anti-amyloid β antibody or its antigen-binding fragment once every about 3 to 5 weeks. In an exemplary embodiment, the method comprises administering to an individual a pharmaceutical composition comprising about 350 mg of an anti-amyloid β antibody or its antigen-binding fragment once every about 3 to 5 weeks. In an exemplary embodiment, the method comprises administering to an individual a pharmaceutical composition comprising about 400 mg of an anti-amyloid β antibody or its antigen-binding fragment once every about 3 to 5 weeks. In an exemplary embodiment, these pharmaceutical compositions are administered as a single subcutaneous injection once every about 3 to 5 weeks (e.g., once every about 4 weeks).

[0218] In an exemplary embodiment, the method comprises administering to an individual a pharmaceutical composition comprising about 250 mg of an anti-amyloid β antibody or its antigen-binding fragment once every about 4 weeks. In an exemplary embodiment, the method comprises administering to an individual a pharmaceutical composition comprising about 300 mg of an anti-amyloid β antibody or its antigen-binding fragment once every about 4 weeks. In an exemplary embodiment, the method comprises administering to an individual a pharmaceutical composition comprising about 350 mg of an anti-amyloid β antibody or its antigen-binding fragment once every about 4 weeks. In an exemplary embodiment, the method comprises administering to an individual a pharmaceutical composition comprising about 400 mg of an anti-amyloid β antibody or its antigen-binding fragment once every about 4 weeks. In an exemplary embodiment, these pharmaceutical compositions are administered as a single subcutaneous injection once every about 4 weeks.

[0219] In an exemplary embodiment, the present method administers a pharmaceutical composition comprising about 70 mg of an anti-amyloid β antibody or its antigen-binding fragment to an individual twice every about 3 to 5 weeks (e.g., once every about 2 weeks). In an exemplary embodiment, the present method administers a pharmaceutical composition comprising about 70 mg of an anti-amyloid β antibody or its antigen-binding fragment to an individual once every about 2 weeks.

[0220] In an exemplary embodiment, the present method administers a pharmaceutical composition comprising about 200 mg of an anti-amyloid β antibody or an antigen-binding fragment thereof to an individual twice every about 3 to 5 weeks (e.g., once every about 2 weeks). In an exemplary embodiment, the present method administers a pharmaceutical composition comprising about 200 mg of an anti-amyloid β antibody or an antigen-binding fragment thereof to an individual once every about 2 weeks.

[0221] In another aspect, the present invention is characterized by administering an antibody as a pharmaceutical composition together with a pharmaceutical carrier. Alternatively, the antibody may be administered to a patient by administering a polynucleotide encoding at least one antibody chain. The polynucleotide is expressed to produce an antibody chain in the patient. Optionally, the polynucleotide encodes the heavy chain and light chain of the antibody. The polynucleotide is expressed to produce the heavy chain and light chain in the patient. In an exemplary embodiment, the level of the administered antibody is monitored in the patient's blood.

[0222] In some embodiments, the pharmaceutical composition comprises a pharmaceutically effective amount of an anti-Aβ antibody or a fragment thereof and a pharmaceutically acceptable diluent. As discussed herein, the anti-Aβ antibody or its antigen-binding fragment, variant, or derivative may be formulated to facilitate administration and promote the stability of the active substance. In certain embodiments, the pharmaceutical composition according to the invention comprises a pharmaceutically acceptable, non-toxic, sterile carrier such as physiological saline, a non-toxic buffer, a preservative, etc.

[0223] The pharmaceutical composition used in the present invention comprises, for example, an ion exchanger, alumina, aluminum stearate, lecithin, a serum protein, such as human serum albumin, a buffering material, such as phosphate, glycine, sorbic acid, potassium sorbate, a mixture of partial glycerides of saturated vegetable fatty acids, water, a salt or an electrolyte, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salt, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, a cellulose-based material, polyethylene glycol, sodium carboxymethylcellulose, polyacrylate, a wax, a polyethylene-polyoxypropylene-block polymer, polyethylene glycol, and a pharmaceutically acceptable carrier such as wool paper.

[0224] Prevention of microbial activity can be achieved by various antibacterial and antifungal agents, e.g., parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, etc. In many cases, isotonic agents, e.g., sugars, polyalcohols, or salts, may be included in the composition. Long-term absorption of the injectable composition can be achieved by including substances that delay absorption, e.g., aluminum monostearate and gelatin, in the composition.

[0225] Preparations for parenteral administration (e.g., intravenous or subcutaneous injection) include sterile aqueous or non-aqueous solutions, suspensions, and emulsions. Examples of non-aqueous solvents include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Aqueous carriers include water, alcoholic / aqueous solutions, emulsions, or suspensions, e.g., saline solution, and buffer media. Parenteral vehicles include sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride, lactate Ringer's solution, or fixative oils. Intravenous vehicles include fluids and nutritional supplements, and electrolyte supplements (e.g., Ringer's dextrose-based substances). Preservatives and other additives, e.g., antimicrobial agents, antioxidants, chelating agents, and inert gases, may also be present. In addition, the pharmaceutical composition of the present invention may further include substances such as dopamine or psychopharmacological drugs depending on the intended use of the pharmaceutical composition.

[0226] The therapeutic composition for use in the method of the present invention is typically substantially pure from unwanted contaminants. This means that the purity of the material with respect to interfering proteins and other contaminants typically arising from manufacturing or purification is at least 50% w / w, but does not exclude the possibility that the material may be combined with an excess of pharmaceutically acceptable carrier(s) or other vehicle intended to facilitate its use. Sometimes, the monoclonal antibody (or other therapeutic material) has a purity of at least 60%, 70%, 80%, 90%, 95%, or 99% w / w with respect to interfering proteins and contaminants arising from manufacturing or purification.

[0227] Pharmacokinetic evaluation indicators

[0228] The present invention provides a dosage regimen for an anti-amyloid β antibody designed to achieve a drug exposure profile in an individual suitable for clearing amyloid plaques and / or treating neurodegenerative diseases (e.g., Alzheimer's disease). To this end, the present invention provides a method for administering an anti-amyloid β antibody to achieve specific pharmacokinetic evaluation indicators in an individual, for example, to achieve the following parameter values ​​suitable for clearing plaques and / or treating the disease: average concentration during the administration interval (C ave ), steady-state concentration during the administration interval (C ss ), maximum concentration during the administration interval (C max ), area under the concentration-time curve from time 0 to infinity AUC 0-∞ , and the area under the concentration-time curve (AUC) during the administration interval 0-tau In various embodiments, these pharmacokinetic indicators can be evaluated in various body fluids collected from an individual, such as whole blood, serum, plasma and / or CSF.

[0229] Maximum drug concentration (C max )

[0230] Accordingly, in another aspect, the present invention C max Value (normal state C max The present invention provides a method for treating Alzheimer's disease in an individual, comprising subcutaneously administering an anti-Aβ antibody to the individual at a dose sufficient to achieve a value of approximately 30 µg / ml to approximately 60 µg / ml. In another aspect, the present invention C max The present invention provides a method for reducing amyloid plaques in an individual, comprising administering an anti-Aβ antibody subcutaneously to the individual at a dose sufficient to achieve a value of about 30 µg / ml to about 60 µg / ml. In another aspect, the present invention C maxThe present invention provides a method for converting an individual from amyloid-positive to amyloid-negative, comprising administering an anti-Aβ antibody subcutaneously to an individual in a dose sufficient to achieve a value of about 30 μg / ml to about 60 μg / ml. In an exemplary embodiment, the anti-Aβ antibody comprises a heavy chain of SEQ ID NO. 11 and a light chain of SEQ ID NO. 12, with or without C-terminal lysine.

[0231] In some embodiments, treatment involves the anti-amyloid β antibody or its antigen-binding fragment C in the individual. max It includes achieving about 30 µg / ml to about 60 µg / ml (e.g., about 35 µg / ml to about 60 µg / ml, about 40 µg / ml to about 60 µg / ml, about 45 µg / ml to about 60 µg / ml, about 30 µg / ml to about 55 µg / ml, about 35 µg / ml to about 55 µg / ml, about 30 µg / ml to about 50 µg / ml, or about 35 µg / ml to about 50 µg / ml). In some embodiments, C max The value is normal state serum C max It is a value. In some implementations, C max The value is normal state plasma C max It is a value.

[0232] Average drug concentration (C ave )

[0233] In another aspect, the present invention relates to serum C ave The present invention provides a method for treating Alzheimer's disease in an individual, comprising subcutaneously administering an anti-Aβ antibody to the individual at a dose sufficient to achieve a value of about 20 µg / ml to about 40 µg / ml. In another aspect, the present invention provides serum C ave The present invention provides a method for reducing amyloid plaques in an individual, comprising subcutaneously administering an anti-Aβ antibody to the individual at a dose sufficient to achieve a value of about 20 µg / ml to about 40 µg / ml. In another aspect, the present invention provides serum C aveThe present invention provides a method for converting an individual from amyloid-positive to amyloid-negative, comprising administering an anti-Aβ antibody subcutaneously to an individual in a dose sufficient to achieve a value of about 20 μg / ml to about 40 μg / ml. In an exemplary embodiment, the anti-Aβ antibody comprises a heavy chain of SEQ ID NO. 11 and a light chain of SEQ ID NO. 12, with or without C-terminal lysine.

[0234] In some embodiments, treatment involves the anti-amyloid β antibody or its antigen-binding fragment C in the individual. max It includes achieving about 20 µg / ml to about 40 µg / ml (e.g., about 23 µg / ml to about 40 µg / ml, about 25 µg / ml to about 40 µg / ml, about 28 µg / ml to about 40 µg / ml, about 30 µg / ml to about 40 µg / ml, about 35 µg / ml to about 40 µg / ml, about 20 µg / ml to about 38 µg / ml, about 23 µg / ml to about 38 µg / ml, about 25 µg / ml to about 38 µg / ml, about 28 µg / ml to about 38 µg / ml, about 20 µg / ml to about 35 µg / ml, about 20 µg / ml to about 30 µg / ml, or about 25 µg / ml to about 30 µg / ml). In some implementations, C ave The value is normal state serum C ave It is a value. In some implementations, C ave The value is normal state plasma C ave It is a value.

[0235] Area under the concentration-time curve (AUC) during the dosing interval 0-tau )

[0236] In another aspect, the present invention relates to the area under the concentration-time curve (AUC) for the dosing interval. 0-tau The present invention provides a method for treating Alzheimer's disease in an individual, comprising subcutaneously administering an anti-Aβ antibody to the individual at a dose sufficient to achieve an AUC of approximately 15,000 hr*µg / ml to approximately 30,000 hr*µg / ml. In another aspect, the present invention provides an AUC 0-tauThe present invention provides a method for reducing amyloid plaques in an individual, comprising subcutaneously administering an anti-Aβ antibody to the individual at a dose sufficient to achieve an AUC of about 15,000 hr*µg / ml to about 30,000 hr*µg / ml. In another aspect, the present invention provides an AUC 0-tau The present invention provides a method for converting an individual from amyloid-positive to amyloid-negative, comprising administering an anti-Aβ antibody subcutaneously to an individual at a dose sufficient to achieve a value of about 15,000 hr*µg / ml to about 30,000 hr*µg / ml. In an exemplary embodiment, the anti-Aβ antibody comprises a heavy chain of SEQ ID NO. 11 and a light chain of SEQ ID NO. 12, with or without C-terminal lysine.

[0237] In some embodiments, treatment is the AUC of an anti-amyloid β antibody or its antigen-binding fragment in an individual 0-tau Value (steady-state AUC) 0-tau Value) includes achieving about 15,000 hr*µg / ml to about 30,000 hr*µg / ml (e.g., 16,000 hr*µg / ml to about 30,000 hr*µg / ml, 18,000 hr*µg / ml to about 30,000 hr*µg / ml, 20,000 hr*µg / ml to about 30,000 hr*µg / ml, 22,000 hr*µg / ml to about 30,000 hr*µg / ml, or 25,000 hr*µg / ml to about 30,000 hr*µg / ml). In some embodiments, treatment comprises achieving an AUC of an anti-amyloid β antibody or its antigen-binding fragment in an individual. 0-tau Value (steady-state AUC) 0-tau Value) includes achieving about 15,000 hr*µg / ml to about 25,000 hr*µg / ml (e.g., 16,000 hr*µg / ml to about 25,000 hr*µg / ml, 18,000 hr*µg / ml to about 25,000 hr*µg / ml, 20,000 hr*µg / ml to about 25,000 hr*µg / ml, or 22,000 hr*µg / ml to about 25,000 hr*µg / ml). In some embodiments, AUC0-tau The value is normal state serum AUC 0-tau It is a value. In some implementations, AUC 0-tau The value is steady-state plasma AUC 0-tau It is a value.

[0238] Amyloid plaque removal

[0239] The present invention further provides a use of anti-amyloid β antibodies for reducing amyloid plaques in individuals. The reduction of amyloid plaques has been identified as correlated with a slowing of cognitive decline during treatment with anti-amyloid β antibodies. For example, M. Shi, et al., Impact of Anti-amyloid-β Monoclonal Antibodies on the Pathology and Clinical Profile of Alzheimer's Disease: A Focus on Aducanumab and Lecanemab . 14 Front. Aging Neurosci. 1 (2022); C.H. van Dyck, et al., Lecanemab in Early Alzheimer's Disease See 388 N. Engl. J. Med. 9 (2023). In fact, the FDA granted expedited approval to both aducanumab and recanemab based on plaque reduction data from clinical trials.

[0240] Accordingly, in another aspect, the present invention provides a method for treating Alzheimer's disease in an individual having amyloid plaques, comprising the following:

[0241] (a) a step of administering to an individual once every approximately 4 weeks a composition comprising about 205 mg to about 400 mg of an anti-amyloid β antibody (e.g., 250 mg, 300 mg, 350 mg, or 400 mg), wherein the anti-amyloid β antibody comprises a heavy chain of SEQ ID NO. 11 and a light chain of SEQ ID NO. 12 having or without C-terminal lysine; and

[0242] (b) Step to reduce amyloid plaques in the individual.

[0243] Accordingly, in another aspect, the present invention provides a method for treating Alzheimer's disease in an individual having amyloid plaques, comprising the following:

[0244] (a) a step of administering to an individual once every two weeks a composition comprising about 45 mg to about 400 mg (e.g., 70 mg, 100 mg, 150 mg, or 200 mg) of an anti-amyloid β antibody, wherein the anti-amyloid β antibody comprises a heavy chain of SEQ ID NO. 11 and a light chain of SEQ ID NO. 12 having or without C-terminal lysine; and

[0245] (b) Step to reduce amyloid plaques in the individual.

[0246] Detection of brain amyloid plaques is performed by methods known to those skilled in the art. In some embodiments, the method further includes evaluating amyloid through positron emission tomography (PET) imaging. In some embodiments, amyloid reduction is determined by PET. PET imaging agents are known to those skilled in the art and include 18F-florbetapir, florbetaben F18, and flutemetamol F18. In some embodiments, amyloid plaques measured by PET are quantified by the composite standard uptake value ratio (SUVR). In some embodiments, amyloid plaques measured by PET are calculated using the centilloid scale. In some embodiments, changes in amyloid plaque burden are measured by changes in SUVR over time. In some embodiments, changes in amyloid plaque burden are measured by changes in centiloid over time. See Navitsky M, Joshi AD, Kennedy I, et al., Standardization of amyloid quantitation with florbetapir standardized uptake value ratios to the Centiloid scale, Alzheimers Dement 2018 14:1565-71 and Oshi AD, Pontecorvo MJ, Lu M, et al., A Semiautomated Method for Quantification of F 18 Florbetapir PET Images, J Nucl Med. 2015; 56(11):1736-41.

[0247] Accordingly, in another aspect, the present invention provides a method for reducing amyloid plaques in an individual, comprising the following:

[0248] (a) a step of administering to an individual once every approximately 4 weeks a composition comprising about 205 mg to about 400 mg of an anti-amyloid β antibody, wherein the anti-amyloid β antibody comprises a heavy chain of SEQ ID NO. 11 and a light chain of SEQ ID NO. 12 having or without C-terminal lysine; and

[0249] (b) A step to reduce amyloid plaques in the individual as determined by PET.

[0250] In another aspect, the present invention provides a method for treating Alzheimer's disease in an individual, comprising the following:

[0251] (a) A step of observing primary amyloid plaque values ​​obtained through a primary PET scan in an individual;

[0252] (b) a step of subcutaneously administering to an individual a composition comprising about 205 mg to about 400 mg of an anti-amyloid β antibody once every about 3-5 weeks, wherein the anti-amyloid β antibody comprises a heavy chain of SEQ ID NO. 11 and a light chain of SEQ ID NO. 12 having or without C-terminal lysine; or

[0253] (c) a step of observing secondary amyloid plaque values ​​obtained through a secondary PET scan in the subject; and

[0254] (d) A step of comparing the primary amyloid plaque value with the secondary amyloid plaque value to observe a reduction in amyloid plaques in the individual.

[0255] In another aspect, the present invention provides a method for treating Alzheimer's disease in an individual with amyloid plaques, comprising:

[0256] (a) A step of performing a primary PET scan on an individual to observe primary amyloid plaque values;

[0257] (b) a step of administering to an individual once every 3 to 5 weeks a composition comprising about 205 mg to about 400 mg of an anti-amyloid β antibody, wherein the anti-amyloid β antibody comprises a heavy chain of SEQ ID NO. 11 and a light chain of SEQ ID NO. 12 having or without C-terminal lysine;

[0258] (c) performing a secondary PET scan on the subject to observe secondary amyloid plaque values; and

[0259] (d) A step of comparing the primary amyloid plaque value with the secondary amyloid plaque value to observe a reduction in amyloid plaques in the individual.

[0260] In another aspect, the present invention provides a method for reducing amyloid plaques in an individual, comprising the following:

[0261] (a) A step of observing primary amyloid plaque values ​​obtained through a primary PET scan in an individual;

[0262] (b) a step of subcutaneously administering to an individual once every 3 to 5 weeks a composition comprising about 205 mg to about 400 mg of an anti-amyloid β antibody, wherein the anti-amyloid β antibody comprises a heavy chain of SEQ ID NO. 11 and a light chain of SEQ ID NO. 12 with or without C-terminal lysine; or

[0263] (c) a step of observing secondary amyloid plaque values ​​obtained through a secondary PET scan in the subject; and

[0264] (d) A step of comparing the primary amyloid plaque value with the secondary amyloid plaque value to observe a reduction in amyloid plaques in the individual.

[0265] In another aspect, the present invention provides a method for reducing amyloid plaques in an individual having amyloid plaques, comprising the following:

[0266] (a) A step of performing a primary PET scan on an individual to observe primary amyloid plaque values;

[0267] (b) a step of administering to an individual once every 3 to 5 weeks a composition comprising about 205 mg to about 400 mg of an anti-amyloid β antibody, wherein the anti-amyloid β antibody comprises a heavy chain of SEQ ID NO. 11 and a light chain of SEQ ID NO. 12 having or without C-terminal lysine;

[0268] (c) performing a secondary PET scan on the subject to observe secondary amyloid plaque values; and

[0269] (d) A step of comparing the primary amyloid plaque value with the secondary amyloid plaque value to observe a reduction in amyloid plaques in the individual.

[0270] In another aspect, the present invention provides a method for reducing amyloid plaques in an individual having amyloid plaques, comprising the following:

[0271] (a) A step of performing a primary PET scan on an individual to observe primary amyloid plaque values;

[0272] (b) a step of subcutaneously administering to an individual a composition comprising about 45 mg to about 200 mg of an anti-amyloid β antibody once every about 2 weeks, wherein the anti-amyloid β antibody comprises a heavy chain of SEQ ID NO. 11 and a light chain of SEQ ID NO. 12 having or without C-terminal lysine;

[0273] (c) performing a secondary PET scan on the subject to observe secondary amyloid plaque values; and

[0274] (d) A step of comparing the primary amyloid plaque value with the secondary amyloid plaque value to observe a reduction in amyloid plaques in the individual.

[0275] In some embodiments, the treatment involves a reduction of amyloid β plaques (i.e., brain amyloid β plaques) in the individual. In some embodiments, a reduction of amyloid β plaques in the individual is achieved by the treatment. In some embodiments, a reduction of amyloid β plaques is achieved in the individual as evaluated by PET.

[0276] In some embodiments, the reduction of amyloid β plaques comprises a reduction of at least about 10 centiroids (e.g., at least about 15 centiroids, at least about 20 centiroids, at least about 25 centiroids, or at least about 30 centiroids). In some embodiments, the reduction of amyloid β plaques comprises a reduction of at least about 30 centiroids (e.g., at least about 35 centiroids, at least about 40 centiroids, at least about 45 centiroids, at least about 50 centiroids, at least about 55 centiroids, or at least about 60 centiroids) after 6 months of treatment. In some embodiments, the reduction of amyloid β plaques is achieved after about about 6 months of treatment. In some embodiments, the reduction of amyloid β plaques is achieved after about 12 months of treatment. In some embodiments, the reduction of amyloid β plaques is achieved after about 18 months of treatment.

[0277] In some embodiments, the reduction of amyloid β plaques comprises a reduction of about 10 centiroids to about 90 centiroids (e.g., about 20 centiroids to about 90 centiroids, about 30 centiroids to about 90 centiroids, about 40 centiroids to about 90 centiroids, or about 50 centiroids to about 90 centiroids). In some embodiments, the reduction of amyloid β plaques comprises a reduction of about 10 centiroids to about 80 centiroids (e.g., about 20 centiroids to about 80 centiroids, about 30 centiroids to about 80 centiroids, about 40 centiroids to about 80 centiroids, or about 50 centiroids to about 80 centiroids). In some embodiments, the reduction of amyloid β plaques comprises a reduction of about 10 centiroids to about 70 centiroids (e.g., about 20 centiroids to about 70 centiroids, about 30 centiroids to about 70 centiroids, about 40 centiroids to about 70 centiroids, or about 50 centiroids to about 70 centiroids). In some embodiments, the reduction of amyloid β plaques comprises a reduction of about 10 centiroids to about 60 centiroids (e.g., about 20 centiroids to about 60 centiroids, about 30 centiroids to about 60 centiroids, about 40 centiroids to about 60 centiroids, or about 50 centiroids to about 60 centiroids). In some embodiments, the reduction of amyloid β plaques is achieved after about 6 months of treatment. In some embodiments, a reduction in amyloid β plaques is achieved after approximately 12 months of treatment. In some embodiments, a reduction in amyloid β plaques is achieved after approximately 18 months of treatment.

[0278] In some embodiments, the reduction of amyloid β plaques includes a reduction of at least about 10 centiroids (e.g., at least about 15 centiroids, at least about 20 centiroids, at least about 25 centiroids, or at least about 30 centiroids) after about 6 months of treatment. In some embodiments, the reduction of amyloid β plaques includes a reduction of at least about 30 centiroids (e.g., at least about 35 centiroids, at least about 40 centiroids, at least about 45 centiroids, or at least about 50 centiroids) after about 6 months of treatment. In some embodiments, the reduction of amyloid β plaques includes a reduction of about 10 centiroids, about 15 centiroids, about 20 centiroids, about 25 centiroids, about 30 centiroids, about 35 centiroids, about 40 centiroids, about 45 centiroids, about 50 centiroids, about 55 centiroids, about 60 centiroids, about 65 centiroids, about 70 centiroids, about 75 centiroids, about 80 centiroids, about 85 centiroids, about 90 centiroids, or about 95 centiroids. In some embodiments, the reduction of amyloid β plaques is achieved after about 6 months of treatment. In some embodiments, the reduction of amyloid β plaques is achieved after about 12 months of treatment. In some embodiments, the reduction of amyloid β plaques is achieved after about 18 months of treatment.

[0279] In some embodiments, the reduction of amyloid β plaques includes a reduction of about 10 centiroids to about 80 centiroids (e.g., about 20 centiroids to about 80 centiroids, about 30 centiroids to about 80 centiroids, about 10 centiroids to about 60 centiroids, or about 10 centiroids to about 50 centiroids) after about 6 months of treatment. In some embodiments, the reduction of amyloid β plaques includes a reduction of about 30 centiroids to about 70 centiroids (e.g., about 40 centiroids to about 70 centiroids, about 50 centiroids to about 70 centiroids, about 30 centiroids to about 60 centiroids, or about 30 centiroids to about 50 centiroids) after about 6 months of treatment.

[0280] In some embodiments, the reduction of amyloid β plaques includes a reduction of at least about 25 centiroids (e.g., at least about 35 centiroids, at least about 40 centiroids, at least about 45 centiroids, or at least about 50 centiroids) after about 12 months of treatment. In some embodiments, the reduction of amyloid β plaques includes a reduction of at least about 40 centiroids (e.g., at least about 45 centiroids, at least about 50 centiroids, at least about 55 centiroids, or at least about 60 centiroids) after about 12 months of treatment.

[0281] In some embodiments, the reduction of amyloid β plaques includes a reduction of about 20 centiroids to about 90 centiroids (e.g., about 30 centiroids to about 90 centiroids, about 40 centiroids to about 90 centiroids, about 20 centiroids to about 80 centiroids, or about 20 centiroids to about 70 centiroids) after about 12 months of treatment. In some embodiments, the reduction of amyloid β plaques includes a reduction of about 45 centiroids to about 80 centiroids (e.g., about 50 centiroids to about 80 centiroids, about 55 centiroids to about 80 centiroids, about 45 centiroids to about 75 centiroids, or about 45 centiroids to about 70 centiroids) after about 12 months of treatment.

[0282] In some embodiments, the reduction of amyloid β plaques includes a reduction of at least about 35 centiroids (e.g., at least about 40 centiroids, at least about 45 centiroids, at least about 50 centiroids, or at least about 55 centiroids) after treatment for about 18 months. In some embodiments, the reduction of amyloid β plaques includes a reduction of at least about 50 centiroids (e.g., at least about 55 centiroids, at least about 60 centiroids, at least about 65 centiroids, or at least about 70 centiroids) after treatment for about 18 months.

[0283] In some embodiments, the reduction of amyloid β plaques comprises a reduction of about 30 centiroids to about 100 centiroids (e.g., about 40 centiroids to about 100 centiroids, about 50 centiroids to about 100 centiroids, about 30 centiroids to about 95 centiroids, or about 30 centiroids to about 90 centiroids) after about 18 months of treatment. In some embodiments, the reduction of amyloid β plaques comprises a reduction of about 50 centiroids to about 85 centiroids (e.g., about 65 centiroids to about 85 centiroids, about 70 centiroids to about 85 centiroids, about 50 centiroids to about 80 centiroids, or about 50 centiroids to about 75 centiroids) after about 18 months of treatment.

[0284] In some embodiments, the reduction of amyloid β plaques comprises a reduction of at least about 30% (e.g., at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, or at least about 70%). In some embodiments, the reduction of amyloid β plaques comprises a reduction of about 30% to about 100% (e.g., about 40% to about 100%, about 50% to about 100%, about 60% to about 100%, or about 70% to about 100%). In some embodiments, the reduction of amyloid β plaques in an individual comprises a reduction of about 30% to about 90% (e.g., about 40% to about 90%, about 50% to about 90%, about 60% to about 90%, or about 70% to about 90%). In some embodiments, the reduction of amyloid β plaques comprises a reduction of about 30% to about 80% (e.g., about 40% to about 80%, about 50% to about 80%, or about 60% to about 80%). In some embodiments, the reduction of amyloid β plaques comprises a reduction of about 30% to about 70% (e.g., about 40% to about 70%, or about 50% to about 70%). In some embodiments, the reduction of amyloid β plaques includes a reduction of about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%. In some embodiments, the reduction of amyloid β plaques is achieved after about 6 months of treatment. In some embodiments, the reduction of amyloid β plaques is achieved after about 12 months of treatment. In some embodiments, the reduction of amyloid β plaques is achieved after about 18 months of treatment.

[0285] In some embodiments, the reduction of amyloid β plaques includes a reduction of at least about 20% (e.g., at least 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, or at least about 50%) after about 6 months of treatment. In some embodiments, the reduction of amyloid β plaques includes a reduction of about 20% to about 90% (e.g., about 30% to about 90%, about 40% to about 90%, or about 50% to about 90%) after about 6 months of treatment. In some embodiments, the reduction of amyloid β plaques includes a reduction of about 30% to about 70% (e.g., about 35% to about 70%, about 40% to about 70%, about 30% to about 65%, or about 30% to about 60%) after about 6 months of treatment.

[0286] In some embodiments, the reduction of amyloid β plaques includes a reduction of at least about 30% (e.g., at least 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, or at least about 60%) after treatment for about 12 months. In some embodiments, the reduction of amyloid β plaques includes a reduction of about 30% to about 100% (e.g., about 40% to about 100%, about 50% to about 100%, or about 50% to about 90%) after treatment for about 12 months. In some embodiments, the reduction of amyloid β plaques includes a reduction of about 60% to about 100% (e.g., about 65% to about 100%, about 70% to about 100%, about 65% to about 95%, or about 65% to about 90%) after treatment for about 12 months.

[0287] In some embodiments, the reduction of amyloid β plaques includes a reduction of at least about 40% (e.g., at least 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, or at least about 70%) after treatment for about 18 months. In some embodiments, the reduction of amyloid β plaques includes a reduction of about 40% to about 100% (e.g., about 50% to about 100%, about 60% to about 100%, or about 50% to about 90%) after treatment for about 18 months. In some embodiments, the reduction of amyloid β plaques includes a reduction of about 65% to about 100% (e.g., about 70% to about 100%, about 75% to about 100%, about 65% to about 95%, or about 65% to about 90%) after treatment for about 18 months.

[0288] In some embodiments, the reduction of amyloid β plaques in an individual comprises a reduction of at least 0.05 PET standard uptake factor ("SUVr") units (e.g., at least 0.10 PET SUVr units, at least 0.15 PET SUVr units, at least 0.20 PET SUVr units, or at least 0.25 PET SUVr units). In some embodiments, the reduction of amyloid β plaques comprises a reduction of at least 0.25 PET SUVr units (e.g., at least 0.30 PET SUVr units, at least 0.35 PET SUVr units, or at least 0.40 PET SUVr units, or at least 0.45 PET SUVr units). In some embodiments, the reduction of amyloid β plaques comprises a reduction of at least 0.50 PET SUVr units (e.g., at least 0.55 PET SUVr units, at least 0.60 PET SUVr units, or at least 0.65 PET SUVr units, or at least 0.70 PET SUVr units).

[0289] In some embodiments, a reduction in amyloid β plaques occurs after treatment for about 6 months (e.g., about 24 weeks). In some embodiments, a reduction in amyloid β plaques occurs after treatment for about 12 months (e.g., about 48 weeks). In some embodiments, a reduction in amyloid β plaques occurs after treatment for about 18 months (e.g., about 72 weeks). In some embodiments, the reduction in amyloid β plaques is based on a baseline (amyloid plaque value before the start of treatment).

[0290] In some embodiments, the treatment makes the object amyloid-negative. In some embodiments, the object transitions from an amyloid-positive state to an amyloid-negative state.

[0291] In another aspect, the present invention provides a method for converting an object from amyloid-positive to amyloid-negative, comprising the following:

[0292] (a) a step of administering to an individual once every approximately 4 weeks a composition comprising about 205 mg to about 400 mg of an anti-amyloid β antibody, wherein the anti-amyloid β antibody comprises a heavy chain of SEQ ID NO. 11 and a light chain of SEQ ID NO. 12 having or without C-terminal lysine; and

[0293] (b) A step of reducing amyloid plaques in an individual so that the individual becomes amyloid-negative as determined by PET.

[0294] In another aspect, the present invention provides a method for converting an object from amyloid-positive to amyloid-negative, comprising the following:

[0295] (a) a step of administering to an individual once every approximately 2 weeks a composition comprising about 45 mg to about 200 mg of an anti-amyloid β antibody, wherein the anti-amyloid β antibody comprises a heavy chain of SEQ ID NO. 11 and a light chain of SEQ ID NO. 12 having or without C-terminal lysine; and

[0296] (b) A step of reducing amyloid plaques in an individual so that the individual becomes amyloid-negative, as determined by PET.

[0297] In some embodiments, the treatment comprises converting at least about 10% of the subjects (e.g., at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 45%, or at least about 50%) from an amyloid-positive state to an amyloid-negative state. In some embodiments, the treatment comprises converting about 10% to about 90% of the subjects (e.g., about 20% to about 90%, about 30% to about 90%, about 40% to about 90%, about 10% to about 80%, about 10% to about 70%, or about 10% to about 60%) from an amyloid-positive state to an amyloid-negative state. In some embodiments, treatment comprises converting about 30% to about 80% of the subjects (e.g., about 40% to about 80%, about 50% to about 80%, about 30% to about 70%, or about 30% to about 60%) from an amyloid-positive state to an amyloid-negative state. In some embodiments, the achievement of an amyloid-negative state occurs after about 6 months of treatment. In some embodiments, the achievement of an amyloid-negative state occurs after about 12 months of treatment. In some embodiments, the achievement of an amyloid-negative state occurs after about 18 months of treatment.

[0298] In some embodiments, treatment comprises converting at least about 5% of the subjects (e.g., at least about 10%, at least about 15%, at least about 20%, or at least about 25%) from an amyloid-positive state to an amyloid-negative state after about 6 months. In some embodiments, treatment comprises converting about 5% to about 50% of the subjects (e.g., about 10% to about 50%, about 20% to about 50%, about 10% to about 45%, or about 10% to about 40%) from an amyloid-positive state to an amyloid-negative state after about 6 months. In some embodiments, treatment includes converting about 10% to about 40% of the subjects (e.g., about 15% to about 40%, about 20% to about 40%, about 10% to about 35%, or about 10% to about 30%) from an amyloid-positive state to an amyloid-negative state after about 6 months.

[0299] In some embodiments, treatment comprises converting at least about 15% of the subjects (e.g., at least about 20%, at least about 25%, at least about 30%, or at least about 35%) from an amyloid-positive state to an amyloid-negative state after about 12 months. In some embodiments, treatment comprises converting about 15% to about 80% of the subjects (e.g., about 20% to about 80%, about 30% to about 80%, about 15% to about 75%, or about 15% to about 70%) from an amyloid-positive state to an amyloid-negative state after about 12 months. In some embodiments, treatment comprises converting about 30% to about 60% of the subjects (e.g., about 35% to about 60%, about 40% to about 60%, about 30% to about 55%, or about 30% to about 50%) from an amyloid-positive state to an amyloid-negative state after about 12 months.

[0300] In some embodiments, treatment comprises converting at least about 25% of the subjects (e.g., at least about 30%, at least about 35%, at least about 40%, or at least about 45%) from an amyloid-positive state to an amyloid-negative state after about 18 months. In some embodiments, treatment comprises converting about 25% to about 100% of the subjects (e.g., about 30% to about 100%, about 40% to about 100%, about 25% to about 95%, or about 25% to about 90%) from an amyloid-positive state to an amyloid-negative state after about 18 months. In some embodiments, treatment comprises converting about 40% to about 80% of the individuals (e.g., about 45% to about 80%, about 50% to about 80%, about 40% to about 75%, or about 40% to about 70%) from an amyloid-positive state to an amyloid-negative state after about 18 months.

[0301] In some embodiments, amyloid β plaques in an individual are measured at about 3 months, 6 months, 12 months, and / or 18 months after the start of treatment. In some embodiments, amyloid β plaques in an individual are measured about once a month, about once every 3 months, about once every 6 months, or about once a year after the start of treatment.

[0302] Cognitive decline

[0303] Cognitive decline is a characteristic of neurodegenerative diseases, including Alzheimer's disease. In Alzheimer's disease, the early stages of cognitive decline may manifest as forgetfulness. However, as the disease progresses, the impact of cognitive decline becomes more widespread, affecting executive functions, language skills, and visuospatial processing. Consequently, this can cause difficulties with decision-making, problem-solving, and independent living. Finally, Alzheimer's disease eventually leads to severe cognitive decline and dementia, causing impairment in basic memory retention and simple daily activities.

[0304] Recent evidence has demonstrated an association between a reduction in brain amyloid load and the slowing of cognitive decline in Alzheimer's patients. For example, Y. Zhang, et al., Amyloid β-based therapy for Alzheimer's disease: challenges, successes and future, See 8 Signal Transduction and Targeted Therapy 248 (2023). For example, in the Phase 2 clinical trial of donanemab, both a reduction in brain amyloid load and a slowing of cognitive decline were demonstrated. More recently, in the Phase 3 clinical trial of recanemab, both a reduction in brain amyloid plaques and a slowing of cognitive decline were also reported. In light of this recent clinical evidence, a causal relationship between amyloid plaque clearance and the slowing of cognitive decline in patients is being established.

[0305] In some embodiments, treatment for Alzheimer's disease may include slowing, stopping, and / or reversing cognitive decline in an individual. In some embodiments, treatment includes slowing, stopping, and / or reversing the decline in cognitive function. In other embodiments, treatment includes reducing (e.g., slowing or stopping) the decline in cognitive function. In other embodiments, treatment includes slowing the decline in cognitive function. In other embodiments, treatment includes stopping the decline in cognitive function. In other embodiments, treatment includes reversing the decline in cognitive function.

[0306] Various cognitive assessment tools are available and may be used in conjunction with the method of the present invention, such as, for example, the Mini-Mental State Examination (MMSE), the Alzheimer's Disease Composite Score (ADCOMS), the Alzheimer's Disease Assessment Scale - Cognitive (ADAS-COG) (e.g., including the 14-item Alzheimer's Disease Assessment Scale - Cognitive (ADAS-Cog14)), Activities of Daily Living for Mild Cognitive Impairment (ADCS-ADL-MCI), Impressions Based on Clinician Interviews (CIBI), Neurological Examination Battery (NTB), Assessment of Dementia (DAD), Clinical Dementia Assessment Scale - Box Total (CDR-SB), and Neuropsychiatric Indicator (NPI). In some embodiments, treatment involves slowing, stopping, and / or reversing cognitive decline as assessed by one of these cognitive assessment tools. In other embodiments, the method of the present invention further comprises monitoring the subject using one or more of these cognitive assessment tools.

[0307] In some embodiments, cognitive function is measured using one or more of CRD-SB, ADAS-Cog14, ADCOMS, and ADCS MCI-ADL. In some embodiments, cognitive function is measured using CRD-SB. In some embodiments, cognitive function is measured using ADAS-Cog14. In some embodiments, cognitive function is measured using ADCOMS. In some embodiments, cognitive function is measured using ADCS MCI-ADL.

[0308] In some embodiments, cognitive function is measured at multiple time points, such as before administering the dose, and at 4 weeks, 16 weeks, 6 months, and / or 1 year after administration. In some embodiments, cognitive function is measured at approximately 3 months, 6 months, 12 months, and / or 18 months after the start of treatment. In some embodiments, cognitive function is measured approximately once a month, once every 3 months, once every 6 months, or once a year after the start of treatment.

[0309] Biomarker regulation

[0310] In another aspect, the present invention provides a method for controlling a biomarker in an individual, comprising administering to an individual once every approximately 3-5 weeks a composition containing about 205 mg to about 400 mg of an anti-amyloid β antibody, wherein the anti-amyloid β antibody comprises a heavy chain of SEQ ID NO. 11 and a light chain of SEQ ID NO. 12, wherein C-terminal lysine is present or absent. In another embodiment, the present invention provides a method for controlling a biomarker in an individual, comprising administering to an individual twice every approximately 3-5 weeks (e.g., once every approximately 2 weeks) a composition containing about 100 mg to about 200 mg of an anti-amyloid β antibody, wherein the anti-amyloid β antibody comprises a heavy chain of SEQ ID NO. 11 and a light chain of SEQ ID NO. 12, wherein C-terminal lysine is present or absent.

[0311] amyloid β ratio

[0312] In some embodiments, the biomarker includes the individual's Aβ 42 / 40 ratio. Aβ 42 / Aβ 40 Ratio (e.g., amyloid β in CSF and / or blood) 42 vs. amyloid β 40 The ratio of ) has been proven to be associated with well-established AD indicators, including amyloid PET and CSF biomarkers, and lower Aβ 42 / Aβ 40 Ratios (e.g., Aβ42 / 40 ratio <0.150) correspond to a higher amyloid plaque burden. For example, C. Delaby, et al., The Aβ1-42 / Aβ1-40 ratio in CSF is more strongly associated to tau markers and clinical progression than Aβ1-42 alone , 14 Alzheimer's Research & Therapy 20 (2022); X. Chang, et al., A Review of Application of Aβ 42 / 40 Ratio in Diagnosis and Prognosis of Alzheimer's Disease See . 90 J. Alzheimer's Disease 495 (2002). For example, total plasma Aβ 42 / Aβ 40 Ratios have been proven useful for identifying individuals with mild cognitive impairment (MCI), predicting progression to dementia, and detecting underlying AD pathology revealed by FDG-PET, amyloid-PET, and CSF biomarkers. For example, V. Perez-Grijalba, et al., Plasma Aβ 42 / 40 Ratio Detects Early Stages of Alzheimer's Disease and Correlates with CSF and Neuroimaging Biomarkers in the AB255 Study Refer to . 6 J. Prevention of Alzheimer's Disease 34 (2019). That is, Aβ 42 / Aβ 40 Changes in ratios can be useful for tracking individuals throughout the entire course of treatment, for example, Aβ during treatment 42 / Aβ 40 An increase in the ratio signifies a decrease in the amyloid plaque burden.

[0313] Furthermore, a new therapeutic trend for Alzheimer's disease (AD) is to shift the target population from patients with dementia or MCI to cognitively healthy individuals at risk of AD. If β-amyloid (Aβ) positivity is a primary eligibility criterion in clinical trials, it is difficult to identify this risk group. Applying this criterion raises the screening failure rate (SRF) for this group to >70%. For example, JD Doecke, et al., Total Aβ 42 / Aβ 40 ratio in plasma predicts amyloid-PET status, independent of clinical AD diagnosis Refer to . 94 Neurology 1580 (2020). To identify this population and track them throughout treatment (e.g., prophylactic treatment), Aβ 42 / Aβ 40 Ratios can be useful.

[0314] Accordingly, the present invention provides a method for controlling the Aβ 42 / 40 ratio in an individual, comprising administering to the individual once every approximately 3 to 5 weeks a composition comprising about 205 mg to about 400 mg of an anti-amyloid β antibody, wherein the anti-amyloid β antibody comprises a heavy chain of SEQ ID NO. 11 and a light chain of SEQ ID NO. 12, with or without C-terminal lysine. In some embodiments, the control comprises increasing the Aβ 42 / 40 ratio in the individual.

[0315] In another aspect, the present invention provides a method for increasing the Aβ 42 / 40 ratio in an individual, comprising administering a composition containing about 205 mg to about 400 mg of an anti-amyloid β antibody to an individual once every about 3 to 5 weeks, wherein the anti-amyloid β antibody comprises a heavy chain of SEQ ID NO. 11 and a light chain of SEQ ID NO. 12, with or without C-terminal lysine.

[0316] In another aspect, the present invention provides a method for increasing the Aβ 42 / 40 ratio in an individual, comprising administering a composition containing about 100 mg to about 200 mg of an anti-amyloid β antibody to an individual twice every about 3 to 5 weeks (e.g., once every about 2 weeks), wherein the anti-amyloid β antibody comprises a heavy chain of SEQ ID NO. 11 and a light chain of SEQ ID NO. 12 with or without C-terminal lysine.

[0317] Methods to increase the Aβ 42 / 40 ratio in individuals, including the following:

[0318] (a) a step comprising administering to an individual once every 3-5 weeks a composition comprising about 205 mg to about 400 mg of an anti-amyloid β antibody, wherein the anti-amyloid β antibody comprises a heavy chain of SEQ ID NO. 11 and a light chain of SEQ ID NO. 12 having or without C-terminal lysine;

[0319] (b) A step of determining an Aβ 42 / 40 ratio value in a sample collected from an individual, wherein the Aβ 42 / 40 ratio value demonstrates an increase in the Aβ 42 / 40 ratio in the individual.

[0320] Methods to increase the Aβ 42 / 40 ratio in individuals, including the following:

[0321] (a) a step comprising administering to an individual twice every 3-5 weeks a composition comprising about 100 mg to about 200 mg of an anti-amyloid β antibody, wherein the anti-amyloid β antibody comprises a heavy chain of SEQ ID NO. 11 and a light chain of SEQ ID NO. 12 having or without C-terminal lysine; and

[0322] (b) A step of determining an Aβ 42 / 40 ratio value in a sample collected from an individual, wherein the Aβ 42 / 40 ratio value demonstrates an increase in the Aβ 42 / 40 ratio in the individual.

[0323] In some embodiments, the Aβ 42 / 40 ratio value increases by at least about 10% (e.g., about 15%, about 20%, about 25%, about 30%, about 35%, or about 40%). In some embodiments, the Aβ 42 / 40 ratio value increases by about 10% to about 150% (e.g., about 20% to about 150%, about 30% to about 150%, about 10% to about 120%, about 20% to about 120%, about 30% to about 120%, about 10% to about 100%, or about 20% to about 100%). In some embodiments, the Aβ 42 / 40 ratio value increases by about 25% to about 100% (e.g., about 30% to about 100%, about 35% to about 100%, about 40% to about 100%, about 25% to about 90%, about 25% to about 80%, about 35% to about 90%, or about 35% to about 80%). In some embodiments, the Aβ 42 / 40 ratio value increases relative to the baseline.

[0324] Phospho-Tau

[0325] Phospho-tau (p-tau) species have emerged as the most promising biomarkers for Alzheimer's disease. For example, S. Janelidze, et al., Head-to-head comparison of 10 plasma phospho-tau assays in prodromal Alzheimer's disease See . 19 Brain 1591-1601 (2023). Tau hyperphosphorylation is a characteristic of Alzheimer's disease pathology and induces self-aggregation of p-tau bundles in diseased individuals. For example, C.-X. Gong, K. Iqbal, Hyperphosphorylation of Microtubule-Associated Protein Tau: A Promising Therapeutic Target for Alzheimer Disease See , 15 Current Med. Chem. 2331 (2009). Phospho-tau levels (e.g., blood) are correlated with amyloid β (Aβ) pathology and disease severity, as well as with established cerebrospinal fluid (CSF) and neuroimaging biomarkers. For example, Kac, PR, et al. Diagnostic value of serum versus plasma phospho-tau for Alzheimer's disease Refer to . 14 Alz Res Therapy 65 (2022). Phospho-tau has also been demonstrated to distinguish biomarker-positive AD dementia from other types of dementia as well as from Aβ-negative controls, thus proving its specificity for AD compared to non-AD neurodegenerative diseases. Therefore, p-tau levels can provide clinical diagnostic and eligibility information for therapies, including treatments using anti-amyloid β antibodies. Furthermore, since p-tau species can be measured in blood pools that do not require lumbar puncture to obtain, unlike cerebrospinal fluid, they have the potential to contribute to expanding access to AD diagnosis globally. For example, F. Gonzalez-Ortiz, et al., Plasma phospho-tau in Alzheimer's disease: towards diagnostic and therapeutic trial applications. See 18 Mol. Neurodegeneration 18 (2023).

[0326] Several phospho-tau species, including p181-tau, p212-tau, p217-tau, p231-tau, and p235-tau, have been identified as biomarkers for Alzheimer's disease. For example, plasma values ​​of p-tau181, p-tau217, and p-tau231 have been proven to be associated with in vivo pathological hallmarks and autopsy-validated diagnoses. Some of these p-tau species are highly accurate in detecting cerebral amyloidosis and predicting whether a patient will progress to cognitive impairment and neurodegeneration. Furthermore, p-tau levels have been found to differ in subjects receiving anti-amyloid β therapy, which is associated with amyloid clearance. See, for example, F. Gonzalez-Ortiz (2023).

[0327] In some aspects, the present invention provides a method for controlling the amount of phospho-tau in an individual, comprising administering to an individual once every 3 to 5 weeks a composition containing about 205 mg to about 400 mg of an anti-amyloid β antibody, wherein the anti-amyloid β antibody comprises a heavy chain of SEQ ID NO. 11 and a light chain of SEQ ID NO. 12, with or without C-terminal lysine. In some aspects, the present invention provides a method for controlling the amount of phospho-tau in an individual, comprising administering to an individual twice every 3 to 5 weeks (e.g., once every 2 weeks) a composition containing about 100 mg to about 200 mg of an anti-amyloid β antibody, wherein the anti-amyloid β antibody comprises a heavy chain of SEQ ID NO. 11 and a light chain of SEQ ID NO. 12, with or without C-terminal lysine. In some embodiments, the control comprises increasing the amount of phospho-tau in an individual.

[0328] Accordingly, in some embodiments, the biomarker includes a phospho-tau value. In some embodiments, the phospho-tau value includes one or more of the following: a p181-tau value, a p212-tau value, a p217-tau value, a p231-tau value, and a p235-tau value. In some embodiments, the phospho-tau value includes a p181-tau value. In some embodiments, the phospho-tau value includes a p212-tau value. In some embodiments, the phospho-tau value includes a p217-tau value. In some embodiments, the phospho-tau value includes a p231-tau value. In some embodiments, the phospho-tau value includes a p235-tau value.

[0329] In some embodiments, the phospho-tau value is reduced by about 5% to about 50% (e.g., about 10% to about 50%, about 15% to about 50%, about 20% to about 50%, about 10% to about 45%, about 10% to about 40%, or about 10% to about 35%). In some embodiments, the phospho-tau value is reduced by about 10% to about 30% (e.g., about 15% to about 30%, about 20% to about 30%, about 10% to about 25%, about 15% to about 25%, or about 20% to about 30%). In some embodiments, the phospho-tau value is reduced relative to the baseline.

[0330] In some embodiments, the p181-tau value is reduced by about 5% to about 50% (e.g., about 10% to about 50%, about 15% to about 50%, about 20% to about 50%, about 10% to about 45%, about 10% to about 40%, or about 10% to about 35%). In some embodiments, the p181-tau value is reduced by about 10% to about 30% (e.g., about 15% to about 30%, about 20% to about 30%, about 10% to about 25%, about 15% to about 25%, or about 20% to about 30%). In some embodiments, the p181-tau value is reduced relative to the baseline.

[0331] In some embodiments, the p217-tau value is reduced by about 5% to about 50% (e.g., about 10% to about 50%, about 15% to about 50%, about 20% to about 50%, about 10% to about 45%, about 10% to about 40%, or about 10% to about 35%). In some embodiments, the p217-tau value is reduced by about 10% to about 30% (e.g., about 15% to about 30%, about 20% to about 30%, about 10% to about 25%, about 15% to about 25%, or about 20% to about 30%). In some embodiments, the p217-tau value is reduced relative to the baseline.

[0332] Amyloid-related imaging abnormalities (ARIA)

[0333] Treatment with amyloid β-targeted passive immunotherapy (e.g., aducanumab (Aduhelm), recanemab, donanemab, and gantenerumab, etc.) carries a significant risk of amyloid-related imaging abnormalities (ARIA). For example, M. Filippi, et al., Amyloid-Related Imaging Abnormalities and β-Amyloid-Targeting Antibodies A Systematic Review See . 79 JAMA Neurol. 291 (2022). AIRA is the most common side effect of anti-amyloid β antibodies and can be classified into ARIA-E (cerebral edema accompanied by disruption of tight endothelial junctions of the blood-brain barrier and resulting fluid accumulation) and ARIA-H (cerebral microhemorrhage (mH), small hemorrhages in the brain often accompanied by sereemia). ARIA-E may be associated with acute neuroinflammation and overloading of the perivascular scavenging system, while ARIA-H may be associated with vascular amyloid scavenging and subsequent weakening and / or rupture of small vessels. For example, H. Hampel, et al., Amyloid-related imaging abnormalities (ARIA): radiological, biological and clinical characteristics , see 146 Brain 4414 (2023).

[0334] ARIA is often asymptomatic and detectable only via MRI, but symptoms may occur in some cases. For example, ARIA has been identified as including various side effects such as headache, worsening confusion, dizziness, visual impairment, nausea, and seizures. Furthermore, to date, one or more deaths associated with ARIA-E during aducanumab treatment and one or more deaths due to ARIA-H during donanemab treatment have been reported. For example, CG Withington & RS Turner, Amyloid-Related Imaging Abnormalities With Anti-amyloid Antibodies for the Treatment of Dementia Due to Alzheimer's Disease See Frontiers in Neurology 1 (2022). The risk of ARIA-H increases with age and cerebrovascular disease, and the rate of ARIA is generally higher in ApoE4 homozygous patients (ApoE4 carriers) compared to ApoE4 non-carriers or ApoE4 heterozygous patients. Additionally, an increased risk of ARIA-E was observed at the start of treatment and was consistent with higher doses and microhemorrhages >4 on baseline MRI.

[0335] In some embodiments, the treatment includes an ARIA-E risk of less than about 70% (e.g., less than about 65%, less than about 60%, less than about 55%, or less than about 50%). In some embodiments, the treatment includes an ARIA-E risk of less than about 45% (e.g., less than about 40%, less than about 35%, less than about 30%, less than about 25%, or less than about 20%). In some embodiments, the treatment includes an ARIA-E risk of less than about 15% (e.g., less than about 14%, less than about 13%, less than about 12%, less than about 11%, or less than about 10%).

[0336] In some embodiments, the proportion of individuals experiencing symptomatic ARIA-E upon treatment is less than about 45% (e.g., less than about 40%, less than about 35%, less than about 30%, less than about 25%, or less than about 20%). In some embodiments, the proportion of individuals experiencing symptomatic ARIA-E upon treatment is less than about 15% (e.g., less than about 14%, less than about 13%, less than about 12%, less than about 11%, or less than about 10%). In some embodiments, the proportion of individuals experiencing symptomatic ARIA-E upon treatment is less than about 10% (e.g., less than about 9%, less than about 8%, less than about 7%, less than about 6%, or less than about 5%).

[0337] In some embodiments, the ARIA-E risk is a severe ARIA-E risk. In some embodiments, the ARIA-E risk is a moderate+ ARIA-E risk. In some embodiments, the ARIA-E risk is a moderate ARIA-E risk. In some embodiments, the ARIA-E risk is a mild+ ARIA-E risk. In some embodiments, the ARIA-E risk is a mild ARIA-E risk. In some embodiments, the ARIA-E risk includes a FLAIR high-intensity signal risk at more than one location, each FLAIR location being 5-10 cm in scale. In some embodiments, the ARIA-E risk includes a FLAIR ultra-high-intensity signal risk at one location, the FLAIR location being 5-10 cm in scale. In some embodiments, the risk of ARIA-E includes the risk of FLAIR ultra-high intensity signals at one or more locations, each FLAIR location has a size of less than 5 cm, and each FLAIR location is localized to the sulcus, cortex, and / or subcortical white matter. In some embodiments, the risk of ARIA-E includes the risk of FLAIR ultra-high intensity signals at one location, the FLAIR location has a size of less than 5 cm, and the FLAIR location is localized to the sulcus, cortex, and / or subcortical white matter.

[0338] In some embodiments, the individual is an APOE4 homozygous individual, and the treatment includes an ARIA-E risk of less than about 75% (e.g., less than about 70%, less than about 65%, less than about 60%, less than about 55%, or less than about 50%) in the APOE4 homozygous individual. In some embodiments, the individual is an APOE4 homozygous individual, and the treatment includes a symptomatic ARIA-E risk of less than about 30% (e.g., less than about 25%, less than about 20%, or less than about 15%) in the APOE4 homozygous individual.

[0339] In some embodiments, the individual is an APOE4 heterozygous individual or an APOE4 negative individual, and the treatment includes an ARIA-E risk of less than about 45% (e.g., less than about 40%, less than about 35%, less than about 30%, less than about 25%, or less than about 20%) in the APOE4 heterozygous individual or the APOE4 negative individual. In some embodiments, the individual is an APOE4 heterozygous individual or an APOE4 negative individual, and the treatment includes a symptomatic ARIA-E risk of less than about 15% (e.g., less than about 14%, less than about 13%, less than about 12%, less than about 11%, or less than about 10%) in the APOE4 heterozygous individual or the APOE4 negative individual. In some embodiments, the risk of ARIA-E is the risk after treatment for about 6 months (e.g., about 24 weeks). In some embodiments, the risk of ARIA-E is the risk after treatment for about 12 months (e.g., about 48 weeks). In some embodiments, the risk of ARIA-E is the risk after treatment for about 18 months (e.g., about 72 weeks).

[0340] In some embodiments, the treatment includes an ARIA-H risk of less than about 25% (e.g., less than about 22%, less than about 20%, less than about 18%, or less than about 16%). In some embodiments, the treatment includes an ARIA-H risk of less than about 15% (e.g., less than about 14%, less than about 13%, less than about 12%, less than about 11%, or less than about 10%).

[0341] In some embodiments, the risk of ARIA-H is a severe risk of ARIA-H. In some embodiments, the risk of ARIA-H is a moderate risk of ARIA-H. In some embodiments, the risk of ARIA-H is a mild risk of ARIA-H. In some embodiments, the risk of ARIA-H includes a risk of ≤4 cases of new microhemorrhage and / or a risk of ≤1 localized area of ​​superficial hemolysis. In some embodiments, the risk of ARIA-H includes a risk of ≤9 cases of new microhemorrhage and / or a risk of ≤2 localized areas of superficial hemolysis.

[0342] In some embodiments, the risk of ARIA-H is the risk after treatment for about 6 months (e.g., about 24 weeks). In some embodiments, the risk of ARIA-H is the risk after treatment for about 12 months (e.g., about 48 weeks). In some embodiments, the risk of ARIA-H is the risk after treatment for about 18 months (e.g., about 72 weeks).

[0343] In some embodiments, the number of individuals experiencing ARIA-H during treatment is achieved to be less than about 25% (e.g., less than about 22%, less than about 20%, less than about 18%, or less than about 16%). In some embodiments, the number of individuals experiencing ARIA-H during treatment is achieved to be less than about 15% (e.g., less than about 14%, less than about 13%, less than about 12%, less than about 11%, less than about 10%, less than about 9%, less than about 8%, less than about 7%, less than about 6%, or less than about 5%).

[0344] In some embodiments, ARIA-E and / or ARIA-H levels (e.g., %) of subjects suffering from ARIA-E and / or ARIA-H are ARIA-E and / or ARIA-H levels after treatment for about 6 months (e.g., about 24 weeks). In some embodiments, ARIA-E and / or ARIA-H levels are ARIA-E and / or ARIA-H levels after treatment for about 12 months (e.g., about 48 weeks). In some embodiments, ARIA-E and / or ARIA-H are ARIA-E and / or ARIA-H levels after treatment for about 18 months (e.g., about 72 weeks).

[0345] In some embodiments, the subject does not experience symptomatic ARIA as evaluated by magnetic resonance imaging (MRI). In some embodiments, the subject does not experience symptomatic ARIA-E as evaluated by MRI. In some embodiments, the subject does not experience symptomatic ARIA-H as evaluated by MRI.

[0346] Treatable patients

[0347] The present invention includes the treatment and / or prevention of amyloid-producing diseases, such as Alzheimer's disease, by administering the antibody, fragment, and pharmaceutical composition of the present invention. Furthermore, the present invention provides the use of an anti-amyloid β antibody to achieve a beneficial therapeutic response in a patient (e.g., induction of Aβ phagocytosis, reduction of plaque burden, inhibition of plaque formation, alleviation of neuropathy, neutralization of soluble toxic Aβ species, improvement of cognitive function and / or reversal of cognitive decline, treatment or prevention). The present invention also relates to the use of the antibodies and fragments disclosed herein in the manufacture of pharmaceuticals for the treatment or prevention of amyloid-producing diseases, for example, using the administration regimen of the present invention, for example, the use of the antibodies and fragments disclosed herein in the manufacture of pharmaceuticals for the treatment or prevention of Alzheimer's disease by administering an anti-amyloid β antibody or a fragment thereof to a patient in a therapeutically effective amount (e.g., 200 mg to 400 mg about once every 4 weeks, 300 mg about once every 4 weeks, 350 mg about once every 4 weeks, 400 mg about once every 4 weeks, or 200 mg about once every 2 weeks). Such a method is useful for preventing or treating Alzheimer's disease in human patients.

[0348] Treatable patients encompass not only asymptomatic individuals at risk of the disease but also patients currently exhibiting symptoms. In the case of Alzheimer's disease, potentially anyone who lives a sufficiently long life carries a risk of the disease. Therefore, this method involves administering the treatment prophylactically to the general public without the need to assess the risk of the target patients. This method is particularly useful for individuals with a known genetic risk of Alzheimer's disease. Such individuals include those with relatives who have experienced the disease, and those with a risk identified by genetic or biochemical marker analysis. Genetic risk markers for Alzheimer's disease include mutations in the APP gene, specifically mutations at positions 717 and 670 and 671, referred to as Hardy and Swedish mutations, respectively. Other risk markers include mutations in the presenilin gene PS1 and PS2, as well as ApoE4, a family history of AD, hypercholesterolemia, or atherosclerosis. Individuals currently suffering from Alzheimer's disease can be identified by the presence of the aforementioned risk factors as well as by characteristic dementia. In addition, various diagnostic tests can also be used to identify individuals with AD. These include measuring CSF tau and Aβ42 levels. An increase in tau levels and a decrease in Aβ42 levels indicate the presence of AD. Individuals with Alzheimer's disease can also be diagnosed using the ADRDA criteria, as discussed in the Examples section.

[0349] Treatment for asymptomatic patients may be initiated at any age (e.g., 10, 20, or 30). However, typically, treatment does not need to be started until the patient reaches 40, 50, 60, or 70 years of age. Treatment typically involves multiple administrations over a period of time. Treatment can be monitored by evaluating antibody levels over time. If the response is poor, a booster is indicated. In the case of a potential patient with Down syndrome, treatment may be initiated before birth by administering the therapeutic substance to the mother, or immediately after birth.

[0350] APOE4 status

[0351] Individuals possessing the apolipoprotein E ε4 allele (APOE4) have an increased risk of ARIA during treatment with anti-amyloid therapy. For example, C. Dagostin, et al., Efficacy of anti-amyloid-beta monoclonal antibody therapy in early Alzheimer's disease: a systematic review and meta-analysis See NEUROLOGICAL SCIENCES (2023). Individuals homozygous for APOE4 have the highest risk levels, partly due to an increased burden of aggregated beta-amyloid within cerebral microvessels. Furthermore, ongoing studies suggest that APOE4 carriers exhibit higher perivascular Aβ scavenging during treatment, leading to higher vascular permeability and extravasation of fluids and red blood cells, thereby implying a higher incidence of ARIA-E and ARIA-H. For example, M. Roytman, et al., Amyloid-Related Imaging Abnomaliities: An Update See . 220 Am. J. Roentgenology 562 (2023).

[0352] In some embodiments, the entity is an APOE4 heterozygous entity or an APOE4 negative entity. In some embodiments, the entity is an APOE4 homozygous entity. In some embodiments, the entity is an APOE4 heterozygous entity. In some embodiments, the entity is an APOE4 negative entity (non-carrier).

[0353] In vivo detection

[0354] In another aspect, the present invention provides a method for detecting amyloid plaques and deposits in patients who have amyloid-producing diseases or are at risk of developing them. Such a method is useful for diagnosing or verifying amyloid-producing diseases or susceptibility thereto. For example, this method can be used in patients with symptoms of dementia, where the observation of abnormal amyloid deposits is highly likely to indicate Alzheimer's disease. This method can also be used in asymptomatic patients. The presence of abnormal amyloid deposits implies susceptibility to future symptomatic disease.

[0355] In some embodiments, the present method comprises administering the antibody or a fragment thereof of the present invention to an individual / patient and detecting the antibody or a fragment thereof bound to Aβ.

[0356] Antibodies and / or fragments thereof may be administered via any suitable means to deliver them to the tissue to be visualized, for example, by direct administration to the brain via intravenous injection into the patient's body or via intracranial injection. The dosage of antibodies and / or fragments thereof may include therapeutic doses, subtherapeutic doses, or therapeutic excess doses. In some embodiments, the antibody or fragment thereof is labeled with a fluorescent label, a paramagnetic label, or a radioactive label. The selection of the label depends on the detection means. For example, a fluorescent label is suitable for visual detection. The use of a paramagnetic label is suitable for detection by tomography without surgical intervention. In some embodiments, the radioactive label is detected using positron emission tomography (PET) or single-photon emission computed tomography (SPECT).

[0357] In another aspect, the present invention provides a method for measuring the efficacy of treatment in an individual being treated for an amyloid-producing disease. In some embodiments, the primary amyloid plaque level in an individual is measured prior to treatment by administering the antibody or a fragment thereof of the present invention and detecting the primary content of the antibody or fragment thereof bound to Aβ in the individual. Then, the therapeutic agent may be administered to the individual, followed by measuring the secondary amyloid plaque level in the individual and detecting the antibody or fragment thereof bound to Aβ in the individual. In some embodiments, a decrease in the amyloid plaque level signifies a positive treatment response, and in some embodiments, no change in the amyloid plaque level or a slight increase in the amyloid plaque signifies a positive treatment response. In some embodiments, the level of amyloid plaque may be measured by utilizing the method for detecting amyloid plaque described herein.

[0358] In some embodiments, the diagnosis of an amyloid-producing disease may be made, for example, by comparing a measured primary level (i.e., baseline) with a subsequent secondary level of amyloid plaques in the subject in terms of the number, size, and / or intensity of the labeled locations. A temporal increase indicates disease progression, no change indicates change, and a very low number or intensity of temporal amyloid plaques indicates remission.

[0359] The material of the present invention may also be administered in combination with other materials that are at least partially effective in treating amyloid-producing diseases. In the case of Alzheimer's and Down syndromes in which amyloid is deposited in the brain, the material of the present invention may also be administered in combination with other materials that enhance the passage of the material of the present invention across the blood-brain barrier.

[0360] Examples

[0361] The following embodiments are incorporated to illustrate the methods described herein. Specific aspects of the following embodiments are described in terms of techniques and procedures that the co-inventors of the invention have identified or are considering to work well in the practice described herein. In light of the invention and the general level of the art, those skilled in the art will understand that the following embodiments are intended as simple examples and that various changes, modifications, and variations may be adopted without departing from the scope of the invention.

[0362] Example 1. Reduction of amyloid plaques in a patient

[0363] To reduce amyloid plaques associated with the inhibition, reduction, and / or reversal of symptoms of Alzheimer's disease, an anti-Aβ antibody (or its antigen-binding fragment), such as one or more of the antibodies described herein, is administered to a patient in a pharmaceutically effective amount.

[0364] Patient: Individuals suspected of or diagnosed with amyloid plaque-related diseases, such as Alzheimer's disease, are selected for treatment with anti-Aβ antibodies.

[0365] Treatment: Administer 300 mg of the anti-Aβ antibody h2731 subcutaneously to the patient approximately once every 4 weeks. Administer 350 mg of the anti-Aβ antibody h2731 subcutaneously to the patient approximately once every 4 weeks. Administer 400 mg of the anti-Aβ antibody h2731 subcutaneously to the patient approximately once every 4 weeks. Administer 200 mg of the anti-Aβ antibody h2731 subcutaneously to the patient approximately once every 4 weeks.

[0366] The reduction of plaque and the improvement of symptoms of Alzheimer's disease can be measured as described herein.

[0367] Patients with Alzheimer's disease who receive 300 mg, 350 mg, or 400 mg of the anti-Aβ antibody h2731 subcutaneously once every approximately 4 weeks are treated by a reduction in amyloid plaque burden as measured by PET imaging. Alternatively, patients with Alzheimer's disease who receive 200 mg of the anti-Aβ antibody h2731 subcutaneously once every approximately 2 weeks are treated by a reduction in amyloid plaque burden as measured by PET imaging. Patients are further treated by a slowing of cognitive decline as measured by the methods described herein.

[0368] Example 2. Phase 1 single-dose escalation study to evaluate the safety, tolerability, immunogenicity, and pharmacokinetics of h2731

[0369] This example describes a Phase 1, randomized, double-blind, placebo-controlled, single-dose escalation (SAD) study to evaluate the safety, tolerability, and immunogenicity of h2731 at doses of 200 mg and 400 mg. The purpose of this study is to determine the plasma pharmacokinetic (PK) profile of h2731 in healthy volunteers (HV) and patients with AD, particularly in patients with AD whose parenchymal amyloid load has been confirmed by molecular imaging. AD subjects must meet the criteria of the National Institute on Aging and Alzheimer's Association (NIA-AA) study criteria and guidelines (McKhann, 2011) for AD or mild cognitive impairment due to AD (MCI) (Albert, 2011).

[0370] Test basis

[0371] Preclinical studies using transgenic mice that overproduce Aβ have demonstrated that antibodies targeting the Aβ N-terminus can enter the brain and reduce amyloid deposits in brain tissue and cerebrovascular structures (Bard, 2000). Clinical evidence shows that monoclonal antibodies targeting N-terminal amyloid can clear Aβ aggregates from the brain, reduce deposition, and alleviate cognitive decline (Sevigny, 2016; Swanson, 2021; Aduhelm USPI, 2021).

[0372] Preclinical studies show that h2731 rapidly and reliably removes Aβ plaques by enhancing microglia-mediated scavenging mechanisms. For example, refer to U.S. Patent 11,440,953. These data suggest that h2731 has the potential to slow clinical decline in AD patients. In Phase 1 clinical trials, the 200 mg and 400 mg doses are based on the CNS fraction occupancy modeled with the clinical exposure prediction at these doses.

[0373] Test purpose

[0374] The primary objective of this study is to evaluate the safety and tolerability of h2731 upon single administration, which includes (1) overall safety, tolerability, and immunogenicity in all subjects, and (2) target-related safety and tolerability in subjects in whom the presence of parenchymal amyloid was confirmed.

[0375] The secondary objective of this study is to determine the pharmacokinetic (PK) profile and cerebrospinal fluid (CSF) PK profile of h2731 after SC administration as a single dose.

[0376] Test design

[0377] Figure 1 is a diagram schematically illustrating the study plan. The study will include at least three dose cohorts (AD Cohort 1, AD Cohort 2, and AD Cohort 3) consisting of individuals with biologically confirmed AD. The study additionally includes two healthy volunteers ("HV") cohorts (HV Cohort 1 and HV Cohort 2). These four cohorts include: AD Cohort 1 (70 mg), AD Cohort 2 (200 mg), AD Cohort 3 (400 mg), HV Cohort 1 (70 mg), and HV Cohort 2 (200 mg), and the corresponding dose is administered subcutaneously ("SC") to each cohort.

[0378] After initial field observation, subjects are returned for four follow-up visits over approximately 12 weeks, during which safety assessment and PK collection are completed. For selected cohorts (HV Cohort A and HV Cohort 2), CSF collection via lumbar puncture may also be performed on days 3 and 29. MRI scans are performed on all subjects on day 0, and additional MRI scans are performed on AD cohorts (AD Cohort 1, AD Cohort 2, and AD Cohort 3) to evaluate ARIA rates.

[0379] Evaluation indicators

[0380] The primary evaluation indicators include the following:

[0381] - Safety and tolerability based on adverse event ("AE") reports (incidence of AE, SAE, and h2731-related AE), ECG, clinical laboratory tests, vital signs, and physical examination

[0382] - Immunogenicity measured by verifying the presence of ADA in plasma

[0383] - Amyloid-related imaging abnormalities (ARIA-H and ARIA-E) and other new radiological findings

[0384] Secondary evaluation indicators include the following:

[0385] - Plasma PK of h2731

[0386] - h2731's CSF PK

[0387] - C of h2731 at each time of sample collection obs

[0388] Inclusion criteria

[0389] Each cohort has a Body Mass Index (BMI) of 18.0 to 32.0 kg / m² 2 It includes approximately 8 individuals.

[0390] AD objects are selected based on selection criteria including the following:

[0391] (a) When diagnosed with confirmed or suspected AD based on evidence of pathophysiological processes of AD according to the National Institute on Aging and Alzheimer's Association (NIA-AA) criteria (McKhann et al., Alzheimers Dement., 7(3):264-9, 2011) or likely to be AD according to NIA-AA criteria (Albert et al., Alzheimers Dement., 7(3):270-79, 2011);

[0392] (b) If there are gradual and progressive changes in memory function reported by the subject or test partner for 6 months or more;

[0393] (c) if the screening Mini-Mental State Examination (MMSE) score is 18 or higher; and

[0394] (d) When there is evidence of an AD pathological process, as confirmed by an amyloid PET scan.

[0395] Exclusion criteria

[0396] Entities are selected based on exclusion criteria including the following. Entities must not fall under any of the exclusion criteria, including the following criteria:

[0397] (a) Impaired blood coagulation (prothrombin time 1.2 x ULN) or other coagulopathy

[0398] (b) history of severe, clinically significant (persistent neurological deficits or structural brain damage) central nervous system (CNS) trauma (e.g., cerebral contusion) or epilepsy

[0399] (c) Any contraindications to MRI studies, including claustrophobia, the presence of contraindicated metal (ferromagnetic) implants, or pacemakers.

[0400] (d) If anticoagulants were taken within 3 months prior to screening and there is no plan to initiate them prior to randomization, or if there is a history of prolonged bleeding after minor trauma. Note: Low-dose aspirin is permitted (max. 162 mg / day).

[0401] (e) History or presence of posterior reversible encephalopathy syndrome (PRES) (Fugate, et al, Posterior reversible encephalopathy syndrome: clinical and radiological manifestations, pathophysiology, and outstanding questions. Lancet Neurol. 2015;14(9):914-25)

[0402] Clinical laboratory evaluation

[0403] Performs laboratory analyses for hematology, clinical chemistry, coagulation, urinalysis, plasma, biomarkers, and CSF. Performs central and regional pregnancy tests.

[0404] Brain MRIs are read locally, and scans are submitted to a central MRI provider for final MRI eligibility determination and to provide a central evaluation of baseline ARIA findings. MRIs must be performed using a 1.5 or 3.0-T scanner, and the same scanner must be used for individual subjects throughout the study period. The first MRI is performed during the screening period as a baseline measure to confirm structural brain imaging-based eligibility criteria. MRI scans include, without restriction, the following sequences: T2-weighted FLAIR, 2-dimensional (2D) T2*-weighted Gradient Echo (GRE), or Sensitivity Weighted Imaging (SWI); Diffusion Weighted, 3-dimensional (3D) T1-weighted GRE. MRI scans are evaluated and read by a central MRI reader, who provides diagnostic readings and evaluations of MRI outcome measures. MRI data (Day 29 MRI data from all subjects and all other available MRI and safety data) are provided for DSMB availability to validate the h2731 dose.

[0405] When performing CSF analysis in a cohort, perform LP twice: the first LP on Day 3 (48 hours after administration of the test drug) and the second LP on Day 29. Analyze the CSF to determine the level of h2731. CSF samples with clear evidence of blood contamination should not be used for PK evaluation. CSF analysis may also, to a non-restrictive extent, include standard assays including pressure, color, glucose, protein, lactate, red blood cells, and white blood cells.

[0406] Amyloid PET imaging is used for the biological confirmation of an AD diagnosis as evidence of the presence of pathological hallmark findings of neuritic plaques composed of β-amyloid. Radiolabeled compounds (tracers) with high affinity for aggregated forms of β-amyloid can provide in vivo evidence of β-amyloid. Three radioligands are used for screening purposes: [18F]florbetapyr / AV45 (Amyvid), [18F]flutemetamol (Vizamyl), and [18F]florbetaben (Neuraceq). Amyloid PET imaging is performed on individuals in cohorts 1–4 to biologically confirm an AD diagnosis. Positive PET scans using [18F]florbetapir / AV45, [18F]flutemetamol, or [18F]florbetaben obtained outside the study protocol within 18 months prior to the first screening visit may be allowed to validate patient selection upon confirmation by central reading.

[0407] APOE4 status (e.g., APOE4 / APOE4, APOE4 / APOE3, APOE3 / APOE3, APOE4 / APOE2, APOE3 / APOE2) is determined by central evaluation in individuals registered in cohorts 1 to 4.

[0408] Additional evaluation

[0409] The Cogstate CBB (Maruff, 2013) is administered to subjects at the time of the first screening visit (-72 to -8 days). The CBB is a simple (approximately 15-minute) computer-based cognitive test battery designed to measure memory, working memory, psychomotor function, and attention. The CBB has been proven to be a sensitive tool for detecting AD-related cognitive decline in healthy older adults and adults with amnestic mild cognitive impairment (Darby, 2002; Lim, 2013), as well as a sensitive tool for detecting cognitive improvement resulting from cognitive-enhancing drug treatment (Davison, 2011; Jaeger, 2011; Nathan, 2013).

[0410] The MMSE (Folstein, 1975) is administered to the individual at the time of the first screening visit (-72 to -8 days) prior to the Cogstate CBB evaluation to determine whether the individual meets the entry criteria for cognitive impairment.

[0411] Plasma samples are collected from subjects to investigate biomarkers for AD pathology, including biomarkers associated with tau pathology such as Aβ42 / 40 and total tau, p181-tau, and p217-tau, without restriction.

[0412] PK samples for plasma and CSF h2731 are collected from the individual.

[0413] Measure plasma anti-H2731 antibody levels (antibody detection by electrochemiluminescence analysis (ECLIA)).

[0414] ARIA Assessment: Individuals with pre-existing angioedema (ARIA-E), >4 microhemorrhages, or >1 site of superficial iron deposition (ARIA H) based on screening MRI scans are excluded. In addition to scheduled MRIs, unscheduled MRIs may be performed at the investigator's discretion if ARIA is suspected based on the onset of symptoms. MRIs are planned to be performed for all individuals prior to administration of the investigational drug (baseline), and for AD individuals at visits on days 29 and 85 (28 and 84 days after administration, respectively), to evaluate, classify, and record radiological evidence of ARIA.

[0415] Example 3: Phase 1 multiple dose escalation study to evaluate the safety, tolerability, immunogenicity, pharmacokinetics, and pharmacodynamics of h2731 in subjects with Alzheimer's disease

[0416] This embodiment describes a Phase 1, randomized, double-blind, placebo-controlled, multiple dose escalation (MAD) study to evaluate the safety, tolerability, immunogenicity, PK, and pharmacodynamic (PD) effects of h2731 in patients with AD. Figure 2 is a diagram schematically illustrating the study plan.

[0417] Test purpose

[0418] As explained in more detail below, the primary objective of this study is to evaluate the safety, tolerability, and immunogenicity of h2731 after multiple SC administrations. The secondary objective of this study is to determine the PK profile of h2731 after multiple SC administrations, to determine the plasma and CSF PK profiles of h2731 after multiple SC administrations, and to evaluate the PD effect of h2731 on brain amyloid plaque deposition after multiple SC administrations. The exploratory objective of this study is to evaluate the PD effect of h2731 on blood and CSF biomarkers after multiple SC administrations and to evaluate ARIA findings according to apolipoprotein E4 (APOE4) status.

[0419] test group

[0420] This study consists of two parts, each part investigating different populations: Group A, AD individuals who are heterozygous or non-carriers of the apolipoprotein E4 (APOE4) allele (referred to as the non-homozygous population) and Group B, AD individuals who are homozygous for APOE4 (referred to as the homozygous population). The h2731 dose levels to be investigated are the same for the non-homozygous (Group A) and homozygous (Group B) populations.

[0421] Apolipoprotein E (APOE) genotype status has been demonstrated to influence the incidence of ARIA following treatment with anti-Aβ antibodies (Arrighi, 2016; Ketter, 2017; Muralidharan, 2022) as well as the onset of AD (Corder, 1993; van Duijn, 1994). The incidence of ARIA is dose-dependent, and most cases occur within the first few months after the initiation of anti-Aβ treatment (Muralidharan, 2022). AD patients with one copy of the APOE4 allele may have an increased risk of anti-Aβ antibody-mediated ARIA compared to non-APOE4 carriers, although the demonstrated risk across clinical trials has been somewhat inconsistent. However, patients with APOE4 homozygous (carrying two alleles) consistently exhibit a higher incidence of ARIA compared to both APOE4 heterozygous and non-carrying patients.

[0422] Basis for capacity selection

[0423] The proposed 300 mg, 350 mg, and 400 mg doses (subcutaneously administered once a month, each) and 200 mg dose (subcutaneously administered twice a month) were based on an analysis of estimated target binding (fractional occupancy [fOcc]) levels attributable to simulated clinical drug exposure levels at these doses, balancing predicted effective exposure with the potential for ARIA induction. These doses are also supported by the results of nonclinical toxicity studies completed with repeated administration for up to 3 months and are validated based on some information obtained from the single dose escalation (SAD) study of Example 2, including the following:

[0424] - All safety and tolerability data up to 15 days in selected cohorts administered 200 mg and / or 400 mg;

[0425] - PK data up to day 29 in selected cohorts administered 70 mg, 200 mg, and / or 400 mg (approximately 8 individuals per cohort; 6 administered h2731, 2 administered placebo); and

[0426] - MRI results at day 29 in the selected cohort administered 70 mg and / or 200 mg (approx. 12 subjects; 9 administered h2731, 3 administered placebo).

[0427] Test design

[0428] A Phase 1, randomized, double-blind, placebo-controlled, multiple dose escalation study is conducted on two dose cohorts of biologically confirmed AD subjects to evaluate the safety, tolerability, immunogenicity, PK, and PD of h2731.

[0429] The study consists of two parts, and each part evaluates different populations: Group A, AD individuals who are heterozygous or non-carriers for the APOE4 allele, and Group B, AD individuals who are homozygous for APOE4. Two dose cohorts for each group are described in Table 4. A cohort treating patients with 200 mg once every two weeks (twice a month) may be evaluated as a fourth cohort (e.g., cohorts A-4 and / or B-4) or instead of any of the cohorts described in Table 4.

[0430] Table 4

[0431] Army A: APOE4 heterozygous (e.g., E3 / E4) or APOE4 non-carrier (e.g., E2 / E3, E2 / E2) Group B: APOE4 homozygous (i.e., E4 / E4) Cohort A-1: 300 mg Cohort B-1: 300 mg Cohort A-2: 350 mg Cohort B-2: 350 mg Cohort A-3: 400 mg Cohort B-3: 400 mg

[0432] AD individuals who are heterozygous or non-carriers for the APOE4 allele are placed in Group A; individuals who are homozygous for APOE4 are placed in Group B.

[0433] For each group A cohort, subjects are randomized to h2731 or placebo in a 3:1 ratio. Randomization is classified according to APOE4 retention status (APOE4 heterozygous or APOE4 non-retainer).

[0434] For each group B cohort, approximately 12 subjects are randomized to h2731 or placebo in a 3:1 ratio: 9 subjects are administered h2731 and 3 subjects are administered placebo.

[0435] Treatment period

[0436] The investigational drug (300 mg, 350 mg, or 400 mg) is administered every 4 weeks (or 200 mg every 2 weeks) for a total of up to 6 doses, starting on Day 1. The subjects receive the first subcutaneous dose of the investigational drug (h2731 or placebo) on Day 1. Blood samples are drawn from the subjects for PK, anti-drug antibody (ADA), and biomarker (BM) analysis, as well as safety assessments including adverse event (AE) monitoring, clinical laboratory tests, vital signs, physical examination, and electrocardiogram (ECG). Subjects are discharged from the study site 8 hours after administration, following the completion of scheduled post-administration evaluations.

[0437] Continue administration every 4 weeks. Complete blood collection for safety assessment and PK, ADA, and BM analysis. MRI findings evaluated by a central reader must be reviewed prior to administration to assess the presence of ARIA.

[0438] After the last administration of the test drug, the subject returns to the study site for a 24-week (169-day) end-of-treatment (EOT) visit to complete a safety assessment, blood collection for PK, ADA, and BM analysis, and amyloid PET imaging evaluation.

[0439] For subjects participating in selective CSF collection, a CSF collection schedule is planned within 1 to 5 days after the imaging visit (MRI and PET) at 24 weeks (169 days). The subject may be discharged after 4 hours of observation.

[0440] Capacity Increase / Capacity Decision

[0441] The dose level for each cohort is determined by a limited number of non-blinded sponsor representatives based on a review and interpretation of all available safety, tolerability, PD, and PK information for h2731.

[0442] Safety and tolerability data are evaluated continuously and periodically throughout the entire course of this study and the SAD study of Example 2. When minimum data requirements are met, safety and tolerability data are evaluated to provide recommendations for cohort enrollment decisions.

[0443] Discontinuation of administration at the individual level

[0444] Administration depends on the presence and severity of amyloid-related imaging findings associated with underlying angioedema (ARIA-E) or hemorrhage (ARIA-H) observed prior to the administration of h2731 or placebo, respectively, based on MRI findings evaluated by a central MRI reader and potential ARIA symptoms reported by the subject or observed by the investigator.

[0445] MRI visits should be scheduled up to 7 days prior to each administration visit. The classification of ARIA severity based on radiological findings is summarized in Table 5. MRI results must be reviewed prior to administration.

[0446] Table 5

[0447] ARIA type Mild Mild+ moderate Moderate+ severe ARIA-E FLAIR high signal intensity localized to folds or cortical / subcortical white matter at one site; scale <5cm FLAIR high signal intensity localized to cortical / subcortical white matter at 1 site; scale <5cm FLAIR high signal intensity at 1 location; scale 5-10cm FLAIR high signal intensity at 1 location; scale 5-10cm each FLAIR high signal intensity measured >10 cm, often accompanied by occurrence in prominent subcortical white matter and / or folds. One or more distinct sites of involvement may be observed. Mild moderate severe ARIA-H / Microbleeding ≤4 new microhemorrhages a 5-9 new microhemorrhages a ≥10 new microhemorrhages a ARIA-H superficial iron deposition 1 superficial iron deposition lesion 2 superficial iron deposition lesions Superficial iron deposition lesions >2 locations ARIA-E = Amyloid-related imaging findings associated with underlying angioedema; ARIA-H = Amyloid-related imaging findings associated with intracerebral hemorrhage; FLAIR = Fluid-attenuated inversion recovery a. New microbleeds were cumulatively calculated compared to the screening visit. Source: Modified from Aduhelm USPI, 2021 and Bracoud, 2017

[0448] All intracranial hemorrhages exceeding 1 cm are considered radiologically severe.

[0449] Administration may be discontinued based on moderate and / or severe ARIA-E findings, depending on the clinical or radiological severity of ARIA-E. In the event of any emerging ARIA-H findings (microhemorrhage or superficial iron deposition), excluding asymptomatic or mild ARIA-H, administration of h2731 should be discontinued in the affected individual.

[0450] If administration is discontinued, all planned administrations should be omitted, and follow-up visits should continue as scheduled. If the individual is able to resume treatment (Section 7.11.3), administration of h2731 or placebo should be resumed at the next scheduled time of administration at the same dose. Missed administrations should not be replaced.

[0451] Evaluation indicators

[0452] The primary evaluation indicators include the following:

[0453] - Safety and tolerability based on AE reporting (incidence of AE, SAE, and h2731-related AE), vital signs, physical and neurological examination, 12-lead ECG, and clinical laboratory tests

[0454] - Injection site reaction based on researcher evaluation

[0455] - MRI findings regarding the nature, frequency, severity, and timing of ARIA, including the incidence of symptomatic ARIA-E and / or ARIA-H; the incidence of isolated ARIA-E (isolated ARIA-E without ARIA-H) and isolated ARIA-H (isolated ARIA-H without ARIA-E); and the incidence of co-occurring ARIA-E and ARIA-H,

[0456] - Presence of ADA in plasma

[0457] Secondary evaluation indicators include the following:

[0458] - Plasma PK of h2731

[0459] - Maximum observed concentration (Cmax)

[0460] - Time taken to reach the highest measured concentration (Tmax)

[0461] - Last concentration point before next administration (Ctrough)

[0462] - Area under the concentration-time curve from time 0 to infinity (AUC0-∞)

[0463] - Area under the plasma concentration-time curve during the administration interval (AUC0-tau)

[0464] - Accumulation of Area Under the Plasma Concentration-Time Curve (RAUC) over one dosing interval from the first to the last dose

[0465] - Apparent volume of distribution (Vd)

[0466] - Average concentration during the administration interval (Cavg)

[0467] - Apparent Total Body Elimination Rate (CL / F)

[0468] - h2731 CSF PK (CSF collection option)

[0469] h2731 concentrations observed in plasma and CSF at each time of CSF collection (Cobs)

[0470] - Changes in brain amyloid plaque deposition measured by amyloid positron emission tomography (PET) scan at 24 weeks (169 days) compared to baseline

[0471] Exploratory evaluation metrics include the following:

[0472] - Non-restrictive changes in blood-based biomarkers from baseline to 24 weeks (169 days), including Aβ42 / 40 ratio, p181-tau, and p217-tau

[0473] - Non-restrictive changes in CSF biomarkers from baseline to 24 weeks (169 days), including Aβ42 / 40 ratio, p181-tau, and p217-tau (applicable only to subjects participating in selective CSF collection)

[0474] - MRI findings regarding the nature, frequency, severity, and timing according to APOE4 status (APOE4 heterozygous or APOE4 non-carrier), including the incidence of symptomatic ARIA-E and / or ARIA-H; the incidence of isolated ARIA-E (ARIA-E alone without ARIA-H) and isolated ARIA-H (ARIA-H alone without ARIA-E); and the incidence of co-occurring ARIA-E and ARIA-H.

[0475] Inclusion criteria

[0476] AD objects are selected based on inclusion criteria that include the following:

[0477] - Ages 55 to 85 with a Body Mass Index of 18.0 to 32.0 kg / m² 2individual object;

[0478] - Gradual and progressive changes in memory function over a period of 6 months or more recorded by the subject or research partner;

[0479] - Pathological changes in Alzheimer's disease accompanied by mild cognitive impairment or mild dementia (stage 2, 3, or 4) according to the National Institute on Aging and Alzheimer's Association (NIA-AA) criteria (Jack, 2018; Appendix 3); and

[0480] - Screening MMSE score ≥18 points.

[0481] Exclusion criteria

[0482] - The exclusion criteria are similar to those in Example 2, and additionally, a family history of dominant hereditary AD is excluded.

[0483] Clinical laboratory evaluation, Cogstate evaluation, MMSE evaluation, PK sampling, biomarker analysis, and ARIA evaluation are performed in a manner similar to the method mentioned in Example 2.

[0484] result

[0485] The results of this MAD study show that the reduction in amyloid plaques (e.g., amyloid reduction as described herein) and the incidence of ARIA (e.g., ARIA incidence and ARIA risk as described herein) are relatively low in treated patients.

[0486] Example 4: Phase 1 open-label extension study to evaluate the safety, tolerability, immunogenicity, pharmacokinetics, and pharmacodynamics of h2731 in subjects with Alzheimer's disease

[0487] This example describes an open-label extension (OLE) study in subjects with Alzheimer's disease who have completed the single dose escalation study (SAD) of Example 2 or completed the treatment period by participating in the multiple dose escalation study (MAD) of Example 3 and meet the eligibility criteria for the OLE additionally described herein.

[0488] Test design

[0489] In this OLE, h2731 is administered to all subjects up to 12 times as summarized in Figure 3. h2731 is administered by subcutaneous injection once every 4 weeks for a total of up to 12 times. All subjects from the SAD study are administered 400 mg of h2731, and subjects from the MAD study are administered 300 mg, 350 mg, or 400 mg of h2731 once a month or 200 mg twice a month at doses according to cohort assignment in the core study (cohort A-1, A-2, A-3, B-1, B-2, or B-3).

[0490] Test purpose

[0491] The primary objective of the OLE is to evaluate the long-term safety, tolerability, and immunogenicity of h2731. The secondary objective of the OLE is to elucidate the PK profile of h2731. Exploratory objectives include evaluating the effect of h2731 on amyloid positron emission tomography (PET) and evaluating the PD effect of h2731 on plasma biomarkers.

[0492] Eligibility Criteria

[0493] For the subjects originating from the SAD test of Example 2, screening and registration for the OLE can be performed after completing the 85th day visit.

[0494] For subjects derived from the MAD study of Example 3, screening and registration for OLE must be performed before 24 weeks / 18 weeks (127 days) have elapsed after the end of treatment (EOT), based on the following:

[0495] In the SAD study of Example 1, if there is no ARIA at the 24-week / EOT time, the subject may enter the OLE if all eligibility criteria are met and the interval between the 24-week / EOT visit and the first dose of the OLE study is not more than 18 weeks. For eligible subjects, administration is recommended within 2 weeks of the 24-week / EOT visit for a smoother transition.

[0496] In the MAD test of Example 2, if an ARIA (new or ongoing) that does not require discontinuation of administration is detected at the 24-week / EOT visit, the subject may proceed with OLE if all eligibility criteria are met and the interval between the 24-week / EOT visit and the first administration of OLE is not more than 18 weeks.

[0497] If an ARIA (new or ongoing) requiring discontinuation of administration is detected at the 24-week / EOT visit of the MAD study, the subject may enter this OLE if (1) the ARIA findings are stable (in the case of ARIA-H) or resolved (in the case of ARIA-E), (2) the interval between the 24-week / EOT visit of the MAD study and the first administration of the OLE is not more than 18 weeks, (3) the resumption of h2731 administration is permissible in the investigator's opinion based on clinical judgment, and (4) all eligibility criteria are met.

[0498] If ARIA is not stabilized or resolved even after 18 weeks (127 days) from the 24-week / EOT visit of the MAD trial, the subject is not eligible to participate in the OLE and completes follow-up in the MAD trial.

[0499] Evaluation indicators

[0500] The primary evaluation indicators include the following:

[0501] - Safety and tolerability based on AE reporting (incidence of adverse events [AE], serious adverse events [SAE], and h2731-related AE), clinical laboratory tests, vital signs, and physical examination;

[0502] - Magnetic resonance imaging (MRI) findings regarding the nature, frequency, severity, and timing of ARIA, such as amyloid-related imaging findings (ARIA E) associated with underlying angioedema; amyloid-related imaging findings (ARIA-H) associated with intracerebral hemorrhage; incidence of symptomatic ARIA-E and / or ARIA-H; and incidence of co-occurring ARIA-E and ARIA-H.

[0503] - Presence of anti-drug antibodies (ADA) in plasma

[0504] Secondary evaluation indicators include the plasma concentration of h2731.

[0505] Exploratory evaluation metrics include the following:

[0506] - Brain amyloid levels measured by PET imaging; and

[0507] - Non-limiting plasma-based biomarkers including Aβ42, Aβ40, amyloid β-peptide ratio 42 / 40 (Aβ42 / 40), p181-tau, and p217-tau.

[0508] Additional analyses may be performed to evaluate changes in brain amyloid centilloids relative to the core trial baseline after 24 and 48 weeks of treatment in OKE. For these analyses, all time points are indicated relative to the start of h2731 exposure. The percentage (%) of subjects achieving amyloid-negative status based on amyloid PET scans at 24 weeks (169 days) and 48 weeks (337 days) is also presented.

[0509] The PK / PD association between centilloid reduction and h2731 cumulative dose can be summarized. Additional analyses may be performed to investigate the PK / PD relationship between centilloid reduction and h2731 plasma exposure.

[0510] The inclusion criteria include the completion of the SAD test of Example 2 (AD cohort alone) or the completion of the treatment period in the MAD test of Example 3, which is the same as Example 3.

[0511] The exclusion criteria include those listed in Example 3, including ARIAs for which administration is prohibited as shown in Tables 4 and 5 of Example 3.

[0512] result

[0513] The results of this OLE show that in treated patients, a reduction in amyloid plaques (e.g., the amyloid reduction described herein) is achieved, and the incidence of ARIA (e.g., the incidence and risk of ARIA described herein) is relatively low.

[0514] All cited publications (GenBank index number, UniProtKB / Swiss-Prot index number, etc.), patents, and patent applications are incorporated herein by reference in their entirety for all purposes, at the same level as specifically and individually indicated that each individual publication, patent, and patent application is incorporated herein by reference in its entirety for all purposes. Any feature, step, element, embodiment, or aspect of the invention may be used in combination with any other unless otherwise specifically stated. Although the invention has been described in some detail by way of example and through examples for the purpose of clarity and facilitation, it will be apparent that some changes and modifications may be made to the appended claims.

Claims

Claim 1 A method for treating Alzheimer's disease in an individual, comprising administering about 205 mg to about 400 mg of an anti-amyloid β antibody or its antigen-binding fragment to the individual once every about 3 to 5 weeks. Claim 2 A method for reducing brain amyloid β plaques in an individual, comprising administering about 205 mg to about 400 mg of an anti-amyloid β antibody or its antigen-binding fragment to the individual once every about 3 to 5 weeks. Claim 3 A method for converting an individual from amyloid-positive to amyloid-negative, comprising administering to the individual about 205 mg to about 400 mg of an anti-amyloid β antibody or its antigen-binding fragment once every about 3 to 5 weeks. Claim 4 A method according to any one of claims 1 to 3, wherein the method comprises administering about 300 mg to about 400 mg of an anti-amyloid β antibody or an antigen-binding fragment thereof. Claim 5 A method according to any one of claims 1 to 3, wherein the method comprises administering about 350 mg to about 400 mg of an anti-amyloid β antibody or an antigen-binding fragment thereof. Claim 6 A method according to any one of claims 1 to 3, wherein the method comprises administering about 300 mg of an anti-amyloid β antibody or an antigen-binding fragment thereof. Claim 7 A method according to any one of claims 1 to 3, wherein the method comprises administering about 350 mg of an anti-amyloid β antibody or an antigen-binding fragment thereof. Claim 8 A method according to any one of claims 1 to 3, wherein the method comprises administering about 400 mg of an anti-amyloid β antibody or an antigen-binding fragment thereof. Claim 9 A method according to any one of claims 1 to 8, wherein the anti-amyloid β antibody is administered once every approximately 4 weeks. Claim 10 A method for treating Alzheimer's disease in an individual, comprising administering about 100 mg to about 200 mg of an anti-amyloid β antibody or its antigen-binding fragment to the individual twice every about 3 to 5 weeks. Claim 11 A method for reducing brain amyloid β plaques in an individual, comprising administering about 100 mg to about 200 mg of an anti-amyloid β antibody or its antigen-binding fragment to the individual twice every about 3 to 5 weeks. Claim 12 A method for converting an individual from amyloid-positive to amyloid-negative, comprising administering about 100 mg to about 200 mg of an anti-amyloid β antibody or its antigen-binding fragment to the individual twice every about 3 to 5 weeks. Claim 13 A method according to any one of claims 10 to 12, wherein the method comprises administering about 150 mg to about 200 mg of an anti-amyloid β antibody or an antigen-binding fragment thereof. Claim 14 A method according to any one of claims 10 to 12, wherein the method comprises administering about 200 mg of an anti-amyloid β antibody or an antigen-binding fragment thereof. Claim 15 A method according to any one of claims 10 to 14, wherein the anti-amyloid β antibody or its antigen-binding fragment is administered once every approximately 2 weeks. Claim 16 A method according to any one of claims 1 to 15, wherein the anti-amyloid β antibody or its antigen-binding fragment binds to an epitope located at the N-terminus of an Aβ peptide, and the epitope comprises one or more amino acids selected from amino acids 1-10 of the Aβ peptide. Claim 17 A method according to claim 16, wherein the anti-amyloid β antibody or its antigen-binding fragment binds to an epitope comprising one or more amino acids selected from amino acids 1-7 of an Aβ peptide. Claim 18 In any one of claims 1 to 17, the anti-amyloid β antibody or its antigen-binding fragment is amyloid β with an apparent KD of about 5 nM or less. 1-42 Method of binding to protopibrill. Claim 19 In any one of claims 1 to 17, the anti-amyloid β antibody or its antigen-binding fragment is amyloid β with an apparent KD of about 1 nM or less. 1-42 Method of binding to protopibrill. Claim 20 In any one of claims 1 to 19, the anti-amyloid β antibody or its antigen-binding fragment is amyloid β with an apparent KD of about 10 nM or less. 1-28 Method of binding to a monomer. Claim 21 A method according to any one of claims 1 to 20, wherein the anti-amyloid β antibody or its antigen-binding fragment is administered as a pharmaceutical composition comprising the anti-amyloid β antibody or its antigen-binding fragment and a pharmaceutically acceptable diluent. Claim 22 A method according to any one of claims 1 to 21, wherein the administration is intravenous or subcutaneous. Claim 23 In paragraph 22, the above administration is a subcutaneous administration. Claim 24 A method according to any one of claims 1 to 23, wherein the anti-amyloid β antibody or the antigen-binding fragment thereof comprises a heavy chain variable region comprising heavy chain CDR1, CDR2 and CDR3 and a light chain variable region comprising light chain CDR1, CDR2 and CDR3, wherein heavy chain CDR1 comprises the amino acid sequence of SEQ ID NO. 3, heavy chain CDR2 comprises the amino acid sequence of SEQ ID NO. 4, heavy chain CDR3 comprises the amino acid sequence of SEQ ID NO. 5, light chain CDR1 comprises the amino acid sequence of SEQ ID NO. 6, light chain CDR2 comprises the amino acid sequence of SEQ ID NO. 7, and light chain CDR3 comprises the amino acid sequence of SEQ ID NO.

8. Claim 25 A method according to claim 24, wherein the portion of the heavy chain variable region excluding the CDR is at least 95% identical to the amino acid sequence of SEQ ID NO. 1, and the portion of the light chain variable region excluding the CDR is at least 95% identical to the amino acid sequence of SEQ ID NO.

2. Claim 26 A method according to claim 25, wherein the portion of the heavy chain variable region excluding the CDR is at least 98% identical to the amino acid sequence of SEQ ID NO. 1, and the portion of the light chain variable region excluding the CDR is at least 98% identical to the amino acid sequence of SEQ ID NO.

2. Claim 27 A method according to claim 26, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO. 1 and the light chain variable region comprises the amino acid sequence of SEQ ID NO.

2. Claim 28 A method according to claim 24, wherein the heavy chain variable region is composed of SEQ ID NO. 1 and the light chain variable region is composed of the amino acid sequence of SEQ ID NO.

2. Claim 29 A method according to any one of claims 1 to 28, wherein the anti-amyloid β antibody is humanized IgG1. Claim 30 A method according to any one of claims 1 to 28, wherein the anti-amyloid β antibody is a total antibody, a chimeric antibody, a CDR-transplant antibody, or a recombinant antibody. Claim 31 A method according to any one of claims 1 to 30, wherein the anti-amyloid β antibody or its antigen-binding fragment further comprises a heavy chain constant region having an amino acid sequence at least 95% identical to SEQ ID NO. 9 and / or a light chain constant region having an amino acid sequence at least 95% identical to SEQ ID NO.

10. Claim 32 A method according to any one of claims 1 to 31, wherein the anti-amyloid β antibody or its antigen-binding fragment further comprises a heavy chain constant region having an amino acid sequence at least 98% identical to SEQ ID NO. 9 and / or a light chain constant region having an amino acid sequence at least 98% identical to SEQ ID NO.

10. Claim 33 A method according to any one of claims 1 to 32, wherein the anti-amyloid β antibody comprises a heavy chain constant region comprising the amino acid sequence of SEQ ID NO. 9, in which C-terminal lysine is present or absent, and a light chain constant region comprising the amino acid sequence of SEQ ID NO.

10. Claim 34 A method according to any one of claims 1 to 33, wherein the anti-amyloid β antibody comprises a heavy chain invariant region essentially composed of the amino acid sequence of SEQ ID NO. 9, in which C-terminal lysine is present or absent, and a light chain invariant region essentially composed of the amino acid sequence of SEQ ID NO.

10. Claim 35 A method according to any one of claims 1 to 34, wherein the anti-amyloid β antibody comprises a heavy chain of SEQ ID NO. 11 and a light chain of SEQ ID NO. 12, wherein C-terminal lysine is present or absent. Claim 36 A method according to any one of claims 1 to 35, wherein the anti-amyloid β antibody is h2731. Claim 37 A method for treating Alzheimer's disease in an individual, comprising administering about 300 mg of an anti-amyloid β antibody subcutaneously to the individual once every about 4 weeks; wherein the anti-amyloid β antibody comprises a heavy chain of SEQ ID NO. 11 and a light chain of SEQ ID NO. 12, with or without C-terminal lysine. Claim 38 A method for treating Alzheimer's disease in an individual, comprising administering approximately 350 mg of an anti-amyloid β antibody subcutaneously to the individual once every approximately 4 weeks; wherein the anti-amyloid β antibody comprises a heavy chain of SEQ ID NO. 11 and a light chain of SEQ ID NO. 12, with or without C-terminal lysine. Claim 39 A method for treating Alzheimer's disease in an individual, comprising administering about 400 mg of an anti-amyloid β antibody subcutaneously to the individual once every about 4 weeks; wherein the anti-amyloid β antibody comprises a heavy chain of SEQ ID NO. 11 and a light chain of SEQ ID NO. 12, with or without C-terminal lysine. Claim 40 A method for treating Alzheimer's disease in an individual, comprising administering approximately 200 mg of an anti-amyloid β antibody subcutaneously to the individual once every approximately 2 weeks; wherein the anti-amyloid β antibody comprises a heavy chain of SEQ ID NO. 11 and a light chain of SEQ ID NO. 12, with or without C-terminal lysine. Claim 41 A method for reducing amyloid plaques in an individual, comprising administering about 300 mg of an anti-amyloid β antibody subcutaneously to the individual once every about 4 weeks; wherein the anti-amyloid β antibody comprises a heavy chain of SEQ ID NO. 11 and a light chain of SEQ ID NO. 12, with or without C-terminal lysine. Claim 42 A method for reducing amyloid plaques in an individual, comprising administering about 350 mg of an anti-amyloid β antibody subcutaneously to the individual once every about 4 weeks; wherein the anti-amyloid β antibody comprises a heavy chain of SEQ ID NO. 11 and a light chain of SEQ ID NO. 12, with or without C-terminal lysine. Claim 43 A method for reducing amyloid plaques in an individual, comprising administering about 400 mg of an anti-amyloid β antibody subcutaneously to the individual once every about 4 weeks; wherein the anti-amyloid β antibody comprises a heavy chain of SEQ ID NO. 11 and a light chain of SEQ ID NO. 12, with or without C-terminal lysine. Claim 44 A method for reducing amyloid plaques in an individual, comprising administering about 200 mg of an anti-amyloid β antibody subcutaneously to the individual once every about 2 weeks; wherein the anti-amyloid β antibody comprises a heavy chain of SEQ ID NO. 11 and a light chain of SEQ ID NO. 12, with or without C-terminal lysine. Claim 45 Anti-Aβ antibodies were administered to subjects at an average concentration of about 20 µg / ml to about 40 µg / ml during the administration interval (C ave A method for treating Alzheimer's disease in an individual, comprising administering subcutaneously in a dose sufficient to achieve a value, wherein the anti-Aβ antibody comprises a heavy chain of SEQ ID NO. 11 and a light chain of SEQ ID NO. 12, with or without C-terminal lysine. Claim 46 Area under the concentration-time curve (AUC) of anti-Aβ antibodies administered to individuals at intervals of approximately 15,000 hr*µg / ml to approximately 30,000 hr*µg / ml 0-tau A method for treating Alzheimer's disease in an individual, comprising administering subcutaneously in a dose sufficient to achieve a value, wherein the anti-Aβ antibody comprises a heavy chain of SEQ ID NO. 11 and a light chain of SEQ ID NO. 12, with or without C-terminal lysine. Claim 47 In any one of claims 1 to 46, the maximum concentration value (C) of the anti-amyloid β antibody or its antigen-binding fragment during the administration interval in the individual max A method in which the value) is about 30 μg / ml to about 60 μg / ml. Claim 48 In any one of claims 1 to 46, C of the anti-amyloid β antibody or its antigen-binding fragment in the individual max A method having a value of about 50 µg / ml to about 60 µg / ml. Claim 49 In any one of claims 1 to 46, C of the anti-amyloid β antibody or its antigen-binding fragment in the individual max A method in which the value does not exceed approximately 60 μg / ml. Claim 50 In any one of paragraphs 47 to 49, the above C max The value of serum C max Value, method. Claim 51 In any one of paragraphs 47 to 49, the above C max The value is plasma C max Value, method. Claim 52 In any one of claims 1 to 51, C of the anti-amyloid β antibody or its antigen-binding fragment in the individual ave A method having a value of about 20 µg / ml to about 40 µg / ml. Claim 53 In any one of claims 1 to 51, C of the anti-amyloid β antibody or its antigen-binding fragment in the individual ave A method having a value of about 30 µg / ml to about 40 µg / ml. Claim 54 In any one of claims 1 to 51, C of the anti-amyloid β antibody or its antigen-binding fragment in the individual ave A method in which the value does not exceed approximately 40 μg / ml. Claim 55 In any one of paragraphs 45 and 52 through 54, the above C ave The value of serum C ave Value, method. Claim 56 In any one of paragraphs 45 and 52 through 54, the above C ave The value is plasma C ave Value, method. Claim 57 In any one of claims 1 to 56, the AUC of the anti-amyloid β antibody or its antigen-binding fragment in the individual 0-tau A method having a value of about 15,000 hr*µg / ml to about 30,000 hr*µg / ml. Claim 58 In any one of claims 1 to 57, the AUC of the anti-amyloid β antibody or its antigen-binding fragment in the individual 0-tau A method having a value of about 20,000 hr*µg / ml to about 30,000 hr*µg / ml. Claim 59 In any one of claims 1 to 58, the AUC of the anti-amyloid β antibody or its antigen-binding fragment in the individual 0-tau A method in which the value does not exceed approximately 30,000 hr*µg / ml. Claim 60 In any one of paragraphs 46 and 57 through 59, the above AUC 0-tau The value is serum AUC 0-tau Value, method. Claim 61 In any one of paragraphs 46 and 57 through 59, the above AUC 0-tau The value is plasma AUC 0-tau Value, method. Claim 62 A method according to any one of claims 1 to 61, wherein brain amyloid β plaques are reduced in the individual. Claim 63 A method according to any one of claims 2, 3 and 62, wherein the reduction of brain amyloid β plaques comprises a reduction of at least about 30 centiloids to about 70 centiloids. Claim 64 A method according to any one of claims 2, 3 and 62, wherein the reduction of brain amyloid β plaques comprises a reduction of about 45 centilloids to about 80 centilloids. Claim 65 A method according to any one of claims 2, 3 and 62, wherein the reduction of brain amyloid β plaques comprises a reduction of about 50 centilloids to about 85 centilloids. Claim 66 A method according to any one of claims 2, 3 and 62, wherein the reduction of brain amyloid β plaques comprises at least about 40% to about 90% reduction. Claim 67 A method according to any one of claims 2, 3 and 62, wherein the reduction of brain amyloid β plaques comprises a reduction of about 60% to about 100%. Claim 68 A method according to any one of claims 2, 3 and 62, wherein the reduction of brain amyloid β plaques comprises a reduction of about 65% to about 100%. Claim 69 A method according to any one of claims 2, 3 and 62 to 68, wherein the reduction of brain amyloid β plaques is a reduction relative to baseline. Claim 70 A method according to any one of claims 2, 3 and 62 to 69, wherein the reduction of brain amyloid β plaques is a reduction compared to the individual before administration of the anti-amyloid β antibody. Claim 71 A method according to any one of claims 2, 3 and 62 to 70, wherein the reduction of brain amyloid β plaques is achieved after approximately 6 months of treatment. Claim 72 A method according to any one of claims 2, 3 and 62 to 70, wherein the reduction of brain amyloid β plaques is achieved after approximately 12 months of treatment. Claim 73 A method according to any one of claims 2, 3 and 62 to 70, wherein the reduction of brain amyloid β plaques is achieved after approximately 18 months of treatment. Claim 74 A method according to any one of paragraphs 2, 3 and 62 to 73, wherein the reduction of brain amyloid β plaques is evaluated by positron emission tomography (PET). Claim 75 A method according to any one of claims 1 to 74, wherein the individual is converted from amyloid-positive to amyloid-negative. Claim 76 A method according to any one of claims 1 to 75, wherein the treatment increases the likelihood of converting an individual from amyloid-positive to amyloid-negative. Claim 77 A method according to any one of claims 1 to 76, comprising increasing the likelihood of the treatment converting the individual from amyloid-positive to amyloid-negative by about 10% to about 40%. Claim 78 A method according to any one of claims 1 to 76, comprising increasing the likelihood that the treatment will convert the individual from amyloid-positive to amyloid-negative by about 30% to about 60%. Claim 79 A method according to any one of claims 1 to 76, comprising increasing the likelihood that the treatment will convert an individual from amyloid-positive to amyloid-negative by about 40% to about 80%. Claim 80 A method according to any one of claims 77 to 79, wherein the possibility of converting the individual from amyloid-positive to amyloid-negative is the possibility after about 6 months of treatment. Claim 81 A method according to any one of claims 77 to 79, wherein the possibility of converting the individual from amyloid-positive to amyloid-negative is the possibility after about 12 months of treatment. Claim 82 A method according to any one of claims 77 to 79, wherein the possibility of converting the individual from amyloid-positive to amyloid-negative is the possibility after approximately 18 months of treatment. Claim 83 A method according to any one of claims 1 to 82, wherein the treatment includes slowing down, stopping, or reversing the decline in cognitive function. Claim 84 In paragraph 83, a method comprising the above treatment slowing down the decline in cognitive function. Claim 85 A method according to claim 83 or 84, wherein the cognitive function is measured by one or more of CRD-SB, ADAS-Cog14, ADCOMS, and ADCS MCI-ADL. Claim 86 In paragraph 85, the above cognitive function is a method measured by ADCOMS. Claim 87 A method for controlling a biomarker in an individual, comprising administering about 205 mg to about 400 mg of an anti-amyloid β antibody to the individual once every about 3 to 5 weeks, wherein the anti-amyloid β antibody comprises a heavy chain of SEQ ID NO. 11 and a light chain of SEQ ID NO. 12 having or without C-terminal lysine. Claim 88 A method for increasing the Aβ 42 / 40 ratio in an individual, comprising administering about 205 mg to about 400 mg of an anti-amyloid β antibody once every about 3 to 5 weeks to the individual, wherein the anti-amyloid β antibody comprises a heavy chain of SEQ ID NO. 11 and a light chain of SEQ ID NO. 12 having or without C-terminal lysine. Claim 89 A method for reducing the amount of phospho-tau in an individual, comprising administering about 205 mg to about 400 mg of an anti-amyloid β antibody to the individual once every about 3 to 5 weeks, wherein the anti-amyloid β antibody comprises a heavy chain of SEQ ID NO. 11 and a light chain of SEQ ID NO. 12, with or without C-terminal lysine. Claim 90 A method for reducing the amount of phospho-tau in an individual, comprising administering about 100 mg to about 200 mg of an anti-amyloid β antibody to the individual twice every about 3 to 5 weeks, wherein the anti-amyloid β antibody comprises a heavy chain of SEQ ID NO. 11 and a light chain of SEQ ID NO. 12 having or without C-terminal lysine. Claim 91 A method according to any one of claims 87 to 90, wherein the administration comprises a subcutaneous injection. Claim 92 A method in which a biomarker is controlled in the individual, in any one of claims 1 to 91. Claim 93 In paragraph 92, a method in which a biomarker in the above-mentioned individual is adjusted compared to a baseline. Claim 94 A method according to any one of claims 1 to 93, further comprising detecting a biomarker in a sample collected from an individual. Claim 95 A method according to any one of claims 1 to 94, further comprising quantifying a biomarker in a sample collected from an individual. Claim 96 A method according to any one of claims 87 and 92 through 95, wherein the biomarker comprises an individual's Aβ 42 / 40 ratio. Claim 97 A method according to either claim 88 or 96, wherein the Aβ 42 / 40 ratio in the individual increases by at least 25%. Claim 98 A method according to either claim 88 or 96, wherein the Aβ 42 / 40 ratio in the individual increases by at least 50%. Claim 99 A method according to either claim 88 or 96, wherein the Aβ 42 / 40 ratio in the individual increases by about 25% to about 100%. Claim 100 A method according to either claim 88 or 96, wherein the Aβ 42 / 40 ratio in the individual increases by about 50% to about 100%. Claim 101 A method according to any one of claims 87 and 92 through 95, wherein the biomarker comprises a phospho-tau value. Claim 102 A method according to any one of claims 89, 90 and 101, wherein the phospho-tau value comprises one or more of the p181-tau value, p212-tau value, p217-tau value, p231-tau value and p235-tau value. Claim 103 A method according to any one of claims 89, 90 and 101, wherein the phospho-tau value includes the p181-tau value. Claim 104 A method according to any one of claims 89, 90 and 101, wherein the phospho-tau value includes a p212-tau value. Claim 105 A method according to any one of claims 89, 90 and 101, wherein the phospho-tau value includes the p217-tau value. Claim 106 A method according to any one of claims 89, 90 and 101, wherein the phospho-tau value includes the p231-tau value. Claim 107 A method according to any one of claims 89, 90 and 101, wherein the phospho-tau value includes a p235-tau value. Claim 108 A method in which the phospho-tau value is reduced in any one of claims 89, 90 and 101 through 107. Claim 109 A method according to any one of claims 89, 90 and 108, wherein the phospho-tau value is reduced by at least about 10%. Claim 110 A method according to any one of claims 89, 90 and 108, wherein the phospho-tau value is reduced by about 10% to about 30%. Claim 111 A method according to any one of claims 89, 90 and 108, wherein the phospho-tau value is reduced by about 20% to about 30%. Claim 112 A method according to claim 94 or 95, wherein the sample comprises blood or a portion thereof collected from an individual. Claim 113 A method according to claim 94 or 95, wherein the sample comprises plasma collected from an individual. Claim 114 A method according to claim 94 or 95, wherein the sample comprises serum collected from an individual. Claim 115 A method according to claim 94 or 95, wherein the sample comprises cerebrospinal fluid (CSF) collected from an individual. Claim 116 A method according to any one of claims 1 to 115, wherein the method comprises an ARIA-E risk of less than about 45%. Claim 117 A method according to any one of claims 1 to 115, wherein the method comprises about 25% to about 45% ARIA-E risk. Claim 118 A method according to any one of claims 1 to 115, wherein the method comprises less than about 75% ARIA-E risk. Claim 119 A method according to any one of claims 1 to 115, wherein the method comprises about 50% to about 75% ARIA-E risk. Claim 120 A method according to any one of claims 1 to 115, wherein the method comprises a symptomatic ARIA-E risk of less than about 15%. Claim 121 A method according to any one of claims 1 to 115, wherein the method comprises a symptomatic ARIA-E risk of less than about 30%. Claim 122 A method according to any one of claims 116 to 121, wherein the ARIA-E risk is a severe ARIA-E risk. Claim 123 A method according to any one of paragraphs 116 to 122, wherein the ARIA-E risk is a risk after approximately 6 months of treatment. Claim 124 A method according to any one of claims 116 to 122, wherein the ARIA-E risk is a risk after approximately 12 months of treatment. Claim 125 A method according to any one of claims 116 to 122, wherein the ARIA-E risk is a risk after approximately 18 months of treatment. Claim 126 A method according to any one of claims 1 to 125, wherein the individual does not experience symptomatic ARIA-E during treatment. Claim 127 A method according to any one of claims 1 to 126, wherein the method comprises an ARIA-H risk of less than about 35%. Claim 128 A method according to any one of claims 1 to 126, wherein the method comprises about 10% to about 35% ARIA-H risk. Claim 129 In paragraph 127 or 128, the method wherein the ARIA-H risk is a severe ARIA-H risk. Claim 130 A method according to any one of claims 127 to 129, wherein the ARIA-H risk is a risk after approximately 6 months of treatment. Claim 131 A method according to any one of claims 1 to 130, wherein the individual does not experience symptomatic ARIA-H during treatment. Claim 132 A method according to any one of claims 116 to 131, wherein the ARIA-E and / or ARIA-H are evaluated by magnetic resonance imaging (MRI). Claim 133 A method according to any one of claims 1 to 132, wherein the individual is an APOE4 homozygous individual. Claim 134 A method according to any one of claims 1 to 132, wherein the individual is an APOE4 heterozygous individual or an APOE4 non-carrier. Claim 135 A method according to any one of claims 1 to 134, wherein the method further comprises determining the APOE4 status of the individual prior to administration. Claim 136 A method according to any one of paragraphs 1 to 135, wherein the treatment period is at least 6 months. Claim 137 A method according to any one of claims 1 to 135, wherein the treatment period is at least 12 months. Claim 138 A method according to any one of claims 1 to 135, wherein the treatment period is at least 18 months. Claim 139 A method according to any one of claims 1 to 138, wherein the administration is performed using a syringe. Claim 140 A method according to any one of claims 1 to 138, wherein the administration is performed using an automatic syringe. Claim 141 A method according to any one of claims 1 to 140, wherein the individual is a mammal. Claim 142 A method according to any one of claims 1 to 141, wherein the individual is a human.

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